Bruce Jancin

DENVER – Elderly patients who are placed on a short-acting opioid analgesic for treatment of arthritis pain are twice as likely to experience a fracture during the subsequent year, compared with those on a long-acting opioid, according to a large cohort study.

The increased fracture risk was particularly strong during the first 2 weeks after initiation of therapy, when the relative risk was almost sevenfold higher in patients on a short-acting opioid, such as propoxyphene or oxycodone, than in those who were started on an nonsteroidal anti-inflammatory drug (NSAID) or long-acting opioid, including fentanyl or sustained-release hydrocodone. After that initial 2-week period, the fracture risk associated with short-acting opioid therapy dropped off but remained about threefold greater than with NSAID therapy, Dr. Matthew Miller reported at the annual meeting of the American Public Health Association.

The fracture risk during the first 2 weeks on a long-acting opioid didn’t differ significantly from that in patients who were placed on an NSAID. Over the course of 1 year, however, the difference grew such that the cumulative fracture risk was 2.6-fold greater in the group on a long-acting opioid than in those on an NSAID. In contrast, the relative risk of fracture at 1 year was increased 5.1-fold in elderly arthritis patients on a short-acting opioid, added Dr. Miller, associate director of the Harvard Injury Control Research Center, Boston.

"Our findings indicate that opioids increase the risk of fractures among older patients with arthritis, and suggest that clinicians should be alert to the possibility that short-acting opioids pose a significantly greater risk of fractures among older adults than do equianalgesic doses of long-acting opioids, especially during the first 2 weeks after initiating therapy," he observed.

These results have the potential to change clinical practice by shifting prescribing in the direction of greater use of long-acting opioids in the elderly. At present, short-acting opioids are prescribed far more often than long-acting ones.

"Our findings, if borne out in other databases, could help inform safer prescribing practices consonant with the latest American Geriatrics Society guidelines on the pharmacological management of pain in older persons, which recommend that all patients with moderate to severe pain, pain-related functional impairment, or diminished quality of life due to pain should be considered for opioid therapy," the physician continued.

His study involved 12,436 Medicare beneficiaries with arthritis who initiated monotherapy with an opioid analgesic, and 4,874 who started on an NSAID. Participants averaged 81 years of age, and 85% were women. Osteoarthritis was the diagnosis in 90%; the rest had rheumatoid arthritis. None of the subjects had been on an opioid within the previous 6 months. Not surprisingly, patients who were started on an opioid tended to be somewhat sicker, with a mean baseline Charlson comorbidity index score of 2.2 in the short-acting opioid group, 2.1 in those on a long-acting opioid, and 1.6 in the NSAID group.

The primary study end point was the 1-year incidence of fractures of the hip, radius, ulna, or wrist. The incidence rate was 25 fractures per 1,000 person-years in the NSAID group, 128 per 1,000 person-years in those on short-acting opioids, and 53 per 1,000 person-years in the group on long-acting opioids.

A dose effect was evident. Patients on a low-dose opioid had a 2.2-fold greater fracture risk than did those on an NSAID, after adjustment for comorbid conditions and other potential confounding variables. Patients on a moderate-dose opioid had a 4.6-fold increased risk. And those on high-dose opioid therapy had a 5.1-fold increased risk.

Among high-dose opioid users, patients who were placed on a short-acting opioid had an adjusted 2.1-fold greater risk of a fracture than did those on a high-dose, long-acting opioid.

Asked why he thought short-acting opioids were prescribed 13-times more frequently than long-acting ones in the study population, Dr. Miller replied that although the study didn’t address this question, it’s his impression that many physicians believe that if they place a patient on a long-acting opioid, the patient may not get pain relief quickly enough. Hence, the patient might take another dose, and then another, perhaps getting into the overdose range. This belief about long-acting opioids’ sluggish onset of action, he added, is erroneous.

"It’s important to recognize that the modern formulations of these long-acting drugs can actually provide adequate analgesia in a time scale that’s similar to that for short-acting drugs, because of the long-acting agents’ biphasic distribution in the bloodstream. Yet 90% of the drugs that we’re prescribing when we’re prescribing opioids in an elderly population are short-acting drugs, raising the question of whether we’re putting people at unnecessary risk," Dr. Miller said.

The Food and Drug Administration recently removed from the U.S. market one of the short-acting opioids in this study – propoxyphene – because of an increased risk for fatal heart rhythm abnormalities associated with its use.

Dr. Miller declared having no relevant financial interests.

DENVER – Elderly patients who are placed on a short-acting opioid analgesic for treatment of arthritis pain are twice as likely to experience a fracture during the subsequent year, compared with those on a long-acting opioid, according to a large cohort study.

The increased fracture risk was particularly strong during the first 2 weeks after initiation of therapy, when the relative risk was almost sevenfold higher in patients on a short-acting opioid, such as propoxyphene or oxycodone, than in those who were started on an nonsteroidal anti-inflammatory drug (NSAID) or long-acting opioid, including fentanyl or sustained-release hydrocodone. After that initial 2-week period, the fracture risk associated with short-acting opioid therapy dropped off but remained about threefold greater than with NSAID therapy, Dr. Matthew Miller reported at the annual meeting of the American Public Health Association.

The fracture risk during the first 2 weeks on a long-acting opioid didn’t differ significantly from that in patients who were placed on an NSAID. Over the course of 1 year, however, the difference grew such that the cumulative fracture risk was 2.6-fold greater in the group on a long-acting opioid than in those on an NSAID. In contrast, the relative risk of fracture at 1 year was increased 5.1-fold in elderly arthritis patients on a short-acting opioid, added Dr. Miller, associate director of the Harvard Injury Control Research Center, Boston.

"Our findings indicate that opioids increase the risk of fractures among older patients with arthritis, and suggest that clinicians should be alert to the possibility that short-acting opioids pose a significantly greater risk of fractures among older adults than do equianalgesic doses of long-acting opioids, especially during the first 2 weeks after initiating therapy," he observed.

These results have the potential to change clinical practice by shifting prescribing in the direction of greater use of long-acting opioids in the elderly. At present, short-acting opioids are prescribed far more often than long-acting ones.

"Our findings, if borne out in other databases, could help inform safer prescribing practices consonant with the latest American Geriatrics Society guidelines on the pharmacological management of pain in older persons, which recommend that all patients with moderate to severe pain, pain-related functional impairment, or diminished quality of life due to pain should be considered for opioid therapy," the physician continued.

His study involved 12,436 Medicare beneficiaries with arthritis who initiated monotherapy with an opioid analgesic, and 4,874 who started on an NSAID. Participants averaged 81 years of age, and 85% were women. Osteoarthritis was the diagnosis in 90%; the rest had rheumatoid arthritis. None of the subjects had been on an opioid within the previous 6 months. Not surprisingly, patients who were started on an opioid tended to be somewhat sicker, with a mean baseline Charlson comorbidity index score of 2.2 in the short-acting opioid group, 2.1 in those on a long-acting opioid, and 1.6 in the NSAID group.

The primary study end point was the 1-year incidence of fractures of the hip, radius, ulna, or wrist. The incidence rate was 25 fractures per 1,000 person-years in the NSAID group, 128 per 1,000 person-years in those on short-acting opioids, and 53 per 1,000 person-years in the group on long-acting opioids.

A dose effect was evident. Patients on a low-dose opioid had a 2.2-fold greater fracture risk than did those on an NSAID, after adjustment for comorbid conditions and other potential confounding variables. Patients on a moderate-dose opioid had a 4.6-fold increased risk. And those on high-dose opioid therapy had a 5.1-fold increased risk.

Among high-dose opioid users, patients who were placed on a short-acting opioid had an adjusted 2.1-fold greater risk of a fracture than did those on a high-dose, long-acting opioid.

Asked why he thought short-acting opioids were prescribed 13-times more frequently than long-acting ones in the study population, Dr. Miller replied that although the study didn’t address this question, it’s his impression that many physicians believe that if they place a patient on a long-acting opioid, the patient may not get pain relief quickly enough. Hence, the patient might take another dose, and then another, perhaps getting into the overdose range. This belief about long-acting opioids’ sluggish onset of action, he added, is erroneous.

"It’s important to recognize that the modern formulations of these long-acting drugs can actually provide adequate analgesia in a time scale that’s similar to that for short-acting drugs, because of the long-acting agents’ biphasic distribution in the bloodstream. Yet 90% of the drugs that we’re prescribing when we’re prescribing opioids in an elderly population are short-acting drugs, raising the question of whether we’re putting people at unnecessary risk," Dr. Miller said.

The Food and Drug Administration recently removed from the U.S. market one of the short-acting opioids in this study – propoxyphene – because of an increased risk for fatal heart rhythm abnormalities associated with its use.

Dr. Miller declared having no relevant financial interests.

DENVER – Elderly patients who are placed on a short-acting opioid analgesic for treatment of arthritis pain are twice as likely to experience a fracture during the subsequent year, compared with those on a long-acting opioid, according to a large cohort study.

The increased fracture risk was particularly strong during the first 2 weeks after initiation of therapy, when the relative risk was almost sevenfold higher in patients on a short-acting opioid, such as propoxyphene or oxycodone, than in those who were started on an nonsteroidal anti-inflammatory drug (NSAID) or long-acting opioid, including fentanyl or sustained-release hydrocodone. After that initial 2-week period, the fracture risk associated with short-acting opioid therapy dropped off but remained about threefold greater than with NSAID therapy, Dr. Matthew Miller reported at the annual meeting of the American Public Health Association.

The fracture risk during the first 2 weeks on a long-acting opioid didn’t differ significantly from that in patients who were placed on an NSAID. Over the course of 1 year, however, the difference grew such that the cumulative fracture risk was 2.6-fold greater in the group on a long-acting opioid than in those on an NSAID. In contrast, the relative risk of fracture at 1 year was increased 5.1-fold in elderly arthritis patients on a short-acting opioid, added Dr. Miller, associate director of the Harvard Injury Control Research Center, Boston.

"Our findings indicate that opioids increase the risk of fractures among older patients with arthritis, and suggest that clinicians should be alert to the possibility that short-acting opioids pose a significantly greater risk of fractures among older adults than do equianalgesic doses of long-acting opioids, especially during the first 2 weeks after initiating therapy," he observed.

These results have the potential to change clinical practice by shifting prescribing in the direction of greater use of long-acting opioids in the elderly. At present, short-acting opioids are prescribed far more often than long-acting ones.

"Our findings, if borne out in other databases, could help inform safer prescribing practices consonant with the latest American Geriatrics Society guidelines on the pharmacological management of pain in older persons, which recommend that all patients with moderate to severe pain, pain-related functional impairment, or diminished quality of life due to pain should be considered for opioid therapy," the physician continued.

His study involved 12,436 Medicare beneficiaries with arthritis who initiated monotherapy with an opioid analgesic, and 4,874 who started on an NSAID. Participants averaged 81 years of age, and 85% were women. Osteoarthritis was the diagnosis in 90%; the rest had rheumatoid arthritis. None of the subjects had been on an opioid within the previous 6 months. Not surprisingly, patients who were started on an opioid tended to be somewhat sicker, with a mean baseline Charlson comorbidity index score of 2.2 in the short-acting opioid group, 2.1 in those on a long-acting opioid, and 1.6 in the NSAID group.

The primary study end point was the 1-year incidence of fractures of the hip, radius, ulna, or wrist. The incidence rate was 25 fractures per 1,000 person-years in the NSAID group, 128 per 1,000 person-years in those on short-acting opioids, and 53 per 1,000 person-years in the group on long-acting opioids.

A dose effect was evident. Patients on a low-dose opioid had a 2.2-fold greater fracture risk than did those on an NSAID, after adjustment for comorbid conditions and other potential confounding variables. Patients on a moderate-dose opioid had a 4.6-fold increased risk. And those on high-dose opioid therapy had a 5.1-fold increased risk.

Among high-dose opioid users, patients who were placed on a short-acting opioid had an adjusted 2.1-fold greater risk of a fracture than did those on a high-dose, long-acting opioid.

Asked why he thought short-acting opioids were prescribed 13-times more frequently than long-acting ones in the study population, Dr. Miller replied that although the study didn’t address this question, it’s his impression that many physicians believe that if they place a patient on a long-acting opioid, the patient may not get pain relief quickly enough. Hence, the patient might take another dose, and then another, perhaps getting into the overdose range. This belief about long-acting opioids’ sluggish onset of action, he added, is erroneous.

"It’s important to recognize that the modern formulations of these long-acting drugs can actually provide adequate analgesia in a time scale that’s similar to that for short-acting drugs, because of the long-acting agents’ biphasic distribution in the bloodstream. Yet 90% of the drugs that we’re prescribing when we’re prescribing opioids in an elderly population are short-acting drugs, raising the question of whether we’re putting people at unnecessary risk," Dr. Miller said.

The Food and Drug Administration recently removed from the U.S. market one of the short-acting opioids in this study – propoxyphene – because of an increased risk for fatal heart rhythm abnormalities associated with its use.

Dr. Miller declared having no relevant financial interests.

SAN ANTONIO – Menopausal hormone therapy with estrogen plus progestin doubles a woman’s risk of death from breast cancer, nearly doubles the risk of death from non–small cell lung cancer, and increases the risk of death from colorectal cancer by 54%, according to an updated analysis of the Women’s Health Initiative randomized trials.

Because breast and lung cancer are the top two causes of cancer mortality in women, these are sobering findings with important clinical implications, Dr. Rowan T. Chlebowski observed at the San Antonio Breast Cancer Symposium.

The 54% increased risk of death after diagnosis of colorectal cancer in Women’s Health Initiative (WHI) participants who were randomized to combined-hormone therapy rather than placebo was a trend that didn’t achieve statistical significance. But it’s nonetheless a finding that crushes the enthusiasm that greeted an earlier WHI report of a 44% reduction in the incidence of colorectal cancer in combined-hormone therapy users after 5.6 years of follow-up (N. Engl. J. Med. 2004;350:991-1004).

"One cannot take forward the 44% relative risk reduction in colorectal cancers as being a positive finding," said Dr. Chlebowski, professor of medicine at the University of California, Los Angeles.

Given the initial observation of fewer colorectal cancers being diagnosed in the combined-therapy arm of the WHI, investigators were quite surprised by the tumor characteristics of these cancers at time of diagnosis: The colorectal cancers arising in the combined-therapy group – although fewer in number – were much higher risk. In all, 76% of them were pathologically staged as regional or metastatic disease, compared with 48% of colorectal cancers in women on placebo, and 59% percent of the colorectal cancers detected in combined-hormone therapy users were lymph node positive, compared with just 29% in placebo-treated controls.

The WHI consisted of two separate National Institutes of Health–funded, randomized trials that profoundly altered the management of menopausal symptoms. In the early 1990s, more than 40% of all postmenopausal women were on hormonal therapy with estrogen alone or in combination with progestin. Following the initial WHI report of multiple adverse effects of estrogen plus progestin, the popularity of hormone therapy dropped off the table.

One WHI study involved 16,608 postmenopausal women aged 50-79 years with an intact uterus who were randomized to estrogen plus progestin or to placebo for a median of 5.6 years. The other study included 10,739 postmenopausal women with prior hysterectomy who were randomized to conjugated equine estrogens alone or placebo for an average of 7.1 years.

In the examination of WHI trends for the big-three (breast, lung, and colorectal) cancers in women, there is a consistent disparity between their relatively modestly increased incidence in dual-hormone therapy users, relative to placebo, and the far larger death rates resulting from these cancers. For example, after 11 years of follow-up, the incidence of breast cancer is up by 25% in the dual-hormone therapy group, relative to placebo. Yet the relative increase in mortality is 96%. Similarly, the incidence of non–small cell lung cancer (NSCLC) was 23% greater in women on combined-hormone therapy than in those on placebo, but the risk of death from NSCLC was 87% greater.

"The greater effect of estrogen and progestin on deaths from breast, lung, and colorectal cancer – [compared with] the effect on incidence – [suggests that] combined-hormone therapy facilitates growth and metastatic spread of established cancers, perhaps mediated by angiogenesis stimulation," the oncologist said, adding that "in a variety of preclinical models, estrogen and progestin are potent angiogenesis stimulators."

The investigators’ initial hypothesis was that nearly all the increase in breast cancers associated with combined-hormone therapy would involve estrogen receptor–positive tumors. Not so. In fact, the new analysis – based upon 11 years of follow-up and 678 cases of breast cancer – shows that all breast cancer subtypes appear to be increased, relative to rates in the placebo arm.

For example, combined-hormone therapy was indeed associated with an adjusted 27% greater increase in estrogen receptor–positive breast cancers than with placebo in a multivariate analysis, but it was also associated with a 40% increase in estrogen receptor–negative tumors, compared with controls. Also noteworthy were the combined-therapy group’s adjusted 78% increase in triple-negative cancers, the twofold increase in HER2-overexpressing tumors, and the 37% increase in HER2-negative tumors.

Nearly all the increase in lung cancer deaths associated with dual-hormone therapy resulted from NSCLC. Hormone therapy had no effect upon small cell lung cancer rates.

Among current smokers, the cumulative risk of death from lung cancer was 3.42% in those who used dual-hormone therapy for 5-plus years and 2.39% in placebo-treated controls. In other words, 1 in 100 current smokers who used estrogen plus progestin for 5-plus years experienced an otherwise-avoidable death from NSCLC. Among past smokers, the rate was 1 in 200. These numbers are worth keeping in mind, given that today roughly 15% of U.S. women are current smokers, and 35% are past smokers, Dr. Chlebowski noted.

Turning to the results of the estrogen-alone WHI trial, he pointed out that the therapy had no impact on incidence or death rates from lung or colorectal cancer, relative to placebo, but there was a nonsignificant 20% reduction in the relative risk of breast cancer in the hormone therapy group. This trend for a breast cancer–reduction benefit achieved significance in the nearly 4,500 study participants who were randomized to estrogen alone or placebo 5 years or more following the last menstrual period, where the hormonal therapy group enjoyed a 37% relative risk reduction. Of course, that’s not how hormone therapy is ordinarily employed in clinical practice, the physician pointed out.

One audience member rose to say that the oft-quoted sharply increased risk of uterine cancer in women with an intact uterus on estrogen alone dates back to older studies using doses that were considerably higher than those available in contemporary practice, as well as older methods of patient monitoring. She asked about the possibility of exploring ways to provide estrogen alone to menopausal women with an intact uterus without exposing them to increased uterine cancer risk.

Dr. Chlebowski said he thinks it’s certainly an appropriate research project, but he’d advise against trying it in clinical practice, given the product labeling and the malpractice lawsuit climate.

His take-home message from the expanded WHI analysis: "Even short-term use of combined-hormone therapy should be reserved for women with limiting climacteric symptoms [that are] not manageable by other means."

In a conference-closing review of the past year’s top developments in early breast cancer, Dr. Alan Coates singled out Dr. Chlebowski’s presentation on the WHI results as hands-down the most important study of the year in the field of cancer epidemiology.

"As we’ve known before, there’s a small but real increase in the incidence of breast cancer with combined-hormone replacement. The new finding is that there’s a massive increase – nearly a doubling – in mortality from breast cancer. And the mortality increase isn’t confined to breast cancer. ... This disparate increase in mortality over incidence in several tumor types suggests that the estrogen and progestin [combination] is doing something to the behavior of existing tumors," commented Dr. Coates of the University of Sydney.

It may be, as Dr. Chlebowski proposed, that the mechanism involves the angiogenic pathway, but other investigators have demonstrated that under certain circumstances, progestagens can stimulate stem cells by a paracrine RANKL (receptor-activated nuclear factor–kappaB ligand) mechanism. This could provide an equally plausible alternative explanation, he said.

Dr. Chlebowski disclosed that he receives grant support from Amgen and is on the speakers bureaus for AstraZeneca and Novartis. Dr. Coates reported having no relevant financial disclosures.

SAN ANTONIO – Menopausal hormone therapy with estrogen plus progestin doubles a woman’s risk of death from breast cancer, nearly doubles the risk of death from non–small cell lung cancer, and increases the risk of death from colorectal cancer by 54%, according to an updated analysis of the Women’s Health Initiative randomized trials.

Because breast and lung cancer are the top two causes of cancer mortality in women, these are sobering findings with important clinical implications, Dr. Rowan T. Chlebowski observed at the San Antonio Breast Cancer Symposium.

The 54% increased risk of death after diagnosis of colorectal cancer in Women’s Health Initiative (WHI) participants who were randomized to combined-hormone therapy rather than placebo was a trend that didn’t achieve statistical significance. But it’s nonetheless a finding that crushes the enthusiasm that greeted an earlier WHI report of a 44% reduction in the incidence of colorectal cancer in combined-hormone therapy users after 5.6 years of follow-up (N. Engl. J. Med. 2004;350:991-1004).

"One cannot take forward the 44% relative risk reduction in colorectal cancers as being a positive finding," said Dr. Chlebowski, professor of medicine at the University of California, Los Angeles.

Given the initial observation of fewer colorectal cancers being diagnosed in the combined-therapy arm of the WHI, investigators were quite surprised by the tumor characteristics of these cancers at time of diagnosis: The colorectal cancers arising in the combined-therapy group – although fewer in number – were much higher risk. In all, 76% of them were pathologically staged as regional or metastatic disease, compared with 48% of colorectal cancers in women on placebo, and 59% percent of the colorectal cancers detected in combined-hormone therapy users were lymph node positive, compared with just 29% in placebo-treated controls.

The WHI consisted of two separate National Institutes of Health–funded, randomized trials that profoundly altered the management of menopausal symptoms. In the early 1990s, more than 40% of all postmenopausal women were on hormonal therapy with estrogen alone or in combination with progestin. Following the initial WHI report of multiple adverse effects of estrogen plus progestin, the popularity of hormone therapy dropped off the table.

One WHI study involved 16,608 postmenopausal women aged 50-79 years with an intact uterus who were randomized to estrogen plus progestin or to placebo for a median of 5.6 years. The other study included 10,739 postmenopausal women with prior hysterectomy who were randomized to conjugated equine estrogens alone or placebo for an average of 7.1 years.

In the examination of WHI trends for the big-three (breast, lung, and colorectal) cancers in women, there is a consistent disparity between their relatively modestly increased incidence in dual-hormone therapy users, relative to placebo, and the far larger death rates resulting from these cancers. For example, after 11 years of follow-up, the incidence of breast cancer is up by 25% in the dual-hormone therapy group, relative to placebo. Yet the relative increase in mortality is 96%. Similarly, the incidence of non–small cell lung cancer (NSCLC) was 23% greater in women on combined-hormone therapy than in those on placebo, but the risk of death from NSCLC was 87% greater.

"The greater effect of estrogen and progestin on deaths from breast, lung, and colorectal cancer – [compared with] the effect on incidence – [suggests that] combined-hormone therapy facilitates growth and metastatic spread of established cancers, perhaps mediated by angiogenesis stimulation," the oncologist said, adding that "in a variety of preclinical models, estrogen and progestin are potent angiogenesis stimulators."

The investigators’ initial hypothesis was that nearly all the increase in breast cancers associated with combined-hormone therapy would involve estrogen receptor–positive tumors. Not so. In fact, the new analysis – based upon 11 years of follow-up and 678 cases of breast cancer – shows that all breast cancer subtypes appear to be increased, relative to rates in the placebo arm.

For example, combined-hormone therapy was indeed associated with an adjusted 27% greater increase in estrogen receptor–positive breast cancers than with placebo in a multivariate analysis, but it was also associated with a 40% increase in estrogen receptor–negative tumors, compared with controls. Also noteworthy were the combined-therapy group’s adjusted 78% increase in triple-negative cancers, the twofold increase in HER2-overexpressing tumors, and the 37% increase in HER2-negative tumors.

Nearly all the increase in lung cancer deaths associated with dual-hormone therapy resulted from NSCLC. Hormone therapy had no effect upon small cell lung cancer rates.

Among current smokers, the cumulative risk of death from lung cancer was 3.42% in those who used dual-hormone therapy for 5-plus years and 2.39% in placebo-treated controls. In other words, 1 in 100 current smokers who used estrogen plus progestin for 5-plus years experienced an otherwise-avoidable death from NSCLC. Among past smokers, the rate was 1 in 200. These numbers are worth keeping in mind, given that today roughly 15% of U.S. women are current smokers, and 35% are past smokers, Dr. Chlebowski noted.

Turning to the results of the estrogen-alone WHI trial, he pointed out that the therapy had no impact on incidence or death rates from lung or colorectal cancer, relative to placebo, but there was a nonsignificant 20% reduction in the relative risk of breast cancer in the hormone therapy group. This trend for a breast cancer–reduction benefit achieved significance in the nearly 4,500 study participants who were randomized to estrogen alone or placebo 5 years or more following the last menstrual period, where the hormonal therapy group enjoyed a 37% relative risk reduction. Of course, that’s not how hormone therapy is ordinarily employed in clinical practice, the physician pointed out.

One audience member rose to say that the oft-quoted sharply increased risk of uterine cancer in women with an intact uterus on estrogen alone dates back to older studies using doses that were considerably higher than those available in contemporary practice, as well as older methods of patient monitoring. She asked about the possibility of exploring ways to provide estrogen alone to menopausal women with an intact uterus without exposing them to increased uterine cancer risk.

Dr. Chlebowski said he thinks it’s certainly an appropriate research project, but he’d advise against trying it in clinical practice, given the product labeling and the malpractice lawsuit climate.

His take-home message from the expanded WHI analysis: "Even short-term use of combined-hormone therapy should be reserved for women with limiting climacteric symptoms [that are] not manageable by other means."

In a conference-closing review of the past year’s top developments in early breast cancer, Dr. Alan Coates singled out Dr. Chlebowski’s presentation on the WHI results as hands-down the most important study of the year in the field of cancer epidemiology.

"As we’ve known before, there’s a small but real increase in the incidence of breast cancer with combined-hormone replacement. The new finding is that there’s a massive increase – nearly a doubling – in mortality from breast cancer. And the mortality increase isn’t confined to breast cancer. ... This disparate increase in mortality over incidence in several tumor types suggests that the estrogen and progestin [combination] is doing something to the behavior of existing tumors," commented Dr. Coates of the University of Sydney.

It may be, as Dr. Chlebowski proposed, that the mechanism involves the angiogenic pathway, but other investigators have demonstrated that under certain circumstances, progestagens can stimulate stem cells by a paracrine RANKL (receptor-activated nuclear factor–kappaB ligand) mechanism. This could provide an equally plausible alternative explanation, he said.

Dr. Chlebowski disclosed that he receives grant support from Amgen and is on the speakers bureaus for AstraZeneca and Novartis. Dr. Coates reported having no relevant financial disclosures.

SAN ANTONIO – Menopausal hormone therapy with estrogen plus progestin doubles a woman’s risk of death from breast cancer, nearly doubles the risk of death from non–small cell lung cancer, and increases the risk of death from colorectal cancer by 54%, according to an updated analysis of the Women’s Health Initiative randomized trials.

Because breast and lung cancer are the top two causes of cancer mortality in women, these are sobering findings with important clinical implications, Dr. Rowan T. Chlebowski observed at the San Antonio Breast Cancer Symposium.

The 54% increased risk of death after diagnosis of colorectal cancer in Women’s Health Initiative (WHI) participants who were randomized to combined-hormone therapy rather than placebo was a trend that didn’t achieve statistical significance. But it’s nonetheless a finding that crushes the enthusiasm that greeted an earlier WHI report of a 44% reduction in the incidence of colorectal cancer in combined-hormone therapy users after 5.6 years of follow-up (N. Engl. J. Med. 2004;350:991-1004).

"One cannot take forward the 44% relative risk reduction in colorectal cancers as being a positive finding," said Dr. Chlebowski, professor of medicine at the University of California, Los Angeles.

Given the initial observation of fewer colorectal cancers being diagnosed in the combined-therapy arm of the WHI, investigators were quite surprised by the tumor characteristics of these cancers at time of diagnosis: The colorectal cancers arising in the combined-therapy group – although fewer in number – were much higher risk. In all, 76% of them were pathologically staged as regional or metastatic disease, compared with 48% of colorectal cancers in women on placebo, and 59% percent of the colorectal cancers detected in combined-hormone therapy users were lymph node positive, compared with just 29% in placebo-treated controls.

The WHI consisted of two separate National Institutes of Health–funded, randomized trials that profoundly altered the management of menopausal symptoms. In the early 1990s, more than 40% of all postmenopausal women were on hormonal therapy with estrogen alone or in combination with progestin. Following the initial WHI report of multiple adverse effects of estrogen plus progestin, the popularity of hormone therapy dropped off the table.

One WHI study involved 16,608 postmenopausal women aged 50-79 years with an intact uterus who were randomized to estrogen plus progestin or to placebo for a median of 5.6 years. The other study included 10,739 postmenopausal women with prior hysterectomy who were randomized to conjugated equine estrogens alone or placebo for an average of 7.1 years.

In the examination of WHI trends for the big-three (breast, lung, and colorectal) cancers in women, there is a consistent disparity between their relatively modestly increased incidence in dual-hormone therapy users, relative to placebo, and the far larger death rates resulting from these cancers. For example, after 11 years of follow-up, the incidence of breast cancer is up by 25% in the dual-hormone therapy group, relative to placebo. Yet the relative increase in mortality is 96%. Similarly, the incidence of non–small cell lung cancer (NSCLC) was 23% greater in women on combined-hormone therapy than in those on placebo, but the risk of death from NSCLC was 87% greater.

"The greater effect of estrogen and progestin on deaths from breast, lung, and colorectal cancer – [compared with] the effect on incidence – [suggests that] combined-hormone therapy facilitates growth and metastatic spread of established cancers, perhaps mediated by angiogenesis stimulation," the oncologist said, adding that "in a variety of preclinical models, estrogen and progestin are potent angiogenesis stimulators."

The investigators’ initial hypothesis was that nearly all the increase in breast cancers associated with combined-hormone therapy would involve estrogen receptor–positive tumors. Not so. In fact, the new analysis – based upon 11 years of follow-up and 678 cases of breast cancer – shows that all breast cancer subtypes appear to be increased, relative to rates in the placebo arm.

For example, combined-hormone therapy was indeed associated with an adjusted 27% greater increase in estrogen receptor–positive breast cancers than with placebo in a multivariate analysis, but it was also associated with a 40% increase in estrogen receptor–negative tumors, compared with controls. Also noteworthy were the combined-therapy group’s adjusted 78% increase in triple-negative cancers, the twofold increase in HER2-overexpressing tumors, and the 37% increase in HER2-negative tumors.

Nearly all the increase in lung cancer deaths associated with dual-hormone therapy resulted from NSCLC. Hormone therapy had no effect upon small cell lung cancer rates.

Among current smokers, the cumulative risk of death from lung cancer was 3.42% in those who used dual-hormone therapy for 5-plus years and 2.39% in placebo-treated controls. In other words, 1 in 100 current smokers who used estrogen plus progestin for 5-plus years experienced an otherwise-avoidable death from NSCLC. Among past smokers, the rate was 1 in 200. These numbers are worth keeping in mind, given that today roughly 15% of U.S. women are current smokers, and 35% are past smokers, Dr. Chlebowski noted.

Turning to the results of the estrogen-alone WHI trial, he pointed out that the therapy had no impact on incidence or death rates from lung or colorectal cancer, relative to placebo, but there was a nonsignificant 20% reduction in the relative risk of breast cancer in the hormone therapy group. This trend for a breast cancer–reduction benefit achieved significance in the nearly 4,500 study participants who were randomized to estrogen alone or placebo 5 years or more following the last menstrual period, where the hormonal therapy group enjoyed a 37% relative risk reduction. Of course, that’s not how hormone therapy is ordinarily employed in clinical practice, the physician pointed out.

One audience member rose to say that the oft-quoted sharply increased risk of uterine cancer in women with an intact uterus on estrogen alone dates back to older studies using doses that were considerably higher than those available in contemporary practice, as well as older methods of patient monitoring. She asked about the possibility of exploring ways to provide estrogen alone to menopausal women with an intact uterus without exposing them to increased uterine cancer risk.

Dr. Chlebowski said he thinks it’s certainly an appropriate research project, but he’d advise against trying it in clinical practice, given the product labeling and the malpractice lawsuit climate.

His take-home message from the expanded WHI analysis: "Even short-term use of combined-hormone therapy should be reserved for women with limiting climacteric symptoms [that are] not manageable by other means."

In a conference-closing review of the past year’s top developments in early breast cancer, Dr. Alan Coates singled out Dr. Chlebowski’s presentation on the WHI results as hands-down the most important study of the year in the field of cancer epidemiology.

"As we’ve known before, there’s a small but real increase in the incidence of breast cancer with combined-hormone replacement. The new finding is that there’s a massive increase – nearly a doubling – in mortality from breast cancer. And the mortality increase isn’t confined to breast cancer. ... This disparate increase in mortality over incidence in several tumor types suggests that the estrogen and progestin [combination] is doing something to the behavior of existing tumors," commented Dr. Coates of the University of Sydney.

It may be, as Dr. Chlebowski proposed, that the mechanism involves the angiogenic pathway, but other investigators have demonstrated that under certain circumstances, progestagens can stimulate stem cells by a paracrine RANKL (receptor-activated nuclear factor–kappaB ligand) mechanism. This could provide an equally plausible alternative explanation, he said.

Dr. Chlebowski disclosed that he receives grant support from Amgen and is on the speakers bureaus for AstraZeneca and Novartis. Dr. Coates reported having no relevant financial disclosures.

DENVER – Raising cigarette taxes has the unwanted effect of increasing alcohol consumption, including binge and heavy drinking.

This relationship is an example of what economists call a cross-price or substitution effect. And it’s something policy makers need to be cognizant of, Deborah L. McLellan said at the annual meeting of the American Public Health Association.

She analyzed 6 years of cross-sectional data from the Centers for Disease Control and Prevention’s annual Behavioral Risk Factor Surveillance System surveys carried out in 2001-2006. Interviews were conducted with 1,323,758 adults living in nearly every state in the country.

Her multivariate logistic regression analysis concluded that for every one dollar increase in the price of a pack of cigarettes, the ranks of current smokers drop by a highly significant 5%. That’s consistent with the classic economic theory of consumer demand, which holds that raising the price of a commodity decreases consumption.

But the analysis also showed that a one dollar per pack price increase was associated with a 29% increase in the odds of having consumed alcohol during the last month, a 12% increase in binge drinking, and a 10% increase in heavy drinking, defined in the study as more than one drink per day in women and more than two in men.

"I want to be clear that the message here is not ‘Let’s stop increasing cigarette taxes.’ That’s not my message at all. But this study is contributing to other literature out there that’s finding there are substitution effects, so advocates and policy makers and indeed researchers need to prepare for some of these unintended consequences of tobacco taxation policy," said Ms. McLellan of the Heller School for Social Policy and Management at Brandeis University, Waltham, Mass.

"There needs to be more collaboration between tobacco control advocates and those who work in alcohol prevention. We all know we tend to work in our silos, but people certainly do drink and smoke, and we need to catch up with them," she added.

The researcher noted that alcohol and tobacco use carry "staggering" human and economic costs. It’s estimated that 438,000 deaths occur annually from tobacco in the United States, and 98,000 because of alcohol. Twenty percent of Americans were smokers in 2006 and 51% were drinkers, including 23% who were binge drinkers and 7% who were heavy drinkers. Twenty-two percent of Americans were co-users.

She declared having no financial conflicts regarding the study, which she is conducting for her dissertation. 

DENVER – Raising cigarette taxes has the unwanted effect of increasing alcohol consumption, including binge and heavy drinking.

This relationship is an example of what economists call a cross-price or substitution effect. And it’s something policy makers need to be cognizant of, Deborah L. McLellan said at the annual meeting of the American Public Health Association.

She analyzed 6 years of cross-sectional data from the Centers for Disease Control and Prevention’s annual Behavioral Risk Factor Surveillance System surveys carried out in 2001-2006. Interviews were conducted with 1,323,758 adults living in nearly every state in the country.

Her multivariate logistic regression analysis concluded that for every one dollar increase in the price of a pack of cigarettes, the ranks of current smokers drop by a highly significant 5%. That’s consistent with the classic economic theory of consumer demand, which holds that raising the price of a commodity decreases consumption.

But the analysis also showed that a one dollar per pack price increase was associated with a 29% increase in the odds of having consumed alcohol during the last month, a 12% increase in binge drinking, and a 10% increase in heavy drinking, defined in the study as more than one drink per day in women and more than two in men.

"I want to be clear that the message here is not ‘Let’s stop increasing cigarette taxes.’ That’s not my message at all. But this study is contributing to other literature out there that’s finding there are substitution effects, so advocates and policy makers and indeed researchers need to prepare for some of these unintended consequences of tobacco taxation policy," said Ms. McLellan of the Heller School for Social Policy and Management at Brandeis University, Waltham, Mass.

"There needs to be more collaboration between tobacco control advocates and those who work in alcohol prevention. We all know we tend to work in our silos, but people certainly do drink and smoke, and we need to catch up with them," she added.

The researcher noted that alcohol and tobacco use carry "staggering" human and economic costs. It’s estimated that 438,000 deaths occur annually from tobacco in the United States, and 98,000 because of alcohol. Twenty percent of Americans were smokers in 2006 and 51% were drinkers, including 23% who were binge drinkers and 7% who were heavy drinkers. Twenty-two percent of Americans were co-users.

She declared having no financial conflicts regarding the study, which she is conducting for her dissertation. 

DENVER – Raising cigarette taxes has the unwanted effect of increasing alcohol consumption, including binge and heavy drinking.

This relationship is an example of what economists call a cross-price or substitution effect. And it’s something policy makers need to be cognizant of, Deborah L. McLellan said at the annual meeting of the American Public Health Association.

She analyzed 6 years of cross-sectional data from the Centers for Disease Control and Prevention’s annual Behavioral Risk Factor Surveillance System surveys carried out in 2001-2006. Interviews were conducted with 1,323,758 adults living in nearly every state in the country.

Her multivariate logistic regression analysis concluded that for every one dollar increase in the price of a pack of cigarettes, the ranks of current smokers drop by a highly significant 5%. That’s consistent with the classic economic theory of consumer demand, which holds that raising the price of a commodity decreases consumption.

But the analysis also showed that a one dollar per pack price increase was associated with a 29% increase in the odds of having consumed alcohol during the last month, a 12% increase in binge drinking, and a 10% increase in heavy drinking, defined in the study as more than one drink per day in women and more than two in men.

"I want to be clear that the message here is not ‘Let’s stop increasing cigarette taxes.’ That’s not my message at all. But this study is contributing to other literature out there that’s finding there are substitution effects, so advocates and policy makers and indeed researchers need to prepare for some of these unintended consequences of tobacco taxation policy," said Ms. McLellan of the Heller School for Social Policy and Management at Brandeis University, Waltham, Mass.

"There needs to be more collaboration between tobacco control advocates and those who work in alcohol prevention. We all know we tend to work in our silos, but people certainly do drink and smoke, and we need to catch up with them," she added.

The researcher noted that alcohol and tobacco use carry "staggering" human and economic costs. It’s estimated that 438,000 deaths occur annually from tobacco in the United States, and 98,000 because of alcohol. Twenty percent of Americans were smokers in 2006 and 51% were drinkers, including 23% who were binge drinkers and 7% who were heavy drinkers. Twenty-two percent of Americans were co-users.

She declared having no financial conflicts regarding the study, which she is conducting for her dissertation. 

GOTHENBURG, SWEDEN – Multimodal therapy with adapalene 0.1% and benzoyl peroxide 2.5% in a fixed-dose combination gel plus oral doxycycline proved safe, effective, and well tolerated for severe acne vulgaris in a large, double-blind, multicenter randomized trial.

Indeed, the combination therapy’s favorable safety profile makes it a compelling first-line treatment choice for all but the most severe, recalcitrant cases of nodular acne, where oral isotretinoin, despite its problematic safety profile, remains the treatment of choice because of its unequalled efficacy, Dr. Alma Cruz said at the annual meeting.

The mechanism of benefit for adapalene 0.1%–benzoyl peroxide 2.5% fixed-dose combination gel (Epiduo) plus oral doxycycline in patients with severe acne appears to involve, at least in part, the combination therapy’s ability to achieve a rapid and sustained reduction in Propionibacterium acnes as documented in the trial by serial fluorescent photography, according to Dr. Cruz, a dermatologist in Carolina, P.R.

At week 4 in the 12-week trial, patients in the combination therapy arm had a mean 60% reduction from baseline in P. acnes compared with a 22% decrease in the vehicle plus doxycycline group. At weeks 8 and 12, the combination therapy group had 73% and 74% reductions from baseline in P. acnes, compared with reductions of 16% and 14% in controls.

The reduction in P. acnes correlated with clinical efficacy. At week 2, one-third of the ultimate reduction in total lesion count in the combination treatment arm had already been achieved, with a mean 21% reduction from baseline, compared with a 13% decrease in controls.

At week 12, patients on Epiduo plus doxycycline had a mean 64% decrease from baseline in total acne lesions, compared with a 41% reduction in controls. The combined therapy outperformed doxycycline plus vehicle in treating both inflammatory and noninflammatory lesions.

The treatment success rate as defined by a rating of clear or almost clear on the investigator’s global assessment scale was 9.9% and 31.5% at weeks 8 and 12 in the combined therapy group, versus 2.6% and 8.4% in the controls.

The trial involved 459 patients with severe acne who were randomized to once-daily application of Epiduo in the evening plus 100 mg/day of doxycycline hyclate for 12 weeks, or to vehicle plus doxycycline.

The overall safety and tolerability of the combination therapy was similar to that of the vehicle plus doxycycline. Just under 10% of patients in both study arms reported gastrointestinal complaints believed to be due to the doxycycline.

A week-12 patient satisfaction survey showed 76% of patients in the combined therapy arm were satisfied or very satisfied overall with their treatment, compared with 50% of the controls. Sixty-seven percent of patients in the combination therapy group indicated they felt a lot better or much better about themselves since starting their therapy, as did 48% of the controls.

Dr. Cruz said he had received a research grant from Galderma Laboratories, which funded the clinical trial.

GOTHENBURG, SWEDEN – Multimodal therapy with adapalene 0.1% and benzoyl peroxide 2.5% in a fixed-dose combination gel plus oral doxycycline proved safe, effective, and well tolerated for severe acne vulgaris in a large, double-blind, multicenter randomized trial.

Indeed, the combination therapy’s favorable safety profile makes it a compelling first-line treatment choice for all but the most severe, recalcitrant cases of nodular acne, where oral isotretinoin, despite its problematic safety profile, remains the treatment of choice because of its unequalled efficacy, Dr. Alma Cruz said at the annual meeting.

The mechanism of benefit for adapalene 0.1%–benzoyl peroxide 2.5% fixed-dose combination gel (Epiduo) plus oral doxycycline in patients with severe acne appears to involve, at least in part, the combination therapy’s ability to achieve a rapid and sustained reduction in Propionibacterium acnes as documented in the trial by serial fluorescent photography, according to Dr. Cruz, a dermatologist in Carolina, P.R.

At week 4 in the 12-week trial, patients in the combination therapy arm had a mean 60% reduction from baseline in P. acnes compared with a 22% decrease in the vehicle plus doxycycline group. At weeks 8 and 12, the combination therapy group had 73% and 74% reductions from baseline in P. acnes, compared with reductions of 16% and 14% in controls.

The reduction in P. acnes correlated with clinical efficacy. At week 2, one-third of the ultimate reduction in total lesion count in the combination treatment arm had already been achieved, with a mean 21% reduction from baseline, compared with a 13% decrease in controls.

At week 12, patients on Epiduo plus doxycycline had a mean 64% decrease from baseline in total acne lesions, compared with a 41% reduction in controls. The combined therapy outperformed doxycycline plus vehicle in treating both inflammatory and noninflammatory lesions.

The treatment success rate as defined by a rating of clear or almost clear on the investigator’s global assessment scale was 9.9% and 31.5% at weeks 8 and 12 in the combined therapy group, versus 2.6% and 8.4% in the controls.

The trial involved 459 patients with severe acne who were randomized to once-daily application of Epiduo in the evening plus 100 mg/day of doxycycline hyclate for 12 weeks, or to vehicle plus doxycycline.

The overall safety and tolerability of the combination therapy was similar to that of the vehicle plus doxycycline. Just under 10% of patients in both study arms reported gastrointestinal complaints believed to be due to the doxycycline.

A week-12 patient satisfaction survey showed 76% of patients in the combined therapy arm were satisfied or very satisfied overall with their treatment, compared with 50% of the controls. Sixty-seven percent of patients in the combination therapy group indicated they felt a lot better or much better about themselves since starting their therapy, as did 48% of the controls.

Dr. Cruz said he had received a research grant from Galderma Laboratories, which funded the clinical trial.

GOTHENBURG, SWEDEN – Multimodal therapy with adapalene 0.1% and benzoyl peroxide 2.5% in a fixed-dose combination gel plus oral doxycycline proved safe, effective, and well tolerated for severe acne vulgaris in a large, double-blind, multicenter randomized trial.

Indeed, the combination therapy’s favorable safety profile makes it a compelling first-line treatment choice for all but the most severe, recalcitrant cases of nodular acne, where oral isotretinoin, despite its problematic safety profile, remains the treatment of choice because of its unequalled efficacy, Dr. Alma Cruz said at the annual meeting.

The mechanism of benefit for adapalene 0.1%–benzoyl peroxide 2.5% fixed-dose combination gel (Epiduo) plus oral doxycycline in patients with severe acne appears to involve, at least in part, the combination therapy’s ability to achieve a rapid and sustained reduction in Propionibacterium acnes as documented in the trial by serial fluorescent photography, according to Dr. Cruz, a dermatologist in Carolina, P.R.

At week 4 in the 12-week trial, patients in the combination therapy arm had a mean 60% reduction from baseline in P. acnes compared with a 22% decrease in the vehicle plus doxycycline group. At weeks 8 and 12, the combination therapy group had 73% and 74% reductions from baseline in P. acnes, compared with reductions of 16% and 14% in controls.

The reduction in P. acnes correlated with clinical efficacy. At week 2, one-third of the ultimate reduction in total lesion count in the combination treatment arm had already been achieved, with a mean 21% reduction from baseline, compared with a 13% decrease in controls.

At week 12, patients on Epiduo plus doxycycline had a mean 64% decrease from baseline in total acne lesions, compared with a 41% reduction in controls. The combined therapy outperformed doxycycline plus vehicle in treating both inflammatory and noninflammatory lesions.

The treatment success rate as defined by a rating of clear or almost clear on the investigator’s global assessment scale was 9.9% and 31.5% at weeks 8 and 12 in the combined therapy group, versus 2.6% and 8.4% in the controls.

The trial involved 459 patients with severe acne who were randomized to once-daily application of Epiduo in the evening plus 100 mg/day of doxycycline hyclate for 12 weeks, or to vehicle plus doxycycline.

The overall safety and tolerability of the combination therapy was similar to that of the vehicle plus doxycycline. Just under 10% of patients in both study arms reported gastrointestinal complaints believed to be due to the doxycycline.

A week-12 patient satisfaction survey showed 76% of patients in the combined therapy arm were satisfied or very satisfied overall with their treatment, compared with 50% of the controls. Sixty-seven percent of patients in the combination therapy group indicated they felt a lot better or much better about themselves since starting their therapy, as did 48% of the controls.

Dr. Cruz said he had received a research grant from Galderma Laboratories, which funded the clinical trial.

CHICAGO – New American College of Cardiology/American Heart Association guidelines on cardiovascular risk assessment in asymptomatic adults may be better remembered for the tests and procedures that received a thumbs-down rather than for those endorsed for routine use.

For example, genetic testing was among the newer, often glamorous tests that have captured intense public and physician interest, yet they were classified as class III – meaning they’re deemed not useful and may be harmful. In other words, don’t do them in people without symptoms of heart disease.

"Genetic testing is a sexy area right now, but we didn’t see it as being ready or as having shown added value," Dr. Sidney C. Smith Jr. said in a press briefing on the new guidelines held during the annual scientific sessions of the American Heart Association.

Other tests that were rated class III included advanced lipid testing with measurement of apolipoproteins and particle size and density, MRI for the detection of arterial plaque, measurement of natriuretic peptide levels, and coronary CT angiography.

"You’ll hear a lot of discussion about the value of coronary CT angiography in people who come into the emergency department with chest pain, but that’s a very different population," said Dr. Smith, a member of the risk assessment guideline writing committee and immediate past chair of the ACC/AHA task force on practice guidelines.

Stress echocardiography, measures of arterial stiffness, and assessment of flow-mediated dilation also received class III status, noted Dr. Smith, professor of medicine and director of the center for cardiovascular science and medicine at the University of North Carolina, Chapel Hill.

In his Ancel Keys Memorial Lecture delivered at the AHA conference, Dr. Philip Greenland, chair of the guideline writing committee, explained that new diagnostic tests have to clear a high bar: They must show evidence of added value beyond that provided by the Framingham Risk Score or another global cardiovascular risk score plus assessment of family history, which are the only class I recommendations in the new report, meaning they should be performed in all adults.

The family history is a new class I recommendation. A positive family history under the Framingham definition is a first-generation male relative with a cardiovascular event at age 50 or younger, or by age 60 or younger in a female relative.

The new guidelines state that a global cardiovascular risk score and family history are essential for everyone, preferably starting at age 20, and should be repeated every 5 years.

For a new risk marker to be considered as useful for risk prediction, it must be shown to be a statistically independent predictor after an accounting for established risk factors. Beyond that, it must also be shown to change predictive risk sufficiently to alter recommended therapy. And then it must be demonstrated that using the novel marker to sort patients and treat them accordingly would actually yield better clinical outcomes than if the marker had not been employed, explained Dr. Greenland, professor of medicine and preventive medicine at Northwestern University in Chicago.

"This is a big question for almost all of our biomarkers in cardiovascular medicine, where we can perhaps show improvement in prediction, but it’s not quite so clear we can show improvement in clinical outcomes," he said. "Generally speaking, we haven’t seen much evidence of improvement of risk prediction with the new markers when you look at the whole picture. The one exception, I would say, is measurement of coronary artery calcium. I came to this as a major skeptic about coronary calcium, and only after seeing some data did I come to believe that coronary calcium might actually have clinical impact. But even with coronary calcium, I think we’re too early in the evaluation process to recommend routine use beyond standard risk measurement."

Indeed, coronary artery calcium scoring gets a class IIa recommendation (meaning it’s reasonable for cardiovascular risk assessment) only in asymptomatic adults who are at intermediate risk, as defined by their global Framingham-type risk assessment, with an estimated 10%-20% risk of a cardiovascular event in the next 10 years. Coronary calcium scoring gets a lesser IIb rating (meaning it ‘may be considered appropriate’) in patients who are at low to intermediate risk, as defined by an estimated 6%-10% risk of an event over 10 years. In patients with less than a 6% 10-year risk, it gets a class III rating.

Investigators in MESA (Multi-Ethnic Study of Atherosclerosis) found that adding coronary artery calcium scores to standard cardiovascular risk factors improved risk discrimination from 77% to 82%, which the committee deemed clinically meaningful, Dr. Smith noted.

Measurement of C-reactive protein, another hot topic, is rated class III (no benefit) in asymptomatic adults who are defined as high-risk by the Adult Treatment Panel III standard of a greater than 20% 10-year risk. Similarly, CRP is class III in low-risk men younger than age 50 and in low-risk women younger than age 60.

However, CRP is beneficial in fine-tuning risk assessment in individuals who are at intermediate 10-year risk based upon their global assessment. CRP gets a class IIa recommendation as a guide to deciding on statin therapy in men aged 50 or older and in women aged 60 and older with an LDL cholesterol level of less than 130 mg/dL. It gets a class IIb recommendation in asymptomatic men and women aged 50 and 60 years, respectively, or younger.

Other tests that are rated class IIa or IIb under various circumstances in intermediate-risk people include ankle-brachial index testing for peripheral artery disease, a resting ECG in patients with hypertension or diabetes, conventional echocardiography in hypertensive patients, an exercise ECG before the start of a vigorous exercise program, carotid intima-media thickness measurement when performed by an expert operator, and measurement of hemoglobin A1c. Testing for microalbuminuria gets a class IIa recommendation in asymptomatic adults with diabetes or hypertension, and is class IIb for intermediate-risk adults without those comorbidities.

The full 54-page guideline was released online in Circulation during the conference.

Dr. Smith declared having no relevant financial interests. Dr. Greenland disclosed serving as a consultant to Pfizer, General Electric, and Toshiba.

CHICAGO – New American College of Cardiology/American Heart Association guidelines on cardiovascular risk assessment in asymptomatic adults may be better remembered for the tests and procedures that received a thumbs-down rather than for those endorsed for routine use.

For example, genetic testing was among the newer, often glamorous tests that have captured intense public and physician interest, yet they were classified as class III – meaning they’re deemed not useful and may be harmful. In other words, don’t do them in people without symptoms of heart disease.

"Genetic testing is a sexy area right now, but we didn’t see it as being ready or as having shown added value," Dr. Sidney C. Smith Jr. said in a press briefing on the new guidelines held during the annual scientific sessions of the American Heart Association.

Other tests that were rated class III included advanced lipid testing with measurement of apolipoproteins and particle size and density, MRI for the detection of arterial plaque, measurement of natriuretic peptide levels, and coronary CT angiography.

"You’ll hear a lot of discussion about the value of coronary CT angiography in people who come into the emergency department with chest pain, but that’s a very different population," said Dr. Smith, a member of the risk assessment guideline writing committee and immediate past chair of the ACC/AHA task force on practice guidelines.

Stress echocardiography, measures of arterial stiffness, and assessment of flow-mediated dilation also received class III status, noted Dr. Smith, professor of medicine and director of the center for cardiovascular science and medicine at the University of North Carolina, Chapel Hill.

In his Ancel Keys Memorial Lecture delivered at the AHA conference, Dr. Philip Greenland, chair of the guideline writing committee, explained that new diagnostic tests have to clear a high bar: They must show evidence of added value beyond that provided by the Framingham Risk Score or another global cardiovascular risk score plus assessment of family history, which are the only class I recommendations in the new report, meaning they should be performed in all adults.

The family history is a new class I recommendation. A positive family history under the Framingham definition is a first-generation male relative with a cardiovascular event at age 50 or younger, or by age 60 or younger in a female relative.

The new guidelines state that a global cardiovascular risk score and family history are essential for everyone, preferably starting at age 20, and should be repeated every 5 years.

For a new risk marker to be considered as useful for risk prediction, it must be shown to be a statistically independent predictor after an accounting for established risk factors. Beyond that, it must also be shown to change predictive risk sufficiently to alter recommended therapy. And then it must be demonstrated that using the novel marker to sort patients and treat them accordingly would actually yield better clinical outcomes than if the marker had not been employed, explained Dr. Greenland, professor of medicine and preventive medicine at Northwestern University in Chicago.

"This is a big question for almost all of our biomarkers in cardiovascular medicine, where we can perhaps show improvement in prediction, but it’s not quite so clear we can show improvement in clinical outcomes," he said. "Generally speaking, we haven’t seen much evidence of improvement of risk prediction with the new markers when you look at the whole picture. The one exception, I would say, is measurement of coronary artery calcium. I came to this as a major skeptic about coronary calcium, and only after seeing some data did I come to believe that coronary calcium might actually have clinical impact. But even with coronary calcium, I think we’re too early in the evaluation process to recommend routine use beyond standard risk measurement."

Indeed, coronary artery calcium scoring gets a class IIa recommendation (meaning it’s reasonable for cardiovascular risk assessment) only in asymptomatic adults who are at intermediate risk, as defined by their global Framingham-type risk assessment, with an estimated 10%-20% risk of a cardiovascular event in the next 10 years. Coronary calcium scoring gets a lesser IIb rating (meaning it ‘may be considered appropriate’) in patients who are at low to intermediate risk, as defined by an estimated 6%-10% risk of an event over 10 years. In patients with less than a 6% 10-year risk, it gets a class III rating.

Investigators in MESA (Multi-Ethnic Study of Atherosclerosis) found that adding coronary artery calcium scores to standard cardiovascular risk factors improved risk discrimination from 77% to 82%, which the committee deemed clinically meaningful, Dr. Smith noted.

Measurement of C-reactive protein, another hot topic, is rated class III (no benefit) in asymptomatic adults who are defined as high-risk by the Adult Treatment Panel III standard of a greater than 20% 10-year risk. Similarly, CRP is class III in low-risk men younger than age 50 and in low-risk women younger than age 60.

However, CRP is beneficial in fine-tuning risk assessment in individuals who are at intermediate 10-year risk based upon their global assessment. CRP gets a class IIa recommendation as a guide to deciding on statin therapy in men aged 50 or older and in women aged 60 and older with an LDL cholesterol level of less than 130 mg/dL. It gets a class IIb recommendation in asymptomatic men and women aged 50 and 60 years, respectively, or younger.

Other tests that are rated class IIa or IIb under various circumstances in intermediate-risk people include ankle-brachial index testing for peripheral artery disease, a resting ECG in patients with hypertension or diabetes, conventional echocardiography in hypertensive patients, an exercise ECG before the start of a vigorous exercise program, carotid intima-media thickness measurement when performed by an expert operator, and measurement of hemoglobin A1c. Testing for microalbuminuria gets a class IIa recommendation in asymptomatic adults with diabetes or hypertension, and is class IIb for intermediate-risk adults without those comorbidities.

The full 54-page guideline was released online in Circulation during the conference.

Dr. Smith declared having no relevant financial interests. Dr. Greenland disclosed serving as a consultant to Pfizer, General Electric, and Toshiba.

CHICAGO – New American College of Cardiology/American Heart Association guidelines on cardiovascular risk assessment in asymptomatic adults may be better remembered for the tests and procedures that received a thumbs-down rather than for those endorsed for routine use.

For example, genetic testing was among the newer, often glamorous tests that have captured intense public and physician interest, yet they were classified as class III – meaning they’re deemed not useful and may be harmful. In other words, don’t do them in people without symptoms of heart disease.

"Genetic testing is a sexy area right now, but we didn’t see it as being ready or as having shown added value," Dr. Sidney C. Smith Jr. said in a press briefing on the new guidelines held during the annual scientific sessions of the American Heart Association.

Other tests that were rated class III included advanced lipid testing with measurement of apolipoproteins and particle size and density, MRI for the detection of arterial plaque, measurement of natriuretic peptide levels, and coronary CT angiography.

"You’ll hear a lot of discussion about the value of coronary CT angiography in people who come into the emergency department with chest pain, but that’s a very different population," said Dr. Smith, a member of the risk assessment guideline writing committee and immediate past chair of the ACC/AHA task force on practice guidelines.

Stress echocardiography, measures of arterial stiffness, and assessment of flow-mediated dilation also received class III status, noted Dr. Smith, professor of medicine and director of the center for cardiovascular science and medicine at the University of North Carolina, Chapel Hill.

In his Ancel Keys Memorial Lecture delivered at the AHA conference, Dr. Philip Greenland, chair of the guideline writing committee, explained that new diagnostic tests have to clear a high bar: They must show evidence of added value beyond that provided by the Framingham Risk Score or another global cardiovascular risk score plus assessment of family history, which are the only class I recommendations in the new report, meaning they should be performed in all adults.

The family history is a new class I recommendation. A positive family history under the Framingham definition is a first-generation male relative with a cardiovascular event at age 50 or younger, or by age 60 or younger in a female relative.

The new guidelines state that a global cardiovascular risk score and family history are essential for everyone, preferably starting at age 20, and should be repeated every 5 years.

For a new risk marker to be considered as useful for risk prediction, it must be shown to be a statistically independent predictor after an accounting for established risk factors. Beyond that, it must also be shown to change predictive risk sufficiently to alter recommended therapy. And then it must be demonstrated that using the novel marker to sort patients and treat them accordingly would actually yield better clinical outcomes than if the marker had not been employed, explained Dr. Greenland, professor of medicine and preventive medicine at Northwestern University in Chicago.

"This is a big question for almost all of our biomarkers in cardiovascular medicine, where we can perhaps show improvement in prediction, but it’s not quite so clear we can show improvement in clinical outcomes," he said. "Generally speaking, we haven’t seen much evidence of improvement of risk prediction with the new markers when you look at the whole picture. The one exception, I would say, is measurement of coronary artery calcium. I came to this as a major skeptic about coronary calcium, and only after seeing some data did I come to believe that coronary calcium might actually have clinical impact. But even with coronary calcium, I think we’re too early in the evaluation process to recommend routine use beyond standard risk measurement."

Indeed, coronary artery calcium scoring gets a class IIa recommendation (meaning it’s reasonable for cardiovascular risk assessment) only in asymptomatic adults who are at intermediate risk, as defined by their global Framingham-type risk assessment, with an estimated 10%-20% risk of a cardiovascular event in the next 10 years. Coronary calcium scoring gets a lesser IIb rating (meaning it ‘may be considered appropriate’) in patients who are at low to intermediate risk, as defined by an estimated 6%-10% risk of an event over 10 years. In patients with less than a 6% 10-year risk, it gets a class III rating.

Investigators in MESA (Multi-Ethnic Study of Atherosclerosis) found that adding coronary artery calcium scores to standard cardiovascular risk factors improved risk discrimination from 77% to 82%, which the committee deemed clinically meaningful, Dr. Smith noted.

Measurement of C-reactive protein, another hot topic, is rated class III (no benefit) in asymptomatic adults who are defined as high-risk by the Adult Treatment Panel III standard of a greater than 20% 10-year risk. Similarly, CRP is class III in low-risk men younger than age 50 and in low-risk women younger than age 60.

However, CRP is beneficial in fine-tuning risk assessment in individuals who are at intermediate 10-year risk based upon their global assessment. CRP gets a class IIa recommendation as a guide to deciding on statin therapy in men aged 50 or older and in women aged 60 and older with an LDL cholesterol level of less than 130 mg/dL. It gets a class IIb recommendation in asymptomatic men and women aged 50 and 60 years, respectively, or younger.

Other tests that are rated class IIa or IIb under various circumstances in intermediate-risk people include ankle-brachial index testing for peripheral artery disease, a resting ECG in patients with hypertension or diabetes, conventional echocardiography in hypertensive patients, an exercise ECG before the start of a vigorous exercise program, carotid intima-media thickness measurement when performed by an expert operator, and measurement of hemoglobin A1c. Testing for microalbuminuria gets a class IIa recommendation in asymptomatic adults with diabetes or hypertension, and is class IIb for intermediate-risk adults without those comorbidities.

The full 54-page guideline was released online in Circulation during the conference.

Dr. Smith declared having no relevant financial interests. Dr. Greenland disclosed serving as a consultant to Pfizer, General Electric, and Toshiba.

CHICAGO – New American College of Cardiology/American Heart Association guidelines on cardiovascular risk assessment in asymptomatic adults may be better remembered for the tests and procedures that received a thumbs-down rather than for those endorsed for routine use.

For example, genetic testing was among the newer, often glamorous tests that have captured intense public and physician interest, yet they were classified as class III – meaning they’re deemed not useful and may be harmful. In other words, don’t do them in people without symptoms of heart disease.

"Genetic testing is a sexy area right now, but we didn’t see it as being ready or as having shown added value," Dr. Sidney C. Smith Jr. said in a press briefing on the new guidelines held during the annual scientific sessions of the American Heart Association.

Other tests that were rated class III included advanced lipid testing with measurement of apolipoproteins and particle size and density, MRI for the detection of arterial plaque, measurement of natriuretic peptide levels, and coronary CT angiography.

"You’ll hear a lot of discussion about the value of coronary CT angiography in people who come into the emergency department with chest pain, but that’s a very different population," said Dr. Smith, a member of the risk assessment guideline writing committee and immediate past chair of the ACC/AHA task force on practice guidelines.

Stress echocardiography, measures of arterial stiffness, and assessment of flow-mediated dilation also received class III status, noted Dr. Smith, professor of medicine and director of the center for cardiovascular science and medicine at the University of North Carolina, Chapel Hill.

In his Ancel Keys Memorial Lecture delivered at the AHA conference, Dr. Philip Greenland, chair of the guideline writing committee, explained that new diagnostic tests have to clear a high bar: They must show evidence of added value beyond that provided by the Framingham Risk Score or another global cardiovascular risk score plus assessment of family history, which are the only class I recommendations in the new report, meaning they should be performed in all adults.

The family history is a new class I recommendation. A positive family history under the Framingham definition is a first-generation male relative with a cardiovascular event at age 50 or younger, or by age 60 or younger in a female relative.

The new guidelines state that a global cardiovascular risk score and family history are essential for everyone, preferably starting at age 20, and should be repeated every 5 years.

For a new risk marker to be considered as useful for risk prediction, it must be shown to be a statistically independent predictor after an accounting for established risk factors. Beyond that, it must also be shown to change predictive risk sufficiently to alter recommended therapy. And then it must be demonstrated that using the novel marker to sort patients and treat them accordingly would actually yield better clinical outcomes than if the marker had not been employed, explained Dr. Greenland, professor of medicine and preventive medicine at Northwestern University in Chicago.

"This is a big question for almost all of our biomarkers in cardiovascular medicine, where we can perhaps show improvement in prediction, but it’s not quite so clear we can show improvement in clinical outcomes," he said. "Generally speaking, we haven’t seen much evidence of improvement of risk prediction with the new markers when you look at the whole picture. The one exception, I would say, is measurement of coronary artery calcium. I came to this as a major skeptic about coronary calcium, and only after seeing some data did I come to believe that coronary calcium might actually have clinical impact. But even with coronary calcium, I think we’re too early in the evaluation process to recommend routine use beyond standard risk measurement."

Indeed, coronary artery calcium scoring gets a class IIa recommendation (meaning it’s reasonable for cardiovascular risk assessment) only in asymptomatic adults who are at intermediate risk, as defined by their global Framingham-type risk assessment, with an estimated 10%-20% risk of a cardiovascular event in the next 10 years. Coronary calcium scoring gets a lesser IIb rating (meaning it ‘may be considered appropriate’) in patients who are at low to intermediate risk, as defined by an estimated 6%-10% risk of an event over 10 years. In patients with less than a 6% 10-year risk, it gets a class III rating.

Investigators in MESA (Multi-Ethnic Study of Atherosclerosis) found that adding coronary artery calcium scores to standard cardiovascular risk factors improved risk discrimination from 77% to 82%, which the committee deemed clinically meaningful, Dr. Smith noted.

Measurement of C-reactive protein, another hot topic, is rated class III (no benefit) in asymptomatic adults who are defined as high-risk by the Adult Treatment Panel III standard of a greater than 20% 10-year risk. Similarly, CRP is class III in low-risk men younger than age 50 and in low-risk women younger than age 60.

However, CRP is beneficial in fine-tuning risk assessment in individuals who are at intermediate 10-year risk based upon their global assessment. CRP gets a class IIa recommendation as a guide to deciding on statin therapy in men aged 50 or older and in women aged 60 and older with an LDL cholesterol level of less than 130 mg/dL. It gets a class IIb recommendation in asymptomatic men and women aged 50 and 60 years, respectively, or younger.

Other tests that are rated class IIa or IIb under various circumstances in intermediate-risk people include ankle-brachial index testing for peripheral artery disease, a resting ECG in patients with hypertension or diabetes, conventional echocardiography in hypertensive patients, an exercise ECG before the start of a vigorous exercise program, carotid intima-media thickness measurement when performed by an expert operator, and measurement of hemoglobin A1c. Testing for microalbuminuria gets a class IIa recommendation in asymptomatic adults with diabetes or hypertension, and is class IIb for intermediate-risk adults without those comorbidities.

The full 54-page guideline was released online in Circulation during the conference.

Dr. Smith declared having no relevant financial interests. Dr. Greenland disclosed serving as a consultant to Pfizer, General Electric, and Toshiba.

CHICAGO – New American College of Cardiology/American Heart Association guidelines on cardiovascular risk assessment in asymptomatic adults may be better remembered for the tests and procedures that received a thumbs-down rather than for those endorsed for routine use.

For example, genetic testing was among the newer, often glamorous tests that have captured intense public and physician interest, yet they were classified as class III – meaning they’re deemed not useful and may be harmful. In other words, don’t do them in people without symptoms of heart disease.

"Genetic testing is a sexy area right now, but we didn’t see it as being ready or as having shown added value," Dr. Sidney C. Smith Jr. said in a press briefing on the new guidelines held during the annual scientific sessions of the American Heart Association.

Other tests that were rated class III included advanced lipid testing with measurement of apolipoproteins and particle size and density, MRI for the detection of arterial plaque, measurement of natriuretic peptide levels, and coronary CT angiography.

"You’ll hear a lot of discussion about the value of coronary CT angiography in people who come into the emergency department with chest pain, but that’s a very different population," said Dr. Smith, a member of the risk assessment guideline writing committee and immediate past chair of the ACC/AHA task force on practice guidelines.

Stress echocardiography, measures of arterial stiffness, and assessment of flow-mediated dilation also received class III status, noted Dr. Smith, professor of medicine and director of the center for cardiovascular science and medicine at the University of North Carolina, Chapel Hill.

In his Ancel Keys Memorial Lecture delivered at the AHA conference, Dr. Philip Greenland, chair of the guideline writing committee, explained that new diagnostic tests have to clear a high bar: They must show evidence of added value beyond that provided by the Framingham Risk Score or another global cardiovascular risk score plus assessment of family history, which are the only class I recommendations in the new report, meaning they should be performed in all adults.

The family history is a new class I recommendation. A positive family history under the Framingham definition is a first-generation male relative with a cardiovascular event at age 50 or younger, or by age 60 or younger in a female relative.

The new guidelines state that a global cardiovascular risk score and family history are essential for everyone, preferably starting at age 20, and should be repeated every 5 years.

For a new risk marker to be considered as useful for risk prediction, it must be shown to be a statistically independent predictor after an accounting for established risk factors. Beyond that, it must also be shown to change predictive risk sufficiently to alter recommended therapy. And then it must be demonstrated that using the novel marker to sort patients and treat them accordingly would actually yield better clinical outcomes than if the marker had not been employed, explained Dr. Greenland, professor of medicine and preventive medicine at Northwestern University in Chicago.

"This is a big question for almost all of our biomarkers in cardiovascular medicine, where we can perhaps show improvement in prediction, but it’s not quite so clear we can show improvement in clinical outcomes," he said. "Generally speaking, we haven’t seen much evidence of improvement of risk prediction with the new markers when you look at the whole picture. The one exception, I would say, is measurement of coronary artery calcium. I came to this as a major skeptic about coronary calcium, and only after seeing some data did I come to believe that coronary calcium might actually have clinical impact. But even with coronary calcium, I think we’re too early in the evaluation process to recommend routine use beyond standard risk measurement."

Indeed, coronary artery calcium scoring gets a class IIa recommendation (meaning it’s reasonable for cardiovascular risk assessment) only in asymptomatic adults who are at intermediate risk, as defined by their global Framingham-type risk assessment, with an estimated 10%-20% risk of a cardiovascular event in the next 10 years. Coronary calcium scoring gets a lesser IIb rating (meaning it ‘may be considered appropriate’) in patients who are at low to intermediate risk, as defined by an estimated 6%-10% risk of an event over 10 years. In patients with less than a 6% 10-year risk, it gets a class III rating.

Investigators in MESA (Multi-Ethnic Study of Atherosclerosis) found that adding coronary artery calcium scores to standard cardiovascular risk factors improved risk discrimination from 77% to 82%, which the committee deemed clinically meaningful, Dr. Smith noted.

Measurement of C-reactive protein, another hot topic, is rated class III (no benefit) in asymptomatic adults who are defined as high-risk by the Adult Treatment Panel III standard of a greater than 20% 10-year risk. Similarly, CRP is class III in low-risk men younger than age 50 and in low-risk women younger than age 60.

However, CRP is beneficial in fine-tuning risk assessment in individuals who are at intermediate 10-year risk based upon their global assessment. CRP gets a class IIa recommendation as a guide to deciding on statin therapy in men aged 50 or older and in women aged 60 and older with an LDL cholesterol level of less than 130 mg/dL. It gets a class IIb recommendation in asymptomatic men and women aged 50 and 60 years, respectively, or younger.

Other tests that are rated class IIa or IIb under various circumstances in intermediate-risk people include ankle-brachial index testing for peripheral artery disease, a resting ECG in patients with hypertension or diabetes, conventional echocardiography in hypertensive patients, an exercise ECG before the start of a vigorous exercise program, carotid intima-media thickness measurement when performed by an expert operator, and measurement of hemoglobin A1c. Testing for microalbuminuria gets a class IIa recommendation in asymptomatic adults with diabetes or hypertension, and is class IIb for intermediate-risk adults without those comorbidities.

The full 54-page guideline was released online in Circulation during the conference.

Dr. Smith declared having no relevant financial interests. Dr. Greenland disclosed serving as a consultant to Pfizer, General Electric, and Toshiba.

CHICAGO – New American College of Cardiology/American Heart Association guidelines on cardiovascular risk assessment in asymptomatic adults may be better remembered for the tests and procedures that received a thumbs-down rather than for those endorsed for routine use.

For example, genetic testing was among the newer, often glamorous tests that have captured intense public and physician interest, yet they were classified as class III – meaning they’re deemed not useful and may be harmful. In other words, don’t do them in people without symptoms of heart disease.

"Genetic testing is a sexy area right now, but we didn’t see it as being ready or as having shown added value," Dr. Sidney C. Smith Jr. said in a press briefing on the new guidelines held during the annual scientific sessions of the American Heart Association.

Other tests that were rated class III included advanced lipid testing with measurement of apolipoproteins and particle size and density, MRI for the detection of arterial plaque, measurement of natriuretic peptide levels, and coronary CT angiography.

"You’ll hear a lot of discussion about the value of coronary CT angiography in people who come into the emergency department with chest pain, but that’s a very different population," said Dr. Smith, a member of the risk assessment guideline writing committee and immediate past chair of the ACC/AHA task force on practice guidelines.

Stress echocardiography, measures of arterial stiffness, and assessment of flow-mediated dilation also received class III status, noted Dr. Smith, professor of medicine and director of the center for cardiovascular science and medicine at the University of North Carolina, Chapel Hill.

In his Ancel Keys Memorial Lecture delivered at the AHA conference, Dr. Philip Greenland, chair of the guideline writing committee, explained that new diagnostic tests have to clear a high bar: They must show evidence of added value beyond that provided by the Framingham Risk Score or another global cardiovascular risk score plus assessment of family history, which are the only class I recommendations in the new report, meaning they should be performed in all adults.

The family history is a new class I recommendation. A positive family history under the Framingham definition is a first-generation male relative with a cardiovascular event at age 50 or younger, or by age 60 or younger in a female relative.

The new guidelines state that a global cardiovascular risk score and family history are essential for everyone, preferably starting at age 20, and should be repeated every 5 years.

For a new risk marker to be considered as useful for risk prediction, it must be shown to be a statistically independent predictor after an accounting for established risk factors. Beyond that, it must also be shown to change predictive risk sufficiently to alter recommended therapy. And then it must be demonstrated that using the novel marker to sort patients and treat them accordingly would actually yield better clinical outcomes than if the marker had not been employed, explained Dr. Greenland, professor of medicine and preventive medicine at Northwestern University in Chicago.

"This is a big question for almost all of our biomarkers in cardiovascular medicine, where we can perhaps show improvement in prediction, but it’s not quite so clear we can show improvement in clinical outcomes," he said. "Generally speaking, we haven’t seen much evidence of improvement of risk prediction with the new markers when you look at the whole picture. The one exception, I would say, is measurement of coronary artery calcium. I came to this as a major skeptic about coronary calcium, and only after seeing some data did I come to believe that coronary calcium might actually have clinical impact. But even with coronary calcium, I think we’re too early in the evaluation process to recommend routine use beyond standard risk measurement."

Indeed, coronary artery calcium scoring gets a class IIa recommendation (meaning it’s reasonable for cardiovascular risk assessment) only in asymptomatic adults who are at intermediate risk, as defined by their global Framingham-type risk assessment, with an estimated 10%-20% risk of a cardiovascular event in the next 10 years. Coronary calcium scoring gets a lesser IIb rating (meaning it ‘may be considered appropriate’) in patients who are at low to intermediate risk, as defined by an estimated 6%-10% risk of an event over 10 years. In patients with less than a 6% 10-year risk, it gets a class III rating.

Investigators in MESA (Multi-Ethnic Study of Atherosclerosis) found that adding coronary artery calcium scores to standard cardiovascular risk factors improved risk discrimination from 77% to 82%, which the committee deemed clinically meaningful, Dr. Smith noted.

Measurement of C-reactive protein, another hot topic, is rated class III (no benefit) in asymptomatic adults who are defined as high-risk by the Adult Treatment Panel III standard of a greater than 20% 10-year risk. Similarly, CRP is class III in low-risk men younger than age 50 and in low-risk women younger than age 60.

However, CRP is beneficial in fine-tuning risk assessment in individuals who are at intermediate 10-year risk based upon their global assessment. CRP gets a class IIa recommendation as a guide to deciding on statin therapy in men aged 50 or older and in women aged 60 and older with an LDL cholesterol level of less than 130 mg/dL. It gets a class IIb recommendation in asymptomatic men and women aged 50 and 60 years, respectively, or younger.

Other tests that are rated class IIa or IIb under various circumstances in intermediate-risk people include ankle-brachial index testing for peripheral artery disease, a resting ECG in patients with hypertension or diabetes, conventional echocardiography in hypertensive patients, an exercise ECG before the start of a vigorous exercise program, carotid intima-media thickness measurement when performed by an expert operator, and measurement of hemoglobin A1c. Testing for microalbuminuria gets a class IIa recommendation in asymptomatic adults with diabetes or hypertension, and is class IIb for intermediate-risk adults without those comorbidities.

The full 54-page guideline was released online in Circulation during the conference.

Dr. Smith declared having no relevant financial interests. Dr. Greenland disclosed serving as a consultant to Pfizer, General Electric, and Toshiba.

SAN ANTONIO – Denosumab delayed time to a first skeletal-related adverse event by a median of 5 months longer than did zoledronic acid in patients with advanced breast cancer and bone metastases, based on updated results from a landmark head-to-head comparative trial of the two osteoclast-inhibiting drugs.

Moreover, time to the composite secondary end point of a first skeletal-related event or hypercalcemia, a feared and life-threatening complication of metastatic bone disease, was prolonged by a median of 7.3 months in the denosumab (Xgeva) group compared with those on zoledronic acid (Zometa), Dr. Alison T. Stopeck reported at the San Antonio Breast Cancer Symposium.

"To put this in some perspective, the average life expectancy of these patients is 2½ to 3 years, so 7 additional months of freedom from these complications is a considerable period of their remaining time," said Dr. Stopeck, director of the clinical breast cancer program at the Arizona Cancer Center at the University of Arizona, Tucson.

She presented a new extended analysis that included 4 more months of blinded treatment than previously reported in the recent publication of data from the pivotal phase III randomized, double-blind, double-dummy study (J. Clin. Oncol. 2010;28:5132-9). The trial involved 2,046 patients with advanced breast cancer and bone metastases, 1% of them men, who were assigned to 120 mg of subcutaneous denosumab or 4 mg of intravenous zoledronic acid, with each drug given every 4 weeks.

In the extended analysis, the median time to the first on-study skeletal-related event, such as fracture, spinal cord compression, or radiotherapy or surgery to bone, was 32.4 months in the denosumab arm, compared with 27.4 months in the zoledronic acid arm. This represented a highly significant 18% delay in the time to these serious events in the denosumab-treated group (P = .0096).

Median time to the first on-study skeletal-related event or hypercalcemia was 32.4 months in the denosumab group and 25.1 months with zoledronic acid (P = .0076).

At the time of the extended analysis out to 3 years, 32.9% of patients in the denosumab group had had one or more skeletal-related events compared with 38.9% in the zoledronic acid arm, for a 15.4% relative risk reduction. One hundred additional skeletal-related events occurred during the extra 4 months of blinded treatment, bringing the total number of such events to 526 in the denosumab arm and 669 with zoledronic acid; this represents a 22% risk reduction (P = .0008). And the event curves are continuing to separate over time, Dr. Stopeck noted.

Overall survival and disease progression rates were similar in the two study arms. In terms of adverse events, renal toxicity was significantly more common in the zoledronic acid arm (9.4% vs. 5.4%), as were acute phase reactions involving bone pain and/or flulike symptoms (28.2% vs. 10.7%). Hypocalcemia occurred in 6.1% of the denosumab group, compared with 3.7% on zoledronic acid. Osteonecrosis of the jaw occurred at similarly low rates – 2.5% or less – in both treatment arms.

On the strength of earlier data from this and two other phase III studies, in November the Food and Drug Administration approved denosumab, a fully human monoclonal antibody that acts as a RANK ligand inhibitor, for the prevention of skeletal-related events in patients with bone metastases from solid tumors.

Dr. Stopeck noted that denosumab offers significant advantages in terms of ease of use. It’s given via a once-monthly subcutaneous injection rather than the intravenous infusion required with zoledronic acid. And unlike for zoledronic acid, there is no need for renal monitoring or dose adjustments with denosumab.

The next phase of development for denosumab will be to study it in the setting of early-stage breast cancer to see if it can prevent metastases to the bone and indeed any other part of the body. The rationale is that bone acts as a reservoir for circulating tumor cells, which may spread to other parts of the body and cause metastases.

"This is a trial I think we’re all enthusiastic about, to see if we can actually prevent cancer from spreading at an earlier stage by manipulating the bone microenvironment. Preventing skeletal-related events is nice, but we’d like to move earlier," Dr. Stopeck explained.

Toward this end, the D-CARE trial, a randomized, double-blind, placebo-controlled phase III study of denosumab as adjuvant treatment for women with early-stage breast cancer at high risk of recurrence, has begun enrolling a planned 4,500 patients. The Amgen-sponsored study is expected to run for 10 years, with bone metastasis–free survival as the primary end point, and overall and disease-free survival among the key secondary end points.

Dr. Stopeck disclosed that she serves as a consultant to and has received research grants from both Amgen, which markets denosumab, and Novartis, which markets zoledronic acid. The trial was sponsored by Amgen in collaboration with Daiichi Sankyo.

SAN ANTONIO – Denosumab delayed time to a first skeletal-related adverse event by a median of 5 months longer than did zoledronic acid in patients with advanced breast cancer and bone metastases, based on updated results from a landmark head-to-head comparative trial of the two osteoclast-inhibiting drugs.

Moreover, time to the composite secondary end point of a first skeletal-related event or hypercalcemia, a feared and life-threatening complication of metastatic bone disease, was prolonged by a median of 7.3 months in the denosumab (Xgeva) group compared with those on zoledronic acid (Zometa), Dr. Alison T. Stopeck reported at the San Antonio Breast Cancer Symposium.

"To put this in some perspective, the average life expectancy of these patients is 2½ to 3 years, so 7 additional months of freedom from these complications is a considerable period of their remaining time," said Dr. Stopeck, director of the clinical breast cancer program at the Arizona Cancer Center at the University of Arizona, Tucson.

She presented a new extended analysis that included 4 more months of blinded treatment than previously reported in the recent publication of data from the pivotal phase III randomized, double-blind, double-dummy study (J. Clin. Oncol. 2010;28:5132-9). The trial involved 2,046 patients with advanced breast cancer and bone metastases, 1% of them men, who were assigned to 120 mg of subcutaneous denosumab or 4 mg of intravenous zoledronic acid, with each drug given every 4 weeks.

In the extended analysis, the median time to the first on-study skeletal-related event, such as fracture, spinal cord compression, or radiotherapy or surgery to bone, was 32.4 months in the denosumab arm, compared with 27.4 months in the zoledronic acid arm. This represented a highly significant 18% delay in the time to these serious events in the denosumab-treated group (P = .0096).

Median time to the first on-study skeletal-related event or hypercalcemia was 32.4 months in the denosumab group and 25.1 months with zoledronic acid (P = .0076).

At the time of the extended analysis out to 3 years, 32.9% of patients in the denosumab group had had one or more skeletal-related events compared with 38.9% in the zoledronic acid arm, for a 15.4% relative risk reduction. One hundred additional skeletal-related events occurred during the extra 4 months of blinded treatment, bringing the total number of such events to 526 in the denosumab arm and 669 with zoledronic acid; this represents a 22% risk reduction (P = .0008). And the event curves are continuing to separate over time, Dr. Stopeck noted.

Overall survival and disease progression rates were similar in the two study arms. In terms of adverse events, renal toxicity was significantly more common in the zoledronic acid arm (9.4% vs. 5.4%), as were acute phase reactions involving bone pain and/or flulike symptoms (28.2% vs. 10.7%). Hypocalcemia occurred in 6.1% of the denosumab group, compared with 3.7% on zoledronic acid. Osteonecrosis of the jaw occurred at similarly low rates – 2.5% or less – in both treatment arms.

On the strength of earlier data from this and two other phase III studies, in November the Food and Drug Administration approved denosumab, a fully human monoclonal antibody that acts as a RANK ligand inhibitor, for the prevention of skeletal-related events in patients with bone metastases from solid tumors.

Dr. Stopeck noted that denosumab offers significant advantages in terms of ease of use. It’s given via a once-monthly subcutaneous injection rather than the intravenous infusion required with zoledronic acid. And unlike for zoledronic acid, there is no need for renal monitoring or dose adjustments with denosumab.

The next phase of development for denosumab will be to study it in the setting of early-stage breast cancer to see if it can prevent metastases to the bone and indeed any other part of the body. The rationale is that bone acts as a reservoir for circulating tumor cells, which may spread to other parts of the body and cause metastases.

"This is a trial I think we’re all enthusiastic about, to see if we can actually prevent cancer from spreading at an earlier stage by manipulating the bone microenvironment. Preventing skeletal-related events is nice, but we’d like to move earlier," Dr. Stopeck explained.

Toward this end, the D-CARE trial, a randomized, double-blind, placebo-controlled phase III study of denosumab as adjuvant treatment for women with early-stage breast cancer at high risk of recurrence, has begun enrolling a planned 4,500 patients. The Amgen-sponsored study is expected to run for 10 years, with bone metastasis–free survival as the primary end point, and overall and disease-free survival among the key secondary end points.

Dr. Stopeck disclosed that she serves as a consultant to and has received research grants from both Amgen, which markets denosumab, and Novartis, which markets zoledronic acid. The trial was sponsored by Amgen in collaboration with Daiichi Sankyo.

SAN ANTONIO – Denosumab delayed time to a first skeletal-related adverse event by a median of 5 months longer than did zoledronic acid in patients with advanced breast cancer and bone metastases, based on updated results from a landmark head-to-head comparative trial of the two osteoclast-inhibiting drugs.

Moreover, time to the composite secondary end point of a first skeletal-related event or hypercalcemia, a feared and life-threatening complication of metastatic bone disease, was prolonged by a median of 7.3 months in the denosumab (Xgeva) group compared with those on zoledronic acid (Zometa), Dr. Alison T. Stopeck reported at the San Antonio Breast Cancer Symposium.

"To put this in some perspective, the average life expectancy of these patients is 2½ to 3 years, so 7 additional months of freedom from these complications is a considerable period of their remaining time," said Dr. Stopeck, director of the clinical breast cancer program at the Arizona Cancer Center at the University of Arizona, Tucson.

She presented a new extended analysis that included 4 more months of blinded treatment than previously reported in the recent publication of data from the pivotal phase III randomized, double-blind, double-dummy study (J. Clin. Oncol. 2010;28:5132-9). The trial involved 2,046 patients with advanced breast cancer and bone metastases, 1% of them men, who were assigned to 120 mg of subcutaneous denosumab or 4 mg of intravenous zoledronic acid, with each drug given every 4 weeks.

In the extended analysis, the median time to the first on-study skeletal-related event, such as fracture, spinal cord compression, or radiotherapy or surgery to bone, was 32.4 months in the denosumab arm, compared with 27.4 months in the zoledronic acid arm. This represented a highly significant 18% delay in the time to these serious events in the denosumab-treated group (P = .0096).

Median time to the first on-study skeletal-related event or hypercalcemia was 32.4 months in the denosumab group and 25.1 months with zoledronic acid (P = .0076).

At the time of the extended analysis out to 3 years, 32.9% of patients in the denosumab group had had one or more skeletal-related events compared with 38.9% in the zoledronic acid arm, for a 15.4% relative risk reduction. One hundred additional skeletal-related events occurred during the extra 4 months of blinded treatment, bringing the total number of such events to 526 in the denosumab arm and 669 with zoledronic acid; this represents a 22% risk reduction (P = .0008). And the event curves are continuing to separate over time, Dr. Stopeck noted.

Overall survival and disease progression rates were similar in the two study arms. In terms of adverse events, renal toxicity was significantly more common in the zoledronic acid arm (9.4% vs. 5.4%), as were acute phase reactions involving bone pain and/or flulike symptoms (28.2% vs. 10.7%). Hypocalcemia occurred in 6.1% of the denosumab group, compared with 3.7% on zoledronic acid. Osteonecrosis of the jaw occurred at similarly low rates – 2.5% or less – in both treatment arms.

On the strength of earlier data from this and two other phase III studies, in November the Food and Drug Administration approved denosumab, a fully human monoclonal antibody that acts as a RANK ligand inhibitor, for the prevention of skeletal-related events in patients with bone metastases from solid tumors.

Dr. Stopeck noted that denosumab offers significant advantages in terms of ease of use. It’s given via a once-monthly subcutaneous injection rather than the intravenous infusion required with zoledronic acid. And unlike for zoledronic acid, there is no need for renal monitoring or dose adjustments with denosumab.

The next phase of development for denosumab will be to study it in the setting of early-stage breast cancer to see if it can prevent metastases to the bone and indeed any other part of the body. The rationale is that bone acts as a reservoir for circulating tumor cells, which may spread to other parts of the body and cause metastases.

"This is a trial I think we’re all enthusiastic about, to see if we can actually prevent cancer from spreading at an earlier stage by manipulating the bone microenvironment. Preventing skeletal-related events is nice, but we’d like to move earlier," Dr. Stopeck explained.

Toward this end, the D-CARE trial, a randomized, double-blind, placebo-controlled phase III study of denosumab as adjuvant treatment for women with early-stage breast cancer at high risk of recurrence, has begun enrolling a planned 4,500 patients. The Amgen-sponsored study is expected to run for 10 years, with bone metastasis–free survival as the primary end point, and overall and disease-free survival among the key secondary end points.

Dr. Stopeck disclosed that she serves as a consultant to and has received research grants from both Amgen, which markets denosumab, and Novartis, which markets zoledronic acid. The trial was sponsored by Amgen in collaboration with Daiichi Sankyo.

SAN ANTONIO – Baseline obesity in breast cancer patients possessing the estrogen receptor–positive, HER2-negative disease subtype was independently associated with a 23% higher risk of recurrence and nearly a 50% increase in all-cause mortality, compared with rates in the nonobese in a first-of-its-kind study.

"Our data suggest that obese patients with this breast cancer subtype are at increased risk of recurrence, and once that occurs there’s a higher rate of progression of disease and a shorter time period between recurrence and death," Dr. Joseph A. Sparano said Dec. 9 at the annual San Antonio Breast Cancer Symposium.

The estrogen receptor–positive, HER2-negative form of breast cancer is the most common subtype, accounting for 50%-60% of all operable invasive breast cancers in the United States. It is generally viewed as having a more favorable prognosis than other subtypes, noted Dr. Sparano, professor of medicine and women’s health at Albert Einstein College of Medicine and associate chairman of oncology at Montefiore Medical Center in Bronx, N.Y.

He presented a retrospective analysis of the Eastern Cooperative Oncology Group (ECOG) E1199 prospective randomized trial of various chemotherapy regimens, for which baseline body mass index data were available on 3,484 of the 5,168 participants. A total of 38% had a body mass index (BMI) of at least 30 kg/m².

As expected based upon other studies, obesity was associated with older age, black race, and a higher rate of postmenopausal status.

In a Cox proportionate hazards model adjusted for these and other potential confounders including tumor size, surgery type, radiation therapy, and chemotherapy dosing and intensity, obese women with hormone receptor–positive, HER2-negative disease were 23% more likely to experience recurrence (P = .035) and had a 46% greater all-cause mortality (P = .002) than nonobese women with the same tumor subtype. In contrast, obesity had no impact on outcomes in women with the other two major breast cancer subtypes: triple-negative disease and HER2-positive breast cancer.

The investigators also examined the association between outcomes and BMI as a continuous rather than a categorical variable. After adjustment for potential confounders, they found that as baseline BMI increased in patients with estrogen receptor–positive, HER2-negative cancer, the risk of recurrence steadily increased in straightforward fashion. For mortality, on the other hand, there was an inflection point at about 30 kg/m², when the mortality curve steepened.

Other studies have documented inferior outcomes in breast cancer patients who are obese, but this is the first to break down the relationship according to disease subtype.

Dr. Sparano and his coworkers validated these findings in retrospective analyses of two smaller ECOG randomized clinical trials having baseline BMI data, the E5188 study involving 1,502 premenopausal women with estrogen receptor–positive breast cancer, and E3189, featuring 613 patients with estrogen receptor–negative disease. The obese women with estrogen receptor–positive breast cancer in E5188 had an adjusted 41% increase in risk of recurrence (P less than .0001) and a 51% higher all-cause mortality (P less than .0001), compared with nonobese patients. In the estrogen receptor–negative E3189 population, however, obesity made no difference in terms of these outcomes.

In the E1199 trial, the only serious adverse event that occurred more frequently in obese patients was grade 4 neutropenia (40% vs. 32%, P less than .0001). Infections were significantly less common in the obese women, as was grade 3/4 neuropathy, noted Dr. Sparano, who is chair of the ECOG breast committee.

He believes obesity may be a surrogate for other as yet unknown host-related factors that contribute to disease recurrence. One such factor might be hyperinsulinemia.

"Hyperinsulinemia is known to be associated with obesity, and estrogen receptor–positive disease in particular has been shown to more highly express the IGF [insulin-like growth factor] signaling pathway and the insulin receptor. So hyperinsulinemia may drive the growth of estrogen-dependent tumors – and hyperinsulinemia is potentially modifiable," he noted.

Other hypothesized mechanisms include differences in treatment adherence or drug metabolism. The investigators are planning to conduct additional studies in ongoing ECOG trials to prospectively identify the key host-related factors related to the increased risk of recurrence in the obese.

Dr. Judy Garber called the study findings "worrisome," particularly in light of the ongoing obesity epidemic in the United States.

"We have much data showing that women tend to gain weight during treatment for breast cancer. And many will become menopausal during treatment, and then weight becomes an even more difficult problem. So this is obviously a disturbing data set, and it will be important to look at others to confirm," commented Dr. Garber, president-elect of the American Association for Cancer Research and director of the Center for Cancer Genetics and Prevention at the Dana-Farber Cancer Institute, Boston.

Dr. Sparano and Dr. Garber declared they have no financial conflicts of interest.

SAN ANTONIO – Baseline obesity in breast cancer patients possessing the estrogen receptor–positive, HER2-negative disease subtype was independently associated with a 23% higher risk of recurrence and nearly a 50% increase in all-cause mortality, compared with rates in the nonobese in a first-of-its-kind study.

"Our data suggest that obese patients with this breast cancer subtype are at increased risk of recurrence, and once that occurs there’s a higher rate of progression of disease and a shorter time period between recurrence and death," Dr. Joseph A. Sparano said Dec. 9 at the annual San Antonio Breast Cancer Symposium.

The estrogen receptor–positive, HER2-negative form of breast cancer is the most common subtype, accounting for 50%-60% of all operable invasive breast cancers in the United States. It is generally viewed as having a more favorable prognosis than other subtypes, noted Dr. Sparano, professor of medicine and women’s health at Albert Einstein College of Medicine and associate chairman of oncology at Montefiore Medical Center in Bronx, N.Y.

He presented a retrospective analysis of the Eastern Cooperative Oncology Group (ECOG) E1199 prospective randomized trial of various chemotherapy regimens, for which baseline body mass index data were available on 3,484 of the 5,168 participants. A total of 38% had a body mass index (BMI) of at least 30 kg/m².

As expected based upon other studies, obesity was associated with older age, black race, and a higher rate of postmenopausal status.

In a Cox proportionate hazards model adjusted for these and other potential confounders including tumor size, surgery type, radiation therapy, and chemotherapy dosing and intensity, obese women with hormone receptor–positive, HER2-negative disease were 23% more likely to experience recurrence (P = .035) and had a 46% greater all-cause mortality (P = .002) than nonobese women with the same tumor subtype. In contrast, obesity had no impact on outcomes in women with the other two major breast cancer subtypes: triple-negative disease and HER2-positive breast cancer.

The investigators also examined the association between outcomes and BMI as a continuous rather than a categorical variable. After adjustment for potential confounders, they found that as baseline BMI increased in patients with estrogen receptor–positive, HER2-negative cancer, the risk of recurrence steadily increased in straightforward fashion. For mortality, on the other hand, there was an inflection point at about 30 kg/m², when the mortality curve steepened.

Other studies have documented inferior outcomes in breast cancer patients who are obese, but this is the first to break down the relationship according to disease subtype.

Dr. Sparano and his coworkers validated these findings in retrospective analyses of two smaller ECOG randomized clinical trials having baseline BMI data, the E5188 study involving 1,502 premenopausal women with estrogen receptor–positive breast cancer, and E3189, featuring 613 patients with estrogen receptor–negative disease. The obese women with estrogen receptor–positive breast cancer in E5188 had an adjusted 41% increase in risk of recurrence (P less than .0001) and a 51% higher all-cause mortality (P less than .0001), compared with nonobese patients. In the estrogen receptor–negative E3189 population, however, obesity made no difference in terms of these outcomes.

In the E1199 trial, the only serious adverse event that occurred more frequently in obese patients was grade 4 neutropenia (40% vs. 32%, P less than .0001). Infections were significantly less common in the obese women, as was grade 3/4 neuropathy, noted Dr. Sparano, who is chair of the ECOG breast committee.

He believes obesity may be a surrogate for other as yet unknown host-related factors that contribute to disease recurrence. One such factor might be hyperinsulinemia.

"Hyperinsulinemia is known to be associated with obesity, and estrogen receptor–positive disease in particular has been shown to more highly express the IGF [insulin-like growth factor] signaling pathway and the insulin receptor. So hyperinsulinemia may drive the growth of estrogen-dependent tumors – and hyperinsulinemia is potentially modifiable," he noted.

Other hypothesized mechanisms include differences in treatment adherence or drug metabolism. The investigators are planning to conduct additional studies in ongoing ECOG trials to prospectively identify the key host-related factors related to the increased risk of recurrence in the obese.

Dr. Judy Garber called the study findings "worrisome," particularly in light of the ongoing obesity epidemic in the United States.

"We have much data showing that women tend to gain weight during treatment for breast cancer. And many will become menopausal during treatment, and then weight becomes an even more difficult problem. So this is obviously a disturbing data set, and it will be important to look at others to confirm," commented Dr. Garber, president-elect of the American Association for Cancer Research and director of the Center for Cancer Genetics and Prevention at the Dana-Farber Cancer Institute, Boston.

Dr. Sparano and Dr. Garber declared they have no financial conflicts of interest.

SAN ANTONIO – Baseline obesity in breast cancer patients possessing the estrogen receptor–positive, HER2-negative disease subtype was independently associated with a 23% higher risk of recurrence and nearly a 50% increase in all-cause mortality, compared with rates in the nonobese in a first-of-its-kind study.

"Our data suggest that obese patients with this breast cancer subtype are at increased risk of recurrence, and once that occurs there’s a higher rate of progression of disease and a shorter time period between recurrence and death," Dr. Joseph A. Sparano said Dec. 9 at the annual San Antonio Breast Cancer Symposium.

The estrogen receptor–positive, HER2-negative form of breast cancer is the most common subtype, accounting for 50%-60% of all operable invasive breast cancers in the United States. It is generally viewed as having a more favorable prognosis than other subtypes, noted Dr. Sparano, professor of medicine and women’s health at Albert Einstein College of Medicine and associate chairman of oncology at Montefiore Medical Center in Bronx, N.Y.

He presented a retrospective analysis of the Eastern Cooperative Oncology Group (ECOG) E1199 prospective randomized trial of various chemotherapy regimens, for which baseline body mass index data were available on 3,484 of the 5,168 participants. A total of 38% had a body mass index (BMI) of at least 30 kg/m².

As expected based upon other studies, obesity was associated with older age, black race, and a higher rate of postmenopausal status.

In a Cox proportionate hazards model adjusted for these and other potential confounders including tumor size, surgery type, radiation therapy, and chemotherapy dosing and intensity, obese women with hormone receptor–positive, HER2-negative disease were 23% more likely to experience recurrence (P = .035) and had a 46% greater all-cause mortality (P = .002) than nonobese women with the same tumor subtype. In contrast, obesity had no impact on outcomes in women with the other two major breast cancer subtypes: triple-negative disease and HER2-positive breast cancer.

The investigators also examined the association between outcomes and BMI as a continuous rather than a categorical variable. After adjustment for potential confounders, they found that as baseline BMI increased in patients with estrogen receptor–positive, HER2-negative cancer, the risk of recurrence steadily increased in straightforward fashion. For mortality, on the other hand, there was an inflection point at about 30 kg/m², when the mortality curve steepened.

Other studies have documented inferior outcomes in breast cancer patients who are obese, but this is the first to break down the relationship according to disease subtype.

Dr. Sparano and his coworkers validated these findings in retrospective analyses of two smaller ECOG randomized clinical trials having baseline BMI data, the E5188 study involving 1,502 premenopausal women with estrogen receptor–positive breast cancer, and E3189, featuring 613 patients with estrogen receptor–negative disease. The obese women with estrogen receptor–positive breast cancer in E5188 had an adjusted 41% increase in risk of recurrence (P less than .0001) and a 51% higher all-cause mortality (P less than .0001), compared with nonobese patients. In the estrogen receptor–negative E3189 population, however, obesity made no difference in terms of these outcomes.

In the E1199 trial, the only serious adverse event that occurred more frequently in obese patients was grade 4 neutropenia (40% vs. 32%, P less than .0001). Infections were significantly less common in the obese women, as was grade 3/4 neuropathy, noted Dr. Sparano, who is chair of the ECOG breast committee.

He believes obesity may be a surrogate for other as yet unknown host-related factors that contribute to disease recurrence. One such factor might be hyperinsulinemia.

"Hyperinsulinemia is known to be associated with obesity, and estrogen receptor–positive disease in particular has been shown to more highly express the IGF [insulin-like growth factor] signaling pathway and the insulin receptor. So hyperinsulinemia may drive the growth of estrogen-dependent tumors – and hyperinsulinemia is potentially modifiable," he noted.

Other hypothesized mechanisms include differences in treatment adherence or drug metabolism. The investigators are planning to conduct additional studies in ongoing ECOG trials to prospectively identify the key host-related factors related to the increased risk of recurrence in the obese.

Dr. Judy Garber called the study findings "worrisome," particularly in light of the ongoing obesity epidemic in the United States.

"We have much data showing that women tend to gain weight during treatment for breast cancer. And many will become menopausal during treatment, and then weight becomes an even more difficult problem. So this is obviously a disturbing data set, and it will be important to look at others to confirm," commented Dr. Garber, president-elect of the American Association for Cancer Research and director of the Center for Cancer Genetics and Prevention at the Dana-Farber Cancer Institute, Boston.

Dr. Sparano and Dr. Garber declared they have no financial conflicts of interest.

GOTHENBURG, SWEDEN - Biologic therapies have brought dermatologists an unprecedented ability to control moderate to severe psoriasis. But with these treatment victories have come questions about how treatment interruptions affect long-term response, according to Dr. Richard Langley.

New evidence indicates most psoriasis patients who are responding well to adalimumab (Humira) and then undergo a treatment interruption or drug holiday will regain nearly the same favorable level of response upon treatment resumption.

But a substantial minority – roughly one-third of those randomized to a treatment interruption in the 3-year open-label extension of the REVEAL trial – will not be able to recapture their prior high level of response, he said at a satellite symposium held during the annual congress of the European Academy of Dermatology and Venereology.

The good news, he added, is that this high-risk subgroup can be identified early in the course of their treatment interruption, in time for corrective action to be taken.

"The take-home message is that in patients who have an early loss of response during the interruption, particularly those who drop to less than Psoriasis Area and Severity Index [PASI] 50, these are people we should think about getting back on treatment. Many of these patients are getting an inferior result compared with what they'd have on continuous therapy or early retreatment," according to Dr. Langley, professor of medicine and director of research in the division of dermatology at Dalhousie University, Halifax, N.S.

The phase III REVEAL (Randomized Controlled Evaluation of Adalimumab Every Other Week Dosing in Moderate to Severe Psoriasis Trial) was a placebo-controlled, 52-week randomized trial in which 490 of the 814 patients randomized to adalimumab at baseline achieved at least a 75% improvement (PASI 75) at weeks 16 and 33, compared with baseline. These good responders were then rerandomized to 19 weeks of continued adalimumab or treatment interruption via placebo. After this 19-week interval, patients could receive an additional 2 years of adalimumab at 40 mg every 2 weeks in a long-term, open-label extension study.

In a new REVEAL analysis presented for the first time at the satellite symposium sponsored by Abbott, Dr. Langley reported that of 227 patients randomized to the 19-week treatment interruption, 45% were still at PASI 75-100 at the start of retreatment, 31% had dropped below PASI 50, and 24% were in between. The mean disease severity scores in these three groups at the start of retreatment were PASI 88, PASI 32, and PASI 64, respectively. Over the next 2 years of open-label retreatment, the patients who started retreatment with less than a PASI 50 showed an inferior response, compared with the other two groups. They climbed to a peak response of PASI 66 at week 24 of retreatment and finished at a mean PASI 58 at week 108.

In contrast, patients who were PASI 75-100 at the start of retreatment, compared with enrollment, peaked at a mean PASI 94 at week 12 of retreatment, finishing at PASI 86 at week 108. Those with PASI 50-74 when retreatment commenced had a peak PASI 79 at week 12 before finishing the extension study with a mean PASI 81, according to Dr. Langley.

Similar findings have been seen in other treatment interruption studies involving etanercept and infliximab: Retreatment of patients who were good responders prior to the interruption restored efficacy in most but not all patients, he continued.

Dr. Langley stressed that in his view the preferred strategy is continuous treatment of good responders to any given biologic agent. He said he is opposed to the idea of drug holidays in patients who have cleared because in a substantial number of cases, their disease will return and their quality of life will plummet.

"Is that truly the sort of holiday we want to take?" he asked. "You can start and stop, and start and stop, but ultimately you are losing control of some of these patients."

Of course, there are circumstances when a treatment interruption is necessary. This happens fairly frequently. Among the situations warranting a temporary halt to biologic therapy are pregnancy, major surgery, live virus vaccination, clinically significant infection, or an adverse event whose cause is uncertain.

Dr. Langley disclosed that he is on the speakers bureau for Abbott Laboratories and has financial relationships with numerous other pharmaceutical companies with an interest in psoriasis therapies.

GOTHENBURG, SWEDEN - Biologic therapies have brought dermatologists an unprecedented ability to control moderate to severe psoriasis. But with these treatment victories have come questions about how treatment interruptions affect long-term response, according to Dr. Richard Langley.

New evidence indicates most psoriasis patients who are responding well to adalimumab (Humira) and then undergo a treatment interruption or drug holiday will regain nearly the same favorable level of response upon treatment resumption.

But a substantial minority – roughly one-third of those randomized to a treatment interruption in the 3-year open-label extension of the REVEAL trial – will not be able to recapture their prior high level of response, he said at a satellite symposium held during the annual congress of the European Academy of Dermatology and Venereology.

The good news, he added, is that this high-risk subgroup can be identified early in the course of their treatment interruption, in time for corrective action to be taken.

"The take-home message is that in patients who have an early loss of response during the interruption, particularly those who drop to less than Psoriasis Area and Severity Index [PASI] 50, these are people we should think about getting back on treatment. Many of these patients are getting an inferior result compared with what they'd have on continuous therapy or early retreatment," according to Dr. Langley, professor of medicine and director of research in the division of dermatology at Dalhousie University, Halifax, N.S.

The phase III REVEAL (Randomized Controlled Evaluation of Adalimumab Every Other Week Dosing in Moderate to Severe Psoriasis Trial) was a placebo-controlled, 52-week randomized trial in which 490 of the 814 patients randomized to adalimumab at baseline achieved at least a 75% improvement (PASI 75) at weeks 16 and 33, compared with baseline. These good responders were then rerandomized to 19 weeks of continued adalimumab or treatment interruption via placebo. After this 19-week interval, patients could receive an additional 2 years of adalimumab at 40 mg every 2 weeks in a long-term, open-label extension study.

In a new REVEAL analysis presented for the first time at the satellite symposium sponsored by Abbott, Dr. Langley reported that of 227 patients randomized to the 19-week treatment interruption, 45% were still at PASI 75-100 at the start of retreatment, 31% had dropped below PASI 50, and 24% were in between. The mean disease severity scores in these three groups at the start of retreatment were PASI 88, PASI 32, and PASI 64, respectively. Over the next 2 years of open-label retreatment, the patients who started retreatment with less than a PASI 50 showed an inferior response, compared with the other two groups. They climbed to a peak response of PASI 66 at week 24 of retreatment and finished at a mean PASI 58 at week 108.

In contrast, patients who were PASI 75-100 at the start of retreatment, compared with enrollment, peaked at a mean PASI 94 at week 12 of retreatment, finishing at PASI 86 at week 108. Those with PASI 50-74 when retreatment commenced had a peak PASI 79 at week 12 before finishing the extension study with a mean PASI 81, according to Dr. Langley.

Similar findings have been seen in other treatment interruption studies involving etanercept and infliximab: Retreatment of patients who were good responders prior to the interruption restored efficacy in most but not all patients, he continued.

Dr. Langley stressed that in his view the preferred strategy is continuous treatment of good responders to any given biologic agent. He said he is opposed to the idea of drug holidays in patients who have cleared because in a substantial number of cases, their disease will return and their quality of life will plummet.

"Is that truly the sort of holiday we want to take?" he asked. "You can start and stop, and start and stop, but ultimately you are losing control of some of these patients."

Of course, there are circumstances when a treatment interruption is necessary. This happens fairly frequently. Among the situations warranting a temporary halt to biologic therapy are pregnancy, major surgery, live virus vaccination, clinically significant infection, or an adverse event whose cause is uncertain.

Dr. Langley disclosed that he is on the speakers bureau for Abbott Laboratories and has financial relationships with numerous other pharmaceutical companies with an interest in psoriasis therapies.

GOTHENBURG, SWEDEN - Biologic therapies have brought dermatologists an unprecedented ability to control moderate to severe psoriasis. But with these treatment victories have come questions about how treatment interruptions affect long-term response, according to Dr. Richard Langley.

New evidence indicates most psoriasis patients who are responding well to adalimumab (Humira) and then undergo a treatment interruption or drug holiday will regain nearly the same favorable level of response upon treatment resumption.

But a substantial minority – roughly one-third of those randomized to a treatment interruption in the 3-year open-label extension of the REVEAL trial – will not be able to recapture their prior high level of response, he said at a satellite symposium held during the annual congress of the European Academy of Dermatology and Venereology.

The good news, he added, is that this high-risk subgroup can be identified early in the course of their treatment interruption, in time for corrective action to be taken.

"The take-home message is that in patients who have an early loss of response during the interruption, particularly those who drop to less than Psoriasis Area and Severity Index [PASI] 50, these are people we should think about getting back on treatment. Many of these patients are getting an inferior result compared with what they'd have on continuous therapy or early retreatment," according to Dr. Langley, professor of medicine and director of research in the division of dermatology at Dalhousie University, Halifax, N.S.

The phase III REVEAL (Randomized Controlled Evaluation of Adalimumab Every Other Week Dosing in Moderate to Severe Psoriasis Trial) was a placebo-controlled, 52-week randomized trial in which 490 of the 814 patients randomized to adalimumab at baseline achieved at least a 75% improvement (PASI 75) at weeks 16 and 33, compared with baseline. These good responders were then rerandomized to 19 weeks of continued adalimumab or treatment interruption via placebo. After this 19-week interval, patients could receive an additional 2 years of adalimumab at 40 mg every 2 weeks in a long-term, open-label extension study.

In a new REVEAL analysis presented for the first time at the satellite symposium sponsored by Abbott, Dr. Langley reported that of 227 patients randomized to the 19-week treatment interruption, 45% were still at PASI 75-100 at the start of retreatment, 31% had dropped below PASI 50, and 24% were in between. The mean disease severity scores in these three groups at the start of retreatment were PASI 88, PASI 32, and PASI 64, respectively. Over the next 2 years of open-label retreatment, the patients who started retreatment with less than a PASI 50 showed an inferior response, compared with the other two groups. They climbed to a peak response of PASI 66 at week 24 of retreatment and finished at a mean PASI 58 at week 108.

In contrast, patients who were PASI 75-100 at the start of retreatment, compared with enrollment, peaked at a mean PASI 94 at week 12 of retreatment, finishing at PASI 86 at week 108. Those with PASI 50-74 when retreatment commenced had a peak PASI 79 at week 12 before finishing the extension study with a mean PASI 81, according to Dr. Langley.

Similar findings have been seen in other treatment interruption studies involving etanercept and infliximab: Retreatment of patients who were good responders prior to the interruption restored efficacy in most but not all patients, he continued.

Dr. Langley stressed that in his view the preferred strategy is continuous treatment of good responders to any given biologic agent. He said he is opposed to the idea of drug holidays in patients who have cleared because in a substantial number of cases, their disease will return and their quality of life will plummet.

"Is that truly the sort of holiday we want to take?" he asked. "You can start and stop, and start and stop, but ultimately you are losing control of some of these patients."

Of course, there are circumstances when a treatment interruption is necessary. This happens fairly frequently. Among the situations warranting a temporary halt to biologic therapy are pregnancy, major surgery, live virus vaccination, clinically significant infection, or an adverse event whose cause is uncertain.

Dr. Langley disclosed that he is on the speakers bureau for Abbott Laboratories and has financial relationships with numerous other pharmaceutical companies with an interest in psoriasis therapies.

GOTHENBURG, SWEDEN – Biologic therapies have brought dermatologists an unprecedented ability to control moderate to severe psoriasis. But with these treatment victories have come questions about how treatment interruptions affect long-term response, according to Dr. Richard Langley.

New evidence indicates most psoriasis patients who are responding well to adalimumab (Humira) and then undergo a treatment interruption or drug holiday will regain nearly the same favorable level of response upon treatment resumption. But a substantial minority – roughly one-third of those randomized to a treatment interruption in the 3-year open-label extension of the REVEAL trial – will not be able to recapture their prior high level of response, he said at a satellite symposium held during the annual congress of the European Academy of Dermatology and Venereology

The good news, he added, is that this high-risk subgroup can be identified early in the course of their treatment interruption, in time for corrective action to be taken.

"The take-home message is that in patients who have an early loss of response during the interruption, particularly those who drop to less than Psoriasis Area and Severity Index [PASI] 50, these are people we should think about getting back on treatment. Many of these patients are getting an inferior result compared with what they’d have on continuous therapy or early retreatment," according to Dr. Langley, professor of medicine and director of research in the division of dermatology at Dalhousie University, Halifax, N.S.

The phase III REVEAL (Randomized Controlled Evaluation of Adalimumab Every Other Week Dosing in Moderate to Severe Psoriasis Trial) was a placebo-controlled, 52-week randomized trial in which 490 of the 814 patients randomized to adalimumab at baseline achieved at least a 75% improvement (PASI 75) at weeks 16 and 33, compared with baseline. These good responders were then rerandomized to 19 weeks of continued adalimumab or treatment interruption via placebo. After this 19-week interval, patients could receive an additional 2 years of adalimumab at 40 mg every 2 weeks in a long-term, open-label extension study.

In a new REVEAL analysis presented for the first time at the satellite symposium sponsored by Abbott, Dr. Langley reported that of 227 patients randomized to the 19-week treatment interruption, 45% were still at PASI 75-100 at the start of retreatment, 31% had dropped below PASI 50, and 24% were in between. The mean disease severity scores in these three groups at the start of retreatment were PASI 88, PASI 32, and PASI 64, respectively. Over the next 2 years of open-label retreatment, the patients who started retreatment with less than a PASI 50 showed an inferior response, compared with the other two groups. They climbed to a peak response of PASI 66 at week 24 of retreatment and finished at a mean PASI 58 at week 108.

In contrast, patients who were PASI 75-100 at the start of retreatment, compared with enrollment, peaked at a mean PASI 94 at week 12 of retreatment, finishing at PASI 86 at week 108. Those with PASI 50-74 when retreatment commenced had a peak PASI 79 at week 12 before finishing the extension study with a mean PASI 81, according to Dr. Langley.

Similar findings have been seen in other treatment interruption studies involving etanercept and infliximab: Retreatment of patients who were good responders prior to the interruption restored efficacy in most but not all patients, he continued.

Dr. Langley stressed that in his view the preferred strategy is continuous treatment of good responders to any given biologic agent. He said he is opposed to the idea of drug holidays in patients who have cleared because in a substantial number of cases, their disease will return and their quality of life will plummet.

"Is that truly the sort of holiday we want to take?" he asked. "You can start and stop, and start and stop, but ultimately you are losing control of some of these patients."

Of course, there are circumstances when a treatment interruption is necessary. This happens fairly frequently. Among the situations warranting a temporary halt to biologic therapy are pregnancy, major surgery, live virus vaccination, clinically significant infection, or an adverse event whose cause is uncertain.

Dr. Langley disclosed that he is on the speakers bureau for Abbott Laboratories and has financial relationships with numerous other pharmaceutical companies with an interest in psoriasis therapies.

GOTHENBURG, SWEDEN – Biologic therapies have brought dermatologists an unprecedented ability to control moderate to severe psoriasis. But with these treatment victories have come questions about how treatment interruptions affect long-term response, according to Dr. Richard Langley.

New evidence indicates most psoriasis patients who are responding well to adalimumab (Humira) and then undergo a treatment interruption or drug holiday will regain nearly the same favorable level of response upon treatment resumption. But a substantial minority – roughly one-third of those randomized to a treatment interruption in the 3-year open-label extension of the REVEAL trial – will not be able to recapture their prior high level of response, he said at a satellite symposium held during the annual congress of the European Academy of Dermatology and Venereology

The good news, he added, is that this high-risk subgroup can be identified early in the course of their treatment interruption, in time for corrective action to be taken.

"The take-home message is that in patients who have an early loss of response during the interruption, particularly those who drop to less than Psoriasis Area and Severity Index [PASI] 50, these are people we should think about getting back on treatment. Many of these patients are getting an inferior result compared with what they’d have on continuous therapy or early retreatment," according to Dr. Langley, professor of medicine and director of research in the division of dermatology at Dalhousie University, Halifax, N.S.

The phase III REVEAL (Randomized Controlled Evaluation of Adalimumab Every Other Week Dosing in Moderate to Severe Psoriasis Trial) was a placebo-controlled, 52-week randomized trial in which 490 of the 814 patients randomized to adalimumab at baseline achieved at least a 75% improvement (PASI 75) at weeks 16 and 33, compared with baseline. These good responders were then rerandomized to 19 weeks of continued adalimumab or treatment interruption via placebo. After this 19-week interval, patients could receive an additional 2 years of adalimumab at 40 mg every 2 weeks in a long-term, open-label extension study.

In a new REVEAL analysis presented for the first time at the satellite symposium sponsored by Abbott, Dr. Langley reported that of 227 patients randomized to the 19-week treatment interruption, 45% were still at PASI 75-100 at the start of retreatment, 31% had dropped below PASI 50, and 24% were in between. The mean disease severity scores in these three groups at the start of retreatment were PASI 88, PASI 32, and PASI 64, respectively. Over the next 2 years of open-label retreatment, the patients who started retreatment with less than a PASI 50 showed an inferior response, compared with the other two groups. They climbed to a peak response of PASI 66 at week 24 of retreatment and finished at a mean PASI 58 at week 108.

In contrast, patients who were PASI 75-100 at the start of retreatment, compared with enrollment, peaked at a mean PASI 94 at week 12 of retreatment, finishing at PASI 86 at week 108. Those with PASI 50-74 when retreatment commenced had a peak PASI 79 at week 12 before finishing the extension study with a mean PASI 81, according to Dr. Langley.

Similar findings have been seen in other treatment interruption studies involving etanercept and infliximab: Retreatment of patients who were good responders prior to the interruption restored efficacy in most but not all patients, he continued.

Dr. Langley stressed that in his view the preferred strategy is continuous treatment of good responders to any given biologic agent. He said he is opposed to the idea of drug holidays in patients who have cleared because in a substantial number of cases, their disease will return and their quality of life will plummet.

"Is that truly the sort of holiday we want to take?" he asked. "You can start and stop, and start and stop, but ultimately you are losing control of some of these patients."

Of course, there are circumstances when a treatment interruption is necessary. This happens fairly frequently. Among the situations warranting a temporary halt to biologic therapy are pregnancy, major surgery, live virus vaccination, clinically significant infection, or an adverse event whose cause is uncertain.

Dr. Langley disclosed that he is on the speakers bureau for Abbott Laboratories and has financial relationships with numerous other pharmaceutical companies with an interest in psoriasis therapies.

GOTHENBURG, SWEDEN – Biologic therapies have brought dermatologists an unprecedented ability to control moderate to severe psoriasis. But with these treatment victories have come questions about how treatment interruptions affect long-term response, according to Dr. Richard Langley.

New evidence indicates most psoriasis patients who are responding well to adalimumab (Humira) and then undergo a treatment interruption or drug holiday will regain nearly the same favorable level of response upon treatment resumption. But a substantial minority – roughly one-third of those randomized to a treatment interruption in the 3-year open-label extension of the REVEAL trial – will not be able to recapture their prior high level of response, he said at a satellite symposium held during the annual congress of the European Academy of Dermatology and Venereology

The good news, he added, is that this high-risk subgroup can be identified early in the course of their treatment interruption, in time for corrective action to be taken.

"The take-home message is that in patients who have an early loss of response during the interruption, particularly those who drop to less than Psoriasis Area and Severity Index [PASI] 50, these are people we should think about getting back on treatment. Many of these patients are getting an inferior result compared with what they’d have on continuous therapy or early retreatment," according to Dr. Langley, professor of medicine and director of research in the division of dermatology at Dalhousie University, Halifax, N.S.

The phase III REVEAL (Randomized Controlled Evaluation of Adalimumab Every Other Week Dosing in Moderate to Severe Psoriasis Trial) was a placebo-controlled, 52-week randomized trial in which 490 of the 814 patients randomized to adalimumab at baseline achieved at least a 75% improvement (PASI 75) at weeks 16 and 33, compared with baseline. These good responders were then rerandomized to 19 weeks of continued adalimumab or treatment interruption via placebo. After this 19-week interval, patients could receive an additional 2 years of adalimumab at 40 mg every 2 weeks in a long-term, open-label extension study.

In a new REVEAL analysis presented for the first time at the satellite symposium sponsored by Abbott, Dr. Langley reported that of 227 patients randomized to the 19-week treatment interruption, 45% were still at PASI 75-100 at the start of retreatment, 31% had dropped below PASI 50, and 24% were in between. The mean disease severity scores in these three groups at the start of retreatment were PASI 88, PASI 32, and PASI 64, respectively. Over the next 2 years of open-label retreatment, the patients who started retreatment with less than a PASI 50 showed an inferior response, compared with the other two groups. They climbed to a peak response of PASI 66 at week 24 of retreatment and finished at a mean PASI 58 at week 108.

In contrast, patients who were PASI 75-100 at the start of retreatment, compared with enrollment, peaked at a mean PASI 94 at week 12 of retreatment, finishing at PASI 86 at week 108. Those with PASI 50-74 when retreatment commenced had a peak PASI 79 at week 12 before finishing the extension study with a mean PASI 81, according to Dr. Langley.

Similar findings have been seen in other treatment interruption studies involving etanercept and infliximab: Retreatment of patients who were good responders prior to the interruption restored efficacy in most but not all patients, he continued.

Dr. Langley stressed that in his view the preferred strategy is continuous treatment of good responders to any given biologic agent. He said he is opposed to the idea of drug holidays in patients who have cleared because in a substantial number of cases, their disease will return and their quality of life will plummet.

"Is that truly the sort of holiday we want to take?" he asked. "You can start and stop, and start and stop, but ultimately you are losing control of some of these patients."

Of course, there are circumstances when a treatment interruption is necessary. This happens fairly frequently. Among the situations warranting a temporary halt to biologic therapy are pregnancy, major surgery, live virus vaccination, clinically significant infection, or an adverse event whose cause is uncertain.

Dr. Langley disclosed that he is on the speakers bureau for Abbott Laboratories and has financial relationships with numerous other pharmaceutical companies with an interest in psoriasis therapies.