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Ponatinib bests older TKIs against Ph+ALL
Every generation aspires to be better than its predecessors, and for the third-generation tyrosine kinase inhibitor ponatinib (Iclusig), that might just be true, investigators claim.
A retrospective analysis comparing clinical trial outcomes for patients with newly diagnosed acute lymphoblastic leukemia positive for the Philadelphia chromosome (Ph+ALL) suggests that first-line ponatinib offers modestly better complete molecular response (CMR) rates and 3-year overall survival (OS) than either first-generation TKIs such as imatinib (Gleevec) or second-generation agents such as dasatinib (Sprycel) and nilotinib (Tasigna).
“Although only 1 relevant study of ponatinib combined with chemotherapy in Ph+ALL has been reported and our ability to adjust for baseline patient characteristics was limited, the results suggest that ponatinib combined with chemotherapy might represent a more effective front-line treatment option than chemotherapy combined with an earlier generation TKI for patients with newly diagnosed Ph+ALL, including those who cannot or choose not to undergo [stem cell transplant],” wrote Elias Jabbour, MD, of the University of Texas MD Anderson Cancer Center in Houston, and his colleagues.
They based their conclusions on a meta-regression analysis of 25 studies looking at first- or second-generation TKIs and one study of ponatinib as frontline therapy for patients with Ph+ALL. They described their results in Clinical Lymphoma, Myeloma & Leukemia.
The investigators created pooled estimates of outcomes from studies of earlier-generation TKIs plus combination chemotherapy using a random-effects meta-analysis method. For the sole ponatinib study – a single-arm trial of combination chemotherapy plus ponatinib – they used a binomial distribution method to calculate 95% confidence intervals (CI). The method essentially estimates the probability of success or failure of a repeated experiment.
They found that 79% of patients in the ponatinib trial achieved a CMR, compared with 34% of patients treated with earlier generation TKIs plus chemotherapy. This translates into an odds ratio (OR) for CMR with ponatinib of 6.09 (P = .034).
Two-year OS rates were 83% with ponatinib versus 58% for all patients treated with other TKIs. Although the OR (3.70) seemed to run in favor of ponatinib, the difference was not statistically significant (P = .062).
For 3-year OS, however, ponatinib was superior to the pooled data for the other TKIs, at 79% versus 50%, translating into an OR of 4.49 (P = .050).
The authors acknowledged that the study was limited by differences in treatment regimens and centers, and a limited ability to adjust for patient characteristics, due to the study’s reliance on only those covariates published across different studies. Head-to-head comparison trials are needed to confirm their results, they noted.
Nonetheless, “[w]e believe that the improved efficacy of ponatinib combined with chemotherapy for newly diagnosed Ph+ALL might prevent the need for allogeneic SCT,” they wrote.
Ariad Pharmaceuticals funded the study. Dr. Jabbour and three coauthors reported research funding from the company; other study authors reported employment or other financial relationships with Ariad or its parent company Takeda.
SOURCE: Jabbour E et al. Clin Lymphoma Myeloma Leuk. 2018 18(4):257-65.
Every generation aspires to be better than its predecessors, and for the third-generation tyrosine kinase inhibitor ponatinib (Iclusig), that might just be true, investigators claim.
A retrospective analysis comparing clinical trial outcomes for patients with newly diagnosed acute lymphoblastic leukemia positive for the Philadelphia chromosome (Ph+ALL) suggests that first-line ponatinib offers modestly better complete molecular response (CMR) rates and 3-year overall survival (OS) than either first-generation TKIs such as imatinib (Gleevec) or second-generation agents such as dasatinib (Sprycel) and nilotinib (Tasigna).
“Although only 1 relevant study of ponatinib combined with chemotherapy in Ph+ALL has been reported and our ability to adjust for baseline patient characteristics was limited, the results suggest that ponatinib combined with chemotherapy might represent a more effective front-line treatment option than chemotherapy combined with an earlier generation TKI for patients with newly diagnosed Ph+ALL, including those who cannot or choose not to undergo [stem cell transplant],” wrote Elias Jabbour, MD, of the University of Texas MD Anderson Cancer Center in Houston, and his colleagues.
They based their conclusions on a meta-regression analysis of 25 studies looking at first- or second-generation TKIs and one study of ponatinib as frontline therapy for patients with Ph+ALL. They described their results in Clinical Lymphoma, Myeloma & Leukemia.
The investigators created pooled estimates of outcomes from studies of earlier-generation TKIs plus combination chemotherapy using a random-effects meta-analysis method. For the sole ponatinib study – a single-arm trial of combination chemotherapy plus ponatinib – they used a binomial distribution method to calculate 95% confidence intervals (CI). The method essentially estimates the probability of success or failure of a repeated experiment.
They found that 79% of patients in the ponatinib trial achieved a CMR, compared with 34% of patients treated with earlier generation TKIs plus chemotherapy. This translates into an odds ratio (OR) for CMR with ponatinib of 6.09 (P = .034).
Two-year OS rates were 83% with ponatinib versus 58% for all patients treated with other TKIs. Although the OR (3.70) seemed to run in favor of ponatinib, the difference was not statistically significant (P = .062).
For 3-year OS, however, ponatinib was superior to the pooled data for the other TKIs, at 79% versus 50%, translating into an OR of 4.49 (P = .050).
The authors acknowledged that the study was limited by differences in treatment regimens and centers, and a limited ability to adjust for patient characteristics, due to the study’s reliance on only those covariates published across different studies. Head-to-head comparison trials are needed to confirm their results, they noted.
Nonetheless, “[w]e believe that the improved efficacy of ponatinib combined with chemotherapy for newly diagnosed Ph+ALL might prevent the need for allogeneic SCT,” they wrote.
Ariad Pharmaceuticals funded the study. Dr. Jabbour and three coauthors reported research funding from the company; other study authors reported employment or other financial relationships with Ariad or its parent company Takeda.
SOURCE: Jabbour E et al. Clin Lymphoma Myeloma Leuk. 2018 18(4):257-65.
Every generation aspires to be better than its predecessors, and for the third-generation tyrosine kinase inhibitor ponatinib (Iclusig), that might just be true, investigators claim.
A retrospective analysis comparing clinical trial outcomes for patients with newly diagnosed acute lymphoblastic leukemia positive for the Philadelphia chromosome (Ph+ALL) suggests that first-line ponatinib offers modestly better complete molecular response (CMR) rates and 3-year overall survival (OS) than either first-generation TKIs such as imatinib (Gleevec) or second-generation agents such as dasatinib (Sprycel) and nilotinib (Tasigna).
“Although only 1 relevant study of ponatinib combined with chemotherapy in Ph+ALL has been reported and our ability to adjust for baseline patient characteristics was limited, the results suggest that ponatinib combined with chemotherapy might represent a more effective front-line treatment option than chemotherapy combined with an earlier generation TKI for patients with newly diagnosed Ph+ALL, including those who cannot or choose not to undergo [stem cell transplant],” wrote Elias Jabbour, MD, of the University of Texas MD Anderson Cancer Center in Houston, and his colleagues.
They based their conclusions on a meta-regression analysis of 25 studies looking at first- or second-generation TKIs and one study of ponatinib as frontline therapy for patients with Ph+ALL. They described their results in Clinical Lymphoma, Myeloma & Leukemia.
The investigators created pooled estimates of outcomes from studies of earlier-generation TKIs plus combination chemotherapy using a random-effects meta-analysis method. For the sole ponatinib study – a single-arm trial of combination chemotherapy plus ponatinib – they used a binomial distribution method to calculate 95% confidence intervals (CI). The method essentially estimates the probability of success or failure of a repeated experiment.
They found that 79% of patients in the ponatinib trial achieved a CMR, compared with 34% of patients treated with earlier generation TKIs plus chemotherapy. This translates into an odds ratio (OR) for CMR with ponatinib of 6.09 (P = .034).
Two-year OS rates were 83% with ponatinib versus 58% for all patients treated with other TKIs. Although the OR (3.70) seemed to run in favor of ponatinib, the difference was not statistically significant (P = .062).
For 3-year OS, however, ponatinib was superior to the pooled data for the other TKIs, at 79% versus 50%, translating into an OR of 4.49 (P = .050).
The authors acknowledged that the study was limited by differences in treatment regimens and centers, and a limited ability to adjust for patient characteristics, due to the study’s reliance on only those covariates published across different studies. Head-to-head comparison trials are needed to confirm their results, they noted.
Nonetheless, “[w]e believe that the improved efficacy of ponatinib combined with chemotherapy for newly diagnosed Ph+ALL might prevent the need for allogeneic SCT,” they wrote.
Ariad Pharmaceuticals funded the study. Dr. Jabbour and three coauthors reported research funding from the company; other study authors reported employment or other financial relationships with Ariad or its parent company Takeda.
SOURCE: Jabbour E et al. Clin Lymphoma Myeloma Leuk. 2018 18(4):257-65.
FROM CLINICAL LYMPHOMA, MYELOMA & LEUKEMIA
Key clinical point:
Major finding: Complete molecular response rates and 3-year overall survival were better with ponatinib in combination with chemotherapy.
Study details: Meta-regression analysis of 26 studies of TKIs in combination with chemotherapy as first-line therapy for patients with Ph+ALL.
Disclosures: Ariad Pharmaceuticals funded the study. Dr. Jabbour and three coauthors reported research funding from the company; other study authors reported employment or other financial relationships with Ariad or its parent company, Takeda.
Source: Jabbour E et al. Clin Lymphoma Myeloma Leuk. 2018 18(4):257-65.
CtDNA agrees (mostly) with tissue analysis in mCRC
For identifying patients with metastatic colorectal cancer who might benefit from therapy with drugs targeted against the epidermal growth factor receptor (EGFR), analysis of plasma for circulating tumor DNA – aka “liquid biopsy” – is about as capable as and considerably faster than tissue analysis of RAS mutational status, investigators contend.
Among 412 chemotherapy-naive patients with metastatic colorectal cancer (mCRC) for whom both plasma and tissue samples were available, the kappa coefficient (a measure of acceptable concordance) between ctDNA RAS mutation detection and tissue-based analysis was 0.71, just over the minimum 0.7, and the accuracy of the liquid biopsy sampling was 85.2%, reported Pierre Laurent-Puig, MD, PhD, of Sorbonne University in Paris, and his colleagues.
“[E]ven if our results are limited to the techniques used with their analytic sensitivity, we show here for the first time in a prospective study an excellent concordance between plasma and tumor RAS mutation status in metastatic colorectal cancer patients, especially those with liver metastases. These results validate the routine use of plasma RAS analysis in patients with colorectal cancer and liver metastases,” they wrote. The report was published in Annals of Oncology.
The investigators found that ctDNA was more likely to yield inconclusive results in patients without liver metastases. In patients with liver metastases, the accuracy of the liquid biopsy using next-generation sequencing (NGS) alone to detect RAS mutations was 93.5%, and when detection of methylated biomarkers was added in, the accuracy was 97%.
In the AGEO RASANC prospective multicenter study, the investigators prospectively collected plasma samples from patients with mCRC and sent them to a central lab for analysis by NGS with the colon/lung cancer V2 Ampliseq panel and with digital polymerase chain reaction dPCR for genes associated with DNA methylation (WIF1 and NPY).
Matched tissue samples from the same patients were analyzed locally according to routine practice.
As noted before, the kappa coefficient was 0.71, indicating that agreement between the tests was at least 70% better than by chance alone.
In 329 patients who had detectable ctDNA, defined as at least one mutation or one methylated biomarker, the kappa coefficient rose to 89% and the accuracy to 94.8%.
Also as noted, in the 293 patients with liver metastases, the accuracy improved to close to 100% with both NGS and methylated biomarker detection.
“Based solely on the plasma analysis using our prespecified analysis, 14 patients would have received ineffective and potentially deleterious anti-EGFR therapy. All were considered as truly RAS wild-type in their plasma because of the presence of other mutations detected by NGS and/or a positive methylation assay,” the researchers wrote.
The lack of sensitivity of ctDNA in these patients may have been due to the fact that the fraction of mutated alleles in these patients was lower than in patients for whom both plasma and tissue analysis were negative for RAS mutations. All of these patients had early metastases, which could explain why the sensitivity of the plasma assay was lower than in patients with advanced-stage disease, they said.
“On the contrary detection of RAS mutations in plasma but not in tumor cells could exclude some patients from potentially effective anti-EGFR therapy,” they added. They identified eight patients with plasma-positive, tissue-negative discordance, which could be due to errors in tissue sampling due to heterogeneity of mutations within tissues, or to a lack of sensitivity of RAS mutation detection in tissues.
The trial was sponsored by AGEO and supported by a grant from Merck Serono. Dr. Laurent-Puig disclosed grants from AGEO and personal fees from Merck Serono and other companies. Multiple coauthors reported fees from Merck Serono and others.
SOURCE: Laurent-Puig P et al. Ann Oncol. 2018 Feb 9. doi: 10.1093/annonc/mdy061/4846852.
Regarding next steps, several studies have now shown a high correlation between RAS testing in plasma versus tissue, and a better understanding of the technical and clinical characteristics of RAS ctDNA testing has helped in increasing the accuracy to almost 100%. With that, RAS ctDNA testing should be ready for its clinical use.
However, as clinicians, we need to remember that the goal of RAS testing is to select patients that will benefit from anti-EGFR therapy, and thus, a threshold of RAS detection in ctDNA that is clinically meaningful needs to be established in future studies.
In summary, Laurent-Puig et al. confirm the high correlation between tissue and ctDNA RAS testing, but more importantly they help by optimizing the limits for its clinical implementation. ctDNA RAS testing is ready for clinical use, but we now know that it may not be a good tool for a minority of patients with specific clinical characteristics.
Clara Montagut, MD, is with Hospital del Mar Medical Research Institute in Barcelona. Dana Tsui, PhD, and Luis Alberto Diaz Jr., MD, are with Memorial Sloan Kettering Cancer Center in New York. Dr. Montagut is an advisory consultant to Merck Serono and other companies. Dr. Diaz is a founder and shareholder of PapGene and Personal Genome Diagnostics and a consultant for Merck and others. Dr. Tsui is a former consultant of Inivata Ltd, and a contributor to patents on cell-free DNA detection methodologies, and may receive royalties related to the licenses of those patents to Inivata Ltd. Their remarks are adapted from an editorial (Ann Oncol. 2018 Feb 9. doi: 10.1093/annonc/mdy091).
Regarding next steps, several studies have now shown a high correlation between RAS testing in plasma versus tissue, and a better understanding of the technical and clinical characteristics of RAS ctDNA testing has helped in increasing the accuracy to almost 100%. With that, RAS ctDNA testing should be ready for its clinical use.
However, as clinicians, we need to remember that the goal of RAS testing is to select patients that will benefit from anti-EGFR therapy, and thus, a threshold of RAS detection in ctDNA that is clinically meaningful needs to be established in future studies.
In summary, Laurent-Puig et al. confirm the high correlation between tissue and ctDNA RAS testing, but more importantly they help by optimizing the limits for its clinical implementation. ctDNA RAS testing is ready for clinical use, but we now know that it may not be a good tool for a minority of patients with specific clinical characteristics.
Clara Montagut, MD, is with Hospital del Mar Medical Research Institute in Barcelona. Dana Tsui, PhD, and Luis Alberto Diaz Jr., MD, are with Memorial Sloan Kettering Cancer Center in New York. Dr. Montagut is an advisory consultant to Merck Serono and other companies. Dr. Diaz is a founder and shareholder of PapGene and Personal Genome Diagnostics and a consultant for Merck and others. Dr. Tsui is a former consultant of Inivata Ltd, and a contributor to patents on cell-free DNA detection methodologies, and may receive royalties related to the licenses of those patents to Inivata Ltd. Their remarks are adapted from an editorial (Ann Oncol. 2018 Feb 9. doi: 10.1093/annonc/mdy091).
Regarding next steps, several studies have now shown a high correlation between RAS testing in plasma versus tissue, and a better understanding of the technical and clinical characteristics of RAS ctDNA testing has helped in increasing the accuracy to almost 100%. With that, RAS ctDNA testing should be ready for its clinical use.
However, as clinicians, we need to remember that the goal of RAS testing is to select patients that will benefit from anti-EGFR therapy, and thus, a threshold of RAS detection in ctDNA that is clinically meaningful needs to be established in future studies.
In summary, Laurent-Puig et al. confirm the high correlation between tissue and ctDNA RAS testing, but more importantly they help by optimizing the limits for its clinical implementation. ctDNA RAS testing is ready for clinical use, but we now know that it may not be a good tool for a minority of patients with specific clinical characteristics.
Clara Montagut, MD, is with Hospital del Mar Medical Research Institute in Barcelona. Dana Tsui, PhD, and Luis Alberto Diaz Jr., MD, are with Memorial Sloan Kettering Cancer Center in New York. Dr. Montagut is an advisory consultant to Merck Serono and other companies. Dr. Diaz is a founder and shareholder of PapGene and Personal Genome Diagnostics and a consultant for Merck and others. Dr. Tsui is a former consultant of Inivata Ltd, and a contributor to patents on cell-free DNA detection methodologies, and may receive royalties related to the licenses of those patents to Inivata Ltd. Their remarks are adapted from an editorial (Ann Oncol. 2018 Feb 9. doi: 10.1093/annonc/mdy091).
For identifying patients with metastatic colorectal cancer who might benefit from therapy with drugs targeted against the epidermal growth factor receptor (EGFR), analysis of plasma for circulating tumor DNA – aka “liquid biopsy” – is about as capable as and considerably faster than tissue analysis of RAS mutational status, investigators contend.
Among 412 chemotherapy-naive patients with metastatic colorectal cancer (mCRC) for whom both plasma and tissue samples were available, the kappa coefficient (a measure of acceptable concordance) between ctDNA RAS mutation detection and tissue-based analysis was 0.71, just over the minimum 0.7, and the accuracy of the liquid biopsy sampling was 85.2%, reported Pierre Laurent-Puig, MD, PhD, of Sorbonne University in Paris, and his colleagues.
“[E]ven if our results are limited to the techniques used with their analytic sensitivity, we show here for the first time in a prospective study an excellent concordance between plasma and tumor RAS mutation status in metastatic colorectal cancer patients, especially those with liver metastases. These results validate the routine use of plasma RAS analysis in patients with colorectal cancer and liver metastases,” they wrote. The report was published in Annals of Oncology.
The investigators found that ctDNA was more likely to yield inconclusive results in patients without liver metastases. In patients with liver metastases, the accuracy of the liquid biopsy using next-generation sequencing (NGS) alone to detect RAS mutations was 93.5%, and when detection of methylated biomarkers was added in, the accuracy was 97%.
In the AGEO RASANC prospective multicenter study, the investigators prospectively collected plasma samples from patients with mCRC and sent them to a central lab for analysis by NGS with the colon/lung cancer V2 Ampliseq panel and with digital polymerase chain reaction dPCR for genes associated with DNA methylation (WIF1 and NPY).
Matched tissue samples from the same patients were analyzed locally according to routine practice.
As noted before, the kappa coefficient was 0.71, indicating that agreement between the tests was at least 70% better than by chance alone.
In 329 patients who had detectable ctDNA, defined as at least one mutation or one methylated biomarker, the kappa coefficient rose to 89% and the accuracy to 94.8%.
Also as noted, in the 293 patients with liver metastases, the accuracy improved to close to 100% with both NGS and methylated biomarker detection.
“Based solely on the plasma analysis using our prespecified analysis, 14 patients would have received ineffective and potentially deleterious anti-EGFR therapy. All were considered as truly RAS wild-type in their plasma because of the presence of other mutations detected by NGS and/or a positive methylation assay,” the researchers wrote.
The lack of sensitivity of ctDNA in these patients may have been due to the fact that the fraction of mutated alleles in these patients was lower than in patients for whom both plasma and tissue analysis were negative for RAS mutations. All of these patients had early metastases, which could explain why the sensitivity of the plasma assay was lower than in patients with advanced-stage disease, they said.
“On the contrary detection of RAS mutations in plasma but not in tumor cells could exclude some patients from potentially effective anti-EGFR therapy,” they added. They identified eight patients with plasma-positive, tissue-negative discordance, which could be due to errors in tissue sampling due to heterogeneity of mutations within tissues, or to a lack of sensitivity of RAS mutation detection in tissues.
The trial was sponsored by AGEO and supported by a grant from Merck Serono. Dr. Laurent-Puig disclosed grants from AGEO and personal fees from Merck Serono and other companies. Multiple coauthors reported fees from Merck Serono and others.
SOURCE: Laurent-Puig P et al. Ann Oncol. 2018 Feb 9. doi: 10.1093/annonc/mdy061/4846852.
For identifying patients with metastatic colorectal cancer who might benefit from therapy with drugs targeted against the epidermal growth factor receptor (EGFR), analysis of plasma for circulating tumor DNA – aka “liquid biopsy” – is about as capable as and considerably faster than tissue analysis of RAS mutational status, investigators contend.
Among 412 chemotherapy-naive patients with metastatic colorectal cancer (mCRC) for whom both plasma and tissue samples were available, the kappa coefficient (a measure of acceptable concordance) between ctDNA RAS mutation detection and tissue-based analysis was 0.71, just over the minimum 0.7, and the accuracy of the liquid biopsy sampling was 85.2%, reported Pierre Laurent-Puig, MD, PhD, of Sorbonne University in Paris, and his colleagues.
“[E]ven if our results are limited to the techniques used with their analytic sensitivity, we show here for the first time in a prospective study an excellent concordance between plasma and tumor RAS mutation status in metastatic colorectal cancer patients, especially those with liver metastases. These results validate the routine use of plasma RAS analysis in patients with colorectal cancer and liver metastases,” they wrote. The report was published in Annals of Oncology.
The investigators found that ctDNA was more likely to yield inconclusive results in patients without liver metastases. In patients with liver metastases, the accuracy of the liquid biopsy using next-generation sequencing (NGS) alone to detect RAS mutations was 93.5%, and when detection of methylated biomarkers was added in, the accuracy was 97%.
In the AGEO RASANC prospective multicenter study, the investigators prospectively collected plasma samples from patients with mCRC and sent them to a central lab for analysis by NGS with the colon/lung cancer V2 Ampliseq panel and with digital polymerase chain reaction dPCR for genes associated with DNA methylation (WIF1 and NPY).
Matched tissue samples from the same patients were analyzed locally according to routine practice.
As noted before, the kappa coefficient was 0.71, indicating that agreement between the tests was at least 70% better than by chance alone.
In 329 patients who had detectable ctDNA, defined as at least one mutation or one methylated biomarker, the kappa coefficient rose to 89% and the accuracy to 94.8%.
Also as noted, in the 293 patients with liver metastases, the accuracy improved to close to 100% with both NGS and methylated biomarker detection.
“Based solely on the plasma analysis using our prespecified analysis, 14 patients would have received ineffective and potentially deleterious anti-EGFR therapy. All were considered as truly RAS wild-type in their plasma because of the presence of other mutations detected by NGS and/or a positive methylation assay,” the researchers wrote.
The lack of sensitivity of ctDNA in these patients may have been due to the fact that the fraction of mutated alleles in these patients was lower than in patients for whom both plasma and tissue analysis were negative for RAS mutations. All of these patients had early metastases, which could explain why the sensitivity of the plasma assay was lower than in patients with advanced-stage disease, they said.
“On the contrary detection of RAS mutations in plasma but not in tumor cells could exclude some patients from potentially effective anti-EGFR therapy,” they added. They identified eight patients with plasma-positive, tissue-negative discordance, which could be due to errors in tissue sampling due to heterogeneity of mutations within tissues, or to a lack of sensitivity of RAS mutation detection in tissues.
The trial was sponsored by AGEO and supported by a grant from Merck Serono. Dr. Laurent-Puig disclosed grants from AGEO and personal fees from Merck Serono and other companies. Multiple coauthors reported fees from Merck Serono and others.
SOURCE: Laurent-Puig P et al. Ann Oncol. 2018 Feb 9. doi: 10.1093/annonc/mdy061/4846852.
FROM ANNALS OF ONCOLOGY
Key clinical point: Circulating tumor DNA (ctDNA) may offer a more rapid method for accurately determining RAS mutational status.
Major finding: In patients with colorectal cancer with liver metastases, concordance between ctDNA and tissues samples was high.
Study details: Prospective study comparing RAS mutational analysis results with plasma ctDNA and tissue analysis in 412 chemotherapy-naive patients with metastatic colorectal cancer.
Disclosures: The trial was sponsored by AGEO and supported by a grant from Merck Serono. Dr. Laurent-Puig disclosed grants from AGEO and personal fees from Merck Serono and other companies. Multiple coauthors reported fees from Merck Serono and others.
Source: Laurent-Puig P et al. Ann Oncol. 2018 Feb 9. doi: 10.1093/annonc/mdy061/4846852.
Updated CLL guidelines incorporate a decade of advances
include new and revised recommendations based on major advances in genomics, targeted therapies, and biomarkers that have occurred since the last iteration in 2008.
The guidelines are an update from a consensus document issued a decade ago by the International Workshop on CLL, focusing on the conduct of clinical trials in patients with CLL. The new guidelines are published in Blood.
Major changes or additions include:
Molecular genetics: The updated guidelines recognize the clinical importance of specific genomic alterations/mutations on response to standard chemotherapy or chemoimmunotherapy, including the 17p deletion and mutations in TP53.
“Therefore, the assessment of both del(17p) and TP53 mutation has prognostic and predictive value and should guide therapeutic decisions in routine practice. For clinical trials, it is recommended that molecular genetics be performed prior to treating a patient on protocol,” the guidelines state.
IGHV mutational status: The mutational status of immunoglobulin variable heavy chain (IGHV) genes has been demonstrated to offer important prognostic information, according to the guidelines authors led by Michael Hallek, MD of the University of Cologne, Germany.
Specifically, leukemia with IGHV genes without somatic mutations are associated with worse clinical outcomes, compared with leukemia with IGHV mutations. Patients with mutated IGHV and other prognostic factors such as favorable cytogenetics or minimal residual disease (MRD) negativity generally have excellent outcomes with a chemoimmunotherapy regimen consisting of fludarabine, cyclophosphamide, and rituximab, the authors noted.
Biomarkers: The guidelines call for standardization and use in prospective clinical trials of assays for serum markers such as soluble CD23, thymidine kinase, and beta-2-microglobulin. These markers have been shown in several studies to be associated with overall survival or progression-free survival, and of these markers, beta-2-microglobulin “has retained independent prognostic value in several multiparameter scores,” the guidelines state.
The authors also tip their hats to recently developed or improved prognostic scores, especially the CLL International Prognostic Index (CLL-IPI), which incorporates clinical stage, age, IGHV mutational status, beta-2-microglobulin, and del(17p) and/or TP53 mutations.
Organ function assessment: Not new, but improved in the current version of the guidelines, are recommendations for evaluation of splenomegaly, hepatomegaly, and lymphadenopathy in response assessment. These recommendations were harmonized with the relevant sections of the updated lymphoma response guidelines.
Continuous therapy: The guidelines panel recommends assessment of response duration during continuous therapy with oral agents and after the end of therapy, especially after chemotherapy or chemoimmunotherapy.
“Study protocols should provide detailed specifications of the planned time points for the assessment of the treatment response under continuous therapy. Response durations of less than six months are not considered clinically relevant,” the panel cautioned.
Response assessments for treatments with a maintenance phase should be performed at a minimum of 2 months after patients achieve their best responses.
MRD: The guidelines call for minimal residual disease (MRD) assessment in clinical trials aimed at maximizing remission depth, with emphasis on reporting the sensitivity of the MRD evaluation method used, and the type of tissue assessed.
Antiviral prophylaxis: The guidelines caution that because patients treated with anti-CD20 antibodies, such as rituximab or obinutuzumab, could have reactivation of hepatitis B virus (HBV) infections, patients should be tested for HBV serological status before starting on an anti-CD20 agent.
“Progressive multifocal leukoencephalopathy has been reported in a few CLL patients treated with anti-CD20 antibodies; therefore, infections with John Cunningham (JC) virus should be ruled out in situations of unclear neurological symptoms,” the panel recommended.
They note that patients younger than 65 treated with fludarabine-based therapy in the first line do not require routine monitoring or infection prophylaxis, due to the low reported incidence of infections in this group.
The authors reported having no financial disclosures related to the guidelines.
include new and revised recommendations based on major advances in genomics, targeted therapies, and biomarkers that have occurred since the last iteration in 2008.
The guidelines are an update from a consensus document issued a decade ago by the International Workshop on CLL, focusing on the conduct of clinical trials in patients with CLL. The new guidelines are published in Blood.
Major changes or additions include:
Molecular genetics: The updated guidelines recognize the clinical importance of specific genomic alterations/mutations on response to standard chemotherapy or chemoimmunotherapy, including the 17p deletion and mutations in TP53.
“Therefore, the assessment of both del(17p) and TP53 mutation has prognostic and predictive value and should guide therapeutic decisions in routine practice. For clinical trials, it is recommended that molecular genetics be performed prior to treating a patient on protocol,” the guidelines state.
IGHV mutational status: The mutational status of immunoglobulin variable heavy chain (IGHV) genes has been demonstrated to offer important prognostic information, according to the guidelines authors led by Michael Hallek, MD of the University of Cologne, Germany.
Specifically, leukemia with IGHV genes without somatic mutations are associated with worse clinical outcomes, compared with leukemia with IGHV mutations. Patients with mutated IGHV and other prognostic factors such as favorable cytogenetics or minimal residual disease (MRD) negativity generally have excellent outcomes with a chemoimmunotherapy regimen consisting of fludarabine, cyclophosphamide, and rituximab, the authors noted.
Biomarkers: The guidelines call for standardization and use in prospective clinical trials of assays for serum markers such as soluble CD23, thymidine kinase, and beta-2-microglobulin. These markers have been shown in several studies to be associated with overall survival or progression-free survival, and of these markers, beta-2-microglobulin “has retained independent prognostic value in several multiparameter scores,” the guidelines state.
The authors also tip their hats to recently developed or improved prognostic scores, especially the CLL International Prognostic Index (CLL-IPI), which incorporates clinical stage, age, IGHV mutational status, beta-2-microglobulin, and del(17p) and/or TP53 mutations.
Organ function assessment: Not new, but improved in the current version of the guidelines, are recommendations for evaluation of splenomegaly, hepatomegaly, and lymphadenopathy in response assessment. These recommendations were harmonized with the relevant sections of the updated lymphoma response guidelines.
Continuous therapy: The guidelines panel recommends assessment of response duration during continuous therapy with oral agents and after the end of therapy, especially after chemotherapy or chemoimmunotherapy.
“Study protocols should provide detailed specifications of the planned time points for the assessment of the treatment response under continuous therapy. Response durations of less than six months are not considered clinically relevant,” the panel cautioned.
Response assessments for treatments with a maintenance phase should be performed at a minimum of 2 months after patients achieve their best responses.
MRD: The guidelines call for minimal residual disease (MRD) assessment in clinical trials aimed at maximizing remission depth, with emphasis on reporting the sensitivity of the MRD evaluation method used, and the type of tissue assessed.
Antiviral prophylaxis: The guidelines caution that because patients treated with anti-CD20 antibodies, such as rituximab or obinutuzumab, could have reactivation of hepatitis B virus (HBV) infections, patients should be tested for HBV serological status before starting on an anti-CD20 agent.
“Progressive multifocal leukoencephalopathy has been reported in a few CLL patients treated with anti-CD20 antibodies; therefore, infections with John Cunningham (JC) virus should be ruled out in situations of unclear neurological symptoms,” the panel recommended.
They note that patients younger than 65 treated with fludarabine-based therapy in the first line do not require routine monitoring or infection prophylaxis, due to the low reported incidence of infections in this group.
The authors reported having no financial disclosures related to the guidelines.
include new and revised recommendations based on major advances in genomics, targeted therapies, and biomarkers that have occurred since the last iteration in 2008.
The guidelines are an update from a consensus document issued a decade ago by the International Workshop on CLL, focusing on the conduct of clinical trials in patients with CLL. The new guidelines are published in Blood.
Major changes or additions include:
Molecular genetics: The updated guidelines recognize the clinical importance of specific genomic alterations/mutations on response to standard chemotherapy or chemoimmunotherapy, including the 17p deletion and mutations in TP53.
“Therefore, the assessment of both del(17p) and TP53 mutation has prognostic and predictive value and should guide therapeutic decisions in routine practice. For clinical trials, it is recommended that molecular genetics be performed prior to treating a patient on protocol,” the guidelines state.
IGHV mutational status: The mutational status of immunoglobulin variable heavy chain (IGHV) genes has been demonstrated to offer important prognostic information, according to the guidelines authors led by Michael Hallek, MD of the University of Cologne, Germany.
Specifically, leukemia with IGHV genes without somatic mutations are associated with worse clinical outcomes, compared with leukemia with IGHV mutations. Patients with mutated IGHV and other prognostic factors such as favorable cytogenetics or minimal residual disease (MRD) negativity generally have excellent outcomes with a chemoimmunotherapy regimen consisting of fludarabine, cyclophosphamide, and rituximab, the authors noted.
Biomarkers: The guidelines call for standardization and use in prospective clinical trials of assays for serum markers such as soluble CD23, thymidine kinase, and beta-2-microglobulin. These markers have been shown in several studies to be associated with overall survival or progression-free survival, and of these markers, beta-2-microglobulin “has retained independent prognostic value in several multiparameter scores,” the guidelines state.
The authors also tip their hats to recently developed or improved prognostic scores, especially the CLL International Prognostic Index (CLL-IPI), which incorporates clinical stage, age, IGHV mutational status, beta-2-microglobulin, and del(17p) and/or TP53 mutations.
Organ function assessment: Not new, but improved in the current version of the guidelines, are recommendations for evaluation of splenomegaly, hepatomegaly, and lymphadenopathy in response assessment. These recommendations were harmonized with the relevant sections of the updated lymphoma response guidelines.
Continuous therapy: The guidelines panel recommends assessment of response duration during continuous therapy with oral agents and after the end of therapy, especially after chemotherapy or chemoimmunotherapy.
“Study protocols should provide detailed specifications of the planned time points for the assessment of the treatment response under continuous therapy. Response durations of less than six months are not considered clinically relevant,” the panel cautioned.
Response assessments for treatments with a maintenance phase should be performed at a minimum of 2 months after patients achieve their best responses.
MRD: The guidelines call for minimal residual disease (MRD) assessment in clinical trials aimed at maximizing remission depth, with emphasis on reporting the sensitivity of the MRD evaluation method used, and the type of tissue assessed.
Antiviral prophylaxis: The guidelines caution that because patients treated with anti-CD20 antibodies, such as rituximab or obinutuzumab, could have reactivation of hepatitis B virus (HBV) infections, patients should be tested for HBV serological status before starting on an anti-CD20 agent.
“Progressive multifocal leukoencephalopathy has been reported in a few CLL patients treated with anti-CD20 antibodies; therefore, infections with John Cunningham (JC) virus should be ruled out in situations of unclear neurological symptoms,” the panel recommended.
They note that patients younger than 65 treated with fludarabine-based therapy in the first line do not require routine monitoring or infection prophylaxis, due to the low reported incidence of infections in this group.
The authors reported having no financial disclosures related to the guidelines.
FROM BLOOD
Sarcopenia, body fat linked with mortality in nonmetastatic breast cancer
Among women with nonmetastatic breast cancer, low muscle mass and excess body fat are significantly associated with worse survival, investigators report.
An observational study of 3,241 women diagnosed with stage II or III breast cancer showed that low muscle mass (sarcopenia) was independently associated with a 41% increase in risk for overall mortality, and that total adipose tissue (TAT) measures were associated with a 35% increase in overall mortality.
Women with sarcopenia and high total TAT scores had a nearly twofold higher risk for death, reported Bette J. Caan, DrPH, of Kaiser Permanente in Oakland, Calif., and her colleagues.
Although low muscle mass was found to be a significant risk factor for death, neither poor muscle quality, measured by radiodensity, nor body mass index (BMI) were significantly associated with overall mortality, the investigators reported in a study published online in JAMA Oncology.
“Both muscle and adiposity represent modifiable risk factors in patients with breast cancer. In addition to weight loss, we should also consider interventions to improve muscle mass, such as resistance training or protein supplementation. In the era of precision medicine, the direct measurement of muscle and adiposity will help to guide treatment plans and interventions to optimize survival outcomes,” they wrote.
Although moderate to severe obesity measured by high BMI has been associated with worse outcomes for patients with breast cancer and other malignancies, the evidence is mixed for those who are merely overweight or have borderline obesity, the authors noted.
BMI is a simple ratio of height to weight, and does not measure body composition, and “low BMI can mask excess adiposity while high BMI can mask low muscularity,” they wrote.
To determine whether associations between measures of body composition could be prognostic for overall mortality, the investigators conducted a retrospective cohort study with patients from Kaiser Permanente Northern California and the Dana-Farber Cancer Institute in Boston.
The cohort included 3,241 women diagnosed with stage II or III invasive breast cancer during 2005-2013 in California and during 2000-2012 in Boston. All of the patients included had either abdominal or pelvic CT scans or PET-CT scans at the time of diagnosis.
The investigators looked at the associations between sarcopenia, TAT, and low muscle radiodensity, and created hazard ratio (HR) estimates of the effects of the various interactions on overall mortality, adjusted for sociodemographics, tumor characteristics, treatment, BMI, and other body composition measures.
They found that after a median follow-up of 6 years, patients with sarcopenia had a significantly greater risk for overall mortality than did patients without sarcopenia (HR, 1.41; 95% confidence interval, 1.18-1.69).
Additionally, patients in the highest tertile of TAT also had significantly higher overall mortality, compared with patients in the lowest tertile (HR, 1.35; CI, 1.08-1.69).
As noted before, poor muscle quality was not significantly associated with overall mortality.
Looking at both sarcopenia and TAT, the authors found that the highest risk for death was in those patients with both sarcopenia and high TAT (HR, 1.88; CI, 1.30-2.73).
However, they also found that BMI was not an independent predictor of overall mortality, and did identify those patients who were at risk because of their body composition.
“We demonstrate that sarcopenia is not a condition restricted to patients with later-stage disease but rather is highly prevalent among patients with nonmetastatic disease across all levels of BMI. Our findings are likely generalizable across many other nonmetastatic cancers because the associations with muscle and improved survival for those with metastatic cancer has been observed across a variety of solid tumors,” Dr. Caan and her associates wrote in their conclusion.
The article did not report a funding source for the study. The investigators reported having no conflicts of interest to disclose.
op@mdedge.com
SOURCE: Cann BJ et al. JAMA Oncol. 2018 Apr 5. doi: 10.1001/jamaoncol.2018.0137.
Obesity is highly prevalent among breast cancer survivors, and in addition to its effects on cancer development and outcomes, it also can affect treatment efficacy and adverse effects and complicate clinical management of breast cancer from obesity-related comorbidities such as hypertension and diabetes. As such, the American Society of Clinical Oncology made obesity and cancer one of their core priorities in 2013 and launched the Obesity & Cancer Initiative with activities ranging from education and awareness to clinical guidance, promotion of research, and policy and advocacy.
Despite its limitations, body mass index remains an easy tool to help health care clinicians identify patients at greater risk for poor outcomes and adverse effects and guide their recommendations, as well as to educate patients in self-assessing their weight status. Weight management and control are likely to have many benefits for breast cancer survivors but should always be tailored to individual patients’ needs. When CT imaging is available, the study by Caan et al. suggests that body composition measures can be useful in identifying women at higher risk of mortality. Their findings are an important reminder that weight loss and/or weight control programs must always incorporate physical activity with the goal of not just reducing adiposity, but also maintaining and increasing muscle mass, which would not only reduce the risk of death, but might also help improve quality of life after a cancer diagnosis.
Elisa V. Bandera, MD, PhD, is with the Rutgers Cancer Institute of New Jersey, Rutgers University, New Brunswick. Esther M. John, PhD, is with Stanford (Calif.) University. Both editorialists reported having no conflicts of interest to disclose. Their remarks are adapted from an accompanying invited commentary (JAMA Oncol. doi: 10.1001/jamaoncol.2018.0137).
Obesity is highly prevalent among breast cancer survivors, and in addition to its effects on cancer development and outcomes, it also can affect treatment efficacy and adverse effects and complicate clinical management of breast cancer from obesity-related comorbidities such as hypertension and diabetes. As such, the American Society of Clinical Oncology made obesity and cancer one of their core priorities in 2013 and launched the Obesity & Cancer Initiative with activities ranging from education and awareness to clinical guidance, promotion of research, and policy and advocacy.
Despite its limitations, body mass index remains an easy tool to help health care clinicians identify patients at greater risk for poor outcomes and adverse effects and guide their recommendations, as well as to educate patients in self-assessing their weight status. Weight management and control are likely to have many benefits for breast cancer survivors but should always be tailored to individual patients’ needs. When CT imaging is available, the study by Caan et al. suggests that body composition measures can be useful in identifying women at higher risk of mortality. Their findings are an important reminder that weight loss and/or weight control programs must always incorporate physical activity with the goal of not just reducing adiposity, but also maintaining and increasing muscle mass, which would not only reduce the risk of death, but might also help improve quality of life after a cancer diagnosis.
Elisa V. Bandera, MD, PhD, is with the Rutgers Cancer Institute of New Jersey, Rutgers University, New Brunswick. Esther M. John, PhD, is with Stanford (Calif.) University. Both editorialists reported having no conflicts of interest to disclose. Their remarks are adapted from an accompanying invited commentary (JAMA Oncol. doi: 10.1001/jamaoncol.2018.0137).
Obesity is highly prevalent among breast cancer survivors, and in addition to its effects on cancer development and outcomes, it also can affect treatment efficacy and adverse effects and complicate clinical management of breast cancer from obesity-related comorbidities such as hypertension and diabetes. As such, the American Society of Clinical Oncology made obesity and cancer one of their core priorities in 2013 and launched the Obesity & Cancer Initiative with activities ranging from education and awareness to clinical guidance, promotion of research, and policy and advocacy.
Despite its limitations, body mass index remains an easy tool to help health care clinicians identify patients at greater risk for poor outcomes and adverse effects and guide their recommendations, as well as to educate patients in self-assessing their weight status. Weight management and control are likely to have many benefits for breast cancer survivors but should always be tailored to individual patients’ needs. When CT imaging is available, the study by Caan et al. suggests that body composition measures can be useful in identifying women at higher risk of mortality. Their findings are an important reminder that weight loss and/or weight control programs must always incorporate physical activity with the goal of not just reducing adiposity, but also maintaining and increasing muscle mass, which would not only reduce the risk of death, but might also help improve quality of life after a cancer diagnosis.
Elisa V. Bandera, MD, PhD, is with the Rutgers Cancer Institute of New Jersey, Rutgers University, New Brunswick. Esther M. John, PhD, is with Stanford (Calif.) University. Both editorialists reported having no conflicts of interest to disclose. Their remarks are adapted from an accompanying invited commentary (JAMA Oncol. doi: 10.1001/jamaoncol.2018.0137).
Among women with nonmetastatic breast cancer, low muscle mass and excess body fat are significantly associated with worse survival, investigators report.
An observational study of 3,241 women diagnosed with stage II or III breast cancer showed that low muscle mass (sarcopenia) was independently associated with a 41% increase in risk for overall mortality, and that total adipose tissue (TAT) measures were associated with a 35% increase in overall mortality.
Women with sarcopenia and high total TAT scores had a nearly twofold higher risk for death, reported Bette J. Caan, DrPH, of Kaiser Permanente in Oakland, Calif., and her colleagues.
Although low muscle mass was found to be a significant risk factor for death, neither poor muscle quality, measured by radiodensity, nor body mass index (BMI) were significantly associated with overall mortality, the investigators reported in a study published online in JAMA Oncology.
“Both muscle and adiposity represent modifiable risk factors in patients with breast cancer. In addition to weight loss, we should also consider interventions to improve muscle mass, such as resistance training or protein supplementation. In the era of precision medicine, the direct measurement of muscle and adiposity will help to guide treatment plans and interventions to optimize survival outcomes,” they wrote.
Although moderate to severe obesity measured by high BMI has been associated with worse outcomes for patients with breast cancer and other malignancies, the evidence is mixed for those who are merely overweight or have borderline obesity, the authors noted.
BMI is a simple ratio of height to weight, and does not measure body composition, and “low BMI can mask excess adiposity while high BMI can mask low muscularity,” they wrote.
To determine whether associations between measures of body composition could be prognostic for overall mortality, the investigators conducted a retrospective cohort study with patients from Kaiser Permanente Northern California and the Dana-Farber Cancer Institute in Boston.
The cohort included 3,241 women diagnosed with stage II or III invasive breast cancer during 2005-2013 in California and during 2000-2012 in Boston. All of the patients included had either abdominal or pelvic CT scans or PET-CT scans at the time of diagnosis.
The investigators looked at the associations between sarcopenia, TAT, and low muscle radiodensity, and created hazard ratio (HR) estimates of the effects of the various interactions on overall mortality, adjusted for sociodemographics, tumor characteristics, treatment, BMI, and other body composition measures.
They found that after a median follow-up of 6 years, patients with sarcopenia had a significantly greater risk for overall mortality than did patients without sarcopenia (HR, 1.41; 95% confidence interval, 1.18-1.69).
Additionally, patients in the highest tertile of TAT also had significantly higher overall mortality, compared with patients in the lowest tertile (HR, 1.35; CI, 1.08-1.69).
As noted before, poor muscle quality was not significantly associated with overall mortality.
Looking at both sarcopenia and TAT, the authors found that the highest risk for death was in those patients with both sarcopenia and high TAT (HR, 1.88; CI, 1.30-2.73).
However, they also found that BMI was not an independent predictor of overall mortality, and did identify those patients who were at risk because of their body composition.
“We demonstrate that sarcopenia is not a condition restricted to patients with later-stage disease but rather is highly prevalent among patients with nonmetastatic disease across all levels of BMI. Our findings are likely generalizable across many other nonmetastatic cancers because the associations with muscle and improved survival for those with metastatic cancer has been observed across a variety of solid tumors,” Dr. Caan and her associates wrote in their conclusion.
The article did not report a funding source for the study. The investigators reported having no conflicts of interest to disclose.
op@mdedge.com
SOURCE: Cann BJ et al. JAMA Oncol. 2018 Apr 5. doi: 10.1001/jamaoncol.2018.0137.
Among women with nonmetastatic breast cancer, low muscle mass and excess body fat are significantly associated with worse survival, investigators report.
An observational study of 3,241 women diagnosed with stage II or III breast cancer showed that low muscle mass (sarcopenia) was independently associated with a 41% increase in risk for overall mortality, and that total adipose tissue (TAT) measures were associated with a 35% increase in overall mortality.
Women with sarcopenia and high total TAT scores had a nearly twofold higher risk for death, reported Bette J. Caan, DrPH, of Kaiser Permanente in Oakland, Calif., and her colleagues.
Although low muscle mass was found to be a significant risk factor for death, neither poor muscle quality, measured by radiodensity, nor body mass index (BMI) were significantly associated with overall mortality, the investigators reported in a study published online in JAMA Oncology.
“Both muscle and adiposity represent modifiable risk factors in patients with breast cancer. In addition to weight loss, we should also consider interventions to improve muscle mass, such as resistance training or protein supplementation. In the era of precision medicine, the direct measurement of muscle and adiposity will help to guide treatment plans and interventions to optimize survival outcomes,” they wrote.
Although moderate to severe obesity measured by high BMI has been associated with worse outcomes for patients with breast cancer and other malignancies, the evidence is mixed for those who are merely overweight or have borderline obesity, the authors noted.
BMI is a simple ratio of height to weight, and does not measure body composition, and “low BMI can mask excess adiposity while high BMI can mask low muscularity,” they wrote.
To determine whether associations between measures of body composition could be prognostic for overall mortality, the investigators conducted a retrospective cohort study with patients from Kaiser Permanente Northern California and the Dana-Farber Cancer Institute in Boston.
The cohort included 3,241 women diagnosed with stage II or III invasive breast cancer during 2005-2013 in California and during 2000-2012 in Boston. All of the patients included had either abdominal or pelvic CT scans or PET-CT scans at the time of diagnosis.
The investigators looked at the associations between sarcopenia, TAT, and low muscle radiodensity, and created hazard ratio (HR) estimates of the effects of the various interactions on overall mortality, adjusted for sociodemographics, tumor characteristics, treatment, BMI, and other body composition measures.
They found that after a median follow-up of 6 years, patients with sarcopenia had a significantly greater risk for overall mortality than did patients without sarcopenia (HR, 1.41; 95% confidence interval, 1.18-1.69).
Additionally, patients in the highest tertile of TAT also had significantly higher overall mortality, compared with patients in the lowest tertile (HR, 1.35; CI, 1.08-1.69).
As noted before, poor muscle quality was not significantly associated with overall mortality.
Looking at both sarcopenia and TAT, the authors found that the highest risk for death was in those patients with both sarcopenia and high TAT (HR, 1.88; CI, 1.30-2.73).
However, they also found that BMI was not an independent predictor of overall mortality, and did identify those patients who were at risk because of their body composition.
“We demonstrate that sarcopenia is not a condition restricted to patients with later-stage disease but rather is highly prevalent among patients with nonmetastatic disease across all levels of BMI. Our findings are likely generalizable across many other nonmetastatic cancers because the associations with muscle and improved survival for those with metastatic cancer has been observed across a variety of solid tumors,” Dr. Caan and her associates wrote in their conclusion.
The article did not report a funding source for the study. The investigators reported having no conflicts of interest to disclose.
op@mdedge.com
SOURCE: Cann BJ et al. JAMA Oncol. 2018 Apr 5. doi: 10.1001/jamaoncol.2018.0137.
FROM JAMA ONCOLOGY
Key clinical point: Helping women with nonmetastatic breast cancer control weight and improve muscle strength could lower their risk of death.
Major finding: Women with sarcopenia and high total adipose tissue had a hazard ratio of 1.89 for overall mortality.
Study details: Retrospective cohort study of 3,241 women diagnosed with stage II or III invasive breast cancer in California and Massachusetts.
Disclosures: The article did not report a funding source for the study. The investigators reported having no conflicts of interest to disclose.
Source: Cann BJ et al. JAMA Oncol. 2018 Apr 5. doi:10.1001/jamaoncol.2018.0137.
21-gene assay predicts survival in male and female breast cancer
A study of the molecular and genomic features of breast cancer in men, compared with those in women, highlights the prognostic value of a 21-gene breast recurrence score in both sexes, investigators say.
Men and women with estrogen receptor (ER)–positive breast cancer who had recurrence scores (RS) of 0 to 30 on the 21-gene assay (Oncotype DX) had excellent breast cancer–specific survival rates, which suggests that such patients could be spared from more aggressive treatments, such as chemotherapy, according to Suleiman Alfred Massarweh, MD, of Stanford (Calif.) University and his colleagues.
“Future adjuvant trials in ER-positive breast cancer may need to focus on targeting endocrine resistance in those patients with RS greater than 31 and may need to consider the weight of competing mortality risk when investigating the value of any additional treatment beyond endocrine therapy,” they wrote in the Journal of Clinical Oncology.
In 2016, an estimated 2,600 men were diagnosed with breast cancer in the United States.
“Approximately 95% of breast cancers diagnosed in men express the estrogen receptor and progesterone receptor (PR), which is a higher percentage than in women and suggests a key role for ER in the biology of breast cancer in men,” the investigators noted.
Although treatment of men with breast cancer has traditionally been extrapolated from treatment of women with breast cancer, genomic studies have suggested some key differences, the investigators noted, citing a study of the genomic landscape of male breast cancers presented at the 2014 San Antonio Breast Cancer Symposium.
In that study, investigators from the Memorial Sloan Kettering Cancer Center in New York and other institutions found that all male breast cancers in their sample of 64 patients were ER+ and human epidermal growth factor receptor 2 (HER2)–negative, predominantly of the luminal B subtype, and that the genetic alterations seen in male breast cancers frequently target DNA-repair fibroblast growth factor pathways. However, the pathways that are known to drive luminal cancers when mutated in women are seen less often among men, said Salvatore Piscuoglio, PhD, then a research fellow at MSKCC.
The current study helps to confirm and expand on the findings from that study, commented Steven J. Isakoff, MD, PhD, of the Massachusetts General Hospital Cancer Center in Boston, who was not involved in either study.
“I think it’s helpful to see in a larger dataset what the spectrum of oncotypes [Oncotype DX] looks like in men. In general, as the study described, we have a real lack of large-scale data in men and certainly no prospective data with oncotypes,” he said in an interview.
To get a better idea of the molecular characteristics of breast cancer in men and how they relate to breast cancer–specific mortality, Dr. Massarweh and his associates looked at deidentified 21-gene assay data from the Genomic Health Laboratory database on 3,806 men and 571,115 women with breast cancer with either no nodal involvement, micrometastases only, or one to three involved lymph nodes.
They also looked at survival data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) population of patients with breast cancer diagnosed during 2004-2012, which included data on 332 men and 55,842 women with ER-positive and/or PR-positive invasive breast cancer.
Among the entire 21-gene assay sample, they found that men were significantly older than women at the time of diagnosis, at a mean age of 64.2 vs. 59.1 years (P less than .001).
Both men and women had infiltrating ductal carcinoma as the most common histology; the prevalence was slightly higher among men at 87.6% versus 81.3% for women.
The average recurrence score in men was 16.8 versus 17.0 in women, a difference that was not statistically significant. A majority of both men and women had RS scores below 18 (65.8% and 58.2%, respectively), although significantly more men than women had RS scores of 31 or higher (12.4% vs. 7.4%; P less than .001).
“This relative predominance of high RS results in men was encountered across age groups but was most prominent in men younger than 40 years of age,” the investigators wrote.
At the other end of the scale, RS lower than 11, especially RS 0, were seen more frequently in men than in women, except among those younger than 40 years.
Looking at individual gene expression profiles, the authors found that mean gene expression was higher in men for genes associated with ER, proliferation, and invasion. ER expression was lowest and PR expression was highest in women younger than 50 years, but ER expression increased progressively with age.
Among men, those younger than 50 years had slightly lower ER and PR expression than did older men.
In the analysis of SEER survival data, they found that 5-year breast cancer severity score (BCSS) was 99% for men with RS below 18, 95.7% for those with RS between18 and 30, and 81% for those with RS of 31 or higher. Among women, 5-year BCSS was 99.5% for those with RS under 18, 98.6% for those with RS between 18 and 30, and 94.9% for those with RS of 31 or higher.
Five-year overall survival estimates were 92.6% for men with RS below 18, 86% for those with RS between 18 and 30, and 69% for those with RS of 31 or higher. Respective 5-year OS rates for women were 95%, 94.2%, and 89.9%.
“The 21-gene RS provided clear prognostic information in our cohort, with a significantly different 5-year BCSS determined by RS in both men and women,” the investigators wrote.
They noted that patients with low and intermediate RS have excellent prognoses regardless of nodal status, which suggests that these patients have more indolent disease and better outcomes than do patients with higher RS.
The more frequent use of adjuvant chemotherapy in the RS 31 and higher group indicates that “the prognostic utility of RS results is evident despite adjuvant chemotherapy use,” they wrote.
Dr. Isakoff pointed out, however, that the population in the study is from a registry of patients eligible for the 21-gene assay, which can only be used for patients with ER-positive and HER2-negative tumors.
“In other words, this is not a random sample. This is a sample of patients for whom the treating physician was on the fence about chemotherapy and in some way thought that getting an oncotype might be helpful,” he said.
He added that although the study findings “don’t change anything we have been doing, they provide reassurance that oncotype is a reasonable test to consider in patients with male breast cancer for whom we’re considering including or avoiding chemotherapy,” he said.
A funding source for the study was not reported. Dr. Massarweh disclosed stock or ownership in Radius Health, consulting for Novartis, and institutional research funding from multiple companies. Three coauthors are employees and stockholders of Genomic Health, maker of the Oncotype DX assay used in the study. Dr. Isakoff reported no conflicts of interest related to the study
SOURCE: Massarweh SA et al. 2018 Mar 27. doi: 10.1200/JCO.2017.76.8861.
A study of the molecular and genomic features of breast cancer in men, compared with those in women, highlights the prognostic value of a 21-gene breast recurrence score in both sexes, investigators say.
Men and women with estrogen receptor (ER)–positive breast cancer who had recurrence scores (RS) of 0 to 30 on the 21-gene assay (Oncotype DX) had excellent breast cancer–specific survival rates, which suggests that such patients could be spared from more aggressive treatments, such as chemotherapy, according to Suleiman Alfred Massarweh, MD, of Stanford (Calif.) University and his colleagues.
“Future adjuvant trials in ER-positive breast cancer may need to focus on targeting endocrine resistance in those patients with RS greater than 31 and may need to consider the weight of competing mortality risk when investigating the value of any additional treatment beyond endocrine therapy,” they wrote in the Journal of Clinical Oncology.
In 2016, an estimated 2,600 men were diagnosed with breast cancer in the United States.
“Approximately 95% of breast cancers diagnosed in men express the estrogen receptor and progesterone receptor (PR), which is a higher percentage than in women and suggests a key role for ER in the biology of breast cancer in men,” the investigators noted.
Although treatment of men with breast cancer has traditionally been extrapolated from treatment of women with breast cancer, genomic studies have suggested some key differences, the investigators noted, citing a study of the genomic landscape of male breast cancers presented at the 2014 San Antonio Breast Cancer Symposium.
In that study, investigators from the Memorial Sloan Kettering Cancer Center in New York and other institutions found that all male breast cancers in their sample of 64 patients were ER+ and human epidermal growth factor receptor 2 (HER2)–negative, predominantly of the luminal B subtype, and that the genetic alterations seen in male breast cancers frequently target DNA-repair fibroblast growth factor pathways. However, the pathways that are known to drive luminal cancers when mutated in women are seen less often among men, said Salvatore Piscuoglio, PhD, then a research fellow at MSKCC.
The current study helps to confirm and expand on the findings from that study, commented Steven J. Isakoff, MD, PhD, of the Massachusetts General Hospital Cancer Center in Boston, who was not involved in either study.
“I think it’s helpful to see in a larger dataset what the spectrum of oncotypes [Oncotype DX] looks like in men. In general, as the study described, we have a real lack of large-scale data in men and certainly no prospective data with oncotypes,” he said in an interview.
To get a better idea of the molecular characteristics of breast cancer in men and how they relate to breast cancer–specific mortality, Dr. Massarweh and his associates looked at deidentified 21-gene assay data from the Genomic Health Laboratory database on 3,806 men and 571,115 women with breast cancer with either no nodal involvement, micrometastases only, or one to three involved lymph nodes.
They also looked at survival data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) population of patients with breast cancer diagnosed during 2004-2012, which included data on 332 men and 55,842 women with ER-positive and/or PR-positive invasive breast cancer.
Among the entire 21-gene assay sample, they found that men were significantly older than women at the time of diagnosis, at a mean age of 64.2 vs. 59.1 years (P less than .001).
Both men and women had infiltrating ductal carcinoma as the most common histology; the prevalence was slightly higher among men at 87.6% versus 81.3% for women.
The average recurrence score in men was 16.8 versus 17.0 in women, a difference that was not statistically significant. A majority of both men and women had RS scores below 18 (65.8% and 58.2%, respectively), although significantly more men than women had RS scores of 31 or higher (12.4% vs. 7.4%; P less than .001).
“This relative predominance of high RS results in men was encountered across age groups but was most prominent in men younger than 40 years of age,” the investigators wrote.
At the other end of the scale, RS lower than 11, especially RS 0, were seen more frequently in men than in women, except among those younger than 40 years.
Looking at individual gene expression profiles, the authors found that mean gene expression was higher in men for genes associated with ER, proliferation, and invasion. ER expression was lowest and PR expression was highest in women younger than 50 years, but ER expression increased progressively with age.
Among men, those younger than 50 years had slightly lower ER and PR expression than did older men.
In the analysis of SEER survival data, they found that 5-year breast cancer severity score (BCSS) was 99% for men with RS below 18, 95.7% for those with RS between18 and 30, and 81% for those with RS of 31 or higher. Among women, 5-year BCSS was 99.5% for those with RS under 18, 98.6% for those with RS between 18 and 30, and 94.9% for those with RS of 31 or higher.
Five-year overall survival estimates were 92.6% for men with RS below 18, 86% for those with RS between 18 and 30, and 69% for those with RS of 31 or higher. Respective 5-year OS rates for women were 95%, 94.2%, and 89.9%.
“The 21-gene RS provided clear prognostic information in our cohort, with a significantly different 5-year BCSS determined by RS in both men and women,” the investigators wrote.
They noted that patients with low and intermediate RS have excellent prognoses regardless of nodal status, which suggests that these patients have more indolent disease and better outcomes than do patients with higher RS.
The more frequent use of adjuvant chemotherapy in the RS 31 and higher group indicates that “the prognostic utility of RS results is evident despite adjuvant chemotherapy use,” they wrote.
Dr. Isakoff pointed out, however, that the population in the study is from a registry of patients eligible for the 21-gene assay, which can only be used for patients with ER-positive and HER2-negative tumors.
“In other words, this is not a random sample. This is a sample of patients for whom the treating physician was on the fence about chemotherapy and in some way thought that getting an oncotype might be helpful,” he said.
He added that although the study findings “don’t change anything we have been doing, they provide reassurance that oncotype is a reasonable test to consider in patients with male breast cancer for whom we’re considering including or avoiding chemotherapy,” he said.
A funding source for the study was not reported. Dr. Massarweh disclosed stock or ownership in Radius Health, consulting for Novartis, and institutional research funding from multiple companies. Three coauthors are employees and stockholders of Genomic Health, maker of the Oncotype DX assay used in the study. Dr. Isakoff reported no conflicts of interest related to the study
SOURCE: Massarweh SA et al. 2018 Mar 27. doi: 10.1200/JCO.2017.76.8861.
A study of the molecular and genomic features of breast cancer in men, compared with those in women, highlights the prognostic value of a 21-gene breast recurrence score in both sexes, investigators say.
Men and women with estrogen receptor (ER)–positive breast cancer who had recurrence scores (RS) of 0 to 30 on the 21-gene assay (Oncotype DX) had excellent breast cancer–specific survival rates, which suggests that such patients could be spared from more aggressive treatments, such as chemotherapy, according to Suleiman Alfred Massarweh, MD, of Stanford (Calif.) University and his colleagues.
“Future adjuvant trials in ER-positive breast cancer may need to focus on targeting endocrine resistance in those patients with RS greater than 31 and may need to consider the weight of competing mortality risk when investigating the value of any additional treatment beyond endocrine therapy,” they wrote in the Journal of Clinical Oncology.
In 2016, an estimated 2,600 men were diagnosed with breast cancer in the United States.
“Approximately 95% of breast cancers diagnosed in men express the estrogen receptor and progesterone receptor (PR), which is a higher percentage than in women and suggests a key role for ER in the biology of breast cancer in men,” the investigators noted.
Although treatment of men with breast cancer has traditionally been extrapolated from treatment of women with breast cancer, genomic studies have suggested some key differences, the investigators noted, citing a study of the genomic landscape of male breast cancers presented at the 2014 San Antonio Breast Cancer Symposium.
In that study, investigators from the Memorial Sloan Kettering Cancer Center in New York and other institutions found that all male breast cancers in their sample of 64 patients were ER+ and human epidermal growth factor receptor 2 (HER2)–negative, predominantly of the luminal B subtype, and that the genetic alterations seen in male breast cancers frequently target DNA-repair fibroblast growth factor pathways. However, the pathways that are known to drive luminal cancers when mutated in women are seen less often among men, said Salvatore Piscuoglio, PhD, then a research fellow at MSKCC.
The current study helps to confirm and expand on the findings from that study, commented Steven J. Isakoff, MD, PhD, of the Massachusetts General Hospital Cancer Center in Boston, who was not involved in either study.
“I think it’s helpful to see in a larger dataset what the spectrum of oncotypes [Oncotype DX] looks like in men. In general, as the study described, we have a real lack of large-scale data in men and certainly no prospective data with oncotypes,” he said in an interview.
To get a better idea of the molecular characteristics of breast cancer in men and how they relate to breast cancer–specific mortality, Dr. Massarweh and his associates looked at deidentified 21-gene assay data from the Genomic Health Laboratory database on 3,806 men and 571,115 women with breast cancer with either no nodal involvement, micrometastases only, or one to three involved lymph nodes.
They also looked at survival data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) population of patients with breast cancer diagnosed during 2004-2012, which included data on 332 men and 55,842 women with ER-positive and/or PR-positive invasive breast cancer.
Among the entire 21-gene assay sample, they found that men were significantly older than women at the time of diagnosis, at a mean age of 64.2 vs. 59.1 years (P less than .001).
Both men and women had infiltrating ductal carcinoma as the most common histology; the prevalence was slightly higher among men at 87.6% versus 81.3% for women.
The average recurrence score in men was 16.8 versus 17.0 in women, a difference that was not statistically significant. A majority of both men and women had RS scores below 18 (65.8% and 58.2%, respectively), although significantly more men than women had RS scores of 31 or higher (12.4% vs. 7.4%; P less than .001).
“This relative predominance of high RS results in men was encountered across age groups but was most prominent in men younger than 40 years of age,” the investigators wrote.
At the other end of the scale, RS lower than 11, especially RS 0, were seen more frequently in men than in women, except among those younger than 40 years.
Looking at individual gene expression profiles, the authors found that mean gene expression was higher in men for genes associated with ER, proliferation, and invasion. ER expression was lowest and PR expression was highest in women younger than 50 years, but ER expression increased progressively with age.
Among men, those younger than 50 years had slightly lower ER and PR expression than did older men.
In the analysis of SEER survival data, they found that 5-year breast cancer severity score (BCSS) was 99% for men with RS below 18, 95.7% for those with RS between18 and 30, and 81% for those with RS of 31 or higher. Among women, 5-year BCSS was 99.5% for those with RS under 18, 98.6% for those with RS between 18 and 30, and 94.9% for those with RS of 31 or higher.
Five-year overall survival estimates were 92.6% for men with RS below 18, 86% for those with RS between 18 and 30, and 69% for those with RS of 31 or higher. Respective 5-year OS rates for women were 95%, 94.2%, and 89.9%.
“The 21-gene RS provided clear prognostic information in our cohort, with a significantly different 5-year BCSS determined by RS in both men and women,” the investigators wrote.
They noted that patients with low and intermediate RS have excellent prognoses regardless of nodal status, which suggests that these patients have more indolent disease and better outcomes than do patients with higher RS.
The more frequent use of adjuvant chemotherapy in the RS 31 and higher group indicates that “the prognostic utility of RS results is evident despite adjuvant chemotherapy use,” they wrote.
Dr. Isakoff pointed out, however, that the population in the study is from a registry of patients eligible for the 21-gene assay, which can only be used for patients with ER-positive and HER2-negative tumors.
“In other words, this is not a random sample. This is a sample of patients for whom the treating physician was on the fence about chemotherapy and in some way thought that getting an oncotype might be helpful,” he said.
He added that although the study findings “don’t change anything we have been doing, they provide reassurance that oncotype is a reasonable test to consider in patients with male breast cancer for whom we’re considering including or avoiding chemotherapy,” he said.
A funding source for the study was not reported. Dr. Massarweh disclosed stock or ownership in Radius Health, consulting for Novartis, and institutional research funding from multiple companies. Three coauthors are employees and stockholders of Genomic Health, maker of the Oncotype DX assay used in the study. Dr. Isakoff reported no conflicts of interest related to the study
SOURCE: Massarweh SA et al. 2018 Mar 27. doi: 10.1200/JCO.2017.76.8861.
FROM THE JOURNAL OF CLINICAL ONCOLOGY
Key clinical point: A 21-gene assay provides useful information about survival odds for men and women with breast cancer.
Major finding: A recurrence score of 31 or greater was associated with worse survival, particularly in men.
Study details: Retrospective review of genomic and surveillance data on 3,806 men and 571,115 women with breast cancer.
Disclosures: A funding source for the study was not reported. Dr. Massarweh disclosed stock or ownership in Radius Health, consulting for Novartis, and institutional research funding from multiple companies. Three coauthors are employees and stockholders of Genomic Health, maker of the Oncotype DX assay used in the study. Dr. Isakoff reported no conflicts of interest related to the study.
Source: Massarweh SA et al. 2018 Mar 27. doi: 10.1200/JCO.2017.76.8861.
Are higher rifampin doses for pulmonary TB more effective?
BOSTON – Current daily doses of rifampin for treating pulmonary tuberculosis may be too low and could be safely increased, results of a randomized phase 2 study suggest.
“Back in the 1970s, rifampin was an expensive drug, and attempts to shorten TB therapy using higher but intermittent doses of rifampin were unsuccessful at that time because of increased toxicity. That line of inquiry was essentially dormant for 40 years,” said Gustavo Velásquez, MD, from Brigham & Women’s Hospital in Boston.
To get a better idea of optimal rifampin dosing for the treatment of pulmonary TB, Dr. Velásquez and his colleagues conducted the HIRIF (High-Dose Rifampin in Patients With TB) trial. The phase 2 study was designed to evaluate the pharmacokinetics, efficacy, and safety of higher daily rifampin doses for pulmonary TB.
They looked at the three parameters across three treatments arms: 10 mg/kg rifampin (the current standard of care), 15 mg/kg, or 20 mg/kg.
Patients in Peru were screened, enrolled, and randomized in cohorts of 60 patients each to one of the three specified dose levels, which they received either as additional rifampin tablets or placebo for the first 8 weeks of treatment, after which all patients were continued on rifampin 10 mg/kg to complete a 6-month regimen. All patients were followed for an additional 6 months to for assessment of TB recurrence.
Rifampin total doses ranged from as low as 300 mg for patients in the 30 kg-37 kg weight range, to as high as 1,500 mg for those weighing more than 70 kg.
The efficacy analysis was by modified intention to treat, excluding 6 patients who had insufficient log10 colony-forming units (CFUs) of TB, and a per-protocol analysis excluding an additional 42 patients whose doses of rifampin were affected by three study halts for adverse events. After each halt and review by the data-safety monitoring board, the trial was allowed to resume, but because enrollment and experimental dosing also were suspended, patients in the 15- and 20-mg/kg arms received 10 mg/kg during the 2-5 week halts. The number of patients in the 10-, 15-, and 20-mg/kg doses included in the per-protocol analysis were 56, 38, and 38, respectively,
Pharmacokinetic evidence from this study, previously published, showed that the median maximum drug concentration (Cmax) in serum in the experimental arms reached the lower end of the targeted range of 8 mcg/mL or greater, whereas the median in the standard-of-care arm was 6.2 mcg/mL. Only 33% of patients in the 10-mg/kg arm reached the minimum 8-mcg/mL level, Dr. Velásquez noted, vs. 72% and 81% of patients in the 15- and 20-mg/kg doses, respectively.
In the modified intention-to-treat population, for every 5-mg/kg increase in rifampin dose, there was a nonsignificant trend toward faster decline in TB CFUs in sputum. Similarly, for every 1-log increase in rifampin AUC/MIC, there was a trend, albeit nonsignificant, toward faster decline.
However, in patients in the per-protocol analysis, every 5-mg/kg dose increase and 1-log increase in rifampin AUC was associated with significantly faster declines in CFUs (P = .022 and .011, respectively).
An analysis of treatment outcomes at 12 months, a secondary endpoint, showed that there were five cases of treatment failure, including three in the control arm and one each in 15- and 20-mg/kg arms, and six cases of recurrence after cure, which occurred in three, one, and two patients, respectively,
The safety analysis by intention-to-treat showed that the incidence of grade 2 or greater rifampin-related adverse events (AEs) were 43.3%, 51.7%, and 38.3% in the 10-, 15-, and 20-mg/kg doses, differences that were not statistically significant.
In addition, there were no significant differences among the treatment arms in either time to first grade 2 or greater rifampin-related AEs, the occurrence of one or more grade 2 or greater hepatic rifampin-AEs, or time to first hepatic rifampin-related AEs of grade 2 or above.
Dr. Velásquez noted that the study was limited by the possibility that the study halts could have biased efficacy effect estimates toward null and by differences in weight distribution among the three treatment arms.
“This actually is the first trial that shows not only a dose response of rifampin but also an exposure response of rifampin in combination therapy,” he said. “Our study supports that even higher doses of rifampin beyond what we studied of 20 mg/kg should be studied for potential treatment shortening.” The evidence also suggests that the current 10-mg/kg dose is low and could be safely increased to a 15- or 20-mg/kg dose, he concluded.
In a media briefing following the presentation, moderator Constance Benson, MD, from the University of California San Diego, who was not involved in the study, commented that with “high-dose rifampin, I think we have a really very robust body of literature to which this study can be added, demonstrating the safety of high-dose rifampin in the context of TB treatment.”
“There are some circumstances where I think using a much higher dose than we’ve been using would be an appropriate thing to do,” she added.
Examples of patients who might benefit include patients with disseminated TB or people with more serious TB than the average case, she said.
The study was supported by the National Institute of Allergy and Infectious Diseases. Dr. Velásquez and Dr. Benson reported no relevant conflicts of interest.
SOURCE: Velásquez GE et al. CROI 2018, Abstract 39LB.
BOSTON – Current daily doses of rifampin for treating pulmonary tuberculosis may be too low and could be safely increased, results of a randomized phase 2 study suggest.
“Back in the 1970s, rifampin was an expensive drug, and attempts to shorten TB therapy using higher but intermittent doses of rifampin were unsuccessful at that time because of increased toxicity. That line of inquiry was essentially dormant for 40 years,” said Gustavo Velásquez, MD, from Brigham & Women’s Hospital in Boston.
To get a better idea of optimal rifampin dosing for the treatment of pulmonary TB, Dr. Velásquez and his colleagues conducted the HIRIF (High-Dose Rifampin in Patients With TB) trial. The phase 2 study was designed to evaluate the pharmacokinetics, efficacy, and safety of higher daily rifampin doses for pulmonary TB.
They looked at the three parameters across three treatments arms: 10 mg/kg rifampin (the current standard of care), 15 mg/kg, or 20 mg/kg.
Patients in Peru were screened, enrolled, and randomized in cohorts of 60 patients each to one of the three specified dose levels, which they received either as additional rifampin tablets or placebo for the first 8 weeks of treatment, after which all patients were continued on rifampin 10 mg/kg to complete a 6-month regimen. All patients were followed for an additional 6 months to for assessment of TB recurrence.
Rifampin total doses ranged from as low as 300 mg for patients in the 30 kg-37 kg weight range, to as high as 1,500 mg for those weighing more than 70 kg.
The efficacy analysis was by modified intention to treat, excluding 6 patients who had insufficient log10 colony-forming units (CFUs) of TB, and a per-protocol analysis excluding an additional 42 patients whose doses of rifampin were affected by three study halts for adverse events. After each halt and review by the data-safety monitoring board, the trial was allowed to resume, but because enrollment and experimental dosing also were suspended, patients in the 15- and 20-mg/kg arms received 10 mg/kg during the 2-5 week halts. The number of patients in the 10-, 15-, and 20-mg/kg doses included in the per-protocol analysis were 56, 38, and 38, respectively,
Pharmacokinetic evidence from this study, previously published, showed that the median maximum drug concentration (Cmax) in serum in the experimental arms reached the lower end of the targeted range of 8 mcg/mL or greater, whereas the median in the standard-of-care arm was 6.2 mcg/mL. Only 33% of patients in the 10-mg/kg arm reached the minimum 8-mcg/mL level, Dr. Velásquez noted, vs. 72% and 81% of patients in the 15- and 20-mg/kg doses, respectively.
In the modified intention-to-treat population, for every 5-mg/kg increase in rifampin dose, there was a nonsignificant trend toward faster decline in TB CFUs in sputum. Similarly, for every 1-log increase in rifampin AUC/MIC, there was a trend, albeit nonsignificant, toward faster decline.
However, in patients in the per-protocol analysis, every 5-mg/kg dose increase and 1-log increase in rifampin AUC was associated with significantly faster declines in CFUs (P = .022 and .011, respectively).
An analysis of treatment outcomes at 12 months, a secondary endpoint, showed that there were five cases of treatment failure, including three in the control arm and one each in 15- and 20-mg/kg arms, and six cases of recurrence after cure, which occurred in three, one, and two patients, respectively,
The safety analysis by intention-to-treat showed that the incidence of grade 2 or greater rifampin-related adverse events (AEs) were 43.3%, 51.7%, and 38.3% in the 10-, 15-, and 20-mg/kg doses, differences that were not statistically significant.
In addition, there were no significant differences among the treatment arms in either time to first grade 2 or greater rifampin-related AEs, the occurrence of one or more grade 2 or greater hepatic rifampin-AEs, or time to first hepatic rifampin-related AEs of grade 2 or above.
Dr. Velásquez noted that the study was limited by the possibility that the study halts could have biased efficacy effect estimates toward null and by differences in weight distribution among the three treatment arms.
“This actually is the first trial that shows not only a dose response of rifampin but also an exposure response of rifampin in combination therapy,” he said. “Our study supports that even higher doses of rifampin beyond what we studied of 20 mg/kg should be studied for potential treatment shortening.” The evidence also suggests that the current 10-mg/kg dose is low and could be safely increased to a 15- or 20-mg/kg dose, he concluded.
In a media briefing following the presentation, moderator Constance Benson, MD, from the University of California San Diego, who was not involved in the study, commented that with “high-dose rifampin, I think we have a really very robust body of literature to which this study can be added, demonstrating the safety of high-dose rifampin in the context of TB treatment.”
“There are some circumstances where I think using a much higher dose than we’ve been using would be an appropriate thing to do,” she added.
Examples of patients who might benefit include patients with disseminated TB or people with more serious TB than the average case, she said.
The study was supported by the National Institute of Allergy and Infectious Diseases. Dr. Velásquez and Dr. Benson reported no relevant conflicts of interest.
SOURCE: Velásquez GE et al. CROI 2018, Abstract 39LB.
BOSTON – Current daily doses of rifampin for treating pulmonary tuberculosis may be too low and could be safely increased, results of a randomized phase 2 study suggest.
“Back in the 1970s, rifampin was an expensive drug, and attempts to shorten TB therapy using higher but intermittent doses of rifampin were unsuccessful at that time because of increased toxicity. That line of inquiry was essentially dormant for 40 years,” said Gustavo Velásquez, MD, from Brigham & Women’s Hospital in Boston.
To get a better idea of optimal rifampin dosing for the treatment of pulmonary TB, Dr. Velásquez and his colleagues conducted the HIRIF (High-Dose Rifampin in Patients With TB) trial. The phase 2 study was designed to evaluate the pharmacokinetics, efficacy, and safety of higher daily rifampin doses for pulmonary TB.
They looked at the three parameters across three treatments arms: 10 mg/kg rifampin (the current standard of care), 15 mg/kg, or 20 mg/kg.
Patients in Peru were screened, enrolled, and randomized in cohorts of 60 patients each to one of the three specified dose levels, which they received either as additional rifampin tablets or placebo for the first 8 weeks of treatment, after which all patients were continued on rifampin 10 mg/kg to complete a 6-month regimen. All patients were followed for an additional 6 months to for assessment of TB recurrence.
Rifampin total doses ranged from as low as 300 mg for patients in the 30 kg-37 kg weight range, to as high as 1,500 mg for those weighing more than 70 kg.
The efficacy analysis was by modified intention to treat, excluding 6 patients who had insufficient log10 colony-forming units (CFUs) of TB, and a per-protocol analysis excluding an additional 42 patients whose doses of rifampin were affected by three study halts for adverse events. After each halt and review by the data-safety monitoring board, the trial was allowed to resume, but because enrollment and experimental dosing also were suspended, patients in the 15- and 20-mg/kg arms received 10 mg/kg during the 2-5 week halts. The number of patients in the 10-, 15-, and 20-mg/kg doses included in the per-protocol analysis were 56, 38, and 38, respectively,
Pharmacokinetic evidence from this study, previously published, showed that the median maximum drug concentration (Cmax) in serum in the experimental arms reached the lower end of the targeted range of 8 mcg/mL or greater, whereas the median in the standard-of-care arm was 6.2 mcg/mL. Only 33% of patients in the 10-mg/kg arm reached the minimum 8-mcg/mL level, Dr. Velásquez noted, vs. 72% and 81% of patients in the 15- and 20-mg/kg doses, respectively.
In the modified intention-to-treat population, for every 5-mg/kg increase in rifampin dose, there was a nonsignificant trend toward faster decline in TB CFUs in sputum. Similarly, for every 1-log increase in rifampin AUC/MIC, there was a trend, albeit nonsignificant, toward faster decline.
However, in patients in the per-protocol analysis, every 5-mg/kg dose increase and 1-log increase in rifampin AUC was associated with significantly faster declines in CFUs (P = .022 and .011, respectively).
An analysis of treatment outcomes at 12 months, a secondary endpoint, showed that there were five cases of treatment failure, including three in the control arm and one each in 15- and 20-mg/kg arms, and six cases of recurrence after cure, which occurred in three, one, and two patients, respectively,
The safety analysis by intention-to-treat showed that the incidence of grade 2 or greater rifampin-related adverse events (AEs) were 43.3%, 51.7%, and 38.3% in the 10-, 15-, and 20-mg/kg doses, differences that were not statistically significant.
In addition, there were no significant differences among the treatment arms in either time to first grade 2 or greater rifampin-related AEs, the occurrence of one or more grade 2 or greater hepatic rifampin-AEs, or time to first hepatic rifampin-related AEs of grade 2 or above.
Dr. Velásquez noted that the study was limited by the possibility that the study halts could have biased efficacy effect estimates toward null and by differences in weight distribution among the three treatment arms.
“This actually is the first trial that shows not only a dose response of rifampin but also an exposure response of rifampin in combination therapy,” he said. “Our study supports that even higher doses of rifampin beyond what we studied of 20 mg/kg should be studied for potential treatment shortening.” The evidence also suggests that the current 10-mg/kg dose is low and could be safely increased to a 15- or 20-mg/kg dose, he concluded.
In a media briefing following the presentation, moderator Constance Benson, MD, from the University of California San Diego, who was not involved in the study, commented that with “high-dose rifampin, I think we have a really very robust body of literature to which this study can be added, demonstrating the safety of high-dose rifampin in the context of TB treatment.”
“There are some circumstances where I think using a much higher dose than we’ve been using would be an appropriate thing to do,” she added.
Examples of patients who might benefit include patients with disseminated TB or people with more serious TB than the average case, she said.
The study was supported by the National Institute of Allergy and Infectious Diseases. Dr. Velásquez and Dr. Benson reported no relevant conflicts of interest.
SOURCE: Velásquez GE et al. CROI 2018, Abstract 39LB.
REPORTING FROM CROI 2018
Key clinical point: Higher rifampin doses than customarily used offer better control of TB with safety, investigators say.
Major finding: In a per-protocol analysis, reduction in TB colony-forming units was significantly faster with 15- or 20-mg/kg rifampin dose vs. the standard 10-mg/kg dose.
Data source: Randomized, controlled trial in 180 Peruvian patients with pulmonary tuberculosis.
Disclosures: The study was supported by the National Institute of Allergy and Infectious Diseases. Dr. Velásquez and Dr. Benson reported no relevant conflicts of interest.
Source: Velásquez GE et al. CROI 2018, Abstract 39LB.
Time to HIV rebound in infants off ART linked to birth health
BOSTON – For infants with HIV infection, baseline immune function and birth health appear to influence viral control after the discontinuation of antiretroviral therapy (ART), an analysis of data from the landmark CHER trial shows.
Among 183 children diagnosed with HIV between 6 and 12 weeks of age who were started on early, time-limited ART, longer time to viral rebound after treatment discontinuation was associated with higher baseline CD4 percentages, higher birth weight, and with achievement of viral suppression within 40 weeks of starting on ART, reported Man Chan, PhD, of the Medical Research Council clinical trials unit at University College London.
The CHER trial compared South African infants with HIV on either 40 or 96 weeks of immediate ART with those on deferred ART. The results showed that early time-limited ART was associated with better clinical and immunologic outcomes than was deferred ART and influenced a change in treatment guidelines (Lancet 2013 Nov 9;382[9904]:1555-63).
In the current analysis, investigators examined viral control after treatment interruption in early-treated children and looked for factors that could influence time to viral rebound after ART cessation.
They measured viral load from stored samples at 1.8 weeks after ART interruption and then every 12 weeks thereafter. They defined viral rebound as two consecutive samples with 400 or more copies/mL.
Of the 183 children in the sample, 177 had a rebound; the remaining six children were censored from the analysis, five because they had restarted ART, and one child who remained in viral suppression with an undetectable viral load and was asymptomatic for 8.5 years off ART.
The estimated cumulative probability of rebound was 70% at 2 months following ART interruption, 80% at 4 months, 94% at 6 months, and 99% at 8 months.
In multivariable analysis, factors significantly associated with longer time to viral rebound included higher baseline CD4 counts (P = .03), higher birth weight (P = .032), and viral suppression within 40 weeks of starting on ART (P = .028)
In contrast, there were no significant associations with other factors in the multivariate model, including sex, baseline viral load, baseline CD8 percentage, HIV stage, status of therapy to prevent mother-to-child transmission, age at ART initiation, length of therapy, or treatment center.
Sensitivity analyses of a few cases in which there was a 4-7 month gap between rebound and the last viral load below 400 copies/mL before rebound showed similar results, Dr. Chan noted.
The study was the U.S. National Institutes of Health. Dr. Chan reported having nothing to disclose.
SOURCE: Violari A et al. CROI 2018, Abstract 137
BOSTON – For infants with HIV infection, baseline immune function and birth health appear to influence viral control after the discontinuation of antiretroviral therapy (ART), an analysis of data from the landmark CHER trial shows.
Among 183 children diagnosed with HIV between 6 and 12 weeks of age who were started on early, time-limited ART, longer time to viral rebound after treatment discontinuation was associated with higher baseline CD4 percentages, higher birth weight, and with achievement of viral suppression within 40 weeks of starting on ART, reported Man Chan, PhD, of the Medical Research Council clinical trials unit at University College London.
The CHER trial compared South African infants with HIV on either 40 or 96 weeks of immediate ART with those on deferred ART. The results showed that early time-limited ART was associated with better clinical and immunologic outcomes than was deferred ART and influenced a change in treatment guidelines (Lancet 2013 Nov 9;382[9904]:1555-63).
In the current analysis, investigators examined viral control after treatment interruption in early-treated children and looked for factors that could influence time to viral rebound after ART cessation.
They measured viral load from stored samples at 1.8 weeks after ART interruption and then every 12 weeks thereafter. They defined viral rebound as two consecutive samples with 400 or more copies/mL.
Of the 183 children in the sample, 177 had a rebound; the remaining six children were censored from the analysis, five because they had restarted ART, and one child who remained in viral suppression with an undetectable viral load and was asymptomatic for 8.5 years off ART.
The estimated cumulative probability of rebound was 70% at 2 months following ART interruption, 80% at 4 months, 94% at 6 months, and 99% at 8 months.
In multivariable analysis, factors significantly associated with longer time to viral rebound included higher baseline CD4 counts (P = .03), higher birth weight (P = .032), and viral suppression within 40 weeks of starting on ART (P = .028)
In contrast, there were no significant associations with other factors in the multivariate model, including sex, baseline viral load, baseline CD8 percentage, HIV stage, status of therapy to prevent mother-to-child transmission, age at ART initiation, length of therapy, or treatment center.
Sensitivity analyses of a few cases in which there was a 4-7 month gap between rebound and the last viral load below 400 copies/mL before rebound showed similar results, Dr. Chan noted.
The study was the U.S. National Institutes of Health. Dr. Chan reported having nothing to disclose.
SOURCE: Violari A et al. CROI 2018, Abstract 137
BOSTON – For infants with HIV infection, baseline immune function and birth health appear to influence viral control after the discontinuation of antiretroviral therapy (ART), an analysis of data from the landmark CHER trial shows.
Among 183 children diagnosed with HIV between 6 and 12 weeks of age who were started on early, time-limited ART, longer time to viral rebound after treatment discontinuation was associated with higher baseline CD4 percentages, higher birth weight, and with achievement of viral suppression within 40 weeks of starting on ART, reported Man Chan, PhD, of the Medical Research Council clinical trials unit at University College London.
The CHER trial compared South African infants with HIV on either 40 or 96 weeks of immediate ART with those on deferred ART. The results showed that early time-limited ART was associated with better clinical and immunologic outcomes than was deferred ART and influenced a change in treatment guidelines (Lancet 2013 Nov 9;382[9904]:1555-63).
In the current analysis, investigators examined viral control after treatment interruption in early-treated children and looked for factors that could influence time to viral rebound after ART cessation.
They measured viral load from stored samples at 1.8 weeks after ART interruption and then every 12 weeks thereafter. They defined viral rebound as two consecutive samples with 400 or more copies/mL.
Of the 183 children in the sample, 177 had a rebound; the remaining six children were censored from the analysis, five because they had restarted ART, and one child who remained in viral suppression with an undetectable viral load and was asymptomatic for 8.5 years off ART.
The estimated cumulative probability of rebound was 70% at 2 months following ART interruption, 80% at 4 months, 94% at 6 months, and 99% at 8 months.
In multivariable analysis, factors significantly associated with longer time to viral rebound included higher baseline CD4 counts (P = .03), higher birth weight (P = .032), and viral suppression within 40 weeks of starting on ART (P = .028)
In contrast, there were no significant associations with other factors in the multivariate model, including sex, baseline viral load, baseline CD8 percentage, HIV stage, status of therapy to prevent mother-to-child transmission, age at ART initiation, length of therapy, or treatment center.
Sensitivity analyses of a few cases in which there was a 4-7 month gap between rebound and the last viral load below 400 copies/mL before rebound showed similar results, Dr. Chan noted.
The study was the U.S. National Institutes of Health. Dr. Chan reported having nothing to disclose.
SOURCE: Violari A et al. CROI 2018, Abstract 137
FROM CROI 2018
Key clinical point: Early initiation of antiretroviral therapy in infants is associated with better outcomes.
Major finding: Longer time to viral rebound was associated with higher baseline CD4, higher birth weight, and viral suppression within 40 weeks of starting ART.
Study details: Analysis of outcomes in 183 infants with HIV infection in the CHER trial.
Disclosures: The study was funded by the U.S. National Institutes of Health. Dr. Chan reported having nothing to disclose.
Source: Violari A et al. CROI 2018, Abstract 137.
Sessile serrated colon polyps may be detectable noninvasively
Sessile serrated polyps (SSPs), notorious for being difficult to detect and for their potential to become malignant colorectal tumors, appear to be caused by a single oncogenic mutation, a finding that could lead to better early detection of some colorectal cancers through noninvasive stool testing, investigators say.
Using a comprehensive battery of genomic testing and DNA methylation profiling, David Jones, PhD, of the Oklahoma Medical Research Foundation in Oklahoma City and his colleagues compared SSPs with familial adenomatous polyps (FAPs), and found that the V600E mutation in BRAF (V-Raf Murine Sarcoma Viral Oncogene Homolog B) was the sole cancer-causing mutation in SSPs.
They also found a distinct DNA methylation pattern unique to SSPs.
“These SSP-specific methylation patterns effectively distinguish SSP from adenomatous polyps, which could be important for both diagnosis and treatment. It also suggests that the BRAF-V600E mutation directly or indirectly results in the remodeling of the epigenome and that this may set a stage for tumor progression,” they wrote in the open-access journal PLOS One.
Approximately one-third of sporadic colorectal cancers, which account for about 95% of all colorectal malignancies, are thought to arise from premalignant serrated lesions, including SSPs, hyperplastic polyps, and traditional serrated adenomas, the authors noted.
Although SSPs and traditional serrated adenomas both have significant potential for malignant transformation, SSPs are much more common, making them important targets for research, diagnosis, and possible interventions.
“Previous surveys of cancer-associated mutations in SSP samples, through targeted analysis of limited known mutations, identified the BRAF-V600E as the key mutation in this disease. However, it is not clear whether other mutations in the same samples contribute to the etiology of this disease,” Dr. Jones and his associates wrote.
To better understand both the inherited (genetic) and acquired (epigenetic) basis for SSP and tumor development, the investigators used whole-exome sequencing, genome-wide mutation detection, and DNA methylation profiling on multiple samples of both SSPs and FAPs.
They performed exome sequencing on DNA extracted from SSP samples from six patients diagnosed with typical SSP-type colon polyps via colonoscopy and pathology. The samples included one each from five patients and three taken from different portions of the colon in one patient. In all of the samples, BRAF-V600E was the only common somatic mutation detected. In the patient from whom the three SSP samples were taken, the mutation was found in each polyp, but not in grossly uninvolved colon from the same patient.
The investigators next performed genome-wide DNA methylation profiling on 15 colon biopsy samples from 11 patients, including five SSPs, two traditional serrated adenomas, three FAPs, two carcinomas, one grossly uninvolved tissue sample, and two normal tissue samples. They found that the BRAF-V600E mutation correlated with a unique and reproducible DNA methylation signature.
They then determined that the DNA methylation signature that they identified is associated with specific markers for molecular characterization of SSPs, and that these markers showed an approximately 3- to 30-fold increase in methylation levels in only SSP samples.
Furthermore, they showed that the unique DNA methylation patterns they identified could be used to distinguish SPPs from adenomatous polyps, with better discrimination than parallel-gene expression profiling.
“The results presented here provide strong evidence that the BRAF-V600E mutation is the main cause of generation of SSP and SSP-specific DNA methylation pattern,” the investigators wrote in the study’s conclusion.
The study was supported by grants from the National Institutes of Health and the Howard Hughes Medical Institute. The authors declared no competing financial interests in the work.
SOURCE: Dehghanizadeh S et al. PLOS One 13(3): e0192499.
Sessile serrated polyps (SSPs), notorious for being difficult to detect and for their potential to become malignant colorectal tumors, appear to be caused by a single oncogenic mutation, a finding that could lead to better early detection of some colorectal cancers through noninvasive stool testing, investigators say.
Using a comprehensive battery of genomic testing and DNA methylation profiling, David Jones, PhD, of the Oklahoma Medical Research Foundation in Oklahoma City and his colleagues compared SSPs with familial adenomatous polyps (FAPs), and found that the V600E mutation in BRAF (V-Raf Murine Sarcoma Viral Oncogene Homolog B) was the sole cancer-causing mutation in SSPs.
They also found a distinct DNA methylation pattern unique to SSPs.
“These SSP-specific methylation patterns effectively distinguish SSP from adenomatous polyps, which could be important for both diagnosis and treatment. It also suggests that the BRAF-V600E mutation directly or indirectly results in the remodeling of the epigenome and that this may set a stage for tumor progression,” they wrote in the open-access journal PLOS One.
Approximately one-third of sporadic colorectal cancers, which account for about 95% of all colorectal malignancies, are thought to arise from premalignant serrated lesions, including SSPs, hyperplastic polyps, and traditional serrated adenomas, the authors noted.
Although SSPs and traditional serrated adenomas both have significant potential for malignant transformation, SSPs are much more common, making them important targets for research, diagnosis, and possible interventions.
“Previous surveys of cancer-associated mutations in SSP samples, through targeted analysis of limited known mutations, identified the BRAF-V600E as the key mutation in this disease. However, it is not clear whether other mutations in the same samples contribute to the etiology of this disease,” Dr. Jones and his associates wrote.
To better understand both the inherited (genetic) and acquired (epigenetic) basis for SSP and tumor development, the investigators used whole-exome sequencing, genome-wide mutation detection, and DNA methylation profiling on multiple samples of both SSPs and FAPs.
They performed exome sequencing on DNA extracted from SSP samples from six patients diagnosed with typical SSP-type colon polyps via colonoscopy and pathology. The samples included one each from five patients and three taken from different portions of the colon in one patient. In all of the samples, BRAF-V600E was the only common somatic mutation detected. In the patient from whom the three SSP samples were taken, the mutation was found in each polyp, but not in grossly uninvolved colon from the same patient.
The investigators next performed genome-wide DNA methylation profiling on 15 colon biopsy samples from 11 patients, including five SSPs, two traditional serrated adenomas, three FAPs, two carcinomas, one grossly uninvolved tissue sample, and two normal tissue samples. They found that the BRAF-V600E mutation correlated with a unique and reproducible DNA methylation signature.
They then determined that the DNA methylation signature that they identified is associated with specific markers for molecular characterization of SSPs, and that these markers showed an approximately 3- to 30-fold increase in methylation levels in only SSP samples.
Furthermore, they showed that the unique DNA methylation patterns they identified could be used to distinguish SPPs from adenomatous polyps, with better discrimination than parallel-gene expression profiling.
“The results presented here provide strong evidence that the BRAF-V600E mutation is the main cause of generation of SSP and SSP-specific DNA methylation pattern,” the investigators wrote in the study’s conclusion.
The study was supported by grants from the National Institutes of Health and the Howard Hughes Medical Institute. The authors declared no competing financial interests in the work.
SOURCE: Dehghanizadeh S et al. PLOS One 13(3): e0192499.
Sessile serrated polyps (SSPs), notorious for being difficult to detect and for their potential to become malignant colorectal tumors, appear to be caused by a single oncogenic mutation, a finding that could lead to better early detection of some colorectal cancers through noninvasive stool testing, investigators say.
Using a comprehensive battery of genomic testing and DNA methylation profiling, David Jones, PhD, of the Oklahoma Medical Research Foundation in Oklahoma City and his colleagues compared SSPs with familial adenomatous polyps (FAPs), and found that the V600E mutation in BRAF (V-Raf Murine Sarcoma Viral Oncogene Homolog B) was the sole cancer-causing mutation in SSPs.
They also found a distinct DNA methylation pattern unique to SSPs.
“These SSP-specific methylation patterns effectively distinguish SSP from adenomatous polyps, which could be important for both diagnosis and treatment. It also suggests that the BRAF-V600E mutation directly or indirectly results in the remodeling of the epigenome and that this may set a stage for tumor progression,” they wrote in the open-access journal PLOS One.
Approximately one-third of sporadic colorectal cancers, which account for about 95% of all colorectal malignancies, are thought to arise from premalignant serrated lesions, including SSPs, hyperplastic polyps, and traditional serrated adenomas, the authors noted.
Although SSPs and traditional serrated adenomas both have significant potential for malignant transformation, SSPs are much more common, making them important targets for research, diagnosis, and possible interventions.
“Previous surveys of cancer-associated mutations in SSP samples, through targeted analysis of limited known mutations, identified the BRAF-V600E as the key mutation in this disease. However, it is not clear whether other mutations in the same samples contribute to the etiology of this disease,” Dr. Jones and his associates wrote.
To better understand both the inherited (genetic) and acquired (epigenetic) basis for SSP and tumor development, the investigators used whole-exome sequencing, genome-wide mutation detection, and DNA methylation profiling on multiple samples of both SSPs and FAPs.
They performed exome sequencing on DNA extracted from SSP samples from six patients diagnosed with typical SSP-type colon polyps via colonoscopy and pathology. The samples included one each from five patients and three taken from different portions of the colon in one patient. In all of the samples, BRAF-V600E was the only common somatic mutation detected. In the patient from whom the three SSP samples were taken, the mutation was found in each polyp, but not in grossly uninvolved colon from the same patient.
The investigators next performed genome-wide DNA methylation profiling on 15 colon biopsy samples from 11 patients, including five SSPs, two traditional serrated adenomas, three FAPs, two carcinomas, one grossly uninvolved tissue sample, and two normal tissue samples. They found that the BRAF-V600E mutation correlated with a unique and reproducible DNA methylation signature.
They then determined that the DNA methylation signature that they identified is associated with specific markers for molecular characterization of SSPs, and that these markers showed an approximately 3- to 30-fold increase in methylation levels in only SSP samples.
Furthermore, they showed that the unique DNA methylation patterns they identified could be used to distinguish SPPs from adenomatous polyps, with better discrimination than parallel-gene expression profiling.
“The results presented here provide strong evidence that the BRAF-V600E mutation is the main cause of generation of SSP and SSP-specific DNA methylation pattern,” the investigators wrote in the study’s conclusion.
The study was supported by grants from the National Institutes of Health and the Howard Hughes Medical Institute. The authors declared no competing financial interests in the work.
SOURCE: Dehghanizadeh S et al. PLOS One 13(3): e0192499.
PLOS ONE
Key clinical point: Sessile serrated polyps appear to arise from a single oncogenic mutation that can be detected noninvasively.
Major finding: A distinct DNA methylation signature can distinguish SSPs from adenomatous polyps.
Study details: Genomic and DNA methylation studies of biopsy samples from patients with SSPs and others with familial adenomatous polyps.
Disclosures: The study was supported by grants from the National Institutes of Health and the Howard Hughes Medical Institute. The authors declared no competing financial interests in the work.
Source: Dehghanizadeh S et al. PLOS One 13(3):e0192499.
Survival worse with alcohol-related HCC, compared with other types
Hepatocellular carcinoma (HCC) related to alcohol use tends to be diagnosed at a later stage than HCC from other causes, which contributes to reduced overall survival among patients with alcoholic HCC, investigators in a prospective French study said.
Among 894 patients diagnosed with HCC, the adjusted median overall survival was 5.7 months for those with alcoholic HCC, compared with 9.7 months for those with nonalcoholic HCC (P = .0002), reported Charlotte E. Costentin, MD, of the Hopital Henri Mondor in Creteil, France, and colleagues.
“Various assumptions can be made to explain why patients with alcohol-related HCC have reduced survival in comparison with patients with non–alcohol-related HCC: a diagnosis at a later stage due to lower rates of HCC screening, worse liver function and/or ongoing alcohol consumption preventing curative options, and discrimination against alcoholic patients leading to less aggressive treatment options,” they wrote in a study published online in Cancer.
The investigators looked at data on clinical features and treatment allocation of patients in the CHANGH cohort (cohorte de Carcinomes Hepatocelulaires de l’Association des hepato-Gastroenterologues des Hopitaux Generaux), a prospective, observational cohort study.
Of 1,207 patients with complete data, 582 had isolated alcohol-related HCC, and 312 had non–alcohol-related HCC, which was caused by either nonalcoholic fatty liver, hepatitis C infections, hepatitis B infections, hemochromatosis, or other etiologies.
As noted before, the median overall survival adjusted for lead-time bias (the length of time between the detection of a disease and its usual diagnosis) was significantly shorter for patients with alcohol-related HCC.
In univariate analysis, alcohol-related HCC, compared with non–alcohol-related HCC, was an independent risk factor for worse overall survival (hazard ratio, 1.39; P = .0002).
Among patients in the alcohol-related HCC group, median overall survival adjusted for lead-time was 5.8 months for patients who had been abstinent for a median of 1 year, compared with 5.0 months for the nonabstinent patients, a difference that was not statistically significant.
In multivariate analysis, factors significantly associated with worse overall survival included advanced HCC at diagnosis (diffuse or metastatic HCC and/or macrovascular invasion), alkaline phosphatase score, alpha-fetoprotein levels, creatinine, performance status, Child-Pugh score, age plus alcohol-related disease, and male sex plus alcohol-related disease. However, alcohol-related versus non–alcohol-related HCC was no longer statistically significant in multivariate analysis.
They noted that for 199 patients who were diagnosed with HCC as part of a cirrhosis follow-up program, the median overall survival adjusted for lead-time was 11.7 months, compared with 5.4 months for patients whose HCC was detected incidentally (P less than .0001).
The investigators noted that other studies have shown that screening rates for HCC are lower in alcohol abusers and that the most common reason for a lack of screening was failure of clinician to order surveillance in patients with known cirrhosis. In addition, alcoholic patients are less likely to be compliant with screening.
“Importantly, Bucci et al (Aliment Pharmacol Ther. 2016 Feb;43[3]:385-99) observed similar survival between alcoholic patients and patients with hepatitis C virus among patients undergoing HCC surveillance according to guidelines. The poorer prognosis of alcohol-related HCC is, therefore, very likely to be related to an advanced stage at diagnosis due to screening failure instead of greater cancer aggressiveness,” they wrote.
“To improve prognosis of liver cancer in the alcoholic population, efforts should be made to implement effective screening programs for both cirrhosis and liver cancer and to improve access to alcoholism treatment services,” Dr. Costentin said in press release. “A smaller tumor burden and a better liver function at diagnosis should translate into higher rates of patients with alcohol-related liver cancer amenable to curative treatment such as tumor resection or ablation and liver transplantation.”
Dr. Costentin did not report conflicts of interest. Several of her coauthors reported personal fees from various companies outside the submitted work.
SOURCE: Costentin CE at al. Cancer. doi: 10.1002/cncr.31215.
Hepatocellular carcinoma (HCC) related to alcohol use tends to be diagnosed at a later stage than HCC from other causes, which contributes to reduced overall survival among patients with alcoholic HCC, investigators in a prospective French study said.
Among 894 patients diagnosed with HCC, the adjusted median overall survival was 5.7 months for those with alcoholic HCC, compared with 9.7 months for those with nonalcoholic HCC (P = .0002), reported Charlotte E. Costentin, MD, of the Hopital Henri Mondor in Creteil, France, and colleagues.
“Various assumptions can be made to explain why patients with alcohol-related HCC have reduced survival in comparison with patients with non–alcohol-related HCC: a diagnosis at a later stage due to lower rates of HCC screening, worse liver function and/or ongoing alcohol consumption preventing curative options, and discrimination against alcoholic patients leading to less aggressive treatment options,” they wrote in a study published online in Cancer.
The investigators looked at data on clinical features and treatment allocation of patients in the CHANGH cohort (cohorte de Carcinomes Hepatocelulaires de l’Association des hepato-Gastroenterologues des Hopitaux Generaux), a prospective, observational cohort study.
Of 1,207 patients with complete data, 582 had isolated alcohol-related HCC, and 312 had non–alcohol-related HCC, which was caused by either nonalcoholic fatty liver, hepatitis C infections, hepatitis B infections, hemochromatosis, or other etiologies.
As noted before, the median overall survival adjusted for lead-time bias (the length of time between the detection of a disease and its usual diagnosis) was significantly shorter for patients with alcohol-related HCC.
In univariate analysis, alcohol-related HCC, compared with non–alcohol-related HCC, was an independent risk factor for worse overall survival (hazard ratio, 1.39; P = .0002).
Among patients in the alcohol-related HCC group, median overall survival adjusted for lead-time was 5.8 months for patients who had been abstinent for a median of 1 year, compared with 5.0 months for the nonabstinent patients, a difference that was not statistically significant.
In multivariate analysis, factors significantly associated with worse overall survival included advanced HCC at diagnosis (diffuse or metastatic HCC and/or macrovascular invasion), alkaline phosphatase score, alpha-fetoprotein levels, creatinine, performance status, Child-Pugh score, age plus alcohol-related disease, and male sex plus alcohol-related disease. However, alcohol-related versus non–alcohol-related HCC was no longer statistically significant in multivariate analysis.
They noted that for 199 patients who were diagnosed with HCC as part of a cirrhosis follow-up program, the median overall survival adjusted for lead-time was 11.7 months, compared with 5.4 months for patients whose HCC was detected incidentally (P less than .0001).
The investigators noted that other studies have shown that screening rates for HCC are lower in alcohol abusers and that the most common reason for a lack of screening was failure of clinician to order surveillance in patients with known cirrhosis. In addition, alcoholic patients are less likely to be compliant with screening.
“Importantly, Bucci et al (Aliment Pharmacol Ther. 2016 Feb;43[3]:385-99) observed similar survival between alcoholic patients and patients with hepatitis C virus among patients undergoing HCC surveillance according to guidelines. The poorer prognosis of alcohol-related HCC is, therefore, very likely to be related to an advanced stage at diagnosis due to screening failure instead of greater cancer aggressiveness,” they wrote.
“To improve prognosis of liver cancer in the alcoholic population, efforts should be made to implement effective screening programs for both cirrhosis and liver cancer and to improve access to alcoholism treatment services,” Dr. Costentin said in press release. “A smaller tumor burden and a better liver function at diagnosis should translate into higher rates of patients with alcohol-related liver cancer amenable to curative treatment such as tumor resection or ablation and liver transplantation.”
Dr. Costentin did not report conflicts of interest. Several of her coauthors reported personal fees from various companies outside the submitted work.
SOURCE: Costentin CE at al. Cancer. doi: 10.1002/cncr.31215.
Hepatocellular carcinoma (HCC) related to alcohol use tends to be diagnosed at a later stage than HCC from other causes, which contributes to reduced overall survival among patients with alcoholic HCC, investigators in a prospective French study said.
Among 894 patients diagnosed with HCC, the adjusted median overall survival was 5.7 months for those with alcoholic HCC, compared with 9.7 months for those with nonalcoholic HCC (P = .0002), reported Charlotte E. Costentin, MD, of the Hopital Henri Mondor in Creteil, France, and colleagues.
“Various assumptions can be made to explain why patients with alcohol-related HCC have reduced survival in comparison with patients with non–alcohol-related HCC: a diagnosis at a later stage due to lower rates of HCC screening, worse liver function and/or ongoing alcohol consumption preventing curative options, and discrimination against alcoholic patients leading to less aggressive treatment options,” they wrote in a study published online in Cancer.
The investigators looked at data on clinical features and treatment allocation of patients in the CHANGH cohort (cohorte de Carcinomes Hepatocelulaires de l’Association des hepato-Gastroenterologues des Hopitaux Generaux), a prospective, observational cohort study.
Of 1,207 patients with complete data, 582 had isolated alcohol-related HCC, and 312 had non–alcohol-related HCC, which was caused by either nonalcoholic fatty liver, hepatitis C infections, hepatitis B infections, hemochromatosis, or other etiologies.
As noted before, the median overall survival adjusted for lead-time bias (the length of time between the detection of a disease and its usual diagnosis) was significantly shorter for patients with alcohol-related HCC.
In univariate analysis, alcohol-related HCC, compared with non–alcohol-related HCC, was an independent risk factor for worse overall survival (hazard ratio, 1.39; P = .0002).
Among patients in the alcohol-related HCC group, median overall survival adjusted for lead-time was 5.8 months for patients who had been abstinent for a median of 1 year, compared with 5.0 months for the nonabstinent patients, a difference that was not statistically significant.
In multivariate analysis, factors significantly associated with worse overall survival included advanced HCC at diagnosis (diffuse or metastatic HCC and/or macrovascular invasion), alkaline phosphatase score, alpha-fetoprotein levels, creatinine, performance status, Child-Pugh score, age plus alcohol-related disease, and male sex plus alcohol-related disease. However, alcohol-related versus non–alcohol-related HCC was no longer statistically significant in multivariate analysis.
They noted that for 199 patients who were diagnosed with HCC as part of a cirrhosis follow-up program, the median overall survival adjusted for lead-time was 11.7 months, compared with 5.4 months for patients whose HCC was detected incidentally (P less than .0001).
The investigators noted that other studies have shown that screening rates for HCC are lower in alcohol abusers and that the most common reason for a lack of screening was failure of clinician to order surveillance in patients with known cirrhosis. In addition, alcoholic patients are less likely to be compliant with screening.
“Importantly, Bucci et al (Aliment Pharmacol Ther. 2016 Feb;43[3]:385-99) observed similar survival between alcoholic patients and patients with hepatitis C virus among patients undergoing HCC surveillance according to guidelines. The poorer prognosis of alcohol-related HCC is, therefore, very likely to be related to an advanced stage at diagnosis due to screening failure instead of greater cancer aggressiveness,” they wrote.
“To improve prognosis of liver cancer in the alcoholic population, efforts should be made to implement effective screening programs for both cirrhosis and liver cancer and to improve access to alcoholism treatment services,” Dr. Costentin said in press release. “A smaller tumor burden and a better liver function at diagnosis should translate into higher rates of patients with alcohol-related liver cancer amenable to curative treatment such as tumor resection or ablation and liver transplantation.”
Dr. Costentin did not report conflicts of interest. Several of her coauthors reported personal fees from various companies outside the submitted work.
SOURCE: Costentin CE at al. Cancer. doi: 10.1002/cncr.31215.
FROM CANCER
Key clinical point: Patients with HCC from alcohol or other causes had better survival if they were under surveillance for cirrhosis.
Major finding: Adjusted median overall survival was 5.7 months with alcohol-related HCC versus 9.7 months for nonalcoholic HCC (P = .0002).
Study details: Analysis of data from a prospective observational cohort of 1,207 patients with HCC in France.
Disclosures: The study was supported by the Association Nationale des Hepato-Gastroenterologues des Hopitaux Généraux group and Roche Pharmaceuticals. Dr. Constentin did not report conflicts of interest. Several of her coauthors reported personal fees from various companies outside the submitted work.
Source: Costentin CE at al. Cancer. doi: 10.1002/cncr.31215.
Nivolumab helps some with advanced NSCLC reach 5-year mark
Some patients with previously treated advanced non-small cell lung cancer (NSCLC), a malignancy with a historically dim prognosis, survived at least 5 years after receiving the immune checkpoint inhibitor nivolumab (Opdivo) in an early phase 1 trial.
For 129 patients with NSCLC treated with nivolumab in the CA209-003 trial, the estimated 5 year overall survival (OS) was 16%. Twelve patients who did not receive any subsequent therapy following completion of nivolumab were alive with no evidence of disease at the 5-year follow-up mark, reported Scott Gettinger, MD, of the Yale Cancer Center in New Haven, Connecticut, and colleagues.
“Considering the historically low 5-year survival rate for patients with metastatic lung cancer, the estimated 5-year OS rate of 16% from the time of nivolumab treatment initiation observed in this cohort of heavily pretreated patients with advanced NSCLC constitutes a milestone in the advancement of lung cancer treatment,” they wrote in the Journal of Clinical Oncology. In the NSCLC cohort of the phase 1 dose-escalation and expansion study, 129 patients with heavily pretreated advanced NSCLC received nivolumab in doses of 1, 3, or 10 mg/kg intravenously once every 2 weeks in 8-week cycles for up to 96 weeks. The investigators previously reportedthat after a median follow-up of 39 weeks, the median overall survival across all three dose groups was 9.9 months. For 37 patients treated at the 3 mg/kg dose chosen for further development, the median 1-, 2-, and 3-year OS rates were 56%, 42%, and 27%, respectively.
In the current study, they followed the patients out to a minimum of 58.25 months. The median OS was 9.9 months, and the estimated 5-year OS rate, as noted before, was 16%. The 5-year OS rates for patients with squamous histology cancers was 16%, and the rate for patients with nonsquamous histology was 15%.
In all, 16 patients survived at least 5 years, with the longest follow-up out to 88.6 months. Two of the patients died before the database lock in November 2016, one from disease progression, and one from chronic obstructive pulmonary disease.
Among 10 long-term survivors who had quantifiable expression of the programmed death-1 ligand 1 (PD-L1), seven had at least 1% PD-L1 expression at baseline.
Of the 16 5-year survivors, 12 (75%) had a partial response to nivolumab according to RECIST (Response Evaluation Criteria in Solid Tumors), version 1. Two others had stable disease, and two had disease progression at the best response.
In all, nine of the 5-year survivors had completed the maximum 96 weeks of nivolumab, four had discontinued due to adverse events, and three had stopped because of disease progression.
“The findings from CA209-003 indicate some patients can derive long-term benefit from nivolumab treatment that is limited to 2 years; however, the question of optimal treatment duration remains to be formally addressed in a prospective controlled trial,” Dr. Gettinger and associates wrote.
The study was supported by Bristol-Myers Squibb and Ono Pharmaceuticals. Dr. Gettinger and multiple co-authors reported consulting/advisory roles and research funding with BMS and other relationships with multiple companies. Several co-authors are BMS employees.
SOURCE: : Getting S et al. J Clin Oncol. 2018 Mar 23 doi: 10.1200/JCO.2017.77.0412 .
Some patients with previously treated advanced non-small cell lung cancer (NSCLC), a malignancy with a historically dim prognosis, survived at least 5 years after receiving the immune checkpoint inhibitor nivolumab (Opdivo) in an early phase 1 trial.
For 129 patients with NSCLC treated with nivolumab in the CA209-003 trial, the estimated 5 year overall survival (OS) was 16%. Twelve patients who did not receive any subsequent therapy following completion of nivolumab were alive with no evidence of disease at the 5-year follow-up mark, reported Scott Gettinger, MD, of the Yale Cancer Center in New Haven, Connecticut, and colleagues.
“Considering the historically low 5-year survival rate for patients with metastatic lung cancer, the estimated 5-year OS rate of 16% from the time of nivolumab treatment initiation observed in this cohort of heavily pretreated patients with advanced NSCLC constitutes a milestone in the advancement of lung cancer treatment,” they wrote in the Journal of Clinical Oncology. In the NSCLC cohort of the phase 1 dose-escalation and expansion study, 129 patients with heavily pretreated advanced NSCLC received nivolumab in doses of 1, 3, or 10 mg/kg intravenously once every 2 weeks in 8-week cycles for up to 96 weeks. The investigators previously reportedthat after a median follow-up of 39 weeks, the median overall survival across all three dose groups was 9.9 months. For 37 patients treated at the 3 mg/kg dose chosen for further development, the median 1-, 2-, and 3-year OS rates were 56%, 42%, and 27%, respectively.
In the current study, they followed the patients out to a minimum of 58.25 months. The median OS was 9.9 months, and the estimated 5-year OS rate, as noted before, was 16%. The 5-year OS rates for patients with squamous histology cancers was 16%, and the rate for patients with nonsquamous histology was 15%.
In all, 16 patients survived at least 5 years, with the longest follow-up out to 88.6 months. Two of the patients died before the database lock in November 2016, one from disease progression, and one from chronic obstructive pulmonary disease.
Among 10 long-term survivors who had quantifiable expression of the programmed death-1 ligand 1 (PD-L1), seven had at least 1% PD-L1 expression at baseline.
Of the 16 5-year survivors, 12 (75%) had a partial response to nivolumab according to RECIST (Response Evaluation Criteria in Solid Tumors), version 1. Two others had stable disease, and two had disease progression at the best response.
In all, nine of the 5-year survivors had completed the maximum 96 weeks of nivolumab, four had discontinued due to adverse events, and three had stopped because of disease progression.
“The findings from CA209-003 indicate some patients can derive long-term benefit from nivolumab treatment that is limited to 2 years; however, the question of optimal treatment duration remains to be formally addressed in a prospective controlled trial,” Dr. Gettinger and associates wrote.
The study was supported by Bristol-Myers Squibb and Ono Pharmaceuticals. Dr. Gettinger and multiple co-authors reported consulting/advisory roles and research funding with BMS and other relationships with multiple companies. Several co-authors are BMS employees.
SOURCE: : Getting S et al. J Clin Oncol. 2018 Mar 23 doi: 10.1200/JCO.2017.77.0412 .
Some patients with previously treated advanced non-small cell lung cancer (NSCLC), a malignancy with a historically dim prognosis, survived at least 5 years after receiving the immune checkpoint inhibitor nivolumab (Opdivo) in an early phase 1 trial.
For 129 patients with NSCLC treated with nivolumab in the CA209-003 trial, the estimated 5 year overall survival (OS) was 16%. Twelve patients who did not receive any subsequent therapy following completion of nivolumab were alive with no evidence of disease at the 5-year follow-up mark, reported Scott Gettinger, MD, of the Yale Cancer Center in New Haven, Connecticut, and colleagues.
“Considering the historically low 5-year survival rate for patients with metastatic lung cancer, the estimated 5-year OS rate of 16% from the time of nivolumab treatment initiation observed in this cohort of heavily pretreated patients with advanced NSCLC constitutes a milestone in the advancement of lung cancer treatment,” they wrote in the Journal of Clinical Oncology. In the NSCLC cohort of the phase 1 dose-escalation and expansion study, 129 patients with heavily pretreated advanced NSCLC received nivolumab in doses of 1, 3, or 10 mg/kg intravenously once every 2 weeks in 8-week cycles for up to 96 weeks. The investigators previously reportedthat after a median follow-up of 39 weeks, the median overall survival across all three dose groups was 9.9 months. For 37 patients treated at the 3 mg/kg dose chosen for further development, the median 1-, 2-, and 3-year OS rates were 56%, 42%, and 27%, respectively.
In the current study, they followed the patients out to a minimum of 58.25 months. The median OS was 9.9 months, and the estimated 5-year OS rate, as noted before, was 16%. The 5-year OS rates for patients with squamous histology cancers was 16%, and the rate for patients with nonsquamous histology was 15%.
In all, 16 patients survived at least 5 years, with the longest follow-up out to 88.6 months. Two of the patients died before the database lock in November 2016, one from disease progression, and one from chronic obstructive pulmonary disease.
Among 10 long-term survivors who had quantifiable expression of the programmed death-1 ligand 1 (PD-L1), seven had at least 1% PD-L1 expression at baseline.
Of the 16 5-year survivors, 12 (75%) had a partial response to nivolumab according to RECIST (Response Evaluation Criteria in Solid Tumors), version 1. Two others had stable disease, and two had disease progression at the best response.
In all, nine of the 5-year survivors had completed the maximum 96 weeks of nivolumab, four had discontinued due to adverse events, and three had stopped because of disease progression.
“The findings from CA209-003 indicate some patients can derive long-term benefit from nivolumab treatment that is limited to 2 years; however, the question of optimal treatment duration remains to be formally addressed in a prospective controlled trial,” Dr. Gettinger and associates wrote.
The study was supported by Bristol-Myers Squibb and Ono Pharmaceuticals. Dr. Gettinger and multiple co-authors reported consulting/advisory roles and research funding with BMS and other relationships with multiple companies. Several co-authors are BMS employees.
SOURCE: : Getting S et al. J Clin Oncol. 2018 Mar 23 doi: 10.1200/JCO.2017.77.0412 .
FROM JOURNAL OF CLINICAL ONCOLOGY
Key clinical point: The programmed death-1 inhibitor nivolumab (Opdivo) is associated with long-term survival in a subset of patients with heavily pre-treated advanced non-small cell lung cancer (NSCLC).Major finding: The estimated 5-year overall survival rate was 16%.Study details: Follow-up study of 129 patients with NSCLC treated with nivolumab in a phase 1 study.
Disclosures: The study was supported by Bristol-Myers Squibb and Ono Pharmaceuticals. Dr. Gettinger and multiple co-authors reported consulting/advisory roles and research finding with BMS and other relationships with multiple companies. Several co-authors are BMS employees.
Source: Gettinger S et al. J Clin Oncol. 2018 Mar 23 doi: 10.1200/JCO.2017.77.0412.