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SAN FRANCISCO – , according to new data from the COMPASS trial reported at the 2019 GI Cancers Symposium.
“We now have two standard chemotherapy regimens that we use in the first-line setting, modified FOLFIRINOX (mFOLFIRINOX) and gemcitabine–nab-paclitaxel, but we lack any real biomarker strategies on which to choose for treatments, and many of our clinical trials in pancreas cancer have failed,” noted senior investigator Jennifer J. Knox, MD, FRCPC, codirector of the McCain Centre for Pancreatic Cancer, Princess Margaret Cancer Centre, Toronto.
In the past year, genomic profiling studies using different platforms have yielded similar results, suggesting that about 30% of patients with pancreatic cancer have actionable mutations that could help guide treatment choices.
The COMPASS trial prospectively recruited patients with advanced pancreatic ductal adenocarcinoma prior to first-line chemotherapy for tumor whole-genome sequencing and RNA sequencing. The trial previously established feasibility, with sequencing successfully completed in more than 90% of patients and availability of whole-genome results before the first disease assessment CT scan at 8 weeks (Clin Cancer Res. 2018;24[6]:1344-54).
New outcomes data for the 150 patients in the intention-to-treat population showed that overall survival was almost 4 months longer for those having a classic modified Moffitt RNA expression signature compared with those having a basal-like one. Similarly, it was more than 2 months longer for those having high versus low expression of the transcription factor GATA6.
In addition, among the subset of patients given mFOLFIRINOX, those having the classic signature were two-thirds less likely to die than were those having the basal-like signature.
“The RNA signature and GATA6 seem to discriminate two prognostic groups in advanced pancreas cancer. The basal-like cohort, or GATA6-low, may be particularly resistant to mFOLFIRINOX,” Dr. Knox said. “GATA6, and perhaps other markers, need to be validated as predictive biomarkers so that we can discover and use more effective therapies earlier on for our patients.
“COMPASS provides a very rich discovery set for other hypotheses and collaborators,” she said, noting that the investigators are adding trial data to the Enhanced Pancreatic Cancer Profiling for Individualized Care (EPPIC) project and to the Accelerate Research in Genomic Oncology (ARGO) project of the International Cancer Genome Consortium.
Rationally based treatment decisions
The COMPASS trial “will show us ... how we should move forward,” said invited discussant Heinz-Josef Lenz, MD, associate director for adult oncology and coleader of the Gastrointestinal Cancers Program, USC Norris Comprehensive Cancer Center, Los Angeles. “We don’t necessarily have the answer today to what the best treatment options are, but this is the first step to understand and develop rationally based treatment decisions for these molecularly characterized groups,” he said.
Whole-genome sequencing has been critically important for finding mutations in single genes, the proverbial needles in the haystack, he maintained. But in the future, the emphasis will likely be on combinations of mutations and other alterations.
Here, RNA is attractive in that it provides information about not only single genes, but also fusions, amplifications, and signatures, as well as treatment-induced changes. “We know that genetic makeup of tumors undergoes significant dynamic changes under treatment pressure. So if we have a gene expression signature associated with sensitivity to chemotherapy, will this change over time if there is progression of disease?” Dr. Lenz said. “That will be the challenge in the future, to better understand the dynamics in order to then recommend second- and third-line treatments.”
Some issues must be overcome to use RNA sequencing in routine clinical care, he acknowledged. For example, this sequencing requires fresh frozen tumor tissue, and it must be largely free of any normal tissue.
“There is no doubt that comprehensive molecular characterization with DNA and RNA will lead to better treatment options and identifying patients who benefit most from very unique treatments,” Dr. Lenz concluded. “The key is, you need to do the testing in order to find and identify the most successful treatments for our patients.”
Study details
Most of the 150 COMPASS patients had metastatic disease (87%), and they were about evenly split between receiving mFOLFIRINOX versus gemcitabine plus nab-paclitaxel as first-line chemotherapy, Dr. Knox reported at the symposium, sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.
Genomic profiling revealed that roughly 40% overall had potentially actionable variants: alterations in the presence of KRAS wild type (8%), homologous recombination deficiency involving BRCA (6%), and others (25%) such as activating PIK3CA mutations or HER2 amplification.
In findings that Dr. Knox called “quite striking,” among patients given mFOLFIRINOX, median progression-free survival was 7.17 months for those with the RNA classic expression signature versus 2.50 months for those with the RNA basal-like signature (hazard ratio, 0.17; P less than .0001). In contrast, among patients given gemcitabine plus nab-paclitaxel, there was no significant difference by signature (5.65 vs. 4.93 months; P = .69).
GATA6 expression was strongly related to signature type, with classic tumors having high expression and basal-like tumors having low expression (P less than .0001).
Overall survival was similarly better for patients with classic versus basal-like tumors (8.8 vs. 5.2 months; HR, 0.53; P = .006) and for patients with GATA6 high- versus low-expression tumors (8.2 vs. 5.8 months; HR, 0.66; P = .08).
In the whole cohort, overall survival differed across subsets according to RNA signature and type of chemotherapy received (P = .0134). When analysis was restricted to patients given mFOLFIRINOX, median overall survival was 10.1 months with the classic signature but just 5.3 months with the basal-like signature (HR, 0.33; P = .0005).
A multivariate analysis among all chemotherapy-treated patients confirmed the survival benefit of classic signature over basal-like signature (HR, 0.55; P = .03).
Dr. Knox disclosed that she has a consulting or advisory role with Lilly, Merck, and Bristol-Myers Squibb; that she receives honoraria from Novartis; and that she receives research funding from AstraZeneca and Merck. The study is sponsored by University Health Network, Toronto.
SOURCE: O’Kane GM et al. GI Cancers Symposium, Abstract 188.
SAN FRANCISCO – , according to new data from the COMPASS trial reported at the 2019 GI Cancers Symposium.
“We now have two standard chemotherapy regimens that we use in the first-line setting, modified FOLFIRINOX (mFOLFIRINOX) and gemcitabine–nab-paclitaxel, but we lack any real biomarker strategies on which to choose for treatments, and many of our clinical trials in pancreas cancer have failed,” noted senior investigator Jennifer J. Knox, MD, FRCPC, codirector of the McCain Centre for Pancreatic Cancer, Princess Margaret Cancer Centre, Toronto.
In the past year, genomic profiling studies using different platforms have yielded similar results, suggesting that about 30% of patients with pancreatic cancer have actionable mutations that could help guide treatment choices.
The COMPASS trial prospectively recruited patients with advanced pancreatic ductal adenocarcinoma prior to first-line chemotherapy for tumor whole-genome sequencing and RNA sequencing. The trial previously established feasibility, with sequencing successfully completed in more than 90% of patients and availability of whole-genome results before the first disease assessment CT scan at 8 weeks (Clin Cancer Res. 2018;24[6]:1344-54).
New outcomes data for the 150 patients in the intention-to-treat population showed that overall survival was almost 4 months longer for those having a classic modified Moffitt RNA expression signature compared with those having a basal-like one. Similarly, it was more than 2 months longer for those having high versus low expression of the transcription factor GATA6.
In addition, among the subset of patients given mFOLFIRINOX, those having the classic signature were two-thirds less likely to die than were those having the basal-like signature.
“The RNA signature and GATA6 seem to discriminate two prognostic groups in advanced pancreas cancer. The basal-like cohort, or GATA6-low, may be particularly resistant to mFOLFIRINOX,” Dr. Knox said. “GATA6, and perhaps other markers, need to be validated as predictive biomarkers so that we can discover and use more effective therapies earlier on for our patients.
“COMPASS provides a very rich discovery set for other hypotheses and collaborators,” she said, noting that the investigators are adding trial data to the Enhanced Pancreatic Cancer Profiling for Individualized Care (EPPIC) project and to the Accelerate Research in Genomic Oncology (ARGO) project of the International Cancer Genome Consortium.
Rationally based treatment decisions
The COMPASS trial “will show us ... how we should move forward,” said invited discussant Heinz-Josef Lenz, MD, associate director for adult oncology and coleader of the Gastrointestinal Cancers Program, USC Norris Comprehensive Cancer Center, Los Angeles. “We don’t necessarily have the answer today to what the best treatment options are, but this is the first step to understand and develop rationally based treatment decisions for these molecularly characterized groups,” he said.
Whole-genome sequencing has been critically important for finding mutations in single genes, the proverbial needles in the haystack, he maintained. But in the future, the emphasis will likely be on combinations of mutations and other alterations.
Here, RNA is attractive in that it provides information about not only single genes, but also fusions, amplifications, and signatures, as well as treatment-induced changes. “We know that genetic makeup of tumors undergoes significant dynamic changes under treatment pressure. So if we have a gene expression signature associated with sensitivity to chemotherapy, will this change over time if there is progression of disease?” Dr. Lenz said. “That will be the challenge in the future, to better understand the dynamics in order to then recommend second- and third-line treatments.”
Some issues must be overcome to use RNA sequencing in routine clinical care, he acknowledged. For example, this sequencing requires fresh frozen tumor tissue, and it must be largely free of any normal tissue.
“There is no doubt that comprehensive molecular characterization with DNA and RNA will lead to better treatment options and identifying patients who benefit most from very unique treatments,” Dr. Lenz concluded. “The key is, you need to do the testing in order to find and identify the most successful treatments for our patients.”
Study details
Most of the 150 COMPASS patients had metastatic disease (87%), and they were about evenly split between receiving mFOLFIRINOX versus gemcitabine plus nab-paclitaxel as first-line chemotherapy, Dr. Knox reported at the symposium, sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.
Genomic profiling revealed that roughly 40% overall had potentially actionable variants: alterations in the presence of KRAS wild type (8%), homologous recombination deficiency involving BRCA (6%), and others (25%) such as activating PIK3CA mutations or HER2 amplification.
In findings that Dr. Knox called “quite striking,” among patients given mFOLFIRINOX, median progression-free survival was 7.17 months for those with the RNA classic expression signature versus 2.50 months for those with the RNA basal-like signature (hazard ratio, 0.17; P less than .0001). In contrast, among patients given gemcitabine plus nab-paclitaxel, there was no significant difference by signature (5.65 vs. 4.93 months; P = .69).
GATA6 expression was strongly related to signature type, with classic tumors having high expression and basal-like tumors having low expression (P less than .0001).
Overall survival was similarly better for patients with classic versus basal-like tumors (8.8 vs. 5.2 months; HR, 0.53; P = .006) and for patients with GATA6 high- versus low-expression tumors (8.2 vs. 5.8 months; HR, 0.66; P = .08).
In the whole cohort, overall survival differed across subsets according to RNA signature and type of chemotherapy received (P = .0134). When analysis was restricted to patients given mFOLFIRINOX, median overall survival was 10.1 months with the classic signature but just 5.3 months with the basal-like signature (HR, 0.33; P = .0005).
A multivariate analysis among all chemotherapy-treated patients confirmed the survival benefit of classic signature over basal-like signature (HR, 0.55; P = .03).
Dr. Knox disclosed that she has a consulting or advisory role with Lilly, Merck, and Bristol-Myers Squibb; that she receives honoraria from Novartis; and that she receives research funding from AstraZeneca and Merck. The study is sponsored by University Health Network, Toronto.
SOURCE: O’Kane GM et al. GI Cancers Symposium, Abstract 188.
SAN FRANCISCO – , according to new data from the COMPASS trial reported at the 2019 GI Cancers Symposium.
“We now have two standard chemotherapy regimens that we use in the first-line setting, modified FOLFIRINOX (mFOLFIRINOX) and gemcitabine–nab-paclitaxel, but we lack any real biomarker strategies on which to choose for treatments, and many of our clinical trials in pancreas cancer have failed,” noted senior investigator Jennifer J. Knox, MD, FRCPC, codirector of the McCain Centre for Pancreatic Cancer, Princess Margaret Cancer Centre, Toronto.
In the past year, genomic profiling studies using different platforms have yielded similar results, suggesting that about 30% of patients with pancreatic cancer have actionable mutations that could help guide treatment choices.
The COMPASS trial prospectively recruited patients with advanced pancreatic ductal adenocarcinoma prior to first-line chemotherapy for tumor whole-genome sequencing and RNA sequencing. The trial previously established feasibility, with sequencing successfully completed in more than 90% of patients and availability of whole-genome results before the first disease assessment CT scan at 8 weeks (Clin Cancer Res. 2018;24[6]:1344-54).
New outcomes data for the 150 patients in the intention-to-treat population showed that overall survival was almost 4 months longer for those having a classic modified Moffitt RNA expression signature compared with those having a basal-like one. Similarly, it was more than 2 months longer for those having high versus low expression of the transcription factor GATA6.
In addition, among the subset of patients given mFOLFIRINOX, those having the classic signature were two-thirds less likely to die than were those having the basal-like signature.
“The RNA signature and GATA6 seem to discriminate two prognostic groups in advanced pancreas cancer. The basal-like cohort, or GATA6-low, may be particularly resistant to mFOLFIRINOX,” Dr. Knox said. “GATA6, and perhaps other markers, need to be validated as predictive biomarkers so that we can discover and use more effective therapies earlier on for our patients.
“COMPASS provides a very rich discovery set for other hypotheses and collaborators,” she said, noting that the investigators are adding trial data to the Enhanced Pancreatic Cancer Profiling for Individualized Care (EPPIC) project and to the Accelerate Research in Genomic Oncology (ARGO) project of the International Cancer Genome Consortium.
Rationally based treatment decisions
The COMPASS trial “will show us ... how we should move forward,” said invited discussant Heinz-Josef Lenz, MD, associate director for adult oncology and coleader of the Gastrointestinal Cancers Program, USC Norris Comprehensive Cancer Center, Los Angeles. “We don’t necessarily have the answer today to what the best treatment options are, but this is the first step to understand and develop rationally based treatment decisions for these molecularly characterized groups,” he said.
Whole-genome sequencing has been critically important for finding mutations in single genes, the proverbial needles in the haystack, he maintained. But in the future, the emphasis will likely be on combinations of mutations and other alterations.
Here, RNA is attractive in that it provides information about not only single genes, but also fusions, amplifications, and signatures, as well as treatment-induced changes. “We know that genetic makeup of tumors undergoes significant dynamic changes under treatment pressure. So if we have a gene expression signature associated with sensitivity to chemotherapy, will this change over time if there is progression of disease?” Dr. Lenz said. “That will be the challenge in the future, to better understand the dynamics in order to then recommend second- and third-line treatments.”
Some issues must be overcome to use RNA sequencing in routine clinical care, he acknowledged. For example, this sequencing requires fresh frozen tumor tissue, and it must be largely free of any normal tissue.
“There is no doubt that comprehensive molecular characterization with DNA and RNA will lead to better treatment options and identifying patients who benefit most from very unique treatments,” Dr. Lenz concluded. “The key is, you need to do the testing in order to find and identify the most successful treatments for our patients.”
Study details
Most of the 150 COMPASS patients had metastatic disease (87%), and they were about evenly split between receiving mFOLFIRINOX versus gemcitabine plus nab-paclitaxel as first-line chemotherapy, Dr. Knox reported at the symposium, sponsored by the American Gastroenterological Association, the American Society for Clinical Oncology, the American Society for Radiation Oncology, and the Society of Surgical Oncology.
Genomic profiling revealed that roughly 40% overall had potentially actionable variants: alterations in the presence of KRAS wild type (8%), homologous recombination deficiency involving BRCA (6%), and others (25%) such as activating PIK3CA mutations or HER2 amplification.
In findings that Dr. Knox called “quite striking,” among patients given mFOLFIRINOX, median progression-free survival was 7.17 months for those with the RNA classic expression signature versus 2.50 months for those with the RNA basal-like signature (hazard ratio, 0.17; P less than .0001). In contrast, among patients given gemcitabine plus nab-paclitaxel, there was no significant difference by signature (5.65 vs. 4.93 months; P = .69).
GATA6 expression was strongly related to signature type, with classic tumors having high expression and basal-like tumors having low expression (P less than .0001).
Overall survival was similarly better for patients with classic versus basal-like tumors (8.8 vs. 5.2 months; HR, 0.53; P = .006) and for patients with GATA6 high- versus low-expression tumors (8.2 vs. 5.8 months; HR, 0.66; P = .08).
In the whole cohort, overall survival differed across subsets according to RNA signature and type of chemotherapy received (P = .0134). When analysis was restricted to patients given mFOLFIRINOX, median overall survival was 10.1 months with the classic signature but just 5.3 months with the basal-like signature (HR, 0.33; P = .0005).
A multivariate analysis among all chemotherapy-treated patients confirmed the survival benefit of classic signature over basal-like signature (HR, 0.55; P = .03).
Dr. Knox disclosed that she has a consulting or advisory role with Lilly, Merck, and Bristol-Myers Squibb; that she receives honoraria from Novartis; and that she receives research funding from AstraZeneca and Merck. The study is sponsored by University Health Network, Toronto.
SOURCE: O’Kane GM et al. GI Cancers Symposium, Abstract 188.
REPORTING FROM THE 2019 GI CANCERS SYMPOSIUM
Key clinical point: Molecular features of pancreatic cancer may help estimate prognosis and predict response to chemotherapy.
Major finding: Compared with peers whose tumors had a classic RNA expression signature, patients whose tumors had a basal-like RNA expression signature had poorer overall survival when given mFOLFIRINOX (hazard ratio, 0.33; P = .0005).
Study details: Prospective trial with whole-genome sequencing and RNA sequencing of tumors in 150 patients with advanced pancreatic ductal adenocarcinoma before start of first-line therapy (COMPASS trial).
Disclosures: Dr. Knox disclosed that she has a consulting or advisory role with Lilly, Merck, and Bristol-Myers Squibb; that she receives honoraria from Novartis; and that she receives research funding from AstraZeneca and Merck. The study is sponsored by University Health Network, Toronto.
Source: O’Kane GM et al. GI Cancers Symposium, Abstract 188.