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Genomic/Somatic Molecular Alteration Evaluation

Panelists: Aditya Bardia, MD, MPH, Massachusetts General Hospital Cancer Center; Erika P. Hamilton, MD, Sarah Cannon Research Institute; Sara A. Hurvitz, MD, UCLA Jonsson Comprehensive Cancer Center; Joyce A. OShaughnessy, MD, Baylor University Medical Center; Debu Tripathy, MD, The University of Texas MD Anderson Cancer Center
Published: Tuesday, Sep 03, 2019



Transcript: 

Joyce A. O’Shaughnessy, MD: We’ve been talking a lot about selecting patients, biomarker evaluation. The question always comes up—who and when should we be thinking about genomic/somatic molecular alteration evaluation in metastatic breast cancer and even triple-negative breast cancer? What do you think, Aditya?

Aditya Bardia, MD, MPH: I think in metastatic breast cancer, specifically for hormone receptor-positive breast cancer, we now have a compelling case that we should be doing sequencing, so we can identify PIK3CA mutations because it’s actionable. If you’re going to identify PIK3CA mutation by an assay—that assay can cover the other genes that are potentially actionable—it makes sense. In triple-negative breast cancer, it makes sense to do sequencing to identify actionable mutations. We don’t have an FDA approved therapy yet that is linked to a specific actionable alteration based on next-generation sequencing, but there are a number of clinical trials, including basket trials, that are specifically designed for certain mutations. I think from a patient perspective, it’s important for that patient to have that information, so they could be eligible for that clinical trial or be referred to an academic center that has that clinical trial.

What is actionable at this time is PD-1 [programmed cell death protein 1], but that is based on IHC [immunohistochemistry]. In the future if we have other assays, then it would be interesting to see if those become actionable as well. As far as PAM50 [Prediction Analysis of Microarray 50 test] is concerned, I think it’s an interesting hypothesis of luminal A/B versus basal, but at this time, that’s not actionable. From a research perspective it’s interesting, but it’s not actionable from a therapy perspective.

Joyce A. O’Shaughnessy, MD: I was just remembering when you were talking about the next-generation sequencing, about 1% or 2% of metastatic breast cancers have microsatellite instability [MSI], because pembrolizumab is FDA approved tumor agnostic for MSI-high. So that’s one. Then at this ASCO [American Society of Clinical Oncology] meeting, there is the TAPUR trial run by ASCO. It is a match trial looking at molecular alterations and trying to match with therapies, looking at high tumor mutational burden. I’ll tell you what I got out of it, and you can please chime in, but there’s a bit of a discrepancy about it or uncertainty about how to actually define high tumor mutational burden. I think it depends on the malignancy. But in metastatic breast cancer, in this TAPUR trial, they said 10 mutations and above per megabase in DNA was what they utilized. It was a small percentage of patients, less than 10%, they had something in the neighborhood of several dozen such patients. They treated them late-line with single-agent pembrolizumab and had definite responses in that patient population. I believe it was in the order, an objective response rate around 20%, and then there was an additional clinical benefit rate on top of that. That’s impressive for a late-line. Tumor mutational burden is perhaps another output from next-generation sequencing that we could utilize on a practical basis.

Erika P. Hamilton, MD: I’ll add in, too, somatic BRCA, right? We pick up germline with Myriad Genetics, Inc or other vendors’ testing, but somatic BRCA is something else that’s actionable even outside of a clinical trial right now.

Joyce A. O’Shaughnessy, MD: Yes, and that’s certainly the case in ovarian cancer. I think the data for breast cancer are being intensively studied. But in ovarian, it’s just as good as the germline to have somatic BRCA. But I think in breast cancer, I haven’t seen data yet on that.

Transcript Edited for Clarity

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Transcript: 

Joyce A. O’Shaughnessy, MD: We’ve been talking a lot about selecting patients, biomarker evaluation. The question always comes up—who and when should we be thinking about genomic/somatic molecular alteration evaluation in metastatic breast cancer and even triple-negative breast cancer? What do you think, Aditya?

Aditya Bardia, MD, MPH: I think in metastatic breast cancer, specifically for hormone receptor-positive breast cancer, we now have a compelling case that we should be doing sequencing, so we can identify PIK3CA mutations because it’s actionable. If you’re going to identify PIK3CA mutation by an assay—that assay can cover the other genes that are potentially actionable—it makes sense. In triple-negative breast cancer, it makes sense to do sequencing to identify actionable mutations. We don’t have an FDA approved therapy yet that is linked to a specific actionable alteration based on next-generation sequencing, but there are a number of clinical trials, including basket trials, that are specifically designed for certain mutations. I think from a patient perspective, it’s important for that patient to have that information, so they could be eligible for that clinical trial or be referred to an academic center that has that clinical trial.

What is actionable at this time is PD-1 [programmed cell death protein 1], but that is based on IHC [immunohistochemistry]. In the future if we have other assays, then it would be interesting to see if those become actionable as well. As far as PAM50 [Prediction Analysis of Microarray 50 test] is concerned, I think it’s an interesting hypothesis of luminal A/B versus basal, but at this time, that’s not actionable. From a research perspective it’s interesting, but it’s not actionable from a therapy perspective.

Joyce A. O’Shaughnessy, MD: I was just remembering when you were talking about the next-generation sequencing, about 1% or 2% of metastatic breast cancers have microsatellite instability [MSI], because pembrolizumab is FDA approved tumor agnostic for MSI-high. So that’s one. Then at this ASCO [American Society of Clinical Oncology] meeting, there is the TAPUR trial run by ASCO. It is a match trial looking at molecular alterations and trying to match with therapies, looking at high tumor mutational burden. I’ll tell you what I got out of it, and you can please chime in, but there’s a bit of a discrepancy about it or uncertainty about how to actually define high tumor mutational burden. I think it depends on the malignancy. But in metastatic breast cancer, in this TAPUR trial, they said 10 mutations and above per megabase in DNA was what they utilized. It was a small percentage of patients, less than 10%, they had something in the neighborhood of several dozen such patients. They treated them late-line with single-agent pembrolizumab and had definite responses in that patient population. I believe it was in the order, an objective response rate around 20%, and then there was an additional clinical benefit rate on top of that. That’s impressive for a late-line. Tumor mutational burden is perhaps another output from next-generation sequencing that we could utilize on a practical basis.

Erika P. Hamilton, MD: I’ll add in, too, somatic BRCA, right? We pick up germline with Myriad Genetics, Inc or other vendors’ testing, but somatic BRCA is something else that’s actionable even outside of a clinical trial right now.

Joyce A. O’Shaughnessy, MD: Yes, and that’s certainly the case in ovarian cancer. I think the data for breast cancer are being intensively studied. But in ovarian, it’s just as good as the germline to have somatic BRCA. But I think in breast cancer, I haven’t seen data yet on that.

Transcript Edited for Clarity
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