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Germline BRCA1/2: A New Subset of Breast Cancer

Panelists:Joyce OShaugnessy, MD, Baylor University Medical Center; Tiffany A. Traina, MD, Memorial Sloan Kettering Cancer Center; Nadine M. Tung, MD, Harvard Medical School
Published: Tuesday, Apr 24, 2018



Transcript: 

Joyce O’Shaughnessy, MD: Do you think, Tiffany, that we now have a new subset of breast cancer? Is this a new type of breast cancer—germline BRCA? Do we need to be looking at it differently—prognostic-wise, treatment-wise?

Tiffany Traina, MD: Great question. I think we’ve all been grappling with and recognizing the heterogeneity of breast cancer and even triple-negative breast cancer (TNBC). We’ve had groups look at molecular characteristics and classifications for TNBC. I think we’ve all suspected that there was a subset of triple-negative breast cancer, in particular, that behaved differently.

These were the more basal-like, highly proliferative tumors. I would say, yes, we now can carve out patients who have a germline BRCA mutation as an actionable biomarker. So, while it certainly has implications in the early-stage setting for risk-reducing interventions, it is now an actionable subset of breast cancer. In my paradigm, for approaching a woman who has a diagnosis of breast cancer, as I’m trying to think about a treatment plan, I feel that I need to know the germline BRCA status to make those appropriate decisions.

In terms of prognosis, I think the data, largely from retrospective series, have been somewhat mixed. At best, we can conclude that the prognosis is really comparable, whether you have germline BRCA mutation or not, once you have adjusted for other known prognostic factors.

Joyce O’Shaughnessy, MD: Nadine, do you agree with that?

Nadine Tung, MD: I would absolutely agree with that.

Joyce O’Shaughnessy, MD: You think of BRCA as a new kind of subtype, if you will? We’ve got luminal A and luminal B tumors. Those are very, very different biologies. Do you think we’ve got a new subtype of breast cancer here?

Nadine Tung, MD: Absolutely. It’s really important to focus your thinking that way so that you don’t forget to do the germline or the somatic testing—for treatments and trials for PARP inhibitors. If we can think about the different subsets of BRCA, this definitely will help us.
Joyce O’Shaughnessy, MD: Even regardless of any family history whatsoever? What are the chances that we’re going to find a BRCA mutation in somebody with no family history? Here they are, in the metastatic setting—triple-negative, ER-positive. What are the chances that we’re going to find it?

Nadine Tung, MD: I think there’s some difference in data. What we’ve learned, in the Ashkenazi Jewish population, for example, is that half of the mutations that we’re finding in the general population are in patients that don’t necessarily have a personal family history. But if we’re thinking about breast cancer, clearly there are some groups that are enriched for this—triple-negative breast cancer, younger age, and, again, Ashkenazi Jewish decent. If somebody has an extremely large family and no family history, certainly the chances are much lower. But I would say, again, in the metastatic setting, if you’re doing somatic testing, you may pick them up. Otherwise, if you would use the PARP inhibitor, it’s worth thinking about the germline testing.

Joyce O’Shaughnessy, MD: I’ve seen estimates up to 11%, 14%, for TNBC. Yikes, that’s pretty high. I’ve seen estimates as low as 5%, though.

Nadine Tung, MD: I think it’s between 10% and 20% for triple-negative. I really do. I think for unselected, all breast cancer, we’re talking about 3% to 5%. But for triple-negative, it’s between 10% and 20%.

Joyce O’Shaughnessy, MD: So it is something, and we don’t want to miss it. We’re just at the tip of the iceberg. We’re just starting to determine how to optimize treatments for these patients.

Another question is, we do still find these variants in the germline. We see them less and less with the BRCA1 and BRCA2 and maybe more and more with some of the other germlines, which we’ll come back to. But if I had a patient who’s got a strong family history, who is kind of suggestive of a germline mutation, but she just has a variant that truly is unknown and now has metastatic disease, and she’s triple-negative, would I be wrong to give her the benefit of the doubt and treat her with olaparib? What do you think, Tiffany?

Tiffany Traina, MD: Well, a patient like that would not have been included in the 2 big, randomized phase III trials that have reported out data. So I don’t know that we have evidence to support that there would be a benefit for that particular patient. I could sense why it’s so compelling to think about an attempt there. Since there are several recruiting trials for PARP inhibitors in metastatic disease, I would favor that approach first. We could try to learn something from the experience.

Nadine Tung, MD: I completely agree. We don’t want to get away from the message that most of VUS [variant of unknown significance] cases, 85% of them, are not going to be pathogenic mutations. So we shouldn’t be treating them like mutations.

Transcript Edited for Clarity
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Transcript: 

Joyce O’Shaughnessy, MD: Do you think, Tiffany, that we now have a new subset of breast cancer? Is this a new type of breast cancer—germline BRCA? Do we need to be looking at it differently—prognostic-wise, treatment-wise?

Tiffany Traina, MD: Great question. I think we’ve all been grappling with and recognizing the heterogeneity of breast cancer and even triple-negative breast cancer (TNBC). We’ve had groups look at molecular characteristics and classifications for TNBC. I think we’ve all suspected that there was a subset of triple-negative breast cancer, in particular, that behaved differently.

These were the more basal-like, highly proliferative tumors. I would say, yes, we now can carve out patients who have a germline BRCA mutation as an actionable biomarker. So, while it certainly has implications in the early-stage setting for risk-reducing interventions, it is now an actionable subset of breast cancer. In my paradigm, for approaching a woman who has a diagnosis of breast cancer, as I’m trying to think about a treatment plan, I feel that I need to know the germline BRCA status to make those appropriate decisions.

In terms of prognosis, I think the data, largely from retrospective series, have been somewhat mixed. At best, we can conclude that the prognosis is really comparable, whether you have germline BRCA mutation or not, once you have adjusted for other known prognostic factors.

Joyce O’Shaughnessy, MD: Nadine, do you agree with that?

Nadine Tung, MD: I would absolutely agree with that.

Joyce O’Shaughnessy, MD: You think of BRCA as a new kind of subtype, if you will? We’ve got luminal A and luminal B tumors. Those are very, very different biologies. Do you think we’ve got a new subtype of breast cancer here?

Nadine Tung, MD: Absolutely. It’s really important to focus your thinking that way so that you don’t forget to do the germline or the somatic testing—for treatments and trials for PARP inhibitors. If we can think about the different subsets of BRCA, this definitely will help us.
Joyce O’Shaughnessy, MD: Even regardless of any family history whatsoever? What are the chances that we’re going to find a BRCA mutation in somebody with no family history? Here they are, in the metastatic setting—triple-negative, ER-positive. What are the chances that we’re going to find it?

Nadine Tung, MD: I think there’s some difference in data. What we’ve learned, in the Ashkenazi Jewish population, for example, is that half of the mutations that we’re finding in the general population are in patients that don’t necessarily have a personal family history. But if we’re thinking about breast cancer, clearly there are some groups that are enriched for this—triple-negative breast cancer, younger age, and, again, Ashkenazi Jewish decent. If somebody has an extremely large family and no family history, certainly the chances are much lower. But I would say, again, in the metastatic setting, if you’re doing somatic testing, you may pick them up. Otherwise, if you would use the PARP inhibitor, it’s worth thinking about the germline testing.

Joyce O’Shaughnessy, MD: I’ve seen estimates up to 11%, 14%, for TNBC. Yikes, that’s pretty high. I’ve seen estimates as low as 5%, though.

Nadine Tung, MD: I think it’s between 10% and 20% for triple-negative. I really do. I think for unselected, all breast cancer, we’re talking about 3% to 5%. But for triple-negative, it’s between 10% and 20%.

Joyce O’Shaughnessy, MD: So it is something, and we don’t want to miss it. We’re just at the tip of the iceberg. We’re just starting to determine how to optimize treatments for these patients.

Another question is, we do still find these variants in the germline. We see them less and less with the BRCA1 and BRCA2 and maybe more and more with some of the other germlines, which we’ll come back to. But if I had a patient who’s got a strong family history, who is kind of suggestive of a germline mutation, but she just has a variant that truly is unknown and now has metastatic disease, and she’s triple-negative, would I be wrong to give her the benefit of the doubt and treat her with olaparib? What do you think, Tiffany?

Tiffany Traina, MD: Well, a patient like that would not have been included in the 2 big, randomized phase III trials that have reported out data. So I don’t know that we have evidence to support that there would be a benefit for that particular patient. I could sense why it’s so compelling to think about an attempt there. Since there are several recruiting trials for PARP inhibitors in metastatic disease, I would favor that approach first. We could try to learn something from the experience.

Nadine Tung, MD: I completely agree. We don’t want to get away from the message that most of VUS [variant of unknown significance] cases, 85% of them, are not going to be pathogenic mutations. So we shouldn’t be treating them like mutations.

Transcript Edited for Clarity
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