BRCA Testing in the Era of PARP Inhibitors for Patients With Breast Cancer

Mark Robson, MD, Memorial Sloan Kettering Cancer Center, discusses BRCA testing and PARP inhibitors, a topic he presented at the 2022 GDU Women’s Oncology virtual meeting.

In his presentation, Dr Robson discussed the approach to genetic testing in the era of PARP inhibitors, highlighting the considerations clinicians should take when advising patients with breast cancer on genetic testing.

Transcript

Good afternoon. My name is Mark Robson. I am an attending physician at Memorial Sloan Kettering and Chief of the Breast Cancer Medicine Service.

I was speaking at the 2022 GDU Women’s Oncology conference about the approach to genetic testing in the era of PARP inhibitors and the reason that this is relevant is severalfold. The most important reason is that PARP inhibitors now have been shown to be active and helpful to women, not only with metastatic cancer and BRCA mutations, but also those with high-risk early breast cancer and BRC mutations.

We've known for quite some time that the traditional criteria used to select who is offered genetic testing are not completely sensitive. In other words, there are people who have BRC mutations who don't meet any of the NCCN criteria often until they themselves are diagnosed. The criteria are sensitive because they were designed to pick up BRC mutations, but they are not complete, and when this has important therapeutic implications, either for surgical approach or for eligibility for PARP inhibitors, missing things can be a problem.

So there has been a movement afoot to offer all women with breast cancer, current or past, testing for BRCA, BRC1, BRC2, potentially PALB2, and potentially other genes that are associated with breast cancer risk, not because they have therapeutic implications, but because they might be informative about second cancer risks and about risks in the family.

There are a number of considerations, one of which is that if you're trying to pick up BRCA mutations, then if you simply test everyone under age 60 to 65, and those who are older but do meet the NCCN criteria, there's only a 0.3% chance that you're going to miss anything. Yet testing people who are outside of that, those who are over 65 who don't meet NCCN criteria, increases the number of tests that you have to perform dramatically, and exposes people to the potential risk of variants of uncertain significance and concern about testing. There are also issues about how this would be done from a logistical standpoint, but we're just here to discuss the science.

The other problem though is that you do miss moderate penetrance genes like PALB2, CHEK2, ATM, when you only test according to NCCN criteria. But whether that is really a huge problem is open to question, because we're still trying to define the risks of those genes clearly. PALB2 does appear to be a high penetrance, high-risk gene, especially in the presence of the family history. But the others are a little bit less clear. Particularly for CHEK2, ATM and other genes, there is a wide degree of individual variation in risk based upon things like polygenic risk scores and conventional risk factors.

Because of that, just providing an average risk to a woman and asking her to act upon that may lead her to either do too little or too much, and so we have to be very cautious if we're going to do testing beyond BRC1 and BRC2, to make sure that we have engagement of cancer genetics professionals, such as cancer genetic counselors, so that individuals who do have moderate penetrance alterations can be appropriately managed and not consider themselves at the same degree of risk as BRC1 and BRC2.

In summary: If people are eligible for PARP inhibitors because they have metastatic disease or because they have high risk early stage disease, my opinion is that there shouldn't be any constraint on BRCA testing in that setting, but if they have a history of breast cancer in the past and there's no direct therapeutic implication, then perhaps just testing those who are under age 65 and selected individuals who are older is a more effective and parsimonious approach.

Thank you very much.

Source

Robson, M. BRCA Testing & PARP Inhibitors. Presented at: Great Debates & Updates in Women’s Oncology. Sep 21-23, 2022. Virtual.