BRCA1/2 Status Does Not Influence Radiation Outcomes in Breast Cancer

Rebecca M. Shulman, MD

Fox Chase Cancer Center

Zachary Kiss, DO

Fox Chase Cancer Center

Treatment with radiotherapy did not appear to yield significant differences in disease-free survival (DFS) or overall survival in patients with breast cancer harboring BRCA1/2 mutations compared with those without BRCA1/2 mutations, according to findings from a study authored by Rebecca M. Shulman, MD, and Zachary Kiss, DO.

During Breast Cancer Awareness Month 2023, Shulman, an assistant professor in the Department of Radiation Oncology at Fox Chase Cancer Center, and Kiss, a third-year resident physician in radiation oncology at Fox Chase, also discussed additional findings from the study, such as how patients with BRCA1/2 mutations tended to be younger and have tumors of higher clinical stages than those without said mutations. They also spoke about how next steps for research may involve investigating the presence of other mutations in conjunction with BRCA1/2 and other factors in this population that impact their sensitivity to radiation.

“Investigating the genetic and biochemical basis of cancer is a monumental task, requiring patience, ingenuity, and a continuing investment of time and resources,” Shulman said. “It’s important to communicate that progress in cancer treatment has been enormous, but that it is also incremental by nature and will require the efforts of many researchers pursuing many different ideas.”

Shulman and Kiss presented these findings as part of a poster session at the 2023 American Society for Radiation Oncology (ASTRO) Annual Meeting.

CancerNetwork^®: What was the rationale for assessing whether the presence of BRCA1/2 mutations affected treatment outcomes with radiation in patients with breast cancer?

Kiss: Conceptually, BRCA1/2 are encoded for gene products that are involved in DNA repair mechanisms. There are preclinical data that suggests that mutations to BRCA1/2 may increase radiation sensitivity in-vivo samples. The question was, is that something that holds true in clinical populations? Does that change response to radiation or the outcome metrics that we assessed?

Shulman: Previous research and clinical experience have taught us that BRCA1/2 genes play an important overall role in determining the behavior of many cancers, and breast cancers in particular. In the lab, we have shown that isolated breast cancer cells with mutations of those genes are often very sensitive to radiation. Once we learned that BRCA1/2 mutations can increase radiation sensitivity, it made sense to turn our attention to finding specific mutations that might improve the way breast cancers respond to treatment. That’s why we think of our research on the BRCA mutations as part of a wider effort to individualize the management of our patients [with cancer].

How did patients with BRCA1/2 mutations respond to treatment?

Kiss: One of the things to keep in mind is whether patients [with BRCA mutations] responded in a way that was consistent with a normal patient population, even though we would expect that they would. One of the things that we looked at was whether the presence of a BRCA mutation changed the local recurrence or death rate in those patient populations. Compared with people who didn’t have BRCA mutations, outcomes were consistent with the outcomes of general patients. In terms of DFS in the different BRCA mutations, we didn’t find a significant difference in those populations.

Shulman: To add to that,we did find that patients with BRCA1/2 mutations were younger and diagnosed at a higher clinical stage than those with normal BRCA genes. When we compared the 2 different types of mutations, we found that patients with BRCA1 mutations were younger and had tumors of higher stages. Patients with BRCA1 mutations were also less likely to have cancers bearing hormone receptors. But surprisingly, these differences did not affect treatment outcomes after radiation therapy, which were the same for both kinds of BRCA mutations. One of the difficulties of studying this patient population or even mutation in general is that we’re limited by sample sizes as well. Because [patients with BRCA mutations] are not that common compared with the whole patient population, our sample sizes are smaller. It’s sometimes harder to detect differences between groups.

Kiss: When we do see these patients, we ask, “Where are they in their disease status?” These patients tend to present younger and also tend to present with a higher histologic grade compared with the patients that didn’t have those mutations. Whether we compare populations or other factors of the disease may slightly change the analysis. Another thing to keep in mind, which I think we’d like to investigate a little bit further, is patients who had BRCA mutations tended to have more mastectomies more commonly than the patients without BRCA mutations. That might be something that influences the outcome, as assessed by the study.

Was there anything about these findings that you wanted to highlight?

Shulman: Sometimes negative findings in research can be as instructive as results that confirm the study hypothesis. In this case, we learned that the results we obtained studying breast cancer in the lab cannot be immediately extrapolated to the clinical setting. Specifically, we showed that the sensitivity to radiation absorbed for mutated breast cancer cells in the lab does not predict the response of patients [with breast cancer] to radiation therapy in a straightforward manner, which is something we commonly see translating science from the lab to the clinic.

Where should research efforts be focused from here?

Kiss: We have a few different questions based on research interests. Because these patients had mutations in DNA repair mechanisms and presented at a higher histologic rate, one of the things that I’m curious about is whether these patients have accumulated additional mutations that influence the natural history of their disease, and where they acquire those mutations along the natural history of the disease. Another question is what types of mutations are these mutations in BRCA? Hypothetically, if there is a mutation that impedes the ability of BRCA to work in [terms of] DNA repair, one would think that a cell has a lesser ability to repair itself in response to radiation or other therapies. If these patients have not shown an increased sensitivity to radiation, at least whatever our proxy is for that in clinical outcomes, what types of mutations do they harbor that prevent that, or what other factors explain that difference when comparing the in-vivo population to the clinical population?

Shulman: Our study of BRCA mutations should be seen as just one aspect of the way expanding knowledge of genetics and molecular biology is advancing the treatment of cancer. We’re focused on finding the vulnerabilities of cancer cells that will allow us to destroy them while leaving normal tissues unaffected. Such vulnerabilities may be specific to individual patients. A better understanding of the mechanisms used by the cancers to evade the effects of radiation and other kinds of therapy is our aim when we study the biomarkers and biochemical pathways associated with growing cancer cells.

What do you hope your colleagues take away from this conversation?

Kiss: Whenever you conduct an experiment or generate a hypothesis and you don’t always get the results you expect, the most important question is, “What can be learned from positive and negative studies?What additional questions can be asked?” The outcomes of this study generate a number of new questions that we may not have anticipated before, which is very helpful and instructive in terms of next directions to take.I think that that’s something that any colleague should be asking themselves.

Reference

Shulman RM, Kiss Z, Handorf E, et al. Mutations of the BRCA1/2 genes in patients with breast cancer do not alter treatment outcomes following radiation therapy (RT). Presented at: 2023 American Society for Radiation Oncology Annual Meeting (ASTRO); October 1-4, 2023; San Diego, CA. Abstract 2443.