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Triple-negative breast cancers may differ based on BRCA1/2 status
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SAN ANTONIO — Multiplatform tumor profiling indicated the molecular makeup of triple-negative breast cancers may differ between patients who are BRCA1/2 negative and positive, according to study results presented at the San Antonio Breast Cancer Symposium.
“Triple-negative breast cancer is negative for the three receptors: ER, PR and HER-2. So, there is no targeted therapy for this disease yet, and that’s why it remains a challenge,” Elias Obeid, MD, MPH, assistant professor in the departments of clinical genetics and medical oncology at Fox Chase Cancer Center, told HemOnc Today. “We understand that there are differences within triple-negative breast cancers, and it is not just one disease. Ideally, we are trying to improve our understanding of the disease and trying to find different targets that we can identify with molecular profiling to improve outcomes.”
Obeid and colleagues conducted multiplatform profiling (Molecular Intelligence, Caris Life Sciences) — which included next generation gene sequencing, protein expression by immunohistochemistry, and gene amplification by fluorescence or chromogenic in situ hybridization — on primary and metastatic specimens from 386 patients with triple-negative breast cancer. Researchers sought to identify differences in BRCA1/2 mutated and non-mutated profiles to inform targeted treatment options.
Overall, 63 patients (16.3%) harbored BRCA1/2 mutations, whereas 83.7% did not.
Proteins with the greatest expression in BRCA1/2 mutated and non-mutated specimens included TOPO1 (63.5% and 63.4%), EGFR (65.2% and 67.4%) and PD-1 (65.1% and 61.9%).
A greater proportion of BRCA1/2 non-mutated specimens harbored immunohistochemistry differences in androgen receptor expression (22% vs. 11.1%) and PTEN (59.6% vs. 47.6%), but this trend did not reach statistical significance.
“There is now an interest in the androgen receptor, and our results in the triple-negative cases demonstrated a trend for a difference between androgen receptor expression in the BRCA-mutated vs. non-mutated tumors,” Obeid said. “This is just preliminary data — it doesn’t tell us anything about the treatment yet — but in the future, that could be considered.”
Based on data from next generation sequencing, TP53 occurred at the highest frequency among gene mutations in BRCA1/2-mutated and non-mutated specimens (80.6% vs. 73.1%).
APC occurred in a greater proportion of BRCA1/2-mutated tumors (6.3% vs. 1.9%), whereas PIK3CA occurred in significantly more BRCA1/2 non-mutated tumors (25.8% vs. 11.1%; P = .0137).
“There were more likely to be mutations in the PI3-kinase pathway in the BRCA1/2 non-mutated tumors, and this could lend to the possibility of exploring mTOR inhibitors or other targets in this pathway,” Obeid said.
“Like some other exploratory analyses, this uncovers more questions that we need to ask, but it also will help us design the next generation of clinical trials so we can understand more who is going to respond to treatment as opposed to just giving treatments to patients without understand the basics of it,” he added. – by Alexandra Todak
Reference:
Arguello D, et al. Abstract P3-07-30. Presented at: San Antonio Breast Cancer Symposium; Dec. 8-12, 2015; San Antonio.
Disclosure: Obeid reports no relevant financial disclosures. Other researchers report employment with Caris Life Sciences.Perspective
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Leif W. Ellisen, MD, PhD
This study importantly points out the challenges that we have had in defining what the differences are between the BRCA-mutant and non-mutant triple negatives. We know soon that we’ll have some specific therapies for BRCA-mutant triple-negative breast cancers, namely PARP inhibitors. We think there are some non-BRCA mutants who may also respond to PARP inhibitors, and we’re trying to find ways to identify those. But, beyond that subset, we do not really know what to do with triple negatives — we don’t know how to treat them. So, the idea is that if we figure out what the key differences are in the different subsets of triple negative breast cancer, particularly among the BRCA-mutant and non-mutant subtypes, we are going to have a better opportunity to have more rational, targeted therapy.
In this study, the researchers tried to do a comprehensive analysis of RNA and proteins, comparing mutants and non-mutants. They identified some interesting trends in pathways that are particularly targetable. They talk about trends in the PTEN gene, which is targetable because it activates PI3-kinasw. mTOR inhibitors like everolimus (Afinitor, Novartis) are approved for breast cancer, but only for ER-positive breast cancer in combination with aromatase inhibitors. But there are a whole host of specific enzymatic PI3-kinase inhibitors which are now entering advanced-phase trials, and one or more of those will be approved in the coming years. The first approval, like the mTOR inhibitors, will probably be in ER-positive disease. But ultimately, these will be breast cancer drugs.
There is some debate about whether having the PIK3CA mutation is really the best predictor there could be of response. In other words, the mutations are only modestly associated with response. A lot of tumors that do not have mutations do respond, and conversely, not everyone with the mutation responds. But, it does give you some signal that, for that population, that can be helpful.
There are also multiple ways to target EGFR that are FDA approved, like cetuximab (Erbitux, Lilly) and all the small-molecule EGFR inhibitors. The detection of PD-1 alludes to the possibility of new checkpoint therapy.
These are all pathways that could, in theory, be targeted. Researchers detected interesting signals of possible differences, but at this point, they amount to trends and not strong differences in expression between the subtypes. Whether it really means that non-BRCA tumors are going to be responsive to these therapies is really not yet clear, and it requires further study.
Further, there are many ways to look at the different subsets. In this study, researchers looked at RNA and proteins, but there are many other ways to look at differences, so there’s more work that could be done.
Overall, this is an important study, because these are the worst breast cancers.
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