Abstract
Whole-exome and transcriptome sequencing have yielded a clearer picture of the molecular differences between ER-positive primary and metastatic breast cancer. Comparing metastatic breast tumor samples with matched primary tumor tissue, researchers found clinically relevant mutations in various genes, including ESR1 and RB1, that were acquired during metastasis. Their findings may better guide the selection of therapies for patients no longer benefiting from ER-targeted agents.
Through whole-exome and transcriptome sequencing, a clearer picture of the molecular differences between estrogen receptor (ER)–positive primary and metastatic breast cancer is emerging. Data from one such genomic analysis were presented by Ofir Cohen, PhD, a computational biologist at the Broad Institute of Harvard and MIT in Cambridge, MA, during the 2016 San Antonio Breast Cancer Symposium in Texas, held December 6–10.
“Effective therapies for ER-positive breast cancer are available, but drug resistance is almost inevitable when metastasis occurs,” Cohen said. “We don't fully understand this disease's genomic landscape in the metastatic, treatment-resistant setting, and our study is part of a growing effort by many researchers to close this knowledge gap.”
Led by Nikhil Wagle, MD, deputy director of Dana-Farber Cancer Institute's Center for Cancer Precision Medicine in Boston, MA, the investigators obtained tumor tissue from 149 women with metastatic breast cancer, most of whom had received at least one ER-targeted therapy, such as tamoxifen or fulvestrant (Faslodex; AstraZeneca), prior to having a biopsy. The team sequenced the exomes of these tumors, as well as the transcriptomes in 128 cases. They found key alterations—mainly single-base changes and small insertions or deletions—in a considerable number of genes: TP53, GATA3, PIK3CA, ESR1, HER2, AKT1, KRAS, and RB1.
Cohen noted that TP53, GATA3, and PIK3CA are known drivers of tumorigenesis because they are also frequently mutated in primary ER-positive disease. On the other hand, when he and his team compared 44 of their metastatic samples with matched primary tumor tissue, they reported that mutations in ESR1 and RB1, for instance, were clearly acquired during metastasis. For both alterations, transcriptome sequencing confirmed associations with unchecked ER activity and cell proliferation, respectively.
“ESR1 mutations promote resistance to aromatase inhibitors like letrozole, and experimental data suggest that inactivating mutations in RB1 predict resistance to drugs that block CDK4/6,” Cohen explained. “So, our findings have clinical implications in terms of guiding second-line and subsequent treatment choices that could ultimately lead to durable disease control.”
Virginia Kaklamani, MD, leader of the breast cancer program at The University of Texas Health Science Center in San Antonio, agreed. “Rather than the cookie-cutter approach used today, we'll be better informed when it comes to selecting specific therapies that are most relevant for individual patients who are no longer responding to ER-targeted agents,” she said.
Given that most of the tumor samples in their study were both metastatic and treatment-resistant, Cohen, Wagle, and colleagues are now using functional assays to sort out which mutations drive metastasis and which confer resistance. They're also adding about 10 to 20 tissue specimens a month to their tumor bank and incorporating serial analyses of cell-free DNA to “better understand the overall tumor burden beyond what can be sampled from a core needle biopsy,” Cohen said. Eventually, the team hopes to merge their functional and clinical findings into a “Resistance Atlas” for metastatic ER-positive breast cancer. –Alissa Poh
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