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Mutational landscape in ER–positive breast cancer varies between primary tumor, metastatic disease
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SAN ANTONIO — The mutational landscape of treatment-resistant ER–positive metastatic breast cancer varies from that observed in primary tumors, according to study results presented at San Antonio Breast Cancer Symposium.
Alterations in many genes — including PIK3CA, ESR1, ERBB2, AKT1 and RB1 — can be acquired in the metastatic setting, and preliminary data showed they can contribute to endocrine therapy resistance.
“Multiple clinically relevant alterations were identified in our study, with implications for choice of next therapy, clinical trial eligibility and even for novel drug targets,” Ofir Cohen, PhD, postdoctoral researcher and computational biologist at Broad Institute and Dana-Farber Cancer Institute, said during a presentation. “This highlights the value of genomic profiling of metastatic biopsies of ER–positive breast cancer.”
Despite considerable treatment advances for ER–positive breast cancer, patients often develop resistance to therapy. Resistant tumors are the primary cause of breast cancer death, but the mechanisms that cause tumor resistance are not well understood.
“There is an urgent need to develop new therapies for patients who no longer respond to these therapies,” Cohen said. “Knowledge of the molecular and genomic landscape of ER–positive metastatic breast cancer is underexplored.”
Cohen and colleagues performed whole-exome and transcriptome sequencing of resistant ER–positive metastatic breast cancers.
They aimed to determine the genetic landscape of ER–positive metastatic breast cancer after ER–targeted therapies, identify the evolutionary changes that can occur between initial ER–positive breast cancers and resistant metastatic disease, and determine how DNA and RNA sequencing can be used to improve the understanding of metastatic breast cancer and treatment resistance.
Researchers analyzed 149 biopsies of ER–positive metastatic breast cancers; these included 64 biopsies collected from 2006 through 2015, and another 85 that were collected in 2015. The majority of patients had received at least one ER–directed therapy — such as tamoxifen, an aromatase inhibitor or fulvestrant — prior to biopsy.
Cohen and colleagues performed whole exome sequencing of the tumor and germline for all 149 metastatic biopsies and 44 matched primary tumors. They performed transcriptome sequencing of tumors for 128 metastatic biopsies.
Their analysis revealed several variations in the mutational landscapes between metastatic breast cancer and primary tumors.
For example:
- Twenty-four percent of metastatic samples harbored ESR1 mutations. Twelve of 13 (92%) ESR1 mutations identified in metastatic samples with matched primaries were acquired;
- Eight percent of metastatic samples harbored ERBB2 mutations. Five of six (83%) of ERBB2 mutations identified in metastatic samples with matched primaries were acquired; and
- Six percent of metastatic samples harbored RB1 mutations. Three of five (60%) RB1 mutations identified in metastatic samples with matched primaries were acquired.
“Even though some of these numbers are small, these findings have clear clinical implications,” Cohen said. “Tumors do evolve. Even if clinicians know the alternations and mutations in the primary setting, that may not be sufficient to guide treatment at the later time point of the metastatic setting.”
The results also have implications for drug development, Cohen said.
“The enrichment of clinically relevant and targetable mutations in the metastatic setting suggests [the need for] new therapeutic strategies to help overcome or prevent resistance,” he said. – by Mark Leiser
Reference: Cohen O, et al. Abstract S1-01. Presented at: San Antonio Breast Cancer Symposium; Dec. 7-10, 2016; San Antonio, Texas.
Disclosure: Cohen reports no relevant financial disclosures. Other researchers report equity ownership in Foundation Medicine; a consultant role with Novartis; and research support from Genentech, Merck and Novartis.
Perspective
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Alberto J. Montero, MD, MBA
This is a really clinically relevant study. In addition to some of the other mutations like PIK3CA that we would normally expect, it confirmed that one of the most common mutations that happened over time in patients from the primary setting to the metastatic setting — or what is called an acquired mutation — is the ESR1 mutation. This was the most common mutation in patients with metastatic disease, and in more than 90% of cases, it was an acquired mutation.
We know certain treatments, such as fulvestrant, may be more effective in ESR1 mutations, so this study provides us the ability to use genomic information to tailor treatment. This is a really important finding … and it provides additional evidence why we probably should utilize ESR1 mutations to personalize treatment for patients and also in future clinical trials.
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