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Poor Endocrine Therapy Response in Primary Breast Cancer Possibly Explained by Rare ESR1 Mutations

NEW YORK – Mutations in the estrogen receptor alpha-coding gene ESR1 appear to occur in a small subset of primary breast cancer tumors, potentially providing a window into cases with poorer-than-usual responses to adjuvant, endocrine-based treatments.

Several prior studies suggest activating mutations in ESR1 can contribute to treatment resistance in metastatic breast cancer cases, explained Malin Dahlgren, a doctoral student in Lao Saal's oncology and pathology lab at Lund University.

But less work has been done to untangle the treatment outcomes associated with ESR1-mutated primary breast cancer cases, if any, according to Dahlgren, who presented the work online on Monday during the American Association for Cancer Research's Virtual Annual Meeting.

"Thus far, the majority of research has focused on the ESR1 mutation as an acquired resistance mechanism," Dahlgren noted. "Whereas mutation occurs in about a third of metastatic disease, analyses of early-stage primary breast cancers have shown that primary ESR1 mutation is rather rare, occurring in about 1 percent of tumors."

To explore the potential treatment response and prognostic consequences of those mutations, she and colleagues from Lund University dug into data collected for breast cancer patients from Sweden, who enrolled in a prospective, observational population study known as SCAN-B. In that study, researchers have been doing genomic profiling on newly diagnosed primary breast cancer patients from 10 hospitals across that country for a decade.

The study has reportedly enrolled more than 15,000 breast cancer patients since 2010, including 10,000 patients who had their tumors assessed with RNA sequencing not long after surgery, Dahlgren said. She noted that the patients have been treated uniformly in accordance with Sweden's national guidelines over the course of the study, making it possible to get a glimpse at treatment responses and outcomes in cases with or without the alterations in ESR1.

"The aim of the study was, first, to ascertain the frequency of primary ESR1 mutations in a population-based cohort and, second, to see whether ESR1 mutations that are present in primary tumors prior to any adjuvant treatment would predict failure of standard endocrine therapies," she explained.

Past studies have unearthed more than 60 mutations in ESR1, Dahlgren noted, with many of these turning up in the portion of the gene that codes for the estrogen receptor's C-terminal ligand binding domain.

At least a subset of those alterations have been functionally found to increase estrogen receptor activity, even when estrogens such as estradiol are not present or when estrogen-blocking drugs such as tamoxifen are used, she added, helping breast cancer cells swerve around such therapeutic roadblocks.

Hints from the new analysis suggest that pattern may hold for some of the ESR1 mutations found in primary breast cancers as well, since patients with ESR1-mutated tumors fared worse on endocrine treatment, showing significant dips in overall survival and progression-free survival.

The researchers searched for more than a dozen ESR1 mutations known for contributing to endocrine treatment resistance using RNA-seq data generated for pre-treatment tumor samples from 3,217 primary breast cancer patients followed over time for SCAN-B. They used a computational pipeline developed to call mutations directly from tumor RNA sequences. The approach unearthed a subset of primary breast cancer cases marked by ESR1 mutations — findings they confirmed with a method known as SAGASafe digital PCR.

Compared to metastatic endocrine-resistant breast cancers cases, where ESR1 mutations have been documented in anywhere from 12 percent to 55 percent of tumors, the team saw ESR1 mutations in 0.9 percent of primary breast cancers overall, and 1.1 percent of the estrogen receptor (ER)-positive cases. That roughly lines up with findings from the Cancer Genome Atlas project, where some 0.8 percent of primary breast cancers contained an ESR1 mutation, Dahlgren said.

After confirming that the detected mutations were somatic in a subset of cases with accompanying blood samples, the team took a look at patient outcomes. They found that the presence of ESR1 mutations tracked with endocrine treatment failure, poorer overall survival, and shorter relapse-free survival times, despite receiving comparable treatments and having broad similarities to breast cancer cases with wild type ESR1.

"These results indicate that ESR1 mutations at diagnosis in untreated primary breast cancers are rare. However, we confirmed for the first time that such early mutations predict eventual resistance to standard hormone therapy in the adjuvant setting," Dahlgren said. "If replicated, we suggest that it could be clinically relevant to screen for resistance mutations in ER-positive disease to aid clinicians deciding on the best course of treatment."

While it remains to be seen which tissue type is best suited for the analysis, the data suggest that ESR1 mutations may predict endocrine therapy resistance and worse outcomes, noted Ben Ho Park, director of precision oncology at Vanderbilt University's Vanderbilt-Ingram Cancer Center and co-leader of its breast cancer research program, who discussed these findings at the AACR meeting.

The analysis did not distinguish between the prevalence of ESR1-mutated primary breast cancers in women who were pre- or post-menopausal, which may help to untangle potential interactions between hormone levels and ESR1-mutated tumor prevalence, he added.

Likewise, Park noted that it remains to be seen whether there are biological differences between primary and metastatic tumors marked by ESR1 mutations, and more research will be needed to explore the contributors and consequences of ESR1 hotspot mutations.

Based on results available so far, though, Park noted that it may eventually become possible to screen for primary breast cancer patients who are unlikely to respond well to endocrine therapy and who might benefit from alterative treatment strategies, such as CDK4/6 inhibitor treatment trials.