American Association for Cancer Research Annual Meeting

American Association for Cancer Research Annual Meeting

Perspective from Natalie Berger, MD
April 28, 2020
3 min read
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ESR1 mutations predict survival, endocrine therapy failure in early breast cancer

Perspective from Natalie Berger, MD
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Although ESR1 mutations are rare at the time of primary breast cancer diagnosis, they predict eventual resistance to standard adjuvant hormone therapy, according to study results presented at the virtual American Association for Cancer Research Annual Meeting.

“If replicated, it could be clinically relevant to screen for resistance mutations in ER-positive disease to aid the clinician when deciding on the best course of treatment,” Malin Dahlgren, doctoral student in oncology and pathology at Lund University in Sweden, said during a presentation. “For example, other evidence suggests that [ER] degraders such as fulvestrant had greater efficacy against ESR1 mutations than modulators or aromatase inhibitors.”

Estrogen receptor alpha is encoded by the ESR1 gene. More than 75% of primary breast cancers are ER positive, for which antiestrogenic endocrine therapy is a standard treatment.

The ESR1 mutation has been established as an acquired mechanism of resistance to adjuvant endocrine therapy, having been reported in approximately one-third of metastatic breast cancers and primarily among those treated with adjuvant endocrine therapy.

Dahlgren and colleagues aimed to characterize ESR1 resistance mutations in primary breast cancer, both in terms of frequency and their association with outcomes and response to endocrine treatment.

The researchers analyzed 3,217 real-world and population-based early-stage primary breast cancers from SCAN-B, a prospective observational study that includes more than 15,000 patients from 10 hospitals in Sweden.

Researchers sampled treatment-naive tissues from initial diagnosis and used RNA sequencing to evaluate for ESR1 mutations. They verified mutations by droplet digital polymerase chain reaction.

RNA sequencing showed ESR1 mutations occurred in 0.9% (n = 30) of primary breast tumors — all but one of which were ER positive — and 1.1% of ER-positive tumors.

The most common mutation was E380Q (n = 10), followed by Y5357S/Y5357C (n = 8), D538G (n = 5) and S463P (n = 5).

Patients found to have ESR1 resistance mutations generally were similar to the larger population of endocrine therapy-treated patients with regard to lymph node status, tumor grade distribution, PR status and rate of HER2-positive disease. Treatments were similar between those groups, as well, with 37% of cases in each group receiving chemotherapy.

Mutant allele frequencies ranged from 2% to 100%.

“We used droplet digital polymerase chain reaction assays for the most frequently occurring hot spots,” Dahlgren said. “We validated their presence in tumor DNA and confirmed 18 out of 18 mutations, with the allele frequencies being generally similar in DNA and RNA. We also had blood available for 11 patients, and we could verify the mutations were somatic in all of these cases.”

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Investigators then analyzed patients who received endocrine therapy, comparing outcomes between those with ESR1 mutations and ESR1 wild-type disease. ESR1 mutations appeared significantly associated with poorer OS (P = .008) and relapse-free interval (P = .007).

“Interestingly, for two of the patients, we also obtained material from tumor relapses and could confirm presence of the same resistance mutations at similar allele frequencies as the primary tumors,” Dahlgren said.

Although the total number of ESR1-mutated tumors was low, researchers performed multivariable analysis adjusting for factors that included age, tumor size, lymph node status, tumor grade and tumor stage.

The unadjusted HR for OS with ESR1 mutation was 2.5. On multivariable analysis, adjusted HRs ranged from 2.1 to 2.6, which were statistically significant for all variables but lymph node status.

Multivariable analysis for relapse-free interval showed ESR1 mutation was an independent factor in all comparisons. The unadjusted HR was 3.6, and HRs in multivariable models ranged from 3.6 to 4.5.

“These results suggest that mutant tumors carry approximately a four times higher risk for relapse at any given time, regardless of adjustment for other factors,” Dahlgren said. – by Mark Leiser

Reference:

Dahlgren M, et al. Abstract CT074. Presented at: AACR Annual Meeting; April 27-28, 2020 (virtual meeting).

Disclosures: Dahlgren reports no relevant financial disclosures. Please see the abstract for all other researchers’ relevant financial disclosures.