Abstract PD15-05: Assessment of estrogen receptor (ESR1) mRNA expression for prediction of extended aromatase inhibitor benefit in HR-positive breast cancer using NRG Oncology/NSABP B-42
Authors: Mamounas Eleftherios , Bandos Hanna , Rastogi Priya , Crager Michael R , Mies Carolyn , Lucas Peter C , Geyer Charles E , Fehrenbacher Louis , Graham Mark L , Chia Stephen KL , Brufsky Adam M , Walshe Janice M , Soori Gamini S , Dakhil Shaker R , Paik Soonmyung , Swain Sandra M , Baehner Frederick L , Shak Steven , Wolmark Norman 
Published: March 2022

Abstract
Background: In NSABP B-14, the quantitative levels of ESR1 mRNA, assessed using the standardized 21-gene assay and qRT-PCR platform predicted tamoxifen benefit (interaction p-value &lt;0.001). NSABP B-42 evaluated the effect of extended letrozole in postmenopausal women with hormone receptor-positive breast cancer who have completed 5 years of hormonal therapy with either an aromatase inhibitor or tamoxifen followed by an aromatase inhibitor. We proposed to determine if ESR1 mRNA, reported as the quantitative ER single gene score, is predictive of the magnitude of benefit from extended adjuvant endocrine therapy with letrozole in patients enrolled in NSABP B-42. Methods: This prospectively planned retrospective study used a stratified cohort sample drawn from the 2,589 B-42 patients with available tumor tissue blocks and appropriate consent. All 133 patients who experienced distant recurrence and 48 patients who experienced local/regional but not distant recurrence were included along with a stratified random sample of 547/2,408 patients without recurrence. The primary endpoint was distant recurrence. The primary analysis tested for the interaction between the continuous ER single gene score and the effect of extended letrozole treatment using a weighted Cox proportional hazards regression model. A secondary analysis considered the ER single gene score categorized using the prespecified cutoff of ≤9.1 versus &gt;9.1. Recurrence-free interval was a secondary endpoint. Results: The results of the assay were available for 587 patients. The median ER score was 10.2 (IQR 9.3-11.0). There were 131 patients (23.2% weighted) with ER ≤9.1 and 456 (76.8% weighted) with ER &gt;9.1. No significant interaction of the effect of extended letrozole treatment was found for either the ER single gene score (interaction hazard ratio letrozole vs. placebo with an IQR change in ER score 1.10, 95% CI 0.66 - 1.82, p=.72) or the categories ER ≤9.1 (treatment HR=0.40, 95% CI 0.15-1.06) or ER &gt;9.1 (treatment HR=0.70, 95% CI 0.43-1.12) (interaction p=.32). There was also no apparent prognostic effect of the ER single gene score for distant recurrence with placebo treatment after 5 years of endocrine therapy (p=.12). Results were similar in analyses of any recurrence, analyses adjusting for the proliferation axis from the 21-gene assay, and subgroup analyses by nodal and HER2-status. Conclusions: The B-42 study provided no evidence that ESR1 mRNA as measured by the ER single gene score can inform decisions regarding extended letrozole therapy after 5 years of adjuvant endocrine therapy. Confidence intervals were relatively wide but rule out a strong predictive effect of the ER single gene score in the expected direction. Support: U10CA180868, -180822, U24CA196067; Novartis; Exact Sciences
Citation Format: Eleftherios Mamounas, Hanna Bandos, Priya Rastogi, Michael R Crager, Carolyn Mies, Peter C Lucas, Charles E Geyer, Jr, Louis Fehrenbacher, Mark L Graham, Stephen KL Chia, Adam M Brufsky, Janice M Walshe, Gamini S Soori, Shaker R Dakhil, Soonmyung Paik, Sandra M Swain, Frederick L Baehner, Steven Shak, Norman Wolmark. Assessment of estrogen receptor (ESR1) mRNA expression for prediction of extended aromatase inhibitor benefit in HR-positive breast cancer using NRG Oncology/NSABP B-42 [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD15-05.