Abstract PO4-05-06: Hormone receptor-positive HER2-low metastatic breast cancer (mBC): evolution of HER2 status after CDK4/6 inhibitor treatment

Abstract Background Trastuzumab deruxtecan (T-DXd) is approved for HER2-low but not HER2-0 mBC. Therefore, identifying HER2-low status is of great clinical importance. Prior studies have shown HER2-low status is dynamic between primary tumor and metastatic relapse and between primary tumor and post-neoadjuvant chemotherapy residual tumor, and expert recommendations are to reiterate biopsies throughout the course of the disease. However, there is no data on when to repeat these biopsies. We provide here the first data on the evolution of HER2-low status in hormone receptor-positive (HR+) mBC before and after endocrine therapy (ET) in association with CDK4/6 inhibitor (CDK4/6i). Methods: Patients with pre-CDK4/6i+ET tumor biopsy were identified from a single large academic center database. Patients with unknown HER2 status were excluded. Pathological, clinical, and demographic data were extracted from clinical files. HER2-low was defined as HER2 IHC 1+, or 2+ with non-amplified HER2 by ISH, and HER2-0 by IHC score of 0+. Pathology central review for all paired pre- and post-treatment biopsies was performed by three expert breast cancer pathologists. Results: 304 consecutive patients with HR+/HER2- mBC treated with CDK4/6i+ET and who had immediate pre-treatment biopsy were included. Of these, 117 (38%) were HER2-0, and 187 (62%) were HER2-low. Clinical and demographic data did not differ between both groups. Patients received CDK4/6i+ET as first-line treatment in 48% of cases. Among this cohort, 49 patients had paired biopsies immediately after CDK4/6i+ET treatment. The discordance rate between pre- and post-CDK4/6i+ET HER2-status was 51% with 64% of HER2-0 patients becoming HER2-low and 38% of HER2-low switching to HER2-0. Among the 49 patients with paired biopsies, 43 had available material to perform a central pathology review. Of these, 22 (51%) were HER2-0, and 21 (49%) were HER2-low. Central pathology review showed a concordance level of 82% with pathology records, resulting in a modification of HER2 status in 7 HER2-0 patients as HER2-low, leading to a total of 65% of patient’s eligibility to T-DXd. Post-CDK4/6i+ET biopsy identified a switch to HER2-low in 10 additional HER2-0 patients resulting in a total of 38/43 (88%) candidates to T-DXd. No case became HER2 3+ after treatment. Neither baseline HER2 status, nor change in HER2 status after treatment affected the clinical outcome on CDK4/6i+ET (objective response, progression-free survival, overall survival). Conclusion: HER2-low status is dynamic, and 64% of mBC HER2-0 patients switched to HER2-low after a line of CDK4/6i+ET treatment. Since such a switch would guide post-progression treatment with T-DXd in patients initially not candidate, these results suggest that biopsy should be repeated early in the course of mBC to assess eligibility for T-DXd therapy. Our central pathology review of pre-treatment biopsies reclassified 24% of HER-0 patients as HER2-low, suggesting that pathology review is a legitimate first step before repeating biopsy or in the case of difficulty to re-biopsy. In our series, 88% of patients had a biopsy sample classified as HER2-low after pathological review of pre-treatment slides, followed by post-CDK4/6i+ET rebiopsy of HER2-0 cases. Citation Format: Alexandre de Nonneville, Pascal Finetti, Laurys Boudin, Lucas Usclade, Lenaïg Mescam, Emeline Durieux, Agathe Boucraut, Frederic Viret, Emilie Mamessier, Anthony Gonçalves, François Bertucci. Hormone receptor-positive HER2-low metastatic breast cancer (mBC): evolution of HER2 status after CDK4/6 inhibitor treatment [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-05-06.