Abstract PO4-15-10: HER2-low Status among Patients with Li-Fraumeni Syndrome and Breast Cancer

Abstract

Abstract Background: The HER2-low status has gained significance as a target for HER2-directed antibody drug conjugates in breast cancer. It is observed in approximately 60% of hormone receptor-positive (HR+) tumors and 30% of hormone receptor-negative (HR-) tumors. Some studies suggest that the HER2-low status by itself does not influence tumor biology or prognosis. Breast cancer in the context of Li-Fraumeni (LFS) syndrome has been characterized by an enrichment in HER2-positive (HER2+, defined as +3 in the immunohistochemistry [IHQ] or +2 in the IHQ with positive in situ hybridization [ISH]) disease. Considering this, we aimed to evaluate whether LFS patients with breast cancer also exhibit a higher frequency of HER2-low status. Methods: This retrospective-prospective cohort study included patients diagnosed with breast cancer who had a pathogenic/likely pathogenic TP53 germline variant and were treated at two cancer institutions between 1999 and 2023. The primary objectives were to determine the overall proportion of HER2-low status and its distribution according to hormone receptor status. HER2-low was defined as IHQ +1 or IHQ +2 with negative ISH. Results: Fifty-three patients (52 female and 1 male) were included in the study. The most common germline TP53 variant was the TP53 R337H (71.7%). The median age at breast cancer diagnosis was 39 years (range 21–62). The majority of patients had breast cancer of no special type (79%) or lobular carcinoma (11.3%), grade 2 (54.7%) or grade 3 (24.5%), and stage I-II (67.9%). Breast cancer subtypes would classically be classified as HER2+ in 34%, HR+HER2- in 58.5%, and triple-negative breast cancer (TNBC) in 7.5% of the patients. Biopsy samples were obtained from the primary tumor in 96.3% of the cases and from lymph nodes in 3.7%. Overall, 15.1% of the cases exhibited HER2-low status, 34% were HER2-negative, and 17% were HER2-negative without IHC details (Table). In a hypothetical scenario assuming all cases without IHC details were HER2-low, the maximum estimated frequency of HER2-low status would be 32.1%. Among HR+ patients, 25.8% had HER2-low status, 45.2% were HER2-negative, and 29% were HER2-negative without IHC details. All four patients with TNBC exhibited HER2-zero status. Conclusion: Contrary to our initial hypothesis, the frequency of HER2-low status in this cohort of LFS patients with breast cancer was lower than anticipated. These results suggest that while breast cancer developing in the context of germline TP53 variants appears to be associated with HER2 amplification, it does not impact lower expressions of HER2. This observation reinforces the concept that HER2-low status does not seem to play a significant role as a driver of tumorigenesis. Further expansion of the study cohort and pathology analysis is planned to confirm these findings. Table HER2 status overall and according to hormone receptor-status (for HER2-negative patients). Abbreviations: IHQ, immunohistochemistry; HR+HER2- BC, hormone receptor-positive HER2-negative breast cancer; TNBC, triple-negative breast cancer. Citation Format: Luciana Auresco, Renata Colombo Bonadio, Vanessa Petry, Laura Testa, Camila Moniz, Jennifer Dos Santos, Maria Del Pilar Estevez-Diz, Rodrigo Santa Cruz Guindalini. HER2-low Status among Patients with Li-Fraumeni Syndrome and Breast Cancer [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 PO4-15-10.