Abstract P3-03-30: Molecular landscape of breast cancer in pre- and postmenopausal women

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Abstract Background: Breast cancer (BC) in younger women is often more aggressive and diagnosed at a later stage. The choice of endocrine therapy (ET) for women with hormone-receptor positive (HR+) BC varies based on whether she is premenopausal (preM) or postmenopausal (postM): tamoxifen is usually selected for preM women, while postM women receive aromatase inhibitors (AIs). Approximately 20-30% of advanced HR+ BCs will develop ET resistance and progress on first-line therapy. Whether at progression or in the advanced/metastatic setting, comprehensive genomic profiling (CGP) may provide subsequent-line treatment options, including molecularly matched therapies. Evidence suggesting preM women with HR+ tumors have poor persistence with ET underscores the importance of identifying targets for later-line therapy to improve clinical outcomes for these younger patients. This study investigates the difference in biomarker alterations in preM and postM BC.. Methods: A retrospective analysis of BC samples analyzed with the OncoExTra® assay, which identifies somatic mutations and gene fusions by whole exome DNA sequencing and whole transcriptome sequencing, was performed. Because menopausal status was not available, patients were classified as preM or postM based on age: patients aged ≤50 years were considered preM, and those >50 years were considered postM. The frequency of alterations in preM and postM HR+ BC was determined separately for samples collected from primary and metastatic sites. Potential associations between alterations and subgroups were evaluated using Fisher’s Exact Test and the Benjamini-Hochberg False Discovery Rate procedure. Results: We analyzed 2,573 BC samples with non-missing age, including 772 (30.0%) samples from preM women and 1,801 (70.0%) samples from postM women. Most samples were HER+/HER2- (1,721 (66.9%)), with smaller proportions of HER2+ (369 (14.3%)), triple-negative BC (TNBC; 377 (14.7%)), and not otherwise specified (106 (4.1%)) samples. In HR+/HER2- BC, alterations in several genes were more frequent in preM compared to postM samples, including: BRCA1 (3.4% vs 0.6%), TP53 (28.5% vs 21.1%), IGF1R (5.3% vs 1.5%), MYC (3.6% vs 1.3%), PPM1D (3.8% vs 1.4%), and GATA3 (19.5% vs 12.2%) (P<0.01 for all comparisons). Conversely, alterations in the following genes were significantly higher in postM compared to preM HR+/HER2- BC samples: alterations in PIK3CA that serve as an FDA-approved companion diagnostic biomarker (CDx; 45.0% vs 35.5%) and PIK3CA non-CDx alterations (7.3% vs 4.5%) as well as ESR1 (8.8%% vs 5.1%), MAP3K1 (11.4% vs 7.4%), and CDH1 (18.5% vs 11.3%) alterations (P<0.05 for all comparisons). In HER2+ BC, ESR1 alterations (5.1% vs 0.7%) were more frequent in postM compared to preM BC, while ERBB2 alterations were more frequent in preM compared to postM BC (79.9% vs 69.8%) (P<0.05 for both comparisons). In TNBC, BRCA1 (18.8% vs 3.6%) and KIT (3.9% vs. 0.0%) alterations were significantly higher in preM compared to postM samples (P<0.01 for both comparisons). BRCA1, IGF1R, and PPM1D alterations predominantly occurred in metastatic preM BC samples (P<0.01 for all comparisons). Also, PIK3CA alterations predominantly occurred in primary postM BC, including both CDx (32.0%) and non-CDx (5.5%) alterations. ESR1 alterations, including mutations, fusions, and amplifications, were present in 21.8% of metastatic postM BC tumors, while ESR1 CDx mutations were found in 15.9% of these tumors. Conclusion: Our analysis uncovered therapeutically relevant differences in biomarker alterations between preM and postM BC. The higher frequency of ESR1 alterations in HR+/HER2- BC samples from postM women may indicate a resistance mechanism to AIs, as postM women with HR+ BC are commonly treated with this class of drugs. Additionally, the frequency of BRCA1 alterations was significantly higher in TNBC as well as HR+/HER2- preM BC. [CR1] [JH2]. I would eliminate this last sentence. This is intuitive and seems self-serving from a CGP-company. [CR1]agree -- at a minimum suggest replacing "increases" with "may have the potential to increase" Citation Format: Sameer Udhane, Pawan Noel, Fadel Alyaqoub, Ariane Kemkes, Cynthia Flannery, Nishitha Therala, Angela Deem, Jean-Paul De La O, Gargi Basu. Molecular landscape of breast cancer in pre- and postmenopausal women [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P3-03-30.

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