Abstract PS16-04: Differences in breast cancer phenotype by germline TP53 variant functional classification

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Abstract Introduction: TP53 is a multi-functional tumor suppressor gene, with several important roles in tumorigenesis. Females who harbor germline TP53 pathogenic/likely pathogenic variants (GPV) have a very high lifetime risk of developing breast cancer (BC), especially hormone receptor positive and HER2 positive tumors. Specific TP53 variants have different functional consequences for molecular pathways and somatic aberrations in cancers, leading to the hypothesis that the type of TP53 GPV could modulate breast tumor phenotype. Objective: To examine differences in TP53 GPV and their predicted functional impact on age at first BC diagnosis and BC subtype (ER and HER2 status). MATERIAL AND METHODS: This multicenter international cohort was comprised of female TP53 GPV carriers diagnosed with any invasive BC (non-metastatic or de novo metastatic). We included TP53 variants classified as GPV in ClinVar, or classified as GPV by at least one major laboratory, or truncating variants. Carriers of a second GPV in other BC genes and carriers of TP53 GPV downgraded to a variant of uncertain significance by the TP53 ClinGen-VCEP were excluded. Clinical data were abstracted from medical records. TP53 GPV were classified according to mutation type: nonsense, frameshift, missense affecting the DNA binding domain (Missense_DBD) or the tetramerization domain (Missense_TD), variants affecting splicing, and copy number variations. For this report, functional classification was performed using Fortuno’s classification based on two germline TP53 databases from commercial labs. Functional classification categories included: missense variants with dominant negative effect (Missense_DNE) and without DNE (Missense_notDNE), truncating and hotspots variants. The bivariate association between tumor phenotype and each of the variables (mutation type and Fortuno’s functional classification) was assessed using two-sample Wilcoxon test for continuous and Fisher’s exact test for nominal categorical variables. Results: Among 301 females who met study criteria,mean age of BC diagnosis was 37.0 years (SD 10.46), 187 (62.1%) met Li-Fraumeni syndrome clinical criteria (revised Chompret or Classic criteria), and 41 (13.6%) had bilateral synchronous BC. The distribution of BC subtypes was: 108 (35.9%) ER+/HER2-, 79 (26.2%) ER+/HER2+, 62 (20.6%) ER-/HER2+, 20 (6.6%) ER-/HER2-, and 32 (10.6%) ER unknown and/or HER2 unknown. Most TP53 GPV were missense variants (n=217; 141 Missense_DBD, 76 Missense_TD). In comparison to Missense_TD, Missense_DBD carriers had a younger age at BC diagnosis (35.7 vs 42.3, p<0.01), lower rates of ER+ disease (63.1% vs 80.3%, p<0.01), and higher rates of HER2+ disease (48.9% vs 27.6%, p<0.01). When considering ER and HER2 subtypes, Missense_TD carriers had more ER+/HER2- BC (51.3% vs 34.8%, p=0.02) and Missense_DBD carriers had more ER-/HER2+ tumors (22.0% vs 5.3%, p=<0.01). According to Fortuno’s classification, 89 (29.6%) TP53 GPV were Missense_notDNE, 59 (19.6%) Missense_DNE, 80 (26.6%) truncating, 49 (16.3%) hotspots variants, and 24 (8.0%) variants unclassified by the method. Among all these categories, Missense_notDNE variants were associated with older ages of BC diagnosis (51.7% above 40 years; p<0.001), higher rates of ER+ disease (79.8%; p<0.001), lower rates of HER2+ tumors (29.2%; p<0.001), and lower rates of bilateral synchronous BC (p=0.003). CONCLUSIONS: These findings suggest that TP53 GPV functional status can influence age at breast cancer presentation and tumor ER/HER2 status which can potentially improve targeted treatment strategies and inform risk prediction and risk reduction strategies. Citation Format: Renata L. Sandoval, Michele Bottosso, Miki Horiguchi, Natalia Polidorio, Anh Le, Brittany L. Bychkovsky, Benjamin Verret, Alessandra Gennari, Sophie Cahill, Alison Schwartz-Levine, Olivier Caron, Marion ImbertBouteille, Catherine Noguès, Pauline Rochefort, Kara N. Mawell, Maria Isabel Achatz, Fabrice Andre, Judy E. Garber. Differences in breast cancer phenotype by germline TP53 variant functional classification [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 PS16-04.

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