Abstract P5-14-06: Tumor Genomic Landscape in Older Women with Metastatic Breast Cancer (MBC)
Authors: Gupta Hersh V. , Freedman Rachel , Hughes Melissa E. , Li Yvonne Y. , Kirkner Gregory , Files Janet L. , Strauss Sarah , Garrido-Castro Ana C. , Buckley Lauren , Barroso-Sousa Romualdo , Bychkovsky Brittany , Tolaney Sara , MacConaill Laura , Lindeman Neal , Johnson Bruce , Meyerson Matthew , Winer Eric , Dillon Deborah A. , Cherniack Andrew , Lin Nancy U. 
Published: March 2023

Background. Patients (pts) who develop MBC at older ages are underrepresented in clinical trials, are less likely to be included in comprehensive biomarker characterization studies, and experience worse breast cancer-specific survival than their younger counterparts. Elucidating genomic underpinnings of MBC and possible therapeutic targets for older breast cancer patients are critical priorities. Methods. We identified pts age &gt;70 years at MBC diagnosis and a younger cohort (ages 50-69; age &lt; 50), who were treated for MBC at a single center and who had their metastatic (or if not available, the primary) tumor, assessed by a targeted, tumor-only next generation sequencing (NGS) platform (OncoPanel) between 2013-2020. The NGS panel included mutations, copy number variation, tumor mutational burden (TMB), and hypermutation (HM) status, with mutations classified as oncogenic using the OncoKB tool and additional annotation. Copy number events were selected as being “oncogenic” if a high amplification was called for an oncogene or a deep deletion for a tumor suppressor. We compared findings for older (age &gt;70) vs. younger (age &lt; 50 and ages 50-69) MBC pts using Chi-Square and Kruskal-Wallis tests. To determine genomic event enrichment, logistic regression (LR) models were used, controlling for age (continuous), background rate, and tumor subtype (those with unknown subtype [n=27] were excluded from models). False discovery rate (FDR) was used to correct for multiple hypothesis testing. Results. The final analytic cohort included 2,380 pts. The median age at MBC diagnosis was 54.1 years overall (range 18.5- 91.9) and 73.6 years for those age &gt;70. A total of 137 metastatic and 76 primary tumors were sequenced in pts age &gt;70; in those age &lt; 70, 1383 metastatic and 784 primary tumors were sequenced (for age &lt; 50 [n=857] and 50-69 [n=1310]). Older pts were more likely to present with HR+/HER2- tumors (70.9% v. 62.4% v. 52.4%), and less likely to present with HER2+ (9.4% v. 14.4% v. 22.8%) or triple-negative breast cancer (TNBC) (18.8% v. 21.9% vs. 24.0%) at MBC diagnosis (listed &gt;70, 50-69, &lt; 50; P=1e-7). Older pts had higher average TMB vs. younger pts (9.57 in pts &gt; 70, 8.56 in ages 50-69, 7.34 in ages &lt; 50; P=3.5e-5). This was due to older pts having a higher incidence of hypermutation status as defined as TMB &gt;10: 26.3% in age &gt;70, 23.2% in ages 50-69, 16.8% in age &lt; 50. Using q=0.1 as the threshold of significance, the presence of CDH1, PIK3CA, MAP3K1, TET2, and AKT oncogenic mutations were also enriched in older pts, while the presence of oncogenic GATA3, BRCA2, and TP53 mutations, as well as any mutation in BRCA1 were enriched in younger pts (too few oncogenic BRCA1 mutations were present for accurate modeling). The frequency of oncogenic PIK3CA mutations in HR+/HER2- tumors was highest in the oldest pts (44.4% in pts age &gt;70 v. 31.6% in age 50-69 v. 26.7% in age &lt; 50). Of pts who had oncogenic BRCA1/2 mutations identified on tumor-only NGS testing and underwent clinical germline testing (n=7 v. 60 v. 67, oldest to youngest), older pts had the lowest incidence of germline BRCA pathogenic variants (14.3% vs. 47.2.% vs. 67.2%; p=0.01); most BRCA mutations identified on NGS testing in older patients were considered likely somatic. When assessing enrichment in copy number events, ERBB2, RAD21, and BRIP1 amplifications were all significantly less frequent in older pts (q&lt; 0.1), even when accounting for tumor subtype. Conclusions. In a large cohort of pts with MBC, the mutational and copy number landscape for older pts differs from that in younger pts, even after controlling for tumor subtype. Key actionable findings include a higher proportion of high TMB and PIK3CA-mutated tumors, emphasizing the importance of genomic profile testing in this pt population and further exploration of efficacy and tolerability of relevant therapies in those age &gt;70 years.

Citation Format: Hersh V. Gupta, Rachel Freedman, Melissa E. Hughes, Yvonne Y. Li, Gregory Kirkner, Janet L. Files, Sarah Strauss, Ana C. Garrido-Castro, Lauren Buckley, Romualdo Barroso-Sousa, Brittany Bychkovsky, Sara Tolaney, Laura MacConaill, Neal Lindeman, Bruce Johnson, Matthew Meyerson, Eric Winer, Deborah A. Dillon, Andrew Cherniack, Nancy U. Lin. Tumor Genomic Landscape in Older Women with Metastatic Breast Cancer (MBC) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P5-14-06.