Abstract 6744: Cell-free DNA detection of alterations in the MAPK pathway in metastatic hormone receptor positive breast cancer: A multi-institutional analysis of incidence and clinical outcomes
Authors: Medford Arielle J. , Niemierko Andrzej , Hensing Whitney L. , Davis Andrew A. , Clifton Katherine , Keenan Jennifer C. , Kiedrowski Lesli , Shah Ami N. , Gerratana Lorenzo , Cristofanilli Massimo , Bardia Aditya 
Published: April 2023

Abstract
Background Alterations in the MAPK pathway are known mechanisms for tumorigenesis in multiple solid tumors. While not major drivers in early breast cancers, activating MAPK pathway alterations have been invoked as potential resistance mechanisms in advanced hormone receptor positive (HR+) breast cancer. While MAPK pathway mutations are believed to be relatively rare in breast cancer, the accessibility of cell-free DNA (cfDNA) analysis allows for evaluation of their prevalence, co-occurring mutations, and associated clinical outcomes. In this study, we evaluated the incidence of MAPK pathway alterations and impact on clinical outcomes among patients with metastatic breast cancer (MBC).
Methods Plasma was collected in patients with HR+ MBC at the Massachusetts General Hospital and Washington University in St. Louis, and cfDNA was analyzed via the Guardant 360 assay, a 74-gene next generation sequencing panel. The impact of MAPK pathway alterations on progression-free survival (PFS) and overall survival (OS) was analyzed using multivariable Cox regression analysis, adjusting for age, number of prior therapies, visceral metastases, de novo metastases, and PIK3CA alterations. PFS and OS were evaluated in the overall study population, as well as in subgroups that received endocrine therapy + CDK4/6 inhibitor, endocrine monotherapy and chemotherapy.
Results Out of 647 HR+ MBC patients, 103 (16%) had non-synonymous mutations in the MAPK pathway detected in cfDNA. Median age was similar (61.9 and 60.7) in MAPK-altered and non-altered patients, respectively. Both groups had received a median of 2 prior lines of therapy (p=0.08). MAPK pathway alterations included NF1 (n = 45, 7.0%), KRAS (n = 22, 3.4%), BRAF (n = 22, 3.4%), MAPK1 (n = 8, 1.2%), MAP2K1 (n = 6, 0.9%), NRAS (n = 5, 0.8%), RAF1 (n = 5, 0.8%), HRAS (n = 4, 0.6%), ARAF (n = 4, 0.6%), MAP2K2 (n = 4, 0.6%), RIT1 (n = 3, 0.5%), and MAPK3 (n = 2, 0.3%). Mutant allele fractions ranged from 0.03 to 26. Co-alterations in PIK3CA occurred in 49% (n = 51), TP53 in 41% (n = 42), and ESR1 in 27% (n = 28). In multivariable analysis, patients with MAPK-altered HR+ MBC had significantly poorer median PFS, 7.6 months vs 11.5 months (HR: 1.6; p = 0.005; 95% CI: 1.2-2.2). There was no statistically significant impact on outcomes when stratifying by treatment type.
Conclusions MAPK pathway alterations are associated with a significantly poorer PFS among patients with HR+ MBC. Further research is needed to independently validate these observations and evaluate the impact of genotype-directed therapy targeting MAPK-altered, HR+ MBC.
Citation Format: Arielle J. Medford, Andrzej Niemierko, Whitney L. Hensing, Andrew A. Davis, Katherine Clifton, Jennifer C. Keenan, Lesli Kiedrowski, Ami N. Shah, Lorenzo Gerratana, Massimo Cristofanilli, Aditya Bardia. Cell-free DNA detection of alterations in the MAPK pathway in metastatic hormone receptor positive breast cancer: A multi-institutional analysis of incidence and clinical outcomes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6744.