Abstract P2-07-02: Genomic predictors of rapid progression to first line endocrine and CDK4/6 inhibitor combination therapy in patients with estrogen receptor positive (ER+) HER-2 negative (HER2-) advanced breast cancer (ABC)
Authors: Velimirovic Marko , Gerratana Lorenzo , Davis Andrew A , Hensing Whitney L , Clifton Katherine , Shah Ami N , D'Amico Paolo , Dai Charles S , Denault Elyssa N , Ma Cynthia X , Wander Seth A , Juric Dejan , Cristofanilli Massimo , Chabner Bruce A , Bardia Aditya 
Published: March 2022

Background: Endocrine therapy with CDK 4/6 inhibitors (ET/CDK4/6i) represents the 1st line therapy for ER+/HER2- ABC. While majority of patients derive clinical benefit with combination therapy, a subset have refractory disease with progression within 6 months. However, predictive biomarkers for rapid progression are lacking. In this study, we evaluated genomic profiles associated with rapid disease progression on ET/CDK4/6i. Methods: We identified 77 patients who received 1st line ET/CDK4/6i combination therapy (AI or SERD with one of the 3 approved CDK4/6is) and had ctDNA analysis performed via plasma based genotyping utilizing the commercially available Guardant360 assay at three sites: Washington University in St. Louis, MO, Northwestern University (Chicago, IL), and Massachusetts General Hospital (Boston, MA). We aimed to look at the differences in patient characteristics and genomic profiles of the tumors assessed from baseline ctDNA specimens between the patients with rapid progression (time to progression TTP&lt;=6 months) vs others. In particular, we focused on growth factor receptors (FGFR, EGFR) given that previous studies have shown that activation of FGFR1 and EGFR signaling may be implicated in resistance to endocrine based therapy in breast cancer. Time to progression was estimated by using Cox regression. Variable associations were estimated via logistic regression. Results: In the combined cohort, FGFR1 amplification (FGFR1amp) was detected in 15/77 patients (19.5%). FGFR1amp was seen in 5/10 (50%) of patients with rapid progression, consistent with existing knowledge that FGFR1amp contributes to resistance to CDK4/6i and/or ET. Presence of FGFR1amp was independently associated with shorter TTP (11.2 vs. 34.7 months, HR=3.14, p=0.02). EGFR mutations (EGFRmut) were detected in 8/77 (10.4%) patients, 3 of which were found among patients with rapid progression and another 5 among those with TTP&lt;=15 months. Presence of EGFRmut was also associated with shorter TTP (8.5 vs. 31.7 months, HR=6.50, p&lt;0.001) in multivariable analysis. Of the 4 patients with shortest TTP (&lt;3 months) 3 harbored both FGFR1amp and EGFRmut. In another 3 patients we observed FGFR1amp and co-activation of genes implicated in G1/S phase cell cycle transition, suggesting that FGFR1 amplified cells may require a co-activating downstream event that ultimately, via multiple pathway cross-talk, renders them resistant to ET/CDK4/6 inhibition. Patients with FGFR1 amplified tumors were younger compared to those without FGFR1amp (54.3 vs. 62.7 years, p=0.04). Presence of FGFR1amp was associated with presence of liver (p=0.01) but not bone or lung metastases which could be one of the explanations why patients with higher liver tumor burden are more resistant to ET/CDK4/6i inhibition. PIK3CA and TP53 gene mutations in our cohort were frequent (found in 41% and 30% of the patients, respectively) but were independently not associated with TTP (PIK3CAmut+ HR=1.31, p=0.55, TP53mut+ HR=0.67, p=0.36). ESR1 mutations were rarely encountered (9%) as the cohort had only been exposed to adjuvant endocrine therapy. Conclusions: These findings highlight how ctDNA can be used for patient stratification prior to initiation of first line of therapy in ER+/HER2- ABC since it is evident that not all patients derive the same benefit from ET/CDK4/6i. Certain genomic alterations, particularly in FGFR1, EGFR, and G1/S phase cell cycle transition are associated with rapid progression to 1st line ET/CDK4/6i therapy, and highlight the need for clinical trials investigating combination/novel therapies for this subgroup of patients with HR+/HER2- ABC. Our findings are hypothesis-generating and require further exploration in larger datasets.

Citation Format: Marko Velimirovic, Lorenzo Gerratana, Andrew A Davis, Whitney L Hensing, Katherine Clifton, Ami N Shah, Paolo D'Amico, Charles S Dai, Elyssa N Denault, Cynthia X Ma, Seth A Wander, Dejan Juric, Massimo Cristofanilli, Bruce A Chabner, Aditya Bardia. Genomic predictors of rapid progression to first line endocrine and CDK4/6 inhibitor combination therapy in patients with estrogen receptor positive (ER+) HER-2 negative (HER2-) advanced breast cancer (ABC) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-07-02.