Abstract PD6-08: Exploring the interplay among ESR1/PIK3CA codon variants, oncogenic pathway alterations and clinical phenotype of metastatic breast cancer (MBC) through circulating tumor DNA (ctDNA) next-generation sequencing (NGS)

Abstract

Abstract Background: High throughput genomic technologies such as NGS are enhancing the ability to dynamically characterize MBC but their role in describing biological evolution of multiple mutations together remains unclear. ESR1 and PIK3CA are central mutations related to the biology and druggability of hormone-receptor positive, HER2 negative (luminal-like) MBC. The aim of this study was to explore the interplay between oncogenic pathway alterations and ESR1 and PIK3CA codon variants on the impact and clinical phenotype of luminal-like MBC. Methods: The study retrospectively analyzed a multi-institutional cohort comprising 1047 MBC patients (pts) characterized for ctDNA through NGS before treatment start at Northwestern University (Chicago, IL), Massachusetts General Hospital (Boston, MA) and Washington University in St. Louis between 2015-2020. The analysis was then focused on luminal-like MBC. Pathway classification was defined based on previous work (Sanchez-Vega F et al, Cell. 2018) (i.e., RTK, RAS, RAF, MEK, NRF2, ER, WNT, MYC, P53, cell cycle, notch, PI3K). Single nucleotide variations (SNVs) were annotated for their oncogenicity through OncoKB and ClinVar. Only pathogenic variants were included in the models. Associations among, pathway classification, and ESR1/PIK3CA codon variants were explored through stepwise logistic regression. Overall survival (OS) was tested through Cox regression. Results: The luminal-like cohort comprised 702 pts. ESR1 mutations were detected in 166 pts (24%) and PIK3CA in 214 pts (31%). The most common ESR1 gene mutations were found in codons 537 (31%), 538 (21%), 536 (8%) and 380 (7%), while alterations in codons 1047 (38%), 545 (25%), and 542 (20%) were the most common for PIK3CA. Other pathogenic SNVs were observed in 33% and 17% of pts for ESR1 and PIK3CA, respectively with the former being polyclonal. SNVs alterations were mainly observed in the PI3K (35%), P53 (32%), ER (28%), RAS (8%), RTK (8%) and cell cycle (5%) pathways, while copy number variations (CNVs) were detected in the RTK (15%), cell cycle (11%), MYC (7%) PI3K (6%) and RAF (5%) pathways. ESR1 537 variants were associated with alterations in the ER and WNT pathways, 538 with cell cycle, 380 with P53 and ER, 536 with RTK. PIK3CA 1047 variants were associated with alterations in the RTK and P53 pathways, 542 with RTK, RAS and RAF, E545 with PI3K, RAS, cell cycle and P53. 1047 and 542 were also associated with CNVs in the PI3K pathway. Independent prognostic factors in terms of OS were ESR1 537/380 codon variants (HR 1.94 P = 0.001 and HR 2.29 P = 0.047), SNVs in the RAS, cell cycle, and P53 pathways (HR 1.74 P = 0.003 HR 1.84 P = 0.009 and HR 1.56 P < 0.001) and CNVs in the cell cycle pathway (HR 1.96 P < 0.001). Conclusions: This study demonstrated how ESR1 and PIK3CA codon variants, together with alterations in specific oncogenic pathways, can differentially impact the biology and clinical phenotype of luminal-like MBC. As novel endocrine therapy agents such as selective estrogen receptor degraders (SERDs) and PI3K inhibitors are being developed, these results highlight the pivotal role of ctDNA NGS to describe tumor evolution and optimize clinical decision making. Odds Ratio95% Confidence IntervalPESR1 Y537ER SNVs3.341.487.530.004WNT SNVs6.251.4127.740.016ESR1 D538cell cycle SNVs5.221.7915.230.003ESR1 E380P53 SNVs4.801.4116.310.012ER SNVs5.331.3321.400.018ESR1 L536RTK CNVs4.511.1517.690.031PIK3CA H1047RTK SNVs3.751.708.290.001P53 SNVs2.611.584.34< 0.001PI3K CNVs6.082.4515.08< 0.001PIK3CA E542RTK SNVs5.001.9412.880.001RAS SNVs3.651.369.770.01RAF SNVs6.011.0733.870.042PI3K CNVs6.302.2917.36< 0.001PIK3CA E545PI3K SNVs2.881.276.530.011RAS SNVs2.871.186.980.02cell cycle SNVs3.071.088.740.035NRF2 SNVs21.431.29356.520.033P53 SNVs3.752.046.89< 0.001 Citation Format: Lorenzo Gerratana, Andrew A Davis, Marko Velimirovic, Katherine Clifton, Whitney L Hensing, Ami N Shah, Charles S Dai, Carolina Reduzzi, Paolo D’Amico, Qiang Zhang, Firas Wehbe, Seth Wander, William J Gradishar, Amir Behdad, Fabio Puglisi, Cynthia X Ma, Aditya Bardia, Massimo Cristofanilli. Exploring the interplay among ESR1/PIK3CA codon variants, oncogenic pathway alterations and clinical phenotype of metastatic breast cancer (MBC) through circulating tumor DNA (ctDNA) next-generation sequencing (NGS) [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 PD6-08.