Authors
Binbin Zheng, Ellen Jaeger, Cody Eslinger, Stamatina Fragkogianni, Unnati Jariwala, Kayla Viets Layng, Taro Shibuki, Daniel Ahn, Oluseyi Abidoye, Celine Hoyek, Angelo Pirozzi, Jeremy C. Jones, Christina Wu, Mitesh J. Borad, Mohamad B. Sonbol, John H. Strickler, Takayuki Yoshino, Masafumi Ikeda, Tanios Bekaii-Saab
Background – DNA damaging agents lead to improved outcomes in mPC with HRR deficiency (HRD), albeit its usage is restricted to <6-9% of patients (pts). We hypothesized BRCA/PALB2wt mPC may exhibit functional HRD based on HRR gene expression. We correlated HRR gene RNA levels with real-world overall survival (rwOS) from first-line (1L) platinum therapy (PT) in mPC.
Methods – De-identified records of pts with mPC diagnosis subjected to Tempus xT DNA and xR RNA assays were stratified by BRCA1/2 or PALB2 status (altered [alt] vs. wt). Pts receiving PT after 1L were excluded. In the wt cohort, pts were classified into high (≥ 75th percentile) vs. low expressors (≤ 25th percentile) based on log2(TPM+1) expression for each gene of interest (ATM, BAP1, BARD1, BLM, BRCA1, BRCA2, BRIP1, CHEK2, DNMT3A, ERCC1, FANCA, FANCF, NBN, PALB2, RAD51, RECQL4, WRN, GATA6). rwOS was calculated from treatment start to death from any cause and risk set adjustment was used to account for immortal time bias.
Results – Among 1,068 pts in the wt cohort, the median age at diagnosis was 66 years and 609 (57%) received 1L PT. In low CHEK2 expressors, median rwOS was longer with PT than without PT (12.7 months [m] (95% CI 10.2-13.9) vs 8 m [95% CI 6.3-9.5]). For high expressors, median rwOS was similar between the PT and no PT groups (8.8 m [95% CI 7.4-9.6] vs 8 m [95% CI 5.5-9.9]). Additionally, rwOS was longer in the PT compared to the non-PT group in low BRCA1 expressors (respective median rwOS: 13 m [95% 10.5-15.7] vs 8m [95% CI 5.5-9.5]), and high expressors of GATA6 (13.5 m [95% CI 11.4-15.8] vs 9.3 m [95% CI 8-11.3]) and NBN [9.6 m (95% CI 8.1-11.4) vs 6.1 m (95% CI 4.3-7.6)]. Of note, low expressors of BRCA1 (n=277) with wtBRCA1/2 and wtPALB2 had similar median rwOS as pts with BRCA1/2 or PALB2 alt (n=70), which were respectively 10.5 m and 13.4 m (HR 0.79, 95% 0.6-1.1, p=0.2).
Conclusions – Comprehensive transcriptomic analysis suggests that HRR genes beyond BRCA1/2 or PALB2 may predict benefit from platinum use in mPC. Identifying functional HRR-deficient or proficient phenotypes may better help select for DNA-damaging strategies. Novel HRD scoring models with gene interaction analysis and external validation are underway.
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