Association of pancreatic adenocarcinoma location (head/body/tail) with DDR mutation status and response to platinum-based therapy.

Abstract

612 Background: Pancreatic adenocarcinoma is an aggressive disease with poor clinical prognosis that can originate from either the head (H) or body/tail (BT). Potential prognostic implications for H versus BT tumors have been reported; however, the molecular underpinnings associated with these differences in survival have not fully been explored. Using a large-scale real-world cohort of H and BT tumors with NGS results available from commercial labs, we retrospectively aim to identify potential differences between H and BT tumors in their response to standard therapies to help understand whether the treatment prioritization for pancreatic adenocarcinoma should take into account anatomical sidedness, as is recognized today with left-sided versus right-sided colorectal cancers. Methods: We analyzed outcomes across 1540 pts with NGS results from Perthera’s Real-World Evidence database who were diagnosed with PDAC originating from the H or BT. Progression-free survival (PFS) was evaluated from initiation of 1st line for advanced disease until discontinuation due to disease progression. Hazard ratios and p-values were computed via Cox regression when comparing PFS between 1st line FOLFIRINOX and gemcitabine/nab-paclitaxel. Differences in frequencies of genomic alterations between proximal and distal were analyzed by Fisher’s exact test. Results: Mutations in BRCA1/ BRCA2/ PALB2 were enriched (unadjusted p-value=0.017) in BT tumors (8.6% of 619) relative to H tumors (5.4% of 921). An expanded set of DDR pathway alterations (e.g. ATM, FANCA, CHEK2, BAP1, BRIP1, etc) were also enriched (unadjusted p-value=0.003) in BT tumors (21.4% of 619) relative to H tumors (15.6% of 921). In BT tumors, mPFS on 1st line FOLFIRINOX was longer (Table) than 1st line gemcitabine/nab-paclitaxel (p=0.0078) but this difference was not observed in H tumors (p=0.34). Overall survival data in these patients and an independent institutional cohort which motivated these analyses will also be discussed. Conclusions: DDR pathway alterations are known predictors of increased benefit from platinums and these real-world insights preliminarily suggest that DDR mutations are more common in BT vs. H. Prospective studies may be warranted to confirm the hypothesis-generating findings that platinum-based regimens should be prioritized in patients with BT tumors while underscoring the importance of routine NGS testing in both BT and H tumors given the prevalence of DDR pathway alterations on both sides of the pancreas.[Table: see text]