587P - Homologous recombination (HR) and DNA damage repair (DDR) somatic alterations in metastatic colorectal cancer (mCRC): Results from the comprehensive genomic profiling (CGP) trial FPG500

Background

Treatment (tx) of MSS/MMRp mCRC relies mainly on oxaliplatin (oxa)- or irinotecan-based doublet chemotherapy regimens, with no biomarker reported so far, allowing the selection of one tx over the other. HR and DDR alterations have been associated with sensitivity to platinum agents in several neoplasms, however, evidence in this setting lacks.

Methods

Data from the mCRC cohort of the prospective monocentric study FPG500 (NCT06020625), which performs a somatic CGP via TSO500HT (identifying SNVs, indels, CNVs in 523 genes and fusions and splicing variants in 55 genes), were mined through cBioportal, classifying tumors as HR-DDR altered (HR-DDRa) or proficient (HR-DDRp) on the basis of the presence of at least 1 oncogenic or likely oncogenic alteration (annotated according to OncoKB) involving genes of HR or DDR pathways. Pts’ and tumors characteristics, tx administered and survival status were retrospectively collected. The objective of the study was to investigate the molecular phenotype of HR-DDRa and its predictive role.

Results

From Jan2022 to Apr2024 306 pts underwent to CGP, with a prevalence of HR-DDRa of 18.6%. Alterations involved mainly ATM (5%), BRCA2 (4%), NBN (2%), CHEK2 (2%), MRE11 (1.6%), BRIP1 (1.6%), PALB2 (1.3%), ATRX (1.3%) and BARD1 (1.3%); alterations of ATR, RAD50, FANCA, FANCD2, BRCA1, FANCE, FANCL, BAP1, CHEK1 and FANCC were reported in < 1%. HR-DDRa was significantly associated with MSI-H or TMB-H (p<.0001). Pts who received a first line tx and whose tx outcome and survival status were available constituted the survival cohort (n=191). At a mFU of 20 months, mPFS was 13.8 months, while mOS was not mature. No significant difference was observed in terms of PFS according to HR-DDR status in the overall cohort and in pts treated with oxa-based tx. In pts with MSS HR-DDRa disease (n=22), oxa-based tx was associated with significantly longer mPFS (13.3 vs 3.2 months; p <.001). No other prognostic factor was associated with PFS at univariate analysis.

Conclusions

HR-DDRa is associated with MSI-H or TMB-H. Pts with MSS HR-DDRa tumors benefit from oxa-based first line treatment. Longer FU, allowing mature OS data, and wider cohorts are warranted.

Clinical trial identification

NCT06020625.

Editorial acknowledgement

Legal entity responsible for the study

Fondazione Policlinico Universitario "Agostino Gemelli".

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.