Impact of homologous recombination repair or mismatch repair gene alteration on first-line FOLFOX chemotherapy in advanced colorectal cancer patients: K-MASTER project

Abstract

Purpose: Homologous recombination repair (HRR) and mismatch repair (MMR) alteration is known to have a good response to platinum-based chemotherapy in both breast and ovarian cancer. However, HRR/MMR alteration and response for 1L FOLFOX chemotherapy in advanced colorectal cancer (CRC) is not fully understood.

Methods: From 2017 to 2021, a number of 1,225 advanced CRC patients with available HRR/MRR alteration data were registered in K-MASTER project. After excluding missing data, adjuvant chemotherapy alone, other chemotherapeutic regimen, 390 patients who received 1L FOLFOX chemotherapy were finally analyzed. Targeted sequencing was conducted using Cancer Scan panel, FIRST panel, and K-MASTER Cancer (v1.0 or v1.1) panel for tumor tissue. If tumor tissue was not available, liquid biopsy was performed. HRR gene defined as follow; ATM, ATR, BARD1, BRCA1, BRCA2, BRIP1, CHEK2, FANCA, FANCD2, FANCG, PALB2, RAD50, RAD51. MMR gene defined as below; MLH1, MSH2, PMS2, MSH6, POLE, ARID1A.

Results: Among 340 patients, 79 patients harbored HRR/MMR alteration. The median progression free survival (PFS) was 5.6 months vs 5.7 months in HRR/MMR alteration and wild-type group, respectively (hazard ratio (HR)=1.19, p-value=0.21). The median overall survival (OS) was comparable between two group (40.6 months vs 34.5 months, respectively; HR=0.71, p-value=0.17). Multivariate cox-proportional hazard model also showed HRR/MRR alteration status was not an independent factor for both PFS and OS (Both p-value>0.05).

Conclusions: Patients harbored HRR/MRR alteration may not be sensitive for 1L oxaliplatin-based chemotherapy than wild-type. The effective treatment targeting high genomic instability populations warrants further investigation in CRC.