Dr. Walden on the RNA Expression of Homologous Recombination Genes in CRC

Daniel Walden, MD, fellow, Hematology/Oncology, Mayo Clinic School of Medicine, Mayo Clinic, discusses the association of low expression of RNA of wild-type homologous recombination genes and survival in colorectal cancer (CRC).

Previous data have demonstrated how efficacy is affected for patients with homologous recombination–deficient (HRD) CRC, Walden explains, adding that patients with ovarian cancer or breast cancer who have tumors that are HRD tend to have increased sensitivity to platinum-based chemotherapy or irinotecan-based therapies.

However, investigators have not observed a similar benefit with treatment with PARP inhibitors for patients with HRD CRC, despite those agents displaying benefits in patients with breast cancer or ovarian cancer, Walden continues. Trials examining PARP inhibitors have showed almost no response in patients with CRC who harbor HRD genes, he adds. Since CRC features a different physiology compared with ovarian cancer or breast cancer, investigators aimed to determine if patients who do not harbor HRD genes but have a low expression of HR RNA could represent a phenotype that may be more sensitive to traditional therapeutics such as oxaliplatin or irinotecan, Walden says.

Data from a real-world study presented at the 2023 Gastrointestinal Cancers Symposium showed that overall survival (OS) data were promising following exposure to irinotecan for patients who had a low RNA expression of PALB2 or BRCA1, Walden continues. OS was measured from time of first dose of irinotecan to death.

Patients with unmutated BRCA1 who were in the bottom 10% of evaluated patients in terms of RNA expression for that gene had a median OS of 61.5 months, compared with 40.3 months for patients who were in the top 10% of RNA expression for BRCA1. Those patients in the bottom 10% of RNA expression for unmutated PALB2 had a median OS of 57.2 months, compared with 49.4 months for those patients in the top 10%. These data were promising in the context of metastatic CRC, where the OS from time of diagnosis is typically around 3 years, Walden concludes.