The Prevalence of Germline Pathogenic Variants in Radiosensitivity Genes and Incidence of Radiation Toxicities among Patients with Prostate Cancer

Purpose: Patients with pathogenic/likely pathogenic variants (P/LPVs) of DNA “gatekeeper” and “caretaker” genes, such as ataxia-telangiectasia mutated (ATM) gene, breast cancer (BRCA1/2) gene, checkpoint kinase 2 (CHEK2) gene, and tumor protein p53 (TP53) gene, have increased rates of toxicities from radiation treatment (RT). Limited studies have reported the prevalence of these variants and toxicities from RT among cancer patients. Here we report the interim analysis from the City of Hope INSPIRE study among a cohort of prostate cancer patients (across all cancer stages) from a single cancer center.

Methodology: Between January 2008 and June 2021, a total of 1164 patients with prostate cancer were enrolled in our institution’s non-intervention prospective Precision Medicine (PMED) program that offered patients the opportunity to undergo germline testing using a large panel of 189 cancer susceptibility and actionable medical disorder genes along with genetic counseling. Patient age, stage, Gleason score, RT dose and fractionation, and toxicities (based on Common Terminology Criteria for Adverse Events [CTCAE], v4.0) documented from on-treatment and follow-up visits were collected from the electronic medical records. Descriptive statistics and chi-square were obtained using R.

Results: Of the 1164 prostate cancer patients enrolled in the PMED program, 200 (17.2%) patients had undergone curative-intent RT for prostate cancer. Among these 200 patients who had RT, 51 (25.5%) patients had at least one P/LPV (four [7.8%] patients with BRCA2 variants, three [5.9%] patients with ATM variants, one [2.0%] patient with CHEK2 variants, one [2.0%] patient with TP53 variants, and none [0.0%] with BRCA1 variants).
Among those with P/LPVs who received RT, two (3.9%) patients (one with a missense CHEK2 mutation; c.1283C>T; p.Ser428Phe and other with a nonsense CFTR mutation; c.1521_1523del; p.Phe508del) developed grade 3 radiation-related toxicity, compared to nine (6.0%) patients without P/LPVs (p=0.57), while 16 (31.4%) patients had grade 2+ toxicities, compared to 41 (27.5%) patients (p=0.60). No patients with P/LPVs experienced grade 4+ toxicities.

Conclusions: In this interim analysis of prostate cancer patients who were enrolled in a single-institution PMED program, we found that 25.5% of patients who underwent curative-intent RT carried at least one P/LPV. Of these, a small percentage were in well-established radiosensitive genes (i.e., 5.9% with ATM variants). A subset of these patients with P/LPVs of radiosensitive genes received curative-intent RT, two patients developed grade 3 toxicity from radiation (non-significant when compared to patients with P/LPVs), and no patients with P/LPVs with grade 4+ toxicities were reported. Larger multi-institutional datasets are needed to confirm these findings and help guide our recommendations for RT in the setting of germline P/LPVs.

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