Study identifies germline genetic variants linked to increased risk of prostate cancer

Findings from the IMPACT study (NCT00261456) published in the Lancet Oncology showed that MSH2 and MSH6 pathogenic variants developed prostate cancer at a higher rate compared with those in an age-matched non-carrier control group.¹

The investigators reported that the incidence rate for prostate cancer was 1.9% (95% CI, 1.1%-2.9%). For patients who were MSH2 carriers, the incidence was 4.3% (95% CI, 2.3%-7.2%) vs 0.5% (95% CI, 0%-2.6%) in the non-carrier arm. Among patients who were MSH6 carriers, the incidence was 3.0% (95% CI, 0.8%-7.4%), and compared with 0.0% in the non-control arm.

Investigators also reported higher prostate cancer incidence using a prostate specific antigen (PSA) score threshold of 3.0 ng/mL or higher in patients with MSH2 (4.3% vs 0.5%; P = .011) and MSH6 variants (3.0% vs 0%; P = .034) compared with noncarriers.

A total of 962 patients were recruited for the study, of whom 86% were mismatched repair (pMMR) deficient; within this cohort, 32% of patients carried MSH1, 47% carried MSH2, and 21% carried MSH6. Within the noncarrier control group, 35% were MSH1 noncarriers, 41% were MSH2 noncarriers, and 23% were MSH6 noncarriers. Additionally, 134 patients were selected from the BRCA1/2 non-carrier cohort in the study to be screened for variants in the MMR genes with the data supplementing the control groups. Of those in the MSH6 cohort, the group did not reach target capacity because of the rarity of the identified carriers.

Baseline PSA screening was available in 99% of patients, with less than 1% of patients having missing or negative PSA data. PSA higher than 3.0 ng/mL was seen in 6% of patients at first screening and 4% of prostate biopsies were completed. A total of 37% of patients declined undergoing a biopsy because of concurrent health conditions, repeat of PSA biopsy, having an MRI with no abnormalities, or patients changing their mind.

Overall, 51% of biopsies detected the presence of cancer, of which 4% were MSH2, 3% were MSH6, and less than 1% were MSH2 non-carrier controls. Patients who had MSH2 variants were more compliant in receiving biopsies at 67% vs 43% among the non-carrier controls (P = .39); similar findings were reported among those who were MSH6 carriers vs noncarriers (100% vs 50%; P = .17).

Off-protocol biopsies were performed in 3 patients after baseline screening, of which 2 had malignant biopsies, including an MSH2 carrier and an MLH1 noncarrier. The third patient, who was an MSH2 carrier, had a benign biopsy and a PSA of 2.98 ng/mL. An atypical small acinar proliferation or high-grade prostate intraepithelial neoplasia was observed in 3 patients, of whom, 1 was an MLH1 carrier, 1 was a MLH1 non-carrier, and 1 was a MSH6 carrier.

Using a PSA threshold of 3.0 ng/mL, the overall biopsy positive predictive value (PPV) was 51.4% (95% CI, 34.0%-68.6%). The PPV for MSH2 carriers was 72.2% (95% CI, 46.5%-90.3%), 33.3% (95% CI, 0.8%-90.6%) for MSH2 noncarriers, and 80.0% (95% CI, 28.4%-99.5%) for MSH6 carriers. When assessing the PPV of biopsy using a PSA threshold higher than 3.0 ng/mL, investigators reported a rate of 32.1% (95% CI, 20.3%-46.0%).

In terms of the PPV based on PSA concentration for disease detection, investigators reported a rate of 48.1% (95% CI, 28.7%-68.1%) in MSH2 carriers, 14.3% (95% CI, 0.4%-57.9%) in MSH2 noncarriers, and 80.0% (95% CI, 28.4%-99.5%) in MSH6 carriers. A significant difference in PPV was found between MSH6 carriers and noncarriers.

Reference

1. Bancroft EK, Page EC, Brook MN, et al. A prospective prostate cancer screening programme for men with pathogenic variants in mismatch repair genes (IMPACT): initial results from an international prospective study. Lancet Oncol. 2021;22(11):1618-1631. doi:10.1016/S1470-2045(21)00522-2