Patients with pathogenic variants in MSH2 and MSH6 have a significantly higher incidence of prostate cancer than do patients without these variants, according to a study published in The Lancet Oncology.

These findings support targeted prostate-specific antigen (PSA) testing in patients with mismatch repair gene pathogenic variants, according to researchers.

The researchers evaluated the usefulness of targeted PSA screening with the IMPACT trial (NCT00261456), a prospective study of patients with a genetically increased risk of prostate cancer.


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Eligible participants were men aged 40 to 69 years who had undergone genetic testing and tested positive or negative for a known familial pathogenic variant (MSH1, MSH2, or MSH6), or if they were at 50% risk of inheriting a pathogenic variant but had not yet undergone testing. Patients with a pathogenic variant were age-matched with noncarrier control individuals in a 1:1 ratio.

Patients had a PSA blood test at enrollment. For those with a PSA concentration higher than 3.0 ng/mL, transrectal, ultrasound-guided, prostate biopsy was recommended. Patients who had a PSA concentration of 3.0 ng/mL or lower were to undergo annual PSA screening for a minimum of 5 years.

A total of 962 patients were recruited, and 828 made up the mismatch repair pathogenic variant cohort. The patients’ median age at enrollment was 53 years, 94% were of European ancestry, 19% had a family history of prostate cancer, and 38% had a previous PSA test.

In all, there were 644 carriers of mismatch repair pathogenic variants — 204 carriers of MLH1, 305 carriers of MSH2, and 135 carriers of MSH6. The remaining 184 patients were noncarrier control individuals — 65 noncarriers of MLH1, 76 noncarriers of MSH2, and 43 noncarriers of MSH6.

In the first screening round, 6% of patients (56/962) had a PSA greater than 3.0 ng/mL (median, 5.1 ng/mL), requiring referral for a prostate biopsy. Of this group, 63% (n=35) had a biopsy.

The overall incidence of prostate cancer was 1.9% (18/962). There were no cancers diagnosed in MLH1 carriers or noncarriers.

The incidence of prostate cancer was 4.3% in MSH2 carriers and 0.5% in noncarriers, a difference of 3.8% (95% CI, 1.3-6.2; P =.011). The incidence of prostate cancer was 3.0% in MSH6 carriers and 0% in noncarriers, a difference of 3.0% (95% CI, 0.1-5.8; P =.034).

The overall positive predictive value of biopsy using a PSA threshold of 3.0 ng/mL was 51.4%, and the overall positive predictive value of PSA concentration higher than 3.0 ng/mL for detecting prostate cancer was 32.1%.

The researchers noted that the number of cancers detected was relatively small, and recruitment to the control groups was lower than their initial target. Still, the team concluded that the results of this study support the use of targeted PSA screening in patients with mismatch repair gene pathogenic variants.

Disclosures: Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.

Reference

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. Published online October 19, 2021. doi:https://doi.org/10.1016/S1470-2045(21)00522-2