Call for targeted PSA screening in men with MMR gene pathogenic variants

GU cancer

By Mardi Chapman

21 Oct 2021

Men with pathogenic variants in the mismatch repair genes associated with Lynch syndrome have a significantly increased risk of prostate cancer compared to men without those genetic variants.

The international IMPACT study recruited 828 men aged 40-69 years with a known familial pathogenic variant (MSH1, MSH2 or MHS6) and 184 non-carrier controls from eight countries including Australia.

The study, published in The Lancet Oncology, found that after one screening round and confirmatory biopsies in men with PSA >3.0 ng/mL, the incidence of prostate cancer was higher in MSH2 carriers than noncarriers (4.3% v 0.5%; p=0.011) and MSH6 carriers compared to non carriers (3.0% v 0%; p=0.034).

No cancers were diagnosed in the MLH1 carriers or non-carriers.

“When looking at the incidence of clinically significant prostate cancer, the incidence among MSH2 carriers was 3·6% (11 of 305; 95% CI 1·8 to 6·4) compared with 0% (none of 210) among MSH2 non-carrier controls (p=0·0037),” the study said.

MSH2 carriers were on average younger with a higher mean PSA value at diagnosis than non-carrier controls.

“Seven of 13 tumours diagnosed in MSH2 carriers had Gleason 4 (grade group 3) as the dominant pattern, and three tumours were Gleason score 8 or 9 (grade groups 4–5) and so were more likely to behave aggressively with a worse prognosis.”

“One MSH2 carrier was found to have nodal involvement and metastatic disease at diagnosis and longer-term follow-up is required to establish whether there is a difference in metastatic events and mortality between carriers and controls.”

The investigators said the findings support the use of targeted PSA screening in men with mismatch repair gene pathogenic variants.

“Using a PSA threshold of 3·0 ng/mL resulted in a low biopsy rate (6%) and a high PPV for the detection of intermediate-risk and high-risk disease in MSH2 and MSH6 carriers.”

“The low incidence of prostate cancer we found, coupled with the high proportion of clinically significant disease detected at biopsy, suggests that screening men with MSH2 and MSH6 pathogenic variants has a low risk of overdiagnosis of indolent cancers.”

The study said that knowledge of mismatch repair pathogenic variant status was also increasingly important from a clinical point of view, because of evidence that mismatch repair-deficient prostate tumours can be sensitive to immune checkpoint inhibitors.

While predominantly used in the metastatic context at present, the use of checkpoint inhibitors was rapidly evolving and would likely move to earlier in the treatment pathway.

An editorial in the journal said the feasibility and cost-effectiveness of genomic testing to identify screening candidates in the overall population or in a subset of men at increased risk remained questionable.

They also suggested that in a Lynch syndrome population also at increased risk of colorectal, stomach, small bowel, urethral, and brain cancers, the actual risk of dying from prostate cancer might be lower than estimated in the general population.

“Therefore, the oncological benefits of a targeted PSA screening programme in this scenario should be assessed before these findings can be translated into clinical practice.”

Further rounds of annual screening in the IMPACT study are ongoing.

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