Sequencing Shows Potential for Identifying Multiple Biomarkers in mCRPC with MSH6 Mutation

Sequencing patients with MSH6-mutated metastatic castrate resistant prostate cancer (mCRPC) to evaluate all classes of genomic alterations showed how the complex structure of MSH6 can help determine the potential utility of multiple biomarkers to see which patients benefit from immunotherapy, according to research presented at the 2021 virtual American Society of Clinical Oncology.¹

5,617 cases of mCRPC were sequenced to evaluate all classes of genomic alterations within this patient population. Seventy-eight of these cases were MSH6-mutated compared to 5,539 patients with MSH6 wild type mCRPC with 11.3 genomic alterations in cases of MSH6 compared to 3.9 in MSH6 wild type cases. While 46% of the MSH6-mutated cases were considered microsatellite instability (MSI) high, researchers concluded that this still exhibited how varied the phenotype is that can help clinicians make treatment decisions. Moreover, MSI-high status in patients with MSH6-mutated tumors was significantly greater than the 2% seen in MSH6 wild type cases (P < .0001).

MSH6-mutated cases had 73.1% short variant mutations, 23.1% had biallelic deletions, and 2.6% had genomic rearrangements. In comparison, in cases that were not MSI high, nor had an mismatch repair (MMR) mutational signature, 87% did not have biallelic loss of MSH6 or any other MMR gene. According to researchers, this confirmed that the monoallelic pathogenic mutations are insufficient to cause the MMR-D phenotype in this patient population. MMR signature was seen in 65% of the MSH6 wild type cases in comparison to 3% in the MSH6 wild type case (P < 0.0001). Forty-five percent of pathogenic MSH6 alleles were germline and 58% of these did not have single MSI high or MMR nucleotide structure.

The loss of function in genomic alterations in MSH6 has been linked to a unique subtype of hypermutated mCRPC, according to researchers, that is microsatellite stable that can occur in sporadic or familial Lynch Syndrome, the most common cause of hereditary colon cancer and linked to a higher likelihood of prostate cancer. Researchers utilized a comprehensive genomic profiling assay to look at these cases, along with their tumor mutational burden (TMB). TMB was calculated from 0.80 mB of sequenced DNA and a median TMB of 21.3 mt/Mb was found in cases of MSH6 mutation compared to 2.5 mt/Mb in MSH6 wild type cases (P < 0.0001). TMB greater than 10 mt/MB or more was found in 67% of MSH6-mutated cases, whereas only 4% was seen in MSH6 wild type cases (P < 0.0001).

Patients with MSH6-mutated mCRPC had fewer TMPRSS2:ERG fusions (P =.01), but had significantly higher frequencies of genomic alterations AR (P =.0002), ATM (P =.04), PIK3CA (P =.0003), APC (P =.005), ERBB2 (P =.001), and CDK6 (P =.046). Researchers believe that this is likely associated with the higher TMB in MSH6-mutated cases, compared to the low TMB in MSH6 wild type cases. Other biomarkers observed in these cases showed that most had a higher presence in MSH6-mutated cases. These included, TP53 (46%), MSH2 (28%), and APC (19%), among others.

“This complex phenotype highlights the potential utility of multiple rather than single biomarkers to understand tumor biology and determine patients who may benefit from immunotherapy,” researchers concluded. Sequencing was performed on 324 cancer-related genes and introns from 28 genes that are commonly rearranged in cancer.

_Reference

_{Gennady B, Decker B, Jacob J, et al. Genomic landscape of MSH6-mutated clinically advanced castrate-resistant prostate cancer (mCRPC). J Clin Oncol. 2021;39 suppl 15; abstr 5062). doi: 10.1200/JCO.2021.39.15_suppl.5062}