TEST:

Ventana MMR RxDx Panel

MSI estimation using NGS is suitable as a quick screening tool. Since thresholds for MSI-H might differ enormously between entities, additional IHC testing is recommended at least in samples where VUS or pathogenic mutations are found in one of the mismatch repair genes. Downloaded from http://karger.com/ort/article-pdf/47/Suppl.

An immunohistochemistry (IHC) panel targeting four MMR proteins (MLH1, PMS2, MSH2, MSH6) has been used to screen for MMRd status in many cancer types and is approved by FDA to identify patients eligible for treatment with ICIs such as pembrolizumab... An unexpected pattern of retained MSH6 IHC is seen in up to 35% of MMRd prostate carcinomas with MSH2 loss, across four participating institutions with three different MSH6 antibody clones. This is a much higher rate compared to only 1% of GI or GYN MMRd cases with isolated MSH2-loss pattern (PMID 36104536). While the mechanisms of this phenomenon remain unknown, the findings suggest against using a two-antibody testing algorithm (PMS2 and MSH6) to screen for MMRd prostate carcinoma.

The Idylla MSI Test is a clinically valid method for dMMR screening in CRC patients, and results of this testing can be used to guide further evaluation of individuals for Lynch syndrome. All percentage agreement point estimates used to determine the success of the study exceeded the 90% benchmark established a priori.

However, 10 of the 34 MSI-high tumors, including the 6 tumors with isolated MSH6 loss, showed only minimal microsatellite shift by MSI-PCR, which may have been erroneously interpreted as MSS or MSI-low. On the basis of these findings, we consider that the FDA-approved immunohistochemical panel can detect MMR variations consistently and is more accurate than MSI-PCR for determining the applicability of immune checkpoint inhibitors for treatment of endometrioid carcinomas.

"The dot-like artifact in MLH1 M1 clone staining was observed in 77% (20/26) of cases, predominantly in the surface area of the tumor, ranging from 5% to 40% (median: 10%). These findings highlight the high concordance between the MMR-IHC assays and emphasize the importance of considering the dot-like artifact in MLH1 M1 clone staining when diagnosing endometrial cancer with MMR deficiency."

Conclusions Although the RTD and FoundationOne CDx assays measure different analytes, they are comparable for the selection of patients with MSI-H/dMMR tumors likely to respond to pembrolizumab. Despite both companion diagnostic assays having lower concordance to the clinical trial assay, they demonstrated high concordance with each other and were able to better identify responders to pembrolizumab than the clinical trial assay.

Background The anti–PD-1 monoclonal antibody pembrolizumab has a tumor-agnostic approval by the US FDA for previously treated advanced tumors characterized as microsatellite instability-high (MSI-H)/deficient mismatch repair (dMMR)...Evaluation of the treatment history of dMMR versus the proficient mismatch repair populations showed that a higher proportion of patients with dMMR tumors received radiation (40.0% vs 23.0%), chemotherapy (70.0% vs 48.5%), and/or treatment with immune checkpoint inhibitors (11.4% vs 4.6%) at some point since their initial diagnosis. Conclusions Prevalence of dMMR and co-occurring loss of MLH1 and PMS2 at the protein level across the 5 different tumor types in Chinese patients are consistent with reports in the literature.

Notably, immune checkpoint inhibitors (ICIs) were administered to a greater proportion of patients with MSI-H/dMMR tumors (34.0%) than to patients with non–MSI-H/proficient MMR tumors (7.2%); most (77.8%) of the MSI-H/dMMR population received ICIs in the second-line or later setting. Table: 261MO Prevalence of MSI-H/dMMR across tumor types in the overall population and regional cohorts % (n/N) Overall population Asia-Pacific (Korea, Singapore, Taiwan) cohort (Ventana MMR RxDx Panel) Japan cohort (MSI-IVD Kit [FALCO]) Biliary tract 3.3 (7/209) 2.7 (3/111) 4.1 (4/98) Gastric 6.3 (18/285) 7.4 (14/189) 4.2 (4/96) Pancreatic 0.4 (2/486) N/A 0.4 (2/486) Cervical 2.6 (5/190) 4.0 (3/75) 1.7 (2/115) Endometrial 18.4 (52/282) 14.6 (19/130) 21.7 (33/152) Ovarian 4.2 (22/518) 4.9 (19/390) 2.3 (3/128) Conclusions The prevalence of MSI-H/dMMR across the 6 tumor types in this analysis of Asian patients was consistent with literature reports on non-Asian patients.

"Roche...announced US Food and Drug Administration (FDA) approval of a label expansion for the VENTANA MMR RxDx Panel. This approval advances the company's commitment to personalised healthcare through tests that determine which patients are most likely to respond to specific and targeted therapies....FDA approval of the label expansion for the VENTANA MMR RxDx Panel provides clinicians with access to a fully automated panel of MMR biomarkers tested by IHC. This label expansion follows the April 2021 FDA approval of the VENTANA MMR RxDx Panel as the first IHC predictive test to identify endometrial carcinoma patients eligible for treatment with the anti-PD1 immunotherapy JEMPERLI (dostarlimab-gxly)."

Notably, a greater proportion of patients with MSI-H/dMMR tumors (34.0%) received treatment with immune checkpoint inhibitors (ICIs) as compared with patients with non–MSI-H/pMMR tumors (7.2%); 77.8% of the MSI-H/dMMR population who received ICIs were treated in the second-line or later setting. Table: 101P Prevalence of MSI-H/dMMR by regional cohorts and tumor type Conclusions The prevalence of MSI-H/dMMR reported across 6 different tumor types in Asian patients was consistent with that reported in literature for non-Asian patients.

"The US Food and Drug Administration...approved Merck's PD-1 inhibitor Keytruda (pembrolizumab) for advanced, previously treated endometrial cancer patients whose tumors express high microsatellite instability (MSI) or harbor DNA mismatch repair deficiencies (dMMR)...The FDA also approved Roche's Ventana MMR RxDx Panel as an immunohistochemistry-based companion diagnostic to select patients with dMMR tumors for Keytruda treatment."