107P - Unveiling mismatch repair deficiency (dMMR) and microsatellite-instability high (MSI-H) detection in cancer patients (pt) using a next-generation sequencing (NGS)-based molecular pre-screening program (MPP)

Background

The highest prevalence of MSI is observed in colorectal (CRC), endometrial, and gastric cancers. Lately, MSI has expanded its clinical utility as predictive biomarker to immunotherapy (IO). IHC and/or PCR are the gold standard methods for MSI detection, though NGS arises as a promising approach to expand the spectrum of malignancies in which we can detect dMMR or MSI-H.

Methods

We performed a multicentric retrospective study of adult pt with advanced solid malignancies evaluated through a coordinated NGS MPP at three different Catalan Institute of Oncology centres in Catalonia, Spain. Tumors were profiled with NGS Oncomine Comprehensive Assay v3 (OCAv3) or with Illumina TruSight Oncology 500 (TSO500) assay. Both tests detected mutations (mut) in MMR genes, but TSO500 also included MSI-H percentage repeats. Molecular results were weekly reviewed in dedicated molecular tumor boards (MTB) and correlated with IHC/PCR. The aim of the study was to describe the characteristics of dMMR/MSI-H pt and their clinical benefit (ClinBen) if treated with IO, defined as response or stable disease >4 months.

Results

From Mar’21 to Jul’23, 1514 pt were NGS analysed and 23 cases were considered dMMR/MSI-H. Histologies were CRC (12), NSCLC (6), endometrial (1) breast (1), carcinoma of unknown origin (CUD; 1), adrenal carcinoma (AC; 1) and glioma (1). Mut in MMR genes were detected in 19 tumors (14/808 OCAv3 and 5/706 TSO500): MLH1mut (9), MSH6mut (5), MSH2mut (5) and PMS2mut (2). Two CRC pt harbored co-existing MSH2/MSH6mut. Before the NGS results, only 10 MMR-mutated pt were previously identified as MSI-H by IHC/PCR and all of them had tumors with high prevalence dMMR/MSI-H (9 CRC, 1 endometrial). Lynch sd. was established in 6 of these cases. Noteworthy, TSO500 detected 9 MSI-H tumors of whom 4 had no underlying MMRmut. ClinBen was achieved in 6 out of 9 pt treated with IO.

Conclusions

Our results show that NGS MPP and MTB help to molecularly characterize multiple tumor types, widening the detection of dMMR/MSI cases. Uncommon histologies, such as CUD, AC or gliomas, can therapeutically benefit from this approach.

Editorial acknowledgement

Clinical trial identification

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

M.A. Bergamino: Financial Interests, Personal, Invited Speaker: Eisai; Financial Interests, Personal, Funding, Travel funding for congress: Novartis; Financial Interests, Personal, Funding, Travel funding for congresses: Eisai.J. Martin-Liberal: Financial Interests, Personal, Invited Speaker: Astellas, Bristol Myers Squibb, MSD, Novartis, Pierre Fabre, Pfizer, Roche, Sanofi; Financial Interests, Personal, Advisory Board: Bristol Myers Squibb, Novartis, Pierre Fabre, Roche, Sanofi, Highlight Therapeutics; Financial Interests, Personal, Other, Travel grant: Bristol Myers Squibb, MSD, Novartis, Pierre Fabre, Pfizer, Roche, Ipsen. C. Lazaro: Financial Interests, Personal, Advisory Board, Advisory boards on BRCA and HRD testing: AstraZeneca; Financial Interests, Personal, Advisory Board, IVDR advisory group: Illumina; Financial Interests, Institutional, Funding: AstraZeneca. C. Hierro: Financial Interests, Personal, Invited Speaker: MSD, Lilly; Financial Interests, Personal, Research Grant, Principal Investigator of Merck Research Grant in Personalized Medicine 2020: Merck; Non-Financial Interests, Personal, Principal Investigator, Clinical Trial: BMS, Zymeworks, ALX Oncology, AstraZeneca; Other, Personal, Other, Travel fees: BMS, Amgen, Roche, Merck. All other authors have declared no conflicts of interest.