Book of the Month: MMR: Science and Fiction

Abstract

endometrial (EC), skin and prostate cancers. The sensitivity of this Pan-Cancer MSI System is being further verified on 14 different cancer types. Methods: Selection of the new microsatellite biomarkers was done by screening 160 patients 55 years with 1 polyp and 100 EC patients 50 years for MSI. The expanded study uses samples from 100 Lynch syndrome colorectal cancers (CRC), 100 sporadic MSI-High CRC, 100 sporadic MSI stable CRC and 219 extra-colonic cancers obtained from the Colon Cancer Family Registry. DNA samples are being tested for MSI using two pan-cancer systems: Promega's MSI Analysis System version 1.2 and the improved prototype Pan-Cancer MSI System. Mutations in mismatch repair (MMR) and BRAF genes were tested, as well as MMR expression by IHC. Results: 2.3% of colon polyps were MSI-High for the MSI Analysis System compared to 5.4% with the new prototype Pan-Cancer MSI System. Sensitivity and specificity of the new biomarker panel for detection of MMR deficient lesions was 100% and 96%. Similarly, sensitivity of the new biomarker panel for EC was about 2-fold higher. Allele size changes for MSI-High samples were significantly larger with the new biomarkers making MSI classification highly accurate and robost. The MSI and IHC results were highly correlated. Evaluation of the new biomarker panel is being performed on over 500 cancer samples from 14 different cancer types. Conclusions: Research results indicate that MSI sensitivity for colonic polyps and many extra-colonic cancers can be increased by at least 2-fold over current MSI systems using the new MSI biomarker panel. The improved sensitivity of the Pan-Cancer MSI System should improve detection of MSI in an expanded number of cancer types and facilitate identification of individuals with both sporadic and hereditary MSI-High cancers. Background: Microsatellite instability (MSI) has been approved as the first pan-cancer biomarker in immune checkpoint inhibitors (ICI) therapies. The tumor tissues of most metastatic cancer patients receiving ICI therapies are usually unavailable. However, polymerase chain reaction (PCR) or immunohistochemistry (IHC), the two conventional MSI evaluation methods, could only be applied to the tumor tissues. Hence, we aimed to develop a next-generation sequencing based method to detect MSI from blood circulating tumor DNA (bMSI). Methods: A training cohort of 40 metastatic cancers patients before first-line treatments were collected to train a linear-based detection model. Then, a validation cohort of 47 metastatic gastrointestinal cancer patients before ICI therapies were collected. The prediction to the responses of ICI by bMSI was compared with that by the mis-match repair (MMR) or MSI from historical tissue specimens. Results: bMSI showed 87.5% accuracy to predict the MMR/MSI status from tissue specimens in the training cohort, and 95.2% sensitivity in the validation cohort. bMSI-H patients had 31.4% objective response rate (ORR) and 45.7% disease control rate (DCR), which were comparable to the dMMR of historical FFPE specimens (33.3% and 47.6% respectively). However, 57.7% pMMR patients were classified as bMSI-H and showed similar ORR (27%) , DCR (40%) and progress free survival to those of dMMR patients. Furthermore, 17% bMSI-H patients with high bMSI scores (larger or equal to 28) showed 66.7% ORR and 100% DCR. Finally, 91.7% patients with controlled diseases over 6 months showed decreasing bMSI scores, and 60% patients with progressive diseases showed increasing bMSI scores during therapies. Conclusions: A significant proportion of pMMR metastatic gastrointestinal cancer patients could be rescued by bMSI and get benefits from ICI. bMSI could further classify the patients to three groups and more precisely predict the response of ICI. The level of bMSI is dynamically related to the response during the therapies. bMSI could potentially improve clinical practices in the future. Background: The Royal Marsden Hospital score (RMHs) (albumin <35 g/L, lactate dehydrogenase [LDH]>upper limit of normal [ULN], and >two sites of metastases [met]) is a validated prognostic index for Ph1 pt selection. Recently, a lung immune prognostic index (LIPI) (derived neutrophil/(leukocytes minus neutrophils) ratio [dNLR]>3, and LDH>ULN) proved to be useful for identifying pts with different outcomes under ICI. We aimed to improve pt selection for ICI Ph1 trials by developing a composite VIO that included all clinical-laboratory (CL) variables linked with worse median Overall Survival (mOS). Methods: Retrospective analysis of pts treated with ICI at VHIO Ph1 Unit from Jan'12 to Oct'17. VIO includes four CL factors previously described (albumin<35g/L, LDH>ULN, >two sites of met, dNLR>3) and a fifth variable (liver met) as per univari-ate Cox modeling. The following VIO clusters were defined based on Kaplan Meier OS estimates: low risk (0 and 1), intermediate risk (2 and 3) and high risk (4 and 5). Results: In total, 174 out of 214 pts (81%) treated with ICI (antiPD1/PDL1 ICI in 93%, combination regimens in 53%) had complete CL data for modeling. Most common tumor types were melanoma (22%) and lung (14%). Overall, best response was PD 47%, SD 38%, PR 12%, CR 2% and mOS 9.8 (95% CI 7.3-12.7) months (m). Concordance index of OS models including LIPI, RMHs or VIO scores were 0.62, 0.66 and 0.69, respectively. Estimated mOS in low risk (40.2% of all pts), intermediate risk (50.3%) and high risk (9.2%) were 22.0 m (10.5.4-33.4), 6.7 m (4.1-9.3) and 3.8 m (2.5-5.1), respectively (log rank test, p < 0.001). PD as best response was higher in high risk VIO group (81%) as compared to intermediate (50%) and low risk (34%, Chi-square p ¼ 0.002). 6m OS rates were 85% (77%-94%), 55% (44%-67%) and 30% (14%-65%) in low, intermediate and high risk VIO groups (log rank test, p < 0.001). Conclusions: Our results suggest that the VIO is a better predictor of OS on ICI in Ph1 trials as compared to existing prognostic scores. The VIO is a helpful tool for identifying Ph1 candidates unlikely to benefit from ICI and with higher chances of death within 6 m of trial recruitment.