Mutational burden on circulating cell-free tumor-DNA testing as a surrogate marker of mismatch repair deficiency/microsatellite instability and/or response to immunotherapy in patients with colorectal cancer.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e15066-e15066
Author(s):  
Saivaishnavi Kamatham ◽  
Dorin Colibaseanu ◽  
Amit Merchea ◽  
Faisal Shahjehan ◽  
Jason Scott Starr ◽  
...  
Keyword(s):  
Microsatellite Instability ◽  
Mismatch Repair ◽  
Somatic Mutations ◽  
Surrogate Marker ◽  
P Value ◽  
Mutational Burden ◽  
Repair Deficiency ◽  
Testing Liquid ◽  
The Mean ◽  
Tumor Dna

e15066 Background: Circulating cell-free tumor-DNA (ctDNA) testing (‘liquid biopsy’) is increasingly being employed both in clinical trials as well as clinical practice. We aimed to contrast and compare the differences in the number of somatic mutations observed on ctDNA testing between mismatch repair deficient/microsatellite instability-high (dMMR/MSI-High) versus mismatch repair proficient/microsatellite stable (pMMR/MSS) colorectal cancers (CRC). Methods: We had 20 patients at Mayo Clinic Florida that were dMMR/MSI-High with testing through the commercially available platform (Guardant360) that uses a 73-gene panel. Median numbers of somatic mutations were compared between the 2 subset of CRC. Results: Patients with dMMR/MSI-High CRC had a median of 8 mutations (range: 2-15) versus a median of 4 mutations (range: 1-22) in pMMR/MSS patients, p-value of 0.001. Similarly, the mean number of somatic mutations were 7.47 (S.D. ± 4.15) versus 5.02 mutations (S.D. ± 3.83) in patients with dMMR/MSI-H and pMMR/MSS, tumors respectively. Though it is simplistic, we could still potentially identify patients who may be candidates for immunotherapy by gauging the mutational burden reported (Table). Furthermore, on serial testing, decline in mutational burden as early as few weeks into therapy was predictive of response later on imaging. Conclusions: Analysis of number of somatic mutations on ctDNA testing can be complementary to MMR/MSI-testing, especially in situations when tissue is not available or safe to obtain. This can also be of value in predicting and/or following response to immunotherapy. The utility of this may go beyond CRC in identifying patients who may benefit from immunotherapy. [Table: see text]

Clinical characterization of pancreatic ductal adenocarcinomas (PDAC) with mismatch repair (MMR) gene mutations.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e15791-e15791 ◽  
Author(s):  
Zishuo Ian Hu ◽  
Anna M. Varghese ◽  
Jinru Shia ◽  
Alice Zervoudakis ◽  
Maeve Aine Lowery ◽  
...  
Keyword(s):  
Mismatch Repair ◽  
Somatic Mutations ◽  
Gene Mutations ◽  
Germline Mutations ◽  
Cancer Center ◽  
Mmr Genes ◽  
Mutational Burden ◽  
Repair Deficiency ◽  
History Of

e15791 Background: Tumors with mismatch repair-deficiency (MMRD) have a high mutational burden and have good responses to immunotherapy (Le, NEJM, 2015). We describe the natural course, clinicopathological, and genomic status of MMRD PDAC patients (pts) at Memorial Sloan Kettering Cancer Center (MSKCC). Methods: MSKCC institutional registry and ICD billing database queried from 2006-2016 for PDAC pts with genetically confirmed mutations in mismatch repair (MMR) genes. Mutation # determined via MSK-IMPACT, a targeted tumor next generation sequencing (NGS) test (Cheng, J Mol Diagn, 2015). Results: 5/607 (0.8%) PDAC pts had Lynch syndrome (LS) (confirmed germline mutations) (Table 1). Of the 5 LS pts, all had > 10 mutations in NGS, with 4 of 5 having > 50 mutations. 4 of 5 (80%) are alive at last follow-up (survival 30-314 months). N=4 had extensive personal/family history of cancer. Of N=3 who had resected disease, all 3 had recurrence at 11, 49 and 311 months, and all are alive (survival: 69-314 months). Of N= 2 pts that had unresectable tumors, one passed away at 30 months while the other is on checkpoint inhibitor trial and is alive at 30 months. In contrast, 7/607 (1.1%) PDAC pts had somatic mutations in MMR genes with an average of 5.7 mutations in NGS, with 4/7 having <5 mutations. 4/7 (57%) are deceased at last follow-up (survival: 10-42 months). Conclusions: All cases with germline mutations in the MMR genes, with one exception, had high mutation #. All cases with somatic mutations in the MMR genes had low mutation #. Germline mutations in MMR genes and high mutational burden may predict for a prognostically favorable subgroup of PDAC pts with high susceptibility to immune oncology agents. [Table: see text]

scholarly journals Mismatch repair deficiency in hematological malignancies with microsatellite instability

Oncogene ◽  
2002 ◽  
Vol 21 (37) ◽  
pp. 5758-5764 ◽  
Author(s):  
Liya Gu ◽  
Brandee Cline-Brown ◽  
Fujian Zhang ◽  
Lu Qiu ◽  
Guo-Min Li
Keyword(s):  
Microsatellite Instability ◽  
Mismatch Repair ◽  
Hematological Malignancies ◽  
Mismatch Repair Deficiency ◽  
Repair Deficiency

Tumor site discordance in mismatch repair deficiency in synchronous endometrial and ovarian cancers

2020 ◽  
Vol 30 (12) ◽  
pp. 1951-1958
Author(s):  
Soyoun Rachel Kim ◽  
Alicia Tone ◽  
Raymond Kim ◽  
Matthew Cesari ◽  
Blaise Clarke ◽  
...  
Keyword(s):  
Lynch Syndrome ◽  
Microsatellite Instability ◽  
Mismatch Repair ◽  
Ovarian Tumor ◽  
Tumor Site ◽  
Mismatch Repair Deficiency ◽  
Ovarian Cancers ◽  
Repair Deficiency ◽  
Endometrial Tumor ◽  
Germline Testing

ObjectivesFor synchronous endometrial and ovarian cancers, most centers rely on mismatch repair testing of the endometrial cancer to identify Lynch syndrome, and neglect the ovarian tumor site completely. We examined the mismatch repair immunohistochemistry and microsatellite instability results from the endometrium and ovary to assess discordance between the tumor sites and between tests.Methods30 women with newly diagnosed synchronous endometrial and ovarian cancer were prospectively recruited from three cancer centers in Ontario, Canada. Both tumor sites were assessed for mismatch repair deficiency by immunohistochemistry and microsatellite instability test; discordance in results between tumor sites and discordance between test results at each site was examined. Cases with discordant results had tumors sequenced with a targeted panel in order to reconcile the findings. All women underwent mismatch repair gene germline testing.ResultsOf 30 patients, 11 (37%) were mismatch repair deficient or microsatellite instable at either tumor site, with 5 (17%) testing positive for Lynch syndrome. Mismatch repair immunohistochemistry expression was discordant between endometrial and ovarian tumor sites in 2 of 27 patients (7%) while microsatellite instability results were discordant in 2 of 25 patients (8%). Relying on immunohistochemistry or microsatellite instability alone on the endometrial tumor would have missed one and three cases of Lynch syndrome, respectively. One patient with Lynch syndrome with a PMS2 pathogenic variant was not detected by either immunohistochemistry or microsatellite instability testing. The rate of discordance between immunohistochemistry and microsatellite instability test was 3.8% in the ovary and 12% in the endometrium.ConclusionsThere was discordance in immunohistochemistry and microsatellite instability results between tumor sites and between tests within each site. Endometrial tumor testing with mismatch repair immunohistochemistry performed well, but missed one case of Lynch syndrome. Given the high incidence of Lynch syndrome (17%), consideration may be given to germline testing in all patients with synchronous endometrial and ovarian cancers.

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