Tumour mutational burden predicts resistance to EGFR/BRAF blockade in BRAF-mutated microsatellite stable metastatic colorectal cancer

2022 ◽  
Vol 161 ◽  
pp. 90-98
Author(s):  
Giovanni Randon ◽  
Rossana Intini ◽  
Chiara Cremolini ◽  
Elena Elez ◽  
Michael J. Overman ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Mutational Burden

scholarly journals Mutational Analysis of Patients With Colorectal Cancer in CALGB/SWOG 80405 Identifies New Roles of Microsatellite Instability and Tumor Mutational Burden for Patient Outcome

2019 ◽  
Vol 37 (14) ◽  
pp. 1217-1227 ◽  
Author(s):  
Federico Innocenti ◽  
Fang-Shu Ou ◽  
Xueping Qu ◽  
Tyler J. Zemla ◽  
Donna Niedzwiecki ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Microsatellite Instability ◽  
Metastatic Colorectal Cancer ◽  
Mutational Analysis ◽  
Gene Mutations ◽  
Phase Iii ◽  
First Line ◽  
Mutational Burden ◽  
Significant Difference ◽  
Tumor Mutational Burden

PURPOSE CALGB/SWOG 80405 was a randomized phase III trial that found no statistically significant difference in overall survival (OS) in patients with first-line metastatic colorectal cancer treated with chemotherapy plus either bevacizumab or cetuximab. Primary tumor DNA from 843 patients has been used to discover genetic markers of OS. PATIENTS AND METHODS Gene mutations were determined by polymerase chain reaction. Microsatellite status was determined by genotyping of microsatellites. Tumor mutational burden (TMB) was determined by next-generation sequencing. Cox proportional hazard models were used, with adjusting factors. Interaction of molecular alterations with either the bevacizumab or the cetuximab arms was tested. RESULTS Patients with high TMB in their tumors had longer OS than did patients with low TMB (hazard ratio [HR], 0.73 [95% CI, 0.57 to 0.95]; P = .02). In patients with microsatellite instability–high (MSI-H) tumors, longer OS was observed in the bevacizumab arm than in the cetuximab arm (HR, 0.13 [95% CI, 0.06 to 0.30]; interaction P < .001 for interaction between microsatellite status and the two arms). Patients with BRAF mutant tumors had shorter OS than did patients with wild-type (WT) tumors (HR, 2.01 [95% CI, 1.49 to 2.71]; P < .001). Patients with extended RAS mutant tumors had shorter OS than did patients with WT tumors (HR, 1.52 [95% CI, 1.26 to 1.84]; P < .001). Patients with triple-negative tumors (WT for NRAS/ KRAS/ BRAF) had a median OS of 35.9 months (95% CI, 33.0 to 38.8 months) versus 22.2 months (95% CI, 19.6 to 24.4 months ) in patients with at least one mutated gene in their tumors ( P < .001). CONCLUSION In patients with metastatic colorectal cancer treated in first line, low TMB, and BRAF and RAS mutations are negative prognostic factors. Patients with MSI-H tumors benefited more from bevacizumab than from cetuximab, and studies to confirm this effect of MSI-H are warranted.

Somatic DNA mutations, tumor mutational burden (TMB), and MSI Status: Association with efficacy in patients (pts) with metastatic colorectal cancer (mCRC) of FIRE-3 (AIO KRK-0306).

2018 ◽  
Vol 36 (15_suppl) ◽  
pp. 3591-3591 ◽  
Author(s):  
Volker Heinemann ◽  
Nicole Kraemer ◽  
Hannes Buchner ◽  
Ludwig Fischer von Weikersthal ◽  
Thomas Decker ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Dna Mutations ◽  
Mutational Burden ◽  
Tumor Mutational Burden

26 ctDNA clearance and radiographic resolution of lymph node metastasis in a patient with metastatic microsatellite stable colorectal cancer on immunotherapy

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A25-A25
Author(s):  
Charles Schneider ◽  
Michael Krainock ◽  
Meenakshi Malhotra ◽  
Paul Billings ◽  
Alexey Aleshin
Keyword(s):  
Colorectal Cancer ◽  
Lymph Node ◽  
Lymph Node Metastasis ◽  
Microsatellite Instability ◽  
Metastatic Colorectal Cancer ◽  
Mismatch Repair ◽  
Node Metastasis ◽  
Mutational Burden ◽  
Tumor Mutational Burden ◽  
Time Point

BackgroundHigh microsatellite instability (MSI-H) in metastatic colorectal cancer (mCRC) is associated with a beneficial response to immunotherapy. Additionally, within MSI-H cancers, tumor mutational burden (TMB) is independently predictive of immunotherapy responsiveness.1 Durable responses to therapy have been demonstrated in patients with MSI-H mCRC treated with Nivolumab and Ipilimumab.2 However, less is known about treatment responsiveness in patients with high mutational burden mCRC that demonstrates microsatellite stability (MSI-L).MethodsWe report on a 55-year-old female with a PALB-2 germline mutation who presented with a right-sided colonic adenocarcinoma with the involvement of the omentum and liver. The patient received 6 cycles of neoadjuvant FOLFOX, followed by an extended right hemicolectomy, omentectomy, and partial liver resection. The surgical specimen revealed a moderately differentiated adenocarcinoma in the cecum demonstrating a poor response to chemotherapy, 0/23 lymph nodes positive, one focus of adenocarcinoma in the liver with clear margins, and focal omental involvement with adenocarcinoma. The patient subsequently underwent 6 cycles of ‘adjuvant’ FOLFOX, with Oxaliplatin omitted after 3 cycles secondary to peripheral neuropathy. Soon after the patient experienced a recurrence that involved the anterior abdominal wall, between the peritoneum, and stomach, which was subsequently resected with negative margins. Molecular profiling of this metastatic focus revealed a TMB of 15.4 mutations per megabase, proficient Mismatch Repair (pMMR), a PDL1 CPS score of 26, and microsatellite stable (MSS) status. First, ctDNA analysis was performed at the time of recurrence and was found to be positive. Based on the TMB score of 15.4 and an elevated PDL1 score, the patient was initiated on Nivolumab and Ipilimumab. ctDNA measurements were obtained at the patient‘s request.ResultsDNA assessment performed after surgery and prior to initiation of immunotherapy revealed an approximate doubling of ctDNA levels, measured in mean tumor molecules (MTM) per mL of plasma, every month. During this period of time and correlating with the rise in ctDNA levels, the patient developed a new and enlarging FDG avid cardiophrenic lymph node. Following 2 cycles of Nivolumab and Ipilimumab, the FDG avid lymph node completely resolved and ctDNA clearance was observed (figure 1).Abstract 26 Figure 1ctDNA time-course demonstrating ctDNA kineticsTime-point A represents the initial ctDNA assay, performed at the time of resection of peritoneal metastasis. An additional time-point (B) drawn a month later reveals a further increase in ctDNA. Time-point C represents a peak in ctDNA levels, concomitant with the new emergence of a PET avid cardiophrenic lymph node. Combination Immunotherapy (IO) was begun shortly after time-point C. Time-point D represents ctDNA clearance and radiographic resolution of lymph node metastasis after two cycles of IO. MTM/mL - mean tumor molecules/milliliter of plasmaConclusionsHere we present a case of ctDNA clearance correlating with a radiographic resolution of metastatic disease in a patient with MSS mCRC. The data is provocative and suggests a possible contributory role of ctDNA-based testing as an additional monitoring parameter to measure disease-responsiveness to immunotherapy. Further investigation is warranted.Ethics ApprovalN/AConsentN/AReferencesSchrock AB, Ouyang C, Sandhu J, Sokol E, Jin D, Ross J8, Miller VA, Lim D, Amanam l, Chao J, Catenacci D, Cho M, Braiteh 7, Klempner SJ, Ali 8M, Fakih M. Tumor mutational burden is predictive of response to immune checkpoint inhibitors in MSl-high metastatic colorectal cancer. Ann Oncol 2019;30(7):1096–1103Overman MJ, et al. Durable Clinical/Benefit With Nivolumab Plus lpilimumab in DNA Mismatch Repair-Deficient/Microsatellite Instability-High Metastatic Colorectal Cancer. Clin Oncol 2018;36(8):773–779.

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