The analysis of microsatellite instability in extracolonic gastrointestinal malignancy

BACKGROUND Somatic mutations have the potential to encode “non-self” immunogenic antigens. We hypothesized that tumors with a large number of somatic mutations due to mismatch-repair defects may be susceptible to immune checkpoint blockade. METHODS We conducted a phase 2 study to evaluate the clinical activity of pembrolizumab, an anti–programmed death 1 immune checkpoint inhibitor, in 41 patients with progressive metastatic carcinoma with or without mismatch-repair deficiency. Pembrolizumab was administered intravenously at a dose of 10 mg per kilogram of body weight every 14 days in patients with mismatch repair–deficient colorectal cancers, patients with mismatch repair–proficient colorectal cancers, and patients with mismatch repair–deficient cancers that were not colorectal. The coprimary end points were the immune-related objective response rate and the 20-week immune-related progression-free survival rate. RESULTS The immune-related objective response rate and immune-related progression-free survival rate were 40% (4 of 10 patients) and 78% (7 of 9 patients), respectively, for mismatch repair–deficient colorectal cancers and 0% (0 of 18 patients) and 11% (2 of 18 patients) for mismatch repair–proficient colorectal cancers. The median progression-free survival and overall survival were not reached in the cohort with mismatch repair–deficient colorectal cancer but were 2.2 and 5.0 months, respectively, in the cohort with mismatch repair–proficient colorectal cancer (hazard ratio for disease progression or death, 0.10 [P<0.001], and hazard ratio for death, 0.22 [P = 0.05]). Patients with mismatch repair–deficient noncolorectal cancer had responses similar to those of patients with mismatch repair–deficient colorectal cancer (immune-related objective response rate, 71% [5 of 7 patients]; immune-related progression-free survival rate, 67% [4 of 6 patients]). Whole-exome sequencing revealed a mean of 1782 somatic mutations per tumor in mismatch repair–deficient tumors, as compared with 73 in mismatch repair–proficient tumors (P = 0.007), and high somatic mutation loads were associated with prolonged progression-free survival (P = 0.02). CONCLUSIONS This study showed that mismatch-repair status predicted clinical benefit of immune checkpoint blockade with pembrolizumab. (Funded by Johns Hopkins University and others; ClinicalTrials.gov number, NCT01876511.)

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Section: Discussionmentioning

confidence: 99%

PD-1 Blockade in Tumors with Mismatch-Repair Deficiency

et al. 2015

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“…Mismatch-repair deficiency occurs in many cancers, including those of the colorectum, uterus, stomach, biliary tract, pancreas, ovary, prostate, and small intestine. 18,[34][35][36][37][38][39][40][41][42] It is possible that patients with mismatch repair-deficient tumors of these types may also benefit from anti-PD-1 therapy, as may patients whose tumors contain other DNA repair deficiencies, such as those with mutations in POLD, POLE, or MYH. 18,43,44 The hypothesis that mismatch repair-deficient tumors stimulate the immune system is not a new idea 45 ; it has been supported by observations of the dense immune infiltration and Th1-associated cytokine-rich environment in mismatch repair-deficient tumors.…”

Section: Discussionmentioning

confidence: 99%

PD-1 blockade in tumors with mismatch repair deficiency.

Uram

Wang

et al. 2015

JCO

587

838

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“…However, in less common cancers, the presence of MSI-high tumors is more difficult to estimate, and the literature reports ranges of 0% to 22% for ampullary cancer, 0% to 3% for pancreatic cancer, and 5% to 45% for small bowel cancers. 61–63 Clinical trials are studying anti-PD-1 mAbs in patients with GI cancer with MSI-high tumors to test the hypothesis that MSI-high tumors respond more effectively to checkpoint mAbs (NCT01876511).…”

Section: Immune Antibodiesmentioning

confidence: 99%

Immune Therapy in GI Malignancies: A Review

Wang

Reiss

Khatri

et al. 2015

JCO

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The balance between tumor-promoting and tumor-suppressing immune responses and the difference between them ultimately determine whether a cancer escapes immune recognition mechanisms. Defining the complex relationships between the tumor itself, the tumor environment, and the immune system has been critical in facilitating the development of successful immunotherapies. This review explores the role of oncogenes in inducing cancer-associated inflammation, the local and systemic factors that lead to immune suppression, and immunotherapy approaches to overcome immune privilege.

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The analysis of microsatellite instability in extracolonic gastrointestinal malignancy

Cited by 27 publications

References 137 publications

PD-1 Blockade in Tumors with Mismatch-Repair Deficiency

PD-1 Blockade in Tumors with Mismatch-Repair Deficiency

PD-1 blockade in tumors with mismatch repair deficiency.

Immune Therapy in GI Malignancies: A Review

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