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Pancreatic cancer 'mismatch' in Lynch syndrome
Andrew E Hendifar1, Brent K Larson2, Rebecca Rojansky2
1Department of Gastrointestinal Malignancies, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
Objective:
Immune therapy with the PD1 inhibitor pembrolizumab has been approved to treat unresectable/metastatic solid tumours exhibiting mismatch repair (MMR) deficiency. Lynch syndrome (LS), caused by autosomal dominant germline mutations of a MMR gene, predisposes to the development of MMR-deficient cancers. We report a case of MSH2-LS with an MMR-intact pancreatic ductal adenocarcinoma (PDAC) ineligible for treatment with pembrolizumab.
Design:
Immunohistochemistry of MMR proteins was performed in each malignancy developed in a MSH2-LS patient to determine MMR status.
Results:
The patient carried a pathogenic MSH2 germline mutation and had a history of LS-type cancers, including endometrial carcinoma, colorectal adenocarcinoma, urothelial carcinoma of the bladder and PDAC. Three malignancies (endometrial, colorectal, urothelial) lacked MSH2 and MSH6 expression, consistent with MSH2-associated tumorigenesis. However, MSH2 and MSH6 expression were intact in the PDAC, suggesting the sporadic occurrence of the pancreatic tumour unrelated to the germline MSH2 mutation. These inconsistent MMR statuses among the tumours rendered the patient ineligible for the immunotherapy pembrolizumab.
Conclusion:
Testing for MMR protein expression is recommended for each tumour in patients with LS, especially pancreatic, as discordant results may have profound effects on treatment opportunities. To our knowledge, this is the first documented case of MMR-intact PDAC in a patient with MSH2-LS.
Insights
In Lynch syndrome (LS), mismatch repair (MMR) deficient tumors are treatable with immunotherapy. However, this case shows an MMR-intact pancreatic tumor in an MSH2-LS patient, highlighting the need for individual tumor testing.
Area of Science:
- Oncology
- Genetics
- Immunotherapy
Background:
- Lynch syndrome (LS) patients have germline mutations in mismatch repair (MMR) genes, predisposing them to MMR-deficient cancers.
- Pembrolizumab, a PD-1 inhibitor, is approved for unresectable/metastatic solid tumors with MMR deficiency.
- MMR deficiency status is crucial for determining eligibility for immunotherapy.
Observation:
- A patient with a pathogenic MSH2 germline mutation and a history of LS-associated cancers presented with pancreatic ductal adenocarcinoma (PDAC).
- While previous LS-related malignancies (endometrial, colorectal, urothelial) showed MMR deficiency (loss of MSH2/MSH6 expression), the PDAC exhibited intact MSH2 and MSH6 expression.
- This discordance indicated a sporadic origin for the PDAC, unrelated to the patient's germline MSH2 mutation.
Findings:
- The PDAC was MMR-intact, making the patient ineligible for pembrolizumab treatment.
- This represents the first documented case of MMR-intact PDAC in a patient with MSH2-LS.
Implications:
- Testing MMR protein expression in each malignancy is crucial for LS patients, particularly for pancreatic tumors.
- Discordant MMR status across tumors can significantly impact treatment options and eligibility for targeted immunotherapies.
- This case underscores the importance of comprehensive molecular profiling for personalized cancer treatment strategies.