Dataset Information

Mismatch Repair Deficiency Drives Durable Complete Remission by Targeting Programmed Death Receptor 1 in a Metastatic Luminal Breast Cancer Patient.

ABSTRACT:

Background

In the field of breast cancer tumor biology, triple-negative breast cancer patients are the main focus of current clinical trials exploring the use of immune checkpoint inhibitors due to higher frequencies of somatic mutations, neoantigens, and resulting tumor-specific T-cell reactivity.

Case report

Here, we present the case of a 66-year-old woman with metastatic luminal breast cancer that rapidly responded to monotherapy with pembrolizumab, a monoclonal anti-PD-1 antibody. This patient obtained a partial clinical response within the first cycle of treatment and an ongoing durable complete remission after 12 weeks. Except for a transient immune-related thyreoiditis, there were no side effects observed offering remarkable quality of life to the patient. To evaluate the underlying mechanisms, we performed immunohistochemistry, explored the mutational landscape by whole-exome sequencing, and identified potential T-cell epitopes by prediction of neoantigens with high affinity binding to one of the patient's HLA. Briefly, we found a strong infiltration of CD8+ T cells without staining for PD-L1 in the tumor stroma. Exome sequencing revealed an enormous frequency of somatic and tumor-specific alterations, mainly C>T/G>A transitions. The mutational pattern was further linked to genome instability and deficient mismatch repair supported by the loss of MSH6 protein expression and therefore leading to susceptibility to immune checkpoint blockade.

Conclusion

Within the overall goal to establish operating procedures for breast cancer immunotherapy, we propose to re-evaluate testing for deficient mismatch repair and to further intensify the search for biomarkers predictive for the success of immune checkpoint modulation including all tumor biologic subtypes of breast cancer.

SUBMITTER: Fremd C

PROVIDER: S-EPMC6465703 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Publications

Mismatch Repair Deficiency Drives Durable Complete Remission by Targeting Programmed Death Receptor 1 in a Metastatic Luminal Breast Cancer Patient.

Fremd Carlo C Hlevnjak Mario M Zapatka Marc M Zoernig Inka I Halama Niels N Fejzibegovic Nino N Thewes Verena V Lichter Peter P Schirmacher Peter P Kloor Matthias M Marmé Frederik F Schütz Florian F Kosaloglu Zeynep Z Sinn Hans Peter HP Jäger Dirk D Schneeweiss Andreas A

Breast care (Basel, Switzerland) 20181114 1

<h4>Background</h4>In the field of breast cancer tumor biology, triple-negative breast cancer patients are the main focus of current clinical trials exploring the use of immune checkpoint inhibitors due to higher frequencies of somatic mutations, neoantigens, and resulting tumor-specific T-cell reactivity.<h4>Case report</h4>Here, we present the case of a 66-year-old woman with metastatic luminal breast cancer that rapidly responded to monotherapy with pembrolizumab, a monoclonal anti-PD-1 antib ...[more]

PMID: 31019444

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Project description:BACKGROUND:While response rates to anti-PD1 therapy are low in unselected metastatic castration resistant prostate cancer (mCRPC) patients, those with inactivating mutations in mismatch repair (MMR) genes (i.e. MMR deficiency; MMRd) or microsatellite instability (MSI) are thought likely to respond favorably. To date, there is limited published data on this biologically distinct and clinically relevant subgroup's natural history and response to treatment. METHODS:We retrospectively identified patients at two academic institutions who had MMRd/MSI-high metastatic prostate cancer (PC). Clinical and pathologic characteristics at the time of diagnosis as well as response to standard therapies and immune checkpoint therapy were abstracted. Descriptive statistics, including PSA50 response (?50% decline in PSA from baseline) and clinical/radiographic progression free survival (PFS), are reported. RESULTS:27 men with MMRd and/or MSI-high metastatic PC were identified. 13 (48%) men had M1 disease at diagnosis and 19 of 24 (79%) men that underwent prostate biopsy had a Gleason score ?8. Median overall survival from time of metastasis was not reached (95% CI: 33.6-NR mos) after a median follow up of 33.6 mos (95% CI: 23.8-50.5 mos). Seventeen men received pembrolizumab, of which 15 had PSA response data available. PSA50 responses to pembrolizumab occurred in 8 (53%) men. Median PFS was not reached (95% CI: 1.87-NR mos) and the estimated PFS at 6 months was 64.1% (95% CI: 33.7%-83.4%). Of those who achieved a PSA50 response, 7 (87.5%) remain on treatment without evidence of progression at a median follow up of 12 months (range 3-20 months). CONCLUSIONS:MMRd PC is associated with high Gleason score and advanced disease at presentation. Response rates to standard therapies are comparable to those reported in unselected patients and response rate to checkpoint blockade is high. Our study is limited by small sample size, and more research is needed to identify additional factors that may predict response to immunotherapy.

Project description:BackgroundMismatch-repair deficiency (dMMR) predicts worse chemoresponsiveness but better survival in early-stage colorectal adenocarcinoma. This study examined metastatic colorectal and appendix cancers with and without peritoneal metastasis (PM) in the National Cancer Database (NCDB), hypothesizing that dMMR tumors show better survival.MethodsStage 4 colon, rectum, and appendix cancers (2010-2016) were identified in the NCDB (including goblet cell carcinoids, excluding neuroendocrine tumors). Stage 4 disease without liver, bone, brain, lung, or distant nodal metastases defined PM. Fisher's exact tests were used to compare proportions, and Kaplan-Meier analysis was used to evaluate survival.ResultsOf 130,125 stage 4 colon, rectum, and appendix cancers, 27,848 (21.4%) had PM. Appendix primary tumors had PM more commonly than colon or rectum cancer (83.6% vs. 20.6% and 12.1% of stage 4 cases; p < 0.0001). More PM patients had MMR testing than patients with other metastasis (OM) (21.4% vs. 16.1%), and testing increased from 9.6% in 2010 to 26.3% in 2016 (both p < 0.0001). Among the PM patients, MMR testing was least common for appendix cancers (9.0%). When tested, PM patients more often had dMMR (22.9% [1122/4900] vs. 15.4% [2532/16,495] of OM patients; p < 0.0001). Colon primary tumor had dMMR most frequently (25.0% vs. 14.6% and 14.5% for rectal and appendix tumor; p < 0.0001). Most PM patients received chemotherapy (66.2%). Immunotherapy use increased over time (1.1% of PM diagnoses in 2010 vs. 20.8% in 2016). For MMR-tested stage 4 patients, dMMR correlated with worse survival (median OM, 19.7 vs. 23.9 months, p < 0.0001; median PM, 19.9 vs. 24.6 months, p = 0.035).ConclusionsThe NCDB showed dMMR predicting worse survival for stage 4 colorectal cancers with and without PM and dMMR existing in 14.5-25% of tested patients, suggesting that increased attention to MMR testing in stage 4 colorectal and appendix cancers can identify many patients who could potentially benefit from immunotherapy.

Project description:The inclusion of DNA mismatch repair (MMR) evaluation as a standard of care for endometrial cancer management will result in a growing population of patients with MMR deficiency and negative germline Lynch syndrome testing (MMR-deficient). In this systematic review and study, the clinicopathologic features of endometrial cancer in patients with MMR-intact, MLH1 methylation positive, MMR-deficient or Lynch syndrome are evaluated. A systematic search of online databases between 1990 and 2018 identified studies of endometrial cancer patients with tumour testing (MMR protein immunohistochemistry or microsatellite instability) and germline assessment for Lynch syndrome. Extracted data included tumour testing, germline genetic testing, age, body mass index (BMI), family history, tumour stage, grade and histologic type. Associations between MMR-intact, MLH1 methylation positive, MMR-deficient and Lynch syndrome groups were analysed using descriptive statistics. The comprehensive search produced 4,400 publications, 29 met inclusion criteria. A total of 7,057 endometrial cancer cases were identified, 1,612 with abnormal immunohistochemistry, 977 with microsatellite instability. Nine-hundred patients underwent germline genetic testing, identifying 212 patients with Lynch syndrome. Patients in the Lynch syndrome and MMR-deficient groups were significantly younger than patients in the MMR-intact and MLH1 methylation positive groups. Patients with MMR-intact tumours had the highest BMI, followed by MMR-deficient, then Lynch syndrome. MMR-intact tumours were more likely to be grade I at diagnosis than other groups. Patients with Lynch syndrome and MMR-deficient tumours were less likely to have stage I disease as compared to patients with MMR-intact tumours. Endometrial cancer patients with MMR-deficient tumours have similar features to those with germline Lynch syndrome mutations, including age, grade, histology and stage. Even in the absence of a germline mutation, tumour evaluation for MMR status may have important clinical implications.

Project description:BackgroundSomatic 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.MethodsWe 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.ResultsThe 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).ConclusionsThis 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.).

Dataset Information

Mismatch Repair Deficiency Drives Durable Complete Remission by Targeting Programmed Death Receptor 1 in a Metastatic Luminal Breast Cancer Patient.

Background

Case report

Conclusion

Publications

Mismatch Repair Deficiency Drives Durable Complete Remission by Targeting Programmed Death Receptor 1 in a Metastatic Luminal Breast Cancer Patient.

Similar Datasets

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