Dataset Information

Mismatch Repair Protein Loss as a Prognostic and Predictive Biomarker in Breast Cancers Regardless of Microsatellite Instability.

ABSTRACT:

Background

Breast cancers that harbor mismatch-repair (MMR) deficiency and/or microsatellite instability (MSI) might be sensitive to immune checkpoint blockade, but there are currently no specific guidelines for assessing MMR status in breast cancer. Here, we sought to define the clinical value of MMR immunohistochemistry (IHC) and MSI analysis in breast cancers.

Methods

We subjected 444 breast cancers to MMR IHC and MSI analysis. Cases were classified as MMR-proficient (pMMR), MMR-deficient (dMMR), and MMR-heterogeneous (hMMR) based on the loss of immunoreactivity; MSI was defined by instability in the five indicators recommended by the National Cancer Institute for endometrial and colorectal cancers. Correlation of MMR status with patients' survival was assessed using the Kaplan-Meier estimator. Statistical tests were two-sided.

Results

Loss of MMR proteins was homogeneous (dMMR) in 75 patients (17%) and heterogeneous (hMMR) in 55 (12%). Among luminal breast cancers, there were similar frequencies of dMMR and hMMR tumors. Overall, the rate of discrepancy between IHC and MSI analysis was high (91%). Women with Luminal B-like dMMR carcinomas (n = 44) showed shorter overall survival (median = 77 months, range = 0-115 months) than those with pMMR (n = 205) or hMMR (n = 35) tumors (median = 84 months, range = 0-127 months) (P = .008). On the contrary, patients with estrogen receptor-negative breast cancers treated with chemotherapy lived longer in cases of dMMR (n = 9) than pMMR (n = 33) or hMMR (n = 7) tumors, with 87 months of median survival (range = 73-123 months) for the former compared with 79 months (range = 8-113 months) for the latter two categories (P < .001).

Conclusions

Immunohistochemistry and MSI are not interchangeable tests in breast carcinomas. MMR protein loss is a more common event than MSI and shows intra-tumor heterogeneity. MMR IHC allows the identification of clinically relevant subclasses of breast cancer patients, provided that multiple areas of the tumor are analyzed.

SUBMITTER: Fusco N

PROVIDER: S-EPMC6649738 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Publications

Mismatch Repair Protein Loss as a Prognostic and Predictive Biomarker in Breast Cancers Regardless of Microsatellite Instability.

Fusco Nicola N Lopez Gianluca G Corti Chiara C Pesenti Chiara C Colapietro Patrizia P Ercoli Giulia G Gaudioso Gabriella G Faversani Alice A Gambini Donatella D Michelotti Anna A Despini Luca L Blundo Concetta C Vaira Valentina V Miozzo Monica M Ferrero Stefano S Bosari Silvano S

JNCI cancer spectrum 20181001 4

<h4>Background</h4>Breast cancers that harbor mismatch-repair (MMR) deficiency and/or microsatellite instability (MSI) might be sensitive to immune checkpoint blockade, but there are currently no specific guidelines for assessing MMR status in breast cancer. Here, we sought to define the clinical value of MMR immunohistochemistry (IHC) and MSI analysis in breast cancers.<h4>Methods</h4>We subjected 444 breast cancers to MMR IHC and MSI analysis. Cases were classified as MMR-proficient (pMMR), MM ...[more]

PMID: 31360876

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Project description:BackgroundMismatch-repair (MMR)/microsatellite instability (MSI) status has therapeutic implications in endometrial cancer (EC). The authors evaluated the concordance of testing and factors contributing to MMR expression heterogeneity.MethodsSix hundred sixty-six ECs were characterized using immunohistochemistry (IHC), MSI testing, and mut-L homolog 1 (MLH1) methylation. Select samples underwent whole-transcriptome analysis and next-generation sequencing. MMR expression of metastatic/recurrent sites was evaluated.ResultsMSI testing identified 27.3% of cases as MSI-high (n = 182), MMR IHC identified 25.1% cases as MMR-deficient (n = 167), and 3.8% of cases (n = 25) demonstrated discordant results. A review of IHC staining explained discordant results in 18 cases, revealing subclonal loss of MLH1/Pms 1 homolog 2 (PMS2) (n = 10) and heterogeneous MMR IHC (mut-S homolog 6 [MSH6], n = 7; MLH1/PMS2, n = 1). MSH6-associated Lynch syndrome was diagnosed in three of six cases with heterogeneous expression. Subclonal or heterogeneous cases had a 38.9% recurrence rate (compared with 16.7% in complete MMR-deficient cases and 9% in MMR-proficient cases) and had abnormal MMR IHC results in all metastatic recurrent sites (n = 7). Tumors with subclonal MLH1/PMS2 demonstrated 74 differentially expressed genes (determined using digital spatial transcriptomics) when stratified by MLH1 expression, including many associated with epithelial-mesenchymal transition.ConclusionsSubclonal/heterogeneous MMR IHC cases showed epigenetic loss in 66.7%, germline mutations in 16.7%, and somatic mutations in 16.7%. MMR IHC reported as intact/deficient missed 21% of cases of Lynch syndrome. EC with subclonal/heterogeneous MMR expression demonstrated a high recurrence rate, and metastatic/recurrent sites were MMR-deficient. Transcriptional analysis indicated an increased risk for migration/metastasis, suggesting that clonal MMR deficiency may be a driver for tumor aggressiveness. Reporting MMR IHC only as intact/deficient, without reporting subclonal and heterogeneous staining, misses opportunities for biomarker-directed therapy.Plain language summaryEndometrial cancer is the most common gynecologic cancer, and 20%-40% of tumors have a defect in DNA proofreading known as mismatch-repair (MMR) deficiency. These results can be used to guide therapy. Tests for this defect can yield differing results, revealing heterogeneous (mixed) proofreading capabilities. Tumors with discordant testing results and mixed MMR findings can have germline or somatic defects in MMR genes. Cells with deficient DNA proofreading in tumors with mixed MMR findings have DNA expression profiles linked to more aggressive characteristics and cancer spread. These MMR-deficient cells may drive tumor behavior and the risk of spreading cancer.

Project description:BackgroundIn 2017, DNA mismatch repair/microsatellite instability (MMR/MSI) testing was nationally recommended for advanced colorectal cancers based on favorable immune checkpoint inhibitor responses among patients with MMR-deficient/MSI-high tumors.MethodsPatients ages ≥20-years-old presenting with stage IV colorectal adenocarcinoma from 2010 to 2017 were identified from the National Cancer Database. 2017 was the latest year with available testing utilization data. Patient, tumor, socioeconomic, and care setting characteristics were evaluated for association with upfront MMR/MSI testing in 2017 using multivariable logistic regression and average adjusted predicted probabilities (%AAP).ResultsAmong 72,830 stage IV colorectal cancers, upfront MMR/MSI testing levels increased from 16.4% in 2010 to 56.4% in 2017. For patients diagnosed in 2017 (i.e., following national recommendations, n = 10,022), testing levels were lower for older patients (Padj < 0.001), and were independent of patients' race/ethnicity and insurance status. Patients from the poorest quartile of households received less testing [49.6%AAP, 99.9% confidence interval (CI) 45.5-53.7] than patients from the 3rd (56.9%AAP, 99.9% CI, 53.3-60.6; Padj < 0.001) or 4th quartiles (57.6%AAP, 99.9% CI, 54.3-60.9; Padj < 0.001). Although testing levels improved most at community programs, they remained lower in 2017 (46.6%AAP, 99.9% CI, 41.0-52.1) compared with academic/NCI-designated comprehensive cancer centers (62.8%AAP, 99.9% CI, 59.7-65.8; Padj < 0.001).ConclusionsUpfront MMR/MSI testing utilization for patients with advanced colorectal cancer has increased but there is still substantial need for optimization. Testing utilization disproportionately lagged for patients who were older, from the poorest quartile of households, or managed at community cancer programs.ImpactOur findings indicate opportunities for improving rates of MMR/MSI testing and reporting, possibly through incorporation into quality control and accreditation metrics.

Dataset Information

Mismatch Repair Protein Loss as a Prognostic and Predictive Biomarker in Breast Cancers Regardless of Microsatellite Instability.

Background

Methods

Results

Conclusions

Publications

Mismatch Repair Protein Loss as a Prognostic and Predictive Biomarker in Breast Cancers Regardless of Microsatellite Instability.

Similar Datasets

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