DNA Mismatch Repair Deficiency in Breast Carcinoma: A Pilot Study on Frequency and Clinicopathological Characteristics in Triple Negative and Non-Triple Negative Tumors
Yong Hannah Wen, Edi Brogi, Muzaffar Akram, Zhaoshi Zeng, Jeff Catalano, Philip Paty, Larry Norton, Jinru Shia. Memorial Sloan-Kettering Cancer Center, New York, NY
Background: DNA mismatch repair (MMR) deficiency has been described in breast cancer; however, data are limited and the characteristics of such tumors are not defined. Triple negative breast carcinomas (TNBCs) often show solid growth and prominent lymphocytic infiltrate, which are morphologic features commonly seen in MMR-deficient tumors. The aim of this pilot study was to analyze the frequency and clinicopathological characteristics of MMR deficiency in breast cancer, utilizing case series of both TNBCs and non-TNBCs.
Design: Study cases consisted of 227 TNBCs and 90 non-TNBCs. Tissue microarrays (TMAs) were utilized. MMR deficiency was evaluated by immunohistochemistry (IHC) for MLH1, PMS2, MSH2, and MSH6. Tumors with positive reactivity on the TMAs were classified as “normal stain”; any negative or equivocal stain on the TMAs was repeated on whole tissue sections and the latter results were used for final analysis. “Abnormal stain” was defined as no nuclear reactivity in a carcinoma evaluated on whole sections. All tumors with abnormal stain and available tissue were further evaluated for microsatellite instability (MSI) by PCR using a 3-marker panel (BAT-26, BAT-25, D2S123).
Results: All 90 non-TNBCs showed “normal stain” for all 4 antibodies tested. Of the 227 TNBCs, 3 (cases 1-3, Table 1) showed loss of both MLH1 and PMS2, whereas 1 case (case 4, Table 1) showed loss of both MSH2 and MSH6. Cases 1-3 had tissue for MSI testing. Case 1 showed instable BAT-26 and case 3 showed instability on all 3 markers. All 4 tumors were invasive ductal carcinoma, with histologic and nuclear grade 3/3. None of the 4 patients met the Amsterdam criteria for Lynch syndrome clinically. Table 1 summarizes additional tumor and patient characteristics, and clinical followup information.
|Case 1||Case 2||Case 3||Case 4|
|Tumor lymphocytic infiltrate||Moderate||Minimal||Extensive||Minimal|
|Followup (F/U), month||82||48||65||21|
|Distant metastasis (time after diagnosis)||None||Lung (34 months)||None||None|
|Status as last F/U||NED||DOD||NED||DOD|