Advertisement

Evaluating Mismatch Repair Status to Screen Clinical Advanced Breast Carcinomas for Immunotherapy: Experience From a Large Academic Institution

  • Vidya Arole
    Affiliations
    The Ohio State University Wexner Medical Center, Columbus, OH

    Department of Pathology, Wexner Medical Center at The Ohio State University, Columbus, OH
    Search for articles by this author
  • Saba Shafi
    Affiliations
    The Ohio State University Wexner Medical Center, Columbus, OH

    Department of Pathology, Wexner Medical Center at The Ohio State University, Columbus, OH
    Search for articles by this author
  • Bindu Challa
    Affiliations
    The Ohio State University Wexner Medical Center, Columbus, OH

    Department of Pathology, Wexner Medical Center at The Ohio State University, Columbus, OH
    Search for articles by this author
  • Anil V. Parwani
    Affiliations
    The Ohio State University Wexner Medical Center, Columbus, OH

    Department of Pathology, Wexner Medical Center at The Ohio State University, Columbus, OH
    Search for articles by this author
  • Gary Tozbikian
    Affiliations
    The Ohio State University Wexner Medical Center, Columbus, OH

    Department of Pathology, Wexner Medical Center at The Ohio State University, Columbus, OH
    Search for articles by this author
  • Zaibo Li
    Correspondence
    Address for correspondence: Zaibo Li, MD, PhD, The Ohio State University Wexner Medical Center, Columbus, OH 43210
    Affiliations
    The Ohio State University Wexner Medical Center, Columbus, OH

    Department of Pathology, Wexner Medical Center at The Ohio State University, Columbus, OH
    Search for articles by this author
Published:January 21, 2022DOI:https://doi.org/10.1016/j.clbc.2022.01.010

      Abstract

      Background

      Very few studies have investigated mismatch repair (MMR) deficiency in breast carcinoma (BC) in clinical setting. Given the recent approval of Pembrolizumab for solid tumors with MMR deficiency, we screened clinically advanced breast carcinoma patients for immunotherapy by examining their MMR status.

      Patients and methods

      The cohort consisted of 163 clinical advanced BCs, including 5 primary, 14 locally recurrent, and 144 metastatic BCs. Immunohistochemistry (IHC) with anti–MMR proteins or next generation sequencing (NGS) to detect microsatellite instability was performed to evaluate MMR status. The relationship between MMR status and clinicopathologic characteristics was evaluated.

      Results

      Among 163 advanced BCs, 19 were hormone receptor (HR)-positive (≥ 10%)/HER2-negative, 17 were HER2+, and 127 were TNBCs/low HR-positive (< 10%). MMR status was evaluated by IHC in 131 cases and by NGS in 32 cases. Among all cases, only 1 case (0.6%) showed MMR deficiency. The case with MMR deficiency showed loss of MLH1 and PMS2 proteins, but no hypermethylation of MLH1 promoter. Sequencing analysis revealed MLH1 genetic alteration with a splice site mutation (208-1G > A), which results in disruption of the N-terminal ATPase-containing domain (amino acids 25-336). All 127 TNBCs/low HR-positive BCs showed preserved MMR. PD-L1 (SP142) testing was performed in 66 cases with 18 (27%) as positive and 48 (73%) as negative, and its expression showed no correlation with MMR status.

      Conclusion

      MMR deficiency exists in an extremely low percentage of breast carcinomas, including TNBCs, suggesting a routine MMR testing to screen BC patients for immunotherapy may not be cost effective.

      Key words

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Clinical Breast Cancer
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Le DT
        • Durham JN
        • Smith KN
        • et al.
        Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade.
        Science. 2017; 357: 409-413
        • Le DT
        • Uram JN
        • Wang H
        • et al.
        PD-1 blockade in tumors with mismatch-repair deficiency.
        N Engl J Med. 2015; 372: 2509-2520
        • Li Z
        • Joehlin-Price AS
        • Rhoades J
        • et al.
        Programmed death ligand 1 expression among 700 consecutive endometrial cancers: strong association with mismatch repair protein deficiency.
        Int J Gynecol Cancer. 2018; 28: 59-68
        • Willis BC
        • Sloan EA
        • Atkins KA
        • Stoler MH
        • Mills AM.
        Mismatch repair status and PD-L1 expression in clear cell carcinomas of the ovary and endometrium.
        Mod Pathol. 2017; 30: 1622-1632
        • Droeser RA
        • Hirt C
        • Viehl CT
        • et al.
        Clinical impact of programmed cell death ligand 1 expression in colorectal cancer.
        Eur J Cancer. 2013; 49: 2233-2242
        • Wen YH
        • Brogi E
        • Zeng Z
        • et al.
        DNA mismatch repair deficiency in breast carcinoma: a pilot study of triple-negative and non-triple-negative tumors.
        Am J Surg Pathol. 2012; 36: 1700-1708
        • Mills AM
        • Dill EA
        • Moskaluk CA
        • Dziegielewski J
        • Bullock TN
        • Dillon PM.
        The relationship between mismatch repair deficiency and PD-L1 expression in breast carcinoma.
        Am J Surg Pathol. 2018; 42: 183-191
        • Hou Y
        • Nitta H
        • Parwani AV
        • Li Z.
        PD-L1 and CD8 are associated with deficient mismatch repair status in triple-negative and HER2-positive breast cancers.
        Hum Pathol. 2019; 86: 108-114
        • Özcan D
        • Lade-Keller J
        • Tramm T.
        Can evaluation of mismatch repair defect and TILs increase the number of triple-negative breast cancer patients eligible for immunotherapy?.
        Pathol Res Pract. 2021; 226153606
        • Freitag CE
        • Mei P
        • Wei L
        • Parwani AV
        • Li Z.
        Genetic alterations and their association with clinicopathologic characteristics in advanced breast carcinomas: focusing on clinically actionable genetic alterations.
        Hum Pathol. 2020; 102: 94-103
        • Freitag CE
        • Mei P
        • Wei L
        • Parwani AV
        • Li Z.
        ESR1 genetic alterations and their association with clinicopathologic characteristics in advanced breast cancer: a single academic institution experience.
        Hum Pathol. 2021; 107: 80-86
        • Schmid P
        • Adams S
        • Rugo HS
        • et al.
        Atezolizumab and nab-paclitaxel in advanced triple-negative breast cancer.
        N Engl J Med. 2018; 379: 2108-2121
        • Adams S
        • Diamond JR
        • Hamilton E
        • et al.
        Atezolizumab plus nab-paclitaxel in the treatment of metastatic triple-negative breast cancer with 2-year survival follow-up: a phase 1b clinical trial.
        JAMA Oncol. 2019; 5: 334-342
        • Hause RJ
        • Pritchard CC
        • Shendure J
        • Salipante SJ.
        Classification and characterization of microsatellite instability across 18 cancer types.
        Nat Med. 2016; 22: 1342-1350
        • Nanda R
        • Chow LQM
        • Dees EC
        • et al.
        Pembrolizumab in patients with advanced triple-negative breast cancer: phase Ib keynote-012 study.
        J Clin Oncol. 2016; 34: 2460-2467
        • Adams S
        • Loi S
        • Toppmeyer D
        • et al.
        Pembrolizumab monotherapy for previously untreated, PD-L1-positive, metastatic triple-negative breast cancer: cohort B of the phase II KEYNOTE-086 study.
        Ann Oncol. 2019; 30: 405-411
        • Schmid P
        • Cortes J
        • Pusztai L
        • et al.
        Pembrolizumab for early triple-negative breast cancer.
        N Engl J Med. 2020; 382: 810-821
        • Schmid P
        • Rugo HS
        • Adams S
        • et al.
        Atezolizumab plus nab-paclitaxel as first-line treatment for unresectable, locally advanced or metastatic triple-negative breast cancer (IMpassion130): updated efficacy results from a randomised, double-blind, placebo-controlled, phase 3 trial.
        Lancet Oncol. 2020; 21: 44-59
        • Emens LA
        • Cruz C
        • Eder JP
        • et al.
        Long-term clinical outcomes and biomarker analyses of Atezolizumab therapy for patients with metastatic triple-negative breast cancer: a phase 1 study.
        JAMA Oncol. 2019; 5: 74-82
        • Rimm DL
        • Han G
        • Taube JM
        • et al.
        A prospective, multi-institutional, pathologist-based assessment of 4 immunohistochemistry assays for PD-L1 expression in non–small cell lung cancerassessment of 4 assays for PD-L1 expression in NSCLC assessment of 4 assays for PD-L1 expression in NSCLC.
        JAMA Oncol. 2017; 3: 1051-1058
        • Schmid P
        • Adams S
        • Rugo HS
        • et al.
        Atezolizumab and nab-paclitaxel in advanced triple-negative breast cancer.
        N Engl J Med. 2018; 379: 2108-2121
        • Emens LA
        • Cruz C
        • Eder JP
        • et al.
        Long-term clinical outcomes and biomarker analyses of atezolizumab therapy for patients with metastatic triple-negative breast cancer: a phase 1 study Atezolizumab therapy for patients with metastatic triple-negative breast cancer Atezolizumab therapy for patients with metastatic triple-negative breast cancer.
        JAMA Oncol. 2019; 5: 74-82
        • Rimm DL
        • Han G
        • Taube JM
        • et al.
        Reanalysis of the NCCN PD-L1 companion diagnostic assay study for lung cancer in the context of PD-L1 expression findings in triple-negative breast cancer.
        Breast Cancer Res. 2019; 21: 72
        • Vennapusa B
        • Baker B
        • Kowanetz M
        • et al.
        Development of a PD-L1 complementary diagnostic immunohistochemistry assay (SP142) for Atezolizumab.
        Appl Immunohistochem Mol Morphol. 2019; 27: 92-100
        • Miles D
        • Gligorov J
        • André F
        • et al.
        Primary results from IMpassion131, a double-blind, placebo-controlled, randomised phase III trial of first-line paclitaxel with or without atezolizumab for unresectable locally advanced/metastatic triple-negative breast cancer.
        Ann Oncol. 2021; 32: 994-1004
        • Cortes J
        • Cescon DW
        • Rugo HS
        • et al.
        KEYNOTE-355: Randomized, double-blind, phase III study of pembrolizumab + chemotherapy versus placebo + chemotherapy for previously untreated locally recurrent inoperable or metastatic triple-negative breast cancer.
        J Clin Oncol. 2020; 38: 1000
        • Rugo JC H.S.
        • Cescon D.W.
        • Im S.
        • et al.
        KEYNOTE-355: final results from a randomized, double-blind phase III study of first-line pembrolizumab + chemotherapy vs placebo + chemotherapy for metastatic TNBC.
        Ann Oncol. 2021; 32 (101016/annonc/annonc741. 2021): S1283-S1346