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Research Article

Association of Tumor Infiltrating Lymphocytes with Homologous Recombination Deficiency and BRCA1/2 Status in Patients with Early Triple-Negative Breast Cancer: A Pooled Analysis

Melinda L. Telli, Charles Chu, Sunil S Badve, Shaveta Vinayak, Daniel P Silver, Steven J. Isakoff, Virginia Kaklamani, William Gradishar, Vered Stearns, Roisin M Connolly, James M Ford, Joshua J. Gruber, Sylvia Adams, Judy Garber, Nadine Tung, Chris Neff, Ryan Bernhisel, Kirsten M Timms and Andrea L. Richardson
Melinda L. Telli
Medicine, Medical Oncology, Stanford University
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  • For correspondence: mtelli@stanford.edu
Charles Chu
Internal Medicine, Stanford University School of Medicine
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Sunil S Badve
Pathology and Laboratory Medicine, Indiana University School of Medicine
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Shaveta Vinayak
Medicine/Oncology, University of Washington School of Medicine
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Daniel P Silver
Medical Oncology, Cancer Biology, Dana Farber Cancer Institute
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Steven J. Isakoff
Heme/Onc, Massachusetts General Hospital
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Virginia Kaklamani
Division of Hematology/Oncology, Cancer Therapy & Research Center
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William Gradishar
Department of Medicine, Northwestern University Feinberg School of Medicine
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Vered Stearns
Department of Oncology, Johns Hopkins University School of Medicine
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Roisin M Connolly
Cancer Research UCC, University College Cork
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James M Ford
Departments of Medicine and Genetics, Stanford University School of Medicine
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Joshua J. Gruber
Department of Genetics, Stanford University School of Medicine
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Sylvia Adams
NYU Cancer Institute
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Judy Garber
Dana-Farber Cancer Institute
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Nadine Tung
Department of Medical Oncology, Beth Israel Deaconess Medical Center
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Chris Neff
Myriad Genetics, Inc.
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Ryan Bernhisel
Clinical Affairs, Myriad Genetic Laboratories, Inc.
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Kirsten M Timms
Myriad Genetics, Inc.
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Andrea L. Richardson
Pathology, Johns Hopkins Medicine
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DOI: 10.1158/1078-0432.CCR-19-0664
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Abstract

Background: Patients with triple-negative breast cancer (TNBC) with homologous recombination deficient tumors achieve significantly higher pathologic complete response (pCR) rates when treated with neoadjuvant platinum-based therapy. Tumor infiltrating lymphocytes (TILs) are prognostic and predictive of chemotherapy benefit in early stage TNBC. The relationship between TILs, BRCA1/2 mutation status and Homologous Recombination Deficiency (HRD) status in TNBC remains unclear. Experimental Design: We performed a pooled analysis of 5 phase II studies that included patients with TNBC treated with neoadjuvant platinum-based chemotherapy to evaluate the association of TILs with HRD status (Myriad Genetics) and tumor BRCA1/2 mutation status. Further, the relationship between pathologic response assessed using the residual cancer burden (RCB) index and HRD status with adjustment for TILs was evaluated. Results: Among 161 patients, stromal TIL (sTIL) density was not significantly associated with HRD status (p=0.107) or tumor BRCA1/2 mutation status (p=0.391). In multivariate analyses, sTIL density (OR 1.23, 95% CI 0.94-1.61, p=0.139) was not associated with pCR, but was associated with RCB 0/I status (OR 1.62, 95% CI 1.20-2.28, p=0.001). HRD was significantly associated with both pCR (OR 12.09, 95% CI 4.11-44.29, p= 7.82 x10-7) and RCB 0/I (OR 10.22, 95% CI 4.11-28.75, p= 1.09 x10-7) in these models. Conclusions: In patients with TNBC treated with neoadjuvant platinum-based therapy, TIL density was not significantly associated with either tumor BRCA1/2 mutation status or HRD status. In this pooled analysis, HRD and sTIL density were independently associated with treatment response, with HRD status being the strongest predictor.

  • Received May 30, 2019.
  • Revision received October 10, 2019.
  • Accepted November 25, 2019.
  • Copyright ©2019, American Association for Cancer Research.

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Published OnlineFirst December 3, 2019
doi: 10.1158/1078-0432.CCR-19-0664

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Association of Tumor Infiltrating Lymphocytes with Homologous Recombination Deficiency and BRCA1/2 Status in Patients with Early Triple-Negative Breast Cancer: A Pooled Analysis
Melinda L. Telli, Charles Chu, Sunil S Badve, Shaveta Vinayak, Daniel P Silver, Steven J. Isakoff, Virginia Kaklamani, William Gradishar, Vered Stearns, Roisin M Connolly, James M Ford, Joshua J. Gruber, Sylvia Adams, Judy Garber, Nadine Tung, Chris Neff, Ryan Bernhisel, Kirsten M Timms and Andrea L. Richardson
Clin Cancer Res December 3 2019 DOI: 10.1158/1078-0432.CCR-19-0664

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Association of Tumor Infiltrating Lymphocytes with Homologous Recombination Deficiency and BRCA1/2 Status in Patients with Early Triple-Negative Breast Cancer: A Pooled Analysis
Melinda L. Telli, Charles Chu, Sunil S Badve, Shaveta Vinayak, Daniel P Silver, Steven J. Isakoff, Virginia Kaklamani, William Gradishar, Vered Stearns, Roisin M Connolly, James M Ford, Joshua J. Gruber, Sylvia Adams, Judy Garber, Nadine Tung, Chris Neff, Ryan Bernhisel, Kirsten M Timms and Andrea L. Richardson
Clin Cancer Res December 3 2019 DOI: 10.1158/1078-0432.CCR-19-0664
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