Homologous Recombination Deficiency (HRD) Score Predicts Response to Platinum-Containing Neoadjuvant Chemotherapy in Patients with Triple-Negative Breast Cancer
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Abstract
Purpose: BRCA1/2-mutated and some sporadic triple-negative breast cancers (TNBC) have DNA repair defects and are sensitive to DNA-damaging therapeutics. Recently, three independent DNA-based measures of genomic instability were developed on the basis of loss of heterozygosity (LOH), telomeric allelic imbalance (TAI), and large-scale state transitions (LST). Experimental Design: We assessed a combined homologous recombination deficiency (HRD) score, an unweighted sum of LOH, TAI, and LST scores, in three neoadjuvant TNBC trials of platinum-containing therapy. We then tested the association of HR deficiency, defined as HRD score ≥42 or BRCA1/2 mutation, with response to platinum-based therapy. Results: In a trial of neoadjuvant platinum, gemcitabine, and iniparib, HR deficiency predicted residual cancer burden score of 0 or I (RCB 0/I) and pathologic complete response (pCR; OR = 4.96, P = 0.0036; OR = 6.52, P = 0.0058). HR deficiency remained a significant predictor of RCB 0/I when adjusted for clinical variables (OR = 5.86, P = 0.012). In two other trials of neoadjuvant cisplatin therapy, HR deficiency predicted RCB 0/I and pCR (OR = 10.18, P = 0.0011; OR = 17.00, P = 0.0066). In a multivariable model of RCB 0/I, HR deficiency retained significance when clinical variables were included (OR = 12.08, P = 0.0017). When restricted to BRCA1/2 nonmutated tumors, response was higher in patients with high HRD scores: RCB 0/I P = 0.062, pCR P = 0.063 in the neoadjuvant platinum, gemcitabine, and iniparib trial; RCB 0/I P = 0.0039, pCR P = 0.018 in the neoadjuvant cisplatin trials. Conclusions: HR deficiency identifies TNBC tumors, including BRCA1/2 nonmutated tumors more likely to respond to platinum-containing therapy. Clin Cancer Res; 22(15); 3764–73. ©2016 AACR.
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Expression-based profiling and Integrative Clusters cannot adequately discriminate HRDetect groups, suggesting HRDetect provides a novel independent angle to TNBC stratification.
“expression-based profiling (e.g., PAM50) and Integrative Clusters13,15 are not adequately able to discriminate HRDetect groups, suggesting that HRDetect provides a novel, independent angle to TNBC stratification.”
From Whole-genome sequencing of triple-negative breast cancers in a population-based clinical study (2019) · cites this paper as [15]
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- Authors
- Telli, M. L., Timms, K. M., Reid, J., Hennessy, B., Mills, G. B., Jensen, K. C., Szallasi, Z., Barry, W. T., Winer, E. P., Tung, N. M., Isakoff, S. J., Ryan, P. D., Greene-Colozzi, A., Gutin, A., Sangale, Z., Iliev, D., Neff, C., Abkevich, V., Jones, J. T., Lanchbury, J. S., Hartman, A.-R., Garber, J. E., Ford, J. M., Silver, D. P., & Richardson, A. L.
- Affiliations
- Stanford Medicine (US)
- Myriad Genetics (US)
- The University of Texas MD Anderson Cancer Center (US)
- 4Denmark Technical University, Lyngby, Denmark.
- Harvard University (US)
- Beth Israel Deaconess Medical Center (US)
- Massachusetts General Hospital (US)
- Dana-Farber Cancer Institute (US)
- Brigham and Women's Hospital (US)
- Corresponding author
- Silver, Daniel P.
- ORCID
- Venue
- Clinical Cancer Research
- Published
- 2016-07-31
- Volume
- 22
- Issue
- 15
- Pages
- 3764-3773
- ISSN
- 1078-0432 (ISSN-L)
- 1557-3265
- PMC
- PMC6773427
- OpenAlex
- W2295085830
- Cited by
- 1,136
- References
- 34
- Citations by year
- 2026: 97 · 2025: 118 · 2024: 140 · 2023: 159 · 2022: 170 · 2021: 151 · 2020: 92 · 2019: 68 · 2018: 55 · 2017: 65 · 2016: 19
- FWCI
- 55.68
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Clinical Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Novo Nordisk Fonden (NNF15OC0016584, NNF14OC0009569)
- National Cancer Institute (P50CA089393, P50CA083639, P50CA168504)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › BRCA gene mutations in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Breast Cancer Treatment Studies
- Health Sciences › Medicine › Oncology › PARP inhibition in cancer therapy
- Keywords
- homologous recombination deficiency, triple-negative breast cancer, neoadjuvant chemotherapy, platinum-based chemotherapy, BRCA mutations, loss of heterozygosity, telomeric allelic imbalance, large-scale state transitions, genomic instability, predictive biomarkers, pathological complete response, residual cancer burden, iniparib, cisplatin, gemcitabine, DNA repair
- MeSH terms
- Antineoplastic Combined Chemotherapy Protocols, Female, Humans, Mutation, Neoplasm Staging, Platinum, Prognosis, Biomarkers, Tumor, Odds Ratio, Telomere, Treatment Outcome, Genes, BRCA1, Loss of Heterozygosity, Allelic Imbalance, Genes, BRCA2, Homologous Recombination, Triple Negative Breast Neoplasms
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