Skip to main content
Erschienen in: Breast Cancer Research and Treatment 3/2018

23.12.2017 | Clinical trial

Homologous recombination deficiency (HRD) status predicts response to standard neoadjuvant chemotherapy in patients with triple-negative or BRCA1/2 mutation-associated breast cancer

verfasst von: Melinda L. Telli, Jessica Hellyer, William Audeh, Kristin C. Jensen, Shikha Bose, Kirsten M. Timms, Alexander Gutin, Victor Abkevich, Rebecca N. Peterson, Chris Neff, Elisha Hughes, Zaina Sangale, Joshua Jones, Anne-Renee Hartman, Pei-Jen Chang, Shaveta Vinayak, Richard Wenstrup, James M. Ford

Erschienen in: Breast Cancer Research and Treatment | Ausgabe 3/2018

Einloggen, um Zugang zu erhalten

Abstract

Purpose

Defects in the homologous recombination (HR) DNA repair pathway sensitize tumors to therapeutics that target this pathway. A significant proportion of triple-negative breast cancers (TNBC) carry HR defects. The HRD assay is highly associated with sensitivity to neoadjuvant platinum-based chemotherapy in TNBC. Standard chemotherapy consists of some combination of an anthracycline, cyclophosphamide, and taxane. This study assesses the association of HR deficiency status with response to standard neoadjuvant chemotherapy in TNBC or BRCA1/2 mutation-associated breast cancer.

Methods

Tumor samples were retrospectively obtained from 45 TNBC patients and 2 BRCA1/2 mutant, hormone receptor-positive/HER2-negative breast cancer patients who received anthracycline- and/or taxane-based neoadjuvant chemotherapy at Stanford University or Cedars-Sinai Medical Centers. The HRD score and tumor BRCA1/2 mutation status were determined from baseline tumor biopsies. HR deficient tumors were those with a HRD score of ≥ 42 or a tumor BRCA1/2 mutation. Response was categorized by the residual cancer burden (RCB) index.

Results

HR deficient patients were more likely to achieve a pathologic complete response (pCR) compared with non-deficient patients (OR 13.06, CI 1.52–11.241, p = 0.0028). Among BRCA1/2 mutation wild-type patients, HR deficient patients were more likely to achieve a pCR (OR 16, 95% CI 1.65–160.41, p = 0.0041) compared with HR non-deficient patients. Further, HRD scores were highly concordant pre- and post-therapy (Spearman correlation > 99%).

Conclusions

HR deficiency status is significantly associated with response to standard neoadjuvant chemotherapy in TNBC. This observation is consistent with the mechanisms of action of doxorubicin and cyclophosphamide as DNA damaging agents.
Literatur
1.
Zurück zum Zitat Dent R, Trudeau M, Pritchard KI, Hanna WM, Kahn HK, Sawka CA, Lickley LA, Rawlinson E, Sun P, Narod SA (2007) Triple-negative breast cancer: clinical features and patterns of recurrence. Clin Cancer Res 13:4429–4434CrossRefPubMed Dent R, Trudeau M, Pritchard KI, Hanna WM, Kahn HK, Sawka CA, Lickley LA, Rawlinson E, Sun P, Narod SA (2007) Triple-negative breast cancer: clinical features and patterns of recurrence. Clin Cancer Res 13:4429–4434CrossRefPubMed
2.
Zurück zum Zitat Gradishar WJ, Anderson BO, Balassanian R et al (2016) Invasive Breast Cancer Version 1.2016, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw 14:324–354CrossRefPubMed Gradishar WJ, Anderson BO, Balassanian R et al (2016) Invasive Breast Cancer Version 1.2016, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw 14:324–354CrossRefPubMed
3.
Zurück zum Zitat Cortazar P, Geyer CE (2015) Pathological complete response in neoadjuvant treatment of breast cancer. Ann Surg Oncol 22:1441–1446CrossRefPubMed Cortazar P, Geyer CE (2015) Pathological complete response in neoadjuvant treatment of breast cancer. Ann Surg Oncol 22:1441–1446CrossRefPubMed
4.
Zurück zum Zitat Symmans WF, Wei C, Gould R et al (2017) Long-term prognostic risk after neoadjuvant chemotherapy associated with residual cancer burden and breast cancer subtype. J Clin Oncol 35:1049–1060CrossRefPubMedPubMedCentral Symmans WF, Wei C, Gould R et al (2017) Long-term prognostic risk after neoadjuvant chemotherapy associated with residual cancer burden and breast cancer subtype. J Clin Oncol 35:1049–1060CrossRefPubMedPubMedCentral
6.
Zurück zum Zitat Telli ML, Timms KM, Reid J et al (2016) Homologous recombination deficiency (HRD) score predicts response to platinum-containing neoadjuvant chemotherapy in patients with triple-negative breast cancer. Clin Cancer Res 22:3764–3773CrossRefPubMed Telli ML, Timms KM, Reid J et al (2016) Homologous recombination deficiency (HRD) score predicts response to platinum-containing neoadjuvant chemotherapy in patients with triple-negative breast cancer. Clin Cancer Res 22:3764–3773CrossRefPubMed
7.
Zurück zum Zitat Couch FJ, Hart SN, Sharma P et al (2015) Inherited mutations in 17 breast cancer susceptibility genes among a large triple-negative breast cancer cohort unselected for family history of breast cancer. J Clin Oncol 33:304–311CrossRefPubMed Couch FJ, Hart SN, Sharma P et al (2015) Inherited mutations in 17 breast cancer susceptibility genes among a large triple-negative breast cancer cohort unselected for family history of breast cancer. J Clin Oncol 33:304–311CrossRefPubMed
8.
Zurück zum Zitat Sharma P, Klemp JR, Kimler BF et al (2014) Germline BRCA mutation evaluation in a prospective triple-negative breast cancer registry: implications for hereditary breast and/or ovarian cancer syndrome testing. Breast Cancer Res Treat 145:707–714CrossRefPubMedPubMedCentral Sharma P, Klemp JR, Kimler BF et al (2014) Germline BRCA mutation evaluation in a prospective triple-negative breast cancer registry: implications for hereditary breast and/or ovarian cancer syndrome testing. Breast Cancer Res Treat 145:707–714CrossRefPubMedPubMedCentral
9.
Zurück zum Zitat Gonzalez-Angulo AM, Timms KM, Hanna WM et al (2011) Incidence and outcome of BRCA mutations in unselected patients with triple receptor-negative breast cancer. Clin Cancer Res 17:1082–1089CrossRefPubMedPubMedCentral Gonzalez-Angulo AM, Timms KM, Hanna WM et al (2011) Incidence and outcome of BRCA mutations in unselected patients with triple receptor-negative breast cancer. Clin Cancer Res 17:1082–1089CrossRefPubMedPubMedCentral
10.
Zurück zum Zitat Telli ML, Jensen KC, Vinayak S et al (2015) Phase II study of gemcitabine, carboplatin, and iniparib as neoadjuvant therapy for triple-negative and BRCA1/2 mutation-associated breast cancer with assessment of a tumor-based measure of genomic instability: PrECOG 0105. J Clin Oncol 33:1895–1901CrossRefPubMedPubMedCentral Telli ML, Jensen KC, Vinayak S et al (2015) Phase II study of gemcitabine, carboplatin, and iniparib as neoadjuvant therapy for triple-negative and BRCA1/2 mutation-associated breast cancer with assessment of a tumor-based measure of genomic instability: PrECOG 0105. J Clin Oncol 33:1895–1901CrossRefPubMedPubMedCentral
11.
Zurück zum Zitat Abkevich V, Timms KM, Hennessy BT et al (2012) Patterns of genomic loss of heterozygosity predict homologous recombination repair defects in epithelial ovarian cancer. Br J Cancer 107:1776–1782CrossRefPubMedPubMedCentral Abkevich V, Timms KM, Hennessy BT et al (2012) Patterns of genomic loss of heterozygosity predict homologous recombination repair defects in epithelial ovarian cancer. Br J Cancer 107:1776–1782CrossRefPubMedPubMedCentral
12.
Zurück zum Zitat Birkbak NJ, Wang ZC, Kim JY et al (2012) Telomeric allelic imbalance indicates defective DNA repair and sensitivity to DNA-damaging agents. Cancer Discov 2:366–375CrossRefPubMedPubMedCentral Birkbak NJ, Wang ZC, Kim JY et al (2012) Telomeric allelic imbalance indicates defective DNA repair and sensitivity to DNA-damaging agents. Cancer Discov 2:366–375CrossRefPubMedPubMedCentral
13.
Zurück zum Zitat Popova T, Manie E, Rieunier G et al (2012) Ploidy and large-scale genomic instability consistently identify basal-like breast carcinomas with BRCA1/2 inactivation. Cancer Res 72:5454–5462CrossRefPubMed Popova T, Manie E, Rieunier G et al (2012) Ploidy and large-scale genomic instability consistently identify basal-like breast carcinomas with BRCA1/2 inactivation. Cancer Res 72:5454–5462CrossRefPubMed
14.
Zurück zum Zitat Timms KM, Abkevich V, Hughes E et al (2014) Association of BRCA1/2 defects with genomic scores predictive of DNA damage repair deficiency among breast cancer subtypes. Breast Cancer Res 16:475CrossRefPubMedPubMedCentral Timms KM, Abkevich V, Hughes E et al (2014) Association of BRCA1/2 defects with genomic scores predictive of DNA damage repair deficiency among breast cancer subtypes. Breast Cancer Res 16:475CrossRefPubMedPubMedCentral
15.
Zurück zum Zitat Kaklamani VG, Jeruss JS, Hughes E et al (2015) Phase II neoadjuvant clinical trial of carboplatin and eribulin in women with triple negative early-stage breast cancer (NCT01372579). Breast Cancer Res Treat 151:629–638CrossRefPubMed Kaklamani VG, Jeruss JS, Hughes E et al (2015) Phase II neoadjuvant clinical trial of carboplatin and eribulin in women with triple negative early-stage breast cancer (NCT01372579). Breast Cancer Res Treat 151:629–638CrossRefPubMed
16.
Zurück zum Zitat Symmans WF, Peintinger F, Hatzis C (2007) Measurement of residual breast cancer burden to predict survival after neoadjuvant chemotherapy. J Clin Oncol 25:4414–4422CrossRefPubMed Symmans WF, Peintinger F, Hatzis C (2007) Measurement of residual breast cancer burden to predict survival after neoadjuvant chemotherapy. J Clin Oncol 25:4414–4422CrossRefPubMed
17.
Zurück zum Zitat Paluch-Shimon S, Friedman E, Berger R et al (2016) Neo-adjuvant doxorubicin and cyclophosphamide followed by paclitaxel in triple-negative breast cancer among BRCA1 mutation carriers and non-carriers. Breast Cancer Res Treat 157:157–165CrossRefPubMed Paluch-Shimon S, Friedman E, Berger R et al (2016) Neo-adjuvant doxorubicin and cyclophosphamide followed by paclitaxel in triple-negative breast cancer among BRCA1 mutation carriers and non-carriers. Breast Cancer Res Treat 157:157–165CrossRefPubMed
18.
Zurück zum Zitat Davies H, Glodzik D, Morganella S et al (2017) HRDetect is a predictor of BRCA1 and BRCA2 deficiency based on mutational signatures. Nat Med 23:517–525CrossRefPubMedPubMedCentral Davies H, Glodzik D, Morganella S et al (2017) HRDetect is a predictor of BRCA1 and BRCA2 deficiency based on mutational signatures. Nat Med 23:517–525CrossRefPubMedPubMedCentral
19.
Zurück zum Zitat Kriege M, Jager A, Hooning MJ et al (2012) The efficacy of taxane chemotherapy for metastatic breast cancer in BRCA1 and BRCA2 mutation carriers. Cancer 118:899–907CrossRefPubMed Kriege M, Jager A, Hooning MJ et al (2012) The efficacy of taxane chemotherapy for metastatic breast cancer in BRCA1 and BRCA2 mutation carriers. Cancer 118:899–907CrossRefPubMed
Metadaten
Titel
Homologous recombination deficiency (HRD) status predicts response to standard neoadjuvant chemotherapy in patients with triple-negative or BRCA1/2 mutation-associated breast cancer
verfasst von
Melinda L. Telli
Jessica Hellyer
William Audeh
Kristin C. Jensen
Shikha Bose
Kirsten M. Timms
Alexander Gutin
Victor Abkevich
Rebecca N. Peterson
Chris Neff
Elisha Hughes
Zaina Sangale
Joshua Jones
Anne-Renee Hartman
Pei-Jen Chang
Shaveta Vinayak
Richard Wenstrup
James M. Ford
Publikationsdatum
23.12.2017
Verlag
Springer US
Erschienen in
Breast Cancer Research and Treatment / Ausgabe 3/2018
Print ISSN: 0167-6806
Elektronische ISSN: 1573-7217
DOI
https://doi.org/10.1007/s10549-017-4624-7

Weitere Artikel der Ausgabe 3/2018

Breast Cancer Research and Treatment 3/2018 Zur Ausgabe

Update Onkologie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.