Homologous recombination deficiency predicts the response to platinum-based neoadjuvant chemotherapy in early-stage triple-negative breast cancer patients: a systematic review and meta-analysis

Background: Recent studies have shown that homologous recombination deficiency (HRD) may be correlated with the pathological complete response (pCR) rate. This meta-analysis aimed to determine the predictive value of HRD for the pCR rate in patients with triple-negative breast cancer (TNBC) receiving platinum-based neoadjuvant chemotherapy (NCT). Methods: Published articles were searched in the PubMed, Embase, Medline, Web of Science, and Cochrane databases up to 1 June 2021, and studies reporting the pCR rate for HRD carriers on platinum-based NCT were selected. Odds ratios (ORs) with 95% confidence intervals (CIs) were determined for the pCR rate, clinical response rate, and Grade 3 or higher adverse events (AEs) using the random-effects model. Bias risk was evaluated using the Cochrane Collaboration tool (PROSPERO, registration number CRD42021249874). Results: Seven studies were eligible. The results showed that HRD carriers had higher pCR rates than non-HRD carriers across all treatment arms (OR = 3.84, 95% CI = [1.93, 7.64], p = 0.0001). Among HRD carriers, the pCR rate was higher in patients on platinum-based NCT than in those without platinum exposure (OR = 1.95, 95% CI = [1.17, 3.23], p = 0.01). We did not observe marked pCR improvements in non-HRD carriers. Among HRD carriers, the pCR rates in the mutant and wild-type breast cancer susceptibility gene (BRCA) groups did not differ significantly (OR = 2.00, 95% CI = [0.77, 5.23], p = 0.16), but HRD carriers with wild-type BRCA had a significant advantage over non-HRD carriers on platinum-based NCT (OR = 3.64, 95% CI = [1.83, 7.21], p = 0.0002). Conclusion: HRD is an effective predictor of increased pCR rates in platinum-based NCT, especially in wild-type BRCA patients. Adding platinum to NCT for non-HRD carriers can increase the incidence of AEs but may not improve the therapeutic effect.

[1]  E. Mayo-Wilson,et al.  The PRISMA 2020 statement: an updated guideline for reporting systematic reviews , 2021, BMJ.

[2]  N. Masuda,et al.  Eribulin-based neoadjuvant chemotherapy for triple-negative breast cancer patients stratified by homologous recombination deficiency status: a multicenter randomized phase II clinical trial , 2021, Breast Cancer Research and Treatment.

[3]  P. Fasching,et al.  Neoadjuvant paclitaxel/olaparib in comparison to paclitaxel/carboplatinum in patients with HER2-negative breast cancer and homologous recombination deficiency (GeparOLA study). , 2020, Annals of oncology : official journal of the European Society for Medical Oncology.

[4]  C. Perou,et al.  TBCRC 030: A phase II study of preoperative cisplatin vs. paclitaxel in triple-negative breast cancer: evaluating the homologous recombination deficiency (HRD) biomarker. , 2020, Annals of oncology : official journal of the European Society for Medical Oncology.

[5]  E. Winer,et al.  TBCRC 031: Randomized Phase II Study of Neoadjuvant Cisplatin Versus Doxorubicin-Cyclophosphamide in Germline BRCA Carriers With HER2-Negative Breast Cancer (the INFORM trial). , 2020, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[6]  V. Welch,et al.  Updated guidance for trusted systematic reviews: a new edition of the Cochrane Handbook for Systematic Reviews of Interventions. , 2019, The Cochrane database of systematic reviews.

[7]  P. Fasching,et al.  GeparOLA: A randomized phase II trial to assess the efficacy of paclitaxel and olaparib in comparison to paclitaxel/carboplatin followed by epirubicin/cyclophosphamide as neoadjuvant chemotherapy in patients (pts) with HER2-negative early breast cancer (BC) and homologous recombination deficiency (H , 2019, Journal of Clinical Oncology.

[8]  F. Caramelo,et al.  The effect of neoadjuvant platinum-based chemotherapy in BRCA mutated triple negative breast cancers -systematic review and meta-analysis , 2019, Hereditary Cancer in Clinical Practice.

[9]  M. Rezai,et al.  Survival analysis of carboplatin added to an anthracycline/taxane-based neoadjuvant chemotherapy and HRD score as predictor of response—final results from GeparSixto , 2018, Annals of oncology : official journal of the European Society for Medical Oncology.

[10]  M. Ceppi,et al.  Platinum-based neoadjuvant chemotherapy in triple-negative breast cancer: a systematic review and meta-analysis , 2018, Annals of oncology : official journal of the European Society for Medical Oncology.

[11]  Shou‐Tung Chen,et al.  Evaluation of homologous recombination deficiency (HRD) status with pathological response to carboplatin +/- veliparib in BrighTNess, a randomized phase 3 study in early stage TNBC. , 2018 .

[12]  Paul Ellis,et al.  Carboplatin in BRCA1/2-mutated and triple-negative breast cancer BRCAness subgroups: the TNT Trial , 2018, Nature Medicine.

[13]  W. Symmans,et al.  Addition of the PARP inhibitor veliparib plus carboplatin or carboplatin alone to standard neoadjuvant chemotherapy in triple-negative breast cancer (BrighTNess): a randomised, phase 3 trial. , 2018, The Lancet. Oncology.

[14]  P. Fasching,et al.  Germline Mutation Status, Pathological Complete Response, and Disease-Free Survival in Triple-Negative Breast Cancer: Secondary Analysis of the GeparSixto Randomized Clinical Trial , 2017, JAMA oncology.

[15]  Fang Yang,et al.  Predictive biomarkers for triple negative breast cancer treated with platinum-based chemotherapy , 2017, Cancer biology & therapy.

[16]  M. Frey,et al.  Homologous recombination deficiency (HRD) testing in ovarian cancer clinical practice: a review of the literature , 2017, Gynecologic Oncology Research and Practice.

[17]  Anne M Wallace,et al.  Adaptive Randomization of Veliparib-Carboplatin Treatment in Breast Cancer. , 2016, The New England journal of medicine.

[18]  Z. Szallasi,et al.  Homologous Recombination Deficiency (HRD) Score Predicts Response to Platinum-Containing Neoadjuvant Chemotherapy in Patients with Triple-Negative Breast Cancer , 2016, Clinical Cancer Research.

[19]  A. Richardson,et al.  Abstract P3-07-12: Homologous recombination deficiency (HRD) as a predictive biomarker of response to neoadjuvant platinum-based therapy in patients with triple negative breast cancer (TNBC): A pooled analysis , 2016 .

[20]  N. Hansen,et al.  Phase II neoadjuvant clinical trial of carboplatin and eribulin in women with triple negative early-stage breast cancer (NCT01372579) , 2015, Breast Cancer Research and Treatment.

[21]  M. Rezai,et al.  Prediction of pathological complete response (pCR) by Homologous Recombination Deficiency (HRD) after carboplatin-containing neoadjuvant chemotherapy in patients with TNBC: Results from GeparSixto. , 2015 .

[22]  James M Ford,et al.  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. , 2015, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[23]  D. Berry,et al.  Impact of the addition of carboplatin and/or bevacizumab to neoadjuvant once-per-week paclitaxel followed by dose-dense doxorubicin and cyclophosphamide on pathologic complete response rates in stage II to III triple-negative breast cancer: CALGB 40603 (Alliance). , 2015, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[24]  Gideon Blumenthal,et al.  Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis , 2014, The Lancet.

[25]  M. Rezai,et al.  Neoadjuvant carboplatin in patients with triple-negative and HER2-positive early breast cancer (GeparSixto; GBG 66): a randomised phase 2 trial. , 2014, The Lancet. Oncology.

[26]  A. Godwin,et al.  Germline BRCA mutation evaluation in a prospective triple-negative breast cancer registry: implications for hereditary breast and/or ovarian cancer syndrome testing , 2014, Breast Cancer Research and Treatment.

[27]  S. Henikoff,et al.  Doxorubicin, DNA torsion, and chromatin dynamics. , 2014, Biochimica et biophysica acta.

[28]  Steven J. M. Jones,et al.  Comprehensive molecular portraits of human breast tumours , 2013 .

[29]  A. Vincent-Salomon,et al.  Ploidy and large-scale genomic instability consistently identify basal-like breast carcinomas with BRCA1/2 inactivation. , 2012, Cancer research.

[30]  G. Mills,et al.  Patterns of genomic loss of heterozygosity predict homologous recombination repair defects in epithelial ovarian cancer , 2012, British Journal of Cancer.

[31]  Steven J. M. Jones,et al.  Comprehensive molecular portraits of human breast tumors , 2012, Nature.

[32]  Z. Szallasi,et al.  Telomeric allelic imbalance indicates defective DNA repair and sensitivity to DNA-damaging agents. , 2012, Cancer discovery.

[33]  J. Sterne,et al.  The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials , 2011, BMJ : British Medical Journal.

[34]  E. Alli,et al.  Enhanced sensitivity to cisplatin and gemcitabine in Brca1-deficient murine mammary epithelial cells , 2011, BMC pharmacology.

[35]  Wolfgang Viechtbauer,et al.  Conducting Meta-Analyses in R with the metafor Package , 2010 .

[36]  Hannah R Rothstein,et al.  A basic introduction to fixed‐effect and random‐effects models for meta‐analysis , 2010, Research synthesis methods.

[37]  P. Johnston,et al.  The role of BRCA1 in the cellular response to chemotherapy. , 2004, Journal of the National Cancer Institute.

[38]  A. Ashworth,et al.  Hallmarks of 'BRCAness' in sporadic cancers , 2004, Nature Reviews Cancer.

[39]  D. Altman,et al.  Measuring inconsistency in meta-analyses , 2003, BMJ : British Medical Journal.

[40]  S. Thompson,et al.  Quantifying heterogeneity in a meta‐analysis , 2002, Statistics in medicine.

[41]  G. Smith,et al.  Bias in meta-analysis detected by a simple, graphical test , 1997, BMJ.