Abstract

Germline mutations in BRCA1/2 predispose individuals to breast cancer (termed germline-mutated BRCA1/2 breast cancer, gBRCA-BC) by impairing homologous recombination (HR) and causing genomic instability. HR also repairs DNA lesions caused by platinum agents and PARP inhibitors. Triple-negative breast cancers (TNBCs) harbor subpopulations with BRCA1/2 mutations, hypothesized to be especially platinum-sensitive. Cancers in putative ‘BRCAness’ subgroups—tumors with BRCA1 methylation; low levels of BRCA1 mRNA (BRCA1 mRNA-low); or mutational signatures for HR deficiency and those with basal phenotypes—may also be sensitive to platinum. We assessed the efficacy of carboplatin and another mechanistically distinct therapy, docetaxel, in a phase 3 trial in subjects with unselected advanced TNBC. A prespecified protocol enabled biomarker–treatment interaction analyses in gBRCA-BC and BRCAness subgroups. The primary endpoint was objective response rate (ORR). In the unselected population (376 subjects; 188 carboplatin, 188 docetaxel), carboplatin was not more active than docetaxel (ORR, 31.4% versus 34.0%, respectively; P = 0.66). In contrast, in subjects with gBRCA-BC, carboplatin had double the ORR of docetaxel (68% versus 33%, respectively; biomarker, treatment interaction P = 0.01). Such benefit was not observed for subjects with BRCA1 methylation, BRCA1 mRNA-low tumors or a high score in a Myriad HRD assay. Significant interaction between treatment and the basal-like subtype was driven by high docetaxel response in the nonbasal subgroup. We conclude that patients with advanced TNBC benefit from characterization of BRCA1/2 mutations, but not BRCA1 methylation or Myriad HRD analyses, to inform choices on platinum-based chemotherapy. Additionally, gene expression analysis of basal-like cancers may also influence treatment selection.

  • Subscribe to Nature Medicine for full access:

    $225

    Subscribe

Additional access options:

Already a subscriber?  Log in  now or  Register  for online access.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

References

  1. 1.

    Kassam, F. et al. Survival outcomes for patients with metastatic triple-negative breast cancer: implications for clinical practice and trial design. Clin. Breast Cancer 9, 29–33 (2009).

  2. 2.

    Sørlie, T. et al. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc. Natl. Acad. Sci. USA 98, 10869–10874 (2001).

  3. 3.

    Curtis, C. et al. The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups. Nature 486, 346–352 (2012).

  4. 4.

    Lehmann, B. D. et al. Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies. J. Clin. Invest. 121, 2750–2767 (2011).

  5. 5.

    Lehmann, B. D. et al. Refinement of triple-negative breast cancer molecular subtypes: implications for neoadjuvant chemotherapy selection. PLoS One 11, e0157368 (2016).

  6. 6.

    Burstein, M. D. et al. Comprehensive genomic analysis identifies novel subtypes and targets of triple-negative breast cancer. Clin. Cancer Res. 21, 1688–1698 (2015).

  7. 7.

    Cheang, M. C. et al. Basal-like breast cancer defined by five biomarkers has superior prognostic value than triple-negative phenotype. Clin. Cancer Res. 14, 1368–1376 (2008).

  8. 8.

    Davies, H. et al. HRDetect is a predictor of BRCA1 and BRCA2 deficiency based on mutational signatures. Nat. Med. 23, 517–525 (2017).

  9. 9.

    Catteau, A. & Morris, J. R. BRCA1 methylation: a significant role in tumour development? Semin. Cancer Biol. 12, 359–371 (2002).

  10. 10.

    Xu, Y. et al. Promoter methylation of BRCA1 in triple-negative breast cancer predicts sensitivity to adjuvant chemotherapy. Ann. Oncol. 24, 1498–1505 (2013).

  11. 11.

    Esteller, M. et al. Promoter hypermethylation and BRCA1 inactivation in sporadic breast and ovarian tumors. J. Natl. Cancer Inst. 92, 564–569 (2000).

  12. 12.

    Baldwin, R. L. et al. BRCA1 promoter region hypermethylation in ovarian carcinoma: a population-based study. Cancer Res. 60, 5329–5333 (2000).

  13. 13.

    Lord, C. J. & Ashworth, A. The DNA damage response and cancer therapy. Nature 481, 287–294 (2012).

  14. 14.

    Levran, O. et al. The BRCA1-interacting helicase BRIP1 is deficient in Fanconi anemia. Nat. Genet. 37, 931–933 (2005).

  15. 15.

    Taniguchi, T. & D’Andrea, A. D. Molecular pathogenesis of Fanconi anemia: recent progress. Blood 107, 4223–4233 (2006).

  16. 16.

    Venkitaraman, A. R. Tracing the network connecting BRCA and Fanconi anaemia proteins. Nat. Rev. Cancer 4, 266–276 (2004).

  17. 17.

    Tutt, A. N. et al. Exploiting the DNA repair defect in BRCA mutant cells in the design of new therapeutic strategies for cancer. Cold Spring Harb. Symp. Quant. Biol. 70, 139–148 (2005).

  18. 18.

    Martín, M. Platinum compounds in the treatment of advanced breast cancer. Clin. Breast Cancer 2, 190–208 (2001).

  19. 19.

    Sledge, G. W. Jr., Loehrer, P. J. Sr., Roth, B. J. & Einhorn, L. H. Cisplatin as first-line therapy for metastatic breast cancer. J. Clin. Oncol. 6, 1811–1814 (1988).

  20. 20.

    Lord, C. J. & Ashworth, A. BRCAness revisited. Nat. Rev. Cancer 16, 110–120 (2016).

  21. 21.

    Turner, N., Tutt, A. & Ashworth, A. Hallmarks of ‘BRCAness’ in sporadic cancers. Nat. Rev. Cancer 4, 814–819 (2004).

  22. 22.

    Birkbak, N. J. et al. Telomeric allelic imbalance indicates defective DNA repair and sensitivity to DNA-damaging agents. Cancer Discov. 2, 366–375 (2012).

  23. 23.

    Timms, K. M. et al. Association of BRCA1/2 defects with genomic scores predictive of DNA damage repair deficiency among breast cancer subtypes. Breast Cancer Res. 16, 475 (2014).

  24. 24.

    Popova, T. et al. Ploidy and large-scale genomic instability consistently identify basal-like breast carcinomas with BRCA1/2 inactivation. Cancer Res. 72, 5454–5462 (2012).

  25. 25.

    Watkins, J. et al. Genomic complexity profiling reveals that HORMAD1 overexpression contributes to homologous recombination deficiency in triple-negative breast cancers. Cancer Discov. 5, 488–505 (2015).

  26. 26.

    Telli, M. L. et al. Homologous recombination deficiency (HRD) score predicts response to platinum-containing neoadjuvant chemotherapy in patients with triple-negative breast cancer. Clin. Cancer Res. 22, 3764–3773 (2016).

  27. 27.

    Miles, D. W. et al. Phase III study of bevacizumab plus docetaxel compared with placebo plus docetaxel for the first-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J. Clin. Oncol. 28, 3239–3247 (2010).

  28. 28.

    Isakoff, S. J. et al. TBCRC009: a multicenter phase II clinical trial of platinum monotherapy with biomarker assessment in metastatic triple-negative breast cancer. J. Clin. Oncol. 33, 1902–1909 (2015).

  29. 29.

    Baselga, J. et al. Randomized phase II study of the anti-epidermal growth factor receptor monoclonal antibody cetuximab with cisplatin versus cisplatin alone in patients with metastatic triple-negative breast cancer. J. Clin. Oncol. 31, 2586–2592 (2013).

  30. 30.

    O’Shaughnessy, J. et al. Phase III study of iniparib plus gemcitabine and carboplatin versus gemcitabine and carboplatin in patients with metastatic triple-negative breast cancer. J. Clin. Oncol. 32, 3840–3847 (2014).

  31. 31.

    Hu, X. C. et al. Cisplatin plus gemcitabine versus paclitaxel plus gemcitabine as first-line therapy for metastatic triple-negative breast cancer (CBCSG006): a randomised, open-label, multicentre, phase 3 trial. Lancet Oncol. 16, 436–446 (2015).

  32. 32.

    Turner, N. C. & Reis-Filho, J. S. Basal-like breast cancer and the BRCA1 phenotype. Oncogene 25, 5846–5853 (2006).

  33. 33.

    Han, H. S. et al. Veliparib with temozolomide or carboplatin/paclitaxel versus placebo with carboplatin/paclitaxel in patients with BRCA1/2 locally recurrent/metastatic breast cancer: randomized phase II study. Ann. Oncol. 29, 154–161 (2018).

  34. 34.

    Ter Brugge, P. et al. Mechanisms of therapy resistance in patient-derived xenograft models of BRCA1-deficient breast cancer. J. Natl. Cancer Inst. 108, (2016).

  35. 35.

    Cancer Genome Atlas Research Network. Integrated genomic analyses of ovarian carcinoma. Nature 474, 609–615 (2011).

  36. 36.

    Chiang, J. W., Karlan, B. Y., Cass, L. & Baldwin, R. L. BRCA1 promoter methylation predicts adverse ovarian cancer prognosis. Gynecol. Oncol. 101, 403–410 (2006).

  37. 37.

    Swisher, E. M. et al. Rucaparib in relapsed, platinum-sensitive high-grade ovarian carcinoma (ARIEL2 Part 1): an international, multicentre, open-label, phase 2 trial. Lancet Oncol. 18, 75–87 (2017).

  38. 38.

    Von Minckwitz, G. 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. J. Clin. Oncol. 33, abstr. 1004 (2015).

  39. 39.

    Mulligan, J. M. et al. Identification and validation of an anthracycline/cyclophosphamide-based chemotherapy response assay in breast cancer. J. Natl. Cancer Inst. 106, djt335 (2014).

  40. 40.

    Wolf, D. et al. Evaluation of an in vitro derived signature of olaparib response (PARPi-7) as a predictive biomarker of response to veliparib/carboplatin plus standard neoadjuvant therapy in high-risk breast cancer: results from the I-SPY 2 TRIAL. Cancer Res. 75, abstr. P3-06-05 (2015).

  41. 41.

    von Minckwitz, G. et al. Neoadjuvant carboplatin in patients with triple-negative and HER2-positive early breast cancer (GeparSixto; GBG 66): a randomised phase 2 trial. Lancet Oncol. 15, 747–756 (2014).

  42. 42.

    Sikov, W. M. 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). J. Clin. Oncol. 33, 13–21 (2015).

  43. 43.

    Geyer, C. E. et al. Phase 3 study evaluating efficacy and safety of veliparib (V) plus carboplatin (Cb) or Cb in combination with standard neoadjuvant chemotherapy (NAC) in patients (pts) with early stage triple-negative breast cancer (TNBC). J. Clin. Oncol. 35, abstr. 520 (2017).

  44. 44.

    Schneeweiss, A. et al. A randomised phase III trial comparing two dose-dense, dose-intensified approaches (EPC and PM(Cb)) for neoadjuvant treatment of patients with high-risk early breast cancer (GeparOcto). J. Clin. Oncol. 35, abstr. 518, poster 118 (2017).

  45. 45.

    Robson, M. et al. Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. N. Engl. J. Med. 377, 523–533 (2017).

  46. 46.

    Lord, C. J. & Ashworth, A. PARP inhibitors: synthetic lethality in the clinic. Science 355, 1152–1158 (2017).

  47. 47.

    Huo, D. et al. Population differences in breast cancer: survey in indigenous African women reveals over-representation of triple-negative breast cancer. J. Clin. Oncol. 27, 4515–4521 (2009).

  48. 48.

    Wallden, B. et al. Development and verification of the PAM50-based Prosigna breast cancer gene signature assay. BMC Med. Genomics 8, 54 (2015).

  49. 49.

    Miller, K. et al. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N. Engl. J. Med. 357, 2666–2676 (2007).

  50. 50.

    Royston, P. & Parmar, M. K. Restricted mean survival time: an alternative to the hazard ratio for the design and analysis of randomized trials with a time-to-event outcome. BMC Med. Res. Methodol. 13, 152 (2013).

Download references

Acknowledgements

The authors would like to thank all subjects and the families of those who took part in the trial and all involved staff at the participating centers. In addition, we acknowledge R. Buus and B. Haynes for laboratory support for NanoString assays, S. Ferree of NanoString for provision of Prosigna reagents and manuscript review and R. Seitz of Insight Genetics for assistance in TNBC type analysis and manuscript review. The authors also acknowledge past and present colleagues on the TNT Trial Management Group, the Independent Data Monitoring Committee and Trial Steering Committee who oversaw the trial, the Response Evaluation Committee who conducted the independent radiology review and Cancer Research UK and Breast Cancer Now (and their legacy charity Breakthrough Breast Cancer) who funded the study (Cancer Research UK grant number CRUK/07/012) as well as the National Institute for Health Research Cancer Research Networks in England and their equivalent NHS research and development (R&D)–funded networks in Scotland, Wales, and Northern Ireland for ‘in-kind’ support. Funding was provided from Myriad Genetics, Inc., to cover costs of nucleic extraction from tumor blocks appropriate for next-generation sequencing, and Prosigna reagent kits were provided by NanoString Technologies, Inc.

Author information

Affiliations

  1. Breast Cancer Now Research Centre, The Institute of Cancer Research, London, UK

    • Andrew Tutt
    •  & Mitchell Dowsett
  2. Breast Cancer Now Research Unit, School of Cancer and Pharmaceutical Sciences, Faculty of Life Sciences and Medicine, King’s College London, Guy’s Hospital, London, UK

    • Andrew Tutt
    • , Patrycja Gazinska
    • , Anita Grigoriadis
    •  & Vandna Shah
  3. Clinical Trials and Statistics Unit, The Institute of Cancer Research, London, UK

    • Holly Tovey
    • , Maggie Chon U. Cheang
    • , Sarah Kernaghan
    • , Lucy Kilburn
    • , Lisa Fox
    •  & Judith M. Bliss
  4. King’s Health Partners Cancer Biobank, King’s College London, London, UK

    • Julie Owen
    • , Cheryl Gillett
    •  & Sarah E. Pinder
  5. Velindre Cancer Centre, Cardiff, UK

    • Jacinta Abraham
    •  & Peter Barrett-Lee
  6. Beatson West of Scotland Cancer Centre, Glasgow, UK

    • Sophie Barrett
  7. Department of Surgery and Cancer, Imperial College London, London, UK

    • Robert Brown
    •  & James M Flanagan
  8. Division of Molecular Pathology, The Institute of Cancer Research, London, UK

    • Robert Brown
  9. Department of Clinical Oncology, Nottingham University Hospitals NHS Trust, Nottingham, UK

    • Stephen Chan
  10. Ralph Lauren Centre for Breast Cancer Research, Royal Marsden Hospital, London, UK

    • Mitchell Dowsett
  11. Myriad Genetics, Inc., Salt Lake City, UT, USA

    • Alexander Gutin
    • , Kirsten M. Timms
    •  & Jerry S. Lanchbury
  12. Kent Oncology Centre, Maidstone and Tunbridge Wells NHS Trust, Kent, UK

    • Catherine Harper-Wynne
  13. Department of Clinical Oncology, Weston Park Hospital, Sheffield, UK

    • Matthew Q. Hatton
  14. Department of Genetics and Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    • Katherine A. Hoadley
    •  & Charles M. Perou
  15. Department of Radiology, Guy’s and St Thomas’ Hospitals NHS Foundation Trust, London, UK

    • Jyoti Parikh
  16. School of Cancer and Pharmaceutical Sciences, King’s College London, Guy’s Medical School Campus, London, UK

    • Peter Parker
  17. Protein Phosphorylation Laboratory, Francis Crick Institute, London, UK

    • Peter Parker
  18. Department of Oncology, University College London Hospitals NHS Foundation Trust and NIHR University College London Hospitals Biomedical Research Centre, London, UK

    • Rebecca Roylance
  19. Department of Medical and Molecular Genetics, Guy’s and St Thomas’ NHS Foundation Trust, London, UK

    • Adam Shaw
  20. Breast Unit, The Royal Marsden NHS Foundation Trust, London, UK

    • Ian E. Smith
  21. NIHR Manchester Clinical Research Facility at The Christie and Division of Cancer Sciences and University of Manchester, Manchester Academic Health Science Centre, Manchester, UK

    • Andrew M. Wardley
  22. The Christie NHS Foundation Trust, Manchester, UK

    • Gregory Wilson
  23. Research Oncology, Division of Cancer Studies, King’s College London, Guy’s Hospital, London, UK

    • Cheryl Gillett
    •  & Sarah E. Pinder
  24. UCSF Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, USA

    • Alan Ashworth
  25. Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK

    • Nazneen Rahman
  26. Cancer Genetics Unit, The Royal Marsden NHS Foundation Trust, London, UK

    • Nazneen Rahman
  27. Department of Medical Oncology, Guy’s and St Thomas Foundation Trust, London, UK

    • Mark Harries
    •  & Paul Ellis

Authors

  1. Search for Andrew Tutt in:

  2. Search for Holly Tovey in:

  3. Search for Maggie Chon U. Cheang in:

  4. Search for Sarah Kernaghan in:

  5. Search for Lucy Kilburn in:

  6. Search for Patrycja Gazinska in:

  7. Search for Julie Owen in:

  8. Search for Jacinta Abraham in:

  9. Search for Sophie Barrett in:

  10. Search for Peter Barrett-Lee in:

  11. Search for Robert Brown in:

  12. Search for Stephen Chan in:

  13. Search for Mitchell Dowsett in:

  14. Search for James M Flanagan in:

  15. Search for Lisa Fox in:

  16. Search for Anita Grigoriadis in:

  17. Search for Alexander Gutin in:

  18. Search for Catherine Harper-Wynne in:

  19. Search for Matthew Q. Hatton in:

  20. Search for Katherine A. Hoadley in:

  21. Search for Jyoti Parikh in:

  22. Search for Peter Parker in:

  23. Search for Charles M. Perou in:

  24. Search for Rebecca Roylance in:

  25. Search for Vandna Shah in:

  26. Search for Adam Shaw in:

  27. Search for Ian E. Smith in:

  28. Search for Kirsten M. Timms in:

  29. Search for Andrew M. Wardley in:

  30. Search for Gregory Wilson in:

  31. Search for Cheryl Gillett in:

  32. Search for Jerry S. Lanchbury in:

  33. Search for Alan Ashworth in:

  34. Search for Nazneen Rahman in:

  35. Search for Mark Harries in:

  36. Search for Paul Ellis in:

  37. Search for Sarah E. Pinder in:

  38. Search for Judith M. Bliss in:

Contributions

A.T., H.T., S.K., L.K., P.B.-L., L.F., C.H.-W, P.P., R.R., I.E.S., A.M.W., C.G., A.A., N.R., M.H., P.E., S.E.P. and J.M.B. are members of the Trial Management Group (TMG), and M.C.U.C, A.Gr., C.M.P., A.S. and R.B. are in the Biological Subcommittee of the TMG. J.P. is a Response Evaluation Committee member. A.T. was the Chief Investigator and chair of the Biological Subcommittee of the TMG and performed trial design and protocol development, including writing of the translational subsection of the protocol at trial outset to test the BRCAness hypotheses. A.T. also performed participant recruitment, data collection, data interpretation and writing of the manuscript. H.T. performed statistical analysis, data interpretation and writing of the manuscript. M.C.U.C. was the lead biostatistician for the translational substudies and performed data analysis of biological data generated from the biomarker assays, including basal-like subtype by NanoString (Prosigna) and IHC, BRCA1 methylation, BRCA1/2 mutation status, HRD score and total RNA-seq, data interpretation and writing of the manuscript. S.K. performed trial management, data collection and data management. L.K. performed trial design, protocol development, statistical analysis, data interpretation and writing of the manuscript. P.G., J.O. and V.S. performed TNT tissues resource preparation. J.A., S.B.,P.B.-L., S.C., C.H.-W., M.Q.H, R.R., I.E.S., A.M.W. and G.W.  performed participant recruitment and data collection. R.B. and J.M.F. performed data analysis of BRCA1 methylation and writing of the manuscript. M.D. performed the NanoString (Prosigna) experiment. L.F. performed trial management and data collection. A.Gr. and A.Gu. performed HRD analysis. K.A.H. and C.M.P. performed total RNA-seq from which BRCA1 mRNA was derived. J.P. performed independent radiology review. A.S. served as a germline genetics advisor for biological analyses and data interpretation, supported the germline BRCA1/2 mutation analysis and performed protocol development and writing of the manuscript. K.M.T. and J.S.L. performed tumor BRCA1/2 mutation analysis, BRCA1 methylation analysis and HRD analysis. C.G. served as the TNT tissue bank lead and performed TNT tissues resource preparation, ER/PgR and HER2 central testing, basal breast cancer subtyping by IHC and gene expression analysis. N.R. served as a germline genetics advisor for biological analyses and data interpretation, led the germline BRCA1/2 mutation analysis and performed protocol development and writing of the manuscript. M.H. and P.E. performed trial design, protocol development, participant recruitment and data collection. S.E.P. served as the study’s lead pathologist and performed ER/PgR, HER2 central testing, and basal breast cancer subtyping by IHC. J.M.B. performed trial design, protocol development, study conduct oversight, statistical analysis, data interpretation and writing of the manuscript. All authors reviewed the manuscript prior to submission.

Competing interests

A.T., H.T., M.C.U.C., S.K., L.K., P.G., J.O., R.B., M.D., L.F., A.G., P.P., V.S., C.G., N.R., S.E.P. and J.M.B. report that their institutional departments have received grants from Breast Cancer Now and/or Cancer Research UK and other support for costs or consumables in this research from Myriad Genetics, Inc. and NanoString Technologies, Inc. during the conduct of the study. M.C.U.C. has a patent: US Patent No. 9,631,239 with royalties paid. M.D. reports receiving personal fees from Myriad Genetics, Inc. outside of the submitted work. A.Gu. reports receiving salary compensation and stock/options from Myriad Genetics, Inc. during conduct of the study and has patent rights assigned to Myriad Genetics. C.M.P. reports receiving personal fees from Bioclassifier LLC, consulting fees from Nanostring Technologies outside the submitted work. In addition, C.M.P. has a patent: U.S. Patent No. 9,631,239 with royalties paid. K.M.T. reports receiving personal fees from Myriad Genetics, Inc. during the conduct of the study and personal fees from Myriad Genetics, Inc. outside the submitted work. In addition, K.T. has the following patents pending: 13/164,499; 14/554,715; 15/010,721; 15/192,497; 14/245,576; 62/000,000; 62/311,231; 62/332,526; 14/962,588; 2802882; 11796544.2; 15189527.3; 2,839,210; 12801070.9; 2014-516031; 2012358244; 2,860,312; 201280070358.0; 12860530.0; 2014-548965; 2014248007; 2,908,745; 14779403.6; 2016-506657; 712,663; PCT/US15/045561; PCT/US15/064473; and the following patents issued to Myriad Genetics, Inc.: 9,279,156; 9,388,427 and 625468. J.S.L. reports salary compensation and stock/options from Myriad Genetics Inc. received during conduct of the study. The other authors declare no competing interests.

Corresponding author

Correspondence to Andrew Tutt.

Supplementary information

  1. Supplementary Text and Figures

    Supplementary Note, Supplementary Figures 1–9 and Supplementary Tables 1–9

  2. Reporting Summary

  3. Supplementary Dataset 1

    Biological data used for subgroup analyses