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Update on the Treatment of Early-Stage Triple-Negative Breast Cancer

  • Priyanka Sharma
Breast Cancer (ML Telli, Section Editor)
  • 772 Downloads
Part of the following topical collections:
  1. Topical Collection on Breast Cancer

Opinion statement

Triple-negative breast cancer (TNBC) accounts for 15% of all breast cancers and is associated with poor long-term outcomes compared to other breast cancer subtypes. Currently, chemotherapy remains the main modality of treatment for early-stage TNBC, as there is no approved targeted therapy for this subtype. The biologic heterogeneity of TNBC has hindered the development and evaluation of novel agents, but recent advancements in subclassifying TNBC have paved the way for further investigation of more effective systemic therapies, including cytotoxic and targeted agents. TNBC is enriched for germline BRCA mutation and for somatic deficiencies in homologous recombination DNA repair, the so-called “BRCAness” phenotype. Together, germline BRCA mutations and BRCAness are promising biomarkers of susceptibility to DNA-damaging therapy. Various investigational approaches are consequently being investigated in early-stage TNBC, including immune checkpoint inhibitors, platinum compounds, PI3K pathway inhibitors, and androgen receptor inhibitors. Due to the biological diversity found within TNBC, patient selection based on molecular biomarkers could aid the design of early-phase clinical trials, ultimately accelerating the clinical application of effective new agents. TNBC is an aggressive breast cancer subtype, for which multiple targeted approaches will likely be required for patient outcomes to be substantially improved.

Keywords

Triple-negative breast cancer (TNBC) Neoadjuvant chemotherapy DNA damage repair BRCA1/2 mutations Gene expression profiling Platinum-based therapy Immune checkpoint inhibitors 

Notes

Compliance with Ethical Standards

Conflict of Interest

Priyanka Sharma has received research funding through grants from Novartis, Celgene, and Bristol-Myers Squibb has received compensation from AstraZeneca, Myriad Genetics, AbbVie, Almac Diagnostics, and TapaImmune for service on advisory boards.

Human and Animal Rights and Informed Consent

All reported studies/experiments with human or animal subjects performed by the authors have been previously published and complied with all applicable ethical standards (including the Helsinki declaration and its amendments, institutional/national research committee standards, and international/national/institutional guidelines).

References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Bauer KR, Brown M, Cress RD, Parise CA, Caggiano V. Descriptive analysis of estrogen receptor (ER)-negative, progesterone receptor (PR)-negative, and HER2-negative invasive breast cancer, the so-called triple-negative phenotype: a population-based study from the California Cancer Registry. Cancer. 2007;109(9):1721–8.  https://doi.org/10.1002/cncr.22618.CrossRefPubMedGoogle Scholar
  2. 2.
    Hammond ME, Hayes DF, Wolff AC, Mangu PB, Temin S. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer. J Oncol Pract. 2010;6(4):195–7.  https://doi.org/10.1200/jop.777003.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Kohler BA, Sherman RL, Howlader N, Jemal A, Ryerson AB, Henry KA, et al. Annual report to the nation on the status of cancer, 1975-2011, featuring incidence of breast cancer subtypes by race/ethnicity, poverty, and state. J Natl Cancer Inst. 2015;107(6)  https://doi.org/10.1093/jnci/djv048.
  4. 4.
    Wolff AC, Hammond MEH, Hicks DG, Dowsett M, McShane LM, Allison KH, et al. Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update. J Clin Oncol. 2013;31(31):3997–4013.  https://doi.org/10.1200/jco.2013.50.9984.CrossRefPubMedGoogle Scholar
  5. 5.
    Carey LA, Dees EC, Sawyer L, Gatti L, Moore DT, Collichio F, et al. The triple negative paradox: primary tumor chemosensitivity of breast cancer subtypes. Clin Cancer Res. 2007;13(8):2329–34.  https://doi.org/10.1158/1078-0432.CCR-06-1109.CrossRefPubMedGoogle Scholar
  6. 6.
    Dent R, Trudeau M, Pritchard KI, Hanna WM, Kahn HK, Sawka CA, et al. Triple-negative breast cancer: clinical features and patterns of recurrence. Clin Cancer Res. 2007;13(15 Pt 1):4429–34.  https://doi.org/10.1158/1078-0432.ccr-06-3045.CrossRefPubMedGoogle Scholar
  7. 7.
    Liedtke C, Mazouni C, Hess KR, Andre F, Tordai A, Mejia JA, et al. Response to neoadjuvant therapy and long-term survival in patients with triple-negative breast cancer. J Clin Oncol. 2008;26(8):1275–81.  https://doi.org/10.1200/jco.2007.14.4147.CrossRefPubMedGoogle Scholar
  8. 8.
    Gonzalez-Angulo AM, Timms KM, Liu S, Chen H, Litton JK, Potter J, et al. Incidence and outcome of BRCA mutations in unselected patients with triple receptor-negative breast cancer. Clin Cancer Res. 2011;17(5):1082–9.  https://doi.org/10.1158/1078-0432.ccr-10-2560.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Livasy CA, Karaca G, Nanda R, Tretiakova MS, Olopade OI, Moore DT, et al. Phenotypic evaluation of the basal-like subtype of invasive breast carcinoma. Mod Pathol. 2006;19(2):264–71.  https://doi.org/10.1038/modpathol.3800528.CrossRefPubMedGoogle Scholar
  10. 10.
    Millikan RC, Newman B, Tse CK, Moorman PG, Conway K, Dressler LG, et al. Epidemiology of basal-like breast cancer. Breast Cancer Res Treat. 2008;109(1):123–39.  https://doi.org/10.1007/s10549-007-9632-6.CrossRefPubMedGoogle Scholar
  11. 11.
    Sharma P, Klemp JR, Kimler BF, Mahnken JD, Geier LJ, Khan QJ, et al. 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. 2014;145(3):707–14.  https://doi.org/10.1007/s10549-014-2980-0.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Trivers KF, Lund MJ, Porter PL, Liff JM, Flagg EW, Coates RJ, et al. The epidemiology of triple-negative breast cancer, including race. Cancer Causes Control. 2009;20(7):1071–82.  https://doi.org/10.1007/s10552-009-9331-1.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Haffty BG, Yang Q, Reiss M, Kearney T, Higgins SA, Weidhaas J, et al. Locoregional relapse and distant metastasis in conservatively managed triple negative early-stage breast cancer. J Clin Oncol. 2006;24(36):5652–7.  https://doi.org/10.1200/jco.2006.06.5664.CrossRefPubMedGoogle Scholar
  14. 14.
    Nielsen TO, Hsu FD, Jensen K, Cheang M, Karaca G, Hu Z, et al. Immunohistochemical and clinical characterization of the basal-like subtype of invasive breast carcinoma. Clin Cancer Res. 2004;10(16):5367–74.  https://doi.org/10.1158/1078-0432.ccr-04-0220.CrossRefPubMedGoogle Scholar
  15. 15.
    Tan DS, Marchio C, Jones RL, Savage K, Smith IE, Dowsett M, et al. Triple negative breast cancer: molecular profiling and prognostic impact in adjuvant anthracycline-treated patients. Breast Cancer Res Treat. 2008;111(1):27–44.  https://doi.org/10.1007/s10549-007-9756-8.CrossRefPubMedGoogle Scholar
  16. 16.
    Cheang MC, Voduc D, Bajdik C, Leung S, McKinney S, Chia SK, et al. Basal-like breast cancer defined by five biomarkers has superior prognostic value than triple-negative phenotype. Clin Cancer Res. 2008;14(5):1368–76.  https://doi.org/10.1158/1078-0432.ccr-07-1658.CrossRefPubMedGoogle Scholar
  17. 17.
    Swain SM, Baselga J, Kim SB, Ro J, Semiglazov V, Campone M, et al. Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. N Engl J Med. 2015;372(8):724–34.  https://doi.org/10.1056/NEJMoa1413513.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    •• Giuliano AE, Connolly JL, Edge SB, Mittendorf EA, Rugo HS, Solin LJ, et al. Breast cancer—major changes in the American Joint Committee on Cancer eighth edition cancer staging manual. CA Cancer J Clin. 2017;67(4):290–303.  https://doi.org/10.3322/caac.21393. Overview of major revisions to breast cancer staging included in the 8th edition of the AJCC staging manual.CrossRefPubMedGoogle Scholar
  19. 19.
    Coates AS, Winer EP, Goldhirsch A, Gelber RD, Gnant M, Piccart-Gebhart M, et al. Tailoring therapies—improving the management of early breast cancer: St Gallen International Expert Consensus on the primary therapy of early breast cancer 2015. Ann Oncol. 2015;26(8):1533–46.  https://doi.org/10.1093/annonc/mdv221.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Senkus E, Kyriakides S, Penault-Llorca F, Poortmans P, Thompson A, Zackrisson S, et al. Primary breast cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2013;24(Suppl 6):vi7–23.  https://doi.org/10.1093/annonc/mdt284.CrossRefPubMedGoogle Scholar
  21. 21.
    Gonzalez-Angulo AM, Litton JK, Broglio KR, Meric-Bernstam F, Rakkhit R, Cardoso F, et al. High risk of recurrence for patients with breast cancer who have human epidermal growth factor receptor 2-positive, node-negative tumors 1 cm or smaller. J Clin Oncol. 2009;27(34):5700–6.  https://doi.org/10.1200/JCO.2009.23.2025.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Early Breast Cancer Trialists’ Collaborative G, Peto R, Davies C, Godwin J, Gray R, Pan HC, et al. Comparisons between different polychemotherapy regimens for early breast cancer: meta-analyses of long-term outcome among 100,000 women in 123 randomised trials. Lancet. 2012;379(9814):432–44.  https://doi.org/10.1016/S0140-6736(11)61625-5.CrossRefGoogle Scholar
  23. 23.
    Khouri MG, Douglas PS, Mackey JR, Martin M, Scott JM, Scherrer-Crosbie M, et al. Cancer therapy-induced cardiac toxicity in early breast cancer: addressing the unresolved issues. Circulation. 2012;126(23):2749–63.  https://doi.org/10.1161/circulationaha.112.100560.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Tan TC, Neilan TG, Francis S, Plana JC, Scherrer-Crosbie M. Anthracycline-induced cardiomyopathy in adults. Compr Physiol. 2015;5(3):1517–40.  https://doi.org/10.1002/cphy.c140059. CrossRefPubMedGoogle Scholar
  25. 25.
    Wolff AC, Blackford AL, Visvanathan K, Rugo HS, Moy B, Goldstein LJ, et al. Risk of marrow neoplasms after adjuvant breast cancer therapy: the national comprehensive cancer network experience. J Clin Oncol. 2015;33(4):340–8.  https://doi.org/10.1200/jco.2013.54.6119.CrossRefPubMedGoogle Scholar
  26. 26.
    Jones SE, Savin MA, Holmes FA, O’Shaughnessy JA, Blum JL, Vukelja S, et al. Phase III trial comparing doxorubicin plus cyclophosphamide with docetaxel plus cyclophosphamide as adjuvant therapy for operable breast cancer. J Clin Oncol. 2006;24(34):5381–7.  https://doi.org/10.1200/JCO.2006.06.5391.CrossRefPubMedGoogle Scholar
  27. 27.
    ••Blum JL, Flynn PJ, Yothers G, Asmar L, Geyer CE Jr, Jacobs SA, et al. Anthracyclines in early breast cancer: the ABC trials-USOR 06-090, NSABP B-46-I/USOR 07132, and NSABP B-49 (NRG Oncology). J Clin Oncol. 2017:JCO2016714147.  https://doi.org/10.1200/JCO.2016.71.4147. In the ABC trials, adjuvant chemotherapy regimens that included doxorubicin were associated with improved invasive disease-free survival, particularly in patients with HER2-negative disease. These results establish anthracycline-containing regimens as standard adjuvant therapy for most patients with TNBC.
  28. 28.
    Rouzier R, Perou CM, Symmans WF, Ibrahim N, Cristofanilli M, Anderson K, et al. Breast cancer molecular subtypes respond differently to preoperative chemotherapy. Clin Cancer Res. 2005;11(16):5678–85.  https://doi.org/10.1158/1078-0432.ccr-04-2421.CrossRefPubMedGoogle Scholar
  29. 29.
    Cortazar P, Geyer CE Jr. Pathological complete response in neoadjuvant treatment of breast cancer. Ann Surg Oncol. 2015;22(5):1441–6.  https://doi.org/10.1245/s10434-015-4404-8.CrossRefPubMedGoogle Scholar
  30. 30.
    Adams S, Gray RJ, Demaria S, Goldstein L, Perez EA, Shulman LN, et al. Prognostic value of tumor-infiltrating lymphocytes in triple-negative breast cancers from two phase III randomized adjuvant breast cancer trials: ECOG 2197 and ECOG 1199. J Clin Oncol. 2014;32(27):2959–66.  https://doi.org/10.1200/jco.2013.55.0491.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Dieci MV, Criscitiello C, Goubar A, Viale G, Conte P, Guarneri V, et al. Prognostic value of tumor-infiltrating lymphocytes on residual disease after primary chemotherapy for triple-negative breast cancer: a retrospective multicenter study. Ann Oncol. 2014;25(3):611–8.  https://doi.org/10.1093/annonc/mdt556.CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    • Loi S, Michiels S, Salgado R, Sirtaine N, Jose V, Fumagalli D, et al. Tumor infiltrating lymphocytes are prognostic in triple negative breast cancer and predictive for trastuzumab benefit in early breast cancer: results from the FinHER trial. Ann Oncol. 2014;25(8):1544–50.  https://doi.org/10.1093/annonc/mdu112. Among TNBC patients from the FinHER clinical trial, each 10% increase in TILs was associated with significantly decreased distant recurrence. Routine pathological evaluation of tumor TILs may be warranted.CrossRefPubMedGoogle Scholar
  33. 33.
    Loi S, Sirtaine N, Piette F, Salgado R, Viale G, Van Eenoo F, et al. Prognostic and predictive value of tumor-infiltrating lymphocytes in a phase III randomized adjuvant breast cancer trial in node-positive breast cancer comparing the addition of docetaxel to doxorubicin with doxorubicin-based chemotherapy: BIG 02-98. J Clin Oncol. 2013;31(7):860–7.  https://doi.org/10.1200/jco.2011.41.0902.CrossRefPubMedGoogle Scholar
  34. 34.
    Salgado R, Denkert C, Demaria S, Sirtaine N, Klauschen F, Pruneri G, et al. The evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer: recommendations by an International TILs Working Group 2014. Ann Oncol. 2015;26(2):259–71.  https://doi.org/10.1093/annonc/mdu450.CrossRefPubMedGoogle Scholar
  35. 35.
    Ayers M, Symmans WF, Stec J, Damokosh AI, Clark E, Hess K, et al. Gene expression profiles predict complete pathologic response to neoadjuvant paclitaxel and fluorouracil, doxorubicin, and cyclophosphamide chemotherapy in breast cancer. J Clin Oncol. 2004;22(12):2284–93.  https://doi.org/10.1200/jco.2004.05.166.CrossRefPubMedGoogle Scholar
  36. 36.
    Gianni L, Zambetti M, Clark K, Baker J, Cronin M, Wu J, et al. Gene expression profiles in paraffin-embedded core biopsy tissue predict response to chemotherapy in women with locally advanced breast cancer. J Clin Oncol. 2005;23(29):7265–77.  https://doi.org/10.1200/jco.2005.02.0818.CrossRefPubMedGoogle Scholar
  37. 37.
    Hatzis C, Pusztai L, Valero V, Booser DJ, Esserman L, Lluch A, et al. A genomic predictor of response and survival following taxane-anthracycline chemotherapy for invasive breast cancer. JAMA. 2011;305(18):1873–81.  https://doi.org/10.1001/jama.2011.593.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Sharma P, Barlow W, Godwin AK, Knight L, Walker S, Kennedy R, et al. Impact of DNA repair deficiency signature on outcomes in triple negative breast cancer (TNBC) patients treated with AC chemotherapy (SWOG S9313) [abstract]. J Clin Oncol. 2017;35(15 suppl):abstr 529.Google Scholar
  39. 39.
    Sharma P, Barlow W, Godwin AK, Pathak H, Isakova K, Hartman A, et al. Impact of homologous recombination deficiency (HRD) biomarkers on outcomes in triple negative breast cancer (TNBC) patients treated with AC chemotherapy (SWOG S9313) [abstract]. Cancer Res. 2017;77(13 Suppl):Abstract nr 1776.  https://doi.org/10.1158/1538-7445.AM2017-1776.CrossRefGoogle Scholar
  40. 40.
    Golshan M, Cirrincione CT, Sikov WM, Berry DA, Jasinski S, Weisberg TF, et al. Impact of neoadjuvant chemotherapy in stage II-III triple negative breast cancer on eligibility for breast-conserving surgery and breast conservation rates: surgical results from CALGB 40603 (Alliance). Ann Surg. 2015;262(3):434–9.  https://doi.org/10.1097/sla.0000000000001417.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Connor CS, Kimler BF, Mammen JM, McGinness MK, Wagner JL, Alsop SM, et al. Impact of neoadjuvant chemotherapy on axillary nodal involvement in patients with clinically node negative triple negative breast cancer. J Surg Oncol. 2015;111(2):198–202.  https://doi.org/10.1002/jso.23790.CrossRefPubMedGoogle Scholar
  42. 42.
    Swain SM, Tang G, Geyer CE Jr, Rastogi P, Atkins JN, Donnellan PP, et al. Definitive results of a phase III adjuvant trial comparing three chemotherapy regimens in women with operable, node-positive breast cancer: the NSABP B-38 trial. J Clin Oncol. 2013;31(26):3197–204.  https://doi.org/10.1200/jco.2012.48.1275.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Wolfgang J, Schneeweiss A, Haeberle L, Fasching PA, Sommer HL, Rezai M, et al. Adjuvant gemcitabine for high-risk breast cancer (BC) patients: final survival results of the randomized phase III SUCCESS—A study. J Clin Oncol. 2014;32(5s):Abstr 1010.Google Scholar
  44. 44.
    Yardley DA, Bosserman LD, Keaton MR, Ackerman MA, Goble SA, Shipley D, et al. TITAN: phase III study of doxorubicin/cyclophosphamide (AC) followed by ixabepilone (Ixa) or paclitaxel (Pac) in early-stage, triple-negative breast cancer (TNBC). J Clin Oncol. 2015;33(Suppl):abstr 1000.Google Scholar
  45. 45.
    Cameron D, Brown J, Dent R, Jackisch C, Mackey J, Pivot X, et al. Adjuvant bevacizumab-containing therapy in triple-negative breast cancer (BEATRICE): primary results of a randomised, phase 3 trial. Lancet Oncol. 2013;14(10):933–42.  https://doi.org/10.1016/s1470-2045(13)70335-8.CrossRefPubMedGoogle Scholar
  46. 46.
    Miller K, O’Neill AM, Dang CT, Northfelt DW, Gradishar WJ, Goldstein LJ, et al. Bevacizumab (Bv) in the adjuvant treatment of HER2-negative breast cancer: final results from Eastern Cooperative Oncology Group E5103. J Clin Oncol. 2014;32(5 Suppl):Abstr 500.Google Scholar
  47. 47.
    • Couch FJ, Hart SN, Sharma P, Toland AE, Wang X, Miron P, et al. 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. 2015;33(4):304–11.  https://doi.org/10.1200/jco.2014.57.1414. Frequency of germline mutations in 17 predisposition genes, including BRCA1 and BRCA2, in patients with TNBC. Panel genes other than BRCA1/2 warrant investigation as factors for clinical HBOC risk assessment.CrossRefPubMedGoogle Scholar
  48. 48.
    Hartman AR, Kaldate RR, Sailer LM, Painter L, Grier CE, Endsley RR, et al. Prevalence of BRCA mutations in an unselected population of triple-negative breast cancer. Cancer. 2012;118(11):2787–95.  https://doi.org/10.1002/cncr.26576.CrossRefPubMedGoogle Scholar
  49. 49.
    National Comprehensive Cancer Network. Genetic/familiar high-risk assessment: breast and ovarian. 2017.Google Scholar
  50. 50.
    • von Minckwitz G, Schneeweiss A, Loibl S, Salat C, Denkert C, Rezai M, 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. 2014;15(7):747–56.  https://doi.org/10.1016/s1470-2045(14)70160-3. In the GeparSixto trial, addition of carboplatin to anthracycline-/taxane-based neoadjuvant chemotherapy significantly improved pCR among patients with TNBC. The optimum dose and schedule of carboplatin needs to be established in future studies.CrossRefGoogle Scholar
  51. 51.
    • Sikov WM, Berry DA, Perou CM, Singh B, Cirrincione CT, Tolaney SM, 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. 2015;33(1):13–21.  https://doi.org/10.1200/jco.2014.57.0572. In CALGB 40603, addition of either carboplatin or bevacizumab to ACT-based neoadjuvant chemotherapy increased breast pCR among patients with TNBC. Further studies are needed to establish the impact of this regimen on patient survival.CrossRefPubMedGoogle Scholar
  52. 52.
    Tamura K, Hashimoto J, Tsuda H, Yoshida M, Yamauchi H, Aogi K, et al. Randomized phase II study of weekly paclitaxel with or without carboplatin followed by cyclophosphamide/epirubicin/5-fluorouracil as neoadjuvant chemotherapy for stage II/IIIA HER2-negative breast cancer [abstract]. J Clin Oncol. 2014;32(5s):abstr 1017.Google Scholar
  53. 53.
    Rugo HS, Olopade OI, DeMichele A, Yau C, van’t Veer LJ, Buxton MB, et al. Adaptive randomization of veliparib-carboplatin treatment in breast cancer. N Engl J Med. 2016;375(1):23–34.  https://doi.org/10.1056/NEJMoa1513749.CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Gluz O, Nitz U, Christgen M, Forstbauer H, Braun M, Warm M, et al. Efficacy of 12 weeks neoadjuvant nab-paclitaxel combined with carboplatinum vs. gemcitabine in triple-negative breast cancer: WSG-ADAPT TN randomized phase II trial [abstract]. J Clin Oncol. 2015;33(Suppl):Abstr 1032.Google Scholar
  55. 55.
    Zhang P, Yin Y, Mo H, Zhang B, Wang X, Li Q, et al. Better pathologic complete response and relapse-free survival after carboplatin plus paclitaxel compared with epirubicin plus paclitaxel as neoadjuvant chemotherapy for locally advanced triple-negative breast cancer: a randomized phase 2 trial. Oncotarget. 2016;7(37):60647–56.  https://doi.org/10.18632/oncotarget.10607. PubMedPubMedCentralGoogle Scholar
  56. 56.
    • Sharma P, Lopez-Tarruella S, Garcia-Saenz JA, Ward C, Connor C, Gomez HL, et al. Efficacy of neoadjuvant carboplatin plus docetaxel in triple negative breast cancer: combined analysis of two cohorts. Clin Cancer Res. 2017;23(3):649–57.  https://doi.org/10.1158/1078-0432.ccr-16-0162. TNBC patients in this study received anthracycline-free taxane/carboplatin-based neoadjuvant chemotherapy and experienced high pCR rates regardless of BRCA mutation status. Furthermore, this regimen was well tolerated, supporting the investigation of anthracycline-free neoadjuvant chemotherapy regimens for TNBC in future randomized, controlled trials.CrossRefPubMedGoogle Scholar
  57. 57.
    von Minckwitz G, Loibl S, Schneeweiss A, Salat CT, Rezai M, Zahm D-M et al. Early survival analysis of the randomized phase II trial investigating the addition of carboplatin to neoadjuvant therapy for triple-negative and HER2-positive early breast cancer (GeparSixto) [abstract]. San Antonio Breast Cancer Symposium; December 8–12; San Antonio, TX2015. p. Abstract S2–04.Google Scholar
  58. 58.
    Silver DP, Richardson AL, Eklund AC, Wang ZC, Szallasi Z, Li Q, et al. Efficacy of neoadjuvant cisplatin in triple-negative breast cancer. J Clin Oncol. 2010;28(7):1145–53.  https://doi.org/10.1200/jco.2009.22.4725.CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Geyer C, O’Shaughnessy J, Untch M, Sikov W, Rugo H, McKee M, 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) [abstract]. J Clin Oncol. 2017;35(15_suppl):abstr 520.Google Scholar
  60. 60.
    Kern P, Kalisch A, Kolberg HC, Kimmig R, Otterbach F, von Minckwitz G, et al. Neoadjuvant, anthracycline-free chemotherapy with carboplatin and docetaxel in triple-negative, early-stage breast cancer: a multicentric analysis of feasibility and rates of pathologic complete response. Chemotherapy. 2013;59(5):387–94.CrossRefPubMedGoogle Scholar
  61. 61.
    • Telli ML, Jensen KC, Vinayak S, Kurian AW, Lipson JA, Flaherty PJ, 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. J Clin Oncol. 2015;33(17):1895–901.  https://doi.org/10.1200/jco.2014.57.0085. In PrECOG 0105, neoadjuvant gemcitabine + carboplatin + iniparib increased pCR among patients with TNBC and BRCA-mutated breast cancer. Additionally, the HRD-LOH assay identified BRCA-wild-type patients who had favorable pathological response to this regimen.CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Sikov W, Berry D, Perou C, Singh B, Cirrincione C, Tolaney S et al. Event-free and overall survival following neoadjuvant weekly paclitaxel and dose-dense AC +/ carboplatin and/or bevacizumab in triple-negative breast cancer: outcomes from CALGB 40603 (Alliance) [abstract]. Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium; 2015 Dec 9; San Antonio, TX: Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium; 2015.Google Scholar
  63. 63.
    Sharma P, Khan Q, Kimler B, Klemp J, Connor C, McGinness M, et al. Results of a phase II study of neoadjuvant platinum/taxane based chemotherapy and erlotinib for triple negative breast cancer [abstract]. Cancer Res. 2010;70(24 Suppl):Abstr P1-11-07.  https://doi.org/10.1158/0008-5472.SABCS10-P1-11-07.CrossRefGoogle Scholar
  64. 64.
    Abkevich V, Timms KM, Hennessy BT, Potter J, Carey MS, Meyer LA, et al. Patterns of genomic loss of heterozygosity predict homologous recombination repair defects in epithelial ovarian cancer. Br J Cancer. 2012;107(10):1776–82.  https://doi.org/10.1038/bjc.2012.451.CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Lips EH, Mulder L, Oonk A, van der Kolk LE, Hogervorst FB, Imholz AL, et al. Triple-negative breast cancer: BRCAness and concordance of clinical features with BRCA1-mutation carriers. Br J Cancer. 2013;108(10):2172–7.  https://doi.org/10.1038/bjc.2013.144.CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Mulligan JM, Hill LA, Deharo S, Irwin G, Boyle D, Keating KE, et al. Identification and validation of an anthracycline/cyclophosphamide-based chemotherapy response assay in breast cancer. J Natl Cancer Inst. 2014;106(1):djt335.  https://doi.org/10.1093/jnci/djt335.CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Sharma P, Barlow W, Godwin A, Pathak H, Isakova K, Williams D et al. Impact of homologous recombination deficiency biomarkers on outcomes in patients with triple-negative breast cancer treated with adjuvant doxorubicin and cyclophosphamide (SWOG S9313). Ann Oncol. 2018;29(3):654–660.Google Scholar
  68. 68.
    Sharma P, Stecklein SR, Kimler BF, Sethi G, Petroff BK, Phillips TA, et al. The prognostic value of BRCA1 promoter methylation in early stage triple negative breast cancer. J Cancer Ther Res. 2014;3(2):1–11.  https://doi.org/10.7243/2049-7962-3-2. PubMedPubMedCentralGoogle Scholar
  69. 69.
    Sharma P. Biology and management of patients with triple-negative breast cancer. Oncologist. 2016;21(9):1050–62.  https://doi.org/10.1634/theoncologist.2016-0067.CrossRefPubMedPubMedCentralGoogle Scholar
  70. 70.
    Birkbak NJ, Wang ZC, Kim JY, Eklund AC, Li Q, Tian R, et al. Telomeric allelic imbalance indicates defective DNA repair and sensitivity to DNA-damaging agents. Cancer Discov. 2012;2(4):366–75.  https://doi.org/10.1158/2159-8290.CD-11-0206.CrossRefPubMedPubMedCentralGoogle Scholar
  71. 71.
    Popova T, Manie E, Rieunier G, Caux-Moncoutier V, Tirapo C, Dubois T, et al. Ploidy and large-scale genomic instability consistently identify basal-like breast carcinomas with BRCA1/2 inactivation. Cancer Res. 2012;72(21):5454–62.  https://doi.org/10.1158/0008-5472.CAN-12-1470.CrossRefPubMedGoogle Scholar
  72. 72.
    •• Timms KM, Abkevich V, Hughes E, Neff C, Reid J, Morris B, et al. Association of BRCA1/2 defects with genomic scores predictive of DNA damage repair deficiency among breast cancer subtypes. Breast Cancer Res. 2014;16(6):475.  https://doi.org/10.1186/s13058-014-0475-x. High frequency of elevated homologous recombination deficiency scores suggests that a significant proportion of all breast cancer subtypes, including TNBC, may carry defects in the repair pathway. The combination of this robust scoring system and FFPE-compatible assay may identify tumors that are susceptible to HRD-targeted agents.CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    McIntosh S, Parkes E, James CR, Lioe T, Lowry K, Keating KE, et al. Neo-DDRD: a biomarker-driven neoadjuvant feasibility study in breast cancer [abstract]. Cancer Res. 2016;76(4 Suppl):abstr OT3-02-7.  https://doi.org/10.1158/1538-7445.SABCS15-OT3-02-07.Google Scholar
  74. 74.
    • Masuda N, Lee SJ, Ohtani S, Im YH, Lee ES, Yokota I, et al. Adjuvant capecitabine for breast cancer after preoperative chemotherapy. N Engl J Med. 2017;376(22):2147–59.  https://doi.org/10.1056/NEJMoa1612645. Addition of capecitabine to adjuvant chemotherapy prolonged DFS and OS in patients with HER2-negative breast cancer who had residual disease after neoadjuvant chemotherapy.CrossRefPubMedGoogle Scholar
  75. 75.
    Lehmann BD, Bauer JA, Chen X, Sanders ME, Chakravarthy AB, Shyr Y, et al. Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies. J Clin Invest. 2011;121(7):2750–67.  https://doi.org/10.1172/jci45014.CrossRefPubMedPubMedCentralGoogle Scholar
  76. 76.
    Perou CM, Sorlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA, et al. Molecular portraits of human breast tumours. Nature. 2000;406(6797):747–52.  https://doi.org/10.1038/35021093.CrossRefPubMedGoogle Scholar
  77. 77.
    Prat A, Perou CM. Deconstructing the molecular portraits of breast cancer. Mol Oncol. 2011;5(1):5–23.  https://doi.org/10.1016/j.molonc.2010.11.003.CrossRefPubMedGoogle Scholar
  78. 78.
    Shah SP, Roth A, Goya R, Oloumi A, Ha G, Zhao Y, et al. The clonal and mutational evolution spectrum of primary triple-negative breast cancers. Nature. 2012;486(7403):395–9.  https://doi.org/10.1038/nature10933. CrossRefPubMedGoogle Scholar
  79. 79.
    •• Lehmann BD, Jovanovic B, Chen X, Estrada MV, Johnson KN, Shyr Y, et al. Refinement of triple-negative breast cancer molecular subtypes: implications for neoadjuvant chemotherapy selection. PLoS One. 2016;11(6):e0157368.  https://doi.org/10.1371/journal.pone.0157368. TNBCtype-4 gene expression subtyping is a refinement of the previous TNBC gene expression classification published by this group. TNBCtype-4 subtypes significantly differ in pathological response to neoadjuvant chemotherapy, with BL1 having the highest rates and BL2 and LAR having the lowest rates.CrossRefPubMedPubMedCentralGoogle Scholar
  80. 80.
    • Ring BZ, Hout DR, Morris SW, Lawrence K, Schweitzer BL, Bailey DB, et al. Generation of an algorithm based on minimal gene sets to clinically subtype triple negative breast cancer patients. BMC Cancer. 2016;16:143.  https://doi.org/10.1186/s12885-016-2198-0. A gene expression model using smaller gene sets (n=101) is sufficient to accurately identify TNBC subtypes and predict clinical response, making its use feasible in the clinical setting.CrossRefPubMedPubMedCentralGoogle Scholar
  81. 81.
    •• Balko JM, Giltnane JM, Wang K, Schwarz LJ, Young CD, Cook RS, et al. Molecular profiling of the residual disease of triple-negative breast cancers after neoadjuvant chemotherapy identifies actionable therapeutic targets. Cancer Discov. 2014;4(2):232–45.  https://doi.org/10.1158/2159-8290.CD-13-0286. Genomic alterations in residual TNBC can guide selection of targeted therapy. In this study, 90% of examined tumors had a genomic alteration that was potentially treatable with currently available targeted therapy.CrossRefPubMedGoogle Scholar
  82. 82.
    Cheung SY, Boey YJ, Koh VC, Thike AA, Lim JC, Iqbal J, et al. Role of epithelial-mesenchymal transition markers in triple-negative breast cancer. Breast Cancer Res Treat. 2015;152(3):489–98.  https://doi.org/10.1007/s10549-015-3485-1.CrossRefPubMedGoogle Scholar
  83. 83.
    Keam B, Im SA, Lee KH, Han SW, Oh DY, Kim JH, et al. Ki-67 can be used for further classification of triple negative breast cancer into two subtypes with different response and prognosis. Breast Cancer Res. 2011;13(2):R22.  https://doi.org/10.1186/bcr2834.CrossRefPubMedPubMedCentralGoogle Scholar
  84. 84.
    Orzechowska M, Jedroszka D, Bednarek AK. Common profiles of Notch signaling differentiate disease-free survival in luminal type A and triple negative breast cancer. Oncotarget. 2017;8(4):6013–32.  https://doi.org/10.18632/oncotarget.13451. CrossRefPubMedGoogle Scholar
  85. 85.
    Prat A, Adamo B, Cheang MC, Anders CK, Carey LA, Perou CM. Molecular characterization of basal-like and non-basal-like triple-negative breast cancer. Oncologist. 2013;18(2):123–33.  https://doi.org/10.1634/theoncologist.2012-0397.CrossRefPubMedPubMedCentralGoogle Scholar
  86. 86.
    Prat A, Parker JS, Karginova O, Fan C, Livasy C, Herschkowitz JI, et al. Phenotypic and molecular characterization of the claudin-low intrinsic subtype of breast cancer. Breast Cancer Res. 2010;12(5):R68.  https://doi.org/10.1186/bcr2635.CrossRefPubMedPubMedCentralGoogle Scholar
  87. 87.
    Zhang J, Shao X, Sun H, Liu K, Ding Z, Chen J, et al. NUMB negatively regulates the epithelial-mesenchymal transition of triple-negative breast cancer by antagonizing Notch signaling. Oncotarget. 2016;7(38):61036–53.  https://doi.org/10.18632/oncotarget.11062. PubMedPubMedCentralGoogle Scholar
  88. 88.
    Emens LA, Braiteh FS, Cassier P, Delord JP, Eder JP, Fasso M, et al. Inhibition of PD-L1 by MPDL3280A leads to clinical activity in patients with metastatic triple-negative breast cancer (TNBC) [abstract]. Cancer Res. 2015;75(15 Suppl):Abtract nr 2859.  https://doi.org/10.1158/1538-7445.AM2015-2859.CrossRefGoogle Scholar
  89. 89.
    Nanda R, Liu M, Yau C, Asare S, Hylton N, Van’t Veer L et al. Pembrolizumab plus standard neoadjuvant therapy for high-risk breast cancer (BC): Results from I-SPY 2 [abstract]. 2017 ASCO Annual Meeting2017.Google Scholar
  90. 90.
    Adams S, Loi S, Toppmeyer D, Cescon D, De Laurentiis M, Nanda R. Phase 2 study of pembrolizumab as first-line therapy for PD-L1-positive metastatic triple-negative breast cancer (mTNBC): preliminary data from KEYNOTE-086 cohort B [abstract]. J Clin Oncol. 2017;35(15_suppl):1088.  https://doi.org/10.1200/JCO.2017.35.15_suppl.1088.Google Scholar
  91. 91.
    Adams S, Schmid P, Rugo H, Winer E, Loirat D, Awada A et al. Phase 2 study of pembrolizumab (pembro) monotherapy for previously treated metastatic triple-negative breast cancer (mTNBC): KEYNOTE-086 cohort A [abstract]. J Clin Oncol. 2017;35(suppl; abstr 1008).Google Scholar
  92. 92.
    Schmid P, Cortes Castan J, Bergh J, Pusztai L, Denkert C, Verma S, et al. KEYNOTE-522: phase III study of pembrolizumab (pembro) + chemotherapy (chemo) vs placebo + chemo as neoadjuvant followed by pembro vs placebo as adjuvant therapy for triple-negative breast cancer (TNBC) [abstract]. Ann Oncol. 2017;28(suppl_5):v68–73.  https://doi.org/10.1093/annonc/mdx364.Google Scholar
  93. 93.
    Audeh MW, Carmichael J, Penson RT, Friedlander M, Powell B, Bell-McGuinn KM, et al. Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer: a proof-of-concept trial. Lancet. 2010;376(9737):245–51.  https://doi.org/10.1016/s0140-6736(10)60893-8.CrossRefPubMedGoogle Scholar
  94. 94.
    Bryant HE, Schultz N, Thomas HD, Parker KM, Flower D, Lopez E, et al. Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature. 2005;434(7035):913–7.  https://doi.org/10.1038/nature03443.CrossRefPubMedGoogle Scholar
  95. 95.
    Farmer H, McCabe N, Lord CJ, Tutt AN, Johnson DA, Richardson TB, et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature. 2005;434(7035):917–21.  https://doi.org/10.1038/nature03445.CrossRefPubMedGoogle Scholar
  96. 96.
    Fong PC, Boss DS, Yap TA, Tutt A, Wu P, Mergui-Roelvink M, et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med. 2009;361(2):123–34.  https://doi.org/10.1056/NEJMoa0900212.CrossRefPubMedGoogle Scholar
  97. 97.
    Kaufman B, Shapira-Frommer R, Schmutzler RK, Audeh MW, Friedlander M, Balmana J, et al. Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation. J Clin Oncol. 2015;33(3):244–50.  https://doi.org/10.1200/jco.2014.56.2728.CrossRefPubMedGoogle Scholar
  98. 98.
    Sandhu SK, Schelman WR, Wilding G, Moreno V, Baird RD, Miranda S, et al. The poly(ADP-ribose) polymerase inhibitor niraparib (MK4827) in BRCA mutation carriers and patients with sporadic cancer: a phase 1 dose-escalation trial. Lancet Oncol. 2013;14(9):882–92.  https://doi.org/10.1016/s1470-2045(13)70240-7.CrossRefPubMedGoogle Scholar
  99. 99.
    Tutt A, Robson M, Garber JE, Domchek SM, Audeh MW, Weitzel JN, et al. Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-of-concept trial. Lancet. 2010;376(9737):235–44.  https://doi.org/10.1016/s0140-6736(10)60892-6.CrossRefPubMedGoogle Scholar
  100. 100.
    Robson M, Im SA, Senkus E, Xu B, Domchek SM, Masuda N, et al. Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. N Engl J Med. 2017;377(6):523–33.  https://doi.org/10.1056/NEJMoa1706450.CrossRefPubMedGoogle Scholar
  101. 101.
    Alba E, Calvo L, Albanell J, De la Haba JR, Arcusa Lanza A, Chacon JI, et al. Chemotherapy (CT) and hormonotherapy (HT) as neoadjuvant treatment in luminal breast cancer patients: results from the GEICAM/2006-03, a multicenter, randomized, phase-II study. Ann Oncol. 2012;23(12):3069–74.Google Scholar

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© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Division of Medical OncologyUniversity of Kansas Medical CenterWestwoodUSA

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