Triple Negative Breast Cancer Pathologic Diagnosis and Current Chemotherapy Treatment Options

European Oncology & Haematology, 2014;10(1):35–42

Abstract:

Triple negative breast cancer (TNBC) comprises 12–20 % of all breast cancers and are a heterogeneous group of tumors, both clinically and pathologically. These cancers are characterized by the lack of expression of the hormone receptors estrogen receptor (ER) and progesterone receptor (PR), combined with the lack of either overexpression or amplification of the human epidermal growth factor receptor-2 (HER2) gene. Conventional cytotoxic chemotherapy and DNA damaging agents continue to be the mainstay of treatment of this disease in the neoadjuvant, adjuvant, and metastatic setting. The lack of predictive markers in identifying potential targets for the treatment of TNBC has left a gap in directed therapy in these patients. Platinum agents have seen renewed interest in TNBC based on an increasing body of preclinical and clinical data suggesting encouraging activity. However, comparisons between chemotherapy regimens are mostly retrospective in nature and the best agents or drug combinations for TNBC have not been established in prospective randomized trials. Numerous studies have now shown that TNBC has significantly higher pathologic complete response (pCR) rates compared with hormone receptor positive breast cancer when treated with neoadjuvant chemotherapy, and pCR correlates well with better outcomes for these patients. Patients with TNBC account for a larger number of deaths in the setting of metastatic breast cancer. There is no preferred treatment for the first-line metastatic setting. Although individual agents are recommended, given the often aggressive nature of TNBC and the presence of extensive visceral disease, the use of a combination of drugs, rather than a single agent, is often advocated. This review article will outline the pathologic diagnosis of TNBC and the treatment options available to these patients in the neoadjuvant, adjuvant, and metastatic setting, including an assessment of future directions of treatment.

Keywords: Breast cancer, triple negative, pathological diagnosis, chemotherapy treatment, neoadjuvant, targeted treatment, adjuvant, metastatic
Disclosure: The authors have no conflicts of interests to declare.
Received: January 20, 2014 Accepted March 30, 2014 Citation European Oncology & Haematology, 2014;10(1):35–42
Correspondence: Bernardo L Rapoport, MD, MMed Int Med (Wits), The Medical Oncology Centre of Rosebank, 129 Oxford Road, Saxonwold 2196, Johannesburg, PO Box 2040, Parklands 2121, South Africa. E: brapoport@icon.co.za

The treatment of triple negative breast cancer (TNBC) is an unmet medical need, which refers to tumors that are estrogen receptor (ER) and progesterone receptor (PR) negative, and where human epidermal growth factor receptor 2 (HER2) is not overexpressed. This subset accounts for approximately 12–20 % of breast cancer patients.1 Gene expression analysis on this heterogenous group of patients demonstrates an overlap between the molecular signature of TNBC and basal-like (BL) breast cancer (BLBC). The concordance rates between the two groups are in the order of 70–90 %. Not all TNBC can be defined as BLBC as a small minority of BLBC patients express ER and HER2 receptors. The purpose of this review is to discuss the pathologic diagnosis, current trends in management of TNBC in the neo-adjuvant, adjuvant, and metastatic disease treatment, and future directions.

Pathologic Features and Diagnosis of Triple Negative Breast Cancer
TNBC, which comprises 12–20 % of all breast cancers, are a heterogeneous group of tumors, clinically and pathologically at the molecular level.1 The defining features of this cohort of breast cancers are a lack of expression of the hormone receptors ER and PR, combined with a lack of either overexpression or amplification of the HER2 gene. The majority (around 70 %) has been demonstrated to be BLBC, and this subtype is defined by an overexpression of epidermal growth factor receptor-1 (EGFR-1) and basal cytokeratins, particularly the cytokeratin 5/6 (CK5/6), as well as cytokeratins 14 and 17. These pathologic basal cell type TNBCs have a typical histopathologic appearance, most being poorly differentiated grade 3 carcinomas, with some or all of the following microscopic features: solid growth pattern, a prominent lympho-plasmacytic infiltrate, and a medullarylike growth pattern. The tumor cells are characteristically markedly pleomorphic with pleomorphic nuclei, prominent mitotic activity, and well-marked cellular apoptosis. There is usually extensive geographic tumor necrosis, which can be associated with the exceptionally high proliferative rate of these tumors. Some exhibit prominent stromal fibrosis. Characteristically, these tumors have a ‘pushing’ rather than an infiltrative border. Most of these tumors show the BL molecular characteristics as described by Perou et al.,2 and some may show squamous differentiation and even spindle cell morphology (metaplastic carcinomas). These last two histologic variants have been regarded to be BL variants.

The PAM50 gene expression assay classifies breast cancers into at least five groups, including luminal A, luminal B, HER2 enriched, BL, and normal breast-like and this classification can be recapitulated with surrogate immunohistochemical markers, including ER, PR, HER2, EGFR1, CK5/6, and Ki67.3–5 More recent gene expression array analysis has identified six different groups of TNBC, including two BL (BL1 and BL2), an immunemodulatory (IM), a mesenchymal (M), a mesenchymal stem-like (MSL), and a luminal androgen receptor subtype (LAR).3 A further group termed unstable (UNS) has been recognized.6 The BL1 and 2 subtypes typically have a higher expression of cell cycle genes, while M and MSL are enriched for epithelial–M transition, and growth factor pathways. LAR, by definition, demonstrates AR overexpression.3 The study of Matsuda et al.6 has confirmed the work of Lehman.3

It is important, therefore, to note that while there is overlap between TNBC and BLBC, these two entities are not synonymous with one another and so the BL carcinoma is best regarded as a subset of TNBC. It has been demonstrated that only 71 % of TNBC are of BL subtype by gene expression profiling, and that only 77 % of molecular BLBC are triple negative.7 Up to 70 % of patients with BRCA1 mutations develop tumors that are morphologically identical to the BLBC and are often triple negative. These probably form a further subset of the basal-type carcinomas, but not all BRCA1-associated tumors are TNBC.

A recent study comparing BL TNBC assessed the three different modalities for defining TNBC, namely morphology, immunohistochemistry (IHC), and transcriptional profiles. In this study by Gazinska et al.,8 those TNBC that were positive for CK5/6 and/or EGFR were designated as core basal, those with pathologic criteria were designated as path-basal, and those designated according to molecular profiling (PAM50) were designated as PAM50 BL.9 The non-core BL carcinomas may also be designated as 5-marker negative panel (5NP). In this study, only 13/116 (11 %) were defined as BL by all three modalities: it is evident that even the manner in which BL carcinomas are defined is problematic. The path–basal group had a significant decrease in nodal metastases, while the highest risk for death was in those immunohistochemically defined ‘core–basal’ TNBC. The path non-basal group included carcinomas that could only be designated as not otherwise specified (NOS). This latter group is associated with a higher risk of lymphovascular invasion and nodal metastases. BLBC, in contrast to normal breast basal or myoepithelial cells, expresses cytokeratins 8 and 18. This calls into question the initial implications of the microarray-based studies of breast cancers that suggest that BL cancers originate from basal myoepithelial cells. They may rather be derived from luminal progenitors.

References:
  1. Dent R, Hanna WM, Trudeau M, et al., Pattern of metastatic spread in triple-negative breast cancer, Breast Cancer Res Treat, 2009;115:423–28.
  2. Perou CM, Sorlie T, Eisen MB, et al., Molecular portraits of human breast tumours, Nature, 2000;406:747–52.
  3. Lehmann BD, Bauer JA, Chen X, et al., Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies, J Clin Invest, 2011;121:2750–67.
  4. Bertucci F, Finetti P, Cervera N, et al., How basal are triplenegative breast cancers?, Int J Cancer, 2008;123:236–40.
  5. Perou CM, Molecular stratification of triple-negative breast cancers, Oncologist, 2011;16(Suppl. 1):61–70.
  6. Matsuda H, Baggerly KA, Wang Y, et al., Comparison of molecular subtype distribution in triple-negative inflammatory and non-inflammatory breast cancers, Breast Cancer Res, 2013;15:R112.
  7. Schnitt SJ, Will molecular classification replace traditional breast pathology?, Int J Surg Pathol, 2010;18:162S–6S.
  8. Gazinska P, Grigoriadis A, Brown JP, et al., Comparison of basal-like triple-negative breast cancer defined by morphology, immunohistochemistry and transcriptional profiles, Mod Pathol, 2013;26:955–66.
  9. Tang P, Skinner KA, Hicks DG, Molecular classification of breast carcinomas by immunohistochemical analysis: are we ready? Diagn Mol Pathol, 2009;18:125–32.
  10. Arnedos M, Bihan C, Delaloge S, Andre F, Triple-negative breast cancer are we making headway at least?, Ther Adv Med Oncol, 2012;4:195–210.
  11. Turner N, Tutt A, Ashworth A, Hallmarks of ‘BRCAness’ in sporadic cancers, Nat Rev Cancer, 2004;4:814–9.
  12. Andre F, Job B, Dessen P, et al., Molecular characterization of breast cancer with high-resolution oligonucleotide comparative genomic hybridization array, Clin Cancer Res, 2009;15:441–51.
  13. Niemeier LA, Dabbs DJ, Beriwal S, et al., Androgen receptor in breast cancer: expression in estrogen receptor-positive tumors and in estrogen receptor-negative tumors with apocrine differentiation, Mod Pathol, 2010;23:205–12.
  14. Shastry M, Yardley DA, Updates in the treatment of basal/ triple-negative breast cancer, Curr Opin Obstet Gynecol, 2013;25:40–8.
  15. von Minckwitz G, Untch M, Blohmer JU, et al., Definition and impact of pathologic complete response on prognosis after neoadjuvant chemotherapy in various intrinsic breast cancer subtypes, J Clin Oncol, 2012;30:1796–804.
  16. Liedtke C, Mazouni C, Hess KR, et al., Response to neoadjuvant therapy and long-term survival in patients with triple-negative breast cancer. J Clin Oncol, 2008;26:1275–81.
  17. Ring AE, Smith IE, Ashley S, et al., Oestrogen receptor status, pathological complete response and prognosis in patients receiving neoadjuvant chemotherapy for early breast cancer, Br J Cancer, 2004;13;91:2012–7.
  18. Mamounas EP, Anderson SJ, Dignam JJ, et al., Predictors of locoregional recurrence after neoadjuvant chemotherapy: results from combined analysis of National Surgical Adjuvant Breast and Bowel Project B-18 and B-27, J Clin Oncol, 2012;30:3960–6.
  19. Rastogi P, Anderson SJ, Bear HD, et al., Preoperative chemotherapy: updates of National Surgical Adjuvant Breast and Bowel Project Protocols B-18 and B-27, J Clin Oncol, 2008;26:778–85.
  20. Darb-Esfahani S, Loibl S, Müller BM, et al., Identification of biology-based breast cancer types with distinct predictive and prognostic features: role of steroid hormone and HER2 receptor expression in patients treated with neoadjuvant anthracycline/taxane-based chemotherapy, Breast Cancer Res, 2009;11:R69.
  21. Silver DP, Richardson AL, Eklund AC, et al., Efficacy of neoadjuvant cisplatin in triple-negative breast cancer, J Clin Oncol, 2010;28:1145–53.
  22. Comen EA, Robson M, Poly(ADP-ribose) polymerase inhibitors in triple-negative breast cancer,. Cancer J, 2010;16:48–52.
  23. Frasci G, Comella P, Rinaldo M, et al., Preoperative weekly cisplatin-epirubicin-paclitaxel with G-CSF support in triple-negative large operable breast cancer, Ann Oncol, 2009;20:1185–92.
  24. Hurley J, Reis IM, Rodgers SE, et al., The use of neoadjuvant platinum-based chemotherapy in locally advanced breast cancer that is triple negative: retrospective analysis of 144 patients, Breast Cancer Res Treat, 2013;138:783–94.
  25. Amir E, Seruga B, Serrano R, Ocana A, Targeting DNA repair in breast cancer: a clinical and translational update, Cancer Treat Rev, 2010;36:557–65.
  26. Hamilton E, Kimmick G, Hopkins J, et al., Nabpaclitaxel/ bevacizumab/carboplatin chemotherapy in first-line triple negative metastatic breast cancer, Clin Breast Cancer, 2013;13:416–20.
  27. Gerber B, Loibl S, Eidtmann H, et al., German Breast Group Investigators. Neoadjuvant bevacizumab and anthracyclinetaxane- based chemotherapy in 678 triple-negative primary breast cancers; results from the GeparQuinto study (GBG 44), Ann Oncol, 2013;24:2978–84.
  28. Bear HD, Tang G, Rastogi P, et al., The effect on pCR of bevacizumab and/or antimetabolites added to standard neoadjuvant chemotherapy: NSABP protocol B-40, J Clin Oncol, 2011;29(Suppl.):LBA1005.
  29. Issa-Nummer Y, Darb-Esfahani S, Loibl S, et al., Prospective Validation of immunological infiltrate for prediction of response to neoadjuvant chemotherapy in HER2-negative breast cancer - a substudy of the neoadjuvant GeparQuinto trial, PLoS One, 2013;2;8:e79775.
  30. Von Minckwitz G, Schneeweiss Am Salat C, et al., A randomized Phase II trial investigating the addition of carboplatin to neoadjuvant therapy for triple-negative and HER2-positive early breast cancer (GeparSixto). Program and abstracts of the American Society of Clinical Oncology Annual Meeting; May 31-June 4, 2013; Chicago, Illinois. Abstract 1004.
  31. Sikov W, Berry DA, Perou CM, et al., Impact of the addition of carboplatin (Cb) and/or bevacizumab (B) to neoadjuvant weekly paclitaxel (P) followed by dose-dense AC on pathologic complete response (pCR) rates in triple-negative breast cancer (TNBC): CALGB 40603 (Alliance). San Antonio Breast Cancer Symposium 2013. Abstract S5-04.
  32. Colleoni M, Cole BF, Viale G, et al., Classical cyclophosphamide, methotrexate, and fluorouracil chemotherapy is more effective in triple-negative, nodenegative breast cancer: results from two randomized trials of adjuvant chemoendocrine therapy for node-negative breast cancer, J Clin Oncol, 2010;28:2966–73.
  33. Munzone E, Curigliano G, Burstein HJ, et al., CMF revisited in the 21st century, Ann Oncol, 2012;23:305–11.
  34. Jacquin JP, Jones S, Magné N, et al., Docetaxel-containing adjuvant chemotherapy in patients with early stage breast cancer. Consistency of effect independent of nodal and biomarker status: a meta-analysis of 14 randomized clinical trials, Breast Cancer Res Treat, 2012;134:903–13.
  35. Martín M, Seguí MA, Antón A, et al., GEICAM 9805 Investigators. Adjuvant docetaxel for high-risk, node-negative breast cancer, N Engl J Med, 2010;363:2200–10.
  36. Hugh J, Hanson J, Cheang MC, et al., Breast cancer subtypes and response to docetaxel in node-positive breast cancer: use of an immunohistochemical definition in the BCIRG 001 trial, J Clin Oncol, 2009;27:1168-76.
  37. National Comprehensive Cancer Network (NCCN), Clinical Practice Guidelines in Oncology: Breast Cancer v2. 2011. Available at: http://www.nccn.org/professionals/physician_ gls/breast.pdf
  38. Goldhirsch A, Winer EP, Coates AS, et al., Personalizing the treatment of women with early breast cancer: highlights of the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2013, Ann Oncol, 2013;9:2206–23.
  39. Aebi S, Davidson T, Gruber G, Cardoso F, ESMO Guidelines Working Group, Primary breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up, Ann Oncol, 2011;22(Suppl. 6):vi12–24.
  40. Cameron D, Brown J, Dent R, et al., Adjuvant bevacizumabcontaining therapy in triple-negative breast cancer (BEATRICE): primary results of a randomized, Phase III trial. Lancet Oncol, 2013;10:933–42.
  41. Hudis CA, Gianni L, Triple-negative breast cancer: an unmet medical need, Oncologist, 2011;16(Suppl. 1):1–11.
  42. Coughlin SS, Ekwueme DU, Breast cancer as a global health concern, Cancer Epidemiol, 2009;33:315–8.
  43. Ismail-Khan R, Bui MM, A review of triple-negative breast cancer, Cancer Control; 2010;17:173–6.
  44. Cardoso F, Bedard PL, Winer EP et al., International guidelines for managementof metastatic breast cancer: combination vs sequential single-agent chemotherapy, J Natl Cancer Inst, 2009;101:1174–81.
  45. Beslija S, Bonneterre J, Burstein HJ, et al., Third consensus on medical treatment of metastatic breast cancer, Ann Oncol, 2009;20:1771–85.
  46. Sparano JA, Makhson AN, Semiglazov VF, et al., Pegylated liposomal doxorubicin plus docetaxel significantly improves time to progression without additive cardiotoxicity compared with docetaxel monotherapy in patients with advanced breast cancer previously treated with neoadjuvant-adjuvant anthracycline therapy: results from a randomized Phase III study, J Clin Oncol, 2009;27:4522–9.
  47. Chacon RD, Costanzo MV, Triple-negative breast cancer, Breast Cancer Res, 2010;12(Suppl. 2):S3.
  48. Foulkes WD, Smith I, Reis-Filho J, Triple-negative breast cancer, N Engl J Med, 2010;363:1938–48.
  49. Koshy N, Quispe D, Shi R et al., Cisplatin-gemcitabine therapy in metastatic breast cancer: improved outcome in triple negative breast cancer patients compared to non-triple negative patients, Breast, 2010;19:246–8.
  50. Isakoff SJ, Goss PE, Mayer EL, et al., TBCRC009: A multicenter Phase II study of cisplatin or carboplatin for metastatic triple-negative breast cancer and evaluation of p63/p73 as a biomarker of response, JCO 29, 2011. Abstract 1025.
  51. Isakoff SJ, Triple-negative breast cancer: role of specific chemotherapy agents, Cancer J, 2010;16:53–61.
  52. Thomas ES, Gomez HL, Li RK, et al., Ixabepilone plus capecitabine for metastatic breast cancer progressing after anthracycline and taxane treatment, J Clin Oncol, 2007;25:5210–7.
  53. Perez EA, Patel T, Moreno-Aspitia A, Efficacy of ixabepilone in ER/PR/HER2-negative (triple-negative) breast cancer, Breast Cancer Res Treat, 2010;121:261–71.
  54. Cortes J, O’Shaughnessy J, Loesch D, et al., Eribulin monotherapy versus treatment of physician’s choice in patients with metastatic breast cancer (EMBRACE): a Phase III open-label randomized study, Lancet, 2011;377:914–23.
  55. Miller K, Wang M, Gralow J, et al., Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer, N Engl J Med, 2007;357:2666–76.
  56. Miles DW, Diéras V, Cortés J, et al., First-line bevacizumab in combination with chemotherapy for HER2-negative metastatic breast cancer: pooled and subgroup analyses of data from 2447 patients, Ann Oncol, 2013;24:2773–80.
  57. Thomssen C, Pierga JY, Pritchard KI, et al., First-line bevacizumab-containing therapy for triple-negative breast cancer: analysis of 585 patients treated in the ATHENA study, Oncology, 2012;82:218–27.
  58. Robert NJ, Diéras V, Glaspy J, et al., RIBBON-1: randomized, double-blind, placebo-controlled, Phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor 2-negative, locally recurrent or metastatic breast cancer, J Clin Oncol, 2011;29:1252–60.
  59. Brufsky AM, Hurvitz S, Perez E, et al., RIBBON-2: a randomized, double-blind, placebo-controlled, Phase III trial evaluating the efficacy and safety of bevacizumab in combination with chemotherapy for second-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer, J Clin Oncol, 2011;29:4286–93.
  60. Carpenter D, Kesselheim AS, Joffe S, Reputation and precedent in the bevacizumab decision, N Engl J Med, 2011;365:e3.
  61. Burstein HJ, Elias AD, Rugo HS, et al., Phase II study of sunitinib malate, an oral multitargeted tyrosine kinase inhibitor, in patients with metastatic breast cancer previously treated with an anthracycline and a taxane, J Clin Oncol, 2008;26:1810–16.
  62. Baselga J, Segalla JG, Roché H, et al., Sorafenib in combination with capecitabine: an oral regimen for patients with HER2- negative locally advanced or metastatic breast cancer, J Clin Oncol, 2012;30:1484-91.
  63. Curigliano G, Pivot X, Cortés J, et al., Randomized Phase II study of sunitinib versus standard of care for patients with previously treated advanced triple-negative breast cancer, Breast, 2013;22:650–6.
  64. Crown JP, Diéras V, Staroslawska E, et al., Phase III trial of sunitinib in combination with capecitabine versus capecitabine monotherapy for the treatment of patients with pretreated metastatic breast cancer. J Clin Oncol. 2013;31:2870-8.
  65. Baselga J, Costa F, Gomez H, et al., A Phase III tRial comparing capecitabinE in combination with SorafenIb or pLacebo for treatment of locally advanced or metastatIc HER2-Negative breast CancEr (the RESILIENCE study): study protocol for a randomized controlled trial. Trials. 2013;14:228.
  66. O’Shaughnessy J, Osborne C, Pippen JE, et al., Iniparib plus chemotherapy in metastatic triple-negative breast cancer, N Engl J Med, 2011;364:205–14.
  67. O’Shaughnessy J, Schwartzberg LS, Danso MA, et al., A randomized Phase III study of iniparib (BSI-201) in combination with gemcitabine/carboplatin (G/C) in metastatic triplenegative breast cancer (TNBC), J Clin Oncol, 2011;29:(Abstr. 1007, presented data—ASCO Annual Meeting 2011).
  68. Corkery B, Crown J, Clynes M, et al., Epidermal growth factor receptor as a potential therapeutic target in triple-negative breast cancer, Ann Oncol, 2009;20:862–7.
  69. Baselga J, Gómez P, Greil R, 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, 2013;31:2586–92.
  70. Carey LA, Rugo HS, Marcom PK, et al., TBCRC 001: randomized Phase II study of cetuximab in combination with carboplatin in stage IV triple-negative breast cancer, J Clin Oncol, 2012;30:2615–23.
  71. Ellard SL, Clemons M, Gelmon KA, et al., Randomized Phase II study comparing two schedules of everolimus in patients with recurrent/metastatic breast cancer: NCIC Clinical Trials Group IND.163, J Clin Oncol, 2009;27:4536–41.
  72. Sharma P, Khan QJ, Kimler BF, et al., Results of a Phase II study of neoadjuvant platinum/taxane based chemotherapy and erlotinib for triple negative breast cancer. Cancer Res 2010;70 (Abstr. P1-11-07, presented data—SABCS 2010).
  73. Gucalp A, Tolaney S, Isakoff SJ, et al., Phase II trial of bicalutamide in patients with androgen receptor-positive, estrogen receptor-negative metastatic Breast Cancer. Translational Breast Cancer Research Consortium (TBCRC 011), Clin Cancer Res, 2013;19:5505–12.
Keywords: Breast cancer, triple negative, pathological diagnosis, chemotherapy treatment, neoadjuvant, targeted treatment, adjuvant, metastatic