Basal-Like and Triple-Negative Breast Cancers

Clinical behavior of Basal-like and Triple-negative Breast Cancers

Basal-like and triple-negative breast cancers, as defined by microarrays or by immunohistochemical surrogates, have been shown to have a more aggressive clinical behavior.^[17,114,115] In fact, some studies have demonstrated that expression of basal keratins is a prognostic factor independent of tumor size, grade, and lymph node status.^[114] However, when compared with either ER− non-basal-like cancers^[72] or grade-matched non-basal-like cancers,^[42] carcinomas with a basal-like phenotype are not associated with a poorer outcome in some studies, whereas a more adverse prognosis is observed in others.^[19,116] The pattern of metastatic spread of tumors with a basal-like phenotype seems to be different from that of non-basal-like cancers: they are reported to less frequently disseminate to axillary nodes and bones^[42,117] and to favor a hematogenous spread,^{[42,117–119]} with a peculiar proclivity to develop metastatic deposits in the brain and lungs.^[120] It should be noted that patients with triple-negative and basal-like cancers tend to develop adverse events and die due to disease within the first 5–8 years after diagnosis. After the 8-year mark, the hazard rate for patients with grade 2 or ER-positive cancers is actually higher than that of patients with basal-like cancers. Finally, some tumors in the 'basal' group have a favorable prognosis, eg, adenoid cystic carcinomas^[40,121] and secretory carcinomas.^[39] This emphasizes that basal phenotype and bad behavior are not inextricably linked and serves to highlight the heterogeneous nature of basal-like carcinomas. It is controversial as to whether these tumors should be classified as the basal-like carcinomas or should represent a distinct group by themselves.

As to treatment response, 17–58% of patients with triple-negative breast cancers have been shown to have a pathological complete response after anthracycline- or anthracycline+taxane-based neoadjuvant chemotherapy^{[25,28,122,123]} and 17% of triple-negative cancers have been shown to have a pathological complete response after neoadjuvant platinum-based chemotherapy.^[124] However, those who fail to achieve pathological complete response have a dismal outcome.^[25,28] It should be noted, however, that markers for the identification of patients with triple-negative and basal-like cancers that benefit most from chemotherapy remain to be defined. Recently, several groups have identified a subgroup of good prognosis ER− cancers, encompassing a subgroup of triple-negative and basal-like tumors, which is characterized by the expression of an immune response module.^[125–128] This transcriptomic profile may prove helpful for the identification of patients with triple-negative and basal-like cancers that have a better outcome. In this context, the finding of higher expression of CT-X antigens (in particular MAGE and NY-ESO) in this subgroup opens up another potential avenue for therapy as vaccines against these antigens are already in clinical trial for lung cancer.^[129]

Finally, as mentioned earlier, a group of basal-like and triple-negative breast carcinomas have been shown to have a dysfunctional BRCA1 pathway.^{[32,65,81–83]} A significant number of these cases lack competent homologous recombination DNA repair. This subgroup may be amenable to specific therapeutic strategies such as inhibitors of the PARP enzyme.^{[32,81,83,130,131]} Consistent with this hypothesis, results of PARP inhibitor phase I and phase II clinical trials that have included patients with BRCA-deficient tumors have been encouraging^[132–134] and sustained responses in patients with BRCA1/2-deficient breast or ovarian metastatic cancers have been observed. Furthermore, preliminary results of a phase II clinical trial revealed that addition of BSI-201, a PARP inhibitor, to gemcitabine/carboplatin chemotherapy led to a significantly increased clinical benefit and longer progression-free survival.^[135] However, the specificity of this compound for PARP has yet to be fully established.

Given these exciting results, several clinical trials testing cross-linking agents (eg carboplatin and cisplatin) and PARP inhibitors in patients with BRCA1 germ-line mutations and sporadic basal-like breast cancers are currently ongoing (for a list of clinical trials, please see clinicaltrials.gov). If positive, these studies may render the identification of tumors lacking competent homologous recombination compulsory in our diagnostic practice.^[130]

Authors and Disclosures

Sunil Badve¹, David J Dabbs², Stuart J Schnitt³, Frederick L Baehner⁴, Thomas Decker⁵, Vincenzo Eusebi⁶, Stephen B Fox⁷, Shu Ichihara⁸, Jocelyne Jacquemier⁹, Sunil R Lakhani¹⁰, José Palacios¹¹, Emad A Rakha¹², Andrea L Richardson¹³, Fernando C Schmitt¹⁴, Puay-Hoon Tan¹⁵, Gary M Tse¹⁶, Britta Weigelt¹⁷, Ian O Ellis¹² and Jorge S Reis-Filho¹⁸

¹Clarian Pathology Lab, Department of Pathology and Internal Medicine, Indiana University, Indianapolis, IN, USA; ²Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA; ³Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA; ⁴Department of Anatomic Pathology, University of California, San Francisco, CA, USA; ⁵Breast-Screening-Pathology, Gerhard Domagk-Institute of Pathology, Reference Centre Münster, University Hospital Münster, Münster, Germany; ⁶Sezione Anatomia Istologia e Citologia Patologica 'M Malpighi', Università-ASL Ospedale Bellaria, Bologna, Italy; ⁷Pathology Department, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia; ⁸Department of Pathology, Nagoya Medical Center, Nagoya, Japan; ⁹Unité d'Anatomie et de Cytologie Pathologiques, Institut Paoli-Calmettes, Marseille, France; ¹⁰Molecular and Cellular Pathology, University of Queensland Centre for Clinical Research, School of Medicine and Pathology Queensland and The Royal Brisbane and Women's Hospital, Brisbane, Australia; ¹¹Servicio de Anatomía Patológica, Hospital Universitario Virgen del Rocío, Sevilla, Spain; ¹²Department of Histopathology, Nottingham City Hospital NHS Trust, Nottingham University, Nottingham, UK; ¹³Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA; ¹⁴Medical Faculty, Institute of Molecular Pathology and Immunology (IPATIMUP), University of Porto, Porto, Portugal; ¹⁵Department of Pathology, Singapore General Hospital, Singapore, Singapore; ¹⁶Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China; ¹⁷Signal Transduction Laboratory, Cancer Research UK London Research Institute, London, UK; ¹⁸The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, UK

Correspondence
Professor S Badve, MD, FRCPath, Department of Pathology and Internal Medicine, Indiana University, 350 W 11th Street, Indianapolis, IN 4010, USA; Professor Jorge S Reis-Filho, MD, PhD, FRCPath, The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK. E-mail: sbadve@iupui.edu or jorge.reis-filho@icr.ac.uk

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