Basal-like and Triple-negative Breast Cancers

A Critical Review With an Emphasis on The Implications for Pathologists and Oncologists

Sunil Badve; David J Dabbs; Stuart J Schnitt; Frederick L Baehner; Thomas Decker; Vincenzo Eusebi; Stephen B Fox; Shu Ichihara; Jocelyne Jacquemier; Sunil R Lakhani; José Palacios; Emad A Rakha; Andrea L Richardson; Fernando C Schmitt; Puay-Hoon Tan; Gary M Tse; Britta Weigelt; Ian O Ellis; Jorge S Reis-Filho

Disclosures

Mod Pathol. 2011;24(2):157-167. 

In This Article

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]

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