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Journal of Clinical Oncology, Vol 26, No 15 (May 20), 2008: pp. 2568-2581 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.13.1748
Basal-Like Breast Cancer: A Critical Review
From the Department of Histopathology, Nottingham City Hospital National Health Service (NHS) Trust; Nottingham University, Nottingham; and the Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, United Kingdom Corresponding author: Ian O. Ellis, FRCPath, Molecular Medical Sciences, University of Nottingham, Department of Histopathology, Nottingham City Hospital NHS Trust, Hucknall Road, Nottingham, NG5 1PB, UK; e-mail: ian.ellis{at}nottingham.ac.uk
Recent gene expression profiling of breast cancer has identified specific subtypes with clinical, biologic, and therapeutic implications. The basal-like group of tumors is characterized by an expression signature similar to that of the basal/myoepithelial cells of the breast and is reported to have transcriptomic characteristics similar to those of tumors arising in BRCA1 germline mutation carriers. They are associated with aggressive behavior and poor prognosis, and typically do not express hormone receptors or HER-2 ("triple-negative" phenotype). Therefore, patients with basal-like cancers are unlikely to benefit from currently available targeted systemic therapy. Although basal-like tumors are characterized by distinctive morphologic, genetic, immunophenotypic, and clinical features, neither an accepted consensus on routine clinical identification and definition of this aggressive subtype of breast cancer nor a way of systematically classifying this complex group of tumors has been described. Different definitions are, therefore, likely to produce variable and contradictory results that may hamper consistent identification and development of treatment strategies for these tumors. In this review, we discuss definition, heterogeneity, morphologic spectrum, relation to BRCA1, and clinical significance of this important class of breast cancer.
Current clinical management of breast cancer still relies on the traditional prognostic and predictive factors including histologic, clinical, and some well-defined biologic factors (ie, hormone receptors and human epidermal growth factor receptor 2 [HER-2] expression). Despite the overall association of these variables with prognosis and outcome,1 they are limited in their ability to capture the nuances of the complex cascade of events that drive the clinical behavior of breast cancer. Tumors of apparently homogenous morphologic characters still vary in response to therapy and have distinct outcomes.2 The introduction of high-throughput technologies that survey hundreds to thousands of genes and their products in a single assay, coupled with powerful analytic tools, opened new avenues for classifying breast cancer into biologically and clinically distinct groups based on gene expression patterns3-9 and DNA copy number alterations.8,10
In their seminal study, Perou et al3 used an intrinsic gene list obtained with cDNA expression microarrays to classify breast cancers according to similarities in gene expression characteristics. These authors examined a series of 65 paired and nonpaired breast specimens that included 36 invasive ductal carcinomas and two lobular carcinomas. Although the samples analyzed in that study were remarkably heterogeneous in terms of clinicopathologic features and systemic therapy, the prognostic associations originally identified in that study have been corroborated by other groups.11 On the basis of unsupervised methods, breast cancer could be classified into at least five distinct molecular subtypes. Multiple independent studies have confirmed and expanded the original results.3-5,12 Subsequent supervised and unsupervised clustering analyses have shown that breast cancer can be divided into two broad groups: estrogen-receptor (ER)-positive and ER-negative groups, which can be further subdivided into additional distinct biologically and clinically significant subgroups. The ER-positive tumors express ER, ER-responsive genes, and other genes that encode characteristic proteins of luminal epithelial cells and therefore, are termed "luminal group". Although subclassification of luminal tumors is still contentious, there seem to be at least two groups of ER-positive breast cancers, commonly defined as luminal A and B tumors depending on the level of expression of the characteristic genes and expression of other genes either pertaining to the proliferation cluster and/or HER-2.5,13,14 The second broad group (ER-negative tumors) was subdivided into three groups: HER-2–positive, basal-like tumors and so-called normal breast–like tumors. HER-2–positive tumors express high levels of genes located in the HER2 amplicon on 17q21, including HER-2 and growth factor receptor-bound protein 7 (GRB7), a high level of nuclear factor (NF)-  B activation, and the transcription factor GATA4, and lack expression of ER and GATA3.15,16 Basal-like tumors lack ER and HER-2 and express genes characteristic of basal epithelial cells. The normal breast–like group resembles normal breast tissue samples with relatively high expression of many genes characteristic of adipose cells and other nonepithelial cell types, and low level of expression of luminal epithelial cell genes. Importantly, these breast cancer subtypes are associated with markedly different clinical outcomes, ranging from the best-prognosis luminal A tumors to the worst-prognosis HER-2 and basal-like tumors.3-5,11,17 In addition, this molecular classification has also captured the attention of oncologists and scientists alike because the molecular subtypes are potentially predictive of patterns of response to specific therapeutic agents. For instance, luminal A tumors are expected to be sensitive to endocrine therapy, HER-2–overexpressing tumors can be targeted with monoclonal antibodies against HER-2 or HER-2 tyrosine kinase inhibitors, and basal-like cancers may respond to specific therapeutic regimens (discussed later herein) and inhibitors of the poly(ADP-ribose) polymerase (PARP) enzyme.
Given the importance of basal and luminal concepts in the genomic signatures identified in the recent molecular classification and the heated debate about the origin of breast cancer stem cells and the relationship between features of different breast cancer classes and type and features of the cells they might be derived from,3,18,19 we will first review the features of the normal parenchymal cells of the mammary gland. In normal human breast, ducts and lobules are lined by two cell layers, an inner/luminal cell population and a distinct outer cell layer, juxtaposed to the basement membrane.20,21 These cells can be distinguished by their immunophenotype, and several markers have been used to define them. It is generally accepted that the luminal epithelial cells are characterized by expression of low molecular weight so-called luminal cytokeratins (CKs) including CK7, CK8, CK18, and CK19, in addition to other markers such as MUC1 alpha-6 integrin, BCL2, ER, progesterone receptor (PgR), GATA3, and epithelial cell adhesion molecules. The outer cell layer is formed of morphologically and immunophenotypically heterogeneous cells depending on their location and on the hormonal status of the tissue. These cells exhibit features of both epithelial and smooth muscle (SM) cells, and they therefore are called myoepithelial (ME) cells. ME cells usually express high molecular weight basal CKs such as CK5, CK14 and CK17, in addition to other markers including SM-specific markers (smooth muscle actin [SMA] and SM myosin heavy chain), calponin, caldesmon, p63, β4 integrin, laminin, maspin, CD10, P-cadherin, caveolin1, nerve growth factor receptor (NGFR), 14-3-3  , and S-100.22-30 ME cells are typically negative for luminal CKs, epithelial membrane antigen (EMA), desmin, ER, and PgR.31-41 ME cells are also called basal cells, which is a term used to refer to a cell population that is adjacent to the basement membrane, "in a basal position" from the ducts to the acini, and expresses basal CKs.39,42 However, in addition to ME cells, basal CKs are also expressed in a variable subpopulation of luminal cells in both large ducts and the terminal duct lobular unit complex, although there is considerable variation in their expression pattern.21,42-44 Therefore, in the normal breast, the term basal has confusingly acquired two meanings: (i) it has become a synonym for ME cells and (ii) it defines a specific subpopulation of basal CK-expressing cells that may be found in either a luminal or basal location. Basal-like tumors express genes characteristic of basal/ME cells. In addition to structural roles, many of the basal-like gene products have been implicated in cellular proliferation, suppression of apoptosis, cell migration and/or invasion, all hallmarks of cancer.45,46 They underexpress ER, ER-responsive genes, and other genes characteristic of luminal epithelial cells of the normal mammary gland, as well as genes located in the HER2 amplicon on 17q21.47 Collectively, the gene-expression profile of basal-like tumors provides myriad candidate genes that might contribute to their aggressive phenotype and, arguably, may suggest a less differentiated "stem/progenitor" cell phenotype or a stem cell origin for these tumors. Table 1 summarizes the genes and functional groups characteristically overexpressed or downregulated in basal-like breast cancers.
Basal-like tumors have been characterized using microarray-based comparative genomic hybridization (array-CGH) in a number of studies.7,8,48 Basal-like cancers are reported to have a greater genetic complexity compared with other breast cancer subtypes, suggesting a greater degree of genetic instability. Bergamaschi et al7 and Chin et al11 have applied array-CGH to invasive breast cancers that were previously characterized by expression arrays. They found that basal-like tumors show the highest frequency of DNA losses and gains compared with other subtypes. However, it is unclear whether this is not related to the fact that basal-like breast cancers are predominantly of high histologic grade, whereas the other groups are composed of a mixture of tumors of different grades. These two groups have also reported that despite the highest prevalence of genomic aberrations, basal-like cancers more frequently show low-level gains and deletions and less frequently show high-level gains/amplifications7,8 than do tumors pertaining to the other molecular subgroups. This pattern of genomic changes may be suggestive of a defect in double-strand DNA break repair mechanisms.49 A recent study has also demonstrated that basal-like cancers frequently harbor a dysfunctional BRCA1 pathway. Interestingly, some of the few recurrent amplifications described to date in basal-like cancers include 7p11.2, involving the EGFR gene,50 7q31, affecting caveolin 151 and 12p13.52 In a previous study, basal-like tumors, as defined by CK14 positivity, showed a lower prevalence of genomic changes compared with grade-matched tumors. Interestingly, basal-like cancers showed a rather distinctive CGH profile, with higher rates of loss at chromosomes 16p, 17q, 19q, and Xp and lower rates of both loss at chromosomes 4q, 9q, and 13q and gains at 17q and 20p.53,54 In addition, genome-wide single nucleotide polymorphism arrays have shown the highest overall rate of loss of heterozygosity (LOH) in the basal-like subset of breast cancers that have been identified on the basis of mRNA expression array data. The fraction of LOH was two to three times higher than that of other subtypes of breast cancer.55 Several other characteristic cytogenetic changes have been reported.7,53,54,56 For example, the locus at 5q11, which has many checkpoint DNA-repair and tumor suppressor genes (including MSH3, RAD17, APC, RAD50, and XRCC4), was lost in 100% of the basal-like cancers,7,55,57 but never in luminal or other subtypes. Basal-like tumors also show the lowest rate of LOH at 16q23-24 and 1p32-ter compared with other classes of breast cancer.55
To date, there is no internationally accepted definition for basal-like cancers. Although the majority of basal-like tumors have common morphologic features,58,59 there are no specific hallmark morphologic features that can identify those tumors reliably in routine practice. Gene expression microarrays cannot be readily applied to clinically available formalin-fixed, paraffin-embedded tissues, remain relatively expensive, and are not established as a robust technology that can be used in routine patient management. Given that the majority of basal-like breast carcinomas lack ER, PR, and HER-2 expression, several groups have adopted a triple-negative (ER–/PR–/HER-2–) definition for basal-like cancers. Although this approach is certainly convenient, given that this information is present in most pathology reports, it should be emphasized that the overlap between triple-negative and basal-like breast cancers, as defined by expression array analysis, is not complete.60,61 It should be noted that although most basal-like cancers do not express ER or HER-2, 15% to 45% are reported to express at least one of these markers4,13,60,62; on the other hand, not all triple-negative cancers are of basal-like profile.4,60,63,64 One study demonstrated that ER and HER-2 were expressed in 14% of basal-like cancers64; on the other hand, only approximately 85% of ER–/HER-2–cancers are of basal-like phenotype by expression arrays.60 Furthermore, in RNA expression analysis experiments, triple-negative tumors included not only basal-like cancers but also the so-called normal breast–like class of breast cancer.3,4,13,14,65 Although the latter group is still poorly characterized, they are reported to have a prognosis which seems to be better than that of basal-like cancers,4,62 and do not seem to respond to neoadjuvant chemotherapy.64,65 In fact, in one study, 45% of patients with basal-like cancer showed pathologic complete response after receiving an anthracycline plus taxane-based neoadjuvant chemotherapy, whereas none of the normal breast–like cancers did so.64 Furthermore, ER expression, as defined by immunohistochemistry (IHC) analysis, has a documented technical false-negative rate,66 and any definition based on all negative results should be generally avoided.60,67 Therefore, it is important to notice that some clinical trials based on triple-negative definition (Table 2) are now underway. Such definitions may arguably lead to inaccurate conclusions as a result of the noise in subtype definition introduced by relying on a triple-negative criterion.
On the basis of the foregoing, the only realistic, potentially objective, and convenient method to identify these basal-like carcinomas in clinical specimens would be through the positive detection of certain markers. In a more pragmatic approach, several IHC surrogates have been proposed for the routine identification of basal-like breast tumors. Nielsen et al60 identified an IHC surrogate based on four markers (ER, HER-2, epidermal growth factor receptor [EGFR], and CK5/6). They classified all HER-2–positive tumors in the HER-2 subtype. Of the remaining cases, ER-positive tumors were considered luminal, whereas ER-negative tumors were classified as either basal-like (ER and HER-2 negative, CK5/6 and/or EGFR positive) or undetermined (negative for all four markers; 22%). In their study, this panel showed a sensitivity of 76% and a specificity of 100% to identify breast carcinomas with a basal-like phenotype as defined by expression profiling analysis. These criteria for definition of basal-like tumors were adopted by many other authors.68-73 In a similar study, Livasy et al58 investigated 23 basal-like tumors identified by cDNA microarrays. They reported that the most consistent immunophenotyping of basal-like tumors was negativity for ER and HER-2, and positivity for vimentin, EGFR, CK8/18, and CK5/6. In addition, other criteria have been used in the definition of basal-like tumors such as "ER, P[g]R, HER-2–negative [triple-negative], and CK5/6 and/or EGFR-positive,"69 "ER-negative, HER-2–negative/positive and [CK5 and/or P-cadherin and/or p63]-positive,"74 and triple-negative.61 Table 3 summarizes the different definitions of basal-like cancer, their percentages, and control groups used in different studies with subsequent association with patients’ outcome. Other markers that have been included in the panel of basal biomarkers include vimentin and laminin,58,68 c-KIT,75 p63,76 nestin,77 osteonectin,78 caveolin 1,51 and NGFR.79
Because basal CKs expression is one of the main characteristic features of basal-like tumors, most but not all IHC studies53,63,76,80-82 have used them to defined basal-like tumors (Table 3).21,83,84 In a previous study of a large series of unselected breast cancers, using different IHC markers,67 we demonstrated that basal CKs are independently associated with poor outcome.4,60,63,84-87 Additional markers used to define basal-like tumors, although associated with basal CK expression, so far have not helped improve the identification of cases with differing outcome compared with those identified using basal CKs alone. These additional markers, if used to define cases of basal-like cancer, would reduce considerably the proportion of cases allocated to this poor-prognosis type of breast cancer. Therefore, a suitable, pragmatic solution would be to use basal CKs expression to define basal-like tumors regardless of the expression of other markers. However, some authors may argue that although both basal CK-positive tumors and basal-like breast cancers share several clinicopathologic and immunohistochemical features, they are not strictly the same entity,88 and basal CKs are not expressed in all tumors classified basal-like by gene microarray analysis.4 Although the prognostic significance is the one of the aims of identifying new classes of cancer, basal-like tumors identified by gene expression arrays also share a distinct molecular profile, which may have therapeutic implications, in addition to their prognostic significance. For example, some of the identified basal markers may have potential therapeutic implications, such as c-kit, EGFR,50 caveolin 1,51,89 and  B crystallin. Another point to be considered here is the considerable degree of variability among different studies in using these basal CKs to identify basal-like tumors (Table 3). Either CK5 (or CK5/6),74,80,90 CK14,53,54,59 combined CK5/6 and C14,75,76,91-93 CK5/6 and 17,3,63,87,94,95 CK14 and CK17,96 or a combination of all the three basal CKs19,78,81,93 have been used to identify basal-like tumors. Their staining patterns are highly variable and heterogeneous.82,87,93 Consequently, this variability has created some degree of discordance and contradictory results. For example, some studies, which used CK14 alone to define basal-like tumors, did not find an association with survival.53,82 Our explanation for these contradictory results is, in addition to difference in the cohort of patients and composition of the control groups, related to the use of a single basal CK to define basal-like tumors. This can be explained by the so-called Will Rogers phenomenon, which is the apparent paradox obtained when moving an element from one set to another set changes the average values of both sets.97 This is supported by our findings98 in which we demonstrated that two basal markers did not identify exactly the same tumors when used alone, and that the associations with overall survival were different between tumors defined by CK14, CK5/6, or both CK14 and/or CK5/6 expression. Consistent with our observation, similar finding with CK5/6 and 1476,99 and CK5 and CK1787 have been reported. Moreover, although it is known that CK5 and CK14 are found in pairs in normal tissues, coexpression of both in tumor tissues is observed in less than 30% of cases. These findings indicate that one basal CK may not be sufficient to identify all basal-like tumors or may not identify the group with a more aggressive clinical behavior. Therefore, achieving an optimal definition of basal-like cancers is not simple and should not be regarded as a trivial task. We would recommend that studies analyzing triple-negative tumors should be labeled as such, whereas the definition used for basal-like phenotype should be clearly stated in those dealing with basal-like breast cancers.
By defining basal-like cancers either in terms of mRNA expression profile or expression of basal IHC markers, studies are consistent in their morphologic description of this class of breast cancer. The basal-like group comprises 8% to 20% of all breast cancers.3,4,53,54,63,75,82,87,98,100 The majority of these tumors are ductal of no special type, but occasionally are tubular mixed,98 metaplastic,92 or medullary cancers101 (Fig 1). They have common features including younger patient age, high histologic tumor grade, marked cellular pleomorphism, high nuclear-cytoplasmic ratio, lack of tubule formation, high mitotic index, frequent apoptotic cells, scant stromal content, a pushing border of invasion, central geographic or comedo-type necrosis. They are also characterized by the presence of metaplastic elements such as spindle cells and squamous cell metaplasia, presence of a central scar, glomeruloid microvascular proliferation, and a stromal lymphocytic response.13,54,59,80,81,98,102-104 In addition, some reports have suggested that basal-like tumors may achieve extraordinarily rapid clinical growth rates.105 The high proliferative activity of basal-like tumors may probably explain why these tumors are overrepresented among the so-called interval breast cancers (eg, cancers arising between annual mammograms).106
Although these features are strongly associated with basal-like cancer and can help in the identification of these tumors for example, almost all metaplastic and medullary carcinomas are basal-like,92,98,101 they are generally not specific, and individual features can be seen in other high-grade tumors regardless of their immunophenotype, thus emphasizing the importance of IHC detection of specific (basal) markers as a realistic and simple method to identify these tumors in routine practice.
Despite differences in the definition and prevalence of basal-like tumors in various studies, the poor outcome of patients with basal-like tumors has been remarkably reproducible across many different patient populations (Table 3).4,5,11,63,69,80,81,91 Basal-like cancer is associated with an aggressive clinical history, development of locoregional and distant metastasis (particularly in the first 5 years82), shorter survival, and a relatively high mortality rate.5,69,80,81,87,98 Previous studies have demonstrated that basal-like phenotype is an independent marker of poor prognosis in breast cancers as a whole,1,9-11 in the lymph node (LN)-negative,63,87 and LN-positive groups.60,83 Basal-like phenotype was found to predict a particularly aggressive course for patients with grade 3, lymph node-negative tumors91 and in patients with metastatic disease.82 In addition, basal-like tumors show a specific pattern of distant metastasis with an increased propensity for visceral metastases to brain and lung—sites know to be associated with a poorer prognosis82,107,108 and less likely metastasize to bone and liver.81,82,102,109,110 These findings suggest that basal-like tumors might also possess a distinct mechanism of metastatic spread. However, it should be also noted that some reported lack of association between basal-like cancer and poor outcome (Table 3).82 Others have also reported a negative association with outcome during the early few years of follow-up, which loses its significance after a long-term period (10 years).88,103 Furthermore, it has been reported that basal-like tumors either defined by the triple-negative phenotype111,112 or by basal CK expression98 are not associated with increased risk for locoregional relapse after conservative surgery. In fact, these findings together with the frequently pushing well-defined border of invasion in these tumors and absence of association with vascular invasion or lymph node involvement13,58,80,82,91,95 do not appear to justify a more radical approach to local or axillary surgery. The potentially aggressive behavior of these tumors may be better approached by use of systemic therapy (described further later herein).
There are several lines of evidence to suggest a link between basal-like breast cancer and BRCA1 deficiency.49 Many phenotypical, immunohistochemical, and clinical characteristics and molecular features are shared by basal-like breast cancers and tumors that arise in carriers of BRCA1 germline mutations. The majority of BRCA1-associated tumors are triple-negative and express basal CKs (in addition to other markers commonly seen in basal-like tumors such as p53, P-cadherin, and EGFR5,76,80,113-117), and, in most studies, both patient groups have a poor outcome.80,118 In keeping with these similarities, clustering analyses of microarray expression profiling data have shown that familial BRCA1 mutant tumors tend to fall into the basal-like category, suggesting similar carcinogenic pathways or causes of these two subtypes.5 As with basal-like tumors, cytogenetic abnormalities are common in BRCA1 mutation-related breast cancers119,120 and a set of characteristic cytogenetic changes in BRCA1-associated breast cancers119,121 has been described in sporadic basal-like cancers.7,54,56 Both sporadic basal-like and BRCA1 breast tumors have frequent loss of X-chromosome inactivation.122,123 Some studies have indicated that BRCA1 mRNA expression was lower in basal-like sporadic cancers than in controls matched for age and grade124 and in approximately 30% of sporadic breast tumors.125 BRCA1 is rarely mutated in sporadic breast cancers126 and, therefore, it is believed that this may be a result of epigenetic mechanisms such as acquired methylation of the BRCA1 gene promoter127,128 or a dysfunction in the upstream pathways that regulate BRCA1 expression, such as overexpression of ID4.124 These sporadic tumors with reduced BRCA1 expression tend to exhibit triple-negative phenotypes remarkably similar to BRCA1-mutated and basal-like tumors.49,117,124,129 In addition, the profound similarities between hereditary BRCA1-related breast tumors and basal-like tumors strongly implicate a fundamental defect in the BRCA1 or associated DNA-repair pathways in sporadic basal-like tumors.117 Although it is not clear whether in humans BRCA1 inactivation is the cause or a consequence of a basal-like phenotype, two hypotheses have been advanced for the similarities between basal-like cancers and tumors arising in BRCA1 mutation carriers: (i) the precursors of basal-like cancers (likely to be basal-like ductal carcinoma in situ19,130,131) and invasive basal-like breast carcinomas may be more tolerant to loss of BRCA1 function than those of other breast cancer subtypes, possibly because of the phenotype of the cell of the initiating event or the concurrent inactivation of other tumor suppressor genes, such as TP53; and alternatively, (ii) BRCA1 may be involved in the differentiation of breast epithelial cells and, therefore, BRCA1 inactivation would lead to tumors with a stem cell–like phenotype.132,133 Furthermore, given the reported action of BRCA1 in regulating the ER pathway,134 BRCA1 dysfunction may actively lead to the development of tumors with a basal-like phenotype.135 Although the aforementioned hypotheses are attractive, there is no definite answer at this moment. However, this is a field that is rapidly evolving, and evidence-based answers may emerge in the near future. Basal-like cancers and tumors arising in BRCA1 germline mutation carriers are remarkably similar at the morphologic, immunohistochemical, transcriptome, and gene copy levels. In fact, there are increasingly more coherent data to suggest that BRCA1 pathway dysfunction may play an important role in the development of not only familial but also sporadic basal-like tumors.49,135 Although BRCA1 somatic gene mutations are unlikely to be commonly found in sporadic basal-like cancers, these tumors have been shown to have a dysfunctional BRCA1 pathway because of BRCA1 gene promoter methylation and/or BRCA1 pathway transcriptional inactivation.49,124 To emphasize the relationship between basal-like tumors and BRCA1, some authors have demonstrated that the use of basal CK staining in combination with ER and morphology provides a more accurate predictor of BRCA1 mutation status than previously available and may be useful in selecting patients for BRCA1 mutation testing.49,78,124 Interestingly, although several studies have demonstrated the relationship between BRCA1 and basal-like tumors, the available evidence suggests that BRCA2 is not involved in the biology of basal-like carcinomas.76,109,136
Basal-like cancer often has a triple-negative phenotype; as a result, the majority of these tumors cannot be managed effectively with existing targeted treatments (trastuzumab and hormonal treatments). Despite their aggressive behavior, current routine diagnostic practice does not specifically recognize these tumors, and their management is still same as that of other grade- and stage-matched breast cancers. This is mainly because the genes that are responsible for their aggressive phenotype are not well understood. Several potential targets are now emerging, including EGFR, which is expressed in > 60%60,67 and amplified and/or aneusomic in a subset of basal-like tumors,50 and its downstream signaling pathways. EGFR signaling has been inhibited in other cancer types with some clinical success, by using either EGFR-directed antibodies or the inhibitors of receptor phosphorylation.137,138 The growth factor receptor, c-KIT, which is expressed in a high proportion of basal-like cancers,60,75,139 has been successfully targeted in other tumor types by imatinib that inhibits c-KIT and platelet-derived growth factor–receptor tyrosine kinases. These findings should be interpreted with caution though, as c-KIT–positive breast tumors have been shown to lack activating KIT gene mutations.139 Dasatinib, an src inhibitor, has been shown in preclinical models to be most effective in triple-negative/basal-like breast cancers.89,140 Although the actual target of this inhibitor in basal-like cancers remains to be determined and no evidence based on clinical experience has been gathered to date, this compound may prove useful for future management of basal-like cancers.89 The fundamental biologic similarities between BRCA1-associated and basal-like tumors suggest that strategies targeting potential BRCA1 pathway dysfunction in basal-like tumors might be effective.141 There is increasing evidence that the DNA-repair defects characteristic of BRCA1-related cancers, especially defective homologous recombination, confer sensitivity to certain systemic agents, such as platinum salts–based chemotherapy agents and PARP inhibitors,141-144 which, therefore, could be relevant to the treatment of basal-like breast cancer. The response of basal-like tumors to chemotherapy is currently under investigation (Table 4). However, most studies were either retrospective, or failed to include a control group, or were not sufficiently powered. Although it has been reported that basal-like tumors may have a better response to chemotherapy,61,104 basal-like phenotype does not seem to be an independent predictor of chemotherapy response after accounting for the contribution of high grade, high proliferation rates, and hormone receptor–negative status of these tumors,64 and a recent study has reported a low response rate of basal-like tumors to neoadjuvant therapy with docetaxel, doxorubicin, cyclophosphamide.65 Whether more aggressive treatment procedures can improve the outcome for these patients and which of the available options provide the greatest benefit are still under investigation (Table 2). However, a caveat should be voiced, given that most clinical trials have so far used a triple-negative definition for these tumors (as described earlier herein). The answer these issues might require carefully designed prospective studies to evaluate the impact of the basal-like phenotype and its individual gene products on response to specific therapy.
Basal-like breast cancer is a distinct group of tumors that show common but heterogeneous morphologic, genetic, and immunophenotypic features and is associated with poor clinical outcome, which would be best seen as a spectrum of lesions. The current definition of basal-like cancers varies widely. In terms of gene expression microarrays, they are defined by a specific gene signature that is similar to that of basal and/or myoepithelial cells of the breast. In terms of IHC identification, they have been defined using either a panel of markers that can define those tumors identified in the microarray studies or according to basal CK expression. This later pragmatic definition is supported by the association between basal CK and poor outcome; however, it seems likely that a consensus definition is far from being achieved. Given the limited number of emerging therapeutic targets in these tumors, routine IHC identification of basal-like subtype as a poor prognostic group of breast cancer, could be based on the expression of basal CKs. A more practical approach is to apply these basal CKs to tumors that are triple negative or show morphologic features suggestive of basal-like phenotype such as high-grade tumors. Although we do not advocate the inclusion of HER2–amplified, basal CK–positive breast cancers in the basal-like group, because of the obvious therapeutic implications (ie, HER-2–positive cancers are already managed in a completely different fashion), it is unclear whether ER- and basal CK–positive breast cancers should be classified. Although the latter accounts for a small minority of breast cancers, further clarity on their response to endocrine therapy is required. We also recommend the use of a combination of basal CKs and a valid and consensus method of interpretation of their results similar to that used for assessment of HER-2. Basal-like tumors may require a more aggressive intervention and should raise the suspicion of a BRCA1 germline mutation, particularly if they are hormone-receptor negative.
The author(s) indicated no potential conflicts of interest.
Conception and design: Emad A. Rakha, Jorge S. Reis-Filho, Ian O. Ellis Manuscript writing: Emad A. Rakha, Jorge S. Reis-Filho, Ian O. Ellis
Terms in blue are defined in the glossary, found at the end of this article and online at www.jco.org. Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
ska R, Potemski P, Jesionek-Kupnicka D, et al: Immunohistochemical identification of basal-type cytokeratins in invasive ductal breast carcinoma–relation with grade, stage, estrogen receptor and HER-2. Pol J Pathol 56:107-110, 2005
