Original articleClinical implications of the intrinsic molecular subtypes of breast cancer
Introduction
Despite that breast cancer mortality has been moderately reduced by current treatments, more than 450,000 estimated deaths due to breast cancer are expected annually worldwide [1]. The most plausible explanation for this scenario is that we lack a complete picture of the biologic heterogeneity of breast cancers. Importantly, this complexity is not fully reflected by the main clinical parameters and pathological markers (oestrogen receptor [ER], progesterone receptor [PR] and human epidermal growth factor 2 [HER2]), all of which are routinely used in the clinic to stratify patients for prognostic predictions, to select treatments and to include patients in clinical trials.
Gene expression profiling has had a considerable impact on our understanding of breast cancer biology. During the last 15 years, we and others have extensively characterized 5 intrinsic molecular subtypes of breast cancer (Luminal A, Luminal B, HER-2 enriched, Basal-like and Claudin-low) and a normal breast-like group [2], [3], [4], [5], [6]. These entities have shown significant differences in terms of their incidence, risk factors, prognosis and treatment sensitivity. Regarding prognosis, the Luminal A subtype has shown repeatedly to have a better outcome than the rest of subtypes across many datasets of patients with early breast cancer, including 6 phase III clinical trials (TransATAC, GEICAM9906, CALGB9741, ABCSG08, NCIC-CTG MA.5 and NCIC-CTG MA.12), where patients received various adjuvant systemic treatments.
A particular piece of data that highlights the importance of intrinsic subtyping in breast cancer comes from one of the most complete molecular characterization studies that have ever been performed in breast cancer. In this study, led by The Cancer Genome Atlas Project (TCGA), more than 500 primary breast cancers were extensively profiled at the DNA (i.e. methylation, chromosomal copy-number changes and somatic and germline mutations), RNA (i.e. miRNA and mRNA expression) and protein (i.e. protein and phosphor-protein expression) levels using the most recent technologies [6]. In a particular analysis of over 300 primary tumours (i.e. shown in Figure 2 of that publication [6]), 5 different data-types (i.e. all except DNA mutations) were combined together in a cluster of clusters in order to identify how many biological homogenous groups of tumours one can identify in breast cancer. The consensus clustering results showed the presence of 4 main entities of breast cancer but, more importantly, these 4 entities were found to be very well recapitulated by the 4 main intrinsic subtypes (Luminal A, Luminal B, HER2-enriched and Basal-like) as defined by mRNA expression only [7]. Overall, these results suggest that intrinsic subtyping captures the vast majority of the biological diversity occurring in breast cancer.
Since 2011, the St. Gallen international expert consensus panel adopted an intrinsic subtype-based approach for recommending adjuvant systemic therapies (i.e. endocrine, chemotherapy and anti-HER2 therapy) in early breast cancer [8]. Although the panel acknowledged the superior accuracy and reproducibility of multi-gene expression molecular assays, these assays are not readily available for all our patients. Thus, over the years, we and others have proposed pathology-based surrogate definitions especially for distinguishing Luminal A from B tumours [9], [10], [11]. However, despite important efforts to improve the various pathology-based surrogate definitions of the intrinsic subtypes, these continue to be suboptimal.
Here, we review the current and the potential future clinical implications of the intrinsic molecular subtypes of breast cancer beyond the pathological-based surrogate classification endorsed by the 2013 St Gallen Consensus Recommendations [8].
Section snippets
Intrinsic subtyping based on gene expression versus histopathology
To date, numerous studies have evaluated and compared the classification of tumours based on the PAM50 gene expression predictor with the pathology-based surrogate definitions [6], [10], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26]. To better understand the concordance between the 2 classification methods, we have combined the data from all of these studies for a total of 5994 independent samples (Table 1). Of note, the vast majority of these studies
Main molecular features of the intrinsic subtypes
Four main intrinsic molecular subtypes of breast cancer (Luminal A, Luminal B, HER2-enriched and Basal-like) have been characterized over the last 15 years. At the RNA and protein level, Luminal A and B subtypes are largely distinguished by the expression of two main biological processes: proliferation/cell cycle-related and luminal/hormone-regulated pathways (Fig. 1). Compared to Luminal A tumours, Luminal B tumours have higher expression of proliferation/cell cycle-related genes or proteins
Basal-like versus not classification: biological and epidemiological implications
The TCGA comprehensive molecular characterization of breast cancer confirmed that among all the intrinsic subtypes, the Basal-like is the most distinct [6]. This observation fits with previous molecular studies and with clinical data that shows that triple-negative breast cancer tends to affect young women, is associated with BRCA1 mutations and is a highly aggressive disease [37]. However, how different is Basal-like disease from the rest of breast cancer subtypes?
Two recent studies have
Prognostic implications
Within HR+/HER2-negative breast cancer, 90–95% of tumours fall into the Luminal A and B subtypes. In early breast cancer, Luminal B disease has worse baseline distant recurrence-free survival at 5- and 10-yrs regardless of adjuvant systemic therapy compared to Luminal A disease. This has now been observed in multiple retrospective datasets, including 6 phase III clinical trials (i.e. CALGB9741 [45], GEICAM9906 [46], TransATAC [19], ABCSG-08 [20], MA.5 [47] and MA.12 [17] trials) coming from
Distribution and biology of the intrinsic subtypes
Similarly as the other pathology-based groups, all the intrinsic molecular subtypes can be identified within clinically HER2-positive disease albeit with different proportions. In our combined analysis of 831 HER2+ tumours (Table 1), 44.6%, 26.8%, 17.6% and 11.0% were identified as HER2-enriched, Luminal B, Luminal A and Basal-like. Interestingly, HR-status by IHC does not fully recapitulate the intrinsic subtypes since 20.9% (1 out of 5 patients) of HER2+/HR+ tumours will be identified as
Distribution and biology of the intrinsic subtypes
In the past, we have used the word TN and Basal-like interchangeably. However, within TN disease, all the intrinsic molecular subtypes can be identified, although the vast majority fall into the Basal-like subtype (86%; range 56%–95%, depending from the study). In our combined analysis of 868 TN tumours (Table 1), 86.1%, 9.1%, 3.2% and 1.6% were identified as Basal-like, HER2-enriched, Luminal B and Luminal A, respectively. Although the correlation between pathological and gene expression
Conclusions
Breast cancer is a clinically and biologically heterogeneous disease. However, the vast majority of the biological diversity coming from the DNA, miRNAs and proteins is captured by the 4 main intrinsic subtypes defined by gene expression-only. At the same time, and contrary to popular belief, intrinsic biology is not sufficiently captured by standard clinical-pathological variables. In this review, we have argued how intrinsic biology identified by gene expression analyses provides, today and
Conflict of interest statement
Aleix Prat has served in an uncompensated advisory role to Nanostring Technologies. There are no other potential conflicts of interest.
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