Though the designation of luminal B first came about with the early gene expression profiling studies of breast cancer near the start of the millennium, it has long been understood that there exists a more aggressive form of ER+ breast cancer. Earlier studies had noted that ~30% of ER+ invasive breast cancers showed no benefit from hormone therapy, suggesting that these cancers either augment or entirely bypass the classical estrogen-stimulated mitogenic pathway.8
Markers predicting hormone therapy response within ER+ cancers have been sought, the most notable of these being PR. Loss of PR expression is thought to represent a surrogate for a more aggressive disease phenotype that is less dependent upon estrogen signaling; in correlative studies, PR loss has been associated with lower ER levels, more positive nodes, aneuploidy, larger tumor size, higher proliferation, and expression of growth factor receptors (GFRs) including EGFR and HER2.1
The advent of DNA microarrays made it possible to profile breast cancers for mRNA expression of thousands of genes. Early profiling studies took a fresh approach to classifying breast cancer, allowing the expression data themselves to segregate human breast tumors, rather than relying on prior biological knowledge and possible biases. Expression profiling first defined five intrinsic molecular subtypes of breast cancer: basal-like, HER2-enriched, normal-like, luminal A, and luminal B. A sixth subtype, claudin-low, was discovered later, perhaps due to its greater rarity.9
Other additional ER− subtypes could include a “molecular apocrine” subtype (ER−/HER2+ but with activation of androgen receptor signaling), and an “interferon” subtype (with high expression of interferon regulated-genes).11
Recently, there have been some suggestions12
that the normal-like breast cancer might be a mere artifact of sample representation (ie, disproportionately high content of normal tissue contamination), though such concerns would not extend to the other subtypes, including luminal B.
As noted above, the mRNA-based classifications, as originally defined by Perou and colleagues, largely reflected the histological-based classifications. The luminal and normal-like subtypes reflect the ER+ form of breast cancer. The designation of luminal was derived due to the finding that these cancers show mRNA and protein expression of keratins 8/18,3
typically associated with luminal epithelial cells (as opposed to basal cells which express keratins 5/6). The luminal subtype of breast cancer was further subdivided into A and B groups, as luminal B showed widespread expression differences as well as substantially worse outcomes.2
In the future, as larger cohorts of breast tumors are profiled at multiple data levels, the molecular designations of breast cancer may be further refined.
While the intrinsic molecular subtypes of breast cancer have been defined and examined on the basis of hundreds of genes,2
in the interests of a more focused gene list for the purposes of a clinical assay, the PAM50 assay was developed, which consists of 50 genes by which breast cancers can be classified by mRNA-based subtype.13
illustrates the patterns of the PAM50 genes, both in an expression profile dataset (N = 240) from the research group which first developed the assay,14
and in a compendium of nine separate datasets17
profiled on the same assay platform (N = 1340, previously collected by Kessler et al).26
It is notable how the PAM50 gene patterns are remarkably consistent between the two datasets. It is also evident that luminal B shares some gene patterns with luminal A (eg, ER genes ESR1
, and BCL2
) and some patterns with basal-like including expression of proliferation markers (eg, Ki-67 gene MKI67
, survivin gene BIRC5
, and cyclin B1 gene). It has been put forth that luminal B might represent the ER+/HER2+ form of breast cancer;4
however, in our compendium dataset, HER2 gene ERBB2
does not show high levels in luminal B ().
Figure 1 Luminal B breast cancer is associated with substantially worse patient outcomes. (A) Expression patterns of the PAM50 gene set13 (41 genes represented on the U133A array platform) in the mRNA profile datasets from Hoadley et al,14 (N = 247) and Kessler (more ...)
Within the compendium dataset,26
as reported elsewhere, luminal B cancers have much worse outcomes compared to luminal A, the outcomes of luminal B being comparable to, if not worse than that of the basal-like and HER2-enriched subtypes (). Between different patient cohorts, the relative outcomes of the intrinsic mRNA-based subtypes may vary; for example, the HER2-enriched subtype may have a better outcome in patients treated with anti-HER2 therapy,27
and in at least one early study using a small cohort, normal-like breast cancers actually showed a worse outcome comparable to that of luminal B.2
However, luminal B has been found to consistently show poor outcomes in studies using sizable datasets, including patients receiving antiestrogen therapy (such as the Loi et al dataset,21
which is represented in our compendium).