Although breast cancer research has helped chart the course for molecularly targeted therapies in oncology, next-generation sequencing (NGS) technologies have revealed a disease so highly complex and heterogeneous that translating these findings into clinically useful therapies has proved daunting.
Indeed, genomic complexities uncovered thus far potentially impact current treatment paradigms because of an increased risk that clinicians are basing decisions on incomplete information. Meanwhile, this complexity limits the broad clinical applicability of any potentially druggable genomic events, affecting future therapeutic developments.
Now, experts are turning increasingly toward newer technologies that will allow them to dissect the cellular outcomes of the many genomic alterations already uncovered, as well as those yet to be revealed. There is hope that shifting focus away from individual mutations and back to the cancer cell as a whole will help to bridge the gap between genomics and clinical action.
A Subtype-Specific View
Currently, clinicians base their treatment decisions for patients with breast cancer on disease histology and the expression of the estrogen receptor (ER), the progesterone receptor (PR) and the human epidermal growth factor receptor 2 (HER2), all of which have well-established roles as drivers of this disease.
A genomic view of the tumors looks beyond that approach. Clinically speaking, there are at least 5 recognized gene expression–based subtypes of breast cancer: luminal A and luminal B, both of which express ER and PR; HER2-enriched tumors, which express the HER2 protein; basal-like tumors; and a normal breast-like subtype that remains ill-defined.
The luminal A and luminal B tumors are the most prevalent among the subtypes. Basal-like tumors, which represent the most heterogeneous subtype, overlap to a large extent with triple-negative breast cancers (TNBCs), defined by their lack of ER, PR, or HER2 expression. Around 75% of TNBCs fall into the basal subtype, while the remaining quarter are distributed across the other subtypes.
In 2012, a series of NGS studies fueled an explosion in the breast cancer genomics field. These studies began to piece together a more comprehensive picture of the genomic events driving breast cancer.
Substantial heterogeneity was observed not only between the different clinical subtypes, but also within them, as well as within individual patients and between the primary tumor and metastases.
Intrapatient heterogeneity was highlighted in a recent study in which single-nucleus genome sequencing was performed on 50 individual cancer cells. Within a single TNBC sample, there were seemingly 3 different cancers and no 2 cancer cells had the same genome.
One of the most comprehensive sequencing studies was performed by The Cancer Genome Atlas (TCGA) research network. Dramatic differences in both the type and frequency of mutations across the clinical breast cancer subtypes were observed (Figures 1 and 2
Overall, across 510 primary tumors that underwent whole-exome sequencing, 35 significantly mutated genes were identified. Many of these genes have been previously implicated in breast cancer, including components of the PI3K pathway, such as PIK3CA
, and AKT1
, and the guardian of the genome, TP53
. However, several of the mutated gene findings were novel, including TBX3
, and CCND3
Luminal A tumors had the highest number of recurrently mutated genes, with the most frequent being the PIK3CA
gene (45%). Other common mutations included MAP3K1
, and MAP2K4
was also mutated in luminal A tumors.
genes are both involved in the JNK signaling pathway. This cascade, mediated by the Jun kinases, is involved in a myriad of cellular processes, including the response to stress.
Together, the 2 genes were mutated at a frequency of 20% in luminal A tumors; these mutations have been observed in several other sequencing studies, potentially implicating this pathway in breast cancer development.
Interestingly, luminal B tumors have a different mutation profile, suggesting another potential determinant of A versus B status. Luminal B tumors had a higher frequency of TP53
mutations, but fewer mutations in PIK3CA
and the PI3K
helical domain E545K
mutations are among the most common aberrations in breast cancer.
gene was mutated at a similar rate in both types of luminal tumors, but the types of mutations differed; in the luminal A subtype they were observed mostly in intron 4, while in the luminal B subtype they occurred predominantly in exon 5.
From a mutational perspective, in the HER2-enriched subtype, the most significantly mutated gene was TP53
and there were few other recurrently mutated genes.