Needles in a haystack: finding recurrent genomic changes in breast cancer

Significant advances over the past decade have enabled scientists to obtain increasingly detailed molecular profiles of breast cancer. The recent analysis by The Cancer Genome Atlas published in the September 2012 issue of Nature is the most comprehensive description of breast cancer 'omics' to date. This study is impressive in its scope and scale, with the findings reconfirming the heterogeneity of breast cancer and highlighting the future challenges in translating these findings for clinical benefit.


Background
Breast cancers are a heterogeneous group of tumors that were originally classifi ed by their clinicopathological features. Improvements in molecular techniques, specifically in gene expression analysis, allowed for the grouping of breast cancers into fi ve subtypes (luminal A, luminal B, basal-like, HER2-enriched (HER2E), and normal-like) over a decade ago [1,2]. Typically, luminal subtypes are associated with the expression of estrogen receptor (ER) and progesterone receptor, while HER2E subtypes usually lack hormone receptor expression but have amplifi cation and/or over-expression of HER2. Basal-like tumors are commonly described as triple-negative breast cancers (TNBCs) lacking in expression of hormone receptors and HER2.
While receptor subtypes are associated with diff erent prognostic and therapeutic implications, the full clinical consequences of these molecular subtypes have not been established. In 2006 and 2007, two studies published in Science detailed the complexity of the breast cancer mutation spectrum and highlighted the major diffi culties this diversity raises in designing therapies [3,4]. In June 2012, fi ve studies were published in Nature examining hundreds of primary breast tumors by integrating various profi ling techniques [5][6][7][8][9]. Th ese recent papers demonstrated a vast array of clonal frequencies and genetic diversity among breast cancers, highlighting that breast cancer is truly many diff erent diseases.

A comprehensive look at a complex molecular landscape
Th e Cancer Genome Atlas (TCGA) is a collective eff ort tasked with providing a comprehensive genomic analysis for 20 cancers, including breast cancer. In this latest study, TCGA analyzed 825 primary breast tumors with matched germline samples using six diff erent platforms (whole exome sequencing, messenger RNA array, genomic DNA copy number array, DNA methylation array, microRNA sequencing and reverse-phase protein array) [10]. Th e sequencing and array data corroborated the mutation and gene expression patterns documented in previous studies. For instance, compared to the noted low frequency of mutation for numerous genes across all breast cancers, TP53 (37%), PIK3CA (36%), and GATA3 (11%) were the only genes found to be mutated at a level greater than 10% overall. In addition, when grouped according to gene expression subtype, the mutations not only tracked well with expected frequency but also with the type of mutation. Notably, basal-like tumors harbored nonsense TP53 mutations while luminal tumors harbored mostly missense mutations. In addition to identifying nearly all genes previously implicated in breast cancer, the authors also discovered a handful of novel mutated genes.
TCGA also parsed out individual, overarching features associated with each of the four subtypes: luminal A, luminal B, HER2E, and basal-like. Despite having a relatively low mutation rate, luminal/ER+ tumors were found to have the most diverse mutation spectrum and heterogeneity. Conversely, basal-like and HER2E tumors had a very high rate of mutation in only a few select genes, such as TP53. Th e data also showed that clinically defi ned TNBCs and HER2+ cancers did not fall exclusively within their classically associated subtypes, basallike and HER2E, respectively. In fact, only 50% of clinically defi ned HER2+ cancers were classifi ed as

Abstract
Signifi cant advances over the past decade have enabled scientists to obtain increasingly detailed molecular profi les of breast cancer. The recent analysis by The Cancer Genome Atlas published in the September 2012 issue of Nature is the most comprehensive description of breast cancer 'omics' to date. This study is impressive in its scope and scale, with the fi ndings reconfi rming the heterogeneity of breast cancer and highlighting the future challenges in translating these fi ndings for clinical benefi t. HER2E while the other half tracked well with ER+ status and other luminal subtype features. As for TNBCs, 25% of tumors comprised the three other mRNA subtypes besides the basal-like group. Interestingly, through further analysis of the basal-like subset of tumors, TCGA noticed strikingly similar characteristics and mutations as in their previous studies with serous ovarian cancers. Both tumor types featured widespread genomic insta bili ty, MYC amplifi cation, and loss of BRCA1, TP53, and RB1, leading to the authors' conclusion that patients with basal-like tumors may benefi t from poly ADP-ribose polymerase (PARP) inhibitors or platinum-based therapies.

Viewpoint
While multiple groups have attempted to create consensus mutation spectrums and molecular landscapes for primary breast cancers, TCGA was able to draw from a large database across multiple platforms and provide the most comprehensive portrait of human breast tumors thus far. All six recent profi ling analyses detailed the same intricate and heterogeneous nature of breast cancers and emphasized the diffi culties this causes with respect to the development of eff ective therapies. However, the sobering truth is that common targets are the exception in breast cancer, and if there were any remaining doubts, TCGA has put them to rest. How to move this information forward for clinical benefi t becomes the challenge for the next decade. Although the technical merits and scale of this study cannot be discredited, in reality no new clinical benefi t can yet be derived, as even the idea to use PARP inhibitors or platinum agents to treat TNBC has already been an intense area of clinical research. In addition, future studies will need to address issues with intratumor heterogeneity and clonal evolution. It is hoped that the classifi cation of breast cancers along with further technologic advances can lead to the development of more rational therapeutics, so that ultimately the vision of individualized therapy for breast cancer becomes a reality.

Competing interests
BHP is a consultant for GlaxoSmithKline and serves on the Scientifi c Advisory Board of Horizon Discovery, Ltd.