A major breast cancer analysis project has catalogued the spectrum of mutations that underpin the four basic categories of the disease, and also found that one of the most aggressive forms of breast tumor shares more features at the mutational level with high-grade serous ovarian tumors than with other subtypes of breast cancer. The data, published in Nature, represents the most comprehensive molecular blueprint of breast cancer generated to date, and could help researchers design and develop more effective drugs and combination treatment regimens that target each subtype of disease according to its molecular background.

The Cancer Genome Atlas (TCGA) consortium used six different analytical techniques (genomic DNA copy number arrays, DNA methylation, exome sequencing, mRNA arrays, microRNA sequencing, and reverse-phase protein arrays) to analyse 825 breast cancer tumors. Their aim was to generate a map of the type and range of mutations displayed by the four categories currently used to subtype breast cancer: luminal A, luminal B, Her2-enriched, and basal-like, a group which includes most cases of Her2-, oestrogen-, and progesterone receptor-negative (triple negative) breast cancer.

One of the most notable findings was that basal-like breast cancer exhibits a similar spectrum of mutations to serous ovarian cancer, and in fact is more similar at this level to ovarian cancer than the other three breast cancer subtypes. The researchers say this result suggests that basal-like tumors may actually be more accurately classified as a different disease, and respond better to the same types of treatment used to fight ovarian cancer than to the anthracycline-based chemotherapy that is most commonly used as the basis for treating breast cancer. “For basal-like breast tumors, it’s clear they are genetically more similar to ovarian tumors than to other breast cancers,” states the project’s co-leader Matthew J. Ellis, M.D., Anheuser-Busch Chair in Medical Oncology at Washington University School of Medicine in St. Louis. “Whether they can be treated the same way is an intriguing possibility that needs to be explored.”

The results of the analyses showed that mutations in just three genes (TP53, PIK3CA, and GATA3) were present in more than 10% of the analyzed tumors across the four breast cancer subtypes. Interestingly, basal-like and Her2E tumors harbored the highest mutation rates, but also the smallest set of mutated genes. In contrast, luminal cancers, which include oestrogen receptor- and progesterone receptor-positive tumors, exhibited the lowest frequency of mutations, but these mutations occurred in a far greater number of genes. This indicates that for luminal cancers each gene that is significantly mutated is likely to play a key role in driving cancer progression, the investigators point out.

Interestingly, 80% of basal-like tumors exhibited mutations in TP53, and about 20% also demonstrated germline or somatic mutations in BRCA1 or BRCA2, “which suggests that one in five basal-like patients might benefit from PARP inhibitors and/or platinum compounds,” the authors write in their published paper, titled “Comprehensive molecular portraits of human breast tumours.”

The data also showed that 45% of luminal A cancers demonstrated mutations in the PIK3CA gene, whereas TP53 mutations were only found in 12% of tumors of this cancer subtype. In luminal B tumors the most common mutations were found in TP53 and PIK3CA.

Combining the results from each of the six analytical techniques has provided a far more detailed picture of breast cancer at the molecular level than ever before, the TGCA researchers claim. “Through the use of multiple different technologies, we were able to collect the most complete picture of breast cancer diversity ever,” concludes corresponding author Charles Perou, Ph.D., May Goldman Shaw Distinguished Professor of Molecular Oncology and a member of the University of North Carolina Lineberger Comprehensive Cancer Center. “This study has now provided a near complete framework for the genetic causes of breast cancer, which will significantly impact clincial medicine in the coming years.”

Data from the study is freely available through the TGCA Data Portal, and will provide a critical resource for identifying new drug targets and biomarkers of therapeutic response. “By tying together those different datasets, we can build a story around the biology of each breast cancer subtype that is dictated by the genome, interpreted by the RNA and played out by the proteins at work inside each tumor,” comments co-author Elaine Mardis, Ph.D., co-director of The Genome Institute. “These data can serve as a backdrop for other questions about how particular mutations affect survival or response to certain drugs.”

TGCA’s publication of its breast cancer data follows on a couple of weeks after the program published data from a lung cancer initiative that identified potential therapeutic targets in lung squamous cell carcinoma.

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