Molecular catalog sheds new light on breast cancer
A molecular analysis of breast cancers defined four primary breast cancer classes, and indicated that one subtype is genetically more similar to ovarian tumors than other breast cancers, according to a study published online Sept. 23 in Nature. The findings may facilitate the comparison of therapeutic data for subtypes of breast and ovarian cancers.

A consortium of researchers analyzed tumors from 825 women with breast cancer using six technologies to examine subsets of tumors for defects in DNA, RNA and proteins. The data had been generated as part of The Cancer Genome Atlas (TCGA).

The genomic analyses confirmed four primary subtypes of breast cancer, each with its own biology and survival outlooks. These are: HER2-enriched, Luminal A, Luminal B and Basal-like.

The TCGA Research Network uncovered marked genomic similarities between the Basal-like subtype and serous ovarian cancer. The mutation spectrum was similar in both cancer types. Further analyses identified several additional common genomic features, such as gene mutation frequency, suggesting that diverse genomic aberrations can converge into a limited number of cancer subtypes.

Computational analyses show that Basal-like breast cancer and serous ovarian cancer might both be susceptible to agents that inhibit blood vessel growth, cutting off the blood supply to the tumor, as well as to compounds that target DNA repair, which include chemotherapy drugs such as cisplatin.

"The molecular similarity of one of the principal subtypes of breast cancer to that found in ovarian cancer gives us additional leverage to compare treatments and outcomes across these two cancers," Harold E. Varmus, MD, director of the National Cancer Institute, said in a press release. Matthew J. Ellis, MD, PhD, co-leader of the research and chair of medical oncology at Washington University School of Medicine in St. Louis, Mo., offered, “Whether they can be treated the same way is an intriguing possibility that needs to be explored.”

Previous studies have suggested that women with basal-like breast tumors don’t benefit from anthracycline-based chemotherapy, which is used to treat many breast cancers.

Basal-like tumors account for approximately 10 percent of all breast cancers, and disproportionately affect younger women and those who are African-American.

Basal-like and HER2 tumors had the highest mutation rates but shortest list of significantly mutated genes. Approximately 80 percent of basal-like tumors had mutations in the TP53 gene, which have been link to poor outcomes. About 20 percent of the tumors had inherited mutations in the BRCA1 or BRCA2 genes.

“This suggests that it takes only a few hits to key genes that drive cancer growth,” Elaine R. Mardis, PhD, co-director of The Genome Institute, said in a press release.

Also of note, when researchers analyzed the genomic findings from tumors determined to be HER2-positive by standard cellular tests, they found that only half of the samples could be characterized as belonging to the HER2-enriched (HER2-E) subtype. The other half were characterized as luminal subtypes, suggesting that there are at least two types of clinically defined HER2-positive tumors.

In general, the luminal subtypes had the lowest overall mutation rate, but by contrast, had the largest number of genes observed to be significantly mutated. This suggests defects in multiple genetic pathways can lead to the development of luminal breast cancers.

Most patients with luminal A cancer have good outcomes. Although some patients with luminal B cancers do well, the cancers tend to recur years after treatment. The most common mutations in these tumors occurred in TP53 gene (linked to poor outcomes) and PIK3CA gene (linked to good outcomes), which might explain the disparate results in patients with luminal B tumors.

“With this information, physicians and scientists can look at their own samples to correlate patients' tumor profiles with treatment response and overall outcomes. That's the challenge for the future— translating a patient's genetic profile into new treatment strategies," Ellis said.

The research was funded by the NCI and the National Human Genome Research Institute.