The more we understand about our genes, the more we understand genetic diseases and eventually, how to best treat them. The recent efforts of a nationwide consortium of researchers suggests that the origins of the type of breast cancer a patient is diagnosed with may inform the most effective course of treatment.
The study, published in Nature on September 23rd, is one of the most comprehensive studies of breast cancer to date. The study revealed that the gene expression profile for one of the most aggressive forms of breast cancer, basal-like carcinoma, is more similar with ovarian tumors than with other breast cancer subtypes.
The four main breast cancer subtypes: Luminal A, Luminal B, HER2, and basal-like, were confirmed and characterized by leading researchers at several institutions as part of The Cancer Genome Atlas Network. The study is part of an NIH funded initiative with the Cancer Genome Atlas Network to build maps of genetic changes in common cancers. While most historical studies of breast cancer have utilized one or two methods to analyze and characterize the gene profiles of breast cancers, six parallel technologies were used for this study to examine mutations and defects in DNA, RNA, and proteins. Consortium scientists analyzed tumors from 507 women, with nearly 350 tumors being analyzed using all six technologies.
Basal-like breast tumors are also known as “triple negative” tumors. Triple-negative tumors lack receptors for the hormones estrogen, progesterone, and human epidermal growth factor 2 (HER2), which are the gene targets of a number of approved chemotherapies such as Tamoxifen and Herceptin. However, no receptor hormones means no drug targets. Basal-like tumors are a considered high-grade, indicative of an abnormal appearance of the cells under a microscope and a tendency to grow and multiply more rapidly. These tumors have a poor prognosis for treatment and are more prevalent in younger women, women with BRCA1 and BRCA2 mutations, and women of African-American descent.
Currently, basal-like breast tumors are treated like most other breast cancers, using similar chemotherapy strategies. However, basal-like breast tumors are aggressive and not been shown to respond well to therapies targeting hormone receptors or to standard chemotherapy regimens. Consortium researchers found that each subtype could be identified by unique genetic markers, and that mutations in only three genes, TP53 (tumor suppressor gene 53), PIK3CA and GATA3, occurred in common with all four subtypes. These findings suggest that not all breast tumors are alike and therefore, may not respond similarly to the same chemotherapy regimens.
Consortium scientists found that basal-like and HER2 tumor subtypes were characterized by the highest mutation rates. Basal-like tumors shared common features with ovarian tumors and lung cancers, including high rates of TP53 mutations, BRCA1 inactivation, and a loss of RB1 and cyclin E genes, which are known to promote genome instability. The study shows that 80% of basal-like tumors had TP53 mutations and approximately 20% also have mutations in the BRCA1 or BRCA2 genes. Mutations in the TP53 gene have been strongly linked to poor treatment outcomes, while BRCA1/2 mutations are known to increase breast and ovarian cancer.
A growing body of research suggests that tumors should be characterized and treated based on the presence of abnormal genes and abnormal gene expression profiles rather than on their location in the body. Consistent with these findings, consortium researchers found that basal-like tumors are genetically more similar to ovarian tumors based on their genetic profiles. Ovarian tumors are also characterized by a high frequency of TP53 mutations, widespread genomic instability and share other gene mutations in common with similar frequency. These results give biologic reasoning to consider the potential benefits to patients with basal-like tumors to be treated with platinum-based chemotherapies currently approved for the treatment of ovarian cancer or PARP inhibitors which target tumors with BRCA1 and 2 defects.
Clinical trials are a lengthy but necessary step to determine if platinum-based compounds, currently used to treat cancers elsewhere in the body, and/or PARP inhibitors hold promise for patients diagnosed with basal-like breast carcinoma. For now, this study offers much needed insight into the origins of the most aggressive form of breast tumor and promising possibilities for future personalized treatments.