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Mutational Profile of Metastatic Breast Cancers: A Retrospective Analysis

By BCRF | January 26, 2017

From tumors to metastases, mutations that lead the way

Metastatic breast cancer occurs when cancer cells break away from the breast and spread to other parts of the body, like vital organs such as the lungs, brain, liver or bones. Metastatic breast cancer, also referred to as stage IV or advanced breast cancer, is treatable but considered an incurable disease, and is responsible for virtually all of the 40,500 breast cancer-related deaths each year.

Studying early breast cancer that remains in the breast led to the understanding that breast cancer is made up of a several different subtypes of disease, like ER+, HER2+ or triple negative. This has led to specific treatments like trastuzumab for HER2+ breast cancer and anti-estrogen therapies for ER+ breast cancer.

Metastatic breast cancer has not had the same extensive research. Recent studies suggest that the cancer cells that spread from the breast have differences in the tumor biology of primary (in the breast) and metastatic lesions. BCRF investigator, Dr. Fabrice André and his team set out to explore this landscape and identify mutations in metastatic disease that could help explain drug resistance and lead to better treatments.

In a study published in PLOS Medicine, Dr. André and his team analyzed the genes of 216 metastatic breast cancer patients. They compared the genome from the metastatic lesions to normal DNA in the patients’ blood. They were also able to compare the mutations they found in the metastatic lesions to mutations known to occur in primary tumors.

Key findings from the study included the identification of two apparent drivers of metastatic breast cancer, the ESR1 and RB1 genes. Mutations in ESR1, the gene that codes for the estrogen receptor, were confined to estrogen receptor (ER)-positive breast cancers that were resistant to anti-estrogen therapies typically used to treat this subtype of breast cancer. Previous studies have shown that ESR1 mutations lead to resistance to aromatase inhibitors.

The unexpected finding that RB1, the gene that codes for a tumor suppressor protein by the same name, was a driver mutation in five percent of the ER+ metastatic breast cancers could have significant clinical implications. CDK 4/6 inhibitors, a new targeted treatment of ER+ metastatic breast cancer require a functional Rb protein. Screening for RB1 gene mutation in patients selected for CDK4/6 inhibitor therapy could identify patients not likely to benefit from the treatment.

Because the ESR1 and RB1 gene mutations were more frequent in metastatic breast cancer than in early breast cancer, they provide important information that can be used to develop new therapies, and predict resistance to current therapies – allowing tailoring of the treatment to the individual.

While this is the first large-scale series of whole exome sequencing of metastatic breast cancers, the authors acknowledge some limitations to the study. 1) Bone metastases were not included due to the difficulty in obtaining samples, 2) The relatively small number of patient samples analyzed makes it difficult to identify rare mutations, 3) The study excludes patients with highly aggressive breast cancers who would not be eligible for the clinical trials from which sample materials were obtained.

Another caveat to the study is that the researchers used normal DNA from patients’ blood as a reference point. The ideal comparison would have been matched metastatic and primary breast cancers, which was not possible in this current study. AURORA EU, a BCRF Founder’s Fund project, will build on this study by overcoming some of these limitations, including comparing primary tumors to metastatic lesions directly in 1000 patients in 14 European countries.

BCRF commits approximately 30 percent of the annual grant-making revenue to metastasis research, totaling more than $16 million in 2016. This is in addition to its more than $30 million Founder’s Fund Initiative. Projects span the spectrum of metastatic breast cancer from understanding the very basics of how cancer cells start and spread to clinical trials and new treatments for stage IV breast cancer.

Click here for more about BCRF investigators studying metastasis.



Citation: Lefebvre C, Bachelot T, Filleron T, Pedrero M, Campone M, Soria J-C, et al. (2016) Mutational Profile of Metastatic Breast Cancers: A Retrospective Analysis. PLoS Med 13(12): e1002201. doi:10.1371/journal.pmed.1002201