A new study from New York might completely change how breast cancer is classified and treated. Researchers have discovered, in a study of triple negative breast cancer in black women, that the molecular mechanisms involved are more closely related to non-breast cancers, and two specific gene mutations may be responsible for the tumor development.
This study would signal a potential treatment breakthrough for patients with this form of breast cancer, which disproportionately affects and tends to develop more aggressively in black women. Triple negative breast cancer is a form of breast cancer that is not hormone driven, and it does not express the estrogen receptor, progesterone receptor, or HER2/neu genes—unlike other forms of the disease, which rely on hormone-driven therapies to control the cancer.
The paper, authored by researchers at The Graduate Center of The City University of New York, Hunter College, Memorial Sloan Kettering Cancer Center, and the University of Chicago, details findings about the interaction between two specific genes during DNA replication that appear to drive growth of malignant cells in patients with triple negative breast cancer.
The research team found the presence of a mutated p53 (a tumor suppressor gene whose mutation often leads to cancer development) and a mutated PARP (a gene that maintains DNA integrity) in a large majority of patients with triple negative breast cancer. Specifically, they found that p53 would interact with replicating DNA and PARP, driving cell growth and division.
This information would suggest that if drugs could specifically target these two mutated genes and the proteins they produce, it would be possible to suppress their actions and slow or stop tumor growth, so the researchers tested this in lab, using drugs developed for other types of cancer. This was indeed the case.
“Our new findings suggest that the presence of both [p53] and PARP could serve as a good identifier of breast cancers that would respond to combined treatment with talazoparib — a PARP inhibitor that was developed to treat breast cancers with the BRCA mutation — and temozolomide — a chemotherapy agent that is used to treat some brain cancers,” said Professor Jill Bargonetti, whose lab conducted the research. “This is an exciting finding because it could lead to the first targeted therapy for triple negative breast cancer, enabling more precise and effective treatment of a very aggressive form of the disease.”
To conduct this study, researchers investigated a variety of breast cancer cell lines, patient-derived xenographs, tissue microarray samples, and data from The Cancer Genome Atlas to tease out the association and interaction between p53 and PARP in triple negative breast cancer.
“Our findings that mutant p53 and PARP participate in the DNA replication pathway will provide mechanism-derived dual biomarkers that aid in the diagnosis and treatment of these therapeutically elusive subsets of breast cancer,” said Gu Xiao, a research associate with Bargonetti’s lab and the paper’s first author.
The scientists had discovered that high levels of these proteins are present on replicating DNA in these types of tumors, suggesting that the unusual presence and levels of these proteins may drive tumor growth. When these researchers reviewed the therapeutic mechanisms of existing cancer drugs, it led the research team to identify talazoparib and temozolomide as existing drugs that could potentially be combined to create a targeted therapy that could effectively suppress the growth of triple negative breast cancer tumors.
Looking to the future, this group plans to test if this combination of drugs can successfully block replication of triple negative breast cancer cells in xenographed animal models. If the therapy can prove to be successful, it would very likely lead to the reclassification of triple negative breast cancer to a category of cancers called mutant p53/PARP1 positive cancers, which are treatable with a combination PARP inhibitor therapies.
With so little in positive news for this particular subset of breast cancer, and many previous clinical trials being disappointing, these new findings are both welcome news to the scientific community, as well as a good explanation as to why this disease has been so hard to treat compared to other forms of breast cancer.
This study gives doctors two new biomarkers to test for in patients, and many new potentials in clinical trials, which can be fast tracked since so many drugs already exist that target these specific genes. While this study only tested out two drugs, there are many other drugs that specifically target p53 and PARP, and many more which can be developed, which may give even better results. Hopefully, there will be many new, positive developments for this disease following this discovery.