Triple negative breast cancer (TNBC) comprises 15-20 percent of all breast cancers, but few treatment options exist outside of chemotherapy. This aggressive form of breast cancer disproportionately affects young women as well as women of African descent and is the most commonly diagnosed breast cancer in women with BRCA1 mutations.
TNBC treatment is complicated by the inherent complexity of the disease. We know from recent research that TNBC is not one disease but a group of diseases, each with unique molecular profiles that may suggest different potential therapies for each subtype of TNBC.
In recent years, we’ve seen the emergence of new therapies for TNBC. This includes immunotherapies called immune checkpoint inhibitors, drugs that target the androgen receptor, DNA damaging agents, such as platinum drugs, antibody-drug conjugates that deliver drugs to cells that have a specific protein on their surface, drugs that block DNA repair pathways called PARP inhibitors, and combination approaches– all of which are being tested in clinical trials.
FDA approves first targeted drug for TNBC
Early this year, the PARP inhibitor olaparib (Lynparza) was approved by the FDA for treatment of advanced breast cancers with BRCA mutations. While not exclusively for patients with TNBC, it provides a new treatment option for the 10-20 percent of patients with TNBC and a BRCA mutation.
“Olaparib is the first targeted therapy to offer a less-toxic alternative to chemotherapy for patients with triple negative breast cancer.” said Dr. Mark Robson, lead investigator on the Phase III OLYMPIAD trial that led to the approval of olaparib for breast cancer.
Results from OLYMPIAD showed a significant improvement in median progression free survival (7.0 months vs. 4.2 months) in patients receiving olaparib as a single agent compared to those receiving standard chemotherapy . Dr. Robson noted that while the average time until cancers progressed was 7 months, for many women receiving olaparib, the time was much longer. These exceptional responders may hold the key to understanding how to improve the response in more patients.
Beyond the BRCA gene
Olaparib was previously approved for treatment of advanced ovarian cancers with BRCA mutations, a demonstration of how research in one type of cancer benefits another type of cancer.
Efforts are now ongoing to test whether the same strategy will work in other cancers, including triple negative breast cancers that acquire a similar DNA repair deficiency but do not have a mutation in the BRCA gene– what researchers often call “BRCA-ness”. Work is underway to develop a clinical assay that could identify patients whose tumors fall into this category.
“I am excited by the fact that we may be able to find other breast cancers that are sensitive to PARP inhibitors,” said Dr. Nadine Tung, co-investigator on the OLMYPIAD trial.
Dr. Tung’s team is embarking on a new trial conducted through the Translational Breast Cancer Research Consortium that will test olaparib in tumors with mutations in other genes associated with DNA repair including PALB2, ATM and CHEK2. “Inherited mutations in these genes increase the chance of developing breast cancer,” Dr. Tung added. “Now we will assess whether PARP inhibitors are effective in treating these hereditary breast cancers as well.”
Next steps: preventing drug resistance
As with any therapy, not all patients respond equally to PARP inhibitors. BCRF investigator Dr. Alan Ashworth was part of the UK team that identified BRCA2 and the BRCA2 mutation in 1995. His laboratory led the way in the development of PARP inhibitors.
Using a process called synthetic lethality, his team discovered that inhibiting the PARP protein, which is involved in another DNA repair pathway, was lethal to cells with BRCA-deficiency. There are currently five PARP inhibitors in clinical trials, several of which include patients with TNBC.
Today Dr. Ashworth’s team conducts studies to identify factors underlying resistance to PARP inhibitors.
“We don’t know all the mechanisms of resistance, he said, “or whether patients who don’t respond to one PARP inhibitor will be resistant to others.”
Efforts are ongoing to improve response to PARP inhibitors by combining them with other targeted drugs, including immunotherapy and CDK 4/6 inhibitors and to identify biomarkers to improve selection of patients most likely to benefit. For more on clinical trials for patients with triple negative breast cancer go to breastcancertrials.org.
Liquid biopsies and triple negative breast cancer
Liquid biopsy is emerging as a non-invasive alternative to tissue biopsy for monitoring disease progression, tumor response to treatment and even to predict prognosis. These blood tests have the potential to change the way breast cancer is diagnosed and followed throughout treatment and recovery.
BCRF researchers are applying this tool in a variety of studies, including those focused on triple negative breast cancer, to identify biomarkers. These can guide treatment decisions in real time that can save or extend lives.
Two notable studies published this past year include:
1) In a study published last November, BCRF researchers used data obtained from liquid biopsies to identify a gene signature to predict outcome for triple negative breast cancer patients.
2)Earlier this year, BCRF researchers used liquid biopsy to analyze cell free DNA (cfDNA) to identify patients with metastatic TNBC who were at a high risk of dying from their disease. The study, published in the Journal of Clinical Oncology, also identified unique genetic alterations in cancer-associated genes in mTNBC compared to primary TNBC (pTNBC).
More than 20 BCRF investigators were instrumental in the advancement of PARP inhibitors. BCRF thanks Dr. Mark Robson, Memorial Sloan Kettering Cancer Center, Dr. Nadine Tung, Beth Israel Deaconess Medical Center and Dr. Alan Ashworth, University of California, San Francisco (formaly of Institute of Cancer Research UK) for contributing the this article.