Dr. Sharma was awarded the 2015 Advanced Clinical Research Award in Breast Cancer from the American Society of Clinical Oncology to continue her research on triple-negative breast cancer detailed below.

Chasing the Invisible Trail of Targeting Triple-Negative Breast Cancer

How do you treat a cancer that does not have a readily identifiable molecular target?

This is currently the case for triple-negative breast cancer, according to Priyanka Sharma, MD, member of the Drug Discovery, Delivery and Experimental Therapeutics Program at The University of Kansas Cancer Center, and associate professor of hematology and oncology at the University of Kansas Medical Center.  Dr. Sharma is working to identify markers that would improve the treatment of triple-negative breast cancer.

Triple-negative breast cancer is a “wastebasket term” because unlike other subtypes of breast cancer that are defined by the presence of therapeutic markers, triple-negative breast cancer is defined by the absence of therapeutic markers (estrogen receptor, progesterone receptors and HER2 protein). And, as Dr. Sharma puts it, “You can’t target something that doesn’t exist. We still haven’t figured out how to define triple-negative breast cancer by the presence of markers that can turn into valid actionable targets.”

What makes up BRCAness?

Dr. Sharma is looking at what she’s calling “BRCAness” or deficiency in DNA damage repair machinery (specifically homologous recombination repair pathway defects) in triple-negative breast cancer as a potential prognostic and predictive marker. Triple-negative breast cancer and cancer that arises in patients with heritable germline BRCA1 mutations share several phenotypic and molecular similarities.

While only about 10 to 20 percent of triple-negative breast cancer patients have a germline BRCA mutation, it is believed that 50 to 70 percent of patients with triple-negative breast cancer may harbor BRCAness. BRCA1 and BRCA2 are genes that code for proteins that are vital in repairing DNA breaks through homologous recombination repair mechanism. In people with a heritable germline mutation on BRCA1 or BRCA2, DNA repair is defective, and this ultimately leads to breast and other types of cancers.

Similarly, this kind of DNA repair deficiency could happen with germline or somatic alterations (mutations, rearrangements, DNA methylation) in other genes that are involved in DNA repair pathway. Researchers, including Dr. Sharma, believe that those BRCA1 mutation-associated cancers and other cancers that express BRCAness can potentially be treated the same way.

As BRCAness is comprised of many distinct properties, a single test is unlikely to identify BRCAness patients that will benefit from BRCA1-directed therapy. Dr. Sharma is studying a platform of four markers to detect BRCAness that include BRCA1 promoter methylation, homologous recombination deficiency score, BRCA1 expression and tumor infiltrating lymphocytes. Dr. Sharma is using data and specimens from an already completed SWOG clinical trial that utilized standard adjuvant chemotherapy treatment.

BRCAness Promoter Region Diagram

A BRCA1 promoter locus. α and β are the two promoters of the human BRCA1 gene. Methylation of BRCA 1 promoter region causes silencing of BRCA1 gene.

By identifying which combination of these markers contributes the most to BRCAness, it would be easier to predict a patient’s prognosis and determine specific triple-negative cases that would be at significant risk for recurrence after primary treatment.

Besides finding targetable biomarkers, one of the other challenges with treating triple-negative breast cancer is that chemotherapy treatment options have not changed significantly in the last 10 years, according to Dr. Sharma. Although it is clear that triple-negative breast cancer is very different from other types of breast cancer, the current standard is to use the same chemotherapy for all sub-types of breast cancers.

Pinpointing the perfect drug

There is renewed interest, however, in studying platinum-based chemotherapies in triple-negative and BRCA-associated breast cancer. Platinum-based chemotherapies (like cisplatin and carboplatin) may be effective for treatment of breast cancers with BRCAness because they bind to DNA and interfere with the cell’s repair mechanism, causing it to die.

“This biomarker project would play an important role in identifying triple-negative breast cancer patients who might benefit the most from robust DNA damaging agents like platinum compounds and PARP inhibitors,” said Dr. Sharma. PARP inhibitors are a type of targeted agents that also impede DNA repair and are being studied in treatment of cancers in patients with BRCA1 and BRCA2 mutations and in patients with triple-negative breast cancer.

The hypothesis that these drugs may be a better treatment option is based off a pilot grant funded by The University of Kansas Cancer Center.  Working in collaboration with Andy Godwin, PhD, deputy director of The University of Kansas Cancer Center and director of the Biospecimen Repository, and Roy Jensen, MD, director of The University of Kansas Cancer Center, Dr. Sharma  looked at the impact of BRCA promoter methylation, expression and mutations and found that “when  BRCAness was present, treatment with a platinum-based chemotherapy was associated with a very good long-term outcome,” said Dr. Sharma.

By researching BRCAness markers like BRCA promoter methylation, expression, homologous recombination deficiency, and gene expression patters, Dr. Sharma is hoping she can give a more concrete definition to the BRCAness phenotype in triple-negative breast cancer.

“The key to improving treatment outcomes in triple-negative breast cancer is to focus research efforts on biomarkers of response and resistance to standard and novel agents,” she said.

 

Funding sources

Relevant publications

  • Sharma, Priyanka, et al. "Germline BRCA mutation evaluation in a prospective triple-negative breast cancer registry: implications for hereditary breast and/or ovarian cancer syndrome testing." Breast cancer research and treatment 145.3 (2014): 707-714.
  • Stecklein, Shane R., and Priyanka Sharma. "Tumor homologous recombination deficiency assays: another step closer to clinical application?." Breast Cancer Research 16.4 (2014): 409.
  • Bhalla, K. N., Rao, R., Sharma, P., Das Gupta, S., Chauhan, L., & Stecklein, S. (2012). Treatment with histone deacetylase inhibitors creates ‘BRCAness’ and sensitizes human triple negative breast cancer cells to PARP inhibitors and cisplatin. Cancer Res, 72(24 Suppl), S3-7.

What Is Triple-Negative Breast Cancer?

  • 1. Triple-negative breast cancer does not express the genes for estrogen receptor, progesterone receptor or the
        HER2 oncogene. Thus there is no obvious drug target for doctors to turn to right away.
  • 2. About 10 to 20 percent of breast cancer cases are triple-negative.
  • 3. The main demographics for this type of cancer are younger women (between the ages of 40 and 50),
        African-American and Hispanic women and people with a BRCA1 mutation.