PARP Inhibitors in BRCA Wild-Type Breast Cancer

Saima Noor Hassan, MD, PhD

Today, ahead of the American Society of Clinical Oncology’s 2015 Breast Cancer Symposium being held in San Francisco, California from September 25th to the 27th, we are speaking with presenter Saima Noor Hassan, MD, PhD, a clinician and researcher at the Oregon Health and Science University in Portland, Oregon. Dr. Hassan is presenting a preclinical study of the response of various poly (ADP-ribose) polymerase or PARP inhibitors currently being tested in clinical trials that may help researchers understand which breast cancer subtypes are most likely to respond to this drug class.

-Interviewed by Anna Azvolinsky, PhD

OncoTherapy Network:Could you tell us what PARP inhibitors are and the rationale for testing these drugs in breast cancer?

Dr. Hassan: Sure. PARP inhibitors are therapeutic agents that inhibit the activity of the PARP enzyme which belongs to the family of enzymes involved in DNA damage repair. Although there are a few proposed theories to help explain the mechanism of action of PARP inhibitors, I will explain the mechanism that is best understood.

In very simplistic terms, if one looks at DNA as a double-stranded helix, DNA damage can occur to either one or both strands. Normally, when there is a single-stranded break in DNA, the PARP enzyme is recruited to the DNA and catalyzes a series of events leading to DNA repair. When there is damage to both strands of DNA, DNA repair can occur via a mechanism called "homologous recombination" where an exchange of DNA strands containing similar nucleotide sequences occurs. PARP inhibition causes a defect in single-strand break repair leading to double-stranded breaks and stalling of the replication fork. Cancers with BRCA mutations have defective homologous recombination causing impaired double-stranded break repair. The combination of PARP inhibition and BRCA mutation leads to a double hit, also known as synthetic lethality, causing cell death.

PARP inhibitors are being tested in breast cancer in two main cohorts. The first are patients with BRCA mutations which consist of about 5% of breast cancer patients and the second are patients who have tumors similar to BRCA-mutated tumors, called "BRCA-ness." These tumors have a molecular, histopathological, and clinical similarities to tumors with BRCA mutations, but do not possess the germline mutation. Triple-negative breast cancers demonstrate BRCA-ness as they are defective in base excision repair and are similar in their hormone, HER2 receptor, and p53 mutation status. Triple-negative breast cancer constitutes 15% to 20% of breast cancer patients, and so there is a strong biological rationale to test PARP inhibitors in breast cancers.

OncoTherapy Network:Could you tell us the major outstanding questions about the potential efficacy of PARP inhibitors in these breast cancer subtypes?

Dr. Hassan: There are several questions with regards to PARP inhibitors; however, I believe there are three main outstanding questions.

First, there are several PARP inhibitors being tested in clinical trials across several types of cancers. Olaparib and veliparib are being tested in over 80 clinical trials each whereas testing with BMN673 has only recently started over the past 2 years. As such, it is not well known which of these PARP inhibitors may have a better therapeutic response albeit as a single-agent or in combination. The second question is to identify the cohort of breast cancer patients that will best respond to PARP inhibition. Triple-negative breast cancer is a very heterogeneous group of cancers and it would be important to better select which group of patients may have improved outcomes with PARP inhibition. There are several genome-derived prediction scores that are under investigation including those that assess loss of heterozygocity and deficiency in homologous recombination, yet these scores are yet to be validated in clinical cohorts in a randomized or prospective manner. The third major question is to better understand when to use PARP inhibition in combination and with which therapeutic agent. PARP inhibitors are being tested in combination with other DNA damaging agents, such as carboplatin which is also used for triple-negative breast cancer and temozolomide, an agent more commonly used for brain tumors. However, it is not well understood if there are other therapeutic agents that may be more effective with anti-PARP therapy, so there has been much progress in the development of PARP inhibitors, but there are significant questions which have yet to be answered.

OncoTherapy Network:Could you tell us about the study you conducted? What was the question you and your colleagues wanted to address and the approach you took?

Dr. Hassan: I conducted a preclinical study in a laboratory with two main objectives. The first was to compare therapeutic efficacy of three different PARP inhibitors: olaparib, veliparib, and BMN673. And the second is to identify biological predictors of response and resistance to PARP inhibition. One of the long-standing challenges that we have with translational research is the disconnect with preclinical therapeutic efficacy and the responses observed in phase II and III clinical trials. Previous studies with PARP inhibitors have used different methodologies and surrogate assays to measure cell viability. We used a panel of triple-negative breast cancer cell lines and high-content imaging which allowed for rapid and direct assessment of cell number and protein expression. High-content imaging also enables single cell analysis. Therefore, in looking at DNA damage response and apoptosis, we observed variability in response across cell lines. In order to better quantify the impact of the PARP inhibitors on cellular phenotype, I created a cell death DNA damage response score. This was able to distinguish which BRCA wild-type breast cancer cell lines may be more responsive to single-agent DNA damage agents or in combination. To summarize, we used a novel cell imaging and analytical approach to better understand response and resistance to PARP inhibition.

OncoTherapy Network:Just briefly, are you following up this work with other preclinical studies or collaborating on clinical trials?

Dr. Hassan: I’m quite excited about these initial findings and there are various avenues that need to be pursued. From a preclinical perspective, we need to broaden the panel of breast cancer cell lines. This will allow us to better characterize the cell lines genomically and to better make correlations between genotype and phenotype, and to determine which breast cancer subtypes may better respond to PARP inhibition. In order to better understand which agents may work best in combination with anti-PARP therapy, a broad panel of therapeutic agents will need to be tested and scored using the cell death DNA damage response score. Furthermore, I am very much interested in validating the score on tissue samples from breast cancer patients. The specific cohort I am looking for are trial patients who are partial or nonresponders to anti-PARP therapies in the neoadjuvant setting. Testing in this setting will not only determine why the response was suboptimal, but how to direct subsequent therapy.

OncoTherapy Network:Thank you so much, Dr. Hassan for joining us and looking forward to your presentation at the symposium.

Dr. Hassan: Thank you very much.

References:

• Hassan SN, Esch A, Heiser L, Gray JW. (2015). Biological indicators of response and resistance to PARP inhibition in BRCA wild-type breast cancer (Abstract #125). American Society of Clinical Oncology (ASCO) 2015 Breast Cancer Symposium.