Breast Cancer Expert Offers Views on Promising Strategies

Published Online: Tuesday, April 1, 2014
Dr. Richard Finn

Richard Finn, MD

 

Associate Professor, Medicine
Geffen School of Medicine
University of California, Los Angeles
Los Angeles, CA

Now that targeted therapies are available for the treatment of various subtypes of breast cancer, and many novel agents are under investigation, it is important for the oncology community to follow the latest advancements to give patients the best available options. OncologyLive discussed various issues regarding new and existing therapies in breast cancer with Richard Finn, MD, associate professor of Medicine, Geffen School of Medicine, Division of Hematology/Oncology, UCLA.

OncologyLive: How might poly(ADP-ribose) polymerase (PARP) inhibition be able to restore DNA repair processes?

Finn: The theory is that tumors that carry defects in BRCA (the breast cancer susceptibility gene), which is part of the DNA repair cascade, are at risk for single-strand DNA breaks, and repairs of those breaks depend on a complex that includes the PARP protein [Figure]. By inhibiting PARP in the context of inherent DNA repair defects, you set up the cell for developing double-strand DNA defects, and then a catastrophic death from irreparable DNA damage.

Because many BRCA-mutated cancers are triple negative, it was rational to evaluate PARP inhibitors for triple-negative breast cancer. The challenge is that most triple- negative breast cancers are not BRCA, even though the converse might be true. The idea of PARP inhibitors outside of BRCA mutations is also an interesting idea, but it still needs to be evaluated in the context of knowing whom to treat or how to select them, or the best combinations.

There also might be potential synergy between DNA-damaging agents and a compound that blocks DNA repair, such as a PARP inhibitor. That led to a randomized, phase II study with iniparib in triple-negative breast cancer that looked very promising, with significant improvement in overall survival with iniparib, platinum, and gemcitabine versus platinum and gemcitabine alone.1 However, in a larger, randomized, phase III study, that benefit was lost, which was a big setback to the PARP field.2

There may be a role for these drugs, but you really need to have a predictive marker for response. Potentially, the best predictive marker we have is BRCA-mutated status, but not all BRCA mutations are the same.

Figure. PARP Mechanism and Inhibition

PARP Mechanism and Inhibition

BER indicates base excision repair;
NAD, nicotinamide adenine dinucleotide.



What is the standard treatment now to prevent the recurrence of HER2+, node-negative tumors?

We know that HER2 amplification is a negative prognosticator in breast cancer. Historically, HER2-amplified breast tumors have one of the worst outcomes. We know that, even in the setting of node-negative disease, HER2 amplification is a marker for increased risk of relapse and recurrence, and, while there are other characteristics of the tumor that might come into play, many of us feel that these patients should receive trastuzumab. My opinion would be that the TCH (taxane/platinum/trastuzumab) regimen offers the best risk-benefit ratio for adjuvant therapy for these women. Specifically, it decreases the risk of anthracycline-associated cardiotoxicity without compromising any disease-control benefits.

Could adding an androgen receptor (AR)-targeted agent to estrogen receptor (ER)-targeted therapy potentially improve outcomes for patients who are both ER+ and AR+?

Expression of the androgen receptor in breast cancer is well documented. The pathologic role of this receptor is not exactly clear. Now that we have very good agents that target the AR, exploring the importance of this receptor in treating patients with breast cancer needs to be evaluated. I would not necessarily rule out the idea that targeting AR may be of benefit. Its presence may be important in breast cancer pathogenesis and treatment, but it needs to be evaluated in clinical trials.

What are your thoughts on combination therapy possibilities?

Combination chemotherapy has been around for many years. The idea of combining biologic agents is of great interest, and, maybe in the next few years, we’ll see that combining two biologics can increase the efficacy of our treatment options without increasing toxicity. In breast cancer, we unfortunately recently saw negative data with the addition of bevacizumab, the vascular endothelial growth factor (VEGF)–targeted antibody, to trastuzumab-based therapy for advanced HER2+ breast cancer.3

Online CME Activities
Free CME from PER
Community Practice Connections: 13th Annual International Congress on the Future of Breast Cancer®
Highlights From the 13th Annual International Congress on the Future of Breast Cancer®
Pancreatic Cancer: Novel and Emerging Approaches to Early Detection and Treatment
Oncology Best Practice: Challenges in Treating Chronic Lymphocytic Leukemia – The Older Patient and Comorbid Conditions
More Reading
$auto_registration$