Breast Cancer Expert Offers Views on Promising Strategies

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

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

Other treatments have added targeted agents, such as everolimus in combination with exemestane in nonsteroidal aromatase inhibitor-resistant ER+ breast cancer. The data have shown this combination to be active, although with some toxicities.⁴ Now combinations of novel agents are being evaluated in the clinic.

What are your thoughts regarding sequencing therapies?

In breast cancer, most of us are convinced that, in most cases, sequential single agents are as effective as combinations of agents. In ER+ breast cancer, we try to sequence a number of hormonal agents before going to chemotherapy combinations, because the hormonal agents can be very active and generally have less toxicity than chemotherapy. There are no strong data to support the use of chemotherapy upfront over anti-estrogen. In HER2+ breast cancer, trastuzumab-based chemotherapy regimens are the standard of care. Now there are newer agents for the treatment of HER2+ disease, such as trastuzumab T-DM1. There are also other HER2 antibodies, such as pertuzumab. Also, recent data suggest some role for the mammalian target of rapamycin (mTOR) inhibitor everolimus.⁴ Treatment of this group of patients really depends on how they were treated in the adjuvant setting and the disease-free interval. Needless to say, the backbone will always be an anti-HER2 agent as we sequence through combination partners.

In triple-negative breast cancer, there’s obviously an area of great unmet medical need. Since there is no targeted agent, you’re generally sequencing through cytotoxics.

How does targeting an entire pathway, such as phosphatidylinositol 3-kinase (PI3K), differ from targeting a molecular abnormality that is unique to cancer cells?

The PI3K pathway is a major regulator of cellular growth and metabolism in both normal and cancerous cells. PI3K mutations have been described with various frequencies in a number of malignancies. In addition, PI3K is downstream from several growth-factor receptors, many of which have been implicated as being important in breast cancer. It raises the question of whether to develop these drugs in the context of a specific PI3K mutation in a population selected just for that versus in patients who do not have mutations in the PI3K pathway per se, but because of its central role in other pathogenetic alterations, targeting it might be of benefit. To date, there has been no correlation of any predictive marker with response to these agents. None of these agents has been approved, although several are in registration studies in various settings, except for mTOR, which is within the PI3K pathway but also is a target for treatment. Targeting mTOR has been shown to be of benefit,⁴ and everolimus is approved in several indications, including breast cancer, kidney cancer, and pancreatic neuroendocrine tumors.

The jury is still out on the role of PI3K inhibitors in cancer until we have positive clinical data that show that targeting the pathway is important.

Are there any novel agents or classes of agents that you think hold particular promise?

We have been very fortunate to be involved in the development of a novel cyclin-dependent kinase 4/6 (CDK 4/6) inhibitor, PD-0332991, or palbociclib, as it is now known. CDKs are very important in the regulation of cell cycle in both normal and malignant cells. The idea was raised many years ago that targeting CDKs might be a way of treating cancer. Over the past decade or more, several CDK inhibitors have been evaluated in the clinic, none of them moving to registration or to approval, none of them showing very robust clinical activity, especially if you consider solid tumor oncology, where these drugs have been pursued and have failed.

At the UCLA laboratory, we evaluated the potential role of palbociclib in preclinical models of breast cancer, not knowing which specific biomarker would be important for selecting patients. The preclinical work identified a very strong role for CDK 4/6 inhibition in models that represented ER+ breast cancer, as well as in models that represented HER2+ breast cancer. We did not see a significant amount of preclinical activity in triple-negative breast cancer with a single agent. We then demonstrated that there was profound synergy preclinically between blocking the CDK 4/6 pathway and the estrogen pathway with tamoxifen.⁵

We used these data to push forward a phase I/II study evaluating anti-estrogen therapy in combination with CDK 4/6. The results from this randomized study of just over 160 patients were quite striking.⁶ This was in postmenopausal women with front-line, ER+ breast cancer. Women were randomized to letrozole versus letrozole plus palbociclib. Looking at the primary endpoint of progression-free survival (PFS), we saw a significant increase in the combination arm, from 7.5 months with letrozole to more than 26 months with the combination. Other endpoints were markedly improved with the addition of palbociclib, such as response rate and disease control rate. Very importantly, the significant increase in PFS was not associated with significant toxicity. The most common side effects were low-grade fatigue and neutropenia, which was often grade 3, but there was no incidence of neutropenic fever. From what we can tell, this leukopenia/neutropenia was really a laboratory observation that did not have any clinical sequelae.⁶

A phase III study is evaluating letrozole plus palbociclib versus letrozole alone using a 2:1 randomization, and the hope is that we will recapitulate the findings of the phase II study.⁷ There are now other studies of palbociclib and other CDK inhibitors in similar populations, including a compound from Novartis, LEE011, as well as a compound from Eli Lilly, that are moving through clinical development, largely based on breast cancer treatment that includes palbociclib.

Do you have any specific advice for community oncologists about the use of targeted therapies for breast cancer?

We’re very excited about the promise of targeted agents. We’ve seen remarkable improvements in patient outcomes with the use of these agents. One of the most important things to keep in mind is that we should continue to use these agents in the settings in which they’ve been studied, in the populations we suspect will benefit, testing for specific biomarkers when they exist. We need to also keep in mind that, for many patients, participation in clinical studies is very important to help us better understand how to move things forward. Even when we have drugs that work pretty well, we can always improve, so participation in and referral to clinical studies need to be priorities for the oncology community.

References

1. O’Shaughnessy J, Osborne C, Pippen JE, et al. Iniparib plus chemotherapy in metastatic triple-negative breast cancer. N Engl J Med. 2011;364(3):205-214.
2. O’Shaughnessy J, Schwartzberg LS, Danso MA, et al. A randomized phase III study of iniparib (BSI-201) in combination with gemcitabine/carboplatin (G/C) in metastatic triple-negative breast cancer (TNBC). J Clin Oncol. 2011;29(suppl 15; abstr 1007).
3. Slamon DJ, Swain SM, Buyse M, et al. Primary results from BETH, a phase 3 controlled study of adjuvant chemotherapy and trastuzumab ± bevacizumab in patients with HER2-positive, node-positive or high risk node-negative breast cancer. Presented at: 2013 San Antonio Breast Cancer Symposium; December 10-14, 2013; San Antonio, TX. Abstract S1-03.
4. Beaver JA, Park BH. The BOLERO-2 trial: the addition of everolimus to exemestane in the treatment of postmenopausal hormone receptor-positive advanced breast cancer. Future Oncol. 2012;658(6):651-657.
5. Finn RS, Dering J, Conklin D, et al. PD 0332991, a selective cyclin-D kinase 4/6 inhibitor, preferentially inhibits proliferation of luminal estrogen receptor-positive human breast cancer cell lines in vitro. Breast Cancer Res. 2009;11(5):R77.
6. Finn RS, Crown JP, Lang I, et al. Results of a randomized phase 2 study of PD 0332991, a cyclin-dependent kinase (CDK) 4/6 inhibitor, in combination with letrozole vs letrozole alone for first-line treatment of ER+/HER2- advanced breast cancer (BC). Presented at the 2012 San Antonio Breast Cancer Symposium; December 5, 2012; San Antonio, TX. Abstract S1-6.
7. ClinicalTrials.gov. A randomized, multicenter, double-blind phase 3 study of PD-0332991 (oral CDK 4/6 inhibitor) plus letrozole versus placebo plus letrozole for the treatment of postmenopausal women with ER (+), HER2 (-) breast cancer who have not received any prior systemic anticancer treatment for advanced disease. Identifier NCT01740427.