Delaying resistance to hormone therapy and prolonging PFS in women with hormone receptor-positive, advanced disease have remained elusive goals in breast cancer treatment.
Delaying resistance to hormone therapy and prolonging progression-free survival (PFS) in women with hormone receptor-positive, advanced disease have remained elusive goals in breast cancer treatment, but research continues to refine the possibilities of potentially promising treatments in subsets of patients with hormone-positive disease.In 2012, the FDA approved everolimus (Afinitor) in combination with the aromatase inhibitor (AI) exemestane (Aromasin) to treat postmenopausal women with advanced hormone-receptor positive, HER2-negative breast cancer (BC) whose cancer had recurred or progressed after treatment with the AIs letrozole (Femara) or anastrozole (Arimidex).1 This approval was based on BOLERO-2, a clinical study of more than 700 patients that showed patients who took the drug in combination with exemestane had a 4.6-month improvement in the median time to disease progression or death compared with patients receiving exemestane alone.2
“Adding everolimus to hormone therapy led to modestly improved outcomes in metastatic disease. This is a drug that has promise, but there are concerns about toxicity and cost,” said Richard M. Elledge, MD, a medical oncologist at The University of Texas Health Science Center at San Antonio. The most common side effects are mouth ulcers, infections, rash, fatigue, diarrhea, and decreased appetite.A phase II study of the Src (proto-oncogene) inhibitor dasatinib (Sprycel) in combination with hormone therapy, presented at the 2013 San Antonio Breast Cancer Symposium (SABCS),3 showed what Elledge called “a somewhat unexpected benefit of adding dasatinib to hormonal therapy, which should be explored in further study.”
“I wasn’t convinced that Src inhibitors could play a significant role in breast cancer treatment overall, but perhaps further refinement of tumor types could cone down on a subset where they may be effective,” he noted. “Alternatively, there is the possibility that the trial findings could be due to an unknown target effect or downstream mechanism, not directly involving Src.”
Src, a tyrosine kinase protein, has been linked to cancer progression, including metastasis to the bone in breast cancer.3Dasatinib has been approved by the FDA for the treatment of chronic myelogenous leukemia.Elledge said that he is still waiting for conclusive confirmation of the efficacy of combining fulvestrant (Faslodex) with the AI anastrozole for the treatment of postmenopausal women with estrogen receptor-positive (ER+) metastatic disease.
Two of the principal studies evaluating the combination show conflicting findings, he noted. While a SWOG study showed a 6-month improvement in survival for patients with hormone receptor (HR)-positive, metastatic BC, a Swedish study showed no sign of prolongation.4
“What’s needed going forward is a molecular analysis of tumor blocks from these studies to see if there is evidence of a particular tumor type that benefits substantially. The SWOG study may have had a higher proportion of ER-positive tumors that were primarily sensitive to hormonal therapy,” Elledge said. “Conversely, if a substantial portion of tumors is primarily refractory to hormonal therapy, adding more or better hormonal therapy won’t improve any outcome, and the signal will be lost in the noise. That’s what may have occurred with the Swedish study.”
SWOG, he said, will in part revist the issue of the combination of fulvestrant and an AI in the future with the S1222 study. It will compare fulvestrant alone to fulvestrant and everolimus versus fulvestrant, everolimus, and anastrozole.“The importance of variation in tumor biology is becoming more clinically relevant in hormone-positive disease,” Elledge added. “While this complexity and variability have been well known for many decades, it becomes important because we now have the pure technical capability to analyze tumor samples to potentially refine treatment, and we also have more options to choose from. We know that targeted therapies are only beneficial in certain breast cancer types, a conceptual paradigm that goes back to the early 1970s.”
Elledge pointed, for example, to studies conducted by Matthew J. Ellis, MD, PhD, and colleagues at the Washington University School of Medicine on genomic differences in ER+ subtypes and their response to treatment.
“Their work has shed light on the wide dispersion of mutations and their linkage to clinical characteristics and response. It gives us knowledge and food for thought on the realistic challenges that we face in the future. Breast cancer is quite diverse and hormone therapy resistance is multifaceted and specific. This is not necessarily what we wanted to find, but it’s an important realization,” he said, noting, for example, “Tumors that are not sensitive to hormonal agents have high proliferation rates and more often worse outcomes. The luminal B subtype of ER-positive breast cancers comprises a large portion of these cancersabout 20%–and they constitute an unmet need.”Looking ahead, Elledge pointed to cyclin-dependent kinases (CDK-4/6) and PI3 kinase inhibitors as targeted therapies with potential. “CDK-4/6 inhibitors appear promising,” he said, pointing to what he described as a small but notable phase II trial of the compound palbociclib in combination with letrozole that significantly extended PFS compared with letrozole alone in postmenopausal women with ER-positive, HER2-negative, locally advanced or metastatic BC. The drug’s maker, Pfizer, received breakthrough therapy designation for the drug in in April 2013. In February 2014, the company announced that the trial had achieved its primary endpoint by demonstrating statistically significant and clinically meaningful improvement in PFS. A randomized, global phase III trial is currently enrolling patients. According to Elledge, CDK-4/6 conceivably may have an impact in more proliferative, ER-positive disease, sometimes labeled luminal B.
Palbociclib is an oral inhibitor of CDK 4 and 6, which both enable tumor cell progression, leading to DNA replication and cell division.5
“Trials have been done for many years in which CDK inhibitors have all failed, but this one succeeded,” Elledge noted. He called PI3 kinase alteration “a potentially important target in ER-positive breast cancer,” but added that clinical studies are still early.
“This is still in phase I for the most part and hyperglycemia is one of the side effects, which is a concern with so much diabetes in this country. We will have to watch that carefully,” he said.At the end of 2013, drug companies Medivation, Inc. and Astellas Pharma announced the initiation of a phase II clinical trial evaluating the safety and efficacy of enzalutamide, an androgen-receptor inhibitor, in combination with exemestane in women with advanced, hormone-positive cancer that is HER2 normal.6
The randomized, phase II study will enroll 240 postmenopausal women with advanced breast cancer that is ER-positive or progesterone receptor (PgR)-positive and HER2 normal who have received no more than one prior chemotherapy and one prior hormonal treatment for their advanced disease. The patients will be divided into two cohorts: a group that has not previously received hormonal treatment for advanced BC and a second group that has progressed following one hormonal treatment for advanced disease. The primary endpoint of the trial is PFS in all patients and in the subset of patients whose tumor expresses the androgen receptor.
Enzalutamide was approved by the FDA in 2012 for the treatment of patients with metastatic castration-resistant prostate cancer. “Androgen receptor is expressed in breast cancer cells and is overall associated with a better prognosis, similar to ER. Inhibition of androgen receptors in vitro by androgen-receptor antagonists can slow breast cancer growth,” Elledge said. Suzanne A. W. Fuqua, PhD, professor of Medicine, Baylor College of Medicine, and colleagues “showed several years ago that androgen receptor expression can cause hormone therapy resistance and that blocking it abrogates that resistance,” Elledge continued. “Enzulamide is a more potent androgen receptor antagonist than earlier ones, a better mouse trap, perhaps. It’s an interesting strategy and one worth following.”In other prevention news, Elledge said he was particularly encouraged by the recent reports emerging from IBIS-II,7a study evaluating the effectiveness of anastrozole in preventing disease in high-risk, postmenopausal women.
Presented at SABCS in 2013 by lead author Jack Cuzick, PhD, head of the Cancer Research UK Centre for Cancer Prevention and director of the Wolfson Institute of Preventive Medicine at Queen Mary University in London, the study’s findings indicated that anastrozole reduced the risk of breast cancer by 53% in postmenopausal women at high risk. The study authors said they planned to continue following patients in the study for at least 10 years and possibly longer to see whether or not the results hold even after stopping treatment and to monitor side effects long-term.7
“IBIS II told us what we already sort of knew, but it cemented it. The drug reduced breast cancer incidence by half, but had no effect on breast cancer death,” he said. “I think the most important contribution of this study was the finding that this drug has few side effects compared to placebo, fewer than most expected. These findings are consistent with results from an earlier exemestane prevention trial.”