Partnering Therapies for Estrogen Receptor–Positive Breast Cancer Requires Close Monitoring and Patient Communication

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William J. Gradishar, MD

There are some distinct side effects that have been demonstrated with abemaciclib, and we will need larger trial results to define the toxicity profile and how it is distinct or not from palbociclib.

—William J. Gradishar, MD

Partnering endocrine therapy with new targeted agents for women with estrogen receptor–positive breast cancer “changes the nature of endocrine therapy from something easily tolerated, with not a lot that you have to do as physicians to monitor it,” William J. Gradishar, MD, of the Robert H. Lurie Comprehensive Cancer Center, Chicago, said in a presentation at the Lynn Sage Breast Cancer Symposium in Chicago.1 Introducing targeted agents, such as CDK 4/6 and mTOR inhibitors, also introduces a different set of toxicities, and “patients have to be made aware of what they can anticipate as they start on these treatment approaches,” Dr. ­Gradishar added.

The 5-Year Benchmark

“Despite our therapies, the successes, and the debate about the duration of endocrine therapy, we still know that a significant fraction of patients with estrogen receptor–positive will recur,” Dr. Gradishar stated. In an interview with The ASCO Post, Dr. Gradishar said that although clinicians generally are aware of “the long tail of estrogen receptor–positive breast cancer” extending over many years, “patients still have in their minds the 5-year benchmark. We don’t try to dissuade them that reaching the 5-year benchmark is a good thing, but we try to make them aware that recurrences can develop even decades later.”

The extended risk of recurrence has driven the search for new partners for endocrine therapy. Guidelines from the National Comprehensive Cancer Network (NCCN) now include therapies targeting mechanisms of endocrine resistance. “Selection is important,” Dr. Gradishar stressed. “These drugs have side effects that aren’t what you would typically associate with antihormone therapy.” They can start to resemble the toxicity profile of some chemotherapy agents.

Targeting CDK 4/6

Palbociclib (Ibrance) is the first drug approved to focus on the CDK 4/6 pathway “as a way of either overcoming resistance or enhancing the effect of endocrine therapy,” Dr. Gradishar stated. “It basically blocks the ability of the cell to progress through the cell cycle.”

Breakthrough Therapy designation for palbociclib in 2013 was based on a phase II trial (PALOMA-1),2 which showed “time to disease progression doubled,” Dr. Gradishar noted, with palbociclib plus letrozole vs letrozole alone as initial treatment for women with newly diagnosed advanced estrogen receptor–positive breast cancer. That led to PALOMA-3, a double-blind, phase III trial of palbociclib with fulvestrant (Faslodex) or fulvestrant with placebo in women with hormone receptor–positive, HER2-negative advanced breast cancer that relapsed or progressed on prior endocrine therapy. Final results of the study are not yet available, but a preplanned interim analysis, reported recently in The New England Journal of Medicine,3 found palbociclib combined with fulvestrant resulted in longer progression-free survival than fulvestrant alone (9.2 vs 3.8 months).

“The toxicity profile seems to be largely restricted to the effects on the blood counts, and patients generally feel pretty well during treatment,” Dr. ­Gradishar revealed. The published interim analysis reported that neutropenia of any grade occurred in 78.8% of patients receiving palbociclib and fulvestrant vs 3.5% of those receiving fulvestrant with placebo. The corresponding rates for other hematologic adverse events were 45.5% vs 4.1% for leukopenia, 26.1% vs 9.9% for anemia, and 19.4% vs 0% for thrombocytopenia.

In response to a question from the audience about which patients to consider for pablociclib, Dr. Gradishar replied that for most patients treated for estrogen receptor–positive breast cancer and taking endocrine therapy, “we at least discuss it now. But patients do have to come in and have their blood counts checked. To a large extent, we are offering it to patients, because it is not a smidgen of an improvement, it is quite a bit of an improvement.”

Newer CDK 4/6 Inhibitors

“There are competitors” to pablociclib, Dr. Gradishar noted. One of them, abemaciclib (LY2835219), “has been shown to have monotherapy activity” in advanced or metastatic breast cancer, he said. In a study presented at the 2014 San Antonio Breast Cancer Symposium by Tolaney et al,4 abemaciclib monotherapy produced overall response rates of 25.5% (12 of 47 patients), but for hormone receptor–positive patients, the rate was 33.3% (12 of 36 patients), vs 0% (0 of 9 patients) for hormone receptor–negative patients.

Other data presented by Tolaney et al at the 2015 ASCO Annual Meeting5 showed changes in tumor size, mostly decreases but some increases as well, when abemaciclib was combined with letrozole, anastrozole, tamoxifen, exemestane, and exemestane plus everolimus (Afinitor). There are also ongoing trials with abemaciclib combined with those and other agents.

“There are some distinct side effects that have been demonstrated with abemaciclib,” Dr. Gradishar said, “and we will need larger trial results to define the toxicity profile and how it is distinct or not from palbociclib.” Neutropenia and leukopenia have been reported when abemaciclib was used in a phase I breast cancer study. In October 2015, Eli Lilly and Company, the drug’s manufacturer, announced that the U.S. Food and Drug Administration granted Breakthrough Therapy designation for abemaciclib for patients with refractory hormone receptor–positive advanced or metastatic breast cancer.6

Another CDK 4/6 inhibitor, ribociclib (LEE011), is also being tested in combination with other drugs in several ongoing trials.

“If it is demonstrated that these drugs, as we would expect, do have activity in conjunction with endocrine therapy,” Dr. Gradishar believes that several questions still need to answered. “If they are in the same class, will they have distinct uses? Will they be able to be used after disease progression? If you happen to progress on one, would you be a candidate for another?”

Histone Deacetylase Inhibitors

Several inhibitors of histone deacetylase are being tested in clinical trials of breast and other cancers, with entinostat being the farthest along in breast cancer. According to Dr. Gradishar, there are preclinical data showing that by adding entinostat to tumors that have already demonstrated resistance to endocrine therapy alone, “you can actually drive down the growth of the tumor.”

ENCORE 301 is a phase II trial that randomized postmenopausal women with metastatic or locally advanced estrogen receptor–positive breast cancer progressing on the nonsteroidal aromatase inhibitors anastrozole or letrozole to exemestane with either entinostat or placebo. “At first blush, the result doesn’t look so good. The progression-free survival curves look almost superimposable,” Dr. Gradishar noted. “But surprisingly, despite progression-free survival not being altered in any way, overall survival was enhanced to a significant degree in this relatively small experience with the addition of entinostat.” Median overall survival was 28.13 months with exemestane plus entinostat vs 19.84 months with exemestane plus placebo.

mTOR Inhibitors

mTOR inhibitors have been approved to treat several different types of cancer, including hormone receptor–positive, HER2-negative advanced breast cancer.

For instance, the phase II GINECO trial randomized 54 women to receive the mTOR inhibitor everolimus plus tamoxifen and 57 women to receive tamoxifen alone.7 “With the combination of tamoxifen plus everolimus, the fraction of patients who benefited, both those responding and with stable disease, was significantly greater than those given tamoxifen alone,” Dr. Gradishar said. In addition, “for patients who had secondary hormone resistance, those who had at one time responded to endocrine therapy seemed to gain the greatest benefit from the addition of an mTOR inhibitor.”

In the BOLERO-2 trial, postmenopausal patients with advanced breast cancer who previously received a nonsteroidal aromatase inhibitor were randomized to receive exemestane with everolimus or with placebo. “It was found that the addition of everolimus to exemestane in this population would significantly improve the progression-free survival outcome, from 3.2 months to 7.8 months.”8 But despite looking at a number of genetic alterations, it wasn’t clearly evident who would benefit from the mTOR inhibitors, Dr. Gradishar reported. “So we don’t have a tool yet to tease out the patients who are most likely to benefit.” The improvement in progression-free survival, however, “didn’t translate, at least at this point, into an improvement in overall survival,” he added.

Everolimus is now being tested in a much larger trial, the SWOG S1222 study. Postmenopausal women with estrogen receptor– and progesterone receptor–positive and HER2-negative previously untreated metastatic breast are randomized to one of three treatment arms: fulvestrant alone, fulvestrant plus everolimus, or fulvestrant, everolimus, and anastrozole. “The rationale for fulvestrant and anastrozole is based on other studies that suggested you may get more benefit from dual antihormone therapy than one. And the strategy of putting all three together also is being evaluated,” Dr. Gradishar said.

Targeting the PI3K Pathway

Mutations that occur in the PI3K pathway are “very common in estrogen receptor–positive breast cancer, and they become very ripe targets for looking at the addition of new agents in combination with endocrine therapy,” Dr. Gradishar stated. “We already know that activation of the PI3K pathway is a prognostic factor. Those with higher expression of PI3 kinase tend to have a worse prognosis,” he added.

“There is no shortage of drugs that are being looked at for this particular pathway,” Dr. Gradishar declared. “To date, none of them have been approved, but there is still hope that they will be.”

There are also concerns about toxicities, including skin and GI toxicities. “If these drugs, either one or as a class, become available, and they look like they are clearly advantageous, one of the things that we will have to think about is how do we make this acceptable to patients. How do we make them aware that they are going to be experiencing things that we don’t typically see with endocrine therapy?”

Don’t Abandon Endocrine Monotherapy

“Based on the trials done to date, you can see that there is an advantage so far that has been demonstrated for partnering endocrine therapy with some of these new agents,” Dr. ­Gradishar summarized. In the PALOMA trial, “clearly, the addition of pablociclib has made a difference. Adding pablociclib incrementally improves the time to progression-free survival. Similarly, if you look at the addition of everolimus to an aromatase inhibitor or tamoxifen, you are also seeing that incremental improvement in outcome,” he said.

“As we go forward, this is likely to be a theme, but I don’t think it erases or eradicates the fact that an individual patient might benefit from monotherapy with endocrine therapy. The NCCN guidelines don’t get rid of monotherapy as an option for patients with estrogen receptor–positive metastatic breast cancer but do afford you the opportunity to look at combinations,” Dr. ­Gradishar stated. He stressed once again that the toxicity profile changes when these agents are added to endocrine therapy, and “you have to communicate that with your patients.” ■

Disclosure: Dr. Gradishar reported no potential conflicts of interest.


1. Gradishar W: New approaches to ER positive metastatic cancer. 2015 Lynn Sage Breast Cancer Symposium. Session 7. Presented October 31, 2015.

2. Finn RS, Crown JP, Lang I, et al: The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): A randomised phase 2 study. Lancet Oncol 16:25-35, 2015.

3. Turner NC, Ro J, André F, et al: Palbociclib in hormone-receptor-positive advanced breast cancer. N Engl J Med 373:209-219, 2015.

4. Tolaney SM, Rosen LS, Beeram M, et al: Clinical activity of abemaciclib, an oral cell cycle inhibitor, in metastatic breast cancer. 2014 San Antonio Breast Cancer Symposium. Abstract P5-19-13.

5. Tolaney SM, Beeram M, Beck JT, et al: A phase IB study of abemaciclib with therapies for metastatic breast cancer. 2015 ASCO Annual Meeting. Abstract 522. Presented May 29, 2015.

6. Lilly receives FDA breakthrough therapy designation for abemaciclib - a CDK 4 and 6 inhibitor - in advanced breast cancer. Eli Lilly and Company press release, October 8, 2015. Available at Accessed December 9, 2015.

7. Bachelot T, Bourgier C, Cropet C, et al: Randomized phase II trial of everolimus in combination with tamoxifen in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer with prior exposure to aromatase inhibitors: A GINECO study. J Clin Oncol 30:2718-2724, 2012.

8. Baselga J, Campone M, Piccart M, et al: Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med 366:520-529, 2012.