Postprogression Treatment of Estrogen Receptor–Positive Breast Cancer: Future Approaches

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AT THE 2019 Miami Breast Cancer Conference, William J. Gradishar, MD, FASCO, presented a vision of the future in the treatment of advanced hormone receptor–positive breast cancer.1 The refinement of disease subsets, the development of agents targeting the PI3K/AKT/mTOR pathway, the use of novel combinations, the development of antibody-drug conjugates, and the application of immunotherapy will greatly expand the therapeutic landscape, said Dr. Gradishar, who is the Betsy Bramsen Professor of Breast Oncology and Professor of Medicine at Northwestern University Feinberg School of Medicine, Chicago.

William J. Gradishar, MD, FASCO

William J. Gradishar, MD, FASCO

Beyond CDK4/6 Inhibition

THE INHIBITORS of cyclin-D kinase 4/6 (CDK4/6) have had a major impact in hormone receptor–positive disease. In their pivotal trials, palbociclib, ribociclib, and abemaciclib showed significant improvements in progression-free survival when combined with aromatase inhibitors or the selective estrogen receptor degrader fulvestrant. These benefits have been consistently observed in both the first- and second-line settings, with efforts underway to evaluate them in adjuvant therapy. Inhibitors of mTOR have also been beneficial.

“Although these agents are very good, disease progression is inevitable,” Dr. Gradishar said, and the question now is what to do next. Should patients continue on the CDK4/6 inhibitor, discontinue it, try a different agent in the class, or switch to endocrine monotherapy? “These are currently data-free zones, but a number of clinical trials are attempting to address this issue,” he said.

“You don’t use up all the advantages of endocrine therapy by combining it with the CDK4/6 inhibitor…, so we shouldn’t abandon endocrine therapy simply because a patient has gone beyond a CDK4/6 inhibitor.”
— William J. Gradishar, MD, FASCO

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More Endocrine Therapy?

A SMALL STUDY presented at the 2018 San Antonio Breast Cancer Symposium2 showed modest activity for single-agent hormonal therapy, single-agent chemotherapy, and, especially, the combination of everolimus plus exemestane. These findings suggested “that you don’t use up all the advantages of endocrine therapy by combining it with the CDK4/6 inhibitor—that you get some mileage out of these agents—so we shouldn’t abandon endocrine therapy simply because a patient has gone beyond a CDK4/6 inhibitor,” Dr. Gradishar said.

Fulvestrant can also be useful in the postprogression setting, but it does have its drawbacks, especially the lack of patient acceptance. Dosing is limited to 500 mg by injection, and the evidence suggests that at that dose, the estrogen receptor may not be completely downregulated or eradicated. “It’s a good drug, and we use it widely, but we need other treatments after patients have disease progression on fulvestrant,” he commented.

Novel Endocrine and Targeted Approaches

ON THE OTHER HAND, LSZ102 is an oral selective estrogen receptor degrader, and it has shown clinical activity after disease progression, suggesting that patients do continue to respond to endocrine therapy. In patients with prior endocrine treatment, a 24-week clinical benefit rate of 50% and a 27% response rate were reported in a small study at the 2018 San Antonio Breast Cancer Symposium. “If LSZ102 meets its goal and is approved, it would be a logical drug to partner with currently available agents,” Dr. Gradishar commented.

LSZ102 is being evaluated as a monotherapy and in conjunction with a CDK4/6 inhibitor or with a PI3K inhibitor.

Targeting PI3 Kinase and AKT

“WE HOPE to have other agents to target certain factors that may emerge when endocrine resistance develops,” he continued. One approach will be to address the signaling pathway that underlies some common mutations. For luminal A and luminal B tumors, this points to PIK3CA mutations, and thus, the PI3K/AKT pathway is an attractive treatment target.

The potential for this approach was shown by the phase III SOLAR-1 trial, in which the alpha-specific PI3K inhibitor alpelisib was combined with fulvestrant and compared to fulvestrant alone in 572 patients.3 In patients with the mutation, the combination led to a 7.4-month improvement in progression-free survival—an outcome superior to what has been achieved with previous PI3K inhibitors. “We are now focusing on more specific PI3 kinase inhibitors that have demonstrated proven principles. We would anticipate that alpelisib is most likely the next drug we’ll have available for estrogen receptor–positive breast cancer,” Dr. Gradishar predicted.

Novel agents for the PI3K/AKT pathway, however, are not limited to the PI3K inhibitors. In fact, multiple targets are actually present within this pathway, which has led to the development of novel agents striking additional targets. One such compound is ipatasertib, which targets PI3K, AKT, and mTOR. In the CO40016 (or IPATunity) trial (which also enrolls patients with triple-negative breast cancer), subjects will receive chemotherapy or the same plus ipatasertib.

“We would anticipate that alpelisib is most likely the next drug we’ll have available for estrogen receptor–positive breast cancer.”
— William J. Gradishar, MD, FASCO

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Novel Chemotherapy

SACITUZUMAB GOVITECAN is an investigational antibody-drug conjugate. In a small cadre of patients with heavily pretreated estrogen receptor–positive/HER2-negative breast cancer, the drug showed a response rate of 31% and a clinical benefit rate of 48%.4 The findings suggest that this is one new chemotherapy agent that may benefit patients other than those with the triple-negative disease subtype.

In fact, a number of other antibody-drug conjugates are in development. DS-8201a (trastuzumab deruxtecan) was designed with the goal of improving some of the critical attributes of antibody-drug conjugates. The drug is being evaluated not only in HER2-positive breast cancer but in patients with “HER2-low” disease—those patients conventionally deemed HER2-negative but with some expression of the oncogene. Small studies have shown high response rates and clinical benefit rates for DS-8201a in HER2-low disease. Similarly, in the small portion of patients with estrogen receptor–positive disease who express HER3, another antibody-drug conjugate, U3-1402, may be effective.

“It’s conceivable as we go forward,” he predicted, “that there will be a subset of estrogen receptor–positive disease in which unique agents may have an effect.”


THE RECENT APPROVAL of atezolizumab for triple-negative breast cancer heralds the “official” entry of immunotherapy into the breast cancer space, Dr. Gradishar commented. While not considered an immunogenic tumor, estrogen receptor–positive breast cancer may, in fact, be susceptible to immunotherapy under some conditions.

“It’s conceivable as we go forward that there will be a subset of estrogen receptor–positive disease in which unique agents may have an effect.”
— William J. Gradishar, MD, FASCO

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Inhibitors of poly (ADP-ribose) polymerase may play a role in turning “cold” tumors into “hot” (or immunogenic) tumors. In a small subset of estrogen receptor–positive patients in the phase I/ II MEDIOLA trial, olaparib plus durvalumab showed benefit.5

Similarly, CDK4/6 inhibitors may “rev up” the immune system and, when combined with immunotherapy, lead to tumor regression, according to preclinical research. Clinical trials are beginning to evaluate these combinations. In a study presented by Hope S. Rugo, MD, and colleagues at the 2017 San Antonio Breast Cancer Symposium, abemaciclib plus pembrolizumab showed strong activity in hormone receptor–positive, HER2-negative metastatic disease, “contrary to what many had thought,” Dr. Gradishar said.6 “There is proof that these strategies do work, and there is reason to think that the use of immunotherapy will not be restricted to triple-negative breast cancer.”

DISCLOSURE: Dr. Gradishar reported no conflicts of interest.


1. Gradishar W: New agents for advanced HR+ breast cancer. 2019 Miami Breast Cancer Conference. Presented March 9, 2019.

2. Giridhar KV, Choong GM, Leon-Ferre RA, et al: Clinical management of metastatic breast cancer after CDK4/6 inhibitors: A retrospective single-institution study. 2018 San Antonio Breast Cancer Symposium. Abstract P6-18-09. Presented December 8, 2018.

3. Andre F, Ciruelos EM, Rubovszky G, et al: Alpelisib + fulvestrant for advanced breast cancer: Results of the phase 3 SOLAR-1 trial. 2018 ESMO Congress. Abstract LBA3. Presented October 20, 2018.

4. Bardia A, Diamond JR, Vahdat LT, et al: Efficacy of sacituzumab govitecan (anti-Trop-2-SN-38 antibody-drug conjugate) for treatment-refractory hormone-receptor positive HER2-negative metastatic breast cancer. 2018 ASCO Annual Meeting. Abstract 1004. Presented June 3, 2018.

5. Domchek SM, Postel-Vinay S, Bang Y-J, et al: An open-label, multitumor, phase II basket study of olaparib and durvalumab (MEDIOLA): Results in germline BRCA-mutated (gBRCAm) HER2-negative metastatic breast cancer (MBC). 2017 San Antonio Breast Cancer Symposium. Abstract PD6-11. Presented December 7, 2017.

6. Rugo HS, Kabos P, Dickler MN, et al: A phase 1b study of abemaciclib plus pembrolizumab for patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC). 2017 San Antonio Breast Cancer Symposium. Abstract P1-09-01. Presented December 6, 2017.