Lori J. Goldstein, MD
Although advances in endocrine therapy for women with estrogen receptor (ER)-positive breast cancer have been made in recent years, de novo and acquired resistance to treatments remain important clinical problems, and efforts to identify effective modalities to overcome this challenge continue.
“Novel approaches to improve the efficacy of endocrine therapy, while minimizing toxicity, are required,” said Lori J. Goldstein, MD, director of the Breast Evaluation Center at Fox Chase Cancer Center in Philadelphia, during her presentation at the 13th Annual International Congress on the Future of Breast Cancer, which Physicians’ Education Resource (PER) hosted July 17-19 in Huntington Beach, California.
The timing of when to initiate treatments for endocrine therapy resistance is another obstacle the clinician faces. “Theoretically, you want to treat patients to avoid selecting for resistance to certain agents but we can’t go right from a new agent to giving an inhibitor in early-stage disease,” said Goldstein.
At the same time, she said, “Hormone resistance is important, not just for people who already have metastatic disease, but to prevent patients from developing metastatic disease by giving them adequate endocrine therapy in the early-stage setting.”
Goldstein presented an overview of research highlighting the mechanisms of endocrine resistance that are currently under study. These mechanisms include ligand-independent activation of the ER; crosstalk between ER and EGFR, HER2, or IGFR; alterations in ER coregulators; and alterations of downstream pathways, such as MAPK/ERK and PI3K/Akt.
Newer studies involve alterations in cell cycle machinery, epigenetic alterations, Src inhibitors, and androgen inhibitors. Thus far, a number of phase III trials investigating CDK4/6 inhibitors and histone deacetylase (HDAC) inhibitors are promising, said Goldstein.
In order to advance new therapies, however, fresh ways of evaluating prospective agents may be necessary, said Goldstein.
“In the past, the endocrine therapy clinical benefit rate was something that we accepted as an endpoint in determining whether an agent should go forward, but in combining hormone therapies with biologics, maybe we really need to think what the appropriate clinically applicable endpoints are for clinical trials,” she said.
“The mechanisms of action for resistance are complex, so future combinations based on mechanisms of sensitivity and resistance are needed with the use of biomarker selection,” said Goldstein.
There is synergy between ER and CDK4/6, which is critical for the efficacy of combinations in ER-positive tumors. Cyclin D1 is a direct transcriptional target of ER and inhibition of cyclin D1 inhibits estrogen-induced S-phase entry. Resistance to endocrine is associated with a persistent cyclin D1 expression and Rb phosphorylation, said Goldstein. Goldstein noted that CDK4/6 inhibitors are most effective in tumors with gene amplification and overexpression of cyclin D1, which is common in ER-positive breast cancer.
“The cyclin CDK4/6-Rb pathway is important for anticancer therapy,” said Goldstein. “It’s an important mediator of cell cycle regulation and is downstream of multiple mitogenic cascades.”
As a result, there are a number of CDK4/6 inhibitors under study in combination with endocrine therapy or other targeted therapies including anti- HER2 agents, PI3K inhibitors, or mTOR inhibitors, said Goldstein.
The oral therapy palbociclib is the most advanced of the CDK4/6 inhibitors under development. Other agents in phase III development for breast cancer settings include LEE011, and abemaciclib (LY2835219) (Table
As a class, Goldstein said CDK4/6 inhibitors “represent a good opportunity to overcome endocrine resistance.”Palbociclib
In April 2013, the FDA granted palbociclib a breakthrough therapy designation based upon interim results from the PALOMA-1 trial, according to Pfizer, which is developing the drug. The company plans to submit a new drug application in the third quarter of this year for palbociclib plus letrozole as first-line treatment for women with ER-positive, HER2-negative locally advanced or metastatic breast cancer.
Several later-stage clinical trials are under way in other settings (Table
Finn et al1
has shown that palbociclib preferentially inhibits proliferation of luminal ER-positive human breast cancer cell lines in vitro compared with other molecular phenotypes (eg, HER2 amplified).
That research also demonstrated that combined inhibition of CDK4/6 and ER signaling increases senescence in ER-positive breast cancer cell lines. Goldstein highlighted results from PALOMA-1,2
a randomized phase II trial of palbociclib (also known as PD0332991) evaluated in combination with letrozole versus letrozole alone for first-line treatment of postmenopausal women with ER-positive, HER2-negative advanced breast cancer.