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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.
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.
In Part 1 of the study, 66 patients were randomized in a 1:1 ratio to receive palbociclib plus letrozole or letrozole. In Part 2 of the study, 99 patients who also were screened for cyclin D1 amplification and/or a loss of p16 were randomized to receive palbociclib plus letrozole versus letrozole alone.
Overall, the objective response rate was 34% among patients who received palbociclib and letrozole in both parts of the trial (n = 84) versus 26% for participants who received letrozole alone (n = 81). The clinical benefit rate, defined as complete and partial responses plus stable disease ≥24 weeks, was 70% for the combination (n = 59) versus 44% (n = 36) for letrozole alone.
Median progression-free survival (PFS), the primary endpoint of the trial, was 26.1 months for patients who received the combination therapy versus 7.5 months for letrozole alone (HR = 0.37, 95% CI 0.21-0.63; P <.001). These results were updated in 20143 with the combination treatment providing a median PFS of 20.2 months versus 10.2 months for patients taking letrozole alone (HR = .488, 95% CI 0.319-0.748; P <.0004) Clark et al4 showed that biomarkers were not predictive of benefit when patients were treated with palbociclib.
Goldstein said the results are “encouraging,” but noted that the findings are from a phase II trial. “This study has now progressed to PALOMA-2, which is a randomized phase III trial,” she noted. To date, the agent has been shown to be well tolerated with frequent uncomplicated neutropenia.
In the epigenetic category, a number of agents have been studied including both HDAC inhibitors and demethylating agents. Thus far, none of the HDAC inhibitors have been indicated in breast cancer, but entinostat has shown some promise, said Goldstein. “Entinostat is a novel, oral HDAC inhibitor with high specificity toward class 1 HDACs and has a unique pharmacologic profile in that it could be administered weekly,” said Goldstein. “Preclinical studies have shown that entinostat restores estrogen receptor sensitivity in vivo.5
In the phase II ENCORE 301 trial,6 entinostat was evaluated in combination with exemestane versus exemestane plus placebo in 130 postmenopausal women with ER-positive locally recurrent or metastatic breast cancer that progressed after nonsteroidal aromatase inhibitor (AI) therapy. PFS was the primary endpoint.
The entinostat regimen resulted in an immediate PFS of 4.28 months among the 64 patients who received the experimental regimen (HR = 0.73) versus 2.27 months for the 66 participants who received exemestane plus placebo. The median OS was 28 months for the entinostat group, compared with 19 months for the placebo cohort (HR = 0.59).
The agent will be further explored in the pivotal phase III E2112 trial of exemestane with or without entinostat in 600 participants with hormone-refractory advanced breast cancer, including men with hormone receptor—positive disease and postmenopausal women (NCT02115282). If positive, the findings will form the basis for a new drug application, according to Syndax Pharmaceuticals, Inc, which is researching the drug.
c-Src is a pleiotropic nonreceptor tyrosine kinase involved in breast cancer invasion, proliferation, and survival. Chen et al7 has demonstrated that aromatase and c-Src inhibition combined showed greater breast cancer antitumor activity than either strategy alone. “c-Src also regulates osteoclast-mediated bone turnover,” said Goldstein.
Researchers are exploring dasatinib (Sprycel), which has been approved for chronic myeloid leukemia, in combination therapies as a way to address the development of resistance to AIs. Dasatanib inhibits c-Src, bcr-abl, c-KIT, PDGFRβ, and ephrin kinases.
Paul et al8 demonstrated that letrozole plus dasatinib had a 71% clinical benefit rate as a first-line treatment for metastatic breast cancer compared with 66% for letrozole alone. “These findings were not statistically significant,” said Goldstein.
However, the combination demonstrated promising median PFS of 20.1 months versus 9.9 months for letrozole alone, noted Goldstein. “These findings suggest dasatinib may actually inhibit the emergence of acquired resistance to AI therapy. More investigation is necessary,” said Goldstein.
She said that the strategy of Src inhibition in general requires further investigation “to select appropriate molecular phenotypes to enrich for potential signals.”
Androgen receptor signaling is attracting renewed interested in breast cancer as a result of genomic analyses, and several agents approved for prostate cancer are now under study.
Joyce A. O’Shaughnessy, MD, who chaired the PER meeting, is among the researchers pursuing this possibility. O’Shaughnessy is co-director of Breast Cancer Research at Baylor Charles A. Sammons Cancer Center in Dallas.
In study BCA2001,9 O’Shaughnessy et al investigated the feasibility of adding abiraterone acetate (Zytiga), which is approved in prostate cancer, plus prednisone to exemestane in postmenopausal women with ER-positive, HER2-negative metastatic breast cancer. The three-arm trial randomized 297 patients to receive abiraterone acetate/prednisone with or without exemestane or exemestane alone. The trial found that there was no statistical difference in PFS between the arms, said Goldstein.
The median PFS for the abiraterone/prednisone/exemestane arm was 4.5 months, compared with 3.7 months for each of the other two arms.
Goldstein theorized that prednisone made an impact on the outcome. “The administration of prednisone at 5 mg adequately suppressed the mineralocorticoid excess effects in postmenopausal metastatic patients and the abiraterone inhibition may not suppress the growth signal in ER-positive metastatic cancer potentially due to an induced increase in progesterone and the heterogeneity of mechanisms of resistance to nonsteroidal AIs,” said Goldstein.
As with other potential methods of addressing endocrine therapy resistance, androgen inhibition requires further study, said Goldstein. “There are other ongoing trials with other agents in progress and, again, further investigation is needed to select the appropriate molecular phenotypes to enrich for potential signal,” she said.
Trial Name
Estimated No. of Patients
Patient Population
Description
ClinicalTrials.gov Identifier
Abemacicliba (LY2835219)
MONARCH 2
550
Abemaciclib plus fulvestrant vs Placebo plus fulvestrant
NCT02107703
LEE011
MONALEESA-2
500
LEE011 plus letrozole vs Placebo plus letrozole
NCT01958021
Palbociclib (PD0332991)
PALOMA-2
650
Palbociclib plus letrozole vs Placebo plus letrozole
NCT01740427
PALOMA-3
417
Palbociclib plus fulvestrant vs Placebo plus fulvestrant
NCT01942135
PEARL
348
Palbociclib plus exemestane vs Capecitabine
NCT02028507
PENELOPE-B
800
Palbociclib with standard endocrine treatment as “background therapy” vs Placebo
NCT01864746
aAgent was previously known as bemaciclib.
BC indicates breast cancer; CPS—EG, clinical pathologic stage—estrogen/grade; ER, estrogen receptor; HER2, human epidermal growth factor receptor 2; HR, hormone receptor; NSAI, nonsteroidal aromatase inhibitor; PR, progesterone receptor.
References
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