Dennis J. Slamon, MD, PhD
The discovery of the estrogen receptor in the mid-twentieth century by Elwood V. Jensen, PhD, marked a new era of treatment for patients with hormone receptor (HR)-positive breast cancer. As researchers continue to learn how to best target the estrogen receptor, new treatments are emerging in this landscape.
Presently, ASCO and NCCN guidelines suggest the use of hormonally targeted therapies rather than chemotherapy for patients with HR-positive breast cancer. In a lecture during the 2018 OncLive®
State of the Science Summit™ on Breast Cancer, Sara A. Hurvitz, MD, and Dennis J. Slamon, MD, PhD, discussed the impact of one of the most impactful treatment options for these patients—CDK4/6 inhibitors.
"It is our knee-jerk reaction as oncologists to give them chemotherapy to get it under control," said Hurvitz, director of the Breast Oncology Program at the University of California, Los Angeles (UCLA) Jonsson Comprehensive Cancer Center. "That really is not the most appropriate way. The most toxic therapy is not always the most effective therapy."
Hurvitz said that in a hormonally driven cancer, hormonally targeted therapies should be used until exhausted in all but the most unusual circumstances of visceral crisis. Response rates with chemotherapy span from 50% to 60%, which does not last long, noted Hurvitz. The time to treatment failure has been recorded as less than 1 year in multiple clinical trials.
Clinical studies of the hormonal therapy fulvestrant (Faslodex) offered the first glimmer of hope that something other than chemotherapy could induce durable, lasting responses in these patients, said Hurvitz. Since then, fulvestrant has become a staple in the treatment of postmenopausal patients with HR-positive breast cancer.
The Introduction of CDK4/6 Inhibitors
For HR-positive patients with estrogen receptor (ER)-positive breast cancer, CDK4/6 inhibitors have emerged as a very potent therapy. Slamon, the director of Clinical/Translational Research, Revlon/UCLA Women's Cancer Research Program, Jonsson Comprehensive Cancer Center, said that this was based on a breakthrough therapy that almost did not happen.
This breakthrough was PD-0332991, which ultimately became known as palbociclib (Ibrance). PD-0332991 had been developed for mantle cell lymphoma and hematopoietic malignancies where cyclin-D amplification is a molecular hallmark. The agent had some activity in these malignancies, but it ultimately was shelved due to safety issues, said Slamon.
"We wanted to look at it in breast cancer, because we had a concept that it might have an impact on some rapidly proliferating cancers," Slamon said.
Palbociclib is an oral, small molecule, selective, potent, reversible inhibitor of CDK4/6. This was one of the first inhibitors specific to CDK4/6, as the previous generation of these inhibitors were considered pan-CDK inhibitors targeting multiple CDKs in the cell cycle.
"There is an incredibly well-orchestrated phenomenon that goes on every time a cell divides,” said Slamon. “This was one of the first inhibitors that hit something specifically, as opposed to multiple CDKs throughout the cell cycle.”
In an evaluation of palbociclib in various cell lines, the drug was shown to be most effective in inhibiting growth in breast cancer, particularly at lower doses. A breast panel compiled by UCLA showed that ER-positive luminal breast cancer was exquisitely sensitive to palbociclib, while a significant number of triple-negative tumors were resistant.
"We were scratching our heads as to why we were seeing what we were seeing. It became very obvious when we looked at the molecular analysis," said Slamon. "When you look at the amount of retinoblastoma protein in these cells relative to their counterparts, it is the ER-positive subsets that have had these incredible high levels of retinoblastoma, which explains why the drug had such unique activity in the group."
This allowed investigators to propose a phase Ib clinical trial with palbociclib specifically targeting recurrences in patients with metastatic ER-positive breast cancer. Slamon said that responses were seen in this initial 12-patient trial, although investigators were strictly evaluating safety.
These findings led to the open-label phase II PALOMA-1 study, which evaluated the safety and efficacy of the combination of palbociclib plus letrozole versus letrozole alone in patients with postmenopausal ER-positive/HER2-negative breast cancer. About halfway to accrual, patients were coming off study because of progressive disease at about a 2:1 ratio in the letrozole alone arm. Slamon said that they then looked at the Kaplan-Meier curves, which showed a huge difference between the 2 arms.