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Categories: Breast cancer CCND1 amplification CDK 4 CDK 6 Cyclin D kinase 4 Cyclin D kinase 6 Estrogen Estrogen receptor positive Breast Cancer HER2 HER2-negative breat cancer Herceptin Letrozole p16 p16 loss PD 0332991 Tamoxifen Trastuzumab

Combination therapy with experimental drug improves outlook for breast cancer patients

A combination therapy using an experimental new drug shows significant promise for women with a common type of breast cancer in which estrogen causes their tumors to grow, researchers with the Revlon/UCLA Women's Cancer Research Program at UCLA's Jonsson Comprehensive Cancer Center report.

The treatment, which incorporates the standard anti-estrogen therapy letrozole and the experimental drug PD 0332991, developed by pharmaceutical company Pfizer Inc., was found to increase progression-free survival time — the length of time a patient is on treatment without tumor growth — in women with estrogen receptor–positive, HER2-negative cancer, compared with letrozole alone.

The results of a two-part, phase 2 clinical trial testing the new combination therapy were announced Dec. 5 at the 2012 CTRC–AACR San Antonio Breast Cancer Symposium in San Antonio, Texas, by Dr. Richard S. Finn, an associate professor of medicine at UCLA and a member of the Jonsson Cancer Center, who led the trial.

The clinical study built on pre-clinical work from the Translational Oncology Research Laboratory directed by Dr. Dennis Slamon, a professor of medicine at the Jonsson Cancer Center and director of the Revlon/UCLA Women's Cancer Research Program.

For the first part of the study, in which 66 patients were enrolled, preliminary results showed significant improvement in median progression-free survival for individuals who were given the new drug combination. The second part of the study enrolled 99 more patients — but only those whose tumors revealed selected biomarkers known as CCND1 amplification and p16 loss.

Retrospective analysis from Part 1 of the suggested there was a clinical benefit from PD 0332991 regardless of the women's biomarker status. All the other demographic features of the patients were similar, so for final trial analysis, the results of the study's two parts were combined for presentation at the San Antonio Breast Cancer Symposium.

The researchers' analysis showed that the median progression-free survival time for patients on the combination therapy was 26.1 months, compared with 7.5 months for those on letrozole alone. Of the patients with measurable disease, 45 percent of those given the combination treatment had confirmed responses, compared with 31 percent on letrozole alone.

And the clinical benefit rates — tumor shrinkage and/or stable disease for a minimum of six months — were 70 percent with the combination therapy and 44 percent with only letrozole, the researchers report.

"This drug combination demonstrated a dramatic and clinically meaningful effect on progression-free survival in women with estrogen receptor–positive breast cancer," said Finn. "These results confirm the pre-clinical work we began at the Translational Oncology Research Laboratory."

Finn and his colleagues published their initial pre-clinical data in 2009, which showed that PD 0332991 blocked two important proteins in cancer cells — cyclin D kinase 4 (CDK 4) and cyclin D kinase 6 (CDK 6) — thus prohibiting the growth of estrogen receptor–positive and HER2-amplified cancer cells in the lab.

With the goal of identifying important targets for cancer therapy in the lab and promptly developing them into patient treatments using the translational paradigm, the investigators then conducted a phase 1 clinical trial in collaboration with Pfizer in which the safety of the drug was tested.

The results of that trial confirmed the safety of PD 0332991, which was taken as a pill and was found to have manageable side effects. This prompted the phase 2 trial comparing the combination of PD 0332991 and letrozole to the standard treatment of letrozole alone.

Critical to the clinical studies were the synergistic interactions observed in the laboratory between PD 0332991 and standard breast cancer drugs tamoxifen and trastuzumab, which are used in treating estrogen receptor–positive and HER2-positive breast cancers, respectively.

"The results of this phase 2 study validate the Translational Oncology Research Laboratory approach," said Slamon, the study's senior author.

"By identifying these targets for treatment, we move forward with personalized oncology that greatly improves the chances for this group of patients," Slamon added. "These results are as exciting as the initial results we saw for trastuzumab (Herceptin) in HER2-positive breast cancers but represent a new approach for a different and larger subset of breast cancers – those that are estrogen receptor–positive."

The core laboratory research for this project was funded primarily through the Revlon/UCLA Women's Cancer Research Program and the longtime philanthropic support of Ronald O. Perelman. Additional resources were provided by a U.S.  Department of Defense Innovator Award (W81XWH-05-1-0395) and the Noreen Frazier Foundation. The clinical trial itself was supported entirely by Pfizer Inc.

Contact: Shaun Mason, Tel: 310-206-2805, Email: smason@mednet.ucla.edu

Source: University of California, Los Angeles (UCLA)

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