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From OncoLog, February 2014, Vol. 59, No. 2

Targeted Drug Shows Promise Against Advanced Breast Cancer

By Bryan Tutt

Photo: Dr. Stacy Moulder
“CDK 4 and 6 inhibitors arrest the cell cycle and do not allow the cancer cells to divide.”
– Dr. Stacy Moulder
Adding the experimental kinase inhibitor palbociclib to standard hormonal therapy may delay disease progression in patients with advanced breast cancer that is estrogen receptor (ER) positive and human epidermal growth factor receptor 2 (HER2) negative.

Aromatase inhibitors such as anastrozole or letrozole inhibit the growth of ER-positive tumors by lowering serum levels of estrogen, whereas the experimental oral drug palbociclib (also called PD 0332991) inhibits cyclin-dependent kinases (CDK) 4 and 6.

“CDK 4 and 6 inhibitors arrest the cell cycle and do not allow the cancer cells to divide,” said Stacy Moulder, M.D., an associate professor in the Department of Breast Medical Oncology at The University of Texas MD Anderson Cancer Center. “There are multiple compounds that target this mechanism in cancer cells, but palbociclib is further along in its development than many of these.”

Clinical studies

The preliminary results of a phase II trial of letrozole with or without palbociclib in postmenopausal women with ER-positive, HER2-negative advanced breast cancer were presented at the 2012 San Antonio Breast Cancer Symposium. These results showed that the median progression-free survival duration of patients treated with letrozole and palbociclib (26.1 months) was significantly longer than that of patients treated with letrozole alone (7.5 months).

The phase II trial’s results have not been finalized or published, but the encouraging preliminary results led to a phase III trial, which is currently enrolling patients at MD Anderson and other institutions. Patients in the study are randomly selected to receive letrozole plus palbociclib or letrozole plus placebo. The patients will continue to receive the treatment until they have evidence of disease progression or withdraw from the study for other reasons.

Eligible patients are postmenopausal women who have ER-positive, HER2-negative metastatic or locoregionally recurrent adenocarcinoma of the breast that is not amenable to potentially curative surgery or radiation therapy and for whom chemotherapy is not clinically indicated. Excluded from the study are patients whose disease recurred during neoadjuvant or adjuvant treatment with anastrozole or letrozole or within 12 months of completing such treatment.

In the phase II trial, the most common side effect of palbociclib was myelosuppression. According to Dr. Moulder, the principal investigator for the phase III trial at MD Anderson, if palbociclib proves to be effective and becomes a part of standard care, patients taking it will need to be seen monthly to have their blood counts checked. In contrast, patients receiving hormonal therapy alone are typically seen every 2–3 months. Dr. Moulder added that the potential for myelosuppression with palbociclib requires other precautions, such as prompt evaluations for patients who have fever or other signs of illness.

Looking ahead

Dr. Moulder said that the next step in the development of palbociclib, if the drug continues to demonstrate safety and efficacy in patients with metastatic disease, is to use the drug in the adjuvant and neoadjuvant therapy settings. She hopes the drug will eventually improve the cure rate for all patients with ER-positive, HER2-negative breast cancer, including those with early-stage disease.

Other drugs that inhibit CDK 4 and 6 are being developed, as are drugs that inhibit CDK 2. “We’re very interested in developing this class of compounds,” Dr. Moulder said, “and we’ll be opening a number of trials in the near future.”

For more information, contact Dr. Stacy Moulder at 713-792-2817.

Other articles in OncoLog, February 2014 issue:

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