According to the National Breast Cancer Foundation, one in eight women will be diagnosed with breast cancer in their lifetime. Additionally, breast cancer is the most common diagnosed cancer in women and it is the second leading cause of death among women. Given its prevalence throughout the population, each person is likely impacted by someone who is afflicted with the disease. For this reason, scientists have put much effort into understanding this breast cancer in order to develop the most effective treatments and save the lives of many.
Unfortunately, cases of breast cancer often differ between patients, which make it difficult to produce effective treatments. Typically, researchers classify breast cancers by the presence or absence of particular genetic markers. Unfortunately, even if the therapy is initially effective, cancers can develop resistance to the drug. Physicians usually resort to chemotherapy for their patients, but it is known to have severe, adverse side effects and minimal success.
Dr. Richard Finn and his colleagues provide hope for women who suffer from metastatic breast cancer with the recent results of their clinical trial on the oral drug palbociclib. Not surprisingly, the drug targets and inhibits activity of the proteins that are crucial for maintenance of the cell cycle, cyclin dependent kinases 4 and 6. When these proteins are overactive, the cell immediately begins to progress through mitosis, which is normally a highly regulated process. This could result in uncontrolled cell division, which is one of the hallmarks of cancer.
|From: Hanahan D., Weinberg R.A. Hallmarks of Cancer: The Next Generation. Cell, 144:(5) 646-674 (2011).|
Prior to enrolling patients in clinical trials, the group tested the drug on various breast cancer cell lines and found that it was effective at halting the cell cycle, which prevented the cancer cells from dividing. It was particularly effective against strains of breast cancer that expressed the hormone receptor oestrogen. Since oestrogen is known to promote growth of the tumor, aromatase inhibitors, which block oestrogen production, are common treatments to try to prevent this hormone-receptor interaction. Since palbociclib was effective against breast cancer cell lines, the group thought that the addition of an aromatase inhibitor might further augment the antitumor effect.
In order to assess this, the group enrolled 165 patients in a clinical trial, and the patients received either the aromatase inhibitor letrozole alone or both letrozole and palbociclib. The majority of the patients in the clinical trial had metastatic disease. Remarkably, the assessed progression free survival time (time in which cancer did not advance) was 20.3 months in the patients that received the combination treatment in comparison to 10.2 months in the patients that received letrozole alone.
An additional concern with any new drug is that it will have serious side effects that outweigh the benefits. Fortunately, the most common side effects observed in the patients that received both letrozole and palbociclib were loss of immune cells (neutropenia and leucopenia) and fatigue, which are predictable and manageable. There were very few patients that experienced serious side effects, such as pulmonary embolism. Of the 84 patients that received the combination therapy, there was only one death throughout the duration of the study due to disease progression.
Overall, the results of this study are promising for postmenopausal women with oestrogen receptor-positive breast cancers. This also provides hope for women with breast cancers are resistant to other anti-hormonal therapies. After publication of the trial, the U.S. Food and Drug Administration (FDA) granted accelerated approval of the palbociclib and letrozole combination therapy. This emphasizes the potential that this drug has for breast cancer. Palbociclib is also currently undergoing clinical trials in combination with other anti-hormonal drugs, which hopefully will be useful to treat other subsets of breast cancer.
Finn RS, Crown JP, Lang I, Boer K, Bondarenko IM, Kulyk SO, Ettl J, Patel R, Pinter T, Schmidt M, Shparyk Y, Thummala AR, Voytko NL, Fowst C, Huang X, Kim ST, Randolph S, Slamon DJ. The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study. The Lancet, 16:(1) 25-35.