The use of letrozole appears superior to tamoxifen when used as neoadjuvant therapy (treatment prior to surgery) in post-menopausal patients with estrogen-receptor positive breast cancer, according to a recent article published in the Journal of Clinical Oncology. Further findings indicate that a significantly higher rate of anticancer responses was achieved with letrozole in patients exhibiting epidermal growth factor and Her2/neu expression.
Estrogen receptor-positive breast cancer is a type of cancer that is stimulated to grow by a naturally occurring female hormone called estrogen. Specific proteins, called estrogen receptors, cover the surface of these cancer cells, and enable estrogen to enter into the cell, ultimately facilitating cancer growth. Currently, many women with estrogen receptor-positive breast cancer are initially treated with a drug called tamoxifen, which blocks estrogen from entering into a cell, thereby eliminating its source for growth. However, a new group of drugs, called anti-aromatase agents, have recently been developed and approved by the FDA for the treatment of estrogen-positive metastatic breast cancer in post-menopausal women. Clinical trials are ongoing to determine the exact role anti-aromatase agents will play in the treatment of breast cancer.
In all women, estrogen is initially produced by the ovaries and adrenal glands in an inactive form. Through a series of biochemical conversions, the inactive form is ultimately converted to the final active form of estrogen, which is the growth stimulant for cancer. The initial conversion step of estrogen is facilitated by a protein called aromatase. The new FDA approved drug, letrozole, works by inhibiting the protein aromatase, which ultimately blocks the entire conversion process that is responsible for creating the active form of estrogen. This reduces levels of the active form of estrogen in the body so cancer cells are depleted of necessary growth stimulation. This is in contrast to tamoxifen, which blocks estrogen from entering a cell by directly binding to estrogen receptors.
Some previous clinical studies have suggested that the presence of two specific proteins found in abundance on the surface of some cancer cells, epidermal growth factor receptor (ErbB-1) and Her2/neu (ErbB-2), may negatively affect responses to tamoxifen. However, not all study results concur with the findings of these associations. ErbB-1 and ErbB-2 mark the existence of two biological pathways within the cancer cell that stimulate growth and replication of the cell. ErbB-1 and ErbB-2 are both proteins that bind to other proteins circulating in the blood called growth factors. The binding action of ErbB-1 and ErbB-2 to their respective growth factors facilitates a biochemical cascade within the cancer cell that stimulates growth and replication of the cell.
Neoadjuvant hormonal therapy is sometimes utilized as treatment in an attempt to shrink the cancer prior to surgery. This may allow for the more complete removal of cancer and greater preservation of the breast. However, neoadjuvant hormonal therapy in the treatment of breast cancer is still in investigative stages, with many physicians utilizing chemotherapy as either the sole or partial component of the neoadjuvant regimen.
A multi-center international clinical trial was recently conducted in order to address several issues regarding neoadjuvant hormonal therapy in patients with advanced breast cancer. Researchers aimed to evaluate and compare letrozole to tamoxifen in patients with differing characteristics including estrogen and progesterone receptor status, ErbB-1 and ErbB-2 status in the neoadjuvant setting. Patients involved in this trial were post-menopausal women who had breast cancer that was too advanced prior to therapy for breast-conserving surgery. Half of the patients received neoadjuvant therapy with letrozole and the other half received tamoxifen. The anti-cancer response rate for patients who were positive for ER, ErbB-1 and ErbB-2 following neoadjuvant therapy was 88% for those treated with letrozole, compared with only 21% for those treated with tamoxifen. The anti-cancer response rate for patients who were ER-positive, but ErbB-1 and ErbB-2 negative was 54% following treatment with letrozole compared with 42% following treatment with tamoxifen. Regardless of ErbB1/ErbB2 status, the overall anti-cancer response rate for ER-positive patients was 60% for those patients treated with letrozole compared to 40% for those treated with tamoxifen. Nearly half of the patients treated with letrozole were able to undergo breast-conserving therapy following neoadjuvant treatment compared with 36% of those treated with tamoxifen. Patients who were ER-negative showed a poor response to both letrozole (19%) and tamoxifen (11%).
The results from this trial may lead to very important indications regarding treatment of breast cancer in post-menopausal women, including further evidence mounting toward the superiority of anti-aromatase agents over tamoxifen, treatment with neoadjuvant hormonal therapy and the consideration of several protein receptors to determine optimal treatment. Future clinical trials combining anti-aromatase agents and Herceptin® or other biological therapies targeting specific receptors are warranted. Patients with breast cancer may wish to speak with their physician about the risks and benefits of participating in a clinical trial further evaluating neoadjuvant hormonal therapy or other promising therapy combinations. Two sources of information regarding clinical trials include comprehensive, easy-to-use listing services provided by the National Cancer Institute (cancer.gov) and eCancerTrials.com. eCancerTrials.com also provides personalized clinical trial searches on behalf of patients. (Journal of Clinical Oncology, Vol 19, No 18, pp 3808-3816, 2001)