Adjuvant systemic therapy refers to the administration of chemotherapy, hormone therapy, and/or trastuzumab (Herceptin(R)) following surgery for early stages of breast cancer. The intent is to eliminate or delay the subsequent appearance of clinically occult micrometastatic disease. These micrometastases are thought to account for distant treatment failures after local treatment alone. Widespread application of adjuvant systemic therapy is thought to be responsible, at least in part, for the reduction in cause-specific mortality from breast cancer seen in almost every Western nation (Barry, Cronin, & Pleurvitis, 2005).

Not all patients with early breast cancer benefit from adjuvant systemic therapy. The need for such therapy, and the choice of modality, is based upon the estimated risk of disease recurrence, as well as the predicted benefits and risks of adjuvant therapy. Increasingly, these issues are influenced not only by clinicopathologic factors such as axillary lymph node status and tumor size but also by biologic and/or molecular factors (Palk, Tang, & Shak, 2006). A major determinant is whether an individual breast cancer is hormonally responsive, as indicated by expression of estrogen (ER) or progesterone (PR) receptors. Adjuvant hormone therapy benefits patients with hormone responsive breast cancers and not those with hormone nonresponsive disease (Sediman, Reichman, & Crown, 1995). Approximately 15% to 20% of breast cancers have an amplification and/or overexpression of the gene encoding the cell surface molecule-HER-2/neu. HER-2/neu is predictive of benefit from the HER-2/neu monoclonal antibody trastuzumab (Herceptin; Coombes, Bliss, & Wils, 1996).

ANTHRACYCLINE CONTAINING CHEMOTHERAPY (AC, EC, CAF, FEC/CEF, 5 FU, MTX)

Prior to the advent of taxenes (Taxol, Taxotere), the most widely used adjuvant chemotherapy regimens were CMF-type regimens and anthracycline-based regimens such as AC (doxorubicin plus cyclophosphamide), EC (epirubicin plus cyclophosphamide), CAF (cyclophosphamide, doxorubicin, 5-Fluorouracil), and FEC/CEF (cyclophosphamide, epirubicin, and 5-Fluorouracil) (Cisman & Lindsey, 1999). The side effect profiles associated with these regimens are different. Anthracycline-based regimens are most often associated with alopecia and vomiting, and they have a long-term risk of cardiomyopathy. In contrast, CMF is more likely to cause nausea and premature ovarian failure.

SERMS

Two classes of drugs are available that act as selective estrogen receptor modulators (SERMS): tamoxifen (Nolvadex(R)) and raloxifene (Evista(R)) are related drugs (Osborne, 1998). Both agents are competitive inhibitors of estrogen binding receptors (ERs), and both drugs have a mixed agonist and antiagonist activity, depending on the target tissue. Tamoxifen's antagonist effect is particularly prominent with respect to breast cancer. In premenopausal women with ER-positive breast cancer, tamoxifen reduces the risk of recurrence and death when given as an adjuvant therapy and can provide palliation in those who have developed metastatic disease ("Effects of chemotherapy," 2005; Fisher, Constantino, & Wickerham, 2005). Unfortunately, ER-positive breast cancers display primary resistance to tamoxifen and all advanced breast cancers will eventually become refractory to tamoxifen treatment. Tamoxifen may also prevent the development of contralateral breast cancer development both in women with a prior diagnosis of breast cancer, and in those women at high risk for breast cancer development (Vogel, Constantino, & Wickerham, 2006).

Newly published results from the National Surgical Adjuvant Breast and Bowel Project's STAR chemoprevention trial demonstrated that raloxifene has a similar protective effect against the development of invasive breast cancer, with a lower risk of thromboembolic events and cataract development, but a higher risk of noninvasive (in situ) breast cancer (Vogel et al., 2006).

Both raloxifene and tamoxifen also induce hot flashes (as an estrogen antagonist effect). Tamoxifen induces endometrial hyperplasia (an estrogen agonist effect; Fisher, Constantino, & Redmond, 1994), and increases the risk of developing endometrial cancer (Fisher et al., 2005; Vogel et al., 2006). Raloxifene, however, does not appear to have an endometrial agonist effect and does not increase the risk of uterine cancer (Cummings, Eckert, & Kruegar, 1999).

HER-2/neu

HER-2/neu is a humanized monoclonal antibody that is commonly known as trastuzumb (Herceptin). The HER-2/neu receptor belongs to the epidermal growth factor receptor family that is one of the receptors that is critical in controlling the pathway for epithelial cell growth and differentiation (Klapper, Glathe, & Vaisman, 1999; Karunagaran, Tzahar, & Beerl, 1996), and possibly angiogenesis. An overexpression of the HER-2/neu protein is observed in 15%-20% of breast cancers (Slamon, Clark, & Wong, 1987; Slamon, Godophin, & Jones, 1989).

Tumor markers may be useful to estimate prognosis, predict treatment response, or monitor patients for disease recurrence. In breast cancer, there are a variety of tissue and/or serum tumor markers, with potential clinical utility including ER/PR, HER-2/neu, CA 15-3, and gene expression, to name a few. ER/PR and HER-2/neu are the only markers in women with breast cancer that have achieved widespread acceptance and are used routinely for clinical decision making. In 2001, an expert panel convened by the American Society of Clinical Oncologists recommended that HER-2/neu overexpression be evaluated in every primary breast cancer (Bast, Ravdin, Hayes, & Hayes, 2001). Since that time, data have become available on the utility of HER-2/neu expression as a predictive marker in women with breast cancer. It is now well accepted that high levels of expression of HER-2/neu identify those patients most likely to respond to trastuzumb in both the adjuvant and metastatic disease settings.

ANASTROZOLES (ARAMATASE INHIBITORS)

Anastrozoles (Arimidex(R) and Arimison(R)) are the second generation of the SERMs and are used only in postmenopausal women. In these women, the principal source of circulating estrogen is a conversion of adrenally generated androsternedione to estrone by aramatase in peripheral tissue with a further conversion of estrone to estradiol (Anastrozole, 2007). Many breast cancers also contain aromatase.

Anastrozoles are a potent and selective nonsteroidal armatase inhibitor and significantly lower serum estradiol concentrations.

Anastrozoles are generally well tolerated with the principal side effect being diarrhea (8.4%) (Anastrozole, 2007). The drug is metabolized primarily in the liver by cytochrome P450; however, at the usual doses there have not be any reported significant drug-drug interactions.

The alphabet soup of chemotherapy has direct implications on our practices. Both the SERM and the antracycline drug classes have numerous side effects including, but not limited to, hypertension, thrombophlebitis (cancer patients are particularly at risk for thromboembolic events), anemia, leukopenia, thrombocytopenia, weight loss, anxiety, nervousness, and breast pain. In addition, when a patient receives an anthracycline-based chemotherapy regimen, the incidence of cardiotoxicity increases and can potentially affect the intra- and postoperative course and surgical outcome. The multitude of chemotherapeutic regimens are complex. It is imperative that a close communication process exists between the surgeon, staff, the patient, and the oncologist to ensure a desirable outcome for all who are involved in the care of these challenging but grateful patients who have come to us to assist in reclaiming a lost part of themselves.

REFERENCES