Breast cancer chemotherapy

, Assistant Editor(s)-In-Chief: Jack Khouri

Overview
Breast cancer chemotherapy refers to the use of cytotoxic drugs (chemotherapy) in the treatment of breast cancer. The aim of chemotherapy is to prevent the growth of micrometastatic disease that is responsible for systemic disease recurrence.

Types
Chemotherapy can be given both before and after surgery. Neoadjuvant chemotherapy is used to shrink the size of a tumor prior to surgery. Adjuvant chemotherapy is given after surgery to reduce the risk of recurrence. Palliative chemotherapy is used to control (but not cure) the cancer in settings in which the cancer has spread beyond the breast and localized lymph nodes.

Regimens
Several different chemotherapy regimens may be used. Determining the appropriate regimen depends on many factors, including the character of the tumor, lymph node status, and the age and health of the patient. In general, chemotherapy has increasing side effects as the patient's age passes 65. The following is a list of commonly used adjuvant chemotherapy for breast cancer:


 * CMF: cyclophosphamide, methotrexate, and 5-fluorouracil given 4-weekly for 6 cycles
 * FAC (or CAF): 5-fluorouracil, doxorubicin, cyclophosphamide given 3-weekly for 6 cycles
 * AC (or CA): Adriamycin (doxorubicin) and cyclophosphamide given 3-weekly for 4 cycles
 * AC-Taxol: AC given 3-weekly for 4 cycles followed by paclitaxel given either 3-weekly for 4 cycles or weekly (at a smaller dose) for 12 weeks
 * TAC: Taxotere (docetaxel), Adriamycin (doxorubicin), and cyclophosphamide given 3-weekly for 6 cycles
 * FEC: 5-fluorouracil, epirubicin and cyclophosphamide given 3-weekly for 6 cycles
 * FECD: FEC given 3-weekly for 3 cycles followed by docetaxel given 3-weekly for 3 cycles
 * TC: Taxotere (docetaxel) and cyclophosphamide given 3-weekly for 4 cycles
 * Dose dense regimen: Some of the regimens above (e.g. AC followed by paclitaxel) may be given in a shorter period (i.e. every 2 weeks instead of every 3 weeks).
 * In addition to chemotherapy, trastuzumab may also be added to the regimen depending on the tumor characteristics (i.e. HER2/neu status) and risk of relapse. It is usually given either 3 weekly or weekly for a total duration of 1 year.

Since chemotherapy affects the production of white blood cells, granulocyte colony-stimulating factor (G-CSF) is sometimes administered along with chemotherapy. This has been shown to reduce, though not completely prevent, the rate of infection and low white cell count. Most adjuvant breast cancer chemotherapy regimens do not routinely require growth factor support except for those associated with a high incidence of bone marrow suppression and infection. These may include chemotherapy given in the dose dense fashion i.e. 2-weekly instead of 3-weekly or TAC chemotherapy (see above).

Risk Stratification
The decision of whether a patient should or not receive adjuvant chemotherapy is generally made by estimating the individual's risk for recurrence and the expected benefit of therapy. Risk stratification is based on tumor size, nodal status, histologic grade, hormone receptor and Her-2 statuses.

Hormone Receptor Status
Hormone receptor status is a definite prognostic and predictive factor. Most breast cancers are Estrogen receptor- positive. ER-negative tumors have higher risk of recurrence during 1 to 2 years after surgery that declines rapidly thereafter; however, ER-positive tumors preserve the ability to recur many years after surgery. The role of ER status as a predictive factor was assessed in a retrospective subset analysis of three cooperative group adjuvant chemotherapy trials in women who had node-positive breast cancer results showed that absolute benefits due to chemotherapy were greater for patients with ER-negative compared with ER-positive tumors: 22.8% more ER-negative patients survived to 5 years disease-free if receiving chemotherapy vs 7.0% for ER-positive patients; corresponding improvements for overall survival were 16.7% vs 4.0%.

HER2 Status
The HER2 receptor is overexpressed in approximately 20% to 25% of breast cancers. HER2 status is an important predictive factor. There is evidence that Trastuzumab exhibits synergy when administered in combination with other cytotoxic therapies, such as taxanes and vinorelbine, among HER2-positive patients.

Oncotype DX
It is a multigene assay used to predict the recurrence risk among women with ER-positive, node-negative, early-stage breast cancer. The 21-gene expression profile categorizes a woman's risk for recurrence as low, intermediate, or high, with associated 10-year distant recurrence rates of 6.8%, 14.3%, and 30.5%, respectively. This assay may be a useful tool in the risk–benefit calculus, ensuring that truly low-risk women are not overtreated and exposed to the deleterious effects of treatment and that women at a higher risk for recurrence may be considered for a more aggressive therapeutic strategy. The ideal management strategy for women at intermediate risk for recurrence is uncertain, however. Chemotherapy is not indicated for patients with low recurrence score (ie, <18) who only benefit from endocrine therapy with tamoxifen or an aromatase inbitor. Chemotherapy is indicated for women who have a high recurrence score (>31).

Indications for systemic chemotherapy in lymph node-negative, estrogen receptor–negative, early-stage breast cancer
There is a modest risk for recurrence for women who have node-negative breast cancer that may be reduced with adjuvant systemic therapy. Three clinical trials conducted by the National Surgical Adjuvant Breast and Bowel Project (NSABP) concluded that a significant risk for recurrence and death persisted among this “low-risk” population after surgery, which could be reduced with adjuvant chemotherapy. In the NSABP trials, CMF (Cyclophosphamide, Methotrexate and 5-FU) administration every 4 weeks or AC (Doxorubicin and Cyclophosphamide) administration every 3 weeks for four cycles showed same Outcomes in all age groupsas. Because of the long-term toxicity associated with anthracyclines, CMF is a reasonable option for patients who have lower-risk tumors. Adjuvant trastuzumab (Trastuzumab) is commonly administered for patients who have HER2-positive node-positive and high-risk, node-negative tumors, frequently in combination with an anthracycline and a taxane (AC-T).

Indications for systemic chemotherapy in lymph node-negative, estrogen receptor–positive, early-stage breast cancer
A recent study was conducted to look at the effect of Oncotype DX recurrence score on treatment recommendations for patients with estrogen receptor-positive early stage breast cancer and the correlation with estimation of recurrence risk by breast cancer specialists. The study had two primary endpoints: 154 patients with ER-positive early stage breast cancer and available RS results were selected. Clinicopathologic data were provided to four surgeons, four medical oncologists, and four pathologists. Participants were asked to estimate recurrence risk category and offer their chemotherapy recommendations initially without and later with knowledge of RS results. The three most important clinicopathologic features guiding their recommendations were requested. 95 (61.7%), 45 (29.2%), and 14 (9.1%) tumors were low, intermediate, and high risk by RS, respectively.
 * To evaluate the impact of Oncotype DX recurrence scores (RS) on chemotherapy recommendations
 * To compare the estimated recurrence risk predicted by breast oncology specialists to RS.

RS significantly correlated with tumor grade, mitotic activity, lymphovascular invasion, hormone receptor, and HER2/neu status. ''Estimated recurrence risk by participants agreed with RS in 54.2% ± 2.3% of cases. Without and with knowledge of RS, 82.3% ± 1.3% and 69.0% ± 6.9% of patients may be overtreated, respectively (p = 0.0322). Inclusion of RS data resulted in a 24.9% change in treatment recommendations''. There was no significant difference in recommendations between groups of participants. The Breast oncology specialists tended to overestimate the risk of tumor recurrence compared with RS. The study concluded that the Oncotype DX recurrence score provides useful information that improves patient selection for chemotherapy and changes treatment recommendations in approximately 25% of cases.

Adjuvant chemotherapy regimens for early stage breast cancer

 * Despite the controversy regarding the superiority of anthracycline-containing regimens to CMF combination chemotherapy, anthracycline-based regimens are believed to be significantly superior and are the most commonly used regimens in the US unless a contraindication to anthracyclines (heart disease) precludes their use.
 * The CMF regimen is reserved for older patients with early stage breast cancer and patients with low risk tumors.
 * Standard adjuvant anthracycline-containing regimens include adriamycin and cyclophosphamide AC; cyclophosphamide, doxorubicin, and 5-fluorouracil (CAF); 5-flourouracil, doxorubicin, and cyclophosphamide (FAC); 5-flourouracil, epirubicin, and cyclophosphamide (FEC or CEF); docetaxel, doxorubicin, and cyclophosphamide (TAC); and AC followed by paclitaxel (AC-T) or docetaxel (AC-D).
 * Several studies have demonstrated the superiority of taxane-containing regimens with paclitaxel or docetaxel in the adjuvant setting, where the addition of 4 cycles of paclitaxel after the completion of a standard course of AC improved the disease-free and overall survival of patients with early breast cancer.
 * The American Society of Clinical Oncology guidelines suggest the use of anthracycline-containing regimens, mainly in patients with node-positive tumors or HER2 overexpression.
 * Taxanes should be added in case of node-positive tumors and high risk (large or ER-negative) node-negative breast cancer.
 * Four 3-week cycles of AC (threshold doses for adriamycin and cyclophosphamide 60 mg/m2 and 600 mg/m2, respectively) followed by four 3-week cycles of paclitaxel is a very popular anthracycline-containing regimen. Currently, it has been largely replaced with the dose-dense (ie, every 2 weeks) AC followed by dose-dense paclitaxel, where dose density was found to improve clinical outcomes significantly.
 * Concomitant administration of chemotherapy and radiotherapy is not recommended due to increased toxicity
 * In clinical practice, patients usually receive postoperative radiation therapy after chemotherapy. This practice does not adversely affect outcome for local-regional recurrence.