A basic assumption underlying adjuvant systemic therapy of early breast cancer is that those therapies that may be only palliative against bulky macroscopic metastases might be curative against microscopic disseminated tumor that is assumed to be present in high-risk patients. To develop effective adjuvant systemic therapy of early disease, one must first identify effective and safe therapies for advanced-stage breast cancer.
Systemic therapy for overt advanced breast cancer began 100 years ago when Beatson observed shrinkage of locally extensive breast cancers after oophorectomy in premenopausal women.6 This phenomenon is based on the trophic effect of estrogen on approximately half of all breast cancers studied. Removal of the ovaries leading to a drop in endogenous estrogen levels in younger women can arrest cancer growth and result in regression. Another approach to depriving breast cancers of estrogen effects is to block estrogen binding to the protein, estrogen receptor (ER), in the breast cancer cell cytoplasm. The receptor-estrogen complex mediates much of the effect of the hormone on the cell, and blocking the interaction, such as by removing estrogen, leads to regression of the hormone-dependent cancer.7 Tamoxifen (Nolvadex) is the prototype competitive inhibitor of estrogen binding at its receptor. The ability to measure estrogen and progesterone receptors and thus predict responsiveness to endocrine therapy made hormonal treatment of overt, metastatic breast cancer a standard approach.8 Oophorectomy in premenopausal women and tamoxifen in women of all ages cause significant regressions of clinically advanced estrogen and or progesterone receptor-containing breast cancers with generally acceptable toxicity. They were obvious candidates to be tried in the adjuvant setting after local therapy of early disease to treat occult micrometastases.
Unfortunately, not all breast cancers are estrogen dependent and responsive to hormonal manipulation. After the introduction of chemo-therapeutic drugs in the 1940s and 1950s, multiple agents were identified that were able to cause temporary shrinkage of tumor in women with disseminated breast cancer. Melphelan (PAM), thiotepa (T), cyclophosphamide (C), methotrexate (M), fluorouracil (F), or vinblas-tine (V) have a 20 to 30 percent chance of causing transient regression of metastatic breast cancer when used alone.9 In the late 1960s Cooper combined five drugs and reported higher regression rates.10 This regimen was the forerunner of the cyclophosphamide methotrexate fluorouracil (CMF) combination regimen, which was in the 1970s the standard chemo-therapeutic treatment of advanced disease (Table 12-1).11 In the late 1970s, doxorubicin (Adriamycin[A]) was introduced and found to be the most active single agent against advanced breast cancer. It was soon combined with other drugs11 (ex-cyclophosphamide adriamycin fluor-ouracil [ex-CAF]) and, in the 1980s, became the new standard treatment of overt metastatic disease (see Table 12-1). Finally, another class of drugs, the taxanes (paclitaxel-Taxol and doc-etaxel-Taxotere) were introduced in the last decade with activity comparable with that of doxorubicin in the palliation of advanced mammary cancer. All these drugs can be given safely, though they have significant toxicity. All were candidates for use in the adjuvant setting.
A recent trend in the treatment of metastatic breast cancer is the use of high-dose chemotherapy, either with cytokine support of the bone marrow or with stem cell or bone marrow stor age and reinfusion ("bone marrow transplantation"). These therapies are based on the assumption of a dose-response curve for drug-induced cancer cell death. While still controversial in advanced breast cancer (and very toxic), such approaches are also candidates for evaluation against the poorest-risk, early-stage disease.
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