Active regimens Preoperative chemotherapy regimens reported to result in high response rates (partial and complete responses) include CAF (cyclophosphamide, doxorubicin [Adriamycin], and fluorouracil [5-FU]), FAC (5-FU, Adriamycin, and cyclophosphamide), CMF (cyclophosphamide, methotrexate, and 5-FU), and CMFVP (cyclophosphamide, methotrexate, 5-FU, vincristine, and prednisone). Combination chemotherapy with an anthracycline-based regimen—FAC or AC—is used most often. Recently published data suggest that the AT regimen of Adriamycin and docetaxel (Taxotere) given concomitantly may produce equivalently high response rates. Combination agents for metastastic breast cancer also include paclitaxel plus trastuzumab (Herceptin) with carboplatin, gemcitabine (Gemzar) and paclitaxel, and capecitabine (Xeloda) and docetaxel (Table 1). Although not yet definitive, recent data indicate that enhancing dose density may increase the pathologic complete response rate for women with locally advanced disease. The doses of these combination chemotherapy regimens are given in Table 1, chapter 10.

There seems to be no difference in survival in women with locally advanced disease who receive chemotherapy before or after surgery. Neoadjuvant chemotherapy results in complete response rates ranging from 20% to 53% and partial response rates (≥ 50% reduction in bidimensionally measurable disease) ranging from 37% to 50%, with total response rates ranging from 80% to 90%. Patients with large lesions are more likely to have partial responses. Pathologic complete responses (pCRs) do occur and are more likely to be seen in patients with smaller tumors. A pCR in the primary tumor is often predictive of a complete axillary lymph node response. Patients with locally advanced breast cancer who have a pCR in the breast and axillary nodes have a significantly improved disease-free survival rate compared with those who have less than a pCR. However, a pCR does not entirely eliminate the risk for recurrence.

Patients should be followed carefully while receiving neoadjuvant systemic therapy to determine treatment response. In addition to clinical examination, it may also be helpful to document photographically the response of ulcerated, erythematous, indurated skin lesions. Physical examination, mammography, and breast ultrasonography are best for assessing primary tumor response, whereas physical examination and ultrasonography are used to evaluate regional nodal involvement.

The role of MRI in evaluating response to preoperative chemotherapy is still evolving. Dynamic contrast-enhanced MRI performed at baseline, during chemotherapy, and before surgery has yielded more than 90% diagnostic accuracy in identifying tumors achieving a pCR and can potentially provide functional parameters that may help to optimize neoadjuvant chemotherapy strategies. However, despite its high sensitivity, a large number of patients still may have either false-negative or false-positive results on MRI scanning.

Multimodality approach

A multimodality treatment plan for locally advanced breast cancer (stages IIIA and IIIB, M1 supraclavicular nodes) is shown schematically in Figure 1. This approach has been shown to result in a 5-year survival rate of 84% in patients with stage IIIA disease and a 44% rate in those with stage IIIB disease. The most striking benefit has been seen in patients with inflammatory breast cancer, with 5-year survival rates of 35% to 50% reported for a multimodality treatment approach including primary chemotherapy followed by surgery and radiation therapy and additional adjuvant systemic therapy. The same chemotherapy drugs, doses, and schedules used for single-modality therapy are employed in the multimodality approach.

Surgery Traditionally, the surgical procedure of choice for patients with locally advanced breast cancer has been mastectomy. In recently published studies, some patients with locally advanced breast cancer who responded to treatment with neoadjuvant chemotherapy became candidates for breast-conservation therapy and were treated with limited breast surgery and adjuvant breast irradiation. Patients who have been downstaged using neoadjuvant chemotherapy should be evaluated carefully before proceeding with conservative treatment. It may be helpful to mark the site of the primary tumor with the placement of a clip during the course of percutaneous biopsy prior to beginning adjuvant therapy. There can sometimes be a complete clinical and/or radiographic response after neoadjuvant chemotherapy or hormonal therapy, and this may facilitate a wide local incision.

The role of sentinel node biopsy in the treatment of breast cancer after neoadjuvant chemotherapy has yet to be defined. Studies have shown that pathologically positive axillary lymph nodes can be sterilized when neoadjuvant chemotherapy is utilized. There are other biologic concerns with sentinel node biopsy after neoadjuvant chemotherapy. The lymphatics may undergo fibrosis or may become obstructed by cellular debris, making the mapping procedure unreliable, with false-negative rates of up to 25%. The rate of conversion from positive to negative nodes can be enhanced when 4 cycles of a doxorubicin-based regimen are followed by 4 cycles of docetaxel. Sentinel node biopsy will only be accurate then if all the metastatic deposits within the axilla respond in a similar fashion to chemotherapy. Preliminary data from the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-27 trial demonstrated an 11% false-negative rate in women who underwent sentinel node biopsy after receiving 4 cycles of doxorubicin and cyclophosphamide followed by 4 cycles of docetaxel. However, patients with clinically positive nodes prior to neoadjuvant chemotherapy should have full node dissection.

Radiation therapy remains an integral component of the management of patients with locally advanced breast cancer. For patients with operable breast cancer undergoing mastectomy, radiation therapy to the chest wall and/or regional lymph nodes (to a total dose of 5,000–6,000 cGy) is usually employed, as discussed in chapter 10. Randomized trials suggest that postmastectomy patients with any number of positive nodes derive a disease-free and/or overall survival benefit from postmastectomy irradiation.

In a retrospective review of over 500 patients on six prospective trials treated with neoadjuvant chemotherapy, mastectomy, and radiation were compared with 134 patients treated with the same therapy, mastectomy, but without radiation. Despite the more unfavorable characteristics, the radiated patients had a lower rate of local-regional relapse than the unirradiated group (11% vs 22%). Patients who presented with clinically advanced stage III or IV disease but subsequently achieved a pathological complete response to neoadjuvant chemotherapy still had a high rate of locoregional response, which was significantly reduced with radiation (10-year rates: 33% vs 3%; P = .006). Radiation improved cause-specific survival (CSS) in the subsets of patients with stage IIIB disease, clinical T4 tumors, and four or more positive nodes.The authors conclude that radiation should be considered for these patients regardless of their response to initial chemotherapy.

Available data do not suggest a problem in delaying radiation therapy until the completion of systemic chemotherapy. Even in patients undergoing high-dose chemotherapy with autologous bone marrow or stem-cell transplantation, irradiation is generally indicated following mastectomy for patients with locally advanced disease (primary tumors ≥ 5 cm and/or ≥ four positive axillary nodes).

For patients whose disease is considered to be inoperable, radiation therapy may be integrated into the management plan prior to surgery.