Preoperative (sometimes called neoadjuvant or primary) treatment for breast cancer is well established as a treatment for locally advanced tumors (1). Early results, principally with chemotherapy, suggested that neoadjuvant chemotherapy could effectively cytoreduce bulky tumors, rendering operable women with extensive primary tumors, including inflammatory breast cancer. On the basis of these results, and the growing literature on adjuvant chemotherapy, neoadjuvant chemotherapy became the standard of care for locally advanced breast cancer.

Neoadjuvant chemotherapy has also been studied among women with earlier stages of breast cancer. The landmark National Surgical Adjuvant Breast and Bowel Project Protocol (NSAPB) B-18 trial randomized women with operable breast cancer to either adjuvant or neoadjuvant chemotherapy (2). This study proved several important treatment principles for preoperative chemotherapy that have been validated in other randomized clinical trials. First, neoadjuvant therapy was tolerable and did not interfere with other treatment modalities, such as surgery or radiation therapy. Secondly, neoadjuvant therapy provided equivalent long-term disease outcomes as adjuvant therapy. Distant disease-free and local-regional disease recurrence rates were equal with either strategy. Third, neoadjuvant therapy had the advantage of surgical downstaging some patients. That is, patients who might otherwise have needed a mastectomy could in some instances have sufficient tumor shrinkage to facilitate breast-conserving surgery. Fourth, neoadjuvant therapy appeared to identify a new prognostic feature, the pathological complete response (pCR). While most patients had tumor response to treatment, only a small fraction—10% to 20%—had complete eradication of detectable tumor within the breast or regional lymph nodes. Those patients who did achieve pCR had a superior long-term breast cancer outcome compared to patients with residual tumor in the breast at the time of surgery. This suggested that pCR following neoadjuvant chemotherapy could be an effective surrogate marker for long-term cancer results.

Because the breast tumor is clinically detectable, measurable, and accessible for tissue sampling or radiological assessment, preoperative treatment offers unparalleled opportunities to study breast cancer biology. In addition, treatment in the preoperative setting is relatively short, and results are available quickly. The potential for pCR to serve as a surrogate for late recurrence risk invites the possibility that long follow-up, which is time-consuming and expensive, might be unnecessary for identifying better treatments. From a methodological viewpoint, preoperative treatment trials may require smaller number of patients. The sample size for clinical studies is governed by the number of "events." In adjuvant trials, events are tumor recurrences that happen in only a fraction of patients. In contrast, events, such as response or pCR in preoperative studies, happen in a larger fraction of patients, potentially lowering the number of needed patients. For all these reasons, preoperative treatment has emerged as a favored model for translational clinical trials.

A challenge for preoperative research has been to define adequately the nature of response to treatment. A variety of criteria for pCR have been developed, as well as grading scales for measuring response less than pCR. While certain consistencies exist within various treatment reports, such as the scoring of residual in situ carcinoma, only, as equivalent to pCR, reporting practices are highly variable. For instance, definitions of pCR variously include response in the breast-alone versus breast- and lymph-node, and differences in the scoring of residual microin-vasive or lymphatic/vascular invasion. The reporting of pCR is also subject to the effort made to sample the surgical specimen; the harder the pathologist searches for residual tumor, the more likely it is that tumor will be found. Treatment plans in the preoperative setting are not uniform and range from several weeks to six months or more. Finally, patient eligibility for neoadjuvant trials differs enormously from one study to another. Some studies include patients with stage I—III breast cancer; others are limited to women with locally advanced disease, only. For these reasons, it has not proven meaningful to compare rates of clinical response or pCR between different clinical trials.

Recent studies utilizing preoperative therapy can be broadly divided into several categories, each with different primary endpoints. Larger, randomized trials have sought to define new standards of treatment suitable for adjuvant therapy. Smaller phase 2 trials have attempted to define the efficacy of specific regimens, including those that incorporate novel agents, in the preoperative setting. Biomarker trials have attempted to analyze serial changes in tumor biology in response to treatment, with the goals of identifying predictors of benefit/response using conventional therapies. Finally, there are "exposure" studies in which patients are offered short treatments with novel therapies in an effort to identify mechanisms of action, relevant biomarkers, or efficacy signals that would be evaluated further in larger trials. The remainder of this chapter discusses some of these recent findings with focus on the methodological lessons that have emerged.

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