Compared with many other malignancies, operable breast cancer (stages I-IIIA) has a long natural history with morbidity and mortality caused primarily by local recurrence and distant metastases. Although local therapy is essential for regional control, it does not completely address the problem of future metastases. Even after aggressive surgery, women with axillary lymph node involvement at the time of diagnosis have a poor prognosis without additional therapy. In 1975, Fisher et al reported that only 25% of women with lymph node involvement at the time of surgery were alive 10 years after diagnosis. In addition, 10% to 50% of patients with negative axillary lymph nodes developed distant metastases following apparently curative surgery.
For many, this low survival rate was due to distant micrometastases already present at the time of surgery. This realization led to a change in the treatment paradigm in the second half of the 20th century, with the introduction of systemic treatment modalities (chemotherapy and endocrine therapy) as "adjuvants" to surgical therapy. Systemic adjuvant therapy of breast cancer has improved survival in all subsets of patients with operable disease by helping to eradicate micrometastases. This has been proven in multiple randomized studies and confirmed in two recent meta-analysesone evaluating the benefit of tamoxifen(Drug information on tamoxifen) and the other evaluating systemic chemotherapy.
Although effective, adjuvant systemic therapy of breast cancer cannot completely eliminate the development of distant metastases. Thus, on the basis of hypotheses generated from preclinical studies and from the use of presurgical chemotherapy as treatment for locally advanced breast cancer, interest in using the neoadjuvant approach to treat early-stage breast cancer has grown.
In animal models, removal of the primary tumor increases proliferation of cancer cells at sites of metastases. It has, therefore, been hypothesized that administering systemic chemotherapy prior to tumor removal helps minimize micrometastases and prevent cancer growth that might otherwise occur after removal of the primary tumor. In fact, one study found that when cyclophosphamide(Drug information on cyclophosphamide) (Cytoxan, Neosar) was administered to mice with implanted mammary adenocarcinomas before removal of their largest tumors, it abrogated the growth spurt of the remaining tumor deposits and provided optimal tumor control.
Tamoxifen administered in the preoperative setting had similar effects. Administration of systemic chemotherapy to patients with intact primary tumors might, therefore, help decrease systemic micrometastases and improve overall survival. It has also been hypothesized that preoperative systemic treatment reaches tumors earlier than does postoperative adjuvant therapy, therefore confronting fewer micrometastases. Preoperative systemic therapy would also reach the primary tumor site before any surgical destruction of vascular access to the tumor-bearing area occurs.
Beyond the benefits observed in research studies evaluating tumors in vitro and in vivo, the benefits of neoadjuvant chemotherapy have been seen in its use as a treatment strategy for locally advanced breast cancer. Induction (neoadjuvant) therapy of locally advanced breast cancer produces an objective response in 60% to 80% of patients, with approximately 10% to 20% achieving a clinical complete response (CR). Many tumors initially considered inoperable can be rendered operable by neoadjuvant chemotherapy or endocrine therapy, and this ability to downstage multiple patients with large tumors could also theoretically translate into improved rates of breast conservation for patients with earlier-stage disease. Some researchers have proposed this approach as a method of testing the in vivo response of cancer to a particular systemic treatment regimen.
Most studies of preoperative systemic therapy have been conducted using chemotherapy, although the results of a few studies of neoadjuvant endocrine therapy are available. Initial nonrandomized studies evaluating the benefit of neoadjuvant chemotherapy in operable breast cancer began in the early 1980s and, over the next 2 decades, confirmed that this approach was feasible for early breast cancer (Table 1).[9-17] These studies were highly heterogeneous in many aspects and, thus, cannot be directly compared to determine the overall efficacy of any one treatment approach. While highlighting the potential of neoadjuvant chemotherapy in the treatment of early-stage breast cancer, these studies (and others) have illustrated many of the difficulties associated with evaluation of the benefits of neoadjuvant chemotherapy.
Predicting Response to Therapy
One theoretical benefit of neoadjuvant chemotherapy is that it provides the ability to evaluate the in vivo response of disease to a specific regimen. This is potentially useful, given that there are no reliable methods of predicting response to postoperative adjuvant chemotherapya procedure that is, therefore, given "blindly." Although multiple attempts have been made to predict response to chemotherapy on the basis of the baseline characteristics of the primary tumor (grade, hormone-receptor status, S-phase fraction, and HER2 or p53 status), no method has proven reliable. Response to therapy, especially pathologic CR, has been reproducibly associated with long-term survival.
During neoadjuvant treatment, a major reduction (> 50%) in tumor dimensions predicts better outcome and encourages continuation of treatment with the same regimen. Conversely, if little apparent benefit is being achieved with a particular treatment, that treatment can be stopped to avoid further risk of side effects and toxicity, and the regimen can be changed to an alternative drug or combination that may produce a superior response. As shown in Table 1, high overall response rates were associated with the various regimens used in clinical trials, despite the very heterogeneous groups of patients included in these studies.
High response rates may allow more patients to be eligible for breast-conserving therapy. In the early studies presented in Table 1, the criteria used to determine eligibility for breast-conserving therapy were not uniform, and, therefore, a comparison of this end point between trials is not possible. Moreover, the results were not compared with those of a control arm of surgery followed by adjuvant chemotherapy. The rates of breast-conserving therapy in these studies varied widely, ranging from 7% to 88%. However, these rates may be misleading, because the criteria used to determine operability were not uniform between trials.
The study by Schwartz et al was apparently initiated in 1979. However, breast-conserving therapy was not routinely used until 1983. Among patients receiving neoadjuvant chemotherapy after 1990, the percentage who undergo breast-conserving therapy has increased to 75% of those evaluated. In some studies, an initial tumor size > 3 cm precluded patients from breast-conserving therapy[11,12]; in others, this approach was offered more liberally, depending only on the ratio of tumor size to breast size. The studies using the first, more restrictive, criteria would likely be more successful in extending the indications for breast-conserving therapy after preoperative chemotherapy than would the studies using a more liberal set of criteria. Overall, these studies illustrate that breast-conserving therapy can be offered to a large percentage of patients who receive neoadjuvant therapy.
Clinical Response and Long-Term Outcome
The response of an individual tumor to treatment could be used as a primary end point to predict long-term outcome. Clinical response has been correlated with survival in trials evaluating neoadjuvant chemotherapy. In the study by Schwartz et al, patients whose tumor responses were amenable to breast-conserving therapy survived longer than did patients with similarly staged disease who were receiving chemotherapy and ultimately required mastectomy, although the differences were not significant. Similar findings were described by Bonadonna et al.[11,12]
Other reviews, by McCready et al and Kuerer et al, found that clinical response to neoadjuvant chemotherapy is a strong predictor of disease-free survival (P = .046).[19,20] In the second study, patients who achieved a clinical CR had a 3-year disease-free survival rate of 95%, whereas patients with a clinical partial response (PR) or minor response had a 3-year disease-free survival rate of only 66%.