ABSTRACT: Neoadjuvant therapy may provide advantages to some women with primary operable breast cancer. Compared to the administration of the same regimen in the adjuvant setting, neoadjuvant chemotherapy does not improve survival outcomes, but may provide other benefits. Neoadjuvant therapy is associated with improved rates of breast-conserving therapy, may offer prognostic information, and enables assessment of in vivo response to therapy. Women who achieve a pathologic complete response following neoadjuvant therapy are expected to have a superior outcome compared to those with extensive residual disease. The neoadjuvant setting has been an attractive area of research for identifying new effective treatment strategies while minimizing treatment-related adverse events, studying drug mechanisms of action, and developing clinically applicable prognostic and predictive biomarkers in an attempt to individualize therapy. In the primary operable setting, it is of great importance to define treatment goals, to select proper candidates for the approach, to assess baseline tumor characteristics, and to provide optimal multidisciplinary monitoring during and following the neoadjuvant therapy.
The improvements in long-term breast cancer–related outcomes in recent decades, including disease-free and overall survival, are attributed to both early screening and optimal multidisciplinary therapy. Traditionally, women undergo a definitive surgical procedure—generally a mastectomy or a lumpectomy with axillary lymph node assessment—to allow for accurate pathologic staging. Because adjuvant systemic therapy significantly improves long-term breast cancer–related outcomes, almost every woman with early-stage disease will be recommended systemic therapy, which may include chemotherapy, endocrine manipulations, targeted therapies, or a combination of these treatment approaches. Systemic treatment recommendations are made based on estimates of risk of recurrence, age, and competing morbidities.
Neoadjuvant therapy, also designated primary systemic or preoperative therapy, was initially employed to downstage inoperable tumors to allow for definitive surgery. Once the long-term benefits of adjuvant therapy were recognized, it was postulated that administration of chemotherapy prior to surgery might be more effective at eradicating micrometastatic disease and therefore could result in improvements in long-term outcomes. Two decades of investigation have demonstrated equivalent survival benefits for the administration of chemotherapy before or after surgery. The neoadjuvant approach may allow for other benefits such as enhancement of breast conservation, but may also be associated with several limitations. It is therefore of great importance to define treatment goals, to select proper candidates, to assess baseline tumor characteristics, and to provide optimal multidisciplinary monitoring during and following neoadjuvant therapy.
Aims of Neoadjuvant Therapy
The primary aims of neoadjuvant therapy for breast cancer are to improve surgical outcomes, to assess response to therapy, and to achieve long-term survival. In patients with locally advanced breast cancer, response to neoadjuvant therapy may lead to improved overall outcomes by allowing for definitive local therapy. In patients with primary operable disease, the neoadjuvant approach provides equivalent disease-free and overall survival compared to those treated with adjuvant therapy, but is associated with improved rates of breast-conserving therapy (BCT). While the administration of neoadjuvant chemotherapy is recommended for women with locally advanced breast cancer, its use in the primary operable setting has been debated and is the focus of this review.
In addition to improvement of surgical outcomes, neoadjuvant therapy may provide other advantages. Response to treatment in an individual woman may predict her long-term outcome. Despite the varied definitions of pathologic complete response (pCR) in trials completed to date, it has been consistently demonstrated that pCR is associated with improved disease-free and overall survival. Women without residual invasive and noninvasive tumor cells in the breast and in the axillary nodes have substantially improved outcomes compared to women with similar stage and tumor characteristics and extensive residual disease. Furthermore, clinical response to therapy can be assessed as early as following one to two cycles and may help predict who will achieve a pCR. Those who appear to be resistant to the chosen treatment should be considered for an alternative therapy, an option that is not currently possible when adjuvant therapy is administered. Therefore, observation of response to treatment can be used as a surrogate marker for disease outcome and treatment may be altered to enhance response.
In addition, because of easy access to the tumor and the ability to assess response to treatment, neoadjuvant therapy has commonly been employed in clinical trials. While administering standard and novel agents, researchers can rapidly investigate the efficacy of the treatment, study drug mechanism of action, and examine potential predictive biomarkers of response to specific treatments. Established or novel imaging techniques may also be utilized to predict response to therapy and long-term outcome using relatively small numbers of patients.
Selection of Patients
A careful staging evaluation should be performed prior to the decision to administer neoadjuvant therapy. Knowledge of the tumor stage and histologic features can help predict who will likely respond to a particular treatment. An International Expert Panel, convened three times over the past decade, has recommended that clinicians should consider neoadjuvant chemotherapy in any patient with primary operable disease for whom adjuvant chemotherapy is clearly indicated. Patient and tumor characteristics can help predict those who will respond to, and therefore benefit from, chemotherapy.
Tumor characteristics that predict an improved response to neoadjuvant chemotherapy include absent or low expression of estrogen receptor (ER), high Ki67 or another proliferation index, high grade, and ductal pathology. Improved response to neoadjuvant chemotherapy and high pCR rates are more likely in women with tumors that amplify or overexpress HER2/neu (HER2-positive) or tumors that lack ER, progesterone(Drug information on progesterone)-receptor (PR), and HER2 (so-called “triple-negative” breast cancer) compared to women with tumors that are low grade or those that express ER. Women with HER2-positive tumors who are candidates for neoadjuvant chemotherapy should receive a trastuzumab(Drug information on trastuzumab) (Herceptin)-based regimen.
While women who do not obtain a pCR have a worse outcome compared to those who achieve pCR, women with hormone receptor–positive tumors are expected to have overall improved outcomes compared to those whose tumors lack ER, likely due to prolonged adjuvant hormone therapy use in the hormone receptor–positive women. For example, women with lobular carcinoma do not respond well to neoadjuvant chemotherapy but have improved survival outcomes. Indeed, recent recommendations suggest that women with large lobular tumors are not good candidates for neoadjuvant chemotherapy, as responses are few and chance for posttreatment breast conservation is low. Together, these observations suggest that treatment aims and tumor subtypes should be considered prior to recommending neoadjuvant therapy.
Certain comorbidities or poor performance status may preclude the safe administration of chemotherapy. Age and race may also predict response and may reflect differences in tumor biology. For example, women under the age of 35 years respond better than older women to neoadjuvant chemotherapy. In a large retrospective study reported by M.D. Anderson Cancer Center investigators, race did not predict differences in pCR rate or breast cancer outcomes in women with triple-negative disease receiving neoadjuvant chemotherapy. However, in a smaller single-institution analysis, African-American women with triple-negative breast cancer were less likely than Caucasian or other women with similar tumor characteristics to achieve a pCR.
Neoadjuvant endocrine therapy is currently favored for patients with low-grade hormone receptor–positive breast cancer who are unlikely to respond to chemotherapy and those whose age or comorbidities preclude the administration of chemotherapy.
Accurate clinical, radiologic, and pathologic evaluation of an individual’s breast cancer is imperative prior to initiating neoadjuvant chemotherapy. Clinical examination can estimate tumor size and presence of lymph node metastases. Baseline ultrasound of the affected breast and bilateral mammography should be performed. If breast conservation is considered, other imaging modalities, such as magnetic resonance imaging (MRI), may be employed, especially if results do not correlate appropriately with clinical findings or if tumors are lobular or multicentric in nature. Image-guided placement of a metal clip into the tumor bed is recommended, ideally at baseline, for women who may become candidates for BCT, as obtaining a pCR may otherwise preclude accurate identification of the original tumor site. A diagnostic core biopsy is essential to determine histologic tumor characteristics, including ER, PR, and HER2 status. Ultrasound-guided fine-needle aspiration (FNA) of the axilla may assist in baseline staging. If the axilla is clinically negative and the FNA has not revealed micrometastases, sentinel lymph node biopsy (SLNB) should be considered to allow for proper axillary staging and determine optimal local therapy.