Clarifying the Role of Neoadjuvant Therapy in Breast Cancer

Large clinical trials have demonstrated that preoperative therapy for primary operable breast cancer improves breast-conservation rates, with equivalent disease-free (DFS) and overall survival (OS) compared to adjuvant therapy.[1] Connolly and Stearns provide an excellent review of additional benefits of neoadjuvant therapy and emphasize the importance of a multidisciplinary approach to treating patients in this setting.

More Expeditious Evaluation

Pathologic complete response (pCR) to neoadjuvant therapy at the time of surgery has been consistently associated with improved DFS and OS. The likelihood of achieving a pCR varies based upon receptor status. Tumors that overexpress HER2/neu or are estrogen-receptor (ER) and progesterone-receptor (PR) negative are more likely to respond to neoadjuvant chemotherapy. Patients with HER2-positive or triple-negative tumors-the vast majority of whom would receive adjuvant chemotherapy-should all be considered for neoadjuvant therapy. This approach enables one to assess the in vivo chemosensitivity of a tumor in addition to improving surgical outcomes and cosmesis.

Using pCR as a surrogate endpoint for long-term outcome, the neoadjuvant setting has provided a more expeditious setting to evaluate novel treatment strategies for early-stage breast cancer. Potentially effective combinations of chemotherapy and targeted therapies can be efficiently identified in phase II studies using pCR as the primary endpoint, rather than performing large adjuvant trials that require long-term follow-up to demonstrate a survival advantage. I-SPY 2 (Investigation of Serial Studies to Predict Your Therapeutic Response With Imaging and Molecular Analysis 2) is an adaptive phase II neoadjuvant clinical trial designed to include women with locally advanced breast cancer, with the goal of rapidly identifying novel, targeted therapies. Approaches such as this will be particularly important in evaluating therapies for triple-negative tumors, for which we currently do not have effective, targeted agents.

Other Assessments

Studies have chiefly used pCR for the primary pathologic assessment of response to neoadjuvant therapy. Other definitions, such as residual cancer burden (RCB), may be more meaningful clinically since patients with minimal residual disease (RD) at the time of surgery have long-term outcomes similar to patients with pCR. RCB is calculated from bidimensional measurements of the primary tumor bed, proportion of invasive carcinoma present in tumor bed, number of involved axillary lymph nodes, and diameter of largest axillary metastasis. Patients are then assigned to one of four groups: RCB-0 (pCR), RCB-1 (minimal RD), RCB-II (moderate RD) and RCB-III (extensive RD).[2]

Unfortunately, patients who have moderate or extensive RD at the time of surgical resection are at increased risk of distant recurrence. For patients who are ER/PR-positive, antiestrogen therapy can reduce risk of recurrence. However, for patients with chemoresistant, triple-negative tumors, there are currently no targeted therapies available to decrease risk of recurrence. Despite the patient’s and physician’s interest in further treatment to lower risk, no data currently support a role for additional chemotherapy in the adjuvant setting. Future clinical trials should investigate novel agents in this high-risk population.

Genomic Profiling

The authors discuss the role of neoadjuvant hormonal therapy as being primarily for postmenopausal patients who have contraindications to chemotherapy. Genomic profiling in the adjuvant setting, using assays such as the 21-gene recurrence score (Oncotype DX) and 70-gene breast cancer signature (Mammaprint), has taught us that not all hormone-receptor–positive patients benefit from chemotherapy. This is particularly important for clinically node-negative patients who are considering preoperative therapy, for whom one might not recommend adjuvant chemotherapy. A more rational approach to preoperative therapy for hormone-receptor–positive patients would be to utilize genomic profiling to tailor recommendations. Studies in the preoperative setting are needed to determine if chemotherapy or hormonal therapy is more effective for patients with highly hormone-responsive disease.

Financial Disclosure: The author has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References:

References

1. Rastogi P, Anderson SJ, Bear HD, et al: Preoperative chemotherapy: Updates of National Surgical Adjuvant Breast and Bowel Project protocols B-18 and B-27. J Clin Oncol 26:778-785, 2008.

2. Symmans WF, Peintinger F, Hatzis C, et al: Measurement of residual breast cancer burden to predict survival after neoadjuvant chemotherapy. J Clin Oncol 25:4414-4422, 2007.