Systemic Therapy for Stages I, II, and III Breast Cancer

The first decision about the use of systemic therapy in patients with stages I, II and III breast cancer is whether it should be given before or after surgery. This section outlines factors to consider when making this decision. Information about the treatment of locally advanced or inflammatory breast cancer is also included in this section.

Preoperative chemotherapy, also known as primary or neoadjuvant chemotherapy, has traditionally been given to patients with locally advanced breast cancer to reduce tumor volume and allow for definitive surgery. Treatment with preoperative chemotherapy can also allow for breast conservation therapy in patients who are not candidates for breast conservation at initial presentation. Preoperative chemotherapy may also reduce the need for an axillary lymph node dissection (ALND) in patients presenting with node-positive disease.

Much of the evidence presented in the following sections on preoperative chemotherapy is discussed in an American Society of Clinical Oncology guideline that describes the selection of options for the management of these patients.[1]

A 2005 meta-analysis of multiple randomized clinical trials demonstrated that preoperative chemotherapy is associated with identical disease-free survival (DFS) and overall survival (OS) as the same therapy in the adjuvant setting.[2][Level of evidence A1]

In 2019, the Early Breast Cancer Trialists’ Collaborative Group performed a meta-analysis using individual patient data from 4,756 women who participated in 10 trials that compared neoadjuvant chemotherapy with the same regimen given in the adjuvant setting.[3] Compared with adjuvant therapy, neoadjuvant therapy was associated with an increased frequency of breast conservation (65% vs. 49%). There were no differences between neoadjuvant chemotherapy and adjuvant therapy in distant recurrence, breast cancer mortality, or death from any cause. However, neoadjuvant therapy was associated with higher 15-year local recurrence rates (21.4% vs. 15.9%; relative risk [RR], 1.37; 95% confidence interval [CI], 1.17−1.61; P = .001).[3][Level of evidence A1]

Pathological complete response (pCR) has been used as a surrogate end point for long-term outcomes, such as DFS, event-free survival (EFS), and OS, in preoperative clinical trials in breast cancer. A pooled analysis (CTNeoBC) of 11 preoperative randomized trials (n = 11,955) determined that pCR, defined as no residual invasive cancer in the breast and axillary nodes with presence or absence of in situ cancer (ypT0/is ypN0 or ypT0 ypN0), was associated with improved outcomes compared with eradication of invasive tumor from the breast alone (ypT0/is).[4] pCR could not be validated in this study as a surrogate end point for improved EFS and OS.[4][Level of evidence C2] Because of a strong association between pCR and substantially improved outcomes in individual patients with more aggressive subtypes of breast cancer, the U.S. Food and Drug Administration (FDA) has supported use of pCR as an end point in preoperative clinical trials for patients with high-risk, early-stage breast cancer.

Unfortunately, categorizing patients as having pCR or residual disease offers no distinction among patients with varied amounts of residual disease. The residual cancer burden (RCB) method was designed to address this and other prognostic deficits. The RCB method provides a standard to evaluate and quantify the extent of residual disease in breast and axillary lymph nodes following neoadjuvant chemotherapy. It is reported as a continuous score, with pCR being scored as RCB-0. There are four RCB classes ranging from RCB-0 to RCB-3. Determining RCB after neoadjuvant treatment has been validated as a prognostic predictor in early breast cancer.

A pooled, multinational, multi-institutional analysis was performed, using participant-level RCB results and clinicopathological data. Data from 5,161 patients were analyzed to assess the association between the continuous RCB score and the primary study outcome, EFS. With a median follow-up of 56 months, the RCB score was prognostic within each breast cancer subtype, with a higher RCB score significantly associated with worse EFS. RCB score was prognostic for EFS in multivariable models adjusted for age, grade, T (tumor) category, and nodal status at baseline. The adjusted hazard ratio (HR) associated with a one-unit increase in RCB ranged from 1.52 in the HER2-negative hormone receptor–positive group to 2.09 in the HER2-positive hormone receptor–negative group (P < .0001 for all subtypes).[5]

Neoadjuvant therapy is particularly favored in patients with triple-negative or HER2-positive disease, when pathological response is used as a guide in choosing the optimal adjuvant therapy after surgery. For more information, see the sections on Stages I, II, and III Triple-Negative Breast Cancer and Stages I, II, and III HER2-Positive Breast Cancer.

Omission of postoperative radiation therapy to the regional nodes in patients who initially present as node positive and become node negative after neoadjuvant therapy is currently being evaluated.