Evolving Role of Lymph Node Biopsies After Neoadjuvant Therapy for Breast Cancer

Twenty-five years ago, breast cancer clinical trials examined whether neoadjuvant therapy—prior to surgery—was as safe as adjuvant therapy. “There was a lot of concern that if the patient progressed on therapy, you would lose the opportunity to operate,” says Kelly K. Hunt, professor of surgical oncology at the MD Anderson Cancer Center in Houston, Texas.

Hunt discussed the management of the axilla after neoadjuvant chemotherapy at the 32nd Annual Miami Breast Cancer Conference. Hunt says breast cancer interventions have progressed in the adjuvant and neoadjuvant setting, as well as the evolving role of sentinel lymph node dissection (SLND) in the neoadjuvant setting.

Earlier trials, which did not distinguish between the breast cancer subtypes—estrogen-receptor positive, triple-negative, and HER2-positive—established that neoadjuvant chemotherapy allows for more patients to undergo breast-conserving surgery rather than mastectomies. Meta-analyses that compared adjuvant to neoadjuvant systemic therapies showed no difference in disease progression, distant disease recurrence, or death from breast cancer, and also showed that neoadjuvant chemotherapy had fewer side effects.

Subsequent studies examined whether a pathological complete response (pCR) following neoadjuvant therapy is a valid surrogate endpoint for longer-term outcomes, such as disease-free survival (DFS) and overall survival (OS). Many of these trials provided evidence that pCR does translate to better OS, but meta-analyses could not confirm that pCR translated into improved OS. “Partly, this is because we now understand that when breast cancers are divided into subtypes, patients with ER-negative and HER-positive disease are more likely to have a pCR from neoadjuvant therapy compared with those with ER-positive disease,” says Hunt.

The National Surgical Adjuvant Breast and Bowel Project (NSABP) Protocols B-18 and B-27 have demonstrated that stacking two chemotherapies in the neoadjuvant setting in women with operable breast cancer results in DFS and OS similar to adjuvant chemotherapy. Now, neoadjuvant studies have moved beyond the neoadjuvant-versus-adjuvant-therapy question to ask which neoadjuvant regimens are optimal for each breast cancer subtype to improve pCR, according to Hunt.

“We have learned that not only are we getting more patients to breast conservation, but that we’re getting more patients to node-negative disease following surgery, even when patients started with biopsy-proven node-positive disease,” Hunt says. She mentioned that this holds true for all breast cancer subtypes, but particularly for women with HER2-positive disease, as a result of available HER2-directed therapies.

One study conducted at MD Anderson of 109 patients with HER2-positive node-positive disease demonstrated a 74 percent axillary pCR after Herceptin (trastuzumab)-containing neoadjuvant chemotherapy followed by breast surgery and complete axillary lymph node dissection.

“This was a single-institution study, but others and also the NSABP B-27 and B-18 studies have shown that when you compare patients that were treated with neoadjuvant and adjuvant systemic therapies, there are fewer node-positive patients in the neoadjuvant compared to the adjuvant groups.”

The National Comprehensive Cancer Network guidelines currently list appropriate neoadjuvant therapy options for women with breast cancer based on subtype. “Neoadjuvant therapy is considered for those patients that have at least T2 disease or node-positive disease,” says Hunt. “Some physicians also consider neoadjuvant therapy for small HER2-positive tumors between 1 and 2 centimeters in size.”

Less Axillary Surgery?

“Neoadjuvant therapy is a powerful way to assess response and to help clinicians understand a patient’s prognosis based on residual tumor burden and disease in the lymph nodes,” says Hunt. “The most proven benefit of neoadjuvant systemic therapy is less subsequent surgery.” The neoadjuvant approach has been established; the question now emerging is whether a targeted axillary node dissection, rather than a full axillary dissection, is as accurate and whether it leads to similar outcomes.

Axillary node dissection removes the entire axillary fat pad, which contains between 15 and 20 lymph nodes in the arm pit. These nodes are then assessed by a pathologist. Sentinel lymph node dissection removes one to three lymph nodes and is the standard way to stage breast cancer in patients with clinically lymph node—negative disease. Typically, women are assessed for lymph node disease at diagnosis with a physical examination and ultrasound.

The American College of Surgeons Oncology Group Z0011 trial from 2011 showed that axillary dissection did not result in survival benefit compared with sentinel node dissection alone in women with metastatic disease confined to one or two sentinel nodes. Avoiding a full axillary node dissection is favored, particularly in early-stage disease, because this results in less lymphedema, shoulder pain, and dysfunction for patients, according to Hunt.

Results from this study led to the question of whether a subgroup of patients with breast cancer and biopsy-confirmed node-positive disease who are undergoing neoadjuvant systemic therapy may also opt out of axillary dissection and receive sentinel node dissection instead. “The majority of people agree that sentinel node [dissection] after chemotherapy is favored in clinically node-negative patients. It’s the biopsy-proven, node-positive patients where the false-negative rates for sentinel node surgery have been higher,” Hunt says.

“There are trials ongoing now to understand if we can eliminate axillary dissection and whether we need to replace it with radiation therapy,” says Hunt. The Alliance for Clinical Trials in Oncology A11202 trial is randomizing almost 3000 patients with stage 2 or 3 breast cancer who have received neoadjuvant chemotherapy and remain node positive following surgery. The trial is testing whether or not axillary node dissection plus radiation therapy improves breast cancer recurrence rate compared with sentinel node dissection alone plus radiation therapy in patients with a positive sentinel node after neoadjuvant chemotherapy.

A second ongoing trial, the NSABP B-51/RTOG 1304 phase III study, is randomizing over 1600 women with stage 2 or 3 breast cancer who have received neoadjuvant therapy to either regional radiotherapy or no radiotherapy following surgery. The trial is studying whether or not regional radiotherapy improves invasive breast cancer recurrence-free rates in patients who present with node-positive disease who subsequently convert to node-negative disease at the time of surgery after neoadjuvant chemotherapy.

“The question now is whether we can reduce the extent of surgery we are doing and whether radiation therapy is needed, because both of these [interventions] have long-term morbidities,” says Hunt. “As the cure rates for women with earlier-stage breast cancers are improving, there is no reason why these patients have to live with long-term negative side effects of these treatments and interventions, if they are not necessary.”

Researchers are also trying different techniques to improve the accuracy of lymph node staging following chemotherapy. According to Hunt, the current optimal sentinel-node-surgery approach is the combination of the blue dye, lymphazurin, with a radioisotope tracer, because sometimes a positive node can be missed with either of the individual techniques. Hunt also suggests that if a biopsy at initial diagnosis finds a positive lymph node, that node should be marked in order to target the node for removal after therapy.

“Sentinel node surgery after chemotherapy can be hard, because patients may develop fibrosis. Marking the node improves accuracy and allows the surgeon to pay close attention to how many lymph nodes are removed during the dissection.”