New research is helping breast cancer specialists understand which patients may be able to avoid surgery and axillary lymph node dissections after neoadjuvant chemotherapy. Recent advances also include new surgical techniques to reduce the risk of lymphedema after axillary node dissections, Dr. Javid says. In particular, she noted studies on:
Early clinical trials of neoadjuvant therapy found that about 25% of patients downstaged from mastectomy to breast-conserving surgery without any increase in the risk of local recurrence, which remained about 10%.
Among patients receiving breast-conserving therapy, more recent studies have recognized the importance of pathologic clinic response (pathCR) vs. complete clinical response in predicting recurrence. For example, a 2016 study of 751 patients with triple negative or HER2+ breast cancer found the 5-year local recurrence rate was <3% in patients who had a pathCR. That compares with 10% to 13% for patients with no pathCR.
Other studies found that pathCR rates vary significantly based on histological subtype. Patients with HR+/HER2- breast cancer have much lower pathCR rates than triple negative and HER2+ patients.
“If we can identify select patients, called “exceptional responders” who will have a pathCR following neoadjuvant chemotherapy, in the future we may be able to consider forgoing surgery for these select patients,” says Dr. Javid.
Past attempts to treat breast cancer without surgery after neoadjuvant chemotherapy resulted in high recurrence rates. This is mainly because physicians assessed clinical response based on physical exam and imaging results rather than pathCR.
A clinical trial published in 2018 looked at the feasibility of using image-guided biopsies to predict residual breast cancer after neoadjuvant therapy. The trial included 40 patients with triple negative and HER2+ breast cancer. The researchers concluded:
“Tissue is the issue,” says Dr. Javid. “Image-guided tissue sampling, in combination with breast imaging and exam, is the most effective means to determine pathCR after neoadjuvant chemotherapy.”
A phase 2 trial is currently underway at four centers in the U.S. to study eliminating breast cancer surgery in triple negative and HER2+ exceptional responders to neoadjuvant therapy.
Axillary lymph nodes also respond well to neoadjuvant therapy. Overall, about 40% of node positive patients are downstaged to pN0 after chemotherapy. The rate of downstaging varies by type, with higher rates in triple negative and HER2+ cancers. It does not vary by N stage.
“Based on this, we feel there is an opportunity to offer less aggressive axillary surgery, or sentinel lymph node biopsy, in place of axillary lymph node dissection,” says Dr. Javid.
A clinical trial published in 2013 looked at this approach in a series of 701 patients with T0 to T4, N1 to N2 disease following neoadjuvant chemotherapy. All patients received a sentinel lymph node biopsy and axillary lymph node dissection. The goal of the trial was to determine the false negative rate of pathCR with sentinel lymph node biopsy based on a pre-specified false negative rate threshold of 10%.
Initial results of the study showed overall false negative rates for N1 and N2 patients above the 10% threshold. However, further analyses revealed fewer false negatives with the removal of three or more sentinel nodes. Further improvements in the false negative rates were noted with the use of a dual tracer to map the sentinel nodes and removal of the clipped node that confirmed node-positive disease prior to chemotherapy.
This study and others have led to the development of the 2021 National Comprehensive Cancer Network guidelines for surgical axillary staging, which Fred Hutch follows.
The guidelines recommend placement of a clip into the node at the time of node positive diagnosis. Patients who respond to neoadjuvant therapy in the axilla based on clinical and imaging findings should be offered a sentinel lymph node biopsy that includes:
Lymphedema is a life-altering complication of axillary node surgery and can occur in 20-25% of women undergoing an axillary node dissection. “Some women decline axillary node dissection to avoid this dreaded condition,” says Dr. Javid. “Until now, treatments to reduce swelling, such as compression garments and physical therapy, have not been very effective.”
Emerging surgical approaches for reducing lymphedema include:
In this procedure, the surgeon injects blue dye into the arm to highlight the upper extremity-draining lymphatic channels. The theory is that the lymphatics that drain the arm are separate from those that drain the breast. During axillary dissection surgery, the surgeon can identify the arm's lymphatic channels and spare them.
A 2016 review of axillary reverse mapping noted several additional benefits. These include:
The authors also identified several disadvantages. In 28% of cases, the sentinel lymph node is an arm node and must be removed. Patients with node-positive disease also have an as-yet undefined risk of cancer being harbored in remaining arm nodes, though this risk declines with neoadjuvant therapy.
Dr. Javid says that a randomized clinical trial will open soon at Fred Hutch to look more closely at cancer recurrence with axillary reverse mapping.
This approach also uses blue dye to highlight lymphatics in the arm. During axillary node dissection, the surgeon removes the arm nodes and attaches a clip to the lymphatic vessels. After the dissection, a plastic surgeon joins the lymph vessels to a collateral venous branch to allow for drainage.
In a small study of LYMPHA, the procedure was successful in 27 of 37 patients. Among those with a successful procedure, 12.5% developed lymphedema compared with 50% of unsuccessfully treated patients. These results and others suggest that LYMPHA may be feasible, safe and effective for the prevention of breast cancer-related lymphedema.
“We are currently offering this procedure to all women who undergo axillary dissection,” says Dr. Javid. “It adds about an hour to the operative time and the plastic surgeons are usually able to reconnect two to four channels. Our data show that the risk of lymphedema is 5% to 10% with LYMPHA, compared to over 20% without. The main concern is the cost of the procedure, which insurers currently do not cover.”
Physicians at Fred Hutch and UW Medicine offer leading edge surgical therapies as well as the latest treatments in breast oncology.
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