Many oncologists have long suspected that surgery may be redundant in some breast cancer patients who have a pathological complete response (pCR) to neoadjuvant systemic treatment. However, early attempts to avoid surgery in such patients were thwarted by high rates of locoregional recurrence, which were likely due to weakly effective agents and insufficient tools for accurately assessing treatment response. But now, armed with advances in early detection, systemic agents, and image-guided biopsy, researchers are revisiting whether surgery can be safely avoided in some breast cancer patients.
“We’ve come to a point where, because of all these improvements, we can consider eliminating surgery for invasive breast cancer in a select group of patients,” said Henry Kuerer, M.D., Ph.D., a professor in the Department of Breast Surgical Oncology at The University of Texas MD Anderson Cancer Center.
Dr. Kuerer is the principal investigator of a clinical trial to determine the feasibility of avoiding surgery in patients who have a pCR to systemic therapy. “If this approach is proven to be safe, it could change the paradigm for the local treatment of breast cancer,” he said.
A new way of assessing response
Some HER2 (human epidermal growth factor receptor 2)–positive and triple-negative (i.e., negative for estrogen receptor, progesterone receptor, and HER2) breast cancers are particularly sensitive to systemic therapy. At least 50% of patients who have these types of tumors and receive neoadjuvant systemic therapy have a pCR, which is generally defined as the absence of invasive disease in the breast and axillary nodes.
“We’ve known for some time that patients with HER2-positive and triple-negative disease are the ones in whom systemic therapy is most likely to wipe out the cancer,” Dr. Kuerer explained. “Patients who have this kind of response are also likely to have long-term overall survival and are markedly less likely to have a recurrence.”
But these favorable outcomes leave a nagging question, Dr. Kuerer said. “If the patients don’t have any residual disease, why do they need surgery?”
The problem is that, until recently, pathological assessment of a surgical specimen was the only way to identify patients who had a pCR to systemic therapy. Physical examination of the breast and axilla to determine clinical response is notoriously inaccurate; and although breast imaging methods have improved substantially, they remain insufficiently sensitive or specific to confirm the absence of residual disease after systemic therapy.
Therefore, Dr. Kuerer and his colleagues turned to image-guided fine-needle biopsy, in which a needle is inserted through the breast into the tumor region under ultrasonography or mammography guidance and is rotated to collect a dozen or so samples from different sites. The researchers performed preoperative image-guided biopsies on 40 patients with triple-negative or HER2-positive breast cancer after neoadjuvant systemic therapy and compared the results with those from traditional examination of the patients’ surgical specimens.
“The bottom line in that study was that image-guided biopsy had an accuracy in identifying residual disease of about 98%,” Dr. Kuerer said. “And for the other 2%, there was just a tiny amount of residual disease that we felt radiation could easily eradicate.” The team published their findings last year in the Annals of Surgery.
Avoiding axillary surgery
Once they found that image-guided biopsy could accurately identify patients with a pCR in the breast, potentially sparing them from breast surgery, Dr. Kuerer and his colleagues wondered if they could go a step further.
“The question for us then became, if there’s no disease in the breast after chemotherapy, how often would we find cancer in the lymph nodes when we do the standard axillary surgery?” Dr. Kuerer said.
The idea of avoiding axillary surgery to assess lymph nodes for disease has been met with some skepticism. Axillary surgery is generally performed in tandem with surgery to remove the primary breast cancer; skip the surgery, the thinking goes, and disease in the lymph nodes could be missed.
To learn whether axillary surgery might sometimes be avoidable, Dr. Kuerer and his colleagues reviewed the records of 527 patients who received systemic therapy followed by surgery for HER2-positive or triple-negative breast cancer. None of the 116 patients whose initial ultrasonography examination revealed node-negative disease and whose breast tumors had a pCR to systemic therapy had residual disease in their lymph nodes after surgery. Of the 237 patients who did have lymph node disease at presentation and whose breast tumors had a pCR, about 90% had node-negative disease on final pathological examination.
The findings, Dr. Kuerer said, justify avoiding axillary surgery in some patients whose breast tumors have a pCR to systemic therapy. Whether the omission of surgery in both the affected breast and axilla is advisable in such patients is now being investigated in a clinical trial.
Clinical trial may pave the way
The trial (No. 2016-0046) is enrolling women 40 years or older who have a pathologically confirmed stage I or II HER2-positive or triple-negative breast tumor that is 5 cm or smaller and for whom initial ultrasonography reveals four or fewer abnormal axillary lymph nodes. The patients receive standard neoadjuvant systemic therapy as directed by their oncologists. After the neoadjuvant treatment, patients who have a pCR as assessed by image-guided biopsy forgo surgery and receive whole-breast radiation therapy; those whose biopsy shows evidence of disease undergo standard breast and nodal surgery before receiving radiation therapy.
During their neoadjuvant therapy, which typically lasts 5–6 months, patients are monitored with breast imaging, as is standard. For patients to be eligible for image-guided biopsy and a chance at skipping surgery, their breast lesion on final imaging must be 2 cm or smaller.
“We chose that size because when the abnormality shrinks down that much, we can get a really good sampling of the area with the needle biopsies, almost as good as with the surgery itself,” Dr. Kuerer said.
In addition, patients in whom initial ultrasonography reveals node-negative disease forgo axillary surgery. Those who have biopsy-proven disease in one to four axillary lymph nodes before systemic therapy will undergo targeted axillary dissection, in which the involved nodes are removed through very small incisions.
The trial is enrolling patients at MD Anderson and other centers, including MD Anderson’s partner institutions MD Anderson Cancer Center at Cooper in Camden, New Jersey, and Banner MD Anderson Cancer Center in Gilbert, Arizona. Thus far, seven patients have been enrolled; ultimately the trial will enroll 50. All patients will be followed up with breast imaging and physical examinations every 6 months for 5 years.
The trial may be among the first steps on a path to providing minimally invasive treatment options to more breast cancer patients.
“We’re constantly identifying new drugs and agents that are getting better and better at killing breast cancer,” Dr. Kuerer said. “So I can imagine that, very far on the horizon, surgery won’t be necessary for the vast majority of patients with breast cancers or other solid tumors.”
Kuerer HM, Rauch GM, Krishnamurthy S, et al. A clinical feasibility trial for identification of exceptional responders in whom breast cancer surgery can be eliminated following neoadjuvant systemic therapy. Ann Surg. 2017;267:945–931.
Kuerer HM, Vrancken Peeters MTFD, Rea DW, et al. Nonoperative management for invasive breast cancer after neoadjuvant systemic therapy: conceptual basis and fundamental international feasibility clinical trials. Ann Surg Oncol. 2017;24:2855–2862.
Tadros AB, Yang WT, Krishnamurthy S, et al. Identification of patients with documented pathologic complete response in the breast after neoadjuvant chemotherapy for omission of axillary surgery. JAMA Surg. 2017; 152:665–670.
OncoLog, May-June 2018, Volume 63, Issue 5-6