13 March 2019
A recent news article has called attention to an ongoing clinical trial, which is evaluating whether certain patients can avoid surgery for breast cancer. The article has raised many questions, so with the help of the trial principal investigator, surgical oncologist Dr. Henry Kuerer from M.D. Anderson, here is some clarification.
The most important point to stress is that currently, surgery is a necessary, “standard of care” component for the management of breast cancer. Patients interested in avoiding surgical resection of the tumor or tumor site should do so only in the context of a prospective controlled clinical trial, which has very specific eligibility requirements and other safety measures in place.
Patients with triple negative and Her2/neu over-expressed (Her2+) breast cancers very often receive a recommendation for chemotherapy (even with no spread to the lymph nodes) due to the more aggressive nature of these tumors and improvements in survival with chemotherapy. Currently, neoadjuvant (before surgery) chemotherapy is usually used, which allows an assessment of tumor response. In about 50% of cases, no residual tumor is found in the area of surgical resection (because the chemotherapy killed all of the cancer cells) – known as a pathologic complete response (pCR). Patients and their surgeons began to ask: “If it’s all gone, why is surgery necessary?” Eligibility for the currently accruing clinical trial includes patients with triple negative or Her2+ cancers that are 5cm or smaller, with 4 or fewer involved axillary (underarm) lymph nodes.
Clinical trial participants first are treated with neoadjuvant chemotherapy. Follow up imaging after chemotherapy, including MRI, is performed. Needle biopsies (similar to those used to make the initial diagnosis) are performed at the original tumor site. If no cancer is found in these biopsy samples, the patient then undergoes a sentinel lymph node biopsy, or targeted axillary dissection (if she had originally biopsy proved axillary nodal disease). Currently, surgical removal of the sentinel / targeted nodes is necessary because it can be very challenging to perform lymph node needle biopsy after chemotherapy. If the lymph nodes are negative (“clear” / no cancer), the patients undergo radiation therapy. If there is residual disease in the lymph nodes after chemotherapy, an axillary dissection is performed prior to radiation therapy.
A small pilot prospective clinical study at M.D. Anderson showed that utilizing image-guided biopsy in those patients who appear to have an excellent response could predict which patients in fact had residual disease in the breast with 98% accuracy – this was the basis for the current study. Another feasibility trial, sponsored by the NRG Oncology cooperative group, in collaboration with the National Cancer Institute (NRG BR005), is ongoing.
A separate study, also performed at M.D. Anderson, was performed to address whether or not axillary surgery is required in these patients. The researchers found that when there is a pCR (including invasive and in-situ disease) after neoadjuvant chemotherapy, the likelihood of having any cancer in the axillary lymph nodes is extremely low if the patient had normal axillary lymph nodes demonstrated on ultrasound prior to beginning therapy. These patients may be able to then avoid any breast or axillary surgery. A much larger study using the US National Cancer Database noted similar findings, but in addition, highlighted the need to perform axillary surgery in cases where there was initial biopsy-proven cancer in the lymph nodes prior to chemotherapy.
Dialing back the extent of surgical therapy for breast cancer is nothing new. Sir William Halsted died in 1922, but the extensive, disfiguring procedure bearing his name (the “Halsted radical mastectomy”) continued to be the standard of care well into the 1950-60’s. Noting that survival was not improving despite the extensive surgery, surgeons at the NSABP, led by Dr. Bernard Fisher, started to ask questions and design clinical trials. NSABP B-04 results demonstrated that there was no difference in overall survival or local recurrence whether patients underwent a radical mastectomy or a total mastectomy, and the radical mastectomy fell out of favor.
With increasing use of screening mammography, cancers were being detected in smaller sizes. Again, surgeons asked questions, and the NSABP B-06 trial was performed – this study found no difference in overall survival whether patients underwent a mastectomy with lymph node removal, a lumpectomy with lymph node removal, or a lumpectomy with lymph node removal and radiation therapy. The women who underwent lumpectomy without radiation had a higher rate of local (in the breast) recurrence (approximately 39% versus 14%), setting the standard that still holds today, for the use of radiation therapy after lumpectomy.
Less aggressive surgery for the axillary lymph nodes has also been carefully researched. Sentinel node biopsy and targeted node dissection, removing a smaller number of carefully identified lymph nodes (even in some settings where the cancer has spread into the lymph nodes) results in lower rates of lymphedema, chronic pain and arm mobility problems without impact on survival or recurrence.
Non-operative ablative therapy is also being researched, and techniques being investigated include cryoablation, as well as high frequency focused ultrasound and laser ablation.
While there may be many eyebrows raised regarding the current research (“no surgery???”), over the years it has been demonstrated through carefully constructed clinical trials that less extensive breast cancer surgery leads to similar outcomes in terms of survival and recurrence, but with lower rates of complications. Advances in the understanding of tumor biology, development of more precise targeted systemic therapy, and improvements in breast imaging and biopsy techniques have resulted in the identification of a subset of patients in whom surgery may not be required. As mentioned at the beginning of this post, this non-operative approach is currently only being offered in the context of a clinical trial, and is not yet considered standard therapy.