By Christina Frangou

Philadelphia—Surgeons from Memorial Sloan Kettering Cancer Center, in New York City, reported convincing evidence that women who have cT1-2N0 breast cancer with one or two metastatic sentinel lymph nodes can safely avoid axillary lymph node dissection, even without preoperative axillary imaging or routine use of nodal radiation therapy.

“This approach has the potential to spare substantial numbers of women the morbidity of axillary lymph node dissection,” the authors wrote, headed by Monica Morrow, MD, chief of the breast service and the Anne Burnett Windfohr Chair of Clinical Oncology at Memorial Sloan Kettering.

This prospective study of 793 patients confirms in a clinical practice setting what was originally, but controversially, reported in 2011 by the American College of Surgeons Oncology Group Z0011 trial: ALND need not be routine for patients with positive SLNs (JAMA 2011;305:569-575).

At the time, the ACOSOG Z0011 recommendations turned standard surgical practice on its head. Critics suggested that the results might not be widely applicable, as the majority of women enrolled were postmenopausal with estrogen receptor–positive cancers; the follow-up of patients was too short; and the effect of variations in nodal irradiation was unclear. An update on the study patients was reported in 2016 and showed—at a median follow-up of 9.25 years—there was no statistically significant difference in local recurrence–free survival (Ann Surg 2016;264:413-420). Cumulative incidence of nodal recurrences at 10 years was 0.5% in the ALND arm and 1.5% in the SLND [sentinel lymph node dissection] -alone arm (P=0.28). Ten-year cumulative locoregional recurrence was 6.2% with ALND and 5.3% with SLND alone (P=0.36).

The new findings mirror the ACOSOG Z0011 conclusions, and fill in some of the answers left by the original trial.

“To our knowledge, this is the first confirmation of the findings of ACOSOG Z0011 in clinical practice and indicates that nodal recurrence rates are extremely low, despite relatively infrequent use of nodal RT,” wrote the authors, in the report published online in the Annals of Surgery (2017 Jul 22. [Epub ahead of print]).

Dr. Morrow presented the results at the 2017 annual meeting of the American Surgical Association (ASA).

In August 2010, breast surgeons at Memorial Sloan Kettering began to apply the results of ACOSOG Z0011 at their cancer center, performing only SLN biopsies on women with cT1-2N0 invasive breast cancer who were undergoing breast-conserving therapy and had one or two positive SLNs by routine hematoxylin and eosin staining. Women with metastases in three or more SLNs, matted nodes or nodes with gross extracapsular extension underwent ALND.

Over the next 6.5 years, the investigators tracked 793 patients who met the ACOSOG Z0011 eligibility criteria and had SLN metastases. Among them, 16% (130) underwent ALND, most often for metastases in three or more sentinel nodes or for SLNs with extracapsular tumor extension. Eight patients eligible for SLND alone underwent ALND because of surgeon or patient preference, with six of these in the surgeons’ first two years of experience. The remaining patients underwent SLND alone.

Only 3% of patients in each group did not receive some form of systemic therapy.

The women studied were a median age of 58 years and had a median clinical tumor size of 1.7 cm. Eighty-four percent had hormone receptor–positive, HER2-negative cancers. Systemic adjuvant therapy was given to 97% of patients and RT to 94%. Receipt of ALND did not vary based on age, estrogen receptor, progesterone receptor or HER2 status. Patients were followed for a median of 29 months.

Five-year event-free survival after SLND alone was 93%. No patient in the SLND group had an isolated axillary node nodal recurrence.

Distant recurrence was the most common type of recurrence, with a five-year cumulative incidence of 5%. The five-year cumulative rates of breast and nodal as well as nodal and distant recurrences were both 0.7%, with a median time to any nodal recurrence of 25 months. The five-year rate of breast-only recurrences was 1.6%.

The value of preoperative axillary imaging has been under debate since the ACOSOG Z0011 results were first reported. In this study, patients did not have preoperative axillary imaging.

In prior studies done at Memorial Sloan Kettering of 425 patients with abnormal axillary imaging (on mammography, ultrasound or MRI), 70% had one to two positive nodes and could avoid ALND. Of the 141 patients with a positive image-guided axillary needle biopsy, 47% could avoid ALND.

“These data confirm that preoperative axillary imaging and even a positive axillary needle biopsy are inadequate to make the decision for ALND, and that for Z0011-eligible patients, a negative clinical examination of the axilla is sufficient,” the investigators said.

Armando Giuliano, MD, the chief investigator in the ACOSOG Z0011 trial and professor of surgery at Cedars-Sinai Medical Center, in Los Angeles, said the new study confirms the findings from the ACOSOG Z0011 trial “in so many ways but also extends and informs that trial as well.”

The study demonstrates that the majority of women can avoid the morbidity and expense of an axillary dissection, with the “extraordinarily low axillary recurrence rates seen in Z0011,” he said. Dr. Giuliano was the official discussant following Dr. Morrow’s presentation at the ASA meeting.

He noted that more than 100 women in the study were treated with prone irradiation, which does not irradiate lymph nodes, yet axillary recurrences were rare in this group (1%), suggesting nodal irradiation provides little benefit to these patients. (The rate of nodal relapse was 1.4% among women who had supine breast RT, and 0% among those who had breast and nodal RT.)

Dr. Morrow responded that patients who were treated prone represented the lowest risk group of the three RT groups. But, she added, other work has shown that not all axillary disease becomes clinically evident. “I think that, plus very high use of systemic therapy in this population, is what accounted for our low rates of axillary recurrence.”

It remains unknown whether failure to irradiate the nodes at all with prone treatment is associated with decreased survival. The Canadian MA.20 trial, which randomly assigned more than 1,800 women to receive whole breast radiation with or without comprehensive regional node irradiation, showed the addition of regional nodal irradiation after breast-conserving therapy in women with node-positive or high-risk node-negative breast cancer did not improve overall survival but did reduce breast cancer recurrence (N Engl J Med 2015;373:307-316).

Dr. Morrow and her colleagues did not apply any high-risk selection criteria—patient age, estrogen receptor status or hormone receptor status—in selecting patients for ALND, which was based solely on the number of SLN metastases or extracapsular extension.

This decision was supported by the results, Dr. Morrow said. The frequency of ALND did not differ significantly between non–high-risk and high-risk patients who had one or more of the following characteristics: age older than 50 years, HER2-positive breast cancer or triple-negative breast cancer. This finding confirms previous studies showing that patients at a higher risk for systemic relapse do not necessarily have a heavier nodal disease burden.