ORLANDO, FL—Don't discount micrometastases found on sentinel lymph-node biopsy, Dutch researchers caution.
Left untreated, nodal metastases 0.2 to 2.00 mm in size may place women with early-stage breast cancer at a significantly higher five-year risk of axillary recurrence, lead author Vivianne C. Tjan-Heijnen, MD, PhD, Professor of Medical Oncology at the Maastricht University Medical Center, told attendees at an oral session on breast cancer at the ASCO Annual Meeting.
“We recommend complete axillary treatment in patients with micrometastases to reduce the axillary-recurrence rate,” she said.
Previous studies—conducted before the sentinel-node era—produced conflicting results as to the prognostic implications of small-nodal metastases, Dr. Tjan-Heijnen explained. As a result, there has been no consensus on whether to use adjuvant therapy.
So the Dutch investigators embarked on the MIRROR (Micrometastases and Isolated Tumor Cells: Relevant and Robust Or Rubbish?) study, the largest cohort study on micrometastases and isolated tumor cells in the sentinel-node era.
Results reported in December at the San Antonio Breast Cancer Symposium showed that in patients who did not receive adjuvant systemic therapy, isolated tumor cells and micrometastases were equally prognostic for poorer disease-free survival rates (de Boer M et al, SABCS Abstract 23).
Fewer than half of patients with isolated tumor cells and micrometastases received further axillary treatment. The second analysis was designed to evaluate the safety and efficacy of axillary follow-up strategies, she said.
The study involved 2,680 early-stage breast cancer patients who underwent a sentinel-node procedure between 1997 and 2005 and had a nodal status of pN0, pN0(i+) [isolated cells], or pN1mi (micrometastases).
Of the total, 1,218 patients had only sentinel-node biopsy; 1,314 women also had complete axillary-node dissection; and 148 also received axillary radiation therapy.
The five-year axillary recurrence rate for the entire study population was 1.7%.
Among patients with negative sentinel nodes, the five-year axillary recurrence rate was 1.6% for those who had complete axillary-node dissection and 2.3% for those who had sentinel-node biopsy only, a nonsignficant difference.
Among patients with isolated tumor cells, the recurrence rate was 0.9% for those who had complete axillary dissection or axial radiotherapy and 2.0% for those who had sentinel-node biopsy only. This translated to a 2.39-fold higher risk of recurrence by five years in the group who did not receive follow-up treatment, but the difference did not reach significance.
Among patients with micrometastases, the risk of recurrence at five years was 5.0% for patients who had sentinel-biopsy alone, compared with 1.0% for those who had complete axillary dissection or axilla radiotherapy. This translated to a significant 4.39-fold higher risk of recurrence in the untreated arm.
“This five-year recurrence rate is much too high. And it will likely increase with longer follow-up,” Dr. Tjan-Heijnen said.
Predictors of Recurrence
In multivariate analysis, other factors that predicted a greater risk of axillary recurrence in patients with micrometastases included a larger tumor size, Grade III histology, and negative hormone-receptor status.
“Unfavorable tumor size, grade, and receptor status should be taken into account when considering ‘sentinel-node-only’ in patients with isolated tumor cells or micrometastases.,” Dr. Tjan-Heijnen said.
Of note was that none of the patients who had axillary radiotherapy after a positive sentinel-node procedure had an axillary recurrence, regardless of whether the sentinel node contained isolated tumor cells or micrometastases, she said.
The number of patients in this subgroup was too small for firm conclusions, but the finding is “provocative, challenging the current recommendation of complete axillary-node dissection,” Dr. Tjan-Heijnen said. “For patients with completely negative nodes, we confirm that omission of axillary therapy is safe and can be considered standard policy. For patients with isolated tumor cells, omission of axillary therapy may be safe only in the presence of otherwise favorable tumor characteristics.”
Discussant Abram Recht, MD, Professor in the Department of Radiation Oncology at Harvard Medical School and Deputy Chief and Senior Radiation Oncologist at Beth Israel Deaconess Medical Center, said that the management of the axilla in patients with positive sentinel-node biopsies is a controversial area: “It's become quite a dilemma for us all given the huge rise in the incidence of patients having sentinel-node biopsy compared with axially dissection [in the past decade].”
Dr. Recht said he was “shocked” by a relatively recent study that showed that 56% of patients whose sentinel-node biopsies revealed micrometastases did not have complete axially-node dissections (Resicgno J et al Ann Surg Oncol 2004;16:687-696), “despite this being the traditional treatment and, some would argue, the standard of care.”
One of the problems, he continued, is the perception, “and I think rightfully so, that the ultimate survival advantage of initial axillary treatment versus later salvage therapy is quite limited.
“So the rationale for why surgeons are reluctant to bring patients back to the operating room is quite clear. But is it justified?,” Dr. Recht asked.
Until now, there has been a dearth of solid, prospective data as to which patients need complete dissection, he said.
“MIRROR is arguably the most important data we'll have on this issue for some time to come, both because of its follow-up and the number of patients.”
Julie R. Gralow, MD, Director of Breast Medical Oncology at Seattle Cancer Care Alliance and Associate Professor in the Oncology Division of the University of Washington School of Medicine, agreed that oncologists struggle with the issue of when and how to treat axillary nodes in women with early-stage breast cancer and micrometastases of 0.2 to 2.0 mm.
While the study does not offer definitive answers, Dr. Gralow said that for now, she feels it would be prudent to discuss the findings with her patients so that they can make more informed decisions.