BREAST NODE NEGATIVE MICROMETASTASES OF LITTLE PROGNOSTIC SIGNIFICANCE

January 20, 2011 — Do micrometastases and isolated tumor cells affect the survival of women with breast cancer who initially have clinically negative axillary lymph nodes?

This is the question that investigators from the National Surgical Adjuvant Breast and Bowel Project (NSABP) trial B-32 have pursued in a study published January 19 in the New England Journal of Medicine.

It is an important question, in part because many surgeons and pathologists are currently seeking out these microscopic pieces of cancer with immunohistochemistry and other approaches that are beyond standard recommendations, one of the coauthors explained.

The standard approach, endorsed by the American Society of Clinical Oncology (ASCO), the American College of Surgeons (ACS), and other groups, is to slice sentinel nodes at 2.0-mm intervals and stain samples with hematoxylin and eosin.

The study found that "occult" metastases — that is, micrometastases and isolated tumor cells found after sentinel lymph node biopsy — are an independent prognostic variable in these women.

Women who had the micromets, as micrometastases and isolated tumor cells are collectively called, had statistically significantly worse overall and disease-free survival.

However — and this is a big however — the magnitude of the difference in overall survival at 5 years was "small" (1.2%) between the women with and without these occult micrometastases and isolated tumor cells, the study authors point out.

The upshot of the findings is that the extensive pursuit of tiny pieces of cancer in such patients is not worth the effort, they suggest.

"These data do not indicate a clinical benefit of additional evaluation, including immunohistochemical analysis, of initially negative sentinel nodes in patients with breast cancer," write the authors, led by Donald Weaver, MD, from the Vermont Cancer Center in Burlington.

"There is an impact on outcomes," said Dr. Weaver in an interview, "but it's so small that it's not worth looking for micrometastases, and you should not change clinical management based on their presence."

Dr. Weaver and his coauthors explain why in their paper: "Identification of occult metastases does not appear to be clinically useful for patients with newly diagnosed disease in whom systemic therapy can be recommended on the basis of the characteristics of the primary tumor."

Dr. Weaver acknowledged that this is difficult for some clinicians to accept. "It takes time to get paradigm shifts," he said. He also said that it is difficult for patients to accept that they do not need an axillary dissection in the event of micromets. "So many women panic if they hear that they have any disease in their lymph nodes," he added.

Despite such concerns, one clinician found the new data worthy of serious consideration.

"In the past, our practice has been to evaluate the sentinel nodes using both hematoxylin and eosin and immunohistochemistry," said Quyen Chu, MD, associate professor of surgery and director of surgical oncology at the Louisiana State University Health Sciences Center in Shreveport. "However, given the recent results, our group is certainly entertaining the possibility of excluding immunohistochemistry altogether when evaluating sentinel lymph nodes."

Treatment Takes Care of the Micromets

In NSABP B-32, more than 5000 women with clinically node-negative breast cancer were randomized to be treated with either sentinel lymph node biopsy with immediate axillary dissection or with sentinel lymph node biopsy alone.

For this pathologic-outcome study, the patients were combined into 2 analytic cohorts: patients in whom occult metastases were detected (n = 616) and patients in whom occult metastases were not detected (n = 3268). Subgroup analysis was performed by metastasis size — isolated tumor-cell clusters (n = 430), micrometastases (n = 172), and macrometastases (n = 14).

Occult metastases were detected in 15.9% (95% confidence interval, 14.7 to 17.1) of the patients with follow-up data available: 11.1% with isolated tumor cell clusters, 4.4% with micrometastases, and 0.4% with macrometastases.

In their outcomes analyses, the investigators excluded macrometastases.

The 5-year Kaplan–Meier survival estimates for patients in whom occult metastases were detected were 94.6% for overall survival, 86.4% for disease-free survival, and 89.7% for distant disease-free interval. The survival estimates for patients in whom occult metastases were not detected were 95.8%, 89.2%, and 92.5%, respectively.

Log-rank tests indicated a significant decrease in overall survival (P = .03), disease-free survival (P = .02), and distant disease-free interval (P = .04) between patients in whom occult metastases were detected and those in whom occult metastases were not detected, report the authors

Although these differences are statistically significant, they are "relatively small," the authors note.

Importantly, the authors also report that "multivariate analysis suggests that multiple factors (e.g., age and tumor size) influence the prevalence of occult metastases and the outcome, and that local radiation therapy and adjuvant systemic therapy, particularly endocrine therapy, attenuate the unfavorable effect of occult metastases."

Another key finding from NSABP B-32, which was previously reported (Lancet Oncol. 2010;11:927-933), is that "the overall outcome in this trial shows no significant disadvantage for women who underwent sentinel lymph node biopsy alone, compared with women who underwent sentinel lymph node biopsy plus axillary dissection," observe the authors.

This is important because it is proof that the widespread adoption of sentinel lymph node biopsy — as opposed to axillary dissection, which is associated with greater morbidity — is a sound choice in clinically node-negative women, suggest the authors.

This finding is similar to that from the ACS Oncology Group, which reported its results at the 2010 ASCO annual meeting.

In that trial, the ACS also found that the difference in 5-year survival between patients in whom occult metastases were detected and those in whom occult metastases were not detected by means of immunohistochemical analysis in initially negative sentinel lymph nodes was not significant (0.7 percentage points; P = .53), observe Dr. Weaver and his colleagues.

Raisin Hunting

In NSABP B-32, the sentinel lymph nodes received a "standard" evaluation — without the routine use of immunohistochemistry or analysis of deeper tissue levels, the authors point out.

Dr. Weaver explained that looking for micromets in the sentinel nodes can be like "baking 1 raisin into a cake and then going after the raisin." If you only take 1 cut of the cake, then chances are that you won't find it, he explained, but taking 300 cuts increases the probability that you will. "The harder you look, the more you will find," said Dr. Weaver about micromets. This is "gratifying," but "it really doesn't make a difference," he added.

Furthermore, as the author note, "no examination detects all occult metastases present."

The authors have disclosed no relevant financial relationships.

New Engl J Med. Published online January 19, 2011.