SAN ANTONIO – Survival is nearly identical in early-stage breast cancer regardless of whether or not bone marrow micrometastases are present, according to the prospective Swiss Multicenter Study Group trial.
Among 410 women with T1 and T2 disease and no palpable axillary lymph nodes, the 5-year overall survival was 92.5% with bone marrow micrometastases (BMM) and 92.7% without (P = .85).
Dr. Igor Langer
The 5-year disease-free survival reached 92.2% in patients with BMM and 93.6% in those without (P = .50), Dr. Igor Langer said during a plenary session at a symposium sponsored by the Society of Surgical Oncology. Micrometastases were detected in 118 patients (29%).
Audience members asked Dr. Langer to explain his findings in light of those from the ACOSOG (American College of Surgeons Oncology Group) Z0010 trial, which also involved T1 and T2 disease. In that trial, BMMs were detected by immunohistochemistry in just 3% of women, and were associated with a significantly lower 5-year survival rate of 90% vs. 95% in patients without BMMs, according to data presented at the 2010 annual meeting of the American Society of Clinical Oncology.
Dr. Langer of the department of surgery at the Lindenhofspital in Bern, Switzerland, replied that most studies looking for BMM can identify them in 15%-40% of patients. "So I don’t know if it is a methodological difference, in terms of preparation of the bone marrow and identification of these cells," he said. "The difference in prognosis is multifactorial."
He pointed out that there is no standardized method to detect BMMs, that different methods were used to identify sentinel lymph nodes (SLNs), that patients received different adjuvant regimens, and that the number of cases who developed BMMs was so low, it could easily change outcomes.
Another attendee asked whether there is a particular cutoff for BMMs, noting that in many cancers the presence of micrometastases has no impact on survival, and that they are prognostic in melanoma only when they are at least 0.2 mm in the lymph nodes. Dr. Langer said that the median number of tumor cells in the analysis was two, but he balked at the possibility of using BMM testing in early breast cancer.
"You shouldn’t do the bone marrow aspiration," he said in an interview. "It might have prognostic impact, but if it doesn’t drive your therapy – if it doesn’t influence what you are doing – you have findings and you don’t know what to do with them. It’s too immature. We first have to standardize the testing."
Dr. Langer reported on 659 women from 13 Swiss centers who underwent intraoperative SLN examination by frozen section and paraffin serial sectioning at a cutting interval of 250 mcm with H&E (hematoxylin and eosin) staining and immunohistochemistry.
As previously reported, SLNs were identified in 98% of patients, including 71% with T1 disease and 29% with T2 disease (Breast Cancer Res. Treat. 2009;113:129-36). Their median age was 59 years, and 80% were postmenopausal. The median tumor size was 17 mm.
Of the 659 patients, 410 also underwent bone marrow aspiration from both iliac crests; these formed the basis of the current analysis. The mononuclear cells of the bone marrow aspirates were isolated by density gradient centrifugation through Ficoll. In all, 2 million bone marrow cells were evaluated, and the presence of one or more tumor cells was regarded as BMM positive, Dr. Langer said.
Cancer cells were stained with monoclonal antibodies A45-B/B3 against cytokeratin 8, 18, and 19 and were counted by an automated, computerized digital microscope. All results were reviewed by one pathologist.
Bone marrow micrometastases were detected in 118 (28.8%) of the 410 women. About 210 women were SLN negative and BMM negative, although considerable discordance was observed, Dr. Langer said. In all, 67 women (16.4%) were BMM positive and SLN negative, whereas 82 women (20%) were BMM negative and SLN positive.
In multivariate logistic regression analysis that included tumor size, tumor grade, tumor receptor status, and menopausal status, the presence of positive SLNs was the only significant independent predictor for the presence of BMM (P = .007; odds ratio, 1.860). T stage was not significant; only N stage was, he said.
In the earlier published analysis, the Swiss researchers identified SLN micrometastases or isolated tumor cells in 47 patients who underwent delayed ALND (axillary lymph node dissection). In 96% of these patients, the second operation was not beneficial because the ALND specimens were free of macrometastases. This finding – coupled with an overall accuracy of frozen section of 90% in the detection of SLN macrometastases – led the group to strongly recommend the routine use of SLN frozen section in early-stage breast cancer.