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Tumor Cells in Marrow May Better Predict Metastases Than Axillary Node Dissection

Tumor Cells in Marrow May Better Predict Metastases Than Axillary Node Dissection

HEIDELBERG, Germany—Evaluation of bone marrow for breast cancer cells proved superior to axillary lymph node dissection in predicting subsequent metastases in a German study of more than 1,000 patients, Ingo J. Diel, MD, said at a general session of the San Antonio Breast Cancer Symposium.

Tumor cell detection in the marrow had the strongest independent association with disease-free survival during a median follow-up of 40 months. In particular, bone marrow tumor cell status proved more accurate than lymph node status as a prognostic factor associated with small tumors. Notably, a third of patients with negative lymph nodes had tumor cells in aspirated marrow samples.

At the very least, the findings warrant consideration of tumor cell detection as a replacement for node dissection in patients with T1 disease, said Dr. Diel, a surgeon at Women's Hospital, University of Heidelberg.

"At present, axillary node status is the best prognostic factor in operable primary breast cancer," he said. "But 30% of node-negative patients will relapse at distant sites, and 10% of all patients with metastatic disease are node negative at first diagnosis."

More than 1,000 Samples

Since 1985, Dr. Diel and his colleagues have performed immunocytologic assays on bone marrow samples from 1,026 breast cancer patients prior to surgery. The samples are collected from both anterior iliac crests, and staining is performed using a monoclonal antibody that reacts with the core protein of TAG-12, a tumor associated glycoprotein expressed by more than 95% of breast cancers.

Bone marrow samples tested positive in 42% (428 cases), and 546 women (53%) were node negative. Tumor cells appeared in 131 of 408 women with stage T1 disease and in 177 of 436 with T2 disease. Almost a third of node-negative women (172) had tumor cells detected by bone marrow assay.

Thus far, 176 patients have developed metastases, and 144 of them (82%) initially had positive bone marrow assays. Similarly, 53 of 73 patients (81%) who have died during follow-up had tumor cells in their bone marrow at the time of surgery.

Women with positive bone marrow assays have had a significantly briefer disease-free survival, a median of 31 months, compared with 43 months for women whose marrow samples were free of tumor cells at the time of surgery. Multivariate analysis showed tumor cell status of bone marrow to be the most important predictor of disease-free survival:

Prognostic Factors for Disease-Free Survival in Breast Cancer: Heidelberg

Prognostic factor RR P
Tumor cell detection 5.3 < .001
Node status 2.4 < .001
Tumor grade 1.6 .012
Progesterone-receptor status 1.5 .025
RR = Relative risk.

A separate analysis of disease-free survival by disease stage showed that tumor cell detection was significantly related to the risk of metastatic recurrence in women with small (stage T1) tumors (RR, 13.9). In contrast, node status did not predict metastasis in women who had T1 disease (RR, 1.9). Both factors were predictive for T2 disease, but tumor cell detection still proved to be a stronger prognostic factor (RR, 3.9 versus 2.4).

"In patients with T2 disease, node status provides additional information, but in T1 patients, tumor cell detection is the most important predictor of disease-free survival. Node status adds no additional prognostic information," Dr. Diel said.

Axillary node dissection is associated with significant morbidity, he noted. Up to 30% of patients develop seromas, the incidence of dysesthesia exceeds 20%, restriction-associated morbidity occurs in 15% to 20% of cases, and lymphedema, infection, and hemorrhage occur in smaller numbers of patients.

In contrast, only one major hemorrhage occurred in association with bone marrow aspiration in the Heidelberg series. The most common adverse effect was hematoma, which occurred in 39 patients. Three others had postoperative pain attributed to the marrow aspiration.

The Question

"The question is, Why don't we replace axillary dissection with bone marrow aspiration tumor cell detection in patients with small tumors?" Dr. Diel said. The Heidelberg team has begun a clinical trial to answer this question. The trial involves women who have small tumors and who are node negative by clinical examination and ultrasound. The patients are randomly assigned to axillary lymph node dissection or tumor cell detection.

In the tumor cell detection cohort, those who test positive will receive adjuvant chemotherapy, and those who are tumor cell negative will receive no chemotherapy after surgery. All patients in the cohort will have follow-up examinations of axillary lymph nodes, and women who have regional relapses will have secondary lymphadenectomies.

"We hope we can diminish the morbidity and cost associated with axillary lymph node dissection, while at the same time maintaining the level of safety for our patients," Dr. Diel said.

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