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Isolated Tumor Cells in Bone Marrow Predict Poor Outcome in M
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Isolated Tumor Cells in Bone Marrow Predict Poor Outcome in
Many Breast Ca Patients
April 01, 2004 | Breast Cancer [1]
SAN ANTONIO—The question of how much weight to give isolated bone marrow micrometastases in
making breast cancer treatment decisions was the focus of three presentations at the 26th San
Antonio Breast Cancer Symposium. Two of these studies confirmed that occult micrometastases are
a warning sign of poor prognosis in many breast cancer patients. The third found that isolated tumor
cells in the sentinel lymph node are not a major problem in patients with ductal carcinoma in situ
(DCIS).
SAN ANTONIO—The question of how much weight to give isolated bone marrow micrometastases in
making breast cancer treatment decisions was the focus of three presentations at the 26th San
Antonio Breast Cancer Symposium. Two of these studies confirmed that occult micrometastases are
a warning sign of poor prognosis in many breast cancer patients. The third found that isolated tumor
cells in the sentinel lymph node are not a major problem in patients with ductal carcinoma in situ
(DCIS).
Stephan Braun, MD, reported on behalf of European researchers in the Collaborative Group on Bone
Marrow Mi-crometastasis that occult metastatic cells in the bone marrow are associated with worse
overall survival for breast cancer patients as a whole and particularly for node-negative patients who
have not received adjuvant therapy (abstract 7). He suggested that patients who test positive for
occult metastatic cells may be candidates for more aggressive treatment strategies and that
adjuvant therapy might not be needed in some patients who do not have such cells in their bone
marrow.
Dr. Braun, of the University Clinic for Obstetrics and Gynecology, Innsbruck, Austria, reported a
pooled analysis of 10-year survival for 4,268 breast cancer patients from eight recently published
studies addressing long-term outcome of patients with and without occult metastatic cells. Patients
received chemotherapy that was standard at the time of the study, but Dr. Braun pointed out that
the study covered quite a long time, over which regimens changed.
The primary study endpoint was overall survival. Patients were free of distant metastases at primary
surgery, 90% were stage T1/T2; 58% were node negative; 70% had received adjuvant therapy.
Occult metastatic cells were detected in the bone marrow of 1,259 patients (30%). The proportion of
patients with occult cells increased significantly (P < .001) across strata of tumor size, nodal status,
and grading.
The pooled analysis showed significantly shorter disease-free survival in patients with occult
metastatic cells (hazard ratio [HR] 2.10, P < .001). Multivariate analysis that included bone marrow
positivity, lymph node positivity, tumor size, tumor grade, and estrogen-receptor (ER) positivity
supported the importance of occult metastatic cells and showed a significant decrease in overall
survival in patients positive for occult cells (HR 2.28, P < .001).
Dr. Braun said that the presence of occult metastatic cells is an independent predictive factor of
survival for patients with stage I-III breast cancer.
The analysis included 10 years of follow-up with median follow-up of 58 months, during which 763
patients (18%) died. Death from any cause was significantly more likely in occult-cell-positive
patients (HR 2.33, P < .001).
In the subgroup of 289 node-negative, occult-cell-positive patients who had not received adjuvant
therapy (23% of the total), both disease-free and overall survival were significantly worse than in
similar patients who did not have occult metastatic cells (P < .001).
"In pathologic node-negative breast cancer patients who have not had adjuvant therapy, this points
to a role for occult metastatic cells in the progression of breast cancer. Occult cells should be used
for risk stratification of patients in future clinical trials," Dr. Braun said. "Cells may leave the tumor
early in the process and form a pool of cells that leads to metastasis later; thus, cells in the
micrometastases may be different from cells in the primary tumor."
During the discussion period, one attendee pointed out that almost 70% of patients who had occult
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Isolated Tumor Cells in Bone Marrow Predict Poor Outcome in M
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metastatic cells did not display overt tumors at 10 years of follow-up, which shows that not all
micrometastases are clinically important. He suggested that cells that are more differentiated have
limited pathologic capacity, and that looking for stem cell markers on micrometastases might
provide more definitive information. Dr. Braun agreed that there is an urgent need to refine the
assays for occult metastatic cells, which he described as "crude at present."
Norwegian Study
Bjorn Naume, MD, of the Norwegian Radium Hospital, Oslo, reported that the presence of isolated
tumor cells in the bone marrow 3 years after diagnosis in disease-free breast cancer patients
predicts an unfavorable outcome (abstract 8). "Bone marrow analysis can be used in the follow-up of
patients for detecting early disseminating disease. Bone marrow positivity at 3 years might help
select patients for secondary adjuvant therapy," he said.
This research group had previously found that isolated tumor cells in bone marrow were an
independent prognostic factor for both distant disease-free survival and breast-cancer-specific
survival in 817 breast cancer patients analyzed at the time of operation. Dr. Naume reported an
analysis of outcomes correlated with results of a second bone marrow exam done at 3 years’
follow-up in 356 initially disease-free patients.
Bone marrow aspirated from the posterior iliac crest bilaterally was stained for immunocytochemical
analysis with anticytokeratin mAbs (AE1/AE3) and alkaline phosphatase/antialkaline phosphatase
reaction. Based on criteria from the European Working Group for Standardization of Tumor Cell
Detection, any bone marrow with 1 or more cells was scored as positive.
At a median of 25.3 months’ follow-up after the second bone marrow aspiration (65.8 months since
diagnosis), 32 patients had relapsed (12 local, 20 systemic). Relapse was significantly more common
in patients who had isolated tumor cells in their bone marrow (21% vs 7%, P = .001).
Ten patients died of breast cancer during the observation period. Survival analyses revealed that
isolated tumor cells in bone marrow predicted reduced distant disease-free and
breast-cancer-specific survival (P < .001), and were an independent prognostic factor for both, Dr.
Naume said. Patients with a positive bone marrow both at diagnosis and after 3 years had an
especially poor prognosis and a systemic relapse rate of 29.4%.
DCIS Sentinel Node Micromets
Jan Wijsman, MD, of the Netherlands Cancer Institute/Antoni van Leeuwen-hoekhuis, Amsterdam,
reported reassuring data showing that micrometastases in sentinel axillary lymph nodes of patients
with ductal carcinoma in situ (DCIS) or small invasive carcinomas of the breast are not a harbinger of
poor survival and should not trigger complete axillary lymph node dissection (ALND) in such patients
(abstract 9).
"We undertook this study because the finding of a positive cell in patients with a nonmetastasizing
disease raised some questions for us," Dr. Wijsman said.
The researchers resectioned all archived lymph node samples from a consecutive series of patients
with DCIS or with invasive ductal or lobular carcinoma (IDC/ILC) of 5 mm or less who had undergone
ALND as part of their treatment.
They compared the incidence of lymph node metastases after routine examination with that after
re-evaluation of new sections of all archived lymph nodes immunostained for the epithelial marker
CAM 5.2. The presence of macro- or micrometastases or solitary cells (ie, clusters of 10 to 20 cells)
was scored and related to survival.
Immunostaining of all retrieved lymph nodes (mean, 14 per patient) showed metastases present in
11% of patients with pure DCIS and in 27% of patients with DCIS and microinvasion (see Table).
"Most of these were single tumor cells or micrometastases. We found tumor cells in a single lymph
node in five patients and in two nodes in two patients. We never found tumor cells in more than two
nodes. All node-positive patients have remained free of disease at a median follow-up of 102
months, without adjuvant therapy."
Routine examination showed one macrometastasis in 71 patients with pure DCIS, no metastases in
12 patients with DCIS with microinvasion, and 1 macro-metastasis in 18 patients with IDC/ILC of 5
mm or less.
"Since no more than two nodes were affected, and survival was excellent, and previous studies have
shown excellent prognosis without ALND in these low-risk tumors, we advise not to perform an ALND
when a micrometastasis is found in the sentinel node of DCIS. ALND may also be omitted in T1a
tumors in the absence of other negative prognostic factors," Dr. Wijsman said.
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