Purpose: The presence of tumor cells in bone marrow has been reported to represent an important prognostic indicator in breast cancer,
but the clinical significance of circulating cells in peripheral ...blood is less well known. The aim of this study was to evaluate
the feasibility of identifying cytokeratin (CK)-expressing cells in peripheral blood with an automat-assisted immunohistochemical
detection system and to compare it with detection of tumor cells in bone marrow samples.
Experimental Design: Cytospun Ficoll fractions of peripheral blood and bone marrow were obtained simultaneously in 114 breast cancer patients
at different stages of the disease (I to IV) before treatment with chemotherapy. The pancytokeratin (CK) monoclonal antibody
A45-B/B3 (anti-CKs 8, 18, and 19) was used for epithelial cell detection. Immunostained cells were detected by an automated
cellular imaging system (ChromaVision Medical System).
Results: CK+ cells were detected in 28 (24.5%) patients in blood and in 67 (59%) patients in bone marrow. Twenty-six (93%) patients
with CK-positive cells in blood also had positive bone marrow ( P < 0.001). Positive cells were detected in peripheral blood in 3/39 (7.5%) operable breast cancers (stage I/II), 9 of 36 (25%)
locally advanced breast cancers (stage III), and 16 of 39 (41%) patients with metastatic disease (stage IV; P = 0.017). In the subgroup of nonmetastatic patients ( n = 75), prognostic factors for poor disease-free survival were: absence of estrogen receptor; presence of CK+ cells in bone
marrow ( P = 0.012); clinical nodal involvement; large tumor size (T4); and presence of tumor emboli. Presence of circulating CK+ cells
in the peripheral blood was not statistically correlated with disease-free survival. On multivariate analysis, independent
indicators for disease-free survival were: absence of estrogen receptor ( P = 0.043) and presence of CK+ cells in bone marrow ( P = 0.076).
Conclusions: The clinical relevance of circulating epithelial cells as a prognostic factor is not supported by the present data, especially
in comparison with tumor cells in the bone marrow. However, this method of detection may be useful to monitor the efficacy
of treatment in advanced or metastatic breast cancer.
There is increasing statistical evidence that the presence of tumour cells in bone marrow detected by immunocytochemistry represents an important prognostic indicator in breast cancer, but their ...individual capacity to become clinical metastases is unknown. The aim of this study was to assess the proliferative capacity of these occult metastatic cells in the bone marrow of patients with various stages of breast cancer. We obtained bone marrow aspirates from 60 patients with breast cancer before treatment with chemotherapy: 17 stage II, 12 stage III and 31 stage IV. After bone marrow culture for 6-34 days (median: 17 days) under specific cell culture conditions, viable epithelial cells were detected by cytokeratin staining in 40 patients (66%). Expansion of tumour cells was poorly correlated with tumour cell detection on primary screening (P=0.06). There was a nonsignificant correlation between the number and the presence of expanded tumour cells and the UICC stage of the patients. On primary screening, tumour cell detection was positive in 56% of patients and was correlated with clinical UICC stage (P=0.01). However, with a median follow-up of 23 months, expansion of tumour cells from bone marrow was associated with decreased patient survival (P=0.04), whereas the survival difference according to detection of CK-positive cells on primary screening was not statistically significant. In conclusion, viable tumour cells can be detected in the bone marrow of breast cancer patients. Their proliferative potential could be predictive of outcome and deserves further investigation.
Clinical studies have shown that a marked lymphoplasmocytic reaction in breast tumors is associated with poor prognosis. Such findings raise the possibility that an inflammatory cell reaction might ...be a tumor-induced response that tends to promote tumor growth.
We assessed the expression of colony-stimulating factor-1 (CSF-1) as well as the prevalence of specific tumor-infiltrating lymphocytes and monocytes in breast tumors.
Tissue sections were obtained from archival paraffin blocks from 196 breast cancer patients. Seventy-eight percent of the women had been treated by mastectomy and 22% by lumpectomy. Median age of the patients was 54 years, and median follow-up was 7.3 years. Immunohistochemical and in situ hybridization techniques were used to characterize the specimens.
Markedly high numbers of CD45RO-positive T- and L26-positive B-cell infiltrates were found in 13% and 17% of the tissue specimens, respectively. CSF-1 receptor-positive monocytes were detected in 48% and CD68-positive monocytes in 90% of the tumors. In turn, tumors with large fractions of CD68-positive monocytes also showed CSF-1 receptor-positive monocytes (P < .0001). CSF-1 was expressed significantly in 74% of the tumors and the CSF-1 receptor in more than 50% of the tumors. Tumors with high percentages of CSF-1 expressing cells also had marked monocyte infiltrates (P = .035). The presence of marked CD45RO-positive T-cell infiltrates and apparent nuclear staining of CSF-1 in tumor cells were associated with the more frequent occurrence of metastases (P = .02 and P = .04, respectively) and with poor survival (P = .02 and P = .03, respectively).
Large numbers of CD45RO-positive (activated memory but noncytotoxic) T cells as well as a predominant nuclear staining pattern for CSF-1 are associated with a poor outcome in breast cancer patients.
Nuclear retention of CSF-1 could reflect CSF-1 turnover and function in tumor cells, but new approaches are needed to establish the significance of these observations. Secreted CSF-1 appears to cause monocyte recruitment and activation, thereby modulating immune functions and potentially the expression of the CD45RO phenotype in T cells.
To screen for factors that might predict the risk of developing metachronous contralateral breast cancer (CBC), taking into account the influence of local or distant recurrence, and to assess the ...annual incidence of CBC.
Of 4,748 women with invasive unilateral breast cancer, clinical stage I to IIIa, treated between 1981 and 1987, 282 metachronous CBCs were diagnosed. Due to competing risks between the occurrence of CBC and other events, several options for multivariate analysis were considered.
The median follow-up time was 80 months (range, 1 to 158). The cumulative rate of CBC was 4.1% +/- 0.3% at 5 years, and the annual incidence rate of CBC increased slowly, while the risk of local recurrence and metastases decreased after the fourth year. Whichever model we chose, age less than 55 years (relative risk RR = 1.40) at the time of diagnosis of the first breast cancer, as well as the presence of lobular type carcinoma (RR = 1.50), was associated with an increased risk of developing a tumor in the contralateral breast. Adjuvant chemotherapy significantly decreased (RR = 0.54) the risk of CBC.
Lobular histology and age less than 55 years are found to increase the risk of CBC, while adjuvant chemotherapy significantly decreased the risk of CBC. The progressive rise in the annual incidence rates of CBC, together with the absence of a link between clinical prognostic factors of the first cancer and CBC, suggested that CBC can be considered as a second primary breast cancer.
Anthracyclines remain an important group of chemotherapeutic agents, despite their inherent cardiotoxicity. This cardiotoxicity may be even more of a concern in the future, as combination therapies ...of anthracyclines with newer agents become routine. Such combinations may be highly effective, but cardiotoxicity may also be increased. Dexrazoxane reduces the incidence of cardiotoxicity, as demonstrated in numerous clinical trials in both adults and children. Evidence from the literature suggests no effect of dexrazoxane on the antitumour efficacy of anthracyclines, and there is no adverse effect on survival. Dexrazoxane is therefore a valuable tool for oncologists using anthracycline-based regimens.
Various parameters have been reported to be correlated with response to interleukin-2 (IL-2) therapy. A multiinstitutional study was performed to assess by multivariate analysis the predictive value ...of known clinical and biologic melanoma prognostic markers recorded before the onset of IL-2 therapy on the likelihood of objective clinical response.
Serum C-reactive protein (CRP), IL-6, and lactate dehydrogenase (LDH) levels were measured in 81 metastatic melanoma patients included in different IL-2-based regimens before the starting of IL-2-therapy. Clinically defined prognostic groups, i.e., patients with superficial or visceral metastases, were also analyzed for response correlates. Patients were evaluated for response to treatment 4 to 6 weeks after completion of one course of therapy.
On univariate analysis, the pretreatment values of CRP (P = .001), IL-6 (P = .007), and LDH (P = .02) and site of metastases (P = .0004) were correlated with clinical response. However, only CRP (P < .007) and clinically defined group (P < .004) were independent predictors on multifactorial analysis. Indeed, when adjusted to CRP, IL-6 tended to improve patient selection, but did not reach statistical significance (P = .07). Furthermore, using multivariate survival analysis based on the Cox proportional hazards model, only CRP was found to be an independent prognostic factor for survival (P < .0001).
In this study, patients with high serum levels of CRP and/or visceral organ involvement before therapy were unlikely to respond to IL-2 therapy. Therefore, clinical classification based on the site of metastases and serum CRP determination before the start of IL-2 therapy may help to improve selection of melanoma patients who may benefit from IL-2 and could prevent unnecessary morbidity.
The purpose of the present paper was to evaluate correlations between clinical response to chemotherapy and outcome in a subgroup analysis of premenopausal patients with tumours considered too large ...for breast conserving surgery, treated with primary chemotherapy (n = 200) from a previously published trial (Scholl S.M., Fourquet A., Asselain B,
et al. Eur J Cancer 1994, 30A, 645–652). Objective response rates amounted to 65% following four courses. In a multivariate Cox regression analysis, comparing seven parameters, the following variables were associated with poor survival: clinically involved nodes Nib: RR: 2.7 (95% CI 1.3–5.3), the failure to respond to chemotherapy D: RR: 2.62 (95% CI 1.3–5) and a raised S phase fraction SPF > 5%: RR: 2.4 (95% CI 1.2–5). Parameters associated with increased metastatic recurrence rates, by order of entry in the model, were: young age < 35: RR: 2.46 (95% CI 1.2–5), large clinical tumour size T3: RR: 2.02 (95% CI 1.2–3.4), poor histological grade (SBR III: RR: 1.93 (95% CI 1.1–3.3) and the failure to respond to chemotherapy D: RR: 1.91 (95% CI 1–3.4). The assessment of both tumour cell proliferation rates as well as possibly drug resistance markers (although not available in the present study) should be helpful in selecting patients likely to benefit from intensified chemotherapy regimens. The most accurate predictor of response in the present study appeared to be the response to chemotherapy treatment itself.
Despite the generalization of induction chemotherapy and a better outcome for chemosensitive diseases, the prognosis of inflammatory breast cancer (IBC) is still poor. In this work, we evaluate ...response and toxicity of high-dose sequential chemotherapy with repeated blood stem cell (BSC) transplantation administered as initial treatment in 100 women with non-metastatic IBC. Ninety-five patients (five patients were evaluated as non-eligible) of median age 46 years (range 26-56) received four cycles of chemotherapy associating: cyclophosphamide (C) 6 g m(-2) - doxorubicin (D) 75 mg m(-2) cycle 1, C: 3 g m(-2) - D: 75 mg m(-2) cycle 2, C: 3 g m(-2) - D: 75 mg m(-2) - 5 FU 2500 mg m(-2) cycle 3 and 4. BSC were collected after cycle 1 or 2 and reinfused after cycle 3 and 4. rG-CSF was administered after the four cycles. Mastectomy and radiotherapy were planned after chemotherapy completion. Pathological response was considered as the first end point of this trial. A total of 366 cycles of chemotherapy were administered. Eighty-seven patients completed the four cycles and relative dose intensity was respectively 0.97 (range 0.4-1.04) and 0.96 (range 0.25-1.05) for C and D. Main toxicity was haematological with febrile neutropenia ranging from 26% to 51% of cycles; one death occurred during aplasia. Clinical response rate was 90% +/- 6%. Eighty-six patients underwent mastectomy in a median of 3.5 months (range 3-9) after the first cycle of chemotherapy; pathological complete response rate in breast was 32% +/- 10%. All patients were eligible to receive additional radiotherapy. High-dose chemotherapy with repeated BSC transplantation is feasible with acceptable toxicity in IBC. Pathological response rate is encouraging but has to be confirmed by final outcome.
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