Metastatic breast cancer (MBC) is considered incurable; therefore, palliative treatment is the only option. The biologic heterogeneity of the disease is reflected in its somewhat unpredictable clinical behavior. The presence of circulating tumor cells (CTCs) in patients with MBC about to start a new line of treatment has been shown to predict progression-free and overall survival. This prognostic value is independent of the line of therapy (eg, first or second line). Moreover, a multivariate analysis has shown the prognostic value of CTCs to be superior to that of site of metastasis, type of therapy, and length of time to recurrence after definitive primary surgery. These data suggest that the presence of CTCs may be used to modify the staging system for advanced disease. Larger studies are needed to confirm these data and evaluate the use of CTC detection in monitoring treatment and furthering our understanding of breast cancer biology when combined with other diagnostic technologies.

https://www.nejm.org/doi/pdf/10.1056/NEJMoa040766

Circulating Tumor Cells, Disease Progression, and Survival in Metastatic Breast Cancer

Purpose National Surgical Adjuvant Breast and Bowel Project (NSABP) Protocol B-18 was designed to determine whether four cycles of doxorubicin and cyclophosphamide (AC) administered preoperatively improved breast cancer disease-free survival (DFS) and overall survival (OS) compared with AC administered postoperatively. Protocol B-27 was designed to determine the effect of adding docetaxel (T) to preoperative AC on tumor response rates, DFS, and OS. Patients and Methods Analyses were limited to eligible patients. In B-18, 751 patients were assigned to receive preoperative AC, and 742 patients were assigned to receive postoperative AC. In B-27, 784 patients were assigned to receive preoperative AC followed by surgery, 783 patients were assigned to AC followed by T and surgery, and 777 patients were assigned to AC followed by surgery and then T. Results Results from B-18 show no statistically significant differences in DFS and OS between the two groups. However, there were trends in favor of preoperative che...

Preoperative Chemotherapy: Updates of National Surgical Adjuvant Breast and Bowel Project Protocols B-18 and B-27

PURPOSE: To assess patient and tumor characteristics associated with a complete pathologic response (pCR) in both the breast and axillary lymph node specimens and the outcome of patients found to have a pCR after neoadjuvant chemotherapy for locally advanced breast cancer (LABC). PATIENTS AND METHODS: Three hundred seventy-two LABC patients received treatment in two prospective neoadjuvant trials using four cycles of doxorubicin-containing chemotherapy. Patients had a total mastectomy with axillary dissection or segmental mastectomy and axillary dissection followed by four or more cycles of additional chemotherapy. Patients then received irradiation treatment of the chest-wall or breast and regional lymphatics. Median follow-up was 58 months (range, 8 to 99 months). RESULTS: The initial nodal status, age, and stage distribution of patients with a pCR were not significantly different from those of patients with less than a pCR (P > .05). Patients with a pCR had initial tumors that were more likely to be es...

Clinical Course of Breast Cancer Patients With Complete Pathologic Primary Tumor and Axillary Lymph Node Response to Doxorubicin-Based Neoadjuvant Chemotherapy

Study design A new surgical strategy for treatment of patients with spinal metastases was designed, and 61 patients were treated based on this strategy. Objectives To propose a new surgical strategy for the treatment of patients with spinal metastases. Summary of background data A preoperative score composed of six parameters has been proposed by Tokuhashi et al for the prognostic assessment of patients with metastases to the spine. Their scoring system was designed for deciding between excisional or palliative procedures. Recently, aggressive surgery, such as total en bloc spondylectomy for spinal metastases, has been advocated for selected patients. Surgical strategies should include various treatments ranging from wide or marginal excision to palliative treatment with hospice care. Methods Sixty-seven patients with spinal metastases who had been treated from 1987-1991 were reviewed, and prognostic factors were evaluated retrospectively (phase 1). A new scoring system for spinal metastases that was designed based on these data consists of three prognostic factors: 1) grade of malignancy (slow growth, 1 point; moderate growth, 2 points; rapid growth, 4 points), 2) visceral metastases (no metastasis, 0 points; treatable, 2 points: untreatable, 4 points), and 3) bone metastases (solitary or isolated, 1 point; multiple, 2 points). These three factors were added together to give a prognostic score between 2-10. The treatment goal for each patient was set according to this prognostic score. The strategy for each patient was decided along with the treatment goal: a prognostic score of 2-3 points suggested a wide or marginal excision for long-term local control; 4-5 points indicated marginal or intralesional excision for middle-term local control; 6-7 points justified palliative surgery for short-term palliation; and 8-10 points indicated nonoperative supportive care. Sixty-one patients were treated prospectively according to this surgical strategy between 1993-1996 (phase 2). The extent of the spinal metastases was stratified using the surgical classification of spinal tumors, and technically appropriate and feasible surgery was performed, such as en bloc spondylectomy, piecemeal thorough excision, curettage, or palliative surgery. Results The mean survival time of the 28 patients treated with wide or marginal excision was 38.2 months (26 had successful local control). The mean survival time of the 13 patients treated with intralesional excision was 21.5 months (nine had successful local control). The mean survival time of the 11 patients treated with palliative surgery and stabilization was 10.1 months (eight had successful local control). The mean survival time of the patients with terminal care was 5.3 months. Conclusions A new surgical strategy for spinal metastases based on the prognostic scoring system is proposed. This strategy provides appropriate guidelines for treatment in all patients with spinal metastases.

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Surgical strategy for spinal metastases.

Purpose Metastatic breast cancer (MBC) is incurable; its treatment is palliative. We investigated whether the presence of circulating tumor cells (CTCs) predicts treatment efficacy, progression-free survival (PFS), and overall survival (OS) in patients with newly diagnosed MBC who were about to start first-line therapy. Patients and Methods One hundred seventy-seven patients with measurable MBC were enrolled onto a prospective study. Eighty-three of the 177 patients were entering first-line treatment, and these patients are the focus of this analysis. CTCs from 7.5 mL of whole blood drawn before treatment initiation (baseline) and monthly thereafter for up to 6 months were isolated and enumerated using immunomagnetics. Results The mean (± standard deviation) follow-up time was 11.1 ± 4.4 months (median, 12.2 months). Forty-three patients (52%) had ≥ five CTCs at baseline. The median PFS was 7.2 months (95% CI, 4.9 to 9.4 months), and the median OS was more than 18 months. Patients with ≥ five CTCs at base...

https://ascopubs.org/doi/pdf/10.1200/jco.2005.08.140

Circulating Tumor Cells: A Novel Prognostic Factor for Newly Diagnosed Metastatic Breast Cancer

Thirty-eight patients with advanced breast cancer, multiple myeloma, and malignant lymphoma were treated with partially purified (about 0.1%) leukocyte interferon. Patients were treated with a remission-induction schedule of 3 million to 9 million antiviral units daily intramuscularly for 4 to 26 weeks. Responding patients were maintained on a schedule of 3 million U three times weekly. Tumor regression was observed in seven of 17 patients with breast cancer. Six of 10 patients with multiple myeloma responded with a decrease of at least 50% in serum myeloma protein levels or Bence Jones protein excretion. Six of the 11 lymphoma patients achieved tumor regression. Complete remissions occurred in two patients. Of the 19 responding patients, five remain on study for 52 to 63 weeks. Toxicity included low-grade fever, fatigue, anorexia, and partial alopecia. Myelosuppression (lowest median leukocyte count, 2500/mm3; granulocytes, 1300/mm3) occurred in most patients. On the basis of this pilot study, we conclude that leukocyte interferon can induce tumor regression in patients with advanced cancer.

Leukocyte Interferon-Induced Tumor Regression in Human Metastatic Breast Cancer, Multiple Myeloma, and Malignant Lymphoma

Six hundred nineteen patients with metastatic breast cancer, treated with a combination of 5-fluorouracil, Adriamycin, and cyclophosphamide, or close variations of this program, with or without immunotherapy were analyzed retrospectively to identify those host, tumor, or treatment characteristics that might be of prognostic importance in predicting response to chemotherapy and survival from onset of the 5-fluorouracil-Adriamycin-cyclophosphamide treatments. Primary tumor characteristics such as size of primary, number of axillary nodes involved, stage at diagnosis, and type of surgery used for primary treatment were not found to be of prognostic significance. Host characteristics such as age, menstrual status, or family history of breast cancer were similarly unrelated to outcome. Non-Caucasian patients had a lower response rate and somewhat shorter survival than did Caucasians. Pretreatment weight loss, poor performance status, and abnormal biochemical and hematological values were of adverse prognostic significance. An estimate of total extent of disease based on criteria for rating extent of involvement at 12 potential sites was a much more important prognostic factor related to response and survival than actual sites of involvement or the traditional "dominant site" classification. There was a trend, however, for patients with bone involvement to have a longer survival than did patients with metastases to other organ sites. Shorter survival times were observed among patients exposed to extensive prior radiotherapy and those who failed to respond to prior hormonal treatment. The prognostic variables identified in this paper should be used for the design and comparison of clinical trials in the future.

https://cancerres.aacrjournals.org/content/canres/39/5/1552.full.pdf

Prognostic factors in metastatic breast cancer treated with combination chemotherapy.

Fifty-two patients with locally advanced primary breast cancer (T3, T4/N2, N3) without distant metastases were treated with three cycles of combination chemotherapy consisting of 5-FU, Adriamycin and cyclophosphamide (FAC) and immunotherapy with Bacillus Calmette-Guerin (BCG) followed by local therapy (simple mastectomy and/or radiotherapy to breast/chest wall and regional lymphatics) and adjuvant chemotherapy to complete two years of treatment. Forty-nine of 52 (94%) patients were rendered free of clinically detectable disease. The median disease-free interval was 24 months. At a median follow-up time of 60 months, 40% of patients remained free of disease, off all therapy. Those patients who completed two years of therapy and started adjuvant chemotherapy promptly after local treatment had a 48% disease-free survival at five years. Local recurrences were observed in 21% of patients. Distant metastases developed in 40% of patients. Despite good tolerance, treatment compliance was poor. The complete remission rate with this multimodal approach is high and long-term disease-free survival is achieved in a considerable number of patients.

Multimodal treatment of locoregionally advanced breast cancer.

Twenty-five breast cancer patients with meningeal carcinomatosis seen over a period of 16 months were reviewed. In all cases, the clinical diagnosis was made in the presence of diverse neurological manifestations by the demonstration of malignant cells in the cerebrospinal fluid. In ten patients, the clinical diagnosis was documented at autopsy. All patients were receiving systemic chemotherapy at the time the diagnosis of meningeal carcinomatosis was made. In 9 of the 25 patients, meningeal involvement was associated with progression of systemic metastases, while 5 exhibited stable or partial remission from systemic metastases and 7 were in complete remission at the time of their CNS relapse. CNS involvement was the first manifestation of recurrent disease from breast cancer in 4 of 25 patients. Meningeal involvement can, therefore, occur at any time during the course of breast cancer. With increasing diagnostic awareness and the employment of several therapeutic strategies, the prognosis of these patients, though poor, was significantly improved over that of historical control patients.

Meningeal carcinomatosis in breast cancer.

Fifty-nine evaluable patients under 65 years of age with measurable metastatic breast cancer and without prior chemotherapy were randomly assigned to treatment with fluorouracil, Adriamycin (Adria Laboratories, Columbus, OH), and cyclophosphamide (FAC) at standard or high doses (100% to 260% higher than standard FAC) following a dose escalation schedule. Patients randomized to the high-dose FAC received the first three cycles of therapy within a protected environment. Subsequent cycles for this group were administered at standard doses of FAC in an ambulatory setting, the same as for the control group. After reaching 450 mg/m2 of Adriamycin, patients in both groups continued treatment with cyclophosphamide, methotrexate, and fluorouracil until there was disease progression. Analysis of pretreatment patient characteristics showed an even distribution for most known pretreatment factors, although the control group had slightly (but nonsignificantly) more favorable prognostic characteristics. Fourteen patients (24%) achieved a complete remission (CR) and 32 (54%) achieved a partial remission (PR), for an overall major response rate of 78%. There were no differences in overall, CR, or PR rates between the high-dose FAC and control groups. The median response durations were 11 and 10 months for the protected environment and control groups, respectively, and the median survival was 20 months for both groups. Hematologic, gastrointestinal (GI), and infection-related complications were significantly more frequent and severe in the group treated with high-dose chemotherapy. Stomatitis, diarrhea, and skin toxicity were dose-limiting. However, there were no treatment-related deaths. High-dose induction combination chemotherapy with the agents used in this study failed to increase the response rate or survival duration, and resulted in a substantial increase in toxicity.

Hwee-Yong Yap

Papers

Leukocyte Interferon-Induced Tumor Regression in Human Metastatic Breast Cancer, Multiple Myeloma, and Malignant Lymphoma

Prognostic factors in metastatic breast cancer treated with combination chemotherapy.

Multimodal treatment of locoregionally advanced breast cancer.

Meningeal carcinomatosis in breast cancer.

Evaluation of high-dose versus standard FAC chemotherapy for advanced breast cancer in protected environment units: a prospective randomized study.