The efficacy and toxicity of leucovorin 500 mg/m2 administered intravenously (IV) over 30 minutes daily for five days followed in one hour by fluorouracil (5-FU) 375 mg/m2 administered IV daily for five days, each given every 3 weeks, was assessed in 54 previously treated patients with metastatic breast cancer. An overall objective response rate of 24% was achieved (95% confidence interval, 13% to 38%), with an additional 56% of patients maintaining stable disease. Eleven of 12 patients who responded had received previous 5-FU therapy. Toxicity of this regimen included grade 3 diarrhea in 13%, grade 3 or 4 mucositis in 33%, grade 3 or 4 granulocytopenia in 65%, and grade 3 or 4 thrombocytopenia in 19%. Delay of treatment was required for hematologic toxicity in 44 patients. Thirty-eight patients required dose reductions due to toxicity. Biochemical evaluation of tumor biopsy specimens obtained from 17 patients used as their own controls with and without leucovorin was performed. These studies reveal an increased stabilization of the 5-fluorodeoxyuridylate (FdUMP)-thymidylate synthase (TS) folate ternary complex with the addition of leucovorin. There was a 71% +/- 14% occupancy or inhibition of the enzyme with the use of both 5-FU and leucovorin, v 30% +/- 13% for 5-FU alone (P2 less than .037). The percent TS bound in responding patients was substantially higher than in those patients with progressive disease. Finally, the mean total tumor TS pre-therapy in seven patients was 31 fmol/mg compared with a mean of 81 fmol/mg in these same seven patients 24 hours after therapy. This 2.6-fold increase suggests that there is an induction of the enzyme, TS, with 5-FU treatment.

Among the processes contributing to the progressive acquisition of the highly malignant phenotype in breast cancer are ovarian-independent growth, antioestrogen resistance and increased metastatic potential. We have previously observed that increased invasiveness and development of ovarian-independent growth occur independently. In an attempt to define the inter-relationships between these processes further, we have compared the phenotypes of ovarian-independent, invasive and antioestrogen-resistant sublines of the ovarian-dependent human breast cancer cell line MCF-7. Cells acquiring ovarian-independent growth can retain sensitivity to anti-oestrogens. One clone of MCF-7 cells selected for stable antioestrogen resistance has become non-tumorigenic but its invasive potential remains unaltered. Thus, acquisition of some characteristics of the progressed phenotype can occur independently. This phenomenon of independent parameters in phenotypic progression could partly explain the considerable intra- and intertumour heterogeneity characteristic of breast tumours.

We reviewed the complete axillary dissection specimens of 136 patients with stage I-II breast cancer to clarify the distribution of axillary lymph node metastases in this disease. Our series included 71 patients undergoing axillary dissection as part of a modified radical mastectomy (MRM) and 65 patients undergoing axillary dissection in conjunction with conservative surgery of the breast and definitive postoperative breast radiotherapy (CAD). These two groups of patients were comparable according to age, menopausal status, tumor size, and clinical stage. In all patients the pectoralis minor muscle was excised and all axillary tissue removed. Each specimen contained a median of 23 lymph nodes. The axillary levels (I, II, III) were determined according to the relationship of axillary tissue to the pectoralis minor muscle (lateral, inferior, medial). Thirty-nine percent of the lymph nodes were contained in level I, 41% in level II, and 20% in level III. There were no significant differences noted in the number of lymph nodes or in the distribution of lymph nodes according to axillary level between dissections performed as part of the MRM or those done as a single procedure (CAD). Sixty-five patients (47.8%) had one or more positive lymph nodes in their axillary specimen. The clinical and pathologic stage was determined and compared for all patients. Among patients judged to have a clinically negative axilla, 37.6% had histologically positive lymph nodes (clinical false-negative rate). For patients with a clinically positive axilla, 11.1% had, histologically, no evidence of metastatic disease (clinical false-positive rate). When the distribution of lymph node metastases according to axillary level was studied, it was found that 29.2% of lymph node-positive patients (or 14.0% of all patients) had metastases only to level II and/or III of the axilla, with level I being negative (skip metastases). This incidence of skip metastases was greater among clinically node-negative than among clinically node-positive patients, but was not related to the size or location of the primary tumor in the breast. In addition, it was found that 20.0% of lymph node-positive patients (or 9.6% of all patients) were converted from three or fewer to four or more positive nodes by analysis of lymph nodes contained in levels II and III. This conversion from three or fewer to four or more positive nodes was due primarily to information contained in level II, with level III contributing to a smaller degree.(ABSTRACT TRUNCATED AT 400 WORDS)

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