Tissue from 54 patients with breast cancer was analyzed for estrogen receptor (ER). From 38 patients, tissue from multiple tumor sites was analyzed to determine ER heterogeneity. In 13 patients (34%) both positive and negative ER values were obtained. ER negative (ER––) results were observed more frequently in metastatic lesions. In 28 patients both the ER and [³H]-thymidine labeling index (LI) were measured in the same lesion. [³H]-Thymidine was administered in vivo. There was a positive correlation between ER positivity and low LI. The mean LI of 8 ER positive (ER+) tumors was 3.4 in contrast to a mean LI of 10.0 for 14 ER-tumors (p < 0.01). LI of 6 mixed ER tumors (ER+/––) was intermediate (mean 5.7). High LI (≧ 8) was associated with decreased survival regardless of the stage of disease at the time of study. ER with LI may provide an improved basis for treatment selection.

Tumor cell kinetic parameters were studied in eight patients with solid tumors following intravenous (i-v.) ['HI thymidine injection, 0 3 mCi/kg. The studies were performed to determine the variability in labeling index (LI) within and among lesions from the same patient, among lesions from different patients with the same disease, and to determine the variation in cell cycle kinetic parameters from lesion to lesion in the same patient. The variation in LI and percent labeled mitosis (PLM) was determined from multiple biopsy or aspirate specimens obtained at intervals following administration of [*HI thymi-dine. In 11 separate tumor lesions the intralesional LI varied from 20% to 405% with a mean variation of 97%. The intralesional LI of nine of the 11 lesions varied by less than 100%. In four patients multiple LI were determined from each of several lesions. The mean LI from lesion to lesion varied from 10% to 276%. Jn three of the four patients the variation was 534%. These data suggest that there may be less interlesional than intralesional variation when mean LJ are compared and that three to five samples per lesion may provide representative LI in patients with solid tumors. In two patients, one with carcinoma of the breast and one with carcinoma of the lung, PLM curves were obtained by sampling two and three lesions, respectively. The results from both patients indicate little interlesional heterogeneity in cell cycle distribution. For the patient with lun8 cancer the TS and T,z+M Were estimated to be 16.5 and 7.5 hours, rqspectively. For the patient with breast cancer the Ts and T G z + M were estimated to be 18 and and 10 hours, respectively. For both patients the Tc was estimated to be >lo0 hours. These data have been compared to existing cell kinetic data in lung and breast cancer.

Twenty-eight patients with lung cancer, 26 with extensive disease, were treated with the drugs Cytoxan (Cyt) and methotrexate (MTX). The schedule was based on cellular kinetics concepts. Initial therapy was with Cyt 1.1 g/m2 (intravenously) followed by MTX 20 mg/m2 orally, twice weekly, started 9 days later, when the tumor was considered to be most susceptible to an S-phasespecific drug. The course was repeated at three-week intervals. Based on dose response curves, Cyt and MTX dose modifications were individually adjusted to the white blood cell counts and platelet counts over a 3-week period. Twenty of 28 patients (five of seven large cell, five of eight adenocarcinoma, 10 of 11 small cell, none of two epidermoid) responded with 250% tumor reduction. Ten patients had complete responses, seven of whom had small cell carcinoma. Two of the nonresponders were nonevaluable. Five patients were alive and the estimated median survival time of the patients is almost 1 year, which compares quite favorably to previous reports. On this schedule of therapy, very high doses of Cyt and MTX were maintained with less than 3% incidence per course of a WBC < 1,500/mm3 or a platelet count <50,000/mm3.