Weekly paclitaxel improves pathologic complete remission in operable breast cancer when compared with paclitaxel once every 3 weeks.

PURPOSE: To determine the impact a change in schedule of paclitaxel administration from once every 3 weeks to frequent administration would have on the pathologic complete response (pCR) rate in the breast and lymph nodes for patients with invasive breast cancer treated with primary systemic chemotherapy (PST). PATIENTS AND METHODS: Patients with clinical stage I-IIIA breast cancer were randomly assigned to receive PST of paclitaxel doses administered either weekly (for a total of 12 doses of paclitaxel) or once every 3 weeks (four cycles), followed by four cycles of fluorouracil/doxorubicin/cyclophosphamide (FAC) in standard doses every 3 weeks. Two different doses of paclitaxel were used based on lymph node status defined by ultrasound and fine needle aspiration. Clinical response and extent of residual disease in the breast and lymph nodes was assessed after completion of all chemotherapy. RESULTS: A total of 258 patients were randomly assigned to receive doses of paclitaxel administered either weekly or once every 3 weeks, followed by FAC. Of these 258 patients, 110 patients had histologic lymph node involvement and 148 patients had clinical N0 disease. Weekly paclitaxel followed by FAC was administered to 127 patients and once-every-3-weeks paclitaxel followed by FAC was administered to 131 patients. Clinical response to treatment was similar between groups (P = .25). Patients receiving weekly paclitaxel had a higher pCR rate (28.2%) than patients treated with once-every-3-weeks paclitaxel (15.7%; P = .02), with improved breast conservation rates (P = .05). CONCLUSION: The change in schedule of paclitaxel from once every 3 weeks to a more frequent administration significantly improved the ability to eradicate invasive cancer in the breast and lymph nodes.

Gene expression profiles obtained from fine-needle aspirations of breast cancer reliably identify routine prognostic markers and reveal large-scale molecular differences between estrogen-negative and estrogen-positive tumors.

PURPOSE: The purpose of this study was to determine whether comprehensive transcriptional profiles (TPs) can be obtained from single-passage fine-needle aspirations (FNAs) of breast cancer and to explore whether profiles capture routine clinicopathological parameters. EXPERIMENTAL DESIGN: Expression profiles were available on 38 patients with stage I-III breast cancer who underwent FNA at the time of diagnosis. [(33)P]dCTP-labeled cDNA probes were generated and hybridized to cDNA membrane microarrays that contained 30,000 human sequence clones, including 10,890 expressed sequence tags. RESULTS: The median total RNA yield from the biopsies was 2 micro g (range, 1-25 micro g). The cellular composition of each biopsy was examined and, on average, 79% of the cells were cancer cells. TP was successfully performed on all 38 of the biopsies. Unsupervised complete-linkage hierarchical clustering with all of the biopsies revealed an association between estrogen receptor (ER) status and gene expression profiles. There was a strong correlation between ER status determined by TP and measured by routine immunohistochemistry (P = 0.001). A similar strong correlation was seen with HER-2 status determined by fluorescent in situ hybridization (P = 0.0002). Using the first 18 cases as the discovery set, we established a cutoff of 2.0 and 18.0 for ER and HER-2 mRNA levels, respectively, to distinguish clinically-negative from -positive cases. We also identified 105 genes (excluding the ER gene) the expression of which correlated highly with clinical ER status. Twenty tumors were used for prospective validation. HER-2 status was correctly identified in all 20 of the cases, based on HER-2 mRNA content detected by TP. ER status was correctly identified in 19 of 20 cases. When the marker set of 105 genes was used to prospectively predict ER status, TP-based classification correctly identified 9 of 10 of the ER-positive and 7 of 10 of the ER-negative tumors. We also explored supervised cluster analysis using various functional categories of genes, and we observed a clear separation between ER-negative and ER-positive tumors when genes involved in signal transduction were used for clustering. CONCLUSIONS: These results demonstrate that comprehensive TP can be performed on FNA biopsies. TPs reliably measure conventional single-gene prognostic markers such as ER and HER-2. A complex pattern of genes (not including ER) can also be used to predict clinical ER status. These results demonstrate that needle biopsy-based diagnostic microarray tests may be developed that could capture conventional prognostic information but may also contain additional clinical information that cannot currently be measured with other methods.

A detailed evaluation of cardiac toxicity: a phase II study of doxorubicin and one- or three-hour-infusion paclitaxel in patients with metastatic breast cancer.

PURPOSE: This Phase II study was designed to determine the efficacy and toxicity of combination doxorubicin and paclitaxel as front-line treatment for metastatic breast cancer. EXPERIMENTAL DESIGN: Eligible patients had no prior anthracycline or taxane therapy and normal cardiac function. They were treated with bolus doxorubicin 60 mg/m2, followed by paclitaxel 200 mg/m2, as either 1- or 3-h infusions for six to seven cycles. Single-agent paclitaxel was continued thereafter. Serial multiple gated acquisition scans were performed, and endomyocardial biopsies were performed for consenting patients. RESULTS: Eighty-two patients were enrolled with a median age of 53 years (range, 32-78 years). Of 79 evaluable patients, 58.2% had an objective response (3.8% complete response + 54.4% partial response), 34.2% had stable disease, and 7.6% had progressive disease. With median follow-up of 37.5 months, median time to progression was 7 months; median survival was 31 months. Multiple gated acquisition scans were performed in 82 of 82 patients at baseline, 75 of 82 patients at a total doxorubicin dose of 60-180 mg/m2, 62 of 68 patients at 200-300 mg/m2, 18 of 52 patients at 310-360 mg/m2, and 4 of 8 patients at 420 mg/m2. Median ejection fractions were 62.5, 60, 57.5, 52.5, and 32%, respectively. Fifteen of 82 (18.3%) patients had a decrease in ejection fraction > or = 15% to an absolute ejection fraction < or = 50%. Eight of these 15 patients (53%) developed clinical congestive heart failure: 4 of 8 (50%) who received a total doxorubicin dose of 420 mg/m2 versus 4 of 74 (5.4%) who received a dose < or = 360 mg/m2 (P = 0.002). CONCLUSIONS: When the doxorubicin dose exceeds 360 mg/m2, the combination of bolus doxorubicin and paclitaxel presents unacceptable cardiac risk.

Breast cancer patient perception of the helpfulness of a prompt sheet versus a general information sheet during outpatient consultation: a randomized, controlled trial.

The purpose of this study was to determine the helpfulness of a prompt sheet versus a general information sheet for patient communication with physicians. Sixty women with breast cancer attending their first outpatient consultation with a breast medical oncologist were randomized to receive either a prompt sheet (PS) or a general information (GI) sheet regarding breast cancer. Analysis of the results found that helpfulness of the written material was rated higher in the PS group (8.5 +/- 2) than the GI group (6.2 +/- 3.6), P = 0.005. The mean score of helpfulness in communicating with physicians was 7.9 +/- 2.4 and 5.7 +/- 3.8, respectively, P = 0.01. There were no significant differences between the groups in the average total number of questions asked by the patients or average physician or patient speaking time. We conclude that a disease-specific prompt sheet provided before medical encounters may assist in communication between patients and physicians.

Treatment decisions for breast carcinoma: patient preferences and physician perceptions.

BACKGROUND: Patient autonomy and participation in treatment decision making have been encouraged in recent years. However, patients and physicians frequently disagree with regard to the patient's needs and perceptions of their illness. To the authors' knowledge to date only limited research has assessed physicians' perceptions of patients' decision-making preferences. The purpose of the current prospective study was to determine the agreement between patient decision-making preferences and physician perceptions of those preferences. METHODS: Women with breast carcinoma who were attending their first outpatient consultation with a breast medical oncologist in a university cancer center were enrolled in the current study. At the end of the consultation, the patients were given a survey regarding their treatment decision-making preferences that included active, shared, and passive roles in decision-making and the patients' attending physicians also were given a survey regarding their perceptions of the patients' decision-making preferences. RESULTS: Fifty-seven patients had complete data and were analyzed. Approximately 89% of these 57 patients preferred either an active or a shared role in decision making. The agreement between patients and physicians with regard to decision-making preference only occurred in 24 cases (42%). The majority of covariates such as age, education, and income were not found to be statistically significant with regard to patient preferences or to the proportion of patients and physicians who agreed on the patient's preferences. CONCLUSIONS: Women with breast carcinoma appear to have a strong desire for involvement in making decisions regarding their treatment. However, physicians do not appear to be consistently able to predict the decision-making preferences of their patients. Enhanced agreement between patient preferences and physician expectations mostly likely will improve communication and patient satisfaction with the treatment decision-making process.

Phase I study of eniluracil and oral 5-fluorouracil in combination with docetaxel in the treatment of patients with metastatic breast carcinoma.

PURPOSE: The authors conducted a single-institution Phase I clinical trial to determine the maximum tolerated doses and to define the toxic effects of oral eniluracil and oral 5-fluorouracil (5-FU) combined with docetaxel in patients with metastatic breast carcinoma. PATIENTS AND METHODS: Patients with metastatic breast carcinoma were eligible if they had disease progression after anthracycline-based therapy and had never been exposed to taxanes. The starting doses of oral eniluracil and oral 5-FU were 11.5 mg/m(2) and 1.15 mg/m(2), respectively, twice daily on Days 1-14. Docetaxel was given intravenously at a starting dose of 50 mg/m(2) on Day 1 only. The dose of docetaxel was escalated among cohorts until a maximum tolerated dose was reached. Courses were repeated every 21 days. RESULTS: The authors treated 19 patients with Stage IV breast carcinoma, of whom 5 had received prior chemotherapy for their metastatic disease. Fifty-three percent had a performance status of 1, and 53% had bone or soft tissue involvement as the dominant site of disease. All patients had received prior therapy with doxorubicin. The dose-limiting toxicity was neutropenic fever. No episodes of sepsis were observed. Significant antitumor activity was observed with a total of two complete and nine partial responses. The recommended doses for Phase II studies are 72 mg/m(2) docetaxel on Day 1 and 10.0/1.0 mg/m(2) oral eniluracil/5-FU twice daily for a total of 14 days, with courses being repeated every 21 days. CONCLUSIONS: The combination of oral eniluracil/5-FU and intravenous docetaxel is a safe and well tolerated regimen. Significant antitumor activity is associated with this combination.

Total RNA yield and microarray gene expression profiles from fine-needle aspiration biopsy and core-needle biopsy samples of breast carcinoma.

BACKGROUND: Gene expression profiling should be applicable to needle biopsy samples if microarray technology is to become practically useful for clinical research or management of breast carcinoma. This study compared gene expression profiles derived from fine-needle aspiration biopsy (FNAB) and from core needle biopsy (CBX). METHODS: Total RNA was extracted from single FNAB and CBX samples. Corresponding pairs of FNAB and CBX were analyzed for similarity of gene expression profiles using cDNA microarrays that contain 30721 human sequences. A subset of genes that distinguished CBX samples from FNAB samples was evaluated in a larger group of needle biopsy samples and in a published genomic database derived from 78 sporadic breast carcinomas with known clinical outcome. RESULTS: Sixty-eight patients with newly diagnosed breast carcinoma were included in the current study. Sixty-five patients underwent FNAB (17 had both FNAB and CBX) and 3 underwent CBX only. Extracted RNA was of suitable quality for hybridization in 46 (71%) FNABs and 15 (75%) CBXs. Total RNA yield in those samples was similar for single-pass FNAB (mean = 3.6 microg and median = 2.2 microg; n = 46) and CBX (mean = 2.8 microg and median = 2.0 microg; n = 15), with 1 microg or more of total RNA in all cases. Transcriptional profiling was performed successfully in all cases when it was attempted, in a total of 50 samples (38 FNABs and 12 CBXs), including matched FNAB and CBX samples from 10 patients. There were differences in gene expression profiles in 10 matched FNAB and CBX sample pairs. Genes that were expressed differently in CBX samples, compared with FNAB samples, were recognized as being predominantly from the endothelium, fibroblasts, myofibroblasts or smooth muscle, and histiocytes. Corresponding microscopic cell counts from FNABs demonstrated means of 80% tumor cells, 15% lymphocytes, and 5% stromal cells, whereas CBXs contained 50% tumor cells, 20% lymphocytes, and 30% stromal cells. Considering that CBXs are approximately six-fold richer in nonlymphoid stromal cells than FNABs and that CBXs differentially express a set of recognized stromal genes, the authors used these biopsies to define a transcriptional profile of breast carcinoma stroma. A set of 120 genes differentially expressed in CBXs was assessed independently in a published breast carcinoma genomic database to classify breast carcinomas based on stromal gene expression. Subgroups of tumors with low or high stromal signal were identified, but there was no correlation with the development of systemic metastases within 5 years. CONCLUSIONS: Both FNAB and CBX yield a similar quality and quantity of total RNA and are suitable for cDNA microarray analyses in approximately 70-75% of single-pass samples. Transcriptional profiles from FNAB and CBX of the same tumor generally are similar and are driven by the tumor cell population. The authors concluded that each technique has relative advantages. The FNABs provide transcriptional profiles that are a purer representation of the tumor cell population, whereas transcriptional profiles from CBXs include more representation from nonlymphoid stromal elements. Selection of the preferred needle biopsy sampling technique for genomic studies of breast carcinomas should depend on whether variable stromal gene expression is desirable in the samples.