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NCI CANCERLIT® Search: Chemotherapy for Breast Cancer - September 2001
Last Modified: November 1, 2001

Table of Contents

CancerMail from the National Cancer Institute

1
UI - 21224424
AU - Hassett G; Harnett P; Manolios N
TI - Scleroderma in association with the use of docetaxel (taxotere) for breast cancer.
SO - Clin Exp Rheumatol 2001 Mar-Apr;19(2):197-200
AD - Department of Rheumatology, Westmead Hospital, Australia.
The taxanes, paclitaxel (Taxol) and docetaxal (Taxotere), are a new class of anti-microtubule agents which have shown cytotoxic activity in a number of solid tumours. Phase I and II trials confirm that docetaxal is highly active in the treatment of metastatic breast cancer. Reported toxicities of docetaxel include, dose limiting neutropenia, alopecia, skin reactions and fluid retention. Here we report the first case of rapid onset, diffuse scleroderma-like illness, which occurred in a 59-year-old female receiving treatment with docetaxel for locally invasive and advanced metastatic breast cancer.

2
UI - 21236461
AU - Kasper CE; Sarna LP
TI - Influence of adjuvant chemotherapy on skeletal muscle and fatigue in women with breast cancer.
SO - Biol Res Nurs 2000 Oct;2(2):133-9
AD - School of Nursing, Johns Hopkins University, Baltimore, MD, USA.
The purpose of this pilot study was to investigate the changes in skeletal muscle size and strength and perception of fatigue in women undergoing adjuvant chemotherapy for breast cancer. The findings of this pilot study suggest that changes in muscle size and strength can occur during chemotherapy. Quadricep muscle size increased for two subjects. These subjects also experienced an increase in muscle strength. This is the first known study to address change in muscle size and fatigue in women during adjuvant chemotherapy for breast cancer from an integrated biobehavioral perspective. Our findings may indicate that muscle size can increase during chemotherapy, but this may not diminish the subjective experiences of fatigue. As the potential for causing serious damage to striated muscle exists, further research into muscle changes and activity during chemotherapy and its role in fatigue is crucial.

3
UI - 21388205
AU - Luo J; Soh JW; Xing WQ; Mao Y; Matsuno T; Weinstein IB
TI - PM-3, a benzo-gamma-pyran derivative isolated from propolis, inhibits growth of MCF-7 human breast cancer cells.
SO - Anticancer Res 2001 May-Jun;21(3B):1665-71
AD - Herbert Irving Comprehensive Cancer Center, Columbia Presbyterian Medical Center, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
Propolis has numerous biologic activities including antibiotic, antifungal, antiviral and anti-inflammatory properties. Several components isolated from propolis have been shown to have anticancer activity. This study demonstrates that the compound PM-3 (3-[2-dimethyl-8-(3-methyl-2-butenyl)benzopyran]-6-propenoic acid) isolated from Brazilian propolis markedly inhibits the growth of MCF-7 human breast cancer cells. This effect was associated with inhibition of cell cycle progression and induction of apoptosis. Treatment of MCF-7 cells with PM-3 arrested cells in the G1 phase and resulted in a decrease in the protein levels of cyclin D1 and cyclin E. PM-3 also inhibited the expression of cyclin D1 at the transcriptional level when examined in cyclin D1 promoter luciferase assays. Induction of apoptosis by PM-3 occurred within 48 hours after treatment of MCF-7 cells. The MCF-7 treated cells also displayed a decrease in the level of the estrogen receptor (ER) protein and inhibition of estrogen response element (ERE) promoter activity. Therefore, PM-3 merits further investigation with respect to breast cancer chemoprevention or therapy.

4
UI - 21388219
AU - Yang DC; Jiang XP; Elliott RL; Head JF
TI - Inhibition of growth of human breast carcinoma cells by an antisense oligonucleotide targeted to the transferrin receptor gene.
SO - Anticancer Res 2001 May-Jun;21(3B):1777-87
AD - Mastology Research Institute of The Elliott Mastology Center, Baton Rouge, LA 70816, USA. emcmri@iamerica.net
Transferrin receptor expression is controlled by the amount of iron required by the cell to maintain its metabolism and therefore tumor cells in a highly proliferative state have a high density of transferrin receptors. In this study, phosphorothioated antisense TfR oligonucleotides (TfR-ODna) targeted to the sequences of TfR mRNA including the AUG initiation codon and the control sense chain (TfR-ODns) were synthesized. The rate of cellular DNA synthesis was determined by [3H]-thymidine incorporation. Administering TfR-ODna to three morphologically distinct breast cancer cell lines (MCF-7, T47D, and MDA-MB-231) and a normal breast cell line (MCF-12A) caused specific inhibition of tumor cell growth. The IC50 (50% inhibition of DNA synthesis) of the TfR-ODna for the MCF-7, T47D and MDA-MB-231 cells were 0.5, 0.5, and 1.0 microM, respectively, whereas the MCF-12A normal breast cells were about 30 times (IC50 of 30 microM) less sensitive to TfR-ODna than the breast cancer cells. The cytotoxicity of the antisense TfR-ODna was 10 to 60 times greater than that of the sense chain (TfR-ODns). TfR mRNA and protein synthesis were demonstrated by RT-PCR and immunohistochemical staining, respectively. Approximately 50% inhibition of the expression of TfR mRNA was observed when breast cancer cells were treated with 1 microM antisense TfR ODNa for 72 hrs but 1 microM antisense only caused 14% inhibition in normal breast cells. The decreased cytotoxicity and inhibition of TfR gene expression when the tumor cells were treated with the same concentration (1 microM) of TfR-ODns demonstrated the specificity of the TfR-ODna for blocking the target TfR gene. The combined cytotoxicities to human breast tumor MCF-7 cells of the antisense TfR-ODna and the iron chelator deferoxamine (DFO) or the ribonucleotide reductase inhibitor hydroxyurea were observed in this study. IC50s (50% inhibition of DNA synthesis) for DFO and hydroxyurea individually were 0.3 microM and 250 microM, respectively. The CalcuSyn program was used to determine the combined effects among the agents and synergism (Combined Indexes (CI) < 1) were found with the following two combinations: TfR-ODna (0.007 microM to 0.15 microM) with DFO (0.15 microM to 5 microM) and TfR-ODna (0.007 microM to 0.15 microM) with hydroxyurea (50 microM to 800 microM). However, inhibition by TfR-ODns was not synergistic with either DFO or hydroxyurea. The synergistic effects on inhibition of DNA synthesis between TfR-ODna and DFO or hydroxyurea suggest that inhibition of breast cancer cell growth by TfR-ODna is produced by depletion of iron pools that are required for DNA synthesis in tumor cells. The fact that TfR-ODna specifically decreases cell viability and proliferation, and reduces TfR mRNA and protein expression in human breast carcinoma cells without affecting normal breast cells, suggests that the antisense oligonucleotide to the transferrin receptor may be a novel therapeutic approach in breast cancer.

5
UI - 21388246
AU - Fraifeld V; Seidman R; Sagi O; Muradian K; Wolfson M
TI - Aurintricarboxylic acid decreases proliferative potential of SKOV3 and MCF7 human carcinoma cells.
SO - Anticancer Res 2001 May-Jun;21(3B):1975-8
AD - Department of Clinical Pharmacology, Center for the Multidisciplinary Research in Aging, Ben-Gurion University of the Negev, Beer-Sheva, Israel. vadimfra@zahav.net.il
The effect of aurintricarboxylic acid (ATA) on cell growth and proliferative capacity was studied in human ovarian SKOV3 and breast MCF7 carcinoma cells. ATA moderately inhibited cell growth measured by a Neutral red assay after a 24-hour incubation of the cells in the presence of ATA. The ATA-treated cells displayed a markedly decreased capacity to proliferate, as was evident from a colony formation assay. The initial and delayed anti-proliferative effects of ATA were dose-dependent. Together, the results indicated that ATA offers the potential of being recognized as an anti-tumor drug, at least in certain types of cancers.

6
UI - 21388261
AU - Raaphorst GP; Cybulski SE; Sobol R; Ng CE
TI - The response of human breast tumour cell lines with altered polymerase beta levels to cisplatin and radiation.
SO - Anticancer Res 2001 May-Jun;21(3B):2079-83
AD - ORCC, Ottawa, Ontario, Canada.
MCF 7 (human breast carcinoma cells) and mutants transfected with the DNA polymerase beta gene were tested for response to cisplatin, radiation and combined treatments. The transfected cells showed a higher level of polymerase beta activity and were more resistant to radiation and cisplatin compared to the parental cell line. Further studies showed that for isosurvival treatments the mutant cells were more effective in sublethal radiation damage repair compared to the parental line. The combination of cisplatin with radiation showed effective radiosensitization which was less in the mutants compared to the parental line. In addition, the sequence of cisplatin before irradiation was more effective then cisplabn after irradiation. Pre-exposure to low levels of cisplatin for up to 24 h before irradiation showed a small significant adaptive response in one mutant line at 8 h and while similar trends were observed in the parental lines at earlier times they were not significant. In summary our data show that polymerase beta and thus base excision repair may play a role in cellular responses to cisplatin and radiation.

7
UI - 21395115
AU - Tartarone A; Sirotova Z; Aieta M; Lelli G
TI - Salvage treatment with epirubicin and/or paclitaxel in metastatic breast cancer patients relapsed after high-dose chemotherapy with peripheral blood progenitor cells.
SO - Tumori 2001 May-Jun;87(3):134-7
AD - Division of Oncology, Ospedale Casa Sollievo della Sofferenza, San Giovanni Rotondo (FG), Italy.
AIMS AND BACKGROUND: To evaluate feasibility and efficacy of paclitaxel as a single agent or in combination with epirubicin in breast cancer taxane-naive patients who have failed previous high-dose chemotherapy. METHODS: Since February 1995, we have treated 32 patients in first relapse or progression after high-dose chemotherapy. Nineteen patients had metastatic breast cancer, 12 more than 3 involved axillary lymph nodes, and 1 inflammatory breast cancer at inclusion to the program. The median time to relapse after high-dose chemotherapy was 12 months (range, 2-43). At relapse, 12 patients were treated with epirubicin (90 mg/m2) plus paclitaxel (175 mg/m2) administered on day 1 every 21 days. In 20 patients who had previously received more than 350 mg/m2 of a cumulative dose of epirubicin and in one patient pretreated with chemotherapy containing mitoxantrone, we employed paclitaxel (175 mg/m2) alone. A median number of five courses was administered (range, 2-10). RESULTS: The overall response rate after 3 courses (29 of 32 patients were assessable) was 55% and after 6 courses (21 of 32 patients were assessable) was 57%. The median time to progression was 7 months (95% CI, 5.7-9.2), and median survival was 27.5 months (95% CI, 17.8-37.0). Toxicity was recorded for 180 cycles (epirubicin + paclitaxel for 62 cycles and paclitaxel alone for 118 cycles). The main toxicity in both regimens was hematologic. We observed WHO grade 3-4 neutropenia (in 8 patients, 25%), for which G-CSF (5 microg/kg/day s.c.) was employed. WHO grade 3-4 thrombocytopenia occurred in 2 patients (6%) and WHO grade 3 anemia in 1 patient (3%). CONCLUSIONS: Our study showed that paclitaxel (alone or in combination with epirubicin) is feasible as salvage treatment in heavily pretreated patients.

8
UI - 21395116
AU - Gori S; Mosconi AM; Tabilio A; Falzetti F; Aristei C; Basurto C; Cherubini R; Latini P; Martelli MF; Tonato M; Colozza M
TI - Results of a prospective study with high-dose etoposide, thiotepa and carboplatin and peripheral blood stem cell rescue for high-risk stage II-IIIA and selected stage IV breast cancer patients.
SO - Tumori 2001 May-Jun;87(3):138-41
AD - Medical Oncology Division, Policlinico Hospital, Perugia, Italy.
AIMS AND BACKGROUND: To investigate the safety and efficacy of a high-dose chemotherapy regimen with etoposide, carboplatin and thiotepa in high-risk stage II-IIIA breast cancer and in responsive metastatic patients. STUDY DESIGN: From April 1992 to December 1998, 24 patients with high-risk stage II-IIIA breast cancer (> or = 9 positive nodes) and 9 responsive metastatic patients were enrolled in the trial. After induction chemotherapy with an anthracycline-based regimen, peripheral blood stem cells were mobilized with cyclophosphamide (7 g/m2) and G-CSF (5-16 microg/kg/s.c./day). The high-dose chemotherapy regimen consisted of etoposide (1000 mg/m2), carboplatin (800 mg/m2) and thiotepa (500 mg/m2). At the end of the high-dose chemotherapy, all stage II-IIIA patients received radiotherapy to the breast or chest wall and draining nodes; stage IV patients were irradiated to sites of disease, if feasible. All ER+ and/or PgR+ patients were treated with hormone therapy. RESULTS: For stage II-IIIA high-risk patients, the median follow-up was 4.36 years (range, 1.93-6.94), and the Kaplan-Meier estimate at 5 years of disease-free survival and overall survival was 54.8 +/- 11% SE and 76.73 +/- 9.4% SE, respectively. For metastatic patients, the median follow-up was 4.93 years (range, 4.15-7.95), and the Kaplan-Meier estimate at 5 years of progression-free survival and overall survival was 22.2 +/- 13.9% SE and 76.2 +/- 14.8% SE, respectively. No treatment-related deaths were observed. CONCLUSIONS: Our results are comparable to those obtained in other high-dose chemotherapy trials but do not seem to be superior to conventional-dose therapy given to similar patients.

9
UI - 21395131
AU - Longo F; Mansueto G
TI - [Evolvement of hormone therapy for breast cancer. Florence, March 14, 2001]
SO - Tumori 2001 May-Jun;87(3):A6-14
AD - Oncologia Medica, Policlinico Umberto I, Roma.

10
UI - 21395065
AU - Bos AM; van der Graaf WT; Willemse PH
TI - A new conservative approach to extravasation of anthracyclines with dimethylsulfoxide and dexrazoxane.
SO - Acta Oncol 2001;40(4):541-2
AD - Department of Internal Medicine, University Hospital Groningen, The Netherlands. bosame@hotmail.com

11
UI - 21398073
AU - Elisaf MS; Bairaktari ET; Nicolaides C; Kakaidi B; Tzallas CS; Katsaraki A; Pavlidis NA
TI - Effect of letrozole on the lipid profile in postmenopausal women with breast cancer.
SO - Eur J Cancer 2001 Aug;37(12):1510-3
AD - Department of Internal Medicine, Medical School, University of Ioannina, GR 451 10 Ioannina, Greece. melisaf@cc.uoi.gr
Hormonal therapy plays a central role in the overall treatment of breast cancer. Aromatase inhibitors can inhibit the aromatase enzyme system resulting in a reduction of oestrogens. Letrozole is a non-steroidal aromatase inhibitor that effectively blocks aromatase activity without interfering with adrenal steroid biosynthesis. The drug can significantly reduce the levels of plasma oestrogens, which remain suppressed throughout the treatment. Data are scarce concerning the influence of these drugs on serum lipid levels. In the present study, we evaluated the effects of letrozole on the serum lipid profile in postmenopausal women with breast cancer. A total of 20 patients with breast cancer were treated with letrozole, 2.5 mg once daily. After an overnight fast, serum lipid parameters (total cholesterol, high density lipoprotein (HDL) cholesterol, low density lipoprotein (LDL) cholesterol, triglycerides, apolipoproteins A1, B and E and lipoprotein (a)) were measured before treatment and at 8 and 16 weeks afterwards. A significant increase in total cholesterol (P=0.05), LDL cholesterol (P<0.01) and apolipoprotein B levels (P=0.05) in the serum, as well as in the atherogenic risk ratios total cholesterol/HDL cholesterol (P<0.005) and LDL cholesterol/HDL cholesterol (P<0.005) was noticed after letrozole treatment. We conclude that letrozole administration in postmenopausal women with breast cancer has an unfavourable effect on the serum lipid profile.

12
UI - 21404773
AU - Anonymous
TI - Adjuvant therapy for breast cancer.
SO - NIH Consens Statement 2000 Nov 1-3;17(4):1-35
OBJECTIVE: To provide health care providers, patients, and the general public with a current consensus on various issues related to the use of adjuvant therapy for breast cancer. PARTICIPANTS: A nonfederal, nonadvocate, 14-member panel representing the fields of oncology, radiology, surgery, pathology, statistics, public health, health policy, and the public; 30 experts in medical oncology, molecular oncology, biostatistics, epidemiology, surgical oncology, and clinical trials who presented data to the consensus panel; a conference audience of approximately 1,000. EVIDENCE: The literature was searched using MEDLINE and an extensive bibliography of references was provided to the panel. Experts prepared abstracts with relevant citations from the literature. Scientific evidence was given precedence over clinical anecdotal experience. CONSENSUS PROCESS: The panel, answering predefined questions, developed their conclusions based on the scientific evidence presented in open forum and the scientific literature. The panel composed a draft statement that was read in its entirety and circulated to the experts and the audience for comment. Thereafter, the panel resolved conflicting recommendations and released a revised statement at the end of the conference. The panel finalized the revisions within a few weeks after the conference. The draft statement was made available on the World Wide Web immediately following its release at the conference and was updated with the panel's final revisions. CONCLUSIONS: During the past 10 years, substantial progress has been made in the treatment of invasive breast cancer. For the first time, breast cancer mortality rates are decreasing in the United States. Refinements of adjuvant treatment have contributed to this advance. Generally accepted prognostic and predictive factors include age, tumor size, lymph node status, histological tumor type, grade, mitotic rate, and hormonal receptor status. Novel technologies, such as tissue and expression microarrays and proteomics, hold exciting potential. Progress, however, will depend on proper design and analysis of clinical and pathological investigations. Decisions regarding adjuvant hormonal therapy should be based on the presence of hormone receptor protein in tumor tissues. Adjuvant hormonal therapy should be offered only to women whose tumors express hormone receptor protein. Because adjuvant polychemotherapy improves survival, it should be recommended to the majority of women with localized breast cancer regardless of nodal, menopausal, or hormone receptor status. The inclusion of anthracyclines in adjuvant chemotherapy regimens produces a small but statistically significant improvement in survival over non-anthracycline-containing regimens. Available data are currently inconclusive regarding the use of taxanes in adjuvant treatment of node-positive breast cancer. The use of adjuvant dose-intensive chemotherapy regimens in high-risk breast cancer and of taxanes in node-negative breast cancer should be restricted to randomized trials. Ongoing studies evaluating these treatment strategies should be supported to determine if they have a role in adjuvant treatment. Studies to date have included few patients older than 70 years. There is a critical need for trials to evaluate the role of adjuvant chemotherapy in these women. There is evidence that women with a high risk of locoregional tumor recurrence after mastectomy benefit from postoperative radiotherapy. This high-risk group includes women with four or more positive lymph nodes or an advanced primary cancer. Currently, the role of post-mastectomy radiotherapy for patients with one to three positive lymph nodes remains uncertain and should be tested in a randomized controlled trial. Individual patients differ in the importance they place on the risks and benefits of adjuvant treatments. Quality-of-life needs to be evaluated in selected randomized clinical trials to examine the impact of the major acute and long-term side effects of adjuvant treatments, particularly premature menopause, weight gain, mild memory loss, and fatigue. Methods to support shared decision-making between patients and their physicians have been successful in trials; they need to be tailored for diverse populations and should be tested for broader dissemination.

13
UI - 21401141
AU - Frasci G; D'Aiuto G; Comella P; Thomas R; Capasso I; Botti G; Cortino GR; De Rosa V; Comella G; Southern Italy Cooperative Oncology Group; National Tumor Institute of Naples
TI - Gemcitabine/cyclophosphamide/5-fluorouracil/folinic acid triplet combination in anthracycline- and taxane-refractory breast cancer patients: a Southern Italy Cooperative Oncology Group phase I/II study.
SO - Semin Oncol 2001 Jun;28(3 Suppl 10):50-6
AD - Division of Medical Oncology, Department of Radiology, National Tumor Institute, via Mariano Semmola 80131, Naples, Italy.
We sought to define the recommended dose of cyclophosphamide (CTX) for subsequent phase II assessment when combined with fixed doses of gemcitabine (Gemzar; Eli Lilly and Company, Indianapolis, IN) and 5-fluorouracil/folinic acid in metastatic breast cancer patients previously treated with anthracyclines and taxanes. Patients age 70 or less, with an Eastern Cooperative Oncology Group performance status 0 to 2, were enrolled. Patients received gemcitabine 1,000 mg/m(2), 5-fluorouracil 425 mg/m(2), folinic acid 100 mg/m(2), and escalating doses of CTX (in 100-mg/m(2) increments), starting at 500 mg/m(2), on days 1 and 8 every 3 weeks. Since March 1999, 46 patients, with a median age of 51 years (range, 38 to 74 years), entered the trial in seven cohorts. Cyclophosphamide dose escalation was stopped at 600 mg/m(2) when three of six patients experienced dose-limiting toxicity (one each with grade 3 thrombocytopenia, grade 3 neutropenia, and persistent grade 2 neutropenia), and then continued with granulocyte colony-stimulating factor support. The CTX dose of 800 mg/m(2) was proven safe and was chosen for phase II study. Two complete and 15 partial responses provided an overall response rate of 37% (95% confidence interval, 23% to 51%). Gemcitabine/CTX/5-fluorouracil/folinic acid is well tolerated by metastatic breast cancer patients pretreated with anthracyclines/taxanes, up to a CTX dose of 800 mg/m(2). The phase II study is ongoing. Semin Oncol 28 (suppl 10):50-56. Copyright 2001 by W.B. Saunders Company.

14
UI - 21401142
AU - Gomez H; Kahatt C; Falcon S; Santillana S; de Mendoza FH; Valdivia S; Vallejos C; Otero J; Pen DL
TI - A phase II study of neoadjuvant gemcitabine plus doxorubicin in stage IIIB breast cancer: a preliminary report.
SO - Semin Oncol 2001 Jun;28(3 Suppl 10):57-61
AD - Department of Medicine, Instituto de Enfermedades Neoplasicas, Avenida Angamos Este 2520, Lima 34, Peru.
The purpose of this ongoing study is to determine the response and safety of a combination of gemcitabine (Gemzar; Eli Lilly and Company, Indianapolis, IN) plus doxorubicin as neoadjuvant therapy for stage IIIB breast cancer. Thirty-nine chemotherapy-naive patients were enrolled in the study. The median age was 54 years (range, 32 to 74 years), and the median Karnofsky performance status was 100. Gemcitabine 1,200 mg/m(2) was given on days 1 and 8, and doxorubicin 60 mg/m(2) on day 1, followed by surgery or radiotherapy. Ninety-seven of 117 cycles (83%) were administered at full dose. An overall response rate of 95% was obtained, with a complete response in 18% (seven patients) and a partial response in 77% (30 patients). Twenty-eight patients (72%) underwent breast surgery after a maximum of three cycles of neoadjuvant therapy. World Health Organization grade 3/4 toxicities included leukopenia in nine cycles (8%), neutropenia in 16 cycles (14%), febrile neutropenia in 11 cycles (9%), and anemia in two cycles (2%). The most important nonhematologic toxicity was grade 2/4 mucositis in 16 cycles (14%), and/or grade 2/3 diarrhea in 10 cycles (9%). Neoadjuvant therapy with gemcitabine plus doxorubicin results in a high tumor response rate with moderate oral and hematologic toxicity. Semin Oncol 28 (suppl 10):57-61. Copyright 2001 by W.B. Saunders Company.

15
UI - 21416733
AU - Koshizuka K; Serizawa M; Mouri N; Muto S; Takano K; Tada Y; Nakagomi H; Hada M
TI - [Effect of weekly docetaxel in patients with recurrent breast cancer]
SO - Gan To Kagaku Ryoho 2001 Aug;28(8):1117-20
AD - Second Dept. of Surgery, Yamanashi Medical University.
A pilot trial was conducted to assess the tolerability and efficacy of a regimen with weekly docetaxel (TXT) in patients with metastatic breast cancer. The chemotherapy regimen consisted of a 30-minute weekly intravenous infusion of docetaxel (22-33 mg/m2/wk). Each 8-week cycle included 6 weekly treatments, followed by two weeks of rest. Thirteen patients were treated. All patients were evaluable for response: 0 CR (0%), 7 PR (53.8%), 3 NC (23.1%), 3 PD (23.1%). These results are almost the same as those with the administration of TXT (60 mg/m2) q3 wks. Toxicities observed were mild (< or = grade 2) and reversible, and included fatigue, nausea, neutropenia, and alopecia. This preliminary experience suggests a high level of clinical activity and excellent tolerability of the chemotherapy regimen at the given dose and schedule in patients with metastatic breast cancer.

16
UI - 21193591
AU - Garufi C; Nistico C; Brienza S; Vaccaro A; D'Ottavio A; Zappala AR; Aschelter AM; Terzoli E
TI - Single-agent oxaliplatin in pretreated advanced breast cancer patients: a phase II study.
SO - Ann Oncol 2001 Feb;12(2):179-82
AD - Service of Complementary Medical Oncology, Regina Elana Cancer Institute, Rome, Italy. garufi@sirio-oncology.it
PURPOSE: Oxaliplatin (L-OHP), a new platinum analogue, is an active drug in colorectal and ovarian cancer. In this phase II study we explored tolerability and activity of oxaliplatin as a single agent in metastatic breast carcinoma patients. PATIENTS AND METHODS: Fourteen anthracycline pretreated advanced breast cancer patients were enrolled. Oxaliplatin was given at 130 mg/m2 on day 1 and repeated every three weeks. Analysis of toxicity, response rate and survival was performed. RESULTS: The median number of courses per patient was four (range 2 6). The median administered dose-intensity was 43.3 mg/m2/week (range 32.5-43.3) which represents 100% of projected dose-intensity. No severe toxicity was encountered. Three patients developed acute transient laryngeal symptoms. Three patients displayed a partial response (21%), (95% confidence interval (CI): 0%-43%), two stable disease (14%) and nine progressed (64%). Response lasted five, four and five months respectively. Median survival was 12 months. CONCLUSIONS: In this limited experience, oxaliplatin appeared to be well tolerated and moderately active in advanced anthracycline-pretreated breast cancer patients. Combination chemotherapy with other active drugs such as 5-fluorouracil (5-FU), anthracyclines and taxanes should represent the next step of development of this new drug.

17
UI - 21193601
AU - Pierga JY; Robain M; Jouve M; Asselain B; Dieras V; Beuzeboc P; Palangie T; Dorval T; Extra JM; Scholl S; Pouillart P
TI - Response to chemotherapy is a major parameter-influencing long-term survival of metastatic breast cancer patients.
SO - Ann Oncol 2001 Feb;12(2):231-7
AD - Medical Oncology Department, Institut Curie, Paris, France. Jean-Yves.Pierga@curie.net
BACKGROUND: In cancer patients, correlation between response to chemotherapy and gain in survival remains debated. We addressed this question in a multivariate analysis evaluating response to chemotherapy as a factor influencing survival of patients with metastatic breast cancer. PATIENTS AND METHODS: From 1977 to 1992, 1430 patients included in eight consecutive prospective trials of anthracycline-based first-line chemotherapy in metastatic breast cancer, were available for assessment. Median follow-up was 155 months. RESULTS: Median survival from the date of randomisation was 24 months. Objective response rate was 63.6%. A complete response (CR) was achieved in 17% (249 patients). In a stepwise forward progression analysis objective response was the first independent prognostic factor for survival. Median survival time was 43 months for complete responders (CR), 29 months for partial responders (PR), 18 months for stable disease (SD), 5 months for progressive disease (PD). The probability of survival at 5 and 10 years was 35% and 15% for CR's and decreased to 18% and 6% for PR's. The timing of best response (at 4 or 8 months) was not related to outcome. CONCLUSIONS: Response to an anthracycline-based chemotherapy is a major independent prognostic factor in metastatic breast cancer. The use of this factor to investigate new drugs seems to be pertinent. The good prognosis of complete responders justifies further evaluation of new treatment strategies for this patient population.

18
UI - 21329010
AU - Turan C; Unal O; Dansuk R; Guzelmeric K; Cengizoglu B; Esim E
TI - Successful management of an ovarian enlargement resembling ovarian hyperstimulation in a premenopausal breast cancer patient receiving tamoxifen with cotreatment of GnRH-agonist.
SO - Eur J Obstet Gynecol Reprod Biol 2001 Jul;97(1):105-7
AD - Department of Obstetrics and Gynecology, Kartal Research Hospital, Petrol-is Mah. Batman Sok. No. 11, D 14, Toprakyol-Kartal, 81410, Istanbul, Turkey.
Tamoxifen use in breast cancer patients may cause ovarian cysts. This report presents a case of complex cyst resembling ovarian hyperstimulation in a premenopausal breast cancer patient receiving tamoxifen which resolved by administering monthly depot GnRH-agonist (GnRH-a) without abandoning the tamoxifen treatment.

19
UI - 21413563
AU - Luker KE; Pica CM; Schreiber RD; Piwnica-Worms D
TI - Overexpression of IRF9 confers resistance to antimicrotubule agents in breast cancer cells.
SO - Cancer Res 2001 Sep 1;61(17):6540-7
AD - Department of Radiology, Washington University Medical School, St. Louis, Missouri 63110, USA.
IRF9/p48/ISGF3gamma (IRF9) is an IFN regulatory factor that mediates signaling by type I IFNs (IFNalpha and IFNbeta). After single-step selection of breast adenocarcinoma cells in paclitaxel, differential display and single gene analysis demonstrated that transcriptional activation of IRF9 and other IFN-responsive genes, independent of IFN, corresponded with resistance to antimicrotubule agents. Transient overexpression of IRF9 reproduced the drug-resistance phenotype and induced expression of IFN-responsive genes. However, drug resistance was not induced by overexpression of Stat1 or Stat2, or treatment with IFNalpha per se. Using a donor-matched array of cDNA prepared from human tumor and normal tissue from a variety of organs, we observed overexpression of IRF9 in approximately one-half of breast and uterine tumors, which indicated that IRF9 may be important in signaling in these tumor types. These data identify a novel IFN-independent role for IRF9 in the development of resistance to antimicrotubule agents in breast tumor cells and may link downstream mediators of IFN signaling to drug resistance in human cancers.

20
UI - 20018253
AU - Jones S; Vogel C; Arkhipov A; Fehrenbacher L; Eisenberg P; Cooper B; Honig S; Polli A; Whaley F; di Salle E; Tiffany J; Consonni A; Miller L
TI - Multicenter, phase II trial of exemestane as third-line hormonal therapy of postmenopausal women with metastatic breast cancer. Aromasin Study Group.
SO - J Clin Oncol 1999 Nov;17(11):3418-25
AD - U.S. Oncology Research at Baylor-Sammons Cancer Center, Dallas, TX, USA.
PURPOSE: To assess the antitumor activity, safety, and hormone-suppressive effects of the irreversible aromatase inactivator, exemestane (Aromasin, Pharmacia & Upjohn, Kalamazoo, MI), administered as third-line hormone therapy to postmenopausal women with metastatic breast cancer that is refractory to tamoxifen and megestrol acetate. PATIENTS AND METHODS: Exemestane was administered at a dose of 25 mg/d orally until patients experienced disease progression. The efficacy and safety of exemestane were clinically and radiographically evaluated. The impact of exemestane treatment on tumor-related signs and symptoms was assessed. The effect of exemestane on serum levels of estrogens and other steroidal hormones was determined. RESULTS: Ninety-one patients were treated. There were four complete responses (CR) and eight partial responses (PR), for an objective response rate of 13% in the entire treated population. The overall success rate (CR, PR, or stable disease [SD] >/= 24 weeks) was 30%. The median duration of response and overall success was 9 months and 8 months, respectively. Most patients with CR/PR (83%; 10 of 12 patients) and SD >/= 24 weeks (80%; 12 of 15 patients) had improved or stable tumor-related signs and symptoms. Mean levels of circulating estrone (E(1)), estradiol (E(2)), and estrone sulfate decreased to 11%, 22%, and 13% of baseline levels, respectively (at week 8 or 16 of treatment). One half of the patients had undetectable E(1) and E(2) levels during treatment, including at the time of disease progression. Mild nausea (20% of patients) and hot flashes (20%) were the most common drug-related adverse events and were generally grade 1. CONCLUSION: Exemestane is an active and well-tolerated third-line hormonal therapy that represents a new treatment option for postmenopausal patients with advanced breast cancer that has become refractory to standard first- and second-line hormonal therapies.

21
UI - 20200492
AU - Kaufmann M; Bajetta E; Dirix LY; Fein LE; Jones SE; Zilembo N; Dugardyn JL; Nasurdi C; Mennel RG; Cervek J; Fowst C; Polli A; di Salle E; Arkhipov A; Piscitelli G; Miller LL; Massimini G
TI - Exemestane is superior to megestrol acetate after tamoxifen failure in postmenopausal women with advanced breast cancer: results of a phase III randomized double-blind trial. The Exemestane Study Group.
SO - J Clin Oncol 2000 Apr;18(7):1399-411
AD - Universitatsklinik, Frankfurt, Germany.
PURPOSE: This phase III, double-blind, randomized, multicenter study evaluated the efficacy, pharmacodynamics, and safety of the oral aromatase inactivator exemestane (EXE) versus megestrol acetate (MA) in postmenopausal women with progressive advanced breast cancer who experienced failure of tamoxifen. PATIENTS AND METHODS: A total of 769 patients were randomized to EXE 25 mg/d (n = 366) or MA (n = 403) 40 mg four times daily. Tumor response, duration of tumor control, tumor-related signs and symptoms (TRSS), quality of life (QOL), survival, and tolerability were evaluated. RESULTS: Overall objective response (OR) rates were higher in patients treated with EXE than in those treated with MA (15.0% v 12.4%); a similar trend was noted in patients with visceral metastases (13.5% v 10.5%). Median survival time was significantly longer with EXE (median not reached) than with MA (123.4 weeks; P =.039), as were the median duration of overall success (OR or stable disease > or = 24 weeks; 60.1 v 49.1 weeks; P =.025), time to tumor progression (20.3 v 16.6 weeks; P =.037), and time to treatment failure (16.3 v 15.7 weeks; P =.042). Compared with MA, there were similar or greater improvements in pain, TRSS, and QOL with EXE. Both drugs were well tolerated. Grade 3 or 4 weight changes were more common with MA (17.1% v 7.6%; P =.001). CONCLUSION: EXE prolongs survival time, time to tumor progression, and time to treatment failure compared with MA and offers a well-tolerated treatment option for postmenopausal women with progressive advanced breast cancer who experienced failure of tamoxifen.

22
UI - 20228913
AU - Horton R
TI - After Bezwoda.
SO - Lancet 2000 Mar 18;355(9208):942-3
AD - The Lancet, London, UK.

23
UI - 21179444
AU - Nabholtz JM
TI - Steroidal side effects of exemestane.
SO - J Clin Oncol 2001 Apr 1;19(7):2107-8

24
UI - 21239585
AU - Smith IC; Miller ID
TI - Issues involved in research into the neoadjuvant treatment of breast cancer.
SO - Anticancer Drugs 2001 Feb;12 Suppl 1():S25-9
AD - Department of Academic Radiology, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, UK. i.c.smith@abdn.ac.uk
Randomized studies have failed to find convincing evidence that neo-adjuvant chemotherapy results in improved overall survival. This may be related to limited efficacy of the regimens used. A sequence of an anthracycline-based primary chemotherapy followed by docetaxel has shown promising results which are briefly discussed. The assessment of the efficacy of neoadjuvant therapy should be based on the evaluation of pathological response and a simple, reproducible method of grading differential response would be of great value. Positive identification of tumor stroma is essential in defining pathological complete response (pCR). This paper presents a grading scheme based purely on microscopic assessment which classifies patients into five groups with significantly different disease-free and overall survival. A system dividing patients into only two groups, i.e. those with pCR or those with any evidence of invasive tumor, may lose information of prognostic value. Assessing the response of metastatic disease in the lymph nodes, as well as response of the primary tumor, may further refine our ability to identify those patients likely to gain most from neoadjuvant chemotherapy.

25
UI - 21230830
AU - Crivellari D; Pagani O; Veronesi A; Lombardi D; Nole F; Thurlimann B; Hess D; Borner M; Bauer J; Martinelli G; Graffeo R; Sessa C; Goldhirsch A; International Breast Cancer Study Group
TI - High incidence of central nervous system involvement in patients with metastatic or locally advanced breast cancer treated with epirubicin and docetaxel.
SO - Ann Oncol 2001 Mar;12(3):353-6
AD - Divisione di Oncologia Medica, Istituto Nazionale Tumori, Aviano, Italy. dcrivellari@ets.it
BACKGROUND: Clinically overt central nervous system (CNS) involvement occurs in 10%-15% of patients with advanced breast cancer. PATIENTS AND METHODS: The International Breast Cancer Study Group (IBCSG) conducted a dose-finding phase I trial of epirubicin (E) and docetaxel (D) as first-line therapy in advanced breast cancer patients. The study was expanded into a phase II at the recommended doses of E 90 mg/m2 and D 75 mg/m2 every three weeks. From July 1996 to May 1998, a total of 92 patients (median age 50 years) entered the two studies. RESULTS: Twenty-eight out of ninety-two patients treated with the combination of E and D (30%) developed CNS metastases (95% confidence limits, 26%-35%), which were cerebral in twenty-five patients, leptomeningeal in two, and both in one. Of these 28 patients, 19 (68%) had an objective response. Median time for the development of CNS metastases from the start of chemotherapy was 15 months (range 5-42), if excluding the 6 patients presenting CNS progression within 3 months from start of treatment. It is notable that 11 patients (39%) had progression in the CNS only. Median survival from appearance of brain metastases in the whole group was only three months (range 1-22). C-erbB-2 overexpression was found in 14 out of 16 patients (87%) in whom the assay was performed (3+ in 10, 2+ in 1 and 1+ in 3 cases). CONCLUSIONS: As anthracycline- and taxane-containing regimens are increasingly used both in the metastatic and in the adjuvant setting, a careful monitoring of any neurological symptom is advisable. Our preliminary observation on the possible increase of incidence of CNS involvement in patients with advanced breast cancer receiving this effective drug combination requires further evaluation.

26
UI - 21230833
AU - Sanguineti G; Del Mastro L; Guenzi M; Ricci P; Cavallari M; Canavese G; Stevani I; Venturini M
TI - Impact of chemotherapy dose-density on radiotherapy dose-intensity after breast conserving surgery.
SO - Ann Oncol 2001 Mar;12(3):373-8
AD - Department of Radiation Oncology, National Cancer Research Institute of Genoa, Italy.
PURPOSE: To evaluate if chemotherapy (CT) dose-intensification jeopardizes radiotherapy (RT) dose-intensity (DI). PATIENTS AND METHODS: From 1992 to 1997, 247 stage I-II breast cancer patients, treated with conserving surgery, were treated at the National Cancer Institute of Genoa in a randomized study comparing the same CEF regimen delivered every two weeks (CEF14) or three weeks (CEF21). RT was applied to the residual breast at a total dose of 50 Gy in five weeks. Allowance was made for treatment at 2.3 Gy per fraction in order to compensate for gaps (hypofractionation). Radiotherapy DI was expressed as the average total dose received each week, i.e., 'weekly dose-rate' (WDR). The effect of various tumour, treatment and patient-related factors on the endpoint (a delivered WDR of RT < 9.5 Gy) was investigated by univariate analysis. Factors found to have P-value < or = 0.20 were entered in multivariate analysis. RESULTS: All but three patients (244 of 247, 98.8%) received a cumulative total dose of RT within +/- 10% of that planned. Moreover, most of them (197 of 247, 79.8%) received an average WDR of > or = 9.5 Gy/wk. With univariate analysis the probability of WDR < 9.5 Gy/wk significantly correlated with age, menopausal status, concomitant administration of RT and CT, and white blood cell toxicity. Moreover, a positive effect on WDR was found in patients treated at 2.3 Gy per fraction. The type of treatment (CEF14 vs. CEF21) did not affect the probability of WDR < 9.5 Gy/wk. With multivariate analysis, age (< or = 55 vs. > 55 years, RR = 3.99, 95% CI: 1.89-8.42, P = 0.0003), RT fractionation (conventional vs. hypofractionation, RR = 0.32, 95% CI: 0.15-0.68, P = 0.017) and WBC toxicity (none vs. some, RR = 1.54, 95% CI: 1.06-2.22, P = 0.027) were independent predictors of WDR < 9.5 Gy. Regarding the CT-RT overlap, patients receiving more than two cycles of chemotherapy during radiotherapy had an increased risk of RT delay compared to other patients (RR = 3.74, 95% CI: 1.44-9.48, P = 0.0063). CONCLUSIONS: There is no evidence of a direct effect of CT dose-density on dose-intensity of RT. However, the concomitant use of CT and RT reduces the possibility of giving a full dose-intensity of RT.

27
UI - 21293157
AU - Xu J; Loo G
TI - Different effects of genistein on molecular markers related to apoptosis in two phenotypically dissimilar breast cancer cell lines.
SO - J Cell Biochem 2001 Apr 2-27;82(1):78-88
AD - Cellular and Molecular Nutrition Research Laboratory, Graduate Program in Nutrition, The University of North Carolina at Greensboro, Greensboro, North Carolina 27402-6170, USA.
The association between consumption of genistein-containing soybean products and lower risk of breast cancer suggests a cancer chemopreventive role for genistein. Consistent with this suggestion, exposing cultured human breast cancer cells to genistein inhibits cell proliferation, although this is not completely understood. To better understand how genistein works, the ability of genistein to induce apoptosis was compared in phenotypically dissimilar MCF-7 and MDA-MB-231 human breast cancer cells that express the wild-type and mutant p53 gene, respectively. After 6 days of incubation with 50 microM genistein, MCF-7 but not MDA-MB-231 cells, showed morphological signs of apoptosis. Marginal proteolytic cleavage of poly-(ADP-ribose)-polymerase and significant DNA fragmentation were also detected in MCF-7 cells. In elucidating these findings, it was determined that after 2 days of incubation with genistein, MCF-7 but not MDA-MB-231 cells, had significantly higher levels of p53. Accordingly, the expression of certain proteins modulated by p53 was studied next. Levels of p21 increased in both of the genistein-treated cell lines, suggesting that p21 gene expression was activated but in a p53-independent manner, whereas no significant changes in levels of the pro-apoptotic protein, Bax, were found. In MCF-7 cells, levels of the anti-apoptotic protein, Bcl-2, decreased slightly at 18-24 h but then increased considerably after 48 h. Hence, the Bax:Bcl-2 ratio initially increased but later decreased. These data suggest that at the genistein concentration tested, MCF-7 cells in contrast to MDA-MB-231 cells were sensitive to the induction of apoptosis by genistein, but Bax and Bcl-2 did not play clear roles. Copyright 2001 Wiley-Liss, Inc.

28
UI - 21303177
AU - Petit T; Borel C; Ghnassia JP; Rodier JF; Escande A; Mors R; Haegele P
TI - Chemotherapy response of breast cancer depends on HER-2 status and anthracycline dose intensity in the neoadjuvant setting.
SO - Clin Cancer Res 2001 Jun;7(6):1577-81
AD - Departments of Medical Oncology, Centre de Lutte Contre le Cancer Paul Strauss, 67085 Strasbourg Cedex, France. tpetit@strasbourg.fnclcc.fr
We evaluated the predictive value of a tumor's HER-2 status for chemotherapy response in the neoadjuvant setting and the effect of anthracycline dose intensity on this predictive value. HER-2 status was evaluated by immunochemistry on microbiopsy before neoadjuvant chemotherapy (monoclonal antibody CB-11; Novocastra) in 39 patients (group A) treated with FEC50 (500 mg/m(2) 5-fluorouracil, 50 mg/m(2) epirubicin, and 500 mg/m(2) cyclophosphamide) and 40 patients (group B) treated with FEC100 (500 mg/m(2) 5-fluorouracil, 100 mg/m(2) epirubicin, and 500 mg/m(2) cyclophosphamide). All tumors were stage II or noninflammatory stage III adenocarcinoma. Overall response rate (OR) was evaluated through ultrasound and mammographic measurements. Pathological complete response was evaluated by tumor excision and axillary node resection after six cycles of chemotherapy. Patient and tumor characteristics (age, tumor size, clinical nodal status, SBR grade, hormonal receptor status, and HER-2 expression) were similar in the two groups. In univariate analyses, anthracycline dose was the only factor predictive of response (OR = 61.5% with FEC50; OR = 82.5% with FEC100; P = 0.038). When anthracycline dose was correlated with HER-2 status, an OR of 73.9% was demonstrated in HER-2- tumors (tumors without HER-2 overexpression), and an OR of 12.5% was demonstrated in HER-2+ tumors (tumors with HER-2 with overexpression) in group A. In group B, an OR of 69.5% was demonstrated in HER-2- tumors, and an OR of 100% was demonstrated in HER-2+ tumors. There was no difference in OR for HER-2- tumors treated with FEC50 or FEC100 (P = 0.74). On the other hand, erbB-2+ tumors treated with FEC100 had a significantly better OR than HER-2+ tumors treated with FEC50 (P = 0.0003). In a multivariate analysis, the most powerful predictive factor of OR was a conditional variable associating anthracycline dose with HER-2 status. Low-dose anthracycline and HER-2+ predicted a poor OR, low- or high-dose anthracycline and HER-2- predicted an intermediate OR, and high-dose anthracycline and HER-2+ predicted a high OR. Our results merit additional studies, given the possibility for choosing anthracycline dose according to a tumor's HER-2 status.

29
UI - 21303178
AU - Kasimir-Bauer S; Mayer S; Bojko P; Borquez D; Neumann R; Seeber S
TI - Survival of tumor cells in stem cell preparations and bone marrow of patients with high-risk or metastatic breast cancer after receiving dose-intensive or high-dose chemotherapy.
SO - Clin Cancer Res 2001 Jun;7(6):1582-9
AD - University of Essen Medical School, Department of Internal Medicine (Cancer Research), West German Cancer Center, D-45122 Essen, Germany. sabine.kasimir-bauer@uni-essen.de
PURPOSE: We evaluated whether dose-intensive or high-dose chemotherapy can eliminate micrometastases in high-risk breast cancer patients. EXPERIMENTAL DESIGN: We monitored cytokeratin (CK)/17-1A positive cells in the bone marrow (BM) and peripheral blood stem cells (PBSC) and studied Her-2/neu serum levels of patients with locally advanced (n = 13; group 1) and metastatic breast cancer (n = 30; group 2) using immunomagnetic separation, immunocytochemistry, and ELISA. RESULTS: CK+ cells were found in the BM of 3 of 13 (23%) group 1 patients before but not after chemotherapy, resulting in an overall survival (OS) of 92% after a median follow-up of 33 months. Contamination of PBSC in 2 of

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