[Rich66]

Hum Cell. 1998 Sep;11(3):109-14.
[Cancer chemo-endocrine therapy and its cell biological basis]

[Article in Japanese]
Nishiya I.
Morioka Red Cross Hospital, Japan.
The aim of our cell kinetic studies is to better understand the effects of chemo-endocrine therapy at the cell biological and molecular level. Cancer cell growth is characterized by uncontrolled proliferation, resulting in DNA distribution pattern in which, at any time, more cells are not G1 phase but in S, G2 and M phase of a shortened cycle. In a recent progress, flow cytometry (FCM) has become a powerful tool for the quantitative analysis of cell cycle parameters by measuring nuclear DNA content in large cell population with high speed. With the aid of FCM in earlier work about 60-80% of ovarian cancers were found to contain aneuploid cells. Now, multi-parameter FCM linked to a computer is available to measure fluorescent intensities not only no base total DNA (Propidium iodide) but also A-T (Hoechst 33342) and G-C (Mithramycin) base pairs in solid cancer nuclei. Since cisplatinum (CDDP) is the most important drug in the treatment of ovarian cancer, we have studied the relationship of CDDP cytotoxicity, pertubations cell cycle kinetis and DNA damage in ovarian adenocarcinoma cells in vitro & in vivo. We employed both CDDP sensitive cell line (KFt) and resistant cell line (KFr) derived from human serous cystoadenocarcinoma of the ovary by Kikuchi et al (JNCI 1986). Comparing cell kinetic pertubations of experimental cells demonstrates a decrease in G1 phase cells concomitant increase in S phase cells. The KFr cells had distinctly a shorter S-phase block up to 24 hrs not A-T but G-C preference in a quick response followed repairing of DNA damage to 48 hrs. However, some fractions of CDDP resistant cell population showed a later onset of G2, M phase accumulation. Comparison with the increase in early S phase cells of KFr in detailed analysis suggests only those damaged cells that are not killed immediately may proceed to G1 phase and start into DNA synthesis in S phase. Measurement of labeling index (L. I.) with Bromodeoxyuridine (BrdU) support our interpretation of differences between sensitivity and resistance to anti-cancer drug. Additionally, we discuss a targeting chemotherapy by coupling cytotoxic drugs with estrogen based on increasing DNA damage into apoptosis and interferes with DNA repair process.

PMID: 10086273 [PubMed - indexed for MEDLINE]


Related?:


Here is the most recent research on pubmed by Rana (maybe explaining benefit of blocking estrogen with chemo in ER+):

Cancer Res. 2010 Feb 15;70(4):1731-40. Epub 2010 Feb 9.
Estrogen Suppresses MLK3-Mediated Apoptosis Sensitivity in ER+ Breast Cancer Cells.

Rangasamy V, Mishra R, Mehrotra S, Sondarva G, Ray RS, Rao A, Chatterjee M, Rana B, Rana A.
Authors' Affiliations: Department of Pharmacology and Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, Stritch School of Medicine, Loyola University Chicago, Maywood, Illinois; Department of Pathology, Scott and White Hospital and Texas A&M Health Science Center, College of Medicine, Temple, Texas; Division of Biochemistry, Department of Pharmaceutical Technology, Jadavpur University, Kolkata, India; and Hines Veterans Affairs Medical Center, Hines, Illinois.
Little knowledge exists about the mechanisms by which estrogen can impede chemotherapy-induced cell death of breast cancer cells. 17beta-Estradiol (E(2)) hinders cytotoxic drug-induced cell death in estrogen receptor-positive (ER(+)) breast cancer cells. We noted that the activity of the proapoptotic mixed lineage kinase 3 (MLK3) kinase was relatively higher in estrogen receptor-negative (ER(-)) breast tumors, suggesting that E(2) might inhibit MLK3 activity. The kinase activities of MLK3 and its downstream target, c-Jun NH(2)-terminal kinase, were rapidly inhibited by E(2) in ER(+) but not in ER(-) cells. Specific knockdown of AKT1/2 prevented MLK3 inhibition by E(2), indicating that AKT mediated this event. Furthermore, MLK3 inhibition by E(2) involved phosphorylation of MLK3 Ser(674) by AKT, attenuating the proapoptotic function of MLK3. We found that a pan-MLK inhibitor (CEP-11004) limited Taxol-induced cell death and that E(2) accentuated this limitation. Taken together, our findings indicate that E(2) inhibits the proapoptotic function of MLK3 as a mechanism to limit cytotoxic drug-induced death of ER(+) breast cancer cells. Cancer Res; 70(4); 1731-40.

PMID: 20145118 [PubMed - in process]




Breast Cancer Res. 2010 Jun 28;12(3):R43. [Epub ahead of print]
The estrogen receptor influences microtubule-associated protein tau (MAPT) expression and the selective estrogen receptor inhibitor fulvestrant downregulates MAPT and increases the sensitivity to taxane in breast cancer cells.

Ikeda H, Taira N, Hara F, Fujita T, Yamamoto H, Soh J, Toyooka S, Nogami T, Shien T, Doihara H, Miyoshi S.
Corresponding author: Naruto Taira ntaira@md.okayama-u.ac.jp

FREE TEXT


ABSTRACT:

INTRODUCTION: Microtubule-associated protein tau (MAPT) inhibits the function of taxanes and high expression of MAPT decreased the sensitivity to taxanes. The relationship between estrogen receptor (ER) and MAPT in breast cancer is unclear. In this study, we examined the correlation of MAPT expression with the sensitivity of human breast cancer cells to taxanes, and the relationship between ER and MAPT. METHODS: The correlation between MAPT expression and sensitivity to taxanes was investigated in 12 human breast cancer cell lines. Alterations in cellular sensitivity to taxanes were evaluated after knockdown of MAPT expression. ER expression was knocked down or stimulated in MAPT- and ER-positive cell lines to examine the relationship between ER and MAPT. The cells were also treated with hormone drugs (fulvestrant and tamoxifen) and taxanes. RESULTS: mRNA expression of MAPT did not correlate with protein expression or the sensitivity to taxanes. However, expression of MAPT protein isoforms of less than 70 kDa was correlated with a low sensitivity to taxanes. Downregulation of MAPT increased cellular sensitivity to taxanes. MAPT protein expression was decreased by downregulation of ER and by fulvestrant, an ER inhibitor; but increased by stimulation with 17-beta-estradiol or tamoxifen. The combination of fulvestrant with taxanes had a synergistic effect, whereas tamoxifen and taxanes had an antagonistic effect. CONCLUSIONS: Expression of MAPT protein isoforms of less than 70 kDa is correlated with a low sensitivity to taxanes in breast cancer cells. ER influences MAPT expression and fulvestrant increased the sensitivity to taxanes in MAPT- and ER-positive breast cancer cells.

PMID: 20579400 [PubMed - as supplied by publisher]

Several mechanisms of taxane resistance have been described, including overexpression of the drug efflux pump MDR-1/P-gp, HER-2 overexpression, tubulin mutation, and variable expression of tubulin isotypes and stathmin [4, 7-12]. Microtubule-associated protein-tau (MAPT), which is implicated in the pathogenesis of Alzheimer’s disease, is associated with another mechanism of taxane resistance. MAPT binds to both the outer and inner surfaces of microtubules, leading to tubulin assembly and microtubule stabilization. Since
taxanes also bind to the inner surface of microtubules, MAPT obstructs the function of the drug [5, 6, 13, 14].
Rouzier et al. found that low MAPT expression was associated with higher rates of a pathologic complete response to preoperative paclitaxel and 5-fluorouracil, doxorubicin, cyclophosphamide (paclitaxel/FAC) chemotherapy [5]. This group also showed that MAPT overexpression was correlated with resistance to paclitaxel and that knockdown of MAPT with small interfering RNA (siRNA) reversed the resistance to taxanes in vitro [5].

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Hormonal drugs play an important role in breast cancer therapy. The selective ER inhibitor, fulvestrant, inhibits estrogen signaling through the ER in two ways: by competing with estradiol binding to the ER, and by increasing the turnover of ER to decrease the ER protein level in breast cancer cells. In contrast, tamoxifen, a selective ER modulator, is an ER antagonist but often displays estrogen-like agonist activity [22-24].
Previous in vitro studies show that tamoxifen has an antagonistic effect on anti-cancer drugs [25, 26]. Several clinical studies that used tamoxifen for hormone therapy have found that it has an antagonistic effect on chemotherapy drugs when it is used concurrently with them, and that the results of the combined use of tamoxifen with chemotherapy drugs is inferior, compared with using the drugs sequentially [27-30]. The effect of combination treatment using other modern hormone therapies, such as aromatase inhibitors or
fulvestrant, has not been examined thoroughly.

Our results suggested that the effect of tamoxifen on ER signaling differs depending on the dose. MAPT protein expression was increased at low concentrations of tamoxifen of 500 nM - 1 μM, but decreased at higher concentrations. Several factors associated with resistance to chemotherapy via regulation by ER signaling have been identified [4, 22, 38-40]. Tamoxifen is thought to exert an antagonistic effect in concomitant use with chemotherapeutic drugs by increasing the expression of these factors via an agonistic effect on the ER. Active metabolites of tamoxifen also have different functions compared with the parent drug [41-43], and more detailed studies are needed to
determine how tamoxifen and its metabolites influence chemotherapy in vivo and in vitro.
Fulvestrant decreased ER and MAPT expression at all concentrations. An MTS assay, flow cytometry, and immunofluorescence all showed that the combination of fulvestrant and taxanes had a synergistic effect, consistent with the finding of Sui et al. that fulvestrant combined with paclitaxel was effective in breast cancer cells in vitro [24]. Fulvestrant assists taxane function by downregulating the ER and ER-regulated factors associated with taxane resistance, and the combination of fulvestrant with taxanes increases the sensitivity of MAPT- and ER-positive breast cancer cells to taxanes.
ER-positive breast cancers clinically show a lower sensitivity to chemotherapy than do ER-negative breast cancers. This may be caused by the ER itself or by ER modulation of factors that result in resistance to chemotherapy. Our study indicates that the combination of modern hormone therapy with modern chemotherapy may become an effective therapy to ER-positive breast cancers.

Br J Cancer. 2008 Nov 18;99(10):1564-71. Epub 2008 Oct 21.
Preoperative bevacizumab combined with letrozole and chemotherapy in locally advanced ER- and/or PgR-positive breast cancer: clinical and biological activity.


Torrisi R, Bagnardi V, Cardillo A, Bertolini F, Scarano E, Orlando L, Mancuso P, Luini A, Calleri A, Viale G, Goldhirsch A, Colleoni M.
Department of Medicine, Research Unit of Medical Senology, European Institute of Oncology Milan, Milan, Italy. rosalba.torrisi@ieo.it
The antiangiogenic agent bevacizumab showed synergistic effects when combined with chemotherapy in advanced breast cancer. We presently investigated the activity of bevacizumab in combination with chemotherapy, including capecitabine and vinorelbine, and endocrine therapy, including letrozole (+triptorelin in premenopausal women), as primary therapy for patients with ER and/or PgR > or =10% T2-T4a-c, N0-N2, M0 breast cancer. Biological end point included the proliferative activity (Ki67), whereas clinical end points were clinical response rate, pathological complete response (pCR) and tolerability. Circulating endothelial cells (CECs) and their progenitors, as surrogate markers of antiangiogenic activity, were measured at baseline and at surgery.Thirty-six women are evaluable. A clinical response rate of 86% (95% CI, 70-95) and no pCR were observed; Ki67 was significantly decreased by 71% (interquartile range, -82%, -62%). Toxicity was manageable: two grade 3 hypertension, four grade 3 deep venous thrombosis and no grade >2 proteinuria were observed. Treatment significantly decreased the percentage of viable CECs and prevented the chemotherapy-induced mobilisation of circulating progenitors. Basal circulating progenitors were positively associated with clinical response. In conclusion, bevacizumab is feasible and active in association with primary chemoendocrine therapy for ER-positive tumours in terms of proliferation inhibition, clinical response and antiangiogenic activity.

PMID: 18941458 [PubMed - indexed for MEDLINE]




Ann Oncol. 2006 Jan;17(1):65-73.
Improved disease-free survival with epirubicin-based chemoendocrine adjuvant therapy compared with tamoxifen alone in one to three node-positive, estrogen-receptor-positive, postmenopausal breast cancer patients: results of French Adjuvant Study Group 02 and 07 trials.

FREE TEXT

Namer M, Fargeot P, Roché H, Campone M, Kerbrat P, Romestaing P, Monnier A, Luporsi E, Montcuquet P, Bonneterre J; French Adjuvant Study Group.
Centre Antoine Lacassagne, Nice, France. moise.namer@wanadoo.fr
BACKGROUND: The purpose was to compare disease-free survival (DFS) between epirubicin-based chemoendocrine therapy and tamoxifen alone in one to three node-positive (N1-3), estrogen-receptor-positive (ER+), postmenopausal early breast cancer (EBC) patients. PATIENTS AND METHODS: We analyzed, retrospectively, 457 patients randomized in FASG 02 and 07 trials who received: tamoxifen alone (30 mg/day, 3 years); or FEC50 (fluorouracil 500 mg/m2, epirubicin 50 mg/m2, cyclophosphamide 500 mg/m2, six cycles every 21 days) plus tamoxifen started concurrently. Radiotherapy was delivered after the third cycle in FASG 02 trial, and after the sixth in FASG 07 trial. RESULTS: The 9-year DFS rates were 72% with tamoxifen and 84% with FEC50-tamoxifen (P = 0.008). The multivariate analysis showed that pathological tumor size >2 cm was an independent prognostic factor (P = 0.002), and treatment effects remained significantly in favor of chemoendocrine therapy (P = 0.0008). The 9-year overall survival rates were 78% and 86%, respectively (P = 0.11). In the multivariate model, there was a trend in favor of chemoendocrine therapy (P = 0.07). CONCLUSION: The addition of FEC50 adjuvant chemotherapy to tamoxifen significantly improves long-term DFS in N1-3, ER+ and postmenopausal women. Chemoendocrine therapy seems to be more effective than tamoxifen in terms of long-term survival.

PMID: 16361531 [PubMed - indexed for MEDLINE]




Breast. 2008 Dec;17(6):654-60. Epub 2008 Jul 1.
Preoperative concurrent chemo- and endocrine therapies for women with large operable breast cancer expressing steroid hormone receptors.

Torrisi R, Dellapasqua S, Ghisini R, Viale G, Veronesi P, Luini A, Intra M, Peruzzotti G, Rocca A, Balduzzi A, Cardillo A, Goldhirsch A, Colleoni M.
Research Unit in Medical Senology, European Institute of Oncology, Via Ripamonti 435, 20141 Milan, Italy. rosalba.torrisi@ieo.it
Preoperative chemotherapy and endocrine therapy yielded low pathological complete remission (pCR) rates in patients with endocrine responsive breast cancer. Patients with large operable (cT2-T3, N0-2, M0), ER > or =10% breast cancer were treated in two consecutive studies with preoperative chemotherapy (Study I: six courses of either fluorouracil, leucovorin, vinorelbine (FLN), or vinorelbine, cisplatin, and continuous infusion of fluorouracil (ViFuP), at the discretion of the treating physician; Study II: capecitabine and oral vinorelbine (CAVINO)). Concurrent letrozole (in association with triptorelin if premenopause) was given. Sixty-five (58 evaluable) and 55 (all evaluable) patients were enrolled in the two studies. In Study I there were 43 objective responders (74%, 95% CI 63-85%), three of whom had pCR. Thirty-nine objective responses (91%) and all pCR were observed in patients with tumors expressing ER > or =50%. In Study II 34 patients (62%, 95% CI 49-75%) had an objective response. Endocrine therapy administered together with new intravenous, containing regimens should be explored in the preoperative treatment of endocrine responsive breast cancer.

PMID: 18595702 [PubMed - indexed for MEDLINE]


Br J Cancer. 2009 Aug 18;101(4):598-604. Epub 2009 Jul 28.
Uracil-tegafur and tamoxifen vs cyclophosphamide, methotrexate, fluorouracil, and tamoxifen in post-operative adjuvant therapy for stage I, II, or IIIA lymph node-positive breast cancer: a comparative study.

Park Y, Okamura K, Mitsuyama S, Saito T, Koh J, Kyono S, Higaki K, Ogita M, Asaga T, Inaji H, Komichi H, Kohno N, Yamazaki K, Tanaka F, Ito T, Nishikawa H, Osaki A, Koyama H, Suzuki T.
Department of Surgery, Toho University School of Medicine, Sakura Hospital, 564-1 Shimoshizu, Sakura 285-8741, Japan. youngjinpark@sakura.med.toho-u.ac.jp
Erratum in:

• Br J Cancer. 2009 Sep 15;101(6):1031.

BACKGROUND: It has been reported that treatment with uracil-tegafur (UFT) has shown significantly better survival and relapse-free survival (RFS) than surgery alone. Therefore, we compared UFT with a combination therapy of cyclophosphamide, methotrexate, and fluorouracil (CMF) in patients who had undergone curative surgery for axillary lymph node-positive breast cancer. METHODS: A total of 377 node-positive patients with stage I, II, or IIIA disease were registered from September 1996 through July 2000 and were randomly assigned to either 6 cycles of CMF or 2 years of UFT. In both arms, tamoxifen (TAM) was concurrently administered for 2 years. The primary end point in this study was the non-inferiority of UFT to CMF. RESULTS: No statistically significant difference between the two groups was observed with regard to the 5-year RFS rate (72.2% in the UFT and 76.3% in the CMF). Adverse event profiles differed between the two groups, with a significantly lower incidence of leukopenia and anaemia in the UFT group, as well as anorexia, nausea/vomiting, stomatitis, and alopecia, which have implications for quality of life. CONCLUSION: UFT administered in combination with TAM holds promise in the treatment of lymph node-positive early breast cancer. On stratified analysis, the recurrence rate in the UFT group was found to be better in oestrogen receptor (ER)-positive patients. Tegafur-based treatment should be evaluated by a prospective randomised trial conducted in ER-positive patients.

PMID: 19638976 [PubMed - indexed for MEDLINE]





Tumori. 2009 Nov-Dec;95(6):804-7.
Inhibition of HER2/estrogen receptor cross-talk, probable relation to prolonged remission of stage IV breast cancer: a case report.

Tisman G.
Whittier Cancer Research Building, 13025 Bailey Street, Suite A, Whittier, CA 90601, USA. glennmd@gmail.com
Metastatic breast cancer to the liver is considered incurable. Though many patients with liver metastases may enjoy response to chemo-, immuno- and hormonal therapy, those so inflicted rarely remain disease-free from the time of diagnosis for longer than 6-11 months. New laboratory and clinical research identified that cross-talk between activation of the epidermal growth factor family of tyrosine kinase transduction pathways (EGF/HER2) and estrogen receptor (ER) activation plays a role in resistance to hormonal therapy. A 59-year-old woman with a 4.5-cm invasive ductal, ER-positive/PR-negative, grade III adenocarcinoma of the breast was treated with mastectomy. Staging revealed biopsy-proven liver metastases. Surgery was immediately followed with vinorelbine, trastuzumab, tamoxifen and exemestane. The patient underwent a bone scan and PET/CT documented complete remission. She has remained in complete remission for 7 years. It is proposed that a possible mechanism for prolonged remission of stage IV breast cancer in this patient may be related to suppression of EGF/HER2 by trastuzumab, thus inhibiting cross-talk-associated tamoxifen/estrogen withdrawal resistance.

PMID: 20210247 [PubMed - in process]






Mol Biol Rep. 2009 Sep 13. [Epub ahead of print]
The growth-inhibition effect of tamoxifen in the combination chemotherapeutics on the human cholangiocarcinoma cell line QBC939.

Liu ZH, He YP, Qin H.
Department of Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yishan Road, 200233, Shanghai, China.
In the individual application of adriamycin, mitomycin, vindesine and their combined application with tamoxifen for the pre-treatment of the human cholangiocarcinoma cell line QBC939, QBC939 was determined by MTT assay to investigate the inhibitive effect and its initial mechanism of TAM on cell growth. Growth cycle and apoptosis of each group were determined by flow cytometry. Concentration of ADM in QBC939 was detected by flow cytometry. The levels of their P-glycoprotein were detected by immunohistochemistry. The mRNA and protein levels of apoptotic-associated genes Bcl-2 and Bax were determined by western blot and real-time PCR. The inhibitive rates of adriamycin, mitomycin, vindesine to QBC939 and the apoptosis rates of QBC939 were enhanced after the pre-treatment of tamoxifen. Influence of tamoxifen in their growth cycle was not so obvious except vindesine group because of the increasing cell numbers of G (2)/M phase in which cells may be blocked. The contents of adriamycin in cells rose after the pre-treatment of tamoxifen. Expression level of the multi-drug resistant protein on cell surface was shown as (+). Furthermore, real-time PCR and Western blot analysis revealed an upregulation of Bcl-2 and a downregulation of Bax in QBC939 after the pre-treatment of tamoxifen. Therefore, tamoxifen may have the ability to enhance the relative sensitivity of QBC939 to chemotherapeutics.

PMID: 19757172 [PubMed - as supplied by publisher]





Gan To Kagaku Ryoho. 2006 Oct;33(10):1423-9.
[A randomized controlled study comparing uracil-tegafur (UFT)+tamoxifen (UFT+TAM therapy) with cyclophosphamide+adriamycin+5-fluorouracil (CAF therapy) for women with stage I , II, or IIIa breast cancer with four or more involved nodes in the adjuvant setting]

[Article in Japanese]
Inaji H, Sakai K, Oka T, Ozawa K, Saito Y, Senoo T, Taguchi T, Terasawa T, Nakao K, Mori T, Koyama H, Oshima A.
Osaka Medical Center for Cancer and Cardiovascular Diseases.
We performed a controlled study to compare the response to cyclophosphamide (CPA), adriamycin (ADM), and fluorouracil (5-FU) (CAF therapy) with that to uracil-tegafur (UFT) plus tamoxifen (TAM) (UFT+TAM therapy), when given as postoperative adjuvant therapy to women with breast cancer. The patients were registered from September 1991 through February 1995 at 51 institutions in the Kinki district of Japan. All patients had stage I, II, or IIIa breast cancer with four or more lymph-node metastases and underwent mastectomy. CAF therapy and UFT+TAM therapy were started within 4 weeks after surgery. CAF therapy consisted of CPA (100 mg/day) on days 1 to 14, followed by 2 weeks of rest, plus ADM (20 mg/m(2)/day) on days 1 and 8 and 5-FU (300 mg/m(2)/day) on days 1 and 8. A total of 6 courses were delivered. UFT+TAM therapy consisted of 3 years of UFT (400 mg/day) plus TAM (20 mg/day), given daily. CAF therapy and UFT+TAM therapy were each assigned to 82 patients. The 5-year survival rate was significantly higher in the UFT+TAM group (82.1%) than in the CAF group (66.2%; p=0.04, logrank test). The 5-year relapse-free survival rate was higher in the UFT+TAM group (61.8%) than in the CAF group (46.3%; p=0.07, logrank test). As for adverse events, the rates of leukopenia, anorexia, nausea and vomiting, general malaise, and hair loss were lower in the UFT+TAM group than in the CAF group. These results suggest that long-term treatment with UFT+TAM may be a useful alternative adjuvant therapy for the management of breast cancer, especially in elderly patients.

PMID: 17033231 [PubMed - indexed for MEDLINE]





Gan To Kagaku Ryoho. 2006 Oct;33(10):1423-9.
[A randomized controlled study comparing uracil-tegafur (UFT)+tamoxifen (UFT+TAM therapy) with cyclophosphamide+adriamycin+5-fluorouracil (CAF therapy) for women with stage I , II, or IIIa breast cancer with four or more involved nodes in the adjuvant setting]

[Article in Japanese]
Inaji H, Sakai K, Oka T, Ozawa K, Saito Y, Senoo T, Taguchi T, Terasawa T, Nakao K, Mori T, Koyama H, Oshima A.
Osaka Medical Center for Cancer and Cardiovascular Diseases.
We performed a controlled study to compare the response to cyclophosphamide (CPA), adriamycin (ADM), and fluorouracil (5-FU) (CAF therapy) with that to uracil-tegafur (UFT) plus tamoxifen (TAM) (UFT+TAM therapy), when given as postoperative adjuvant therapy to women with breast cancer. The patients were registered from September 1991 through February 1995 at 51 institutions in the Kinki district of Japan. All patients had stage I, II, or IIIa breast cancer with four or more lymph-node metastases and underwent mastectomy. CAF therapy and UFT+TAM therapy were started within 4 weeks after surgery. CAF therapy consisted of CPA (100 mg/day) on days 1 to 14, followed by 2 weeks of rest, plus ADM (20 mg/m(2)/day) on days 1 and 8 and 5-FU (300 mg/m(2)/day) on days 1 and 8. A total of 6 courses were delivered. UFT+TAM therapy consisted of 3 years of UFT (400 mg/day) plus TAM (20 mg/day), given daily. CAF therapy and UFT+TAM therapy were each assigned to 82 patients. The 5-year survival rate was significantly higher in the UFT+TAM group (82.1%) than in the CAF group (66.2%; p=0.04, logrank test). The 5-year relapse-free survival rate was higher in the UFT+TAM group (61.8%) than in the CAF group (46.3%; p=0.07, logrank test). As for adverse events, the rates of leukopenia, anorexia, nausea and vomiting, general malaise, and hair loss were lower in the UFT+TAM group than in the CAF group. These results suggest that long-term treatment with UFT+TAM may be a useful alternative adjuvant therapy for the management of breast cancer, especially in elderly patients.

PMID: 17033231 [PubMed - indexed for MEDLINE]




Gan To Kagaku Ryoho. 2000 Nov;27(13):2113-6.
[A case of advanced breast cancer that responded remarkably to chemotherapy]

[Article in Japanese]
Watanabe Y, Kaiga T, Ueda T, Fujii M.
1st Dept. of Surgery, National Hospital, Tokyo Disaster Medical Center.
The case of a 49-year-old woman with axillary lymph nodes, multiple bone and multiple lung metastases from advanced breast cancer is reported. The patient responded remarkably to combination chemo- and endocrine-therapy. This patient was discharged after receiving 2 cycles of cyclophosphamide, pirarubicin and 5'-DFUR, while continuing to receive daily oral doses of 5'-DFUR and MPA. The patient experienced few adverse effects during chemotherapy. The patient enjoys an improved quality of life. This combined regimen has been confirmed to be an effective treatment for patients in advanced stages of breast cancer.

PMID: 11103244 [PubMed - indexed for MEDLINE]




Chemother. 2010 Jun;22(3):201-4. Oral metronomic chemo-hormonal-therapy of metastatic breast cancer with cyclophosphamide and megestrol acetate.

Licchetta A, Correale P, Migali C, Remondo C, Francini E, Pascucci A, Magliocca A, Guarnieri A, Savelli V, Piccolomini A, Carli AF, Francini G.
Section of Medical Oncology, Department Giorgio Segre of Pharmacology, Siena University School of Medicine, Italy.



Abstract

Metronomic chemotherapy is an anticancer strategy which uses conventional cytotoxic drugs administered at very low dose in close intervals. We have designed a phase II trial to investigate the safety and antitumor activity of the newest metronomic chemo-hormonal-therapy with daily cyclophosphamide and twice daily megestrol acetate (mCM regimen) in patients with metastatic pretreated breast cancer.Twenty-nine pretreated post-menopausal patients with multiple metastatic sites were enrolled. four patients had a triple negative status, nineteen a positive hormonal ER and PgR status, and three ERB-B2 over-expression. Patients received treatment with cyclophosphamide (50 mg/daily day 1-21/q28) and fractionated megestrol acetate (80 mg twice a day). The overall objective response rate was 31.0%, disease control rate 41.3%, mean time to tumor progression 7.4 months (CI 95%, 3.8-10.88, range 1-48 months) and mean overall survival 13.4 months (CI 95%, 7.24-17.18, range 1-53 months). The mCM regimen was active and well tolerated.

PMID: 20566427 [PubMed - in process]









Gan To Kagaku Ryoho. 2000 Dec;27(14):2235-8.
[A case of breast cancer with multiple organ metastases responding remarkably to combination therapy of CAF (cyclophosphamide, adriamycin and 5-FU), 5'-DFUR and MPA (medroxyprogesterone acetate)]

[Article in Japanese]
Maruyama S, Okumoto T, Kawasaki K, Ino H, Kanaya Y, Otani J, Yokoyama N, Soda M.
Dept. of Surgery, Himeji St. Mary's Hospital.
A 52-year-old woman complaining of breast tumor was diagnosed as having advanced breast cancer (T4bN1M1-Stage IV), with metastasis of multiple organs (lung, liver, mediastinal and unilateral axillary lymph nodes) after which she underwent tumorectomy. Postoperative adjuvant therapy was performed using combined chemoendocrine therapy (CAF + 5'-DFUR + MPA). Following the endocrine therapy, the metastatic lesions of the liver and lung had disappeared. The adverse effects were not remarkable. Complete remission was continued for 2 years and 3 months, and the patient enjoyed a favorable quality of life.

PMID: 11142168 [PubMed - indexed for MEDLINE]





Gan To Kagaku Ryoho. 1999 Jun;26(7):983-7.
[Effective chemo-endocrine combination therapy for obstructive-jaundice caused by multiple liver metastasis of recurrent breast cancer--a case report]

[Article in Japanese]
Hoshino K, Nakamura M, Ikeda H, Koyama T, Morishita Y.
Dept. of Surgery, Imai Hospital.
A 68-year-old woman complained of obstructive jaundice 9 years after a radical mastectomy. CT scan demonstrated multiple metastasis of the liver and two coin lesions of the right lung. The biliary tract was completely obstructed at the portal fissure. Multiple liver and lung metastasis of breast cancer were diagnosed because of high CA 15/3 serum levels and normal gastrointestinal study. Following unsuccessful treatment with tamoxifen (TAM), we used toremifene (TORE) and 5'-deoxy-5-fluorouridine (5'-DFUR) followed by percutaneous transhepatic cholangiodrainage (PTCD). The biliary tract was reopening and jaundice disappeared with improvement of the general condition. Then endocrine therapy with medroxy progesterone acetate and UFT and chemotherapy with CAF (Cyclophosphamide, Adriamycin, 5-FU) were begun. A partial response (PR) was obtained with the disappearance of liver metastasis and two coin lesions of the lung 5 months after the first treatment. The effect of chemo-endocrine combination therapy continued for 5 months. Survival time from recurrence was 13 months. In our case, PR was obtained by using chemo-endocrine combination therapy, although a poor prognosis has been reported in patients with obstructive jaundice caused by multiple liver metastasis of recurrent breast cancer.

PMID: 10396328 [PubMed - indexed for MEDLINE]



Jpn J Clin Oncol. 1999 Aug;29(8):390-4.
Multiple liver metastases of breast cancer: report of a case successfully treated with hormone-cytokine-chemotherapy.

Naomoto Y, Sadamori H, Matsukawa H, Shirakawa Y, Yamatsuji T, Saito S, Hino N, Isozaki H, Takakura N, Tanaka N.
First Department of Surgery, Okayama University Medical School, Japan.
The prognosis of patients with hepatic metastasis from breast cancer is usually extremely poor. We present the case of a 39-year-old Japanese woman diagnosed with multiple liver metastasis from breast cancer. A novel approach consisting of hormone-cytokine-chemotherapy with an arterial infusion therapy was carried out. Computed tomography and ultrasonography revealed that the multiple liver metastases were reduced with remaining calcification. Tumor markers decreased rapidly. Complete regression was achieved after these treatments. To date, there has been no relapse during the 8-year follow-up period. These results suggest that the hormone-cytokine-chemotherapy might be a rational modality of treatment against multiple metastatic breast cancer.

PMID: 10494924 [PubMed - indexed for MEDLINE]



Gan To Kagaku Ryoho. 2007 Jan;34(1):69-72.
[A patient with advanced breast cancer refractory to chemotherapy accompanied by carcinomatous pleurisy and multiple bone metastasis that responded to combination therapy with high-dose toremifene and docetaxel]

[Article in Japanese]
Suzuki M.
Dept. of Surgery, Yamagata Prefectural Nihonkai Hospital.
The patient was a 76-year-old woman, who found a mass in her left breast around summer of 2003 but ignored it. She visited our hospital in April 2004 because of dyspnea and low-back pain. As there was a mass accompanied by partial ulceration all over the left precordium and bilateral pleural effusion, she was admitted for further evaluation and treatment. The patient was judged to be almost in a life-threatening condition, and thus thoracentesis was performed to remove pleural fluid, and chemotherapy with FEC was also performed. In addition, the patient was placed on oral exemestane (EXE). After four courses of therapy with FEC were completed, the drug was changed to paclitaxel (PTX) and chemotherapy was continued for another 3 months. It was confirmed that the tumor size had been reduced markedly and that the volume of pleural effusion had not increased. The patient was in a state of remission for a short time, but subsequently the tumor size increased again and the tumor bled continually in small amounts. The chemotherapeutic drug was changed to capecitabine, while EXE, which had been continued, was withdrawn and oral administration of 120 mg/day of toremifene (TOR) was started. However, the tumor size was not reduced. TOR was continued, while capecitabine was changed to docetaxel (DOC). Then, the tumor size was reduced again, until the breast became almost flat after 3 months and the patient no longer bled from the tumor. The volume of pleural effusion did not increase, nor did the patient have any more dyspnea. At present, she has been in a state of remission and is living at home with a certain QOL.


J Neurooncol. 2010 Jun 20. [Epub ahead of print]
Prolonged survival of neoplastic meningitis from breast cancer with letrozole and intrathecal methotrexate: a case report.

Peroukides S, Onyenadum A, Starakis I, Koutras A, Makatsoris T, Bouboukas G, Kalofonos H.
Department of Medical Oncology, School of Medicine, University of Patras, 26504 Rio, Patras, Greece, panio@upatras.gr.



Abstract

Neoplastic meningitis from breast cancer has a dismal prognosis and short survival. Treatment is based on the intrathecal administration of chemotherapeutic agents, cranial or craniospinal radiotherapy, and systemic chemotherapy. In this report we describe the case of a woman with neoplastic meningitis from breast carcinoma who developed an excellent response to letrozole combined with intrathecal methotrexate, resulting in long-term survival of more than 36 months. Based on the findings of this case report, we suggest that addition of letrozole to the standard therapeutic approach may be beneficial for some patients.

PMID: 20563832 [PubMed - as supplied by publisher]