Chemo+endocrine, endocrine + endocrine

[Rich66]

(Let+Cyc or Nav, Cyc+ Meg Ace, Fulv+Dox or Pac or Etop or Vin or 5FU, TAM w/5FU or Mitoxantrone or Dox in ER+, w/Adriamycin or Taxotere or Cisplatin or mitomycin in ER-, w/Herceptin. MPA with 5FU,Torem+Doc,
Let+Fulv, Aromasin+TAM, rationale)



CHEMO + ENDOCRINE
(more ER+ issues here)

Clin Oncol. 2006 Aug 1;24(22):3623-8.
Randomized phase II trial of letrozole and letrozole plus low-dose metronomic oral cyclophosphamide as primary systemic treatment in elderly breast cancer patients.

FULL TEXT HERE

Bottini A, Generali D, Brizzi MP, Fox SB, Bersiga A, Bonardi S, Allevi G, Aguggini S, Bodini G, Milani M, Dionisio R, Bernardi C, Montruccoli A, Bruzzi P, Harris AL, Dogliotti L, Berruti A.
Breast Unit and Anatomia Patologica, Azienda Ospedaliera Istituti Ospitalieri Cremona, Italy.
PURPOSE: To investigate the activity of letrozole plus/minus oral metronomic cyclophosphamide as primary systemic treatment (PST) in elderly breast cancer patients. METHODS: One hundred fourteen consecutive elderly women with T2-4 N0-1 and estrogen receptor-positive breast cancer were randomly assigned to primary letrozole therapy (2.5 mg daily for 6 months) or a combination of letrozole plus oral cyclophosphamide (50 mg/daily for 6 months) in an open-labeled, randomized phase II trial. Tumor response was assessed clinically, and tumor Ki67 index and vascular endothelial growth factor (VEGF) -A levels were measured before and after treatment. RESULTS: Overall response rate was 71.9% (95% CI, 60.0 to 83.8) in the 57 patients randomly assigned to receive primary letrozole and 87.7% (95% CI, 78.6 to 96.2) in the 57 patients randomly assigned to receive letrozole plus cyclophosphamide. The difference in activity between treatment arms was predominantly confined to patients with ductal histology. There was a significantly greater suppression of Ki67 and VEGF-A expression in the letrozole/cyclophosphamide-treated group than in the letrozole-treated group, leading to lower Ki67 and VEGF expression at post-treatment residual histology (P = .03 and P = .002, respectively). CONCLUSION: Both letrozole and letrozole plus cyclophosphamide treatments appeared active as PST in elderly breast cancer patients. Metronomic scheduling of cyclophosphamide may have an antiangiogenic effect and the combination of letrozole plus cyclophosphamide warrants testing in a randomized phase III trial.

PMID: 16877730 [PubMed - indexed for MEDLINE]


Quote:

Chemotherapy efficacy is dependent mainly on proliferative activity, whereas endocrine therapies are cytostatic, so that an antagonistic interaction between the two treatment modalities is expected when they are administered concomitantly.14 The results of a large randomized clinical trial published recently are in line
with these assumptions.15
Because the target of the metronomic chemotherapy is not the proliferating cancer cells, this treatment modality could potentiate the efficacy of endocrine therapy.

Quote:

In this article, we explored the activity of the combination of LET-CYC administration as PST in elderly breast cancer patients as compared to standard LET. The response rate of 72% in patients randomly assigned to the LET arm was higher than the 60% obtained in a previous randomized trial with primary LET therapy.2 The different patient population and the longer exposure of our patients to LET (6 months v 4 months) can account for the observed difference.
The response rate obtained in the LET-CYCarm(88%) was high.
The study design was not aimed at testing the difference in response rates in the two treatment arms, and both passed the test of activity. However, the comparison with the randomized control arm indicates that the high activity of the experimental arm was not caused by a biased sample,22 and suggests that the addition of CYC is associated with an increase in the activity of LET in this patient population (OR, 2.79). Although these results are encouraging, they failed to be confirmed by pathCR, a known predictor of long-term outcome. pathCR was observed in two patients (3.5%), one in each arm. A very low pathCR with primary LET therapy (1.7%) was obtained in the randomized trial comparing LET versus tamoxifen,2 suggesting that this condition is not a sensitive end point for primary endocrine therapy. The addition of metronomic CYC failed to increase the pathCR rate. Others have also found that patients with ER tumors have a low propensity to obtain pathCR after chemotherapy.23,24

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]





Clin Cancer Res. 2009 Feb 1;15(3):1046-51.
Immunomodulation of FOXP3+ regulatory T cells by the aromatase inhibitor letrozole in breast cancer patients.

Generali D, Bates G, Berruti A, Brizzi MP, Campo L, Bonardi S, Bersiga A, Allevi G, Milani M, Aguggini S, Dogliotti L, Banham AH, Harris AL, Bottini A, Fox SB.
Molecular Oncology Laboratories, Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom.
PURPOSE: We have shown previously that tumor infiltration by FOXP3+ regulatory T cells (Treg) is associated with increased relapse and shorter survival of patients with both in situ and invasive breast cancer. Because estrogen regulates Treg numbers in mice and promotes the proliferation of human Tregs, we hypothesized that blocking estrogen receptor-alpha signaling would abrogate Tregs and be associated with response to hormonal therapy and increased survival. EXPERIMENTAL DESIGN: FOXP3+ Tregs were quantified in tumor samples collected at baseline by incisional biopsy and after 6 months at definitive surgery in 83 elderly breast cancer patients (T2-4 N0-1) enrolled in a randomized phase II trial based on 6 months of primary letrozole (2.5 mg/d) or 6 months of letrozole plus oral "metronomic" cyclophosphamide (50 mg/d). RESULTS: Treg number ranged from 0 to 380 (median, 30) before treatment and from 0 to 300 (median, 8) after treatment. There was a significant reduction in Tregs in letrozole and letrozole-cyclophosphamide patients (P < 0.0001 and P < 0.002, respectively) after treatment. Treg number at residual histology was inversely related with response (P < 0.03 and P = 0.50, respectively) and a greater Treg reduction was observed in responding patients (P < 0.03). CONCLUSION: This study suggests that aromatase inhibitors may have an indirect antitumor mechanism of action through reducing Tregs in breast tumors and may be of use in estrogen receptor-alpha-negative tumors in combination with immunotherapy approaches.

PMID: 19188178 [PubMed - indexed for MEDLINE]





Breast. 2010 Jan 28. [Epub ahead of print]
Preoperative therapy with trastuzumab and oral vinorelbine (+/- endocrine therapy) in patients with HER2-positive breast cancer.

Iorfida M, Bagnardi V, Balduzzi A, Dellapasqua S, Cardillo A, Luini A, Intra M, Minchella I, Veronesi P, Viale G, Goldhirsch A, Colleoni M.
Unit of Research in Medical Senology, European Institute of Oncology, Via Ripamonti 435, 20141, Milan, Italy; Department of Medicine, European Institute of Oncology Milan, via Ripamonti 435, Milan 20141, Italy.
BACKGROUND: Combined trastuzumab and intravenous vinorelbine yielded high clinical activity as preoperative treatment in patients (pts) with HER 2/neu positive breast cancer. PATIENTS AND METHODS: We tested a preoperative combination of trastuzumab with oral vinorelbine (oV) in pts with locally advanced (T2-T4 N0-3 M0) HER2-positive breast cancer. Trastuzumab was administered i.v q 3 wks and oV was administered at the dose of 55 mg/sqm on days 1 and 3 q 3 wks, for 8 courses. Pts with ER >/= 10% tumors received endocrine therapy with letrozole 2.5 mg/day, plus monthly triptorelin if premenopausal. RESULTS: Forty-five pts entered the study. The overall response rate (CR + PR) was 76% (95% CI: 60%-87%). pCR was observed in 4 pts (10%). Among ER-positive tumors 21/25 pts obtained a clinical response (84%) and two pts obtained a pCR (8%). CONCLUSIONS: The combination of trastuzumab and oral vinorelbine demonstrated encouraging activity in patients with HER 2 positive ER-positive tumors. Alternative strategies should be investigated in patients with endocrine non responsive disease. Copyright © 2010. Published by Elsevier Ltd.

PMID: 20117001 [PubMed - as supplied by publisher]




Text:
http://www.cinj.org/documents/PRAACR...hfield0309.pdf
Contact: Michele Fisher
Media Relations Specialist 732/235-9872
fisherm2@umdnj.edu

Researchers Find Way to Maximize Treatment for Estrogen Receptive Positive Breast Cancer

Study from The Cancer Institute of New Jersey Presented at 100^{th Annual AACR Meeting}

^{New Brunswick, N.J., April 20, 2009 – Researchers from The Cancer Institute of New Jersey (CINJ) are converging on Denver for the 100th Annual Meeting of the American Association for Cancer Research (AACR) to share their findings on a combined treatment targeting breast cancer that is stimulated by the hormone estrogen (estrogen receptive positive). They are joining other top investigators from around the globe for the event, which is highlighting interdisciplinary approaches to cancer research. CINJ is a Center of Excellence of UMDNJ-Robert Wood Johnson Medical School.
Among the abstracts being presented is one focusing on how the FDA-approved therapy fulvestrant can influence the effects of chemotherapy drugs on breast cancer cells. Fulvestrant is commonly used in postmenopausal women to treat estrogen receptive positive breast cancer that has spread to other parts of the body.
Breast cancers that respond to female hormones, such as estrogen, generate specific proteins that help tumor cells survive and grow. One such protein, HDM2, is known to be present in higher levels in many cancers including breast. These higher protein levels are strongly correlated with the presence of the estrogen receptor on breast cancer cells, which can affect how well chemotherapy works. Targeting the receptor is a common treatment for breast cancer.
Lead author Adriana V. Jager, PhD, a postdoctoral fellow at CINJ, and her colleagues focused on adding fulvestrant to the traditional chemotherapy agents doxorubicin, etoposide and paclitaxel, as fulvestrant is known to degrade the estrogen receptor and result in less stimulation of tumor cell growth. They found that in two estrogen receptor positive breast cancer cell lines, fulvestrant decreased HDM2 levels and enhanced the sensitivity of these cells to chemotherapy. This enhancement was better than either fulvestrant or chemotherapy alone.
According to the American Cancer Society, 183,000 cases of breast cancer were diagnosed nationwide last year, with 6,300 new cases in New Jersey alone. With such statistics, the team is hopeful that this laboratory-based research can be expanded to a clinical trial with patients in order to further explore improved outcomes.
The author team also includes William N. Hait, MD, PhD, Johnson and Johnson/Centocor; Deborah Toppmeyer, MD, CINJ; Bruce G. Haffty, MD, CINJ; Kim Hirshfield, MD, PhD, CINJ; and Jin-Ming Yang, PhD, Penn State.
The work represented by CINJ members is among the 6,000 abstracts being presented at the gathering, which is featuring more than 17,000 researchers, healthcare professionals, and patient advocates. The goal of the annual AACR event is to provide a forum in which the latest in cutting-edge laboratory, clinical and translational research can be shared.
About The Cancer Institute of New Jersey
The Cancer Institute of New Jersey (www.cinj.org) is the state’s first and only National Cancer Institute-designated Comprehensive Cancer Center, and is dedicated to improving the prevention, detection, treatment and care of patients with cancer. CINJ’s physician-scientists engage in translational research, transforming their laboratory discoveries into clinical practice, quite literally bringing research to life. The Cancer Institute of New Jersey is a center of excellence of UMDNJ-Robert Wood Johnson Medical School. To support CINJ, please call the Cancer Institute of New Jersey Foundation at 1-888-333-CINJ.
The Cancer Institute of New Jersey Network is comprised of hospitals throughout the state and provides a mechanism to rapidly disseminate important discoveries into the community. Flagship Hospital: Robert Wood Johnson University Hospital. Major Clinical Research Affiliate Hospitals: Carol G. Simon Cancer Center at Morristown Memorial Hospital, Carol G. Simon Cancer Center at Overlook Hospital, Jersey Shore University Medical Center. Affiliate Hospitals: Bayshore Community Hospital, CentraState Healthcare System, Cooper University Hospital*, JFK Medical Center, Raritan Bay Medical Center, Robert Wood Johnson University Hospital at Hamilton (CINJ at Hamilton), Saint Peter’s University Hospital, Somerset Medical Center, Southern Ocean County Hospital, The University Hospital/UMDNJ-New Jersey Medical School*, and University Medical Center at Princeton. *Academic Affiliate
###}




Cancer Res. 2007 Jun 1;67(11):5337-44.
Estrogen receptor alpha mediates breast cancer cell resistance to paclitaxel through inhibition of apoptotic cell death.

Sui M, Huang Y, Park BH, Davidson NE, Fan W.
Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, South Carolina 29425, USA.
Estrogen receptors (ER) are expressed in approximately 65% of human breast cancer. Cumulative data from clinical trials and retrospective analyses suggest that some chemotherapeutic agents may be less effective in patients with ER-positive (ER+) tumors than those with ER-negative (ER-) tumors. Paclitaxel is an active agent used in breast cancer chemotherapy. To investigate the possible influence of ER on the therapeutic efficacy of paclitaxel and its underlying mechanism, we established several isogenic ER+ cell lines by stable transfection of ERalpha expression vectors into ER- breast cancer BCap37 cells. We showed that 17-beta estradiol significantly reduces the overall cytotoxicity of paclitaxel in BCap37-expressing ERalpha but has no influence on the ER- parental cells. Further analyses indicate that expression of ERalpha in BCap37 cells mainly interferes with paclitaxel-induced apoptotic cell death, without affecting paclitaxel-induced microtubule bundling and mitotic arrest. Moreover, we found that the addition of ICI 182,780 (Fulvestrant), a selective ER down-regulator, could completely reverse the resistance of ER+ BCap37 cells to paclitaxel. These findings showed that ERalpha-mediated breast tumor cell resistance to paclitaxel was through selective inhibition of paclitaxel-induced tumor cell apoptosis. Additionally, the combination of ICI 182,780 also sensitizes MCF-7 and T47D cell lines to the treatment of paclitaxel, which further confirmed the correlation between ERalpha and drug resistance in ER+ tumor cells. The results obtained from this study provide useful information for understanding ER-mediated resistance to paclitaxel and possibly other antineoplastic agents.

PMID: 17545614 [PubMed - indexed for MEDLINE]

1: Breast Cancer Res Treat. 2009 Jul 22. [Epub ahead of print] Links

Fulvestrant (ICI 182,780) sensitizes breast cancer cells expressing estrogen receptor alpha to vinblastine and vinorelbine.

Sui M, Jiang D, Hinsch C, Fan W.
Program of Innovative Cancer Therapeutics, First Affiliated Hospital, Zhejiang University School of Medicine, 310003, Hangzhou, China.
Cumulative data suggest that some chemotherapeutic agents may be less effective in estrogen receptor alpha positive (ER+) breast tumors than ER negative (ER-) tumors, which has raised a clinically relevant question as to how to reverse this ER-mediated chemoresistance in ER+ breast tumors. This study is to investigate the possible influence of estrogen receptor alpha (ERalpha) on the therapeutic effects of vinblastine and vinorelbine on breast cancer cells and explore whether combination of anti-estrogen agent fulvestrant (ICI 182, 780) may enhance the sensitivity of ERalpha+ cells to these chemotherapeutic agents. Through comparing ER+ with ER- human breast tumor cells or through stable transfection of an ERalpha expression vector into ER negative human breast cancer BCap37 cells, a series of assays were applied to determine the sensitivity of ER+ and ER- breast tumor cells to vinblastine and vinorelbine in the presence or absence of 17-beta-estradiol and/or fulvestrant. 17-beta-Estradiol showed no effect on the sensitivity of ER- MDA-MB-468 and BCap37 cells to the treatment of vincristine or vinblastine, but it significantly reduced the sensitivity of ER+ T47D cells and BCap37 cells expressing ERalpha to the two drugs mentioned. Further analyses show that ERalpha has little effect on vinca alkaloids-induced mitotic arrest, but dramatically affects their ability to induce tumor cell apoptosis. Moreover, through a series of assays, we also demonstrated that the combination of fulvestrant, a selective ER down-regulator, could reverse the resistance of ER+ breast tumor cells to vinca alkaloids and even produce synergistic effects. The findings obtained from this study have provided important evidence that expression and subsequent activation of ERalpha are associated with resistance of breast cancer cells to vinca alkaloids. This study also suggested that the combination of anti-estrogen agents, such as fulvestrant, might be a novel strategy to reverse ER-mediated chemoresistance or sensitize ER+ breast tumors to vinca alkaloids and possibly other chemotherapeutic agents.

Surg Today. 1999;29(2):149-56.
Effects of experimental chemoendocrine therapy with a combination of a pure antiestrogen and 5-fluorouracil on human breast cancer cells implanted in nude mice.

Ogasawara Y, Doihara H, Shiroma K, Kanaya Y, Shimizu N.
Department of Surgery II, Okayama University Medical School, Japan.
The antitumor effects of an experimental chemoendocrine therapy combining a new pure antiestrogen ICI 182780 and 5-fluorouracil (5-FU) were studied on MCF-7 human breast cancer cells implanted in nude mice. ICI 182780 had a dose-dependent antitumor activity, which was potentiated by the concomitant use of 5-FU. When compared with the control group, the estrogen receptor (ER) level in the ICI 182780 group was lower and that in the combination group was markedly lower. Cell cycle analysis by flow cytometry (FCM) resulted in a lower percentage of S-phase cells (%S) in the treated mice. No significant difference was observed in the 5-FU concentrations in tumor cells, while the 5-FU content in RNA was significantly higher in the combination group. The changes in free thymidylate synthetase (TS) concentration indicated TS synthesis after the administration of 5-FU to be more greatly suppressed in the combination group than in the 5-FU group. These results suggest that ICI 182780 and 5-FU exert their combination effect mainly on ER-positive cells, and that the suppression of TS synthesis in tumor cells and the potentiation of the 5-FU-induced metabolic dysfunction of RNA are thus involved in the mode of action of this combination therapy.

PMID: 10030740 [PubMed - indexed for MEDLINE]





http://www.springerlink.com/content/9n75721824648854/

Cancer Chemother Pharmacol. 2009 May 20. [Epub ahead of print]
Preclinical rationale for combined use of endocrine therapy and 5-fluorouracil but neither doxorubicin nor paclitaxel in the treatment of endocrine-responsive breast cancer.

Kurebayashi J, Nukatsuka M, Sonoo H, Uchida J, Kiniwa M.
Department of Breast and Thyroid Surgery, Kawasaki Medical School, 577 Matsushima, Kurashiki, Okayama, 701-0192, Japan, kure@med.kawasaki-m.ac.jp.
PURPOSE: Our previous study indicated that concurrent administration of 4-OH-tamoxifen (TAM) and 5-fluorouracil (5-FU), but not doxorubicin (Dox), resulted in additive antitumor effects on endocrine-responsive breast cancer cells. We further clarified the effects of combined administration of endocrine therapy with chemotherapeutic agents in this study. METHODS: Concurrent treatment with 4-OH-TAM and paclitaxel (Ptx) was investigated in estrogen receptor (ER)-positive breast cancer cells. Additionally, the combined effects of estrogen depletion from culture medium mimicking estrogen ablative therapy with 5-FU, Dox, and Ptx were investigated. RESULTS: Concurrent treatment with 4-OH-TAM and Ptx yielded less than additive antitumor effects in ER-positive breast cancer cells, as observed with Dox in our previous study. More interestingly, estrogen depletion with 5-FU, but with neither Dox nor Ptx, yielded additive antitumor effects on these cells. We also performed preliminary experiments to elucidate the mechanisms of action responsible for the combined antitumor effects observed. Ptx up-regulated the level of expression of one of the molecules related to TAM resistance, Eph-A2, as observed with Dox in our previous study. Estrogen depletion down-regulated the level of expression of one of the molecules related to 5-FU resistance, thymidylate synthase, as observed with 4-OH-TAM in our previous study. CONCLUSIONS: These findings, together with those of our previous study, suggest that concurrent treatment with endocrine therapy, administration of TAM, or estrogen ablative therapy and 5-FU but neither Dox nor Ptx may yield additive antitumor effects on endocrine-responsive breast cancer.

PMID: 19455332 [PubMed - as supplied by publisher]




Cancer Chemother Pharmacol. 2007 Mar;59(4):515-25. Epub 2006 Aug 10.
Additive antitumor effect of concurrent treatment of 4-hydroxy tamoxifen with 5-fluorouracil but not with doxorubicin in estrogen receptor-positive breast cancer cells.

Kurebayashi J, Nukatsuka M, Nagase H, Nomura T, Hirono M, Yamamoto Y, Sugimoto Y, Oka T, Sonoo H.
Department of Breast and Thyroid Surgery, Kawasaki Medical School, 577 Matsushima, Kurashiki, Okayama, 701-0192, Japan. kure@med.kawasaki-m.ac.jp
PURPOSE: The sequential addition of tamoxifen (TAM) to chemotherapy seems superior to its concurrent addition in patients with breast cancer. This study was conducted to clarify the hypothesis that there are differential interactions among TAM and chemotherapeutic agents. METHODS: Estrogen receptor (ER)-alpha-positive or -negative breast cancer cells were treated with 4-hydroxy TAM (4OHT), 5-fluorouracil (FU) and/or doxorubicin (Dox). Changes in the expression levels of genes related to sensitivity and resistance to TAM, 5-FU or Dox were tested. RESULTS: Concurrent treatment of 4OHT with 5-FU but not with Dox additively inhibited the growth of ER-alpha-positive cells. 5-FU did not change the expression levels of any tested genes related to either sensitivity or resistance to TAM. Although Dox did not change the expression levels of any genes related to the sensitivity to TAM, Dox significantly increased the expression levels of some genes related to TAM resistance, Eph A-2, ER-beta, Fos and vascular endothelial growth factor. 4OHT significantly decreased thymidilate synthase (TS) activity. CONCLUSIONS: Although the antitumor effect of concurrent 4OHT and 5-FU was additive, that of concurrent 4OHT and Dox was less than additive in ER-alpha-positive cells. The increased expression of genes related to TAM resistance by Dox might be responsible for the interaction. Decreased TS activity by 4OHT might increase the antitumor activity of 5-FU. These findings may provide a preclinical rationale for concurrent use with 5-FU and TAM.

PMID: 16900372 [PubMed - indexed for MEDLINE]



In vivo and in vitro efficacy of capecitabine (X) + tamoxifen (TAM) in breast cancer (BC)

Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings (Post-Meeting Edition).
Vol 25, No 18S (June 20 Supplement), 2007: 21092

K. Mori, Y. Yamaguchi, N. Sawada, K. Kondoh and S. Hayashi Chugai Pharmaceutical Co, Kamakura, Japan; Saitama Cancer Center, Ina-machi, Japan; School of Medicine, Tohoku University, Sendai, Japan
21092
Background: In vitro studies in BC cell lines suggested antagonism between TAM and 5-FU. Thymidine phosphorylase (TP) activates X to 5-FU in tumors. X activity correlates with tumor TP concentrations in vivo. Methods: We studied antitumor efficacy of X + TAM in vivo and in vitro in human BC models. Nude mice were inoculated s.c. with estradiol, then MCF-7 cells 1 day later. When tumors were 300 mm³, mice received 6 weeks’ oral vehicle (control), X (d1–14 q21d) at MTD (539 mg/kg) or 2/3 MTD, and/or TAM at 100 or 30 mg/kg/d. We also analyzed impact of 5-FU and doxifluridine (5'-DFUR, an intermediate of X) + TAM on estrogen receptor (ER) signals in an in-vitro culture system. ER signals were monitored by expression of green fluorescent protein (GFP) in MCF-7 BC cells transfected with the estrogen-responsive element (ERE)-GFP gene (MCF-7-E10). GFP expression was induced in MCF-7-E10 cells in the presence of estradiol at 3 pM or BC tissue supernatant. Results: X at 2/3 MTD + TAM 30 mg/kg were significantly more active than the highest dose of X or TAM alone. Tumor TP concentrations were significantly higher in TAM- than vehicle-treated mice. In the ER signal system, GFP expression of MCF-7-E10 was reduced by 4-hydroxytamoxifen (4-OHT, active form of TAM) at 0.01 and 0.1 nM. When added to 4-OHT, 5-FU 0.3–30 µM or 5'-DFUR 3–10 µM reduced GFP expression more than either agent alone. In vitro, 5-FU and 5'-DFUR inhibited proliferation of MCF-7-E10 cells regardless of 4-OHT. Additive effects could not be confirmed as 4-OHT alone showed only marginal anti- proliferative activity at 0.01–0.1 nM. Conclusion: X and TAM are not antagonistic in this model. TAM may augment X activity via TP upregulation in BC tissues. TAM and X intermediates showed no clear antagonism in vitro in an ER signal system. All-oral X + TAM merits evaluation as combination therapy in breast cancer.




Br J Cancer. 1997;75(6):884-91.
Synergistic antiproliferative activity of tamoxifen and docetaxel on three oestrogen receptor-negative cancer cell lines is mediated by the induction of apoptosis.

FULL TEXT: http://www.ncbi.nlm.nih.gov/pmc/arti...00183-0110.pdf

Ferlini C, Scambia G, Distefano M, Filippini P, Isola G, Riva A, Bombardelli E, Fattorossi A, Benedetti Panici P, Mancuso S.
Department of Obstetrics and Gynecology, Catholic University of Sacred Heart, Rome, Italy.
The taxanes are a promising family of anti-tumour drugs that block cell cycle replication by interfering with the microtubule network. The clinical use of these drugs involves some problems related to their low solubility and occurrence of resistance, which is mainly dependent on the multidrug-resistant (MDR) phenotype. To investigate the possible interaction between docetaxel and tamoxifen (TAM), three oestrogen receptor-negative cancer cell lines, MDR- MDA-MB 231, MDR + CEM-VBLr and MCF-7 ADRr, were used. In all three cell lines, the combination of docetaxel and TAM was more effective in terms of growth inhibition than single drug exposure. Isobolic analysis confirmed the presence of synergism in all cell lines when docetaxel was used at 0.2 microM and TAM at a dose equal to or higher than 1 microM. Flow cytometric DNA analysis performed on the three cell lines showed that TAM was able to increase the G2/M blocking activity of docetaxel. This blocking activity was followed by an increased flow cytometric DNA fragmentation suggestive of the presence of apoptosis, which was confirmed by DNA gel fragmentation and morphological analysis. While an antagonistic effect on P-glycoprotein (P-gp) activity may contribute to the synergistic effect of tamoxifen and docetaxel on CEM-VBLr and MCF-7 ADRr, other mechanisms must be involved, as the synergistic effect is also apparent with a P-gp-negative cell line.

1: Biochem Pharmacol. 2005 Sep 1;70(5):725-32. Links

Modulation of epirubicin cytotoxicity by tamoxifen in human breast cancer cell lines. Ebtehal

El-Demerdash: ebtehal_dm@yahoo.com
Azab SS, El-Demerdash E, Abdel-Naim AB, Youssef E, El-Sharkawy N, Osman AM.
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, Egypt.

The present study was designed to investigate the modulatory effect of the anti-estrogen, tamoxifen (Tam) on epirubicin (Epi) cytotoxicity in breast cancer cell lines; MCF-7 and NCI-adr. Using sulphorhodamine-B assay, NCI-adr cell line was found to be five-folds more resistant to the cytotoxic effect of Epi as compared to MCF-7 cell line. Pretreatment of cells with Tam was observed to enhance Epi cytotoxicity by 4.3- and 6.5-folds in MCF-7 and NCI-adr cells, respectively. Tam-Epi interaction was found to be additive in MCF-7 cells and synergistic in NCI-adr cells. Flowcytometric DNA ploidy analysis revealed that, Epi induced cell arrest at G2/M phase. Tam pretreatment enhanced the blocking activity of low dose of Epi in MCF-7 and induced nearly two-fold increase in the percentage of S phase in NCI-adr cells. Determination of cellular Epi level revealed that Tam induced a significant increase in intracellular Epi accumulation only in NCI-adr cells after 48 h. However, analysis of P-gp function revealed that Tam failed to modulate P-gp function in both cell lines. Also, assessment of topoisomerae IIalpha gene expression showed that neither Epi nor Tam managed to change its expression level. In conclusion, Tam potentiates Epi cytotoxicity in sensitive and resistant breast cancer cell lines.enhancement of cell accumulation in S and G2/M phase, at which the cells are most sensitive to the cytotoxic effect This potentiation can be explained by an of Epi as well as an increase in the intracellular level of Epi in resistant cell line.
PMID: 16005435 [PubMed - indexed for MEDLINE

1: Cancer Lett. 1996 Nov 12;108(1):7-14. Links

Tamoxifen synergizes the antiproliferative effect of cisplatin in human ovarian cancer cells: enhancement of DNA platination as a possible mechanism.

Ercoli A, Scambia G, De Vincenzo R, Alimonti A, Petrucci F, Fattorossi A, Isola G, Benedetti Panici P, Caroli S, Mancuso S.
Department of Gynecology, Catholic University, Rome, Italy.
We investigated the chemosensitizing activity of tamoxifen (TAM) on estrogen receptor negative ovarian cancer cell lines sensitive (A2780 WT) and resistant to cisplatin (CP) (A2780 CP3). Our results showed that the treatment of both cell lines with the association TAM + CP (concentration range 0.01-1 microN and 0.1-1 microgram/ml, respectively) results in a synergistic antiproliferative activity and a complete reversal of the acquired CP-resistant phenotype. We demonstrated that in A2780 cells the addition of TAM to CP treatment is able to significantly enhance at every tested CP dose (P < 0.001) the amount of platinum (Pt) bound to the DNA. Since Pt-DNA levels in the genome are clearly related to the growth inhibitory effect of CP (correlation value = 0.97, P < 0.001) in our experimental model, we hypothesized that TAM could act synergistically with CP and overcome the acquired CP-resistance by enhancing Pt binding to the DNA. We suggest that, from a clinical point of view, TAM may be usefully included in CP-based chemotherapy regimens for ovarian cancer patients since plasma concentrations of the drug capable of in vitro CP resistance modulation are achievable in vivo. A prospective clinical trial to verify the clinical usefulness of combined TAM + CP treatment in ovarian cancer patients refractory to prior Pt-based chemotherapy is now underway in our department.

[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]

[Rich66]

Clin Breast Cancer. 2010 Aug 1;10(4):313-7.
Exemestane and Chemotherapy as First-line Treatment of Metastatic Breast Cancer: Results of a Phase II Study.

de la Haba-Rodriguez J, Mancha RG, Manga GP, Aguilar EA, Baena Cañada JM, Rovira PS, Conejo EA.
Hospital Reina SofÃ*a, Córdoba, Spain.
Abstract

Background: Metastatic breast cancer remains largely incurable. Strategies involving the combination of the selective estrogen receptor modulator tamoxifen and chemotherapy have been abandoned in view of unacceptable toxicity because of thromboembolic events. The aim of this study was to investigate the safety and efficacy of the third-generation steroidal aromatase inhibitor exemestane plus chemotherapy. Patients and Methods: Postmenopausal women with advanced breast cancer received 6 cycles of intravenous chemotherapy (5-fluorouracil [5-FU], epirubicin, and cyclophosphamide) and exemestane 25 mg/day that was continued after chemotherapy was completed. The primary efficacy endpoint was time to progression (TTP), and response rates were also assessed. Safety was assessed from adverse events. Results: Twenty-three patients (median age, 62 years) were included in this study. Twenty patients completed 6 chemotherapy cycles. Median TTP was 13.7 months. Overall response was achieved by 20 patients (73.9%), and the clinical benefit rate was 87%. During the chemotherapy plus exemestane treatments, 50 adverse events were reported in 14 of the 23 patients (60.9%). As expected, the incidence of adverse events decreased during the phase of exemestane treatment alone (19 adverse events in 10 of 20 patients [50%]). There were 2 grade 4 events reported, pulmonary embolism and pneumonia, although pneumonia was not considered to be related. Conclusion: Although a small number of patients were included, the combination of exemestane and chemotherapy was well tolerated and only 1 thromboembolic event was reported. Response rates were similar to other comparable series and may encourage further studies to confirm the efficacy of chemotherapy in combination with an aromatase inhibitor.

PMID: 20705565 [PubMed - in process]

-----------------------------------------------

Endocrine+Endocrine

Fulvestrant (F) and letrozole (L) combination in second-line or more for estrogen receptor (ER)-positive (+) metastatic breast cancer (MBC): Efficacy and predictive factors of response. Sub-category: ER+ Category: Breast Cancer - HER2/ER Meeting: 2011 ASCO Annual Meeting Abstract No: e11137 Citation: J Clin Oncol 29: 2011 (suppl; abstr e11137)

Publication-only abstracts (abstract number preceded by an "e"), published in conjunction with the 2011 Annual Meeting but not presented at the Meeting, can be found online only. The publication-only abstracts are not included in the print or USB versions of the ASCO Annual Meeting Proceedings Part I, but they are citable to the Journal of Clinical Oncology as a supplement (see citation on left).

Author(s): A. M. Obermiller, M. S. Copur, M. Bolton, R. C. Ramaekers, R. Hays, D. Nelson, H. Benzel, M. Mickey, M. Norvell, J. Olsen, M. Tharnish, B. Luebbe, S. Schneider, S. Woodward, B. Keenportz, S. Frankforter, L. Mlinar; Saint Francis Cancer Treatment Center, Grand Island, NE; St. Francis Medical Center, Grand Island, NE; University of Nebraska Medical Center, Grand Island, NE; Grand Island Surgery Group, Grand Island, NE; Surgery Group of Grand Island, Grand Island, NE; Saint Francis Medical Center, Grand Island, NE

Abstract Disclosures

Abstract:
Background: Preclinical data show that complete estrogen blockade, by down regulating ER and inhibiting estrogen synthesis, has greater effect on tumor growth than either treatment alone. Combination of an aromatase inhibitor (AI) and F may be an optimal second-line therapy by preventing activation of growth factor pathways and possible cross talk with ER. One clinical study has shown no benefit of adding anastrozole (A) to F at first relapse. No clinical data on combination L and F in the second line or more MBC is available. Methods: ER+, progesterone receptor(PgR) + or negative (-) MBC patients (pts) with prior chemo and/or non-AI endocrine(E) therapy were treated with L and F. Pts with complete/partial response, or stable disease were considered to have clinical benefit (CR+PR+SD). The predictive effect of age, number of prior regimens, ER/PgR status, and lobular histology were examined using Chi-square test. Results: 32 pts received L (2.5 mg/d po) plus F (250 mg/month, im). Mean age was 70 (Range: 35-92), median number of prior treatments was 2 (range1-6). 25 pts had ER+/PgR+, 7 pts had ER+/PgR- tumors. 25 pts had prior non-AI E therapy. 8 pts had lobular histology. Overall clinical benefit rate was 71% (3 CR, 7 PR, 13 SD). Mean duration of the clinical benefit was 15 months (range 2-38). 8 pts progressed under therapy. Age > 65 vs younger (89% vs 46%, p=0.007), prior treatments< 4 vs more (87% vs 25%, p=0.0007) and ER+/PgR+ vs ER+/PgR- (84% vs 42%, p<0.05) were predictive of clinical benefit; lobular histology and prior E therapy did not have any effect on clinical benefit (p>0.05). Conclusions: In pretreated MBC, combination of L and F can be effective with mean clinical benefit duration of 15 months. Older age, < 4 prior lines of therapy, and expression of both ER/PgR are predictive of clinical benefit while lobular histology and prior E therapy are not. L and F combination can be a reasonable option in selected group of MBC pts and should be further evaluated in larger studies using high dose F schedule.


Gathered info:
Researchers note that efficacy may be even better with new higher dose Fulvestrant (500mg/mo) and that the combination of Fulvestrant and AIs is safe and worth trying. And since steroidal exemestane (Aromasin) is thought to often work after failed non-steroidal AIs (Arimidex, Femara), combining fulvestrant with Exemestane after other AIs may be especially worthwhile.


Breast Cancer Res Treat. 2011 Jul 27. [Epub ahead of print]
A phase II neoadjuvant trial of anastrozole, fulvestrant, and gefitinib in patients with newly diagnosed estrogen receptor positive breast cancer.

Massarweh S, Tham YL, Huang J, Sexton K, Weiss H, Tsimelzon A, Beyer A, Rimawi M, Cai WY, Hilsenbeck S, Fuqua S, Elledge R.
Source

The Department of Internal Medicine, University of Kentucky, Lexington, KY, 40536, USA, massarweh@uky.edu.


LINK


Abstract

Endocrine therapy in patients with breast cancer can be limited by the problem of resistance. Preclinical studies suggest that complete blockade of the estrogen receptor (ER) combined with inhibition of the epidermal growth factor receptor can overcome endocrine resistance. We tested this hypothesis in a phase II neoadjuvant trial of anastrozole and fulvestrant combined with gefitinib in postmenopausal women with newly diagnosed ER-positive breast cancer. After a baseline tumor core biopsy, patients were randomized to receive anastrozole and fulvestrant or anastrozole, fulvestrant, and gefitinib (AFG) for 3 weeks. After a second biopsy at 3 weeks, all patients received AFG for 4 months and surgery was done if the tumor was operable. The primary endpoint was best clinical response by RECIST criteria and secondary endpoints were toxicity and change in biomarkers. The study closed after 15 patients were enrolled because of slow accrual. Median patient age was 67 years and median clinical tumor size was 7 cm. Four patients had metastatic disease present. Three patients withdrew before response was assessed. In the remaining 12 patients, there were two complete clinical responses (17%), three partial responses (25%), five had stable disease (41%), and two (17%) had progressive disease. Most common adverse events were rash in four patients, diarrhea in four, joint symptoms in three, and abnormal liver function tests in three. There were no grade 4 toxicities and all toxicities were reversible. At 3 weeks, cell proliferation as measured by Ki-67 was significantly reduced in the AFG group (P value = 0.01), with a parallel reduction in the expression of the Cyclin D1 (P value = 0.02). RNA microarray data showed a corresponding decrease in the expression of cell cycle genes. These results suggest that AFG was an effective neoadjuvant therapy and consistently reduced proliferation in ER-positive tumors.

PMID:

21792626

[PubMed - as supplied by publisher]

Cancer Res. 2005 Jun 15;65(12):5439-44.
Additive antitumor effect of aromatase inhibitor letrozole and antiestrogen fulvestrant in a postmenopausal breast cancer model.

Jelovac D, Macedo L, Goloubeva OG, Handratta V, Brodie AM.
Department of Pharmacology and Experimental Therapeutics, School of Medicine, University of Maryland, Baltimore, Maryland, USA.



Blocking estrogen receptors with antiestrogens and blocking estrogen synthesis with aromatase inhibitors are two strategies currently being used for reducing the effect of estrogen in postmenopausal estrogen receptor-positive breast cancer patients. To optimize these treatment strategies, we have investigated whether tumor progression can be delayed by combining the pure antiestrogen fulvestrant with the nonsteroidal aromatase inhibitor letrozole. These studies were done in ovariectomized, athymic mice bearing tumors of estrogen receptor-positive human breast cancer cells stably transfected with the aromatase gene (MCF-7Ca). Groups of mice with equivalent tumor volumes were injected s.c. daily with vehicle (control; n = 6), fulvestrant (1 mg/d; n = 7), letrozole (10 microg/d; n = 18), or letrozole (10 microg/d) plus fulvestrant (1 mg/d; n = 5). All treatments were effective in suppressing tumor growth compared with controls (P < 0.001). Tumor volumes of the fulvestrant-treated group had doubled in 10 weeks. After 19 weeks of letrozole (10 microg/d) treatment when tumors had nearly doubled in volume, mice (n = 18) were assigned to second-line therapy with letrozole (100 microg/d; n = 6), tamoxifen (100 microg/d; n = 6), or remained on letrozole treatment (10 microg/d; n = 6). However, tumors continued to increase in volume in these groups. Tumors of animals treated with the combination of letrozole plus Faslodex regressed over 29 weeks of treatment by 45%. Thus, the combination of letrozole plus fulvestrant was more effective in suppressing tumor growth than either letrozole or fulvestrant alone or sequential therapies with tamoxifen or a higher dose of letrozole (100 microg/d).


11/09 researcher off the record:
"I think it is not clear from the current clinical tirals. There appears to be no difference between anatsrozole and anastrozole + fulvestrant in the trials so far. It may be that with more time there will be a difference."



http://clinicaltrials.gov/ct2/show/NCT00570323

Arimidex With or Without Faslodex In Postmenopausal Women With HR Positive Breast Cancer (PACT 001)
This study is currently recruiting participants.
Verified by Baylor Breast Care Center, August 2009
First Received: December 6, 2007 Last Updated: August 3, 2009 History of Changes

Sponsor:	Baylor Breast Care Center
Collaborator:	AstraZeneca
Information provided by:	Baylor Breast Care Center
ClinicalTrials.gov Identifier:	NCT00570323

Purpose Over the last 3 decades, a steady shift has occurred in the management of breast cancer. Because it was traditionally viewed as a local disease, many advocated the use of radical surgery to achieve maximum survival benefit. This view has been slowly replaced by a broader biologic view that recognizes the often systemic nature of breast cancer, even when it appears to be localized to the breast. Results from randomized clinical trials have demonstrated that less extensive surgery, or lumpectomy plus radiation therapy, are optimal for local management of early breast cancer. In addition to the less radical approach to surgical treatment of breast cancer, other randomized clinical trials have established the value of postoperative systemic therapy in improving overall survival by eradicating micrometastatic disease, the major cause of mortality from breast cancer. Despite the well-documented benefits of adjuvant systemic therapy, it is not effective in preventing death from breast cancer in all patients who are candidates for such treatment. The worth of such therapy can only be judged in retrospect upon disease relapse, a time when breast cancer is nearly always incurable. Currently, there are few reliable methods to predict the success or failure of a particular postoperative treatment modality, and better ways to predict and optimize outcome are needed.
Combination endocrine therapy: Using endocrine agents with different mechanisms of action together has the potential advantage of more effectively blocking ER signaling, thus improving the efficacy of such agents against breast cancer. In the past, attempts to combine endocrine agents for ER-positive breast cancer have had mixed results, depending on the setting and the patient population studied.
Endocrine agents without any agonist effect could potentially be used in combination with aromatase inhibitors, under the rationale that the combination would maximally blockade estrogen receptor signaling, thus potentially improving the antitumor effect. Fulvestrant (FASLODEX) is a pure estrogen antagonist with no known agonist effect; thus, it has the potential to provide additional benefit when combined with an aromatase inhibitor. This concept provides the rationale for using the combination of anastrazole and fulvestrant in this study.

Condition	Intervention	Phase
Breast Cancer	Drug: Arimidex with Faslodex Drug: Arimidex without Faslodex	Phase II

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]

Tamoxifen and exemestane were started after discontinuation of vinorelbine after only 6 weeks of therapy due to a vinorelbine-induced rash. Complete clinical response was confirmed after 2 months from the start of therapy. The patient has remained free of disease for 7 years and receives trastuzumab 6 mg/kg every 6 weeks, tamoxifen 20 mg daily, and exemestane 25 mg daily.

The ATAC study reported less than optimal activity for the combination of tamoxifen and anastrozole when compared to the AI alone20. It was decided, however, to continue this patient on the combination of tamoxifen plus AI because of the early success of therapy.

It is conjectured that this patient’s prolonged complete remission of 7+ years may represent the result of inhibition of EGFR/HER2-ER cross-talk, thus prolonging benefit from hormonal therapy. However, it is also possible – though less likely – that the independent effects of trastuzumab, tamoxifen and exemestane inhibition of tumor growth is responsible as well.

Maybe the interaction is different between Tam+Anastrazole vs TAM+Exemestane:

Clin Cancer Res. 2005 Dec 15;11(24 Pt 1):8722-7.
Effect of exemestane on tamoxifen pharmacokinetics in postmenopausal women treated for breast cancer.

Hutson PR, Love RR, Havighurst TC, Rogers E, Cleary JF.
School of Pharmacy, University of Wisconsin, Madison, Wisconsin 53705-2222, USA. prhutson@pharmacy.wisc.edu
PURPOSE: Rodent models of human breast cancer suggest that the combination of the steroidal aromatase inhibitor exemestane with tamoxifen may have additive activity. Clinical trials combining tamoxifen with letrozole or anastrazole have shown minor pharmacokinetic drug interactions. We did an open-label crossover clinical trial of the effect of exemestane on tamoxifen pharmacokinetics. DESIGN: Thirty-two postmenopausal women who were clinically disease-free following primary treatments for breast cancer receiving tamoxifen for at least 3 months were studied. Blood was collected for pharmacokinetic analysis after at least 4 months of receiving 20 mg tamoxifen daily. Subjects then began 8 weeks of oral exemestane (25 mg daily), followed by another set of blood samples. RESULTS: There were no serious toxicities noted when the two drugs were combined. There was no significant effect of exemestane on the area under the plasma concentration versus time curve (AUC) of tamoxifen at steady state before [3.04 mg h/L; 90% confidence interval (90% CI), 2.71-3.44] and during exemestane treatment (3.05 mg h/L; 90% CI, 2.72-3.41). There were no significant changes in the formation of primary tamoxifen metabolites. Oral clearance of exemestane averaged 602 L/h based on an average plasma exemestane AUC of 41.5 microg h/L (90% CI, 36.7-62.6). Plasma concentrations of estradiol, estrone, and estrone sulfate decreased when exemestane was begun; estradiol concentrations consistently decreased below the limit of quantitation. CONCLUSIONS: There is no pharmacokinetic interaction between tamoxifen and exemestane. No modification in the standard regimen of either drug seems to be indicated if they are used in combination. The combination of the two drugs was well tolerated during the 8-week evaluation period.

PMID: 16361559 [PubMed - indexed for MEDLINE]

[gdpawel]

Existing genomic tests for breast cancer provide information about future risk in general, but not the likely benefit of each treatment option separate from a patient's overall prognosis if no treatment followed surgery.

It is important to independently assess each predictor - prognosis, of sensitivity to chemotherapy and sensitivity to hormone therapy. It is important to know the sensitivity of the cancer to chemo- or endocrine therapies independent of the risk of recurrence alone.

The Microarray (gene chips), a device that measures differences in gene sequence, gene expression or protein expression in biological samples. Microarrays may be used to compare gene or protein expression under different conditions, such as cells found in cancer.

Hence the headlong rush to develop tests to identify molecular predisposing mechansims whose presence still does not guarantee that a drug will be effective for an individual patient. Nor can they, for any patient or even large group of patients, discriminate the potential for clinical activity among different agents of the same class.

Genetic profiles are able to help doctors determine which patients will probably develop cancer, and those who will most likely relapse. However, it cannot be suitable for specific treatments for individual patients.

In the new paradigm of requiring a companion diagnostic as a condition for approval of new targeted therapies, the pressure is so great that the companion diagnostics they’ve approved often have been mostly or totally ineffective at identifying clinical responders (durable and otherwise) to the various therapies.

Cancer cells often have many mutations in many different pathways, so even if one route is shut down by a targeted treatment, the cancer cell may be able to use other routes. Targeting one pathway may not be as effective as targeting multiple pathways in a cancer cell.

Another challenge is to identify for which patients the targeted treatment will be effective. Tumors can become resistant to a targeted treatment, or the drug no longer works, even if it has previously been effective in shrinking a tumor. Drugs are combined with existing ones to target the tumor more effectively. Most cancers cannot be effectively treated with targeted drugs alone. Understanding “targeted� treatments begins with understanding the cancer cell.

If you find one or more implicated genes in a patient's tumor cells, how do you know if they are functional (is the encoded protein actually produced)? If the protein is produced, is it functional? If the protein is functional, how is it interacting with other functional proteins in the cell?

All cells exist in a state of dynamic tension in which several internal and external forces work with and against each other. Just detecting an amplified or deleted gene won't tell you anything about protein interactions. Are you sure that you've identified every single gene that might influence sensitivity or resistance to a certain class of drug?

Assuming you resolve all of the preceeding issues, you'll never be able to distinguish between susceptibility of the cell to different drugs in the same class. Nor can you tell anything about susceptibility to drug combinations. And what about external facts such as drug uptake into the cell?

Gene profiling tests, important in order to identify new therapeutic targets and thereby to develop useful drugs, are still years away from working successfully in predicting treatment response for individual patients. Perhaps this is because they are performed on dead, preserved cells that were never actually exposed to the drugs whose activity they are trying to assess.

It will never be as effective as the cell "function" method, which exists today and is not hampered by the problems associated with gene expression tests. That is because they measure the net effect of all processes within the cancer, acting with and against each other in real time, and it tests living cells actually exposed to drugs and drug combinations of interest.

It would be more advantageous to sort out what's the best "profile" in terms of which patients benefit from this drug or that drug. Can they be combined? What's the proper way to work with all the new drugs? If a drug works extremely well for a certain percentage of cancer patients, identify which ones and "personalize" their treatment. If one drug or another is working for some patients then obviously there are others who would also benefit. But, what's good for the group (population studies) may not be good for the individual.

Patients would certainly have a better chance of success had their cancer been chemo-sensitive rather than chemo-resistant, where it is more apparent that chemotherapy improves the survival of patients, and where identifying the most effective chemotherapy would be more likely to improve survival above that achieved with "best guess" empiric chemotherapy through clinical trials.

It may be very important to zero in on different genes and proteins. However, when actually taking the "targeted" drugs, do the drugs even enter the cancer cell? Once entered, does it immediately get metabolized or pumped out, or does it accumulate? In other words, will it work for every patient?

All the validations of this gene or that protein provides us with a variety of sophisticated techniques to provide new insights into the tumorigenic process, but if the "targeted" drug either won't "get in" in the first place or if it gets pumped out/extruded or if it gets immediately metabolized inside the cell, it just isn't going to work.

To overcome the problems of heterogeneity in cancer and prevent rapid cellular adaptation, oncologists are able to tailor chemotherapy in individual patients. This can be done by testing "live" tumor cells to see if they are susceptible to particular drugs, before giving them to the patient. DNA microarray work will prove to be highly complementary to the parellel breakthrough efforts in targeted therapy through cell function analysis.

As we enter the era of "personalized" medicine, it is time to take a fresh look at how we evaluate new medicines and treatments for cancer. More emphasis should be put on matching treatment to the patient, through the use of individualized pre-testing.

Upgrading clinical therapy by using drug sensitivity assays measuring "cell death" of three dimensional microclusters of "live" fresh tumor cell, can improve the situation by allowing more drugs to be considered. The more drug types there are in the selective arsenal, the more likely the system is to prove beneficial.

Literature Citation: Eur J Clin Invest 37 (suppl. 1):60, 2007