A randomized phase 2 trial of low dose (6 mg daily) versus high dose (30 mg daily) estradiol for patients with estrogen receptor positive aromatase inhibitor resistant advanced breast cancer.

Ellis, MJ; Dehdahti, F; Kommareddy, A.; Jamalabadi-Majidi, Shohreh; Crowder, Robert J.; Jeffe, DB; Gao, Fei; Fleming, Gini F.; Silverman, Paula; Dickler, M; Carey, LA; Marcom, P. Kelly

doi:10.1158/0008-5472.sabcs-16

Cited by 9 publications

(14 citation statements)

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“…In a second study, Ellis et al [4] randomised 66 patients with metastatic breast cancer previously exposed to an aromatase inhibitor withinB24 weeks prior to commencing therapy to estradiol 6 mg versus 30 mg daily. They obtained one PR and seven SD among 32 patients in the 30 mg arm with corresponding figures of three PR and seven SD among 34 patients in the 6 mg arm.…”

Section: Estrogens As Additive Treatment In Breast Cancermentioning

confidence: 99%

“…However, many patients are in need of second-and third-line treatment options as well, underlining the need for more treatment options. Now, estrogen additive therapy has been successfully reintroduced in this setting [3,4], revealing anti-tumour efficacy even among heavily pre-treated patients [3]. This finding should trigger a critical examination of conventional endocrine treatment exploring whether other therapeutic options may serve a place in treatment of advanced disease as well.…”

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confidence: 99%

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Additive endocrine therapy for advanced breast cancer – back to the future

Lønning

2009

Acta Oncologica

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While novel endocrine treatment options have been implemented in the advanced - as well as adjuvant setting, recent results suggest a place for "old-fashioned" additive treatment with estrogens in advanced breast cancer. This paper reviews the biological rationale for endocrine therapy in general and additive treatment with estrogens in particular. The finding that patients becoming resistant to treatment with aromatase inhibitors may subsequently respond to estrogen therapy adds important information to our understanding of therapy resistance in general. Moreover, the return of a therapeutic option abandoned more than 20 years ago, now to be used in a different sequential setting, suggests a critical examination whether there may be other conventional treatment options still earning a place as treatment in advanced disease as well. While ablative therapies including surgical oophorectomy, hypophysectomy and adrenalectomy are not candidate treatment options due to morbidity, there are additive treatment options apart from estrogen therapy that may be considered. Androgens administered at therapeutic doses are not feasible for toxicity reasons; yet, the potential of adding androgens in small doses as adjuvant to aromatase inhibitors should be further explored. Whether patients become resistant to other treatment options may still benefit from megestrol acetate, remains to be explored.

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Section: Estrogens As Additive Treatment In Breast Cancermentioning

confidence: 99%

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confidence: 99%

Additive endocrine therapy for advanced breast cancer – back to the future

Lønning

2009

Acta Oncologica

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“…In a recent study presented at the 31st annual San Antonio Breast Cancer Symposium, Ellis and coworkers [120] reported that a daily dose of 6 mg estradiol could stop the growth of tumors or even cause them to shrink in about 25% of women with metastatic breast cancer that had developed resistance to standard antihormonal therapy (Table 1A). In our own case, we are recruiting patients with metastatic breast cancer who have succeeded and experienced treatment failure with at least two successive endocrine therapies and we are determining the efficacy of a 12-week purge of high-dose oestradiol (30 mg daily) therapy (Fig.…”

Section: Clinical Exploitation Of Oestrogen-induced Apoptosismentioning

confidence: 99%

“… a reference [98] b reference [120] c reference [129] d reference [133] e reference [134] f reference [135] g reference [145] h reference [147] …”

Section: Figures and Tablementioning

confidence: 99%

The Paradox of Oestradiol-Induced Breast Cancer Cell Growth and Apoptosis

Maximov

Lewis-Wambi

Jordan

2009

CST

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High dose oestrogen therapy was used as a treatment for postmenopausal patients with breast cancer from the 1950s until the introduction of the safer antioestrogen, tamoxifen in the 1970s. The anti-tumour mechanism of high dose oestrogen therapy remained unknown. There was no enthusiasm to study these signal transduction pathways as oestrogen therapy has almost completely been eliminated from the treatment paradigm. Current use of tamoxifen and the aromatase inhibitors seek to create oestrogen deprivation that prevents the growth of oestrogen stimulated oestrogen receptor (ER) positive breast cancer cells. However, acquired resistance to antihormonal therapy does occur, but it is through investigation of laboratory models that a vulnerability of the cancer cell has been discovered and is being investigated to provide new opportunities in therapy with the potential for discovering new cancer-specific apoptotic drugs. Laboratory models of resistance to raloxifene and tamoxifen, the selective oestrogen receptor modulators (SERMs) and aromatase inhibitors demonstrate an evolution of drug resistance so that after many years of oestrogen deprivation, the ER positive cancer cell reconfigures the survival signal transduction pathways so oestrogen now becomes an apoptotic trigger rather than a survival signal. Current efforts are evaluating the mechanisms of oestrogen-induced apoptosis and how this new biology of oestrogen action can be amplified and enhanced, thereby increasing the value of this therapeutic opportunity for the treatment of breast cancer. Several synergistic approaches to therapeutic enhancement are being advanced which involve drug combinations to impair survival signaling with the use of specific agents and to impair bcl-2 that protects the cancer cell from apoptosis. We highlight the historical understanding of oestrogen’s role in cell survival and death and specifically illustrate the progress that has been made in the last five years to understand the mechanisms of oestrogen-induced apoptosis. There are opportunities to harness knowledge from this new signal transduction pathway to discover the precise mechanism of this oestrogen-induced apoptotic trigger. Indeed, the new biology of oestrogen action also has significance for understanding the physiology of bone remodeling. Thus, the pathway has a broad appeal in both physiology and cancer research.

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“…The progress (44) being made by translating the laboratory studies(45) of low dose apoptotic oestradiol therapy into clinical practice must be amplified to bring further benefits to a select group of patients. Those patients with Phase II resistant metastatic breast cancer are a significant proportion of all those who respond initially to adjuvant endocrine therapy.…”

Section: Question 3 Can We Enhance Oestrogen-induced Apoptosis?mentioning

confidence: 99%

New hypotheses and opportunities in endocrine therapy: amplification of oestrogen-induced apoptosis

et al. 2009

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Aims-To outline the progress being made in the understanding of acquired resistance to long term therapy with the selective oestrogen receptor modulators (SERMs, tamoxifen and raloxifene) and aromatase inhibitors. The question to be addressed is how we can amplify the new biology of oestrogen-induced apoptosis to create more complete responses in exhaustively antihormone treated metastatic breast cancer.Methods and Results-Three questions are posed and addressed.1.) Do we know how oestrogen works? 2.) Can we improve adjuvant antihormonal therapy? 3.) Can we enhance oestrogen-induced apoptosis?The new player in oestrogen action is GPR30 and there are new drugs specific for this target to trigger apoptosis. Similarly, anti-angiogenic drugs can be integrated into adjuvant antihormone therapy or to enhance oestrogen-induced apoptosis in Phase II antihormone resistant breast cancer. The goal is to reduce the development of acquired antihormone resistance or undermine the ability of breast cancer cells to undergo apoptosis with oestrogen respectively. Finally, drugs to reduce the synthesis of glutathione, a subcellular molecule compound associated with drug resistance, can enhance oestradiol-induced apoptosis.Conclusions-We propose an integrated approach for the rapid testing of agents to blunt survival pathways and amplify oestrogen-induced apoptosis and tumour regression in Phase II resistant metastatic breast cancer. This Pharma platform will provide rapid clinical results to predict efficacy in large scale clinical trials.

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A randomized phase 2 trial of low dose (6 mg daily) versus high dose (30 mg daily) estradiol for patients with estrogen receptor positive aromatase inhibitor resistant advanced breast cancer.

Cited by 9 publications

References 0 publications

Additive endocrine therapy for advanced breast cancer – back to the future

Additive endocrine therapy for advanced breast cancer – back to the future

The Paradox of Oestradiol-Induced Breast Cancer Cell Growth and Apoptosis

New hypotheses and opportunities in endocrine therapy: amplification of oestrogen-induced apoptosis

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