A Randomized Trial of Letrozole in Postmenopausal Women after Five Years of Tamoxifen Therapy for Early-Stage Breast Cancer

Goss, Paul E.; Ingle, James N.; Martino, Silvana; Robert, Nicholas J.; Muss, Hyman B.; Piccart, Martine; Castiglione, M.; Tu, Dongsheng; Shepherd, Lois E.; Pritchard, Kathleen I.; Livingston, Robert B.; Davidson, Nancy E.; Norton, Larry; Perez, Edith A.; Abrams, Jeffrey S.; Therasse, Patrick; Palmer, Michael; Pater, Joseph L.

doi:10.1056/nejmoa032312

Cited by 1,677 publications

(926 citation statements)

References 35 publications

Supporting

Mentioning

873

Contrasting

Unclassified

Order By: Relevance

“…These tumors are therefore useful for studying and comparing the effects of both antiestrogens (AEs) and AIs in the same model system (Yue et al 1994). Clinical trials (BIG 1-98, ATAC, MA-17) have now confirmed the results of our xenograft model (Baum et al 2002, Goss et al 2003, 2005, Thurlimann et al 2005, Goss 2006 …”

Section: Discussionsupporting

confidence: 78%

A nude mouse model of obesity to study the mechanisms of resistance to aromatase inhibitors

Schech¹,

Yu²,

Goloubeva³

et al. 2015

Endocrine-Related Cancer

View full text Add to dashboard Cite

Obesity is a risk factor for breast cancer progression. Breast cancer patients who are overweight or obese or have excess abdominal fat have an increased risk of local or distant recurrence and cancer-related death. Hormone depletion therapies can also cause weight gain, exacerbating the risk for these patients. To understand the effect of obesity on hormone-dependent human breast cancer tumors, we fed ovariectomized athymic nude mice a diet containing 45% kcal fat and 17% kcal sucrose (high fat sucrose diet (HFSD)), 10% kcal fat (low fat diet (LFD)), or a standard chow diet (chow). The mice fed the HFSD developed metabolic abnormalities consistent with the development of obesity such as weight gain, high fasting blood glucose, and impaired glucose tolerance. These mice also developed hyperinsulinemia and insulin resistance. The obese mice also had a higher tumor growth rate compared to the lean mice. Furthermore, the obese mice showed a significantly reduced responsiveness to letrozole. To understand the role of obesity in this reduced responsiveness, we examined the effect of insulin on the growth of MCF-7Ca cells in response to estrogen or letrozole. The presence of insulin rendered MCF-7Ca cells less responsive to estrogen and letrozole. Exogenous insulin treatment of MCF-7Ca cells also resulted in increased p-Akt as well as ligand-independent phosphorylation of ERa. These findings suggest that diet-induced obesity may result in reduced responsiveness of tumors to letrozole due to the development of hyperinsulinemia. We conclude that obesity influences the response and resistance of breast cancer tumors to aromatase inhibitor treatment. Key Words" aromatase inhibitors " diet-induced-obesity " MCF-7Ca xenografts " breast cancer

show abstract

Section: Discussionsupporting

confidence: 78%

A nude mouse model of obesity to study the mechanisms of resistance to aromatase inhibitors

Schech¹,

Yu²,

Goloubeva³

et al. 2015

Endocrine-Related Cancer

View full text Add to dashboard Cite

show abstract

“…Newer therapies targeting ER via different mechanisms, such as aromatase inhibitors (AI; Goss et al 2003) and selective ER downregulators (e.g. ICI182780; Robertson 2002), or potential new therapies, such as electrophilic modulators of ER zinc fingers (Wang et al 2004), were all developed from basic research into molecular mechanisms of ER action, but development of therapy resistance is likely also to be a problem clinically.…”

Section: Introductionmentioning

confidence: 99%

Clinical significance of estrogen receptor phosphorylation

Murphy

Seekallu²,

Watson³

2010

Endocrine Related Cancer

127

106

View full text Add to dashboard Cite

Multiple sites of phosphorylation on human estrogen receptor a (ERa) have been identified by a variety of methodologies. Now with the emerging availability of phospho-site-specific antibodies to ERa, the relevance of phosphorylation of ERa in human breast cancer in vivo is being explored. Multiple phosphorylated sites in ERa can be detected in multiple breast tumor biopsy samples, providing evidence of their relevance to human breast cancer in vivo. Published data suggest that the detection in primary breast tumors of phosphorylation at some sites in ERa is associated with a better clinical outcome while phosphorylation at other sites is associated with a poorer clinical outcome most often in patients who have been treated with tamoxifen. This suggests the hypothesis that phospho-profiling of ERa in human breast tumors to establish an 'ERa phosphorylation code', may be a more accurate marker of prognosis and/or response to endocrine therapy in human breast cancer.

show abstract

“…Only in 2003(the year SOFT and TEXT started accrual) were the results of MA.17 published showing that an AI(letrozole) after 5 years of TAM reduced DFS events in postmenopausal women with resected breast cancer [17]. Even then, there was a concern that patients premenopausal at diagnosis who lost ovarian function before the 5-year point would not benefit from further decreases in estrogen levels induced by blockade of aromatase.…”

Section: The Analysis Ignored the Efficacy Of Endocrine Therapy Aftermentioning

confidence: 99%

“…This treatment suffers from a paucity of data showing that further endocrine therapy is effective after 5 years of an AI. In contrast, we know that more TAM improves survival after 5 years of TAM [18,19], and an AI improves DFS after 5 years of TAM [9,17]. By the end of 2016, one study had been published [20] and 3 more had been presented at the 2016 San Antonio Breast Cancer symposium showing little or no benefit for extending AI therapy beyond 5 years except for continued suppression of new contralateral breast cancers [21][22][23].…”

Section: Little Benefit From Hormonal Therapy After Ai For 5 Yearsmentioning

confidence: 99%

Adjuvant ovarian suppression for resected breast cancer: 2017 critical assessment

Vogl

2017

Breast Cancer Res Treat

View full text Add to dashboard Cite

Currently available data supporting adjuvant ovarian function suppression for resected breast cancer in premenopausal women in addition to standard chemotherapy and tamoxifen are not persuasive, even though an ASCO guideline supports them. Available information from the key trial, called ''SOFT,'' has only 5-year followup in a 15-year disease. It employs breast cancer events as an endpoint, rather than distant metastases, or better still, death from any cause. The small advantages reported to date may disappear when aromatase inhibitors are given after the occurrence of menopause in the control population. Caution should be exercised in recommending ovarian suppression in all but the highest-risk situations.

show abstract

A Randomized Trial of Letrozole in Postmenopausal Women after Five Years of Tamoxifen Therapy for Early-Stage Breast Cancer

Abstract: As compared with placebo, letrozole therapy after the completion of standard tamoxifen treatment significantly improves disease-free survival.

Cited by 1,677 publications

References 35 publications

A nude mouse model of obesity to study the mechanisms of resistance to aromatase inhibitors

A nude mouse model of obesity to study the mechanisms of resistance to aromatase inhibitors

Clinical significance of estrogen receptor phosphorylation

Adjuvant ovarian suppression for resected breast cancer: 2017 critical assessment

Contact Info

Product

Resources

About