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Anthropometric, clinical and molecular determinants of treatment outcomes in postmenopausal, hormone receptor positive metastatic breast cancer patients treated with fulvestrant: Results from a real word setting.

ABSTRACT: To characterize determinants of treatment outcome in a real world population of 161 post-menopausal hormone receptor-positive metastatic breast cancer patients treated with fulvestrant. Descriptive statistics for demographics, anthropometrics, clinical and molecular characteristic were compared across subgroups of sensitivity/resistance to prior endocrine therapy and tested in uni/multivariate models. Clinical benefit was more common in sensitive patients with higher estrogen receptor expression and when fulvestrant was given in first line (p=0.02 and 0.046). In resistant patients, PFS was longer with lower BMI (p=0.01). Among endocrine sensitive women, longer PFS was associated with fulvestrant in first-line, single metastasis and no visceral involvement (p=0.01, 0.003 and 0.01). OS was shorter in resistant patients with HER2-positive disease and if fulvestrant was given in second and subsequent line (p=0.03). In sensitive patients, we observed worse OS with multiple metastases (p=0.008). Multivariate analyses confirmed longer PFS in resistant patients with lower BMI and older age (p=0.002 and 0.007). OS in resistant patients was negatively influenced by HER2 positivity and fulvestrant in second and subsequent line (p=0.04). In sensitive women, multiple metastases were associated with poorer survival (p=0.002). This evidence encourages considering patient and disease characteristics in decision making and outcome interpretation for patients candidate to fulvestrant.

SUBMITTER: Pizzuti L

PROVIDER: S-EPMC5620318 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Anthropometric, clinical and molecular determinants of treatment outcomes in postmenopausal, hormone receptor positive metastatic breast cancer patients treated with fulvestrant: Results from a real word setting.

Pizzuti Laura L Natoli Clara C Gamucci Teresa T Mauri Mariella M Sergi Domenico D Di Lauro Luigi L Paoletti Giancarlo G Ruggeri Enzo E Iezzi Laura L Sperduti Isabella I Mentuccia Lucia L Fabbri Agnese A Maugeri-Saccà Marcello M Moscetti Luca L Barba Maddalena M Vici Patrizia P

Oncotarget 20170409 40

To characterize determinants of treatment outcome in a real world population of 161 post-menopausal hormone receptor-positive metastatic breast cancer patients treated with fulvestrant. Descriptive statistics for demographics, anthropometrics, clinical and molecular characteristic were compared across subgroups of sensitivity/resistance to prior endocrine therapy and tested in uni/multivariate models. Clinical benefit was more common in sensitive patients with higher estrogen receptor expression ...[more]

PMID: 28978178

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Project description:Title: Transcriptome analysis of human endometrial tissues from healthy post-menoupausal women reflecting the endometrial response to 3-weeks treatment with tibolone, E2 and E2+MPA. In an observational, open, non-randomized, controlled study uterine tissues were collected in order to generate endometrial gene expression profiles. healthy postmenopausal women were enrolled into the following treatment groups: Control-group; Tibolone-group, 2,5 mg of tibolone (administered orally) every day, starting 21 days prior to surgery; Estradiol-group, 2 mg of estradiol (administered orally) every day, starting 21 days prior to surgery; Estradiol+progestagen-group, 2 mg of estradiol (administered orally) and 5 mg of MPA (Medroxy Progesteroneacetate, administered orally) every day, starting 21 days prior to surgery. Pure (100%) endometrium was isolated from the snap-frozen uterine tissues and used for RNA isolation. RNA was labeled and hybridized to whole genome Affymetrix U133plus2 GeneChips containing 54,614 probe sets, representing approximately 47,000 transcripts. Relative to the control group, 940 genes are regulated in the endometrium of E2 treated patients, whereas only 198 genes are significantly regulated in endometria from tibolone or E2+MPA treated patients. Furthermore, only 9% of E2 regulated genes are also regulated by tibolone (85 out of 940), only 5% are also regulated by E2+MPA treatment and the overlap between tibolone and E2+MPA treatment is about 10%. This indicated that tibolone-treatment results in a weak endometrial profile similarity to E2 treatment and no profile similarity to E2+MPA treatment. A more detailed analysis showed that down stream processes, such as regulation of the cell cycle, angiogenesis and cell proliferation are almost not affected by tibolone treatment but, in contrast, are significantly affected by E2. For example, upon staining with Ki67, a marker for mitotic activity, significantly increased stromal as well as glandular cell proliferation was observed in the endometria from the E2-only treated group, while tibolone treatment resulted only in a slight increase in stromal cell proliferation (and no increase in glandular cell proliferation). These results indicate that in contrast to long-term tibolone use, short-term (21-days) use results in some estrogenic stimulation of the endometrium, which is clearly far less and rather different from what is observed during E2 treatment. References: Klaassens et al., 2006 Hanifi-Moghaddam et al., 2007 Verheul et al., 2007

Project description:ImportanceRandomized clinical trials have demonstrated a substantial benefit of adding everolimus to endocrine therapy. Everolimus inhibits the mammalian target of rapamycin complex 1 (mTORC1) complex but not mTORC2, which can set off an activating feedback loop via mTORC2. Vistusertib, a dual inhibitor of mTORC1 and mTORC2, has demonstrated broad activity in preclinical breast cancer models, showing superior activity to everolimus.ObjectiveTo evaluate the safety and efficacy of vistusertib in combination with fulvestrant compared with fulvestrant alone or fulvestrant plus everolimus in postmenopausal women with estrogen receptor-positive advanced or metastatic breast cancer.Design, setting, and participantsThe MANTA trial is an open-label, phase 2 randomized clinical trial in which 333 patients with estrogen receptor-positive breast cancer progressing after prior aromatase inhibitor treatment underwent randomization (2:3:3:2) between April 1, 2014, and October 24, 2016, at 88 sites in 9 countries: 67 patients were assigned to receive fulvestrant, 103 fulvestrant plus vistusertib daily, 98 fulvestrant plus vistusertib intermittently, and 65 fulvestrant plus everolimus. Treatment was continued until disease progression, development of unacceptable toxic effects, or withdrawal of consent. Analysis was performed on an intention-to-treat basis.InterventionsFulvestrant alone or in combination with vistusertib (continuous or intermittent dosing schedules) or everolimus.Main outcomes and measuresThe primary end point was progression-free survival (PFS).ResultsAmong the 333 women in the study (median age, 63 years [range, 56-70 years]), median PFS was 5.4 months (95% CI, 3.5-9.2 months) with fulvestrant, 7.6 months (95% CI, 5.9-9.4 months) with fulvestrant plus daily vistusertib, 8.0 months (95% CI, 5.6-9.9 months) with fulvestrant plus intermittent vistusertib, and 12.3 months (95% CI, 7.7-15.7 months) with fulvestrant plus everolimus. There was no significant difference in PFS between those receiving fulvestrant plus daily or intermittent vistusertib and fulvestrant alone (hazard ratio, 0.88 [95% CI, 0.63-1.24]; P = .46; and hazard ratio, 0.79 [95% CI, 0.55-1.12]; P = .16).Conclusions and relevanceThe combination of fulvestrant plus everolimus demonstrated significantly longer PFS compared with fulvestrant plus vistusertib or fulvestrant alone. The trial failed to demonstrate a benefit of adding the dual mTORC1 and mTORC2 inhibitor vistusertib to fulvestrant.Trial registrationClinicalTrials.gov identifier: NCT02216786 and EudraCT number: 2013-002403-34.

Dataset Information

Anthropometric, clinical and molecular determinants of treatment outcomes in postmenopausal, hormone receptor positive metastatic breast cancer patients treated with fulvestrant: Results from a real word setting.

Publications

Anthropometric, clinical and molecular determinants of treatment outcomes in postmenopausal, hormone receptor positive metastatic breast cancer patients treated with fulvestrant: Results from a real word setting.

Similar Datasets

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