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Prudence A Francis - One of the best experts on this subject based on the ideXlab platform.

  • tailoring adjuvant endocrine therapy for premenopausal breast cancer
    The New England Journal of Medicine, 2018
    Co-Authors: Prudence A Francis, Istvan Lang, Olivia Pagani, Gini F Fleming, Barbara Walley, Marco Colleoni, Henry L Gomez, Carlo Tondini, Eva Ciruelos
    Abstract:

    Abstract Background In the Suppression of Ovarian Function Trial (SOFT) and the Tamoxifen and Exemestane Trial (TEXT), the 5-year rates of recurrence of breast cancer were significantly lower among premenopausal women who received the aromatase inhibitor Exemestane plus ovarian suppression than among those who received tamoxifen plus ovarian suppression. The addition of ovarian suppression to tamoxifen did not result in significantly lower recurrence rates than those with tamoxifen alone. Here, we report the updated results from the two trials. Methods Premenopausal women were randomly assigned to receive 5 years of tamoxifen, tamoxifen plus ovarian suppression, or Exemestane plus ovarian suppression in SOFT and to receive tamoxifen plus ovarian suppression or Exemestane plus ovarian suppression in TEXT. Randomization was stratified according to the receipt of chemotherapy. Results In SOFT, the 8-year disease-free survival rate was 78.9% with tamoxifen alone, 83.2% with tamoxifen plus ovarian suppression,...

  • treatment efficacy adherence and quality of life among women younger than 35 years in the international breast cancer study group text and soft adjuvant endocrine therapy trials
    Journal of Clinical Oncology, 2017
    Co-Authors: Poornima Saha, Prudence A Francis, Olivia Pagani, Henry L Gomez, Meredith M Regan, Barbara A Walley, Karin Ribi, Jurg Bernhard, Harold J Burstein
    Abstract:

    Purpose To describe benefits and toxicities of adjuvant endocrine therapies in women younger than 35 years with breast cancer (n = 582) enrolled in the Suppression of Ovarian Function Trial (SOFT) and Tamoxifen and Exemestane Trial (TEXT). Methods In SOFT, women still premenopausal after surgery with or without chemotherapy were randomly assigned to tamoxifen alone, tamoxifen plus ovarian function suppression (OFS), or Exemestane plus OFS. In TEXT, all received OFS with or without concomitant chemotherapy and were randomly assigned to Exemestane plus OFS or tamoxifen plus OFS. We summarize treatment efficacy, quality of life, and adherence of the cohort of women younger than 35 years in SOFT and TEXT, alongside data from the cohort of older premenopausal women. Results For 240 human epidermal growth factor receptor 2-negative patients younger than 35 years enrolled in SOFT after receiving chemotherapy, the 5-year breast cancer-free interval (BCFI) was 67.1% (95% CI, 54.6% to 76.9%) with tamoxifen alone, 75.9% with tamoxifen plus OFS (95% CI, 64.0% to 84.4%), and 83.2% with Exemestane plus OFS (95% CI, 72.7% to 90.0%). For 145 human epidermal growth factor receptor 2-negative patients younger than 35 years in TEXT, 5-year BCFI was 79.2% (95% CI, 66.2% to 87.7%) with tamoxifen plus OFS and 81.6% (95% CI, 69.8% to 89.2%) with Exemestane plus OFS. The most prominent quality of life symptom for patients younger than 35 years receiving OFS was vasomotor symptoms, with the greatest worsening from baseline at 6 months (on the order of 30 to 40 points), but loss of sexual interest and difficulties in becoming aroused were also clinically meaningful (≥ 8-point change). The level of symptom burden was similar in older premenopausal women. A total of 19.8% of women younger than 35 years stopped all protocol-assigned endocrine therapy early. Conclusion In women younger than 35 years with hormone receptor-positive breast cancer, adjuvant OFS combined with tamoxifen or Exemestane produces large improvements in BCFI compared with tamoxifen alone. Menopausal symptoms are significant but are not worse than those seen in older premenopausal women.

  • treatment efficacy adherence and quality of life among women younger than 35 years in the international breast cancer study group text and soft adjuvant endocrine therapy trials
    Journal of Clinical Oncology, 2017
    Co-Authors: Poornima Saha, Prudence A Francis, Barbara Walley, Henry L Gomez, Meredith M Regan, Harold J Burstein, Karin Ribi, Jurg Bernhard, O. Pagani, Vani Parmar
    Abstract:

    PurposeTo describe benefits and toxicities of adjuvant endocrine therapies in women younger than 35 years with breast cancer (n = 582) enrolled in the Suppression of Ovarian Function Trial (SOFT) and Tamoxifen and Exemestane Trial (TEXT).MethodsIn SOFT, women still premenopausal after surgery with or without chemotherapy were randomly assigned to tamoxifen alone, tamoxifen plus ovarian function suppression (OFS), or Exemestane plus OFS. In TEXT, all received OFS with or without concomitant chemotherapy and were randomly assigned to Exemestane plus OFS or tamoxifen plus OFS. We summarize treatment efficacy, quality of life, and adherence of the cohort of women younger than 35 years in SOFT and TEXT, alongside data from the cohort of older premenopausal women.ResultsFor 240 human epidermal growth factor receptor 2–negative patients younger than 35 years enrolled in SOFT after receiving chemotherapy, the 5-year breast cancer–free interval (BCFI) was 67.1% (95% CI, 54.6% to 76.9%) with tamoxifen alone, 75.9% ...

  • twelve month estrogen levels in premenopausal women with hormone receptor positive breast cancer receiving adjuvant triptorelin plus Exemestane or tamoxifen in the suppression of ovarian function trial soft the soft est substudy
    Journal of Clinical Oncology, 2016
    Co-Authors: Meritxell Bellet, Kathryn P Gray, Prudence A Francis, Istvan Lang, Eva Ciruelos, Ana Lluch, Miguel Angel Climent, Gustavo Catalan, Antoni Avella, Uriel Bohn
    Abstract:

    PurposeTo describe estradiol (E2), estrone (E1), and estrone sulfate (E1S) levels during the first year of monthly triptorelin plus Exemestane or tamoxifen and to assess possible suboptimal suppression while receiving Exemestane plus triptorelin.Patients and MethodsPremenopausal patients with early breast cancer on the Suppression of Ovarian Function Trial who selected triptorelin as the ovarian suppression method and were randomly assigned to Exemestane plus triptorelin or tamoxifen plus triptorelin were enrolled until the target population of 120 patients was reached. Blood sampling time points were 0, 3, 6, 12, 18, 24, 36, and 48 months. Serum estrogens were measured with a highly sensitive and specific assay. This preplanned 12-month analysis evaluated E2, E1, E1S, follicle-stimulating hormone, and luteinizing hormone levels in all patients and the proportion of patients with E2 levels greater than 2.72 pg/mL at any time point during treatment with Exemestane plus triptorelin.ResultsOne hundred sixtee...

  • Adjuvant ovarian function suppression and cognitive function in women with breast cancer
    British Journal of Cancer, 2016
    Co-Authors: Kelly-anne Phillips, Meritxell Bellet, Prudence A Francis, Meredith M Regan, Karin Ribi, Fabio Puglisi, Simon Spazzapan, Per Karlsson, Daniel R Budman, Khalil Zaman
    Abstract:

    Background: To examine the effect on cognitive function of adjuvant ovarian function suppression (OFS) for breast cancer. Methods: The Suppression of Ovarian Function (SOFT) trial randomised premenopausal women with hormone receptor-positive breast cancer to 5 years adjuvant endocrine therapy with tamoxifen+OFS, Exemestane+OFS or tamoxifen alone. The Co-SOFT substudy assessed objective cognitive function and patient reported outcomes at randomisation (T0), and 1 year later (T1); the primary endpoint was change in global cognitive function, measured by the composite objective cognitive function score. Data were compared for the pooled tamoxifen+OFS and Exemestane+OFS groups vs the tamoxifen alone group using the Wilcoxon rank-sum test. Results: Of 86 participants, 74 underwent both T0 and T1 cognitive testing; 54 randomised to OFS+ either tamoxifen (28) or Exemestane (26) and 20 randomised to tamoxifen alone. There was no significant difference in the changes in the composite cognitive function scores between the OFS+ tamoxifen or Exemestane groups and the tamoxifen group (mean±s.d., −0.21±0.92 vs −0.04±0.49, respectively, P =0.71, effect size=−0.20), regardless of prior chemotherapy status, and adjusting for baseline characteristics. Conclusions: The Co-SOFT study, although limited by small samples size, provides no evidence that adding OFS to adjuvant oral endocrine therapy substantially affects global cognitive function.

Jacek Jassem - One of the best experts on this subject based on the ideXlab platform.

  • evaluation of applying ihc4 as a prognostic model in the translational study of intergroup Exemestane study ies pathies
    Breast Cancer Research and Treatment, 2018
    Co-Authors: Maggie C U Cheang, Per Eystein Lonning, J M Bliss, Giuseppe Viale, Valerie Speirs, Carlo Palmieri, Abeer M Shaaban, James P Morden, Nuria Porta, Jacek Jassem
    Abstract:

    Background Intergroup Exemestane Study (IES) was a randomised study that showed a survival benefit of switching adjuvant endocrine therapy after 2–3 years from tamoxifen to Exemestane. This PathIES aimed to assess the role of immunohistochemical (IHC)4 score in determining the relative sensitivity to either tamoxifen or sequential treatment with tamoxifen and Exemestane.

  • long term follow up of the intergroup Exemestane study
    Journal of Clinical Oncology, 2017
    Co-Authors: James P Morden, Robert E. Coleman, Lucy Kilburn, Jacek Jassem, Stephen E Jones, Isabel Alvarez, G Bertelli, Alan S Coates, Lesley Fallowfield, Per Eystein Lonning
    Abstract:

    Purpose The Intergroup Exemestane Study, an investigator-led study of 4,724 postmenopausal patients with early breast cancer (clinical trial information: ISRCTN11883920), has previously demonstrated that a switch from adjuvant endocrine therapy after 2 to 3 years of tamoxifen to Exemestane was associated with clinically relevant improvements in efficacy. Here, we report the final efficacy analyses of this cohort. Patients and Methods Patients who remained disease free after 2 to 3 years of adjuvant tamoxifen were randomly assigned to continue tamoxifen or switch to Exemestane to complete a total of 5 years of adjuvant endocrine therapy. Given the large number of non-breast cancer-related deaths now reported, breast cancer-free survival (BCFS), with censorship of intercurrent deaths, was the primary survival end point of interest. Analyses focus on patients with estrogen receptor-positive or unknown tumors (n = 4,599). Results At the time of the data snapshot, median follow-up was 120 months. In the population that was estrogen receptor positive or had unknown estrogen receptor status, 1,111 BCFS events were observed with 508 (22.1%) of 2,294 patients in the Exemestane group and 603 (26.2%) of 2,305 patients in the tamoxifen group. The data corresponded to an absolute difference (between Exemestane and tamoxifen) at 10 years of 4.0% (95% CI, 1.2% to 6.7%), and the hazard ratio (HR) of 0.81 (95% CI, 0.72 to 0.92) favored Exemestane. This difference remained in multivariable analysis that was adjusted for nodal status, prior use of hormone replacement therapy, and prior chemotherapy (HR, 0.80; 95% CI, 0.71 to 0.90; P < .001). A modest improvement in overall survival was seen with Exemestane; the absolute difference (between Exemestane and tamoxifen) at 10 years in the population that was estrogen receptor positive or had unknown estrogen receptor status was 2.1% (95% CI, -0.5% to 4.6%), and the HR was 0.89 (95% CI, 0.78 to 1.01; P = .08). For the intention-to-treat population, the absolute difference was 1.6% (95% CI, -0.9% to 4.1%); the HR was 0.91 (95% CI, 0.80 to 1.03, P = .15). No statistically significant difference was observed in the proportion of patients who reported a fracture event in the post-treatment period. Conclusion The Intergroup Exemestane Study and contemporaneous studies have established that a strategy of switching to an aromatase inhibitor after 2 to 3 years of tamoxifen can lead to sustained benefits in terms of reduction of disease recurrence and breast cancer mortality.

  • disease related outcomes with long term follow up an updated analysis of the intergroup Exemestane study
    Journal of Clinical Oncology, 2012
    Co-Authors: J M Bliss, Robert E. Coleman, Lucy Kilburn, Jacek Jassem, T Delozier, Stephen E Jones, Alan S Coates, John F Forbes, Jorn Andersen, R Paridaens
    Abstract:

    Purpose Intergroup Exemestane Study (IES), an investigator-led study in 4,724 postmenopausal patients with early-stage breast cancer has demonstrated clinically important benefits from switching adjuvant endocrine therapy after 2 to 3 years of tamoxifen to Exemestane. Now, with longer follow-up, a large number of non–breast cancer–related events have been reported. Exploratory analyses describe breast cancer–free survival (BCFS) and explore incidence and patterns of the different competing events. Patients and Methods Patients who were disease-free after 2 to 3 years of adjuvant tamoxifen were randomly assigned to continue tamoxifen or switch to Exemestane to complete 5 years of adjuvant endocrine therapy. At this planned analysis, the median follow-up was 91 months. Principal analysis focuses on 4,052 patients with estrogen receptor (ER) –positive and 547 with ER-unknown tumors. Results In all, 930 BCFS events have been reported (Exemestane, 423; tamoxifen, 507), giving an unadjusted hazard ratio (HR) of...

  • long term endometrial effects in postmenopausal women with early breast cancer participating in the intergroup Exemestane study ies a randomised controlled trial of Exemestane versus continued tamoxifen after 2 3 years tamoxifen
    Annals of Oncology, 2010
    Co-Authors: G Bertelli, Jacek Jassem, R C Coombes, Emma Hall, E Ireland, Claire Snowdon, K Drosik, H Karnickamlodkowska, J M Bliss
    Abstract:

    Background: The antiestrogen tamoxifen may have partial estrogen-like effects on the postmenopausal uterus. Aromatase inhibitors (AIs) are increasingly used after initial tamoxifen in the adjuvant treatment of postmenopausal early breast cancer due to their mechanism of action: a potential benefit being a reduction of uterine abnormalities caused by tamoxifen. Patients and methods: Sonographic uterine effects of the steroidal AI Exemestane were studied in 219 women participating in the Intergroup Exemestane Study: a large trial in postmenopausal women with estrogen receptor-positive (or unknown) early breast cancer, disease free after 2-3 years of tamoxifen, randomly assigned to continue tamoxifen or switch to Exemestane to complete 5 years adjuvant treatment. The primary end point was the proportion of patients with abnormal (5 mm) endometrial thickness (ET) on transvaginal ultrasound 24 months after randomisation. Results: The analysis included 183 patients. Two years after randomisation, the proportion of patients with abnormal ET was significantly lower in the Exemestane compared with tamoxifen arm (36% versus 62%, respectively; P = 0.004). This difference emerged within 6 months of switching treatment (43.5% versus 65.2%, respectively; P = 0.01) and disappeared within 12 months of treatment completion (30.8% versus 34.7%, respectively; P = 0.67). Conclusion: Switching from tamoxifen to Exemestane significantly reverses endometrial thickening associated with continued tamoxifen.

  • survival and safety of Exemestane versus tamoxifen after 2 3 years tamoxifen treatment intergroup Exemestane study a randomised controlled trial
    The Lancet, 2007
    Co-Authors: R C Coombes, Robert E. Coleman, Robert Paridaens, Jacek Jassem, T Delozier, Stephen E Jones, Claire Snowdon, L S Kilburn, Cjh Van De Velde, Isabel Alvarez
    Abstract:

    Summary Background Early improvements in disease-free survival have been noted when an aromatase inhibitor is given either instead of or sequentially after tamoxifen in postmenopausal women with oestrogen-receptor-positive early breast cancer. However, little information exists on the long-term effects of aromatase inhibitors after treatment, and whether these early improvements lead to real gains in survival. Methods 4724 postmenopausal patients with unilateral invasive, oestrogen-receptor-positive or oestrogen-receptor-unknown breast cancer who were disease-free on 2–3 years of tamoxifen, were randomly assigned to switch to Exemestane (n=2352) or to continue tamoxifen (n=2372) for the remainder of a 5-year endocrine treatment period. The primary endpoint was disease-free survival; overall survival was a secondary endpoint. Efficacy analyses were intention-to-treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN11883920. Results After a median follow-up of 55·7 months (range 0–89·7), 809 events contributing to the analysis of disease-free survival had been reported (354 Exemestane, 455 tamoxifen); unadjusted hazard ratio 0·76 (95% CI 0·66–0·88, p=0·0001) in favour of Exemestane, absolute benefit 3·3% (95% CI 1·6–4·9) by end of treatment (ie, 2·5 years after randomisation). 222 deaths occurred in the Exemestane group compared with 261 deaths in the tamoxifen group; unadjusted hazard ratio 0·85 (95% CI 0·71–1·02, p=0·08), 0·83 (0·69–1·00, p=0·05) when 122 patients with oestrogen-receptor-negative disease were excluded. Conclusions Our results suggest that early improvements in disease-free survival noted in patients who switch to Exemestane after 2–3 years on tamoxifen persist after treatment, and translate into a modest improvement in overall survival.

J M Bliss - One of the best experts on this subject based on the ideXlab platform.

  • evaluation of applying ihc4 as a prognostic model in the translational study of intergroup Exemestane study ies pathies
    Breast Cancer Research and Treatment, 2018
    Co-Authors: Maggie C U Cheang, Per Eystein Lonning, J M Bliss, Giuseppe Viale, Valerie Speirs, Carlo Palmieri, Abeer M Shaaban, James P Morden, Nuria Porta, Jacek Jassem
    Abstract:

    Background Intergroup Exemestane Study (IES) was a randomised study that showed a survival benefit of switching adjuvant endocrine therapy after 2–3 years from tamoxifen to Exemestane. This PathIES aimed to assess the role of immunohistochemical (IHC)4 score in determining the relative sensitivity to either tamoxifen or sequential treatment with tamoxifen and Exemestane.

  • Evaluation of applying IHC4 as a prognostic model in the translational study of Intergroup Exemestane Study (IES): PathIES.
    'Springer Science and Business Media LLC', 2018
    Co-Authors: Cheang Mcu, J M Bliss, Viale G, Palmieri C, Shaaban A, Morden J, Porta N, Jassem J
    Abstract:

    BACKGROUND:Intergroup Exemestane Study (IES) was a randomised study that showed a survival benefit of switching adjuvant endocrine therapy after 2-3 years from tamoxifen to Exemestane. This PathIES aimed to assess the role of immunohistochemical (IHC)4 score in determining the relative sensitivity to either tamoxifen or sequential treatment with tamoxifen and Exemestane. PATIENTS AND METHODS:Primary tumour samples were available for 1274 patients (27% of IES population). Only patients for whom the IHC4 score could be calculated (based on oestrogen receptor, progesterone receptor, HER2 and Ki67) were included in this analysis (N = 430 patients). The clinical score (C) was based on age, grade, tumour size and nodal status. The association of clinicopathological parameters, IHC4(+C) scores and treatment effect with time to distant recurrence-free survival (TTDR) was assessed in univariable and multivariable Cox regression analyses. A modified clinical score (PathIEscore) (N = 350) was also estimated. RESULTS:Our results confirm the prognostic importance of the original IHC4, alone and in conjunction with clinical scores, but no significant difference with treatment effects was observed. The combined IHC4 + Clinical PathIES score was prognostic for TTDR (P 

  • disease related outcomes with long term follow up an updated analysis of the intergroup Exemestane study
    Journal of Clinical Oncology, 2012
    Co-Authors: J M Bliss, Robert E. Coleman, Lucy Kilburn, Jacek Jassem, T Delozier, Stephen E Jones, Alan S Coates, John F Forbes, Jorn Andersen, R Paridaens
    Abstract:

    Purpose Intergroup Exemestane Study (IES), an investigator-led study in 4,724 postmenopausal patients with early-stage breast cancer has demonstrated clinically important benefits from switching adjuvant endocrine therapy after 2 to 3 years of tamoxifen to Exemestane. Now, with longer follow-up, a large number of non–breast cancer–related events have been reported. Exploratory analyses describe breast cancer–free survival (BCFS) and explore incidence and patterns of the different competing events. Patients and Methods Patients who were disease-free after 2 to 3 years of adjuvant tamoxifen were randomly assigned to continue tamoxifen or switch to Exemestane to complete 5 years of adjuvant endocrine therapy. At this planned analysis, the median follow-up was 91 months. Principal analysis focuses on 4,052 patients with estrogen receptor (ER) –positive and 547 with ER-unknown tumors. Results In all, 930 BCFS events have been reported (Exemestane, 423; tamoxifen, 507), giving an unadjusted hazard ratio (HR) of...

  • long term endometrial effects in postmenopausal women with early breast cancer participating in the intergroup Exemestane study ies a randomised controlled trial of Exemestane versus continued tamoxifen after 2 3 years tamoxifen
    Annals of Oncology, 2010
    Co-Authors: G Bertelli, Jacek Jassem, R C Coombes, Emma Hall, E Ireland, Claire Snowdon, K Drosik, H Karnickamlodkowska, J M Bliss
    Abstract:

    Background: The antiestrogen tamoxifen may have partial estrogen-like effects on the postmenopausal uterus. Aromatase inhibitors (AIs) are increasingly used after initial tamoxifen in the adjuvant treatment of postmenopausal early breast cancer due to their mechanism of action: a potential benefit being a reduction of uterine abnormalities caused by tamoxifen. Patients and methods: Sonographic uterine effects of the steroidal AI Exemestane were studied in 219 women participating in the Intergroup Exemestane Study: a large trial in postmenopausal women with estrogen receptor-positive (or unknown) early breast cancer, disease free after 2-3 years of tamoxifen, randomly assigned to continue tamoxifen or switch to Exemestane to complete 5 years adjuvant treatment. The primary end point was the proportion of patients with abnormal (5 mm) endometrial thickness (ET) on transvaginal ultrasound 24 months after randomisation. Results: The analysis included 183 patients. Two years after randomisation, the proportion of patients with abnormal ET was significantly lower in the Exemestane compared with tamoxifen arm (36% versus 62%, respectively; P = 0.004). This difference emerged within 6 months of switching treatment (43.5% versus 65.2%, respectively; P = 0.01) and disappeared within 12 months of treatment completion (30.8% versus 34.7%, respectively; P = 0.67). Conclusion: Switching from tamoxifen to Exemestane significantly reverses endometrial thickening associated with continued tamoxifen.

  • quality of life in the intergroup Exemestane study a randomized trial of Exemestane versus continued tamoxifen after 2 to 3 years of tamoxifen in postmenopausal women with primary breast cancer
    Journal of Clinical Oncology, 2006
    Co-Authors: Lesley Fallowfield, J M Bliss, Stephen E Jones, Claire Snowdon, Lucy S Porter, Miranda H Price, Charles R Coombes, Emma Hall
    Abstract:

    PURPOSE: To compare and describe the quality of life (QOL) of women allocated to tamoxifen or Exemestane within the Intergroup Exemestane Study (IES). PATIENTS AND METHODS: Postmenopausal women with primary breast cancer who were disease free after 2 to 3 years were randomly assigned to switch from tamoxifen to Exemestane or continue with tamoxifen until 5 years of treatment were completed. A subset of IES centers participated in a QOL substudy. The Functional Assessment of Cancer Therapy-Breast (FACT-B) and endocrine subscale (ES) were administered before random assignment and at predefined follow-up times. The primary end point was the FACT-B composite Trial Outcome Index (TOI). Secondary end points included total FACT-B+ES score, total ES score, and severity of individual endocrine symptoms. This analysis reports QOL up to 24 months. RESULTS: Five hundred eighty-two patients from eight countries were enrolled onto the substudy. Completion and return of questionnaires was excellent, with 85% available for analysis. QOL was generally good and stable over 2 years, with no clinically meaningful differences found between groups in TOI or ES. Prevalence of severe endocrine symptoms at trial entry was high for vasomotor complaints and sexual problems, which persisted for both groups during the study. No significant differences between groups were seen for any endocrine symptoms apart from vaginal discharge, which was more pronounced with tamoxifen (P < .001). CONCLUSION: The switch from tamoxifen to Exemestane neither increased nor decreased endocrine symptoms present after 2 to 3 years of tamoxifen; the switch also did not initiate significant reports of new symptoms. Results indicate that the clinical benefits of Exemestane over tamoxifen are achieved without significant detrimental effect on QOL.

Harriet Richardson - One of the best experts on this subject based on the ideXlab platform.

  • Variation in the UGT2B17 genotype, Exemestane metabolism and menopause-related toxicities in the CCTG MAP.3 trial
    Breast Cancer Research and Treatment, 2020
    Co-Authors: Vikki Ho, Romain Pasquet, Gang Chen, Paul Goss, Dongsheng Tu, Philip Lazarus, Harriet Richardson
    Abstract:

    Purpose To examine associations between the UGT2B17 gene deletion and Exemestane metabolites, and commonly reported side effects (fatigue, hot flashes, and joint pain) among postmenopausal women participating in the MAP.3 chemoprevention trial. Methods The analytical samples for the UGT2B17 analysis comprised 1752 women on Exemestane and 1721 women on placebo; the Exemestane metabolite analysis included 1360 women on Exemestane with one-year serum samples. Both the UGT2B17 gene deletion and metabolites were measured in blood. The metabolites were conceptualized as a ratio (17-DHE-Gluc:17-DHE). Symptoms were assessed using the CTCAE v4.0 at approximately 1-year intervals. Log-binomial regression was used to examine the associations between UGT2B17 deletion, Exemestane metabolites and each side effect at 1 and up to 5-year follow-up, adjusting for potential confounders. Results Among individuals on Exemestane with the UGT2B17 gene deletion (i.e., lower detoxification), a higher risk of severe fatigue (RR = 2.59 95% CI: 1.14–5.89) was observed at up to 5-year follow-up. Among individuals on placebo, those with the UGT2B17 gene deletion had a higher risk of any fatigue (RR = 1.39, 95% CI: 1.02–1.89) at year 1. A lower metabolite ratio (poor detoxification) was associated with a higher risk of any fatigue, hot flashes and joint pain at year 1 (fatigue: RR = 1.89, 95% CI: 1.16–3.09; hot flashes: RR = 1.77, 95% CI: 1.40–2.24; joint pain: RR = 2.05, 95% CI: 1.35–3.12); similar associations were observed at 5-year follow-up. Conclusion Variation in the metabolism of Exemestane through the UGT2B17 -mediated pathway is associated with subsequent risk of commonly reported symptoms in MAP.3.

  • variation in the ugt2b17 genotype Exemestane metabolism and menopause related toxicities in the cctg map 3 trial
    Breast Cancer Research and Treatment, 2020
    Co-Authors: Romain Pasquet, Paul E. Goss, Gang Chen, Philip Lazarus, Shaman Luo, Harriet Richardson
    Abstract:

    To examine associations between the UGT2B17 gene deletion and Exemestane metabolites, and commonly reported side effects (fatigue, hot flashes, and joint pain) among postmenopausal women participating in the MAP.3 chemoprevention trial. The analytical samples for the UGT2B17 analysis comprised 1752 women on Exemestane and 1721 women on placebo; the Exemestane metabolite analysis included 1360 women on Exemestane with one-year serum samples. Both the UGT2B17 gene deletion and metabolites were measured in blood. The metabolites were conceptualized as a ratio (17-DHE-Gluc:17-DHE). Symptoms were assessed using the CTCAE v4.0 at approximately 1-year intervals. Log-binomial regression was used to examine the associations between UGT2B17 deletion, Exemestane metabolites and each side effect at 1 and up to 5-year follow-up, adjusting for potential confounders. Among individuals on Exemestane with the UGT2B17 gene deletion (i.e., lower detoxification), a higher risk of severe fatigue (RR = 2.59 95% CI: 1.14–5.89) was observed at up to 5-year follow-up. Among individuals on placebo, those with the UGT2B17 gene deletion had a higher risk of any fatigue (RR = 1.39, 95% CI: 1.02–1.89) at year 1. A lower metabolite ratio (poor detoxification) was associated with a higher risk of any fatigue, hot flashes and joint pain at year 1 (fatigue: RR = 1.89, 95% CI: 1.16–3.09; hot flashes: RR = 1.77, 95% CI: 1.40–2.24; joint pain: RR = 2.05, 95% CI: 1.35–3.12); similar associations were observed at 5-year follow-up. Variation in the metabolism of Exemestane through the UGT2B17-mediated pathway is associated with subsequent risk of commonly reported symptoms in MAP.3.

  • abstract b46 the influence of Exemestane on breast density in postmenopausal women a cohort study nested within the ncic ctg map 3 chemoprevention trial
    Cancer Prevention Research, 2015
    Co-Authors: Harriet Richardson, Paul E. Goss, Melanie Walker, Doris Jabs, Will D King
    Abstract:

    Background: Endogenous estradiol blood levels and high breast density are both associated with an increased risk for breast cancer (BC), but, there is conflicting evidence about whether or not they influence breast cancer risk through a shared pathway. Exemestane is an aromatase inhibitor that blocks the synthesis of estrogen and has been demonstrated to reduce the incidence of breast cancer in postmenopausal women by 65%. However the effects of Exemestane on breast density remain unclear. Objectives: The primary objective of this research was to prospectively examine the relationship between Exemestane versus placebo and changes in mammographic breast density (BD) in postmenopausal women during 3 or more years of treatment. Methods: The NCIC Clinical Trials Group conducted a phase III randomized controlled trial (RCT) comparing Exemestane (E), with placebo (P) in postmenopausal women at higher than average risk for BC (MAP.3). This study was nested within the MAP.3 RCT using data from 568 participants across Canada and Buffalo, New York. Information on treatment allocation and established risk factors for BC was previously collected and data on the outcome measures was obtained from mammograms. Baseline and follow-up mammograms were collected from participating centres and were measured (percent density) using Cumulus software by our team radiologist (DJ). Multivariable linear regression was used to estimate the effect of Exemestane treatment on >=3 year change in percent BD from randomization controlling for potential confounding variables. Results: Percent BD was measured for 386 participants (E=200, P=186) with a baseline and >=3 year follow-up mammogram that was matching in format (i.e. film or digital). The average age of women at study entry was 63 years and the average Gail score was 2.8%. The mean BD was similar in both arms at baseline (P: 12.9% (SD: 14.5) and E: 13.7% (SD: 14.4)). Similarly, the annual mean change in percent BD was not significantly different between the two treatment arms (P: 0.63% (SD: 1.82) vs E: .077% (SD: 1.80); p=0.90). After controlling for potential confounders (age, body mass index, first degree family history of BC and prior use of HRT), Exemestane was not predictive of change in percent BD (p-value=0.641). Neither age ( =60 yrs) nor BMI modified the Exemestane-breast density relationship significantly. Conclusion: We found no association between >=3 years of Exemestane use and change in percent BD among a subset of postmenopausal women participating in MAP.3. These results suggest that estrogen and breast density may have independent pathways in breast cancer etiology. Citation Format: Harriet Richardson, Paul E. Goss, Melanie Walker, Doris Jabs, Will King. The influence of Exemestane on breast density in postmenopausal women: A cohort study nested within the NCIC CTG MAP.3 chemoprevention trial. [abstract]. In: Proceedings of the Thirteenth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2014 Sep 27-Oct 1; New Orleans, LA. Philadelphia (PA): AACR; Can Prev Res 2015;8(10 Suppl): Abstract nr B46.

Stephen E Jones - One of the best experts on this subject based on the ideXlab platform.

  • long term follow up of the intergroup Exemestane study
    Journal of Clinical Oncology, 2017
    Co-Authors: James P Morden, Robert E. Coleman, Lucy Kilburn, Jacek Jassem, Stephen E Jones, Isabel Alvarez, G Bertelli, Alan S Coates, Lesley Fallowfield, Per Eystein Lonning
    Abstract:

    Purpose The Intergroup Exemestane Study, an investigator-led study of 4,724 postmenopausal patients with early breast cancer (clinical trial information: ISRCTN11883920), has previously demonstrated that a switch from adjuvant endocrine therapy after 2 to 3 years of tamoxifen to Exemestane was associated with clinically relevant improvements in efficacy. Here, we report the final efficacy analyses of this cohort. Patients and Methods Patients who remained disease free after 2 to 3 years of adjuvant tamoxifen were randomly assigned to continue tamoxifen or switch to Exemestane to complete a total of 5 years of adjuvant endocrine therapy. Given the large number of non-breast cancer-related deaths now reported, breast cancer-free survival (BCFS), with censorship of intercurrent deaths, was the primary survival end point of interest. Analyses focus on patients with estrogen receptor-positive or unknown tumors (n = 4,599). Results At the time of the data snapshot, median follow-up was 120 months. In the population that was estrogen receptor positive or had unknown estrogen receptor status, 1,111 BCFS events were observed with 508 (22.1%) of 2,294 patients in the Exemestane group and 603 (26.2%) of 2,305 patients in the tamoxifen group. The data corresponded to an absolute difference (between Exemestane and tamoxifen) at 10 years of 4.0% (95% CI, 1.2% to 6.7%), and the hazard ratio (HR) of 0.81 (95% CI, 0.72 to 0.92) favored Exemestane. This difference remained in multivariable analysis that was adjusted for nodal status, prior use of hormone replacement therapy, and prior chemotherapy (HR, 0.80; 95% CI, 0.71 to 0.90; P < .001). A modest improvement in overall survival was seen with Exemestane; the absolute difference (between Exemestane and tamoxifen) at 10 years in the population that was estrogen receptor positive or had unknown estrogen receptor status was 2.1% (95% CI, -0.5% to 4.6%), and the HR was 0.89 (95% CI, 0.78 to 1.01; P = .08). For the intention-to-treat population, the absolute difference was 1.6% (95% CI, -0.9% to 4.1%); the HR was 0.91 (95% CI, 0.80 to 1.03, P = .15). No statistically significant difference was observed in the proportion of patients who reported a fracture event in the post-treatment period. Conclusion The Intergroup Exemestane Study and contemporaneous studies have established that a strategy of switching to an aromatase inhibitor after 2 to 3 years of tamoxifen can lead to sustained benefits in terms of reduction of disease recurrence and breast cancer mortality.

  • disease related outcomes with long term follow up an updated analysis of the intergroup Exemestane study
    Journal of Clinical Oncology, 2012
    Co-Authors: J M Bliss, Robert E. Coleman, Lucy Kilburn, Jacek Jassem, T Delozier, Stephen E Jones, Alan S Coates, John F Forbes, Jorn Andersen, R Paridaens
    Abstract:

    Purpose Intergroup Exemestane Study (IES), an investigator-led study in 4,724 postmenopausal patients with early-stage breast cancer has demonstrated clinically important benefits from switching adjuvant endocrine therapy after 2 to 3 years of tamoxifen to Exemestane. Now, with longer follow-up, a large number of non–breast cancer–related events have been reported. Exploratory analyses describe breast cancer–free survival (BCFS) and explore incidence and patterns of the different competing events. Patients and Methods Patients who were disease-free after 2 to 3 years of adjuvant tamoxifen were randomly assigned to continue tamoxifen or switch to Exemestane to complete 5 years of adjuvant endocrine therapy. At this planned analysis, the median follow-up was 91 months. Principal analysis focuses on 4,052 patients with estrogen receptor (ER) –positive and 547 with ER-unknown tumors. Results In all, 930 BCFS events have been reported (Exemestane, 423; tamoxifen, 507), giving an unadjusted hazard ratio (HR) of...

  • cost effectiveness of switching to Exemestane after 2 to 3 years of therapy with tamoxifen in postmenopausal women with early stage breast cancer
    Value in Health, 2007
    Co-Authors: David M Thompson, Stephen E Jones, Douglas C A Taylor, Eduardo L Montoya, Eric P Winer, Milton C Weinstein
    Abstract:

    Abstract Objective Data from the Intergroup Exemestane Study (IES) suggest that switching to the aromatase inhibitor, Exemestane, after 2 to 3 years of tamoxifen therapy prolongs disease-free survival versus continuing on tamoxifen therapy. We sought to evaluate the cost-effectiveness of this management strategy. Methods A Markov model was developed to predict patients' transitions across various health states based on treatment strategy (continuing tamoxifen vs. switching to Exemestane), breast cancer status (no recurrence, local or distant recurrence, contralateral breast cancer), and other related health events (osteoporosis, endometrial cancer, death). Rates of disease-related events (recurrence and contralateral breast cancer) were estimated using data from the IES. Survival and lifetime medical-care costs by type of disease-related event were estimated using SEER-Medicare data. The model was used to estimate direct costs (in 2004 USdollars), life expectancy, quality-adjusted life-years (QALYs), and incremental cost-effectiveness. Results Switching to Exemestane versus continuing tamoxifen therapy was associated with increased disease-free survival (181 vs. 172 months), QALYs (12.21 vs. 11.89), and net discounted lifetime costs of cancer care ($12,124 vs. $7724 per patient). The incremental cost-effectiveness ratio of Exemestane was $20,100 per QALY gained (95% confidence interval: $12,100, $59,000). Sensitivity analyses showed that results were robust to plausible variations in recurrence rates, costs, and utilities. Conclusion Switching postmenopausal early-stage breast cancer patients to Exemestane after 2 to 3 years of tamoxifen appears to be a cost-effective treatment strategy versus completing a 5-year course of tamoxifen.

  • survival and safety of Exemestane versus tamoxifen after 2 3 years tamoxifen treatment intergroup Exemestane study a randomised controlled trial
    The Lancet, 2007
    Co-Authors: R C Coombes, Robert E. Coleman, Robert Paridaens, Jacek Jassem, T Delozier, Stephen E Jones, Claire Snowdon, L S Kilburn, Cjh Van De Velde, Isabel Alvarez
    Abstract:

    Summary Background Early improvements in disease-free survival have been noted when an aromatase inhibitor is given either instead of or sequentially after tamoxifen in postmenopausal women with oestrogen-receptor-positive early breast cancer. However, little information exists on the long-term effects of aromatase inhibitors after treatment, and whether these early improvements lead to real gains in survival. Methods 4724 postmenopausal patients with unilateral invasive, oestrogen-receptor-positive or oestrogen-receptor-unknown breast cancer who were disease-free on 2–3 years of tamoxifen, were randomly assigned to switch to Exemestane (n=2352) or to continue tamoxifen (n=2372) for the remainder of a 5-year endocrine treatment period. The primary endpoint was disease-free survival; overall survival was a secondary endpoint. Efficacy analyses were intention-to-treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN11883920. Results After a median follow-up of 55·7 months (range 0–89·7), 809 events contributing to the analysis of disease-free survival had been reported (354 Exemestane, 455 tamoxifen); unadjusted hazard ratio 0·76 (95% CI 0·66–0·88, p=0·0001) in favour of Exemestane, absolute benefit 3·3% (95% CI 1·6–4·9) by end of treatment (ie, 2·5 years after randomisation). 222 deaths occurred in the Exemestane group compared with 261 deaths in the tamoxifen group; unadjusted hazard ratio 0·85 (95% CI 0·71–1·02, p=0·08), 0·83 (0·69–1·00, p=0·05) when 122 patients with oestrogen-receptor-negative disease were excluded. Conclusions Our results suggest that early improvements in disease-free survival noted in patients who switch to Exemestane after 2–3 years on tamoxifen persist after treatment, and translate into a modest improvement in overall survival.

  • quality of life in the intergroup Exemestane study a randomized trial of Exemestane versus continued tamoxifen after 2 to 3 years of tamoxifen in postmenopausal women with primary breast cancer
    Journal of Clinical Oncology, 2006
    Co-Authors: Lesley Fallowfield, J M Bliss, Stephen E Jones, Claire Snowdon, Lucy S Porter, Miranda H Price, Charles R Coombes, Emma Hall
    Abstract:

    PURPOSE: To compare and describe the quality of life (QOL) of women allocated to tamoxifen or Exemestane within the Intergroup Exemestane Study (IES). PATIENTS AND METHODS: Postmenopausal women with primary breast cancer who were disease free after 2 to 3 years were randomly assigned to switch from tamoxifen to Exemestane or continue with tamoxifen until 5 years of treatment were completed. A subset of IES centers participated in a QOL substudy. The Functional Assessment of Cancer Therapy-Breast (FACT-B) and endocrine subscale (ES) were administered before random assignment and at predefined follow-up times. The primary end point was the FACT-B composite Trial Outcome Index (TOI). Secondary end points included total FACT-B+ES score, total ES score, and severity of individual endocrine symptoms. This analysis reports QOL up to 24 months. RESULTS: Five hundred eighty-two patients from eight countries were enrolled onto the substudy. Completion and return of questionnaires was excellent, with 85% available for analysis. QOL was generally good and stable over 2 years, with no clinically meaningful differences found between groups in TOI or ES. Prevalence of severe endocrine symptoms at trial entry was high for vasomotor complaints and sexual problems, which persisted for both groups during the study. No significant differences between groups were seen for any endocrine symptoms apart from vaginal discharge, which was more pronounced with tamoxifen (P < .001). CONCLUSION: The switch from tamoxifen to Exemestane neither increased nor decreased endocrine symptoms present after 2 to 3 years of tamoxifen; the switch also did not initiate significant reports of new symptoms. Results indicate that the clinical benefits of Exemestane over tamoxifen are achieved without significant detrimental effect on QOL.