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Regan M.M.,Dana-Farber Cancer Institute | Regan M.M.,Harvard University | Pagani O.,International Breast Cancer Study Group | Pagani O.,Institute of Oncology of Southern Switzerland IOSI | And 20 more authors.
Breast | Year: 2013

Objectives: In 2003 the International Breast Cancer Study Group (IBCSG) initiated the TEXT and SOFT randomized phase III trials to answer two questions concerning adjuvant treatment for premenopausal women with endocrine-responsive early breast cancer: 1-What is the role of aromatase inhibitors (AI) for women treated with ovarian function suppression (OFS)? 2-What is the role of OFS for women who remain premenopausal and are treated with tamoxifen? Methods: TEXT randomized patients to receive exemestane or tamoxifen with OFS. SOFT randomized patients to receive exemestane with OFS, tamoxifen with OFS, or tamoxifen alone. Treatment was for 5 years from randomization. Results: TEXT and SOFT successfully met their enrollment goals in 2011. The 5738 enrolled women had lower-risk disease and lower observed disease-free survival (DFS) event rates than anticipated. Consequently, 7 and 13 additional years of follow-up for TEXT and SOFT, respectively, were required to reach the targeted DFS events (median follow-up about 10.5 and 15 years). To provide timely answers, protocol amendments in 2011 specified analyses based on chronological time and median follow-up. To assess the AI question, exemestane+OFS versus tamoxifen+OFS, a combined analysis of TEXT and SOFT became the primary analysis (. n=4717). The OFS question became the primary analysis from SOFT, assessing the unique comparison of tamoxifen+OFS versus tamoxifen alone (. n=2045). The first reports are anticipated in mid- and late-2014. Conclusions: We present the original designs of TEXT and SOFT and adaptations to ensure timely answers to two questions concerning optimal adjuvant endocrine treatment for premenopausal women with endocrine-responsive breast cancer.Trial RegistrationTEXT: Clinicaltrials.gov NCT00066703SOFT: Clinicaltrials.gov NCT00066690. © 2013 Elsevier Ltd. Source

Leyland-Jones B.,Avera Cancer Institute | Gray K.P.,Dana-Farber Cancer Institute | Abramovitz M.,VM Institute of Research | Bouzyk M.,AKESOgen Inc. | And 24 more authors.
Breast Cancer Research and Treatment | Year: 2015

Estrogen receptor 1 (ESR1) and ESR2 gene polymorphisms have been associated with endocrine-mediated physiological mechanisms, and inconsistently with breast cancer risk and outcomes, bone mineral density changes, and hot flushes/night sweats. DNA was isolated and genotyped for six ESR1 and two ESR2 single-nucleotide polymorphisms (SNPs) from tumor specimens from 3691 postmenopausal women with hormone receptor-positive breast cancer enrolled in the BIG 1-98 trial to receive tamoxifen and/or letrozole for 5 years. Associations with recurrence and adverse events (AEs) were assessed using Cox proportional hazards models. 3401 samples were successfully genotyped for five SNPs. ESR1 rs9340799(XbaI) (T>C) variants CC or TC were associated with reduced breast cancer risk (HR = 0.82,95 % CI = 0.67–1.0), and ESR1 rs2077647 (T>C) variants CC or TC was associated with reduced distant recurrence risk (HR = 0.69, 95 % CI = 0.53–0.90), both regardless of the treatments. No differential treatment effects (letrozole vs. tamoxifen) were observed for the association of outcome with any of the SNPs. Letrozole-treated patients with rs2077647 (T>C) variants CC and TC had a reduced risk of bone AE (HR = 0.75, 95 % CI = 0.58–0.98, Pinteraction = 0.08), whereas patients with rs4986938 (G>A) genotype variants AA and AG had an increased risk of bone AE (HR = 1.37, 95 % CI = 1.01–1.84, Pinteraction = 0.07). We observed that (1) rare ESR1 homozygous polymorphisms were associated with lower recurrence, and (2) ESR1 and ESR2 SNPs were associated with bone AEs in letrozole-treated patients. Genes that are involved in estrogen signaling and synthesis have the potential to affect both breast cancer recurrence and side effects, suggesting that individual treatment strategies can incorporate not only oncogenic drivers but also SNPs related to estrogen activity. © 2015, Springer Science+Business Media New York. Source

Christinat A.,Institute of Oncology of Southern Switzerland IOSI | Pagani O.,Institute of Oncology of Southern Switzerland IOSI
Breast | Year: 2013

In unselected populations, less than 10% of breast cancers are associated with germline mutations in predisposing genes. Breast cancer type 1 and 2 (BRCA1 and BRCA2) susceptibility genes are the most common involved genes and confer a 10-30 times higher risk of developing the disease compared to the general population. A personal or family history suggestive of inherited breast cancer syndrome may be further evaluated to assess the risk of genetic predisposition and the presence of a genetic mutation. Breast cancer genetic counseling should include a careful risk assessment with associated psychosocial evaluation and support, possible molecular testing, personalized discussion of results. Knowledge of BRCA status can influence individualized cancer risk-reduction strategies. i.e. active surveillance, prophylactic surgery and/or pharmacoprevention. © 2013 Elsevier Ltd. Source

Di Lascio S.,Institute of Oncology of Southern Switzerland IOSI | Di Lascio S.,Breast Unit of Southern Switzerland CSSI | Pagani O.,Institute of Oncology of Southern Switzerland IOSI | Pagani O.,Breast Unit of Southern Switzerland CSSI
Breast Care | Year: 2014

A distinctive subset of metastatic breast cancer is represented by the so called 'oligometastatic' disease, characterized by single/few detectable metastatic lesions. A more aggressive multidisciplinary approach can be considered in this patient population: available data report favorable results of 'radical' local therapy for limited metastatic disease at least in a subset of selected patients. Selection bias and the retrospective nature of data do not allow for generalization of the results: the use of such approaches must be individualized and managed within a multidisciplinary team of dedicated specialists. Improvement in surgical and radiation techniques, development of new tools to deliver local chemotherapy, and new procedures (i.e. cryosurgery, laser and microwave ablation) mandate careful evaluation of such single and combined modalities in controlled clinical trials. A more accurate identification of patients with limited metastases and better definition of treatment endpoints will also allow correct patient selection for locally aggressive therapies. This paper focusses on local treatment of the primary tumor and of the most frequent distant disease sites in the presence of oligometastatic disease. © 2014 S. Karger GmbH, Freiburg. Source

Rossi L.,Institute of Oncology of Southern Switzerland IOSI | Pagani O.,Institute of Oncology of Southern Switzerland IOSI
Breast Care | Year: 2015

The optimal endocrine therapy for premenopausal women with early and advanced breast cancer still remains an important and controversial issue. For over 30 years, tamoxifen has been the gold standard in the adjuvant setting. New therapeutic options, such as the addition of ovarian function suppression to oral endocrine therapy (either tamoxifen or aromatase inhibitors), can improve outcomes over tamoxifen alone in well-selected patients. Treatment duration has also been revisited, and extended therapy is becoming a new standard of care, especially in high-risk patients. Endocrine therapy for advanced disease still represents a challenge and a research priority. New drugs and combinations able to overcome endocrine resistance are at the horizon, and their role in premenopausal women should be better elucidated. Side effects and quality of life (including family planning considerations) play an important role in treatment selection and in the patients' treatment adherence and should always be discussed before start of treatment. The paper will specifically focus on how to integrate all new treatment options in the current armamentarium of endocrine therapy of premenopausal women, with the aim of best fine-tuning treatment selections according to the individual risk/benefit evaluation. © 2015 S. Karger GmbH, Freiburg. Source

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