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    Effect of low-dose tamoxifen after surgical excision of ductal intraepithelial neoplasia: results of a large retrospective monoinstitutional cohort study. Guerrieri-Gonzaga A,Lazzeroni M,Botteri E,Serrano D,Rotmensz N,Varricchio M-C,Cazzaniga M,Bollani G,Mora S,Montefrancesco C,Pruneri G,Viale G,Intra M,Galimberti V,Goldhirsch A,Bagnardi V,Bonanni B,DeCensi A Annals of oncology : official journal of the European Society for Medical Oncology BACKGROUND:Postsurgical treatment of ductal intraepithelial neoplasia (DIN) with standard doses of tamoxifen has not reached a consensus yet. Given positive results of low-dose tamoxifen on breast cancer biomarkers modulation, we analyzed a large cohort of DIN patients treated with low-dose tamoxifen or no treatment as per institutional guidelines. PATIENTS AND METHODS:All consecutive women operated on at the European Institute of Oncology for estrogen receptor (ER)-positive DIN (474 treated with low-dose tamoxifen and 509 untreated patients) were followed up for a median of 7 years. RESULTS:Compared with untreated patients, a significant 30% reduction in breast cancer risk was observed on low-dose tamoxifen with an adjusted hazard ratio (HR) = 0.70 [95% confidence interval (CI) 0.51-0.94], with a greater benefit in postmenopausal (HR = 0.57; 95% CI 0.34-0.94) than in premenopausal women (HR = 0.79; 95% CI 0.54-1.17). Treated patients with ER and progesterone receptor (PgR) >50% DIN had a lower incidence of breast events than untreated ones (HR = 0.61; 95% CI 0.40-0.94), whereas no protective effect has been observed in patients with ER or PgR <50% DIN. Drug discontinuation resulted in a doubled risk of recurrence in premenopausal women only (HR = 1.95; 95% CI 0.98-3.89). No excess of endometrial cancer occurred. CONCLUSIONS:Low-dose tamoxifen is a promising and safe strategy for highly endocrine responsive DIN. Treatment adherence is crucial in premenopausal women. A definitive trial is ongoing. 10.1093/annonc/mdt113
    A pooled analysis of CYP2D6 genotype in breast cancer prevention trials of low-dose tamoxifen. Johansson Harriet,Gandini Sara,Serrano Davide,Gjerde Jennifer,Lattanzi Monia,Macis Debora,Guerrieri-Gonzaga Aliana,Aristarco Valentina,Mellgren Gunnar,Lien Ernst,DeCensi Andrea,Bonanni Bernardo Breast cancer research and treatment Decreased CYP2D6 activity is associated with lower levels of active tamoxifen metabolites. We examined the impact of CYP2D6 genotype on tamoxifen pharmacokinetics, biomarker activity, and efficacy in a pooled analysis of low-dose tamoxifen. Four randomized breast cancer prevention trials of very-low-dose (1 mg/day, n = 52 or 10 mg/week, n = 152) or low-dose tamoxifen (5 mg/day, n = 171) were pooled. DNA from 367 subjects was genotyped for CYP2D6 alleles associated with absent (PM allele: *3, *4, *5, *6, *7, *8, *12, and *14), reduced (IM allele: *9, *10, *17, *29, *41), normal (EM allele), or increased (UM: *XN) enzyme activity. Associations of tamoxifen, metabolites, activity biomarkers, and event-free survival with rapid (UM/EM, UM/IM, EM/EM, EM/IM, or EM/PM alleles) versus slow metabolizers (PM/IM or PM/PM) were investigated through random effects models, with 'study' as the random factor, and Cox regression models, adjusting for confounders. Rapid metabolizers had higher endoxifen levels than slow metabolizers: 15.3 versus 12.2 ng/mL (P = 0.018) with 5 mg/day, and 3.8 versus 2.8 ng/mL (P = 0.004) with 1 mg/day or 10 mg/week tamoxifen. The IGF-I decrease correlated with endoxifen (P = 0.002) and 4-hydroxytamoxifen levels, demonstrating steeper decreases at higher metabolite levels (P = 0.001). After a median follow-up of 12 years, rapid metabolizers with prior history of breast neoplasms allocated to tamoxifen 5 mg/day had a 60 % reduction of risk of recurrences (HR = 0.40, 95 % CI: 0.16-0.99) compared to slow metabolizers. CYP2D6 genotype may have an impact on tamoxifen efficacy at low doses. Trials investigating tamoxifen dose adjustments based on the woman's hormonal context and CYP2D6 genotype are warranted. 10.1007/s10549-016-3932-7
    Comparative effectiveness of tamoxifen, toremifene, letrozole, anastrozole, and exemestane on lipid profiles in breast cancer patients: A network meta-analysis. He Tao,Yang Wenhao,Zhang Xinyi,Li Ping,Yang Dandan,Wu Yunhao,Fan Yuan,Xiang Mengya,Huang Qianqian,Chen Jing,Zhou Runke,Lv Qing,Chen Jie Medicine BACKGROUND:Adjuvant endocrine therapy is a vital portion of postoperative comprehensive treatment for breast cancer patients. In recent years, studies have shown that endocrine therapy has a certain impact on the serum lipids of breast cancer patients, and the changes of lipid profiles may bring a series of problems. However, very few studies focus on this issue to date. The results of these studies are inconsistent, and the influence of different adjuvant endocrine modalities on lipid profiles still remains controversial. In order to better explore this issue, we conduct this network meta-analysis. METHOD:The protocol followed preferred reporting items for systematic reviews and meta-analyses protocols. Three main databases (PubMed, Embase, and the Cochrane Library) will be searched systematically for eligible randomized controlled trials without language restriction. In addition, a manual search of the references of relevant published studies will also be considered. Two reviewers will conduct studies selection, data extraction, and risk of bias assessment independently. The primary outcome is the variation of biochemical parameters - the serum lipid profiles (cholesterol, triglyceride, high-density lipoprotein, low low-density lipoprotein). RESULTS:The results will provide useful information about the side effects of different adjuvant endocrine drugs on lipid profiles in postoperative breast cancer patients (estrogen receptor-positive and/or progesterone receptor-positive). CONCLUSION:The findings of this study will be published in a peer-reviewed journal. PROSPERO REGISTRATION NUMBER:CRD42019129850. 10.1097/MD.0000000000018550
    Toremifene for breast cancer: a review of 20 years of data. Vogel Charles L,Johnston Mary Ann,Capers Christi,Braccia Deborah Clinical breast cancer Endocrine therapy is a cornerstone of medical treatment for estrogen receptor-positive breast cancer. The discovery of selective estrogen receptor modulators (SERMs) > 40 years ago represented a revolutionary advance in the treatment of breast cancer. As a therapeutic class, SERMs have either estrogenic or antiestrogenic activity, depending on the target tissue and the hormonal environment. In breast tissue, SERMs are antiestrogenic, making them a major treatment option for women with hormone-sensitive breast cancer. Toremifene citrate was developed > 20 years ago with the goal of achieving efficacy similar to that of tamoxifen and with an improved safety profile. Although studies to date have not confirmed a clear safety advantage or disadvantage for toremifene, clinical data support the efficacy and safety of toremifene for the treatment of breast cancer in postmenopausal patients. Toremifene also has a pharmacokinetic profile and metabolic pathway different from that of tamoxifen, which may provide a therapeutic advantage in certain patients. In addition, because of the selective estrogenic effects of SERMs in bone and on lipid levels along with a different side effect profile compared with the aromatase inhibitors (AIs), toremifene is a viable option to the AIs for some patients. Despite a number of clinical trials and over 500,000 patient years of use, many oncologists have limited familiarity with toremifene data. This article will examine the rationale for the use of toremifene in the treatment of women with breast cancer and review data from 20 years of clinical experience with this agent. 10.1016/j.clbc.2013.10.014
    Tamoxifen Initiation After Ductal Carcinoma In Situ. Nichols Hazel B,Bowles Erin J A,Islam Jessica,Madziwa Lawrence,Stürmer Til,Tran Diem-Thy,Buist Diana S M The oncologist BACKGROUND:Endocrine therapy initiation after ductal carcinoma in situ (DCIS) is highly variable and largely unexplained. National guidelines recommend considering tamoxifen for women with estrogen receptor-positive (ER+) DCIS or who undergo excision alone. We evaluated endocrine therapy use after DCIS over a 15-year period in an integrated health care setting to identify factors related to initiation. METHODS:Female Group Health Cooperative enrollees ages 18-89 years with a DCIS diagnosis during 1996-2011 were eligible for inclusion. Endocrine therapy was identified through pharmacy records. Tumor and treatment information were from tumor registry reports; demographics and other risk factors were from questionnaires and electronic medical records. Relative risks (RRs) and 95% confidence intervals (CIs) for endocrine therapy initiation were calculated using multivariable generalized linear models. RESULTS:We identified 727 women with a DCIS diagnosis, including 163 (22%) who initiated endocrine therapy (149 tamoxifen, 14 aromatase inhibitor). Younger women were more likely to initiate endocrine therapy (RR 1.69; 95% CI 1.16-2.46 for ages 45-54 vs. 65-74 years). Compared with breast-conserving surgery (BCS) with radiation, women who had BCS alone (RR 0.46; 95% CI 0.25-0.84) or mastectomy (RR 0.54; 95% CI 0.39-0.75) were less likely to use endocrine therapy. ER testing increased from 4% of DCIS cases in 2001 to 71% in 2011; however, endocrine therapy initiation decreased from 58% of ER+ DCIS in 2001-2005 to 37% in 2009-2011. CONCLUSION:Increasing ER testing since 2001 has not corresponded to parallel increases in endocrine therapy initiation. Age, surgery, and radiation were the primary factors associated with initiation. IMPLICATIONS FOR PRACTICE:National guidelines recommend considering tamoxifen for women with ductal carcinoma in situ (DCIS) who are estrogen receptor-positive (ER+) or who undergo excision alone. In this study, the rapid increase in ER testing caused by tamoxifen's approval in 2000 did not lead to increases in endocrine therapy initiation, despite recognition of an increasing number of DCIS tumors as ER+ each year. Contrary to the suggested guidelines, women who had breast-conserving surgery without radiation were less likely to use tamoxifen than those who had radiation. Future Food and Drug Administration approval of new endocrine agents for DCIS (such as aromatase inhibitors) may provide an opportunity to reemphasize benefits by ER and surgery status. 10.1634/theoncologist.2015-0310
    Benefit of low-dose tamoxifen in a large observational cohort of high risk ER positive breast DCIS. Guerrieri-Gonzaga Aliana,Sestak Ivana,Lazzeroni Matteo,Serrano Davide,Rotmensz Nicole,Cazzaniga Massimiliano,Varricchio Clara,Pruneri Giancarlo,Leonardi Maria Cristina,Orecchia Roberto,Galimberti Viviana,Bonanni Bernardo,DeCensi Andrea International journal of cancer Low-dose tamoxifen has comparable antiproliferative effect to the standard dose of 20 mg/day in biomarker trials, but its clinical efficacy remains unclear. We assessed the effect of low-dose tamoxifen on ipsilateral recurrence in ductal carcinoma in situ (DCIS) patients treated in a referral Institution between 1996 and 2008. Following conserving surgery, women received radiotherapy and/or low-dose tamoxifen upon clinical judgment and patient preferences. Cox regression analyses were used with and without confounding factors. Among 1,091 women with DCIS and median age 53 years (IQR: 46-62), 544 (49.9%) received radiotherapy. Of the 833 women with oestrogen receptor (ER) positive DCIS, 467 (56.1%) received low-dose tamoxifen. After a median of 7.7 years, 235 ipsilateral recurrences and 62 contralateral breast tumors were observed. Low-dose tamoxifen significantly decreased any breast event (HR = 0.70, 95% CI: 0.54-0.91) and ipsilateral DCIS recurrence (HR = 0.66, 95% CI: 0.49-0.88), but not ipsilateral invasive recurrence or contralateral tumors. Radiotherapy showed a large significant reduction for any breast event (HR = 0.55, 95% CI: 0.42-0.72). Tamoxifen was more effective on all breast events in women aged >50 years than in women aged ≤50 (HR = 0.51, 95% CI: 0.33-0.77 versus HR = 0.84, 95% CI: 0.60-1.18, p-interaction = 0.03). Age ≤50 years, positive margins, high Ki67, high grade and low BMI were independent predictors of ipsilateral recurrence. No increase of endometrial cancers and fewer deaths (p = 0.015) were observed on tamoxifen. Low-dose tamoxifen seems to be safe and effective in reducing ipsilateral recurrence in ER positive DCIS in women aged >50 years. A randomized trial is underway to confirm these findings. 10.1002/ijc.30254
    Ductal intraepithelial neoplasia: postsurgical outcome for 1,267 women cared for in one single institution over 10 years. Guerrieri-Gonzaga Aliana,Botteri Edoardo,Rotmensz Nicole,Bassi Fabio,Intra Mattia,Serrano Davide,Renne Giuseppe,Luini Alberto,Cazzaniga Massimiliano,Goldhirsch Aaron,Colleoni Marco,Viale Giuseppe,Ivaldi Giovanni,Bagnardi Vincenzo,Lazzeroni Matteo,Decensi Andrea,Veronesi Umberto,Bonanni Bernardo The oncologist INTRODUCTION:Diagnosis of breast ductal intraepithelial neoplasia (DIN) has increased over the last decades, but proper postsurgical treatment remains controversial. We analyzed risk factors and treatment outcome in a large series of women treated at one institution. METHODS:Women undergoing surgery for DIN at the European Institute of Oncology between 1996 and 2005, with follow-up until December 2006, were included. RESULTS:We evaluated the postsurgical treatment outcome of 974 and 293 patients who underwent breast-conserving surgery (BCS) or mastectomy, respectively. The 5-year cumulative incidence of breast cancer (BC) events was 11.8%, with a significant trend according to age (from 43% in women <36 years to 8% in women >65 years). Among the 727 BCS patients with DIN2-DIN3 histology, 414 (57%) received radiotherapy (RT), and they were both younger and with worse prognostic factors than the 313 patients who did not receive it. In these groups, the adjusted hazard ratio (HR) for RT versus non-RT was 0.40 (95% confidence interval [CI], 0.26-0.63). Among the 691 BCS patients with estrogen receptor (ER)(+) disease, 329 (48%) received low-dose tamoxifen (either 5 mg/day or 20 mg once a week) and they were younger than the 362 who did not receive it. In these groups, the adjusted HR for tamoxifen versus no tamoxifen was 0.68 (95% CI, 0.43-1.07), and the HR was 0.55 (95% CI, 0.32-0.97) after excluding human epidermal growth factor receptor (HER)2/neu-overexpressing DIN. CONCLUSIONS:BC events were more frequent in young patients. RT was associated with a lower incidence of BC events. Low-dose tamoxifen was associated with a lower incidence of BC events in patients with ER(+) disease when HER-2 was not overexpressed. Further prospective studies should confirm our observations. 10.1634/theoncologist.2008-0203
    Low-dose tamoxifen in the treatment of breast ductal intraepithelial neoplasia: results of a large observational study. Guerrieri-Gonzaga A,Botteri E,Lazzeroni M,Rotmensz N,Goldhirsch A,Varricchio C,Serrano D,Cazzaniga M,Bassi F,Luini A,Bagnardi V,Viale G,Mora S,Bollani G,Albertazzi E,Bonanni B,Decensi A Annals of oncology : official journal of the European Society for Medical Oncology BACKGROUND:Tamoxifen's cost-benefit ratio for breast ductal intraepithelial neoplasia (DIN) is unclear. Since low-dose tamoxifen showed a favorable modulation of breast cancer biomarkers in phase II trials, a monoinstitutional cohort of women with DIN treated with low-dose tamoxifen or no systemic treatment was analyzed. PATIENTS AND METHODS:A total of 309 patients with DIN received low-dose tamoxifen as part of institutional guidelines and were compared with 371 patients with DIN who received no systemic treatment after surgery. RESULTS:Women with estrogen receptor (ER)/progesterone receptor (PgR) >50% DIN who were not treated had a higher incidence of breast events than women on tamoxifen [hazard ratio (HR) 1.76; 95% confidence interval (CI) 1.00-3.12] or women with ER/PgR <50% DIN (HR 1.72; 95% CI 1.14-2.58). Among untreated patients with ER >50% DIN, recurrence was higher in PgR > or =50% DIN than in PgR <50% DIN, whereas it was similar among low PgR (<50%) DIN against which tamoxifen had no effect. No difference in endometrial cancer incidence was noted. CONCLUSIONS:High ER and especially high PgR expression is a significant adverse prognostic indicator of DIN, and low-dose tamoxifen appears to be an active treatment. Women with low-expression ER or PgR DIN do not seem to benefit from tamoxifen. A definitive clinical trial is warranted. 10.1093/annonc/mdp408
    Management and 5-year outcomes in 9938 women with screen-detected ductal carcinoma in situ: the UK Sloane Project. Thompson Alastair M,Clements Karen,Cheung Shan,Pinder Sarah E,Lawrence Gill,Sawyer Elinor,Kearins Olive,Ball Graham R,Tomlinson Ian,Hanby Andrew,Thomas Jeremy St J,Maxwell Anthony J,Wallis Matthew G,Dodwell David J, European journal of cancer (Oxford, England : 1990) BACKGROUND:Management of screen-detected ductal carcinoma in situ (DCIS) remains controversial. METHODS:A prospective cohort of patients with DCIS diagnosed through the UK National Health Service Breast Screening Programme (1st April 2003 to 31st March 2012) was linked to national databases and case note review to analyse patterns of care, recurrence and mortality. RESULTS:Screen-detected DCIS in 9938 women, with mean age of 60 years (range 46-87), was treated by mastectomy (2931) or breast conserving surgery (BCS) (7007; 70%). At 64 months median follow-up, 697 (6.8%) had further DCIS or invasive breast cancer after BCS (7.8%) or mastectomy (4.5%) (p < 0.001). Breast radiotherapy (RT) after BCS (4363/7007; 62.3%) was associated with a 3.1% absolute reduction in ipsilateral recurrent DCIS or invasive breast cancer (no RT: 7.2% versus RT: 4.1% [p < 0.001]) and a 1.9% absolute reduction for ipsilateral invasive breast recurrence (no RT: 3.8% versus RT: 1.9% [p < 0.001]), independent of the excision margin width or size of DCIS. Women without RT after BCS had more ipsilateral breast recurrences (p < 0.001) when the radial excision margin was <2 mm. Adjuvant endocrine therapy (1208/9938; 12%) was associated with a reduction in any ipsilateral recurrence, whether RT was received (hazard ratio [HR] 0.57; 95% confidence interval [CI] 0.41-0.80) or not (HR 0.68; 95% CI 0.51-0.91) after BCS. Women who developed invasive breast recurrence had a worse survival than those with recurrent DCIS (p < 0.001). Among 321 (3.2%) who died, only 46 deaths were attributed to invasive breast cancer. CONCLUSION:Recurrent DCIS or invasive cancer is uncommon after screen-detected DCIS. Both RT and endocrine therapy were associated with a reduction in further events but not with breast cancer mortality within 5 years of diagnosis. Further research to identify biomarkers of recurrence risk, particularly as invasive disease, is indicated. 10.1016/j.ejca.2018.06.027
    Invasive breast cancer and breast cancer mortality after ductal carcinoma in situ in women attending for breast screening in England, 1988-2014: population based observational cohort study. Mannu Gurdeep S,Wang Zhe,Broggio John,Charman Jackie,Cheung Shan,Kearins Olive,Dodwell David,Darby Sarah C BMJ (Clinical research ed.) OBJECTIVE:To evaluate the long term risks of invasive breast cancer and death from breast cancer after ductal carcinoma in situ (DCIS) diagnosed through breast screening. DESIGN:Population based observational cohort study. SETTING:Data from the NHS Breast Screening Programme and the National Cancer Registration and Analysis Service. PARTICIPANTS:All 35 024 women in England diagnosed as having DCIS by the NHS Breast Screening Programme from its start in 1988 until March 2014. MAIN OUTCOME MEASURES:Incident invasive breast cancer and death from breast cancer. RESULTS:By December 2014, 13 606 women had been followed for up to five years, 10 998 for five to nine years, 6861 for 10-14 years, 2620 for 15-19 years, and 939 for at least 20 years. Among these women, 2076 developed invasive breast cancer, corresponding to an incidence rate of 8.82 (95% confidence interval 8.45 to 9.21) per 1000 women per year and more than double that expected from national cancer incidence rates (ratio of observed rate to expected rate 2.52, 95% confidence interval 2.41 to 2.63). The increase started in the second year after diagnosis of DCIS and continued until the end of follow-up. In the same group of women, 310 died from breast cancer, corresponding to a death rate of 1.26 (1.13 to 1.41) per 1000 women per year and 70% higher than that expected from national breast cancer mortality rates (observed:expected ratio 1.70, 1.52 to 1.90). During the first five years after diagnosis of DCIS, the breast cancer death rate was similar to that expected from national mortality rates (observed:expected ratio 0.87, 0.69 to 1.10), but it then increased, with values of 1.98 (1.65 to 2.37), 2.99 (2.41 to 3.70), and 2.77 (2.01 to 3.80) in years five to nine, 10-14, and 15 or more after DCIS diagnosis. Among 29 044 women with unilateral DCIS undergoing surgery, those who had more intensive treatment (mastectomy, radiotherapy for women who had breast conserving surgery, and endocrine treatment in oestrogen receptor positive disease) and those with larger final surgical margins had lower rates of invasive breast cancer. CONCLUSIONS:To date, women with DCIS detected by screening have, on average, experienced higher long term risks of invasive breast cancer and death from breast cancer than women in the general population during a period of at least two decades after their diagnosis. More intensive treatment and larger final surgical margins were associated with lower risks of invasive breast cancer. 10.1136/bmj.m1570
    A model to predict upstaging to invasive carcinoma in patients preoperatively diagnosed with ductal carcinoma in situ of the breast. Kondo Takafumi,Hayashi Naoki,Ohde Sachiko,Suzuki Koyu,Yoshida Atsushi,Yagata Hiroshi,Niikura Naoki,Iwamoto Takayuki,Kida Kumiko,Murai Michiko,Takahashi Yuko,Tsunoda Hiroko,Nakamura Seigo,Yamauchi Hideko Journal of surgical oncology BACKGROUND:The aims of this study were to determine clinicopathological factors associated with postoperative upstaging to invasive carcinoma in patients preoperatively diagnosed with ductal carcinoma in situ (DCIS) and to develop a model to predict the risk of upstaging. METHODS:Pre- and post-operative pathological diagnoses and radiological findings were assessed for 1,187 consecutive patients. RESULTS:Of the patients, 306 (25.8%) were upstaged on the surgical specimen. In multivariate analysis, the following four factors were significantly associated with upstaging: 1) the presence of sclerosing adenosis on the preoperative biopsy specimen (odds ratio [OR] 0.46, P = 0.013); 2) pleomorphic calcifications on the mammogram (OR 1.68, P = 0.009); 3) a mass suspicious for invasive carcinoma on ultrasonography and/or MRI (OR 2.13, P < 0.001); 4) tumor size ≥2 cm on ultrasonography (OR 1.80, P = 0.032). HER2-positive (OR 1.54, P = 0.062) and comedo necrosis (OR 1.42, P = 0.056) demonstrated a trend towards significance. A prediction model incorporating these variables demonstrated that the risk of upstaging was 5.1% with score 0-2 and was 58.1% with score 10. CONCLUSIONS:The prediction model incorporating clinicopathological features may be used to guide the selection of patients with DCIS for sentinel lymph node biopsy. 10.1002/jso.24037
    Randomized Placebo Controlled Trial of Low-Dose Tamoxifen to Prevent Local and Contralateral Recurrence in Breast Intraepithelial Neoplasia. DeCensi Andrea,Puntoni Matteo,Guerrieri-Gonzaga Aliana,Caviglia Silvia,Avino Franca,Cortesi Laura,Taverniti Cristiana,Pacquola Maria Grazia,Falcini Fabio,Gulisano Marcella,Digennaro Maria,Cariello Anna,Cagossi Katia,Pinotti Graziella,Lazzeroni Matteo,Serrano Davide,Branchi Daniela,Campora Sara,Petrera Marilena,Buttiron Webber Tania,Boni Luca,Bonanni Bernardo Journal of clinical oncology : official journal of the American Society of Clinical Oncology PURPOSE:Tamoxifen administered for 5 years at 20 mg/d is effective in breast cancer treatment and prevention, but toxicity has limited its broad use. Biomarker trials showed that 5 mg/d is not inferior to 20 mg/d in decreasing breast cancer proliferation. We hypothesized that a lower dose given for a shorter period could be as effective in preventing recurrence from breast intraepithelial neoplasia but have a lower toxicity than the standard dose. PATIENTS AND METHODS:We conducted a multicenter randomized trial of tamoxifen, 5 mg/d or placebo administered for 3 years after surgery in women with hormone-sensitive or unknown breast intraepithelial neoplasia, including atypical ductal hyperplasia and lobular or ductal carcinoma in situ. The primary end point was the incidence of invasive breast cancer or ductal carcinoma in situ. RESULTS:Five hundred women 75 years of age or younger were included. After a median follow-up of 5.1 years (interquartile range, 3.9-6.3 years), there were 14 neoplastic events with tamoxifen and 28 with placebo (11.6 23.9 per 1,000 person-years; hazard ratio, 0.48; 95% CI, 0.26 to 0.92; = .02), which resulted in a 5-year number needed to treat of 22 (95% CI, 20 to 27). Tamoxifen decreased contralateral breast events by 75% (three 12 events; hazard ratio, 0.25; 95% CI, 0.07 to 0.88; = .02). Patient-reported outcomes were not different between arms except for a slight increase in frequency of daily hot flashes with tamoxifen ( = .02). There were 12 serious adverse events with tamoxifen and 16 with placebo, including one deep vein thrombosis and one stage I endometrial cancer with tamoxifen and one pulmonary embolism with placebo. CONCLUSION:Tamoxifen at 5 mg/d for 3 years can halve the recurrence of breast intraepithelial neoplasia with a limited toxicity, which provides a new treatment option in these disorders. 10.1200/JCO.18.01779
    A Quantitative Centrosomal Amplification Score Predicts Local Recurrence of Ductal Carcinoma . Mittal Karuna,Toss Michael S,Wei Guanhao,Kaur Jaspreet,Choi Da Hoon,Melton Brian D,Osan Remus M,Miligy Islam M,Green Andrew R,Janssen Emiel A M,Søiland Håvard,Gogineni Keerthi,Manne Upender,Rida Padmashree,Rakha Emad A,Aneja Ritu Clinical cancer research : an official journal of the American Association for Cancer Research PURPOSE:The purpose of this study is to predict risk of local recurrence (LR) in ductal carcinoma (DCIS) with a new visualization and quantification approach using centrosome amplification (CA), a cancer cell-specific trait widely associated with aggressiveness. EXPERIMENTAL DESIGN:This first-of-its-kind methodology evaluates the severity and frequency of numerical and structural CA present within DCIS and assigns a quantitative centrosomal amplification score (CAS) to each sample. Analyses were performed in a discovery cohort (DC, = 133) and a validation cohort (VC, = 119). RESULTS:DCIS cases with LR exhibited significantly higher CAS than recurrence-free cases. Higher CAS was associated with a greater risk of developing LR (HR, 6.3 and 4.8 for DC and VC, respectively; < 0.001). CAS remained an independent predictor of relapse-free survival (HR, 7.4 and 4.5 for DC and VC, respectively; < 0.001) even after accounting for potentially confounding factors [grade, age, comedo necrosis, and radiotherapy (RT)]. Patient stratification using CAS ( < 0.0001) was superior to that by Van Nuys Prognostic Index (VNPI; HR for CAS = 6.2 vs. HR for VNPI = 1.1). Among patients treated with breast-conserving surgery alone, CAS identified patients likely to benefit from adjuvant RT. CONCLUSIONS:CAS predicted 10-year LR risk for patients who underwent surgical management alone and identified patients who may be at low risk of recurrence, and for whom adjuvant RT may not be required. CAS demonstrated the highest concordance among the known prognostic models such as VNPI and clinicopathologic variables such as grade, age, and comedo necrosis. 10.1158/1078-0432.CCR-19-1272
    Endocrine Therapy Initiation and Medical Oncologist UtilizationAmong Women Diagnosed with Ductal Carcinoma in Situ
    Ductal Carcinoma in Situ: A French National Survey. Analysis of 2125 Patients. Cutuli Bruno,Lemanski Claire,De Lafontan Brigitte,Chauvet Marie-Pierre,De Lara Christine Tunon,Mege Alice,Fric Daniele,Richard-Molard Marion,Mazouni Chafica,Cuvier Caroline,Carre Agnes,Kirova Youla Clinical breast cancer BACKGROUND:Ductal carcinoma in situ (DCIS) represents 15% of all breast cancers in France. The first national survey was conducted in 2003. The present multi-center real-life practice survey aimed at assessing possible changes in demographic, clinical, pathologic, and treatment features. MATERIAL AND METHODS:From March 2014 to September 2015, patients diagnosed with DCIS from 71 centers with complete information about age, diagnostic features, and treatment modalities were prospectively included. RESULTS:A total of 2125 patients with a median age of 58.6 years from 71 centers were studied. DCIS was diagnosed by mammography in 87.5% of cases. Preoperative biopsy was performed in 96% of cases. The median tumor size was 15 mm. Nuclear grade was low, intermediate, and high in 12%, 36%, and 47% of cases, respectively. Margins were considered to be negative in 83% of cases. Overall mastectomy and lumpectomy rates were 25% and 75%, respectively. The immediate breast reconstruction rate was 50%. Sentinel node biopsy and axillary dissection rates were 41% and 2.6%, respectively. After lumpectomy, 97% of patients underwent radiotherapy, and 32% received a boost dose. Only 1% of patients received endocrine therapy. Compared with our previous survey, the median tumor size remained the same, and the proportion of high-grade lesions increased by 9%. The mastectomy rate decreased by 4%. CONCLUSIONS:The clinical practice identified in this survey complies with French DCIS guidelines. About 10% of patients with low-grade DCIS may be eligible to participate in treatment de-escalation trials. 10.1016/j.clbc.2019.08.002
    The 2019 WHO classification of tumours of the breast. Hoon Tan Puay,Ellis Ian,Allison Kimberly,Brogi Edi,Fox Stephen B,Lakhani Sunil,Lazar Alexander J,Morris Elizabeth A,Sahin Aysegul,Salgado Roberto,Sapino Anna,Sasano Hironobu,Schnitt Stuart,Sotiriou Christos,van Diest Paul,White Valerie A,Lokuhetty Dilani,Cree Ian A, Histopathology The newly published World Health Organization (WHO) Classification of Tumours of the breast features significant changes compared to earlier editions. In this review, we outline the major changes in this important reference source for those diagnosing tumours, or engaged in cancer research, and describe the significant changes. For breast cancer, the overview acknowledges the treatment-relevant subtypes of invasive carcinoma (based on ER and HER2 status) and new data is added to support the differences in pathogenesis, treatment response and prognosis of these clinically relevant groupings. The WHO Classification of Tumours is increasingly evidence-based, with a clear update cycle, improved quality of illustrations, as well as content, led by an editorial board comprising pathologists, but increasingly incorporating input from other disciplines. The advent of the new website allows the use of whole slide images, and hyperlinks to evidence or external bodies that produce guidance on staging or reporting. 10.1111/his.14091
    The COMET (Comparison of Operative versus Monitoring and Endocrine Therapy) trial: a phase III randomised controlled clinical trial for low-risk ductal carcinoma in situ (DCIS). Hwang E Shelley,Hyslop Terry,Lynch Thomas,Frank Elizabeth,Pinto Donna,Basila Desiree,Collyar Deborah,Bennett Antonia,Kaplan Celia,Rosenberg Shoshana,Thompson Alastair,Weiss Anna,Partridge Ann BMJ open INTRODUCTION:Ductal carcinoma in situ (DCIS) is a non-invasive non-obligate precursor of invasive breast cancer. With guideline concordant care (GCC), DCIS outcomes are at least as favourable as some other early stage cancer types such as prostate cancer, for which active surveillance (AS) is a standard of care option. However, AS has not yet been tested in relation to DCIS. The goal of the COMET (Comparison of Operative versus Monitoring and Endocrine Therapy) trial for low-risk DCIS is to gather evidence to help future patients consider the range of treatment choices for low-risk DCIS, from standard therapies to AS. The trial will determine whether there may be some women who do not substantially benefit from current GCC and who could thus be safely managed with AS. This protocol is version 5 (11 July 2018). Any future protocol amendments will be submitted to Quorum Centralised Institutional Review Board/local institutional review boards for approval via the sponsor of the study (Alliance Foundation Trials). METHODS AND ANALYSIS:COMET is a phase III, randomised controlled clinical trial for patients with low-risk DCIS. The primary outcome is ipsilateral invasive breast cancer rate in women undergoing GCC compared with AS. Secondary objectives will be to compare surgical, oncological and patient-reported outcomes. Patients randomised to the GCC group will undergo surgery as well as radiotherapy when appropriate; those in the AS group will be monitored closely with surgery only on identification of invasive breast cancer. Patients in both the GCC and AS groups will have the option of endocrine therapy. The total planned accrual goal is 1200 patients. ETHICS AND DISSEMINATION:The COMET trial will be subject to biannual formal review at the Alliance Foundation Data Safety Monitoring Board meetings. Interim analyses for futility/safety will be completed annually, with reporting following Consolidated Standards of Reporting Trials (CONSORT) guidelines for non-inferiority trials. TRIAL REGISTRATION NUMBER:NCT02926911; Pre-results. 10.1136/bmjopen-2018-026797
    Toremifene and tamoxifen are equally effective for early-stage breast cancer: first results of International Breast Cancer Study Group Trials 12-93 and 14-93. ,Pagani Olivia,Gelber Shari,Price Karen,Zahrieh David,Gelber Richard,Simoncini Edda,Castiglione-Gertsch Monica,Coates Alan S,Goldhirsch Aron Annals of oncology : official journal of the European Society for Medical Oncology BACKGROUND:Toremifene is a chlorinated derivative of tamoxifen, developed to improve its risk-benefit profile. The International Breast Cancer Study Group (IBCSG) conducted two complementary randomized trials for peri- and postmenopausal patients with node-positive breast cancer to compare toremifene versus tamoxifen as the endocrine agent and simultaneously investigate a chemotherapy-oriented question. This is the first report of the endocrine comparison after a median follow-up of 5.5 years. PATIENTS AND METHODS:1035 patients were available for analysis: 75% had estrogen receptor (ER)-positive primary tumors, the median number of involved axillary lymph nodes was three and 81% received prior adjuvant chemotherapy. RESULTS:Toremifene and tamoxifen yielded similar disease-free (DFS) and overall survival (OS): 5-year DFS rates of 72% and 69%, respectively [risk ratio (RR)=0.95; 95% confidence interval (CI)=0.76-1.18]; 5-year OS rates of 85% and 81%, respectively (RR = 1.03; 95% CI = 0.78-1.36). Similar outcomes were observed in the ER-positive cohort. Toxicities were similar in the two treatment groups with very few women (<1%) experiencing severe thromboembolic or cerebrovascular complications. Quality of life results were also similar. Nine patients developed early stage endometrial cancer (toremifene, six; tamoxifen, three). CONCLUSIONS:Toremifene is a valid and safe alternative to tamoxifen in postmenopausal women with endocrine-responsive breast cancer. 10.1093/annonc/mdh463
    A comparison of survival outcomes and side effects of toremifene or tamoxifen therapy in premenopausal estrogen and progesterone receptor positive breast cancer patients: a retrospective cohort study. Gu Ran,Jia Weijuan,Zeng Yunjie,Rao Nanyan,Hu Yue,Li Shunrong,Wu Jiannan,Jin Liang,Chen Lijuan,Long Meijun,Chen Kai,Chen Lili,Xiao Qiaozhen,Wu Mei,Song Erwei,Su Fengxi BMC cancer BACKGROUND:In premenopausal women, endocrine adjuvant therapy for breast cancer primarily consists of tamoxifen alone or with ovarian suppressive strategies. Toremifene is a chlorinated derivative of tamoxifen, but with a superior risk-benefit profile. In this retrospective study, we sought to establish the role of toremifene as an endocrine therapy for premenopausal patients with estrogen and/or progesterone receptor positive breast cancer besides tamoxifen. METHODS:Patients with early invasive breast cancer were selected from the breast tumor registries at the Sun Yat-Sen Memorial Hospital (China). Premenopausal patients with endocrine responsive breast cancer who underwent standard therapy and adjuvant therapy with toremifene or tamoxifen were considered eligible. Patients with breast sarcoma, carcinosarcoma, concurrent contralateral primary breast cancer, or with distant metastases at diagnosis, or those who had not undergone surgery and endocrine therapy were ineligible. Overall survival and recurrence-free survival were the primary outcomes measured. Toxicity data was also collected and compared between the two groups. RESULTS:Of the 810 patients reviewed, 452 patients were analyzed in the study: 240 received tamoxifen and 212 received toremifene. The median and mean follow up times were 50.8 and 57.3 months, respectively. Toremifene and tamoxifen yielded similar overall survival values, with 5-year overall survival rates of 100% and 98.4%, respectively (p = 0.087). However, recurrence-free survival was significantly better in the toremifene group than in the tamoxifen group (p = 0.022). Multivariate analysis showed that recurrence-free survival improved independently with toremifene (HR = 0.385, 95% CI = 0.154-0.961; p = 0.041). Toxicity was similar in the two treatment groups with no women experiencing severe complications, other than hot flashes, which was more frequent in the toremifene patients (p = 0.049). No patients developed endometrial cancer. CONCLUSION:Toremifene may be a valid and safe alternative to tamoxifen in premenopausal women with endocrine-responsive breast cancer. 10.1186/1471-2407-12-161