Years Of Endocrine Therapy Research Articles

Association of Modifiable Risk Factors With Early Discontinuation of Adjuvant Endocrine Therapy

Early discontinuation of adjuvant endocrine therapy (ET) is problematic among breast cancer survivors, with previous studies suggesting that up to 50% of women do not adhere to the recommended full 5 years of ET treatment. To identify the association between early discontinuation of ET in the Trial Assigning Individualized Options for Treatment (TAILORx) and modifiable risk factors, polypharmacy, and types of additional medications such as antidepressants and opioids. This post hoc analysis includes a subgroup of 954 patients with breast cancer in TAILORx, a randomized clinical trial conducted from April 7, 2006, to October 6, 2010. All participants received a diagnosis of hormone receptor-positive, ERBB2-negative, axillary node-negative breast cancer and started ET within a year of study entry. Analyses were conducted in the intent-to-treat population. Statistical analysis took place from January 15, 2020, to April 6, 2021. Participants completed measures on cancer-related health-related quality of life including physical well-being and social well-being prior to initiating ET. Early discontinuation of ET was defined as discontinuation less than 4 years from initiation for reasons other than death or recurrence. Kaplan-Meier estimates were used to calculate discontinuation, and Cox proportional hazards regression joint prediction models were used to analyze the association between rates of adherence to ET with patient-level factors. A total of 954 women (mean [SD] age, 56.6 [8.9] years) were included in this analysis. In a joint model, receipt of chemoendocrine therapy (vs receipt of ET only; hazard ratio [HR], 0.57; 95% CI, 0.35-0.92; P = .02) and age older than 40 years (vs ≤40 years; HR for 41-50 years, 0.39; 95% CI, 0.18-0.85; P = .02; HR for 51-60 years, 0.28; 95% CI, 0.13-0.60; P = .001; HR for 61-70 years, 0.40; 95% CI, 0.18-0.86; P = .02; and HR for >70 years, 0.23; 95% CI, 0.07-0.77; P = .02) were associated with a lower probability of early discontinuation of ET. Adjusted for these factors, a history of depression compared with no history of depression (HR, 1.82; 95% CI, 1.19-2.77; P = .005), worse physical well-being compared with better physical well-being (HR, 2.12; 95% CI, 1.30-3.45; P = .002), and worse social well-being compared with better social well-being (HR, 1.94; 95% CI, 1.20-3.13; P = .006) were individually and significantly associated with a higher probability of early discontinuation of ET. Only antidepressant use at study baseline was associated with early discontinuation (HR, 1.87; 95% CI, 1.23-2.84; P = .003). In this post hoc analysis of a randomized clinical trial, baseline patient-reported health-related quality of life components, such as poor social well-being, poor physical well-being, and comorbid depression, were significant risk factors for early discontinuation of endocrine therapies. These results support systematic screening for patient-reported outcomes and depressive symptoms to identify women at risk for discontinuation of ET. ClinicalTrials.gov Identifier: NCT00310180.

Abstract MP65: Transgender Adolescents Have High Prevalence Of Atherosclerotic Cardiovascular Disease Risk Factors Before And After Taking Hormone Therapy For 1 Year

Introduction: The United States has a growing population of transgender adolescents aged 12-21y presenting for medical transition via gender affirming hormone therapy (HT). Transgender people do not identify with their sex assigned at birth while cisgender people do. HT involves estrogen for trans females, those who identify as female, and testosterone for trans males, those who identify as male. Initiation of HT is beginning in adolescence and is a lifelong commitment for many transgender individuals. Little is known about how HT affects ASCVD risk factors in transgender adolescents. Studies of cisgender adults show cardioprotective effects of estrogen, and an estimated 37% of normal-weight cis gender adolescents have at least 1 ASCVD risk factor; but little investigation exists for transgender people, especially adolescents. Although some studies involving the transgender population have reproducible results, few include adolescents and comparison to acceptable ASCVD risk factor profiles. Guidelines for transgender health recommend laboratory assessment before starting HT and annually. This study expands on current knowledge and informs clinical practice by comparing ASCVD risk biomarkers of transgender adolescents taking HT to acceptable clinical values for adolescents. Hypothesis: Estrogen therapy for trans females will ameliorate ASCVD risk factors while testosterone therapy for trans males will worsen ASCVD risk factors. Methods: Retrospective chart review identified 300 transgender patients receiving HT at an academic adolescent medicine gender clinic. Of those 300, 50 trans female and 50 trans male were randomly selected for evaluation of ASCVD risk parameters at baseline and 1 year after initiating HT. ASCVD risk factors were compared to the International Diabetes Federation guidelines for metabolic syndrome. Parameters included lipids, glucose, and blood pressure. BMI ≥30 was used as proxy for obesity. Results: At baseline, at least one abnormal value was found for 50% (n=25, of these 5 had obesity) of trans females and 66% (n=33, of these 13 had obesity) of trans males. At 1 year, at least one abnormal value was found for 30% (n=15) of trans females and 70% (n=35) of trans males. At baseline, 50% (n=25) of trans females and 82% (n=41) of trans males, and at 1 year 20% (n=10) of trans females and 48% (24) of trans males had all parameters measured. Paired t-tests (α=.05) showed no significant change in ASCVD risk factors for trans females, and significant decrease in HDL and significant increase in BMI for trans males after 1 year of HT. Conclusions: The prevalence of having at least 1 ASCVD risk factor is greater among transgender adolescents than normal weight cisgender adolescents. HT may worsen HDL and BMI for trans males. We recommend baseline parameters for all and follow up and lab surveillance for patients with abnormal baseline parameters.

De-escalation of five years adjuvant endocrine therapy duration in patients with ER-low positive (immunohistochemical 1% to 10%) early-stage breast cancer: A propensity-matched analysis from the prospectively maintained database.

538 Background: There are limited data on endocrine therapy benefits for patients with estrogen receptor (ER)-low positive breast cancer (staining 1% to 10% of tumor nuclei by immunohistology). We aimed to compare the effect of short-term 2-3 years versus standard 5 years of adjuvant endocrine therapy on survival outcomes in patients with ER-low positive early breast cancer. Methods: We used data from the prospectively maintained Breast Surgery Database of Fudan University Shanghai Cancer Center for this propensity-matched analysis. Women with ER-low positive, operable, and unilateral early-stage invasive ductal breast cancer were enrolled in this study. Patients with advanced disease, having received neoadjuvant chemotherapy or ovarian function suppression, or with unknown duration or longer than 5 years of adjuvant endocrine therapy were excluded. Enrolled patients were divided into three groups: received no endocrine therapy; received 2-3 years of endocrine therapy; and received approximately 5 years of endocrine therapy. The primary endpoint was disease-free survival (DFS). Multivariate Cox regression analysis and propensity score matching were performed to minimize bias. Hazard ratios (HR) with 95% CIs were calculated. Results: From 2012 to 2017, 634 patients with ER-low positive breast cancer in the database met the inclusion criteria. At a median follow-up of 60 months (interquartile range, 46-74), the 5-year DFS of the whole cohort was 84.9%, with 77.6% for patients who received no endocrine therapy (N = 89), 83.7% for patients who received 2-3 years endocrine treatment (N = 185), and 87.5% for patients who received 5 years endocrine therapy (N = 360). When compared with those receiving no endocrine therapy, patients receiving 5 years treatment was associated with a significantly improved DFS (HR, 0.55; 95% CI 0.32-0.95; P = 0.03); however, there was no significant difference in DFS between patients receiving 2-3 years and 5 years endocrine therapy (HR, 0.79; 95% CI, 0.48-1.28; P = 0.33). In the multivariate Cox regression analysis of the propensity score-matched samples of 360 patients, the DFS was not significantly better for patients who received 5 years of endocrine therapy than 2-3 years treatment (HR, 0.74; 95% CI 0.41-1.34; P = 0.32). An exploratory analysis of re-biopsy of the recurrence lesions indicated more than half of relapsed disease displayed ER-negative, and less than 5% lesions were proved to be ER ≥10% positive. Conclusions: Our data did not support the necessity of 5 years duration of endocrine therapy for patients with ER-low positive breast cancer. Short-term 2-3 years duration might be an alternative option. Further translational research on identifying endocrine-sensitive cases within ER-low positive patients is needed.

EMonarcHER: A phase 3 study of abemaciclib plus standard adjuvant endocrine therapy in patients with HR+, HER2+, node-positive, high-risk early breast cancer.

TPS596 Background: Hormone receptor positive (HR+), human epidermal growth factor receptor 2-positive (HER2+) breast cancer (BC) with high-risk characteristics has a high risk of disease recurrence. Novel therapeutic options for this population are urgently needed. Abemaciclib is an oral, selective, and potent CDK4 & 6 inhibitor administered on a continuous schedule which is approved for HR+, HER2- advanced BC (ABC) as monotherapy and in combination with endocrine therapy (ET). Abemaciclib combined with ET demonstrated a statistically significant improvement in invasive disease-free survival (IDFS) in participants (pt) with HR+, HER2-, node-positive, high risk early breast cancer (EBC) and also clinical activity in HR+, HER2+ ABC. The eMonarcHER trial investigates whether abemaciclib plus ET will improve IDFS in pts with HR+, HER2+, node-positive, high risk EBC. Methods: eMonarcHER is a phase 3 global, randomized, double-blinded, placebo (PB)-controlled trial in participants with HR+, HER2+, node-positive, high risk EBC who have completed adjuvant HER2-targeted therapy (tx). Eligible participants are randomized 1:1 to receive either abemaciclib 150 mg twice daily or PB, plus standard ET. Study intervention period will be ≤26 cycles (approximately 2 years) followed by ≤8 years of ET as medically indicated. Participants must have undergone definitive surgery of the primary breast tumor and have high-risk disease. High-risk disease is defined as (i) detection of residual axillary nodal disease at the time of definitive surgery in participants with prior neoadjuvant (neoadj) tx; or (ii) in patients not receiving neoadj tx, must have either ≥4 pathologically positive axillary lymph nodes (pALNs), or 1-3 pathological pALNs and either: histologic Grade 2-3 and/or primary invasive tumor size ≥5 cm. Participants must have received either adjuvant pertuzumab plus trastuzumab with chemotherapy or adjuvant T-DM1. Stratification factors include treatment with neoadj tx, menopausal status, and region. The study is powered at approximately 80% to detect the superiority of abemaciclib plus ET over PB plus ET in terms of IDFS (as defined by the STEEP system) at a 1-sided α =.025 using a log-rank test. Assuming a hazard ratio of 0.73, this requires approximately 324 events at final IDFS analysis. Key secondary objectives include overall survival, distant relapse free survival, safety, pharmacokinetics, and patient-reported outcomes. The study is planned to start in March 2021. Approximately 525 centers in 23 countries plan to enroll ̃2450 participants. Clinical trial information: NCT04752332.

Survival following locoregional recurrence in breast cancer by clinical subtype.

543 Background: We sought to explore the impact of locoregional recurrence (LRR) on survival in breast cancer (BC) patients in British Columbia treated in the modern era. Methods: A retrospective cohort study design identified patients diagnosed with stage I-III BC from 04/2005-12/2013 treated with surgery and who had a subsequent LRR. Exclusions were death or distant metastasis within 120 days of LRR, bilateral previous/synchronous BC, and other invasive cancers. After LRR, overall survival (OS) and factors associated with OS, including clinical subtype and adjuvant therapy (AdTx), were examined. We defined clinical subtypes as: Luminal (Lum) A-estrogen receptor (ER) and progesterone receptor (PR) positive, HER2 negative, and grade 1 or 2; Lum B-as Lum A but grade 3, or as Lum A but only one of ER or PR positive; triple negative (TNBC)-ER and PR and HER2 negative; and HER2 positive (with any ER, PR). In the absence of earlier LRR, we defined adequate AdTx as: (a) TNBC: >=50% of planned chemotherapy (Chx), (b) HER2 positive: >=50% of planned Chx and >=8 cycles of anti-HER2 therapy, (c) Lum A, B: >=4 years of endocrine therapy and (d) after partial mastectomy or positive final margins: >=50% of radiation therapy dosage. Results: The final cohort had 492 patients with a median follow-up of 7.2 years from LRR and 11.8 years from diagnosis. LRR was local in 69.3% (n=341) and regional +/- local in 30.7% (n=151). Compared with local only, regional recurrences were associated with higher T and N stage, grade, and Lum status (p<=0.01). Biomarkers were re-evaluated at LRR in 82% and changed from initial diagnosis in 32% of those tested: ER expression 3.8% gain, 6.1% loss; PR expression 9.1% gain, 15.1% loss; HER2 overexpression 3.7% gain and 4.8% loss. Over half of patients (n=255, 52%) did not receive adequate AdTx, either by choice or recommendation. A similar proportion with local vs. regional recurrence had inadequate AdTx. Time to death from 1st LRR did not vary significantly between local vs. regional recurrences (median 2.7 years). OS after LRR was lowest in TNBC (median 3.1 years, 24.2% 10-year OS) and longest in Lum A (median not reached, 64.7% 10-year OS) (Table). Conclusions: Our data provide rates of OS after LRR in the era of modern adjuvant therapy. OS after LRR varied by clinical subtype, with TNBC faring the worst, and Lum A the best. Over half had not received adequate AdTx. Despite similar treatment options, OS after LRR was significantly longer for Lum A than B subtypes, underscoring the need for therapy tailored to biology. OS was low in all other subtypes, emphasizing the importance of avoiding LRR.[Table: see text]

7P An optimized Breast Cancer Index node-positive (BCIN+) prognostic model for late distant recurrence in patients with hormone receptor-positive (HR+) node-positive breast cancer

BCI is a gene expression-based assay that reports a prognostic BCI score that significantly predicts risk of overall (10y), early (0-5y), and late (≥5y) distant recurrence (DR) in HR+, node-negative (N0) and node-positive (N1) breast cancer. The BCIN+ prognostic model was trained in the Trans-ATAC cohort, which evaluated primary adjuvant anastrozole versus tamoxifen. The current study optimized the BCIN+ prognostic model for late DR in N+ patients from the arm treated with 7.5 years of endocrine therapy in the translational cohort of the IDEAL trial.

Early Discontinuation of Endocrine Therapy and Recurrence of Breast Cancer among Premenopausal Women.

Premenopausal women diagnosed with estrogen receptor (ER)-positive breast cancer are prescribed 5-10 years of endocrine therapy to prevent or delay recurrence. In this study, we evaluated the association between early discontinuation of endocrine therapy and breast cancer recurrence in a cohort of premenopausal women. We identified 4,503 patients with premenopausal ER-positive breast cancer who initiated adjuvant endocrine therapy and were registered in the Danish Breast Cancer Group clinical database (2002-2011). Women were excluded if they had a recurrence or were lost to follow-up less than 1.5 years after breast cancer surgery. Endocrine therapy was considered complete if the patient received at least 4.5 years of treatment or discontinued medication less than 6 months before recurrence. Exposure status was updated annually and modeled as a time-dependent variable. We accounted for baseline and time-varying confounders via time-varying weights, which we calculated from multivariable logistic regression models, and included in regression models to estimate HRs and 95% confidence intervals (CIs) associating early discontinuation with recurrence. Over the study follow-up, 1,001 (22%) women discontinued endocrine therapy. We observed 202 (20%) recurrences among those who discontinued endocrine therapy, and 388 (11%) among those who completed the recommended treatment. The multivariable-adjusted estimated rate of recurrence was higher in women who discontinued endocrine therapy relative to those who completed their treatment (hazard ratio, 1.67; 95% CI, 1.25-2.14). These results highlight the importance of clinical follow-up and behavioral interventions that support persistence of adjuvant endocrine therapy to prevent breast cancer recurrence.

Mapping of Genomic Vulnerabilities in the Post-Translational Ubiquitination, SUMOylation and Neddylation Machinery in Breast Cancer.

Simple SummaryBreast cancer is a major cause of death worldwide and remains incurable in advanced stages. The dysregulation of the post-translational machinery has been found to underlie tumorigenesis and drug resistance in preclinical models but has only recently led to early trials in cancer patients. We performed an in silico analysis of the most common genomic alterations occurring in ubiquitination and ubiquitin-like SUMOylation and neddylation using data from publicly available repositories and with the aim of identifying those with prognostic and predictive value and those exploitable for therapeutic intervention. Clinical and statistical criteria were used to sort out the best candidates and the results were validated in independent datasets. UBE2T, UBE2C, and BIRC5 amplifications predicted a worse survival and poor response to therapy across different intrinsic subtypes of breast cancer. Mutated USP9X and USP7 also conferred detrimental outcome. Leveraging these molecular vulnerabilities as biomarkers or drug targets could benefit breast cancer patients.The dysregulation of post-translational modifications (PTM) transversally impacts cancer hallmarks and constitutes an appealing vulnerability for drug development. In breast cancer there is growing preclinical evidence of the role of ubiquitin and ubiquitin-like SUMO and Nedd8 peptide conjugation to the proteome in tumorigenesis and drug resistance, particularly through their interplay with estrogen receptor signaling and DNA repair. Herein we explored genomic alterations in these processes using RNA-seq and mutation data from TCGA and METABRIC datasets, and analyzed them using a bioinformatic pipeline in search of those with prognostic and predictive capability which could qualify as subjects of drug research. Amplification of UBE2T, UBE2C, and BIRC5 conferred a worse prognosis in luminal A/B and basal-like tumors, luminal A/B tumors, and luminal A tumors, respectively. Higher UBE2T expression levels were predictive of a lower rate of pathological complete response in triple negative breast cancer patients following neoadjuvant chemotherapy, whereas UBE2C and BIRC5 expression was higher in luminal A patients with tumor relapse within 5 years of endocrine therapy or chemotherapy. The transcriptomic signatures of USP9X and USP7 gene mutations also conferred worse prognosis in luminal A, HER2-enriched, and basal-like tumors, and in luminal A tumors, respectively. In conclusion, we identified and characterized the clinical value of a group of genomic alterations in ubiquitination, SUMOylation, and neddylation enzymes, with potential for drug development in breast cancer.

Abstract PS6-25: Cts5 tested in a Brazilian population: A tool that can predict global survival in early breast cancer ER+/HER2-, as well as the response to extended endocrine therapy

Abstract Background: Breast cancer (BC) accounts for 30% of female cancer, is the most commonly diagnosed cancer worldwide and the second most common cause of cancer-related deaths among females. The majority (79%) of breast cancers express the estrogen receptor (ER+) and 91% of them are diagnosed at an early stage. But it is also known that late recurrence (5 years or more after diagnosis) represents about 50% of all recurrences of ER+ BC. Identify those patients who are at greatest risk for late recurrence and develop strategies to prevent it has emerged as a major unmet need in ER+ BC. In an attempt to reduce late recurrences, several studies have recently proposed that endocrine therapy (ET) prolonged beyond five years would achieve this goal. Conversely, extended ET increases the rates of side-effects, compared to conventional ET. Therefore, selecting patients who would really benefit from extended ET is crucial, as this would spare low-risk patients from potentially greater side effects and impacts in quality of life, restricting the treatment only for those who really could take advantage of this approach. That is why, currently, the subject late recurrence is being studied so much. CTS 5 (Clinical Treatment Score after 5 years) is a simple clinical-pathological tool developed to estimate the residual risk of distant recurrence after 5 years of ET. Objective: To assess the prognostic and predictive impact of CTS5 in overall survival (OS) of ER+BC patients treated with conventional or extended ET in a Brazilian Cancer Center. Study design and statistical analysis: A retrospective cohort study was conducted, selecting, through administrative databases of AC Camargo Cancer Center, 1085 ER+ BC patients with at least 5 years of adjuvant ET. Patients who missed follow-up before completing ET were excluded, but we kept those who presented any event related to illness or treatment. Statistical analysis includes a Kaplan-Meier analysis and the Log Rank test. Prognostic factors were assessed using univariate and multivariate Cox analysis. Results: The demographic and clinical characteristics of patients are described in table 1. In this cohort, continuous CTS5 was a significant predictor for OS (HR = 4,49 [3.12-6.46], p<0.001). In addition, in the high CTS5 group a significant benefit was observed with prolongation of adjuvant ET beyond 5 years (HR = 4,91 [3.41-7.06], p<0.001), not observed for low and intermediate risks. Conclusion: In this cohort, composed of real-life Brazilian women with ER+/ HER2- BC, irrespective of menopausal status, CTS5 proved to be an excellent predictor of OS. In addition, it was shown to be a predictor of response to extended ET. CTS5 score can identify a group of high-risk patients who benefits from extended ET. We consider that it would be of great value to expand the study population and follow-up, especially to analyze whether this tool also has a predictive value in contraindicating extended ET in low- risk and intermediate-risk patients. Table 1. Demographic and Clinical CharacteristicsCharacteristicNo. (%)Age, yearsMedian53IQR26-91< 50 years446 (41.1)>50 years639 (58.9)Tumor size, mm≤ 10285 (24.1)10-20458 (38.7)20-50378 (31.9)>5060 (5.1)GradeWell142 (11,9)Intermediate385 (32,5)Poor654 (55,2)Nodal status (No. of positive nodes)0756 (64.0)1 -3305 (25.8)≥4120 (10.2)ChemotherapyAdjuvant592 (50.1)Neoadjuvant118 (10.0)Endocrine TerapyET 5 years1060 (89,7)ET extendend100 (8.4)ET for less than 5 years.21 (1,8)CTS5Low587 (49.6)Intermediate344 (29.1)High250 (21.1)RecurrenceDistant147 (12,4)Local 39 (3,3) Citation Format: Lucas Vian, Ronaldo Souza, Vladmir Claudio Cordeiro de Lima, Daniella Yumi Tsuji Honda, Samara Theodoro Pacheco, Caio Dabbous de Liz, Luciana Beatriz Mendes Gomes, Bruno Cezar Mendonça Uchôa Júnior, Paula Tavares Guimarães, Celso Silva e Souza Filho, Andréa Paiva Guimarães, Maria Fernanda Evangelista Simões, Mauro Daniel Spina Donadio, Angelo Bezerra de Souza Fêde, Augusto Obuti Saito, Adriana Regina Gonçalves Ribeiro, Joyce Maria Lisboa Maia, Iara Karoline Freire Lustosa, Fabricio de Souza Castro, Monique Celeste Tavares, Marcelle Goldner Cesca, Marcelo Corassa, Noam Falbel Pondé, Solange Sanches. Cts5 tested in a Brazilian population: A tool that can predict global survival in early breast cancer ER+/HER2-, as well as the response to extended endocrine therapy [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS6-25.

Abstract PD5-03: Ipsilateral invasive cancer risk after diagnosis with ductal carcinoma in situ in patients with and without index surgery: The effects of endocrine therapy and radiation treatment

Abstract Background. Ongoing clinical trials are evaluating active surveillance as a potential alternative to immediate surgery in patients diagnosed with low-risk ductal carcinoma in situ (DCIS). Among women undergoing lumpectomy, the risk of ipsilateral invasive breast cancer (iIBC) after a diagnosis of DCIS can be reduced with adjuvant therapy, including endocrine therapy (ET) and radiation treatment (RT). Here we characterize the effects of ET and RT on iIBC risk after diagnosis with DCIS in a national cohort, in patients who received breast conserving surgery (BCS) within 6 months of diagnosis (BCS group) compared to patients who did not receive any locoregional treatment within 6 months of diagnosis (surveillance [SV] group). Methods. A treatment-stratified random sample of patients diagnosed with biopsy-confirmed DCIS in 2008-14 was selected from 1,330 Commission on Cancer-accredited facilities (20/site). Patients who received a mastectomy within 6 months of diagnosis were excluded. Subsequent breast events were abstracted up to 10 years after diagnosis. Primary outcomes were the population-averaged 8-year absolute risks of iIBC for the following five treatment modalities: BCS alone, SV alone, BCS + ET, SV+ET, BCS+RT, and BCS+ET+RT (where ET was defined as ≥5 years of continuous treatment). Secondary outcomes were the average treatment effects (ATE) of SV+ET vs SV, BCS+RT vs SV+ET, and BCS+RT+ET vs SV+ET. A propensity score (PS) model for treatment choice BCS vs SV was fitted with sampling design (SD) weighting and random effects for patients within facilities. Relative treatment effects (hazard ratios [HR]) for the five treatment groups were obtained using multivariable Cox proportional hazards models adjusted for tumor and patient characteristics. The models were weighted by SD and PS and included a robust sandwich covariance estimator to account for clustering of patients within facilities. Population-averaged risks and ATEs were derived from the marginal outcome probabilities: assuming that the entire population received the treatment of interest, each patient’s counterfactual probability of an iIBC event by 8 years was predicted, and then averaged across the weighted population. 95% confidence intervals (CI) were obtained by bootstrapping. Results. The final analytic cohort contained 14,245 (88.2%) BCS and 1,914 (11.8%) SV patients. Overall, median age at diagnosis was 61 years (IQR: 52-69) and median follow-up was 5.8 years (95% CI 5.7-6.1). The majority of patients were Caucasian (81.9%), with hormone receptor-positive (79.9%), and nuclear grade I/II (54.5%) DCIS. Uptake of any ET was 48.5% and 23.7% in BCS and SV patients, respectively. The relative treatment effects (HR) for the receipt of BCS, RT and ≥5 years of ET were 1.65 (95% CI: 1.14-2.39), 0.40 (95% CI: 0.27-0.61) and 0.55 (95% CI: 0.17-1.72) respectively. The 8-year population-averaged iIBC risks and corresponding ATEs are shown Table 1. Conclusion. The 8-year risk of iIBC was below 7% for all six management options. Relative and absolute treatment effects of ET and RT were comparable to previously reported estimates. In SV patients, receipt of ≥5 years of ET nearly halved the 8-year risk, indicating a substantial risk reduction potential for ET in patients who do not receive immediate surgery after diagnosis. Table 1: Population-averaged 8-year iIBC risk and ATEs.TreatmentiIBC risk (%)95% CISurveillance6.906.79-7.01Surveillance + ET3.903.83-3.96BCS4.264.21-4.31BCS + RT1.761.73-1.79BCS + ET2.392.35-2.43BCS + ET + RT0.980.96-0.99Treatment comparisonATE (%)95% CISV+ET vs SV3.02.95-3.04BCS+RT vs SV+ET2.142.11-2.17BCS+RT+ET vs SV+ET2.922.78-2.97 Citation Format: Marc D Ryser, Christel N Rushing, Samantha M Thomas, Thomas Lynch, Anne McCarthy, Zahed A Mohammed, Amanda B Francescatti, Elizabeth S Frank, Anne H Partridge, Alastair M Thompson, Terry Hyslop, E. Shelley Hwang. Ipsilateral invasive cancer risk after diagnosis with ductal carcinoma in situ in patients with and without index surgery: The effects of endocrine therapy and radiation treatment [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD5-03.

Abstract PS6-63: Validation of CTS5 as a predictor of distant late recurrence risk in HER2 negative luminal breast cancer: Latin American experience

Abstract Background: Breast cancer (BC) is the most commonly diagnosed cancer worldwide, 91% diagnosed in early stages and 80% of them expressing estrogen receptor (ER +). It is known that distant late recurrence (DLR) represents about 50% of all relapses. Thus, identifying patients with a higher risk of DLR is a essential need in ER + BC, leading to a potential personalized management. Within this scope, CTS 5 (Clinical Treatment Score after 5 years) was developed as a simple clinical-pathological tool that aims to estimate the residual risk of distance recurrence after 5 years of endocrine therapy (ET). Methodology: The validity of CTS5 was tested in a retrospective cohort. Patients diagnosed between 2005 and 2011 with early BC, ER+/HER2- tumors, alive and without recurrence within the first 5 years were selected. The primary endpoint was the time for distant late recurrence (DLR). Cox regression models were used to determine the prognostic value of CTS5 and to produce Kaplan-Meier curves with associated risks of DLR. Results: A total of 797 women were included with a median follow-up of 105 months. According to the CTS5, 424 (53.2%), 239 (30.0%), and 134 (16.8%) patients were classified into the low-, intermediate-, and high-risk of DLR, respectively (table 1). CTS5 results were prognostic for DLR: patients with CTS5-high showed a fivefold relative risk of developing an DLR compared to patients with CTS5-low (HR, 5.1 IC95% [2.24-11.47], p <0.0001) (table 2). When assessing continuously, an one-point increase in CTS5 increased the relative risk of DLR by 87% (HR, 1,87 95% CI [1,324 - 2,632] p <0.0001). These results were confirmed when we stratified by age (age≤50 years vs. age>50 years). Conclusion: Our results support its use in clinical practice as a predictor for patients with early-stage BC, ER +, and HER2- in real life. Besides, our study serves as a hypothesis generator for future confirmations through prospective studies. Thus, we will be able to assess, through prospective studies, whether the CTS5 can be used to personalize the patient's follow-up or even evaluate its usefulness in the decision to prolong or not ET. Such results would be extremely important, given the known difficulty in accessing genomic assays, especially in developing countries. Table 1 Risk groups classifed according to the CTS5 and the clinicopathological characteristicsFactorsNo. (%)P valueTotalLowIntermediateHigh424 (53.2)239 (30.0)134 (16.8)Age, years<50175 (41.3)100 (41.8)47 (35.1).383322 (40.4)>50249 (58.7)139 (58.2)87 (64.9)475 (59.6)Number of the positive nodes0389 (91.7)133 (55.6)12 (9.0)<.0001534 (67.0)131 (7.3)81 (33.5)28 (20.9)139 (17.4)2-32 (0.5)21 (8.8)41 (30.6)64 (8.0)4-92 (0.5)3 (1.7)32 (23.9)38 (4.8)9+0 (0.0)1 (0.4)21 (15.7)22 (2.8)Histological grade188 (20.7)25 (10.4)7 (5.2)<.0001120 (15.0)2196 (46.2)129 (48.5)38 (28.4)363 (45.6)3140 (33.1)85 (35.6)89 (66.4)314 (39.4)Tumor size, mm<10193 (45.5)9 (3.8)3 (2.2)<.0001205 (25.7)10-20199 (47.0)94 (39.3)29 (21.6)322 (40.4)20-3022 (5.2)82 (34.3)41 (30.6)145 (18.2)> 3010 (2.3)54 (22.6)61 (45.5)125 (15.7)Histological TypeDuctal342 (80.7)207 (86.6)112 (83.6)<.0001661 (82.9)Tubular57 (13.4)21 (8.8)17 (12.7)95 (11.9)Others25 (5.9)11 (4.6)5 (3.7)41 (5.1)ChemotherapyNeoadjuvant10 (2.4)22 (9.2)25 (18.7)<.000157 (7.2)Adjuvant153 (36.1)146 (61.1)92 (68.7)391 (49.1)RadiotherapyYes271 (63.9)184 (77.0)119 (88.8)<.0001574 (72.0)No153 (36.1)55 (23)15(11.2)223 (28)Administered endocrine therapy5 years tamoxifen183 (43.2)66 (27.6)29 (21.6)<.0001278 (34.9)5 years used aromatase inhibitor210 (49.5)146 (61.1)78 (58.2)434 (54.4)> 5 years tamoxifen20 (4.7)18 (7.5)19 (14.2)57 (7.2)> 5 years used aromatase inhibitor11 (2.6)9 (3.8)8 (6.0)28 (3.5)ET time, years5393 (92.7)212 (88.7)107 (79.9)<.0001712 (89.3)7 - 1031 (7.3)27 (11.3)27 (20.1)85 (10.7)Vital statusAlive420 (99.1)236 (98.7)128 (95.5).016784 (98.3)Dead4 (0.9)3 (1.3)6 (4.5)13 (1.7)Distant recurrenceNo415 (97.9)222 (92.9)118 (88.1)<.0001755 (94.7)Yes9 (2.1)17 (7.1)16 (11.9)42 (5.3) Table 2. Survival analyses for DLR and Overall Survival in diferent subgroups (CTS5 as categorical)Distance Late RecurrenceLow riskIntermediate risk HR (95% CI)pHigh risk HR (95% CI)pAll patientsReference3.155 (1.406 - 7.080).0055.067 (2.239 - 11.467)< .0001>50 years oldReference2.889 (1.049 - 7.952).0404.701 (1.737 - 12.723).002<50 years oldReference3.730 (.964 - 14.435).0575.494 (1.311 - 23.029).02Overall SurvivalLow riskIntermediate risk HR (95% CI)pHigh risk HR (95% CI)pAll patientsReference1.152 (.258 - 5.150).8533.948 (1.113 - 14.00).034 Citation Format: Lucas Vian, Ronaldo Souza, Vladmir C. C. Lima, Daniella Y. T. Honda, Samara T. Pacheco, Caio D. Liz, Luciana B.M. Gomes, Bruno C. M. U. Júnior, Paula T. Guimarães, Celso S. S. Filho, Andréa P. Guimarães, Mauro D. S. Donadio, Angelo B.S. Fêde, Augusto O. Saito, Adriana R.G. Ribeiro, Joyce M. L. Maia, Iara K. F. Lustosa, Fabricio S. Castro, Monique C. Tavares, Marcelle G. Cesca, Marcelo Corassa, Noam F. Pondé, Solange Sanches. Validation of CTS5 as a predictor of distant late recurrence risk in HER2 negative luminal breast cancer: Latin American experience [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS6-63.

Optimal duration of endocrine therapy with extended aromatase inhibitors for postmenopausal patients with hormone receptor-positive breast cancer: a meta-analysis.

The optimal duration of endocrine therapy for patients with hormonereceptor-positive (HR-positive) breast cancer is still unclear. This meta-analysis aims to determine the optimal duration of endocrine therapy with extended aromatase inhibitors(AI) for postmenopausal patients with HR-positive early breast cancer who have finished 5years of endocrine therapy. Eligible randomized controlled trials were classified into three categories according to the whole duration of endocrine therapy (10years versus 5years, 7-8years versus 5years, and 10years versus 7-8years). For each category, hazard ratio (HR) for disease-free survival (DFS) and overall survival (OS), and risk ratio (RR) for the incidence of adverse events were pooled. Altogether 9 RCTs enrolling a total of 22,313 postmenopausal women with HR-positive breast cancer were included. Pooled data showed an improvement in DFS when extending endocrine therapy from 5 to 7-8years (HR = 0.79 [0.69, 0.91]), specifically among those who had been treated with only tamoxifen (HR = 0.40 [0.22, 0.73]) or sequential tamoxifen followed by AI (HR = 0.82 [0.71, 0.95]), with tumors that were node-positive (HR = 0.72 [0.56, 0.93]), estrogen receptor (ER) and progesterone receptor (PR) positive (HR = 0.61 [0.47, 0.78]), or ≥ 2cm in size (HR = 0.72 [0.51, 0.98]). However, no improvement in DFS was obtained when extending from 7-8 to 10years (HR = 0.98 [0.87, 1.11]). In addition, the extension of endocrine therapy was not associated with an improvement in OS, but was associated with an increased risk of bone fracture and osteopenia/osteoporosis. Patients who have been treated with AI for 5years, with tumors that are node-negative, ER+/PR- or ER-/PR+, and < 2cm in size do not need to receive extended AI therapy. For those who have been treated with only tamoxifen or sequential tamoxifen followed by an AI for a total of 5years, with tumors that are node-positive, ER+/PR+ or ≥ 2cm in size, 2-3years of extended AI is necessary and maybe enough.

Dynamic Impact of Hormone Therapy on Laboratory Values in Transgender Patients over Time.

Known physiological changes occur while transgender patients are taking hormone therapy (HT). However, knowledge is limited about when laboratory values stabilize and if there are any long-term impacts, making it challenging for physicians to provide adequate gender-affirming care. We aim to analyze laboratory values with HT use over 5 years and after discontinuation of HT to define when values achieve stability. We performed a multicenter retrospective analysis of 126 transgender women (TW) and 91 transgender men (TM) at consecutive clinic visits. Labs included complete metabolic panel, complete blood count, lipids, and hormone levels and were monitored for 5 years. Absolute measurement and percentage change from baseline were calculated for each analyte value. We collected the laboratory studies described from patients off HT and the duration of discontinuation to determine the time to return to baseline levels. During HT, red blood cell (RBC; erythrocyte) indexes reach stable levels within 6 months (P < 0.001) and are unchanged long term. Some analytes such as HDL and platelets showed increases beyond the first year of HT in TW (P = 0.001 and P < 0.001, respectively). LDL and alanine aminotransferase increased beyond 1 year in TM (P < 0.005 and P < 0.001, respectively), whereas HDL decreased beyond 1 year (P < 0.001). Time for laboratory values to return to baseline occurred around 10 weeks. Most analytes reach stable levels within 6 months (RBC and creatinine), whereas others change in the long term (LDL, HDL, platelets). This information can be used to guide physicians as they monitor their transgender patients in all stages of their progress through HT.

Preservation of white matter integrity on DTI 3 years after early menopausal hormone therapies

AbstractBackgroundThe critical‐period theory of menopausal hormone therapy (mHT) suggests that if menopausal hormone therapy begins shortly after menopause, it may have beneficial effects on brain structure and cognitive health. We investigated white matter integrity with diffusion tensor MRI (DTI) 3 years after the end of mHT trial in recently menopausal women who were randomized shortly after menopause.MethodParticipants of this study were enrolled in the Kronos Early Estrogen Prevention Study (aged 42–56 years; 5–36 months past menopause). Participants received the following treatments: 0.45 mg/d oral conjugated equine estrogen (oCEE, n=19); 50 μg/d transdermal 17β‐estradiol (tE2, n=22); or placebo (n=33) for 4 years. Oral progesterone (200 mg/d) was given to hormone therapy groups for 12 days each month. DTI was performed 3 years after the end of 4 years of hormone therapy (n=75), which corresponded to 7 years after randomization. Voxel‐based analysis was performed on DTI to evaluate fractional anisotropy (FA) and mean diffusivity (MD) differences between treatment groups (uncorrected p&lt;0.001).ResultVoxel based analysis showed higher FA, a measure of white matter integrity, in the superior corona radiata, anterior limb of the internal capsule and splenium of the corpus callosum of participants treated with oCEE compared to placebo (p &lt;0.001, Figure 1A). Furthermore, higher FA was observed in the superior corona radiata, anterior limb of internal capsule and thalamus in participants treated with tE2 compared to placebo (p &lt;0.001, Figure 1B). There were no differences in FA findings between oCEE and tE2 groups, and no MD differences between treatments groups.ConclusionA relatively higher FA in a variety of white matter regions in the oCEE and tE2 groups compared to placebo suggest that mHT may have long‐term protective effects on white matter integrity. Previously, we had shown that women in the tE2 group preserved their dorsolateral prefrontal cortex volumes better than the placebo group over 7 years. Our findings suggest that the tracts that connect the dorsolateral prefrontal cortex and the thalamus such as the superior corona radiata and the anterior limb of internal capsule may particularly benefit from mHT.

Widespread Metastasis to the Stomach 10 Years After Primary Breast Cancer: A case report and review of the literature.

Rationale:Breast cancer is a common malignant tumor. The most common metastatic sites of breast cancer are the bone, brain, liver and lung, and gastrointestinal metastases are rare. Considering that the median time interval from the initial breast cancer diagnosis to stomach metastasis is 77.5 months, gastrointestinal metastases are rarely observed 10 years after primary breast cancer.Patient concerns:Here, we present a 63-year-old female with unusual endoscopy results that revealed scattered polyps and mucosal infiltration throughout the stomach, which were later confirmed to be metastatic lobular carcinoma of the breast that had been surgically removed 10 years earlier.Diagnosis:The patient was diagnosed with gastric metastases of breast cancer by immunohistochemistry.Interventions:The patient underwent endocrine therapy with palbociclib and tamoxifen.Outcomes:After 1 year of endocrine therapy, the symptoms of upper abdominal discomfort and fatigue were relieved and a new gastroscopy revealed there had been no significant progression of the gastric metastasis. According to the Response Evaluation Criteria in Solid Tumors (RECIST), the patient reached a state of stable disease.Lessons:Gastric metastases of breast cancer are rare in the clinical setting. However, considering the possibility of gastric metastases from breast cancer and performing an upper endoscopy are crucial for patients who present with any subtle gastric symptoms and have a past medical history of breast cancer, even if the breast cancer occurred more than 10 years ago.

Clinical validity of clinical treatment score 5 (CTS5) for estimating risk of late recurrence in unselected, non-trial patients with early oestrogen receptor-positive breast cancer

PurposeClinical Treatment Score at 5 years (CTS5) is a prognostic tool to estimate distant recurrence (DR) risk after 5 years of endocrine therapy for postmenopausal women with oestrogen receptor-positive (ER-positive) breast cancer.MethodsThe validity of CTS5 was tested in a retrospective cohort of patients diagnosed with early ER-positive breast cancer. The primary endpoint was DR in years 5–10. The primary analysis cohort consisted of postmenopausal women, with premenopausal women as a secondary analysis cohort. Cox regression models were used to determine the prognostic value of CTS5 and Kaplan–Meier curves were used with associated 10-year DR risks (%).Results2428 women were included with a median follow-up of 13.4 years. The CTS5 was significantly prognostic in both postmenopausal (N = 1662, HR = 2.18 95% CI (1.78–2.67)) and premenopausal women (N = 766, HR = 1.84 95% CI (1.32–2.56)). The 10-year DR risks were 2.9% (1.9–4.5), 7.2% (5.3–9.9), and 12.9% (10.0–16.7) for low, intermediate and high risk in postmenopausal women and 3.8% (2.2–6.7), 6.9% (4.4–10.8), and 11.1% (7.4–16.5) in premenopausal women, respectively. The number of observed DRs was significantly greater than expected in those predicted to be at high risk by CTS5 but this discordance was lost when those receiving more than 60 months of endocrine therapy were excluded.ConclusionsThe CTS5 demonstrated clinical validity for predicting late DR within a large cohort of unselected postmenopausal patients but less so in premenopausal patients. Calibration of the CTS5 was good in patients who did not receive extended endocrine therapy. The CTS5 low-risk cohort has risk of DR so low as to not warrant extended endocrine therapy.

A clinical study of curative partial breast irradiation for stage I breast cancer using carbon ion radiotherapy

Background and purposeOur institute initiated carbon ion radiotherapy research for patients with stage I breast cancer in April 2013. The purpose of this article is to evaluate the treatment outcome of cases treated outside clinical trial up to May 2020.Materials and methodsEligibility criteria of the patients were having untreated stage I breast cancer and being unsuitable for operation for physical or mental reasons. The irradiated volume was defined as the gross tumor including intraductal components. The dose escalation study was initially conducted four times a week for a total of 52.8 Gy [relative biological efficacy (RBE)]. After confirming that adverse effects were within acceptable range, the total dose was increased to 60.0 Gy (RBE).ResultsBetween April 2013 and November 2015, 14 cases were treated. The median follow up period was 61 months. No adverse toxicities were observed except for grade 1 acute skin reaction in 10 cases. The time required from carbonion radiotherapy to tumor disappearance was 3 months in 1 case, 6 months in 3 cases, 12 months in 4 cases, and 24 months in 5 cases. The third case developed local recurrence 6 months after radiotherapy. Twelve patients with luminal subtype received 5-year endocrine therapy. Thirteen of 14 tumors have been maintaining complete response with excellent cosmetic results.ConclusionsThe time from carbon ion radiotherapy to tumor disappearance was longer than expected, but complete tumor disappearance was observed except for one high-grade case. With careful patient selection, carbonion radiotherapy in patients with stage I breast cancer is deemed effective and safe, and further research is recommended.

My first year on testosterone: Analyzing the trans experience through YouTube channels

This article aims to contribute to a better understanding of the experience of hormone therapy with testosterone as perceived by trans people. An analysis of video blogs on YouTube for and by transmasculine individuals during their first year of hormone therapy with testosterone was conducted. A total of 63 video blogs from five YouTube channels of North American trans men and one non-binary person taking testosterone were analyzed. The transmasculine people's video blogs discuss how people experienced testosterone on a daily basis, how they negotiated their expectations and lived the impacts of their hormone therapy. The results identified the elements to be taken into account in accompanying the transition with testosterone, both bodily and symbolic, and reflected the multifaceted nature of the subjective experience of testosterone. They showed that changes are envisioned according to three levels of expectation: highly hoped for, neutrally expected and dreaded. Among these, voice seems to be the most important change, followed by the disappearance of menstruation and the appearance of hairiness. This methodological research underscores the importance and uniqueness of educating and training trans and non-binary people through online resources for and by peers. It also highlights the very active and unique experience of gender transitioning and the investment of their trans male bodies which are not copies of cisgender men but new constructions of the body. The knowledge produced and consumed by transmasculine people on the Internet must be recognized for their complementary contribution to the medical literature, as they provide new expert knowledge on transition with testosterone used by transmasculine people.

Risque sénologique chez les patients transgenres : à propos des recommandations américaines sur le dépistage des néoplasies mammaires

Transgender patients have a poorly understood breast cancer risk despite their growing number and social acceptance. Epidemiological data are generally extrapolated from cisgender and postmenopausal women. A transgender woman is the result of the transition from male to female. These patients will benefit from hormone therapy based on estradiol in order to acquire female secondary sex characteristics. The incidence of breast neoplasia is similar to that of cisgender men. Nevertheless, it has later onset than for cisgender women and is often discovered at a more advanced stage. After the age of 50 years-old and after 5 years of hormone therapy, transgender women can benefit from a screening mammogram without a clearly defined rhythm. A transgender man is the result of the transition from female to male. These patients will benefit from hormone therapy based on testosterone in order to acquire male secondary sex characteristics. These patients can benefit from a total and bilateral mastectomy with nipple transplant called “top surgery”. Depending on family risk factors, the surgeon can prescribe a preoperative assessment, remaining at his discretion. Without breast surgery, only conventional biennial screening is admitted. Some guidelines recommend an annual clinical examination of the chest wall if “top surgery” has been done. Radiologists must know the specifics related to management of transgender patients for better care.

Evaluation of endocrine therapy and patients preferences in early breast cancer: results of Elena study.

The development of the adjuvant therapy requires that clinicians and patients should discuss the magnitude of benefit of treatment for individual patient, estimating the pros and cons and the personal preferences. The aim of the present study was to determine the preferences of women treated with adjuvant hormonal therapy (HT) for breast cancer. The analyses were conducted into three different groups of early breast cancer patients to evaluate the survival benefit needed to make treatment worthwhile before starting HT (A), after a few months from the beginning (B) and after several years of HT (C). The questionnaires, showing hypothetical scenarios based on potential survival times and rates without HT, were used to determine the lowest gains women judged necessary to make the treatment worthwhile. A total of 452 patients were included in the study: 149 in group A, 150 in group B and 153 in group C. In group C, 65% of patients were receiving HT with aromatase inhibitors (with or without a LHRH analogue). In the groups A, B, C 8%, 20% and 26%, respectively, received adjuvant chemotherapy. Overall, 355 women (79%) had children. The responses were quite similar between the three groups. A median gain of 10years was judged necessary to make adjuvant HT worthwhile based on the hypothetical scenario of untreated mean survival time of 5 and 15years. Median gain of 20% more women surviving was judged necessary to make adjuvant HT worthwhile based on an untreated 5-year survival rate expectation of 60%. Cognitive dysfunction was considered the side effect least compatible with the continuation of treatment in all three groups. This is a large study of patient preferences on HT. Compared with other studies with similar design, the patients included in the present study required larger benefits to make adjuvant therapy worthwhile.