Impact Of Hormone Therapy Research Articles

Rethinking prostate cancer screening in transgender women

Introduction: Over the years, the number of people openly identifying as transgender has steadily increased, leading to a greater need for transgender-specific healthcare information. Among transgender women (TW), there remains a risk of prostate cancer since the prostate is not removed during gender-affirming hormone therapy (GAHT) or surgery; however, there is limited knowledge about prostate cancer screening in the transgender population. Although there are few reported cases of prostate cancer screening or prostate-specific antigen (PSA) testing in TW, the impact of hormone therapies on PSA levels is well-documented. Notably, GAHT for TW and hormone therapy for treating prostate cancer share similarities. Drawing on these similarities, we aimed to develop guidelines for baseline PSA levels and prostate cancer screening in TW. Methods: Through a systematic review, we examined the existing PubMed publications on PSA levels and prostate cancer screening in TW, as well as expected PSA levels in patients with prostate cancer undergoing hormone therapies. We also investigated other aspects considered for the diagnosis of prostate cancer. Given the limited research on TW, we also included relevant case studies. These publications and case reports were reviewed and analyzed to create a comprehensive overview of expected baseline PSA levels and prostate cancer screening guidelines for TW. Results: Currently, there are no established guidelines for PSA or prostate cancer screening in TW; however, these case studies indicated a range of PSA values from 3.3 to <100 ng/ml. Existing literature on expected PSA levels in prostate cancer patients undergoing hormone therapy shows a reduction in PSA of over 50% post-therapy. This evidence suggests that PSA values in TW presenting with prostate cancer may be lower than those observed in cisgender males with the disease. Conclusions: While TW exhibit lower prostate cancer incidence compared to cisgender men, the impact of hormone therapy on PSA levels presents significant challenges for screening and diagnosis. The parallels between PSA level reductions in TG women and cisgender men undergoing estrogen therapy highlight the need for revised screening protocols. Addressing these challenges through targeted research and personalized care approaches will be vital for improving prostate cancer management in transgender individuals.

The Impact of Hormone Therapy on Inflammatory Bowel Disease in Transgender and Nonbinary Individuals.

Inflammatory bowel disease (IBD) is a global healthcare problem that affects around 3 million people in the United States. Although the impact of gender-affirming hormone therapy (GAHT) on IBD severity has been studied in cisgender patients, there is currently no literature on the impact of exogenous hormone therapy (HT) in transgender and nonbinary (TGNB) individuals. We conducted a retrospective chart review of TGNB adults diagnosed with IBD and treated with HT for gender dysphoria at Johns Hopkins Hospital (2015-2022). We aimed to determine whether the use of GAHT was associated with subsequent increase in IBD severity. We compared the incidence of flares before vs after GAHT. Twenty-two patients were analyzed. More than half (59%) of them were assigned female at birth, identified as transmen, and underwent masculinizing HT. Their median (interquartile range) age was 30 (25-36) years. More patients had Crohn's disease compared with ulcerative colitis (13 [59.1%] vs 9 [40.9%], P = .23) with a median IBD duration of 6.2 (1.8-12.3) years. Nine (41%) patients were on biologics. Of 15 patients on HT, 8 (36.3%) experienced at least one flare. Most of them were treated with steroids (66.7%), and 6 (40%) required hospital or emergency room admission. The proportion of patients who flared after GAHT was similar to that before GAHT: 9 (60%) vs 8 (53.3%), P = 1.0. GAHT was not associated with increased incidence of flares. Larger prospective randomized studies are needed to confirm our findings and understand the interaction between GAHT and IBD in TGNB individuals.

Hypertension and menopause: physiopathology and impact of the hormonal therapy

Menopause, as a consequence of ovarian follicular decline, induces estrogen deficiency and metabolic changes that increase the cardiovascular risk in women. In particular, there is an increase in blood pressure during menopause. Menopausal hormonal therapy can be prescribed to women with symptoms of menopause to improve their quality of life. This article reviews the current literature on the pathophysiological mechanisms that explain blood pressure changes at menopause and describes the impact of menopausal hormone therapy on blood pressure.

Impact of hormonal therapy on HIV-1 immune markers in cis women and gender minorities.

Although sex hormones are recognized to induce immune variations, the effect of hormonal therapy use on immunity is only poorly understood. Here, we quantified how hormonal therapy use affects HIV-1 immune markers in cis women (CW) and trans women and non-binary people (TNBP) with HIV. We considered CD4, CD8 and lymphocyte measurements from cis men (CM), CW and TNBP in the Swiss HIV Cohort Study. We modelled HIV-1 markers using linear mixed-effects models with an interaction between 'gender' (CW, TNBP) and 'hormonal therapy use' (yes/no). Models were adjusted on age, ethnicity, education level, time since start of antiretroviral therapy and use of intravenous drugs. We assessed the inflammatory effect of hormonal therapy use in 31 TNBP using serum proteomics measurements of 92 inflammation markers. We included 54 083 measurements from 3092 CW and 83 TNBP, and 147 230 measurements from 8611 CM. Hormonal therapy use increased CD4 count and CD4:CD8 ratio in TNBP more than in CW (pinteraction = 0.02 and 0.007, respectively). TNBP with hormonal therapy use had significantly higher CD4 counts [median = 772 cells/μL, interquartile range (IQR): 520-1006] than without (617 cells/μL, 426-892). This was similar to the effect of CW versus CM on CD4 T cells. Hormonal therapy use did not affect serum protein concentrations in TNBP. This study highlights the potential role of hormonal therapy use in modulating the immune system among other biological and social factors, especially in TNBP with HIV.

The immunomodulatory impacts of endocrine therapy on host immunity in early-stage hormone receptor positive, HER2 negative breast cancer.

572 Background: Endocrine therapy (ET) reduces mortality in hormonally driven breast cancer (BC). The impacts of ET on the estrogen receptor are well known; however, there is limited data on the impact of ET on the host's immune system. This project aims to elucidate the potential immunomodulatory effects of ET-induced estrogen deprivation in HR+/HER2 negative early-stage breast cancer patients (pts) as well as baseline differences between BC pts and healthy controls (HC). Methods: Pts with Stage I-III HR+/HER2- BC initiating ET after completion of local regional therapy and/or chemotherapy were enrolled (NCT03719495). Whole blood, E1 (estrone) and E2 (estradiol) levels were collected at baseline (T1), 4 weeks (T2), 12 weeks (T3) and 24 weeks (T4) after ET initiation. 5 cohorts were enrolled: premenopausal and postmenopausal HCs, premenopausal pts on tamoxifen (TAM) or aromatase inhibitors (AIs) plus ovarian suppression, postmenopausal pts on AIs. Bulk RNA sequencing of whole blood was performed using NuGEN mRNA-seq on the Illumina Nova-seq platform. Differential expression analysis was performed using DESeq2 between HC and ET groups at T1, and between T1 and T4 within BC pts. The Benjamini-Hochberg method was used to adjust the P values for multiple comparisons. A curated set of 192 immune related gene signatures was used in the gene signature analysis. For each signature/module, a score was computed by taking the median of the expression values from all genes in each gene signature. CIBERSORT analysis was performed using the LM22 signature gene file and 100 permutations. Paired t-test was performed to compare T1 and T4. Results: Between 2019 and 2023, 64 pts were enrolled. Pts with missing samples or prior chemotherapy were excluded in this analysis. T1 samples of 25 pts with BC versus 14 HCs revealed marked changes in circulating immune cell (IC) composition with 537 DEGs (p value < 0.05). Circulating ICs in BC pts had marked upregulation of genes associated with oxidative phosphorylation, adipogenesis, interferon alpha, reactive oxygen species compared to HCs. Immune cell composition was inferred by CIBERSORT analysis which suggests that BC pts had fewer circulating naïve B cells (p=0.048) whereas regulatory T cells (p=0.025) and activated NK cells (p=0.0039) were higher in BC pts than HCs at T1. BC pts with reductions in E1/E2 levels 6 months after ET had 77 DEGs in PBMCs between T1 and T4. Gene signature analysis shows that B cells and NK cells (p=0.0077) signatures are elevated post ET whereas a reduction of neutrophil signature (p=0.0034) was noted. Conclusions: There are significant differences in the baseline IC repertoire/activity in BC pts compared to HCs. The reduction in B cell activity/number and an increase in regulatory T cell number suggests a possible compromised immune system in BC pts. After surgery and 6 months of ET, these suppressed immune phenotypes reversed. Clinical trial information: NCT03719495 .

The impact of female sex hormones on cardiovascular disease: from mechanisms to hormone therapy.

Cardiovascular disease remains the leading cause of mortality in women, yet it has not raised the awareness from the public. The pathogenesis of cardiovascular disease differs significantly between females and males concerning the effect of sex hormones. Estrogen and progestogen impact cardiovascular system through genomic and non-genomic effects. Before menopause, cardiovascular protective effects of estrogens have been well described. Progestogens were often used in combination with estrogens in hormone therapy. Fluctuations in sex hormone levels, particularly estrogen deficiency, were considered the specific risk factor in women's cardiovascular disease. However, considerable heterogeneity in the impact of hormone therapy was observed in clinical trials. The heterogeneity is likely closely associated with factors such as the initial time, administration route, dosage, and formulation of hormone therapy. This review will delve into the pathogenesis and hormone therapy, summarizing the effect of female sex hormones on hypertension, pre-eclampsia, coronary heart disease, heart failure with preserved ejection fraction, and cardiovascular risk factors specific to women.

Abstract PO4-01-09: The Prognostic Impact of Adjuvant Endocrine Therapy by Age for Patients with Small Estrogen Receptor-Positive (ER+), Human Epidermal Growth Factor 2 Negative (HER2-) Breast Cancer

Abstract Backgrounds: We previously reported an analysis of the impact of adjuvant endocrine therapy (ET) for patients with ER+ and HER2- T1a/bN0M0 breast cancer (BC) at ASCO 2023 (Abstract #538). For the whole cohort, adjuvant ET significantly reduced distant metastases, but the absolute overall survival (OS) difference was small. The presence of medical comorbidities related to treatment toxicity and the estimated life-expectancy differ based on age, affecting the clinical impact of ET. There may be settings where comorbidities result in a sufficiently short, expected OS such that the benefit of ET will not outweigh risk. In multivariate analysis, age (<55 vs >55) was not an independent risk factor for distant metastasis. Here we evaluate the impact of adjuvant ET for ER+/HER2- T1a/bN0M0 breast cancer by age-specific subgroups, focusing on younger (< 40) and older (>65) population. Methods: This is a multicenter retrospective cohort study that evaluated the impact of adjuvant ET for patents with ER+/HER2- T1a/bN0M0 BC who underwent primary breast cancer surgery between 2008 and 2012 in 47 institutes of the Japan Clinical Oncology Group (JCOG). We analyzed distant metastatic-free survival (DMFS) and OS using Kaplan-Meier estimates with log-rank test in patients treated with and without ET in each of three age-specific subgroups (<40, 41-64 and 65> years of age). Results: Median follow-up was 9.2 years; the median age of the entire cohort was 55 years. Of 4756 eligible patients, 417 patients were age 65 (1025 (82%) with ET and 227 (18%) without ET). Of all 3989 (84%) patients with ET (2053 (51%) with Tamoxifen, 2142 (54%) with Aromatase inhibitor, 595 (15%) with LH-RH analog and 76 (2%) with others, includes duplicates). In the < 40 subgroup, 9-year DMFS was 97.2% with ET and 91.0% without ET (p=0.023) and 9-year OS was 97.8% with ET and 97.0% without ET (p=0.954). In the > 65 subgroup), 9-year DMFS was 92.6% with ET and 84.0% without ET (p< 0.01) and 9-year OS was 93.8% with ET and 84.9% without ET (p< 0.01). In those aged 41-64, no significant difference was observed in both 9-year DMFS and OS between patients with and without ET (p=0.328 and p=0.731, respectively) See Table for details. Conclusions: Adjuvant endocrine therapy was associated with improved distant metastatic-free survival in the younger (<40) and older (>65) population in this large Japanese dataset and was associated with improved overall survival in those >65. Our findings suggest clinically relevant benefit from ET in both younger and older unselected patients with very small ER+ BC. The lack of benefit in patients aged 41-64 is likely due to individual tumor and treatment factors, which will be evaluated and described in detail at the meeting. Table. The 9-year DMFS and OS of each age-specific three subgroups. *They are analyzed by using Kaplan-Meier estimates with log-rank test between patients treated with and without ET. Citation Format: Yuko Takahashi, Shinsuke Sasada, Naoto Kondo, Hiroya Hashimoto, Kaori Terata, Kumiko Kida, Yasuaki Sagara, Yoichi Naito, Keisei Anan, Takayuki Ueno, Akihiko Suto, Chizuko Kanbayashi, Mina Takahashi, Rikiya Nakamura, Toshiyuki Ishiba, Michiko Tsuneizumi, Seiichiro Nishimura, Yukinori Ozaki, Akihiko Shimomura, Takehiko Sakai, Tsuguo Iwatani, Hideo Shigematsu, Kenji Tamura, Tomomi Fujisawa, Takashi Hojo, Fumitaka Hara, Tadahiko Shien, Hiroji Iwata. The Prognostic Impact of Adjuvant Endocrine Therapy by Age for Patients with Small Estrogen Receptor-Positive (ER+), Human Epidermal Growth Factor 2 Negative (HER2-) Breast Cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-01-09.

Exploring Progesterone Deficiency in First-Trimester Miscarriage and the Impact of Hormone Therapy on Foetal Development: A Scoping Review.

Background and Objectives: Progesterone deficiency during pregnancy may lead to various complications, including first-trimester miscarriage, which is the most common pregnancy complication. However, progesterone therapy may play a role in pregnancy maintenance and foetal development. The aim of this scoping review is to present evidence on the link between progesterone deficiency and first-trimester miscarriage among pregnant women and assess the impact of progesterone therapy on foetal development. Methods: A comprehensive global systematic search of mainly primary research studies was conducted using several databases. Peer-reviewed studies published between 2010 and 2023 were included. The scoping review was conducted using the framework outlined by the Joanna Briggs Institute (JBI) and reported using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses-Extension for Scoping Reviews (PRISMA-ScR) statement. Results: Twenty-three articles (which included 35,862 participants) were included in the analysis. Most studies were conducted in mid- to high-income countries. All 23 articles reported a significant positive relationship between progesterone deficiency and first-trimester miscarriage. Furthermore, the majority of studies reported a higher risk of miscarriage when lower levels of progesterone are combined with other declined hormones. While most studies reported that progesterone therapy may reduce the rate of first-trimester miscarriage among pregnant women, no evidence of health-related harm to offspring development was reported. Conclusions: The findings from this systematic-scoping review indicate possible benefits of progesterone replacement therapy in maintaining a healthy pregnancy and foetal development. Rigorous studies that include large sample sizes and systematic reviews are required to confirm these findings further.

Abstract 7568: Molecular effects of neo-adjuvant hormone therapy for locally advanced prostate cancer: An ancillary study of the ARNEO phase 2 trial

Abstract Intensified hormone therapy in combination with radiotherapy improves outcome for very high-risk locally advanced prostate cancer. The impact of hormone therapy with surgery, however, is uncertain. In order to understand this better, we ran an ancillary translational study on ARNEO (NCT03080116), a Phase 2 clinical trial, which randomized 89 locally-advanced prostate cancer patients to 12 weeks LHRHa +/- apalutamide (APA) followed by prostatectomy. We performed clinical-grade transcriptome-wide expression array analysis (Veracyte, Inc. San Diego, CA) of FFPE diagnostic core biopsies (N=89) and tumors removed at prostatectomy (N=32 LHRHa, N=23 LHRHa + APA). We also performed RNASeq on fresh frozen biopsies of prostatectomy tumors (N=42 LHRHa, N=45 LHRHa + apalutamide) and LHRHa-naive control cases (N=61) matched for clinical and pathological risk factors. Pre-surgery serum PSA decreased by a median of 98% (IQR:90.2-99.3) after hormone treatment. This decrease was better associated with tumor AR signaling (r2=0.11) versus pre-treatment serum PSA (r2=0.0005), or between pre-treatment serum PSA with diagnostic biopsies (r2=0.008). We confirmed APA more potently suppressed AR signaling than LHRHa alone, with no detectable difference in direction of effect for differentially regulated genes/pathways. LHRHa + APA had less residual tumor (median Residual Cancer Burden, RCB=0.48cm3) than in LHRHa (median RCB=1.7cm3) but in cases with sufficient tumor, we observed residual active AR signaling pathways at prostatectomy in both treatment arms. To orthogonally confirm this, we selected 28 ERG positive cases (by IHC pre-treatment) and found retained ERG expression in 12/13 on LHRHa and 10/15 on LHRHa + APA. Using pathway analysis in the RNAseq data, we identified LHRHa +/- APA induced down-regulation of AR, metabolic pathways, as well as DNA repair, and up-regulation of hallmark NOTCH, Hedgehog, TGF-beta, WNT and immune signaling (adjusted p-value cutoff=0.001). Comparing differentially expressed genes on RNASeq between treatment-naïve versus LHRHa +/- APA treated tumors, we observed STING1 as significantly higher in LHRHa +/- APA vs control (Wilcoxon rank sum test p-value <0.001). We found that expression of STING1 was positively correlated with hallmark interferon alpha response (r=0.7, rs=0.6) that was correlated with apoptosis (r=0.5, rs=0.5). Whilst we show that adding APA to LHRHa increases suppression of AR activity and ERG expression, we find that 12 weeks is insufficient to abrogate AR signaling in most tumors, despite ~98% decrease in serum PSA. We identify novel processes modulated in humans by potent suppression of androgen activity, including upregulation of STING1-type 1 interferon response as a potential key modulator of treatment effect. Citation Format: Mazlina Ismail, Wout Devlies, Marina Parry, Gaetan Devos, Stefanie Friedrich, Charles Parker, Larissa Mendes, Elai Davicioni, Mark Linch, Frank Claessens, Steven Joniau, Gerhardt Attard. Molecular effects of neo-adjuvant hormone therapy for locally advanced prostate cancer: An ancillary study of the ARNEO phase 2 trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7568.

Castration-resistant prostate cancer (CRPC) on PSMA-PET: Imaging features, disease distribution, and a comparison to castration-sensitive prostate cancer (CSPC).

e17062 Background: 18F-DCFPyL PET/CT is increasingly used in the staging and response assessment of patients (pts) with prostate cancer. Recent studies suggest that short-term ADT increases prostate-specific membrane antigen (PSMA) expression, whereas long-term ADT suppresses PSMA. Changes in PSMA expression after the development of CRPC are uncertain. We described 18F-DCFPyL PET findings in pts with CRPC and compared them to findings in CSPC. Methods: We analyzed 538 18F-DCFPyL scans performed at our large academic center. CRPC was defined as rising PSA w/ testosterone < 50 ng/dL on ADT. M0 CRPC was defined as absence of extra-pelvic disease (dz) and oligometastatic CRPC (oCRPC) was defined as ≤ 5 LN + osseous lesions and absence of visceral dz. Highest SUV max (hSUVmax) was abstracted from radiologist impression. Means between groups were compared using two-tailed t-tests; undetectable PSA levels were scored as “0”. Logistic regression was used to compare dz distribution between castrate states. Significance was defined as p < 0.05. Results: There were 81 pts with CRPC, 72 pts with metastatic CRPC (mCRPC) and 123 pts with mCSPC. The median ages of pts with mCRPC (74.5 years) and mCSPC (71) were similar. The mean PSAs of mCSPC (20.2 ng/mL) and mCRPC (69.4) were significantly different. hSUVmax was higher in mCRPC (mean 40.3, 95% CI 32.7 – 47.8) than in mHSPC (22.6, 18.4 – 26.9), p < 0.001. Distribution of mCRPC lesions was as follows: prostate bed (26.4%), local pelvic LN (25%), distant LN (M1a, 41.7%), osseous (M1b, 16.7%), and visceral (M1c, 16.7%). In a multivariate analysis mCRPC pts had lower rates of pelvic LN dz and higher rates of M1c, with a trend toward increased M1b (p < 0.10), compared to mCSPC pts. ADT and androgen pathway inhibition did not affect hSUVmax in CRPC. Within CRPC, there were 9 pts with M0 dz, 24 pts with oCRPC, and 48 pts with polymetastatic dz (pmCRPC). The ages (Table) of pmCRPC and oCRPC pts were similar. The mean PSA of pmCRPC (100.9) was higher than that of oCRPC (8.8) and M0 CRPC (5.7). hSUVmax between oCRPC (40.3) and pmCRPC (40.3) was similar. Conclusions: The greater hSUVmax in mCRPC may implicate the effect of ADT on PSMA expression or may describe differing tumor biology. mCRPC pts had less local dz and more frequent distant metastases, likely reflecting more advanced disease. These findings will help inform detection of developing castrate resistance on PSMA-PET. More data are needed on the classification of oligometastatic dz on PSMA-PET and the impact of hormone therapy on PSMA in CRPC. [Table: see text]

ODP619 Trends in Obesity in Gender Diverse Adolescents in Northern Nevada

Abstract Obesity in the pediatric population is increasing with 19.3% of adolescents having a body mass index (BMI) at or above 95th percentile. Childhood obesity impacts physical and psychological health, increasing the risk of developing various diseases. Studies show that prevalence of gender diverse (GD) adolescents is increasing and is estimated to be 7 per 1000 in the US. GD adolescents are at increased risk for cardiovascular disease and mental health disorders. GD adolescents who are diagnosed with obesity are at an increased risk for poor health outcomes. There is a lack of research regarding the prevalence of obesity and the impact of hormone therapy in GD adolescents. A retrospective chart review was conducted at Renown Regional Medical Center in Reno, NV. A total of 119 adolescents, aged 8-21, diagnosed with gender dysphoria prior to June 2021, were enrolled using ICD-10 codes. Patient demographics including age, sex assigned at birth, gender identity, BMI, and use of puberty blockers or hormone therapy were retrieved. Patients were categorized into two groups - no treatment and treatment with puberty blockers and/or testosterone. Average change in BMI was calculated. Fisher exact tests were conducted using SAS version 9.4. Nineteen of the 119 GD patients enrolled were classified as obese using age and sex appropriate BMI charts (15.9%). Thirteen participants were assigned female at birth (AFAB) and six were assigned male at birth (AMAB). Of these participants, 12 had no medical interventions and 7 were treated with puberty blockers and/or without testosterone. No participants received estrogen therapy. The average change in BMI was +1.84 (no treatment group) and + 3.70 (treatment group). The average change in BMI for AFAB participants was +2.24 and +3.16 for AMAB participants. Association of obesity with treatment compared to no treatment was not found to be statistically significant (p=0.4125). The prevalence of obesity in this population was similar to the prevalence of obesity in non-GD adolescents regionally. In Nevada, obesity in adolescents age 10-17 increased from 12.9% to 16% from 2018-2021. We expected to observe a higher prevalence of obesity in the adolescent GD population compared to the non-GD pediatric population. Additionally, we expected to see a greater increase in BMI in the group of GD patients receiving treatment. Although the results were not statistically significant, patients undergoing treatments did experience a greater average increase in BMI compared to those who had no medical intervention. The lack of statistical significance is likely due to having a small sample size. Further research is needed to observe obesity trends in adolescent GD populations, as well as the effects of hormone therapy on BMI. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

Effect of the use of prediagnosis hormones on breast cancer prognosis: MCC-Spain study.

To extend knowledge about the long-term use of hormones in hormone therapy or oral contraception as prognostic factors in breast cancer. The MCC-Spain project is a cohort of 1,685 women with incident breast cancer recruited in Spain. Recruitment was carried out between 2007 and 2010, and the follow-up finished in December 2017. The impact of hormone therapy or oral contraception on breast cancer prognosis was analyzed considering year of birth and menopausal status (1,095 women [65%] were postmenopausal). Hazard ratios (HRs) were estimated using Cox regression models. Death by any cause was considered as the event, and hormone therapy or oral contraception were analyzed as regressors. Oral contraception use for less than 5 years shows an HR of 1.10 (95% CI, 0.75 to 1.62), whereas use for 5 or more years shows an HR of 1.46 (95% CI, 0.95 to 2.25), with a P trend of 0.01, showing a dose-dependent response. Regarding hormone therapy and restricting the analysis to postmenopausal women born between1940 and 1959, where most hormone therapy (consumption) is concentrated, the results did not show any trend. Concerning oral contraception use, our results demonstrate that their use is related to poor prognosis in breast cancer. However, research in this field is limited and controversial, indicating the need for more research in this area. Regarding hormone therapy consumption, our results indicate no association with better prognosis, which contradicts what has previously been published.

Cytidine deaminase activity increases in the blood of breast cancer patients

Cytidine deaminase (CDA), an enzyme of the pyrimidine salvage pathway, deaminates cytidine, deoxycytidine and analogs, such as gemcitabine. Constitutive low levels of CDA activity have been reported in the blood of patients with hematological malignancies or suffering from gemcitabine toxicity. We previously reported that cellular CDA deficiency leads to genetic instability. We therefore hypothesized that constitutive CDA deficiency might confer a predisposition to cancer. We analyzed CDA activity and expression in blood samples from breast cancer (BC) patients with a suspected predisposition to the disease, and in healthy controls. Contrary to our hypothesis, we found that both CDA activity and mRNA levels were higher in blood samples from BC patients than in those from controls, and that this difference was not due to excess neutrophils. CDA activity levels were significantly higher in the serum samples of BC patients treated by radiotherapy (RT) than in those of untreated healthy controls, and hormone therapy in RT-treated BC patients was associated with significantly lower levels of CDA activity. A preliminary analysis of CDA activity in the serum of the very few BC patients who had undergone no treatment other than surgery suggested that the increase in CDA activity might be due to the breast cancer itself. Our findings raise important questions, which should lead to studies to elucidate the origin and significance of the increase in CDA activity in the serum of BC patients, and the impact of hormone therapy.

Assessing the benefit of adjuvant endocrine therapy in patients following breast-conserving surgery with or without radiation stratified by a 7-gene predictive DCIS biosignature.

502 Background: Breast conserving surgery (BCS) followed by radiotherapy (RT) has been the mainstay for DCIS treatment. Adjuvant endocrine therapy (ET) has often been recommended based on multiple randomized clinical trials (RCT). However, these studies have failed to identify subsets of patients who did or did not benefit from adjuvant RT/ET therapy after BCS. We evaluated the association of a 7-gene predictive DCIS biosignature (PreludeDx, Laguna Hills, CA) to assess the impact of ET on 10-yr ipsilateral breast recurrence (IBR) risk after BCS alone or with RT. Methods: DCISionRT with integrated Residual Risk subtype (RRt) reported a decision score (DS) and three risk groups, a) Low Risk (DS≤2.8), b) Elevated Risk (DS > 2.8 without RRt) and c) Residual Risk (DS > 2.8 with RRt). DCISionRT/RRt was evaluated in 926 patients from 4 cohorts who were treated with BCS alone or with RT/ET. The three risk groups were assessed for 10-yr total (invasive and in situ) IBR risk by Kaplan Meier and Cox proportional hazards survival analysis. Results: DCISionRT/RRt classified 338 (37%) women as Low Risk, 399 (43%) as Elevated Risk, and 189 (20%) as Residual Risk. Overall, patients treated with ET had a significantly lower 10-yr IBR risk in multivariable analysis independent of RT (HR = 0.55, p = 0.033). In the Low Risk group treated with BCS without RT, the average 10-yr IBR risk was 5.6% (95% CI 2.5-12.1%, n = 124) and was not significantly different with vs without ET (p = 0.33). The 10-yr IBR risk after BCS alone was 22.6% in the Elevated Risk group and 50.3% in the Residual Risk group. Compared to BCS alone, the 10-year IBR risk tended to be lower in patients prescribed ET without RT in the Elevated (11.6%, 95% CI 3.9-32%) and Residual (15.4%, 95% CI 4.1-49%) Risk groups. 10-yr IBR risk was not significantly reduced by RT within the Low Risk group (p = 0.7) but was significantly reduced to 6.3% (95% CI 3.4-12%) by RT within the Elevated Risk (HR = 0.2, p < 0.001) and to 12.5% (95% CI 6.4-23%) within the Residual Risk (HR = 0.2, p < 0.001) groups. 10-yr IBR risk was significantly higher after RT in the Residual (HR = 2.5, p = 0.013) vs. Elevated Risk groups. After BCS and RT, there was no significant reduction in 10-yr IBR risk for those treated with vs without ET in the Elevated (p = 0.22) and Residual (p = 0.87) risk groups. Conclusions: The DCISionRT/RRt biosignature demonstrated prognostic and predictive RT response in Elevated and Residual Risk patients. Consistent with prior RCT data, ET was associated with lower 10-yr IBR risk overall, and within the DCISionRT Elevated and Residual Risk groups without RT. However, neither ET nor RT were asssociated with significant risk reduction in the Low Risk group. There was no added benefit of ET in the Elevated and Residual Risk groups after BCS+RT; the Residual Risk group patients still had a high IBR risk after RT.

200P Increase of vertebral fractures in patients with metastatic breast cancer treated with endocrine therapy combined with CDK 4/6 inhibitor

CDK4/6 inhibitors (CDK4/6i) combined with endocrine therapy (ET) represent the standard of care for HR-positive, HER2-negative metastatic breast cancer (mBC). ET increases the risk of bone fracture; moreover, it has been suggested that CDK6 plays a critical role in controlling osteoblast, osteoclast, and chondrocyte differentiation. The possible impact of ET combined with CDK4/6i on bone health has not already been explored. The main aim of the current study is to evaluate the proportion and the evolution of vertebral fractures (VFs) in mBC HR+ patients (pts) treated with ET combined with CDK4/6i. We retrospectively evaluated a series of 170 mBC HR+ treated with combination of CDK4/6i + ET at Medical Oncology and Breast Unit of ASST Spedali Civili, Brescia, from 2017 to 2020. VFs were evaluated through CT scan at baseline and at subsequent restaging CT and classified in mild, moderate, and severe based on Genant classification. Patients were all female, with a median age of 64 years (38-81). Endocrine treatments were Aromatase Inhibitor (AI) and fulvestrant in 44 and 66 % of pts respectively. CDKi treatments administered were palbocilib, ribociclib, and abemaciclib in 61.2, 22.9, and 15,9% of cases respectively. At baseline, 60.0% of pts had visceral metastases, 54.7% had bone metastases and 44.7% were receiving bone modified agents (BMA). More than half of pts experienced partial response as best response to CDK4/6i treatment and almost all (90%) had clinical benefit. VFs were detected at baseline in 22.9% of cases and after a median follow-up (mfu) of 27 months in 37.1% of pts. Nearly 20% of pts had a worsening of VFs in terms of new VFs or worsening of pre-existing VFs. Correlation between fracture risk factors with the onset of new or worsening of pre-existing VFs as well as the interaction with BMA will be present at the meeting. These preliminary data suggest a detrimental effect of the combination of CDK4/6i and ET on bone health after a mfu of 27 months. To our knowledge, this is the first study analyzing the impact of CDK4/6i on bone health. Studies with longer follow-up are needed to better explore this issue.

Abstract P3-19-12: Impact of endocrine therapy (ET) noncompliance following intra-operative radiation therapy (IORT) in treatment of early-stage breast cancer patients (pts) enrolled in the ExBRT trial

Abstract Purpose: To investigate the association between ET noncompliance and ipsilateral breast tumor recurrence (IBTR) in the ExBRT trial (“A Safety and Efficacy Study of Intra-Operative Radiation Therapy [IORT] Using the Xoft® Axxent® Electronic Brachytherapy [eBx®] System at the Time of Breast Conservation Surgery for Early-Stage Breast Cancer”). Methods: The IRB-approved single arm prospective nonrandomized multi-institutional ExBRT trial was designed to determine the efficacy and outcome of a single 20 Gy fraction of IORT delivered at the time of lumpectomy for early-stage breast cancer. The trial included women age ≥ 40 years with invasive ductal carcinoma (IDC) or ductal carcinoma in situ (DCIS) of all molecular subtypes documented by pre-operative biopsy which were ≤ 30 mm by clinical and radiographic evaluation. Tumors with pre-operative lymphovascular invasion and intra-operative positive lymph nodes and/or margins were excluded. ET was defined as treatment with tamoxifen, anastrozole, letrozole, and/or exemestane. Pts were classified as “Compliant with ET” if they completed a 60-month ET course or were compliant with ongoing ET. Pts were defined as “Discontinued ET” if they stopped ET prior to completing a 60-month ET course. Pts were classified as “Declined ET” if they did not initiate recommended ET. Data, collected at enrollment and at 1, 6, 12, 18 and 24 months, then yearly, included demographics, histopathology, estrogen receptor positivity (ER+), progesterone receptor positivity (PR+), adjuvant therapy, IBTR, and survival. The primary endpoint was IBTR. Preliminary results evaluating the impact of ET noncompliance on pts who successfully completed treatment with a single 20 Gy fraction of IORT per protocol are presented. Results: Between May 2012 - July 2018, 1105 pts (mean age 64 years) with pre-operative biopsy-proven IDC or DCIS successfully completed a single fraction of IORT treatment per protocol. Mean follow-up was 4.0 years (range 2-8 years). One-hundred fifteen (10%) pts, who were either ER negative or had an unknown ER status, are not included in this analysis. Pt cohorts and tumor characteristics are presented in Table 1. There were 39 (3.93%) IBTR in the ER+ subset at mean follow-up of 4 years. IBTR in the “Compliant with ET” group was 2.53%. Although the percentages were greater in the “Discontinued ET” (5.68%) and “Declined ET” (7.10%) cohorts, this did not reach statistical significance (Chi square test, p-value = 0.147). Conclusion: IORT allows pts to conveniently receive both their surgery and electronic brachytherapy radiation treatment in one setting. Early-stage ER+ breast cancer pts compliant with a subsequent course of ET in this study experienced a lower IBTR rate, improving the collective outcome of their multidisciplinary treatment. These preliminary ExBRT trial results demonstrate that IBTR rates are improved with ET compliance. Although this has not reached statistical significance in this trial, it may partially explain the slight differences in IBTR rates noted in comparison with similar electronic brachytherapy early-stage breast cancer studies. Table 1.IORT pt cohorts and tumor characteristicsCompliant with ETDiscontinued ETDeclined ETNNNER +631176183PR +597170162Mean age (years)65.766.366.7Postmenopausal580162161Mean tumor size (mm)11.110.712.7Tumor HistologyIDC524136120grade I2116055grade II2535955grade III54159Unknown grade621DCIS933756Low grade2099Intermediate grade421925High grade30922Unknown grade100Infiltrating lobular ca505Other932Chemotherapy given4286Ethnicity/RaceCaucasian498143151African American351013Hispanic46188Asian/Pacific Islander2812Native American211Other2238Recurrences16 (2.53%)10 (5.68%)13 (7.10%) Citation Format: Barbara Schwartzberg, AMNisar Syed, Robert Cohen, William Dooley, Maen Farha, Veronica Jones, Wesley Hodge. Impact of endocrine therapy (ET) noncompliance following intra-operative radiation therapy (IORT) in treatment of early-stage breast cancer patients (pts) enrolled in the ExBRT trial [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-19-12.

Impact of endocrine therapy on overall survival in ER negative/PR positive locoregional breast cancer: An analysis of the National Cancer Database.

545 Background: Breast cancer expressing PR, but not ER (ER-/PR+) are uncommon, comprising 2–8% of breast cancers, with less known about their characteristics and responsiveness to therapy. The role of adjuvant endocrine therapy (ET) in ER-/PR+ locoregional breast cancer is unclear as these patients have been largely excluded from prospective clinical trials. Despite a lack of data patients are often treated with adjuvant ET due to perceived possible benefit. We used the National Cancer Data Base (NCDB) to assess role of adjuvant ET in ER-/PR + breast cancer. Methods: Using the NCDB, we included adults ≥ 18 and ≤ 70 years old in order to minimize the non-cancer related deaths. We selected only female patients with stage I, II, and III. Patients have received definitive surgery (lumpectomy with radiation or mastectomy) with negative margins. Systemic therapy (ST) was defined as receipt of chemotherapy and/or immunotherapy. We excluded those who had unknown ST status, unknown ET status, unknown HER 2 status, who did not receive definitive surgery and those whose survival time was missing. Patients were stratified into four groups based on HER2 status and receipt of ET. Both Multivariable Cox proportional hazards regression modeling was utilized to determine predictors of overall survival (OS). A propensity score matched cohort was developed based on relevant demographic and clinical factors. The primary endpoint assessed was OS. All analyses were performed using SAS 9.4. Results: We identified 5344 patients (74% were Caucasian, 20% were African American and 6% were others) with ER-/PR+(74% were HER2 - and 26% were HER2 +) locoregional breast cancer (51% were Stage I, 38 % were stage II and 11% were stage III). Grade 1 cancer was seen in 2%, grade 2 in 18%, and majority being grade 3 in 80%. Of which 3093 (58%) patients received ET and 4462 (83%) received ST. Majority of patients were in age group 50-70 comprising of 69% patients, 8 % in age 18—39, 23% in age 40-49 with Charlson-Deyo Score of 0 in 83%, 1 in13%, 2-3 in 4%. In a propensity matched cohort (N=3980), ET was not significantly associated with OS among HER2 negative (HER2-) patients (HR=1.05, 95% CI 0.86-1.28, p=0.63). In HER2+ patient ET was associated with significantly improved OS (HR=0.65, 95% CI 0.42-0.99, p=.047). Conclusions: Receiving ET was not associated with improved OS in locoregional ER-/PR+/HER2- breast cancer based on our study using a propensity matched cohort in the NCDB. However, was frequently administered. Interestingly, improved OS was seen in locoregional ER-/PR+/HER2+ breast cancer with adjuvant ET.

P156 - Impact of endocrine therapy on quality of life in early stage breast cancer patients: prospective patient reported outcomes from the international registry INSPIRE

P156 - Impact of endocrine therapy on quality of life in early stage breast cancer patients: prospective patient reported outcomes from the international registry INSPIRE

Short-term impact of surgically induced menopause on cognitive function and wellbeing in women at high risk for ovarian cancer following risk-reducing bilateral salpingo-oophorectomy.

Risk-reducing bilateral salpingo-oophorectomy (RRSO) is an effective strategy to prevent pelvic serous carcinoma for women at high risk of developing ovarian cancer; however, it results in premature menopause. Data is lacking to adequately counsel these women about potential effects of premature menopause on cognition and quality of life. A prospective study in premenopausal women at high risk of ovarian cancer to determine changes in cognition over time after RRSO and the impact of hormone therapy (HT) on cognition. Participants were surveyed before and after surgery using the Functional Assessment of Cancer Therapy-Cognitive questionnaire and questions regarding domains of wellbeing at 6, 12 and 18 months. Data was tested for changes across time using mixed model regression and logistic regression. Fifty-seven women were included. Sixty-three percent of participants used HT. At 6 months postoperatively, perceived cognitive impairment declined by 5.5 points overall (4.4 in non-HT users and 6 in HT users), P = 0.003. The other domains of cognition assessed did not change significantly over time and the use of HT did not impact scores. Sleep disruption was common in this cohort and was not mitigated by HT. Self-reported depression improved after RRSO (P = 0.004). Women at high risk of ovarian cancer who choose RRSO may experience declines in cognition within the first 6 months of surgical menopause. HT may cause small declines in perceived cognitive impairment at 6 months after RRSO. Women can expect more sleep disruption after menopause, which is not mitigated by HT.

Abstract PO-083: Prostate cancer and COVID-19: Impact of hormonal therapy on severe outcomes

Abstract Background: Early reports on cancer patients infected with COVID-19 have suggested a high risk of hospitalization and death compared to the general population. Limited data are available on outcomes in specific cancer types. We aim to identify whether hormonal treatment impacts severe outcomes (rate of hospitalization, ICU admission, intubation, and death) in prostate cancer patients. Methods: We conducted a multicenter study in the state of Louisiana, throughout the Ochsner Health System, in both tertiary and nontertiary centers. Patients must carry a diagnosis of prostate cancer and have a completed SARS-CoV-2 test between March 1st and April 30th, 2020. Chi-squared and Fisher’s exact tests were performed to compare the proportion of patients experiencing severe outcomes between treatment groups. Results: As of April 30, 2020, a total of 56 patients with prostate cancer who had a positive SARS-COV-2 test were identified. Median age 69, median BMI 28.8, 78.6% (n=44) black, 58.9% (n=33) current/former smokers, HTN, DM2, and CKD were the most common comorbidities, and 12.5% (n=7) of patients had stage IV disease. Of these patients, 26.8% (n=15) were on hormonal treatment (received within 90 days of COVID+ test). In terms of severe outcomes, 58.9% (n=33) of patients required hospitalization, 17.9% (n=10) required ICU admission with 14.3% (n=8) patients requiring intubation, and 23.2% (n=13) of patients died. There was no statistical difference in rate of severe outcomes (rate of hospitalization, ICU admission, intubation, and death) among prostate cancer patients receiving hormonal therapy vs. those receiving no hormonal therapy. Conclusion: With an ongoing global pandemic of COVID-19, it is important to identify characteristics leading to increased risk of severe events in cohorts of cancer patients. This small cohort does not identify hormonal therapy as a risk factor for increased rate of severe outcomes in patients with prostate cancer. Further analyses describing impact of specific hormonal regimens on risk of hospitalization and death will be completed by time of presentation. Citation Format: Karine Tawagi, Jeff Burton, Diana Maslov, Michael Lunski, Marc Matrana, Daniel Johnson. Prostate cancer and COVID-19: Impact of hormonal therapy on severe outcomes [abstract]. In: Proceedings of the AACR Virtual Meeting: COVID-19 and Cancer; 2020 Jul 20-22. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(18_Suppl):Abstract nr PO-083.