Initiation Of Hormone Therapy Research Articles

The Women's Health Initiative trials of menopausal hormone therapy: lessons learned.

The Women's Health Initiative (WHI) assessed oral conjugated equine estrogens (CEE) taken with or without medroxyprogesterone acetate (MPA) for prevention of chronic disease in postmenopausal women aged 50-79 years. Women with an intact uterus (n = 16,608) were randomized to CEE+ MPA therapy or placebo for a median of 5.6 years; women with hysterectomy (n = 10,739) were randomized to CEE-alone therapy or placebo for a median of 7.2 years. Both cohorts have been followed for 18 years. In the overall study population (mean age, 63 y), neither estrogen-progestin therapy (EPT) nor estrogen-only therapy prevented coronary heart disease or led to a favorable balance of chronic-disease benefits and risks. Subgroup analyses, however, suggest that timing of hormone therapy (HT) initiation influences the relation between HT and coronary risk, as well as its overall benefit-risk balance, with more favorable effects in women who are younger (age < 60 year) or recently menopausal (within 10 year) than in women who are older or further past the menopausal transition. In younger women who entered the trial of estrogen-only therapy with oophorectomy, the intervention was associated with a significant 32% reduction in all-cause mortality over long-term follow-up. WHI findings indicate important differences in HT-related clinical outcomes by age and time since menopause. Systemic HT has an acceptable safety profile for menopause management when initiated among healthy women who are younger (or recently menopausal) and not at elevated risk for cardiovascular disease or breast cancer. Initiation of treatment in older women who are distant from menopause onset, however, should be avoided. Other HT formulations and routes of delivery warrant further study.(WHI clinicaltrials.gov identifier: NCT00000611).

Oligopelvis-GETUG P07: A multicenter phase II trial of combined salvage radiotherapy and hormone therapy in oligorecurrent pelvic node relapses of prostate cancer.

93 Background: Oligorecurrent pelvic nodal relapse of prostatic cancer is a challenge for regional salvage treatments. We conducted OLIGOPELVIS – GETUG P07, a phase II trial of combined salvage radiotherapy and hormone therapy in oligorecurrent pelvic node relapses of prostate cancer (NCT02274779). Methods: OLIGOPELVIS–GETUG P07 was a prospective multi-center phase II trial investigating high-dose salvage pelvic irradiation with an additional dose to the fluorocholine-based positron-emission-tomography (FCH- PET)-positive pelvic lymph nodes (PLN), combined with six-month androgen blockade (LH-RH agonist or antagonist injections). The prescribed dose was 54 Gy in 1.8 Gy fractions with up to 66 Gy in 2.2 Gy fractions to the pathological PLN. Toxicity (CTCAE v4) and complete response rates (PSA &lt; 0.20 ng/ml) were analyzed. The main objective was to assess biochemical-clinical failure defined by a cluster of events including PSA progression (≥25 % and ≥ 2 ng/ml above the nadir) or clinical evidence of local or metastatic progression or post- treatment initiation of hormonal therapy or prostate cancer-related death. We hypothesized that salvage treatment would achieve a 2-year relapse-free survival of 70 %. Results: Seventy-four patients were recruited in fifteen French radiation oncology departments between August 2014 and July 2016. Seven were excluded before treatment because of violation of the inclusion criteria. The intention-to-treat analysis therefore included sixty-seven patients. Half of them had received prior prostatic/prostate bed irradiation. Median age was 67.7. Grade 2+ two-year urinary and intestinal toxicity were 10% and 2% respectively. At 2 and 3 years, 73.1 and 45.9% of patients achieved a persisting complete response respectively. After a median follow-up of 34 months, the 2-year progression-free survival rate was 77.6%. Median progression-free survival was 40.1 months. Conclusions: Combined pelvic salvage radiotherapy and hormone therapy allowed for prolonged tumor control in oligorecurrent pelvic node relapses of prostate cancer with limited toxicity. Clinical trial information: NCT02274779.

Abstract P1-19-41: Relationship between depression status and daily and weekly mood in the MADELINE study

Abstract Background: MADELINE is an observational, multicenter study of women in the United States with advanced/metastatic breast cancer (ABC/MBC) receiving palbociclib in combination with either an aromatase inhibitor (AI) as initial endocrine therapy or fulvestrant after progression on prior endocrine therapy. A novel mobile application was used to collect real-time patient-reported outcome (PRO) data to assess patient functioning and quality of life through daily, weekly, and monthly questionnaires for 6 months. Methods: Patients completed the Center for Epidemiologic Studies Depression Scale (CES-D-10) at each cycle; total scores range from 0 to 30, where 10 or more is considered to indicate depression. Based on CES-D-10 scores patients’ depression status could vary cycle-to-cycle. Data on patient’s mood was collected using a daily seven-level mood rating (“very sad” to “most happy”) and a weekly five-level question on breast cancer or its treatment’s negative effect on mood or emotions (“not at all” to “a great deal”). A descriptive analysis examining the relationship between depression (CES-D-10), and the two mood questions was conducted among patients with a completed baseline electronic case report form and relevant mobile app data as of May 1, 2019. Results: Twenty-three sites contributed 137 patients (median [range] age 60 [34, 82]; white: 84%; ECOG 0-1: 87%; initiated palbociclib plus AI at enrollment: 62%). At cycle 1, 48 patients were classified as without depression (score &amp;lt;10) and 33 patients with depression (score &amp;gt;10). During week 1 of cycle 1, the average percentage of days where patients without depression reported a mood of “Neutral” was 37.8%, “Content” was 34.8%, and “Happy” was 22.9% compared to patients with depression reporting 55.2% for “Neutral”, 21.6% for “Content”, and 2.6% for “Happy”. In the same reporting period, 56% (15/27), 19% (5/27), and 4% (1/27) of patients with depression indicated breast cancer or its treatment had negatively impacted their mood or emotions “moderately”, “quite a bit”, or “a great deal” respectively whereas 13% (5/38) of patients without depression indicated it negatively impacted their mood or emotions “moderately” and 0% indicated either “quite a bit” or “a great deal”. Results were relatively similar across the cycles overall and for patients that initiated either palbociclib plus AI or palbociclib plus fulvestrant. Conclusions: The majority of patients in the MADELINE study did not report symptoms indicating depression based on the CES-D-10 at the beginning of treatment and across cycles. Results suggest that the mood and emotions of patients with depression was more negatively impacted by breast cancer or its treatment compared with patients without depression. Citation Format: David Richardson, Lin Zhan, Maria Reynolds, Dawn Odom, Lynn McRoy, Debanjali Mitra, Jeffrey Hargis. Relationship between depression status and daily and weekly mood in the MADELINE study [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-19-41.

Abstract P1-19-35: Trends in daily mood, pain, and fatigue among participants in the MADELINE study

Abstract Background: MADELINE is an observational, multicenter study of women in the United States with metastatic breast cancer (MBC) receiving palbociclib in combination with an aromatase inhibitor (AI) as initial endocrine therapy, or fulvestrant after progression on prior endocrine therapy. A novel mobile application is used to collect real-time patient-reported outcome (PRO) data to assess patient functioning and quality of life through daily, weekly, and monthly questionnaires for 6 months. Methods: An interim analysis of select PRO data was conducted among completed and ongoing patients with a minimum of baseline mobile app and eCRF data as of May 1, 2019. PROs analyzed included daily assessments of seven-level mood rating (very sad to most happy), pain and fatigue severity measured using an 11-point (0 to 10 with 10 being the worst possible pain or fatigue) numeric rating scale (NRS), and pain location. Analyses were descriptive and daily data were averaged to create weekly scores. Results: Twenty-three sites contributed 137 patients (mean [± standard deviation] age 59.7 ± 11.74; white: 84%; ECOG 0-1: 87%; initiated palbociclib plus AI at enrollment: 62%). At the start of cycle 1, the average percentage of days where patients reported a mood of “Neutral” was 44.5%, followed by “Content” with 26.5%; results were relatively stable across the study. The average daily level of pain was 2.3 (2.32) on the NRS during cycle 1, week 1 with no substantial numerical changes across the study [cycle 6, week 4: mean± standard deviation 2.0 (2.13)]. Pain was indicated throughout the body but reported more frequently in the lower body, legs and chest. The average daily fatigue severity on the NRS during the following time points were [mean ± standard deviation]: cycle 1, week 1: 2.8 (2.25); cycle 3, week 1: 2.5 (2.31); and cycle 6, week 1: 2.3 (1.91). Results were relatively similar for patients that initiated either palbociclib plus AI or palbociclib plus fulvestrant. Average daily pain and fatigue scores for week 1 by cycle are shown in the table. Conclusions: Daily reported PRO collected in the MADELINE study suggest a low level of pain and fatigue that does not change substantially over time. The most commonly reported mood ratings among patients were neutral or content. Average daily pain and fatigue scores by cyclePalbociclib + AI(N = 85)Palbociclib + Fulvestrant(N = 52)Overall(N = 137)nMean (SD) scorenMean (SD) scorenMean (SD) scoreCycle 1/Week 1Pain842.4 (2.41)462.0 (2.16)1302.3 (2.32)Fatigue842.7 (2.31)462.9 (2.16)1302.8 (2.25)Cycle 2/Week 1Pain691.9 (2.15)411.7 (2.09)1101.8 (2.12)Fatigue692.4 (2.34)412.6 (2.37)1102.5 (2.34)Cycle 3/Week 1Pain621.9 (2.18)341.4 (1.79)961.7 (2.05)Fatigue622.6 (2.33)352.3 (2.28)972.5 (2.31)Cycle 4/Week 1Pain562.1 (2.23)271.8 (2.45)832.0 (2.29)Fatigue562.6 (2.45)272.3 (2.35)832.5 (2.41)Cycle 5/Week 1Pain491.7 (1.89)211.5 (1.78)701.7 (1.85)Fatigue492.4 (2.19)212.1 (2.03)702.3 (2.13)Cycle 6/Week 1Pain381.7 (1.97)151.8 (2.17)531.7 (2.01)Fatigue382.3 (1.89)152.6 (2.00)532.3 (1.91) Citation Format: David Richardson, Lin Zhan, Maria Reynolds, Kelly Hollis, Lynn McRoy, Debanjali Mitra, Reshma Mahtani. Trends in daily mood, pain, and fatigue among participants in the MADELINE study [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-19-35.

Abstract P1-19-34: The role of hormone receptor (HR) status on initial treatment choices and outcomes for human epidermal growth factor receptor (HER)-2 positive advanced breast cancer: A study of the southeast Netherlands advanced breast cancer (SONABRE) registry

Abstract Background Previously, we reported that patients with HR+/HER2+ advanced breast cancer diagnosed in 2007-2009 had a better overall survival (OS) than patients with HR-/HER2+ advanced breast cancer (SONABRE Registry, Lobbezoo et al. BCRT 2013). This differential outcome suggests an impact of biology and/or used systemic therapies. The objective of the current study was to present initial palliative systemic therapy choices and its impact on OS and progression-free survival (PFS) in patients diagnosed with HER2+ advanced breast cancer in the Netherlands in 2007-2017, stratified by HR status. Patients and methods From our ongoing SONABRE Registry, we selected all consecutive patients diagnosed with HER2+ advanced breast cancer in six hospitals in the Netherlands in 2007-2017. OS and PFS by HR status were obtained using the Kaplan-Meier method and compared by the log-rank test. The multivariable Cox proportional hazards model for OS and PFS on initial systemic therapy were stratified by HR status and included the potential prognostic variables age, cardiovascular disease, metastatic-free interval, initial metastatic sites, (neo-) adjuvant therapy and (type of) initial palliative systemic therapy. Results Of the 376 patients included, 221 (59%) patients were diagnosed with HR+/HER2+ and 155 (41%) with HR-/HER2+ advanced breast cancer. Patients with HR+/HER2+ disease were most frequently diagnosed with bone metastases (74%), whereas the majority of patients with HR-/HER2+ disease were diagnosed with visceral metastases (66%) as initial dominant metastatic site. Of patients with HR+/HER2+ disease, 95% received at least one line of palliative systemic therapy among which 56% initially included HER2-targeted based therapy. Among patients with HR-/HER2+ disease, 77% received systemic therapy of which 87% initially included HER2-targeted based therapy. Median OS was 29 months (95% CI: 24-34) for HR+/HER2+ and 17 months (95% CI: 14-22) for HR-/HER2+ disease (logrank p=0.03). In patients with HR+/HER2+ disease, initial endocrine therapy without HER2-targeted therapy (n=80) did not significantly impact OS (hazard ratio: 1.12, 95% CI: 0.75-1.68), even though it was associated with a shorter initial PFS (hazard ratio: 1.48, 95% CI: 0.94-2.34) when compared with initial HER2-targeted therapy plus chemotherapy (n=81). On the other hand, in patients with HR-/HER2+ disease, receiving initial chemotherapy without HER2-targeted therapy (n=15) was associated with a shorter OS (hazard ratio:2.15, 95% CI 1.11-4.16) and PFS (hazard ratio =3.15, 95% CI 1.37-7.24) when compared with receiving initial HER2-targeted therapy plus chemotherapy (n=97). Conclusions In this extended real-life study with a long follow-up, we confirmed our previous findings that among patients with HER2+ advanced breast cancer the HR+ subtype had a more favorable outcome. We were able to show a differential metastatic pattern by HR status underlining its biological relevance. Immediate use of HER2-targeted therapy had no statistically significant positive effect on OS in the HR+ subtype, in contrast to the positive effect of immediate HER2-targeting therapy in the HR- subtype. Translational studies are warranted to shed more light on the cross-talk between the HR and HER2 pathways to improve selection for HER2-targeted therapies. Citation Format: Sandra M.E. Geurts, Khava I.E. Ibragimova, Nathalie JA Teeuwen, Frans Erdkamp, Birgit EPJ Vriens, Marien O den Boer, M Wouter Dercksen, Manon JAE Pepels, Maaike de Boer, Vivianne CG Tjan-Heijnen. The role of hormone receptor (HR) status on initial treatment choices and outcomes for human epidermal growth factor receptor (HER)-2 positive advanced breast cancer: A study of the southeast Netherlands advanced breast cancer (SONABRE) registry [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-19-34.

Abstract GS5-00: Long-term influence of estrogen plus progestin and estrogen alone use on breast cancer incidence: The Women's Health Initiative randomized trials

Abstract Background: Breast cancer outcomes from the Women’s Health Initiative (WHI) Estrogen plus Progestin and Estrogen-alone trials have been reported but issues remain regarding long- term, post-intervention influence on breast cancer incidence and the influence of time from menopause to hormone therapy initiation (gap time) on breast cancer findings. Design and methods: Postmenopausal women aged 50 to 79 years with no prior breast cancer and with mammogram clearance enrolled in one of two randomized clinical trials at 40 US centers from 1993 to1998, with follow up through September, 2016. The randomized, placebo-controlled trial interventions were: conjugated equine estrogens (CEE, 0.625 mg/d) plus medroxyprogesterone acetate (MPA, 2.5 mg/d) (n = 8,506) vs placebo (n = 8,102) for 5.6 years (median) for women with a uterus or CEE-alone (n = 5,310) vs placebo (n = 5,429) for 7.2 years (median) for women with prior hysterectomy. Annual mammography was mandated through the originally specified completion date in both trials (March 31, 2005). Incident breast cancers were verified by medical record review. Hazard ratios (HRs) were estimated using multi-variable Cox proportional hazards models. The primary outcome for these analyses was time-specific invasive breast cancer incidence rates. In each trial, participants were instructed to stop all study pills coincident with the publication of each trial’s results, in 2002 and 2004, respectively. Results: During the intervention period, with 238 incident breast cancers, CEE-alone significantly reduced breast cancer incidence (hazard ratio [HR] 0.76 95% confidence interval [CI] 0.58, 0.98, P = 0.04). As previously reported, subgroup analyses indicated CEE-alone was particularly beneficial for women with no prior HT use (interaction P = 0.04) and women with gap time &amp;gt;= 5 years (interaction P = 0.01). Post-intervention, through 16.1 years of cumulative follow-up, with 520 incident breast cancers, CEE-alone use continued to significantly reduce breast cancer incidence (HR 0.77 95% CI 0.65-0.92, P = 0.005) while subgroup differences were attenuated and were no longer statistically significant. During the intervention period, with 360 incident breast cancers, CEE plus MPA use significantly increased breast cancer incidence (HR 1.26 95% CI 1.02, 1.56, P = 0.04) with increase in breast cancer incidence greater in women with prior HT use (interaction P = 0.02) and women with gap time &amp;lt; 5 years (interaction P = 0.002). Post-intervention, through 18.3 years cumulative follow-up, with 1,003 incident breast cancers, CEE plus MPA continued to significantly increase breast cancer incidence (HR 1.29 95% CI 1.14, 1.47, P &amp;lt; 0.001) while subgroup differences were attenuated and were no longer statistically significant. Conclusions: CEE-alone and CEE plus MPA use have opposite effects on breast cancer incidence. CEE alone significantly decreases breast cancer incidence which is long term and persists over a decade after discontinuing use. CEE plus MPA use significantly increases breast cancer incidence which is long term and persists over a decade after discontinuing use. As a result of the attenuation of subgroup interactions: all postmenopausal women with prior hysterectomy using CEE-alone have the potential benefit of experiencing a reduction in breast cancer incidence while all postmenopausal women using CEE plus MPA have the potential risk of experiencing an increase in breast cancer incidence. Citation Format: Rowan T Chlebowski, Garnet L Anderson, Aaron K Aragaki, JoAnn E Manson, Marcia Stefanick, Kathy Pan, Wendy Barrington, Lewis H Kuller, Michael S. Simon, Dorothy Lane, Karen C Johnson, Thomas E. Rohan, Margery L.S. Gass, Jane A Cauley, Electra D. Paskett, Maryam Sattari, Ross L Prentice. Long-term influence of estrogen plus progestin and estrogen alone use on breast cancer incidence: The Women's Health Initiative randomized trials [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr GS5-00.

Does preventive oophorectomy increase the risk of depression in BRCA mutation carriers?

BRCA mutation carriers are advised to undergo bilateral salpingo-oophorectomy to prevent ovarian cancer. The abrupt hormonal withdrawal associated with early surgical menopause has been shown to increase the risk of depression and anxiety among women in the general population. The impact in women with a BRCA1 or BRCA2 mutation is not known. We undertook a matched prospective study of BRCA mutation carriers to evaluate the impact of oophorectomy on self-reported initiation of antidepressant use. We identified women with no personal history of cancer or depression and prospectively evaluated the frequency of self-reported medication use after surgery. Each exposed participant (oophorectomy) was randomly matched to a control participant (no oophorectomy) according to year of birth (within 3 years), BRCA mutation type (BRCA1 or BRCA2), and country of residence (Canada, United States, Poland). A total of 506 matched sets were included. We estimated the odds ratio (OR) and 95% confidence intervals (CIs) of antidepressant use (ever/never) following preventive oophorectomy in the entire study population and stratified by age at oophorectomy and by use of hormone therapy. Oophorectomy was not associated with more frequent antidepressant use among BRCA mutation carriers (OR = 0.46; 95% CI 0.22-0.96). We observed reductions in the odds of antidepressant medication use among women who underwent oophorectomy before the age of 50 years (OR = 0.33; 95% CI 0.14-0.78) and among those who initiated hormone therapy use after oophorectomy (OR = 0.35; 95% CI 0.14-0.90). Findings were similar when the analysis was based on self-reported depression (rather than antidepressant use). Although based on a small number of women, these findings suggest that oophorectomy does not increase psychological distress among women at an elevated risk of ovarian cancer.

Sexual Desire Changes in Transgender Individuals Upon Initiation of Hormone Treatment: Results From the Longitudinal European Network for the Investigation of Gender Incongruence

IntroductionSeveral steps in the transitioning process may affect sexual desire in transgender people. This is often underexposed by those providing gender-affirming care. AimTo prospectively assess sexual desire during the first 3 years of hormonal therapy (HT) in transgender people. MethodsThis prospective cohort study was part of the European Network for the Investigation of Gender Incongruence. At baseline, different psychological questionnaires were administered. Sex steroids were measured at each follow-up visit. Data were analyzed cross-sectionally and prospectively. Main Outcome MeasureProspective analysis of total, dyadic (with another person), and solitary (with oneself) sexual desire in 766 participants (401 transgender women [TW], 364 transgender men [TM]) was carried out using the Sexual Desire Inventory (SDI) questionnaire during a 3-year follow-up period, starting at the initiation of HT. Other factors associated with prospective changes were assessed. ResultsIn TW, total, dyadic, and solitary SDI scores decreased during the first 3 months of HT. However, after 36 months, total and dyadic SDI scores were higher than baseline scores. Solitary scores after 36 months were comparable with baseline scores. In TM, total, dyadic, and solitary SDI scores increased over the first 3 months, remaining stable thereafter. However, total and dyadic SDI scores after 36 months were comparable with baseline scores, whereas solitary scores remained higher than baseline. Factors associated with a prospective increase in SDI scores included having undergone gonadectomy, no longer experiencing menstrual bleeding or higher gender dysphoria levels at baseline (in TM only). Clinical ImplicationsThis study offers clear data on the time course of sexual desire after starting HT and thereby helps to inform people who want to start HT. Transgender people can be informed that changes in sexual desire after initiating HT are temporary. Over a longer period of time, the current research does not suggest induction of hypoactive sexual disorder in TW or long-term increased sexual desire in TM. Strength & LimitationsStrengths include the prospective design of this large multicentric study, the well-defined cohort, controlling for HT, sex steroids, and other factors. Limitations include performing a data lock, the absence of an objective measure of sexual desire, and the timing of laboratory measurements. ConclusionGender-affirming HT only induces short-term changes in sexual desire in transgender people. Over a longer period of time, a net increase in dyadic sexual desire in TW receiving feminizing HT and sexual desire scores comparable with baseline in TM receiving virilizing HT, were observed.Defreyne J, Elaut E, Kreukels B, et al. Sexual Desire Changes in Transgender Individuals Upon Initiation of Hormone Treatment: Results From the Longitudinal European Network for the Investigation of Gender Incongruence Study. J Sex Med 2020;17:812–825.

Hormone therapy decision-making processes: Transgender youth and parents

IntroductionThis study explored how transgender (trans) youth and parents of trans youth made decisions around hormone therapy initiation as well as trans youth experiences of barriers to care. MethodsParticipants included 21 trans youth (ages 14–18) and 15 parents of trans youth who resided in British Columbia, Canada. Data for this grounded theory research consisted of transcripts and lifeline drawings collected through semi-structured interviews conducted August 2016 through February 2017. ResultsThe decision-making processes of youth and of parents are illustrated in three-phase temporal models, starting with discovery, leading to (inter)action while seeking care, and reflection after hormone therapy initiation. Youth who sought hormone therapy were clear about their decision to access this care. Throughout these processes, youth experienced numerous parent- and system-related barriers to care. Youth with the lowest levels of parent support experienced more system barriers, with non-binary/genderfluid youth experiencing greater barriers and less support for hormone therapy than youth with binary genders. A new barrier identified in this study was health care provider imposed requirements for parental involvement and/or approval, which rendered some youth unable access to hormone therapy. ConclusionsHealth care providers should be aware of the deliberation and information-seeking in which youth engage prior to seeking care as well as the temporally misaligned decision-making processes of youth and parents. Understanding the challenges trans youth experience due to insufficient parental support and system barriers can provide important context for health care providers striving to provide accessible, gender-affirming care and decision-making support for trans youth.

Fertility Preservation in the Transgender Population

Hormonal and surgical treatments for transgender individuals can severely impact reproductive potential. In this review, we discuss the role of fertility preservation in both male-to-female and female-to-male transgender patients. We focus on the effects of hormone replacement therapy on the gonads and discuss current methods and techniques available for fertility preservation. Moreover, we review the current literature on patient attitudes toward fertility preservation and existing barriers to care. The literature supports the notion that feminizing therapy negatively impacts spermatogenesis, as evidenced by impaired semen parameters. The degree of such decline lies on a spectrum and can be somewhat unpredictable. Similarly, masculinizing therapy with testosterone has variable effects on ovarian function, gynecologic organs, and future fertility potential. Further research is required to better elucidate the long-term effects of such therapies. Optimal timing for fertility preservation is in the postpubertal period prior to initiation of hormonal therapy. This is however not always possible. A multitude of barriers to pursuing fertility preservation exist, including lack of appropriate counseling, the potentially invasive nature of some fertility preservation methods, and the financial burden placed on the patients. Fertility preservation in the transgender population remains poorly utilized. For transgender women, cryopreservation of sperm ideally is performed prior to initiation of hormone replacement therapy. Nonetheless, studies have shown that a degree of spermatogenesis is seen in some individuals without discontinuation of hormonal therapy. This could allow for less disruption, both physically and emotionally. Fertility preservation in transgender men remains invasive with oocyte retrieval as the main technique. Cessation of therapy, ovarian stimulation, and invasive testing has potential to be traumatic and enhance dysphoria. The possibility of fertility preservation at the time of gonadectomy is promising. Prepubertal fertility preservation is also on the horizon, though still experimental. Cost of preservation techniques and storage is currently prohibitive for many patients. Recent changes to state insurance mandates may soon make fertility preservation more accessible. Future research may demonstrate that fertility preservation is possible at the time of gender confirmation surgery, with the goal of being both effective and nontraumatic to the patient.

Protocol for a Systematic Review Assessing Surgery versus Primary Endocrine Therapy in Operable Breast Cancer. Prep for Pandemic

IntroductionIn COVID-19 pandemic epicenters cancer care was severely impacted. All elective and semi-elective procedures, as well as select urgent cases, were postponed in order to preserve resources and protect patients and staff from SARS-CoV-2 exposure. Structured decision making for breast cancer treatment resulted in deferment of surgery with initiation of endocrine therapy. Moreover, the waitlist for elective breast cancer procedures after mitigation is a challenge for prioritization. Objective and significanceWe aim to summarize the current body of evidence, comparatively evaluate oncological outcomes of surgery versus primary endocrine therapy (PET), and determine whether PET is a viable long-term alternative to surgery in the context of crisis management strategy for early, operable hormone receptor positive (HRP) breast cancer. PET could potentially be an acceptable bridging or maintenance therapy in select patients during pandemic crisis or for those choosing to forgo surgery in the treatment of breast cancer. Methods and analysisThe database search includes PubMed, EMBASE, and MEDLINE (via Ovid). This systematic review includes women 18 years or older undergoing one of two interventions for HRP breast cancer: surgery (with or without endocrine therapy post-surgery) or solely PET. Studies comparing one of the two interventions of interest to a non-relevant intervention and studies reporting only descriptive data will not be included in the quantitative synthesis of data. After selection of eligible studies based on title and abstract, these studies will be further screened through full text articles by two independent reviewers, with a third as an arbitrator. Eligible studies will be critically appraised at the study level for methodological quality. Cochrane methodology will be utilized for meta-analysis. Ethics and disseminationThis study does not require an institutional review board approval given its summary design nature. Findings of this systematic review will be published in a peer-reviewed journal.

Premature Ovarian Insufficiency: Management from a Primary Care perspective

Premature ovarian Insufficiency is loss of ovarian activity occurring in women under 40 years of age. It is frequently under-diagnosed and poorly managed, with many health professionals unaware of the condition. Timely diagnosis with a clear understanding of the various comorbidities that can arise due to estrogen-deficiency and its effect on emotional health, fertility, sexual function, bone health and cardiovascular health is vital to appropriately counsel and treat these patients. Prompt initiation of hormone therapy is critical to control the menopausal symptoms that many women experience and to prevent long-term health complications. Primary health care physicians play a vital role in the identification, diagnosis, referral and long-term management of such patients. This review narrates the care of patients with Premature Ovarian Insufficiency in Primary care.

Ectopic breast tissue carcinoma - a case report

Background: Ectopic breast cancer is a rare entity and an important diagnostic and treatment challenge. Case Presentation: 46-year-old female with previous history of resection of ectopic axillary breast tissue who was referred to our Institution after a second resection following an increase in left axillary volume. Histology reported a ductal ectopic breast tissue carcinoma that invaded the deep layer of the dermis and was positive for estrogen and progesterone receptors and Human Epidermal growth factor Receptor-type 2. After being referred to our Institution, surgical margin re-excision and sentinel node biopsy were performed. The patient initiated hormone therapy and underwent adjuvant radiotherapy to the breast and axilla (50 Gy/25 fractions, in daily 2 Gy fractions with a 3D conformal radiation therapy technique) and boost with bolus to the axilla (to complete 60 Gy). She remains in follow-up, with no recurrence to date. Conclusion: A high index of suspicion is required for the timely diagnosis of this rare condition. Since there are no specific guidelines, treatment remains a challenge.

Management of Menopause and the Role For Hormone Therapy.

Hormone therapy remains the most effective treatment for menopausal symptoms but decisions are complex, requiring an assessment of benefits and risks and determination of best treatment type, dose, and duration. Benefits exceed risks for most women with bothersome menopausal symptoms or high risk for fracture if initiated under age 60 years or within 10 years since menopause. Long-term mortality and safety data from the Women's Health Initiative is reassuring, with no increase in deaths from cardiovascular disease or cancer compared with placebo after 18 years of follow-up and a trend towards less mortality in those who initiate hormone therapy ages 50 to 59 years.

Lifetime estrogen exposure and cognition in late life: the Cache County Study.

Prevalence of Alzheimer's disease (AD) is higher for women, possibly influenced by sex-dependent effects of the estrogen. We examined the association between estrogen and cognitive decline in over 2,000 older adult women in a 12-year population-based study in Cache County, Utah. The baseline sample included 2,114 women (mean age = 74.94 y, SD = 6.71) who were dementia-free at baseline and completed a women's health questionnaire, asking questions regarding reproductive history and hormone therapy (HT). Endogenous estrogen exposure (EEE) was calculated taking the reproductive window (age at menarche to age at menopause), adjusted for pregnancy and breastfeeding. HT variables included duration of use, HT type (unopposed; opposed), and time of HT initiation. A modified version of the Mini-Mental State Examination (3MS) was administered at four triennial waves to assess cognitive status. Linear mixed-effects models examined the relationship between estrogen exposure and 3MS score over time. EEE was positively associated with cognitive status (β = 0.03, P = 0.054). In addition, longer duration of HT use was positively associated with cognitive status (β = 0.02, P = 0.046) and interacted with age; older women had greater benefit compared with younger women. The timing of HT initiation was significantly associated with 3MS (β = 0.55, P = 0.048), with higher scores for women who initiated HT within 5 years of menopause compared with those initiating HT 6-or-more years later. Our results suggest that longer EEE and HT use, especially in older women, are associated with higher cognitive status in late life.

Thrombotic Outcomes Following Hormonal Treatment of Heavy Menstrual Bleeding in Pediatric Patients Taking Anticoagulation

Introduction: Anticoagulant-associated heavy menstrual bleeding (HMB) is a common and under recognized complication in women who are being treated for venous thromboembolism (VTE), leading to complications such as anemia and decreased quality of life. The appropriate management of HMB in this population is complex and often requires hormonal therapy which may significantly increase the risk for VTE. Additionally, combined oral contraceptives may need to be used to control heavy menstrual bleeding despite contributing to the overall risk for VTE. Due to limited adult and pediatric data, there are currently no expert consensus guidelines for the treatment of anticoagulant-associated HMB. We describe a single institutional experience and thrombotic outcomes following hormonal therapy for anticoagulation-associated HMB in adolescents. Methods: A retrospective cohort of pediatric females ages 9-21 years treated at Children's Healthcare of Atlanta were identified between January 2016 and July 2019. Patients were identified using common ICD codes for both HMB and anticoagulation/thrombosis. Patient demographic information, clinical characteristics, and thrombotic outcomes were abstracted from review of the electronic medical record. Patients receiving anti-platelet therapy with clopidogrel were included due to the reported similarity of bleeding complications compared to anticoagulants. Summary statistics were performed and Student's t test, Fisher's exact test, and Chi square test were used for statistical analysis (SAS v9.4, 2012, Cary, NC, USA). A p value &lt;0.05 was considered statistically significant. Results: The cohort was comprised of 17 adolescent females with confirmed anticoagulation-associated HMB. Among the cohort, 59% identified as White, 35% Black, and 6% Asian. Body Mass Index was normal in 41%, while 24% were obese and 35% were underweight. Indications for anticoagulation included VTE (n=11), pulmonary embolism (n=6), May-Thurner Syndrome with placement of iliac vein stent (n=3), and other vascular anomalies with confirmed stenosis/thrombosis (n=2). The most common risk factor for thrombosis was initiation of combined hormone oral contraceptives within 3 months of the event that led to initiation of anticoagulation (35%). Anticoagulant medications used included lovenox (n=13), clopidogrel (n=3), and lovenox/aspirin (n=1). The median age at initiation of hormonal therapy for HMB was 17.3 years (min-max, 12.6-18.3 years), with a median time between starting anticoagulation and initiation of hormonal therapy of 11 days (min-max, 0-529 days). Medications used to treat HMB included medroxyprogesterone (n=9), norethindrone (n=6), norethindrone-ethinyl estradiol (n=1), and etonogestrel implant (n=1). After initiating hormonal therapy, amenorrhea or menstrual suppression was reported in all but one individual (n=16/17). Following initiation of hormonal therapy with medroxyprogesterone, only one adolescent experienced a new VTE event. This adolescent had the additional risk factors of May-Thurner anatomy, heterozygous FV Leiden and prothrombin gene mutations, and antiphospholipid antibody syndrome. The median length of follow-up from initiation of hormonal therapy was 325 days (min-max, 43-932 days). Statistical differences between groups were not feasible due to small sample size and few outcome events. Conclusions: The proper treatment of anticoagulation-associated HMB using hormonal therapy in the pediatric population is unclear, but our data suggest that treatment with hormonal therapy reduces anticoagulation-associated HMB while adding minimal risk for VTE. The only VTE event that occurred in our cohort was in the setting of multiple strong risk factors for VTE. Larger pediatric studies are required in order to confirm these findings. Disclosures White: National Hemophilia Foundation: Other: Shire Clinical Fellowship Program. Sidonio:Novo Nordisk: Membership on an entity's Board of Directors or advisory committees; Kedrion: Research Funding; Uniqure: Membership on an entity's Board of Directors or advisory committees; Biomarin: Membership on an entity's Board of Directors or advisory committees; Grifols: Membership on an entity's Board of Directors or advisory committees, Research Funding; Octapharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bioverativ: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda-Shire: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genetech: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Heavy Menstrual Bleeding Under-Recognized in Menstruating Women Treated with Oral Anticoagulants

Background: Reproductive-age women are at increased risk of venous thromboembolism (VTE) due to increased estrogen states, such as pregnancy and the use of estrogen-based medications. The use of oral anticoagulants (OACs), the standard of care for VTE, is associated with increased rates of heavy menstrual bleeding (HMB), defined as &amp;gt;80 mL loss of blood per cycle, in this patient population. In addition to a need for interventions, ranging from initiation of hormonal therapy to surgical management of bleeding, HMB is a deterrent for adherence to OAC. Decreased adherence, such as temporary discontinuation, is associated with an increased risk of recurrent VTE. This is particularly true for women treated with rivaroxaban, for whom the literature suggests the risk of HMB and other forms of abnormal uterine bleeding is increased two-fold, as compared to warfarin. Methods: We performed a retrospective cohort study of reproductive-aged (18-50 years) women receiving oral anticoagulant therapy at a single tertiary care center between January 1, 2012 and December 31, 2018. Female subjects within the appropriate age range were identified using a Cohort Discovery Tool, a web-based interface which allows investigators to query an underlying research data warehouse that contains electronic health record data for the Oregon Health &amp; Science University healthcare system. Medical record review was performed on all identified records to confirm inclusion criteria, including a documented visit with a primary care provider within 6 months following initial prescription. Exclusions included surgical menopause, pregnancy within 6 months of initial prescription, and lactation within 3 months. We abstracted demographic information, initial anticoagulant prescription and indication, menstrual bleeding history, hormonal therapy and HMB specific medical or surgical treatment within 6 months of initial prescription. Results: A total of 236 eligible subjects were identified. The majority (40.6%) were prescribed rivaroxaban as compared to apixaban (25.2%) or warfarin (34.2%). Most (67.1%) were receiving anticoagulation for the treatment of VTE although 20.1% were anticoagulated for 'other' reasons, including superficial thrombophlebitis and prophylaxis in the post-operative setting or for travel. For the majority of subjects (59.8%), no discussion of menstrual history was documented prior to or at the time of initial prescription. Twenty-nine percent of women received medical (including hormonal) or surgical therapy for HMB, including 32.6% of women treated with rivaroxaban, 23.7% of women treated with apixaban and 28.8% of women treated with warfarin (p &amp;lt;0.001). Discussion: Our study confirms prior reports of increased prevalence of HMB and other abnormal uterine bleeding in women prescribed rivaroxaban as compared to apixaban or warfarin. Our overall numbers, however, are lower than those previously reported in the literature, where HMB, defined as blood loss of &amp;gt;80mL/cycle or a pictorial blood loss assessment chart score of &amp;gt;100, is reported in 66% of warfarin users. We used a different definition of HMB, which was any menstrual bleeding severe enough to require an intervention, including hormonal therapy, surgery or iron replacement, which may explain this difference. Not all women with standardly defined HMB may require such therapies. However, since the vast majority of providers did not assess for menstrual bleeding at the time of drug initiation, it is possible that HMB was unrecognized. Our next step will be to survey women who received an initial prescription in 2017 or 2018 regarding symptoms of HMB, in order to assess the proportion of subjects whose diagnosis of HMB went undetected. Our findings underscore the importance of addressing and discussing menstrual bleeding with menstruating women using oral anticoagulants. Disclosures No relevant conflicts of interest to declare.

Delayed adjuvant hormonal therapy and its impact on mortality in women with breast cancer.

Adjuvant hormonal therapy (HT) is important for the management of hormone-sensitive breast cancer. However, the timeliness for adjuvant HT and the consequences of delayed initiation of treatment have not been analyzed. The purpose of this study was to characterize delays to HT and assess the impact on clinical outcomes. The study cohort consisted of female patients with invasive ductal and/or lobular, hormone receptor-positive breast cancer diagnosed between 2010 and 2015. Initiation of HT >6months (180days) after surgery was defined as delayed. Patients receiving chemotherapy were excluded from the study cohort. Multivariable logistic regression modeling was performed to establish associations between delayed HT and demographic, facility, and clinical factors. Survival analysis was performed using the Kaplan-Meier estimation and Cox proportional hazards regression to evaluate overall survival. Of 179590 women assessed in the National Cancer Database, 3.2% had a delay in the initiation of adjuvant HT. Positive demographic-related risk factors were younger age, ethnic minority groups, and multiple comorbidities. Clinical factors significantly associated with delayed initiation of adjuvant HT were high-grade tumor, larger tumor size, greater lymph node involvement, having an unplanned readmission within 30days of surgery, and positive final surgical margins. Adjusted survival analysis showed a survival disadvantage of delayed initiation of HT. Risk factors for delayed initiation of HT specific to demographic and clinical characteristics were identified. Delayed initiation of HT was associated with a survival detriment.

327P - Palbociclib plus an aromatase inhibitor as first-line therapy for metastatic breast cancer in US clinical practices: Real-world progression-free survival analysis

BackgroundCDK4/6 inhibitor in combination with an aromatase inhibitor (AI) as initial endocrine therapy has become standard of care for patients with HR+/HER2– advanced/metastatic breast cancer (mBC). Large representative studies are needed to understand effectiveness of CDK4/6 inhibitor + AI in the real-world clinical setting. This study describes patient characteristics and real-world progression-free survival (rwPFS) in mBC patients treated with Palbociclib + AI in the first line setting. MethodsThe Flatiron longitudinal database contains information from 2 million cancer patients treated in the US from 275 cancer clinics. From this database, 878HR+/HER2– mBC women treated with Palbociclib + AI as first-line therapy between February 2015 and August 2018 with at least 3 months of follow-up available were identified. Patients were followed from start of Palbociclib + AI therapy to November 2018, death, or last visit, whichever came first. rwPFS was defined as months from start of Palbociclib + AI to death or disease progression based on clinical assessment or radiographic progression with or without biopsy confirmation. Kaplan-Meier methods were used to estimate survival proportions in rwPFS. ResultsIn our cohort of 878 eligible patients with a median follow-up of 19.4 months, 66.9% were white, mean age was 65.2 years, 50.8% had visceral disease (liver and/or lung involvement). Among these patients, 92.7% received Letrozole along with Palbociclib. Median rwPFS was 21.9 months (95%CI = 20.1 – 28.2). Table presents median rwPFS by subgroups. ConclusionsThese findings from a large cohort of patients in US routine clinical practices support first-line Palbociclib + AI therapy as standard of care for HR+/HER2- advanced/metastatic breast cancer.Table327P Real-world progression-free survival (rwPFS) by subgroupsTableNMedian rwPFS (months)95%CIAll patients87821.920.1 – 28.2Age, year18-6440721.818.8—26.465-7429421.416.1—29.9≥ 7517728.620.1—NEEthnicityWhite58722.620.3—28.6Black62NE11.3—NEAsian1813.87.8—NEHispanic28NE5.9—NEOther/unknown18319.916.1—NEMenopausal statusPremenopausal (Age≤50)6719.514.3—25.9Postmenopausal (Age>50)81122.420.2—28.7Disease stage at initial diagnosis1 or 231121.917.6—33.1311921.013.1—28.64 (De novo)35922.219.5—32.7Unknown8926.515.5—NEECOG Score032222.418.9—NE1+22521.016.5—28.3No bone-only disease62317.314.6—20.2Bone-only disease255NENEVisceral disease44614.812.7—18.3Nonvisceral disease43233.128.3—NENo# of metastic sites1352NENE226620.217.1—33.03+25611.39.8—13.7NE = not estimable Legal entity responsible for the studyPfizer Inc. FundingPfizer Inc. DisclosureM. Torres: Full / Part-time employment: Emory University; Research grant / Funding (self): Pfizer Inc. X. Liu: Shareholder / Stockholder / Stock options, Full / Part-time employment: Pfizer Inc. J. Mardekian: Shareholder / Stockholder / Stock options, Full / Part-time employment: Pfizer Inc. L. McRoy: Shareholder / Stockholder / Stock options, Full / Part-time employment: Pfizer Inc.

Baseline Mental Health and Psychosocial Functioning of Transgender Adolescents Seeking Gender-Affirming Hormone Therapy.

Research suggests that adolescents seeking gender-affirming hormone therapy experience elevated rates of depression, anxiety, and difficulties with peer relationships. Less is known regarding more specific aspects of mental health and psychosocial functioning. Furthermore, few studies have explored variations in mental health and psychosocial functioning by age, gender, degree of physical dysphoria, and informant type (adolescent, mother, and father). Participants are adolescents (n = 149) and parents/guardians (n = 247) who presented to a multidisciplinary gender clinic in Dallas, TX for an initial assessment before initiation of gender-affirming hormone therapy. Adolescents completed the Youth Self-Report (YSR) and the Body Image Scale (a measure of physical dysphoria), and parents/guardians completed the Child Behavior Checklist (CBCL). Approximately half of participants reported clinically significant difficulties with internalizing symptoms and psychosocial functioning (particularly engagement in activities), with approximately one-third indicating significant difficulties with depression, anxiety, obsessive compulsive, and posttraumatic stress symptoms. Parents reported fewer symptoms than adolescents across several subscales, but differences were generally small. By contrast, gender differences were found across all internalizing subscales and were generally large. Age and body dissatisfaction were not independently associated with broadband measures but, in combination with gender, were strongly associated with variance in YSR and CBCL reports of internalizing symptoms. Elevated rates of depression, anxiety, and competency difficulties were broadly consistent with the previous literature and demonstrate the need for investment in the clinical training and infrastructure to provide comprehensive care to this population. Differences in mental health and psychosocial functioning by gender and clinic location appear to be less straightforward.