Stewart, Elizabeth A.

Objective: To compare 12-month post-treatment health-related quality of life (HR-QoL) and symptom severity (SS) changes among patients with symptomatic uterine fibroids (SUF) not seeking fertility and undergo a hysterectomy, abdominal myomectomy (AM), or uterine artery embolization (UAE). Materials and Methods: The Comparing Options for Management: Patient-Centered Results for Uterine Fibroids (COMPARE-UF) Registry is a multi-institutional prospective observational cohort study of patients treated for SUF. A subset of 1465 women 31–45 years of age, who underwent either hysterectomy ( n = 741), AM ( n = 446), or UAE ( n = 155) were included in this analysis. Demographics, fibroid history, and symptoms were obtained by baseline questionnaires and at 1 year post-treatment. Results were stratified by all treatments and propensity score weighting to adjust for differences in baseline characteristics. Results: Women undergoing UAE reported the lowest baseline HR-QoL and highest SS scores (mean = 40.6 [standard deviation (SD) = 23.8]; 62.3 [SD = 24.2]) followed by hysterectomy (44.3 [24.3]; 59.8 [SD = 24.1]). At 12 months, women who underwent a hysterectomy experienced the largest change in both HR-QoL (48.7 [26.2]) and SS (51.9 [25.6]) followed by other uterine-sparing treatments. Propensity score weighting revealed all treatments produced substantial improvement, with hysterectomy patients reporting the highest HR-QoL score (92.0 [17.8]) compared with myomectomy (86.7 [17.2]) and UAE (82.6 [21.5]) ( p < 0.0001). Similarly, hysterectomy patients reported the lowest SS scores (8.2 [15.1]) compared with myomectomy (16.5 [15.1]) and UAE (19.6 [17.5]) ( p < 0.0001). Conclusion: All procedures showed improvement in HR-QoL and reduction in SS score at 12 months, hysterectomy showing maximum improvement. Of importance, at 12 months, patients who underwent either a myomectomy or UAE reported comparable symptom relief and HR-QoL. Clinicaltrials.Gov Identifier: NCT02260752.

INTRODUCTION: Iron-deficiency anemia is common in women with uterine fibroid (UF)-related heavy menstrual bleeding. Severe anemia is defined as hemoglobin (Hb) levels <10g/dL. The effect of linzagolix, an oral GnRH antagonist, on UF-related severe anemia was assessed in two Phase 3 trials. METHODS: PRIMROSE 1 and 2 are randomized, double-blind, placebo-controlled Phase 3 trials investigating the efficacy and safety of linzagolix 100 mg and 200 mg once daily, with or without hormonal add-back therapy (ABT) in the treatment of UF. Subjects were considered responders if an increase of ≥2g/dL from baseline was achieved. Patients with severe anemia were given iron supplements until they reached the Hb levels >12g/dL. RESULTS: In PRIMROSE 1, of 165 subjects with severe anemia, 57.9%, 61.5%, 82.1% and 65.2% of patients were responders at 24 weeks, in the respective treatment groups (100 mg, 100 mg+ABT, 200 mg and 200 mg+ABT), compared to 50% in the placebo group. In PRIMROSE 2, of 93 patients with severe anemia, 62.5%, 75%, 60% and 73.7%, respectively, were responders, compared to 46.2% for placebo. Given the small sample sizes, statistical significance was not reached. Improvements were maintained at week 52: in PRIMROSE 1, 69.2%, 62.5%, 81.3% and 75% of patients were responders in the respective treatment groups, compared to 40% in placebo, in PRIMROSE 2, 66.7%, 100%, 80%, 87% were responders, respectively. CONCLUSION: High and low doses of linzagolix improved Hb levels in patients with UF suffering from severe anemia.

Abstract Introduction: Breast cancer treatments can impair fertility via direct gonadotoxicity (chemotherapy) as well as by introducing delays in childbearing that allow natural ovarian aging. Guidelines strongly recommend fertility counseling and consideration of fertility preservation techniques for premenopausal women who have not completed their desired childbearing at the time of cancer diagnosis. Prior studies have identified high rates of fertility concern but relatively low rates of fertility counseling and use of fertility preservation techniques. We sought to investigate rates of fertility counseling, use of fertility preservation techniques, and how fertility concerns impact cancer treatment decisions in a modern cohort of patients with breast cancer at a large academic medical center in the United States. Methods: All patients seen at Mayo Clinic Rochester with a new diagnosis (within the year prior) of stage 0-4 breast cancer were invited (by mail or in person) to participate in the Mayo Clinic Breast Registry. After informed consent, participants were asked to complete a baseline survey and annual follow-up surveys. On baseline and one-year surveys, patients were queried about desire for future children and fertility concerns. Nurse chart abstraction was used to collect information about tumor subtype, stage, and treatments received. We examined survey data from women diagnosed under the age of 50 who expressed an interest in having future biological children on either the baseline or year 1 survey between February 2015 and October 2020. Descriptive statistics were used to summarize the degree of fertility concern in this population, the impact of that concern on cancer treatment decisions, and steps taken to preserve fertility. Results: Between February 2015 and October 2020, 865 women under age 50 at diagnosis consented to the registry. Of these women, 627 completed a baseline and/or 1-year survey and 100 answered either “yes” or “unsure” to the question: “At the present time, do you wish to have any more biological children in the future?” on one or both surveys. Among the 100 women expressing interest in future child-bearing, 92% were white, 27% had node-positive and one had distant metastatic disease at diagnosis. The age at diagnosis ranged from 19 to 49 years, with a mean age of 33.8 years. Of the 75 who reported a desire for future children at baseline, 28% felt “somewhat concerned” about their future fertility and 40% felt “very concerned.” Of the 70 who reported a desire for future children on the year 1 survey, 17% felt “somewhat concerned” and 59% felt “very concerned.” For those “very concerned” about future fertility at year 1, 65% reported that this concern had a major impact on their treatment decisions. Often, that treatment modification entailed using endocrine therapy for less than 5 years; 52% of those who specified the type of treatment modification they had made indicated this option. Of note, six women who reported no desire for future biological children at baseline were “unsure” at year 1. At year 1, 93% of women recalled a discussion about fertility with their doctor prior to starting treatment, and 49% had taken steps to preserve fertility (32.5% with embryo cryopreservation, 20% with oocyte cryopreservation and 65% with a GnRH agonist; some selected multiple options). Conclusion: We found a reassuringly high rate of patient-reported fertility counseling and use of reproductive endocrinology technologies to preserve fertility in women who reported a desire for additional children at or soon after diagnosis with breast cancer. Consistent with prior studies, fertility concerns frequently impacted breast cancer treatment decisions. It is important to err on the side of inclusivity when providing fertility counseling because desire for fertility can change over time. Citation Format: Samantha Mannion, Alexandra Higgins, Elizabeth A Stewart, Zaraq Khan, Chandra Shenoy, Nicole Larson, Hazel B Nichols, H Irene Su, Ann H Partridge, Fergus J Couch, Janet E Olson, Kathryn Ruddy. Prevalence and impact of fertility concerns in young women with breast cancer [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 P4-11-02.

Uterine fibroids (leiomyomas) are present in >75% of women and can cause serious morbidity. They are by far the leading cause of hysterectomy. Fibroids are a complex mixture of cells that include fibroblasts and smooth muscle cells. Rich in extracellular matrix, they typically arise through somatic mutations, most commonly MED12. Their lack of growth inhibition and their ability to have facets of malignancy yet be histologically and biologically benign provide opportunities to explore basic processes. To date, the mechanisms responsible for growth and development of leiomyomas are an enigma. This review provides an overview of current understanding and future directions for clinical and basic research of fibroids.

Background Infertility is a global public health issue. Therapies such as intrauterine insemination (IUI) are effective but may be associated with considerable anxiety. Preliminary data suggest that decreasing this anxiety might lead to improved outcomes. Objective To determine whether lavender aromatherapy (LA) reduces anxiety during an IUI procedure. Methods A randomized controlled trial of women undergoing IUI at a hospital-based fertility clinic. The intervention and comparison were the use of LA vs water. Measurements were the change in anxiety level during an IUI procedure, with secondary assessment of pain scores, patient satisfaction, and pregnancy rates. Results In total, 67 women were screened, and 62 women randomly assigned to either placebo (n = 31) or LA (n = 31). No differences were observed in baseline demographic characteristics or visual analog scores for anxiety before IUI (mean [95% CI], 33.9 [25.2 to 45.6] mm vs 41.0 [33.0 to 49.0] mm) in the LA and placebo groups. However, a statistically significant change in anxiety was observed after LA inhalation during the procedure (mean [95% CI], −11.2 [−19.1 to −3.2]) compared with placebo (mean [95% CI], 1.3 [−5.6 to 8.2]; P = .02). No significant difference was observed in pain during IUI in the LA group vs placebo group. Patient satisfaction was high, with 93% of respondents in the LA group satisfied with the aromatherapy during their procedure. Additionally, 76% of participants who received placebo reported that they would prefer to use LA during their IUI. No statistically significant difference was detected in pregnancy rates between the 2 groups: 19.4% with LA vs 9.7% with placebo ( P = .47). Conclusion LA reduced anxiety and was preferred by women during IUI fertility treatments.

Uterine fibroids are noncancerous tumors associated with significant morbidity among symptomatic patients. While medical and surgical treatments have expanded, hysterectomy remains common. We interviewed women diagnosed with uterine fibroids ( n = 47) to explore their experiences and recommendations for shared decision-making. A majority were non-Hispanic Black, highly educated (51.1%), and had graduate degrees (40.4%). Participants with both positive and negative provider experiences expressed a desire for a more proactive therapeutic approach, including a presentation by their provider of the spectrum of medical and surgical treatment options, and greater provider recognition of the impact of symptoms on quality of life. Women advocated for expanded shared decision-making that acknowledged their contribution to their own treatment plan and felt early screening and improved patient/provider education of uterine fibroid symptoms would facilitate greater congruence between treatment approaches and patient goals. Perceptions of insufficient input into their treatment plans frequently served as a barrier to care-seeking and treatment acceptance among women with uterine fibroid symptoms. Improved discussion of treatment options in the context of the unique symptom burden and values of the patient may facilitate greater provider trust and acceptance of uterine fibroid treatment.

Objective: To assess outcomes of women with uterine fibroids (UFs) and heavy menstrual bleeding (HMB) treated with 300 mg elagolix twice daily plus add-back therapy (E2 1 mg/NETA 0.5 mg once daily) or placebo who were not considered responders in pooled analysis of two phase 3, 6-month randomized clinical trials (Elaris UF-1 and UF-2). Methods: Responders were defined as women who met both primary end point bleeding criteria (<80 mL menstrual blood loss [MBL] during the final month and ≥50% reduction in MBL from baseline to the final month) and either completed the study or discontinued due to predefined reasons. Thus, women termed nonresponders who were analyzed in this study who met neither or one bleeding end point or met both criteria but prematurely discontinued treatment because of adverse events, perceived lack of efficacy, or required surgical or interventional treatment for UFs were analyzed in this study. This post hoc analysis assessed mean changes from baseline in MBL, as well as adverse events. Results: Among 367 women receiving elagolix with add-back with observed data, 89 (24%) were not considered responders. Within this subset, 17 (19%) women met both bleeding criteria but prematurely discontinued treatment for the reasons mentioned above, while 23 (26%) met one bleeding criterion and 49 (55%) met neither bleeding criteria, regardless of discontinuation status. Among all nonresponders, a numerical trend toward greater mean reductions in MBL was observed in those receiving elagolix with add-back, compared with placebo group nonresponders. No differences in adverse events were observed between responders and nonresponders. Conclusion: Forty of 89 (45%) women with HMB and UFs who were classified as nonresponders in the UF-1 or UF-2 trials may have had a clinically meaningful response to elagolix with add-back therapy because they met at least one of the objective bleeding criteria. Clinical Trial Registration: Clinicaltrials.gov, NCT02654054 and NCT02691494. (NEJM 2020; 382:328–340) DOI: 10.1056/NEJMoa1904351

Abstract Study question What is the effect of relugolix combination therapy (Relugolix-CT) on symptom burden and health-related quality-of-life (HR-QoL) in patients with uterine fibroids (UF) over 52 weeks? Summary answer Relugolix-CT demonstrated sustained, clinically meaningful improvement in patient-reported symptom severity and HR-QoL over 52 weeks in women with UF. What is known already In LIBERTY 1 and 2 randomized clinical trials, once-daily Relugolix-CT (40 mg relugolix, an oral gonadotropin-releasing hormone receptor antagonist, estradiol 1 mg, norethindrone acetate 0.5 mg) significantly reduced menstrual blood loss (MBL) and UF-associated pain versus placebo in women with UF and heavy menstrual bleeding (HMB), and was well tolerated, with bone mineral density (BMD) preservation through 24 weeks. In the LIBERTY long-term extension study, a sustained reduction in MBL was observed along with no new safety signals and BMD maintenance through 52 weeks. Relugolix-CT was previously shown to significantly improve patient-reported symptom severity and HR-QoL through 24 weeks. Study design, size, duration In the LIBERTY 1 and 2 studies, 770 premenopausal women with ultrasound-documented clinically significant UF and alkaline-hematin documented HMB were randomized 1:1:1 to Relugolix-CT for 24 weeks, relugolix 40 mg for 12 weeks followed by Relugolix-CT for 12 weeks, or placebo for 24 weeks. Women who completed the pivotal studies were eligible to enroll in the 28-week extension study (N = 477 enrolled). Patients included in the extension study received open-label once-daily Relugolix-CT. Participants/materials, setting, methods Changes from baseline to Weeks 24 and 52 in the Uterine Fibroid Symptom (UFS)-QoL symptom severity scale, Bleeding and Pelvic Discomfort scale (BPD; assessing distress due to HMB, passing blood clots, pelvic pressure/tightness); and HR-QoL (sub)scales were assessed. Higher symptom severity and BPD scores reflect higher severity and distress, respectively; higher HR-QoL scores indicate better outcomes. Least-squares mean changes were provided for the original pivotal-study randomized treatment groups Relugolix-CT and placebo. Main results and the role of chance A sustained improvement in symptom severity was observed for the Relugolix-CT group from baseline to Weeks 24 and 52, with LS mean changes of –36.9 and –37.3 points, respectively. In patients initially treated with placebo, small changes were observed at Week 24 (–10.8 points), whereas a greater reduction from baseline was demonstrated at Week 52 (–35.0 points) after transitioning to Relugolix-CT. Considering the BPD, measuring distress from key UF symptoms, LS mean changes of –50.9 and –51.3 points were observed in the Relugolix-CT group from baseline to Week 24 and 52, respectively. In patients initially treated with placebo, small changes were observed at Week 24 (–15.9 points), whereas a greater reduction from baseline was demonstrated at Week 52 (–48.6 points) after transitioning to Relugolix-CT. Treatment with Relugolix-CT also resulted in a sustained improvement in different aspects of HR-QoL. LS mean total HR-QoL score increased from baseline to Weeks 24 and 52 by 40.8 and 40.4 points, respectively. In patients initially treated with placebo, small changes were observed at Week 24 (11.4 points), whereas a greater increase from baseline was demonstrated at Week 52 (39.0 points) after transitioning to Relugolix-CT at Week 24. Limitations, reasons for caution The 28-week LIBERTY long-term extension study was non-comparative. Analyses were performed in a subset of patients who completed the LIBERTY pivotal studies and were eligible for the extension study. However, it is important to note that the demographic and baseline disease characteristics were similar between pivotal and long-term extension populations. Wider implications of the findings Relugolix-CT resulted in a sustained reduction in UF symptom burden, particularly in terms of distress from key UF symptoms, and a sustained improvement of HR-QoL over 52 weeks. Improvements observed after transitioning from placebo to Relugolix-CT at 24 weeks confirmed the positive effect of Relugolix-CT on UF-associated symptoms and HR-QoL. Trial registration number NCT03412890

Background: Women with uterine fibroids often seek uterine-preserving treatments, rather than hysterectomy. Imaging-defined endpoints following nonsurgical treatments for fibroids are limited. Materials and Methods: Fibroid Interventions: Reducing Symptoms Today and Tomorrow (FIRSTT), a randomized controlled trial of uterine artery embolization (UAE) versus magnetic resonance imaging-guided focused ultrasound surgery (MRgFUS), enrolled premenopausal women with symptomatic uterine fibroids. In this subanalysis, we report imaging results up to 36 months after UAE or MRgFUS. Magnetic resonance imaging (MRI) was performed at baseline for all women and during the 36 months after treatment if they did not meet other study endpoints. The main outcome of this subanalysis was fibroid volume reduction (defined both in terms of total fibroid load and volume of the largest fibroid), uterine volume reduction, and nonperfused volume. Results: During 2010–2014, 25 of the 37 women who were randomized and treated at Mayo Clinic had a 24-month follow-up MRI (11 UAE; 14 MRgFUS); among these women, 15 (7 UAE and 8 MRgFUS) had a 36-month follow-up MRI. Average age for the cohort was 44.1 (standard deviation, SD = 4.4) years. Nine patients had a second fibroid procedure by 36 months (seven in the MRgFUS arm and two in UAE arm). Median total fibroid load reduction was ∼50% in both treatment arms at both 24- and 36-month follow-up. Volume of the largest fibroid decreased more in the MRgFUS arm, whereas uterine volume decreased more in the UAE arm (neither reached statistical significance). At 24 months, median nonperfused volume was higher in the UAE arm (92%) than the MRgFUS arm (10%). Conclusions: Similar fibroid volume reduction was seen for the MRgFUS and UAE treatments in this comparative effectiveness study. Nonperfused volume 24 months after the procedure was higher in the UAE arm than in the MRgFUS arm. Clinical Trial Registration Number: NCT00995878, clinicaltrials.gov