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Sarah Sharman Moser,1 Lior Apter,1,2 Idit Livnat,3 Roni Ginsburg,3 Adva Yarden,3 Michal Drori,1 Anat Drizon,1 Gabriel Chodick,1,4 Nava Siegelmann-Danieli1,4 1Maccabi Institute for Research and Innovation (Maccabitech), Maccabi Healthcare Services, Tel Aviv, Israel; 2Department of Health Systems Management, Ben-Gurion University of the Negev, Beer-Sheva, Israel; 3Medical Affairs, AstraZeneca, Kefar Sava, Israel; 4Faculty of Medicine, Tel Aviv University, Tel Aviv, IsraelCorrespondence: Sarah Sharman Moser, Email moser_sa@mac.org.ilBackground: In this observational study, we analyzed the treatment patterns and clinical outcomes of patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (mBC) who developed brain metastases during their disease in a 2.7 million-member public health-provider in Israel.Methods: Newly diagnosed patients with mBC who initiated first-line treatment between January 2013 and June 2021 were identified. Time on treatment (ToT) and overall survival (OS) were assessed at a minimum of 6 months follow-up (cutoff: December 2021).Results: We identified a total of 61 patients: 98.4% females, median age 50 years (IQR = 44– 63), 85% invasive ductal tumors, 44% hormone receptor positive, 51% performance status 0– 1. The median duration of follow-up was 6.2 years. All patients initiated a combination treatment of trastuzumab, pertuzumab, and chemotherapy (TPC), and 72% moved to second-line treatment during the study follow-up period (82% ado-trastuzumab emtansine). The median ToT for first-line and second-line treatments were 16.9 months (95% CI = 13.9– 27.7) and 7.9 months (95% CI = 5.6– 10.9), respectively. The median overall survival (OS) was 45.5 months (95% CI = 35.4– 71.2) from the initiation of first-line treatment. When considering the timing of brain metastases, the median OS was 36.3 months (95% CI = 10.0–NR) for those diagnosed upfront (n = 15, 25%), 59.1 months (95% CI = 32.5–NR) for those diagnosed while on TPC (n = 25, 41%), and 40.8 months (95% CI = 35.4–NR) for those diagnosed at a later stage (n = 21, 34%). The median OS from brain metastases diagnosis was 25.1 months (95% CI = 17.0– 34.6).Conclusion: Patients with upfront brain involvement at the time of mBC diagnosis had shorter survival compared to those who started TPC without brain metastases. Nonetheless, the overall results from this study compare favorably with previous studies and contribute to understanding the value of traditional treatment options, which will serve as a baseline for future treatment strategies in the real-world setting.Keywords: HER2 positive, metastatic, breast cancer, observational study, real-world

Clara Weil,1,* Roni Adiri,2,* Gabriel Chodick,1,3 Merril Gersten,2 Eran Cohen Barak4,5 1Maccabitech Institute for Research and Innovation, Maccabi Healthcare Services, Tel Aviv, Israel; 2Pfizer Israel, Herzliya Pituah, Israel; 3Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; 4Dermatology Department, Emek Medical Center, Afula, Israel; 5Bruce and Ruth Rappaport Faculty of Medicine, Technion, Haifa, Israel*These authors contributed equally to this workCorrespondence: Gabriel Chodick, Maccabitech Institute for Research and Innovation, Maccabi Healthcare, Keufmann 4 St, Tel Aviv, 68125, Israel, Tel +972-514-3755, Email hodik_g@mac.org.ilBackground: In recent years, new treatments dedicated to atopic dermatitis (AD) have become available in Israel, including crisaborole, a small molecule with unique benzoxaborole chemistry.Objective: To describe baseline characteristics, history of AD therapies, and use of health-care services of early crisaborole users in real-world settings.Methods: A retrospective cohort study was performed using the data of a large health provider in Israel. AD patients treated with crisaborole since it became commercially available in Israel in July 2019 through end of Sep 2020, were included. Baseline demographics and clinical characteristics, prior AD-related treatments and healthcare resource utilization were collected.Results: A total of 441 patients were included (57.8% females, median age = 21.1y; interquartile range = 10.5– 40.8). In 62.1%, a dermatologist prescribed the first dispensed crisaborole. Median time from AD diagnosis to crisaborole treatment was 6.6 years. Up to 12 months prior to crisaborole treatment, low-, mid- and high-potency TCS were used by 30.8%, 31.1% and 55.8% of patients, respectively. Treatments related to moderate-to-severe AD were dispensed to 38.5% of patients in the prior 5 years. Asthma and allergic rhinitis were documented among 22.2% and 37.2%, respectively. In the past year, patients had a median of 9 visits to primary care physicians, 84.6% visited a dermatologist (≥ 5 visits: 12.9%).Conclusion: While crisaborole is indicated for mild-to-moderate disease, results suggest that a significant proportion of patients had history of advanced AD therapies suggestive of moderate-to-severe AD.Keywords: atopic dermatitis, topical calcineurin inhibitors, real-world data

Vered Rosenberg,1 Avital Bareket-Samish,2 Gabriel Chodick,1,3 Nava Siegelmann-Danieli3,4 1Maccabi Institute for Research and Innovation, Maccabi Healthcare Services, Tel Aviv, Israel; 2BioInsight Ltd, Binyamina, Israel; 3Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; 4Department of Professional Medicine, Maccabi Healthcare Services, Tel Aviv, IsraelCorrespondence: Nava Siegelmann-Danieli Email danieli_na@mac.org.ilPurpose: The study examined trends in breast cancer incidence, mammography testing rates, hormone-replacement therapy (HRT) use and breast cancer subtypes in a large Israeli health maintenance organization during 2000– 2014.Methods: Annual rates of mammography tests and HRTs use were analyzed in women age ≥ 45. Annual incidence rates of breast cancer were analyzed in women age ≥ 20. Estimated annual percentage changes were used to test changes in incidence rates. Invasive breast cancer subtypes were approximated by treatments received. We compared annual rates and duration of HRTs use between women diagnosed with breast cancer and those who were not, as well as HRT use between subtypes of invasive breast cancer.Results: We identified 14,092 breast cancer cases (88% invasive, 12% in situ). The age-adjusted incidence rate of invasive breast cancer peaked in 2005, consistent with increased mammography screening that year, and decreased thereafter. HRT use decreased from 13.2% in 2002 to 4.6% in 2014. The subtypes distribution of 7771 patients diagnosed with invasive breast cancer during 2007– 2014 was: luminal A and B without HER2 over-expression (HR+/HER2-), 69.7%; Luminal B with HER2 over-expression (HR+/HER2+), 8.9%; Hormone receptor-negative HER2 enriched (HR-/HER2+), 5.4%; triple negative (HR-/HER2-), 10.0%; unknown, 6.0%. Overall, in women age ≥ 45 diagnosed with invasive breast cancer, 76– 86% did not have HRT exposure vs 14– 24% who were current (within 1 year before the breast cancer diagnosis), recent (within 2– 5 years), or past users (> 5 years). Current/recent HRT use was statistically significantly higher in luminal vs non-luminal/unknown breast cancer subtypes (13.9% vs 8.9%, respectively; p < 0.001).Conclusion: Our results show a decrease in breast cancer incidence that parallels the global and local decrease in HRT use. Yet, our results imply that current/recent HRT exposure may contribute to the incidence of luminal breast cancer tumors in particular. The magnitude of the effect supports findings from population-based studies.Keywords: breast cancer, epidemiology, hormone-replacement therapy, incidence, mammography

Sarah Sharman Moser,1 Gabriel Chodick,1,2 Shikma Bar-On,3 Varda Shalev1,2 1Kahn-Sagol-Maccabi Research and Innovation Institute, Maccabi Healthcare Services, Tel Aviv, Israel; 2Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; 3Lis Maternity Hospital, Tel-Aviv Medical Center, Tel-Aviv, IsraelCorrespondence: Sarah Sharman MoserKahn-Sagol-Maccabi Research and Innovation Institute, Maccabi Healthcare Services, 27 Hamered St, Tel Aviv 6812509, IsraelTel +972-37462778Email moser_sa@mac.org.ilObjective: Self-reported studies estimated that as many as 50– 75% of women experience symptoms during menopause; however, limited real-world clinical data are available to support this observation. The electronic databases of Maccabi Healthcare Services were used to describe the prevalence of menopause symptoms in Israel and to characterize patients with regard to socioeconomic status, comorbidities and use of healthcare services.Methods: Females aged 45– 54 years diagnosed with menopausal symptoms (N=17,046, cumulative incidence of 8% during the study period) were identified from the Maccabi Healthcare Services electronic database and matched to female members without menopause symptoms, one-to-one on birth year and enumeration area.Results: Symptomatic peri- and post-menopausal women, and particularly those under 52 years, were more likely to have a higher prevalence of comorbid conditions such as depression, anxiety, osteoporosis and insomnia in the year following index. Correspondingly, selective serotonin reuptake inhibitors, serotonin norepinephrine reuptake inhibitors and hypnotic drug use were significantly higher in symptomatic women as was healthcare utilization including hospitalization (OR=1.10; 95% CI=1.00– 1.20), primary care visits (1.90; 1.73– 2.08), gynecologist visits (24.84; 22.36– 27.59) and hysterectomy procedures (2.26; 1.63– 3.14).Conclusion: Medically documented menopausal symptoms are associated with increased burden of disease (particularly among women diagnosed with menopausal symptoms prior to age 52 years), healthcare utilization and greater likelihood of undergoing hysterectomy within one year of diagnosis. This burden is expected to rise further as awareness and social acceptance of peri- and post-menopausal symptoms increase.Keywords: menopause, peri-menopause, real-world study, healthcare utilization

Study Question: Is there a difference in the breast cancer risk among women who underwent ART treatments compared to those who underwent medically assisted reproduction (MAR) infertility treatments or women of reproductive age in the general population?Summary Answer: The risk of breast cancer among women treated by ART was similar to the risk among women treated by MAR and women who did not undergo fertility treatments.What Is Known Already: Studies investigating breast cancer risk in women who have undergone fertility treatments have provided conflicting results.Study Design, Size, Duration: A retrospective, population-based cohort study included women who underwent ART or MAR treatments and women who did not undergo fertility treatments from 1994 to 2019.Participants/materials, Setting, Methods: Women who underwent ART were matched one to one with women who underwent MAR treatments and one to one with woman from the general population of reproductive age, by year of birth and year of first delivery or nulliparity status. MAR women were also matched to ART women by treatment initiation calendar year. All included women were members of Maccabi Healthcare Services. Data regarding demographics, fertility treatments, BRCA mutation and possible confounders were obtained from the computerized database of electronic health records. The incidence of breast cancer after fertility treatments was compared to the matched controls.Main Results and the Role Of Chance: Of 8 25 721 women of reproductive age, 32 366 women who underwent ART were matched with patients treated by MAR (n = 32 366) and 32 366 women of reproductive age. A total of 984 women (1.0%) were diagnosed with breast cancer (mean follow-up period, 9.1 ± 6.3 years; interquartile range [IQR], 3.8-13.7 years). The incidence rates of breast cancer per 10 000 person-years were 11.9 (95% CI, 10.7-13.3), 10.7 (95% CI, 9.6-11.9) and 10.7 (95% CI, 9.6-12.0) in the ART group, MAR group and general population, respectively. The crude risk for breast cancer was similar in the ART group compared with the general population (hazard ratio (HR) = 1.10, 95% CI, 0.94-1.28) and in the ART group compared with the MAR group (HR = 1.00, 95% CI, 0.86-1.16). Further adjustment for age, BMI, smoking, socioeconomic status and parity did not substantially impact the hazard rates for breast cancer (ART vs general population: HR = 1.10, 95% CI, 0.94-1.28; ART vs MAR: HR = 0.99, 95% CI, 0.85-1.16). Among women diagnosed with breast cancer, the prevalence of BRCA1/2 mutations and tumour staging did not differ between the ART, MAR and general population groups. Among women who underwent ART, no correlation was found between breast cancer and the number of ART cycles or the use of recombinant medications or urine-derived medications.Limitations, Reasons For Caution: The mean age of women at the end of follow-up was only 42 years thus the study was not powered to detect potential differences in the risk of postmenopausal breast cancer. In addition, we did not sub-classify the exposed patients by the reason for infertility.Wider Implications Of the Findings: Breast cancer incidence following ART was comparable to that in the general population or following MAR. Women undergoing fertility treatments and their clinicians may be reassured about the safety of assisted reproduction technologies in terms of premenopausal breast cancer risk.Study Funding/competing Interest(s): No specific funding was used and there are no competing interests.Trial Registration Number: N/A. [ABSTRACT FROM AUTHOR]