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Background: Sexual concerns are common and problematic for breast cancer survivors. Partner and relationship factors often play a key role in determining survivors' sexual adjustment, making it likely that couple-based interventions that integrate survivors' partners could be especially promising for addressing survivors' sexual concerns. Yet few such interventions have been tested. The objective of this study was to evaluate the efficacy of the Intimacy Enhancement (IE) intervention, a four-session, couple-based intervention addressing breast cancer survivors' sexual concerns by telephone in a randomized controlled trial., Methods: Female posttreatment breast cancer survivors reporting sexual concerns and their intimate partners (N = 120 couples; 240 participants) were randomized either to the IE intervention or to Living Healthy Together (LHT), an active control intervention of equivalent length. Outcomes (measured at baseline, postintervention, and at 3 and 6 months postintervention) included breast cancer survivors' sexual function (primary), partners' sexual function (secondary), and survivors' and partners' psychosocial and relationship outcomes (secondary). Mixed linear regression models examined intervention effects on outcomes at all follow-ups., Results: Model-based estimates of intervention effects showed greater improvements in survivors' overall sexual function, sexual satisfaction, arousal, lubrication, and orgasm at postintervention (p < .05). Effects on survivors' 3-month and 6-month sexual functioning or other secondary outcomes were minimal. Most couples completed all IE sessions (97%) and LHT (92%), and satisfaction ratings were high., Conclusions: Compared with an active control intervention, the IE intervention had significant short-term benefits for survivors' sexual function. Efforts may be needed to increase the longevity of the positive effects, such as more frequent or adjunctive treatments., (© 2024 American Cancer Society.)

Studies in SIV-infected macaques show that the virus reservoir is particularly refractory to conventional suppressive antiretroviral therapy (ART). We posit that optimized ART regimens designed to have robust penetration in tissue reservoirs and long-lasting antiviral activity may be advantageous for HIV or SIV remission. Here we treat macaques infected with RT-SHIV with oral emtricitabine/tenofovir alafenamide and long-acting cabotegravir/rilpivirine without (n = 4) or with (n = 4) the immune activator vesatolimod after the initial onset of viremia. We document full suppression in all animals during treatment (4-12 months) and no virus rebound after treatment discontinuation (1.5-2 years of follow up) despite CD8 + T cell depletion. We show efficient multidrug penetration in virus reservoirs and persisting rilpivirine in plasma for 2 years after the last dose. Our results document a type of virus remission that is achieved through early treatment initiation and provision of ultra long-lasting antiviral activity that persists after treatment cessation., Competing Interests: Competing interests: J.G.G.-L., M.B.D., W.H., P.W., and W.S. are named in a US Patent Application (No. 18/002,494) entitled “Methods for achieving viral remission using long-acting antiretroviral agents”. The remaining authors declare no competing interests., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Menopausal hormone therapy (MHT) users are at increased breast cancer (BC) risk and decreased colorectal cancer (CRC) risk compared with never users, but these opposing associations might differ by familial risk of BC and CRC. We harmonized data from three cohorts and generated separate BC and CRC familial risk scores (FRS) based on cancer family history. We defined moderate/strong family history as FRS ≥ 0.4, where 0.4 was equivalent to a 50-year-old woman with one parent diagnosed with either cancer at age 55 years. Of 24,486 women, 1,243 and 405 were diagnosed with incident BC and CRC, respectively. For BC, MHT hazard ratios (HRs) were 1.27 (95%CI = 1.11-1.45) for FRSBC<0.4, 1.01 (95%CI = 0.82-1.25) for FRSBC≥0.4 (P-difference = 0.08). For CRC, MHT HRs were 0.63 (95%CI = 0.50-0.78) for FRSCRC<0.4, 1.21 (95%CI = 0.73-2.00) for FRSCRC≥0.4 (P-difference = 0.03). Associations with MHT that apply to the general population might not hold for women at moderate/strong familial risk of these cancers., (© The Author(s) 2024. Published by Oxford University Press.)

Background: Breast cancer (BC) incidence is increasing in women under age 40 years, underscoring the need for research on BC risk factors for younger women., Methods: We used data from an international family cohort (n=26,348) to examine whether recreational physical activity (RPA) during adolescence and early adulthood are associated with BC risk before age 40. The cohort includes 2,502 women diagnosed with BC before age 40, including 2,408 diagnosed before study enrollment (68% within 5 years of enrollment). Women reported their average hours-per-week of moderate and strenuous RPA during adolescence (12-17 years) and early adulthood (25-34 years), which were converted to total age-adjusted metabolic equivalents-per-week and categorized into quartiles. We conducted attained age analyses until age 40 (follow-up time began at age 18) using Cox proportional hazards regression models adjusted for study center, race and ethnicity, and education., Results: Being in the highest versus lowest quartile of RPA during adolescence and early adulthood were respectively associated with 12% [HR (95% CI): 0.88 (0.78, 0.98)] and 16% [HR (95% CI): 0.84 (0.74, 0.95) lower BC risks before age 40. Being in the highest quartile of RPA during both adolescence and early adulthood (Pearson correlation=0.52) versus neither timepoint was associated with a 22% lower risk [HR (95% CI): 0.78 (0.68, 0.89)]., Conclusions: Findings suggest that RPA during adolescence and early adulthood may lower BC risk before age 40., Impact: Policies promoting physical activity during adolescence and early adulthood may be important for reducing the growing burden of breast cancer in younger women.

Purpose: It is uncertain whether, and to what extent, hormonal contraceptives increase breast cancer (BC) risk for germline BRCA1 or BRCA2 mutation carriers., Methods: Using pooled observational data from four prospective cohort studies, associations between hormonal contraceptive use and BC risk for unaffected female BRCA1 and BRCA2 mutation carriers were assessed using Cox regression., Results: Of 3,882 BRCA1 and 1,509 BRCA2 mutation carriers, 53% and 71%, respectively, had ever used hormonal contraceptives for at least 1 year (median cumulative duration of use, 4.8 and 5.7 years, respectively). Overall, 488 BRCA1 and 191 BRCA2 mutation carriers developed BC during median follow-up of 5.9 and 5.6 years, respectively. Although for BRCA1 mutation carriers, neither current nor past use of hormonal contraceptives for at least 1 year was statistically significantly associated with BC risk (hazard ratio [HR], 1.40 [95% CI, 0.94 to 2.08], P = .10 for current use; 1.16 [0.80 to 1.69], P = .4, 1.40 [0.99 to 1.97], P = .05, and 1.27 [0.98 to 1.63], P = .07 for past use 1-5, 6-10, and >10 years before, respectively), ever use was associated with increased risk (HR, 1.29 [95% CI, 1.04 to 1.60], P = .02). Furthermore, BC risk increased with longer cumulative duration of use, with an estimated proportional increase in risk of 3% (1%-5%, P = .002) for each additional year of use. For BRCA2 mutation carriers, there was no evidence that current or ever use was associated with increased BC risk (HR, 0.70 [95% CI, 0.33 to 1.47], P = .3 and 1.07 [0.73 to 1.57], P = .7, respectively)., Conclusion: Hormonal contraceptives were associated with increased BC risk for BRCA1 mutation carriers, especially if used for longer durations. Decisions about their use in women with BRCA1 mutations should carefully weigh the risks and benefits for each individual.

Purpose: Individuals with Lynch syndrome (LS) are at a high lifetime risk of colorectal cancer (CRC) and other cancers. Aspirin (ASA), a nonsteroidal anti-inflammatory drug (NSAID), has proven chemopreventive benefits in LS, with the CAPP2 randomized double-blind placebo-controlled trial demonstrating a 60% relative risk reduction for CRC among participants who adhered to ASA for 2 years or more. This study sought to characterize uptake of ASA/NSAIDs among individuals with LS and to understand factors associated with use., Methods: Individuals with LS were invited (June 2020-August 2022) to complete a one-time electronic survey about LS screening behaviors, uptake of ASA/NSAIDs, and current/emerging cancer prevention options. Participants were recruited from the Fox Chase Cancer Center (FCCC) Risk Assessment Program Registry and through a research invitation posted to two patient-facing LS advocacy websites., Results: Two hundred and ninety-six participants completed the survey including 116 (39.2%) from FCCC and 180 (60.8%) recruited via the Internet, including 14.9% non-US based individuals. Uptake of regular ASA or NSAIDs was modest at 34.8% and was even lower (25.7%) when focusing on individuals taking ASA or NSAIDs solely for chemoprevention of LS. More than half (55%) were taking <100 mg ASA daily. In multivariable modeling, lower perceived threat of LS (odds ratio [OR], 0.84 [95% CI, 0.72 to 0.98]), lower concern for side effects (OR, 0.86 [95% CI, 0.76 to 0.99]), and higher likelihood of recommending ASA/NSAIDs to family or a friend were all associated with ASA/NSAIDs use (OR, 1.70 [95% CI, 1.37 to 2.10])., Conclusion: Uptake of ASA/NSAIDs chemoprevention is modest among individuals with LS. Patient perceptions of the pros and cons of ASA, more so than demographic and disease-related factors, were associated with chemoprevention uptake.

Background: Pig-tailed macaques (PTMs) are commonly used as preclinical models to assess antiretroviral drugs for HIV prevention research. Drug toxicities and disease pathologies are often preceded by changes in blood hematology. To better assess the safety profile of pharmaceuticals, we defined normal ranges of hematological values in PTMs using an Isolation Forest (iForest) algorithm., Methods: Eighteen female PTMs were evaluated. Blood was collected 1-24 times per animal for a total of 159 samples. Complete blood counts were performed, and iForest was used to analyze the hematology data to detect outliers., Results: Median, IQR, and ranges were calculated for 13 hematology parameters. From all samples, 22 outliers were detected. These outliers were excluded from the reference index., Conclusions: Using iForest, we defined a normal range for hematology parameters in female PTMs. This reference index can be a valuable tool for future studies evaluating drug toxicities in PTMs., (Published 2024. This article is a U.S. Government work and is in the public domain in the USA. Journal of Medical Primatology published by John Wiley & Sons Ltd.)

Introduction: DESTINY B04 provided clinical meaning to a new classification of human epidermal growth factor 2 (HER2) expression in breast cancer: HER2-low. Patients with germline breast cancer type 1 gene pathogenic variants (gBRCA1) often develop triple negative breast cancer (TNBC), but the proportion who could be classified as HER2-low and qualify for an additional targeted therapy option is unknown. This study aims to characterize the proportion of gBRCA1 or germline breast cancer type 2 gene pathogenic variants patients for whom these novel targeted therapies may be an option., Methods: We performed a retrospective chart review of patients with gBRCA1/2 treated at our institution for invasive breast cancer from 2000 to 2021. Synchronous or metachronous contralateral breast cancers were recorded separately. HER2 status was determined by immunohistochemistry and fluorescence in situ hybridization. We excluded patients without complete HER2 data., Results: Among the 95 breast cancers identified in our cohort of 85 gBRCA1/2 patients, 41 (43%) were TNBC, 38 (40%) were hormone receptor positive (HR+)/HER2-negative, and 16 (17%) were HER2-positive based on standard conventions. We found that 82% of the HR+/HER2-cancers and 66% of TNBCs would be reclassified as HER2-low. After stratifying by BRCA gene status, 64% of cancers in patients with gBRCA1 and 58% of cancers in patients with germline breast cancer type 2 gene pathogenic variants were HER2-low., Conclusions: A significant portion of gBRCA1/2 patients who were previously diagnosed with TNBC or HR+/HER2- breast cancer would now be classified as HER2-low and could be considered for the use of trastuzumab deruxtecan in the metastatic setting. Outcome differences from therapy changes in this cohort should now be assessed., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Pubertal timing varies considerably and is associated with later health outcomes. We performed multi-ancestry genetic analyses on ~800,000 women, identifying 1,080 signals for age at menarche. Collectively, these explained 11% of trait variance in an independent sample. Women at the top and bottom 1% of polygenic risk exhibited ~11 and ~14-fold higher risks of delayed and precocious puberty, respectively. We identified several genes harboring rare loss-of-function variants in ~200,000 women, including variants in ZNF483, which abolished the impact of polygenic risk. Variant-to-gene mapping approaches and mouse gonadotropin-releasing hormone neuron RNA sequencing implicated 665 genes, including an uncharacterized G-protein-coupled receptor, GPR83, which amplified the signaling of MC3R, a key nutritional sensor. Shared signals with menopause timing at genes involved in DNA damage response suggest that the ovarian reserve might signal centrally to trigger puberty. We also highlight body size-dependent and independent mechanisms that potentially link reproductive timing to later life disease., (© 2024. The Author(s).)

Background: There is limited research on whether physical activity (PA) in early childhood is associated with the timing of pubertal events in girls., Methods: We used data collected over 2011-16 from the LEGACY Girls Study (n = 984; primarily aged 6-13 years at study enrolment), a multicentre North American cohort enriched for girls with a breast cancer family history (BCFH), to evaluate if PA is associated with age at thelarche, pubarche and menarche. Maternal-reported questionnaire data measured puberty outcomes, PA in early childhood (ages 3-5 years) and total metabolic equivalents of organized PA in middle childhood (ages 7-9 years). We used interval-censored Weibull parametric survival regression models with age as the time scale and adjusted for sociodemographic factors, and we tested for effect modification by BCFH. We used inverse odds weighting to test for mediation by body mass index-for-age z-score (BMIZ) measured at study enrolment., Results: Being highly active vs inactive in early childhood was associated with later thelarche in girls with a BCFH [adjusted hazard ratio (aHR) = 0.39, 95% CI = 0.26-0.59), but not in girls without a BCFH. In all girls, irrespective of BCFH, being in the highest vs lowest quartile of organized PA in middle childhood was associated with later menarche (aHR = 0.70, 95% CI = 0.50-0.97). These associations remained after accounting for potential mediation by BMIZ., Conclusion: This study provides new data that PA in early childhood may be associated with later thelarche in girls with a BCFH, also further supporting an overall association between PA in middle childhood and later menarche., (© The Author(s) 2024; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.)