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Purpose PI3K/AKT pathway alterations are frequent in hormone receptor-positive (HR+) breast cancers. IPATunity130 Cohort B investigated ipatasertib–paclitaxel in PI3K pathway-mutant HR+ unresectable locally advanced/metastatic breast cancer (aBC). Methods Cohort B of the randomized, double-blind, placebo-controlled, phase 3 IPATunity130 trial enrolled patients with HR+ HER2-negative PIK3CA/AKT1/PTEN-altered measurable aBC who were considered inappropriate for endocrine-based therapy (demonstrated insensitivity to endocrine therapy or visceral crisis) and were candidates for taxane monotherapy. Patients with prior chemotherapy for aBC or relapse 2, days 1, 8, 15), every 28 days until disease progression or unacceptable toxicity. The primary endpoint was investigator-assessed progression-free survival (PFS). Results Overall, 146 patients were randomized to ipatasertib–paclitaxel and 76 to placebo–paclitaxel. In both arms, median investigator-assessed PFS was 9.3 months (hazard ratio, 1.00, 95% CI 0.71–1.40) and the objective response rate was 47%. Median paclitaxel duration was 6.9 versus 8.8 months in the ipatasertib–paclitaxel versus placebo–paclitaxel arms, respectively; median ipatasertib/placebo duration was 8.0 versus 9.1 months, respectively. The most common grade ≥ 3 adverse events were diarrhea (12% with ipatasertib–paclitaxel vs 1% with placebo–paclitaxel), neutrophil count decreased (9% vs 7%), neutropenia (8% vs 9%), peripheral neuropathy (7% vs 3%), peripheral sensory neuropathy (3% vs 5%) and hypertension (1% vs 5%). Conclusion Adding ipatasertib to paclitaxel did not improve efficacy in PIK3CA/AKT1/PTEN-altered HR+ HER2-negative aBC. The ipatasertib–paclitaxel safety profile was consistent with each agent’s known adverse effects. Trial registration NCT03337724.

To evaluate racial and/or ethnic and sex disparities in allogeneic and autologous red blood cell (RBC) transfusions in cardiac surgery.A retrospective observational study.2007 to 2018 data from FL, MD, KY, WA, NY, and CA from the State Inpatient Databases (SID), Healthcare Cost and Utilization Project (HCUP), Agency for Healthcare Research and Quality.A total of 710,296 inpatients who underwent elective or emergency coronary artery bypass grafting (CABG), cardiac valve surgery,or combination CABG and/or valve surgery.None.Patients were cohorted by race and/or ethnicity and sex, as defined by SID-HCUP. Demographic characteristics and comorbidities were compared. Rates and risk-adjusted odds ratios (aOR) were calculated for allogeneic and autologous RBC transfusion (primary outcomes). Additional secondary analyses were conducted for in-hospital mortality, 30-day readmission, 90-day readmission, hospital length of stay, and total charges to examine the effect of RBC transfusion status. Effect modification between race and sex was assessed. When controlling for patient demographics, comorbidities, and hospital characteristics, non-White patients were more likely to receive an allogeneic RBC transfusion during cardiac surgery than White patients (Black: aOR 1.17, 99% CI 1.13-1.20, p0.001, Hispanic: aOR 1.22, 99% CI 1.19-1.22, p0.001). Women were more likely to receive allogeneic RBC than men (aOR 1.69, 99% CI 1.66-1.72, p0.001). In interaction models, non-White women had the highest odds of allogeneic blood transfusion as compared to White men (reference category; Black women: aOR 2.04, 99% CI 1.91-2.17, p0.001, Hispanic women: aOR 2.03, 99% CI 1.90-2.16, p0.001).These findings highlighted the differences in the rates of allogeneic RBC transfusion for non-White and female patients undergoing cardiac surgery, which is a well-established marker of poorer outcomes.

Purpose In MONARCH 1 (NCT02102490), single-agent abemaciclib demonstrated promising efficacy activity and tolerability in a population of heavily pretreated women with refractory HR+, HER2− metastatic breast cancer (MBC). To help interpret these results and put in clinical context, we compared overall survival (OS) and duration of therapy (DoT) between MONARCH 1 and a real-world single-agent chemotherapy cohort. Methods The real-world chemotherapy cohort was created from a Flatiron Health electronic health records-derived database based on key eligibility criteria from MONARCH 1. The chemotherapies included in the cohort were single-agent capecitabine, gemcitabine, eribulin, or vinorelbine. Results were adjusted for baseline demographics and clinical differences using Mahalanobis distance matching (primary analysis) and entropy balancing (sensitivity analysis). OS and DoT were analyzed using the Kaplan–Meier method and Cox proportional hazards regression. Results A real-world single-agent chemotherapy cohort (n = 281) with eligibility criteria similar to the MONARCH 1 population (n = 132) was identified. The MONARCH 1 (n = 108) cohort was matched to the real-world chemotherapy cohort (n = 108). Median OS was 22.3 months in the abemaciclib arm versus 13.6 months in the matched real-world chemotherapy cohort with an estimated hazard ratio (HR) of 0.54. The median DoT was 4.1 months in MONARCH 1 compared to 2.9 months in the real-world chemotherapy cohort with HR of 0.76. Conclusions This study demonstrates an approach to create a real-world chemotherapy cohort suitable to serve as a comparator for trial data. These exploratory results suggest a survival advantage and place the benefit of abemaciclib monotherapy in clinical context.

Predicció de risc de càncer de mama; Dones europees; Variant patògena heterozigota Predicción del riesgo de cáncer de mama; Mujeres europeas; Variante patógena heterocigota Breast cancer risk prediction; European women; Heterozygous pathogenic variant Purpose To evaluate the association between a previously published 313 variant–based breast cancer (BC) polygenic risk score (PRS313) and contralateral breast cancer (CBC) risk, in BRCA1 and BRCA2 pathogenic variant heterozygotes. Methods We included women of European ancestry with a prevalent first primary invasive BC (BRCA1 = 6,591 with 1,402 prevalent CBC cases; BRCA2 = 4,208 with 647 prevalent CBC cases) from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), a large international retrospective series. Cox regression analysis was performed to assess the association between overall and ER-specific PRS313 and CBC risk. Results For BRCA1 heterozygotes the estrogen receptor (ER)-negative PRS313 showed the largest association with CBC risk, hazard ratio (HR) per SD = 1.12, 95% confidence interval (CI) (1.06–1.18), C-index = 0.53; for BRCA2 heterozygotes, this was the ER-positive PRS313, HR = 1.15, 95% CI (1.07–1.25), C-index = 0.57. Adjusting for family history, age at diagnosis, treatment, or pathological characteristics for the first BC did not change association effect sizes. For women developing first BC

Infections cause morbidity and mortality in patients with glomerular disease. The relative contributions from immunosuppression exposure and glomerular disease activity to infection risk are not well characterized. To address this unmet need, we characterized the relationship between time-varying combinations of immunosuppressant exposure and infection-related acute care events while controlling for disease activity, among individuals with glomerular disease.Prospective, multicenter, observational cohort study.Adults and children with biopsy-proven minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, or immunoglobulin A nephropathy/vasculitis were enrolled at 71 clinical sites in North America and Europe. A total of 2,388 Cure Glomerulonephropathy Network participants (36% aged 18 years) had at least 1 follow-up visit and were included in the analysis.Immunosuppression exposure modeled on a weekly basis.Infections leading to an emergency department visit or hospitalization.Marginal structural models were used to estimate the effect of time-varying immunosuppression exposure on hazard of first infection-related acute care event while accounting for baseline sociodemographic and clinical factors, and time-varying disease activity.A total of 2,388 participants were followed for a median of 3.2 years (interquartile range, 1.6-4.6), and 15% experienced at least 1 infection-related emergency department visit or hospitalization. Compared to no immunosuppression exposure, steroid exposure, steroid with any other immunosuppressant, and nonsteroid immunosuppressant exposure were associated with a 2.65-fold (95% CI, 1.83-3.86), 2.68-fold (95% CI, 1.95-3.68), and 1.7-fold (95% CI, 1.29-2.24) higher risk of first infection, respectively.Absence of medication dosing data, lack of a control group, and potential bias in ascertainment of outcome events secondary to the coronavirus 2 pandemic.Corticosteroids with or without concomitant additional immunosuppression significantly increased risk of infection leading to acute care utilization in adults and children with glomerular disease.

Supplemental Digital Content is available in the text., Background and Purpose: Chronic kidney disease with reduced estimated glomerular filtration rate or elevated albuminuria increases risk for ischemic and hemorrhagic stroke. This study assessed the effects of sodium glucose cotransporter 2 inhibitors (SGLT2i) on stroke and atrial fibrillation/flutter (AF/AFL) from CREDENCE (Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation) and a meta-analysis of large cardiovascular outcome trials (CVOTs) of SGLT2i in type 2 diabetes mellitus. Methods: CREDENCE randomized 4401 participants with type 2 diabetes mellitus and chronic kidney disease to canagliflozin or placebo. Post hoc, we estimated effects on fatal or nonfatal stroke, stroke subtypes, and intermediate markers of stroke risk including AF/AFL. Stroke and AF/AFL data from 3 other completed large CVOTs and CREDENCE were pooled using random-effects meta-analysis. Results: In CREDENCE, 142 participants experienced a stroke during follow-up (10.9/1000 patient-years with canagliflozin, 14.2/1000 patient-years with placebo; hazard ratio [HR], 0.77 [95% CI, 0.55–1.08]). Effects by stroke subtypes were: ischemic (HR, 0.88 [95% CI, 0.61–1.28]; n=111), hemorrhagic (HR, 0.50 [95% CI, 0.19–1.32]; n=18), and undetermined (HR, 0.54 [95% CI, 0.20–1.46]; n=17). There was no clear effect on AF/AFL (HR, 0.76 [95% CI, 0.53–1.10]; n=115). The overall effects in the 4 CVOTs combined were: total stroke (HRpooled, 0.96 [95% CI, 0.82–1.12]), ischemic stroke (HRpooled, 1.01 [95% CI, 0.89–1.14]), hemorrhagic stroke (HRpooled, 0.50 [95% CI, 0.30–0.83]), undetermined stroke (HRpooled, 0.86 [95% CI, 0.49–1.51]), and AF/AFL (HRpooled, 0.81 [95% CI, 0.71–0.93]). There was evidence that SGLT2i effects on total stroke varied by baseline estimated glomerular filtration rate (P=0.01), with protection in the lowest estimated glomerular filtration rate (

Background The multinational BREAKOUT study (NCT03078036) sought to determine the prevalence of germline BRCA1/2 (gBRCA1/2) and somatic BRCA1/2 (sBRCA1/2) mutations and mutations in other homologous recombination repair (HRR) genes in women with HER2-negative metastatic breast cancer (MBC) starting first-line chemotherapy. Methods Genetic testing for gBRCA, sBRCA, and HRR gene mutations was performed in patients who started first-line chemotherapy for MBC in the last 90 days (341 patients across 14 countries) who were not selected based on risk factors for gBRCA mutations. We report data from the Asian cohort, which included patients in Japan (7 sites), South Korea (10 sites), and Taiwan (8 sites). Results Of 116 patients screened, 104 patients were enrolled in the Asian cohort. The median age was 53.0 (range 25–87) years. gBRCA1/2, gBRCA1, and gBRCA2 mutations were detected in 10.6% (11/104), 5.8% (6/104), and 4.8% (5/104) of patients, respectively; none had mutations in both gBRCA1 and gBRCA2. gBRCA1/2 mutations were detected in 10.0% (6/60) and 11.6% (5/43) of patients with hormone receptor-positive and triple-negative MBC, respectively. HRR gene mutations were tested in 48 patients without gBRCA mutations, and 5 (10.4%) had at least one HRR mutation in sBRCA, ATM, PALB2, and CHEK2. Conclusion We report for the first time the prevalence of gBRCA and HRR mutations in an Asian cohort of patients with HER2-negative MBC. Our results suggest that BRCA mutation testing is valuable to determine appropriate treatment options for patients with hormone receptor-positive or triple-negative MBC. Study registration NCT03078036.

Objective/Background We performed a retrospective analysis of longitudinal real-world data (RWD) from patients with breast cancer to replicate results from clinical studies and demonstrate the feasibility of generating real-world evidence. We also assessed the value of transcriptome profiling as a complementary tool for determining molecular subtypes. Methods De-identified, longitudinal data were analyzed after abstraction from records of patients with breast cancer in the United States (US) structured and stored in the Tempus database. Demographics, clinical characteristics, molecular subtype, treatment history, and survival outcomes were assessed according to strict qualitative criteria. RNA sequencing and clinical data were used to predict molecular subtypes and signaling pathway enrichment. Results The clinical abstraction cohort (n = 4000) mirrored the demographics and clinical characteristics of patients with breast cancer in the US, indicating feasibility for RWE generation. Among patients who were human epidermal growth factor receptor 2-positive (HER2+), 74.2% received anti-HER2 therapy, with ∼70% starting within 3 months of a positive test result. Most non-treated patients were early stage. In this RWD set, 31.7% of patients with HER2+ immunohistochemistry (IHC) had discordant fluorescence in situ hybridization results recorded. Among patients with multiple HER2 IHC results at diagnosis, 18.6% exhibited intra-test discordance. Through development of a whole-transcriptome model to predict IHC receptor status in the molecular sequenced cohort (n = 400), molecular subtypes were resolved for all patients (n = 36) with equivocal HER2 statuses from abstracted test results. Receptor-related signaling pathways were differentially enriched between clinical molecular subtypes. Conclusions RWD in the Tempus database mirrors the overall population of patients with breast cancer in the US. These results suggest that real-time, RWD analyses are feasible in a large, highly heterogeneous database. Furthermore, molecular data may aid deficiencies and discrepancies observed from breast cancer RWD.

We investigated first-line (1L) treatment patterns and predictors of taxane use to better understand the evolving metastatic triple-negative breast cancer (mTNBC) treatment landscape. This retrospective analysis of the Truven Health MarketScan® (Somers, NY, USA) Database included women with mTNBC who received 1L therapy within six months of diagnosis (January 2005–June 2015). Multivariate logistic regression models identified predictors of taxane use, adjusting for prognostic factors. A total of 2271 women with newly diagnosed mTNBC received 1L treatment during the study period. Half received a 1L taxane (53%), more often in combination than as monotherapy (58% versus 42%), though this varied by specific taxane. Nab-Paclitaxel monotherapy increased substantially after 2010. More recent treatment year (odds ratio, 2.16 (95% CI 1.69–2.76]) and number of metastases (≥3 versus 1: 1.73 (1.25–2.40)) predicted taxane monotherapy versus combination. Having a health maintenance organization versus a preferred provider organization plan predicted less nab-paclitaxel versus paclitaxel (0.32 (0.13–0.80)) or docetaxel (0.30 (0.10–0.89)) use. More recent index year (2011–2015 vs. 2005–2010) was the only predictor favoring nab-paclitaxel versus paclitaxel (2.01 (1.26–3.21)) or docetaxel (3.63 (2.11–6.26)). Taxane-containing regimens remained the most common 1L mTNBC treatments. Paclitaxel and nab-paclitaxel use changed substantially over time, with nab-paclitaxel use associated with insurance coverage.

Introduction: Patients with chronic health conditions, particularly chronic kidney disease, are at heightened risk for psychiatric disorders; yet, there are limited data on those with primary glomerular disease. Methods: This study included patients with glomerular disease enrolled in the kidney research network multisite patient registry. Registry data include encounter, diagnoses, medication, laboratory, and vital signs data extracted from participants’ electronic health records. ICD-9/10 diagnosis codes were used to identify a subset of psychiatric disorders focused on anxiety, mood, and behavioral disorders. Time-varying Cox proportional hazard models were used to analyze time from the onset of kidney disease to diagnosis of psychiatric disorder. Adjusted models retained significant covariates from the full list of potential confounders, including age, sex, race, ethnicity, time-varying treatment, the estimated glomerular filtration rate, and proteinuria (urine protein-to-creatinine ratio [UPCR]). Analogous models examined diagnosis of psychiatric disorder as a predictor of time to end-stage kidney disease (ESKD). Results: Data were available for 950 participants, with a median of 58 months of follow-up. 110 (12%) participants were diagnosed with psychiatric disorder during the follow-up. The estimated rate of psychiatric diagnosis after kidney disease was 14.7 cases per 1,000 person-years and was highest among those of adolescent age at the time of kidney disease diagnosis. Adjusted analyses found adolescent age (vs. adult, hazard ratio [HR] = 3.11, 95% confidence interval [CI] 1.87–5.17) and Asian race (vs. white, HR = 0.34, 95% CI 0.16–0.71) were associated with psychiatric diagnosis. A higher UPCR per 1 log unit (HR 1.13, 95% CI 1.01–1.27) and a higher total number of oral medications were associated with psychiatric disorder (p < 0.001). Psychiatric diagnosis was also associated with progression to ESKD (HR = 2.45, 95% CI 1.53–3.92) in adjusted models. Discussion/Conclusion: Psychiatric disorders were documented in approximately one-eighth of patients with glomerular disease and correlated with clinical disease characteristics such as age, race, proteinuria, and oral medication burden. These findings suggest mental health screening is warranted in patients of all ages with glomerular disease.

In MONARCH 3, continuous dosing of abemaciclib with an aromatase inhibitor (AI) conferred significant clinical benefit to postmenopausal women with HR+, HER2− advanced breast cancer. We report data for clinically prognostic subgroups: liver metastases, progesterone receptor status, tumor grade, bone-only disease, ECOG performance status, and treatment-free interval (TFI) from an additional 12-month follow-up (after final progression-free survival [PFS] readout). In the intent-to-treat population, after median follow-up of approximately 39 months, the updated PFS was 28.2 versus 14.8 months (hazard ratio [HR], 0.525; 95% confidence interval, 0.415–0.665) in abemaciclib versus placebo arms, respectively. Time to chemotherapy (HR, 0.513), time to second disease progression (HR, 0.637), and duration of response (HR, 0.466) were also statistically significantly prolonged with the addition of abemaciclib to AI. Treatment benefit was observed across all subgroups, as evidenced by objective response rate change from the addition of abemaciclib to AI, with the largest effects observed in patients with liver metastases, progesterone receptor-negative tumors, high-grade tumors, or TFI

Access to specialized diabetes care is limited due to shortage of endocrinologists and distance to specialty clinics. In addition, referrals to out-of-network providers frequently results in suboptimal care coordination. Tele-mentoring models such as ECHO (Extension for Community Healthcare Outcomes) extends specialty knowledge to primary care providers. Prior to the implementation of a series of ECHO sessions, we assessed provider confidence in managing type 2 diabetes (T2D) . Methods: Prescribing providers (PP) from three VA Health Care Systems in Florida (North Florida/South Georgia) , Texas (Valley Coastal Bend) and Wisconsin (Milwaukee) were invited to participate. We asked questions about practice patterns, prescription habits, and confidence level treating T2D. Results: A total of 49 PP completed the assessment. Mean age was 42.5 years and 74% were females. They were clinical pharmacists (63%) , physicians (22%) , ARNP (8%) , and the rest were trainees. Clinical experience < 5 year was present in 14.2%, whereas 67% had > years. Half of the providers felt very or extremely confident managing a complicated case (A1c>8% on two oral agents) , whereas only 14% of providers felt either “not at all” or somewhat confident. Most of the providers felt very or extremely confident obtaining a diabetes-focused history (63%) , educating patients about complications (69%) , or changing insulin regimens (61%) . Although most of the providers prescribed a glucose meter very often or always (81%) , only 6% of them prescribed a continuous glucose monitor frequently. When sending a referral, 32% mentioned either lack of local endocrinologists or long waiting time as main barriers. Providers felt that patients prefer to stay with their local VA PCP for diabetes care instead of seeing a specialist (65%) Conclusions: A third of providers perceive significant barriers to access specialized diabetes care. There are opportunities to improve provider confidence and skills managing diabetes. Disclosure C.E.Mendez: Advisory Panel; Monarch Medical Technologies . K.Hazen: None. L.M.Semeah: None. J.A.Leey: None. E.A.Mattox: None. S.Kadiyala: None. M.Xhikola: None. K.Yantsides: None. A.D.Oien: None. I.O'shaughnessy: None. A.E.Hansen: None. J.Lucas: None. Funding Veterans Rural Health Resource Center - 00RH

Systemic Therapies for HER2-Positive Metastatic Breast Cancer Study (SystHERs, NCT01615068) was a prospective, observational disease registry designed to identify treatment patterns and clinical outcomes in patients with HER2-positive metastatic breast cancer (MBC) in real-world treatment settings. SystHERs enrolled patients aged ≥ 18 years with recently diagnosed HER2-positive MBC. Treatment regimens and clinical management were determined by the treating physician. In this analysis, patients were compared descriptively by first-line treatment, age, or race. Multivariate logistic regression was used to examine the associations between baseline variables and treatment selections. Clinical outcomes were assessed in patients treated with trastuzumab (Herceptin [H]) + pertuzumab (Perjeta [P]). Patients were enrolled from June 2012 to June 2016. As of February 22, 2018, 948 patients from 135 US treatment sites had received first-line treatment, including HP (n = 711), H without P (n = 175), or no H (n = 62) (with or without chemotherapy and/or hormonal therapy). Overall, 68.7% received HP + taxane and 9.3% received H without P + taxane. Patients aged

Background: Trophoblast cell-surface antigen-2 (Trop-2) is highly expressed in many epithelial tumors, including triple-negative breast cancer (TNBC). Sacituzumab govitecan (SG) is an antibody-drug conjugate composed of an anti-Trop-2 antibody coupled to SN-38, an active metabolite of irinotecan, via a unique hydrolyzable linker that allows for SN-38 release intracellularly and in the tumor microenvironment (bystander effect). Preclinical studies have shown a great range of efficacy with SG in mice bearing tumors with low, moderate, and high Trop-2 expression levels. We report subgroup analyses by Trop-2 expression from ASCENT, a randomized, phase 3 confirmatory study of SG versus standard-of-care chemotherapy in patients with metastatic TNBC (mTNBC). Methods: In the global, multicenter, open-label, phase 3 ASCENT study (NCT02574455), 529 patients with mTNBC refractory to or relapsing after at least 2 prior chemotherapies were randomized 1:1 to receive SG (10 mg/kg intravenously on days 1 and 8 every 21 days) or single-agent treatment of physician’s choice (capecitabine, eribulin, vinorelbine, or gemcitabine) until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS) measured by central independent review per RECIST v1.1. Secondary endpoints included objective response rate (ORR) per RECIST v1.1, duration of response, overall survival (OS), and safety. Exploratory endpoints included biomarker assessments, including Trop-2 and BRCA1/2. Trop-2 expression was assessed using a validated immunohistochemistry assay. Results: Subgroup analyses by biomarker expression including Trop-2 and BRCA1/2 were performed, and outcomes by PFS, OS, ORR, and safety results will be reported. Conclusions: These analyses will provide further insights into the relationship of Trop-2 expression and the activity of SG in previously treated patients with mTNBC. Citation Format: Sara A. Hurvitz, Sara M. Tolaney, Kevin Punie, Delphine Loirat, Mafalda Oliveira, Kevin Kalinsky, Amelia Zelnak, Philippe Aftimos, Florence Dalenc, Sagar Sardesai, Erika Hamiltion, Priyanka Sharma, Sabela Recalde, Eva Ciruelos Gil, Tiffany Traina, Joyce O'Shaughnessy, Javier Cortés, Michaela Tsai, Linda Vahdat, Véronique Diéras, Lisa Carey, Hope S. Rugo, David M. Goldenberg, Quan Hong, Martin Olivo, Loretta M. Itri, Aditya Bardia. Biomarker evaluation in the phase 3 ASCENT study of sacituzumab govitecan versus chemotherapy in patients with metastatic triple-negative breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr GS3-06.

Background: CDK4/6 inhibitors have emerged as the standard of care for HR+ MBC. However, there is limited insight into the potential benefit of abemaciclib following prior progression on palbociclib or ribociclib. Based on a multi-center cohort of patients with HR+ MBC who had received abemaciclib after prior palbociclib progression (Wander SA et al ASCO 2019), we have previously reported that abemaciclib after prior CDK4/6i progression was well tolerated and that a subset of patients derived durable clinical benefit. Identifying molecular predictors of sensitivity to abemaciclib after prior CDK4/6i progression constitutes an important area of research. Given the high frequency of ESR1 mutations in HR+ MBC with antiestrogen resistance, we evaluated the translational impact of ESR1 mutations in mediating response to abemaciclib in this setting. Methods: To evaluate abemaciclib sensitivity in ESR1 mutant cell lines, T47D HR+ breast cancer cells were modified to over-express multiple mutant ESR1 isoforms via lentiviral infection and antibiotic selection. These isoforms included ESR1 Y537S, Y537N, and D538G. In an additional T47D cell line, RB1 expression was knocked down via CRISPR. The resulting derivative cell lines were grown in the absence of estrogen (via charcoal-stripped serum, CSS) or in escalating doses of abemaciclib. Cell viability was measured via cell-titer-glo assay. For clinical validation, we identified patients with MBC who had ESR1 mutations detected by targeted sequencing of cell-free DNA (cfDNA), via CLIA certified Guardant assay, and had abemaciclib exposure following prior progression on palbociclib or ribociclib in the existing multi-center cohort from six US institutions. Results: All ESR1 mutant derivative cells demonstrated enhanced growth in estrogen deprivation compared to GFP controls, as expected, and were similarly sensitive to escalating doses of abemaciclib monotherapy in vitro, suggesting that ESR1 mutations do not confer resistance to abemaciclib. Interestingly, two patients with ESR1 mutations (in the absence of concurrent driver alterations in RB1, FGFR, CCNE2, and ERBB2) demonstrated progression on palbociclib and sensitivity to abemaciclib. In one patient, cfDNA obtained prior to palbociclib and fulvestrant exposure failed to reveal any ESR1 alteration. Following progression on palbociclib, and prior to sequential exposure to abemaciclib, an ESR1 Y537N alteration was identified. The patient went on to receive 16 months of abemaciclib monotherapy. In a second patient, an ESR1 D538G alteration was identified following progression on palbociclib and fulvestrant. The patient had several intervening regimens, and subsequently went on to receive abemaciclib and fulvestrant for 16 months. RB1-null T47D cells were resistant to abemaciclib monotherapy in vitro, as expected and, in the clinical dataset, the presence of alterations in previously identified genomic mediators of CDK4/6i resistance, such as RB1, were associated with progression on both palbociclib and abemaciclib. Conclusions: HR+ breast cancer cells expressing mutant ESR1 isoforms were resistant to estrogen deprivation but retained sensitivity to abemaciclib in vitro. Furthermore, patients harboring ESR1 mutations via targeted sequencing of cfDNA, in the absence of other known mediators of CDK4/6i resistance, were shown to derive clinical benefit from abemaciclib following prior progression on palbociclib. These results suggest that patients with HR+ MBC, ESR1 mutation, and clinical resistance to anti-estrogen treatment and palbociclib may be candidates for abemaciclib treatment. Further research is warranted to confirm these novel translational observations. Citation Format: Seth A. Wander, Hyo S. Han, Gabriela N. Johnson, Maxwell R. Lloyd, Pingping Mao, Utthara Nayar, Kailey Kowalski, Casey R. Stein, Veronica Mariotti, Leslie SL Kim, Maren Levin, Jing Xi, Apurva Pandey, Siobhan Dunne, Azadeh Nasrazadani, Adam Brufsky, Kevin Kalinsky, Cynthia X Ma, Joyce O’Shaughnessy, Nikhil Wagle, Aditya Bardia. Esr1 mutation as a potential predictor of abemaciclib benefit following prior cdk4/6 inhibitor (cdk4/6i) progression in hormone receptor-positive (hr+) metastatic breast cancer (mbc): A translational investigation [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS5-10.

Background: Trophoblast cell-surface antigen-2 (Trop-2) is highly expressed in many epithelial tumors, including triple-negative breast cancer (TNBC). Sacituzumab govitecan (SG) is an antibody-drug conjugate composed of an anti-Trop-2 antibody coupled to SN-38, the active metabolite of irinotecan, via a unique hydrolyzable linker that allows SN-38 release intracellularly and in the tumor microenvironment (bystander effect). SG received accelerated approval in April 2020 for the treatment of patients with metastatic TNBC (mTNBC) who received at least 2 prior therapies for metastatic disease. The most common adverse events (AEs) observed with SG are neutropenia and gastrointestinal toxicity, also seen with irinotecan. To provide further information on SG, additional safety analyses from ASCENT, a randomized, phase 3 confirmatory study of SG versus standard-of-care chemotherapy in patients with mTNBC, will be reported. Methods: In the global, multicenter, open-label, phase 3 ASCENT study (NCT02574455), 529 patients with mTNBC refractory to or relapsing after at least 2 prior chemotherapies were randomized 1:1 to receive SG (10 mg/kg intravenously on days 1 and 8 every 21 days) or single-agent treatment of physician’s choice (capecitabine, eribulin, vinorelbine, or gemcitabine) until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival measured by central independent review per RECIST v1.1. Secondary endpoints included objective response rate, duration of response, overall survival, and safety. An exploratory analysis of incidence of grade 3-5 AEs by UGT1A1 genotype was also performed. Post-hoc analysis of the time to onset and duration of key AEs will be performed, and descriptive analyses on alopecia, nausea and vomiting will also be provided. Results: Exploratory safety analyses by UGT1A1 allele status will be shown as well as time to onset and duration of neutropenia and diarrhea. Further descriptive analyses on alopecia, nausea, and vomiting will be provided along with AE management strategies. Conclusions: These analyses will provide further insights into the safety profile of SG and appropriate AE management strategies for patients with previously treated mTNBC to allow optimal therapeutic exposure. Citation Format: Hope S. Rugo, Sara M. Tolaney, Delphine Loirat, Kevin Punie, Aditya Bardia, Sara A. Hurvitz, Joyce O'Shaughnessy, Javier Cortés, Véronique Diéras, Lisa Carey, Luca Gianni, Martine J. Piccart, Sibylle Loibl, David M. Goldenberg, Quan Hong, Martin Olivo, Loretta M. Itri, Kevin Kalinsky. Impact of UGT1A1 status on the safety profile of sacituzumab govitecan in the phase 3 ASCENT study in patients with metastatic triple-negative breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS11-09.

BACKGROUND: A subset of TNBCs have homologous recombination deficiency with upregulation of compensatory DNA repair pathways. The combination of TAK-228 and TAK-117 (PIKTOR), investigational oral TORC1/2 and PI3Kα selective inhibitors, respectively, is hypothesized to increase genomic instability (GI) and to increase DDRD, leading to increased sensitivity to DNA damaging chemotherapy and to checkpoint inhibitors in metTNBC pts. METHODS: 10 metTNBC pts received 4 mg PO TAK-228 and 200 mg PO TAK-117 QDx3d QW until disease progression (PD), followed by cis 75 mg/m2 plus nab pac 220 mg/m2 for up to 6 cycles. Primary endpoints were objective response rate with cis/nab pac and safety. Blood samples and biopsies of metastatic lesions were collected prior to and at PD on PIKTOR. Blood CTC analyses included enumeration, cell morphology, phenotypic heterogeneity, and predicted genomic instability (pGI) derived from cell phenotypes. RESULTS: 10 pts received PIKTOR followed by cis/nab pac. Median age: 51 yrs; median number of prior chemotherapy regimens was 3 (range, 1-5); 7 pts had prior carboplatin; sites of metastases: lymph nodes (n=8); lung (n=6); chest wall (n=1); bone (n=1); brain (n=1). Median time on PIKTOR was 8 wks (range, 3-14). With cis/nab pac, 1 pt had PR, 2 had SD > 6 mos, 1 had SD and 6 had PD. 2 SD pts (sites LNs and bone) and 1 PD pt (sites LNs), all carboplatin-pretreated, whose pre-PIKTOR BCs were PDL1-negative (2 pts) or unknown (1 pt) have durable SD on pembrolizumab post-cis/nab pac for 1+ yrs. PIKTOR related AEs ≥30% included: fatigue (90%); nausea (80%); diarrhea (60%); vomiting (40%); stomatitis (40%); hyperglycemia (30%); rash (30%); cough (30%); chest pain (30%). Incidence and grade of cis/nab pac-related AEs were not greater than expected with this regimen. At PD on PIKTOR, higher CTC burden and pGI+ CTCs were observed in a subset of pts suggesting that some CTCs may have developed greater GI with PIKTOR treatment. Next generation sequencing (NGS) and reverse phase protein array (RPPA) analyses of biomarkers of DNA repair pathways pre-and post-PIKTOR tissues are underway and will be presented at the meeting. CONCLUSIONS: Priming pts’ metTNBC with PIKTOR did not lead to durable responses with cis/nab pac in most pts in this pretreated population. However, 3/10 pts who had carboplatin-pretreated disease in LNs +/- bone, have highly durable SD on pembrolizumab following PIKTOR therapy. Citation Format: Joyce O'Shaughnessy, Esther San Roman Rodriguez, Priscilla Ontiveros, Rick Wenstrup, Tiziano Pramparo, Jessica Lang, Victoria Zismann, Natalia Briones, William Hendricks, Virginia Espina, Claudius Mueller, Maren K Levin. Pilot trial of priming with oral TAK-228 and TAK-117 (PIKTOR) to increase DNA damage repair deficiency (DDRD) followed by cisplatin (cis) and nab paclitaxel (nab pac) in chemotherapy-pretreated metastatic triple negative breast cancer (metTNBC) pts [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS11-25.

Background Trilaciclib is an intravenous (IV) cyclin-dependent kinase 4/6 (CDK4/6) inhibitor. Preliminary data showed that adding trilaciclib prior to gemcitabine plus carboplatin (GCb) significantly increased overall survival (OS) compared with GCb alone among patients with metastatic triple-negative breast cancer (mTNBC) (Tan et al., Lancet Oncol. 2019;20:1587-1601). Here, final antitumor efficacy results (objective response rate [ORR], progression-free survival [PFS], and OS) are reported for the whole study population, and in cohorts according to CDK4/6 dependence and level of programmed death ligand-1 (PD-L1) expression. Methods This was a randomized, open-label, phase 2 study of patients with mTNBC who had received ≤2 previous lines of chemotherapy in the recurrent/metastatic setting (NCT02978716). Patients were randomized (1:1:1) to receive GCb on days 1 and 8 (group 1, n=34), trilaciclib prior to GCb on days 1 and 8 (group 2, n=33), or trilaciclib alone on days 1 and 8 and prior to GCb on days 2 and 9 (group 3, n=35), in 21-day cycles. PFS and OS (prespecified secondary endpoints) were assessed in the intention-to-treat (ITT) population, and ORR in response-evaluable patients. Patient tumors were characterized as CDK4/6 independent (basal-like) or indeterminate (HER2-enriched, normal-like, luminal A/B) according to the established PAM50 signature, or CDK4/6 dependent (luminal androgen receptor) or indeterminate (basal-like 1/2, mesenchymal) according to the established Lehmann signature. PD-L1 expression was scored as negative or positive if Results Median follow-up was 8.4 months (range: 0.1-25.7) for group 1, 14.0 months (1.3-33.6) for group 2, and 15.3 months (3.5-33.7) for group 3. The ORR among response-evaluable patients was 7/24 (29.2%) in group 1, 15/30 (50.0%) in group 2, and 12/31 (38.7%) in group 3. Median PFS (95% confidence interval [CI]) in the ITT population was 5.7 (3.3, 9.9) months in group 1, 9.4 (6.1, 11.9) months in group 2, and 7.3 (6.2, 13.9) months in group 3, with hazard ratios (HRs) of 0.62 (P = 0.2099) and 0.63 (P = 0.1816), for groups 2 and 3 versus group 1, respectively. Overall, 73.5%, 39.4%, and 57.1% of patients in groups 1, 2, and 3 had died. Median OS (95% CI) was 12.6 (6.3, 15.6) months in group 1, not reached (NR) (10.2, NR) in group 2 (HR = 0.31, P = 0.0016), and 17.8 (12.9, 32.7) months in group 3 (HR = 0.40, P = 0.0004). For groups 2 and 3 combined, median OS was 19.8 (14.0, NR) months (HR = 0.37, P Conclusions Mature data from this study confirm that administering trilaciclib prior to GCb enhances antitumor efficacy compared with GCb alone, with statistically significant improvements in OS. Subgroup analyses suggest that adding trilaciclib prior to GCb benefits patients regardless of CDK4/6 dependence status and PD-L1 expression. Additional immune subtyping analyses are ongoing and will be presented. Group 1Group 2Group 3PD-L1 +vePD-L1 –vePD-L1 +vePD-L1 –vePD-L1 +vePD-L1 –vePatients, n171016101616ORR, n (%)4 (23.5)3 (30.0)8 (50.0)4 (40.0)7 (43.8)4 (25.0)Median PFS, months (95% CI)3.5 (2.2, NR)9.5 (5.2, NR)7.9 (4.3, NR)11.9 (8.8, NR)9.0 (6.2, NR)6.9 (6.4, NR)P value (Wald Test)––0.3470.6040.0690.766HR (95% CI)––0.70 (0.3, 1.5)0.76 (0.3, 2.2)0.46 (0.2, 1.1)1.16 (0.4, 3.1)Median OS, months (95% CI)10.5 (6.3, 18.8)13.9 (12.6, NR)20.1 (10.2, NR)NR (9.4, NR)32.7 (15.3, NR)17.8 (12.9, NR)P value (Wald Test)––0.0280.0830.020.239HR (95% CI)––0.35 (0.1, 0.9)0.34 (0.1, 1.2)0.33 (0.1, 0.8)0.57 (0.2, 1.5)HR and P values are for comparisons between group 2 versus group 1, and group 3 versus group 1.+ve, positive; –ve, negative; CI, confidence interval; HR, hazard ratio; NR, not reached; ORR, objective response rate; OS, overall survival; PD-L1, programmed death ligand-1; PFS, progression-free survival. Citation Format: Joyce O'Shaughnessy, Gail S Wright, Anu R Thummala, Michael A Danso, Lazar Popovic, Timothy J Pluard, Hyo S Han, Željko Vojnović, Nikola Vasev, Ling Ma, Donald A Richards, Sharon T Wilks, Dušan Milenković, Jie Xiao, Jessica A Sorrentino, Janet Horton, Antoinette R Tan. Trilaciclib improves overall survival when given with gemcitabine/carboplatin in patients with metastatic triple-negative breast cancer: Final analysis of a randomized phase 2 trial [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD1-06.

Background Trophoblast cell-surface antigen-2 (Trop-2) is expressed in epithelial cancers, including hormone receptor-positive (HR+) metastatic breast cancer (mBC). Sacituzumab govitecan (SG; Trodelvy®) is an antibody–drug conjugate composed of a humanized anti-Trop-2 monoclonal antibody coupled to SN-38 at a high drug-to-antibody ratio via a unique hydrolyzable linker that delivers SN-38 intracellularly and in the tumor microenvironment. SG was granted accelerated FDA approval for metastatic triple-negative BC treatment in April 2020. Patients and methods We analyzed a prespecified subpopulation of patients with HR+/human epidermal growth factor receptor 2-negative (HER2−) HR+/HER2− mBC from the phase I/II, single-arm trial (NCT01631552), who received intravenous SG (10 mg/kg) and whose disease progressed on endocrine-based therapy and at least one prior chemotherapy for mBC. End points included objective response rate (ORR; RECIST version 1.1) assessed locally, duration of response (DOR), clinical benefit rate, progression-free survival (PFS), overall survival (OS), and safety. Results Fifty-four women were enrolled between 13 February 2015 and 1 June 2017. Median (range) age was 54 (33-79) years and all received at least two prior lines of therapy for mBC. At data cut-off (1 March 2019), 12 patients were still alive. Key grade ≥3 treatment-related toxicities included neutropenia (50.0%), anemia (11.1%), and diarrhea (7.4%). Two patients discontinued treatment due to treatment-related adverse events. No treatment-related deaths occurred. At a median follow-up of 11.5 months, the ORR was 31.5% [95% confidence interval (CI), 19.5%–45.6%; 17 partial responses]; median DOR was 8.7 months (95% CI 3.7–12.7), median PFS was 5.5 months (95% CI 3.6–7.6), and median OS was 12 months (95% CI 9.0–18.2). Conclusions SG shows encouraging activity in patients with pretreated HR+/HER2− mBC and a predictable, manageable safety profile. Further evaluation in a randomized phase III trial (TROPiCS-02) is ongoing (NCT03901339). Trial registration ClinicalTrials.gov NCT01631552; https://clinicaltrials.gov/ct2/show/NCT01631552

Introduction: Prior cross-sectional studies suggest that health-related quality of life (HRQOL) worsens with more severe glomerular disease. This longitudinal analysis was conducted to assess changes in HRQOL with changing disease status. Methods: Cure Glomerulonephropathy (CureGN) is a cohort of patients with minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, IgA vasculitis, or IgA nephropathy. HRQOL was assessed at enrollment and follow-up visits 1 to 3 times annually for up to 5 years with the Patient-Reported Outcomes Measurement Information System (PROMIS). Global health, anxiety, and fatigue domains were measured in all; mobility was measured in children; and sleep-related impairment was measured in adults. Linear mixed effects models were used to evaluate HRQOL responsiveness to changes in disease status. Results: A total of 469 children and 1146 adults with PROMIS scores were included in the analysis. HRQOL improved over time in nearly all domains, though group-level changes were modest. Edema was most consistently associated with worse HRQOL across domains among children and adults. A greater number of symptoms also predicted worse HRQOL in all domains. Sex, age, obesity, and serum albumin were associated with some HRQOL domains. The estimated glomerular filtration rate (eGFR) was only associated with fatigue and adult physical health; proteinuria was not associated with any HRQOL domain in adjusted models. Conclusion: HRQOL measures were responsive to changes in disease activity, as indicated by edema. HRQOL over time was not predicted by laboratory-based markers of disease. Patient-reported edema and number of symptoms were the strongest predictors of HRQOL, highlighting the importance of the patient experience in glomerular disease. HRQOL outcomes inform understanding of the patient experience for children and adults with glomerular diseases.

Background: Pathologic complete response (pCR) is a common efficacy endpoint in neoadjuvant therapy trials for triple-negative breast cancer (TNBC). Previous studies have shown that pCR is strongly associated with improved long-term survival outcomes, including event-free survival (EFS) and overall survival (OS). However, the trial-level associations between treatment effect on pCR and long-term survival outcomes are not well established. This study sought to evaluate these associations by incorporating more recent clinical trials in TNBC. Methods: A literature review identified published randomized controlled trials (RCTs) of neoadjuvant therapy for TNBC that reported results for both pCR and EFS/OS. Meta-regression models were performed to evaluate the association of treatment effect on pCR and EFS/OS. Sensitivity analyses were conducted to assess the impact of divergent study designs. Results: Ten comparisons from 8 RCTs (N=2,478 patients) were identified from the literature review. The log (odds ratio) of pCR was a significant predictor of the log (hazard ratio) of EFS (P=.003), with a coefficient of determination of 0.68 (95% CI, 0.41–0.95). There was a weaker association between pCR and OS (P=.18), with a coefficient of determination of 0.24 (95% CI, 0.01–0.77). Consistent results were found in the exploratory analysis and sensitivity analyses. Conclusions: This is the first study that has shown a trial-level association between pCR and survival outcomes in TNBC. By incorporating the most up-to-date RCTs, this study showed a significant trial-level association between pCR and EFS. A positive association between pCR and OS was also recorded.

PurposeThe safety and efficacy of X-82, an orally administered inhibitor of vascular endothelial growth factor (VEGF) and platelet-derived growth factor, was investigated for treatment of wet age-related macular degeneration (AMD) in a phase II clinical trial.MethodsThis phase II, randomised, double-masked, placebo-controlled trial enrolled subjects with a prior diagnosis of exudative AMD having received at least two intravitreal injections of anti-VEGF therapy. Subjects were randomised equally into four groups that received either daily 50mg, 100mg or 200mg dosages of X-82 or a placebo tablet. At each 4-week interval visit for 52 weeks, subjects were to be assessed to determine if rescue treatment was needed with anti-VEGF therapy.Results157 patients were enrolled. Due to gastrointestinal and hepatobiliary adverse events and the fulfilment of the primary endpoint, the trial was stopped prematurely after a second interim analysis. The primary endpoint of non-inferiority of visual acuity compared with placebo was demonstrated in all groups receiving X-82 (pConclusionsX-82 oral therapy in combination withpro re nataanti-VEGF injections showed non-inferiority in visual acuity outcomes while achieving a dose-dependent decrease in the number of anti-VEGF injections compared with placebo. Given the limited tolerability and safety issues observed, X-82 does not have a sufficient benefit to risk profile in treatment of patients with AMD.

Introduction Glomerular diseases are characterized by variable disease activity over many years. We aimed to analyze the relationship between clinical disease activity and duration of glomerular disease. Methods Disease activity in adults with chronic minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, and IgA nephropathy (IgAN; first diagnostic biopsy >5 years before enrollment; Of Longstanding Disease [OLD] cohort, n = 256) followed at Columbia University Medical Center (CUMC), was compared with disease activity of an internal and external cohort of patients with first diagnostic biopsy, Graphical abstract

Purpose: We report treatments and outcomes in a contemporary patient population with HER2-positive metastatic breast cancer (MBC) by hormone receptor (HR) status from the Systemic Therapies for HER2-positive Metastatic Breast Cancer Study (SystHERs). Experimental Design: SystHERs (NCT01615068) was an observational, prospective registry study of U.S.-based patients with newly diagnosed HER2-positive MBC. Endpoints included treatment patterns and clinical outcomes. Results: Of 977 eligible patients (enrolled from 2012 to 2016), 70.1% (n = 685) had HR-positive and 29.9% (n = 292) had HR-negative disease. Overall, 59.1% (405/685) of patients with HR-positive disease received any first-line endocrine therapy (with or without HER2-targeted therapy or chemotherapy); 34.9% (239/685) received HER2-targeted therapy + chemotherapy + sequential endocrine therapy. Patients with HR-positive versus HR-negative disease had longer median overall survival (OS; 53.0 vs 43.4 months; hazard ratio, 0.70; 95% confidence interval, 0.56–0.87). Compared with patients with high HR-positive staining (10%–100%, n = 550), those with low HR-positive staining (1%–9%, n = 60) received endocrine therapy less commonly (64.2% vs 33.3%) and had shorter median OS (53.8 vs 40.1 months). Similar median OS (43.4 vs 40.1 months) was observed in patients with HR-negative versus low HR-positive tumors (1%–9%). Conclusions: Despite evidence that first-line HER2-targeted therapy, chemotherapy, and sequential endocrine therapy improves survival in patients with HR-positive, HER2-positive disease, only 34.9% of patients in this real-world setting received such treatment. Patients with low tumor HR positivity (1%–9%) had lower endocrine therapy use and worse survival than those with high tumor HR positivity (10%–100%).

Aim: The aim of the study was to assess patient preference for the fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection (PH FDC SC) in patients with HER2-positive early breast cancer in PHranceSCa (NCT03674112). Materials and methods: Patients who completed neoadjuvant P + H + chemotherapy + surgery were randomised 1:1 to three intravenous (IV) P + H cycles followed by three cycles of PH FDC SC or vice versa (crossover) and then chose subcutaneous (SC) injection or IV infusion to continue up to 18 cycles (continuation). Assessments were via patient and healthcare professional (HCP) questionnaires. Results: One hundred and sixty patients were randomised (cut-off: 24 February 2020); 136 (85.0%, 95% confidence interval: 78.5–90.2%) preferred SC; 22 (13.8%) preferred IV; 2 (1.3%) had no preference. The main reasons for SC preference were reduced clinic time (n = 119) and comfort during administration (n = 73). One hundred and forty-one patients (88.1%) were very satisfied/satisfied with SC injection versus 108 (67.5%) with IV infusion; 86.9% chose PH FDC SC continuation. HCP perceptions of median patient treatment room time ranged from 33.0–50.0 min with SC and 130.0–300.0 min with IV. Most adverse events (AEs) were grade 1/2 (no 4/5s); serious AE rates were low. AE rates before and after switching were similar (cycles 1–3 IV → cycles 4–6 SC: 77.5% → 72.5%; cycles 1–3 SC → cycles 4–6 IV: 77.5% → 63.8%). Conclusion: Most patients strongly preferred PH FDC SC over P + H IV. PH FDC SC was generally well tolerated, with no new safety signals (even when switching), and offers a quicker alternative to IV infusion.

McArdle disease is a glycogen-storage disorder that typically presents with features including exercise intolerance, muscle pain and early fatigue. It can however result in muscle cell ischaemia and rhabdomyolysis, potentially causing myoglobinuria, renal failure and compartment syndrome. This paper outlines a case of bilateral atraumatic forearm compartment syndrome that resulted in a consequent diagnosis of McArdle disease when the patient presented with recurrent symptoms. It also discusses the mounting evidence to support an increased risk of compartment syndrome in association with this relatively young disease. Although rare, it is important to consider the diagnosis of McArdle disease in cases of atraumatic compartment syndrome, as this patient cohort warrants specific consideration, given their significant risk of rhabdomyolysis, compartment syndrome and renal failure. Level of evidence: Level V, Diagnostic study.

Contains fulltext : 229292.pdf (Publisher’s version ) (Open Access) PURPOSE: We assessed the associations between population-based polygenic risk scores (PRS) for breast (BC) or epithelial ovarian cancer (EOC) with cancer risks for BRCA1 and BRCA2 pathogenic variant carriers. METHODS: Retrospective cohort data on 18,935 BRCA1 and 12,339 BRCA2 female pathogenic variant carriers of European ancestry were available. Three versions of a 313 single-nucleotide polymorphism (SNP) BC PRS were evaluated based on whether they predict overall, estrogen receptor (ER)-negative, or ER-positive BC, and two PRS for overall or high-grade serous EOC. Associations were validated in a prospective cohort. RESULTS: The ER-negative PRS showed the strongest association with BC risk for BRCA1 carriers (hazard ratio [HR] per standard deviation = 1.29 [95% CI 1.25-1.33], P = 3×10(-72)). For BRCA2, the strongest association was with overall BC PRS (HR = 1.31 [95% CI 1.27-1.36], P = 7×10(-50)). HR estimates decreased significantly with age and there was evidence for differences in associations by predicted variant effects on protein expression. The HR estimates were smaller than general population estimates. The high-grade serous PRS yielded the strongest associations with EOC risk for BRCA1 (HR = 1.32 [95% CI 1.25-1.40], P = 3×10(-22)) and BRCA2 (HR = 1.44 [95% CI 1.30-1.60], P = 4×10(-12)) carriers. The associations in the prospective cohort were similar. CONCLUSION: Population-based PRS are strongly associated with BC and EOC risks for BRCA1/2 carriers and predict substantial absolute risk differences for women at PRS distribution extremes.

Càncer de mama; Marcadors predictius; Pronòstic Cáncer de mama; Marcadores predictivos; Pronóstico Breast cancer; Predictive markers; Prognosis Prior pooled analysis of eribulin studies (301 and 305) indicated eribulin prolonged overall survival (OS) in patients with locally advanced/metastatic breast cancer (MBC) regardless of visceral or nonvisceral disease. This hypothesis-generating post hoc analysis examined the efficacy of eribulin according to the location of metastatic sites at baseline in 1864 pretreated patients with locally advanced/MBC from studies 301 and 305. Analyses included OS, progression-free survival (PFS), and objective response rate; OS and PFS were also analyzed according to estrogen-receptor status. Eribulin appeared efficacious in patients with locally advanced/MBC, irrespective of the location of metastases at baseline. A nominally significant difference in OS in favor of patients randomized to eribulin compared with control in patients with bone, lymph node, and chest wall/breast/skin metastases at baseline was observed. Additionally, a difference in OS was also seen in patients with liver metastases randomized to eribulin versus control (median: 13.4 versus 11.3 months, respectively; hazard ratio, 0.84 [95% CI: 0.72, 0.97]). Results of this exploratory analysis suggest that eribulin may be efficacious for the treatment of locally advanced/MBC for patients with bone, liver, lung, lymph node, and chest wall/breast/skin metastases. This study was funded by Eisai Inc., Woodcliff Lake, NJ. Medical writing support was provided by Jeffrey Bratz, PhD, Oxford PharmaGenesis, Newtown, PA, USA, and was funded by Eisai Inc., Woodcliff Lake, NJ, USA.

Objective: Limited evidence exists on the role that the cause of chronic kidney disease plays in determining pregnancy outcomes. The aim of this systematic review and meta-analysis was to examine the association between chronic kidney disease and adverse pregnancy outcomes by the cause and severity of chronic kidney disease where reported. The protocol was registered under the International Prospective Register of Systematic Reviews (CRD42020211925). Data Sources: PubMed, Embase, and Web of Science were searched until May 24, 2021, supplemented with reference list checking. Study Eligibility Criteria: Studies that compared the pregnancy outcomes in women with or without chronic kidney disease were included. Two reviewers independently screened titles, abstracts, and full-text articles according to a priori defined inclusion criteria. Methods: Data extraction and quality appraisal were performed independently by 3 reviewers. The grading of recommendations, assessment, development, and evaluation approach was used to assess the overall certainty of the evidence. Random-effects meta-analyses were used to calculate the pooled estimates using the generic inverse variance method. The primary outcomes included preeclampsia, cesarean delivery, preterm birth (

In the BrighTNess trial, carboplatin added to neoadjuvant chemotherapy (NAC) was associated with increased pathologic complete response (pCR) rates in patients with stage II/III triple-negative breast cancer (TNBC). In this matched cohort study, cases with a germline BRCA1/2 mutation (gBRCA; n = 75) were matched 1:2 with non-gBRCA controls (n = 150) by treatment arm, lymph node status, and age to evaluate pCR rates and association of benefit from platinum/PARP inhibitors with validated RNA expression-based immune, proliferation, and genomic instability scores among gBRCA with the addition of carboplatin ± veliparib to NAC. Among the well-matched cohorts, odds of pCR were not higher in gBRCA cancers who received standard NAC with carboplatin (OR 0.24, 95% CI [0.04-1.24], p = 0.09) or with carboplatin/veliparib (OR 0.44, 95% CI [0.10-1.84], p = 0.26) compared to non-gBRCA cancers. Higher PAM50 proliferation, GeparSixto immune, and CIN70 genomic instability scores were each associated with higher pCR rate in the overall cohort, but not specifically in gBRCA cases. In this study, gBRCA carriers did not have higher odds of pCR than non-gBRCA controls when carboplatin ± veliparib was added to NAC, and showed no significant differences in molecular, immune, chromosomal instability, or proliferation gene expression metrics.

BackgroundClassification of nephrotic syndrome relies on clinical presentation and descriptive patterns of injury on kidney biopsies. This approach does not reflect underlying disease biology, limiting the ability to predict progression or treatment response.MethodsSystems biology approaches were used to categorize patients with minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) based on kidney biopsy tissue transcriptomics across three cohorts and assessed association with clinical outcomes. Patient-level tissue pathway activation scores were generated using differential gene expression. Then, functional enrichment and non-invasive urine biomarker candidates were identified. Biomarkers were validated in kidney organoid models and single nucleus RNA-seq (snRNAseq) from kidney biopsies.ResultsTranscriptome-based categorization identified three subgroups of patients with shared molecular signatures across independent North American, European and African cohorts. One subgroup demonstrated worse longterm outcomes (HR 5.2, p = 0.001) which persisted after adjusting for diagnosis and clinical measures (HR 3.8, p = 0.035) at time of biopsy. This subgroup’s molecular profile was largely (48%) driven by tissue necrosis factor (TNF) activation and could be predicted based on levels of TNF pathway urinary biomarkers TIMP-1 and MCP-1 and clinical features (correlation 0.63, p ConclusionsMolecular profiling identified a patient subgroup within nephrotic syndrome with poor outcome and kidney TNF pathway activation. Clinical trials using non-invasive biomarkers of pathway activation to target therapies are currently being evaluated.Significance StatementMechanistic, targeted therapies are urgently needed for patients with nephrotic syndrome. The inability to target an individual’s specific disease mechanism using currently used diagnostic parameters leads to potential treatment failure and toxicity risk. Patients with focal segmental glomerulosclerosis (FSGS) and minimal change disease (MCD) were grouped by kidney tissue transcriptional profiles and a subgroup associated with poor outcomes defined. The segregation of the poor outcome group was driven by tumor necrosis factor (TNF) pathway activation and could be identified by urine biomarkers, MCP1 and TIMP1. Based on these findings, clinical trials utilizing non-invasive biomarkers of pathway activation to target therapies, improve response rates and facilitate personalized treatment in nephrotic syndrome have been initiated.

Background Previous trials showed promising antitumor activity and an acceptable safety profile associated with pembrolizumab in patients with early triple-negative breast cancer. Whether ...

Background: Chemotherapy treatments with robust efficacy that preserve quality of life are needed. Tesetaxel is a novel, oral taxane that has potential advantages over currently available taxanes, including: oral administration with a low pill burden and once every 3 week (Q3W) dosing; no observed hypersensitivity reactions; preclinical evidence of central nervous system (CNS) penetration; and improved activity against chemotherapy-resistant tumors. More than 600 patients have been treated with tesetaxel in clinical studies. Tesetaxel had robust monotherapy activity in a Phase 2 study in 38 patients with HER2-, HR+ MBC, with a confirmed objective response rate (ORR) per RECIST 1.1 of 45% and median PFS of 5.4 months. The confirmed ORR in taxane-pretreated patients also was 45%. Preclinical and clinical studies suggest that reducing the dose of capecitabine in combination with a taxane may result in reduced toxicity without a reduction in efficacy. CONTESSA investigates tesetaxel plus a reduced dose of capecitabine as an all-oral regimen in patients with HER2-, HR+ MBC. Trial design: CONTESSA is a 600-patient, multinational, multicenter, randomized (1:1), Phase 3 registration study comparing tesetaxel (27 mg/m2 on Day 1 of a 21-day cycle) plus a reduced dose of capecitabine (1,650 mg/m2/day on Days 1-14 of a 21-day cycle) to the approved dose of capecitabine alone (2,500 mg/m2/day on Days 1-14 of a 21-day cycle) in patients with HER2-, HR+ MBC who have received no more than one chemotherapy regimen for advanced disease and have received a taxane in the (neo)adjuvant setting. Patients with known CNS metastases are eligible. The primary endpoint is progression-free survival (PFS) assessed by an Independent Radiologic Review Committee (IRC). CONTESSA is 90% powered to detect a 42% improvement in PFS (HR = 0.71). Secondary endpoints are overall survival, ORR and disease control rate. Enrollment began in December 2017. In June 2019, the Independent Data Monitoring Committee for CONTESSA recommended that the study continue with no modifications following a planned interim efficacy futility analysis. The interim efficacy futility analysis was based on a pre-specified analysis of the first approximate 100 PFS events that occurred in the study. For further information on this trial, email joconnell@odonate.com or visit clinicaltrials.gov (NCT03326674). Citation Format: Joyce O'Shaughnessy, Martine Piccart, Lee Schwartzberg, Javier Cortes, Nadia Harbeck, Seock-Ah Im, Hope Rugo, Michael Untch, Denise Yardley, Igor Bondarenko, Veronique Dieras, Mark Pegram, Stew Kroll, Joseph O'Connell, Jeff Vacirca, Thomas Wei, Kevin Tang, Andrew Seidman. CONTESSA: A multinational, multicenter, randomized, phase 3 registration study of tesetaxel plus a reduced dose of capecitabine in patients with HER2-, hormone receptor + (HR+) metastatic breast cancer (MBC) who have previously received a taxane [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 OT1-08-09.

Elevated expression of AURKA adversely affects prognosis in ER+ breast cancer and is associated with resistance to taxanes, endocrine therapy, and PI3K inhibitors. A recent randomized phase II trial of combined paclitaxel plus alisertib (P+A) in recurrent ovarian cancer patients (pts) showed improved progression-free survival (PFS) compared to paclitaxel (P) alone (Falchook G. JAMA Oncol 2019). We conducted a randomized phase II trial of P alone versus P+A in pts with ER+ HER2- metastatic breast cancer (MBC). Methods: The primary objective of the trial was PFS in the intent-to-treat (ITT) population with secondary endpoints of overall survival (OS), overall response rate (ORR), clinical benefit rate (CBR; CR+PR+SD>6 mos), safety and analysis of archival breast cancer for molecular predictors of benefit from alisertib. ER+ HER2- MBC pts who had had prior endocrine therapy, 0 or 1 prior chemotherapy regimens for MBC, > 12 mos treatment-free interval from neo/adjuvant taxane therapy, and who had measurable or evaluable lytic bone disease were randomized to receive P 90 mg/m2 IV D1, 8, 15 on a 28-day cycle or P 60mg/m2 D1, 8, 15 plus A 40 mg PO BID D1-3, 8-10, 15-17 on a 28-day cycle until disease progression or unacceptable toxicity. Pts were stratified by prior neo/adjuvant taxane (yes/no) and by whether they were receiving first (1L)- or second (2L)-therapy for MBC. Proportions of ORR and CBR were compared using Chi-square test between the two study arms. Kaplan-Meier estimator was applied to estimate OS and PFS and univariate Cox regression was used to assess the hazard ratio of study treatment. Results: 139 pts were randomized (69 to P+A; 70 to P) in the US Oncology Network between 2/2015 and 2/2018 and 136 pts received treatment on trial. At data cut-off, 76% of pts had had a documented PFS event and the median followup was 19.7 mos. The median age was 62 and 69% of pts received trial therapy as 1L treatment; 41% had had prior neo/adjuvant taxane therapy. Median PFS in the ITT population was 10.2 mos with P+A vs 7.1 mos with P alone, HR 0.56, 95% CI 0.37-0.84, p=0.005. Median OS was 29.8 mos with P+A vs 24.4 mos with P alone, HR 0.85, p=0.486. ORR and CBR in the response evaluable population were 31% and 67%, respectively, in the P+A arm vs 34% and 57%, respectively, in the P alone arm (p>0.05). Grade 3/4 adverse events (AEs) occurred in 83% of P+A pts vs 47% with P alone. The main grade 3/4 AEs with P+A vs P were neutropenia 59% vs 15%, anemia 10% vs 1%, febrile neutropenia 1.5% vs 0, diarrhea 11% vs 0, stomatitis 15% vs 0, peripheral neuropathy 1.5% vs 9%. 1 pt died of sepsis with P+A. Conclusions: Addition of oral A to weekly P significantly improved PFS, the primary endpoint, compared with P alone, and toxicity with P+A was manageable with A dose reduction. These data support further evaluation of alisertib in ER+ HER2- MBC pts. Citation Format: Joyce O'Shaughnessy, Kristi McIntyre, Sharon Wilks, Ling Ma, William Fintel, Margaret Block, David Andorsky, Michael Danso, Nicholas Koutrelakos, Tracy Locke, Amy Scales, Lauren Steckel, Yunfei Wang. Randomized, multicenter phase II trial of weekly paclitaxel with or without the oral selective aurora kinase A (AURKA) inhibitor, Alisertib, in patients with ER+ HER2- metastatic breast cancer [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 PD7-10.

Background: Abemaciclib plus nonsteroidal aromatase inhibitors (AI) demonstrated efficacy with a tolerable safety profile as initial treatment for postmenopausal women with HR+, HER2− advanced breast cancer in the MONARCH 3 trial. In the intent-to-treat (ITT) population, the updated progression-free survival (PFS) with 12 months of additional follow-up was 28.2 versus 14.8 months (HR [95% CI]: 0.525 [0.415, 0.665]; p Methods: In MONARCH 3, a randomized, double-blind, phase III trial, 493 postmenopausal women with HR+, HER2− advanced breast cancer and no prior systemic therapy in the advanced setting, received an AI (anastrozole or letrozole) plus abemaciclib or placebo. From the October 31, 2018 cutoff, secondary endpoints including objective response rate ([ORR], complete response [CR] + partial response [PR]), time to response (TTR), and duration of response ([DoR], time from a confirmed CR or PR until disease progression or death) were assessed in the ITT population and exploratory subgroups previously reported as significantly prognostic. Waterfall plots will be used to illustrate the magnitude of change in tumor size for each subgroup (to be presented). Results: In patients with measurable disease, the ORR was 62.5% (95% CI: 56.7, 68.2) in the abemaciclib plus AI arm and 44.7% (95% CI: 36.2, 53.2) in the placebo plus AI arm (p≤.001). Additional follow-up confirmed that all prognostic subgroups received benefit from the addition of abemaciclib to AI, consistent with the ITT population, as evidenced by change in ORR, with the largest effects observed in subgroups of patients with liver metastases, progesterone receptor-negative tumors, high grade tumors, or treatment-free interval of Conclusions: Extended follow-up in the MONARCH 3 trial further confirmed that the addition of abemaciclib to AI is associated with durable tumor responses, including those in patients with clinically poor prognostic characteristics. References: Di Leo A et al. NPJ Breast Cancer. 2018;4:41. Clinical trial information: NCT02246621 This study was funded by Eli Lilly and Company Table: Objective Response RateAbemaciclib + AIPlacebo + AIORR ChangeNn (%)Nn (%)%Measurable disease population269168 (62.5)13259 (44.7)17.8Liver metastasesYes4727 (57.45)306 (20.00)37.45No222141 (63.51)10253 (51.96)11.55Progesterone receptor statusNegative6137 (60.66)298 (27.59)33.07Positive206130 (63.11)10351 (49.51)13.60Treatment-free interval Citation Format: Joyce O’Shaughnessy, Stephen Johnston, Miguel Martin, Jens Huober, Masakazu Toi, Valerie AnneMarie Andre, Holly Rene Martin, Molly Catherine Hardebeck, Angelo Di Leo, Matthew Philip Goetz. Updated subgroup tumor response of abemaciclib plus aromatase inhibitor for hormone receptor positive (HR+), HER2 negative advanced breast cancer (MONARCH 3) [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 P1-19-09.

Background: Chemotherapy treatments with robust efficacy that preserve quality of life are needed. Tesetaxel is a novel, oral taxane that has potential advantages over currently available taxanes, including: oral administration with a low pill burden and once every 3 week (Q3W) dosing; no observed hypersensitivity reactions; preclinical evidence of central nervous system (CNS) penetration; and improved activity against chemotherapy-resistant tumors. More than 600 patients have been treated with tesetaxel in clinical studies. Tesetaxel had robust monotherapy activity in a Phase 2 study in 38 patients with HER2-, HR+ MBC, with a confirmed objective response rate (ORR) per RECIST 1.1 of 45%. Preclinical and clinical studies suggest that reducing the dose of capecitabine in combination with a taxane may result in reduced toxicity without a reduction in efficacy. CONTESSA 2 investigates tesetaxel plus a reduced dose of capecitabine as an all-oral regimen in taxane-naïve patients with HER2-, HR+ MBC. Trial design: CONTESSA 2 is a 125-patient, multinational, multicenter, single-arm, Phase 2 study of tesetaxel (27 mg/m2 on Day 1 of a 21-day cycle) plus a reduced dose of capecitabine (1,650 mg/m2/day for 14 days of each 21-day cycle) in patients with HER2-, HR+ MBC who have received no more than one chemotherapy regimen for advanced disease and have not previously been treated with a taxane in any setting. Patients with CNS metastases are eligible. The primary endpoint is confirmed ORR assessed by an Independent Radiologic Review Committee (IRC). A sample size of 125 will allow the ORR to be estimated with a maximum standard error of < 5%. Secondary endpoints include duration of response, pharmacokinetics (PK) of tesetaxel and potential for a PK interaction between tesetaxel and capecitabine. Enrollment was initiated in January 2019. For further information on this trial, email joconnell@odonate.com or visit clinicaltrials.gov (NCT03858972). Citation Format: Lee Schwartzberg, Jamil Asselah, Igor Bondarenko, YeeSoo Chae, Noshir DaCosta, Yin-Hsun Feng, Yann Izarzugaza, Julie Lemieux, Mei-Ching Liu, Gavin Marx, Joyce O'Shaughnessy, Mafalda Oliveira, Hope Rugo, Andrew Seidman, Gail Wright, Joseph O'Connell, Thomas Wei, Sung-Bae Kim. CONTESSA 2: A multinational, multicenter, phase 2 study of tesetaxel plus a reduced dose of capecitabine in patients with HER2-, HR+ metastatic breast cancer (MBC) who have not previously received a taxane [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 OT1-08-07.

Background: Corticosteroids (CS) have immunosuppressive properties that may diminish the efficacy of cancer immunotherapy (CIT). In retrospective analyses of clinical trial data, the use of CS for immune-mediated adverse events after starting CIT does not clearly appear to adversely affect outcomes; however, patients (pts) receiving CS at the start of CIT may have shorter overall and progression-free survival (Arbour, J Clin Oncol, 2018). With the increasing use of CIT for pts with metastatic triple-negative breast cancer (mTNBC) following the approval of atezolizumab in combination with nab-paclitaxel, it is important to understand the landscape of CS use as part of first-line (1L) treatment. Here we describe patterns of CS use in pts receiving 1L therapy for mTNBC, with a focus on taxanes. Methods: A total of 974 pts with confirmed mTNBC diagnosed from Jan 1, 2011, to Jul 5, 2018, and treated in the 1L setting from the de-identified Flatiron Health electronic health record-derived database were included in the study. Pts were categorized as having no CS use during 1L treatment, CS use at the start of 1L treatment or CS use after the start of 1L treatment. Results: The median age at mTNBC diagnosis was 60 years. The majority of pts were female (99%), treated at community centers (94%), and had recurrent disease (59%). Among the most common regimens in 1L were those containing capecitabine (n=208), paclitaxel (n=204), or nab-paclitaxel (n=131) (Table 1). Capecitabine was administered as monotherapy more frequently than paclitaxel and nab-paclitaxel (86% vs 67% and 52%, respectively). Most pts receiving capecitabine did not receive CS during 1L therapy (79%), whereas the majority of pts receiving paclitaxel and nab-paclitaxel did (>95% and 78%, respectively). However, among pts treated with nab-paclitaxel, CS use during 1L was more common in pts receiving combination regimens (88%) than those receiving monotherapy (67%). In general, pts who were treated with paclitaxel or nab-paclitaxel and initiated CS use at the start of 1L treatment continued it throughout their 1L treatment. CS was given (orally or intravenously) with 92% of paclitaxel administrations, 67% of nab-paclitaxel monotherapy administrations, 77% of nab-paclitaxel combination therapy administrations, and 81% of administrations when agents were given in combination with capecitabine. Among pts who received nab-paclitaxel monotherapy, pts who used CS during 1L tended to be younger and less likely to have visceral metastases or recurrent disease than pts who did not use CS. Conclusions: Overall, CS use was common at 1L initiation of most regimens used for the treatment of mTNBC, with the exception of capecitabine. Among pts who were treated with taxanes, those who initiated CS at 1L treatment tended to continue CS treatment for the duration of 1L. Despite the lack of requirement for the use of CS with nab-paclitaxel, the majority of pts treated with nab-paclitaxel monotherapy still received CS at the start of 1L treatment, suggesting use as premedication. None of the assessed pt characteristics were associated with CS use in pts who were treated with nab-paclitaxel monotherapy; however, due to widespread use of CS in the population and small sample size, definitive conclusions are difficult. Larger data sets with reasons for CS use are needed to further understand the observed patterns. Table 1CapecitabinePaclitaxelNab-Paclitaxel Othera(n=208)(n=204)(n=431)MonotherapyCombination(n=63)(n=68)Key baseline characteristicsAge at mBC diagnosis, median (IQR), years63 (53, 74)62 (53, 71)63 (57, 72)60 (52, 67)58 (61, 67)White, non-Hispanic, n (%)133 (64)115 (56)35 (56)41 (60)260 (60)De novo mBC, n (%)35 (17)106 (52)22 (35)23 (34)142 (33)mBC diagnosis later than 2015, n (%)112 (54)111 (54)42 (33)38 (56)261 (61)Bone-only mets at diagnosis, n (%)44 (21)38 (19)198 (>97)42 (67)60 (88)343 (80)Chemotherapy administrations with CS given on the same day, n (%)No39 (19)b177 (8)285 (33)231 (23)820 (27)Yes163 (81)b2104 (92)587 (67)780 (77)2236 (73)a Top 5 other regimens were carboplatin + gemcitabine (n=77), cyclophosphamide + doxorubicin (n=56), eribulin (n=25), carboplatin + docetaxel (n=23), and docetaxel (n=19).b These numbers comprise capecitabine combination regimens only, as chemotherapy administrations did not capture oral capecitabine monotherapy.1L, first-line; CS, corticosteroid; IQR, interquartile range; IV, intravenous injection administration; mBC, metastatic breast cancer; met, metastasis. Citation Format: MK Downer, Patricia Luhn, David Miles, Matthew Kent, Kenneth Russell, Joyce O’Shaughnessy. Systemic corticosteroid use in patients with metastatic triple-negative breast cancer treated with first-line therapy in the United States [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 P2-15-09.

Introduction The 2012 Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guidelines for Glomerulonephritis recommend that patients with membranous nephropathy (MN) at risk for progression receive immunosuppressive therapy (IST), usually after 6 months of observation. A cyclophosphamide (CYC) or calcineurin inhibitor (CNI)–based regimen is recommended as first-line IST. However, the extent to which KDIGO recommendations are adopted in practice remains largely unknown. Methods We evaluated prescribing practice among patients with primary MN (diagnosed 2010–2018) enrolled in the Cure Glomerulonephropathy Network (CureGN) cohort study. We also evaluated the availability of testing for phospholipase A2 receptor (PLA2R) in the contemporary era. Results Among 361 patients (324 adults and 37 children) with MN who were IST-naïve at biopsy and had at least 6 months of follow-up, 55% of adults and 58% of children initiated IST, Graphical abstract

Introduction: Data on percutaneous kidney biopsy (KBx) incidence and frequencies of hemorrhagic complications among inpatients are limited. Methods: Using nationally representative US hospitalization discharge data, we report temporal trends in inpatient KBx rates from 2007 to 2014 and estimate frequencies of, and risk factors for, utilization of packed red blood cell (pRBC) transfusion and renal angiography. Results: From 2007 to 2014, rates of native KBx among adult inpatients increased from 8.2 to 10.0 per 100,000, while transplant KBx rates declined from 3.6 to 3.1 per 100,000. We studied 35,183 and 14,266 discharge records with native and transplant KBx. We found that 5.7% (95% confidence interval [CI]: 5.3%–6.0%) of inpatients undergoing native KBx and 4.9% (4.2%–5.5%) of those undergoing transplant KBx received a pRBC transfusion within 2 days of biopsy. Similarly, 0.6% (0.5%–0.7%) of inpatients undergoing native KBx and 0.4% (0.2%–0.5%) undergoing transplant KBx received a renal angiogram within 2 days of KBx. For inpatient native KBx, female sex, older age, higher chronic kidney disease stage, acute renal failure, lupus, vasculitis, cirrhosis, multiple myeloma/paraproteinemia, and anemia of chronic disease were independently associated with increased odds of pRBC transfusion; cirrhosis and end-stage renal disease (ESRD) were associated with increased odds, and nephrotic syndrome was associated with decreased odds, of renal angiography. Conclusions: In this large population-based study of inpatient KBx practices, we demonstrate increasing rates of inpatient native KBx among US adults and provide accurate estimates of the frequencies of, and risk factors for, pRBC transfusion and renal angiography following inpatient KBx. Keywords: acute kidney injury, glomerular disease, renal biopsy

The non-receptor tyrosine kinase Src activation plays a role in the malignant progression of breast cancer, including development of endocrine therapy resistance and survival of bone metastases. This study investigated whether adding Src kinase inhibitor dasatinib to aromatase inhibitor (AI) therapy improved outcomes in estrogen receptor (ER)-positive, HER2-negative metastatic breast cancer (MBC). Postmenopausal patients with ER-positive, HER2-negative MBC (0–1 prior chemotherapies and no prior AI for MBC) were eligible for this non-comparative, parallel group, phase-II study. Patients were randomized to letrozole (2.5 mg/day PO) alone or with dasatinib (100 mg/day PO). Patients with disease progression on letrozole alone could crossover to dasatinib plus continued letrozole. The primary endpoint was clinical-benefit-rate (CBR; complete response + partial response + stable disease ≥6 months). A total of 120 patients were randomized. The CBR of 71% (95% CI 58–83%) was observed with letrozole + dasatinib versus the projected CBR of the combination of 56%. The CBR of 66% (95% CI 52–77%) with letrozole alone also exceeded the projected CBR of 39% with letrozole alone. The CBR was 23% in the crossover arm of letrozole plus dasatinib in patients progressing on letrozole alone. Median progression-free survival with the combination was 20.1 months and 9.9 months with letrozole alone. Letrozole plus dasatinib was well tolerated, although 26% of patients required dasatinib dose reductions. In this non-comparative phase-II trial, the CBR of 71% and the median PFS of 20.1 months with letrozole + dasatinib are encouraging and suggest that dasatinib may inhibit the emergence of acquired resistance to AI therapy.

Background: Four computed tomography (CT) imaging-based clusters have been identified in a study of the Severe Asthma Research Program (SARP) cohort and have been significantly correlated with clinical and demographic metrics (J Allergy Clin Immunol 2017; 140:690–700.e8). We used a computational fluid dynamics (CFD) model to investigate air flow and aerosol deposition within imaging archetypes representative of the four clusters. Methods: CFD simulations for air flow and 1–8 μm particle transport were performed using CT-based airway models from two healthy subjects and eight asthma subjects. The subject selection criterion was based on the discriminant imaging-based flow-related variables of J(Total) (average local volume expansion in the total lung) and D(h)*(sLLL) (normalized airway hydraulic diameter in the left lower lobe), where reduced J(Total) and D(h)*(sLLL) indicate reduced regional ventilation and airway constriction, respectively. The analysis focused on the comparisons between all clusters with respect to healthy subjects, between cluster 2 and cluster 4 (nonsevere and severe asthma clusters with airway constriction) and between cluster 3 and cluster 4 (two severe asthma clusters characterized by normal and constricted airways, respectively). Results: Nonsevere asthma cluster 2 and severe asthma cluster 4 subjects characterized by airway constriction had an increase in the deposition fraction (DF) in the left lower lobe. Constricted flows impinged on distal bifurcations resulting in large depositions. Although both cluster 3 (without constriction) and cluster 4 (with constriction) were severe asthma, they exhibited different particle deposition patterns with increasing particle size. The statistical analysis showed that D(h)*(sLLL) plays a more important role in particle deposition than J(Total), and regional flow fraction is correlated with DF among lobes for smaller particles. Conclusions: We demonstrated particle deposition characteristics associated with cluster-specific imaging-based metrics such as airway constriction, which could pertain to the design of future drug delivery improvements.

Several endocrine-based therapies have recently been evaluated as treatments for premenopausal women with hormone-receptor-positive/human-epidermal-growth-factor-receptor 2 negative (HR+/HER2-) metastatic breast cancer (mBC). We conducted a systematic review and assessed the feasibility of an indirect treatment comparison (ITC) to characterize the comparative efficacy of endocrine-based therapies in this setting. A systematic literature review (SLR) of Medline, EMBASE, Cochrane Library and key conferences was performed to identify randomized clinical trials (RCTs) satisfying the following criteria: (a) included pre/perimenopausal women with HR+/HER2- mBC, (b) included endocrine-based therapies, (c) reported efficacy, safety, or quality of life outcomes, and (d) was published in 2007 or later (when HER2 testing was standardized). The clinical and methodological similarities across trials were assessed to evaluate the feasibility of an ITC. Four RCTs (PALOMA-3, MONARCH-2, KCSG BR10-04 and MONALEESA-7) and eight regimens (palbociclib + fulvestrant + goserelin, fulvestrant + goserelin, abemaciclib + fulvestrant + gonadotropin-releasing hormone agonist [GnRHa], fulvestrant + GnRHa, anastrozole + goserelin, goserelin, ribociclib + NSAI/tamoxifen + goserelin and NSAI/tamoxifen + goserelin) were selected. MONALEESA-7 was the only phase 3 trial investigating endocrine-based therapies as first-line in only pre/perimenopausal women with HR+/HER2- mBC; the other three trials focused on the ET-failure setting and their pre/perimenopausal populations were relatively small. ITCs were methodologically unfeasible due to critical differences in treatment settings and lack of common comparators across trials. Therefore, we were not able to characterize the relative efficacy of the different endocrine-based therapies available in the premenopausal HR+/HER2- mBC setting. This systematic review provides a comprehensive assessment of the available trial evidence on the efficacy and safety of endocrine-based therapies for premenopausal women with HR+/HER2- mBC. Only four trials have reported relevant data in this setting, and MONALEESA-7 is currently the only trial focused on premenopausal HR+ HER2- mBC in the first-line setting.

BACKGROUND: Whole-body MRI (WB-MRI) could be an alternative to multimodality staging of colorectal cancer, but its diagnostic accuracy, effect on staging times, number of tests needed, cost, and effect on treatment decisions are unknown. We aimed to prospectively compare the diagnostic accuracy and efficiency of WB-MRI-based staging pathways with standard pathways in colorectal cancer.METHODS: The Streamline C trial was a prospective, multicentre trial done in 16 hospitals in England. Eligible patients were 18 years or older, with newly diagnosed colorectal cancer. Exclusion criteria were severe systemic disease, pregnancy, contraindications to MRI, or polyp cancer. Patients underwent WB-MRI, the result of which was withheld until standard staging investigations were complete and the first treatment decision made. The multidisciplinary team recorded its treatment decision based on standard investigations, then on the WB-MRI staging pathway (WB-MRI plus additional tests generated), and finally on all tests. The primary outcome was difference in per-patient sensitivity for metastases between standard and WB-MRI staging pathways against a consensus reference standard at 12 months, in the per-protocol population. Secondary outcomes were difference in per-patient specificity for metastatic disease detection between standard and WB-MRI staging pathways, differences in treatment decisions, staging efficiency (time taken, test number, and costs), and per-organ sensitivity and specificity for metastases and per-patient agreement for local T and N stage. This trial is registered with the International Standard Randomised Controlled Trial registry, number ISRCTN43958015, and is complete.FINDINGS: Between March 26, 2013, and Aug 19, 2016, 1020 patients were screened for eligibility. 370 patients were recruited, 299 of whom completed the trial; 68 (23%) had metastasis at baseline. Pathway sensitivity was 67% (95% CI 56 to 78) for WB-MRI and 63% (51 to 74) for standard pathways, a difference in sensitivity of 4% (-5 to 13, p=0·51). No adverse events related to imaging were reported. Specificity did not differ between WB-MRI (95% [95% CI 92-97]) and standard pathways (93% [90-96], p=0·48). Agreement with the multidisciplinary team's final treatment decision was 96% for WB-MRI and 95% for the standard pathway. Time to complete staging was shorter for WB-MRI (median, 8 days [IQR 6-9]) than for the standard pathway (13 days [11-15]); a 5-day (3-7) difference. WB-MRI required fewer tests (median, one [95% CI 1 to 1]) than did standard pathways (two [2 to 2]), a difference of one (1 to 1). Mean per-patient staging costs were £216 (95% CI 211-221) for WB-MRI and £285 (260-310) for standard pathways.INTERPRETATION: WB-MRI staging pathways have similar accuracy to standard pathways and reduce the number of tests needed, staging time, and cost.FUNDING: UK National Institute for Health Research.

Background Eribulin mesylate is a nontaxane microtubule dynamics inhibitor approved for second-line (European Union) or third-line (United States) treatment of metastatic breast cancer. Two phase 2 single trials, evaluating first-line eribulin as monotherapy (Study 206; NCT01268150) or in combination with trastuzumab (Study 208; NCT01269346) in locally recurrent or metastatic breast cancer, demonstrated objective response rates of 28.6 and 71.2%, respectively. Median progression-free survival was 6.8 and 11.6 months, respectively. Tolerability profiles were similar to those from previous studies. This secondary analysis was conducted to assess health-related quality of life (HRQoL) in both phase 2 trials. Methods Patients received eribulin mesylate 1.4 mg/m2 intravenously on days 1 and 8 of each 21-day cycle. Patients in Study 208 also received intravenous trastuzumab on day 1 of each cycle (8 mg/kg in cycle 1, then 6 mg/kg). HRQoL was assessed by the European Organization for Research and Treatment of Cancer Quality-of-Life (QLQ-C30) assessment tool and the Quality-of-Life Questionnaire for Breast Cancer (QLQ-BR23) at baseline and cycles 2, 4, and 6. Results for clinically meaningful changes were based on previously published minimum important differences. Results Of the 108 patients (56 in Study 206 and 52 in Study 208) treated, 57 and 87%, respectively, completed 6 cycles. Completion rates for both questionnaires were 94 and 98%, respectively, at cycle 6. Most patients had stable/improved HRQoL scores with some exceptions; for example, more patients experienced a worsening in cognitive functioning and systemic therapy side effects than experienced improvement. Mean QLQ-C30 symptom scores correlated with corresponding adverse event rates for nausea/vomiting, dyspnea, appetite loss, constipation, and diarrhea in Study 206 and for fatigue, nausea/vomiting, pain, dyspnea, insomnia, constipation, and diarrhea in Study 208. Conclusions First-line eribulin ± trastuzumab therapy did not lead to deterioration of overall HRQoL in most patients, with more than 60% of patients having stable/improved global health status/quality-of-life scores. Eribulin has been demonstrated to be comparable with other chemotherapy agents with an acceptable safety profile. Therefore, further evaluation is warranted to determine whether eribulin ± trastuzumab therapy may be a potential option for first-line treatment in some patients with metastatic breast cancer who were recently treated in the neoadjuvant setting. Trial registration NCT01268150 (December 29, 2010), NCT01269346 (January 4, 2011) Electronic supplementary material The online version of this article (10.1186/s12885-019-5674-5) contains supplementary material, which is available to authorized users.

Eribulin is a novel microtubule inhibitor with mitotic and nonmitotic mechanisms of action. Both pooled and subgroup analyses from large-scale Phase III clinical trials demonstrated that eribulin has substantial activity in patients with pretreated (anthracycline and a taxane) advanced or metastatic breast cancer. We review recent pharmacological and clinical findings pertaining to eribulin use in metastatic breast cancer – particularly highlighting eribulin in difficult-to-treat and aggressive disease, and safety data in specific patient populations. Additionally, recent advancements in our understanding of the mechanism of action of eribulin and potential future directions for its clinical development are discussed. Ongoing studies of eribulin in combination with immunotherapies and established cytotoxic agents may help shape the future landscape of breast cancer treatment.

Background Mammalian target of rapamycin (mTOR) inhibitor-associated stomatitis (mIAS) is a frequent adverse event (AE) associated with mTOR inhibitor therapy and can impact treatment adherence. The objectives are to evaluate two steroid-based mouthrinses for preventing/ameliorating mIAS in patients with metastatic breast cancer (MBC) treated with everolimus. Materials and Methods This prospective, randomized phase II study enrolled 100 postmenopausal patients with hormone receptor-positive MBC within the US Oncology Network who were initiating therapy with an aromatase inhibitor + everolimus (AIE; 10 mg/day). Patients were randomized to prophylactic therapy with one of two oral rinses (Arm 1: Miracle Mouthwash [MMW] 480 mL recipe: 320 mL oral Benadryl [diphenhydramine; Johnson & Johnson, New Brunswick, NJ, USA], 2 g tetracycline, 80 mg hydrocortisone, 40 mL nystatin suspension, water; or Arm 2: prednisolone [P] 15 mg/5 mL oral solution, 1.8% alcohol). Patients were instructed to swish/expectorate 10 mL of the assigned rinse for 1–2 minutes four times daily starting with day 1 of AIE treatment, for the first 12 weeks. Results A total of 100 patients received treatment (49 MMW; 51 P). The incidence of stomatitis/oral AEs during the first 12 weeks was 35% (n = 17/49) and 37% (19/51) in the MMW and P arms, respectively. The incidence of grade 2 oral AEs was 14% (7/49) and 12% (6/51) with MMW or P, respectively. There were two grade 3 oral AEs (MMW arm) and no grade 4 events. There was one everolimus dose reduction (MMW) and six dose delays (four MMW, two P) and one dose reduction + delay (MMW) during the first 12 weeks of treatment. No patients stopped steroid mouthwash therapy because of rinse-related toxicity. Conclusion Prophylactic use of steroid-containing oral rinses can prevent/ameliorate mIAS in patients with MBC treated with AIE. MMW + hydrocortisone is an affordable option, as is dexamethasone oral rinse. Implications for Practice This prospective phase-II study showed that two steroid-containing mouthrinses substantially reduced incidences of all-grade and grade ≥2 stomatitis and related oral adverse events (AEs), and the number of everolimus dose-delays and/or dose-reduction in metastatic breast cancer (MBC) patients receiving everolimus treatment plus an aromatase inhibitor. Both oral rinses were well tolerated and demonstrated similar efficacy. Prophylactic use of steroid mouth rinse provides a cost-effective option that substantially decreases the incidence and severity of mammalian target of rapamycin (mTOR) inhibitor-associated stomatitis and related oral AEs as well as the need for dose modification in MBC patients undergoing treatment with an mTOR inhibitor.

Cortical heterotopias are clusters of ectopic neurons in the brain and are associated with neurodevelopmental disorders like epilepsy and learning disabilities. We have previously characterized the robust penetrance of a heterotopia in a rat model, induced by thyroid hormone (TH) disruption during gestation. However, the specific mechanism by which maternal TH insufficiency results in this birth defect remains unknown. Here we first determined the developmental window susceptible to endocrine disruption and describe a cellular mechanism responsible for heterotopia formation. We show that five days of maternal goitrogen treatment (10 ppm propylthiouracil) during the perinatal period (GD19-PN2) induces a periventricular heterotopia in 100% of the offspring. Beginning in the early postnatal brain, neurons begin to aggregate near the ventricles of treated animals. In parallel, transcriptional and architectural changes of this region were observed including decreased Sonic hedgehog (Shh) expression, abnormal cell adhesion, and altered radial glia morphology. As the ventricular epithelium is juxtaposed to two sources of brain THs, the cerebrospinal fluid and vasculature, this progenitor niche may be especially susceptible to TH disruption. This work highlights the spatiotemporal vulnerabilities of the developing brain and demonstrates that a transient period of TH perturbation is sufficient to induce a congenital abnormality.