Stratified Cox Proportional Hazards Model Research Articles

Association between centrally active angiotensin‐converting enzyme inhibitors with dementia risk

AbstractBackgroundHypertension is a well‐established risk factor for dementia and antihypertensive treatments could be important for disease prevention. Observational and animal studies suggest Angiotensin‐Converting Enzyme Inhibitors (ACEIs) are associated with reduced dementia risk whereas genetic studies show these drugs increase risk. One plausible explanation of this heterogeneity is that not all ACEIs cross the blood–brain barrier (BBB) and their association with disease risk may depend on whether or not the specific molecule crosses the blood brain barrier. We investigated the association of centrally vs non‐centrally active ACEIs with incident dementia compared using medical records from the USA (OPTUM).MethodsThis is a retrospective new‐user comparative cohort study using patients ≥50 years old with hypertension who were new users of centrally active ACEIs (captopril, fosinopril, lisinopril, perindopril, ramipril, trandolapril; n = 327,663 or non‐centrally active ACEIs (n = 30,867) (benazepril, enalapril, moexipril, quinapril). Patients were followed for up to 10 years (2006‐2018) during which 11,422 dementia cases were diagnosed. Stratified Cox proportional hazards models were used to estimate the hazard ratio (HR) of incidence all‐cause dementia and sub types over the follow up period, controlling for age, demographics such as geographic location and other comorbidities such as stroke, myocardial infarction and diabetes.ResultsIn unadjusted and adjusted models, new users of centrally active ACEIs had a slightly greater risk for all cause dementia and vascular dementia but not for Alzheimer’s disease. HR for unadjusted models were 1.08 (95% CI 1.01‐1.15), 1.34 (95% CI 1.13‐1.60) and 1.00 (95% CI 0.90‐1.12) for all cause dementia, vascular dementia and Alzheimer’s disease respectively. Whereas HR for adjusted models for all cause dementia, vascular dementia and Alzheimer’s disease were 1.16 (95% CI 1.09‐1.24), 1.35 (95% CI 1.12‐1.62) and 1.10 (95% CI 0.98‐1.23) respectively.ConclusionsOur results potentially indicate centrally active ACEIs are associated with a slightly higher risk of all‐cause dementia compared to non‐centrally active ACEIs. This work supports causal genetics studies which indicate links between ACE inhibitors in the brain with increased dementia risk. Future work will investigate whether other antihypertensive drug classes differ in risk based on blood brain barrier penetrating ability.

OS analysis of patients with different short-term response and progression patterns of donafenib versus sorafenib as first-line therapy for advanced hepatocellular carcinoma: An exploratory subgroup analysis of ZGDH3.

e16143 Background: Donafenib, a deuterated derivative of sorafenib, significantly prolonged overall survival (OS) in patients with advanced hepatocellular carcinoma in an open, randomized, parallel-controlled phase II/III trial (ZGDH3) compared with sorafenib. The purpose of this study was to explore and analyse the OS benefits of donafenib and sorafenib treatment in patients with different short-term response and progression patterns. Methods: This analysis was based on the ITT population of ZGDH3 study (defined as all randomized patients). The median OS of donafenib and sorafenib was assessed by the Kaplan-Meier method and was compared according to different short-term response (SD, others) and progression patterns (intrahepatic lesion growth, intrahepatic new lesion, extrahepatic lesion growth, extrahepatic new lesion). The stratified Cox proportional hazard model was used to calculate the hazard ratio and its 95% confidence interval. Results: 668 patients were included in the analysis (334 in each group). Donafenib was associated with a trend of improved OS benefit when compared with sorafenib in most subgroups (HR < 1), including best short-term response of SD or others, confirmed short-term response of SD or others, intrahepatic lesion growth or not, intrahepatic new lesion or not, extrahepatic new lesion or not, no extrahepatic lesion growth. The benefit was statistically significant in the following subgroups: in patients with response of SD, the mOS of donafenib and sorafenib were 19.3 and 15.5 months, respectively (HR 0.714, 95%CI 0.550-0.928). Among patients with confirmed response of SD, the mOS was 29.0 and 22.8 months, respectively (HR 0.641, 95% CI 0.418-0.983). Among patients without extrahepatic lesion growth (defined as lesion growth ≥20% from baseline), the mOS was 12.6 months and 10.0 months, respectively (HR 0.783, 95% CI 0.648-0.945). Among patients without new extrahepatic lesions, the mOS was 13.1 months and 11.0 months (HR 0.816, 95% CI 0.677-0.998), respectively. Conclusions: Donafenib exhibited better survival benefit than sorafenib in most subgroups, especially in patients with the best response and confirmed best response of SD, which further confirmed the excellent efficacy of donafenib in first-line treatment of advanced HCC. Clinical trial information: NCT02645981 . [Table: see text]

Development and validation of a prediction model for the recurrence of stage 1 EGFR mutation positive NSCLC in patients using machine learning with WES-based gene sets.

8563 Background: Predicting the risk of postoperative recurrence is becoming increasingly important in EGFR mutation positive ( EGFR-m) non-small cell lung cancer (NSCLC). Only a few reports conducted whole exome sequencing (WES) for genomic profiling in large scale EGFR-m NSCLC cases. Methods: We conducted WES and analyzed the clinical course of patients (pts) with NSCLC who underwent surgery between 1985 and 2019 in the PRISM project of our institute. We evaluated the EGFR-m patients’ characteristics, recurrence-free survival (RFS), and developed a prediction model using machine learning, Overlapping Group LASSO to predict whether the EGFR-m patients will recur within 5 years or not as "high-risk" and "low-risk". To develop and validate the prediction model, we divided the data from 2006 as the training cohort data set and the data before 2006 as the validation cohort data set. After the development of the prediction model, we performed a stratified Cox proportional hazards model to compare the RFS between the predicted groups. Results: A total of 585/1351(43.3%) pts were EGFR-m included in the PRISM project. Of all pts, stage I, EGFR-m were 205 pts. The median RFS of the stage I, EGFR-m 123.1 months (m). In the training cohort, the model detected 43 pts for high-risk and 88 pts for low-risk. In the validation cohort, the model predicted 29 pts for high-risk and 45 pts for low-risk. Median RFS of high-risk vs. low-risk were 52.2 m vs. 105 m (HR 2.43, p=0.01). The 1-year RFS rate, 2-year RFS rate, and 5-year RFS rates for high-risk and low-risk pts were 100% vs. 98.5%, 66.7% vs. 89.2%, and 41.7% vs. 66.1%, respectively. Twenty-eight gene set coefficients were non-zero in the prediction model. The gene sets with large positive coefficients that were considered important for prediction as "high risk" were the gene sets affected by KRAS gene overexpression and p53 gene knockdown. In contrast, gene sets repressed by mTOR inhibition and genes repressed by TBK1 gene knockdown and KRAS gene overexpression had large negative coefficients. Conclusions: We developed and validated the prediction model whether the EGFR-m patients will recur within 5 years or not. EGFR-m NSCLC recurrence appears to be high risk with pathways associated with KRAS and p53 genes, and low risk with mutations in the gene sets suppressed by the mTOR pathway and TBK1 gene. [Table: see text]

Deutenzalutamide, an oral deuterated androgen receptor inhibitor, vs placebo for patients with mCRPC who have experienced treatment failure with abiraterone and docetaxel: Results of the HC-1119-04 phase 3 trial.

5065 Background: Deutenzalutamide (HC-1119) is a novel deuterated derivative of enzalutamide with a different metabolic profile while maintaining biologic activity at a lower dose. Abiraterone and docetaxel are widely used in mCRPC, however, resistance mechanisms eventually occur. Methods: The HC-1119-04 (NCT03851640), a multicenter, randomized, double-blind phase 3 trial in China enrolled patients with mCRPC who have failed abiraterone, or failed or were not eligible for docetaxel. Patients were randomized 2:1 to deutenzalutamide (80 mg orally daily) or placebo. Stratification factors included lesion site (visceral/non-visceral), prior docetaxel treatment (yes/no). The primary endpoint was investigator-assessed radiographic PFS. Secondary endpoints included: OS, independent radiologic review committee (IRC)-assessed rPFS, ORR, and PSA response. The hazard ratio (HR) and its 95% confidence interval (CI) between the two groups were calculated using a stratified Cox proportional hazards model. Results: The HC-1119-04 study enrolled 417 subjects between April 2019 – Nov 2021, with 276 randomized to deutenzalutamide and 141 to placebo. Demographics and disease characteristics were well-balanced across treatment arms. All subjects were previously treated with abiraterone. Most of the subjects received docetaxel (68.8% vs. 68.1%); visceral lesions accounted for 27.9% in the deutenzalutamide and 27.7% in the placebo group. The study met its primary endpoint with a 42% reduction in the risk of progression or death in the deutenzalutamide arm (HR = 0.58 [95% CI: 0.439, 0.770]; P= 0.001. The median rPFS (95% CI) was 5.55 (4.830, 7.360) months for deutenzalutamide vs 3.71 (2.860, 5.490) months for placebo. Results in the pre-specified subgroups, including visceral metastases, and prior docetaxel were consistent with the overall outcome. The median OS (95% CI) was 14.98 (9.560, -) months and 11.24 (9.890, 15.510) months in the deutenzalutamide and placebo group, respectively, with an HR (95% CI) of 0.88 (0.577, 1.331). Common treatment-related adverse events (TEAE) ( > 10%) with deutenzalutamide vs placebo included: weight decreased (23.4% vs 18.6%), platelet count decreased (12.8% vs 10.7%), lymphocyte count decreased (10.2% vs 7.9%), and hypercholesterolemia (10.9% vs 4.3%), mostly grade 1/2. The overall incidence of ≥ Grade 3 study drug related TEAEs in the deutenzalutamide group was not significantly different from placebo, except anemia (6.6% vs 2.9%) and hypertension (2.2% vs 0.7%). Conclusions: Deutenzalutamide demonstrated a statistically significant improvement of PFS vs placebo in a randomized phase 3 study in patients with mCRPC who have failed abiraterone, and who failed or were intolerant to docetaxel. Deutenzalutamide was well tolerated and has the potential as additional treatment option. Clinical trial information: NCT03851640 .

Health-related quality of life (HRQoL) in the phase 3 KEYNOTE-966 study of pembrolizumab (pembro) plus gemcitabine and cisplatin (gem/cis) versus placebo plus gem/cis for advanced biliary tract cancer (BTC).

4003 Background: In the randomized, double-blind, phase 3 KEYNOTE-966 trial (N = 1069; NCT04003636), pembro + gem/cis significantly improved OS versus placebo + gem/cis (HR 0.83; 95% CI 0.72-0.95; P = 0.0034) and had an expected and manageable safety profile as first-line therapy for unresectable locally advanced or metastatic BTC. We present the protocol-specified exploratory patient-reported outcomes (PROs) from KEYNOTE-966. Methods: PROs were assessed using the EORTC QLQ-C30, EORTC QLQ-BIL21, and EQ-5D-5L questionnaires. The analysis population included all treated patients (pts) who completed ≥1 HRQoL assessment for the specific endpoint. A constrained longitudinal analysis model (covariates: treatment, time, treatment by time interaction, and stratification factors) was used to compare least squares mean (LSM) score changes from baseline (BL) to wk 18 (ie, latest timepoint that completion was ≥60% and compliance was ≥80%) in QLQ-C30 global health status (GHS)/QoL, physical functioning (PF), and role functioning (RF), QLQ-BIL21 jaundice and pain, and EQ-5D-5L visual analogue scale (VAS). A stratified Cox proportional hazards model was used to assess the magnitude of the between-arm difference in time to deterioration (TTD) in GHS/QoL, PF, RF, jaundice, and pain (ie, time to first onset of ≥10-point deterioration from BL in each scale/subscale confirmed by ≥10-point deterioration from BL at the next visit; established as clinically relevant). Results: Questionnaire compliance was >87% from BL to wk 18 in both arms. LSM changes from BL to wk 18 in QLQ-C30 GHS/QoL, PF, and RF, QLQ-BIL21 jaundice and pain, and EQ-5D-5L VAS were similar between arms. Time to deterioration was also similar between arms: median not reached (NR) vs 21.2 mo for GHS/QoL (HR 0.86, 95% CI 0.70-1.07), NR vs 12.0 mo for PF (HR 0.95, 95% CI 0.78-1.17), 6.5 mo vs 5.8 mo for RF (HR 0.98, 95% CI 0.81-1.18), NR vs NR for jaundice (HR 1.20, 95% CI 0.94-1.54), and NR vs NR for pain (HR 0.79, 95% CI 0.59-1.05). Conclusions: HRQoL was maintained when pembro was added to gem/cis. Together with the efficacy and safety data, these results support pembro + gem/cis as a new first-line treatment option for advanced BTC. Clinical trial information: NCT04003636 . [Table: see text]

Persistent symptoms and risk factors predicting prolonged time to symptom-free after SARS‑CoV‑2 infection: an analysis of the baseline examination of the German COVIDOM/NAPKON-POP cohort

PurposeWe aimed to assess symptoms in patients after SARS-CoV-2 infection and to identify factors predicting prolonged time to symptom-free.MethodsCOVIDOM/NAPKON-POP is a population-based prospective cohort of adults whose first on-site visits were scheduled ≥ 6 months after a positive SARS-CoV-2 PCR test. Retrospective data including self-reported symptoms and time to symptom-free were collected during the survey before a site visit. In the survival analyses, being symptom-free served as the event and time to be symptom-free as the time variable. Data were visualized with Kaplan–Meier curves, differences were tested with log-rank tests. A stratified Cox proportional hazard model was used to estimate adjusted hazard ratios (aHRs) of predictors, with aHR < 1 indicating a longer time to symptom-free.ResultsOf 1175 symptomatic participants included in the present analysis, 636 (54.1%) reported persistent symptoms after 280 days (SD 68) post infection. 25% of participants were free from symptoms after 18 days [quartiles: 14, 21]. Factors associated with prolonged time to symptom-free were age 49–59 years compared to < 49 years (aHR 0.70, 95% CI 0.56–0.87), female sex (aHR 0.78, 95% CI 0.65–0.93), lower educational level (aHR 0.77, 95% CI 0.64–0.93), living with a partner (aHR 0.81, 95% CI 0.66–0.99), low resilience (aHR 0.65, 95% CI 0.47–0.90), steroid treatment (aHR 0.22, 95% CI 0.05–0.90) and no medication (aHR 0.74, 95% CI 0.62–0.89) during acute infection.ConclusionIn the studied population, COVID-19 symptoms had resolved in one-quarter of participants within 18 days, and in 34.5% within 28 days. Over half of the participants reported COVID-19-related symptoms 9 months after infection. Symptom persistence was predominantly determined by participant’s characteristics that are difficult to modify.

Markers of imminent myocardial infarction

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – EU funding. Main funding source(s): AFA Insurance and the European Commission Seventh Framework Programme. Background and Purpose Myocardial infarction is a leading cause of death globally, but is notoriously difficult to predict. While most studies to date have considered long timeframes for etiological and prediction models, we aimed to identify biomarkers of an imminent first myocardial infarction and design relevant prediction models. Methods We used a novel case–cohort consortium of 2018 persons without prior cardiovascular disease (420 cases, 1598 subcohort representatives) from six European cohorts. We investigated associations of 817 proteins, 1025 metabolites, and 16 clinical variables at baseline with subsequent risk of a first myocardial infarction within 6 months after baseline. Associations in weighted, stratified Cox proportional hazards models that passed multiple testing bounds in the discovery sample were verified in an independent validation sample. We also developed a prediction model for clinical use. Results Forty-eight proteins, 43 metabolites, age, sex, and systolic blood pressure were associated with risk of an imminent first myocardial infarction in models adjusted for technical covariates only (Figure 1). Brain natriuretic peptide (BNP) was most consistently associated with imminent myocardial infarction risk, in models adjusting for additional covariates including age and sex. Using clinically readily available variables, we devised a prediction model (Figure 2) with good ability to discriminate between subsequent cases and non-cases (cross-validated C-index 0.78) to which the addition of BNP did not improve performance. Conclusion We found 94 biomarkers associated with risk of a first myocardial infarction within 6 months in persons without prior cardiovascular disease, and devised a prediction model with good discriminative ability for an imminent first myocardial infarction in the general population, with potential for motivating primary prevention efforts.

Chronic disease management program applied to type 2 diabetes patients and prevention of diabetic complications: a retrospective cohort study using nationwide data

BackgroundThe outcomes of education and counseling by medical professionals for patients with type 2 diabetes mellitus (T2DM) are unclear. This study examined the effects of the Chronic Disease Management Program (CDMP), a health insurance fee-for-service benefit, on the incidence of diabetic complications in patients newly diagnosed with T2DM using the National Health Insurance data.MethodsPatients newly diagnosed with T2DM aged ≥ 20 years from 2010 to 2014 were followed up until 2015. Selection bias was minimized using propensity score matching. A stratified Cox proportional hazards model was used to analyze the association between the CDMP and the risk of incident diabetic complications. Subgroup analysis was performed for patients with high medication adherence, which was indicated by a medication possession ratio (MPR) ≥ 80.ResultsAmong the 11,915 patients with T2DM in the cohort, 4,617 were assigned to the CDMP and non-CDMP group each. The CDMP helped reduce the overall and microvascular risks of complications compared to the non-CDMP group; however, the protective effect against macrovascular complications was only observed in those aged ≥ 40 years. Subgroup analysis of the group aged ≥ 40 years with high adherence (an MPR ≥ 80) showed that the CDMP effectively reduced the incidence of micro- and macrovascular complications.ConclusionsEffective management of T2DM is crucial in preventing complications in patients with the condition, and includes regular monitoring and adjustment of treatment by qualified physicians. Nevertheless, long-term prospective studies on the effects of CDMP are required to confirm this finding.

School achievement in adolescence and the risk of mental disorders in early adulthood: a Finnish nationwide register study

School grades in adolescence have been linked to later psychiatric outcomes, but large-scale nationwide studies across the spectrum of mental disorders are scarce. In the present study, we examined the risk of a wide array of mental disorders in adulthood, as well as the risk of comorbidity, associated with school achievement in adolescence. We used population-based cohort data comprising all individuals born in Finland over the period 1980–2000 (N = 1,070,880) who were followed from age 15 or 16 until a diagnosis of mental disorder, emigration, death, or December 2017, whichever came first. Final grade average from comprehensive school was the exposure, and the first diagnosed mental disorder in a secondary healthcare setting was the outcome. The risks were assessed with Cox proportional hazards models, stratified Cox proportional hazard models within strata of full-siblings, and multinomial regression models. The cumulative incidence of mental disorders was estimated using competing risks regression. Better school achievement was associated with a smaller risk of all subsequent mental disorders and comorbidity, except for eating disorders, where better school achievement was associated with a higher risk. The largest associations were observed between school achievement and substance use disorders. Overall, individuals with school achievement more than two standard deviations below average had an absolute risk of 39.6% of a later mental disorder diagnosis. By contrast, for individuals with school achievement more than two standard deviations above average, the absolute risk of a later mental disorder diagnosis was 15.7%. The results show that the largest mental health burden accumulates among those with the poorest school achievement in adolescence.

Association between SARS-CoV-2 infection and newly diagnosed hypertension during pregnancy: prospective, population based cohort study

ObjectiveTo study the association between SARS-CoV-2 infection and newly diagnosed hypertension during pregnancy.DesignProspective, population based cohort study.SettingAll singleton pregnancies after 22 completed gestational weeks registered in the Swedish Pregnancy Register...

Bidirectional association between Parkinson's disease and obstructive sleep apnea: a cohort study.

Chronic intermittent hypoxia due to obstructive sleep apnea (OSA) causes oxidative stress, which may contribute to the pathophysiology of Parkinson's disease (PD). However, the bidirectional relationship between PD and OSA has not been satisfactorily established. The objective of this study was to try to estimate whether there is a bidirectional relationship between PD and OSA through a retrospective cohort study in the South Korean population. This study used data from the Korean National Health Information Database of the National Health Insurance Service, which contains data from 3.5 million individuals evenly distributed. In study 1, patients with OSA were matched in a 1:2 ratio with non-OSA controls. In study 2, patients with PD were matched in a 1:2 ratio with non-PD controls. A stratified Cox proportional hazards model was used to calculate hazard ratios. In study 1, which included 6,396 patients with OSA and 12,792 non-OSA controls, the incidence of PD per 10,000 person-years was 11.59 in the OSA group and 8.46 in the non-OSA group. The OSA group demonstrated a 1.54-fold higher incidence of PD than the non-OSA group (95% confidence interval, 1.14-2.07; P < .05). In study 2, which included 3,427 patients with PD and 6,854 non-PD controls, the incidence of OSA per 10,000 person-years was 14.97 in the PD group and 7.72 in the non-PD group. The PD group demonstrated a 1.92-fold higher incidence of OSA than the non-PD group (95% confidence interval, 1.32-2.78; P < .05). This study supports a possible bidirectional relationship between PD and OSA. Jeon S-H, Hwang YS, Oh S-Y, etal. Bidirectional association between Parkinson's disease and obstructive sleep apnea: a cohort study. J Clin Sleep Med. 2023;19(9):1615-1623.

Abstract GS5-10: Utility of the 70-gene MammaPrint test for prediction of extended endocrine therapy benefit in patients with early-stage breast cancer in the IDEAL Trial

Abstract Background: The IDEAL trial showed no significant benefit of 5 years extended endocrine therapy (EET) using letrozole in postmenopausal patients with hormone receptor positive (HR+) breast cancer (BC) versus 2.5 years. Genomic classifiers may assist with treatment decisions by predicting EET benefit. The 70-gene MammaPrint (MP) test classifies tumors as having a higher or lower risk of distant metastasis in HR+ early-stage BC. A MP lower risk result can be further classified as either Ultra-Low risk or Low risk of distant metastasis. In the NSABP B42 trial, MP predicted a statistically significant absolute benefit from EET in patients with a MP Low Risk result. Here, we aimed to determine the utility of MP in identifying a subgroup of patients enrolled in the IDEAL trial for which 5 years of EET is beneficial compared to 2.5 years. Methods: A total of 869 patients had available primary tumor tissue for testing. MP results were available for 545/869 patients, of which 515 did not have an event at 2.5 year after randomization and were used for our analyses. The MP result for each patient was calculated by Agendia while blinded to patient clinical outcomes. The primary endpoint was distant recurrence (DR). Secondary endpoints were recurrence free interval (RFI) and breast cancer free interval (BCFI) as defined by STEEP criteria. Patients were classified as higher risk (score -1.000 - 0) or lower risk (score 0.001 - 1.000). Lower risk tumors were further classified as either MP Ultra-Low (score &amp;gt; 0.355) or MP Low Risk (score ≥ 0.001, ≤ 0.355). Likelihood ratio test based on stratified Cox proportional hazards (PH) model were used to evaluate treatment by risk group interaction. Differences in endpoints between treatment groups were assessed by stratified log-rank tests. Hazard ratios (HR) and 95% Confidence Intervals (CI) were computed based on the stratified Cox PH model. Results: The clinical characteristics of the 515 IDEAL samples with a MP result were comparable to the whole IDEAL cohort (n=1820). Within the 2.5 year EET group, 50.6% (n=134) were MP higher risk and 49.4% (n=131) MP lower risk, of which 14.5% (n=19/131) were MP Ultra-Low. Within the 5 year EET group, 50.0% (n=125) were MP higher risk and 50.0% (n=125) MP lower risk, of which 11.2% (n=14/125) were MP Ultra-Low. Among patients with MP lower risk tumors, 5 years vs. 2.5 years of EET resulted in a significant absolute benefit of 9.8% for DR (HR=0.42, [95% CI 0.174-0.996]), 9.8% for RFI (HR=0.43, [95% CI 0.198-0.934]), and 8.8% (HR=0.53, [95% CI 0.264-1.055]) for BCFI, whereas patients with MP higher risk tumors did not derive significant benefit (Table 1). Within the MP lower risk group, 5 year vs 2.5 year EET benefit was more pronounced in MP Low tumors, which exhibited a significant benefit of 10.1% for DR (HR=0.32, [95% CI 0.116-0.866]), 11.7% for RFI (HR=0.35, [95% CI 0.147-0.824]), and 9.7% for BCFI (HR=0.48, [95% CI 0.225-1.015]); MP Ultra Low tumors did not derive significant benefit. Treatment-by-risk group interaction was statistically significant for RFI. Conclusion: A significant EET benefit was observed for MammaPrint lower risk tumors but not for MP higher risk tumors. MammaPrint Low tumors exhibited the largest absolute benefit of 5 years of EET compared to 2.5 years. Consistent with the findings in the NSABP B42 trial, the results from this second randomized trial provide clinically meaningful implications in patient selection for extended endocrine therapy. Table 1. IDEAL: 10-year outcome analysis comparing 5 years vs. 2.5 years of EET using letrozole stratified by MP risk. **MammaPrint Lower Risk &amp; Higher Risk (n=515) and *** MammaPrint Low Risk &amp; High Risk (n=482) Citation Format: Gerrit-Jan Liefers, Elma Meershoek-Klein Kranenbarg, Marjolijn Duijm-de Carpentier, Cornelis J.H. van de Velde, Miranda Kleijn, Christa Dreezen, Andrea Menicucci, Laura van’t Veer, William Audeh. Utility of the 70-gene MammaPrint test for prediction of extended endocrine therapy benefit in patients with early-stage breast cancer in the IDEAL Trial [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr GS5-10.

Abstract PD13-11: PD13-11 Final Overall Survival Analysis of Monarch 2 : A Phase 3 trial of Abemaciclib Plus Fulvestrant in Patients with Hormone Receptor-Positive, HER2-Negative Advanced Breast Cancer

Abstract Background Abemaciclib is approved for patients (pts) with hormone receptor-positive (HR+), HER2-negative (HER2-) advanced breast cancer (ABC) with progression on prior endocrine therapy (ET). The MONARCH 2 trial showed a statistically significantly benefit in progression-free survival (PFS) (hazard ratio [HR]: 0.553; 95% CI: 0.449-0.681; p &amp;lt; 0.001), overall survival (OS) (HR: 0.757; 95% CI: 0.606-0.945; p = 0.01) and a manageable safety profile for abemaciclib plus fulvestrant compared with fulvestrant alone. Here we report the pre-specified final overall survival (OS) analysis from the MONARCH 2 trial (NCT02107703). Methods MONARCH 2 was a global, randomized, placebo-controlled, double-blind phase 3 trial of abemaciclib or placebo, plus fulvestrant for treatment of pre-, peri- or postmenopausal women with CDK 4 &amp; 6 inhibitor naïve HR+, HER2- ABC that progressed during ET. Pts were randomized 2:1 to receive abemaciclib or placebo, 150 mg twice daily, plus fulvestrant. Randomization was stratified based on site of metastasis (visceral, bone only, or other) and resistance to prior ET (primary versus secondary). OS and safety were key secondary endpoints, and chemotherapy-free survival was an exploratory endpoint defined as the time from randomization to initiation of chemotherapy or death, whichever occurs the earliest. Kaplan-Meier (KM) method was used to analyze time-to-event variables. A stratified Cox proportional hazards model was used to estimate treatment effect hazard ratio (HR). The prespecified final analysis was planned to occur based on approximately 441 OS events. Data cutoff was March 18, 2022. Results 669 women were randomized 2:1 to receive abemaciclib (n = 446) or placebo (n = 223), plus fulvestrant. Baseline characteristics have been previously reported (Sledge et. al., Jama Oncol 2020). The median follow-up time was approximately 80 months and at the time of the data cutoff, 11% of pts were still receiving study drug in the abemaciclib arm versus 2% in the placebo arm. 440 OS events were observed in the ITT population (abemaciclib arm: 283 events; placebo arm: 157 events). The median OS was 45.8 months in the abemaciclib arm and 37.2 months in the placebo arm (HR: 0.784; 95% CI: 0.644-0.955). The maintained separation of the KM curves beyond the medians is illustrated by the differences in the estimated 5- and 6-year OS rates between arms (5-year: 41.2% versus 29.2%; 6-year: 34.7% versus 23.7%; abemaciclib versus placebo respectively). While OS benefit was generally consistent across subgroups, a more pronounced benefit is noted in subgroups associated with a poorer prognosis such as visceral disease (HR: 0.643; 95% CI: 0.499-0.829), primary resistance to ET (HR: 0.634; 95% CI: 0.436-0.922) or negative progesterone receptor status (HR: 0.623; 95% CI: 0.405-0.959). Moreover, the addition of abemaciclib to fulvestrant deferred the initiation of chemotherapy (HR: 0.674; 95% CI: 0.562-0.809), with substantial difference in yearly chemotherapy-free survival rates (3 year: 42% vs 29.3%; 4 year: 37% vs 18.6%; 5 year: 32.4% vs 14.7%). Notably with longer exposure to abemaciclib, no new additional safety risks or cumulative toxicities were identified. Conclusions At the prespecified final OS analysis of the MONARCH 2 trial, with a median follow-up of 6.5 years, the statistically significant benefit previously demonstrated was confirmed and maintained. OS benefit was generally consistent across subgroups, with numerically greater effect size observed among patients with poorer prognosis. Importantly, the survival benefit came with a substantial extension of the chemotherapy-free survival time, which is an important consideration for pts with ABC. The results also provide assurance of the safety of abemaciclib with longer-term use. Citation Format: Antonio Llombart-Cussac, George Sledge, Masakazu Toi, Patrick Neven, Joo Hyuk Sohn, Kenichi Inoue, Xavier Pivot, Meena Okera, Norikazu Masuda, Peter A. Kaufman, Han Koh, Eva-Maria Grischke, PierFranco Conte, Valerie Andre, Yuanyuan Bian, Ashwin Shahir, Gertjan van Hal. PD13-11 Final Overall Survival Analysis of Monarch 2 : A Phase 3 trial of Abemaciclib Plus Fulvestrant in Patients with Hormone Receptor-Positive, HER2-Negative Advanced Breast Cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD13-11.

Abstract P4-07-01: Overall survival with locoregional surgery in de novo metastatic breast cancer

Abstract Background: Breast cancer remains the most frequent type of cancer in women, with de novo metastatic breast cancer (dnMBC) accounting for approximately 6-10% of patients. Advances in treatment of dnMBC have led to an increase in overall survival (OS), but the role of locoregional surgery remains unclear. Aim: To determine the value of locoregional surgery compared with no surgery on OS of women with dnMBC Settings and design: This study was designed as a randomized clinical study and was approved by the Ethics Committee of the Ethics Committee of Cangzhou Clinical College of Integrated Traditional Chinese and Western Medicine of Hebei Medical University (NO.20200212). Methods: Patient characteristics were previously reported in ASCO2022. Eighty-six patients with dnMBC were randomised to surgery of the primary tumor followed by systemic therapy (surgery group) or to primary systemic therapy without surgery (non-surgery group), by a computer generated block randomisation sequence. Randomisation was stratified by site of distant metastases, number of metastatic lesions, and molecular subtypes. Follow-up visits were conducted during treatment, monthly in first year, every 3 months thereafter. The primary endpoint was overall survival analysed by intention to treat. The stratified log-rank test and Cox proportional hazards model were used to compare OS between groups. The level for significance was set at p&amp;lt; 0.05. All analyses were performed with STATA 17. Results: Between Jan 3, 2019, and Mar 29, 2021, of the 103 women presenting with dnMBC, we randomly assigned 86 patients: 44 to surgery of the primary tumor followed by systemic therapy and 42 to primary systemic therapy without surgery. At data cut-off of Dec 1, 2021, median follow-up was 27 months with 44 deaths (surgery group n=21, non-surgery group n=23). The 2-year OS was 45.2% without and 52.3% with locoregional surgery (hazard ratio=0.59; 95% CI, 0.32 to 1.12; p = 0.11). The median OS was 25.5 months (95% CI, 23.52 to 29.38) in non-surgery group and 33 months (95% CI, 27.43 to 34.53) in surgery group. Conclusions: Our prospective randomized trial showed that compared with non-surgery counterparts, locoregional surgery does not improve OS of patients with dnMBC. Large, well-designed studies involving a large number of cases, multi-institution trials and longer follow-up are needed to verify the finding. Citation Format: Ren Chongxi, Sun Jianna, Kong Lingjun. Overall survival with locoregional surgery in de novo metastatic breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-07-01.

OlympiAD extended follow-up for overall survival and safety: Olaparib versus chemotherapy treatment of physician's choice in patients with a germline BRCA mutation and HER2-negative metastatic breast cancer

BackgroundIn the Phase III OlympiAD study, olaparib significantly prolonged progression-free survival versus chemotherapy treatment of physician's choice (TPC) in patients with germline BRCA-mutated (gBRCAm), human epidermal growth factor receptor 2-negative metastatic breast cancer (mBC). In the final pre-specified analysis (64% maturity), median overall survival (OS) was 19.3 months for olaparib and 17.1 months for TPC (P = 0.513). Post-hoc extended follow-up, 25.7 months longer than previously reported for OS, is reported. Patients and methodsPatients with gBRCAm, human epidermal growth factor receptor 2-negative mBC, who had received ≤2 lines of chemotherapy for metastatic disease, were randomised 2:1 to olaparib (300 mg bid) or TPC. During extended follow-up, OS was analysed every 6 months using the stratified log-rank test (overall population) and Cox proportional hazards model (pre-specified subgroups). ResultsIn the overall population (302 patients; 76.8% maturity), median OS was 19.3 months for olaparib and 17.1 months for TPC (hazard ratio 0.89, 95% confidence interval 0.67–1.18); median follow-up was 18.9 and 15.5 months, respectively. Three-year survival was 27.9% for olaparib versus 21.2% for TPC. With olaparib, 8.8% of patients received study treatment for ≥3 years versus none with TPC. In first-line mBC, median OS was longer for olaparib than TPC (22.6 versus 14.7 months; hazard ratio 0.55, 95% confidence interval 0.33–0.95) and 3-year survival was 40.8% for olaparib versus 12.8% for TPC. No new serious adverse events related to olaparib were observed. ConclusionsOS was consistent with previous analyses from OlympiAD. These findings support the possibility of meaningful long-term survival benefit with olaparib, particularly in first-line mBC.

Association of Long-term Exposure to Air Pollution With Late-Life Depression in Older Adults in the US

Emerging evidence has suggested harmful associations of air pollutants with neurodegenerative diseases among older adults. However, little is known about outcomes regarding late-life mental disorders, such as geriatric depression. To investigate if long-term exposure to air pollution is associated with increased risk of late-life depression diagnosis among older adults in the US. This population-based longitudinal cohort study consisted of US Medicare enrollees older than 64 years. Data were obtained from the US Centers for Medicare and Medicaid Services Chronic Conditions Warehouse. The participants were continuously enrolled in the Fee-for-Service program and both Medicare Part A and Part B. After the 5-year washout period at entry, a total of 8 907 422 unique individuals were covered over the study period of 2005 to 2016, who contributed to 1 526 690 late-onset depression diagnoses. Data analyses were performed between March 2022 and November 2022. The exposures consisted of residential long-term exposure to fine particulate matter (PM2.5), measured in micrograms per cubic meter; nitrogen dioxide (NO2), measured in parts per billion; and ozone (O3), measured in parts per billion. Late-life depression diagnoses were identified via information from all available Medicare claims (ie, hospital inpatient, skilled nursing facility, home health agency, hospital outpatient, and physician visits). Date of the first occurrence was obtained. Hazard ratios and percentage change in risk were estimated via stratified Cox proportional hazards models accounting for climate coexposures, neighborhood greenness, socioeconomic conditions, health care access, and urbanicity level. A total of 8 907 422 Medicare enrollees were included in this study with 56.8% being female individuals and 90.2% being White individuals. The mean (SD) age at entry (after washout period) was 73.7 (4.8) years. Each 5-unit increase in long-term mean exposure to PM2.5, NO2, and O3 was associated with an adjusted percentage increase in depression risk of 0.91% (95% CI, 0.02%-1.81%), 0.61% (95% CI, 0.31%- 0.92%), and 2.13% (95% CI, 1.63%-2.64%), respectively, based on a tripollutant model. Effect size heterogeneity was found among subpopulations by comorbidity condition and neighborhood contextual backgrounds. In this cohort study among US Medicare enrollees, harmful associations were observed between long-term exposure to air pollution and increased risk of late-life depression diagnosis.

Health-related quality of life (HRQoL) impact of lenvatinib (len) plus pembrolizumab (pembro) versus len plus placebo (pbo) as first-line (1L) therapy for advanced hepatocellular carcinoma (aHCC): Phase 3 LEAP-002 study.

506 Background: In LEAP-002 (NCT03713593), len + pembro achieved a median OS of 21.2 mo vs 19.0 mo with len + pbo with manageable safety in both arms in 1L aHCC, although the significance thresholds for OS and PFS were not met. We present here the results of prespecified exploratory patient (pt)-reported outcomes (PROs). Methods: 794 pts were randomized. PROs were assessed by EORTC QLQ-C30, EuroQol-5D5L (EQ5D-5L), and EORTC QLQ-HCC18 questionnaires. Analysis population for HRQoL endpoints included pts who received ≥1 dose of study Tx and completed ≥1 HRQoL assessment. Least squares mean (LSM) score changes from baseline (BL) to wk 27 were compared using a constrained longitudinal data analysis model (covariates: Tx, time, Tx by time interaction, and stratification factors). Kaplan-Meier method was used to estimate time to deterioration (TTD, time to 1st onset of ≥10 [out of 100] deterioration from BL in a given scale or subscale/confirmed by a 2nd adjacent ≥10 deterioration from BL) for EORTC QLQ-C30 global health status (GHS)/QoL, physical functioning (PF), and EORTC QLQ-HCC18 abdominal swelling, pain and fatigue, as reported by pts. Stratified Cox proportional hazards model was used to assess the magnitude of the Tx difference (HR) between arms in TTD. Results: Compliance with PRO assessments was &gt;91% from BL until wk 27 in both arms. From BL to wk 27, LSM changes in GHS/QoL, PF, role functioning (RF), QLQ-HCC18 functional/domain scores and EQ5D-5L VAS were generally similar between the two arms (Table). Treatment with len + pembro delayed deterioration of patient-reported quality of life vs len + pbo (median TTD, 11.5 vs 4.3 mo; HR, 0.80; 95% CI, 0.65-0.98). LSM score difference (95% CI) was 0.5 (-2.5, 3.4) for GHS/QoL, -1.7 (-4.5, 1.1) for PF, -1.0 (-4.9, 2.9) for RF, 1.0 (-2.2, 4.3) for abdominal swelling, 2.0 (-1.2, 5.2) for fatigue, 2.0 (-1.0, 5.0) for pain, and 0.6 (-2.0, 3.2) for EQ5D-5L VAS. Median TTD in QLQ-C30 PF (5.7 vs 9.1 mo; HR, 1.14; 95% CI, 0.93-1.41) and QLQ-HCC18 abdominal swelling (NR vs NR; HR, 1.19; 95% CI, 0.89-1.60) /fatigue (2.9 vs 2.8 mo; HR, 0.98; 95% CI, 0.81-1.19)/pain (9.6 vs 7.9 mo; HR, 0.93; 95% CI, 0.75-1.16) was similar between the arms. Conclusions: Len + pembro generally preserved HRQoL vs len + pbo in 1L for aHCC. Combined with efficacy and safety results from LEAP-002, these findings support continued development of len + pembro in HCC. Clinical trial information: NCT03713593 . [Table: see text]

Frailty modifies the effect of polypharmacy and multimorbidity on the risk of death among nursing home residents: Results from the SHELTER study.

Frailty, disability, and polypharmacy are prevalent in nursing home (NH) residents, often co-occurring with multimorbidity. There may be a complex interplay among them in terms of outcomes such as mortality. Aims of the study were to (i) assess whether nursing home residents with polypharmacy (5-9 medications) or hyperpolypharmacy (≥10 drugs), have an increased risk of death and (ii) whether any association is modified by the co-presence of frailty or disability. Cohort study with longitudinal mortality data including 4,023 residents from 50 European and 7 Israeli NH facilities (mean age = 83.6 years, 73.2% female) in The Services and Health for Elderly in Long Term care (SHELTER) cohort study. Participants were evaluated with the interRAI-LongTerm Care assessment tool. Frailty was evaluated with the FRAIL-NH scale. Hazard ratio (HR) of death over 12 months was assessed with stratified Cox proportional hazards models adjusted for demographics, facilities, and cognitive status. 1,042 (25.9%) participants were not on polypharmacy, 49.8% (n = 2,002) were on polypharmacy, and 24.3% (n = 979) on hyperpolypharmacy. Frailty and disability mostly increased risk of death in the study population (frailty: HR = 1.85, 95%CI 1.49-2.28; disability: HR = 2.10, 95%CI 1.86-2.47). Among non-frail participants, multimorbidity (HR = 1.34, 95%CI = 1.01-1.82) and hyperpolypharmacy (HR = 1.61, 95%CI = 1.09-2.40) were associated with higher risk of death. Among frail participants, no other factors were associated with mortality. Polypharmacy and multimorbidity were not associated with mortality after stratification for disability. Frailty and disability are the strongest predictors of death in NH residents. Multimorbidity and hyperpolypharmacy increase mortality only in people without frailty. These findings may be relevant to identify patients who could benefit from tailored deprescription.

Time-varying association of acute and post-acute COVID-19 with new-onset diabetes mellitus among hospitalized and non-hospitalized patients

IntroductionPrevious studies have shown disruption of glycometabolic control and new diabetes mellitus (DM) diagnosis among patients with COVID-19. It is still unclear how the association of COVID-19 and new-onset DM...

The Risk of BPPV, Meniere's Disease, and Vestibular Neuronitis in Patients with Gout: A Longitudinal Follow-Up Study Using a National Health Screening Cohort.

This study evaluated the impact of pre-existing gout on the occurrence of benign paroxysmal positional vertigo (BPPV), Meniere’s disease, and vestibular neuronitis, with the goal of identifying novel associations of gout with other comorbid diseases. The 2002−2019 Korean National Health Insurance Service Health Screening Cohort data were retrospectively analyzed. 23,827 patients with gout were matched to 95,268 controls without gout for age, sex, income, region of residence, and index date. The occurrence of BPPV, Meniere’s disease, and vestibular neuronitis was evaluated in both groups. The hazard ratios (HRs) of gout for BPPV, Meniere’s disease, and vestibular neuronitis were calculated using a stratified Cox proportional hazard model. Participants with gout demonstrated a 1.13-fold higher risk of BPPV (95% CI, 1.06−1.21, p < 0.001) and a 1.15-fold higher risk of Meniere’s disease (95% CI, 1.15−1.37, p < 0.001) than the matched control group. However, the HR for vestibular neuronitis was not significantly higher in the gout group (adjusted HR = 1.06, 95% CI, 0.93−1.21, p = 0.391). A previous history of gout was related to a higher risk of BPPV and Meniere’s disease. Additional studies are necessary to elucidate the mechanism underlying the relationship between gout and comorbid diseases such as BPPV and Meniere’s disease.