Longitudinal trajectories of a claims-based frailty measure during adjuvant chemotherapy in women with stage I-III breast cancer.

BACKGROUND: Frailty is a dynamic syndrome characterized by reduced physiological reserve to maintain homeostasis. Prospective studies have reported frailty worsening in women with breast cancer during chemotherapy, with improvements following treatment. We evaluated whether the Faurot frailty index, a validated claims-based frailty measure, could identify changes in frailty during chemotherapy treatment and identified predictors of trajectory patterns. METHODS: We included women (65+ years) with stage I-III breast cancer undergoing adjuvant chemotherapy in the SEER-Medicare database (2003-2019). We estimated the Faurot frailty index (range: 0-1; higher scores indicate greater frailty) at chemotherapy initiation, 4 months postinitiation, and 10 months postinitiation. Changes in frailty were compared to a matched noncancer comparator cohort. We identified patterns of frailty trajectories during the year following chemotherapy initiation using K-means clustering. RESULTS: Twenty-one thousand five hundred and ninety-nine women initiated adjuvant chemotherapy. Mean claims-based frailty increased from 0.037 at initiation to 0.055 4 months postchemotherapy initiation and fell to 0.049 10 months postinitiation. Noncancer comparators experienced a small increase in claims-based frailty over time (0.055-0.062). We identified 6 trajectory patterns: a robust group (78%), 2 resilient groups (16%), and 3 nonresilient groups (6%). Black women and women with claims for home hospital beds, wheelchairs, and Parkinson's disease were more likely to experience nonresilient trajectories. CONCLUSIONS: We observed changes in a claims-based frailty index during chemotherapy that are consistent with prior studies using clinical measures of frailty and identified predictors of nonresilient frailty trajectories. Our study demonstrates the feasibility of using claims-based frailty indices to assess changes in frailty during cancer treatment.

Performance of a Claims-Based Frailty Proxy Using Varying Frailty Ascertainment Lookback Windows.

BACKGROUND: Frailty is an aging-related syndrome of reduced physiological reserve to maintain homeostasis. The Faurot frailty index has been validated as a Medicare claims-based proxy for predicting frailty using billing information from a user-specified ascertainment window. OBJECTIVES: We assessed the validity of the Faurot frailty index as a predictor of the frailty phenotype and 1-year mortality using varying frailty ascertainment windows. RESEARCH DESIGN: We identified older adults (66+ y) in Round 5 (2015) of the National Health and Aging Trends Study with Medicare claims linkage. Gold standard frailty was assessed using the frailty phenotype. We calculated the Faurot frailty index using 3, 6, 8, and 12 months of claims prior to the survey or all-available lookback. Model performance for each window in predicting the frailty phenotype was assessed by quantifying calibration and discrimination. Predictive performance for 1-year mortality was assessed by estimating risk differences across claims-based frailty strata. RESULTS: Among 4253 older adults, the 6 and 8-month windows had the best frailty phenotype calibration (calibration slopes: 0.88 and 0.87). All-available lookback had the best discrimination (C-statistic=0.780), but poor calibration. Mortality associations were strongest using a 3-month window and monotonically decreased with longer windows. Subgroup analyses revealed worse performance in Black and Hispanic individuals than counterparts. CONCLUSIONS: The optimal ascertainment window for the Faurot frailty index may depend on the clinical context, and researchers should consider tradeoffs between discrimination, calibration, and mortality. Sensitivity analyses using different durations can enhance the robustness of inferences. Research is needed to improve prediction across racial and ethnic groups.

The association between wealth and sleep medication use in a nationally-representative sample of older Medicare beneficiaries.

BACKGROUND: Sleep disorders are common among older adults, leading to high prevalence of over-the-counter and prescription sleep medication use. Socioeconomically disadvantaged individuals have higher prevalence of sleep disorders. Frequent use of sleep medications can increase the risk of falls. Little is known about the association between wealth and sleep medication use in older adults. METHODS: We conducted a cross-sectional analysis using a nationwide sample of 7603 Medicare beneficiaries (65+ years) from Round 1 (2011) of the National Health and Aging Trends Study. We measured self-reported wealth as the sum of assets (retirement savings, stocks/bonds, checking/savings accounts, business assets, and home value) minus liabilities (mortgage, credit card, and medical debt). Self-reported sleep medication use in the past month was categorized as frequent (5-7 nights/week), sometimes (1-4 nights/week), or never (0 night/week). We estimated differences in the prevalence of sleep medication use by quintiles of wealth using crude and adjusted binomial regression models. Individuals missing sleep medication information were excluded. RESULTS: Median wealth was $152 582 (IQR: $24 023-412 992). Sixteen percent reported frequent sleep medication use, 15% reported some use, and 70% reported no use. Frequent sleep medication use was more common in lower wealth quintiles (lowest: 20%, highest: 12%). Alternatively, some use was more common in higher wealth quintiles (lowest: 11%, highest: 18%). Results were similar after adjustment for demographic factors, anxiety, depression, and sleep disorders. CONCLUSIONS: In this study, less wealthy older adults had higher prevalence of frequent sleep medication use. This may lead to dependency or increased fall risk in this vulnerable population.

Big Data for Geriatric Oncology Research.

Cancer is the second leading cause of death in North Carolina and approximately half of cancers are diagnosed in older adults (≥65 years). Cancer clinical trials in older adults are limited and there is a lack of evidence on optimal care strategies in this population. We highlight how big data can fill in gaps in geriatric oncology research.

Translation of a Claims-Based Frailty Index From the International Classification of Diseases, Ninth Revision, Clinical Modification to the Tenth Revision.

The Faurot frailty index (FFI) is a validated algorithm that uses enrollment and International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM)-based billing information from Medicare claims data as a proxy for frailty. In October 2015, the US health-care system transitioned from the ICD-9-CM to the International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM). Applying the Centers for Medicare and Medicaid Services General Equivalence Mappings, we translated diagnosis-based frailty indicator codes from the ICD-9-CM to the ICD-10-CM, followed by manual review. We used interrupted time-series analysis of Medicare data to assess the comparability of the pre- and posttransition FFI scores. In cohorts of beneficiaries enrolled in January 2015-2017 with 8-month frailty look-back periods, we estimated associations between the FFI and 1-year risk of aging-related outcomes (mortality, hospitalization, and admission to a skilled nursing facility). Updated indicators had similar prevalences as pretransition definitions. The median FFI scores and interquartile ranges (IQRs) for the predicted probability of frailty were similar before and after the International Classification of Diseases transition (pretransition: median, 0.034 (IQR, 0.02-0.07); posttransition: median, 0.038 (IQR, 0.02-0.09)). The updated FFI was associated with increased risks of mortality, hospitalization, and skilled nursing facility admission, similar to findings from the ICD-9-CM era. Studies of medical interventions in older adults using administrative claims should use validated indices, like the FFI, to mitigate confounding or assess effect-measure modification by frailty.

Preferred Feedback Styles Among Different Groups in an Academic Medical Center.

INTRODUCTION: Feedback is an essential component in complex work environments. Different generations have been shown to have different sets of values, derived from societal and cultural changes. We hypothesize that generational differences may be associated with preferred feedback patterns among medical trainees and faculty in a large academic institution. METHODS: A survey was distributed to all students, residents/fellows, and faculty at a large academic medical institution from April 2020 through June 2020. Survey questions evaluated feedback methods for six domains: preparedness, performance, attitude, technical procedures, inpatient, and outpatient care. Participants selected a preferred feedback method for each category. Patient demographics and survey responses were described using frequency statistics. We compared differences in feedback preferences based on generation and field of practice. RESULTS: A total of 871 participants completed the survey. Preferred feedback patterns in the medical field do not seem to align with sociologic theories of generational gaps. Most participants preferred to receive direct feedback after an activity away from their team, irrespective of their age or medical specialty. Individuals preferred direct feedback during an activity in front of their team only for technical procedures. Compared to nonsurgeons, surgeons were more likely to prefer direct feedback in front of team members for preparedness, performance, and attitude. CONCLUSIONS: Generational membership is not significantly associated with preferred feedback patterns in this complex medical academic environment. Variations in feedback preferences are associated with field of practice that may be due to specialty-specific differences in culture and personality traits present within certain medical specialties, particularly surgery.

Sociodemographic and Clinical Predictors of Neoadjuvant Chemotherapy in cT1-T2/N0 HER2-Amplified Breast Cancer.

BACKGROUND: The optimal treatment strategy for small node-negative human epidermal growth factor receptor 2-positive (HER2+) breast cancer remains controversial. Neoadjuvant chemotherapy may risk overtreatment, whereas surgery first fails to identify patients with residual disease in need of escalated adjuvant systemic therapy. We investigated patient characteristics associated with receipt of neoadjuvant chemotherapy. METHODS: Adult women with cT1-T2/N0, HER2+ breast cancer between 2013 and 2017 in the National Cancer Database who underwent surgery within 8 months of diagnosis were included. Patients were classified as receiving neoadjuvant chemotherapy versus a surgery-first approach. We assessed the sociodemographic and clinical predictors of neoadjuvant chemotherapy versus surgery first and associations between neoadjuvant chemotherapy and breast cancer treatments using multivariable regression models. RESULTS: We identified 56,784 women, of whom 12,758 (22%) received neoadjuvant chemotherapy, 29,139 (53%) received adjuvant chemotherapy, 12,907 (24%) received no chemotherapy, and 1980 were missing chemotherapy information. After adjustment, cT2 stage was the strongest predictor of neoadjuvant chemotherapy compared with surgery first. Younger age and later diagnosis year were positively associated with receipt of neoadjuvant chemotherapy. In contrast, hormone receptor positivity, Black race, rural county, and government-funded or no health insurance were inversely associated with neoadjuvant chemotherapy. In multivariable analyses, patients who received neoadjuvant chemotherapy were more likely to have a mastectomy (vs. lumpectomy) and sentinel lymph node biopsy or no nodal surgery (vs. axillary lymph node dissection). Patients who received neoadjuvant chemotherapy were more likely to receive multi-agent (vs. single-agent) chemotherapy than those who received adjuvant chemotherapy. CONCLUSIONS: Substantial differences in the utilization of neoadjuvant chemotherapy exist in women with HER2+ breast cancer, which reflect both clinical parameters and disparities. Optimal treatment strategies should be implemented equitably across sociodemographic groups.

Trends in the use of disease-modifying therapies among reproductive-aged women with multiple sclerosis in the United States from 2010 to 2019.

PURPOSE: Multiple sclerosis (MS) is a chronic disease of the central nervous system that disproportionately affects women, with typical onset during reproductive age. Several disease-modifying therapies (DMTs) are FDA-approved to slow disease progression, but are not indicated for use during pregnancy. Our objective was to describe trends over time (2010-2019) in monthly point prevalence of DMT use among reproductive-age women, overall and by generic name. METHODS: This study used administrative claims data from the US during 2009-2019 to identify women age 15-44 with MS and continuous insurance coverage for ≥12 months. DMTs were identified using prescription fills and procedural claims for alemtuzumab, daclizumab, dimethyl fumarate, fingolimod, glatiramer acetate, interferon beta, mitoxantrone, natalizumab, ocrelizumab, and teriflunomide. Monthly prevalent use was defined as ≥1 days' supply of a DMT in the month. Age- and region-standardized monthly prevalence was estimated nonparametrically. RESULTS: Among 42 281 reproductive-aged women over 818 179 person-months, DMT use increased from a minimum monthly prevalence of 49.3% (February, 2011) to a maximum of 58.7% (April, 2019). In 2010, prevalence of injectable DMTs was 43.1% compared to 2.5% for oral DMTs; by 2014, however, oral DMTs (26.5%) surpassed injectable DMTs (23.7%) as the most common route of administration. In the most recent data available (December, 2019), the most common DMTs were dimethyl fumarate, glatiramer acetate, and fingolimod. CONCLUSIONS: DMT use among reproductive-aged women has rapidly evolved during the past decade. Collaborative treatment decision making between women with MS and clinicians may help optimize MS care and improve DMT uptake during reproductive years.

Minimally invasive, benign foregut surgery is not associated with long-term, persistent opioid use postoperatively: an analysis of the IBM® MarketScan® database.

BACKGROUND: It is unknown if opioid naïve patients who undergo minimally invasive, benign foregut operations are at risk for progressing to persistent postoperative opioid use. The purpose of our study was to determine if opioid naïve patients who undergo minimally invasive, benign foregut operations progress to persistent postoperative opioid use and to identify any patient- and surgery-specific factors associated with persistent postoperative opioid use. METHODS: Opioid-naïve, adult patients who underwent laparoscopic fundoplication, hiatal hernia repair, or Heller myotomy from 2010 to 2018 were identified within the IBM® MarketScan® Commercial Claims and Encounters Database. Daily drug logs of the preoperative and postoperative period were evaluated to assess for changes in drug use patters. The primary outcome of interest was persistent postoperative opioid use, defined as at least 33% of the proportion of days covered by opioid prescriptions at 365-day follow-up. Patient demographic information and clinical risk factors for persistent postoperative opioid use at 365 days postoperatively were estimated using log-binomial regression. RESULTS: A total of 17,530 patients met inclusion criteria; 6895 underwent fundoplication, 9235 underwent hiatal hernia repair, and 1400 underwent Heller myotomy. 9652 patients had at least one opioid prescription filled in the perioperative period. Sixty-five patients (0.4%) were found to have persistent postoperative opioid use at 365 days postoperatively. Lower Charlson comorbidity index scores and a history of mental illness or substance use disorder had a statistically but not clinically significant protective effect on the risk of persistent postoperative opioid use at 365 days postoperatively. CONCLUSIONS: Only half of opioid naïve patients undergoing minimally invasive, benign foregut operations filled an opioid prescription postoperatively. The risk of progression to persistent postoperative opioid use was less than 1%. These findings support the current guidelines that limit the number of opioid pills prescribed following general surgery operations.

Gender Disparities in Aortoiliac Revascularization in Patients with Aortoiliac Occlusive Disease.

BACKGROUND: Gender disparities have been previously reported in aortic aneurysm and critical limb ischemia outcomes; however, limited info is known about disparities in aortoiliac occlusive disease. We sought to characterize potential disparities in this specific population. MATERIAL AND METHODS: Patients who underwent aortobifemoral bypass and aortic thromboendarterectomy (Current Procedural Terminology codes 35646 and 35331) between 2012 and 2019 were identified in the National Surgical Quality Improvement Program database. A binomial regression model was used to estimate gender differences in 30-day morbidity and mortality. Inverse probability weighting was used to standardize demographic and surgical characteristics. RESULTS: We identified 1,869 patients, of which 39.8% were female and the median age was 61 years. Age, body composition, and other baseline characteristics were overall similar between genders; however, racial data were missing for 26.1% of patients. Females had a higher prevalence of preexisting chronic obstructive pulmonary disease (20.9% vs. 14.7%, prevalence difference 6.1%, P < 0.01), diabetes mellitus (25.4% vs. 19.4%, prevalence difference 6.0%, P < 0.01), and high-risk anatomical features (39.4% vs. 33.7%, prevalence difference 5.8%, P = 0.01). Preprocedural medications included a statin in only 68.2% of patients and antiplatelet agent in 76.7% of patients. Females also had a higher incidence of bleeding events when compared to males (25.2% vs. 17.5%, standardized risk difference 7.2%, P < 0.01), but were less likely to have a prolonged hospitalization greater than 10 days (18.2% vs. 20.9%, standardized risk difference -5.0%, P = 0.01). The 30-day mortality rate was not significantly different between genders (4.7% vs. 3.6%, standardized risk difference 1.2%, P = 0.25). CONCLUSIONS: Female patients treated with aortobifemoral bypass or aortic thromboendarterectomy are more likely to have preexisting chronic obstructive pulmonary disease, diabetes mellitus, and high-risk anatomical features. Regardless of a patient's gender, there is poor adherence to preoperative medical optimization with both statins and antiplatelet agents. Female patients are more likely to have postoperative bleeding complications while males are more likely to have a prolonged hospital stay greater than 10 days. Future work could attempt to further delineate disparities using databases with longer follow-up data and seek to create protocols for reducing these observed disparities.

Longitudinal Changes in a Claims-Based Frailty Proxy Measure Compared to Concurrent Changes in the Fried Frailty Phenotype.

BACKGROUND: Frailty is a dynamic aging-related syndrome, but measuring frailty transitions is challenging. The Faurot frailty index is a validated Medicare claims-based frailty proxy based on demographic and billing information. We evaluated whether 3-year changes in the Faurot frailty index were consistent with concurrent changes in the frailty phenotype in a cohort of older adults. METHODS: We used longitudinal data from the National Health and Aging Trends Study (NHATS) with Medicare claims linkage (2010-2018). We identified older adults (66+ years) in the 2011 and 2015 NHATS cohorts with at least 1 year of Medicare fee-for-service continuous enrollment (N = 6 951). We described annual changes in mean claims-based frailty for up to 3 years, based on concurrent transitions in the frailty phenotype. RESULTS: At baseline, 32% were robust, 48% prefrail, and 19% frail based on the frailty phenotype. Mean claims-based frailty for older adults who were robust at baseline and worsened to frail increased over 3 years (0.09-0.25). Similarly, those who worsened from prefrail to frail experienced an increase in mean claims-based frailty (0.14-0.26). Improvements in the frailty phenotype did not correspond to decreases in claims-based frailty. Older adults whose frailty phenotype improved over time had a lower baseline claims-based frailty score than those who experienced stable or worsening frailty. CONCLUSIONS: Older adults who experienced a frailty phenotype worsening over 3 years experienced concurrent increases in the Faurot frailty index. Our results suggest that claims data may be used to identify clinically meaningful worsening in frailty.

Functional Status Associations With Treatment Receipt and Outcomes Among Older Adults Newly Diagnosed With Multiple Myeloma.

PURPOSE: Multiple myeloma (MM) is a prevalent hematologic malignancy in older adults, who often experience physical disability, increased health care usage, and reduced treatment tolerance. Home health (HH) services are frequently used by this group, but the relationship between disability, HH use, and MM treatment receipt is unclear. This study examines the connections between disability, treatment receipt, and survival outcomes in older adults with newly diagnosed MM using a nationwide data set. METHODS: The SEER-Medicare data set was used to identify adults aged 66 years and older diagnosed with MM from 2010 to 2017, who used HH services the year before diagnosis. Disability was assessed with the Outcome and Assessment Information Set, using a composite score derived from items related to ability to complete activities of daily living. Mortality, therapy receipt, and health care utilization patterns were evaluated. RESULTS: Of 37,280 older adults with MM, 6,850 (18.2%) used HH services before diagnosis. Moderate disability at HH assessment resulted in similar MM-directed therapy receipt as mild disability, with comparable health care usage after diagnosis to severe disability. HH users had a higher comorbidity burden and higher mortality (adjusted risk ratio for 3-year mortality: 1.59 [95% CI, 1.55 to 1.64]). Severe functional disability before diagnosis was strongly related to postdiagnosis mortality. CONCLUSION: Among older adults with MM receiving HH services, disability is a predictor of early mortality. Moderately disabled individuals undergo similar therapy intensity as the mildly disabled but experience increased acute care utilization. Previous HH use could identify patients with MM requiring intensive support during therapy initiation.

Prognosis of older adults with chronic lymphocytic leukemia: A Surveillance, Epidemiology, and End Results-Medicare cohort study.

INTRODUCTION: While prognosis for patients with chronic lymphocytic leukemia (CLL) has improved over time in younger adults, only modest improvements have occurred in older adults. We conducted a descriptive study of prognosis in older adults with CLL. MATERIALS AND METHODS: We used data from the Surveillance, Epidemiology, and End Results (SEER)-Medicare database from 2003 to 2016. We identified older adults (≥66 years) diagnosed with primary CLL between 2004 and 2015 (Overall Cohort). A subset who initiated CLL-directed therapy during the year following diagnosis was also identified (Treated Cohort). Both cohorts were matched to Medicare beneficiaries without cancer based on age, sex, and region. For each year from 2004 to 2013, three-year survival for patients with CLL and non-cancer comparators was described using Kaplan-Meier analysis. Inverse probability weighted Cox regression models were used to compare survival in the CLL and non-cancer comparator cohorts, accounting for demographic information and comorbidity and frailty indices. Among older adults with CLL, ten-year cause-specific cumulative mortality was estimated using Aalen-Johansen estimators that accounted for competing risks. Predictors of cause-specific mortality, including comorbidity and frailty burden, were assessed using sub-distribution hazards models. RESULTS: In the Overall Cohort, three-year survival increased non-monotonically from 71.4% in 2004 to 73.4% in 2013, with a peak of 74.4% in 2011, and was lower than survival in non-cancer comparators (78.3% in 2004 to 83.2% in 2013). In the Treated Cohort, three-year survival was 56.3% in 2004 and 56.5% in 2013, with a peak of 64.2% in 2011. Cox models suggested that survival in the Treated Cohort was approaching survival in non-cancer comparators after 2011 (hazard ratio = 1.04, 95% confidence interval, 0.93-1.17). Ten-year cumulative mortality was 68.6% in the Overall Cohort and 81.7% in the Treated Cohort, with most deaths attributed to non-CLL causes. In the sub-distribution hazards models, age, year of diagnosis, frailty, and comorbidities were all associated with prognosis. DISCUSSION: Prognosis in older adults has been stable over time and most patients with CLL die from non-CLL causes. CLL-directed treatment decision-making in older adults should consider age-related factors, such as comorbidity and frailty.

Costs and recurrence of inguinal hernia repair in premature infants during neonatal admission.

BACKGROUND: Timing of inguinal hernia repair (IHR) in premature infants remains variable, yet the impact of IHR timing on procedure costs and recurrence is unclear. We sought to compare cost and recurrence rates of IHR in premature infants based on timing of repair. METHODS: We performed a retrospective cohort study using MarketScan insurance claims data from 2007 to 2018 to evaluate IHR occurring within 365 days of birth in preterm infants (gestational age [GA]<37 weeks at birth). Patients were stratified based on timing of IHR: those occurring during and after neonatal discharge. Hernia recurrences within one year following IHR were identified. Patient demographic characteristics and costs were compared between groups. Time to recurrence and cumulative recurrence hazards were estimated using Kaplan Meier analysis and Cox proportional hazards regression. RESULTS: We identified 3,662 preterm infants with IHR within 365 days of birth; 1,054(28.8%) occurred early. Infants with IHR during NICU stay were more likely to have GA at birth≤32 weeks (74.7% vs. 37.2%; p<0.01) and birthweight<1500 g (83.0% vs. 40.3%; p<0.01) compared to post-NICU IHR. The hernia recurrence rate was higher and total procedure costs lower in early IHR. Early IHR (HR:1.86, 95% CI: 1.56-2.22), incarcerated/strangulated hernia (HR:1.86, 95% CI:1.49-2.32), GA≤32 weeks (HR: 1.40, 95% CI: 1.19-1.65), and congenital anomalies (HR: 1.32, 95% CI: 1.12-1.57) were predictors of hernia recurrence. CONCLUSION: Using insurance claims data, IHR performed during initial neonatal admission was associated with lower cost, but higher recurrence rate, when compared to delayed repairs in preterm infants. TYPE OF STUDY: Retrospective study LEVEL OF EVIDENCE: Level III.

Missing data approaches in longitudinal studies of aging: A case example using the National Health and Aging Trends Study.

PURPOSE: Missing data is a key methodological consideration in longitudinal studies of aging. We described missing data challenges and potential methodological solutions using a case example describing five-year frailty state transitions in a cohort of older adults. METHODS: We used longitudinal data from the National Health and Aging Trends Study, a nationally-representative cohort of Medicare beneficiaries. We assessed the five components of the Fried frailty phenotype and classified frailty based on their number of components (robust: 0, prefrail: 1-2, frail: 3-5). One-, two-, and five-year frailty state transitions were defined as movements between frailty states or death. Missing frailty components were imputed using hot deck imputation. Inverse probability weights were used to account for potentially informative loss-to-follow-up. We conducted scenario analyses to test a range of assumptions related to missing data. RESULTS: Missing data were common for frailty components measured using physical assessments (walking speed, grip strength). At five years, 36% of individuals were lost-to-follow-up, differentially with respect to baseline frailty status. Assumptions for missing data mechanisms impacted inference regarding individuals improving or worsening in frailty. CONCLUSIONS: Missing data and loss-to-follow-up are common in longitudinal studies of aging. Robust epidemiologic methods can improve the rigor and interpretability of aging-related research.

The Timing, the Treatment, the Question: Comparison of Epidemiologic Approaches to Minimize Immortal Time Bias in Real-World Data Using a Surgical Oncology Example.

BACKGROUND: Studies evaluating the effects of cancer treatments are prone to immortal time bias that, if unaddressed, can lead to treatments appearing more beneficial than they are. METHODS: To demonstrate the impact of immortal time bias, we compared results across several analytic approaches (dichotomous exposure, dichotomous exposure excluding immortal time, time-varying exposure, landmark analysis, clone-censor-weight method), using surgical resection among women with metastatic breast cancer as an example. All adult women diagnosed with incident metastatic breast cancer from 2013-2016 in the National Cancer Database were included. To quantify immortal time bias, we also conducted a simulation study where the "true" relationship between surgical resection and mortality was known. RESULTS: 24,329 women (median age 61, IQR 51-71) were included, and 24% underwent surgical resection. The largest association between resection and mortality was observed when using a dichotomized exposure [HR, 0.54; 95% confidence interval (CI), 0.51-0.57], followed by dichotomous with exclusion of immortal time (HR, 0.62; 95% CI, 0.59-0.65). Results from the time-varying exposure, landmark, and clone-censor-weight method analyses were closer to the null (HR, 0.67-0.84). Results from the plasmode simulation found that the time-varying exposure, landmark, and clone-censor-weight method models all produced unbiased HRs (bias -0.003 to 0.016). Both standard dichotomous exposure (HR, 0.84; bias, -0.177) and dichotomous with exclusion of immortal time (HR, 0.93; bias, -0.074) produced meaningfully biased estimates. CONCLUSIONS: Researchers should use time-varying exposures with a treatment assessment window or the clone-censor-weight method when immortal time is present. IMPACT: Using methods that appropriately account for immortal time will improve evidence and decision-making from research using real-world data.

Pathologic complete response and survival after neoadjuvant chemotherapy in cT1-T2/N0 HER2+ breast cancer.

Women with small HER2+ breast cancers may have excellent prognosis with adjuvant single-agent chemotherapy and HER2-targeted therapy. The role of de-escalated therapy in the neoadjuvant setting, however, remains uncertain. We conducted a cohort study of adult women with T1-2/cN0 HER2+ breast cancer diagnosed 2013-2016 in the National Cancer Database treated with neoadjuvant chemotherapy (NAC) and HER2-targeted therapy. Factors associated with pathologic complete response (pCR) and overall survival were examined. In total, 6994 patients were included, 32% cT1 and 68% cT2. Multi-agent NAC was given to 90% of women while single-agent NAC was given to 10% of women. pCR was achieved in 46% of cT2 patients and 43% of cT1, and in 46% of patients treated with multi-agent versus 38% single agent. Patients receiving multi-agent chemotherapy were younger, had fewer comorbidities, and had higher cT stage and grade. In all patients, pCR was associated with improved survival (p < 0.01). Multi-agent chemotherapy (OR 1.3, p = 0.003), hormone receptor negative (OR 2.6, p < 0.001), higher grade (OR 2.2, p < 0.001), younger age (OR 1.4, p = 0.011), and later year of diagnosis (OR 1.3, p = 0.005) were associated with achieving pCR. Multi-agent chemotherapy was associated with higher likelihood of pCR, but this effect was modest compared to other factors. Single-agent NAC with HER2-directed therapy in selected patients may provide excellent outcome with reduced toxicity, while allowing escalated therapy in the adjuvant setting for patients with residual disease. Prospective studies are needed to determine effects of de-escalation in the neoadjuvant setting on survival and optimal selection strategies.