Real-World Impact of Comprehensive Genomic Profiling on Biomarker Detection, Receipt of Therapy, and Clinical Outcomes in Advanced Non-Small Cell Lung Cancer.

PURPOSE: Therapeutic decision making for patients with advanced non-small cell lung cancer (aNSCLC) includes a growing number of options for genomic, biomarker-guided, targeted therapies. We compared actionable biomarker detection, targeted therapy receipt, and real-world overall survival (rwOS) in patients with aNSCLC tested with comprehensive genomic profiling (CGP) versus small panel testing (SP) in real-world community health systems. METHODS: Patients older than 18 years diagnosed with aNSCLC between January 1, 2015, and December 31, 2020, who received biomarker testing were followed until death or study end (September 30, 2021), and categorized by most comprehensive testing during follow-up: SP (≤52 genes) or CGP (>52 genes). RESULTS: Among 3,884 patients (median age, 68 years; 50% female; 73% non-Hispanic White), 20% received CGP and 80% SP. The proportion of patients with ≥one actionable biomarker (actionability) was significantly higher in CGP than in SP (32% v 14%; P < .001). Of patients with actionability, 43% (CGP) and 38% (SP) received matched therapies (P = .20). Among treated patients, CGP before first-line treatment was associated with higher likelihood of matched therapy in any line (odds ratio, 3.2 [95% CI, 1.84 to 5.53]). CGP testing (hazard ratio [HR], 0.80 [95% CI, 0.72 to 0.89]) and actionability (HR, 0.84 [95% CI, 0.77 to 0.91]) were associated with reduced risk of mortality. Among treated patients with actionability, matched therapy receipt showed improved median rwOS in months in CGP (34 [95% CI, 21 to 49] matched v 14 [95% CI, 10 to 18] unmatched) and SP (27 [95% CI, 21 to 43] matched v 10 [95% CI, 8 to 14] unmatched). CONCLUSION: Patients who received CGP had improved detection of actionable biomarkers and greater use of matched therapies, both of which were associated with significant increases in survival.

Epidemiology of interstitial lung disease in patients with metastatic breast cancer at baseline and after treatment with HER2-directed therapy: a real-world data analysis.

PURPOSE: Using real-world data, interstitial lung disease (ILD) prevalence before and after HER2-directed therapy was estimated. Potential ILD risk factors in patients receiving HER2-directed therapy for metastatic breast cancer (mBC) were evaluated. METHODS: Adults with HER2-directed therapy for mBC initiated between September 25, 1998, and February 22, 2020 were, included. ILD was defined broadly as one or more of 64 lung conditions. Patients were followed until incident ILD, death, last contact, or study end. RESULTS: In total, 533 patients were identified with median age at mBC of 57, 51% had de novo mBC, 43% were ever smokers, 30% had lung metastases, 9% had thoracic radiation, 6% had chronic obstructive pulmonary disease, and 16% had prevalent ILD. ILD cumulative incidence at one year was 9% (95% CI 6%, 12%), with a median follow-up of 23 months. Smoking (HR 2.2, 95% CI 1.1, 4.8) and Black/African-American race (HR 3.4, 95% CI 1.6, 7.5) were significantly associated with ILD; HRs for preexisting lung conditions (HR 1.8, 95% CI 0.9, 3.8) and thoracic radiation (HR 2.3, 95% CI 0.8, 7.1) were not statistically significant. Prevalent ILD was associated with 13-fold greater occurrence of incident ILD. 85% of patients with prevalent or incident ILD were symptomatic. CONCLUSIONS: This real-world population of patients with mBC had a high prevalence of ILD prior to HER2-directed therapy, reflecting the multifactorial causation of interstitial lung changes. The cumulative incidence of ILD in patients receiving HER2-directed therapy for mBC augments prior reports. Symptomatic presentation suggests an opportunity for early intervention.

Implementing Real-World RECIST-based Tumor Response Assessment in Patients With Metastatic Non-small Cell Lung Cancer.

BACKGROUND: To accelerate drug approvals while maintaining scientific rigor in the evaluation of a therapeutic's efficacy and safety, the United States Food and Drug Administration now considers real-world data (RWD) to support New Drug Applications and expanded indications. Response Evaluation Criteria in Solid Tumors (RECIST) are the gold standard in clinical trials, but the derivation of RECIST-based treatment response from RWD is unproven. This study investigated the feasibility of implementing RECIST criteria in RWD by comparing lung cancer response assessments from RECIST-based measurement of lesions on archived radiologic films with results from medical oncologist and radiologist narratives recorded in electronic health records (EHR). MATERIALS AND METHODS: Response to index treatment via different assessment approaches was compared among 30 metastatic non-small cell lung cancer (mNSCLC) patients receiving systemic treatment (index) after progression on a platinum or anti-PD(L)-1-containing regimen. Specifically, responses based on assessments documented in the medical oncologists' narratives were compared to a radiologist's assessments of archived images using RECIST v1.1 criteria. Each patient's best overall response was characterized as complete or partial (CR/PR), stable disease (SD), progressive disease (PD), or not evaluable (NE). RESULTS: Similar distributions of best overall response and substantial concordance (77%) between medical oncologist-reported and radiologist re-assessed responses were observed. There were no instances of CR/PR to PD or PD to CR/PR discordance. CONCLUSIONS: Results suggest that accurate treatment responses, similar to RECIST, may be derived using RWD. Further validation and improvement of real-world response assessment are needed to develop a scalable real-world approach for response assessment.

The Friends of Cancer Research Real-World Data Collaboration Pilot 2.0: Methodological Recommendations from Oncology Case Studies.

The purpose of this study was to evaluate the potential collective opportunities and challenges of transforming real-world data (RWD) to real-world evidence for clinical effectiveness by focusing on aligning analytic definitions of oncology end points. Patients treated with a qualifying therapy for advanced non-small cell lung cancer in the frontline setting meeting broad eligibility criteria were included to reflect the real-world population. Although a trend toward improved outcomes in patients receiving PD-(L)1 therapy over standard chemotherapy was observed in RWD analyses, the magnitude and consistency of treatment effect was more heterogeneous than previously observed in controlled clinical trials. The study design and analysis process highlighted the identification of pertinent methodological issues and potential innovative approaches that could inform the development of high-quality RWD studies.

Real-world Overall Survival Using Oncology Electronic Health Record Data: Friends of Cancer Research Pilot.

In prior work, Friends of Cancer Research convened multiple data partners to establish standardized definitions for oncology real-world end points derived from electronic health records (EHRs) and claims data. Here, we assessed the performance of real-world overall survival (rwOS) from data sets sourced from EHRs by evaluating the ability of the end point to reflect expected differences from a previous randomized controlled trial across five data sources, after applying inclusion/exclusion criteria. The KEYNOTE-189 clinical trial protocol of platinum doublet chemotherapy (chemotherapy) vs. programmed cell death protein 1 (PD-1) in combination with platinum doublet chemotherapy (PD-1 combination) in first-line nonsquamous metastatic non-small cell lung cancer guided retrospective cohort selection. The Kaplan-Meier product limit estimator was used to calculate 12-month rwOS with 95% confidence intervals (CIs) in each data source. Cox proportional hazards models estimated hazard ratios (HRs) and associated 95% CIs, controlled for prognostic factors. Once the inclusion/exclusion criteria were applied, the five resulting data sets included 155 to 1,501 patients in the chemotherapy cohort and 36 to 405 patients in the PD-1 combination cohort. Twelve-month rwOS ranged from 45% to 58% in the chemotherapy cohort and 44% to 68% in the PD-1 combination cohort. The adjusted HR for death ranged from 0.80 (95% CI: 0.69, 0.93) to 1.15 (95% CI: 0.71, 1.85), controlling for age, gender, performance status, and smoking status. This study yielded insights regarding data capture, including ability of real-world data to precisely identify patient populations and the impact of criteria on end points. Sensitivity analyses could elucidate data set-specific factors that drive results.

Rapid real-world data analysis of patients with cancer, with and without COVID-19, across distinct health systems.

BACKGROUND: The understanding of the impact of COVID-19 in patients with cancer is evolving, with need for rapid analysis. AIMS: This study aims to compare the clinical and demographic characteristics of patients with cancer (with and without COVID-19) and characterize the clinical outcomes of patients with COVID-19 and cancer. METHODS AND RESULTS: Real-world data (RWD) from two health systems were used to identify 146 702 adults diagnosed with cancer between 2015 and 2020; 1267 COVID-19 cases were identified between February 1 and July 30, 2020. Demographic, clinical, and socioeconomic characteristics were extracted. Incidence of all-cause mortality, hospitalizations, and invasive respiratory support was assessed between February 1 and August 14, 2020. Among patients with cancer, patients with COVID-19 were more likely to be Non-Hispanic black (NHB), have active cancer, have comorbidities, and/or live in zip codes with median household income <$30 000. Patients with COVID-19 living in lower-income areas and NHB patients were at greatest risk for hospitalization from pneumonia, fluid and electrolyte disorders, cough, respiratory failure, and acute renal failure and were more likely to receive hydroxychloroquine. All-cause mortality, hospital admission, and invasive respiratory support were more frequent among patients with cancer and COVID-19. Male sex, increasing age, living in zip codes with median household income <$30 000, history of pulmonary circulation disorders, and recent treatment with immune checkpoint inhibitors or chemotherapy were associated with greater odds of all-cause mortality in multivariable logistic regression models. CONCLUSION: RWD can be rapidly leveraged to understand urgent healthcare challenges. Patients with cancer are more vulnerable to COVID-19 effects, especially in the setting of active cancer and comorbidities, with additional risk observed in NHB patients and those living in zip codes with median household income <$30 000.

COVID-19 Evidence Accelerator: A parallel analysis to describe the use of Hydroxychloroquine with or without Azithromycin among hospitalized COVID-19 patients.

BACKGROUND: The COVID-19 pandemic remains a significant global threat. However, despite urgent need, there remains uncertainty surrounding best practices for pharmaceutical interventions to treat COVID-19. In particular, conflicting evidence has emerged surrounding the use of hydroxychloroquine and azithromycin, alone or in combination, for COVID-19. The COVID-19 Evidence Accelerator convened by the Reagan-Udall Foundation for the FDA, in collaboration with Friends of Cancer Research, assembled experts from the health systems research, regulatory science, data science, and epidemiology to participate in a large parallel analysis of different data sets to further explore the effectiveness of these treatments. METHODS: Electronic health record (EHR) and claims data were extracted from seven separate databases. Parallel analyses were undertaken on data extracted from each source. Each analysis examined time to mortality in hospitalized patients treated with hydroxychloroquine, azithromycin, and the two in combination as compared to patients not treated with either drug. Cox proportional hazards models were used, and propensity score methods were undertaken to adjust for confounding. Frequencies of adverse events in each treatment group were also examined. RESULTS: Neither hydroxychloroquine nor azithromycin, alone or in combination, were significantly associated with time to mortality among hospitalized COVID-19 patients. No treatment groups appeared to have an elevated risk of adverse events. CONCLUSION: Administration of hydroxychloroquine, azithromycin, and their combination appeared to have no effect on time to mortality in hospitalized COVID-19 patients. Continued research is needed to clarify best practices surrounding treatment of COVID-19.

Maternal Experience of Multiple Hardships and Fetal Growth: Extending Environmental Mixtures Methodology to Social Exposures.

BACKGROUND: Women can be exposed to a multitude of hardships before and during pregnancy that may affect fetal growth, but previous approaches have not analyzed them jointly as social exposure mixtures. METHODS: We evaluated the independent, mutually adjusted, and pairwise joint associations between self-reported hardships and birthweight for gestational age z-scores in the Chemicals in Our Bodies-2 prospective birth cohort (N = 510) using G-computation. We examined financial hardship, food insecurity, job strain, poor neighborhood environment, low community standing, caregiving, high burden of stressful life events, and unplanned pregnancy collected via questionnaire administered in the second trimester of pregnancy. We used propensity scores to ensure our analyses had sufficient data support and estimated absolute differences in outcomes. RESULTS: Food insecurity was most strongly associated with reduced birthweight for gestational age z-scores individually, with an absolute difference of -0.16, 95% confidence interval (CI) -0.45, 0.14. We observed an unexpected increase in z-scores associated with poor perceived neighborhood environment (0.18, 95% CI -0.04, 0.41). Accounting for coexposures resulted in similar findings. The pairwise joint effects were strongest for food insecurity in combination with unplanned pregnancy (-0.45, 95% CI -0.93, 0.02) and stressful life events (-0.42, 95% CI -0.90, 0.05). Poor neighborhood environment in combination with caregiving was associated with an increase in z-scores (0.47, 95% CI -0.01, 0.95). CONCLUSIONS: Our results are consistent with the hypothesis that experiencing food insecurity during pregnancy, alone and in combination with stressful life events and unplanned pregnancy, may affect fetal growth.

Bisphosphonate Treatment Beyond 5 Years and Hip Fracture Risk in Older Women.

Importance: Clinical trials have demonstrated the antifracture efficacy of bisphosphonate drugs for the first 3 to 5 years of therapy. However, the efficacy of continuing bisphosphonate for as long as 10 years is uncertain. Objective: To examine the association of discontinuing bisphosphonate at study entry, discontinuing at 2 years, and continuing for 5 additional years with the risk of hip fracture among women who had completed 5 years of bisphosphonate treatment at study entry. Design, Setting, and Participants: This cohort study included women who were members of Kaiser Permanente Northern and Southern California, 2 integrated health care delivery systems, and who had initiated oral bisphosphonate and completed 5 years of treatment by January 1, 2002, to September 30, 2014. Data analysis was conducted from January 2018 to August 2020. Exposure: Discontinuation of bisphosphonate at study entry (within a 6-month grace period), discontinuation at 2 years (within a 6-month grace period), and continuation for 5 additional years. Main Outcomes and Measures: The outcome was hip fracture determined by principal hospital discharge diagnoses. Demographic, clinical, and pharmacological data were ascertained from electronic health records. Results: Among 29 685 women (median [interquartile range] age, 71 [64-77] years; 17 778 [60%] non-Hispanic White individuals), 507 incident hip fractures were identified. Compared with bisphosphonate discontinuation at study entry, there were no differences in the cumulative incidence (ie, risk) of hip fracture if women remained on therapy for 2 additional years (5-year risk difference [RD], -2.2 per 1000 individuals; 95% CI, -20.3 to 15.9 per 1000 individuals) or if women continued therapy for 5 additional years (5-year RD, 3.8 per 1000 individuals; 95% CI, -7.4 to 15.0 per 1000 individuals). While 5-year differences in hip fracture risk comparing continuation for 5 additional years with discontinuation at 2 additional years were not statistically significant (5-year RD, 6.0 per 1000 individuals; 95% CI, -9.9 to 22.0 per 1000 individuals), interim hip fracture risk appeared lower if women discontinued after 2 additional years (3-year RD, 2.8 per 1000 individuals; 95% CI, 1.3 to 4.3 per 1000 individuals; 4-year RD, 9.3 per 1000 individuals; 95% CI, 6.3 to 12.3 per 1000 individuals) but not without a 6-month grace period to define discontinuation. Conclusions and Relevance: In this study of women treated with bisphosphonate for 5 years, hip fracture risk did not differ if they discontinued treatment compared with continuing treatment for 5 additional years. If women continued for 2 additional years and then discontinued, their risk appeared lower than continuing for 5 additional years. Discontinuation at other times and fracture rates during intervening years should be further studied.

The association of maternal psychosocial stress with newborn telomere length.

BACKGROUND: Telomere length in early life predicts later length, and shortened telomere length among adults and children has been linked to increased risk of chronic disease and mortality. Maternal stress during pregnancy may impact telomere length of the newborn. METHODS: In a diverse cohort of 355 pregnant women receiving prenatal and delivery care services at two hospitals in San Francisco, California, we investigated the relationship between self-reported maternal psychosocial stressors during the 2nd trimester of pregnancy and telomere length (T/S ratio) in newborn umbilical cord blood leukocytes. We examined financial strain, food insecurity, high job strain, poor neighborhood quality, low standing in one's community, experience of stressful/traumatic life events, caregiving for a dependent family member, perceived stress, and unplanned pregnancy. We used linear regression and Targeted Minimum Loss-Based Estimation (TMLE) to evaluate the change in the T/S ratio associated with exposure to each stressor controlling for maternal age, education, parity, race/ethnicity, and delivery hospital. RESULTS: In TMLE analyses, low community standing (-0.09; 95% confidence interval [CI]-0.19 to 0.00) and perceived stress (-0.07; 95% CI -0.15 to 0.021 was marginally associated with shorter newborn telomere length, but the associations were not significant after adjusting for multiple comparisons. All linear regression estimates were not statistically significant. Our results also suggest that the association between some maternal stressors and newborn telomere length varies by race/ethnicity and infant sex. CONCLUSIONS: This study is the first to examine the joint effect of multiple stressors during pregnancy on newborn TL using a flexible modeling approach.

Risk of complete atypical femur fracture with Oral bisphosphonate exposure beyond three years.

BACKGROUND: Bisphosphonate (BP) therapy has been associated with atypical femur fracture (AFF). However, the threshold of treatment duration leading to increased AFF risk is unclear. In a retrospective cohort of older women initiating BP, we compared the AFF risk associated with treatment for at least three years to the risk associated with treatment less than three years. METHODS: We used observational data from a large population of female members of an integrated healthcare system who initiated oral BP during 2002-2014. Women were retrospectively followed for incident AFF confirmed by radiologic adjudication. Demographic data, pharmacologic exposures, comorbidity, bone density, and fracture history were ascertained from electronic health records. Inverse probability weighting was used to estimate risk differences comparing the cumulative incidence (risk) of AFF if women discontinued BP within three years to the cumulative incidence of AFF if women continued BP for three or more years, adjusting for potential time-dependent confounding by the aforementioned factors. RESULTS: Among 87,820 women age 45-84 years who initiated BP (mean age 68.6, median T-score - 2.6, 14% with prior major osteoporotic fracture), 16,180 continued BP for three or more years. Forty-six confirmed AFFs occurred during follow-up in the two groups. AFF-free survival was greater for BP treatment < 3 years compared to treatment ≥3 years (p = 0.004 comparing areas under survival curves). At five years, the risk of AFF was 27 per 100,000 (95% confidence interval, CI: 8-46) if women received BP treatment < 3 years and 120 per 100,000 (95% CI: 56-183) if women received BP treatment ≥3 years (risk difference 93 per 100,000, 95% CI: 30-160). By ten years, the risks were 27 (95% CI: 8-46) and 363 (95% CI: 132-593) per 100,000 for BP treatment < 3 and ≥ 3 years, respectively (risk difference 336 per 100,000, 95% CI: 110-570). CONCLUSIONS: Bisphosphonate treatment for 3 or more years was associated with greater risk of AFF than treatment for less than 3 years. Although AFFs are uncommon among BP-treated women, this increased risk should be considered when counseling women about long-term BP use. Future studies should further characterize the dose-response relationship between BP duration and incident AFF and identify patients at highest risk.

Associations between prenatal maternal exposure to per- and polyfluoroalkyl substances (PFAS) and polybrominated diphenyl ethers (PBDEs) and birth outcomes among pregnant women in San Francisco.

BACKGROUND: Perfluoroalkyl substances (PFAS) and polybrominated diphenyl ethers (PBDEs) are used in consumer products for their water repellent and flame retardant properties, respectively. However, there is widespread prenatal exposure and concern about their potential harm to the developing fetus. Here, we utilized data from a demographically diverse cohort of women in San Francisco, CA to examine associations between prenatal exposure to PFAS and PBDEs with gestational age and birth weight for gestational age z-scores. METHODS: Women included in this analysis were enrolled in the Chemicals in our Bodies (CIOB) cohort study (N = 506). PFAS and PBDEs were measured in serum obtained during the second trimester of pregnancy. Linear regression models were used to calculate crude and adjusted ß coefficients for the association between PFAS and PBDE concentrations in tertiles and gestational age and birth weight z-scores. Individual PFAS and PBDE concentrations, as well as their sums, were examined in separate models. RESULTS: The highest compared to lowest tertile of BDE-47 was associated with shorter gestational age (ß = - 0.49, 95% confidence interval [CI] = - 0.95, - 0.02). Additionally, exposure to BDE-47 and BDE-99 in the middle tertile was also associated with a reduction in birth weight z-scores (ß = - 0.26, 95% CI = -0.48, - 0.04; ß = - 0.25, 95% CI = -0.47, - 0.04, respectively) compared to those in the lowest tertile of exposure. No consistent associations were observed between increasing PFAS concentrations and gestational age or birth weight z-scores. DISCUSSION: Among a diverse group of pregnant women in the San Francisco Bay Area, we found non-linear associations between prenatal exposure to PBDEs during the second trimester of pregnancy and birth weight z-scores. However, most PFAS congeners were not associated with adverse birth outcomes. PFAS and PBDE concentrations were lower in our cohort relative to other studies. Future research should assess the effects of emerging and persistent PFAS and PBDEs on birth outcomes, as some congeners are being phased out and replaced by chemically similar structures.

Relationships between psychosocial stressors among pregnant women in San Francisco: A path analysis.

Pregnant women who experience psychosocial stressors, such as stressful life events, poor neighborhood quality, and financial hardship, are at an increased risk for adverse pregnancy outcomes. Yet, few studies have examined associations between multiple stressors from different sources, which may be helpful to better inform causal pathways leading to adverse birth outcomes. Using path analysis, we examined associations between multiple self-reported stressor exposures during and before pregnancy in the Chemicals in Our Bodies-2 study (N = 510), a demographically diverse cohort of pregnant women in San Francisco. We examined associations between eight self-reported exposures to stressors and three responses to stress which were assessed via interview questionnaire at the 2nd trimester. Stressors included: neighborhood quality, stressful life events, caregiving, discrimination, financial strain, job strain, food insecurity, and unplanned pregnancy. Perceived stress, depression, and perceived community status were included as indicators of self-reported stress response. Our model indicated that women who experienced discrimination and food insecurity had a 3.76 (95% confidence interval [CI] = 1.60, 5.85) and 2.67 (95% CI = 1.31, 4.04) increase in depression scale scores compared to women who did not experience discrimination and food insecurity, respectively. We additionally identified job strain and caregiving for an ill family member as strong predictors of increased depressive symptoms (ß = 1.63, 95% CI = 0.29, 3.07; ß = 1.48, 95% CI = 0.19, 2.70, respectively). Discrimination, food insecurity, and job strain also influenced depression indirectly through the mediating pathway of increasing perceived stress, although indirect effects were less precise. In our study population, women who experienced discrimination, food insecurity, job strain and caregiving for an ill family member had an increased number of depressive symptoms compared to women who did not experience these stressors. Results from our study highlight the complex relationships between stressors and stress responses and may help to identify possible mediating pathways leading to adverse pregnancy outcomes.

Determinants of Oral Bisphosphonate Use Beyond 5 Years.

BACKGROUND: Few studies have examined factors that determine bisphosphonate (BP) continuation beyond 5 years in clinical practice. OBJECTIVE: To investigate factors associated with BP continuation among women who completed 5 years of BP therapy. METHODS: Women who received 5 consecutive years of oral BP treatment entered the cohort during 2002-2014 and were followed up to 5 additional years. Multivariable logistic regression was used to evaluate the association of demographic and clinical factors with adherent treatment continuation. RESULTS: The cohort included 19,091 women with a median age of 72 years. Baseline and time-varying factors associated with increased odds of BP continuation after 5 years were (a) most recent bone mineral density (BMD) T-score -2 to -2.4 (OR = 1.31, 95% CI = 1.25-1.38), T-score -2.5 to -2.9 (OR = 1.48, 95% CI = 1.39-1.57), and T-score ≤ -3.0 (OR = 1.57, 95% CI = 1.47-1.68) versus T-scores above -2.0; (b) index date before 2008 (OR =1.35, 95% CI = 1.29-1.41); and (c) diabetes mellitus (OR = 1.08, 95% CI = 1.01-1.16). In contrast, factors associated with decreased odds of BP continuation were (a) recent hip (OR = 0.61, 95% CI = 0.52-0.71) or humerus (OR = 0.79, 95% CI = 0.66-0.94) fracture or fracture other than hip, wrist, spine, or humerus (OR = 0.90, 95% CI = 0.84-0.97); (b) Charlson Comorbidity Index score > 2 (OR = 0.91, 95% CI = 0.84-0.98); (c) history of rheumatoid arthritis (OR = 0.89, 95% CI = 0.80-0.99); (d) Hispanic (OR = 0.89, 95% CI=0.85-0.94) or Asian (OR = 0.90, 95% CI = 0.85-0.94) race/ethnicity; and (e) use of proton pump inhibitors (OR = 0.65, 95% CI = 0.59-0.71). Patient age and fracture before BP initiation were not associated with treatment continuation. CONCLUSIONS: Clinical factors predicting continued BP treatment beyond 5 years include low BMD T-score, absence of recent fracture, and earlier era of treatment. Use of proton pump inhibitors was associated with lower likelihood of BP continuation. Other clinical and demographic factors were also noted to have variable effects on BP treatment continuation. DISCLOSURES: This study was supported by a grant from the National Institute on Aging and National Institute of Arthritis, Musculoskeletal and Skin Diseases at the National Institutes of Health (NIH; R01AG047230, S1). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH or Kaiser Permanente. Lo has received previous research funding from Amgen and Sanofi, unrelated to the current study. Adams has received previous research funding from Merck, Amgen, Otsuka, and Radius Health, unrelated to the current study. Ettinger has served as an expert witness for Teva Pharmaceuticals, unrelated to the current study. Ott previously attended a scientific advisory meeting for Amgen but declined the honorarium. The other authors have nothing to disclose. These data were presented at the 2018 Annual Meeting of the American Society of Bone and Mineral Research (ASBMR), September 28-October 1, 2018, Montreal, Quebec, Canada.

Heightened susceptibility: A review of how pregnancy and chemical exposures influence maternal health.

Pregnancy is a unique period when biological changes can increase sensitivity to chemical exposures. Pregnant women are exposed to multiple environmental chemicals via air, food, water, and consumer products, including flame retardants, plasticizers, and pesticides. Lead exposure increases risk of pregnancy-induced hypertensive disorders, although women's health risks are poorly characterized for most chemicals. Research on prenatal exposures has focused on fetal outcomes and less on maternal outcomes. We reviewed epidemiologic literature on chemical exposures during pregnancy and three maternal outcomes: preeclampsia, gestational diabetes, and breast cancer. We found that pregnancy can heighten susceptibility to environmental chemicals and women's health risks, although variations in study design and exposure assessment limited study comparability. Future research should include pregnancy as a critical period for women's health. Incorporating biomarkers of exposure and effect, deliberate timing and method of measurement, and consistent adjustment of potential confounders would strengthen research on the exposome and women's health.

Using Pharmacy Data and Adherence to Define Long-Term Bisphosphonate Exposure in Women.

BACKGROUND: Assigning drug exposure is a necessary first step in examining bisphosphonate (BP) treatment in observational studies using pharmacy data. OBJECTIVE: To determine whether the choice of adherence level using the proportion of days covered (PDC) affected BP exposure assignment. METHODS: 10,381 female health plan members who initiated oral BP therapy between 2002 and 2010 and had received 5 consecutive years of treatment were identified and subsequently followed up to 5 additional years. In each 90-day interval of follow-up, a woman was considered "on treatment" if she received the drug for more than a predetermined PDC based on pharmacy days supply and "off treatment" if she received the drug for less than that PDC. Women who continued on therapy above the PDC threshold during follow-up were considered continuously on therapy. Women who were off treatment during the first 90-days of follow-up were classified as off therapy and were followed to determine if they remained continuously off treatment. This study evaluated the extent to which varying the PDC threshold (≥ 0.5, ≥ 0.6, and ≥ 0.7) affected the proportion of women classified as "continuously on" or "continuously off" BP during follow-up. RESULTS: Under PDC thresholds of 0.5, 0.6, and 0.7, 48%, 43%, and 36% of women who remained on follow-up were categorized as continuously on treatment at year 2 of follow-up, and 18%, 14%, and 12% were categorized as continuously on treatment by the end of follow-up. Using these same PDC thresholds, 9%, 12%, and 15% of women were categorized as off therapy during the first quarter of follow-up and were highly likely to remain off therapy: 4%, 5%, and 5% were classified as continuously off therapy at year 2, and 4% of women were classified as such by the end of follow-up for all 3 thresholds. CONCLUSIONS: A PDC of 0.6 was chosen as a practical threshold for drug adherence. Varying the PDC to 0.5 or 0.7 resulted in modest changes in the proportions of women considered continuously on BP therapy. DISCLOSURES: This study was supported by a grant from the National Institute of Aging and National Institute of Arthritis, Musculoskeletal and Skin Diseases at the National Institutes of Health (R01AG047230, S1). Lo has received previous research funding from Amgen and Sanofi, outside of the current study. Chandra has received previous research funding from Amgen outside of the current study. Adams has received previous research funding from Merck, Amgen, Otsuka, and Radius Health, outside of the current study. Ott previously attended a scientific advisory meeting for Amgen but declined the honorarium. Ettinger previously served as an expert witness for Teva Pharmaceuticals.

Metalworking Fluids and Colon Cancer Risk: Longitudinal Targeted Minimum Loss-based Estimation.

Metalworking fluids (MWFs) are a class of complex mixtures of chemicals and oils, including several known carcinogens that may pose a cancer hazard to millions of workers. Reports on the relation between MWFs and incident colon cancer have been mixed. METHODS: We investigated the relation between exposure to straight, soluble, and synthetic MWFs and the incidence of colon cancer in a cohort of automobile manufacturing industry workers, adjusting for time-varying confounding affected by prior exposure to reduce healthy worker survivor bias. We used longitudinal targeted minimum loss-based estimation (TMLE) to estimate the difference in the cumulative incidence of colon cancer comparing counterfactual outcomes if always exposed above to always exposed below an exposure cutoff while at work. Exposure concentration cutoffs were selected a priori at the 90th percentile of total particulate matter for each fluid type: 0.034, 0.400, and 0.003 for straight, soluble, and synthetic MWFs, respectively. RESULTS: The estimated 25-year risk differences were 3.8% (95% confidence interval [CI] = 0.7, 7.0) for straight, 1.3% (95% CI = -2.3, 4.8) for soluble, and 0.2% (95% CI = -3.3, 3.7) for synthetic MWFs, respectively. The corresponding risk ratios were 2.39 (1.12, 5.08), 1.43 (0.67, 3.04), and 1.08 (0.51, 2.30) for straight, soluble, and synthetic MWFs, respectively. CONCLUSIONS: By controlling for time-varying confounding affected by prior exposure, a key feature of occupational cohorts, we were able to provide evidence for a causal effect of straight MWF exposure on colon cancer risk that was not found using standard analytical techniques in previous reports.

Chronic inflammation and risk of lung cancer in older adults in the health, aging and body composition cohort study.

OBJECTIVES: We examined the association between three inflammatory markers (Interleukin (IL)-6, C-reactive protein (CRP), tumor necrosis factor (TNF)-α) and incident lung cancer using baseline, updated, and averaged inflammatory measures in older adults. METHODS: We fitted multivariable Cox models to assess whether circulating levels of inflammation markers were associated with incident lung cancers in the Health Aging, Body and Composition (HealthABC) prospective cohort of 3075 older adults aged 70-79 years at baseline. IL-6 and CRP were measured biennially, whereas TNF-α was measured at baseline. RESULTS: Baseline levels of IL-6 were significantly associated with incident lung cancer risk in a model that adjusted for age, gender, race, and site (Model 1) (Hazard RatioT3 vs. T1: 3.34, 95% Confidence Interval: 1.91, 5.85) and in a model adjusted for health factors linked to chronic inflammation (Model 2) (HR T3 vs. T1: 2.57, 95% CI: 1.41, 4.65). The associations observed in time-updated IL-6 (HR T3 vs. T1: 2.47, 95% CI: 1.43, 4.28), cumulatively averaged IL-6 (HR T3 vs. T1: 2.47, 95% CI: 1.43, 4.35), and baseline CRP levels (HR T3 vs. T1: 1.85, 95% CI: 1.11, 3.08) with incident lung cancer in Model 1 were not statistically significant in Model 2. CONCLUSIONS: Baseline CRP and IL-6 levels were associated with increased risk of lung cancer in Model 1 and both models, respectively. Chronic IL-6 inflammation, as quantified by repeated measures was associated with incident lung cancer in Model 1, but not Model 2. Further research is needed to understand the role of CRP and IL-6 in lung carcinogenesis.

Contrasting Causal Effects of Workplace Interventions.

Occupational exposure guidelines are ideally based on estimated effects of static interventions that assign constant exposure over a working lifetime. Static effects are difficult to estimate when follow-up extends beyond employment because their identifiability requires additional assumptions. Effects of dynamic interventions that assign exposure while at work, allowing subjects to leave and become unexposed thereafter, are more easily identifiable but result in different estimates. Given the practical implications of exposure limits, we explored the drivers of the differences between static and dynamic interventions in a simulation study where workers could terminate employment because of an intermediate adverse health event that functions as a time-varying confounder. The two effect estimates became more similar with increasing strength of the health event and outcome relationship and with increasing time between health event and employment termination. Estimates were most dissimilar when the intermediate health event occurred early in employment, providing an effective screening mechanism.