Purpose:While various studies have highlighted the prognostic significance of pathologic complete response (pCR) after neoadjuvant chemotherapy (NAT), the impact of additional adjuvant therapy after pCR is not known.Experimental Design:PubMed was searched for studies with NAT for breast cancer and individual patient-level data was extracted for analysis using plot digitizer software. HRs, with 95% probability intervals (PI), measuring the association between pCR and overall survival (OS) or event-free survival (EFS), were estimated using Bayesian piece-wise exponential proportional hazards hierarchical models including pCR as predictor.Results:Overall, 52 of 3,209 publications met inclusion criteria, totaling 27,895 patients. Patients with a pCR after NAT had significantly better EFS (HR = 0.31; 95% PI, 0.24–0.39), particularly for triple-negative (HR = 0.18; 95% PI, 0.10–0.31) and HER2+ (HR = 0.32; 95% PI, 0.21–0.47) disease. Similarly, pCR after NAT was also associated with improved survival (HR = 0.22; 95% PI, 0.15–0.30). The association of pCR with improved EFS was similar among patients who received subsequent adjuvant chemotherapy (HR = 0.36; 95% PI, 0.19–0.67) and those without adjuvant chemotherapy (HR = 0.36; 95% PI, 0.27–0.54), with no significant difference between the two groups (P = 0.60).Conclusions:Achieving pCR following NAT is associated with significantly better EFS and OS, particularly for triple-negative and HER2+ breast cancer. The similar outcomes with or without adjuvant chemotherapy in patients who attain pCR likely reflects tumor biology and systemic clearance of micrometastatic disease, highlighting the potential of escalation/deescalation strategies in the adjuvant setting based on neoadjuvant response.See related commentary by Esserman, p. 2771

ObjeCtivesTo investigate the cardiovascular safety of nonsteroidal anti-inflammatory drugs (NSAIDs) and estimate the risk of hospital admission for heart failure with use of individual NSAIDs. DesignNested case-control study.setting Five population based healthcare databases from four European countries (the Netherlands, Italy, Germany, and the United Kingdom). PartiCiPantsAdult individuals (age ≥18 years) who started NSAID treatment in 2000-10. Overall, 92 163 hospital admissions for heart failure were identified and matched with 8 246 403 controls (matched via risk set sampling according to age, sex, year of cohort entry). Main OutCOMe MeasureAssociation between risk of hospital admission for heart failure and use of 27 individual NSAIDs, including 23 traditional NSAIDs and four selective COX 2 inhibitors. Associations were assessed by multivariable conditional logistic regression models. The dose-response relation between NSAID use and heart failure risk was also assessed.

Despite falls in rates, absolute numbers of cancer deaths are stable in Europe. The gap between Western and former nonmarket economy countries will likely persist.

Purpose: Deviations from proportional hazards (DPHs), which may be more prevalent in the era of precision medicine and immunotherapy, can lead to underpowered trials or misleading conclusions. We used a meta-analytic approach to estimate DPHs across cancer trials, investigate associated factors, and evaluate data-analysis approaches for future trials.Experimental Design: We searched PubMed for phase III trials in breast, lung, prostate, and colorectal cancer published in a preselected list of journals between 2014 and 2016 and extracted individual patient-level data (IPLD) from Kaplan-Meier curves. We re-analyzed IPLD to identify DPHs. Potential efficiency gains, when DPHs were present, of alternative statistical methods relative to standard log-rank based analysis were expressed as sample-size requirements for a fixed power level.Results: From 152 trials, we obtained IPLD on 129,401 patients. Among 304 Kaplan-Meier figures, 75 (24.7%) exhibited evidence of DPHs, including eight of 14 (57%) KM pairs from immunotherapy trials. Trial type [immunotherapy, odds ratio (OR), 4.29; 95% confidence interval (CI), 1.11-16.6], metastatic patient population (OR, 3.18; 95% CI, 1.26-8.05), and non-OS endpoints (OR, 3.23; 95% CI, 1.79-5.88) were associated with DPHs. In immunotherapy trials, alternative statistical approaches allowed for more efficient clinical trials with fewer patients (up to 74% reduction) relative to log-rank testing.Conclusions: DPHs were found in a notable proportion of time-to-event outcomes in published clinical trials in oncology and was more common for immunotherapy trials and non-OS endpoints. Alternative statistical methods, without proportional hazards assumptions, should be considered in the design and analysis of clinical trials when the likelihood of DPHs is high.

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ObjectivesTo develop and validate a new algorithm to identify patients with rheumatoid arthritis (RA) and estimate disease prevalence using administrative health databases (AHDs) of the Italian Lombardy region.DesignCase–control and cohort diagnostic accuracy study.MethodsIn a randomly selected sample of 827 patients drawn from a tertiary rheumatology centre (training set), clinically validated diagnoses were linked to administrative data including diagnostic codes and drug prescriptions. An algorithm in steps of decreasing specificity was developed and its accuracy assessed calculating sensitivity/specificity, positive predictive value (PPV)/negative predictive value, with corresponding CIs. The algorithm was applied to two validating sets: 106 patients from a secondary rheumatology centre and 6087 participants from the primary care. Alternative algorithms were developed to increase PPV at population level. Crude and adjusted prevalence estimates taking into account algorithm misclassification rates were obtained for the Lombardy region.ResultsThe algorithms included: RA certification by a rheumatologist, certification for other autoimmune diseases by specialists, RA code in the hospital discharge form, prescription of disease-modifying antirheumatic drugs and oral glucocorticoids. In the training set, a four-step algorithm identified clinically diagnosed RA cases with a sensitivity of 96.3 (95% CI 93.6 to 98.2) and a specificity of 90.3 (87.4 to 92.7). Both external validations showed highly consistent results. More specific algorithms achieved >80% PPV at the population level. The crude RA prevalence in Lombardy was 0.52%, and estimates adjusted for misclassification ranged from 0.31% (95% CI 0.14% to 0.42%) to 0.37% (0.25% to 0.47%).ConclusionsAHDs are valuable tools for the identification of RA cases at the population level, and allow estimation of disease prevalence and to select retrospective cohorts.

BackgroundData on utilization patterns and safety of non-steroidal anti-inflammatory drugs (NSAIDs) in children are scarce. The purpose of this study was to investigate the utilization of NSAIDs among children in four European countries as part of the Safety Of non-Steroidal anti-inflammatory drugs (SOS) project.MethodsWe used longitudinal patient data from seven databases (GePaRD, IPCI, OSSIFF, Pedianet, PHARMO, SISR, and THIN) to calculate prevalence rates of NSAID use among children (0–18 years of age) from Germany, Italy, Netherlands, and United Kingdom. All databases contained a representative population sample and recorded demographics, diagnoses, and drug prescriptions. Prevalence rates of NSAID use were stratified by age, sex, and calendar time. The person-time of NSAID exposure was calculated by using the duration of the prescription supply. We calculated incidence rates for serious adverse events of interest. For these adverse events of interest, sample size calculations were conducted (alpha = 0.05; 1-beta = 0.8) to determine the amount of NSAID exposure time that would be required for safety studies in children.ResultsThe source population comprised 7.7 million children with a total of 29.6 million person-years of observation. Of those, 1.3 million children were exposed to at least one of 45 NSAIDs during observation time. Overall prevalence rates of NSAID use in children differed across countries, ranging from 4.4 (Italy) to 197 (Germany) per 1000 person-years in 2007. For Germany, United Kingdom, and Italian pediatricians, we observed high rates of NSAID use among children aged one to four years. For all four countries, NSAID use increased with older age categories for children older than 11. In this analysis, only for ibuprofen (the most frequently used NSAID), enough exposure was available to detect a weak association (relative risk of 2) between exposure and asthma exacerbation (the most common serious adverse event of interest).ConclusionsPatterns of NSAID use in children were heterogeneous across four European countries. The SOS project platform captures data on more than 1.3 million children who were exposed to NSAIDs. Even larger data platforms and the use of advanced versions of case-only study designs may be needed to conclusively assess the safety of these drugs in children.

Background: While the prognostic significance of pathological complete response (pCR) after neoadjuvant chemotherapy is relatively well established, the impact of adjuvant therapy in modulating relationship between pCR and long term outcomes is less clear. The primary objective of this study was to conduct a systematic review of published neoadjuvant chemotherapy studies to comprehensively evaluate the association between pCR with subsequent breast cancer recurrence and mortality, stratified by breast cancer subtypes and adjuvant chemotherapy usage. Methods: Based on PRISMA guidelines, a search of PubMed from inception until September 2016 was performed to identify eligible studies. Inclusion criteria were clinical trials or studies featuring neoadjuvant chemotherapy that reported pCR results as well as recurrence and/or survival. Hazard Ratios (HRs) and 95% probability intervals (PI) were estimated for endpoints using hierarchical models. We obtained the individual patient-level data for statistical analysis using plot digitizer software. Hazard ratios (HRs), with 95% PIs, measuring the association between pCR and OS or recurrence, were estimated using Bayesian piecewise-exponential proportional hazards hierarchical models including pCR as a predictor. Random effects model was utilized to account for between-study variability in baseline hazards and the variability of the pCR effect between studies. P-value of 0.05 was considered statistically significant. Results: A total of 3,209 citations with associated abstracts were reviewed, and 27,895 patients from 52 studies met inclusion criteria. Attainment of pCR, as compared to absence of pCR, was associated with significantly reduced disease recurrence overall (HR 0.31, 95% PI: 0.24-0.39), and in triple negative (HR 0.18, 95% PI: 0.10-0.31), human epidermal growth factor 2-positive (HER2+) (HR 0.32, 95% PI: 0.21-0.47), and trended towards significance for HR+ breast cancer (HR 0.15, 95% PI: 0.02-1.10). Similarly, pCR after neoadjuvant chemotherapy was also associated with reduced mortality overall (HR 0.22, 95% PI: 0.15-0.30), and among all three major disease subtypes. The association of pCR with reduced recurrence was similar among studies where patients received subsequent adjuvant chemotherapy (HR 0.34, 95% PI: 0.18-0.61) and those without adjuvant chemotherapy (95% HR 0.36, PI: 0.27-0.54). The association between magnitude of pCR change and corresponding change in survival will be presented at the meeting. Conclusion: Achieving pCR following neoadjuvant chemotherapy is associated with significantly improved disease recurrence and survival, particularly for triple negative and HER2+ breast cancer. The similar outcomes with/without adjuvant chemotherapy in patients who attain pCR after neoadjuvant chemotherapy likely reflects tumor biology and suggests adjuvant chemotherapy could potentially be abbreviated in certain circumstances, and highlights the need for further research to evaluate clinical utility of escalation/de-escalation strategies in the adjuvant setting based on neoadjuvant response for patients with localized breast cancer. Citation Format: Spring LM, Fell G, Arfe A, Trippa L, Greenup R, Reynolds K, Smith BL, Moy B, Isakoff SJ, Parmigiani G, Bardia A. Pathological complete response after neoadjuvant chemotherapy and impact on breast cancer recurrence and mortality, stratified by breast cancer subtypes and adjuvant chemotherapy usage: Individual patient-level meta-analyses of over 27,000 patients [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr GS2-03.