Breast Cancer Risk after Metformin Initiation in Older Women: the Role of Study Design, Potential Confounding by Body Mass Index, and Differential Detection

Several observational studies reported that metformin may reduce breast cancer risk; however, many of these studies were affected by time-related biases. Additionally, confounding by unmeasured body mass index (BMI) and differential detection for breast cancer have not been examined in metformin-breast cancer studies. The dissertation aimed to examine the relative risk of breast cancer for older women initiating metformin versus sulfonylureas, avoiding time-related bias and accounting for potential bias due to unmeasured confounding and differential screening mammography. Using 2007-2011 US Medicare claims data, we identified cohorts of cancer-free women aged 65+ who initiated monotherapy with metformin or sulfonylureas. Hazard ratios of breast cancer were estimated comparing metformin to sulfonylureas initiators, using weighted Cox models. Unmeasured confounding by BMI and smoking was adjusted by propensity score calibration using external information from Medicare Current Beneficiary Survey 2006-2009 panels. Among new users of Medicare claims, we compared the risks of screening mammograms and screen-detected breast cancer in 12 months pre- and post-initiation between metformin and sulfonylureas initiators. Metformin initiators did not have reduced risks of breast cancer compared with sulfonylureas initiators (Hazard Ratio: 1.08; 95% Confidence Interval: 0.81 to 1.44). Externally controlling for BMI and smoking did not affect the estimate, indicating a little independent effect of BMI and smoking on metformin relative to sulfonylureas prescribing. Metformin initiators were not only more frequently screened for breast cancer than sulfonylureas initiators, but they also had higher probabilities of screen-detected breast cancer both in 12 months before and after initiation. The results indicate possible detection bias due to differential screening mammography, but the absolute difference in screen-detected breast cancer is too small to explain observing no metformin-breast cancer association assuming a real protective effect of metformin. This study provides no support for reduced risks of breast cancer after initiation of metformin compared with a clinical alternative, sulfonylureas, in older women. Our findings support the notion that reduced breast cancer risks in metformin users observed in previous studies is likely due to time-related biases, and emphasize the importance of conducting observational studies with rigorous, state-of-the art design to avoid observing spurious effects or missing real ones.Doctor of Philosoph

Risk of colorectal cancer after initiation of orlistat : matched cohort study

To examine the risk of colorectal cancer after orlistat initiation in the UK population.; Retrospective matched cohort study.; Data from the UK Clinical Practice Research Datalink from September 1998 to December 2008.; 33,625 adults aged 18 years or over who started treatment with orlistat; each orlistat initiator was matched to up to five non-initiators (n=160,347) on age, sex, body mass index, and calendar time.; Associations between orlistat initiation and the risk of colorectal cancer, assessed by calculating hazard ratios with propensity score adjusted Cox proportional hazard models.; Of 193,972 patients with a median age of 47 (interquartile range 37-57) years, 77% were women and approximately 90% were obese (body mass index ≥ 30). Orlistat initiators were more likely to have a previous history of diabetes or hypertension and to receive prescriptions for anti-diabetes drugs, statins, and aspirin compared with non-initiators. In the intention to treat analysis, 57 colorectal cancer events were identified among orlistat initiators and 246 among non-initiators, with median follow-up times of 2.96 and 2.86 years, respectively. The calculated incidence rate of colorectal cancer per 100,000 person years was 53 (95% confidence interval 41 to 69) for orlistat initiators and 50 (44 to 57) for non-initiators. Orlistat initiation was not associated with a higher risk of colorectal cancer (adjusted hazard ratio 1.11, 95% confidence interval 0.84 to 1.47). Findings were robust in the as treated analyses and in patients who were aged 50 years or over, were morbidly obese, or had a history of diabetes.; This study found no evidence of an increased risk of colorectal cancer after the initiation of orlistat. It is limited by the relatively short follow-up time, and the possibility of adverse effects of long term orlistat use on risk of colorectal cancer cannot be excluded

Real-World Response and Outcomes in Patients With NSCLC With EGFR Exon 20 Insertion Mutations

Introduction: This study describes treatment patterns and outcomes in patients with NSCLC with EGFR exon 20 insertions (EGFRex20ins) in the United States. Methods: The Flatiron Health electronic health record database was used to select three cohorts among patients diagnosed with NSCLC with EGFRex20ins (January 1, 2011–February 29, 2020): (1) first-line (1L) or patients receiving 1L therapy after documented EGFRex20ins; (2) second or later-line (≥2L) or patients receiving ≥2L therapy after documented EGFRex20ins; and (3) ≥2L postplatinum trial-aligned, or ≥2L patients previously treated with platinum chemotherapy whose baseline characteristics aligned with key eligibility criteria (initiating new treatment after documented EGFRex20ins and ≥1 previous treatment excluding mobocertinib or amivantamab) of the mobocertinib trial NCT02716116. Real-world end points were confirmed overall response rate, overall survival, and progression-free survival. Results: Of 237 patients with EGFRex20ins-mutated NSCLC, 129 and 114 patients were included in the 1L and ≥2L cohorts, respectively. In 1L patients, platinum chemotherapy plus nonplatinum chemotherapy (31.0%) and EGFR tyrosine kinase inhibitors (28.7%) were the most common regimens. In ≥2L patients, immuno-oncology monotherapy (28.1%) and EGFR tyrosine kinase inhibitors (17.5%) were the most common index treatments. For any 1L, ≥2L, and ≥2L postplatinum trial-aligned patients, the confirmed overall response rate was 18.6%, 9.6%, and 14.0%, respectively; the median overall survival was 17.0, 13.6, and 11.5 months; the median progression-free survival was 5.2, 3.7, and 3.3 months, respectively. Conclusions: The outcomes for patients with NSCLC with EGFRex20ins were poor. This real-world study provides a benchmark on treatment outcomes in this patient population and highlights the unmet need for improved therapeutic options

The impact of TP53 co-mutations and immunologic microenvironment on outcome of lung cancer with EGFR exon 20 insertions

Background: EGFR exon20 insertions (ex20ins) are targeted by novel compounds in non-small-cell lung cancer (NSCLC). However, data about outcome under conventional therapies and the influence of molecular features are scarce. Patients and methods: We retrospectively analysed 118 patients with evaluation of radiologic response based on RECIST v1.1. TP53 status was available for 88 cases. Results: Platinum doublets and chemoimmunotherapy showed similar response rates (20-25%), disease control rates (80%) and median progression-free survival (mPFS, asymptotic to 7 months), which were longer compared to monochemotherapy (9%, 59%, 4.1 months), EGFR inhibitors (0%, 46%, 3.0) and PD-(L)1 inhibitors (0%, 30%, 2.1; p 1 year) occasionally occurred under EGFR inhibitors for both 'near-' and 'far-loop' variants. Conclusions: Platinum doublets and chemoimmunotherapy have the highest activity with ORR of 20-25% and mPFS of approximately 7 months, regardless of the cytotoxic partner, while PD-(L)1 inhibitors show limited efficacy. TP53 mutations, brain metastases and a lower tumour CD8/Th1-cell ratio are independently associated with shorter survival. (C) 2022 Elsevier Ltd. All rights reserved