Hazard Ratio Estimates Research Articles

Abstract P1-21-03: Efficacy of tyrosine kinase inhibitors (TKI) in the treatment of patients with HER2-positive (HER2+) breast cancer with or without brain metastases: A systematic review and meta-analysis

Abstract BACKGROUND: Brain metastases (BM) occur in up to 50% of patients (pts) with HER2+ metastatic breast cancer (MBC) and are associated with high morbidity and mortality. While the treatment outcomes of patients (pts) without BM are largely determined by their extra-cranial activity, the outcomes of pts with BM are also influenced by the treatment’s activity in the central nervous system (CNS). TKI-based regimens, have been incorporated into the management of pts with HER2+ MBC. This systematic review aims to assess the clinical outcomes of in pts with or without BM treated with TKI-containing regimens vs those treated with non-TKI-containing regimens. METHODS: A systematic literature search of PubMed, Embase, CENTRAL, and conference proceedings (ASCO, SABCS, ESMO, and ESMO Breast) up to June 20, 2021, was conducted to identify randomized clinical trials (RCT) comparing systemic therapies with anti-HER2 TKI-containing regimens and non-TKI-regimens in pts with HER2+ MBC (PROSPERO ID: CRD42021252332). Studies were screened for the availability of data on progression-free survival (PFS) and overall survival (OS) in subgroups of pts with and without BM at baseline. A random-effect model was used to calculate PFS and OS, reported as pooled hazard ratio (HR) with 95% confidence intervals (CI). The Higgins I2 index was used to evaluate the heterogeneity between studies. To assess whether the pooled HRs estimates were stable or strongly dependent on one or few studies, sensitivity analyses were conducted by interactively recalculating the pooled HRs estimates after exclusion of each single study. RESULTS: Of 1,671 identified records, 5 RCT were included involving 2,437 pts (490 with and 1,947 without BM at baseline). Intervention arms included tucatinib, lapatinib, pyrotinib or afatinib in combination with cytotoxic chemotherapy ± trastuzumab; control arms included cytotoxic chemotherapy ± trastuzumab or T-DM1. No trial evaluating neratinib met inclusion criteria. All trials allowed the inclusion of pts with stable and asymptomatic BM, while one (HER2CLIMB) also included pts with progressing/untreated BM. Previous treatment with trastuzumab was reported in 92.8% (n=2,262) of the pts. Regarding PFS, a non-statistically significant trend favoring TKI-containing regimens was observed both in pts with BM (HR 0.67, 95% CI 0.41-1.12, p=0.13) and without BM (HR 0.55, 95% CI 0.24-1.26, p=0.16). Substantial heterogeneity was detected in both subgroups (I2 = 64.4%, p=0.024 and I2 = 95.6%, p 0.001, respectively). Sensitivity analysis, excluding each study one by one, demonstrated a significant PFS benefit favoring TKI-containing regimens in pts with BM after the exclusion from the analysis of afatinib (Lux-Breast1), a non-HER2-specific TKI (HR 0.56, 95% CI 0.35-0.90, p=0.016), with no significant heterogeneity (I2 = 46.9%, p=0.13). Regarding OS, a non-statistically significant trend favoring non-TKI regimens was observed both in pts with BM (HR 1.28, 95% CI 0.48-3.40, p=0.62) and without BM (HR 1.02, 95% CI 0.53-1.98, p=0.94). Substantial heterogeneity was detected in both subgroups (I2 = 86.8%, p=0.001 and I2 = 85.7%, p=0.008, respectively). Sensitivity analysis showed no significant impact on OS after exclusion of each study one by one. No publication bias was detected by Egger’s test. CONCLUSION: Our results suggest a similar magnitude of OS and PFS benefit from anti-HER2 TKI-containing regimens in pts with or without BM. Sensitivity analysis including only trials that evaluated regimens containing tucatinib, lapatinib or pyrotinib demonstrated a significant PFS benefit favoring TKI-containing regimens in pts with BM, emphasizing the relevance of CNS involvement for the interpretation of the results of studies evaluating this class of agents. Citation Format: Guilherme Nader-Marta, Diogo Martins-Branco, Elisa Agostinetto, Marco Bruzzone, Marcello Ceppi, Matteo Lambertini, Nuria Kotecki, Ahmad Awada, Evandro de Azambuja. Efficacy of tyrosine kinase inhibitors (TKI) in the treatment of patients with HER2-positive (HER2+) breast cancer with or without brain metastases: A systematic review and meta-analysis [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-21-03.

Statins Reduce Hepatocellular Carcinoma Risk in Patients with Chronic Kidney Disease and End-Stage Renal Disease: A 17-Year Longitudinal Study.

Simple SummaryStatins are medicines used to treat patients with high lipid levels (hyperlipidemia). Studies have reported that patients undergoing statin therapy are at reduced risk of developing liver cancer. In this study, we compared the risk of developing liver cancer among hyperlipidemic patients with and without statin therapy in three patient groups classified by renal function: normal renal function (NRF) group, chronic kidney disease (CKD) not requiring dialysis, and dialysis-dependent end stage of real disease (ESRD). Our results showed that the risk of developing liver cancer increased progressively from NRF group to CKD and ESRD groups, but was lower for patients receiving statins treatment than non-treated patients. We also found that the statin therapy effectiveness was better in patients taking hydrophilic statins than in those taking lipophilic statins, and in patients taking statin-ezetimibe combination than in those taking statin alone, particularly in the NRF group. Ezetimibe is also an effective option of treating hyperlipidemia.Hepatocellular carcinoma (HCC) is the most common cancer in end-stage renal disease (ESRD) patients in Taiwan. Whether statin therapy associated with the HCC risk in hyperlipidemic patients with chronic kidney disease (CKD) and ESRD is unclear. Using population-based insurance claim data from Taiwan, we identified from hyperlipidemic patients taking statins or not (677,364 versus 867,707) in 1999–2015. Among them, three pairs of propensity score matched statin and non-statin cohorts were established by renal function: 413,867 pairs with normal renal function (NRF), 46,851 pairs with CKD and 6372 pairs with ESRD. Incidence rates of HCC were compared, by the end of 2016, between statin and non-statin cohorts, between hydrophilic statins (HS) and lipophilic statins (LS) users, and between statin-ezetimibe combination therapy (SECT) and statin monotherapy (SM) users. The HCC incidence increased progressively from NRF to CKD and ESRD groups, was lower in the statin cohort than in the non-statin cohort, with the differences of incidence per 10,000 person-years increased from (7.77 vs. 21.4) in NRF group to (15.8 vs. 37.1) in CKD group to (19.1 vs. 47.8) in ESRD group. The incidence increased with age, but the Cox method estimated hazard ratios showed a greater statin effectiveness in older patients. Among statin users, the HCC incidence was lower in HS users than in LS users, and lower in SECT users than in SM users, but the difference was significant only in the NRF group. Hyperlipidemic patients with CKD and ESRD receiving statins are at reduced HCC risks; the treatment effectiveness is superior for HS users than for LS users, and for SECT users than for SM users, but not significant.

Glucagon-Like Peptide 1 Receptor Agonists and Risk of Anaphylactic Reaction Among Patients With Type 2 Diabetes: A Multisite Population-Based Cohort Study.

Case reports and a pharmacovigilance analysis have linked glucagon-like peptide 1 receptor agonists (GLP-1 RAs) with anaphylactic reactions, but real-world evidence for this possible association is lacking. Using databases from the United Kingdom (Clinical Practice Research Datalink) and the United States (Medicare, Optum (Optum, Inc., Eden Prairie, Minnesota), and IBM MarketScan (IBM, Armonk, New York)), we employed a new-user, active comparator study design wherein initiators of GLP-1 RAs were compared with 2 different active comparator groups (initiators of dipeptidyl peptidase 4 (DPP-4) inhibitors and initiators of sodium-glucose cotransporter 2 (SGLT-2) inhibitors) between 2007 and 2019. Propensity score fine stratification weighted Cox proportional hazards models were fitted to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for an anaphylactic reaction. Database-specific HRs were pooled using random-effects models. Compared with the use of DPP-4 inhibitors (n=1,641,520), use of GLP-1 RAs (n=324,098) generated a modest increase in the HR for anaphylactic reaction, with a wide 95% CI (36.9 per 100,000 person-years vs. 32.1 per 100,000 person-years, respectively; HR=1.15, 95% CI: 0.94, 1.42). Compared with SGLT-2 inhibitors (n=366,067), GLP-1 RAs (n=259,929) were associated with a 38% increased risk of anaphylactic reaction (40.7 per 100,000 person-years vs. 29.4 per 100,000 person-years, respectively; HR=1.38, 95% CI: 1.02, 1.87). In this large, multisite population-based cohort study, GLP-1 RAs were associated with a modestly increased risk of anaphylactic reaction when compared with DPP-4 inhibitors and SGLT-2 inhibitors.

Analysis of survival trends, clinical, and molecular characteristics of patients with early-onset colorectal cancer (EOCRC).

59 Background: Over the last decades the incidence of EOCRC (age 50 or less) has dramatically increased, and so has the scientific interest in this field, given that clinical and molecular characteristics in these patients are not well understood, and may be critical to identify prognostic factors. Methods: We conducted a retrospective analysis of 554 patients with metastatic colorectal cancer (mCRC), analyzing the PFS and OS of 68 (12.25%) patients with EOCRC, as well as their clinical and molecular characteristics. We used a log-rank test to compare PFS and OS, and the estimate of hazard ratio (HR) between the studied groups was calculated by means of Cox proportional hazard model. We also used the exact test of Fisher to identify significant association between categoric variants, while Mann-Whitney test was applied to identify significant differences between numeric values. Results: We performed a survival analysis: those patients with EOCRC had significantly higher median PFS in first line of treatment (16.2 vs. 11.3 months, p = 0.042) and significantly higher median OS (121.5 vs. 58.1 months, p = 0.011). Several characteristics were significantly more frequent in patients with EOCRC (n=68): BMI < 18.5 (n = 16, OR = 1.9, p = 0.046), primary tumor site at transverse colon (n = 9, OR = 2.61, p = 0.03) and ECOG 0 (n = 32, OR = 2.21, p = 0.003). Having peritoneal metastases almost reached statistical signification (n = 17, OR = 1.82, p = 0.055). Some other characteristics were less frequent: BMI 25-30 (n = 13, OR = 0.51, p = 0.046), primary tumor site at sigmoid colon (n = 14, OR = 0.49, p = 0.038) and former-smoker status (n = 7, OR = 0.44, p = 0.048). Moreover, mean values of LDH at diagnosis were significantly higher in EOCRC patients (359 U/L vs. 280 U/L, p = 0.015). EOCRC patients received a significantly higher number of lines of chemotherapy (2.94 vs. 2.38, p = 0.027) and underwent more surgeries (2,42 vs. 1.24, p < 0,001) than patients with > 50 years. Significant differences in tumor mutational status (BRAF, KRAS, NRAS, MSI, PI3K and HER2), sex, primary tumor resection or number of metastatic sites between groups were not found. Conclusions: This retrospective analysis showed that EOCRC patients had significant higher rates of PFS in first-line treatment and OS. Moreover, EOCRC patients had more frequently BMI < 18.5, primary tumor located at transverse colon and ECOG 0.

A randomized phase III trial of mFOLFOX7 or CapeOX plus bevacizumab versus 5-FU/l-LV or capecitabine plus bevacizumab as initial therapy in elderly patients with metastatic colorectal cancer: JCOG1018 study (RESPECT).

10 Background: It is uncertain if the addition of oxaliplatin (OX) to fluoropyrimidine plus bevacizumab (BEV) is suitable as initial therapy in elderly patients (pts) with metastatic colorectal cancer (MCRC). Therefore, we conducted a randomized controlled trial to confirm the superiority of the addition of OX in terms of progression-free survival (PFS). This JCOG trial was originally planned as a paralell study with NCCTG, but the NCCTG trial was terminated early. Methods: Key eligibility criteria included unresectable metastatic colorectal cancer, and histologically confirmed adenocarcinoma, aged 70-74 with PS 2 or 75 or older with ECOG PS 0-2. Eligible pts were randomized (1:1) to either no addition of OX or addition. Whether using 5-FU+levoleucovorin calcium (5-FU/ l-LV) or capecitabine (CAPE) was declared before study entry; options included 5-FU/ l-LV+BEV (C), CAPE+BEV (D), mFOLFOX7+BEV (E), or CapeOX+BEV (F). 5-FU/ l-LV regimen omitted bolus 5-FU from the original sLV5FU regimen. The dose of CAPE was adjusted by estimated creatinine clearance. The primary endpoint was PFS. The planned sample size was 250 pts in total to detect a hazard ratio (HR) of 0.75, with a one-sided alpha of 5% and 70% power. The decision rule is that the primary endpoint is met, and the point estimate of HR of overall survival (OS) is less than 0.8. Results: Between Sep 2012 and Mar 2019, 251 pts were randomized. 125 pts were allocated to no addition of OX and 126 pts to addition. Median age was 79, aged 70-74/75-79/80-84/85+:5%/45%/37%/13%, PS 0/1/2:53%/39%/7%. Of 251 pts, 241 pts had PFS events and 223 pts had OS events. Median PFS (mPFS) was 9.4 months (M) (95%CI 8.3–10.3) in no addition of OX and 10.0M (9.0–11.2) in addition (HR 0.837, 90.5%CI [0.673–1.042], one-sided p = 0.086). Median OS was 21.3M (18.7-24.3) in no addition and 19.7M (15.5–25.5) in addition of OX (HR 1.054 [0.810–1.372]). Response rate was 29.5% (21.2-38.8) in no addition of OX and 47.7% (38.1-57.5) in addition. Proportion of pts whose EQ-5D scores improved from baseline to post-treatment in overall score did not differ (odds ratio 0.94 (0.51-1.75)). The deaths of 1 pt in no addition of OX and in 3 pts in addition were deemed treatment-related. Conclusions: The addition of OX has no survival benefit over no addition. OX was not recommended for elderly MCRC pts as initial therapy. Clinical trial information: UMIN000008866.[Table: see text]

Comparative analysis of overall survival in patients with HER2-amplified treatment-refractory metastatic colorectal cancer treated with pertuzumab plus trastuzumab in Mypathway and patients treated in the real-world.

36 Background: ML28897 (MyPathway) is a multi-basket trial evaluating the efficacy and safety of targeted therapies in non-indicated tumor types harboring relevant genetic alterations. In MyPathway, patients with treatment-refractory HER2-amplified metastatic colorectal cancer (mCRC) were enrolled and received pertuzumab plus trastuzumab. In order to facilitate contextualization of the outcome of pertuzumab plus trastuzumab in MyPathway, we conducted a retrospective study to compare with the outcome in real-world HER2-amplified mCRC patients. Methods: Overall survival (OS) was used as the endpoint to compare outcomes from MyPathway (PER/HER arm) and the external control of HER2-amplified mCRC patients treated with any therapy except anti-HER2 therapy in the refractory setting (EC arm) from the US-based de-identified Flatiron Health-Foundation Medicine Clinico-Genomic Database (CGDB). The de-identified data originated from approximately 280 US cancer clinics (̃800 sites of care). OS was defined as time from first treatment to death in the PER/HER arm and from index date (initiation of treatment in the refractory setting) to death in the EC arm. For patients in the CGDB who had met study eligibility criteria at multiple index dates, all eligible index dates were used for the analysis. Standardized mortality ratio weighting based on propensity score was used for deriving the pseudo-population (post-weighting population). In the post-weighting population, multivariate Cox regression models and Kaplan-Meier analyses were used to compare between the arms. A series of sensitivity analyses were conducted to investigate the robustness and consistency of the primary analysis results. Results: The PER/HER arm consisted of 57 patients who had treatment-refractory mCRC with HER2 amplification and enrolled in the MyPathway by August 1, 2017 data cutoff. For the EC arm, 64 HER2-amplified mCRC patients were selected from CGDB collected between January 1, 2011 and December 31, 2019. After applying the predefined inclusion/exclusion criteria set to be similar to those in the MyPathway, 27 eligible index dates were selected from 18 eligible patients and used for primary analysis. In the post-weighting population, the hazard ratio (HR) for OS estimated by multivariate Cox regression model was 0.729 (95% CI: 0.184-3.900) and median survival in the PER/HER arm and the EC arm were 11.47 months (95% CI: 7.72-22.11) and 9.72 months (95% CI: 7.43-22.21), respectively. The results of the all sensitivity analyses were consistent with those in the primary analysis in terms of the point estimate of HR. Conclusions: Despite a small sample size, the totality of findings suggests that the combination of pertuzumab and trastuzumab could have a potential benefit in OS for this population.

Comparative Outcomes of First-Line Chemotherapy for Metastatic Pancreatic Cancer Among the Regimens Used in Japan

Various first-line chemotherapy treatment regimens for patients with metastatic pancreatic cancer have been approved in Japan, including gemcitabine (GEM); fluorouracil, leucovorin, irinotecan, and oxaliplatin combination (FOLFIRINOX); GEM plus albumin-bound paclitaxel (GEM+NPTX), and S-1 (tegafur + gimeracil + oteracil). However, direct comparisons of these chemotherapy regimens are limited. To assess the short-term and long-term outcomes associated with first-line chemotherapy regimens for metastatic pancreatic cancer compared with chemotherapy regimens recommended in Japanese guidelines. In this systematic review and network meta-analysis, the bibliographic databases PubMed, Cochrane Library, and Web of Science, as well as medical journals published between January 1, 2002, and December 31, 2018, were searched for clinical trials comparing chemotherapy regimens. Randomized 2-arm clinical trials evaluating first-line chemotherapy for advanced or metastatic pancreatic cancer were included. The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) Extension Statement for Reporting of Systematic Reviews Incorporating Network Meta-analyses of Health Care Interventions was followed for data abstractions. Data were pooled using a random-effects model. The SIGN 50 Quality Assessment Instrument was used to assess the risk of bias and overall study quality of the selected trials. The primary end point was overall survival (OS), and the secondary end point was progression-free survival (PFS) compared with GEM for first-line chemotherapy for metastatic pancreatic cancer. The Kaplan-Meier curve of GEM from the literature and the estimated hazard ratios (HRs) were used to model the long-term associations to calculate the area under the curve (AUC) (person-months) for OS and PFS of each chemotherapy. Sensitivity analyses with multiple functional models were conducted to confirm the long-term estimations. A total of 22 regimens (25 studies) for OS and a total of 18 regimens (21 studies) for PFS were identified from literature. The total number of participants was 10 186, with 5856 male (57.5%) and 4330 female (42.5%). The FOLFIRINOX and GEM+NPTX regimens were associated with reduction in the risk of death, with an HR of 0.57 (95% CI, 0.41-0.79) and 0.72 (95% CI, 0.55-0.95) compared with GEM, respectively. The curve estimation also showed that FOLFIRINOX had the largest AUC for survival at 15.49 person-months (range, 13.84-15.51 person-months), followed by GEM+NPTX with 12.36 person-months (range, 10.98-12.59 person-months), GEM+ERLO with 10.84 person-months (range, 9.66-11.23 person-months), S-1 with 8.44 person-months (range, 8.26-9.74 person-months), and GEM with 8.10 person-months (range, 7.93-9.38 person-months). The results of this network meta-analysis support the relative short-term and long-term outcomes associated with first-line chemotherapy for metastatic pancreatic cancer used clinically in Japan.

Surgery for brain metastases—impact of the extent of resection

BackgroundSurgical resection of brain metastases improves symptoms and survival in selected patients. The benefit of gross total resection is disputed, as most patients are believed to succumb from their non-CNS tumor burden. We investigated the association between overall survival and residual tumor after surgery for single brain metastases.MethodsWe reviewed adults who underwent surgery for a single brain metastasis at a regional referral center (2011–2018). Gross total resection was defined as no visible residual tumor on cerebral MRI 12–48 h postoperatively.ResultsWe included 373 patients. The most common primary tumors were lung cancer (36%) and melanoma (24%). We identified gross total resection in 238 patients (64%). Median overall survival was 11.0 months, 8.0 (6.2–9.8) months for patients with subtotal resection and 13.0 (9.7–16.3) months for patients with gross total resection. In a multivariate regression analysis including preoperative prognostic factors, gross total resection was associated with longer overall survival (HR: 0.66, p = 0.003). Postoperative radiotherapy administered within 6 weeks did not significantly alter the hazard ratio estimates for grade of resection.ConclusionsOur study suggests improved survival with gross total resection compared to subtotal resection. The importance of extent of resection in surgery for brain metastases should not be discarded.

Comparison of statistical methods for the analysis of recurrent adverse events in the presence of non-proportional hazards and unobserved heterogeneity: a simulation study

BackgroundIn preventive drug trials such as intermittent preventive treatment for malaria prevention during pregnancy (IPTp), where there is repeated treatment administration, recurrence of adverse events (AEs) is expected. Challenges in modelling the risk of the AEs include accounting for time-to-AE and within-patient-correlation, beyond the conventional methods. The correlation comes from two sources; (a) individual patient unobserved heterogeneity (i.e. frailty) and (b) the dependence between AEs characterised by time-dependent treatment effects. Potential AE-dependence can be modelled via time-dependent treatment effects, event-specific baseline and event-specific random effect, while heterogeneity can be modelled via subject-specific random effect. Methods that can improve the estimation of both the unobserved heterogeneity and treatment effects can be useful in understanding the evolution of risk of AEs, especially in preventive trials where time-dependent treatment effect is expected.MethodsUsing both a simulation study and the Chloroquine for Malaria in Pregnancy (NCT01443130) trial data to demonstrate the application of the models, we investigated whether the lognormal shared frailty models with restricted cubic splines and non-proportional hazards (LSF-NPH) assumption can improve estimates for both frailty variance and treatment effect compared to the conventional inverse Gaussian shared frailty model with proportional hazard (ISF-PH), in the presence of time-dependent treatment effects and unobserved patient heterogeneity. We assessed the bias, precision gain and coverage probability of 95% confidence interval of the frailty variance estimates for the models under varying known unobserved heterogeneity, sample sizes and time-dependent effects.ResultsThe ISF-PH model provided a better coverage probability of 95% confidence interval, less bias and less precise frailty variance estimates compared to the LSF-NPH models. The LSF-NPH models yielded unbiased hazard ratio estimates at the expense of imprecision and high mean square error compared to the ISF-PH model.ConclusionThe choice of the shared frailty model for the recurrent AEs analysis should be driven by the study objective. Using the LSF-NPH models is appropriate if unbiased hazard ratio estimation is of primary interest in the presence of time-dependent treatment effects. However, ISF-PH model is appropriate if unbiased frailty variance estimation is of primary interest.Trial registrationClinicalTrials.gov; NCT01443130

Ethnic disparities in mortality among overweight or obese adults with newly diagnosed type 2 diabetes: a population-based cohort study

PurposeEthnic variation in risk of type 2 diabetes is well established, but its impact on mortality is less well understood. This study investigated the risk of all-cause and cardiovascular mortality associated with newly diagnosed type 2 diabetes in White, Asian and Black adults who were overweight or obese.MethodsThis population-based cohort study used primary care records from the UK Clinical Practice Research Datalink, linked with secondary care and death registry records. A total of 193,528 obese or overweight adults (BMI of 25 or greater), with ethnicity records and no pre-existing type 2 diabetes were identified between 01 January 1995 and 20 April 2018. Multivariable Cox proportional hazards regression estimated hazards ratios (HR) for incident type 2 diabetes in different ethnic groups. Adjusted hazards ratios for all-cause and cardiovascular mortality were determined in individuals with newly diagnosed type 2 diabetes.ResultsDuring follow-up (median 9.8 years), the overall incidence rate of type 2 diabetes (per 1,000 person-years) was 20.10 (95% CI 19.90–20.30). Compared to Whites, type 2 diabetes risk was 2.2-fold higher in Asians (HR 2.19 (2.07–2.32)) and 30% higher in Blacks (HR 1.34 (1.23–1.46)). In individuals with newly diagnosed type 2 diabetes, the rates (per 1,000 person-years) of all-cause mortality and cardiovascular mortality were 24.34 (23.73–24.92) and 4.78 (4.51–5.06), respectively. Adjusted hazards ratios for mortality were significantly lower in Asians (HR 0.70 (0.55–0.90)) and Blacks (HR 0.71 (0.51–0.98)) compared to Whites, and these differences in mortality risk were not explained by differences in severity of hyperglycaemia.Conclusions/InterpretationType 2 diabetes risk in overweight and obese adults is greater in Asian and Black compared to White ethnic populations, but mortality is significantly higher in the latter. Greater attention to optimising screening, disease and risk management appropriate to all communities with type 2 diabetes is needed.

Exploring the Potential of External Control Arms created from Patient Level Data: A case study in non-small cell lung cancer

ABSTRACT Randomized controlled trials (RCTs) are the gold standard for evaluation of new medical products. However, RCTs may not always be ethical or feasible. In cases where the investigational product is available outside the trial (e.g., through accelerated approval), patients may fail to enroll in clinical trials or drop out early to take the investigational product. These challenges to enrolling or maintaining a concurrent control arm may compromise timely recruitment, retention, or compliance. This can threaten the study’s integrity, including the validity of results. External control arms (ECAs) may be a promising augmentation to RCTs when encountered with challenges that threaten the feasibility and reliability of a randomized controlled clinical trial. Here, we propose the use of ECAs created from patient-level data from previously conducted clinical trials or real-world data in the same indication. Propensity score methods are used to balance observed disease characteristics and demographics in the previous clinical trial or real-world data with those of present-day trial participants assigned to receive the investigational product. These methods are explored in a case study in non-small cell lung cancer (NSCLC) derived from multiple previously conducted open label or blinded phase 2 and 3 multinational clinical trials initiated between 2004 and 2013. The case study indicated that when balanced for baseline characteristics, the overall survival estimates from the ECA were very similar to those of the target randomized control, based on Kaplan–Meier curves and hazard ratio and confidence interval estimates. This suggests that in the future, a randomized control may be able to be augmented by an ECA without compromising the understanding of the treatment effect, assuming sufficient knowledge, measurement, and availability of all or most of the important prognostic variables.

Abstract PO-219: The implications of genetic ancestry and allostatic load on clinical outcomes in the ECOG-ACRIN adjuvant breast cancer trial E5103

Abstract Introduction: Elevated allostatic load (AL) has been associated with poor tumor prognostic features in Black breast cancer patients and worse disease specific and overall survival among cancer patients. To date, there are no studies evaluating the relationship between genetic ancestry, allostatic load and clinical trial endpoints such as completion of chemotherapy per protocol or overall survival. Prior evaluations of the ECOG-ACRIN adjuvant breast cancer trial E5103 suggests African ancestry is associated with a worse invasive disease-free survival and lower odds of chemotherapy completion. The objective of this study is to evaluate the association of genetic ancestry and AL with trial completion per protocol and with overall survival among patients in E5103. Methods: ECOG-ACRIN E5103 was a clinical trial that compared doxorubicin and cyclophosphamide (AC) for four cycles, followed by 12 weeks of weekly paclitaxel with placebo (Arm A) to the same chemotherapy with either concurrent bevacizumab (Arm B) or with concurrent plus sequential bevacizumab (Arm C) among women with node positive or high-risk node negative HER2 negative disease. Genetic ancestry groups of African ancestry (AA), European ancestry (EA) and other ancestry (OA) were determined using genome-wide single nucleotide polymorphisms. AL, at trial entry, was comprised of the biomarkers body mass index, systolic blood pressure, diastolic blood pressure, creatinine, IL6, IL10, and TNF alpha. To calculate AL, patients were awarded a point if their biomarker value was above the 75 percentile of the study sample. Logistic regression and Cox-Proportional Hazard models (odds ratio(OR) and hazard ratio (HR) estimates with corresponding 95% confidence intervals (CI)) were used to assess association with chemotherapy completion and with overall mortality. Estimates for AL were adjusted for genetic ancestry. Results: There were 348 patients in the study. The majority of the sample was of EA (EA 80%, AA 10%, OA 10%). Median (range) of AL was 2(0-6). Patients of AA (2.1(1.3)) and EA (1.88(1.4)) had a higher mean (SD) AL score compared to OA patients (0.91(1.1). On adjusted analysis, a 1 unit increased in AL was associated with a 15% reduction in the odds of completing chemotherapy per protocol (OR 0.85, 95% CI 0.72-0.99). Additionally, a 1 unit increase in AL was associated with a 14% increase in the hazard of death (HR 1.14, 95%CI 1.02-1.29). There was no association between ancestry and chemotherapy completion (AA OR 0.95, 95%CI 0.47-1.93; OA 1.82, 95%CI 0.78-4.23; ref EA) or survival (AA HR 1.40, 95% CI 0.85-2.31), OA 0.89 (0.46-1.73; ref EA). Moreover, there was no interaction between AL and ancestry. Conclusion: Among patients enrolled in E5103, AL appeared to be a better predictor of chemotherapy completion and overall survival than genetic ancestry. These results suggest life course exposure to chronic stress has implication in clinical outcomes even within the context of equivalent access to and quality of care. Citation Format: Samilia Obeng-Gyasi, Anne ONeill, Kathy D. Miller, Bryan P. Schneider, Ann H. Patridge, Lava R. Timsina, George W. Sledge, Lynne Wagner, Ruth C. Carlos. The implications of genetic ancestry and allostatic load on clinical outcomes in the ECOG-ACRIN adjuvant breast cancer trial E5103 [abstract]. In: Proceedings of the AACR Virtual Conference: 14th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2021 Oct 6-8. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr PO-219.

Association of Smoking Status with Efficacy of First-line Immune Checkpoint Inhibitors in Advanced Non-small Cell Lung Cancers: A Systematic Review and Meta-analysis.

Background: Although smoking status has potential as a biomarker for immune checkpoint blockade in advanced non-small cell lung cancer (NSCLC), its clinical significance remains obscure. This meta-analysis aims to assess the impact of the smoking status on the efficacy of first-line immunotherapy and to find better treatment in never-smoker and ever-smoker patients.Methods: We searched the MEDLINE, EMBASE, and Cochrane database for trials comparing immunotherapy with conventional chemotherapy as front-line treatment for advanced NSCLC. Random-effects models were used to pool estimates of hazard ratios (HRs) for overall survival with 95% confidence intervals (CIs). Predefined subgroup analysis was performed to investigate the difference in the efficacy between the single checkpoint blockade and checkpoint inhibitor plus chemotherapy combination in the never-smokers and current/former smokers.Results: Twelve trials involving 6,446 patients were included in the analysis. A statistically significant overall survival benefit over conventional chemotherapy was found for both checkpoint inhibitor monotherapy (HR, 0.71; 95% CI, 0.59-0.85) and checkpoint inhibitor plus chemotherapy (HR, 0.75; 95% CI, 0.63-0.90) in the current/former smoker group. There was no subgroup difference between monotherapy and combination treatment (p=0.67). However, there was an inconsistent survival outcome in the never-smoker group; checkpoint blockade monotherapy did not show significantly better efficacy than chemotherapy alone (HR, 1.05; 95% CI, 0.81-1.37), but combination treatment showed an overall survival benefit (HR, 0.64; 95% CI, 0.43-0.94). A significant subgroup difference existed between monotherapy and combination therapy (p=0.04). Similarly, there was a significant difference in efficacy of monotherapy between the current/former smoker and never-smoker group (p=0.01), but the efficacy of the combination treatment was comparable between the two groups (p=0.45).Conclusion: Smoking status, which is easily available information, could be used as a guide in clinical practice to choose better treatment in the front-line setting for advanced NSCLC patients.

Association of antipsychotic use with breast cancer: a systematic review and meta-analysis of observational studies with over 2 million individuals.

Despite reports of an elevated risk of breast cancer associated with antipsychotic use in women, existing evidence remains inconclusive. We aimed to examine existing observational data in the literature and determine this hypothesised association. We searched Embase, PubMed and Web of Science™ databases on 27 January 2022 for articles reporting relevant cohort or case-control studies published since inception, supplemented with hand searches of the reference lists of the included articles. Quality of studies was assessed using the Newcastle-Ottawa Scale. We generated the pooled odds ratio (OR) and pooled hazard ratio (HR) using a random-effects model to quantify the association. This study was registered with PROSPERO (CRD42022307913). Nine observational studies, including five cohort and four case-control studies, were eventually included for review (N = 2 031 380) and seven for meta-analysis (N = 1 557 013). All included studies were rated as high-quality (seven to nine stars). Six studies reported a significant association of antipsychotic use with breast cancer, and a stronger association was reported when a greater extent of antipsychotic use, e.g. longer duration, was operationalised as the exposure. Pooled estimates of HRs extracted from cohort studies and ORs from case-control studies were 1.39 [95% confidence interval (CI) 1.11-1.73] and 1.37 (95% CI 0.90-2.09), suggesting a moderate association of antipsychotic use with breast cancer. Antipsychotic use is moderately associated with breast cancer, possibly mediated by prolactin-elevating properties of certain medications. This risk should be weighed against the potential treatment effects for a balanced prescription decision.

Placental characteristics and risks of maternal mortality 50 years after delivery.

Adverse pregnancy outcomes such as preterm delivery and preeclampsia are associated with a higher maternal risk for subsequent cardiovascular disease (CVD) and all-cause mortality. While such pregnancy conditions are related to abnormal placentation, little research has investigated whether pathologic placental measures could serve as a risk factor for future CVD mortality in mothers. Longitudinal study of 33,336 women from the Collaborative Perinatal Project (CPP; 1959-1966) linked to mortality information through December 2016. Pathologists took extensive morphological and histopathological measures. Apart from assessing associations with morphological features, we derived an overall composite score and specific inflammation-related, hemorrhage-related, and hypoxia-related pathologic placenta index scores. Cox regression estimated hazard ratios (HR) and 95% confidence intervals (CI) for mortality adjusting for covariates. Thirty-nine percent of women died with mean (standard deviation, SD) time to death of 39 (12) years. Mean (SD) placental weight and birthweight were 436g (98) and 3156g (566), respectively. Placenta-to-birthweight ratio was associated with all-cause mortality (adjusted HR 1.03: 1.01, 1.05 per SD in ratio). In cause-specific analyses, it was significantly associated with respiratory (HR 1.06), dementia (HR: 1.10) and liver (HR 1.04) related deaths. CVD, cancer, diabetes and kidney related deaths also tended to increase, whereas infection related deaths did not (HR 0.94; 0.83, 1.06). Placental measures of thickness, diameters, and histopathological measures grouped by inflammatory, hemorrhagic, or hypoxic etiology were not associated with mortality. Placental weight in relation to birthweight was associated with long-term maternal mortality but other histopathologic or morphologic features were not.

Long-chain omega-3 polyunsaturated fatty acids and the risk of heart failure.

Aims:Adequate intake of long-chain (LC) omega-3 polyunsaturated fatty acids (n-3 PUFAs) is considered important for cardiovascular health. However, the effects of LC n-3 PUFAs on the risk of heart failure (HF) remain unclear. This systematic review and meta-analysis aimed to determine the role of LC n-3 PUFAs in the incidence of HF.Materials and Methods:Electronic databases were searched for studies up to 31 July 2021. Studies were included for the meta-analysis if they reported the adjusted associations between different dietary intakes or circulating concentrations of LC n-3 PUFAs and the risk of HF. A random-effect model was used to calculate the pooled estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for higher LC n-3 PUFA concentrations.Results:Thirteen studies were included in the meta-analysis. Eight studies comprising 316,698 individuals (11,244 incident HF cases), with a median follow-up of 10.7 years, showed that a higher dietary intake of LC n-3 PUFAs was associated with a lower risk of HF (highest versus lowest quintile: HR = 0.84, 95% CI = 0.75–0.94). Six studies, comprising 17,163 participants (2520 HF cases) with a median follow-up of 9.7 years, showed that higher circulating LC n-3 PUFA concentrations were associated with a lower risk of HF (highest versus lowest quintile: HR = 0.59, 95% CI = 0.39–0.91). Higher circulating docosahexaenoic acid concentrations were associated with a decreased risk of HF (top versus bottom quintile: HR = 0.44, 95% CI = 0.26–0.77). The associations between eicosapentaenoic acid (HR = 0.58, 95% CI = 0.26–1.25), docosahexaenoic acid (HR = 0.66, 95% CI = 0.24–1.82), and the risk of HF were not significant.Conclusion:High LC n-3 PUFA concentrations measured by dietary intake or circulating biomarkers are associated with a lower risk of developing HF.

The depressed frail phenotype as a risk factor for mortality in older adults: A prospective cohort in Peru

IntroductionFrailty and depression can coexist as depressed frail phenotype, useful for the comprehensive evaluation of older adults and prevention of adverse outcomes. The objective of this study was to evaluate the role of the depressed frail phenotype and its components as risk factors for mortality in older adults of the Centro Médico Naval (CEMENA) of Peru during 2010–2015. Material and methodsWe carried out a secondary data analysis of a prospective cohort that included older adults (60 years and older) treated in the Geriatrics service of CEMENA between the years 2010–2015. Frailty was defined as the presence of three or more Fried phenotype criteria and depression was determined using a Yesavage ultrashort scale score of three or more. The presence of both conditions was defined as depressed frail phenotype. In addition, sociodemographic characteristics, medical and personal history, and performance-based measures were included. We employed crude and adjusted Cox regression models to evaluate the association of interest and estimate Hazard Ratios (HR) with their respective 95% confidence intervals (95% CI). Results946 older adults were included in the analysis, with a mean age of 78.0 ± 8.5 years. 559 (59.1%) were male, 148 (15.6%) were found to be frail, 231 (24.4%) had depressive symptoms, 105 (11.1%) had depressed frail phenotype, and 79 (8.3%) participants died during follow-up. The adjusted Cox regression analysis revealed that depressed frail phenotype (HR = 3.53; 95%CI: 2.07–6.00; p < 0.001) was a risk factor for mortality in older adults. ConclusionsThe depressed frail phenotype was associated with a higher risk of mortality in older adults. It is necessary to develop longitudinal studies that allow estimating this phenotype's impact on mortality and evaluate interventions to improve quality of life and reduce the risk of adverse outcomes.

Does periodontal disease have an association with prostate cancer?

Data sources The electronic databases PubMed, Embase and the Cochrane Oral Health Group's Trials Register up to 7 July 2020 were searched to identify eligible studies. Information sources in the grey literature were not cited.Study selection Cohort studies and case-control studies in English were selected by two reviewers independently. All articles had to include a control patient group (without periodontal disease) and a group with periodontal disease and both groups with prostate cancer outcomes. Also, all articles reported the hazard ratio (HR), relative risk (RR) or odds ratio (OR) estimates with their 95% confidence intervals (CIs).Data extraction and synthesis Data extraction and risk of bias assessments were performed by two reviewers independently and any disagreements between these authors were resolved through discussion or by consulting a third author. Data were synthesised qualitatively by the Newcastle-Ottawa Scale. RR with 95% CI was used as the pooled estimate to assess the association of periodontal disease and the risk of prostate cancer. When the outcome of interest was rare, it was considered that the OR approximated the RR (24). HR was also treated as RR when pooled in this meta-analysis. The heterogeneity across studies was evaluated by Q test (statistical significance was considered when P <0.1) and the I2 statistic (I2 ≥50% indicated significant heterogeneity).Results Seven studies were included in the meta-analyses, with four being prospective cohort studies and three retrospective cohort studies. All studies were of high quality except one study that was considered to be of moderate quality. Pooled estimates indicated that periodontal disease had a significant statistical relationship with the risk of prostate cancer (RR = 1.17; 95% CI = 1.07-1.27; P = 0.001). No significant heterogeneity across studies was observed (P = 0.383; I2 = 5.8%). The studies include Asian, European and American populations.Conclusions The authors of this review concluded that periodontal disease could be a possible risk for prostate cancer and that the male public, and clinicians, should be aware of the importance of maintaining good periodontal health.

P-P23 Adjuvant chemotherapy in the treatment of intraductal papillary mucinous neoplasms of the pancreas: systematic review and meta-analysis

Abstract Background The present systematic review aimed to compare survival outcomes of invasive intraductal papillary mucinous neoplasms (IIPMNs) treated with adjuvant chemotherapy versus surgery alone and to identify pathologic features that may predict survival benefit from adjuvant chemotherapy. Methods A systematic search of Medline, Pubmed, Scopus, and EMBASE was performed using the PRISMA framework. Studies comparing adjuvant chemotherapy and surgery alone for patients with IIPMNs were included. Primary endpoint was overall survival (OS). A narrative synthesis was performed to identify pathologic features that predicted survival benefits from adjuvant chemotherapy. Results Eleven studies and 3393 patients with IIPMNs were included in the meta-analysis. Adjuvant chemotherapy significantly reduced risk of death in the overall cohort (HR 0.57, 95%-CI:0.38-0.87, p = 0.009) and node-positive patients (HR 0.29, 95%-CI:0.13-0.64, p = 0.002). Weighted median survival difference between adjuvant chemotherapy and surgery alone in node-positive patients was 11.6 months (95%-CI:3.83-19.38, p = 0.003) favouring chemotherapy. Adjuvant chemotherapy had no impact on OS in node-negative patients (HR 0.53, 95%-CI:0.20-1.43, p = 0.209). High heterogeneity (I2&amp;gt;75%) was observed in pooled estimates of hazard ratios. Improved OS following adjuvant chemotherapy were reported for patients with stage III/IV disease, tumour size &amp;gt;2 cm, node-positive status, grade 3 tumour differentiation, positive margin status, tubular carcinoma subtype, and presence of perineural or lymphovascular invasion. Conclusions Adjuvant chemotherapy was associated with improved OS in node-positive IIPMNs. However, the findings were limited by marked heterogeneity. Future large multicentre prospective studies are needed to confirm these findings and explore additional predictors of improved OS to guide patient selection for adjuvant chemotherapy.

OP437 Use Of Real-World Evidence In Survival Analysis Adjusting For Treatment Crossover In Cutaneous T-Cell Lymphoma

Real-World Evidence is useful for validating crossover adjustment approaches, particularly when the adjustment is required because a trial does not accurately reflect a health technology assessment (HTA)-relevant population. We use the MAVORIC trial advanced stage mycosis fungoides and Sézary syndrome cutaneous T-cell lymphoma population and data from the Hospital Episodes Statistics to explore and validate crossover adjustment methods.IntroductionThe MAVORIC trial compared mogamulizumab to vorinostat in patients with mycosis fungoides (MF) or Sézary syndrome (SS), subtypes of cutaneous T-cell lymphoma. However, the treatment comparison within MAVORIC may not represent an HTA relevant population from a UK perspective: (i) 72.6 percent of patients randomized to vorinostat switched to mogamulizumab and (ii) vorinostat is not used in current clinical practice in the UK. This study explores methods to adjust treatment effect estimates using different crossover adjustment methods and Real-World Evidence.This medicine is subject to additional monitoring. This will allow quick identification of new safety information. See www.mhra.gov.uk/yellowcard for how to report side effects.MethodsAn advanced stage (stage ≥IIB MF and all SS) population was included. Three methods were considered for treatment crossover adjustment. A synthetic control arm was created using the Hospital Episodes Statistics (HES) dataset. Predicted survival for the MAVORIC control arm, post-crossover adjustment, was compared to the HES to inform the selection of the appropriate methods for adjustment. A direct comparison between mogamulizumab (reweighted to represent the distribution of MF/SS patients in the HES) and the synthetic control was also conducted.ResultsFollowing crossover adjustment of the vorinostat arm, using the inverse probability of censoring weighting method, the overall survival (OS) hazard ratio (HR) estimate for mogamulizumab vs. vorinostat was 0.45 (95% confidence interval (CI): 0.19, 1.07). This adjustment method was considered the most appropriate based on an assessment of assumptions and a comparison of OS between the adjusted vorinostat data and the HES data. The OS HR estimate for reweighted mogamulizumab vs. synthetic control from HES was 0.33 (CI: 0.21, 0.50).ConclusionsReal World Evidence from the HES database can be used to validate crossover adjustment methods and to better reflect current clinical practice in the UK. Results using both methods support each other.