deepAFT: A nonlinear accelerated failure time model with artificial neural network.

The Cox regression model or accelerated failure time regression models are often used for describing the relationship between survival outcomes and potential explanatory variables. These models assume the studied covariates are connected to the survival time or its distribution or their transformations through a function of a linear regression form. In this article, we propose nonparametric, nonlinear algorithms (deepAFT methods) based on deep artificial neural networks to model survival outcome data in the broad distribution family of accelerated failure time models. The proposed methods predict survival outcomes directly and tackle the problem of censoring via an imputation algorithm as well as re-weighting and transformation techniques based on the inverse probabilities of censoring. Through extensive simulation studies, we confirm that the proposed deepAFT methods achieve accurate predictions. They outperform the existing regression models in prediction accuracy, while being flexible and robust in modeling covariate effects of various nonlinear forms. Their prediction performance is comparable to other established deep learning methods such as deepSurv and random survival forest methods. Even though the direct output is the expected survival time, the proposed AFT methods also provide predictions for distributional functions such as the cumulative hazard and survival functions without additional learning efforts. For situations where the popular Cox regression model may not be appropriate, the deepAFT methods provide useful and effective alternatives, as shown in simulations, and demonstrated in applications to a lymphoma clinical trial study.

Adjunctive Statistical Standardization of Adjuvant Estrogen Receptor and Progesterone Receptor in Canadian Cancer Trials Group MA.27 Postmenopausal Breast Cancer Trial of Exemestane Versus Anastrozole.

PURPOSE: ASCO/College of American Pathologists guidelines recommend reporting estrogen receptor (ER) and progesterone receptor (PgR) as positive with (1%-100%) staining. Statistically standardized quantitated positivity could indicate differential associations of positivity with breast cancer outcomes. METHODS: MA.27 (ClinicalTrials.gov identifier: NCT00066573) was a phase III adjuvant trial of exemestane versus anastrozole in postmenopausal women with early-stage breast cancer. Immunochemistry ER and PgR HSCORE and % positivity (%+) were centrally assessed by machine image quantitation and statistically standardized to mean 0 and standard deviation (SD) 1 after Box-Cox variance stabilization transformations of square for ER; for PgR, (1) natural logarithm (0.1 added to 0 HSCOREs and 0%+) and (2) square root. Our primary end point was MA.27 distant disease-free survival (DDFS) at a median 4.1-year follow-up, and secondary end point was event-free survival (EFS). Univariate survival with cut points at SDs about a mean of 0 (≤-1; (-1, 0]; (0, 1]; >1) was described with Kaplan-Meier plots and examined with Wilcoxon (Peto-Prentice) test statistic. Adjusted Cox multivariable regressions had two-sided Wald tests and nominal significance P < .05. RESULTS: Of 7,576 women accrued, 3,048 women's tumors had machine-quantitated image analysis results: 2,900 (95%) for ER, 2,726 (89%) for PgR, and 2,582 (85% of 3,048) with both ER and PgR. Higher statistically standardized ER and PgR HSCORE and %+ were associated with better univariate DDFS and EFS (P < .001). In multivariable assessments, ER HSCORE and %+ were not significantly associated (P = .52-.88) with DDFS in models with PgR, whereas higher PgR HSCORE and %+ were significantly associated with better DDFS (P = .001) in models with ER. CONCLUSION: Adjunctive statistical standardization differentiated quantitated levels of ER and PgR. Patients with higher ER- and PgR-standardized units had superior DDFS compared with those with HSCOREs and %+ ≤-1.

Canadian cancer trials group LY.17: A randomized phase II study evaluating novel salvage therapy pre-autologous stem cell transplant in relapsed/refractory diffuse large B-cell lymphoma-outcome of rituximab-dose-intensive cyclophosphamide, etoposide, cisplatin (R-DICEP) versus R-GDP.

The Canadian Cancer Trials Group (CCTG) LY.17 is an ongoing multi-arm randomized phase II trial evaluating novel salvage therapies compared with R-GDP (rituximab, gemcitabine, dexamethasone and cisplatin) in autologous stem cell transplantation (ASCT)-eligible patients with relapsed/refractory diffuse large B-cell lymphoma (RR-DLBCL). This component of the LY.17 trial evaluated a dose-intensive chemotherapy approach using a single cycle of inpatient R-DICEP (rituximab, dose-intensive cyclophosphamide, etoposide and cisplatin) to achieve both lymphoma response and stem cell mobilization, shortening time to ASCT. This report is the result of the protocol-specified second interim analysis of the 67 patients who were randomized to either 1 cycle of R-DICEP or to 3 cycles of R-GDP. The overall response rate (ORR) was 65.6% for R-DICEP and 48.6% for R-GDP. The ASCT rate was 71.9% versus 54.3%, and 1-year progression-free survival rate was 42% versus 32%, respectively, for R-DICEP versus R-GDP. Although the improvement in ORR for R-DICEP versus R-GDP exceeded the pre-specified 10% threshold to proceed to full accrual of 64 patients/arm, higher rates of grade 3-5 toxicities, and the need for hospitalization led to the decision to stop this arm of the study. CCTG LY.17 will continue to evaluate different salvage regimens that incorporate novel agents.

Evaluating the Utility and Privacy of Synthetic Breast Cancer Clinical Trial Data Sets.

PURPOSE: There is strong interest from patients, researchers, the pharmaceutical industry, medical journal editors, funders of research, and regulators in sharing clinical trial data for secondary analysis. However, data access remains a challenge because of concerns about patient privacy. It has been argued that synthetic data generation (SDG) is an effective way to address these privacy concerns. There is a dearth of evidence supporting this on oncology clinical trial data sets, and on the utility of privacy-preserving synthetic data. The objective of the proposed study is to validate the utility and privacy risks of synthetic clinical trial data sets across multiple SDG techniques. METHODS: We synthesized data sets from eight breast cancer clinical trial data sets using three types of generative models: sequential synthesis, conditional generative adversarial network, and variational autoencoder. Synthetic data utility was evaluated by replicating the published analyses on the synthetic data and assessing concordance of effect estimates and CIs between real and synthetic data. Privacy was evaluated by measuring attribution disclosure risk and membership disclosure risk. RESULTS: Utility was highest using the sequential synthesis method where all results were replicable and the CI overlap most similar or higher for seven of eight data sets. Both types of privacy risks were low across all three types of generative models. DISCUSSION: Synthetic data using sequential synthesis methods can act as a proxy for real clinical trial data sets, and simultaneously have low privacy risks. This type of generative model can be one way to enable broader sharing of clinical trial data.

Effect of Metformin Versus Placebo on New Primary Cancers in Canadian Cancer Trials Group MA.32: A Secondary Analysis of a Phase III Randomized Double-Blind Trial in Early Breast Cancer.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned coprimary or secondary analyses are not yet available. Clinical trial updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.Metformin has been associated with lower cancer risk in epidemiologic and preclinical research. In the MA.32 randomized adjuvant breast cancer trial, metformin (v placebo) did not affect invasive disease-free or overall survival. Here, we report metformin effects on the risk of new cancer. Between 2010 and 2013, 3,649 patients with breast cancer younger than 75 years without diabetes with high-risk T1-3, N0-3 M0 breast cancer (any estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2) were randomly assigned to metformin 850 mg orally twice a day or placebo twice a day for 5 years. New primary invasive cancers (outside the ipsilateral breast) developing as a first event were identified. Time to events was described by the competing risks method; two-sided likelihood ratio tests adjusting for age, BMI, smoking, and alcohol intake were used to compare metformin versus placebo arms. A total of 184 patients developed new invasive cancers: 102 metformin and 82 placebo, hazard ratio (HR), 1.25; 95% CI, 0.94 to 1.68; P = .13. These included 48 contralateral invasive breast cancers (27 metformin v 21 placebo), HR, 1.29; 95% CI, 0.72 to 2.27; P = .40 and 136 new nonbreast primary cancers (75 metformin v 61 placebo), HR, 1.24; 95% CI, 0.88 to 1.74; P = .21. Metformin did not reduce the risk of new cancer development in these nondiabetic patients with breast cancer.

Power and sample size calculation for incremental net benefit in cost effectiveness analyses with applications to trials conducted by the Canadian Cancer Trials Group.

BACKGROUND: Historically, a priori power and sample size calculations have not been routinely performed cost-effectiveness analyses (CEA), partly because the absence of published cost and effectiveness correlation and variance data, which are essential for power and sample size calculations. Importantly, the empirical correlation between cost and effectiveness has not been examined with respect to the estimation of value-for-money in clinical literature. Therefore, it is not well established if cost-effectiveness studies embedded within randomized-controlled-trials (RCTs) are under- or over-powered to detect changes in value-for-money. However, recently guidelines (such as those from ISPOR) and funding agencies have suggested sample size and power calculations should be considered in CEAs embedded in clinical trials. METHODS: We examined all RCTs conducted by the Canadian Cancer Trials Group with an embedded cost-effectiveness analysis. Variance and correlation of effectiveness and costs were derived from original-trial data. The incremental net benefit method was used to calculate the power of the cost-effectiveness analysis, with exploration of alternative correlation and willingness-to-pay values. RESULTS: We identified four trials for inclusion. We observed that a hypothetical scenario of correlation coefficient of zero between cost and effectiveness led to a conservative estimate of sample size. The cost-effectiveness analysis was under-powered to detect changes in value-for-money in two trials, at willingness-to-pay of $100,000. Based on our observations, we present six considerations for future economic evaluations, and an online program to help analysts include a priori sample size and power calculations in future clinical trials. CONCLUSION: The correlation between cost and effectiveness had a potentially meaningful impact on the power and variance of value-for-money estimates in the examined cost-effectiveness analyses. Therefore, the six considerations and online program, may facilitate a priori power calculations in embedded cost-effectiveness analyses in future clinical trials.

Association Between Omega-3 Fatty Acid Intake and Dyslipidemia: A Continuous Dose-Response Meta-Analysis of Randomized Controlled Trials.

Background Previous results provide supportive but not conclusive evidence for the use of omega-3 fatty acids to reduce blood lipids and prevent events of atherosclerotic cardiovascular disease, but the strength and shape of dose-response relationships remain elusive. Methods and Results This study included 90 randomized controlled trials, reported an overall sample size of 72 598 participants, and examined the association between omega-3 fatty acid (docosahexaenoic acid, eicosapentaenoic acid, or both) intake and blood lipid changes. Random-effects 1-stage cubic spline regression models were used to study the mean dose-response association between daily omega-3 fatty acid intake and changes in blood lipids. Nonlinear associations were found in general and in most subgroups, depicted as J-shaped dose-response curves for low-/high-density lipoprotein cholesterol. However, we found evidence of an approximately linear dose-response relationship for triglyceride and non-high-density lipoprotein cholesterol among the general population and more evidently in populations with hyperlipidemia and overweight/obesity who were given medium to high doses (>2 g/d). Conclusions This dose-response meta-analysis demonstrates that combined intake of omega-3 fatty acids near linearly lowers triglyceride and non-high-density lipoprotein cholesterol. Triglyceride-lowering effects might provide supportive evidence for omega-3 fatty acid intake to prevent cardiovascular events.

Contact Days Associated With Cancer Treatments in the CCTG LY.12 Trial.

BACKGROUND: When cancer treatments have similar oncologic outcomes, the number of days with in-person healthcare contact (""contact days'') can help contextualize expected time use with each treatment. We assessed contact days in a completed randomized clinical trial. PATIENTS AND METHODS: We conducted a secondary analysis of the CCTG LY.12 RCT that evaluated 2-3 cycles of gemcitabine, dexamethasone, and cisplatin (GDP) vs. dexamethasone, cytarabine, and cisplatin (DHAP) in 619 patients with relapsed/refractory lymphoma prior to stem cell transplant. Primary analyses reported similar response rates and survival. We calculated patient-level "contact days" by analyzing trial forms. The study period was from assignment to progression or transplant. Days without healthcare contact were considered "home days''. We compared measures of contact days across arms. RESULTS: The study period was longer in the GDP arm (median 50, vs. 47 days, P = .007). Contact days were comparable in both arms (median 18 vs 19, P = 0.79), but home days were higher in the GDP arm (median 33 vs 28, P < .001). The proportion of contact days was lower in the GDP arm (34%, vs. 38%, P = .009). The GDP arm experienced more contact days related to planned outpatient chemotherapy (median, 10 vs. 8 days), but the DHAP arm experienced many more inpatient contact days (median, 11 vs. 0 days). CONCLUSIONS: Measures of time use, such as contact days, can be extracted from RCTs. In LY.12, despite comparable oncologic outcomes, GDP was associated with fewer contact days. Such information can guide decision-making for patients with hematological cancers, who already face significant healthcare contact.

A Novel Wide-Band Directional MUSIC Algorithm Using the Strength Proportion.

The directional multiple signal classification (Dir-MUSIC) algorithm based on the antenna gain array manifold has been proposed to find the direction of the partial discharge (PD) source in substations. However, PD signals are wideband signals and the antenna gain pattern functions are always different at different frequencies; therefore, the accuracy can be improved using a wideband Dir-MUSIC algorithm. In this paper, wideband Dir-MUSIC algorithms are discussed and a novel wideband Dir-MUSIC algorithm using the strength proportion (DirSP) is proposed. This algorithm estimates a focusing PD signal at a certain frequency using the strength proportion among different directions, and then the Dir-MUSIC algorithm can process the focusing PD signal at this frequency. In simulations, when the antenna gain functions among different frequency bins are quite different, the Dir-MUSIC algorithm loses accuracy; meanwhile, DirDP performs very well. In the experiments, we deal with six sets of samples, and the mean error and standard deviation are both smaller than 4° better than other methods.

Metformin, placebo, and endocrine therapy discontinuation among participants in a randomized double-blind trial of metformin vs placebo in hormone receptor-positive early-stage breast cancer (CCTG MA32).

BACKGROUND: The MA32 study investigated whether 5 years of metformin (versus placebo) improves invasive disease-free survival in early-stage breast cancer (BC). Non-adherence to endocrine therapy (ET) and medications for chronic conditions is common and increases with drug toxicity and polypharmacy. This secondary analysis evaluates rates and predictors of early discontinuation of metformin, placebo, and ET among participants with HR-positive BC. METHODS: Patients with high-risk non-metastatic BC were randomized to 60 months of metformin (850 mg BID) or placebo BID. Patients were administered bottles of metformin/placebo every 180 days. Metformin/placebo adherence was defined as a bottle dispensed at month 48 or later. The ET adherence analysis included patients with HR-positive BC who received ET with start and stop date reported, with adherence defined as > 48 months of use. Associations of covariates with study drug and ET adherence were examined using multivariable models. RESULTS: Among the 2521 HR-positive BC patients, 32.9% were non-adherent to study drug. Non-adherence was higher among patients on metformin vs placebo (37.1% vs 28.7%, p < 0.001). Reassuringly, ET discontinuation rates were similar between treatment arms (28.4% vs 28.0%, p = 0.86). Patients who were non-adherent to ET were more likely to discontinue study therapy (38.8% vs 30.1%, p < 0.0001). In a multivariable analysis, study drug non-adherence was increased with metformin vs placebo (OR: 1.50, 95% CI 1.25-1.80; p < 0.0001); non-adherence to ET (OR: 1.47, 95% CI 1.20-1.79, p < 0.0001); grade 1 or greater GI toxicity during the first 2 years; lower age; and higher body mass index. CONCLUSION: While non-adherence was higher among patients on metformin, it was still considerable among patients on placebo. Reassuringly, treatment arm allocation did not impact ET adherence. Attention to global medication adherence is needed to improve BC and non-oncological outcomes in cancer survivors. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01.

Health-related quality of life in early-stage Hodgkin lymphoma: a longitudinal analysis of the ABVD arm in the randomized controlled trial HD.6.

Early-stage Hodgkin lymphoma has become one of the most curable hematologic malignancies. Depending upon the disease location, possible toxicities, and patient preference, chemotherapy alone with ABVD remains an accepted treatment modality for this disease. There remains a paucity of data regarding the longitudinal trajectory of health-related quality of life (HRQoL) in patients treated for HL. The impact of disease and treatment on HRQoL is increasingly important to understand as the number of long-term survivors increases. We report the longitudinal HRQoL using data prospectively collected from diagnosis up to 10 years post-treatment in the ABVD arm of the HD.6 randomized controlled trial for early-stage HL patients (N=169). We analyzed HRQoL using the EORTC QLQ-C30 collected at baseline, 3 months, 6 months, and 12 months after completion of chemotherapy and yearly up to year 10. Clinically and statistically significant improvements were noted for specific domains including emotional (3 months post-treatment), social (12 months post-treatment) and financial functioning (2 years post-treatment), and the specific symptom of fatigue (6 months post-treatment) during the follow-up period. To our knowledge, this is the first prospective, longitudinal analysis of HRQoL specifically among patients with early-stage HL treated with ABVD therapy alone. Although improvements were noted, sustained clinically and statistically significant improvements were noted only in select symptoms emphasizing the need to better understand and optimize HRQoL among this patient group.

A nonparametric simultaneous confidence band for biomarker effect on the restricted mean survival time.

Study of prognostic and predictive biomarkers plays an important role in the design and analysis of clinical trials. The Cox proportional hazards model is often used to study the biomarker main effect and the treatment-biomarker interaction effect for survival data. The estimated effects can be biased if the proportional hazards assumption is violated. The restricted mean survival time is becoming popular in clinical studies for having a clear intuitive interpretation. In this article, we first propose nonparametric methods to make statistical inference for the one-sample problem of the biomarker effect on the restricted mean survival time; we then extend the methods to the two-sample problem for studying the difference in the biomarker effects between treatment groups in clinical trials. For a given biomarker, the restricted mean survival time is estimated by kernel smoothing methods with the inverse probability of censoring weights. We prove the consistency for the estimates and develop simultaneous confidence bands for the biomarker effects on the restricted mean survival time. The simultaneous confidence bands are evaluated in extensive simulation studies and are found to have good finite sample performance. We then apply the proposed methods to a breast cancer study conducted by the Breast International Group (BIG) to illustrate how the Ki67 biomarker, a protein marker of cell proliferation, affects the survival time of patients, compared between the treatment groups.

Dir-MUSIC Algorithm for DOA Estimation of Partial Discharge Based on Signal Strength Represented by Antenna Gain Array Manifold.

Inspection robots are widely used in the field of smart grid monitoring in substations, and partial discharge (PD) is an important sign of the insulation state of equipment. PD direction of arrival (DOA) algorithms using conventional beam forming and time difference of arrival (TDOA) require large-scale antenna arrays and high computational complexity, making them difficult to implement on inspection robots. To address this problem, a novel directional multiple signal classification (Dir-MUSIC) algorithm for PD direction finding based on signal strength is proposed, and a miniaturized directional spiral antenna circular array is designed in this paper. First, the Dir-MUSIC algorithm is derived based on the array manifold characteristics. This method uses strength intensity information rather than the TDOA information, which could reduce the computational difficulty and the requirement of array size. Second, the effects of signal-to-noise ratio (SNR) and array manifold error on the performance of the algorithm are discussed through simulations in detail. Then, according to the positioning requirements, the antenna array and its arrangement are developed and optimized. Simulation results suggested that the algorithm has reliable direction-finding performance in the form of six elements. Finally, the effectiveness of the algorithm is tested by using the designed spiral circular array in real scenarios. The experimental results show that the PD direction-finding error is 3.39°, which meets the need for partial discharge DOA estimation using inspection robots in substations.

Omega-3 Polyunsaturated Fatty Acids Intake and Blood Pressure: A Dose-Response Meta-Analysis of Randomized Controlled Trials.

Background Current evidence might support the use of omega-3 fatty acids (preferably docosahexaenoic acid and eicosapentaenoic acid) for lowering blood pressure (BP), but the strength and shape of the dose-response relationship remains unclear. Methods and Results This study included randomized controlled trials published before May 7, 2021, that involved participants aged ≥18 years, and examined an association between omega-3 fatty acids (docosahexaenoic acid, eicosapentaenoic acid, or both) and BP. A random-effects 1-stage cubic spline regression model was used to predict the average dose-response association between daily omega-3 fatty acid intake and changes in BP. We also conducted stratified analyses to examine differences by prespecified subgroups. Seventy-one trials were included, involving 4973 individuals with a combined docosahexaenoic acid+eicosapentaenoic acid dose of 2.8 g/d (interquartile range, 1.3 g/d to 3.6 g/d). A nonlinear association was found overall or in most subgroups, depicted as J-shaped dose-response curves. The optimal intake in both systolic BP and diastolic BP reductions (mm Hg) were obtained by moderate doses between 2 g/d (systolic BP, -2.61 [95% CI, -3.57 to -1.65]; diastolic BP, -1.64 [95% CI, -2.29 to -0.99]) and 3 g/d (systolic BP, -2.61 [95% CI, -3.52 to -1.69]; diastolic BP, -1.80 [95% CI, -2.38 to -1.23]). Subgroup studies revealed stronger and approximately linear dose-response relations among hypertensive, hyperlipidemic, and older populations. Conclusions This dose-response meta-analysis demonstrates that the optimal combined intake of omega-3 fatty acids for BP lowering is likely between 2 g/d and 3 g/d. Doses of omega-3 fatty acid intake above the recommended 3 g/d may be associated with additional benefits in lowering BP among groups at high risk for cardiovascular diseases.

Results of the phase I CCTG IND.231 trial of CX-5461 in patients with advanced solid tumors enriched for DNA-repair deficiencies.

CX-5461 is a G-quadruplex stabilizer that exhibits synthetic lethality in homologous recombination-deficient models. In this multicentre phase I trial in patients with solid tumors, 40 patients are treated across 10 dose levels (50-650 mg/m2) to determine the recommended phase II dose (primary outcome), and evaluate safety, tolerability, pharmacokinetics (secondary outcomes). Defective homologous recombination is explored as a predictive biomarker of response. CX-5461 is generally well tolerated, with a recommended phase II dose of 475 mg/m2 days 1, 8 and 15 every 4 weeks, and dose limiting phototoxicity. Responses are observed in 14% of patients, primarily in patients with defective homologous recombination. Reversion mutations in PALB2 and BRCA2 are detected on progression following initial response in germline carriers, confirming the underlying synthetic lethal mechanism. In vitro characterization of UV sensitization shows this toxicity is related to the CX-5461 chemotype, independent of G-quadruplex synthetic lethality. These results establish clinical proof-of-concept for this G-quadruplex stabilizer. Clinicaltrials.gov NCT02719977.

Real-world colorectal cancer diagnostic pathways in Ontario, Canada: A population-based study.

OBJECTIVE: This study aimed to identify colorectal cancer (CRC) diagnostic pathways and describe patients in those pathway groups. METHODS: This was a cross-sectional study of CRC patients in Ontario, Canada, diagnosed 2009-2012 that used linked administrative data at ICES. We used cluster analysis on 11 pathway variables characterising patient presentation, symptoms, procedures and referrals. We assessed associations between patient- and disease-related characteristics and diagnostic pathway group. We further characterised the pathways by diagnostic interval and number of related physician visits. RESULTS: Six diagnostic pathways were identified, with three adhering to provincial diagnostic guidelines: screening (N = 4494), colonoscopy (N = 10,066) and imaging plus colonoscopy (N = 3427). Non-adherent pathways were imaging alone (N = 2238), imaging and emergency presentation (N = 2849) and no pre-diagnostic workup (N = 887). Patients in adherent pathways were younger, had fewer comorbidities, lived in less deprived areas and had earlier stage disease. The median diagnostic interval length varied across pathways from 12 to 126 days, correlating with the number of CRC-related visits. CONCLUSIONS: This study demonstrated substantial variations in real-world CRC diagnostic pathways and 25% were diagnosed through non-adherent pathways. Those patients were older, had more comorbid disease and had higher stage cancer. Further research needs to identify and describe the reasons for divergent diagnostic processes.

Effect of Metformin vs Placebo on Invasive Disease-Free Survival in Patients With Breast Cancer: The MA.32 Randomized Clinical Trial.

Importance: Metformin, a biguanide commonly used to treat type 2 diabetes, has been associated with potential beneficial effects across breast cancer subtypes in observational and preclinical studies. Objective: To determine whether the administration of adjuvant metformin (vs placebo) to patients with breast cancer without diabetes improves outcomes. Design, Setting, and Participants: MA.32, a phase 3 randomized, placebo-controlled, double-blind trial, conducted in Canada, Switzerland, US, and UK, enrolled 3649 patients with high-risk nonmetastatic breast cancer receiving standard therapy between August 2010 and March 2013, with follow-up to October 2020. Interventions: Patients were randomized (stratified for hormone receptor [estrogen receptor and/or progesterone receptor {ER/PgR}] status, positive vs negative; body mass index, ≤30 vs >30; human epidermal growth factor receptor 2 [ERBB2, formerly HER2 or HER2/neu], positive vs negative; and any vs no chemotherapy) to 850 mg of oral metformin twice a day (n = 1824) or oral placebo twice a day (n = 1825) for 5 years. Main Outcomes and Measures: The primary outcome was invasive disease-free survival in hormone receptor-positive breast cancer. Of the 8 secondary outcomes, overall survival, distant relapse-free survival, and breast cancer-free interval were analyzed. Results: Of the 3649 randomized patients (mean age, 52.4 years; 3643 women [99.8%]), all (100%) were included in analyses. After a second interim analysis, futility was declared for patients who were ER/PgR-, so the primary analysis was conducted for 2533 patients who were ER/PgR+. The median duration of follow-up in the ER/PgR+ group was 96.2 months (range, 0.2-121 months). Invasive disease-free survival events occurred in 465 patients who were ER/PgR+. The incidence rates for invasive disease-free survival events were 2.78 per 100 patient-years in the metformin group vs 2.74 per 100 patient-years in the placebo group (hazard ratio [HR], 1.01; 95% CI, 0.84-1.21; P = .93), and the incidence rates for death were 1.46 per 100 patient-years in the metformin group vs 1.32 per 100 patient-years in the placebo group (HR, 1.10; 95% CI, 0.86-1.41; P = .47). Among patients who were ER/PgR-, followed up for a median of 94.1 months, incidence of invasive disease-free survival events was 3.58 vs 3.60 per 100 patient-years, respectively (HR, 1.01; 95% CI, 0.79-1.30; P = .92). None of the 3 secondary outcomes analyzed in the ER/PgR+ group had statistically significant differences. Grade 3 nonhematological toxic events occurred more frequently in patients taking metformin than in patients taking placebo (21.5% vs 17.5%, respectively, P = .003). The most common grade 3 or higher adverse events in the metformin vs placebo groups were hypertension (2.4% vs 1.9%), irregular menses (1.5% vs 1.4%), and diarrhea (1.9% vs 7.0%). Conclusions and Relevance: Among patients with high-risk operable breast cancer without diabetes, the addition of metformin vs placebo to standard breast cancer treatment did not significantly improve invasive disease-free survival. Trial Registration: ClinicalTrials.gov Identifier: NCT01101438.

The Futility of Futility Analyses in Adjuvant Trials in Hormone Receptor-Positive Breast Cancer.

An interim analysis is commonly used in phase III superiority trials to compare treatment arms, with the goal of terminating exposure of patients to ineffective or unsafe drugs or to identify highly effective therapies for earlier public disclosure. Traditionally, interim analyses have been designed to identify early evidence of extremely large benefit of the experimental approach, potentially leading to early dissemination of effective treatments. Increasingly, interim analysis has also involved analysis of futility, which may lead to early termination of a trial that will not yield additional useful information. This presents an important challenge in early stage hormone receptor-positive breast cancer, where recurrence often occurs late, with a steady annual event rate up to 20 years. Early analysis of events may miss late treatment effects that can be observed only with longer follow-up. We discuss approaches to futility analysis in adjuvant clinical trials in hormone receptor-positive breast cancer, the role of the Data Safety Monitoring Committee in such analyses, considerations of the potential harms vs benefits of treatment, and the risks of continuing vs early termination of a trial.

Cancer Antigen 15-3/Mucin 1 Levels in CCTG MA.32: A Breast Cancer Randomized Trial of Metformin vs Placebo.

Background: Circulating levels of cancer antigen (CA) 15-3, a tumor marker and regulator of cellular metabolism, were reduced by metformin in a nonrandomized neoadjuvant study. We examined the effects of metformin (vs placebo) on CA 15-3 in participants of MA.32, a phase III randomized trial in early-stage breast cancer. Methods: A total of 3649 patients with T1-3, N0-3, M0 breast cancer were randomly assigned; pretreatment and 6-month on-treatment fasting plasma were centrally assayed for CA 15-3. Genomic DNA was analyzed for the rs11212617 single nucleotide polymorphism. Absolute and relative change of CA 15-3 (metformin vs placebo) were compared using Wilcoxon rank and t tests. Regression models adjusted for baseline differences and assessed key interactions. All statistical tests were 2-sided. Results: Mean (SD) age was 52.4 (10.0) years. The majority of patients had T2/3, node-positive, hormone receptor-positive, HER2-negative breast cancer treated with (neo)adjuvant chemotherapy and hormone therapy. Mean (SD) baseline CA 15-3 was 17.7 (7.6) and 18.0 (8.1 U/mL). At 6 months, CA 15-3 was statistically significantly reduced in metformin vs placebo arms (absolute geometric mean reduction in CA 15-3 = 7.7% vs 2.0%, P < .001; relative metformin: placebo level of CA 15-3 [adjusted for age, baseline body mass index, and baseline CA 15-3] = 0.94, 95% confidence interval = 0.92 to 0.96). This reduction was independent of tumor characteristics, perioperative systemic therapy, baseline body mass index, insulin, and the single nucleotide polymorphism status (all Ps > .11). Conclusions: Our observation that metformin reduces CA 15-3 by approximately 6% was corroborated in a large placebo-controlled randomized trial. The clinical implications of this reduction in CA 15-3 will be explored in upcoming efficacy analyses of breast cancer outcomes in MA.32.

A Prospective Economic Analysis of Early Outcome Data From the Alliance A041202/ CCTG CLC.2 Randomized Phase III Trial Of Bendamustine-Rituximab Compared With Ibrutinib-Based Regimens in Untreated Older Patients With Chronic Lymphocytic Leukemia.

INTRODUCTION: The Alliance A041202/CCTG CLC.2 trial demonstrated superior progression-free survival with ibrutinib-based therapy compared to chemoimmunotherapy with bendamustine-rituximab (BR) in previously untreated older patients with chronic lymphocytic leukemia. We completed a prospective trial-based economic analysis of Canadian patients to study the direct medical costs and quality-adjusted benefit associated with these therapies. METHODS: Mean survival was calculated using the restricted mean survival method from randomization to the study time-horizon of 24 months. Health state utilities were collected using the EuroQOL EQ-5D instrument with Canadian tariffs applied to calculate quality-adjusted life years (QALYs). Costs were applied to resource utilization data (expressed in 2019 US dollars). We examined costs and QALYs associated ibrutinib, ibrutinib with rituximab (IR), and BR therapy. RESULTS: A total of 55 patients were enrolled; two patients were excluded from the analysis. On-protocol costs (associated with protocol-specified resource use) were higher for patients receiving ibrutinib (mean $189,335; P < 0.0001) and IR (mean $219,908; P < 0.0001) compared to BR (mean $51,345), driven by higher acquisition costs for ibrutinib. Total mean costs (over 2-years) were $192,615 with ibrutinib, $223,761 with IR, and $55,413 with BR (P < 0.0001 for ibrutinib vs. BR and P < 0.0001 for IR vs. BR). QALYs were similar between the three treatment arms: 1.66 (0.16) for ibrutinib alone, 1.65 (0.24) for IR, and 1.66 (0.17) for BR; therefore, a formal cost-utility analysis was not conducted. CONCLUSIONS: Direct medical costs are higher for patients receiving ibrutinib-based therapies compared to chemoimmunotherapy in frontline chronic lymphocytic leukemia, with the cost of ibrutinib representing a key driver.