A Randomized Trial of Two Remote Health Care Delivery Models on the Uptake of Genetic Testing and Impact on Patient-Reported Psychological Outcomes in Families With Pancreatic Cancer: The Genetic Education, Risk Assessment, and Testing (GENERATE) Study.

BACKGROUND & AIMS: Genetic testing uptake for cancer susceptibility in family members of patients with cancer is suboptimal. Among relatives of patients with pancreatic ductal adenocarcinoma (PDAC), The GENetic Education, Risk Assessment, and TEsting (GENERATE) study evaluated 2 online genetic education/testing delivery models and their impact on patient-reported psychological outcomes. METHODS: Eligible participants had ≥1 first-degree relative with PDAC, or ≥1 first-/second-degree relative with PDAC with a known pathogenic germline variant in 1 of 13 PDAC predisposition genes. Participants were randomized by family, between May 8, 2019, and June 1, 2021. Arm 1 participants underwent a remote interactive telemedicine session and online genetic education. Arm 2 participants were offered online genetic education only. All participants were offered germline testing. The primary outcome was genetic testing uptake, compared by permutation tests and mixed-effects logistic regression models. We hypothesized that Arm 1 participants would have a higher genetic testing uptake than Arm 2. Validated surveys were administered to assess patient-reported anxiety, depression, and cancer worry at baseline and 3 months postintervention. RESULTS: A total of 424 families were randomized, including 601 participants (n = 296 Arm 1; n = 305 Arm 2), 90% of whom completed genetic testing (Arm 1 [87%]; Arm 2 [93%], P = .014). Arm 1 participants were significantly less likely to complete genetic testing compared with Arm 2 participants (adjusted ratio [Arm1/Arm2] 0.90, 95% confidence interval 0.78-0.98). Among participants who completed patient-reported psychological outcomes questionnaires (Arm 1 [n = 194]; Arm 2 [n = 206]), the intervention did not affect mean anxiety, depression, or cancer worry scores. CONCLUSIONS: Remote genetic education and testing can be a successful and complementary option for delivering genetics care. (Clinicaltrials.gov, number NCT03762590).

Latinas in medicine: evaluating and understanding the experience of Latinas in medical education: a cross sectional survey.

BACKGROUND: The percentage of physicians identifying as Latina has not improved despite improvements in recruitment of Latina medical students, suggesting barriers to retention and career advancement. Discriminatory experiences and mental health inflictions throughout training may contribute to difficulties in recruitment, retainment, and advancement of Hispanic/Latinx trainees, a notably understudied population. METHODS: An anonymous, online survey was distributed to Latinas in the continental U.S. between June 22 to August 12, 2022. Eligibility criteria included: self-identifying as Hispanic/Latina, female/woman, and completing or have completed medical school, residency, or fellowship in the continental U.S. in the past 10 years. Recruitment was done via the Twitter account @LatinasInMed and outreach to Latino Medical Student Association chapters. Descriptive statistics summarized the self-reported experiences. RESULTS: The survey included 230 Hispanic/Latinx women, mostly medical students (46.9%). A majority (54.5%) reported negative ethnicity-based interactions from patients and/or patients' families; 71.8%, from others in the medical field. High rates of depression (76.2%) and anxiety (92.6%) during training were reported by Latinas, especially medical students. Feelings of imposter syndrome and burnout were high at 90.7% and 87.4%, respectively. CONCLUSIONS: This is the first study evaluating the unique experiences of Latinas in medicine, who reported discrimination and mental health struggles, specifically during medical school, at alarmingly high rates. Our findings could aid in creating the needed interventions to support Latinas in medical training to reduce the existing exodus of Latinas from medicine.

Vascular injury markers associated with cognitive impairment in people with HIV on suppressive antiretroviral therapy.

Objective: Human immunodeficiency virus (HIV)-associated neurocognitive disorders (HAND) remain prevalent despite viral suppression on antiretroviral therapy (ART). Vascular disease contributes to HAND, but peripheral markers that distinguish vascular cognitive impairment (VCI) from HIV-related etiologies remain unclear. Design: Cross-sectional study of vascular injury, inflammation, and central nervous system (CNS) injury markers in relation to HAND. Methods: Vascular injury (VCAM-1, ICAM-1, CRP), inflammation (IFN-γ, IL-1ß, IL-6, IL-8, IL-15, IP-10, MCP-1, VEGF-A), and CNS injury (NFL, total Tau, GFAP, YKL-40) markers were measured in plasma and CSF from 248 individuals (143 HIV+ on suppressive ART and 105 HIV- controls). Results: Median age was 53 years, median CD4 count, and duration of HIV infection were 505 cells/µl and 16 years, respectively. Vascular injury, inflammation, and CNS injury markers were increased in HIV+ compared with HIV- individuals (p<0.05). HAND was associated with increased plasma VCAM-1, ICAM-1, and YKL-40 (p<0.01) and vascular disease (p=0.004). In contrast, inflammation markers had no significant association with HAND. Vascular injury markers were associated with lower neurocognitive T scores in age-adjusted models (p<0.01). Furthermore, plasma VCAM-1 correlated with NFL (r=0.29, p=0.003). Biomarker clustering separated HAND into three clusters: two clusters with high prevalence of vascular disease, elevated VCAM-1 and NFL, and distinctive inflammation profiles (CRP/ICAM-1/YKL-40 or IL-6/IL-8/IL-15/MCP-1), and one cluster with no distinctive biomarker elevations. Conclusions: Vascular injury markers are more closely related to HAND and CNS injury in PWH on suppressive ART than inflammation markers and may help to distinguish relative contributions of VCI to HAND.

PREMM5 distinguishes sporadic from Lynch syndrome-associated MMR-deficient/MSI-high colorectal cancer.

Current algorithms for diagnosing Lynch syndrome (LS) include multistep molecular tumor tests to distinguish LS-associated from sporadic colorectal cancer (CRC), which add cost and complexity to the evaluation. We hypothesized that PREMM5, a clinical LS prediction tool, could be an alternative approach to screen for LS, thereby lessening the need for specialized molecular diagnostics. We reviewed a consecutively ascertained institutional cohort of 1058 CRC patients on whom pathologic and clinical data were available, including prior LS germline testing. Data from MMR-D/MSI-H CRC patients were reviewed and PREMM5 scores were calculated for each individual. Using a PREMM5 score cutoff ≥ 2.5% to characterize the need for germline testing, we determined the rate of pathogenic/likely pathogenic germline variants (PGVs) in LS genes in patients with PREMM5 scores ≥ 2.5% versus < 2.5%. Sensitivity and negative predictive values (NPV) of PREMM5 were calculated for all MMR-D/MSI-H CRC patients, and those with MLH1-deficient CRC. MMR IHC and/or MSI results were available on 572/1058 cases. We identified 74/572 (12.9%) cases as MMR-D/MSI-H, of which 28/74 (37.8%) harbored a LS PGV. 11/49 (22.4%) patients with MLH1-deficient CRC harbored a LS PGV. PREMM5 had 100% sensitivity (95% CI: 87.7-100 for any MMR-D/MSI-H; 95% CI: 71.5-100 for MLH1-deficient CRC) and 100% NPV (95% CI: 83.2-100 for any MMR-D/MSI-H; 95% CI: 82.4-100 for MLH1-deficient CRC) for identifying LS PGVs in these cohorts. PREMM5 accurately distinguishes LS- from non-LS-associated MMR-D/MSI-H CRC without additional somatic molecular testing. These findings are particularly relevant for limited-resource settings where advanced molecular diagnostics may be unavailable.

Vascular injury markers associated with cognitive impairment in people with HIV on suppressive antiretroviral therapy.

OBJECTIVE: Human immunodeficiency virus (HIV)-associated neurocognitive disorders (HAND) remain prevalent despite viral suppression on antiretroviral therapy (ART). Vascular disease contributes to HAND, but peripheral markers that distinguish vascular cognitive impairment (VCI) from HIV-related etiologies remain unclear. DESIGN: Cross-sectional study of vascular injury, inflammation, and central nervous system (CNS) injury markers in relation to HAND. METHODS: Vascular injury (VCAM-1, ICAM-1, CRP), inflammation (IFN-γ, IL-1ß, IL-6, IL-8, IL-15, IP-10, MCP-1, VEGF-A), and CNS injury (NFL, total Tau, GFAP, YKL-40) markers were measured in plasma and CSF from 248 individuals (143 HIV+ on suppressive ART and 105 HIV- controls). RESULTS: Median age was 53 years, median CD4 + cell count, and duration of HIV infection were 505 cells/µl and 16 years, respectively. Vascular injury, inflammation, and CNS injury markers were increased in HIV+ compared with HIV- individuals ( P < 0.05). HAND was associated with increased plasma VCAM-1, ICAM-1, and YKL-40 ( P  < 0.01) and vascular disease ( P  = 0.004). In contrast, inflammation markers had no significant association with HAND. Vascular injury markers were associated with lower neurocognitive T scores in age-adjusted models ( P  < 0.01). Furthermore, plasma VCAM-1 correlated with NFL ( r  = 0.29, P  = 0.003). Biomarker clustering separated HAND into three clusters: two clusters with high prevalence of vascular disease, elevated VCAM-1 and NFL, and distinctive inflammation profiles (CRP/ICAM-1/YKL-40 or IL-6/IL-8/IL-15/MCP-1), and one cluster with no distinctive biomarker elevations. CONCLUSIONS: Vascular injury markers are more closely related to HAND and CNS injury in PWH on suppressive ART than inflammation markers and may help to distinguish relative contributions of VCI to HAND.

Mentorship Experiences Are Not All the Same: A Survey Study of Oncology Trainees and Early-Career Faculty.

PURPOSE: Physician workforce diversity can be a driver of institutional excellence, improving innovation and reducing health disparities. However, the current diversity of the hematology/oncology (HO) workforce does not reflect that of the US population. METHODS: We conducted a cross-sectional online survey of current trainees and faculty within 5 years of completing terminal training in oncology specialties. RESULTS: Of the 306 respondents, 64 (21%) were under-represented in medicine (URiM) and 161 (53%) identified as male. URiM participants were less likely to have a primary mentor (66%) than non-URiM participants (80%; P = .015). Among those who had a primary mentor, URiMs met less frequently (once every 3-6 months or less) with their mentor (19% v 7% non-URiM; P = .003). Furthermore, URiMs were more likely to report having mentors outside their own institution (47% v 40% non-URiM; P = .002) and making compromises to gain access to mentorship (36% v 23% non-URiM; P ≤ 0.001). URiMs were also less likely to apply for grants (34% v 42% non-URiM; P = .035) and awards (28% v 43% non-URiM; P = .019). In multivariable models, URiM individuals were more likely to make compromises to gain access to mentors (odds ratio [OR], 1.96; 95% CI, 1.01 to 3.82) and this remained significant for females (OR, 2.17; 95% CI, 1.26 to 3.75). CONCLUSION: URiM individuals may be less likely to have effective mentorship and apply for awards and grant support. Understanding the challenges of URiM trainees can help shape training environments in academic medicine to ensure that they are grounded in diversity, inclusion, and retention.

Clinical factors associated with skin neoplasms in individuals with Lynch syndrome in a longitudinal observational cohort.

BACKGROUND: Little is known about patient-specific risk factors for skin neoplasia in individuals with Lynch syndrome (LS). OBJECTIVE: Identify clinical factors associated with development of skin neoplasms in LS. METHODS: Clinical data were systematically collected on a cohort of LS carriers (confirmed pathogenic germline variants in MLH1, MSH2, MSH6, PMS2, or EPCAM) age ≥18 undergoing clinical genetics care at Dana-Farber Cancer Institute from January 2000 to March 2020. Multivariable logistic regression was performed to evaluate clinical factors associated with skin neoplasia. RESULTS: Of 607 LS carriers, 9.2% had LS-associated skin neoplasia and 15.0% had non-LS-associated skin neoplasia; 58.2% (353/607) had documentation of prior dermatologic evaluation; 29.7% (38/128) with skin neoplasms lacked a history of visceral LS-associated malignancy. LS-associated skin neoplasms were significantly associated with male sex, age, race, MLH1 pathogenic germline variants, MSH2/EPCAM pathogenic germline variants, and personal history of non-LS skin neoplasms. Non-LS-associated skin neoplasms was significantly associated with age, number of first- and second-degree relatives with non-LS-associated skin neoplasms, and personal history of LS-associated skin neoplasms. LIMITATIONS: Single-institution observational study; demographic homogeneity. CONCLUSIONS: Skin neoplasms are common in individuals with LS. We identified clinical factors associated with LS- and non-LS-associated skin neoplasms. Regular dermatologic surveillance should be considered for all LS carriers.

On assessing survival benefit of immunotherapy using long-term restricted mean survival time.

The pattern of the difference between two survival curves we often observe in randomized clinical trials for evaluating immunotherapy is not proportional hazards; the treatment effect typically appears several months after the initiation of the treatment (ie, delayed difference pattern). The commonly used logrank test and hazard ratio estimation approach will be suboptimal concerning testing and estimation for those trials. The long-term restricted mean survival time (LT-RMST) approach is a promising alternative for detecting the treatment effect that potentially appears later in the study. A challenge in employing the LT-RMST approach is that it must specify a lower end of the time window in addition to a truncation time point that the RMST requires. There are several investigations and suggestions regarding the choice of the truncation time point for the RMST. However, little has been investigated to address the choice of the lower end of the time window. In this paper, we propose a flexible LT-RMST-based test/estimation approach that does not require users to specify a lower end of the time window. Numerical studies demonstrated that the potential power loss by adopting this flexibility was minimal, compared to the standard LT-RMST approach using a prespecified lower end of the time window. The proposed method is flexible and can offer higher power than the RMST-based approach when the delayed treatment effect is expected. Also, it provides a robust estimate of the magnitude of the treatment effect and its confidence interval that corresponds to the test result.

Ratio and difference of average hazard with survival weight: New measures to quantify survival benefit of new therapy.

The hazard ratio (HR) has been the most popular measure to quantify the magnitude of treatment effect on time-to-event outcomes in clinical research. However, the traditional Cox's HR approach has several drawbacks. One major issue is that there is no clear interpretation when the proportional hazards (PH) assumption does not hold, because the estimated HR is affected by study-specific censoring time distribution in non-PH cases. Another major issue is that the lack of a group-specific absolute hazard value in each group obscures the clinical significance of the magnitude of the treatment effect. Given these, we propose average hazard with survival weight (AH-SW) as a summary metric of event time distribution and will use difference in AH-SW (DAH-SW) or ratio of AH-SW (RAH-SW) to quantify the treatment effect magnitude. The AH-SW is interpreted as a person-time incidence rate that does not depend on random censoring. It is defined as the ratio of cumulative incidence probability and restricted mean survival time (RMST), which can be estimated non-parametrically. Numerical studies demonstrate that DAH-SW and RAH-SW offer almost identical power to Cox's HR-based tests under PH scenarios and can be more powerful for delayed-difference patterns often seen in immunotherapy trials. Like median and RMST differences, the proposed approach is a good model-free alternative to the HR-based approach for evaluating the treatment effect magnitude. Such a model-free measure will increase the likelihood that results from clinical studies are correctly interpreted and generalized to future populations.

Development and Validation of the PREMMplus Model for Multigene Hereditary Cancer Risk Assessment.

PURPOSE: With the availability of multigene panel testing (MGPT) for hereditary cancer risk assessment, clinicians need to assess the likelihood of pathogenic germline variants (PGVs) across numerous genes in parallel. This study's aim was to develop and validate a clinical prediction model (PREMMplus) for MGPT risk assessment. MATERIALS AND METHODS: PREMMplus was developed in a single-institution cohort of 7,280 individuals who had undergone MGPT. Logistic regression models with Least Absolute Shrinkage and Selection Operator regularization were used to examine candidate predictors (age, sex, ethnicity, and personal/family history of 18 cancers/neoplasms) to estimate one's likelihood of carrying PGVs in 19 genes (broadly categorized by phenotypic overlap and/or relative penetrance: 11 category A [APC, BRCA1/2, CDH1, EPCAM, MLH1, MSH2, MSH6, biallelic MUTYH, PMS2, and TP53] and eight category B genes [ATM, BRIP1, CDKN2A, CHEK2, PALB2, PTEN, RAD51C, and RAD51D]). Model performance was validated in nonoverlapping data sets of 8,691 and 14,849 individuals with prior MGPT ascertained from clinic- and laboratory-based settings, respectively. RESULTS: PREMMplus (score ≥ 2.5%) had 93.9%, 91.7%, and 89.3% sensitivity and 98.3%, 97.5%, and 97.8% negative-predictive value (NPV) for identifying category A gene PGV carriers in the development and validation cohorts, respectively. PREMMplus assessment (score ≥ 2.5%) had 89.9%, 85.6%, and 84.2% sensitivity and 95.0%, 93.5%, and 93.5% NPV, respectively, for identifying category A/B gene PGV carriers. Decision curve analyses support MGPT for individuals predicted to have ≥ 2.5% probability of a PGV. CONCLUSION: PREMMplus accurately identifies individuals with PGVs in a diverse spectrum of cancer susceptibility genes with high sensitivity/NPV. Individuals with PREMMplus scores ≥ 2.5% should be considered for MGPT.

Familial Burden and Other Clinical Factors Associated With Various Types of Cancer in Individuals With Lynch Syndrome.

BACKGROUND & AIMS: Lynch syndrome (LS) is associated with increased risks of various gastrointestinal, gynecologic, genitourinary, and other cancers. Many clinical practice guidelines recommend that LS carriers' screening strategies be devised based on their family history of various cancers, in addition to age-, sex-, and gene-specific considerations. The aim of this study was to examine the association between family history and other clinical factors with LS carriers' histories of various cancers. METHODS: Two cohorts of LS carriers were analyzed: a laboratory-based cohort of consecutively ascertained individuals undergoing germline LS testing and a clinic-based cohort of LS carriers undergoing clinical care at an academic medical center. Multivariable logistic regression was performed to assess clinical factors associated with LS carriers' histories of various cancers/neoplasms. Familial burden was defined as LS carriers' aggregate number of first-/second-degree relatives with a history of a given malignancy. RESULTS: Multivariable analysis of the laboratory-based cohort (3828 LS carriers) identified familial burden as being incrementally associated with LS carriers' personal history of endometrial (odds ratio [OR], 1.37 per affected first-/second-degree relative; 95% confidence interval [CI], 1.21-1.56), urinary tract (OR, 2.72; 95% CI, 2.02-3.67), small bowel (OR, 3.17; 95% CI, 1.65-6.12), gastric (OR, 1.93; 95% CI, 1.24-3.02), and pancreaticobiliary cancers (OR, 2.10; 95% CI, 1.21-3.65) and sebaceous neoplasms (OR, 7.39; 95% CI, 2.71-20.15). Multivariable analysis of the clinic-based cohort (607 LS carriers) confirmed a significant association of familial burden of endometrial and urinary tract cancers. CONCLUSIONS: Familial burden - in addition to age, sex, and specific LS gene - should be used to assess LS carriers' risks of specific cancers and guide decision-making about organ-specific surveillance.

Comparison of Colorectal and Endometrial Microsatellite Instability Tumor Analysis and Premm5 Risk Assessment for Predicting Pathogenic Germline Variants on Multigene Panel Testing.

PURPOSE: Tumor testing for microsatellite instability and/or mismatch repair-deficiency (MSI/IHC) and clinical prediction models effectively screen for Lynch syndrome (LS)-associated colorectal cancer (CRC) and endometrial cancer (EC), but they have not been assessed for their ability to identify non-LS forms of inherited risk. The aim of this study was to compare MSI/IHC and the PREMM5 prediction model to identify carriers of LS and non-LS pathogenic variants (PVs) among patients with CRC and EC. PATIENTS AND METHODS: Data were retrospectively analyzed from two single-institution cohorts: 706 patients with CRC and/or EC referred for genetic evaluation/testing (high-risk cohort) and 1,058 consecutively ascertained patients with CRC (oncology clinic cohort), unselected for familial risk. All participants underwent germline multigene panel testing. PREMM5 scores were calculated from personal/family cancer history. The primary outcome was the proportion of individuals with germline PVs (LS PVs, high-penetrance PVs, and any PVs) who had abnormal MSI/IHC testing and/or PREMM5 score ≥ 2.5%. RESULTS: MSI/IHC and PREMM5 had comparable sensitivity for identifying LS carriers in high-risk (89.3% v 85.7%; P = .712) and oncology clinic patients (96.6% v 96.6%; P = 1.000), although MSI/IHC had significantly superior specificity for LS (81.3% v 20.1%; P < .001; 92.3% v 24.3%; P < .001). In both cohorts, PREMM5 had superior sensitivity to MSI/IHC at identifying patients with any high-penetrance PVs and any low-, moderate-, and high-penetrance PVs. Among patients with normal MSI/IHC, PREMM5 identified 84.2% and 83.3% of high-risk patients with CRC/EC and oncology clinic CRC patients with high-penetrance PVs, respectively. CONCLUSION: MSI/IHC and PREMM5 effectively identify patients with CRC and/or EC with LS, although MSI/IHC has better specificity for LS. Because PREMM5 identifies non-LS, high-penetrance germline PVs, patients with CRC and/or EC with PREMM5 score ≥ 2.5%, including those with normal MSI/IHC, should be offered multigene panel testing.

Empirical power comparison of statistical tests in contemporary phase III randomized controlled trials with time-to-event outcomes in oncology.

BACKGROUND: More than 95% of recent cancer randomized controlled trials used the log-rank test to detect a treatment difference making it the predominant tool for comparing two survival functions. As with other tests, the log-rank test has both advantages and disadvantages. One advantage is that it offers the highest power against proportional hazards differences, which may be a major reason why alternative methods have rarely been employed in practice. The performance of statistical tests has traditionally been investigated both theoretically and numerically for several patterns of difference between two survival functions. However, to the best of our knowledge, there has been no attempt to compare the performance of various statistical tests using empirical data from past oncology randomized controlled trials. So, it is unknown whether the log-rank test offers a meaningful power advantage over alternative testing methods in contemporary cancer randomized controlled trials. Focusing on recently reported phase III cancer randomized controlled trials, we assessed whether the log-rank test gave meaningfully greater power when compared with five alternative testing methods: generalized Wilcoxon, test based on maximum of test statistics from multiple weighted log-rank tests, difference in t-year event rate, and difference in restricted mean survival time with fixed and adaptive τ. METHODS: Using manuscripts from cancer randomized controlled trials recently published in high-tier clinical journals, we reconstructed patient-level data for overall survival (69 trials) and progression-free survival (54 trials). For each trial endpoint, we estimated the empirical power of each test. Empirical power was measured as the proportion of trials for which a test would have identified a significant result (p value < .05). RESULTS: For overall survival, t-year event rate offered the lowest (30.4%) empirical power and restricted mean survival time with fixed τ offered the highest (43.5%). The empirical power of the other types of tests was almost identical (36.2%-37.7%). For progression-free survival, the tests we investigated offered numerically equivalent empirical power (55.6%-61.1%). No single test consistently outperformed any other test. CONCLUSION: The empirical power assessment with the past cancer randomized controlled trials provided new insights on the performance of statistical tests. Although the log-rank test has been used in almost all trials, our study suggests that the log-rank test is not the only option from an empirical power perspective. Near universal use of the log-rank test is not supported by a meaningful difference in empirical power. Clinical trial investigators could consider alternative methods, beyond the log-rank test, for their primary analysis when designing a cancer randomized controlled trial. Factors other than power (e.g. interpretability of the estimated treatment effect) should garner greater consideration when selecting statistical tests for cancer randomized controlled trials.

On permutation tests for comparing restricted mean survival time with small sample from randomized trials.

Between-group comparison based on the restricted mean survival time (RMST) is getting attention as an alternative to the conventional logrank/hazard ratio approach for time-to-event outcomes in randomized controlled trials (RCTs). The validity of the commonly used nonparametric inference procedure for RMST has been well supported by large sample theories. However, we sometimes encounter cases with a small sample size in practice, where we cannot rely on the large sample properties. Generally, the permutation approach can be useful to handle these situations in RCTs. However, a numerical issue arises when implementing permutation tests for difference or ratio of RMST from two groups. In this article, we discuss the numerical issue and consider six permutation methods for comparing survival time distributions between two groups using RMST in RCTs setting. We conducted extensive numerical studies and assessed type I error rates of these methods. Our numerical studies demonstrated that the inflation of the type I error rate of the asymptotic methods is not negligible when sample size is small, and that all of the six permutation methods are workable solutions. Although some permutation methods became a little conservative, no remarkable inflation of the type I error rates were observed. We recommend using permutation tests instead of the asymptotic tests, especially when the sample size is less than 50 per arm.

How Do the Accrual Pattern and Follow-Up Duration Affect the Hazard Ratio Estimate When the Proportional Hazards Assumption Is Violated?

In randomized clinical trials, the magnitude of the treatment effect is often reported using the hazard ratio (HR) even when the proportional hazards (PH) assumption is not met. Conducting numerical studies, this commentary illustrates how/why the HR estimate via the standard Cox's procedure is difficult to interpret even as an "average" treatment effect for non­PH cases.

A flexible and coherent test/estimation procedure based on restricted mean survival times for censored time-to-event data in randomized clinical trials.

In randomized clinical trials where time-to-event is the primary outcome, almost routinely, the logrank test is prespecified as the primary test and the hazard ratio is used to quantify treatment effect. If the ratio of 2 hazard functions is not constant, the logrank test is not optimal and the interpretation of hazard ratio is not obvious. When such a nonproportional hazards case is expected at the design stage, the conventional practice is to prespecify another member of weighted logrank tests, eg, Peto-Prentice-Wilcoxon test. Alternatively, one may specify a robust test as the primary test, which can capture various patterns of difference between 2 event time distributions. However, most of those tests do not have companion procedures to quantify the treatment difference, and investigators have fallen back on reporting treatment effect estimates not associated with the primary test. Such incoherence in the "test/estimation" procedure may potentially mislead clinicians/patients who have to balance risk-benefit for treatment decision. To address this, we propose a flexible and coherent test/estimation procedure based on restricted mean survival time, where the truncation time τ is selected data dependently. The proposed procedure is composed of a prespecified test and an estimation of corresponding robust and interpretable quantitative treatment effect. The utility of the new procedure is demonstrated by numerical studies based on 2 randomized cancer clinical trials; the test is dramatically more powerful than the logrank, Wilcoxon tests, and the restricted mean survival time-based test with a fixed τ, for the patterns of difference seen in these cancer clinical trials.