Unstratified Analyses Research Articles

Interaction of chronic diseases and levels of mastery on the course of depression.

Chronic diseases may negatively interfere with the course of depression. Our aim was to examine whether the association between chronic disease and course of depression is moderated by mastery. N=1146 persons, aged 18-88, with depressive disorder according to DSM-IV criteria were followed for two years. Outcomes were change in depression severity (change in IDS-SR) (n=945), chronic course (life chart interview) (n=971), depression at follow-up (DSM-diagnosis) (n=971), and time to remission (life chart interview) (n=799). Predictors were number of chronic somatic diseases and mastery. Regression models (linear, logistic and Cox) were used, adjusted for depression severity, sociodemographics, loneliness, smoking and alcohol use. Next, an interaction term (chronic diseases*mastery) was added to the models. We only found significant interaction between mastery and chronic diseases (p=0.02), when outcome was defined as change in depression severity. In analyses, stratified for level of mastery, chronic diseases were significantly associated with chronic course in persons with moderate (B=1.03; p=0.03) and high (B=1.10; p=0.02) mastery levels. In unstratified analyses, mastery was associated with both chronic course (B=-0.18, p=0.03) and time to remission (B=1.03; p<0.001). Chronic diseases did not reach significance in three outcomes. While impact of chronic diseases on depression trajectories was less consistent than expected, when present, this association was moderated by mastery, suggesting that persons with higher levels of mastery may have difficulties coping with somatic illnesses. In clinical practice, attention to the impact of somatic diseases and coping strategies, in persons with higher levels of mastery, is warranted.

Evaluating the impact of stratification on the power and cross-arm balance of randomized phase 2 clinical trials.

Randomized clinical trials often use stratification to ensure balance between arms. Analysis of primary endpoints of these trials typically uses a "stratified analysis," in which analyses are performed separately in each subgroup defined by the stratification factors, and those separate analyses are weighted and combined. In the phase 3 setting, stratified analyses based on a small number of stratification factors can provide a small increase in power. The impact on power and type-1 error of stratification in the setting of smaller sample sizes as in randomized phase 2 trials has not been well characterized. We performed computational studies to characterize the power and cross-arm balance of modestly sized clinical trials (less than 170 patients) with varying numbers of stratification factors (0-6), sample sizes, randomization ratios (1:1 vs 2:1), and randomization methods (dynamic balancing vs stratified block). We found that the power of unstratified analyses was minimally impacted by the number of stratification factors used in randomization. Analyses stratified by 1-3 factors maintained power over 80%, while power dropped below 80% when four or more stratification factors were used. These trends held regardless of sample size, randomization ratio, and randomization method. For a given randomization ratio and sample size, increasing the number of factors used in randomization had an adverse impact on cross-arm balance. Stratified block randomization performed worse than dynamic balancing with respect to cross-arm balance when three or more stratification factors were used. Stratified analyses can decrease power in the setting of phase 2 trials when the number of patients in a stratification subgroup is small.

How Many Stratification Factors Are Reasonable and Can There be Too Many? Evaluation of Analysis Strategies in the Context of a Randomized Phase 2 Trial in Acute Myeloid Leukemia within the Myelomatch Platform

Background: Stratification is frequently used to ensure balance between arms in randomized clinical trials. Analysis of primary endpoints trials using stratified randomized typically uses a "stratified analysis,” in which the primary endpoint is analyzed separately in each subgroup defined by the stratification factors and then those separate analyses are combined in a weighted fashion based on the size of the subgroups. In our experience designing trials, increasing attention has been paid to stratification factors, with larger numbers of stratification factors being proposed. However, the issues with performing some statistical tests with small sample sizes are well-recognized. We performed computational studies to characterize the power and type-1 error in a clinical trial under development with varying numbers of stratification factors. Patients and Methods: We simulated data per the design assumptions of a randomized Phase 2 acute myeloid leukemia trial in development (design initially based on un-stratified calculations). The endpoint was overall survival and we assumed 1:1 randomization, exponential survival (median 7 vs 12 months in the two arms; corresponds to hazard ratio [HR] = 0.58), 84 total patients, a one-sided alpha of 15% based on a log-rank test at 70 deaths. Simulations were conducted, but with a progressive increase in the number of stratification factors; the HR within each stratification factor subgroup was constant and equal to the original design HR (0.58). Power and type-1 error were estimated using 10,000 replications. All stratification factors had two levels with 50/50 distribution. Dynamic balancing was used for randomization with 75% weighted allocation to the arm with better balance. Results: The design with no stratification factors (first row of table) corresponds to the properties initially used to determine the sample size for the trial. With this Phase 2 sample size (n=84 total), a stratified analysis with 1-2 stratification factors maintains power and type-1 error. With 4 or 6 stratification factors, stratified analyses have decreased power with type-1 error controlled. Stratifying by a subset of factors (1 or 2 of the 4 or 6) decreases power in this setting by a small amount (1-2%). The power and type-1 error of unstratified analyses is minimally impacted in the setting of stratified randomization. Conclusion: In the setting of a modestly-sized randomized Phase 2 trial, stratified analyses accounting for 4 or 6 stratification factors can lead to unacceptable decreases in power. Unstratified analyses or analyses accounting for 1 or 2 of the stratification factors led to small (1-2%) decreases in power. Stratified randomization can ensure balance between arms for covariates. When the covariates used in stratified randomization are prognostic (and with > 1 stratification factor, are independently prognostic), using a stratified analysis will often be associated with an increase in power over an unstratified analysis. That increase in power is not guaranteed, as shown in this example. When the number of stratification factors leads to subgroups with small numbers of patients and/or events, stratified analyses can decrease power. Performing a stratified analysis accounting for a subset of the covariates can improve the power compared to an analysis accounting for all stratification factors, though the power is still lower than in a design with fewer stratification factors. Support: NIH/NCI grants CA180888 and CA180819. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

LBA19 Pyrotinib or placebo in combination with trastuzumab and docetaxel for HER2-positive metastatic breast cancer (PHILA): A randomized phase III trial

Pyrotinib (pyro, an irreversible pan-HER inhibitor) plus capecitabine has demonstrated antitumor activity as 2L treatment in HER2-positive metastatic breast cancer (mBC) (Lancet Oncol 2021). Pertuzumab combined with trastuzumab (H) and docetaxel (T) is the standard 1L dual anti-HER2 therapy for HER2-positive mBC. Here, we report the efficacy and safety of dual anti-HER2 regimen of Pyro+H+T (PyroHT) compared with placebo+H+T (HT) in untreated HER2-positive mBC. Eligible pts were randomized (1:1) to receive oral Pyro (400 mg QD) or placebo, both combined with intravenous H (8 mg/kg in cycle 1 and 6 mg/kg in subsequent cycles) and T (75 mg/m2) on day 1 of each 21-day cycle. The primary endpoint was PFS per investigator (INV). Data cutoff for this prespecified interim analysis was May 25, 2022. Between May 2019 and Jan 2022, 590 eligible pts from 40 centers were randomized and treated (297 with PyroHT and 293 with HT). Median follow-up was 15.8 mo and 14.9 mo, respectively. PFS per INV of PyroHT was significantly longer than HT (median, 24.3 mo [95% CI 19.1-33.0] vs 10.4 mo [95% CI 9.3-12.3]; HR, 0.41 [95% CI 0.32-0.53]; P < 0.0001; subgroup results are in the Table), which was consistent with PFS per IRC (median, 33.0 vs 10.4 mo; HR, 0.35 [95% CI 0.27-0.46]). The most common grade ≥3 TRAEs were decreased neutrophil count (62.6% vs 65.2%), decreased WBC count (53.2% vs 50.9%), and diarrhea (46.5% vs 3.1%). Grade 3 diarrhea occurred mainly during cycle 1 and substantially decreased in cycle 2 and thereafter. No grade 4 or 5 diarrheas occurred. Serious TRAEs occurred in 24.9% vs 6.1% of pts and treatment-related deaths occurred in 0 vs 0.3% of pts, respectively.Table: LBA19Subgroup analyses of PFS per INVPyroHTHTHR (95% CI)n/NPFS (median, mo)n/NPFS (median, mo)ECOG performance status055/16427.596/15510.40.42 (0.30-0.59)144/13322.282/13810.30.39 (0.27-0.57)Prior neoadjuvant or adjuvant therapyYes49/14827.891/15310.60.43 (0.30-0.62)No50/14919.587/14010.30.38 (0.26-0.54)Prior neoadjuvant or adjuvant trastuzumabYes11/46NA32/429.30.23 (0.12-0.46)No88/25121.9146/25110.40.45 (0.34-0.59)Treatment-free interval with prior adjuvant therapy≥12 - <24 mo8/30NA25/388.30.22 (0.10-0.50)≥24 mo34/9922.258/10013.00.57 (0.37-0.87)n/N=events/patients. HRs are from unstratified analyses. Open table in a new tab n/N=events/patients. HRs are from unstratified analyses. PyroHT significantly prolonged PFS over HT in pts with HER2-positive mBC. The safety is manageable. To our knowledge, this is the second phase 3 trial to demonstrate PFS benefit from dual HER2 inhibition in 1L treatment of HER2-positive mBC.

992P Updated analyses from the CROWN study of first-line lorlatinib vs crizotinib in Asian patients with ALK-positive non-small cell lung cancer (NSCLC)

Lorlatinib improved progression-free survival (PFS) and demonstrated intracranial (IC) activity in patients with untreated advanced ALK+ non-small cell lung cancer (NSCLC) in the phase III CROWN study (NCT03052608) of lorlatinib vs crizotinib. Here, we report updated results in the Asian subgroup from this study after 36 months of follow-up. Patients were randomized 1:1 to receive lorlatinib 100 mg once daily or crizotinib 250 mg twice daily, stratified by presence of brain metastases (yes/no) and ethnicity (Asian/non-Asian). The primary endpoint was PFS by based on blinded independent central review (BICR). Key secondary endpoints included objective response rate (ORR), intracranial ORR (IC ORR), IC time to progression (IC TTP), and safety. Endpoints were analyzed using unstratified analyses in the Asian subgroup. In the Asian subgroup, 120 patients were randomized to lorlatinib (n=59) or crizotinib (n=61) arm. At data cutoff (Sep 20, 2021), median PFS by BICR was not reached with lorlatinib and 11.1 months with crizotinib (HR 0.40; 95% CI, 0.230-0.710; Table). Both ORR and IC ORR were clinically improved with lorlatinib vs crizotinib. The HR of IC TTP with lorlatinib vs crizotinib was 0.03 (95% CI, 0.004-0.200). All-cause grade 3/4 treatment-emergent adverse events (TEAEs) and TEAEs leading to treatment discontinuation were reported in 79.7% and 8.5% of patients with lorlatinib and 61.7% and 13.3% of patients with crizotinib, respectively. No new safety signals emerged.Table: 992PEfficacy in CROWN Asian subgroupaEndpointLorlatinib (n=59)Crizotinib (n=61)PFS, median (95% CI), monthsNR (33.1-NR)11.1 (9.2-14.8)HR (95% CI)0.40 (0.230-0.710)ORR (95% CI), %78.0 (65.3-87.7)57.4 (44.1-70.0)IC TTP (95% CI), monthsNR (NR-NR)16.6 (11.0-NR)HR (95% CI)0.03 (0.004-0.200)Patients with brain metastases at baselineLorlatinib (n=11)Crizotinib (n=15)IC ORR (95% CI), %72.7 (39.0-94.0)20.0 (4.3-48.1)HR, hazard ratio; IC, intracranial; NR, not reached; ORR, objective response rate; PFS, progression-free survival; TTP, time to progression. aBy blinded independent central review unless stated otherwise. Open table in a new tab HR, hazard ratio; IC, intracranial; NR, not reached; ORR, objective response rate; PFS, progression-free survival; TTP, time to progression. aBy blinded independent central review unless stated otherwise. Efficacy and safety results in the Asian subgroup were consistent with those in the overall population in the CROWN study. Our data support the use of lorlatinib as a first-line treatment option in Asian patients with ALK+ NSCLC.

Third-Trimester Maternal Dietary Patterns Are Associated with Sleep Health among Adolescent Offspring in a Mexico City Cohort

BackgroundMaternal diet during gestation has been linked to infant sleep; whether associations persist through adolescence is unknown. ObjectivesWe explored associations between trimester-specific maternal diet patterns and measures of sleep health among adolescent offspring in a Mexico City birth cohort. MethodsData from 310 mother–adolescent dyads were analyzed. Maternal diet patterns were identified by principal component analysis derived from FFQs collected during each trimester of pregnancy. Sleep duration, midpoint, and fragmentation were obtained from 7-d actigraphy data when adolescents were between 12 and 20 y old. Unstratified and sex-stratified association analyses were conducted using linear regression models, adjusted for potential confounders. ResultsMean ± SD age of offspring was 15.1 ± 1.9 y, and 52.3% of the sample was female. Three diet patterns were identified during each trimester of pregnancy: the Prudent Diet (PD), high in lean proteins and vegetables; the Transitioning Mexican Diet (TMD), high in westernized foods; and the High Meat & Fat Diet (HMFD), high in meats and fat products. Mean ± SD sleep duration was 8.5 ± 1.5 h/night. Most associations were found in the third trimester. Specifically, PD maternal adherence was associated with shorter sleep duration among offspring (−0.57 h; 95% CI: −0.98, −0.16 h, in the highest tertile compared with the lowest) and earlier sleep midpoint among females (−0.77 h; 95% CI: −1.3, −0.26 h). Adherence to the HMFD and TMD was nonlinearly associated with less fragmented sleep, with the latter only evident among females. ConclusionsFindings indicate that maternal dietary patterns, especially during the third trimester of pregnancy, may have long-term impacts on offspring sleep.

Tuberculosis treatment intermittency in the continuation phase and mortality in HIV-positive persons receiving antiretroviral therapy

BackgroundSome tuberculosis (TB) treatment guidelines recommend daily TB treatment in both the intensive and continuation phases of treatment in HIV-positive persons to decrease the risk of relapse and acquired drug resistance. However, guidelines vary across countries, and treatment is given 7, 5, 3, or 2 days/week. The effect of TB treatment intermittency in the continuation phase on mortality in HIV-positive persons on antiretroviral therapy (ART), is not well-described.MethodsWe conducted an observational cohort study among HIV-positive adults treated for TB between 2000 and 2018 and after enrollment into the Caribbean, Central, and South America network for HIV epidemiology (CCASAnet; Brazil, Chile, Haiti, Honduras, Mexico and Peru). All received standard TB therapy (2-month initiation phase of daily isoniazid, rifampin or rifabutin, pyrazinamide ± ethambutol) and continuation phase of isoniazid and rifampin or rifabutin, administered concomitantly with ART. Known timing of ART and TB treatment were also inclusion criteria. Kaplan–Meier and Cox proportional hazards methods compared time to death between groups. Missing model covariates were imputed via multiple imputation.Results2303 patients met inclusion criteria: 2003(87%) received TB treatment 5–7 days/week and 300(13%) 2–3 days/week in the continuation phase. Intermittency varied by site: 100% of patients from Brazil and Haiti received continuation phase treatment 5–7 days/week, followed by Honduras (91%), Peru (42%), Mexico (7%), and Chile (0%). The crude risk of death was lower among those receiving treatment 5–7 vs. 2–3 days/week (HR = 0.68; 95% CI = 0.51—0.91; P = 0.008). After adjusting for age, sex, CD4, ART use at TB diagnosis, site of TB disease (pulmonary vs. extrapulmonary), and year of TB diagnosis, mortality risk was lower, but not significantly, among those treated 5–7 days/week vs. 2–3 days/week (HR 0.75, 95%CI 0.55–1.01; P = 0.06). After also stratifying by study site, there was no longer a protective effect (HR 1.42, 95%CI 0.83–2.45; P = 0.20).ConclusionsTB treatment 5–7 days/week was associated with a marginally decreased risk of death compared to TB treatment 2–3 days/week in the continuation phase in multivariable, unstratified analyses. However, little variation in TB treatment intermittency within country meant the results could have been driven by other differences between study sites. Therefore, randomized trials are needed, especially in heterogenous regions such as Latin America.

Abstract PD8-05: Overall survival (OS) results from the phase III PHENIX trial of HER2+ metastatic breast cancer treated with pyrotinib plus capecitabine

Abstract Background: Pyrotinib (an irreversible tyrosine kinase inhibitor targeting EGFR, HER2, and HER4) plus capecitabine previously demonstrated a statistically significant improvement in progression-free survival (PFS) over placebo plus capecitabine for HER2-positive local relapsed or metastatic breast cancer after prior trastuzumab and taxanes in the interim analysis of the PHENIX trial (NCT02973737; Jiang Z et al. Oral presentation at ASCO 2019, Abstract 1001). It is shown that patients also benefit from subsequent pyrotinib monotherapy after progressed on capecitabine alone. Here we present an updated OS from a follow-up period with a median of 42.1 months. Methods: This PHENIX trial enrolled patients with HER2-positive local relapsed or metastatic breast cancer who had received prior trastuzumab and taxanes and up to two prior lines of chemotherapy for relapsed or metastatic disease. Eligible patients were randomized 2:1 to receive pyrotinib (400 mg orally once daily) in combination with capecitabine (1000 mg/m2 orally twice daily on days 1-14 for 21-day cycles; P+C group) or placebo plus capecitabine followed by pyrotinib monotherapy upon disease progression (C-P group). Randomization was stratified by the presence of visceral disease (yes vs. no) and the hormone receptor status (estrogen receptor [ER]- and/or progesterone receptor [PR]-positive vs. ER- and PR-negative). The primary endpoint was the independent review committee-assessed PFS. The data cutoff for the updated OS analysis was January 15, 2021. Results: A total of 279 eligible patients were randomized, with 185 to P+C group and 94 to C-P group. As of data cutoff, the median duration of follow-up was 41.7 months (95% CI 40.2-42.4) in P+C group and 43.1 months (95% CI 38.8-44.5) in C-P group. 71 out of 94 patients who progressed on placebo plus capecitabine received pyrotinib monotherapy as the first subsequent anti-cancer therapy according to protocol. Excluding the protocol prespecified pyrotinib monotherapy, 129 (69.7%) patients in the P+C group and 74 (78.7%) patients in the C-P group received anti-cancer therapy after discontinuing study treatment, and 107 (57.8%) patients and 61 (64.9%) patients received post-discontinuation anti-HER2 drugs, respectively. 98 (53.0%) of the 185 patients in P+C group and 59 (62.8%) of the 94 patients in C-P group died by the time of data cutoff. Kaplan-Meier estimated median OS was 34.9 months (95% CI 28.4-42.1) in P+C group and 23.6 months (95% CI 19.3-34.4) in C-P group (HR 0.74, 95% CI 0.54-1.02; p=0.068). The 2-year OS rate was 65.2% (95% CI 57.6%-71.8%) versus 48.9% (95% CI 38.1%-58.7%), respectively. Subgroup analyses of OS were generally consistent with the overall result (Table 1). Conclusion: The updated OS analysis highlighted the long-term efficacy of pyrotinib plus capecitabine in pretreated HER2-positive local relapsed or metastatic breast cancer. We did not observe a statistically significant difference in OS between pyrotinib plus capecitabine group and capecitabine group followed by subsequent pyrotinib monotherapy upon disease progression. Table 1.Subgroup analysis of OS.Pyrotinib plus capecitabine (n=185)Placebo plus capecitabine (n=94)HR (95% CI) *Brain metastasesPresentEvents14/21 (66.7)8/10 (80.0)Median OS22.9 (19.7-35.0)17.3 (1.6-34.4)0.77 (0.32-1.84)AbsentEvents84/164 (51.2)51/84 (60.7)Median OS36.7 (30.7-43.0)23.6 (21.5-40.4)0.72 (0.51-1.02)Previous chemotherapyNoneEvents29/60 (48.3)12/22 (54.5)Median OS37.5 (34.2-NA)32.6 (18.9-NA)0.75 (0.38-1.47)1 lineEvents34/70 (48.6)27/47 (57.4)Median OS35.6 (25.9-NA)31.6 (18.0-NA)0.73 (0.44-1.21)2 linesEvents30/44 (68.2)13/18 (72.2)Median OS21.1 (13.6-33.4)15.9 (5.4-44.0)0.77 (0.40-1.49)Data are n/N (%) or median (95% CI). NA, not available. *HRs are from unstratified analyses. Citation Format: Zefei Jiang, Min Yan, Li Bian, Tao Wang, Xichun Hu, Qingyuan Zhang, Quchang Ouyang, Jifeng Feng, Yongmei Yin, Tao Sun, Zhongsheng Tong, Xiaojia Wang, Herui Yao, Shuping Jiang, Xiaoyu Zhu, Jianjun Zou. Overall survival (OS) results from the phase III PHENIX trial of HER2+ metastatic breast cancer treated with pyrotinib plus capecitabine [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 PD8-05.

Abstract GS3-02: Updated overall survival (OS) results from the phase 3 PHOEBE trial of pyrotinib versus lapatinib in combination with capecitabine in patients with HER2-positive metastatic breast cancer

Abstract Background: Pyrotinib (an irreversible tyrosine kinase inhibitor targeting EGFR, HER2 and HER4) plus capecitabine significantly improved progression-free survival (PFS) compared with that for lapatinib plus capecitabine in women with HER2-positive metastatic breast cancer after treatment with trastuzumab and taxanes in the interim analysis of the PHOEBE trial (NCT03080805; Xu et al. Lancet Oncology, 2021). In this report, we present an updated analysis of the overall survival data from this trial. Methods: This PHOEBE trial enrolled patients with HER2-positive metastatic breast cancer who had received prior trastuzumab and taxanes and up to two prior lines of chemotherapy for metastatic disease. Patients were randomly assigned (1:1) to receive either oral pyrotinib 400 mg or lapatinib 1250 mg once daily, combined with oral capecitabine 1000 mg/m² twice daily on days 1-14 of each 21-day cycle. Stratification factors were hormone receptor status (estrogen receptor [ER]- and/or progesterone receptor [PR]-positive vs. ER- and PR-negative) and previous lines of chemotherapy for metastatic disease (≤1 vs 2). The primary endpoint was PFS assessed by masked independent central review. Data cutoff for the updated overall survival analysis was March 31, 2021. Results: Between July 31, 2017 and October 30, 2018, 267 eligible patients were enrolled and randomized to either pyrotinib plus capecitabine (pyrotinib group) or lapatinib plus capecitabine (lapatinib group). 134 patients in pyrotinib group and 132 in lapatinib group started the assigned treatment. At data cutoff, the median follow-up duration was 33.2 months (95% CI 31.4-34.2) in the pyrotinib group and 31.8 months (95% CI 31.2-34.1) in the lapatinib group. 78 (58.2%) patients in the pyrotinib group and 98 (74.2%) patients in the lapatinib group received post-discontinuation therapy, with trastuzumab (60 [44.8%] in the pyrotinib group and 65 [49.2%] in the lapatinib group) being the most common. As of data cutoff date, 54 (40.3%) of 134 patients randomly assigned to the pyrotinib group and 69 (52.3%) of the 132 patients randomly assigned to lapatinib group had died. Median OS was not reached (95% CI 34.0-not reached) in the pyrotinib group and 26.9 months (22.4-not reached) in the lapatinib group (HR 0.69 [95% CI 0.48-0.98]; P=0.019). Kaplan-Meier estimated OS at 24 months was 66.6% (95% CI 57.7-74.0) and 58.8% (95% CI 49.7-66.7), respectively. 99 (73.9%) patients in the pyrotinib group and 121 (91.7%) in the lapatinib group had disease progression or had died. Pyrotinib plus capecitabine significantly improved PFS assessed by investigator compared with that for lapatinib plus capecitabine (12.5 months [95% CI 9.8-13.8] vs 5.6 months [95% CI 5.5-7.0]; HR 0.48 [95% CI 0.37-0.63]; P&amp;lt;0.0001). The benefits of pyrotinib plus capecitabine were observed in most clinically relevant subgroups for the updated analysis of both OS and PFS (Table 1). Conclusion: With extended follow-up, pyrotinib plus capecitabine demonstrated statistically significant OS improvement compared with lapatinib plus capecitabine in patients with HER2-positive metastatic breast cancer after trastuzumab and chemotherapy. This updated analysis of overall survival in the PHOEBE trial reaffirmed pyrotinib plus capecitabine as an established treatment option in this patient population. Table 1.Subgroup analysis of OS and PFS per investigator.HR for OSHR for PFSAll Patients0.69 (0.48-0.98)0.48 (0.37-0.63)Trastuzumab therapy for metastatic disease&amp;lt;3 months0.67 (0.33-1.35)0.34 (0.17-0.69)3-6 months0.78 (0.34-1.76)0.66 (0.32-1.34)≥3 months0.79 (0.37-1.66)0.44 (0.26-0.75)Trastuzumab resistanceNo0.60 (0.39-0.91)0.44 (0.32-0.61)Yes0.94 (0.48-1.85)0.58 (0.35-0.98)HER2 amplification by FISH0.76 (0.39-1.51)0.57 (0.35-0.92)Pathological gradingII0.65 (0.33-1.28)0.51 (0.31-0.85)III0.82 (0.41-1.65)0.51 (0.31-0.83)Unknown0.70 (0.41-1.21)0.45 (0.29-0.70)Visceral lesionsVisceral0.59 (0.40-0.88)0.45 (0.33-0.62)Non-visceral1.28 (0.55-2.95)0.57 (0.31-1.04)ECOG performance status00.72 (0.40-1.29)0.42 (0.26-0.66)10.67 (0.43-1.04)0.50 (0.36-0.71)Estrogen and progesterone receptor statusPositive0.74 (0.44-1.25)0.58 (0.39-0.86)Negative0.64 (0.39-1.04)0.41 (0.28-0.60)Previous lines of chemotherapy for metastatic disease00.72 (0.38-1.35)0.47 (0.30-0.74)10.73 (0.44-1.22)0.49 (0.32-0.73)20.56 (0.24-1.32)0.56 (0.28-1.08)Data are median (95% CI). HRs are from unstratified analyses. Citation Format: Binghe Xu, Min Yan, Fei Ma, Xichun Hu, Jifeng Feng, Quchang Ouyang, Zhongsheng Tong, Huiping Li, Qingyuan Zhang, Tao Sun, Xian Wang, Yongmei Yin, Ying Cheng, Wei Li, Xiaoyu Zhu, Chunxia Chen, Jianjun Zou. Updated overall survival (OS) results from the phase 3 PHOEBE trial of pyrotinib versus lapatinib in combination with capecitabine in patients with HER2-positive metastatic breast cancer [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 GS3-02.

Abstract P1-10-05: Evidence that body mass index modifies breast tissue collagen peptide response pattern to treatment with the non-steroidal anti-inflammatory drug sulindac

Abstract Background. In observational studies, regular use of non-steroidal anti-inflammatory drugs (NSAIDs) is associated with reduced breast cancer risk and disease recurrence with evidence that the benefit is greater in overweight/obese women. This parallels findings that obesity is associated with an increase in proinflammatory processes with possible effects on the breast stroma and extracellular matrix. Methods. To assess if body mass index (BMI kg/m2) alters breast tissue response to NSAIDs, we conducted exploratory analyses of change in breast tissue collagen-associated peptides following 6 months of treatment with the NSAID sulindac (150 mg bid) by BMI category: normal (18.5-24.9 n=6), overweight (25-29.9 n=14) and obese (≥30 n=11). Samples for this study were non-cancer core needle breast biopsies from postmenopausal women with a history of hormone receptor positive breast cancer enrolled to study sulindac effect on breast tissue biomarkers. At completion, 36 of 50 patients underwent baseline biopsy and 31 had sufficient tissue for paired analyses. Tissue collagen-associated peptides were studied using whole slide tissue imaging mass spectrometry proteomics. Individual peptide signals were normalized to total ion current and mean peak intensity per area across the entire biological specimen were used to generate a score per patient. Change in stroma peptides was evaluated by BMI status using the Wilcoxon matched pairs signed rank test. Unsupervised hierarchical clustering and heatmap visualization were used to assess differential expression of the peaks. Results. Approximately, 550 peptide peaks were found by targeted collagen tissue imaging proteomics. Striking differences in response to sulindac were observed by BMI. In overweight patients, 6 peptides related to COL1A1, COL6A1, COL6A3 and VIM on database matching differed significantly before and after sulindac treatment. Three were also altered in obese women. Two of the peptides overlapped 10 peptide changes identified in unstratified analyses reported in a separate submitted abstract on the main effect of sulindac on tissue collagen. Interestingly, these peptides were not altered in patients with normal BMI. In addition, on study 15 patients experienced a decrease in BMI and 12 experienced an increase. Two collagen peptides showed inverse relationships dependent on change in BMI status during the study. Conclusion. Six-month treatment with the non-selective NSAID sulindac was associated with changes in collagen-associated peptide differently by BMI status and by weight change. Our findings are most consistent with changes in post-translational hydroxylated proline modifications of collagen variation in the triple helical region. Ongoing work may provide insights on inflammation/adiposity-associated inflammation and effects on breast tissue collagen. Citation Format: Denys Rujchanarong, Peggi M. Angel, Alison Stopeck, Christina Preece, Pavani Chalasani, Patricia A. Thompson. Evidence that body mass index modifies breast tissue collagen peptide response pattern to treatment with the non-steroidal anti-inflammatory drug sulindac [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 P1-10-05.

Intraoperative Fractions of Inspiratory Oxygen Are Associated With Recurrence-Free Survival After Elective Cancer Surgery.

Background: Choice of the fraction of inspiratory oxygen (FiO2) is controversial. The objective of this analysis was to evaluate whether intraoperative FiO2 was associated with recurrence-free survival after elective cancer surgery.Methods and Analysis: In this single-center, retrospective study, we analyzed 1,084 patients undergoing elective resection of pancreatic (n = 652), colorectal (n = 405), or hepatic cancer (n = 27) at Heidelberg University Hospital between 2009 and 2016. Intraoperative mean FiO2 values were calculated. For unstratified analyses, the study cohort was equally divided into a low- and a high-FiO2 group. For cancer-stratified analyses, this division was done within cancer-strata. The primary outcome measure was recurrence-free survival until the last known follow-up. Groups were compared using Kaplan–Meier analysis. A stratified log rank test was used to control for different FiO2 levels and survival times between the cancer strata. Cox-regression analyses were used to control for covariates. Sepsis, reoperations, surgical-site infections, and cardiovascular events during hospital stay and overall survival were secondary outcomes.Results: Median FiO2 was 40.9% (Q1–Q3, 38.3–42.9) in the low vs. 50.4% (Q1–Q3, 47.4–54.7) in the high-FiO2 group. Median follow-up was 3.28 (Q1–Q3, 1.68–4.97) years. Recurrence-free survival was considerable higher in the high-FiO2 group (p < 0.001). This effect was also confirmed when stratified for the different tumor entities (p = 0.007). In colorectal cancer surgery, increased FiO2 was independently associated with increased recurrence-free survival. The hazard for the primary outcome decreased by 3.5% with every 1% increase in FiO2. The effect was not seen in pancreatic cancer surgery and we did not find differences in any of the secondary endpoints.Conclusions: Until definite evidence from large-scale trials is available and in the absence of relevant clinical conditions warranting specific FiO2 values, perioperative care givers should aim for an intraoperative FiO2 of 50% in abdominal cancer surgery as this might benefit oncological outcomes.

Outcomes of patients (pts) with advanced urothelial carcinoma (aUC) treated with immune checkpoint inhibitors (ICIs): Associations with age, race, sex and smoking history.

e16526 Background: ICIs have altered the therapeutic landscape in pts with aUC and new biomarkers are needed to better predict response and outcomes with ICIs. It is unclear whether demographics, such as race, age, sex and history of smoking, are associated with outcomes with ICIs. We hypothesized that specific demographic groups (sex, age, race, smoking history) would be associated with outcomes with ICIs in aUC. Methods: We performed a retrospective cohort study across 25 institutions. Data collected included demographic and clinicopathologic factors, response and outcomes. We calculated observed response rate (ORR), Progression-Free Survival (PFS) and overall survival (OS) for specific demographic groups. We built multivariable models (logistic regression for ORR; Cox regression for PFS and OS) with all demographic groups to assess outcomes. Analysis was done for the overall population and stratified by treatment line (first line [1L]; salvage [2+L]). The stratified analysis was also adjusted for known prognostic risk scores (internally developed for 1L; Bellmunt for 2+L); p-value &lt; 0.05 was significant. Results: We identified 1026 pts; 754, 744 and 780 were included in OS, ORR and PFS analysis. Overall, median age at ICI initiation was 70; 26% female; 75% White, 11% Hispanic, 5% Black, 8% other; 69% had smoking history; 28% with mixed histology; 17% with upper tract UC. In the unstratified analysis, age 65-74 (vs &lt; 65) was significantly associated with higher ORR (32% vs 22%) and median PFS (5 vs 3 mo HR 0.8); otherwise no significant difference was noted among groups for ORR, PFS, OS in both the stratified and unstratified analyses (Table). Conclusions: We did not identify significant associations between age, sex, race or smoking history and ORR, PFS, OS with ICIs in pts with aUC. Limitations include retrospective nature, lack of randomization, possible selection and confounding factors. Further research is required to identify prognostic and predictive biomarkers for ICI therapy in aUC.[Table: see text]

Temperature modifies the association between air pollution and cardiovascular disease hospital admissions in the Vaal Triangle Air Pollution Priority Area, South Africa

Background: Very few studies in Africa investigated effect modification by a temperature indicator (e.g. apparent temperature, Tapp) on the human health effects of air pollution. Due to climate change, an increase of 3-4°C in ambient temperature is projected along the South African coast and 6-7°C inland during the next 80 years. Methods: Cardiovascular disease (CVD) hospital admission data (ICD10 I00-I99) were obtained from a private hospital group; after ethics approval. The study period was 1 January 2011 to 31 October 2016. NO2, SO2, PM2.5, PM10, temperature and relative humidity data were obtained from the Department of Environmental Affairs. A case-crossover epidemiological study design was applied. The present study focused on lag0-1; as most other studies. Models were adjusted for public holidays and Tapp. Days with Tapp below and above/equal the 25th (9.6°C) and 75th percentiles (20.1°C) were classified as cold and warm days, respectively. Results: Of the 15 237 admissions, 45.9% were from women and 39.0% from 15-65 year olds. The daily NO2, SO2, PM2.5 and PM10 levels were 30.3, 17.1, 35.4 and 60.8 μm/m3, respectively, and exceeded the WHO guidelines between 25% to 50% of the days. None of the air pollutants had significant associations with CVD admissions on cold or warm days. The elderly appeared to be more at risk to PM10 on normal days compared to all groups combined, e.g. RR 1.037 95%CI 1.009-1.065 per 10 μm/m3 increase compared to the unstratified analyses RR 1.017 95%CI 1.001-1.035. The same was observed for males RR 1.026 95%CI 1.003-1.050. PM2.5 had a stronger association than PM10 among the elderly on normal days: RR 1.068 95%CI 1.008-1.133. Conclusions: These results indicate that the risk of CVD admissions due to ambient air pollution exposure is different on cold, normal and warm days in Cape Town.

Temperature modifies the association between air pollution and respiratory disease mortality in Cape Town, South Africa

Background: Due to climate change, an increase of 3-4°C in ambient temperature is projected along the South African coast and 6-7°C inland during the next 80 years. Very few studies in Africa investigated effect modification by a temperature indicator (e.g. apparent temperature, Tapp) on the human health effects of air pollution. Methods: Respiratory disease (RD) mortality data (ICD10 J00-J99) were obtained from Statistics South Africa; after ethics approval. The study period was 1 January 2006 to 31 October 2015. NO2, SO2, PM10, temperature and relative humidity data were obtained from the City of Cape Town municipality. A case-crossover epidemiological study design was applied. The present study focused on lag0-1; as most other studies. Models were adjusted for public holidays and Tapp. Days with Tapp below and above/equal the 25th (12.6°C) and 75th percentiles (20.3°C) were classified as cold and warm days, respectively. Results: Of the 20376 RD deaths, approximately equal numbers were from females, males, 15-64 and 65+ year olds. The daily NO2, SO2, and PM10 levels were 16.0, 9.2, and 29.9 μm/m3, respectively. Daily air pollutant levels regularly exceeded the WHO guidelines. In general, none of the air pollutants had significant associations with RD mortality on cold days. The younger age group seemed to be more vulnerable to NO2 and PM10 on normal days compared to the elderly. On warm days, females were more susceptible to PM10, e.g. RR 1.065 95%CI 1.001-1.133 compared to the unstratified analyses RR 1.034 95%CI 0.991-1.078. On warm days, the 15-64 year old group were more vulnerable to NO2 and SO2. Conclusions: These results indicate that the risk of RD deaths due to ambient air pollution exposure is different on cold, normal and warm days in the Vaal Triangle Air Pollution Priority Area.

Mercury exposure in relation to sleep duration, timing, and fragmentation among adolescents in Mexico City

IntroductionMercury intoxication is known to be associated with adverse symptoms of fatigue and sleep disturbances, but whether low-level mercury exposure could affect sleep remains unclear. In particular, children may be especially vulnerable to both mercury exposures and to poor sleep. We sought to examine associations between mercury levels and sleep disturbances in Mexican youth. MethodsThe study sample comprised 372 youth from the Early Life Exposures to Environmental Toxicants (ELEMENT) cohort, a birth cohort from Mexico City. Sleep (via 7-day actigraphy) and concurrent urine mercury were assessed during a 2015 follow-up visit. Mercury was also assessed in mid-childhood hair, blood, and urine during an earlier study visit, and was considered a secondary analysis. We used linear regression and varying coefficient models to examine non-linear associations between Hg exposure biomarkers and sleep duration, timing, and fragmentation. Unstratified and sex-stratified analyses were adjusted for age and maternal education. ResultsDuring the 2015 visit, participants were 13.3 ± 1.9 years, and 48% were male. There was not a cross-sectional association between urine Hg and sleep characteristics. In secondary analysis using earlier biomarkers of Hg, lower and higher blood Hg exposure was associated with longer sleep duration among girls only. In both boys and girls, Hg biomarker levels in 2008 were associated with later adolescent sleep midpoint (for Hg urine in girls, and for blood Hg in boys). For girls, each unit log Hg was associated with 0.2 h later midpoint (95% CI 0 to 0.4), and for boys each unit log Hg was associated with a 0.4 h later sleep midpoint (95% CI 0.1 to 0.8). ConclusionsThere were mostly null associations between Hg exposure and sleep characteristics among Mexican children. Yet, in both boys and girls, higher Hg exposure in mid-childhood (measured in urine and blood, respectively) was related to later sleep timing in adolescence.

Age and sex specific incidence for depression from early childhood to adolescence: A 13-year longitudinal analysis of German health insurance data

BackgroundEpidemiological studies indicate a disproportionate increase of depression incidence among adolescent girls, compared with boys. Since results regarding the age of onset of this sex difference are heterogeneous, this study aimed to investigate this difference on a large and representative sample. A second investigation sought to clarify whether there is a relevant sex difference in prepubertal onset of depression regarding the further course. MethodsHealth insurance data of 6–18-year-old Barmer insured patients, representing a 7.9% sample of the German population born in 1999 (N = 61.199), were analyzed. The incidence of depression episodes (ICD-10 F32.x) was evaluated. Subsequently, the absolute and relative risk of a depression diagnosis (F32.x/F33.x) in early/late adolescence was analyzed based on the diagnosis of depression in primary school age in unstratified and stratified univariate analyses performed in SAS. ResultsFrom 13 years of age, we found a significantly higher incidence of depressive disorders in girls than in boys. More than a fifth of the children with a depression diagnoses in primary school age had a depression relapse in early or late adolescence (early: 23.2%; 95% CI 19.6–26.9/late: 22.9%; 95% CI 19.3–26.5). Boys with depression in primary school age have a significantly higher relative risk for a depression relapse in late adolescence than girls (boys RR 4.2, 95% CI 3.3–5.2, girls RR: 2.1, 95% CI 1.7–2.7). LimitationsThe analysis is based on administrative data. Low sensitivity for depression in primary care setting and low service utilization leads to an underestimation of the incidence. ConclusionsDuring puberty the risk for a first depressive episode increases more steeply in girls than in boys. Childhood depression has a high risk of relapse for both sexes, but is much more pronounced for boys.

Effects of Dietary Quality on Associations of Meat Consumption with Cardiometabolic Biomarkers in the Jackson Heart Study

Abstract Objectives Red and processed meat consumption is adversely related to cardiometabolic risk, but the impact of overall dietary quality on this association has not been systematically investigated. We examined the influence of dietary quality on associations of meat intake with biomarkers of cardiometabolic risk. Methods Data are from the Jackson Heart Study, a cohort of African Americans (baseline age 55 y, 66% female, 20% diabetes, 9% CVD). We analyzed those with biomarker data available at Visit 1 (2000–04) and at Visit 2 (2005–09) or 3 (2009–13). Diet was assessed by food frequency questionnaire (Visit 1). Total observations used were: Visit 1 (n = 3725), Visit 2 (n = 2736), and Visit 3 (n = 3319). Unprocessed red meat included beef and pork, and processed meat included sausage, lunch, and cured meats. Diet quality was measured by a modified Healthy Eating Index 2010 score (m-HEI) that excluded meat contributions. Modified HEI stratified and unstratified analyses were conducted using linear mixed modeling. Fasting HbA1c and CRP values were log transformed. Results Meat consumption was not associated with HbA1c in m-HEI stratified or unstratified analyses. A 1 oz/1000 kcal/wk increase in unprocessed red and total meat was associated with a 1.3% ± 0.5% (P = 0.02) and 1.1% ± 0.3% (P = 0.005) higher CRP in unstratified analyses, respectively. Unprocessed red meat was positively associated with CRP in m-HEI tertiles 1 (2.0% ± 0.8%, P = 0.01) and 3 (2.2% ± 0.8%, P = 0.008). Total meat was associated with CRP in m-HEI tertile 1 (2.0% ± 0.6%, P = 0.001) and trended in tertile 3 (1.1% ± 0.6%, P = 0.09); processed meat also approached significance in m-HEI tertile 1 (2.1% ± 1.2%, P = 0.08). There was evidence that m-HEI modified the associations between processed meat and CRP (P-interaction = 0.04), but not for other associations. Excluding those with diabetes or CVD did not alter these results. Conclusions Our results do not support that meat intake is associated with HbA1c, or that overall dietary quality modifies these associations. Unprocessed red and total meat intakes were associated with greater CRP in unstratified and subsets of stratified analyses. Associations of processed meat with CRP appeared stronger among those with the poorest diet quality. These data suggest that reduction in red meat intake could benefit inflammation among African American adults. Funding Sources The Beef Checkoff.

Omega-3 Fatty Acids and Depressive Symptomology and the Influence of Psychosocial Stress: The Hispanic Community Health Study/Study of Latinos

Abstract Objectives The literature on n-3 fatty acid (FA) intake and depressive symptoms is inconsistent, potentially due in part to the influence of psychosocial stress. Some evidence supports that n-3 intake may have greater benefit on depressive symptoms among those with high oxidative stress. We quantified the associations between dietary and plasma n-3 FA and 6-y depressive symptoms and measured the modifying effect of psychosocial stress. Methods Data are from the Hispanic Community Health Study/Study of Latinos (age 48 y, 63% female). At baseline (2008–11), EPA, DHA and n-3 very-long-chain FAs (n-3VLCFAs) were estimated using two 24-hr recalls and the NCI method. Plasma n-3 FAs were measured by mass spectrometry. Depressive symptoms were measured at baseline and 6-y follow-up with the 10-item Center for Epidemiological Studies Depression Scale (CESD). Approximately 9 months from baseline, the 10-item Perceived Stress (PSS) and Chronic Burden of Stress scales were obtained. Unstratified and psychosocial stress-stratified associations were analyzed using survey linear regression among those with dietary (n = 3537) and plasma (n = 718) FA data. Model covariates included, but were not limited to, baseline CESD score, ethnicity, study site, antidepressant use, total energy intake, and dietary or plasma n-6 FA. Results Baseline DHA and n-3VLCFA intake were inversely associated with 6-y CESD (P &amp;lt; 0.05). All examined dietary n-3 FA exposures were inversely associated with CESD among those in the highest PSS quartile (Q4) (P &amp;lt; 0.05), but this was attenuated after considering n-6 FA intake. DHA and n-3VLCFA intakes were associated with lower CESD among those with 2 chronic stressors, but not &amp;lt;1 or &amp;gt;2 stressors. Plasma n-3 FAs were not associated with CESD in PSS stratified and unstratified analyses. However, plasma n-3 FA were associated with lower CESD score among those with only 2 chronic stressors. Conclusions Dietary n-3VLCFAs, but not plasma, were inversely associated with 6-y CESD. Psychosocial stress did not clearly modify these associations. These results provide some evidence that greater n-3VLCFA intake may reduce depressive symptoms among Hispanic/Latino adults. However, considering the limitations of self-reported intake, further research is needed using biomarkers of long-term n-3 consumption and psychosocial stress to confirm our findings. Funding Sources None.

Sex and APOE \u03b54 genotype modify the Alzheimer\u2019s disease serum metabolome

Late-onset Alzheimer’s disease (AD) can, in part, be considered a metabolic disease. Besides age, female sex and APOE ε4 genotype represent strong risk factors for AD that also give rise to large metabolic differences. We systematically investigated group-specific metabolic alterations by conducting stratified association analyses of 139 serum metabolites in 1,517 individuals from the AD Neuroimaging Initiative with AD biomarkers. We observed substantial sex differences in effects of 15 metabolites with partially overlapping differences for APOE ε4 status groups. Several group-specific metabolic alterations were not observed in unstratified analyses using sex and APOE ε4 as covariates. Combined stratification revealed further subgroup-specific metabolic effects limited to APOE ε4+ females. The observed metabolic alterations suggest that females experience greater impairment of mitochondrial energy production than males. Dissecting metabolic heterogeneity in AD pathogenesis can therefore enable grading the biomedical relevance for specific pathways within specific subgroups, guiding the way to personalized medicine.

Objective response (OR) by mRECIST to predict overall survival (OS) in patients with hepatocellular carcinoma (HCC) treated with sorafenib in the SILIUS trial.

534 Background: In SILIUS (NCT01214343) trial, combination of sorafenib and hepatic arterial infusion chemotherapy did not significantly improve OS in patients with advanced HCC compared with sorafenib alone (Kudo M, et al. Lancet Gastroenterol Hepatol 2018). In this study, we explored the relationship between OR and OS in the sorafenib group in the SILIUS trial. Methods: Association between OR and OS in patients treated with sorafenib ( n = 103) were analyzed. The median OS of responders was compared with that of non-responders by using Mantel-Byar test to exclude guarantee-time bias. Landmark analyses were performed, as sensitivity analyses, and the effect on OS was evaluated by Cox regression analysis with OR as a time-dependent covariate, with other prognostic factors. Results: OS of responders ( n = 18) was significantly better than that of non-responders ( n = 78) ( p &lt; 0.0001), where median OS was 27.2 (95% CI, 16.0–not reached) months for responders and 8.9 (95% CI, 6.5–12.6) months for non-responders. HRs from landmark analyses at 4, 6, and 8 months were 0.45 ( p = 0.0330), 0.37 ( p = 0.0053), and 0.36 ( p = 0.0083), respectively. OR by sorafenib was an independent predictor of OS based on unstratified Cox regression analyses. Conclusions: In the SILIUS trial, OR achieved by sorafenib per mRECIST is an independent predictor for OS in patients with HCC. [Table: see text]