Disease-free Survival Hazard Ratio Research Articles

Long-Term Analysis of NRG Oncology RTOG 0415: A Randomized Phase III Noninferiority Study Comparing Two Fractionation Schedules in Patients With Low-Risk Prostate 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 co-primary 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.NRG Oncology RTOG 0415 is a randomized phase III noninferiority (NI) clinical trial comparing conventional fractionation (73.8 Gy in 41 fractions) radiotherapy (C-RT) with hypofractionation (H-RT; 70 Gy in 28) in patients with low-risk prostate cancer. The study included 1,092 protocol-eligible patients initially reported in 2016 with a median follow-up of 5.8 years. Updated results with median follow-up of 12.8 years are now presented. The estimated 12-year disease-free survival (DFS) is 56.1% (95% CI, 51.5 to 60.5) for C-RT and 61.8% (95% CI, 57.2 to 66.0) for H-RT. The DFS hazard ratio (H-RT/C-RT) is 0.85 (95% CI, 0.71 to 1.03), confirming NI (P < .001). Twelve-year cumulative incidence of biochemical failure (BF) was 17.0% (95% CI, 13.8 to 20.5) for C-RT and 9.9% (95% CI, 7.5 to 12.6) for H-RT. The HR (H-RT/C-RT) comparing biochemical recurrence between the two arms was 0.55 (95% CI, 0.39 to 0.78). Late grade ≥3 GI adverse event (AE) incidence is 3.2% (C-RT) versus 4.4% (H-RT), with relative risk (RR) for H-RT versus C-RT 1.39 (95% CI, 0.75 to 2.55). Late grade ≥3 genitourinary (GU) AE incidence is 3.4% (C-RT) versus 4.2% (H-RT), RR 1.26 (95% CI, 0.69 to 2.30). Long-term DFS is noninferior with H-RT compared with C-RT. BF is less with H-RT. No significant differences in late grade ≥3 GI/GU AEs were observed between assignments (ClinicalTrials.gov identifier: NCT00331773).

Abstract PO1-27-09: TRIPTORELIN (11.25MG) vs TRIPTORELIN (3.75MG) IN PREMENOPAUSAL WOMEN WITH HIGH-RISK EARLY STAGE BREAST CANCER RH(+) and HER2(-) REAL WORLD EXPERIENCE. TRIPTO3 RESULTS

Abstract Background. Premenopausal women with high risk early stage BC HR+/Her2- present as a complex disease and generally have worse survival outcomes compared to postmenopausal women with the same disease. There are pathological clinical factors and genomic platforms that help us in therapeutic decisions. The use of triptorelin 3.75mg associated with AI promotes favorable results in terms of survival for premenopausal women with high-risk Early stage BC. TEXT/SOFT trial. TRIPTO3 study evaluates the use of Triptorelin 11.25mg vs. Triptorelin 3.75mg in this specific patient population. Methods: We reviewed medical records of premenopausal female patients with high-risk early stage breast cancer who have been treated and received triptorelin 3.75mg and triptorelin 11.25mg as part of their treatment. All patients were treated at a private Oncology Center between 2013 and 2020. The primary objective was disease-free survival. Results: 52 patients were found who met the inclusion criteria. 28(53.8%) patients received triptorelin 11.25mg and 24(46.2%) patients received triptorelin 3.75mg respectively. The median follow-up was 63 months and the disease-free survival for the Triptorelin 11.25mg group was 91.2% and for the Triptorelin 3.75mg group was 86.8% respectively (Hazard Ratio of disease-free survival was 1.2; 95% IC (0.2-7.2). Disease-free survival for both groups regardless of triptorelin dose was 89% at 5 years. The median disease-free survival was not reached in both groups. Conclusions: Our findings show that triptorelin 11.25 mg is similar to the use of triptorelin 3.75 mg in terms of disease-free survival for premenopausal women with high-risk early stage breast cancer. Citation Format: Ronald Limon, Mariano Lopez-Pereyra, Mario Gianella, Neysa Espinoza, Denize Ramirez, Carlos Antelo, Claudia Sitic, Wara Cortez, Oscar Niño De Guzman, Silvia Neciosup, Natalia Valdivieso. TRIPTORELIN (11.25MG) vs TRIPTORELIN (3.75MG) IN PREMENOPAUSAL WOMEN WITH HIGH-RISK EARLY STAGE BREAST CANCER RH(+) and HER2(-) REAL WORLD EXPERIENCE. TRIPTO3 RESULTS [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-27-09.

Abstract PO2-17-03: Patient reported outcomes (PROs) and survival with toremifene versus aromatase inhibitors (AI) in patients with moderate/high-risk premenopausal hormone receptor (HR)-positive breast cancer: A real-world study

Abstract Background: The selective estrogen receptor modulator (SERM) toremifene, a synthetic analogue of tamoxifen, has shown similar efficacy to tamoxifen in patients with HR-positive breast cancer and is widely used in China for the treatment of premenopausal women with breast cancer. Multiple studies have confirmed the benefit of ovarian function suppression (OFS) combined with AI and SERMs in premenopausal women with HR-positive breast cancer. However, to date, there are no data comparing the efficacy and safety of toremifene plus OFS versus AI plus OFS. In this real-world study, we compared PROs and survival with toremifene or AI combined with OFS in patients with moderate/high-risk premenopausal HR-positive breast cancer. Methods: We enrolled premenopausal female patients with HR-positive, moderate/high-risk breast cancer who received OFS combined with toremifene or AI between January 1, 2010 and December 31, 2017 at the Breast Cancer Center of Sun Yat-sen Memorial Hospital. The primary endpoint was PROs, which were collected from January 1 to March 31, 2023, including the SF-36 and five-level EuroQol five-dimensional (EQ-5D-5L) questionnaires. Disease-free-survival (DFS) and safety were secondary endpoints. Associations between treatment group and SF-36 scores were evaluated using a Student’s t test and between treatment group and EQ-5D-5L scores using nonparametric tests. DFS was assessed using the Kaplan–Meier method and Cox regression. Results: A total of 392 patients were enrolled; 171 (43.6%) received toremifene and 221 (56.4%) received AI. Mean ± standard deviation scores for the role physical and general health dimensions of SF-36 were higher in the toremifene group versus the AI group (7.44±1.21 vs 7.15±1.48, P=0.034 and 22.90±3.95 vs 21.78±4.33, P=0.009, respectively). Scores on the anxiety/depression (AD) dimension of EQ-5D-5L were significantly different between the toremifene and AI treatment groups (mean rank: 184.14 vs 206.07, P=0.038); ‘no problems’ was selected by 49.7% and 37.1% of patients in the toremifene and AI groups, respectively. There were no significant differences in the other dimensions of SF-36 and EQ-5D-5L between the toremifene and AI groups (P&amp;gt;0.05). Similar estimated 5- and 8-year DFS rates were reported for the toremifene and AI groups; 96.5% (95% CI: 93.7-99.2) and 91.9% (95% CI: 88.2-95.5), and 87.4% (95% CI: 81.1-93.8) and 87.8% (95% CI: 81.1-94.4), respectively, and the hazard ratio for DFS was 0.75 (95% CI: 0.38-1.46), P=0.39. DFS was also comparable in the two treatment groups when stratified by HER2 status, age (≤40y vs &amp;gt;40y) and estrogen receptor expression level (≤20% vs &amp;gt;20%). Adverse event rates were generally similar in the two treatment groups, except for a higher rate of endometrial thickening (17.5% vs 1.8%, p&amp;lt; 0.001) and a lower rate of morning stiffness (7.6% vs 14.5%, p&amp;lt; 0.001) in the toremifene versus the AI group. Conclusion: Patients who received toremifene plus OFS had better role physical and general health dimensions on SF-36 and AD dimensions of EQ-5D-5L than those receiving AI plus OFS. There were no significant differences in 5- or 8-year DFS between the toremifene and AI groups. Both treatments were generally well tolerated. Citation Format: Yaping Yang, Fengxia Gan, Wenqian Yang, Yuan Xia, Qiang Liu, Chang Gong. Patient reported outcomes (PROs) and survival with toremifene versus aromatase inhibitors (AI) in patients with moderate/high-risk premenopausal hormone receptor (HR)-positive breast cancer: A real-world study [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-17-03.

Abstract PO1-03-07: Revisiting the potential of pathological complete response as a surrogate for long-term survival outcomes in triple-negative breast cancer at the trial-level

Abstract Background: Pathological complete response (pCR) has been used as a primary endpoint in neoadjuvant clinical trials for non-metastatic breast cancer and as a surrogate endpoint for long-term survival outcomes. The U.S. Food and Drug Administration (FDA) accepted pCR as a surrogate endpoint for the approval of new drugs in the neoadjuvant setting in high-risk early-stage breast cancer. However, though the Collaborative Trials in Neoadjuvant Breast Cancer (CTNeoBC) pooled analysis in 2014 showed that at the patient level achieving pCR was associated with longer overall survival (OS) and event-free survival (EFS), at the trial-level the association between high pCR rate and better OS and EFS outcomes was weak (coefficient of difference [R2]; 0.03 and 0.24, respectively) among all subtypes of breast cancer. A recent study reported that this association at the trial-level was similarly weak among Human Epidermal Growth Factor Receptor-2 (HER-2) positive breast cancer (R2; 0.02 and 0.23, respectively). However, the potential surrogacy of pCR rate for OS and EFS in triple-negative breast cancer (TNBC) in the neoadjuvant setting has not been well studied in a comprehensive manner. Moreover, because of significant advances in systemic treatment strategies in TNBC over the past decade including a combination of immune checkpoint inhibitors (ICIs) with conventional cytotoxic agents, the trial-level surrogacy needs to be reassessed in recently published neoadjuvant clinical trials for TNBC. Our primary objective is to assess the association between pCR rate and survival outcomes in neoadjuvant clinical trials for TNBC by collecting data from articles published after the CTNeoBC article in 2014. Methods: We performed a systematic literature search based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines in the PubMed, Cochrane Library, and Web of Science databases. Articles published between January 1, 2014, and March 31, 2023, were searched. We included only randomized control trials of neoadjuvant treatments for clinical stage I-III TNBC that compared two or more regimens followed by curative intent breast surgery. The selected trials had data for odds ratio (OR) for pCR and hazard ratios (HRs) either for OS or for EFS or disease-free survival (DFS). We excluded trials including estrogen receptor positive, progesterone receptor-positive, or HER-2 positive diseases, and those without data enough to obtain ORs for pCR, HRs for OS, EFS, or DFS. Unpublished data as a full article was also excluded. If EFS could not be obtained from the articles, DFS was used in place of EFS. Two independent investigators (TY and TF) searched and extracted data. Any disagreement was resolved by discussion with the third author (ZZ). A linear regression model on a logarithmic scale weighted by the sample size of each trial was performed and the R2 was used to assess the trial-level association between OR for pCR and HRs for OS or EFS. Results: We identified eight trials with a total of 2,926 patients. Three of the eight trials used ICIs in the intervention arm. One trial did not provide OS data and was not included in the OS analysis. In four trials, EFS was not available and DFS was used for EFS analysis. The R2 was 0.191 (95% confidence interval [CI], 0.165 to 0.218) for OS and 0.193 (95% CI, 0.167 to 0.219) for EFS. Conclusions: Similarly to the previous reports, our findings suggest that the surrogacy of the pCR rate for OS and EFS in recent neoadjuvant clinical trials for TNBC is weak. At this moment, there is no strong evidence to support using pCR as a surrogate for long-term survival outcomes in neoadjuvant clinical trials for TNBC. Citation Format: Toru Yoshino, Zao Zhang, Ryota Sato, Stanley Lipkowitz, Takeo Fujii. Revisiting the potential of pathological complete response as a surrogate for long-term survival outcomes in triple-negative breast cancer at the trial-level [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-03-07.

High keratin 15 expression reflects favorable prognosis in early cervical cancer patients.

Keratin 15 (KRT15) exhibits inconsistent prognostic roles in different cancers, and its prognostic value in early cervical cancer patients who receive tumor resection remains unknown. This study aimed to assess the relationship of KRT15 expression with prognosis in these patients. Totally, 147 early cervical cancer patients who received tumor resection were reviewed in this retrospective study. KRT15 was detected in formalin-fixed paraffin-embedded tumor tissue by immunohistochemistry (IHC). KRT15 IHC scores were computed by multiplying the percentage of positively stained cells (scored as 0-4) and corresponding staining intensity (scored as 0-3), ranging from 0 to 12. Elevated KRT15 IHC score was linked with moderate to well differentiation (P = 0.005), tumor size ≤ 4cm (P = 0.017), and International Federation of Gynecology and Obstetrics (FIGO) stage Ia/Ib (P < 0.001). KRT15 IHC score was inversely associated with adjuvant radiotherapy (P = 0.025) and adjuvant chemotherapy (P = 0.016). KRT15 IHC score ≥ 1 was linked with increased disease-free survival (DFS) (P = 0.003) and overall survival (OS) (P = 0.049). Meanwhile, KRT15 IHC score ≥ 1 independently predicted increased DFS (hazard ratio = 0.213, P = 0.017), but not OS (P > 0.05). KRT15 IHC score ≥ 3 and KRT15 IHC score ≥ 6 could not predict DFS or OS (all P > 0.05). By subgroup analyses, KRT15 IHC score ≥ 1 forecasted favorable DFS in patients with age > 45years, human papillomavirus-positive, squamous carcinoma, and tumor size ≤ 4cm (all P < 0.05). KRT15 IHC score ≥ 1 and KRT15 IHC score ≥ 3 predicted ascended DFS in patients without adjuvant radiotherapy or adjuvant chemotherapy (all P < 0.05). High KRT15 expression reflects favorable tumor features and longer survival in early cervical cancer patients who receive tumor resection.

Randomized, Double-Blind Phase III Study of Pazopanib Versus Placebo in Patients With Metastatic Renal Cell Carcinoma Who Have No Evidence of Disease After Metastasectomy: ECOG-ACRIN E2810.

Patients with no evidence of disease (NED) after metastasectomy for renal cell carcinoma are at high risk of recurrence. Pazopanib is an inhibitor of vascular endothelial growth factor receptor and other kinases that improves progression-free survival in patients with metastatic RCC (mRCC). We conducted a randomized, double-blind, placebo-controlled multicenter study to test whether pazopanib would improve disease-free survival (DFS) in patients with mRCC rendered NED after metastasectomy. Patients with NED after metastasectomy were randomly assigned 1:1 to receive pazopanib 800 mg once daily versus placebo for 52 weeks. The study was designed to observe an improvement in DFS from 25% to 45% with pazopanib at 3 years, corresponding to 42% reduction in the DFS event rate. From August 2012 to July 2017, 129 patients were enrolled. The study was unblinded after 83 DFS events (92% information). The study did not meet its primary end point. An updated analysis at 60.5-month median follow-up from random assignment (95% CI, 59.3 to 71.0) showed that the 3-year DFS was 27.4% (95% CI, 17.9 to 41.7) for pazopanib and 21.9% (95% CI, 13.3 to 36.2) for placebo. Hazard ratio (HR) for DFS was 0.90 ([95% CI, 0.60 to 1.34]; Pone-sided = .29) in favor of pazopanib. Three-year overall survival (OS) was 81.9% (95% CI, 72.7 to 92.2) for pazopanib and 91.4% (95% CI, 84.4 to 98.9) for placebo. The HR for OS was 2.55 (95% CI, 1.23 to 5.27) in favor of placebo (Ptwo-sided = .012). Health-related quality-of-life measures deteriorated in the pazopanib group during the treatment period. Pazopanib did not improve DFS as the primary end point compared with blinded placebo in patients with mRCC with NED after metastasectomy. In addition, there was a concerning trend favoring placebo in OS.

Disease-free survival as a surrogate for overall survival in HR+/HER2– early breast cancer: A correlation analysis

BackgroundOverall survival (OS) is a universally accepted measure of clinical benefit; however, prolonged follow-up is needed to observe sufficient events. Disease-free survival (DFS) has been widely adopted as a primary endpoint for early breast cancer (EBC) trials, as follow-up is comparatively shorter. Here, we present an analysis evaluating DFS as a surrogate for OS for adjuvant treatment of hormone receptor–positive/human epidermal growth factor receptor 2–negative (HR+/HER2–) EBC. MethodsA systematic literature review which included randomized controlled trials (RCTs) with ≥80% of adult patients with HR+/HER2– EBC was conducted. The RCTs evaluated various systemic therapeutic categories; key inclusion criteria included reporting of DFS and OS hazard ratios (HRs) and mature OS data. Spearman rank correlation and weighted linear regression analyses evaluated DFS and OS HR correlation. A scenario analysis tested base-case analysis robustness, and a parallel analysis using patient-level data was conducted. ResultsThe base case (N = 14 RCTs) showed an unweighted Spearman coefficient of 0.81 between OS and DFS (weighted: 0.81), with 84% of the variability in OS explained by DFS differences (R2 from weighted regression). The surrogate threshold effect (Burzykowski T, Buyse M. Pharm Stat. 2006;5:173–186) was 0.82 for DFS/OS HR. Scenario analysis (n = 9 RCTs), which excluded chemotherapy trials, and patient-level analysis using FACE trial data were consistent with the base-case analysis. ConclusionsThese analyses support DFS as a reliable surrogate endpoint for OS in adjuvant HR+/HER2− EBC trials. Using DFS as a surrogate measure will permit timelier access to novel treatments for patients with HR+/HER2− EBC.

Abstract A102: Secreted frizzled related-protein 2 is prognostic for survival in pancreatic cancer

Abstract INTRODUCTION: Secreted frizzled-related protein 2 (SFRP2) is overexpressed in several tumor types and blocks tumor apoptosis, increases angiogenesis, and promotes T-cell exhaustion. It has also been shown to be associated with fibrosis in non-neoplastic pathologies. We hypothesize SFRP2 is prognostic for survival and associated with PDAC fibrosis and mesenchymal transformation. METHODS: SFRP2 gene expression and protein levels in patients with PDAC were analyzed using NCI’s The Cancer Genome Atlas (TCGA) data and data from resected tumors analyzed for protein levels by western blot. Disease free survival (DFS) and overall survival (OS) were analyzed using Kaplan Meier test. The association of stroma content and SFPR2 RNA expression in human PDAC was studied using Spearman correlation between the ESTIMATE algorithm stromal score and TCGA data. The GEPIA tool was used to compare SFRP2 mRNA levels between PDAC and normal pancreas tissue. Immunohistochemistry (IHC) for SFRP2 in KPC PDAC tumors were correlated with fibrosis stains Picrosirus red and Massone trichome. The role of SFRP2 in mesenchymal transformation was assessed by western blot in fibroblasts. RESULTS: TCGA RNAseq analysis of SFRP2 expression showed highest SFRP2 mRNA levels in pancreatic cancer out of 32 cancer types. GEPIA analysis of PDAC (n=179) and normal pancreas (n=177) mRNA data showed higher levels of SFRP2 mRNA in PDAC compared to normal pancreas (p&amp;lt;.01). High SFRP2 mRNA levels were associated with decreased disease-free survival hazard ratio = 2.6; p=0.0097). PDAC tissue showed higher SFRP2 protein compared to matched normal-adjacent tissue (n=24, p=0.0003). High SFRP2 expression was associated with decreased OS (p=0.0158. The ESTIMATE stromal score correlated with SFRP2 expression in human PDAC (Spearman correlation coefficient 0.81). Fibrosis levels in KPC PDAC tumors correlated with SFRP2 IHC (Spearman correlation coefficient 0.75). Fibroblasts treated with SFRP2 and TGFβ showed higher mesenchymal markers compared to untreated control. CONCLUSIONS: SFRP2 is increased in PDAC, associated with tumor fibrosis, and prognostic for survival. SFRP2 is a novel therapeutic target in PDAC. Citation Format: Lillian Hsu, Julie Siegel, Patrick Nasarre, Rupak Mukherjee, Meghan Gormley, Bailey Richardson, Jordan Morningstar, Imran Khan, Eleanor Hilliard, John O’Bryan, Krist Helke, Laura Spruill, Nathan Dolloff, Nancy Klauber-Demore. Secreted frizzled related-protein 2 is prognostic for survival in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr A102.

Long non-coding RNA as a potential diagnostic and prognostic biomarker in melanoma: A systematic review and meta-analysis.

Recently, long noncoding RNAs (lncRNAs) have been applied as biomarkers for melanoma patients. In this systematic review and meta-analysis, we investigated the diagnostic and prognostic value of lncRNAs. We used the keywords 'lncRNA' and 'melanoma' to search databases for studies published before June 14th, 2023. The specificity, sensitivity and AUC were utilized to assess diagnostic accuracy and the prognostic value was assessed using overall survival, progression-free survival and disease-free survival hazard ratios. After screening 1191 articles, we included seven studies in the diagnostic evaluation section and 17 studies in the prognosis evaluation section. The Reitsma bivariate model estimated a cumulative sensitivity of 0.724 (95% CI: 0.659-0.781, p < 0.001) and specificity of 0.812 (95% CI: 0.752-0.859, p < 0.001). The pooled AUC was 0.780 (95% CI: 0.749-0.811, p < 0.0001). The HR for overall survival was 2.723 (95% CI: 2.259-3.283, p < 0.0001). Two studies reported an HR for overall survival less than one, with an HR of 0.348 (95% CI: 0.200-0.607, p < 0.0002). The HR for progression-free survival was 2.913 (95% CI: 2.050-4.138, p < 0.0001). Four studies reported an HR less than one, with an HR of 0.457 (95% CI: 0.256-0.817). The HR for disease-free survival was 2.760 (95% CI: 2.009-3.792, p < 0.0001). In conclusion, the expression of lncRNAs in melanoma patients affects survival and prognosis. LncRNAs can also be employed as diagnostic biomarkers.

Adjuvant Osimertinib in Patients With Stage IB to IIIA EGFR Mutation-Positive NSCLC After Complete Tumor Resection: ADAURA China Subgroup Analysis

IntroductionIn Chinese patients with NSCLC, prevalence of EGFR-mutated (EGFRm) disease is high. In the global phase 3 ADAURA study (NCT02511106), adjuvant osimertinib was found to have a statistically significant and clinically meaningful improvement in disease-free survival (DFS) versus placebo in resected stage IB to IIIA EGFRm NSCLC. We present efficacy and safety data from a subgroup analysis of 159 Chinese patients enrolled in the People’s Republic of China from ADAURA. MethodsIn ADAURA, patients with completely resected stage IB to IIIA EGFRm (exon 19 deletion/exon 21 L858R) NSCLC were randomized 1:1 to receive osimertinib (80 mg once daily) or placebo for 3 years or until disease recurrence/discontinuation. Adjuvant chemotherapy was permitted before randomization, per physician/patient choice. Primary end point was investigator-assessed DFS in stage II to IIIA disease; secondary end points included DFS in stage IB to IIIA (overall population), overall survival, health-related quality of life (HRQoL), and safety. ResultsOf 682 patients enrolled globally, 159 patients in the People’s Republic of China were included in this subgroup analysis (osimertinib n = 77; placebo n = 82). Baseline characteristics were balanced across the treatment arms. At data cutoff, stage II to IIIA DFS hazard ratio (HR) was 0.23 (95% confidence interval [CI]: 0.13–0.42; maturity 59%); stage IB to IIIA DFS HR was 0.29 (95% CI: 0.17–0.48; maturity 42%). At 13% maturity (21 deaths), HR for overall survival in the stage IB to IIIA population was 0.51 (95% CI: 0.21–1.20). HRQoL was maintained from baseline, and safety was consistent with the global population. ConclusionsIn this population of Chinese patients from ADAURA, adjuvant osimertinib was found to have a clinically meaningful improvement in DFS versus placebo, with maintained HRQoL and a safety profile consistent with the global study population.

Blood regulator of G protein signalling 1 as a potential prognostic biomarker in surgical nonsmall cell lung cancer patients: Correlation with clinical features and survival.

Regulator of G protein signalling 1 (RGS1) closely regulates malignant phenotypes and tumour immunity in several cancers, while its clinical value in nonsmall cell lung cancer (NSCLC) is by far rarely reported. Consequently, this study aimed to explore the linkage of blood RGS1 with clinical features and prognosis in surgical NSCLC patients. Two-hundred and ten surgical NSCLC patients were consecutively enrolled in this study, whose RGS1 in peripheral blood mononuclear cells was determined before treatment via reverse transcriptional-quantitative polymerase chain reaction. Additionally, the blood RGS1 was also collected from 30 healthy controls (HCs). Blood RGS1 was increased in NSCLC patients compared with HCs (P < 0.001). Elevated blood RGS1 was related to lymph node (LYN) metastasis (P = 0.001), higher tumour-nodes-metastasis (TNM) stage (P = 0.004), neoadjuvant chemotherapy administration (P = 0.044), shortened accumulative disease-free survival (DFS) (P = 0.008) and overall survival (OS) (P = 0.013) in NSCLC patients. A multivariate Cox's regression analysis showed that blood RGS1 high expression could independently reflect shortened DFS (hazard ratio = 1.499, P = 0.023), whereas it could not independently predict OS (P > 0.050). Furthermore, blood RGS1 high expression was associated with shortened OS (P = 0.020) in patients with neoadjuvant therapy and with worse DFS (P = 0.028) and OS (P = 0.026) in patients with adjuvant therapy, while blood RGS1 was not linked with DFS or OS in patients without neoadjuvant or adjuvant therapy (all P > 0.050). Elevated blood RGS1 correlates with LYN metastasis, neoadjuvant chemotherapy administration, worse DFS and OS, which might serve as a useful prognostic biomarker for surgical NSCLC patients.

Tumor characteristics and survival rate of HER2-low breast cancer patients: a retrospective cohort study

HER2 is an important prognostic marker in breast cancer (BC) patients, which also plays a crucial role in their therapeutic plan. Consequently, a great desire is to thoroughly assess the patients based on their HER2 status. In the current study, we aimed to evaluate HER2-low breast cancer as a new subtype in the standard classification of BC patients and review its characteristics and survival rate in a tertiary center in Iran. We retrospectively evaluated disease-free survival (DFS), overall survival (OS), and clinicopathological characteristics of BC patients referred to the Cancer Research Center in Tehran, Iran from 1991 to 2022. Patients’ clinical characteristics, including HER2 status, which is classified as HER2-low, HER2-positive, or HER2-negative, were obtained from prospectively maintained registries. Among the total 3582 recruited patients, 60.2%, 13.6%, and 26.2% were HER2-negative, HER2-low, and HER2-positive, respectively. HER2-positive patients showed a significantly higher Hazard Ratio (HR) for DFS (HR 1.44, 95% CI 1.01–2.05) and OS (HR 2.05, 95% CI 1.31–3.20), compared to HER2-low. Moreover, HER2-low and HER2-negative were found to show the same proportion of high-grade tumors (28 and 28.4%), while 40% of the HER2-positive tumors were high-grade. Accordingly, HER2-low patients had a lower metastasis risk than the others (P-value = 0.01). The Ki67 percentage was significantly lower in the HER2-low group compared to the HER2-positive (P-value < 0.001). HER2-low, a new subtype of HER2-status classification with distinct biological and clinicopathological traits, represented the highest survival rate and less invasive characteristics. This difference was statistically significant when compared to HER2-positive, but not when compared to HER2-negative.Research registration unique identifying number: NCT05754047.

Long-Term Follow-Up Analysis of NRG Oncology RTOG 0415: A Randomized Phase III Non-Inferiority Study Comparing Two Fractionation Schedules in Patients with Favorable-Risk Prostate Cancer

To assess whether the efficacy of a hypofractionated (H) schedule is no worse than a conventional (C) schedule in men with low-risk prostate cancer. Accrual began April 2006 and ended in December 2009. 1115 men with favorable-risk prostate cancer were randomly assigned 1:1 to a conventional (C) schedule (73.8 Gy in 41 fractions over 8.2 weeks) or to a hypofractionated (H) schedule (70 Gy in 28 fractions over 5.6 weeks). The trial was designed to establish with 90% power and alpha = 0.05 that (H) results in 5-year disease-free survival (DFS) that is not lower than (C) by more than 7% (hazard ratio (HR) < 1.52). Protocol specified secondary endpoints evaluated for noninferiority include: biochemical recurrence (BR), local progression, disease-specific survival, and overall survival. One thousand ninety-two protocol eligible men were analyzed: 542 to C and 550 to H. Median follow-up is 12.75 years. Baseline characteristics were not different according to treatment arm. The estimated 12-year DFS is 56.1% (95% CI 51.5, 60.5) in the C arm and 61.8% (57.2, 66.0) in the H arm. The DFS hazard ratio (H/C) is 0.85 (0.71-1.03), confirming non-inferiority (p<0.001). Twelve-year cumulative incidence of biochemical recurrence (BR) was 17.0% (CI 13.8, 20.5) in the C-RT and 9.9% (CI 7.5, 12.6) in the H-RT arm; (HR = 0.56, (0.40-0.78) suggesting improved efficacy with H. Additional pre-specified secondary endpoints were non-inferior Late Grade ≥ 3 GI toxicity is 3.2% (C) vs. 4.4% (H), Relative risk (RR) for H vs. C 1.39 (CI 0.75, 2.55) Late Grade ≥ 3 GU toxicity is 3.4% (C) vs. 4.2% (H), RR = 1.26 (CI 0.69, 2.30). In men with favorable-risk prostate cancer, long-term disease-free survival is non-inferior with 70 Gy in 28 fractions compared to 73.8 Gy in 41 fractions. The risk of BR is reduced with moderate hypofractionation. No differences in late Grade ≥3 GI/GU toxicity were observed between the arms. (ClinicalTrials.gov identifier: NCT00331773).

Circulating exosomal microRNA-4497 as a potential biomarker for metastasis and prognosis in non-small-cell lung cancer.

Circulating exosomal microRNAs (miRNAs) have shown great potential for the diagnosis, prognosis, and treatment monitoring of patients with non-small-cell lung cancer (NSCLC). Our main purpose was to determine the clinical value of serum exosomal miR-4497 as a new non-invasive biomarker for NSCLC. The exoRNeasy Kit (QIAGEN, Hilden, Germany) was used to isolate exosomes and exoRNA from the serum of 84 patients with NSCLC (NSCLC group), 30 patients with benign lung lesion (BLL group), and 47 healthy controls. Six serum exosomal miRNAs (Let-7b-5p, miR-122-5p, miR-155-5p, miR-223-3p, miR-320c, and miR-4497) were selected as candidate miRNAs and analyzed using real-time qPCR, among which miR-4497 displayed the most striking differences. Exosomal miR-4497 expressed significantly lower in NSCLC than in BLL patients and healthy controls (P < 0.001). Further investigation showed that miR-4497 was negatively correlated with the malignant characteristics of tumors (tumor size, tumor-node-metastasis [TNM] stage, and distant metastasis) and was an independent tumor suppressor (P < 0.05). According to receiver operating characteristic (ROC) analysis, exosomal miR-4497 independently exhibited excellent diagnostic efficacy, which could be improved by combining it with traditional markers (for identifying tumor size, the area under the curve [AUC] = 0.761; TNM stage, AUC = 0.878; distant metastasis, AUC = 0.895; all P < 0.001). Moreover, longitudinal analysis revealed that exosomal miR-4497 levels increased after chemoradiotherapy (P < 0.001). According to the survival analysis, poor overall survival (OS) and disease-free survival (DFS) were associated with low exosomal miR-4497 levels (P < 0.05). Moreover, exosomal miR-4497 was an independent protective factor affecting DFS (hazard ratio = 0.190, P = 0.009) in the Cox proportional hazards model. Therefore, serum exosomal miR-4497 can be used as a potential biomarker to identify NSCLC and healthy individuals or BLL patients for early screening or as a biomarker for staging and grading, prognosis, and monitoring recurrence, metastasis, and the therapeutic effects in patients with NSCLC.

Appropriateness of 14-year cutoff in pediatric differentiated thyroid cancer: Comparison of clinical characteristics and long-term outcomes in 14years and younger and 15-18years age groups.

Pediatric differentiated thyroid cancers (DTCs) differ in pathophysiology, presentation, and clinical outcomes from adult DTCs. However, the cutoff age for defining pediatric DTCs remains debatable, with the American Thyroid Association (ATA) and International Incidence of Childhood Cancer (IICC) report recommending different cutoffs of 18 and 14years, respectively. In this study, we investigated the appropriateness of 14-year cutoff by comparing the clinical characteristics and long-term outcomes in the 14years and younger and 15-18years age groups. Data of DTC patients, aged 18years and older, from 1981 to 2016, were sequentially extracted and compared between two age groups: ≤14 and 15-18years. Total of 176 pediatric DTC patients were included (age group ≤14years: n=75; age group 15-18years: n=101). None of the baseline clinical characteristics were significantly different between the two age groups. At 2-year follow-up, patients in the age group ≤14years had significantly higher incomplete response rate compared to those in the age group 15-18years (69% vs. 42%, respectively, p<.001). However, over a median follow-up of 10.6years (interquartile range: 7.7-15.5), the 5- and 10-year Disease-free survival (DFS) probabilities were not significantly different (p=.406). On multivariate analysis, incomplete response at 2-year follow-up was the sole independent predictor of poor DFS (hazard ratio: 5.85, 95% confidence interval: 1.69-20.23). Subdivision of pediatric DTCs into less than or equal to 14years and 15-18years age groups did not have any long-term predictive value. The cutoff of 18years as recommended by ATA is reasonable and should be uniformly followed to avoid inconsistencies and confusion.

Prognostic Utility of Neck Lymph Node-to-Primary Tumor Standardized Uptake Value Ratio in Oral Cavity Cancer.

We investigated the prognostic utility of preoperative neck lymph node-to-primary tumor maximum standardized uptake value ratios (NTRs) in oral cavity squamous cell carcinoma (OSCC). We retrospectively reviewed the medical records of 141 consecutive patients who were diagnosed as having OSCC and had received fluorodeoxyglucose-positron emission tomography within 2 weeks prior to radical surgery between 2009 and 2018. To determine the optimal NTR cutoff, receiver operating characteristic analysis for overall survival (OS) was executed. The NTR's prognostic value for disease-free survival (DFS) and OS were determined through Cox proportional hazards analysis and the Kaplan-Meier method. We determined the median (range) follow-up duration to be 35.2 (2.1-122.4) months. The optimal NTR cutoff was 0.273, and patients with a higher NTR (≥0.273) exhibited significantly worse DFS and OS (p = 0.010 and 0.003, respectively). A higher NTR (≥0.273) predicted poorer DFS (hazard ratio: 2.696, p = 0.008) and OS (hazard ratio: 4.865, p = 0.003) in multivariable analysis. We created a nomogram on the basis of the NTR, and it could accurately predict OS (concordance index: 0.774). Preoperative NTRs may be a useful prognostic biomarker for DFS and OS in patients with OSCC who have undergone surgery. NTR-based nomograms may also be helpful prognostic tools in clinical trials.

The public health impact of poor sleep on severe COVID-19, influenza and upper respiratory infections.

Poor sleep is associated with an increased risk of infections and all-cause mortality but the causal direction between poor sleep and respiratory infections has remained unclear. We examined if poor sleep contributes as a causal risk factor to respiratory infections. We used data on insomnia, influenza and upper respiratory infections (URIs) from primary care and hospital records in the UK Biobank (N≈231,000) and FinnGen (N≈392,000). We computed logistic regression to assess association between poor sleep and infections, disease free survival hazard ratios, and performed Mendelian randomization analyses to assess causality. Utilizing 23 years of registry data and follow-up, we discovered that insomnia diagnosis associated with increased risk for infections (FinnGen influenza Cox's proportional hazard (CPH) HR=4.34 [3.90, 4.83], P=4.16×10-159, UK Biobank influenza CPH HR=1.54 [1.37, 1.73], P=2.49×10-13). Mendelian randomization indicated that insomnia causally predisposed to influenza (inverse-variance weighted (IVW) OR=1.65, P=5.86×10-7), URI (IVW OR=1.94, P=8.14×10-31), COVID-19 infection (IVW OR=1.08, P=0.037) and risk of hospitalization from COVID-19 (IVW OR=1.47, P=4.96×10-5). Our findings indicate that chronic poor sleep is a causal risk factor for contracting respiratory infections, and in addition contributes to the severity of respiratory infections. These findings highlight the role of sleep in maintaining sufficient immune response against pathogens. Instrumentarium Science Foundation, Academy of Finland, Signe and Ane Gyllenberg Foundation, National Institutes of Health.

Microvessel density in patients with gastrointestinal stromal tumors: A systematic review and meta-analysis.

Gastrointestinal stromal tumors (GISTs) are considered the most common mesenchymal tumors of the gastrointestinal tract. Microvessel density (MVD) constitutes a direct method of vascularity quantification and has been associated with survival rates in multiple malignancies. To appraise the effect of MVD on the survival of patients with GIST. This study adhered to Systematic reviews and Meta-Analyses guidelines and the Cochrane Handbook for Systematic Reviews of Interventions. Electronic scholar databases and grey literature repositories were systematically screened. The Fixed Effects or Random Effects models were used according to the Cochran Q test. In total, 6 eligible studies were identified. The pooled hazard ratio (HR) for disease free survival (DFS) was 8.52 (95%CI: 1.69-42.84, P = 0.009). The odds ratios of disease-free survival between high and low MVD groups at 12 and 60 mo did not reach statistical significance. Significant superiority of the low MVD group in terms of DFS was documented at 36 and 120 mo (OR: 8.46, P < 0.0001 and OR: 22.71, P = 0.0003, respectively) as well as at metastases rate (OR: 0.11, P = 0.0003). MVD significantly correlates with the HR of DFS and overall survival rates at 36 and 120 mo. Further prospective studies of higher methodological quality are required.

PROSPECT: A randomized phase III trial of neoadjuvant chemoradiation versus neoadjuvant FOLFOX chemotherapy with selective use of chemoradiation, followed by total mesorectal excision (TME) for treatment of locally advanced rectal cancer (LARC) (Alliance N1048).

LBA2 Background: Radiation with sensitizing fluoropyrimidine (5FUCRT) is a standard curative intent treatment for LARC. It improves disease-free survival (DFS) by decreasing pelvic recurrence but has short- and long-term toxicity. The PROSPECT trial compares FOLFOX chemotherapy with selective use of 5FUCRT (intervention) to 5FUCRT (control) for neoadjuvant treatment prior to TME for LARC. Methods: Eligible patients (pts) had cT2N+, cT3N-, cT3N+ rectal cancers deemed appropriate for neoadjuvant therapy prior to low anterior resection with TME. Pts with distal, T4 tumors, threatened radial margins or &gt; 4 enlarged lymph nodes were ineligible. Pts were randomized 1:1 without blinding. Pts in the control group received 5FUCRT with 5040 cGy over 5.5 weeks with either capecitabine or 5FU. Pts in the intervention group had 6 cycles of mFOLFOX6 followed by restaging. If tumor regression was &gt; 20%, then TME was performed without radiation; if &lt; 20%, 5FUCRT was given before TME. DFS was the 1°outcome, defined as time from randomization to any recurrence or death, analyzed in the per-protocol population. One interim analysis was conducted with α spending = 0.001. Noninferiority (NI) of the intervention could be claimed if the upper limit of the 2-sided 90.2% confidence interval (CI) of the DFS hazard ratio did not exceed 1.29 (NI margin). Secondary endpoints included overall survival (OS), local recurrence free survival, R0 resection, pathologic complete response (CR), and toxicity. Results: From June 2012 to December 2018, 1194, pts were randomized and 1128 initiated protocol-assigned treatment. Median age was 57, 34.5% were women and 61.9% had clinically positive nodes. 53 of 585 pts in the intervention group (9%) received preop 5FUCRT. DFS was analyzed after 227 events and median follow-up of 58 months. Conclusions: FOLFOX chemotherapy with selective use of 5FUCRT is non-inferior to 5FUCRT for neoadjuvant treatment of LARC prior to low anterior resection with TME. Patients and physicians have alternative strategies for management of LARC. Clinical trial information: NCT01515787 . [Table: see text]

Overall survival analysis from the ADAURA trial of adjuvant osimertinib in patients with resected EGFR-mutated (EGFRm) stage IB–IIIA non-small cell lung cancer (NSCLC).

LBA3 Background: Osimertinib is a third-generation, central nervous system (CNS) active EGFR-TKI, that potently and selectively inhibits EGFR-TKI sensitizing and EGFR T790M resistance mutations. In the primary analysis from the Phase III ADAURA study (NCT02511106), adjuvant osimertinib demonstrated a clinically meaningful, statistically significant, and practice-changing disease-free survival (DFS) benefit vs placebo in patients with completely resected EGFRm (ex19del/L858R) NSCLC ± adjuvant chemotherapy. In an updated DFS analysis, with 2 years additional follow-up, DFS and CNS DFS benefit with adjuvant osimertinib were sustained (stage II–IIIA DFS hazard ratio [HR] 0.23; 95% confidence interval [CI] 0.18, 0.30; stage IB–IIIA DFS HR 0.27; 95% CI 0.21, 0.34; stage II–IIIA CNS DFS HR 0.24; 95% CI 0.14, 0.42), with a tolerable safety profile observed over the extended treatment duration. Here, we report the planned final overall survival (OS) analysis from ADAURA. Methods: Eligible patients (aged ≥18 years [≥20 in Japan and Taiwan], WHO PS 0/1 with completely resected EGFRm (ex19del/L858R) stage IB, II or IIIA [AJCC/UICC 7th edition] NSCLC; adjuvant chemotherapy allowed) were randomized 1:1 to osimertinib 80 mg once daily or placebo until disease recurrence, treatment completion (3 years), or a discontinuation criterion was met. The primary endpoint was investigator-assessed DFS in stage II–IIIA. Key secondary endpoints: DFS in stage IB–IIIA, OS and safety. Data cut-off: January 27, 2023. Results: Globally, 682 patients were randomized; osimertinib n=339, placebo n=343. Adjuvant osimertinib significantly improved OS vs placebo. In patients with stage II–IIIA disease, OS HR was 0.49 (95% CI 0.33, 0.73; p=0.0004; 100/470 events, 21% maturity); 5-year OS rate was 85% with osimertinib vs 73% with placebo. Median follow-up for OS in stage II–IIIA was 59.9 months (osimertinib) and 56.2 months (placebo). In the overall population (stage IB–IIIA), OS HR was 0.49 (95% CI 0.34, 0.70; p&lt;0.0001; 124/682 events, 18% maturity); 5-year OS rate was 88% with osimertinib vs 78% with placebo, with a median follow-up for OS of 60.4 months (osimertinib) and 59.4 months (placebo). Median OS was not reached in either population or treatment group. Conclusions: Adjuvant osimertinib demonstrated an unprecedented, highly statistically significant and clinically meaningful OS benefit in patients with EGFRm stage IB–IIIA NSCLC after complete tumor resection, with or without adjuvant chemotherapy. ADAURA is the first global Phase III study to demonstrate a statistically significant DFS and OS benefit with targeted treatment for patients with EGFRm stage IB–IIIA NSCLC. Clinical trial information: NCT02511106 .