Disease-free Survival Hazard Ratio Research Articles

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 .

Disease-free survival (DFS) as a surrogate for overall survival (OS) in patients (pts) with HR+/HER2− early breast cancer (EBC): A correlation analysis.

535 Background: DFS has been widely adopted as a clinically meaningful primary endpoint in EBC trials in place of OS, which needs extensive follow-up to observe sufficient events and fails to assess survival benefit early. However, a rigorous validation of DFS as a surrogate endpoint for OS is required for each given setting. The objective of this analysis was to evaluate DFS as surrogate for OS in the adjuvant treatment of HR+/HER2− EBC. Methods: A systematic literature review (SLR) was conducted using biomedical literature databases (ie, Embase, PubMed, and Medline [from database inception to January 2023]) and key conferences to identify published studies in EBC. The eligibility criteria for the SLR were RCTs that included ≥80% of adult pts with HR+/HER2− EBC and assessing different treatment options (ie, cyclin-dependent kinase 4/6 inhibitors [CDK4/6i], endocrine therapies [ET], and chemotherapies [CT]). Studies were considered for correlation analysis if hazard ratios (HRs) were reported for both DFS and OS. The analysis excluded observational studies and trials with immature OS data. Spearman rank correlation (rs) and weighted linear regression analyses (measured by coefficient of determination [R2]) were performed to evaluate the correlation between HRs for OS and DFS. Considering heterogeneity, multiple scenario analyses were conducted. Surrogate threshold effect (STE) was also estimated; STE is defined as the maximum value of the HR for DFS that needs to be observed in a trial to ensure the possibility of concluding that a significant effect on OS occurred. Correlation was also assessed using pt-level data from the FACE trial (letrozole vs anastrozole in postmenopausal pts with HR+/HER2− EBC) to validate findings of the trial-level analysis. Results: A total of 14 RCTs (N = 31,668) were included (CDK4/6, 2; ET, 7; CT, 5). Trial-level analysis showed that rs between OS and DFS was 0.81 (95% CI, 0.56-0.94), which when weighted by variance was 0.81. Regression analysis showed that 84% of the variability in OS was explained by DFS (R2 = 0.84). A meta-regression model estimated an STE of 0.82 for HR of DFS, which can be leveraged to validate the surrogacy based on the DFS estimated from a future trial. Analysis of pt-level data from the FACE trial demonstrated a correlation between DFS and OS (rs = 0.75). Additionally, correlation coefficients estimated by the Pearson method and iterative imputation were 0.83 and 0.89, respectively. Conclusions: Both trial-level and pt-level analyses demonstrate a positive correlation between DFS and OS. These results support the use of DFS as a reliable surrogate endpoint for OS in HR+/HER2− EBC trials to give an early access to innovative therapies.

Adjuvant everolimus in patients (Pts) with localized non-clear cell renal cell carcinoma (RCC): Subgroup analysis from the Everest trial (SWOG S0931).

4546 Background: In S0931, adjuvant treatment with the mTOR inhibitor everolimus respectively yielded disease-free survival (DFS) and overall survival (OS) hazard ratios (HR) of 0.85 (95% CI 0.71-1.00) and 0.90 (95% CI 0.71-1.13) in pts with resected, localized RCC. Previously, everolimus had been shown to be active in chromophobe RCC (chRCC; Tannir et al Eur Urol 2016) and papillary RCC (papRCC; Escudier et al Eur J Cancer 2016). We sought to evaluate the efficacy of everolimus within these non-clear cell subsets of EVEREST. Methods: 1545 adult pts with treatment-naïve, non-metastatic, fully-resected RCC at intermediate high- (pT1 G3-4 N0 to pT3a G1-2 N0) or very high-risk (pT3a G3-4 to pT4 G-any or N+) for recurrence were randomized 1:1 to 54 weeks of everolimus 10 mg PO daily or placebo within 12 weeks of radical or partial nephrectomy. Exploratory analyses of RFS and OS chromophobe and papillary subgroups were performed. Results: A total of 99 eligible pts had chRCC; 109 had papRCC (16 type I; 37 type II; 56 NOS). Median follow-up is 6.3 years. Pt characteristics were balanced between the 2 arms in each histological group. Thirty-four (34%) pts in the chRCC subgroup and 50 (46%) pts in the papRCC subgroup had very high-risk disease. Fewer pts completed all 54 weeks of everolimus in each subgroup compared to placebo (49% vs. 74% in the ChRCC subgroup and 46% vs. 71% in the papillary subgroup). DFS and OS for each subgroup are shown. Conclusions: Non-clear cell histology accounted for a considerable proportion (~13%) of S0931 pts. The estimated everolimus HRs for DFS and OS in the chRCC subset are consistent with the overall trial result, but those same modest HRs were not seen in papRCC, in contrast to prior reports of mTOR inhibitor activity in this subtype. Although inferences are limited by sample size and wide CIs, this is the largest experience in chRCC or papRCC among any adjuvant trials presented to date. Clinical trial information: NCT01120249 . [Table: see text]

Tumor keratin 15 expression links with less extent of invasion and better prognosis in papillary thyroid cancer patients receiving tumor resection.

Keratin 15 (KRT15) is identified as a useful biomarker in several solid tumors, while its clinical role in papillary thyroid cancer (PTC) remains unknown. Herein, this study is intended to explore the correlation of tumor KRT15 with clinical features and survival in PTC patients who received tumor resection. This study retrospectively screened 350 PTC patients who received tumor resection and 50 thyroid benign lesions (TBL) patients. KRT15 in formalin-fixed paraffin-embedded lesion specimens of all subjects was detected by immunohistochemistry (IHC). KRT15 was reduced in PTC patients compared to TBL patients (P < 0.001). Furthermore, KRT15 was negatively associated with tumor size (P = 0.017), extrathyroidal invasion (P = 0.007), pathological tumor (pT) stage (P < 0.001), and postoperative radioiodine application (P = 0.008) in PTC patients. Regarding prognostic value, high KRT15 (cut-off by an IHC value of 3) is linked with prolonged accumulating disease-free survival (DFS) (P = 0.008) and overall survival (OS) (P = 0.008) in PTC patients. Also, the multivariate Cox regression model showed that high KRT15 (vs. low) was an independent factor for longer DFS (hazard ratio = 0.433, P = 0.049), but not for OS (P > 0.050) in PTC patients. Subgroup analyses revealed that KRT15 possessed a better prognostic value in PTC patients with age ≥ 55years, tumor size > 4cm, pathological node stage 1, or pathological tumor-node-metastasis stage ≤ 2 (all P < 0.050). Increased tumor KRT15 associates with a lower invasive degree, prolonged DFS, and OS, revealing its prognostic utility in PTC patients undergoing tumor resection.

Prognostic Factors and the Role of Adjuvant Chemotherapy in Pathological Node-Negative T3 Gastric Cancer

The role of adjuvant chemotherapy in pathological T3N0M0 (pT3N0M0) gastric cancer (GC) remains unclear. The aim of this study was to analyze the prognostic factors of patients with pT3N0M0 GC and to clarify which ones could benefit from adjuvant chemotherapy. A total of 137 patients with pT3N0M0 GC were recruited between 1994 and 2020. Clinicopathological factors and adjuvant chemotherapy regimens were retrospectively collected. Prognostic factors of disease-free survival (DFS) and cancer-specific survival (CSS) were determined using univariate and multivariate analyses. The chemotherapy group was younger (p = 0.012), had had more lymph nodes retrieved (p = 0.042) and had higher percentages of vascular invasion (p = 0.021) or perineural invasion (p = 0.030) than the non-chemotherapy group. There were no significant differences in DFS (p = 0.222) and CSS (p = 0.126) between patients treated with or without adjuvant chemotherapy. Stump cancer, tumor size and perineural invasion were associated with higher rates of recurrence. Tumor size was an independent prognostic factor for DFS (hazard ratio, 4.55; confidence interval, 1.59-12.99; p = 0.005) and CSS (hazard ratio, 3.97; confidence interval, 1.38-11.43; p = 0.011). Tumor size independently influenced survival outcomes in pT3N0M0 patients who underwent radical surgery with and without adjuvant chemotherapy.

Abstract P2-02-01: Benefit of adjuvant bisphosphonates in early breast cancer treated with contemporary systemic therapy: A meta-analysis of randomized control trials

Abstract Introduction: Based on trials performed over a 25-year period, the Early Breast Cancer Trialists Collaborative Group (EBCTCG) identified a small but significant benefit of adjuvant bisphosphonates (BP) in reducing bone recurrence with a subsequent modest improvement in breast cancer-specific survival in post-menopausal women. Multiple studies show that contemporary event rates in early-stage breast cancer are much lower than those observed over a decade ago. This observation likely reflects the impact of modern adjuvant systemic therapy such as anthracycline and taxane chemotherapy and aromatase inhibitors. Therefore, re-evaluating the benefit of adjuvant bisphosphonate in the modern era is warranted. Methods: We reviewed reports of randomized trials of adjuvant BP that accrued patients exclusively beyond 2000 and extracted 5-year disease free survival (DFS) and overall survival (OS) in BP and control group arm along with hazard ratios (HR) when reported. The mean 5-year DFS and OS weighted by study sample size was calculated for each group. HR for DFS and OS were pooled in a meta-analysis using generic inverse variance and random effects modelling. Trial level absolute differences in DFS and OS between BP and control arms were calculated. Meta-regression comprising linear regression weighted by sample size (mixed effects) was then performed to explore association between disease and treatment related factors and absolute differences in benefit from BP. Quantitative significance was explored using methods described by Burnand et al. Analyses were performed using SPSS version 28 (IBM Corp, Armonk NY) and Review manager v5.4. Results: Twelve trials comprising 24109 patients were included in the analysis. Weighted mean DFS and OS in patients receiving BP were 85.8% and 91.7% respectively. For control group patients, these estimates respectively were 83.4% and 91.0%. For DFS, pooled HR across trials was 0.89 (0.81-0.97) with a 2.9% weighted mean difference favoring BP over control. Among patients receiving anthracycline and taxane based chemotherapy (n=3007), relative benefits were smaller; (HR DFS 0.94, 0.85-1.05). There was no significant OS benefit with BP (HR 0.92, 0.82-1.03) and this finding was observed irrespective of type of chemotherapy. The impact of BP on OS was smaller in both relative and absolute terms in studies with recruitment occurring more recently. Meta-regression results are shown in Table. There was lesser benefit in higher risk patients (node+, larger tumor size, ER-, grade 3 or those receiving chemotherapy). Overall, 1.13% patients experienced osteonecrosis related to BP therapy. Conclusions: Compared to EBCTCG data, relative and absolute benefit from BP is similar or modestly lower among more recent trials. Benefit from adjuvant BP appears smaller in patients treated with more contemporary adjuvant systemic therapy especially anthracycline and taxane containing chemotherapy. It is uncertain if the impact of BP on OS (rather than breast-cancer specific survival) is of a clinically meaningful magnitude. Despite de-escalated dosing compared to metastatic disease, osteonecrosis was observed in &amp;gt;1% of patients. It is possible that the benefits of BP are driven by patients with clinically low-risk disease rather than those with at high-risk. The balance between benefits and risks of adjuvant BP should be considered in individual patients. Table 1: Metaregression Results Citation Format: Abhenil Mittal, Faris Tamimi, Consolacion Molto Valiente, Massimo Di Iorio, Eitan Amir. Benefit of adjuvant bisphosphonates in early breast cancer treated with contemporary systemic therapy: A meta-analysis of randomized control trials [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-02-01.

Adjuvant pembrolizumab (pembro) for renal cell carcinoma (RCC) across UCLA Integrated Staging System (UISS) risk groups and disease stage: Subgroup analyses from the KEYNOTE-564 study.

679 Background: Adjuvant pembro prolonged disease-free survival (DFS) for patients (pts) with RCC at increased risk of recurrence after nephrectomy in the phase 3 KEYNOTE-564 study (NCT03142334). This post hoc exploratory analysis evaluated efficacy of adjuvant pembro in pt subgroups based on UISS and disease stage. Methods: Pts with histologically confirmed clear cell RCC (pT2, Grade [G] 4 or sarcomatoid, N0, M0; pT3 or pT4, any G, N0, M0; any pT, any G, N+, M0; or M1 NED) were randomly assigned 1:1 to receive pembro 200 mg IV or placebo (pbo) every 3 weeks for ≤17 cycles (~1 y). DFS was assessed by investigator. UISS risk groups were derived retrospectively from TNM stage, Fuhrman nuclear grade, and ECOG PS. UISS groups were intermediate risk (pT2, G4, N0, M0; pT3, G1, N0, M0; or pT3, G2-4, N0, M0, ECOG 0), high risk (pT3, G2-4, N0, M0, ECOG PS 1; pT4, any G, N0, M0; or N1, M0), or M1 NED. Other subgroups were evaluated based on disease stage. Results: Baseline characteristics were balanced within subgroups. Median follow-up was 30.1 mo (range 20.8-47.5). Of 994 enrolled pts, most had UISS intermediate risk (n = 732, 73.6%; pembro n = 359; pbo n = 373); 195 pts (19.6%; pembro n = 100; pbo n = 95) had UISS high risk, and 58 pts (5.8%; pembro and pbo n = 29 each) had M1 NED. In the UISS intermediate risk group, the hazard ratio (HR) for DFS was 0.65 (95% CI, 0.48-0.88; 24-mo rates, pembro: 81.5%, pbo: 72.4%). In the UISS high-risk group, HR for DFS was 0.77 (95% CI, 0.49-1.20; 24-mo rates, pembro: 65.0%, pbo: 55.9%). In the M1 NED group, HR for DFS was 0.28 (95% CI, 0.12-0.66; 24-mo rates, pembro: 78.4%, pbo: 37.9%). DFS by disease stage is in the Table. Conclusions: Consistent with the results of the intention-to-treat (ITT) population, adjuvant pembro prolonged DFS compared with pbo for all subgroups. Results of this exploratory analysis further support the use of adjuvant pembro after nephrectomy as standard of care for pts with RCC at increased risk of recurrence. Clinical trial information: NCT03142334 . [Table: see text]

Disease-free survival (DFS) as a surrogate endpoint (SE) for overall survival (OS) in early-stage resected esophageal/gastroesophageal junction cancer (EC/GEJC): An analysis of SEER-Medicare data.

321 Background: OS is the gold standard efficacy measure in oncology; however, its need for prolonged follow-up motivates the establishment of SEs for earlier assessments of emerging treatments. We assessed DFS as a candidate SE for OS in early-stage EC/GEJC using data from Medicare beneficiaries with cancer in the SEER registry. Methods: Patients aged &gt; 65 years in the US with resective surgery after a primary diagnosis of stage 2 or 3 EC/GEJC between 2009-2017 were analyzed (N=925; median follow-up 26.2 months). Surrogacy was assessed via both individual-level association of DFS to OS, and via the association between the treatment effects on DFS and OS. Strength of individual-level association was measured via Spearman’s rank correlation (ρ) non-parametrically and Kendall’s τ using copula functions. The strength of correlation between the treatment effects on DFS and OS—measured by the coefficient of determination (R2) and the surrogate threshold effect (STE), which is the minimum DFS benefit that would translate into statistically significant OS benefit—was derived from a regression model predicting OS hazard ratio (HR) from DFS HR. Patients were classified in clusters based on treatments they received and baseline characteristics (age, sex, index year, staging, and race/ethnicity). Propensity score matching addressed imbalances in baseline characteristics between the treatment and control groups in the constructed clusters. Predictive accuracy of the surrogacy equation was assessed internally via leave-one-out cross-validation and externally via predictions made for 26 RCTs of early-stage EC/GEJC. Results: Patients were mostly male (84%), non-Hispanic white (89.3%), with median age of 71.8 years and almost evenly distributed between cancer stages 2 (50.4%) and 3 (49.6%). Among patients receiving adjuvant (23.6%) or neoadjuvant (82.8%) treatment, most (81.7% of adjuvant and 92.0% of neoadjuvant therapies) received multi-agent chemotherapy. Spearman’s ρ was estimated to be 0.76 (95% CI: 0.70, 0.89) whereas estimates for Kendall’s τ ranged between 0.62 and 0.79. Estimated R2 for the correlation between treatment effects was 0.92 (95% CI: 0.56, 1.00) and estimated from the surrogacy equation log(HROS) = 0.02 + 1.09 × log(HRDFS) with a corresponding STE of 0.86. The 95% prediction intervals generated from this equation contained the raw OS HRs for 91% of the clusters in the internal validation, and 89% of the RCTs in the external validation. Conclusions: Correlations between DFS and OS, and between the treatment effects on these endpoints, were both moderate. The highly accurate surrogacy equation between the treatment effects can enable earlier assessments of OS benefit from the DFS benefit for early-stage EC/GEJC treatments in the real-world setting.

Low pretreatment prognostic nutritional index predicts poor survival in breast cancer patients: A meta-analysis.

Prognostic nutritional index (PNI), as an indicator of nutritional immune status, has been shown to be associated with therapeutic effects and survival of solid tumors. However, the prognostic role of PNI before treatment in human breast cancer (BC) is still not conclusive. Hence, we performed this meta-analysis to assess the value of it in prognosis prediction for BC patients. We searched PubMed, Embase, Web of Science and EBSCO to identify the studies evaluating the association between PNI and survival such as overall survival (OS), disease-free survival (DFS) of BC, and computed extracted data into hazard ratios (HRs) for OS, DFS and clinicopathological features with STATA 12.0. A total of 2322 patients with BC from 8 published studies were incorporated into this meta-analysis. We discovered that low pretreatment PNI was significantly associated with worse OS, but not with DFS in BC patients. In stratified analyses, the result showed that decreased PNI before treatment was remarkably related with lower 3-year, 5-year, 8-year and 10-year OS, but not with 1-year survival rate in BC. In addition, although reduced PNI could not impact 1-year, 3-year or 5-year DFS, it considerably deteriorated 8-year and 10-year DFS in patients. Low pretreatment PNI deteriorated OS, 8-year and 10-year DFS in BC patients, implicating that it is a valuable prognostic index and improving the nutritional immune status may offer a therapeutic strategy for these patients.

Polo-like kinase (PLK) 5, a new member of the PLK family, serves as a biomarker to indicate anabatic tumor burden and poor prognosis for resectable non-small cell lung cancer.

A review argues that polo-like kinase 5 (PLK5) may be linked to unfavorable prognosis in non-small cell lung cancer (NSCLC) patients, which contradicts the discoveries from The Human Protein Atlas database (derived from TCGA analysis). This study intended to comprehensively confirm the association of PLK5 with clinical characteristics and prognosis in NSCLC patients. This two-center, retrospective, cohort study enrolled 210 NSCLC patients receiving surgical resection. PLK5 protein and mRNA were detected by immunohistochemistry and RT-qPCR in tumor and nontumor tissues. Moreover, RNA FPKM data for 994 lung cancer patients were obtained from The Human Protein Atlas database. PLK5 protein was decreased in tumor tissue compared to nontumor tissue (P < 0.001). Additionally, decreased PLK5 protein was linked with increased pathological grade (P = 0.002), lymph node metastasis presence (P = 0.001), elevated tumor-node-metastasis (TNM) stage (P = 0.003), and abnormal cancer antigen 125 (CA125) (P = 0.002). Meanwhile, low PLK5 protein was correlated with shortened disease-free survival (DFS) (P = 0.007) and overall survival (OS) (P = 0.038); further multivariable Cox regression analysis revealed that low PLK5 protein independently predicted unfavorable DFS (hazard ratio = 0.573, P = 0.022). PLK5 mRNA was reduced in tumor tissue compared with nontumor tissue (P < 0.001); its decline was linked with enhanced pathological grade (P = 0.034), climbed TNM stage (P = 0.032), and abnormal CA125 (P = 0.002). Furthermore, low PLK5 mRNA was correlated with unfavorable DFS (P = 0.046). The Human Protein Atlas database also disclosed the link between low PLK5 mRNA and worse OS (P = 0.046). A PLK5 decrement reflects anabatic tumor burden and poor prognosis in NSCLC patients.

Clinical significance of adjuvant chemotherapy for pathological complete response rectal cancer patients with acellular mucin pools after neoadjuvant chemoradiotherapy.

Approximately 15-30% of locally advanced rectal cancer (LARC) patients achieved pathological complete response (pCR) after neoadjuvant chemoradiotherapy (CRT) and total mesorectal excision, but the clinical significance of adjuvant chemotherapy (ACT) for pCR patients remains unclear. To determine whether LARC pCR patients can benefit from the administration of ACT. Single center retrospective study. This study retrospectively included 280 LARC patients who achieved pCR after CRT and surgery from 2011 to 2019. The information of patients was recorded. Main outcome measures included 5-year disease-free survival (DFS) and 5-year overall survival. Subgroup analysis was conducted on whether pCR patients with acellular mucin pools received ACT or not. A total of 74/280 (26.4%) patients were identified with acellular mucin pools. Disease recurrence occurred in 38/280 (13.6%) patients, and in the subgroup of patients with acellular mucin pools, 15/74 (20.3%) patients developed distant metastases. The existence of acellular mucin pools was associated with worse DFS (79.7% versus 88.8%, P = 0.037). Among pCR patients with acellular mucin pools, 9/25 (36.0%) of non-ACT patients occurred recurrence, and ACT was beneficial for improving DFS (hazard ratio: 0.245; 95% confidence interval: 0.084-0.719; P = 0.010). The existence of acellular mucin pools may represent a sign of invasive tumor biology, which indicated a negative prognosis. ACT can improve the prognosis of patient with acellular mucin pools, so ACT should be considered for them.

Prognosis and clinicopathological characteristics of metaplastic breast cancer: A meta-analysis

To compare the clinicopathological characteristics and prognosis of metaplastic breast cancer (MBC) and triple-negative breast cancer (TNBC). A meta-analysis was performed on relevant cohort or case-control studies retrieved by a literature search of the PubMed, EMBASE, Ovid, and Web of Science databases. Hazard ratio (HR) was used to evaluate disease-free survival (DFS) and overall survival (OS), and the odds ratio (OR) and corresponding 95% confidence interval (CI) was used to evaluate clinicopathological characteristics, including age, tumor diameter, lymph node metastasis status, distant metastasis status, TNM staging, and histological grade. Nine studies were included in the meta-analysis. Compared with TNBC patients, the HRs for 5-year DFS and 5-year OS of those with MBC were 1.64 (95% confidence interval [CI] 1.36 - 1.98; P < .001) and 1.52 (95% CI 1.27 - 1.81; P < .001), respectively. The OR for age ≥ 50 years, tumor diameter ≤ 5 cm, lymph node-negative, distant metastasis, TNM stage III and IV, and histological grade 3 was 1.63 (95% CI 1.45-1.84), 0.29 (95% CI 0.14-0.58), 1.46 (95% CI 1.13-1.88), 1.59 (95% CI 0.89-2.81), 1.49 (95% CI 0.80-2.77), and 2.25 (95% CI 0.85-5.97), respectively. Patients with MBC had worse prognosis than those with TNBC. Furthermore, regarding clinicopathological characteristics, patients with MBC mostly presented at ≥ 50 years of age, with tumor diameter > 5 cm, and negative lymph nodes at first diagnosis. Moreover, there were no statistically significant differences in the occurrence of distant metastasis, TNM stages III and IV, or histological grade 3. MBC treatment was not assessed in this study. Data from randomized controlled trials are needed to guide the treatment of patients with MBC.

Oesophagectomy following noncurative endoscopic resection for oesophageal carcinoma: does interval matter?

Oesophagectomy was always recommended after noncurative endoscopic resection (ER). And the optimal time interval from ER to oesophagectomy remains unclear. This study was to explore the effect of interval on pathologic stage and prognosis. We included 155 patients who underwent ER for cT1N0M0 oesophageal cancer and then received subsequent oesophagectomy from 2009 to 2019. Overall survival and disease-free survival (DFS) were analysed to find an optimal cut-off of interval from ER to oesophagectomy. In addition, pathologic stage after ER was compared to that of oesophagectomy. Logistic regression model was built to identify risk factors for pathological upstage. The greatest difference of DFS was found in the groups who underwent oesophagectomy before and after 30 days (P = 0.016). Among total 155 patients, 106 (68.39%) received oesophagectomy within 30 days, while 49 (31.61%) had interval over 30 days. Comparing the pathologic stage between ER and oesophagectomy, 26 patients had upstage and thus had worse DFS (hazard ratio = 3.780, P = 0.042). T1b invasion, lymphovascular invasion and interval >30-day group had a higher upstage rate (P = 0.014, P < 0.001 and P < 0.001, respectively). And they were independent risk factors for pathologic upstage (odds ratio = 3.782, 4.522 and 2.844, respectively). It was the first study exploring the relationship between time interval and prognosis in oesophageal cancer. The longer interval between noncurative ER and additional oesophagectomy was associated with a worse DFS, so oesophagectomy was recommended performed within 1 month after ER. Older age, T1b stage, lymphovascular invasion and interval >30 days were significantly associated with pathologic upstage, which is related to the worse outcome too.