Adjuvant Trials Research Articles

Improving clinical trial performance using adult-learning methods.

11025 Background: Timely and efficient accrual to oncology treatment trials is among the most vital components of clinical research. However, more than 80% of trials fail to reach enrollment targets, compromising outcome interpretation and cost. We hypothesized that a novel and customized application of adult-learning methods would enhance clinical trial screening and randomization. Methods: In collaboration with a multinational sponsor, Vaniam Group (VG) introduced a structured set of interventions to sites in 3 global randomized trials. Sites choosing to “opt in” formed the experimental group (EG). EG received tailored interventions: interactive Trial Educational Discussions (iTEDs: 30-min virtual meetings), and/or interactive Trial Acceleration Meetings (iTAMs: 4-hr live workshops of 10-30 investigators), and standard study support. Adult-learning techniques including the Socratic Method, case studies, and teach-back were used. Control group (CG) comprised sites receiving only standard study support. Primary endpoints were screening rate (SR) and randomization rate (RdR) compared atbaseline (6 mos prior to intervention) and 6 mos post-intervention (M6). Nonparametric statistical analyses compared between-group (Mann–Whitney U test) and within-group (Wilcoxon Signed-Rank test) differences. Results: Trial 1, a phase 3 placebo-controlled adjuvant trial had been open for 45 mos (54% enrolled) prior to intervention. At baseline, SR and RdR were similar between groups ( P>0.05). At M6, SR increased 100% and RdR increased 37% in the EG; in the CG, SR did not change and RdR decreased 7%. For both endpoints, EG performed better than CG ( P=0.018, P=0.014). Trial 2, a phase 3 neoadjuvant trial had been open for 49 mos (86% enrolled) with a projected 18 mos to completion. At M6, SR increased 3% in the EG, but decreased 39% in the CG. RdR increased 15% in the EG but decreased 33% in the CG. While changes in performance were not significant between groups ( P >0.05), study met its target enrollment goal with no further delays. Trial 3, a phase 2 recurrence trial was 30% behind enrollment with a projected 51 mos to completion. At M6, increases in SR were recorded in both EG and CG at 116% and 18%, respectively. RdR increased in both EG and CG (90% and 50%, respectively), augmented by protocol amendment. Despite increases in both groups, SR and RdR were significantly enhanced by VG intervention ( P=0.009 and P=0.015). Conclusions: Our novel, site-focused intervention strategy structured upon adult-learning methods significantly enhanced clinical trial performance, as measured by SR and RdR. Future work will expand these findings to different trial designs and outcome measures such as endpoint fidelity and cost. [Table: see text]

Clinical management of typical and atypical carcinoids/neuroendocrine tumors in ENETS centres of excellence (CoE): Survey from the ENETS lung NET task force.

Lung carcinoid tumours are neuroendocrine neoplasms originating from the bronchopulmonary tract's neuroendocrine cells, accounting for only 1%-3% of all lung cancers but 30% of all neuroendocrine tumours. The incidence of lung carcinoids, both typical and atypical, has been increasing over the years due to improved diagnostic methods and increased awareness among clinicians and pathologists. The most recent WHO classification includes a subgroup of lung carcinoids with atypical morphology and higher mitotic count and/or Ki67 labelling index. Despite appropriate surgery, the 5-year survival rate for atypical carcinoids barely exceeds 50%-70%. The role of adjuvant therapy in lung carcinoids is not well-defined, and clinical decisions are generally based on the presence of high-risk features. Long-term follow-up is essential to monitor for recurrence, although the optimal follow-up protocol remains unclear. To address the lack of consensus in clinical management decisions, the European Neuroendocrine Tumor Society (ENETS) initiated a survey among 20 expert centres. The survey identified varied opinions on approaches to imaging, surgery, use of adjuvant therapy, and follow-up protocols. Notably, the absence of dedicated multidisciplinary lung neuroendocrine tumour boards in some centres was evident. Experts agreed on the need for a prospective adjuvant trial in high-risk patients, emphasizing the feasibility of such a study. In conclusion, the study highlights the need for a more uniform adoption of existing guidelines in the management of lung carcinoid tumours and emphasizes the importance of international collaboration to advance research and patient care. Close collaboration between healthcare providers and patients is vital for effective long-term surveillance and management of these rare tumours.

Evaluating the utility of ZNF331 promoter methylation as a prognostic and predictive marker in stage III colon cancer: results from CALGB 89803 (Alliance)

ABSTRACT While epigenomic alterations are common in colorectal cancers (CRC), few epigenomic biomarkers that risk-stratify patients have been identified. We thus sought to determine the potential of ZNF331 promoter hypermethylation (mZNF331) as a prognostic and predictive marker in colon cancer. We examined the association of mZNF331 with clinicopathologic features, relapse, survival, and treatment efficacy in patients with stage III colon cancer treated within a randomized adjuvant chemotherapy trial (CALGB/Alliance89803). Residual tumour tissue was available for genomic DNA extraction and methylation analysis for 385 patients. ZNF331 promoter methylation status was determined by bisulphite conversion and fluorescence-based real-time polymerase chain reaction. Kaplan-Meier estimator and Cox proportional hazard models were used to assess the prognostic and predictive role of mZNF331 in this well-annotated dataset, adjusting for clinicopathologic features and standard molecular markers. mZNF331 was observed in 267/385 (69.4%) evaluable cases. Histopathologic features were largely similar between patients with mZNF331 compared to unmethylated ZNF331 (unmZNFF31). There was no significant difference in disease-free or overall survival between patients with mZNF331 versus unmZNF331 colon cancers, even when adjusting for clinicopathologic features and molecular marker status. Similarly, there was no difference in disease-free or overall survival across treatment arms when stratified by ZNF331 methylation status. While ZNF331 promoter hypermethylation is frequently observed in CRC, our current study of a small subset of patients with stage III colon cancer suggests limited applicability as a prognostic marker. Larger studies may provide more insight and clarity into the applicability of mZNF331 as a prognostic and predictive marker.

Abstract PO1-03-03: STEEP criteria v2.0 validation: A multi-trial analysis using GEICAM and TRIO adjuvant trials to evaluate surrogate endpoints for overall survival

Abstract Background: Standardized definitions of efficacy endpoints are needed to improve clinical trial designs, data reporting and interpretation of results, and to allow cross-trial comparisons. STEEP (Standardized Definitions for Efficacy Endpoints) criteria were proposed in 2007 by an expert panel from the National Cancer Institute (NCI) to provide common definitions for clinical trials in early breast cancer (BC). Invasive disease-free survival (IDFS) was selected as a candidate surrogate endpoint for overall survival (OS) in adjuvant trials and has been widely used in the last 15 years. Advances in BC systemic treatment led to review these criteria (STEEP v2.0), with the definition of a new modified endpoint: invasive BC-free survival (IBCFS). IBCFS excludes second primary non-breast invasive cancers from IDFS which may better detect efficacy effects when the toxicity profile of the intervention is well-known and the risk of second primary cancer is small. Methods: We proposed a multi-trial analysis of 8 adjuvant chemotherapy (CT) trials from GEICAM and TRIO to evaluate the different surrogate endpoints defined in the STEEP v2.0. Trial-level surrogacy was assessed through correlation between the ln hazard ratio (HR) of OS and the ln HR of the different studied endpoints across trials. The correlation was estimated by the weighted, by trial size, least squares regression (WLS) line and evaluated comparing the R2 values between OS and the corresponding endpoint tested. Primary analyses evaluated the correlation of OS with IDFS/IBCFS. Secondary analyses evaluated the correlation of OS with other STEEP v2.0 endpoints (distant disease-free survival [DDFS], distant relapse-free survival [DRFS], recurrence-free survival [RFS], recurrence-free interval [RFI] and distant recurrence-free interval [DRFI]) and explored the surrogacy between OS and all endpoints in specific groups of patients (pts) according to their risk of relapse: hormone receptors positive (HR+)/HER2-negative (HER2-) pts with intermediate/high and high-risk and triple negative (TN) pts. Results: A total of 14,473 pts were included. Median age was 50 years (range, 20–82). All were female, and 51.8% were postmenopausal. With a median follow-up of 115 months (range, 0.0–188) we found 2,504 OS events, 4,146 IDFS events (60.9% being distant recurrences) and 3,810 IBCFS events (62.4% being distant recurrences). For each trial, HR of OS, IDFS and IBCFS indicated same conclusions. If HR< 1 for OS, it was also for IDFS and IBCFS and the same was true when HR >1. R2 results of the weighted linear correlations between the ln HR of OS versus (vs) IDFS and OS vs IBCFS were 0.86 and 0.89, respectively. Confidence intervals (CI) at 95% were both overlapping. All other efficacy endpoints showed strong correlation with OS in the overall analysis. R2 values for HR+/HER2- intermediate/high and high-risk pts were 0.89 (OS vs IDFS) and 0.84 (OS vs IBCFS). For TN pts the correlations were weaker, being 0.63 (OS vs IDFS) and 0.73 (OS vs IBCFS). All WLS R2 values are described in the table. Conclusions: All tested STEEP v2.0 endpoints were strongly correlated with OS (R2 close to 1), meaning that their use as surrogate endpoints for adjuvant CT trials is appropriate. Notably, no differences were found between them in this multi-trial analysis. Therefore, none of them is more appropriate than other to discriminate the value of a new intervention vs comparator in adjuvant CT studies with mature data and long-term follow-up. Table: Citation Format: Sara López-Tarruella, Marina Pollan, Ander Urriticoechea, Eva Carrasco, Gonzalo Spera, Miguel Martín, Begoña Bermejo, Linnea Chap, Manuel Ruíz - Borrego, John Crown, Jose Angel García-Sáenz, Arlene Chan, Angel Guerrero, Valerie Bee, Lourdes Calvo, Rodrigo Fresco, Andrea Blasco, Andrés Hernando, Dennis Slamon. STEEP criteria v2.0 validation: A multi-trial analysis using GEICAM and TRIO adjuvant trials to evaluate surrogate endpoints for overall survival [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 PO1-03-03.

Abstract GS03-07: Protocol-defined biomarker analysis in the PALLAS (AFT-05) adjuvant trial: Genomic subtype derived from RNA sequencing of HR+/HER2- early breast cancer

Abstract Background. The phase 3 PALLAS trial (NCT02513394) compared two years of the CDK4/6 inhibitor palbociclib with endocrine therapy of provider choice, versus endocrine therapy alone, as adjuvant treatment for patients with Stage II-III hormone receptor-positive HER2-negative (HR+/HER2-) breast cancer. Genomic subtype (PAM50 intrinsic subtype) measured from whole-transcriptome RNA sequencing data was defined in the protocol of the PALLAS trial as the primary biomarker for analysis of prediction and prognosis. Clinical data have been previously presented (Gnant et al, JCO 2022), and the trial now has 5-year median follow-up. Methods. As part of trial eligibility, all participants in PALLAS provided a tumor tissue block prior to randomization (surgical if primary resection, core biopsy if neoadjuvant treatment) for translational analyses (TRANS-PALLAS). The biorepository and laboratory were blinded to identity and processed samples in random order, to minimize bias. Nucleic acids were extracted from samples with sufficient tumor tissue and cellularity (>25 mm2 with ≥20% cancer nuclei). The Genome Sequencing Center at Washington University St. Louis performed whole-transcriptome RNA sequencing. Libraries were prepared from 1 µg DNase-1 treated total RNA, if total RNA DV200 >28 (Agilent Bioanalyzer), using an unbiased library protocol of RNA HyperPrep kit with RiboErase (HMR) (Kapa Biosystems, Wilmington, MA). 100 bp paired-end sequencing was performed on NovaSeq 6000 using S4 Reagent Kit (Illumina, San Diego, CA), with 48 libraries pooled per lane. Intrinsic subtype was determined using Bioclassifier package (Research PAM50 script, Parker et al.) only for the analysis population of primary breast cancer samples that had not been exposed to prior neoadjuvant therapy. Invasive disease-free survival (IDFS) will be visualized using Kaplan-Meier plots, with log-rank test between groups. Cox models of proportional hazards will be developed to evaluate prognosis adjusted for known clinical covariates, or for predictive interactions. The pre-defined level of significance is a two-sided 0.05. Results. From the total study population of 5796 enrolled patients, 4655 tissue blocks had sufficient tumor content to process for RNA, with 3931 yielding sufficient RNA for sequencing, and 2669/4655 (57.3%) submitted tissue blocks had DV200 ≥28 and were successfully sequenced. Clinical unblinding revealed 2370 unique patients (1182 in the palbociclib treatment arm and 1188 in the control arm) with intrinsic subtype defined from their untreated primary tumor: 1555 (65.6%) luminal A, 287 (12.1%) luminal B, 167 (7.0%) HER2-enriched, 310 (13.1%) basal-like, 51 (2.2%) normal-like. We will report the results for association of molecular subtype, proliferation score, and Risk of Recurrence (ROR) scores with invasive disease-free survival (IDFS) by treatment arm at the meeting. Conclusions. The TRANS-PALLAS cohort represents one of the largest biorepositories of HR+/HER2- early breast cancer reflecting contemporary systemic management in the framework of a prospectively randomized global trial. Required tumor block submission in this phase 3 trial yielded data from unbiased whole-transcriptome RNA sequencing of the primary tumor prior to treatment from 41% of the PALLAS participants. The proportion of luminal A cancers was unexpectedly high (66%), indicating a lower-risk distribution of cancers in this population. The planned analyses of prediction and prognosis are ongoing and those results will be presented at the time of the meeting. Support: AFT, ABCSG, Pfizer, ECOG-ACRIN, NSABP Foundation, GBG, BIG; Clinicaltrials.gov Identifier: NCT02513394; https://acknowledgments.alliancefound.org Citation Format: Daniel Stover, Dominik Hlauschek, Erica Mayer, W. Fraser Symmans, Mark Watson, Iros Barozzi, Martin Filipits, Karla Ballman, Meritxell Bellet- Ezquerra, Justin Balko, Gabor Rubovszky, Nicholas Zdenkowski, Adam Brufsky, Guenther Steger, Claudine Isaacs, Sibylle Loibl, Fernando Henao, Meredith Regan, Yuan Liu, Christian Fesl, Patrick O'Brien, Angela DeMichele, Michael Gnant, Otto Metzger. Protocol-defined biomarker analysis in the PALLAS (AFT-05) adjuvant trial: Genomic subtype derived from RNA sequencing of HR+/HER2- early breast cancer [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 GS03-07.

Abstract PO3-17-01: Brazilian Real-world data of HR+ HER2- early-stage Breast Cancer (BC) patients are poor when compared to control arms of recent adjuvant clinical trials

Abstract INTRODUCTION: In Brazil, BC is the most common neoplasm among women, with 73k new cases annually. Adjuvant hormone therapy (HT) options are evolving with personalized strategies based on risk stratification. Real-world data (RWD) plays a crucial role in understanding the outcomes in BC patients (pts) in low- and middle-income countries, where significant health disparities, access gaps, and barriers to the implementation of guidelines exist. This study aims to assess the epidemiologic profile, practice patterns, and real-world outcomes of pts with ER+ HER2- stage I-III BC treated in the largest network of private oncology services in Brazil and compare results with control arms of recent clinical trials evaluating CDK4/6 inhibitors in adjuvant setting. METHODS: Retrospective RWD study from Oncoclínicas Group with longitudinal EHR data from 2017 to 2022 merged in a platform where structured variables (demographics, tumor staging, pharmacy records) are integrated with unstructured data from physician notes and digitized pathology-molecular reports using technology-based abstraction performed by expert human curators that follow mCODE standards and predefined ontology. Treatment patterns and invasive disease-free survival (IDFS) outcomes were collected. Regarding risk stratification, pts were classified as high-risk (HR) if: (i) 4+ axillary lymph nodes (LN), or (ii) 1-3 LN and grade 3 and/or Ki620% and/or high-risk ODX/Mammaprint; intermediate-risk (IR) if: (iii) 1-3 LN with grade 1-2 and/or Ki67 < 20% and/or non-high-risk ODX/Mammaprint, or (iv) N0 with grade 2-3 and/or Ki67 >20% and/or high-risk ODX/Mammaprint; and low-risk (LR) if: (v) all other stages I and IIA not having the risk factors above. RESULTS: From over 30k BC pts in Oncoclínicas Database, 19k had HR+/HER2- early BC, 12k were treated in high-volume clinics, and 1,786 cases were selected for the study (diagnosis and first treatment in the last 6 years, complete histopathology and pharmacy registries). The median age was 57 years (27-96), 566 (32%) pts were premenopausal, 1052 (59%) had stage I disease, 372 (21%) stage IIA, 165 (9%) stage IIB and 197 (11%) stage III BC. Regarding risk stratification, 1,179 (66%) were LR, 351 (20%) IR, and 256 (14%) HR. In post-menopausal pts, aromatase inhibitor (AI) was used by 74% of pts with LR, 79% with IR and 83% with HR. In premenopausal pts, ovarian function suppression (OFS) – combined with tamoxifen or AI – was prescribed to 18% of LR pts, 15% of IR pts, and 48% of HR pts. Chemotherapy (CT) was offered to 32%, 38%, and 73% of postmenopausal pts in LR, IR, and HR groups. In premenopausal pts, 55%, 57%, and 78% received CT in LR, IR, and HR groups. The 3-year iDFS in the general population was 85%, reaching 80% in premenopausal and 86% in postmenopausal pts. The overall 3y iDFS was 87% in the LR, 86% in IR, and 72% in HR. Among premenopausal pts, the 3y iDFS was 81% in LR, 92% in IR, and 64% in the HR group. While the risk distribution of our cohort is similar to recent clinical trials, the 3y iDFS outcomes were numerically lower to those observed in the control groups of the pivotal trials evaluating adjuvant CDK4/6 inhibitors. In the HR group, the 3y iDFS was 72% (versus 84% 3y iDFS in the control arm of the MonarchE trial). Combining the IR/HR groups, the 3y iDFS was 80% (versus 87% in the control arm of NATALEE trial). CONCLUSION: In this large RWD cohort treated in a private setting in Brazil, most pts are diagnosed with stage I and LR BC. In this cohort, a significant proportion of premenopausal pts with IR/HR are not treated with OFS and do not receive CT. Real-world survival outcomes of Brazilian women with HR+ HER2- early BC treated in private clinic are inferior to those observed in recent clinical trials, especially in the premenopausal pts. In public healthcare system, where prevalence of HR disease is higher and access to essential treatments more limited, outcomes might even be worsened compared to the ones presented here. Citation Format: Aline Goncalves, Tomas Reinert, Max S. Mano, Heloisa Cruz, Cristiano Resende, Gustavo Bretas, Carlos Barrios, Matheus Costa e Silva, Rafael Paes, Guilherme Silva, Erika Martins, Fernanda Koyama, Bruno Ferrari, Carlos Gil Ferreira, Pedro Aguiar Junior, Rodrigo Dienstmann. Brazilian Real-world data of HR+ HER2- early-stage Breast Cancer (BC) patients are poor when compared to control arms of recent adjuvant clinical trials [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 PO3-17-01.

Abstract PO4-19-10: Selective Avoidance of Sentinel Lymph Node Biopsy After Neoadjuvant Chemotherapy In HER-2 Positive/Triple Negative Breast Cancer Patients With Excellent Radiologic Response to the Breast and Axilla

Abstract Background Neoadjuvant chemotherapy (NACT) for breast cancer (BC) is downstaging inoperable tumors into operable tumors and de-escalating breast/axillary surgery. According to advanced NACT, dual human epidermal growth factor-2 (HER2) blockage in HER2-positive BC, carboplatin, and immunotherapy in triple-negative breast cancer (TNBC) revealed pathologic complete response (ypCR) rates of up to 68% and 80%, the indications for NACT have expanded to early BC and the expected ypCR rate has increased. Therefore, it may be reasonable to consider omitting surgery in cases with excellent responses to NACT. Although sentinel lymph node biopsy (SLNB) is minimally invasive, some patients still experience complications such as lymphedema, pain, sensory loss, and axillary web syndrome. Several recent retrospective studies and pilot prospective studies have reported axillary pathologic complete response (ApCR) is highly correlated with breast pathologic complete response (BpCR). In cN0 with HER2+ BC and TNBC, the ApCR rate in BpCR after NACT was reported up to 100%, and in cN1 with HER2+ BC and TNBC, the ApCR rate in BpCR after NACT was reported about 85%. There are many studies predicting BpCR using radiologic imaging such as breast mammography (MMG), ultrasonography (USG), and magnetic resonance imaging (MRI). However, the combination of tri-modality (MMG, USG, MRI) could not confirm BpCR. The current study is screened in cT1-3N0-1M0, HER2+ or TNBC, and planned breast-conserving surgery (BCS) patients after NACT with excellent response at the combination of tri-modality imaging (breast MMG, breast USG, breast MRI) and with expected BpCR at physical examination. Methods Trial design The ASLAN trial is a prospective, multicenter, single-arm, clinical study. The five tertiary care hospitals in South Korea are participating which are members of the Korean Breast Cancer Study Group (KBCSG). Eligibility Inclusion criteria: women aged 20-69; cT1-3N0-1M0; HER2+ or TNBC (defined by ER-negative (< 10% positive cells in IHC) and PR-negative (< 10% positive cells in IHC)); expected complete remission at physical examination and radiological expected Tumor size ≤ 2cm or non-mass enhancement ≤ 4cm at breast MRI after standard NACT; planned breast-conserving surgery (BCS) with whole-breast irradiation; ECOG performance status 0-1. Exclusion criteria: SLNB before NACT; previous axillary surgery; bilateral BC; pregnancy. Intervention In eligible patients, BCS was performed. After BCS, patients who showed BpCR are enrolled with the omission of SLNB. Patients with no BpCR proceed with routine axillary surgery. Sample size calculation The assumption for an acceptable 5-year RFS ≥84% is based on previous study findings. The calculated total case number for per-protocol analysis is N=178. By Jun 2023, 153 patients had been enrolled and the target accrual of 178 patients is expected to be complete by Dec 2023. Study outcomes Primary endpoint: 5-year recurrence-free survival. Secondary endpoint: local recurrence-free survival, breast cancer-specific survival, overall survival, ipsilateral axillary recurrence interval, distant metastasis-free survival, contralateral breast-free survival, re-operation rate according to breast biopsy after NACT, adverse event, and quality of life. Accrual Plans The first patient was enrolled on Sep 2021. Among 223 patients who were screened, 153 patients have been enrolled in Jun 2023. We plan to complete the target accrual by Dec 2023. Conclusion The primary aim of the ASLAN trial is to demonstrate the oncologic safety of omitting axillary surgery for the excellent response after NACT in HER2+ or TNBC, early breast cancer patients undergoing BCS and adjuvant RT ASLAN trial, altogether with the EUBREAST-01 and ASCIS trials, will answer the very important question that may alter the axillary surgery in highly selected patients after NACT Citation Format: Jai Min Ryu, Wonshik Han, Han-Byoel Lee, Sung Gwe Ahn, Hee Jeong Kim, Hyung Seok Park, Ji Soo Choi, Hyunjun Lee, Hae Young Kim, Jeong Eon Lee. Selective Avoidance of Sentinel Lymph Node Biopsy After Neoadjuvant Chemotherapy In HER-2 Positive/Triple Negative Breast Cancer Patients With Excellent Radiologic Response to the Breast and Axilla [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 PO4-19-10.

Comparative investigation of neoadjuvant immunotherapy versus adjuvant immunotherapy in perioperative patients with cancer: a global-scale, cross-sectional, and large-sample informatics study.

Neoadjuvant and adjuvant immunotherapies for cancer have evolved through a series of remarkable and critical research advances; however, addressing their similarities and differences is imperative in clinical practice. Therefore, this study aimed to examine their similarities and differences from the perspective of informatics analysis. This cross-sectional study retrospectively analyzed extensive relevant studies published between 2014 and 2023 using stringent search criteria, excluding nonpeer-reviewed and non-English documents. The main outcome variables are publication volume, citation volume, connection strength, occurrence frequency, relevance percentage, and development percentage. Furthermore, an integrated comparative analysis was conducted using unsupervised hierarchical clustering, spatiotemporal analysis, regression statistics, and Walktrap algorithm analysis. This analysis included 1373 relevant studies. Advancements in neoadjuvant and adjuvant immunotherapies have been promising over the last decade, with an annual growth rate of 25.18 vs. 6.52% and global collaboration (International Co-authorships) of 19.93 vs. 19.84%. Respectively, five dominant research clusters were identified through unsupervised hierarchical clustering based on machine learning, among which Cluster 4 (Balance of neoadjuvant immunotherapy efficacy and safety) and Cluster 2 (Adjuvant immunotherapy clinical trials) [Average Publication Year (APY): 2021.70±0.70 vs. 2017.54±4.59] are emerging research populations. Burst and regression curve analyses uncovered domain pivotal research signatures, including microsatellite instability (R 2 =0.7500, P =0.0025) and biomarkers (R 2 =0.6505, P =0.0086) in neoadjuvant scenarios, and the tumor microenvironment (R 2 =0.5571, P =0.0209) in adjuvant scenarios. The Walktrap algorithm further revealed that 'neoadjuvant immunotherapy, nonsmall cell lung cancer (NSCLC), immune checkpoint inhibitors, melanoma' and 'adjuvant immunotherapy, melanoma, hepatocellular carcinoma, dendritic cells' (Relevance Percentage: 100 vs. 100%, Development Percentage: 37.5 vs. 17.1%) are extremely relevant to this field but remain underdeveloped, highlighting the need for further investigation. This study identified pivotal research signatures and provided substantial predictions for neoadjuvant and adjuvant cancer immunotherapies. In addition, comprehensive quantitative comparisons revealed a notable shift in focus within this field, with neoadjuvant immunotherapy taking precedence over adjuvant immunotherapy after 2020; such a qualitative finding facilitate proper decision-making for subsequent research and mitigate the wastage of healthcare resources.

Abstract SY08-01: Does exercise or fitness deter cancer progression after diagnosis

Abstract SY08-01: Does exercise or fitness deter cancer progression after diagnosis

Abstract 5151: High serum kidney injury marker-1 and high baseline tumor PD-L1 protein expression levels are independently associated with treatment effect in adjuvant nivolumab plus ipilimumab vs placebo in localized clear cell renal cell carcinoma

Abstract Introduction: CheckMate 914 (CM-914) Part A is a double-blind, phase III randomized trial of the Nivolumab (NIVO) plus Ipilimumab (IPI) vs placebo (PBO) in localized ccRCC. Our prior report from this study suggested a disease-free survival (DFS) benefit for NIVO+IPI among patients with Fuhrman grade 4, TNM stages PT2a and PT4, or sarcomatoid features, although the sample size was limited. It is known that high circulating KIM-1 is associated with worse DFS after nephrectomy. In this exploratory post hoc analysis, we investigated whether high KIM-1 may help identify a subset of patients who benefit from adjuvant NIVO+IPI. Methods: Patients (n=816) with RCC after nephrectomy were randomized in CM-914 Part A to receive NIVO+IPI or PBO as previously described. Assessment of KIM-1 levels was performed using enzyme linked immunoassay (ELISA) on pre-treatment (n=584) and matched on-treatment blood samples (n=584). We used pre-treatment tumor samples to assess PD-L1% tumor cell expression (%TC) in an PD-L1 IHC 28-8 pharm Dx assay. The association between biomarkers and DFS outcomes was investigated by Kaplan-Meier (KM) and Cox proportional hazards analysis. Results: Median baseline serum KIM-1 level was 102 (9.9 - 1055.7) pg/mL. Serum KIM-1 levels were higher in males vs females, ≥65 yrs vs <65 yrs, Asian vs white patients, and patients with partial vs radical nephrectomy. In the PBO arm, subjects with highest quartile of pre-treatment KIM-1 had significantly worse DFS than those from the three lower quartiles. In contrast, this DFS risk among the subjects within the highest KIM-1 quartile was mitigated with NIVO+IPI treatment. Among patients within the highest quartile of pre-treatment KIM-1, there was trend for better DFS for NIVO+IPI versus PBO, HR=0.6 (0.34-1.04). Increase in KIM-1 during study therapy was positively associated with higher DFS rate in both arms. Multivariable analysis showed that PD-L1 %TC was predictive at predefined PD-L1 cutoffs (>=1%, >=5%, and >=10%), associating with improved DFS compared to placebo. Subjects with high PD-L1 expression had a DFS benefit from NIVO+IPI independent of KIM-1. Conclusion: Circulating KIM-1 and tumor PD-L1 expression may enrich for benefit from IO therapy in adjuvant ccRCC and hence holds promise for informing risk stratification and patient inclusion in neoadjuvant or adjuvant clinical trials. Citation Format: Sai Vikram Vemula, Wenxin Xu, Yu Wang, Xiaowen Liu, Jorge Ruiz de Somocurcio, David McDermott, Jun Li, Rupal Bhatt, Chung-Wei Lee, Burcin Simsek, Saurabh Gupta, Robert Motzer. High serum kidney injury marker-1 and high baseline tumor PD-L1 protein expression levels are independently associated with treatment effect in adjuvant nivolumab plus ipilimumab vs placebo in localized clear cell renal cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5151.

Abstract 7160: Germline predictors for bevacizumab induced hypertensive crisis in ECOG-ACRIN 5103 and BEATRICE

Abstract Introduction: Bevacizumab is a beneficial therapy in several advanced cancer types. Predictive biomarkers to better understand which patients are destined to benefit or experience toxicity are needed. Associations between bevacizumab induced hypertension and survival have been reported but with conflicting conclusions. Methods: We performed post-hoc analyses to evaluate the association in 3,124 patients from two phase III adjuvant breast cancer trials, E5103 and BEATRICE. Differences in invasive disease-free survival (IDFS) and overall survival (OS) between patients with hypertension and those without were compared. Hypertension was defined as systolic blood pressure (SBP) ≥ 160 mmHg (n=346) and SBP ≥ 180 mmHg (hypertensive crisis) (n=69). Genomic analyses were performed to evaluate germline genetic predictors for the hypertensive crisis. Results: Hypertensive crisis was significantly associated with superior IDFS (p = 0.015) and OS (p = 0.042), but only IDFS (p = 0.029; HR = 0.28) remained significant after correction for prognostic factors. SBP ≥ 160 mmHg was not associated with either IDFS or OS. A common single-nucleotide polymorphism, rs6486785, was significantly associated with hypertensive crisis (p = 8.4 × 10−9; OR = 5.2). Conclusion: Bevacizumab-induced hypertensive crisis is associated with superior outcomes and rs6486785 predicted an increased risk of this key toxicity. Citation Format: Fei Shen, Guanglong Jiang, Santosh Philips, Erica Cantor, Laura Gardner, Gloria Xue, Geneva Cunningham, Nawal Kassem, Anne Oneil, David Cameron, Thomas Suter, Kathy Miller, George Sledge, Bryan Schneider. Germline predictors for bevacizumab induced hypertensive crisis in ECOG-ACRIN 5103 and BEATRICE [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7160.

Abstract 1185: Novel association of an autoimmune-related axis and anti-CTLA-4-based toxicities in adjuvant immunotherapy-treated melanoma patients

Abstract Intro: Immune checkpoint inhibition (ICI) for metastatic unresectable melanoma has markedly improved survival, and has shown benefit as adjuvant (AT) and neoadjuvant (NAT) therapy. Although ICI treatments confer survival benefit, they frequently induce immune-related adverse events (irAEs), which are a substantial clinical problem, particularly in AT/NAT, where ICI is used in less advanced disease to prevent recurrence. As such, the biomarkers predicting irAE risk, in particular in AT/NAT, are urgently needed to improve patient outcomes. Methods: We assessed RNA from pre-treatment peripheral CD4+ and CD8+ T cells from adjuvant clinical trial patients (CheckMate-915; n=212 patients) treated with Nivolumab (n=130) or Ipilimumab/Nivolumab (Combo) (n=82). We performed RNA-seq differential expression analysis to identify baseline differences in the immune profiles of patients with no/mild toxicity (grade 0-2) versus severe toxicity (grade 3-5). Results: Gene ontology analysis of the differentially expressed genes (DEGs) among those with severe toxicity reveals significant enrichment of immune-related pathways (IL-2, IFN-gamma, T-cell receptors, Toll-like receptors). These are shared among cell types (CD4+/CD8+) and between treatments (Nivo/Combo). From predicted DEG protein-protein interactions, we identified a treatment- and cell-type-specific expression signature associated with irAE development in CD4+ cells from Combo-treated patients. This signature, involving genes in the spleen tyrosine kinase (SYK) pathway, correctly predicts severe irAE patients with 73% accuracy (chi-squared p-value=0.001). The signature also identifies patients with mild to moderate irAEs in organ systems previously found in autoimmune traits to be associated with SYK upregulation (including skin, GI, liver, and pancreas), with 96% of all predicted patients experiencing at least one of these SYK-related toxicities, and 79% experiencing two or more. Importantly, the signature is not associated with disease recurrence (p=0.79). Conclusions: We have identified baseline expression differences in key immune pathways in peripheral T cells from ICI-treated patients with severe irAEs, and defined an SYK-related gene signature correctly identifying over half of severe irAE patients in the Combo-treated cohort. This finding aligns with our previous work linking anti-CTLA-4 irAEs with a germline variant associated with high SYK expression. This gene signature may not only serve as a baseline biomarker of severe irAEs, but it may also help guide treatment decisions, reducing toxicity while retaining efficacy, which will be particularly important in the adjuvant setting. Citation Format: Kelsey R. Monson, Robert Ferguson, Joanna Handzlik, Jiahan Xiong, Sasha Dagayev, Leah Morales, Vylyny Chat, Anabelle Bunis, Chaitra Sreenivasaiah, Sonia Dolfi, Daniel Tenney, Iman Osman, Jeffrey Weber, Tomas Kirchhoff. Novel association of an autoimmune-related axis and anti-CTLA-4-based toxicities in adjuvant immunotherapy-treated melanoma patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1185.

Abstract 6411: The gut microbiome is associated with recurrence free survival in patients with resected Stage III or Stage IV melanoma treated with immune checkpoint inhibitors

Abstract The gut microbiome (GMB) plays a crucial role in immune checkpoint blockade (ICB) therapy outcomes for metastatic melanoma patients, yet there remains a lack of consensus regarding the specific microbiota associated with clinical outcomes, particularly across different geographic regions. Furthermore, investigations into the relationship between GMB and melanoma outcomes in the adjuvant setting are notably absent. This highlights the pressing need for a comprehensive, large-scale study spanning diverse geographic locations within a well-controlled clinical trial environment. In this study, we conducted shotgun sequencing on pre-treatment stool samples collected from 674 melanoma patients participating in an international, randomized, double-blind, phase III adjuvant trial evaluating clinical outcomes following adjuvant nivolumab plus ipilimumab versus nivolumab. Our recruitment encompassed three continents and five geographically distinct regions. Given the significant influence of geographic region on GMB composition, we employed three analytical approaches: (a) region-specific analyses, (b) combined meta-analyses across regions, and (c) sub-set paired analyses involving subjects closely matched for overall GMB. Additionally, we assessed GMB stability by examining samples collected serially prior to therapy and at weeks 7 and 29 of ICB treatment. Through region-specific and meta-analyses, we identified ten pre-treatment gut bacterial markers, including Eubacterium, Ruminococcus, Clostridium, and Firmicutes, which exhibited associations with melanoma recurrence in the adjuvant setting. The predictive capacity of these microbial markers was directly proportion to GMB similarity (Spearman correlation = 0.86, p<0.001 for AUC vs. beta-diversity). Notably, for closely matched patients in terms of their GMB composition, the prediction of recurrence using the recurrence-associated markers, in conjunction with clinical characteristics, yielded an AUC of 0.917 (95% CI: 0.825-1.00). Furthermore, GMB remained largely stable across serial samples collected before and after treatment (PERMANOVA R2 = 0.867, p-val<0.001, at baseline, week 7, and week 29). This study underscores the remarkable stability of GMB during adjuvant ICB therapy for melanoma and identifies specific bacterial biomarkers that hold promise for predicting melanoma recurrence within the adjuvant treatment setting. The gut microbiome emerges as a potential source of microbial biomarkers for individualized prediction of melanoma recurrence in clinical practice. Citation Format: Mykhaylo Usyk, Richard B. Hayes, Rob Knight, Antonio Gonzalez, Huilin Li, Iman Osman, Jeffrey S. Weber, Jiyoung Ahn. The gut microbiome is associated with recurrence free survival in patients with resected Stage III or Stage IV melanoma treated with immune checkpoint inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6411.

Intermediate clinical endpoints in early-stage breast cancer: an analysis of individual patient data from the Gruppo Italiano Mammella and Mammella Intergruppo trials

Intermediate clinical endpoints (ICEs) are frequently used as primary endpoint in randomised trials (RCTs). We aim to assess whether changes in different ICEs can be used to predict changes in overall survival (OS) in adjuvant breast cancer trials. Individual patient level data from adjuvant phase III RCTs conducted by the Gruppo Italiano Mammella (GIM) and Mammella Intergruppo (MIG) study groups were used. ICEs were computed according to STEEP criteria. Using a two-stage meta-analytic model, we assessed the surrogacy of each ICE at both the outcome (i.e., OS and ICE are correlated irrespective of treatment) and trial (i.e., treatment effects on ICE and treatment effect on OS are correlated) levels. The following ICEs were considered as potential surrogate endpoints of OS: disease-free survival (DFS), distant disease-free survival (DDFS), distant relapse-free survival (DRFS), recurrence-free survival (RFS), recurrence-free interval (RFI), distant recurrence-free interval (DRFI), breast cancer-free interval (BCFI), and invasive breast cancer-free survival (IBCFS). The estimates of the degree of correlation were obtained by copula models and weighted linear regression. Kendall's τ and R2≥0.70 were considered as indicators of a clinically relevant surrogacy. Among the 12,397 patients enrolled from November 1992 to July 2012 in six RCTs, median age at enrolment was 57 years (interquartile range (IQR) 49-65). After a median follow-up of 10.3 years (IQR 6.4-14.5), 2131 (17.2%) OS events were observed, with 1390 (65.2%) attributed to breast cancer. At the outcome-level, Kendall's τ ranged from 0.69 for BCFI to 0.84 for DRFS. For DFS, DDFS, DRFS, RFS, RFI, DRFI, BCFI, and IBCFS endpoints, over 95% of the 8-year OS variability was attributable to the variation of the 5-year ICE. At the trial-level, treatment effects for the different ICEs and OS were strongly correlated, with the highest correlation for RFS and DRFS and the lowest for BCFI. Our results provide evidence supporting the use of DFS, DDFS, DRFS, RFS, RFI, DRFI, and IBCFS as primary endpoint in breast cancer adjuvant trials. This analysis was supported by the Italian Association for Cancer Research ("Associazione Italiana per la Ricerca sul Cancro", AIRC; IG 2017/20760) and by Italian Ministry of Health-5×1000 funds (years 2021-2022).

Treatment of Stage III Resectable Melanoma-Adjuvant and Neoadjuvant Approaches.

Patients with stage III resectable melanoma carry a high risk of melanoma recurrence that ranges from approximately 40% to 90% at 5 years following surgical management alone. Postoperative systemic adjuvant therapy targets residual micrometastatic disease that could be the source of future recurrence and death from melanoma. Randomized phase III adjuvant trials reported significant improvements in overall survival with high-dose interferon α in 2 of 3 studies (compared with observation and GMK ganglioside vaccine) and with anti-cytotoxic T-lymphocyte antigen 4 ipilimumab at 10 mg/kg compared with placebo and ipilimumab 3 mg/kg compared with high-dose interferon α. In the modern era, more recent phase III trials demonstrated significant recurrence-free survival improvements with anti-programmed cell death protein 1, pembrolizumab, and BRAF-MEK inhibitor combination dabrafenib-trametinib (for BRAF mutant melanoma) versus placebo. Furthermore, anti-programmed cell death protein 1, nivolumab and pembrolizumab have both been shown to significantly improve recurrence-free survival as compared with ipilimumab 10 mg/kg. For melanoma patients with clinically or radiologically detectable locoregionally advanced disease, emerging data support an important role for preoperative systemic neoadjuvant therapy. Importantly, a recent cooperative group trial (S1801) reported superior event-free survival rates with neoadjuvant versus adjuvant therapy. Collectively, current data from neoadjuvant immunotherapy and targeted therapy trials support a future change in clinical practice in favor of neoadjuvant therapy for eligible melanoma patients.

Influence of microbiota-associated metabolic reprogramming on clinical outcome in patients with melanoma from the randomized adjuvant dendritic cell-based MIND-DC trial

Tumor immunosurveillance plays a major role in melanoma, prompting the development of immunotherapy strategies. The gut microbiota composition, influencing peripheral and tumoral immune tonus, earned its credentials among predictors of survival in melanoma. The MIND-DC phase III trial (NCT02993315) randomized (2:1 ratio) 148 patients with stage IIIB/C melanoma to adjuvant treatment with autologous natural dendritic cell (nDC) or placebo (PL). Overall, 144 patients collected serum and stool samples before and after 2 bimonthly injections to perform metabolomics (MB) and metagenomics (MG) as prespecified exploratory analysis. Clinical outcomes are reported separately. Here we show that different microbes were associated with prognosis, with the health-related Faecalibacterium prausnitzii standing out as the main beneficial taxon for no recurrence at 2 years (p = 0.008 at baseline, nDC arm). Therapy coincided with major MB perturbations (acylcarnitines, carboxylic and fatty acids). Despite randomization, nDC arm exhibited MG and MB bias at baseline: relative under-representation of F. prausnitzii, and perturbations of primary biliary acids (BA). F. prausnitzii anticorrelated with BA, medium- and long-chain acylcarnitines. Combined, these MG and MB biomarkers markedly determined prognosis. Altogether, the host-microbial interaction may play a role in localized melanoma. We value systematic MG and MB profiling in randomized trials to avoid baseline differences attributed to host-microbe interactions.

Neoadjuvant and adjuvant therapy for biliary tract cancer: Advances and limitations.

Biliary tract cancers (BTC), a rare and aggressive consortium of malignancies, consisting of intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma and gallbladder carcinoma. While most patients present with metastatic disease, a minority of patients with BTC are eligible for curative surgical resection at the time of presentation. However, these patients have poor 5-year overall survival rates and high rates of recurrence, necessitating the improvement of the neoadjuvant and adjuvant treatment of BTC. In this review, we assess the neoadjuvant and adjuvant clinical trials for the treatment of BTC and discuss the challenges and limitations of clinical trials, as well as future directions for the treatment of BTC.

Non-Metastatic Clear Cell Renal Cell Carcinoma Immune Cell Infiltration Heterogeneity and Prognostic Ability in Patients Following Surgery.

Predicting which patients will progress to metastatic disease after surgery for non-metastatic clear cell renal cell carcinoma (ccRCC) is difficult; however, recent data suggest that tumor immune cell infiltration could be used as a biomarker. We evaluated the quantity and type of immune cells infiltrating ccRCC tumors for associations with metastatic progression following attempted curative surgery. We quantified immune cell densities in the tumor microenvironment and validated our findings in two independent patient cohorts with multi-region sampling to investigate the impact of heterogeneity on prognostic accuracy. For non-metastatic ccRCC, increased CD8+ T cell infiltration was associated with a reduced likelihood of progression to metastatic disease. Interestingly, patients who progressed to metastatic disease also had increased percentages of exhausted CD8+ T cells. Finally, we evaluated the spatial heterogeneity of the immune infiltration and demonstrated that patients without metastatic progression had CD8+ T cells in closer proximity to ccRCC cells. These data strengthen the evidence for CD8+ T cell infiltration as a prognostic biomarker in non-metastatic ccRCC and demonstrate that multi-region sampling may be necessary to fully characterize immune infiltration within heterogeneous tumors. Tumor CD8+ T cell infiltration should be investigated as a biomarker in adjuvant systemic therapy clinical trials for high-risk non-metastatic RCC.

Adjuvant Therapy in Renal Cell Cancer

A number of adjuvant trials have attempted to improve outcomes for patients following nephrectomy for renal cell carcinoma (RCC). This was initially with cytokines and then Vascular Endothelial Growth Factor (VEGF) targeted therapies. More recently, a series of adjuvant immune checkpoint inhibitor (ICI) studies have been published. To date, only the KEYNOTE— 564 study using adjuvant pembrolizumab has positive Disease-Free Survival (DFS) data with an acceptable toxicity profile. There are many negative ICI and anti-VEGF adjuvant trials, which raises uncertainty. Further randomised trials may be required but importantly biomarker studies are needed to identify those individuals who may benefit from adjuvant therapy.

Tuna Ethanol Extract reduces CRP and Edema in Animal Models of Adjuvant Arthritis

Rheumatic arthritis is an inflammatory joint disease caused by an autoimmune process. Tuna contains many nutrients that act as antioxidants and anti-inflammatories in the form of vitamins, minerals, and essential fatty acids. This study aims to determine the effect of Tuna fish extract on inflammation in the legs of animal models of adjuvant arthritis. Twenty-four male Rattus norvegicus which were partitioned into P1 groups of no treatment rats, P2 groups of adjuvant arthritis (AA) rats, were nduced with Complete Freund's Adjuvant (CFA), P3 groups are rats with adjuvant arthritis who were given Thunnus obesus fish ethanol extricate orally for seven consecutive days from the primary day of the emergence of symptoms of AA, and given with the dosage of 12 grams/kg of body weight, beginning on the 22nd day. At the last day of the study, the CRP and swelling feet joints of all groups of rats were measured (on day 29). Tuna ethanol extracts significantly decrease the mean volume of edema (p = 0.034) and CRP levels (p=0.022) in adjuvant arthritis rats. The content of active ingredients in Tuna has been shown to inhibit the inflammatory process through the inhibition of cox-2, resulting in a reduction of the volume of animal leg joint edema and CRP levels in adjuvant arthritis trials. Administration of Tuna fish extract at a dose of 12g/kg BW can reduce leg edema of adjuvant arthritis experimental animals and serum CRP levels of adjuvant arthritis experimental animals.