Citations

3520 Background: Recent analyses highlight nonhierarchical outcomes using the 8 th Edition AJCC staging system for CC. For instance, the 5-year survival rate for stages I and IIIa patients (pts) closely align. Additionally, tumor deposits (TDs) have been established as significant prognostic indicators. The AJCCCCEP commissioned this study to develop an updated pathological staging system for CC focused specifically on pts without distant metastasis (M0), while retaining the existing stage IV classification. Methods: Individual patient data (IPD) from pts diagnosed with cc (2010- 2017) in the NCDB were divided into training (70%) and internal validation (30%) datasets. External validation used IPD from clinical trials. The primary endpoint was overall survival (OS). Risk classification development for M0 pts incorporated ungrouped data on pathologic T categories, the number of involved regional lymph nodes (LN+), and TD counts. Recursive partitioning and regression tree analyses were applied to construct hierarchical staging levels. Pre-specified criteria required survival probabilities to be consecutive and show clear separations using Kaplan-Meier (KM) estimates with pairwise log-rank test P of < 0.005 for the training and < 0.05 for validation analyses. Results: Data from 281,997 pts (median age 67 years, 50% male, 81% white, 55% T3, 19% T4, 44% N+, 26% M+, and 11% with ≥1 TD) were analyzed, with a median follow-up of 7.3 years. The updated staging system (Table) met pre-specified criteria, with all observed pairwise P < 0.0001 in the development and internal validation sets. KM OS curves displayed a hierarchical separation across all sub-levels after the 1 st year of diagnosis. Consistent results were seen in pts treated with adjuvant chemotherapy in 4 trials (all pair-wise P < 0.0001). Conclusions: The proposed pathological staging system for M0 pts fulfills pre-specified criteria for hierarchical risk stratification, validated both internally and externally, and provides an evidence-based update. Pending review process, the AJCCCCEP will recommend that these changes be made to the Version 9 staging protocol for colon cancer to improve prognostication for CC pts. Stage T, # of LN+, # of TD M % of pts 1y OS (CI), % 3y OS (CI), % 5y OS (CI), % I T1, 0, 0 0 5 96 (95-97) 91 (90-92) 84 (83-86) IIa T2, 0, 0 0 10 95 (94-95) 88 (88-89) 80 (79-81) IIb T1, 0, 1+T1, 1+, 0T2, 0, 1+T2, 1-4, 0T3, 0, 0 0 27 93 (92-93) 84 (84-85) 75 (75-76) IIIa T1, 1+, 1+T2, 1-4, 1+T2, 5+, 0T3, 0, 1+T3, 1-4, 0 0 14 92 (91-92) 80 (80-81) 71 (70-72) IIIb T2, 5+, 1+T3, 1-4, 1+T3, 5+, 0T4a, 0-4, 0T4b, 0-2, 0 0 13 86 (86-87) 69 (68-70) 58 (57-59) IIIc T3, 5+, 1+T4a, 0-4, 1+T4a, 5+, anyT4b, 0-2, 1+T4b, 3+, any 0 5 78 (77-80) 53 (51-54) 40 (38-41) IVa Any 1a 19 59 (58-60) 28 (28-29) 17 (16-18) IVb Any 1b 7 43 (42-44) 14 (13-14) 6 (6-7) CI: 95% confidence internal; Peritoneum involvement data were not available before 2018 in NCDB. Thus, IVa/b were based on 7 th Edition.

BACKGROUND Treatment of tubo-ovarian high-grade serous carcinoma (HGSC) includes cytoreductive surgery, platinum-based chemotherapy, and often poly(ADP-ribose) polymerase (PARP) inhibitors. While homologous recombination (HR) deficiency is a well-established predictor of therapy sensitivity, over 50% of HR-proficient HGSCs also exhibit sensitivity. Currently, there are no biomarkers to identify which HR-proficient HGSCs will be sensitive to standard-of-care therapy. Replication stress may serve as a key determinant of response. METHODS We evaluated phospho–RPA2-T21 (p-RPA2) foci via immunofluorescence as a biomarker of replication stress in formalin-fixed, paraffin-embedded HGSC samples collected at diagnosis from patients treated with platinum chemotherapy (discovery cohort, n = 31; validation cohort, n = 244) or PARP inhibitors ( n = 63). Recurrent HGSCs ( n = 38) were also analyzed. p-RPA2 score was calculated using automated imaging analysis. RESULTS Samples were defined as p-RPA2-high if more than 16% of cells had ≥2 p-RPA2 foci on automated analysis. In the discovery cohort, HR-proficient, p-RPA2-high HGSCs demonstrated significantly higher rates of a chemotherapy response score of 3 to platinum chemotherapy than HR-proficient, p-RPA2-low HGSCs. In the validation cohort, patients with HR-proficient, p-RPA2-high HGSCs had significantly longer survival after platinum treatment than those with HR-proficient, p-RPA2-low HGSCs. Additionally, the p-RPA2 assay effectively predicted survival outcomes in patients treated with PARP inhibitors and in recurrent HGSC samples. CONCLUSION Our study underscores the importance of considering replication stress markers, such as p-RPA2, alongside HR status in therapeutic planning. This approach has the potential to increase the number of patients receiving effective therapy while reducing unnecessary toxicity. FUNDING The Reproductive Scientist Development Program, GOG Foundation, Pilot Translational and Clinical Studies function of the Washington University Institute of Clinical and Translational Sciences, the Foundation for Barnes-Jewish Hospital, Washington University School of Medicine Dean’s Scholar Program, The Cancer Biology Pathway Training Grant (5T32CA113275-17), The Lucy, Anarcha, and Betsey (L.A.B.) Award from the Department of Obstetrics and Gynecology at Washington University School of Medicine, and Veterans Affairs Office of Research and Development (I01BX006020).

Importance Neoadjuvant therapy (NT) is an increasingly used treatment strategy for patients with localized pancreatic ductal adenocarcinoma (PDAC). Little research has been conducted on cancer care delivery during NT, and the standards for optimal delivery of NT have not been defined. Objective To develop consensus best practices for delivering NT to patients with localized PDAC. Design, Setting, and Participants This study used a modified Delphi approach consisting of 2 rounds of voting, and a series of virtual conferences (from October to December 2023) to reach expert consensus on candidate best practice statements generated from a systematic review of the literature and expert opinion. An interdisciplinary panel was formed including 47 North American experts from surgical, medical, and radiation oncology, radiology, pathology, gastroenterology, integrative oncology, anesthesia, pharmacy, nursing, cancer care delivery research, and nutrition as well as patient and caregiver stakeholders. Main Outcome and Measures Statements that reached 75% agreement or greater were included in final consensus statements. Results Of the 47 participating panel members, 27 (57.64%) were male, and the mean (SD) age was 47.6 (8.2) years. Physicians reported completing training a mean (SD) 14.6 (8.6) years prior and seeing a mean (SD) 110.6 (38.4) patients with PDAC annually; 35 (77.7%) were in academic practice. Final consensus was reached on 82 best practices for delivering NT. Of these, 38 statements focused on pre-NT practices, including diagnosis and staging (n = 15), evaluation and optimization (n = 20), and decision-making (n = 3); 29 statements defined best practices during NT, including initiation (n = 3), delivery of therapy (n = 8), restaging practices (n = 12), and management of complications during NT (n = 6); and 15 best practices were identified to guide treatment post-NT, focusing on surgery (n = 7), pathology (n = 4), and follow-up (n = 3). Conclusions Using a modified Delphi consensus technique, best practice guidelines were developed focusing on the optimal standards for delivering NT to patients with localized PDAC. Given the prognostic importance of completing multimodality therapy, efforts to standardize and optimize the delivery of NT represent an immediate opportunity to decrease care variation and improve outcomes for patients with PDAC. Future research should focus on validating and implementing best practice standards into clinical practice.

Abstract The American Joint Committee on Cancer (AJCC) staging system for all cancer sites, including gastroenteropancreatic neuroendocrine tumors (GEP‐NETs), is meant to be dynamic, requiring periodic updates to optimize AJCC staging definitions. This entails the collaboration of experts charged with evaluating new evidence that supports changes to each staging system. GEP‐NETs are the second most prevalent neoplasm of gastrointestinal origin after colorectal cancer. Since publication of the AJCC eighth edition, the World Health Organization has updated the classification and separates grade 3 GEP‐NETs from poorly differentiated neuroendocrine carcinoma. In addition, because of major advancements in diagnostic and therapeutic technologies for GEP‐NETs, AJCC version 9 advocates against the use of serum chromogranin A for the diagnosis and monitoring of GEP‐NETs. Furthermore, AJCC version 9 recognizes the increasing role of endoscopy and endoscopic resection in the diagnosis and management of NETs, particularly in the stomach, duodenum, and colorectum. Finally, T1NXM0 has been added to stage I in these disease sites as well as in the appendix.

256 Background: Current staging for colon cancer utilizing the American Joint Committee on Cancer TNM framework stratifies disease into groups according to how advanced the disease is and provides important standardized, individual prognostic information. Ideally, staging systems should exhibit hierarchical logic, with increasing stage reflecting worse prognosis. We sought to evaluate hierarchy within the 8th edition AJCC staging system for colon cancer. Methods: All patients with primary colon (including rectosigmoid) cancer diagnosed 2010-2017 were identified from the National Cancer Database (NCDB). Patients were only included if they carried a histologic diagnosis of invasive primary (non-recurrent) cancer, underwent radical surgery, and had complete pathologic staging data (T, N, M category data). Patients with missing follow-up data were excluded. Kaplan-Meier curves were used to assess overall survival by AJCC 8th edition pathologic summary stage group to determine whether staging was hierarchical for colon cancer. Multivariable modeling and log likelihood ratio test was then used to identify relative contributions of T and N variables to overall survival. Results: Among 270,584 colon cancer patients, pathologic staging was noted to be hierarchical by T category alone and by N category alone. However, summary staging was non-hierarchical in both instances. Multivariable modeling confirmed the AJCC non-hierarchy issue (colon HRs: 1, 1.54, 2.62, 2.60, 1.02, 2.15, and 4.38 for stage 1 as reference, 2a, 2b, 2c, 3a, 3b, 3c respectively). Multivariable modeling demonstrated that high T category (T4a, T4b) conferred the greatest risk of mortality based on hazard ratio (T4a HR 2.76, T4b HR 3.04), while high T category as well as high N category (N2a, N2b) contributed substantially to the survival model based on z-score. Further modeling assessing the predictive power of T and N category with respect to overall survival demonstrated that T category more strongly predicted overall survival than N category in colon cancer (likelihood chi-square test statistic pT:7009 vs pN:3586). Conclusions: Hierarchy in survival based on AJCC summary stage was not observed for patients with stage II-III colon cancer resulting in a paradoxical better observed survival with some stage III cancer subgroups compared to stage II cancer subgroups. High T category appears to more significantly impact survival than N category for patients with N0-N1 disease, while high N category appears more important for patients with T1-3 disease. Future revisions of the AJCC staging system should account for the differential impact of T and N category identified herein to more accurately confer prognostic information.

Background Combining immunotherapy and antiangiogenic agents is a promising treatment strategy in endometrial cancer. To date, no biomarkers for response have been identified and data on post-immunotherapy progression are lacking. We explored the combination of a checkpoint inhibitor (nivolumab) and an antiangiogenic agent (cabozantinib) in immunotherapy-naïve endometrial cancer and in patients whose disease progressed on previous immunotherapy with baseline biopsy for immune profiling. Patients and methods In this phase II trial (ClinicalTrials.gov NCT03367741, registered December 11, 2017), women with recurrent endometrial cancer were randomized 2:1 to nivolumab with cabozantinib (Arm A) or nivolumab alone (Arm B). The primary endpoint was Response Evaluation Criteria in Solid Tumors-defined progression-free survival (PFS). Patients with carcinosarcoma or prior immune checkpoint inhibitor received combination treatment (Arm C). Baseline biopsy and serial peripheral blood mononuclear cell (PBMC) samples were analyzed and associations between patient outcome and immune data from cytometry by time of flight (CyTOF) and PBMCs were explored. Results Median PFS was 5.3 (90% CI 3.5 to 9.2) months in Arm A (n=36) and 1.9 (90% CI 1.6 to 3.4) months in Arm B (n=18) (HR=0.59, 90% CI 0.35 to 0.98; log-rank p=0.09, meeting the prespecified statistical significance criteria). The most common treatment-related adverse events in Arm A were diarrhea (50%) and elevated liver enzymes (aspartate aminotransferase 47%, alanine aminotransferase 42%). In-depth baseline CyTOF analysis across treatment arms (n=40) identified 35 immune-cell subsets. Among immunotherapy-pretreated patients in Arm C, non-progressors had significantly higher proportions of activated tissue-resident (CD103+CD69+) ɣδ T cells than progressors (adjusted p=0.009). Conclusions Adding cabozantinib to nivolumab significantly improved outcomes in heavily pretreated endometrial cancer. A subgroup of immunotherapy-pretreated patients identified by baseline immune profile and potentially benefiting from combination with antiangiogenics requires further investigation.

Abstract Purpose: Chemoradiotherapy for locally advanced cervical cancer fails in over a third of patients. Biomarkers with therapeutic implications are therefore needed. We investigated the relationship between an established prognostic marker, maximum standardized uptake value (SUVmax) on 18F-fluorodeoxyglucose positron emission tomography, and the inflammatory and immune state of cervical cancers. Experimental Design: An SUVmax most prognostic for freedom from progression (FFP) was identified and compared with known prognostic clinical variables in a cohort of 318 patients treated with definitive radiation with prospectively collected clinical data. Gene set enrichment analysis (GSEA) and CIBERSORT of whole-transcriptome data from 68 patients were used to identify biological pathways and immune cell subpopulations associated with high SUVmax. IHC using a tissue microarray (TMA, N = 82) was used to validate the CIBERSORT findings. The impact of macrophages on cervical cancer glucose metabolism was investigated in coculture experiments. Results: SUVmax &lt;11.4 was most prognostic for FFP (P = 0.001). The GSEA showed that high SUVmax is associated with increased gene expression of inflammatory pathways, including JAK/STAT3 signaling. CIBERSORT and CD68 staining of the TMA showed high SUVmax tumors are characterized by a monocyte-predominant immune infiltrate. Coculture of cervical cancer cells with macrophages or macrophage-conditioned media altered glucose uptake, and IL6 and JAK/STAT3 signaling contribute to this effect. Conclusions: SUVmax is a prognostic marker in cervical cancer that is associated with activation of inflammatory pathways and tumor infiltration of myeloid-derived immune cells, particularly macrophages. Macrophages contribute to changes in cervical cancer glucose metabolism. See related commentary by Williamson et al., p. 4136

AbstractThe WHO Classification of Tumours provides the international standards for the classification and diagnosis of tumours. It enables direct comparisons to be made between different countries. In the new fifth edition, the series has gone digital with the launch of a website as well as a series of books, known widely as the WHO Blue Books. The first volume to be produced is on the classification of Digestive System tumours, replacing the successful 2010 version. It has been rewritten and updated accordingly. This article summarises the major diagnostic innovations that have occurred over the last decade and that have now been incorporated in the classification. As an example, it incorporates the recently proposed classification of neuroendocrine tumours, based on the recognition that neuroendocrine tumours and carcinomas differ substantially in the genetic abnormalities that drive their growth, findings relevant to treatment selection and outcome prediction. Several themes have emerged during the production process. One is the importance of the progression from hyperplasia to dysplasia to carcinoma in the evolution of the malignant process. Advances in imaging techniques and endoscopy have resulted in enhanced access to precancerous lesions in the gastrointestinal and biliary tract, necessitating both changes in classification schema and clinical practice. Diagnosis of tumours is no longer the sole purview of pathologists, and some patients now receive treatment before tissue is obtained, based on clinical, radiological and liquid biopsy results. This makes the classification relevant to many disciplines involved in the care of patients with tumours of the digestive system.

6010 Background: The efficacy of treatment for recurrent endometrial cancer (EC) remains limited. Vascular endothelial growth factor and inflammatory chemokines are proangiogenic factors and immune modulators involved in immune suppression. Reprogramming the tumor microenvironment by combining antiangiogenic and immunotherapy (IO) could enhance antitumor responses. Methods: A 2:1 randomized phase 2 trial compared the combination of cabozantinib and nivolumab (Arm A) versus nivolumab (Arm B) in recurrent EC. Primary endpoint was progression free survival (PFS) assessed by RECIST 1.1 (NCT03367741). Women with recurrent measurable EC were eligible. There were no limits on prior therapy, but at least one prior platinum-based chemotherapy was required. Patients (pts) were stratified according to MSI status and assessed by CT every 8 weeks. Cabozantinib was given at 40 mg daily (Arm A) and nivolumab at 240 mg, on D1 and D15 of a 28-day cycle for 4 cycles, followed by 480 mg every 4 weeks (Arms A & B). Pts with carcinosarcoma or prior IO were enrolled in an exploratory cohort and received combination treatment (Arm C). A baseline biopsy was required for all pts. CyTOF analysis was performed on fresh biopsies. Results: 76 evaluable pts were enrolled (Arm A: 36, Arm B: 18, Arm C: 9 carcinosarcoma, and 20 post IO including 7 pts crossed over from Arm B). 55% of pts had received ≥3 prior lines of therapy. Two pts were MSI high in Arm A and none in Arm B. The Kaplan-Meier estimated median PFS was 5.3 (95% CI: 3.5-9.5) months in Arm A and 1.9 (95% CI: 1.6-3.8) months in Arm B, with a log-rank p = 0.07, which met the significance level of 0.1 used for sample size calculation. Objective response rate (ORR) was 25% for Arm A and 16.7% for Arm B; stable disease (SD) was seen in 44.4% vs 11.1%, respectively. Clinical benefit (ORR+SD) was significantly higher in arm A vs B (p < 0.001). In Arm C-carcinosarcoma, one patient had a partial response (11.9 months duration) and four SD. In Arm C-prior IO, six pts responded and eight had SD. The most common related AEs in Arm A were diarrhea (47.2%), elevated liver enzymes (44.4%), fatigue (38.9%), anorexia, hypertension, and nausea (30.6%), mainly grade 1/2. Preliminary CyTOF analysis across treatment arms identified multiple immune subsets for further interrogation including activated CD8+ and CD4+ T cells. Conclusions: Cabozantinib plus nivolumab demonstrates improved PFS compared to nivolumab in heavily pre-treated women with recurrent EC. In-depth CyTOF analysis of the tumor microenvironment to identify predictive immune biomarkers of response is ongoing. Clinical trial information: NCT03367741.