Frédéric Bibeau’s research while affiliated with University of Franche-Comté and other places

High-grade appendiceal mucinous neoplasm (HAMN) is used to describe a rare epithelial neoplasm of the appendix characterized by pushing-type invasion and high-grade cytologic atypia. Its implications regarding lymph node spread and the necessity of right colectomy are currently debate. The objective of the present study was to assess the clinicopathologic characteristics , the risk of lymph node and peritoneal metastasis, and long-term outcomes of patients diagnosed as HAMN in comparison to low-grade appendiceal mucinous neoplasm (LAMN) and appendiceal adenocarcinoma, treated by right hemi-colectomy. A total of 443 patients diagnosed with LAMN (n = 246), HAMN (n = 34), or appendiceal adenocarcinoma (n = 163) and who underwent right colectomy with lymph node dissection in all cases within 32 institutions of the French Network for Rare Peritoneal Malignancies (RENAPE) were included. The median age was 56.5 years (range: 21 to 91), and the majority were female (n = 250, 56.4%) without difference between groups (P = 0.604). Lymph node metastases were identified in 17.8% of appendiceal adenocarcinoma cases (29/163); none were found among LAMN or HAMN cases. A higher number of lymph nodes were analyzed in those treated for appendiceal adenocarcinoma than LAMN (P < 0.001) and HAMN (P = 0.035). Regarding peritoneal metastasis, a higher proportion of cases were classified as high-grade with/without signet cells in patients treated for HAMN (P < 0.001) and appendiceal ad-enocarcinoma (P < 0.001) than those treated for LAMN. Among patients with perforation of the appendix, those treated for LAMN had longer overall survival (OS; P < 0.001) and progression free survival (PFS; P < 0.0001) than those treated for appendiceal adenocarcinoma or those treated for HAMN; among patients without perforation, those treated for LAMN and HAMN had longer OS (P = 0.042) and PFS (P = 0.012) than those treated for appendiceal adenocarcinoma. No lymph node metastases were observed in patients treated for HAMN, and those without appendix perforation had a similar prognosis to LAMN. This study supports staging HAMN using the same system as LAMN and treating it with appendectomy alone in the absence of appendix perforation.

241 Background: Neoadjuvant treatment with immune check point inhibitors has shown promising results in localized deficient mismatch repair/microsatellite instability (dMMR/MSI) colorectal cancer (CRC), notably in terms of pathologic response. However, pathologic response has rarely been precisely assessed on both primary tumor and its corresponding lymph nodes (LN) as an end-point. We performed this analysis on the CRC samples selected from the IMHOTEP trial, a multicenter, single-arm study evaluating peri-operative Pembrolizumab in 4 different cohorts of patients with localized resectable dMMR/MSI tumors. Methods: We analyzed pathologic response on the 56 surgical specimens available from the CRC cohort. Pathologic response was assessed on primary tumor according to the percentage of Residual Viable Tumor (RVT) score, encompassing 4 groups : 0% = pathologic Complete Response (pCR) ; ≤10% = Major Pathologic Response (MPR) ; >10% < 50% = partial Pathologic Response (pPR) ; > 50% = lack of response (noPR). Pathologic response was assessed on lymph node (LN) according to 4 groups : negative LN without sign of sterilization (yN0 reg-), negative LN with sterilization (yN0 reg+) ; metastatic LN without tumor regression (yN+ reg-) ; metastatic LN with tumor regression (yN+ reg+).The type of regression, including colloid, fibrotic and necrotic features was reported, as well as the presence of tertiary lymphoid structures (TLS). pCR and MPR corresponded to pathologic responder patients and pPR and noPR to pathologic non responder patients. Results: In thisCRC cohort pCR, MPR, pPR and noPR were observed in n= 33 (58.9%), 7 (12.5%), 5 (8.9%) and 11 (19.6 %) cases and yN0 reg-, yN0 reg+, yN+ reg-, yN+ reg+ in 41 (73.2%) , 7 (12.5%), 7 (12.5%), and 1 (1.8 % ) cases. There was a significant association between pathologic responders (pCR + MPR) and negative LN status encompassing sterilized LN (p=0.04). Pathologic responders were more frequently associated with classical (Lieberkuhnian) adenocarcinoma than with other CRC special subtypes (mucinous, signet ring-cell, poorly cohesive subtypes)(p<0.01). Colloid response was the most frequent pattern of regression, observed in 42 (75%) cases, and predominant (>80% of pathologic response areas) in 14 (25%) cases. TLS were seen in 46 (82%) cases, without any significant association with the RVT score. However TLS were observed in all CRC cases with MPR. Conclusions: These preliminary results show pembrolizumab efficacy as a neoadjuvant monotherapy in terms of pathologic response on both primary CRC and corresponding LN, highlighting the need for a new and more accurate pathologic score. It also illustrates the potential impact of the histological subtypes. Complementary data will be available after updated pathologic reviewing of additional specimens from CRC patients and will also be correlated with outcome. Clinical trial information: NCT04795661 .

Background/Objectives: Pancreatic ductal adenocarcinoma (PDAC) is a cancer with very poor prognosis despite early surgical management. To date, only clinical variables are used to predict outcome for decision-making about adjuvant therapy. We sought to generate a deep learning approach based on hematoxylin and eosin (H&E) or hematoxylin, eosin and saffron (HES) whole slides to predict patients’ outcome, compare these new entities with known molecular subtypes and question their biological significance; Methods: We used as a training set a retrospective private cohort of 206 patients treated by surgery for PDAC cancer and a validation cohort of 166 non-metastatic patients from The Cancer Genome Atlas (TCGA) PDAC project. We estimated a multi-instance learning survival model to predict relapse in the training set and evaluated its performance in the validation set. RNAseq and exome data from the TCGA PDAC database were used to describe the transcriptomic and genomic features associated with deep learning classification; Results: Based on the estimation of an attention-based multi-instance learning survival model, we identified two groups of patients with a distinct prognosis. There was a significant difference in progression-free survival (PFS) between these two groups in the training set (hazard ratio HR = 0.72 [0.54;0.96]; p = 0.03) and in the validation set (HR = 0.63 [0.42;0.94]; p = 0.01). Transcriptomic and genomic features revealed that the poor prognosis group was associated with a squamous phenotype. Conclusions: Our study demonstrates that deep learning could be used to predict PDAC prognosis and offer assistance in better choosing adjuvant treatment.

PURPOSE The clinical course of pulmonary carcinoids ranges from indolent to fatal disease, suggesting that specific molecular alterations drive progression toward the fully malignant state. A similar spectrum of clinical phenotypes occurs in pediatric neuroblastoma, in which activation of telomerase reverse transcriptase ( TERT ) is decisive in determining the course of disease. We therefore investigated whether TERT expression defines the clinical fate of patients with pulmonary carcinoid. METHODS TERT expression was examined by RNA sequencing in a test cohort and a validation cohort of pulmonary carcinoids (n = 88 and n = 105, respectively). A natural TERT expression cutoff was determined in the test cohort on the basis of the distribution of TERT expression, and its prognostic value was assessed by Kaplan-Meier survival estimates and multivariable analyses. Telomerase activity was validated by telomere repeat amplification protocol assay. RESULTS Similar to neuroblastoma, TERT expression exhibited a bimodal distribution in pulmonary carcinoids, separating tumors into TERT -high and TERT- low subgroups. A natural TERT cutoff discriminated unfavorable from favorable clinical courses with high accuracy both in the test cohort (5-year overall survival [OS], 0.547 ± 0.132 v 1.0; P < .001) and the validation cohort (5-year OS, 0.788 ± 0.063 v 0.913 ± 0.048; P < .001). In line with these findings, telomerase activity was largely absent in TERT -low tumors, whereas it was readily detectable in TERT- high carcinoids. In multivariable analysis considering TERT expression, histology (typical v atypical carcinoid), and stage (≤IIA v ≥IIB), high TERT expression was an independent prognostic marker for poor survival, with a hazard ratio of 5.243 (95% CI, 1.943 to 14.148; P = .001). CONCLUSION Our data demonstrate that high TERT expression defines clinically aggressive pulmonary carcinoids with fatal outcome, similar to neuroblastoma, indicating that activation of TERT may be a defining feature of lethal cancers.

Background: Advances in precision oncology led to approval of tumour-agnostic molecularly guided treatment options (MGTOs). The minimum requirements for claiming tumour-agnostic potential remain elusive. Methods: The European Society for Medical Oncology (ESMO) Precision Medicine Working Group (PMWG) coordinated a project to optimise tumour-agnostic drug development. International experts examined and summarised the publicly available data used for regulatory assessment of the tumour-agnostic indications approved by the US Food and Drug Administration and/or the European Medicines Agency as of December 2023. Different scenarios of minimum objective response rate (ORR), number of tumour types investigated, and number of evaluable patients per tumour type were assessed for developing a screening tool for tumour-agnostic potential. This tool was tested using the tumour-agnostic indications approved during the first half of 2024. A taxonomy for MGTOs and a framework for tumour-agnostic drug development were conceptualised. Results: Each tumour-agnostic indication had data establishing objective response in at least one out of five patients (ORR ! 20%) in two-thirds (!4) of the investigated tumour types, with at least five evaluable patients in each tumour type. These minimum requirements were met by tested indications and may serve as a screening tool for tumour-agnostic potential, requiring further validation. We propose a conceptual taxonomy classifying MGTOs based on the therapeutic effect obtained by targeting a driver molecular aberration across tumours and its modulation by tumour-specific biology: tumour-agnostic, tumour-modulated, or tumour-restricted. Volume xxx-Issue xxx-2024 https://doi.org/10.1016/j.annonc.2024.07.730 1 informed mechanistic rationale, early regulatory advice, and adequate trial design demonstrating signs of biology-driven tumour-agnostic activity, followed by confirmatory evidence, should be the principles for tumour-agnostic drug development. Conclusion: The ESMO Tumour-Agnostic Classifier (ETAC) focuses on the interplay of targeted driver molecular aberration and tumour-specific biology modulating the therapeutic effect of MGTOs. We propose minimum requirements to screen for tumour-agnostic potential (ETAC-S) as part of tumour-agnostic drug development. Definition of ETAC cutoffs is warranted.