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Cancer-associated fibroblasts (CAFs) are orchestrators of the pancreatic ductal adenocarcinoma (PDAC) microenvironment. Previously we described four CAF subtypes with specific molecular and functional features. Here, we have refined our CAF subtype signatures using RNAseq and immunostaining with the goal of defining bioinformatically the phenotypic stromal and tumor epithelial states associated with CAF diversity. We used primary CAF cultures grown from patient PDAC tumors, human data sets (in-house and public, including single-cell analyses), genetically engineered mouse PDAC tissues, and patient-derived xenografts (PDX) grown in mice. We found that CAF subtype RNAseq signatures correlated with immunostaining. Tumors rich in periostin-positive CAFs were significantly associated with shorter overall survival of patients. Periostin-positive CAFs were characterized by high proliferation and protein synthesis rates and low α-smooth muscle actin expression and were found in peri-/pre-tumoral areas. They were associated with highly cellular tumors and with macrophage infiltrates. Podoplanin-positive CAFs were associated with immune-related signatures and recruitment of dendritic cells. Importantly, we showed that the combination of periostin-positive CAFs and podoplanin-positive CAFs was associated with specific tumor microenvironment features in terms of stromal abundance and immune cell infiltrates. Podoplanin-positive CAFs identified an inflammatory CAF (iCAF)-like subset, whereas periostin-positive CAFs were not correlated with the published myofibroblastic CAF (myCAF)/iCAF classification. Taken together, these results suggest that a periostin-positive CAF is an early, activated CAF, associated with aggressive tumors, whereas a podoplanin-positive CAF is associated with an immune-related phenotype. These two subpopulations cooperate to define specific tumor microenvironment and patient prognosis and are of putative interest for future therapeutic stratification of patients. © 2022 The Authors. The Journal of Pathology published by John WileySons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Resume Introduction L’Association d’enseignement et de recherche des internes en oncologie (AERIO) a mene une enquete nationale aupres des internes en « phase socle » de la promotion 2020 du diplome d’etudes specialisees d’oncologie. L’objectif etait de recueillir et decrire leurs motivations, ainsi que les objectifs et les obstacles de vie et de carriere de ces internes, lors de cette premiere annee de leur cursus. Methodes Un questionnaire comprenait 45 questions fermees reparties en six sections permettant de decrire : les caracteristiques demographiques de la population interrogee, l’engagement et les attentes cliniques et liees a la recherche des etudiants, leur formation, leurs objectifs de vie et de carriere, ainsi que leur engagement associatif. Resultats Soixante-dix-huit internes sur 119 ont participe (66 %), dont 68 (87 %) ayant complete le questionnaire dans son integralite. La population etait constituee en majorite de femmes (60 %) avec un âge median de 24 ans. Le choix entre oncologie option medicale ou option radiotherapie etait le plus souvent indetermine (87 %), 15 % des internes ont songe au droit au remord. Le temps de travail hospitalier moyen declare etait majoritairement situe entre 45 et 65 heures par semaine (83 %). Soixante-neuf pour cent souhaitaient s’investir dans la recherche clinique. Environ un interne sur deux (52 %) n’avait pas acces a la demi-journee de formation en autonomie. Conclusion Cette etude nationale a permis de decrire la perception des internes en phase socle d’oncologie vis a vis de leur formation, ainsi que leurs aspirations de carriere et leur rapport a la recherche.

Since its launch in 2006, Twitter has become a commonly used platform for sharing medical information, especially in the field of oncology. However, its role and impact on young oncologists’ education remain unclear. Moreover, COVID-19 and congress virtualization is likely to have modified Twitter use by the medical society. We conducted a national survey (27 questions) in France among medical oncology, hematology, and radiation therapy young doctors to help better understand the role played by Twitter on their medical education. One hundred eighty-three young oncologists participated in our survey. A majority does not use Twitter (72.1%), mostly to reduce their time spent on social media. Participants using Twitter (27.9%) often use it more than once a week, mostly by scrolling on their news feed. Interestingly, they rarely express their own opinion on Twitter: a majority of them (75.5%) tweet less than once a month while the rest of them mostly retweet others’ tweets. They mainly follow English-speaking experts, scientific societies, and medical journals. Pharmaceutical laboratories’ accounts are of less significance. Overall Twitter usage seems increasing since COVID-19 pandemic and the consequent digitalization of congresses. No statistical difference was observed between the baseline characteristics of Twitter users and non-users. This survey shows that Twitter is a relevant mean of continuous medical education used by around a third of French young oncologists, especially since COVID-19 pandemic and the virtualization of congresses. This media should be considered and evaluated for its educational advantages or potential biases. Supplementary Information The online version contains supplementary material available at 10.1007/s13187-021-02119-7.

Background The IMMUNOBIL PRODIGE 57 trial is a non-comparative randomized phase II study assessing the efficacy and safety of the durvalumab (an anti-PD-L1) and tremelimumab (an anti-CTLA4) combination with or without weekly paclitaxel in patients with advanced biliary tract carcinoma (BTC) after failure of platinum-based chemotherapy. Taxanes have already been safely combined with immune checkpoint inhibitors in other tumors. We report results of the 20-patient safety run-in. Methods Patients received durvalumab (1500 mg at day 1 [D1] of each cycle)/tremelimumab (75 mg at D1 for 4 cycles; Arm A) or durvalumab/tremelimumab with paclitaxel (80 mg/m2 at D1, D8, D15; Arm B) every 28 days. Results Twenty patients were enrolled (Arm A/B: 10/10). There were no dose-limiting toxicities (DLTs) in Arm A. Six DLTs were observed in five patients (50%) in Arm B, meeting a stopping rule for the trial inclusions. DLTs included three serious anaphylactic reactions (with one cardiac arrest), two enterocolitis, and one infectious pneumopathy with septic shock. There were no patients with history of personal or familial auto-immune disease. Conclusion The safety run-in part of IMMUNOBIL PRODIGE 57 raised concerns regarding co-administration of paclitaxel with durvalumab and tremelimumab in BTC, with an unexpected increase in anaphylactic adverse events. Phase II of the study will only evaluate the durvalumab and tremelimumab combination arm. ClinicalTrials registration NCT03704480 .

PURPOSE The COVID-19 pandemic has severely affected clinical practice in oncology, leading to organizational, ethical, and medical issues. In particular, it has raised challenges in the context of competing care priorities between COVID-19 and cancer treatment. Residents on the front line face difficulties related to increasing care needs and urgent reorganization of health care systems while managing psychological stress and uncertainty. We aimed to evaluate the impact of the COVID-19 pandemic on oncology residents. METHODS AND MATERIALS We conducted a national survey (39 questions) in France among oncology and radiation therapy residents to determine the psychological impact and professional difficulties (eg, reassignment, training/research time, supervision, teleworking, management of patients) associated with the first peak of the COVID-19 pandemic. RESULTS Overall, 222 residents (medical oncologists, 61%; radiation therapists, 39%) participated in our survey, representing approximately one third of all residents and fellows in France. One third of respondents had been reassigned to a COVID-19 ward. Training and research activity decreased for 89% and 41% of respondents, respectively. Two thirds (70%) of respondents declared that they had faced ethical issues, 35% felt worried about their own health, and 23% experienced psychological distress. According to the Hospital Anxiety and Depression Scale, 32% were anxious and 17% depressed. Consumption of tobacco, psychostimulants, and alcohol increased in 31%, 24%, and 29% of respondents, respectively. CONCLUSION French oncology residents were highly affected by the first peak of the COVID-19 pandemic in terms of professional activity and psychological impact. This national survey can be used as a basis for improved management, medical reorganization, and training of residents during the ongoing COVID-19 pandemic.

Patients enrolled in oncology phase 1 trials (ph1) usually have advanced heavily pre-treated cancers with few therapeutic options. Quality of life (QoL) is one of the key cancer-treatment outcome measures, especially in ph1, and sexuality is an important part of Qol but rarely explored. This prospective study aims to assess supportive care needs, QoL and sexuality in ph1.Between September 2020 and June 2021, we prospectively recruited patients enrolled in ph1 at Gustave Roussy in France. Supportive care needs, QoL (EORTC QLQ-C30) and sexuality (female sexual function index for women, male sexual health questionnaire [MSHQ] for men) were assessed at baseline, one, three and 5 months. We performed multivariate analyses to identify associations between clinical characteristics, QoL and quality of sexual life over time.At baseline, we analyzed 187 patients (45% women (n = 84) and 55% men (n = 103)). Patients expressed the need for consultations in pain management, nutrition, psychology and sexology in 28%, 26%, 19% and 9%, respectively. Lower global QoL was independently associated with Royal Marsden Hospital score (p = 0.012), urogenital location tumor (p = 0.021), elevated CRP levels (p = 0.014) and pain intensity (p = 0.005). Ninety-two percent of women had sexual dysfunction. In men, a lower MSHQ score was independently associated with urogenital location tumor (p = 0.021), ECOG Performance Status (p = 0.006), comorbidity at risk (p = 0.024) and pain intensity (p = 0.004).There are significant needs for supportive care in ph1, especially in some subgroups of patients. New models of care should be developed to improve early phase pathways.

Hepatocellular carcinoma (HCC) is the second deadliest cancer worldwide, due to its high incidence and poor prognosis. Frequent initial presentation at advanced stages along with impaired liver function limit the use of a broad therapeutic arsenal in patients with HCC. Although main HCC oncogenic drivers have been deciphered in recent years (TERT, TP53, CTNNB1 mutations, miR122 and CDKN2A silencing), therapeutic applications derived from this molecular knowledge are still limited. Given its high vascularization and immunogenicity, antiangiogenics and immune checkpoint inhibitors (ICI), respectively, are two therapeutic approaches that have shown efficacy in HCC. Depending on HCC immune profile, combinations of these therapies aim to modify the protumoral/antitumoral immune balance, and to reactivate and favor the intratumoral trafficking of cytotoxic T cells. Combination therapies involving antiangiogenics and ICI may be synergistic, because vascular endothelial growth factor A inhibition increases intratumoral infiltration and survival of cytotoxic T lymphocytes and decreases regulatory T lymphocyte recruitment, resulting in a more favorable immune microenvironment for ICI antitumoral activity. First results from clinical trials evaluating combinations of these therapies are encouraging with response rates never observed before in patients with HCC. A better understanding of the balance and interactions between protumoral and antitumoral immune cells will help to ensure the success of future therapeutic trials. Here, we present an overview of the current state of clinical development of antitumoral therapies in HCC and the biological rationale for their use. Moreover, translational studies on tumor tissue and blood, prior to and during treatment, will help to identify biomarkers and immune signatures with predictive value for both clinical outcome and response to combination therapies.

Per literature, patients with epidermal growth factor receptor (EGFR) exon-20 insertions respond poorly to tyrosine kinase inhibitors (TKIs). This study analyzed real-world data to examine the prognostic and predictive value of these mutations.We conducted a retrospective cohort study using Czech TULUNG Registry data, with data on multiple mutation types, collected in 2011-2020.We analyzed 554 (95.85%) patients with EGFR exon-19 deletions or exon-21 L858R substitutions and 24 (4.15%) patients with exon-20 insertions who received first-line high-value therapies. We summarized clinical characteristics and outcomes in all patients and by cohort. The risk of progression was statistically significantly higher (86%) in the exon-20 insertion cohort compared to the cohort with other mutations. Although not statistically significant, the risk of death was 44% higher in patients with exon-20 insertions.Advanced NSCLC patients with rare EGFR exon-20 insertions have a high risk of progression.

Next generation immunotherapies have limited efficacy in colorectal cancer. Immune checkpoints inhibitors demonstrated their benefit in mismatch repair-deficient tumors, which also exhibit microsatellite instability (MSI). The Consensual Molecular Subtype (CMS) classification has been recently proposed and highlights specific immune escape mechanisms for each subtype. CMS1 "immune" subtype is hypermutated with a favorable immune microenvironment for immune checkpoints inhibitors activity. Importantly, CMS1 is not restricted to MSI tumors and includes also exonucleasic domain POLE mutated tumors which are good candidates for immunotherapy. The scope of this comprehensive review is to described immune anomalies and propose immunomodulating strategies for each CMS subtype in colorectal cancer. Finally, the potential interest of tumor mutation burden and the Immunoscore® in colorectal cancer is discussed taking into account the molecular classification and obstacles to antitumoral immune activity.

4148 Background: OSE2101 is a multiple neoepitope vaccine restricted to HLA-A2 positive Pts. This study aimed to assess the efficacy and safety of OSE2101 ± anti-PD1 nivo as maintenance therapy in Pts with aPDAC after FOLFIRINOX induction chemotherapy. Methods: TEDOPaM-PRODIGE 63 was initially a 3-arm, open-label, randomized, non-comparative phase II study. Pts with aPDAC, HLA-A2 positive (blood) and no progression after 8 cycles of (modified) FOLFIRINOX were randomized 1:1:1 to receive FOLFIRI (standard Arm A), OSE2101 (subcutaneous injection on D1 Q3W x 6 doses then Q8W until M12 then Q12W up to M24, experimental Arm B) or OSE2101 + nivo (360 mg IV on D1 Q3W x 6 then 480 mg Q4W up to M24, experimental Arm C). FOLFIRI was reintroduced at disease progression in Arms B and C. Primary endpoint was overall survival (OS) rate at 12 months (M12) (Fleming two-stage design, H0: 25%; H1: 50%, one-sided alpha: 2.5%, power: 90%). 156 Pts were planned. Results: Following the occurrence of 2 tumor flares in Arm C, an Independent Data Monitoring Committee (IDMC) recommended to continue FOLFIRI as backbone in experimental Arm B and stop Arm C. Interim analysis results refer to 29 randomized Pts: 9/10/10 in Arm A/B/C, respectively. Median age was 63 years, 52% were men, 55% had ECOG PS 0, and 83% were metastatic. Best response to induction FOLFIRINOX was partial response in 48% and stable disease in 52%. With a median follow-up of 23 months, M12-OS rate was 44%, 40%, and 30% in Arm A, B and C. Other efficacy results are summarized in Table below. No OSE2101-related toxicity of grade ≥ 3 (G≥3) were observed in Arm B; 1 G3 cytokine-release syndrome (OSE2101-related) and 2 tumor flares (nivo-related) leading to death were observed in Arm C. Conclusions: Maintenance OSE2101 monotherapy showed a favorable safety profile and encouraging time to strategy failure warranting further evaluation. OSE2101 + nivo was associated with poorer outcomes leading to close Arm C. Following IDMC recommendation, the study is ongoing with the new design (maintenance FOLFIRI vs. FOLFIRI + OSE2101). Clinical trial information: NCT03806309. [Table: see text]

Simple Summary In oncology, a new era has emerged in the last ten years with the development of targeted and immune therapies. In hepatocellular carcinoma (HCC), several targeted agents (sorafenib, lenvatinib, cabozantinib, regorafenib, and ramucirumab) are approved and immunotherapy is now validated in combination with bevacizumab, while theragnostic biomarkers are lacking for patient selection. Conversely, in biliary tract cancer (BTC), immune therapies are still investigational while targeted therapies are now crucial considering the complex molecular landscape of BTC. In this review, we provide an overview of (i) the main prognostic biomarkers in HCC and BTC, (ii) the main theragnostic biomarkers in both tumors, and lastly (iii) what is recommended in clinical practice. Abstract Hepatocellular carcinoma (HCC) and biliary tract cancers (BTC) exhibit a poor prognosis with 5-year overall survival rates around 15%, all stages combined. Most of these primary liver malignancies are metastatic at diagnostic, with only limited therapeutic options, relying mainly on systemic therapies. Treatment modalities are different yet partially overlapping between HCC and BTC. The complex molecular profile of BTC yields to several actionable therapeutic targets, contrary to HCC that remains the field of antiangiogenic drugs in non-molecularly selected patients. Immunotherapy is now validated in the first line in HCC in combination with bevacizumab, while clinical activity of single agent immunotherapy appears limited to a subset of patients in BTC, still poorly characterized, and combinations are currently under investigation. In this review, we provide a critical evaluation and grading of clinical relevance on (i) the main prognostic biomarkers in HCC and BTC, (ii) the main theragnostic biomarkers in both tumors, and lastly (iii) what is recommended in clinical practice.

Changes in the oral microbiome, particularly Fusobacterium nucleatum, are associated with oral squamous cell carcinoma (OSCC). F. nucleatum has been reported to modulate local immunity in cancers. We aimed to assess the association between intratumoral F. nucleatum and clinico-pathological features, relapse, and overall survival (OS) in two independent cohorts of patients with OSCC, and to explore the interplay with immune-related genes. We retrospectively analyzed tissue samples from a first cohort of 122 patients with head and neck squamous cell carcinoma, including 61 OSCC (cohort #1), and a second cohort of 90 additional OSCC (cohort #2). We then performed a sensitivity analysis on the merged cohort of OSCC patients (N = 151). F. nucleatum 16S rRNA gene sequences were quantified using real-time quantitative PCR. The presence of gram-negative bacteria and macrophages was confirmed by LPS and CD163 immunostainings, respectively. F. nucleatum positivity was associated with older age, less alcohol and combined alcohol plus tobacco consumption, and less frequent lymph node invasion. There was a trend for a lower recurrence rate in F. nucleatum-positive cases, with less metastatic relapses compared to F. nucleatum-negative tumors, and significantly longer OS, relapse-free and metastasis-free survival. F. nucleatum status was independently associated with OS in multivariate analysis. Immune-related gene and immunohistochemistry analyses showed that gram-negative bacteria load inversely correlated with M2 macrophages. F. nucleatum-associated OSCC has a specific immune microenvironment, is more frequent in older, non-drinking patients, and associated with a favorable prognosis.

Simple Summary A new era has emerged in oncology in the last ten years with the development of immune therapies. However, single-agent immune therapy such as immune checkpoint inhibitors seems to have a limited clinical activity in biliary tract cancers and are still largely investigational, except for the few patients with microsatellite-instable tumors. Here, we review: (i) the molecular and immune landscape of biliary tract cancers, (ii) the existing results of immune therapies in biliary tract cancers, and (iii) the future of immune therapies in biliary tract cancers, with the identification of predictive biomarkers for response to these therapies, and the ongoing therapeutic trials. Abstract Biliary tract cancers are rare tumors with a poor prognosis. Two-thirds of these primary liver malignancies are diagnosed at advanced stages where therapeutic options are limited. Whereas several molecular targeted therapies emerge in biliary tract cancers, immunotherapy is still investigational, the only approved immunotherapy to date being the immune checkpoint inhibitor pembrolizumab for the small fraction of patients with microsatellite-instable tumors. In microsatellite-stable, pre-treated biliary tract cancers, single-agent immune checkpoint blockade has a limited albeit often long-lasting clinical activity in a still ill-defined subgroup of patients. The identification of predictive biomarkers will allow a better selection of patients that may benefit from immunotherapy. Combinations of immunotherapies with each other, with chemotherapy or targeted molecular therapies are being investigated in early lines of therapy, including first-line.

International audience; Background: Few patients with pancreatic adenocarcinoma (PAC) are eligible for surgery. Patients with early relapse have a poor prognosis and might be better candidates for a medical approach. Clinical and pathological parameters only partially predict recurrence and are only obtained after surgery. PAC subtypes based on gene expression were proposed, and we assessed if they could predict the risk and type of recurrence independently of clinicopathological parameters. Methods: Patients with curative-intent surgery for PAC without pretreatment were selected and divided into two independent cohorts defined as discovery (n = 381) and validation (n = 149) cohorts. Transcriptomic analyses were performed on formalin-fixed paraffin-embedded surgical samples to characterise tumour and stroma compartments using previously defined signatures. We associated molecular and clinicopathological characteristics with general, distant, and local recurrences using Cox regression analyses. Results: We found that tumour biology predicted distant recurrence contrary to local recurrence, which was directly related to resection margin status. Pure basal-like and stroma-activated subtypes were strongly associated with distant recurrence, independently of clinicopathological factors (hazard ratios [HRs] = 5.85, p < 0.001 and HR = 1.75, p = 0.007, respectively). By dissecting tumoural and stromal compartments, we demonstrated that the basal-like tumour component positively correlated with distant recurrence in both cohorts (HR = 1.45, p < 0.001 and HR = 1.90, p < 0.001), whereas the inactive structural stroma component was protective against distant recurrence (HR = 0.68, p < 0.001 and HR = 0.72, p < 0.001). Conclusions: In addition to suggesting a different mechanism for local and distant relapse (incomplete resection and high metastatic potential, respectively), our results show the potency of molecular phenotype to predict patient outcome regarding distant recurrences.

International audience; Herbs, food and dietary supplements (HFDS), can interact significantly with anticancer drug treatments via cytochrome p450 isoforms (CYP) CYP3A4, CYP2D6, CYP1A2, and CYP2C8. The objective of this review was to assess the influence of HFDS compounds on these cytochromes. Interactions with CYP activities were searched for 189 herbs and food products, 72 dietary supplements in Web of Knowledge® databases. Analyses were made from 140 of 3,125 clinical trials and 236 of 3,374 in vitro, animal model studies or case reports. 18 trials were found to report direct interactions between 9 HFDS with 8 anticancer drugs. 21 HFDS were found to interact with CYP3A4, a major metabolic pathway for many anticancer drugs. All 261 HFDS were classified for their interaction with the main cytochromes P450 involved in the metabolism of anticancer drugs. We provided an easy-to-use colour-coded table to easily match potential interactions between 261 HFDS and 117 anticancer drugs.

ObjectivesSarcopenia, present in more than 50% of digestive oncology patients, has a negative impact on clinical outcomes. Nutrition and adapted physical activity are two major interventions for the management of sarcopenia. However, young hepato-gastroenterologists, oncologists and surgeons in France have limited awareness on these topics. We aimed to evaluate the need for training programmes of physicians (residents and senior doctors) involved in digestive oncology on nutrition and adapted physical activity.MethodsA 42-question survey was developed, by a working group of clinicians, dieticians and adapted physical activity teachers, to assess five areas related to demographics of respondents, nutrition practices, nutrition training, adapted physical activity practices and adapted physical activity training. The national survey was undertaken between April and July of 2019.Results230 physicians participated in the survey; 34% were hepato-gastroenterologists, 31% were oncologists, 23% were surgeons and 40% were residents. Sixty-one per cent of participants had received training in nutrition and only 21% in adapted physical activity. Ninety per cent of the physicians expressed their desire for more effective training on these two topics. Disparities in clinical practices were observed between hepato-gastroenterologists, oncologists and surgeons.ConclusionsMore initial and continuing training on nutrition and adapted physical activity is needed for French physicians in the current digestive oncology clinical practice.

Background: Gemcitabine is a nucleoside analog, widely used either alone or in combination, for the treatment of multiple cancers. However, gemcitabine may also be associated with cardiovascular adverse-drug-reactions (CV-ADR). Methods: First, we searched for all cases of cardiotoxicity associated with gemcitabine, published in MEDLINE on 30 May 2019. Then, we used VigiBase, the World Health Organization&rsquo, s global database of individual case safety reports, to compare CV-ADR reporting associated with gemcitabine against the full database between inception and 01 April 2019. We used the information component (IC), an indicator value for disproportionate Bayesian reporting. A positive lower end of the 95% credibility interval for the IC (IC025) &ge, 0, is deemed significant. Results: In VigiBase, 46,898 reports were associated with gemcitabine on a total of 18,908,940 in the full database. Gemcitabine was associated with higher reporting for myocardial ischemia (MI, n: 119), pericardial diseases (n: 164), supraventricular arrhythmias (SVA, n: 308) and heart failure (HF, n: 484) versus full database with IC025 ranging between 0.40 and 2.81. CV-ADR were associated with cardiovascular death in up to 17% of cases. Conclusion: Treatment with gemcitabine is associated with potentially lethal CV-ADRs, including MI, pericardial diseases, SVA and HF. These events should be considered in patient care and clinical trial design.

International audience; Hepatocellular carcinoma (HCC) and biliary tract cancers (BTC) display a poor prognosis with 5-year overall survival rates around 15%, all stages taken together. These primary liver malignancies are often diagnosed at advanced stages where therapeutic options are limited. Recently, immune therapy has opened new opportunities in oncology. Based on their high programmed death-ligand 1 expression and tumor-infiltrating lymphocytes, HCC and BTC are theoretically good candidates for immune checkpoint blockade. However, clinical activity of single agent immunotherapy appears limited to a subset of patients, which is still ill-defined, and combinations are under investigation. In this review, we provide an overview of (i) the biological rationale for immunotherapies in HCC and BTC, (ii) the current state of their clinical development, and (iii) the predictive value of immune signatures for both clinical outcome and response to these therapies.

International audience; Metastatic pancreatic ductal adenocarcinomas (PDACs) are now more effectively controlled using chemotherapy combinations such as FOLFIRINOX and gemcitabine plus nab-paclitaxel (NabP) regimens with a subset of patients who achieve a sustained tumor stabilization or response. The next challenge is to design maintenance therapies that result in continued tumor control with minimal toxicity. Quality of life should always be a priority in these patients with prolonged survival. Gradually tapering off the intensity of chemotherapy by suppressing drug(s) in the combination is one option. Thus, maintenance with 5-fluorouracil or gemcitabine as single agents after FOLFIRINOX or gemcitabine-NabP induction, respectively, seems to be a promising approach to minimize neurotoxicity while maintaining efficacy. Another option is to introduce maintenance drug(s) with different anti-tumoral actions. The recent example of olaparib in patients with BRCA mutated PDAC provides a promising proof-of-concept of a switch maintenance strategy in this setting.

Simple Summary A growing number of studies suggest that cancer-associated fibroblasts (CAFs) modulate both myeloid and lymphoid cells through secretion of molecules (i.e., chemical function) and production of the extracellular matrix (ECM), i.e., physical function. Even though targeting functions CAFs is a relevant strategy, published clinical trials solely aimed at targeting the stroma showed disappointing results, despite being based on solid preclinical evidence. Our review dissects the interactions between CAFs and immune cells and explains how a deeper understanding of CAF subpopulations is the cornerstone to propose relevant therapies that will ultimately improve survival of patients with cancer. Abstract Cancer-associated fibroblasts (CAFs) are prominent cells within the tumor microenvironment, by communicating with other cells within the tumor and by secreting the extracellular matrix components. The discovery of the immunogenic role of CAFs has made their study particularly attractive due to the potential applications in the field of cancer immunotherapy. Indeed, CAFs are highly involved in tumor immune evasion by physically impeding the immune system and interacting with both myeloid and lymphoid cells. However, CAFs do not represent a single cell entity but are divided into several subtypes with different functions that may be antagonistic. Considering that CAFs are orchestrators of the tumor microenvironment and modulate immune cells, targeting their functions may be a promising strategy. In this review, we provide an overview of (i) the mechanisms involved in immune regulation by CAFs and (ii) the therapeutic applications of CAFs modulation to improve the antitumor immune response and the efficacy of immunotherapy.

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers, mostly due to its resistance to treatment. Of these, checkpoint inhibitors (CPI) are inefficient when used as monotherapy, except in the case of a rare subset of tumors harboring microsatellite instability (< 2%). This inefficacy mainly resides in the low immunogenicity and non-inflamed phenotype of PDAC. The abundant stroma generates a hypoxic microenvironment and drives the recruitment of immunosuppressive cells through cancer-associated-fibroblast activation and transforming growth factor β secretion. Several strategies have recently been developed to overcome this immunosuppressive microenvironment. Combination therapies involving CPI aim at increasing tumor immunogenicity and promoting the recruitment and activation of effector T cells. Ongoing studies are therefore exploring the association of CPI with vaccines, oncolytic viruses, MEK inhibitors, cytokine inhibitors, and hypoxia- and stroma-targeting agents. Adoptive T-cell transfer is also under investigation. Moreover, translational studies on tumor tissue and blood, prior to and during treatment may lead to the identification of biomarkers with predictive value for both clinical outcome and response to immunotherapy.

Resume Introduction La demographie des internes en oncologie a change depuis 2010 avec l’elargissement de l’effectif des promotions. L’evolution des aspirations des internes vis-a-vis de la recherche et de leur exercice futur en parallele de ces changements demographiques, n’a pas ete evaluee. Methodes Un questionnaire a ete elabore par le groupe jeune/translationnel Dig’IN du GERCOR (groupe cooperateur en oncologie), impliquant des cliniciens, des chercheurs, membres du GERCOR et des internes. Il comprenait 62 questions reparties en 7 sections : demographie, these de medecine, post-internat, mobilite, activite de recherche, recherche fondamentale et recherche clinique/translationnelle. L’enquete nationale a ete diffusee par l’Association d’enseignement et de recherche des internes en oncologie (AERIO). Resultats Au total, 143 internes ont participe, dont 116 (81,1 %) ayant complete le questionnaire dans son integralite. La population etait representative de la demographie actuelle avec une majorite de femmes (65,0 %) et un âge median de 28 ans. L’analyse non supervisee a revele quatre profils d’internes dont un profil tres interesse par la recherche, avec une volonte d’implication forte (16,8 %), un profil majoritaire avec volonte d’implication intermediaire (41,3 %) et un profil ne semblant pas du tout vouloir s’impliquer dans la recherche (14,7 %). L’incertitude quant a l’obtention d’un poste, le manque de temps et d’interactions avec les chercheurs apparaissaient comme les principales barrieres a l’implication dans la recherche. Conclusion Cette etude nationale a permis d’analyser plus finement le rapport des internes a la recherche academique. Elle pourra servir de base a la proposition de mesures adaptees a leurs attentes.

The demographics of oncology residents has changed since 2010 with the increase in the size of promotions. The evolution of the residents' aspirations towards research and their future exercise in parallel with these demographic changes has not been assessed.A questionnaire was developed by a working group from GERCOR (cooperative group in oncology), involving clinicians, researchers, GERCOR members, and residents. It consisted of 62 questions divided into 7 sections: demographics, medical thesis, post-residency, mobility, publication activity, basic research, and clinical/translational research. The national survey was published online by the Association d'enseignement et de recherche des internes en oncologie (AERIO).In total, 143 residents participated, of which 116 (81.1%) completed the questionnaire entirely. The population was representative of the current demographics, with a majority of women (65.0%), a median age of 28 years, and 39.7% of residents from Paris region. The unsupervised analysis revealed four profiles of residents, including one group strongly committed to research (16.8%), one group with moderate involvement (41.3%) and one group that did not seem interested in research (14.7%). Uncertainty about future position and lack of time and interaction with researchers appeared to be the main barriers to involvement of residents in research.This national survey provided useful information about the residents' perspective to academic research. It may serve as a basis for proposing measures adapted to their expectations.

International audience; Body composition has gained increasing attention in oncology in recent years due to fact that sarcopenia has been revealed to be a strong prognostic indicator for survival across multiple stages and cancer types and a predictive factor for toxicity and surgery complications. Accumulating evidence over the last decade has unraveled the "pharmacology" of sarcopenia. Lean body mass may be more relevant to define drug dosing than the "classical" body surface area or flat-fixed dosing in patients with cancer. Since sarcopenia has a major impact on patient survival and quality of life, therapeutic interventions aiming at reducing muscle loss have been developed and are being prospectively evaluated in randomized controlled trials. It is now acknowledged that this supportive care dimension of oncological management is essential to ensure the success of any anticancer treatment. The field of sarcopenia and body composition in cancer is developing quickly, with (i) the newly identified concept of sarcopenic obesity defined as a specific pathophysiological entity, (ii) unsolved issues regarding the best evaluation modalities and cutoff for definition of sarcopenia on imaging, (iii) first results from clinical trials evaluating physical activity, and (iv) emerging body-composition-tailored drug administration schemes. In this context, we propose a comprehensive review providing a panoramic approach of the clinical, pharmacological and therapeutic implications of sarcopenia and body composition in oncology.

Pancreatic ductal adenocarcinoma (PDAC) incidence and related-deaths are increasing worldwide. PDAC is characterized by poor prognosis due to late diagnosis, high metastatic capacity and resistance to therapy. This is partially due to its specific microenvironment, where the stroma is prominent over tumor cells. Besides the oral and gut microbiota, the intratumor microbiome, i.e. the bacterial and fungal microorganisms present within the tumor, was recently introduced as a new partner of the tumor microenvironment of PDAC modulating pancreatic carcinogenesis, intratumor immune infiltrates, and response to chemotherapy. In this review, we propose an overview of current knowledge about the roles of bacteria and fungi in PDAC development and biology, and discuss potential therapeutic implications.

Background: The COVID-19 pandemic deeply impacted clinical practices in oncology leading to organizational, ethical, and medical issues. It has raised challenges in a context of competing care priorities between COVID-19 and cancer treatment. Residents and fellows were in the front line and had to face difficulties related to increasing care needs and urgent reorganization of the health care system while managing stress and uncertainty. Methods: We conducted a national survey (39 questions) in France among all oncology and radiation therapy residents to describe psychological impact and difficulties encountered by residents (i.e., reassignment, training/research time, supervision, teleworking, management of patients) during the COVID-19 pandemic. Results: Overall, 222 residents (oncologists: 61% and radiation therapists: 39%) participated in our survey (representing around one third of all residents and fellows in France). Reassignment in COVID-19 wards involved 32% of respondents. Training and research activity were decreased for 89% and 41% of respondents, respectively. 70% have been confronted with ethical issues, 35% felt worried about their health, and 23% experienced psychological distress. According to the Hospital Anxiety and Depression Scale, 32% were anxious and 17% depressive. Consumption of tobacco, psychostimulants, and alcohol was increased in 45%, 40%, and 24%, respectively. Conclusion: French oncology residents were highly impacted by the COVID-19 pandemic in terms of training and emotions. This national survey can be used as a basis for improved management, medical reorganization, and training of residents during the COVID-19 pandemic, especially when further waves are not excluded. Citation Format: Marc Hilmi, Alice Boilève, Anabelle Ducousso, Morgan Michalet, Anthony Turpin, Cindy Neuzillet, Natacha Naoun. Professional and psychological impact of COVID-19 pandemic on medical and radiation oncology residents: Results of a national survey [abstract]. In: Proceedings of the AACR Virtual Meeting: COVID-19 and Cancer; 2020 Jul 20-22. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(18_Suppl):Abstract nr PO-033.

4106 Background: Recent studies suggest that ATB increase the overall risk of CRC incidence through disruption of gut microbiota. Impact of ATB on the risk of CRC recurrence after curative resection remains unknown. Methods: Using the French nation-wide Institut National du Cancer (INCa – Système National des Données de Santé) database of cancer patients, all newly diagnozed localized CRC patients resected between 01/2012 and 12/2014 were involved. The perioperative ATB intake (6 month before until 1 year after surgery) was classified according to the spectrum, doses and period of use. The primary endpoint was 3-year Disease-Free Survival (3-DFS), stratified on chemotherapy (chemo) administration (yes/no), and assessed using multivariate Cox models. Results: Out of 219,884 CRC patients, the present study included 36,640 patients: male 53%, age≥75 years 39%, left colon/rectal 59%, exposure to chemo 44%, at least one ATB intake 74%. At 3-years, 29% of patients had recurred and 18% had died. In multivariate analysis, in patients not receiving chemo, ATB intake as an out-patient was significantly associated with better 3-DFS [HR (one ATB only) = 0.88 (0.82-0.94)]. This effect remained in the same range whatever the number of ATB or cumulative exposure to ATB. In patients receiving chemo, ATB intake as an out-patient had a significant detrimental effect on 3-DFS [HR (one ATB only) = 1.15 (1.08-1.23)], increasing with the number of ATB [HR (≥5 ATB) = 1.54 (1.39-1.71)] and longer exposure [HR ( > 30 days) = 1.39 (1.31-1.48)]. Penicillin A, quinolones and ATB combinations were associated with worse 3-DFS. The timing of ATB intake related to chemo revealed that the strongest deleterious effect was observed when ATB were taken during chemo [HR = 1.64 (1.53-1.75)]. No difference in the mean number of chemo cycle was observed comparing patients receiving ATB or not. Conclusions: This nation-wide study is the first to suggest that ATB modulate 3-DFS in resected CRC with a differential impact according to chemo exposure. Importantly, ATB intake with chemo is detrimental in a dose- and time-dependent manner suggesting that dysbiosis of gut microbiota during adjuvant chemo might increase risk of recurrence.

Next generation immunotherapies have limited efficacy in colorectal cancer. Immune checkpoints inhibitors demonstrated their benefit in mismatch repair-deficient tumors, which also exhibit microsatellite instability (MSI). The Consensual Molecular Subtype (CMS) classification has been recently proposed and highlights specific immune escape mechanisms for each subtype. CMS1 "immune" subtype is hypermutated with a favorable immune microenvironment for immune checkpoints inhibitors activity. Importantly, CMS1 is not restricted to MSI tumors and includes also exonucleasic domain POLE mutated tumors which are good candidates for immunotherapy. The scope of this comprehensive review is to described immune anomalies and propose immunomodulating strategies for each CMS subtype in colorectal cancer. Finally, the potential interest of tumor mutation burden and the Immunoscore