Management of biliary tract cancers in early-onset patients: A nested multicenter retrospective study of the ACABI GERCOR PRONOBIL cohort.

BACKGROUND & AIMS: Accumulating data has shown the rising incidence and poor prognosis of early-onset gastrointestinal cancers, but few data exist on biliary tract cancers (BTC). We aimed to analyse the clinico-pathological, molecular, therapeutic characteristics and prognosis of patients with early onset BTC (EOBTC, age ≤50 years at diagnosis), versus olders. METHODS: We analysed patients diagnosed with intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, and gallbladder adenocarcinoma between 1 January 2003 and 30 June 2021. Baseline characteristics and treatment were described in each group and compared. Progression-free survival, overall survival and disease-free survival were estimated in each group using the Kaplan-Meier method. RESULTS: Overall, 1256 patients were included, 188 (15%) with EOBTC. Patients with EOBTC demonstrated fewer comorbidities (63.5% vs. 84.5%, p < .0001), higher tumour stage (cT3-4: 50.0% vs. 32.3%, p = .0162), bilobar liver involvement (47.8% vs. 32.1%, p = .0002), and metastatic disease (67.6% vs. 57.5%, p = .0097) compared to older. Patients with EOBTC received second-line therapy more frequently (89.5% vs. 81.0% non-EOBTC, p = .0224). For unresectable patients with BTC, median overall survival was 17.0 vs. 16.2 months (p = .0876), and median progression-free survival was 5.8 vs. 6.0 months (p = .8293), in EOBTC vs. older. In advanced stages, fewer actionable alterations were found in EOBTC (e.g., IDH1 mutations [7.8% vs. 16.6%]; FGFR2-fusion [11.7% vs. 8.9%]; p = .029). CONCLUSIONS: Patients with EOBTC have a more advanced disease at diagnosis, are treated more heavily at an advanced stage but show similar survival. A distinctive molecular profile enriched for FGRF2 fusions was found.

Gemcitabine and Paclitaxel Versus Gemcitabine Alone After 5-Fluorouracil, Oxaliplatin, and Irinotecan in Metastatic Pancreatic Adenocarcinoma: A Randomized Phase III PRODIGE 65-UCGI 36-GEMPAX UNICANCER Study.

PURPOSE: GEMPAX was an open-label, randomized phase III clinical trial designed to assess the efficacy and tolerability of gemcitabine plus paclitaxel versus gemcitabine alone as second-line treatment for patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) who previously received 5-fluorouracil, oxaliplatin, and irinotecan. METHODS: Patients with histologically or cytologically confirmed mPDAC were randomly assigned (2:1) to receive GEMPAX (paclitaxel 80 mg/m2 + gemcitabine 1,000 mg/m2; IV; once at day (D) 1, D8, and D15/arm A) or gemcitabine (arm B) alone once at D1, D8, and D15 every 28 days until progression, toxicity, or patient's decision. The primary end point was overall survival (OS). Secondary end points included progression-free survival (PFS), objective response rate (ORR), quality of life, and safety. RESULTS: Overall, 211 patients (median age, 64 [30-86] years; 62% male) were included. After a median study follow-up for alive patients of 13.4 versus 13.8 months in arm A versus arm B, the median OS (95% CI) was 6.4 (5.2 to 7.4) versus 5.9 months (4.6 to 6.9; hazard ratio [HR], 0.87 [0.63 to 1.20]; P = 0.4095), the median PFS was 3.1 (2.2 to 4.3) versus 2.0 months (1.9 to 2.3; HR, 0.64 [0.47 to 0.89]; P = 0.0067), and the ORR was 17.1% (11.3 to 24.4) versus 4.2% (0.9 to 11.9; P = 0.008) in arm A versus arm B, respectively. Overall, 16.7% of patients in arm A and 2.9% in arm B discontinued their treatment because of adverse events (AEs). One grade 5 AE associated with both gemcitabine and paclitaxel was reported in arm A (acute respiratory distress), and 58.0% versus 27.1% of patients experienced grade ≥3 treatment-related AEs in arm A versus arm B, among which 15.2% versus 4.3% had anemia, 15.9% versus 15.7% had neutropenia, 19.6% versus 4.3% had thrombocytopenia, 10.1% versus 2.9% had asthenia and 12.3% versus 0.0% had neuropathy. CONCLUSION: While GEMPAX did not meet the primary end point of OS versus gemcitabine alone in patients with mPDAC in the second-line setting, both PFS and ORR were significantly improved.

CD3-CD8 immune score associated with a clinical score stratifies PDAC prognosis regardless of adjuvant or neoadjuvant chemotherapy.

Stratification of the prognosis of pancreatic cancer (PDAC) patients treated by surgery is based solely on clinical variables, such as tumor stage and node status. The development of biomarkers of relapse is needed, especially to drive administration of adjuvant therapy in this at-risk population. Our study evaluates the prognostic performance of a CD3- and CD8-based immune score. CD3, CD8 and Foxp3 expression were evaluated on whole slides in two retrospective PDAC cohorts totaling 334 patients. For this study, we developed an immune score to estimate CD3 and CD8 infiltration in both tumor core and invasive margin using computer-guided analysis with QuPath software. Variables were combined in a dichotomous immune score. The association between immune and clinical scores, and both PFS and OS was investigated. We observed that a dichotomous immune score predicts both PFS and OS of localized PDAC. By univariate and multivariate analysis, immune score, tumor grade, adjuvant therapy, lymph node status, and adjuvant chemotherapy administration were associated with PFS and OS. We subsequently associated the PDAC immune score and clinical variables in a combined score. This combined score predicted patient outcomes independently of adjuvant or neoadjuvant treatment, and improved patient prognostic prediction compared to clinical variables or immune score alone.

Evaluation of the interest to combine a CD4 Th1-inducer cancer vaccine derived from telomerase and atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma: a randomized non-comparative phase II study (TERTIO - PRODIGE 82).

BACKGROUND: Several cancer immunotherapies that target the PD-L1/PD-1 pathway show promising clinical activity in patients with hepatocellular carcinoma (HCC). However, the standard of care in first-line treatment with atezolizumab (anti-PD-L1 therapy) in combination with bevacizumab is associated with a limited objective response rate. Telomerase reverse transcriptase (TERT) activation meets the criteria of oncogenic addiction in HCC and could be actionable therapeutic target and a relevant tumor antigen. Therefore we hypothesized that combining anti-PD-1/PD-L1 therapy with an anti-telomerase vaccine might be an attractive therapy in HCC. UCPVax is a therapeutic cancer vaccine composed of two separate peptides derived from telomerase (human TERT). UCPVax has been evaluated in a multicenter phase I/II study in non-small cell lung cancers and has demonstrated to be safe and immunogenic, and is under evaluation in combination with atezolizumab in a phase II clinical trial in tumors where telomerase reactivation contributes to an oncogene addiction (HPV+ cancers). The aim of the TERTIO study is to determine the clinical interest and immunological efficacy of a treatment combining the CD4 helper T-inducer cancer anti-telomerase vaccine (UCPVax) with atezolizumab and bevacizumab in unresectable HCC in a multicenter randomized phase II study. METHODS: Patients with locally advanced, metastatic or unresectable HCC who have not previously received systemic anti-cancer treatment are eligible. The primary end point is the objective response rate at 6 months. Patients will be allocated to a treatment arm with a randomization 2:1. In both arms, patients will receive atezolizumab at fixed dose of 1200 mg IV infusion and bevacizumab at fixed dose of 15 mg/kg IV infusion, every 3 weeks, according to the standard of care. In the experimental arm, these treatments will be combined with the UCPVax vaccine at 0.5 mg subcutaneously. DISCUSSION: Combining anti-PD-1/PD-L1 therapy with an anti-telomerase vaccine gains serious consideration in HCC, in order to extend the clinical efficacy of anti-PD-1/PD-L1. Indeed, anti-cancer vaccines can induce tumor-specific T cell expansion and activation and therefore restore the cancer-immunity cycle in patients lacking pre-existing anti-tumor responses. Thus, there is a strong rational to combine immune checkpoint blockade therapy and anticancer vaccine (UCPVax) in order to activate antitumor T cell immunity and bypass the immunosuppression in the tumor microenvironment in HCC. This pivotal proof of concept study will evaluate the efficacy and safety of the combination of a CD4 Th1-inducer cancer vaccine derived from telomerase (UCPVax) and atezolizumab plus bevacizumab in unresectable HCC, as well as confirming their synergic mechanism, and settling the basis for a new combination for future clinical trials. TRIAL REGISTRATION: NCT05528952.

DCF versus doublet chemotherapy as first-line treatment of advanced squamous anal cell carcinoma: a multicenter propensity score-matching study.

Triplet DCF (docetaxel, cisplatin and 5-flurouracil) and doublet CP/CF (carboplatin and paclitaxel/cisplatin and 5-fluorouracil) regimens were prospectively evaluated in advanced squamous anal cell carcinoma (SCCA), and validated as standard treatments. Even though the high efficacy and good tolerance of DCF regimen were confirmed in 3 independent prospective trials, doublet CP regimen is still recommended in several guidelines based in its better safety profile with similar efficacy compared to CF regimen. We performed a propensity score-adjusted method with inverse probability of treatment weighted (IPTW) and matched case control (MCC) comparison among patients with metastatic or non-resectable locally advanced recurrent SCCA, treated with chemotherapy as first line regimen. The primary endpoint was the overall survival (OS), and the secondary endpoint was the progression-free survival (PFS). 247 patients were included for analysis. 154 patients received DCF and 93 patients received a doublet regimen. The median OS was 32.3 months with DCF and 18.3 months with doublet regimens (HR 0.53, 95%CI 0.38-0.74; p = 0.0001), and the median PFS was 11.2 months with DCF versus 7.6 months with doublet regimens (HR 0.53, 95%CI 0.39-0.73; p < 0.0001). The hazard ratios by IPTW and MCC analyses were 0.411 (95% CI, 0.324-0.521; p < 0.0001) and 0.406 (95% CI, 0.261-0.632; p < 0.0001) for OS, and 0.466 (95% CI, 0.376-0.576; p < 0.0001) and 0.438 (95% CI, 0.298-0.644; P < 0.0001) for PFS. The triplet DCF regimen provides a high and significant benefit in OS and PFS over doublet regimens, and should be considered as upfront treatment for eligible patients with advanced SCCA.

SALL4-related gene signature defines a specific stromal subset of pancreatic ductal adenocarcinoma with poor prognostic features.

Pancreatic ductal adenocarcinoma (PDAC) is marked by molecular heterogeneity and poor prognosis. Among the stemness-related transcription factors, Spalt-like Transcription Factor 4 (SALL4) is correlated with unfavorable outcomes; however, its roles in PDAC remain unclear. SALL4high expression defines a PDAC subpopulation characterized by a shortened patient survival. Although SALL4 expression was mostly evaluated in tumor cells, our findings identify this embryonic transcription factor as a new biomarker in PDAC-derived stroma. Gene expression analysis reveals that the SALL4high PDAC subset is enriched in cancer stem cell properties and stromal enrichment pathways; notably, an interaction with cancer-associated fibroblasts (CAF) activated by TGF-ß. A particular oncogenic network was unraveled where Netrin-1 and TGF-ß1 collaborate to induce SALL4 expression in CAF and drive their cancer-stemness-promoting functions. A 7-gene stromal signature related to SALL4high PDAC samples was highlighted and validated by immunochemistry for prognosis and clinical application. This SALL4-related stroma discriminated pancreatic preinvasive from invasive lesions and was enriched in short-term survivors. Our results show that SALL4 transcriptional activity controls a molecular network defined by a specific stromal signature that characterizes PDAC invasiveness and worse clinical outcomes.

CD8+ CD226high T cells in liver metastases dictate the prognosis of colorectal cancer patients treated with chemotherapy and radical surgery.

CD226 has been reported to participate in the rescue of CD8+ T cell dysfunction. In this study, we aimed to assess the prognostic value of CD226 in tumor-infiltrating lymphocytes (TILs) derived from colorectal cancer (CRC) liver metastases treated with chemotherapy and radical surgery. TILs from 43 metastases were isolated and analyzed ex vivo using flow cytometry. CD155 and CD3 levels in the tumor microenvironment were assessed by immunohistochemistry. Exploration and validation of biological processes highlighted in this study were performed by bioinformatics analysis of bulk RNA-seq results for 28 CRC liver metastases pretreated with chemotherapy as well as public gene expression datasets. CD226 expression contributes to the definition of the immune context in CRC liver metastases and primary tumors. CD226 on CD8+ T cells was not specifically coexpressed with other immune checkpoints, such as PD1, TIGIT, and TIM3, in liver metastases. Multivariate Cox regression analysis revealed CD226 expression on CD8+ T cells to be an independent prognostic factor (p = 0.003), along with CD3 density at invasion margins (p = 0.003) and TIGIT expression on CD4+ T cells (p = 0.019). CD155 was not associated with the prognostic value of CD226. Gene expression analysis in a validation dataset confirmed the prognostic value of CD226 in CRC liver metastases but not in primary tumors. Downregulation of CD226 on CD8+ TILs in the liver microenvironment was restored by IL15 treatment. Overall, CD226 expression on liver metastasis-infiltrating CD8+ T cells selectively contributes to immune surveillance of CRC liver metastases and has prognostic value for patients undergoing radical surgery.

Modified DCF (Docetaxel, Cisplatin and 5-fluorouracil) chemotherapy is effective for the treatment of advanced rectal squamous cell carcinoma.

Background: Advanced rectal squamous cell carcinoma (rSCC) is a very rare and aggressive entity, and the best initial management is crucial for long survival as well as organ preservation and quality of life. Whereas local diseases are treated with chemo-radiotherapy and salvage surgery, data are scarce on how to treat more advanced diseases, and the role of induction chemotherapy is unknown. Methods: We retrospectively analyzed all consecutive patients with advanced rSCC and treated with modified DCF (docetaxel, cisplatin, 5-fluorouracil; mDCF) regimen, from January 2014 and December 2021 in two French centers. Exploratory endpoints were efficacy (overall survival, recurrence-free survival, response rate, organ preservation rate) and safety. Results: Nine patients with locally advanced or metastatic diseases received a mDCF regimen and were included for analysis. The median age was 62.0 years, 7 patients (77.8%) were women, and all eight available tumors were positive for HPV, mostly (85.7%) to genotype 16. With a median follow-up of 33.1 months, 77.8% of patients were still alive and disease-free, and the median overall survival was not reached at six years. The objective response rate was 87.5% after mDCF, and the complete response rate was 25.0% after mDCF and was increased to 75.0% after chemoradiotherapy. Only one patient underwent surgery on the primary tumor, with a complete pathological response. The median mDCF cycle was eight over eight scheduled, and all patients received the complete dose of radiotherapy without interruptions. Conclusions: Induction mDCF chemotherapy followed by chemoradiotherapy is safe and highly effective in patients with advanced rSCC, and should be considered as an option in metastatic stage or locally advanced disease with an organ-preservation strategy.

Chemokine switch regulated by TGF-ß1 in cancer-associated fibroblast subsets determines the efficacy of chemo-immunotherapy.

Combining immunogenic cell death-inducing chemotherapies and PD-1 blockade can generate remarkable tumor responses. It is now well established that TGF-ß1 signaling is a major component of treatment resistance and contributes to the cancer-related immunosuppressive microenvironment. However, whether TGF-ß1 remains an obstacle to immune checkpoint inhibitor efficacy when immunotherapy is combined with chemotherapy is still to be determined. Several syngeneic murine models were used to investigate the role of TGF-ß1 neutralization on the combinations of immunogenic chemotherapy (FOLFOX: 5-fluorouracil and oxaliplatin) and anti-PD-1. Cancer-associated fibroblasts (CAF) and immune cells were isolated from CT26 and PancOH7 tumor-bearing mice treated with FOLFOX, anti-PD-1 ± anti-TGF-ß1 for bulk and single cell RNA sequencing and characterization. We showed that TGF-ß1 neutralization promotes the therapeutic efficacy of FOLFOX and anti-PD-1 combination and induces the recruitment of antigen-specific CD8+ T cells into the tumor. TGF-ß1 neutralization is required in addition to chemo-immunotherapy to promote inflammatory CAF infiltration, a chemokine production switch in CAF leading to decreased CXCL14 and increased CXCL9/10 production and subsequent antigen-specific T cell recruitment. The immune-suppressive effect of TGF-ß1 involves an epigenetic mechanism with chromatin remodeling of CXCL9 and CXCL10 promoters within CAF DNA in a G9a and EZH2-dependent fashion. Our results strengthen the role of TGF-ß1 in the organization of a tumor microenvironment enriched in myofibroblasts where chromatin remodeling prevents CXCL9/10 production and limits the efficacy of chemo-immunotherapy.

Prognostic role of HPV integration status and molecular profile in advanced anal carcinoma: An ancillary study to the epitopes-HPV02 trial.

Squamous Cell Carcinoma of the Anal canal (SCCA) is a rare disease associated with a Human Papillomavirus (HPV) infection in most cases, predominantly the HPV16 genotype. About 15% of SCCA are diagnosed in metastatic stage and some will relapse after initial chemoradiotherapy (CRT). Treatment of patients by Docetaxel, Cisplatin and 5-fluorouracil (DCF) has been recently shown to improve their complete remission and progression-free survival. The aim of this retrospective study was to explore the impact of HPV infection, HPV DNA integration, TERT promoter mutational status and somatic mutations of oncogenes on both progression-free (PFS) and overall survivals (OS) of patients treated by DCF. Samples obtained from 49 patients included in the Epitopes-HPV02 clinical trial, diagnosed with metastatic or non-resectable local recurrent SCCA treated by DCF, were used for analyses. Median PFS and OS were not associated with HPV status. Patients with episomal HPV had an improved PFS compared with SCCA patients with integrated HPV genome (p=0.07). TERT promoter mutations were rarely observed and did not specifically distribute in a subset of SCCA and did not impact DCF efficacy. Among the 42 genes investigated, few gene alterations were observed, and were in majority amplifications (68.4%), but none were significantly correlated to PFS. As no biomarker is significantly associated with patients' survival, it prompts us to include every patient failing CRT or with metastatic disease in DCF strategy.

Long-Term Disease Control After locoregional Pelvic Chemoradiation in Patients with Advanced Anal Squamous Cell Carcinoma.

Introduction: The incidence of metastatic squamous cell carcinoma of the anus (SCCA) is increasing. Even if systemic docetaxel, cisplatin, and 5-Fluorouracil (DCF) provide a high rate of long-term remission, the role of pelvic chemoradiation (CRT) is unknown in this setting. We reported the safety and efficacy of local CRT in patients with synchronous metastatic SCCA who achieved objective response after upfront DCF. Methods: Patients included in Epitopes HPV01 or Epitopes HPV02 or SCARCE trials and treated with DCF followed by pelvic CRT were included. Concurrent chemotherapy was based on mitomycin (MMC) (10 mg/m² for two cycles) and fluoropyrimidine (capecitabine 825 mg/m² twice a day at each RT treatment day or two cycles of intra-venous 5FU 1000 mg/m² from day 1 to day 4). Primary endpoints were safety, local complete response rate, and local progression-free survival (PFS). Secondary endpoints were PFS, overall survival (OS), and metastasis-free survival (MFS). Results: From 2013 to 2018, 16 patients received DCF followed by a complementary pelvic CRT for advanced SCCA. Median follow-up was 42 months [range, 11-71]. All patients received the complete radiation dose. Compliance to concurrent CT was poor. Overall, 13/15 of the patients (87%) had at least one grade 1-2 acute toxicity and 11/15 of the patients (73%) had at least one grade 3-4 toxicity. There was no treatment-related death. The most frequent grade 3-4 adverse effects were neutropenia (36%), dermatitis (40%), and anitis (47%). Eleven patients (73%) had at least one chronic grade 1 or 2 toxicity. One patient had a grade 4 chronic rectitis (7%). Complete local response rate was 81% at first evaluation and 62.5% at the end of the follow-up. Median local PFS was not reached and the 3-year local PFS was 77% (95%CI 76.8-77). Conclusions: In patients with metastatic SCCA who had a significant objective response after upfront DCF, local CRT was feasible with high complete local response rate. The good local control rate, despite interruptions due to toxicities and low CT compliance, underline the role of pelvic RT. The high rate of toxicity prompts the need to adapt CRT regimen in the metastatic setting.

A Phase II Study Evaluating the Interest to Combine UCPVax, a Telomerase CD4 TH1-Inducer Cancer Vaccine, and Atezolizumab for the Treatment of HPV Positive Cancers: VolATIL Study.

Background: There is a strong rational of using anti-programmed cell death protein-1 and its ligand (anti-PD-1/L1) antibodies in human papillomavirus (HPV)-induced cancers. However, anti-PD-1/L1 as monotherapy induces a limited number of objective responses. The development of novel combinations in order to improve the clinical efficacy of an anti-PD-1/L1 is therefore of interest. Combining anti-PD-1/L1 therapy with an antitumor vaccine seems promising in HPV-positive (+) cancers. UCPVax is a therapeutic cancer vaccine composed of two separate peptides derived from telomerase (hTERT, human telomerase reverse transcriptase). UCPVax is being evaluated in a multicenter phase I/II study in NSCLC (non-small cell lung cancer) and has demonstrated to be safe and immunogenic. The aim of the VolATIL study is to evaluate the combination of atezolizumab (an anti-PD-L1) and UCPVax vaccine in a multicenter phase II study in patients with HPV+ cancers. Methods: Patients with HPV+ cancer (anal canal, head and neck, and cervical or vulvar), at locally advanced or metastatic stage, and refractory to at least one line of systemic chemotherapy are eligible. The primary end point is the objective response rate (ORR) at 4 months. Patients will receive atezolizumab every 3 weeks at a fixed dose of 1,200 mg in combination with the UCPVax vaccine at 1 mg subcutaneously. Discussion: Anti-cancer vaccines can restore cancer-immunity via the expansion and activation of tumor-specific T cells in patients lacking pre-existing anti-tumor responses. Moreover, preclinical data showed that specific TH1 CD4 T cells sustain the quality and homing of an antigen-specific CD8+ T-cell immunity. In previous clinical studies, the induction of anti-hTERT immunity was significantly correlated to survival in patients with advanced squamous anal cell carcinoma. Thus, there is a strong rational to combine an anti-cancer hTERT vaccine and an immune checkpoint inhibitor to activate and promote antitumor T-cell immunity. This pivotal proof of concept study will evaluate the efficacy and safety of the combination of a telomerase-based TH1 inducing vaccine (UCPVax) and an anti-PD-L1 (atezolizumab) immunotherapy in HPV+ cancers, as well as confirming their synergic mechanism, and settling the basis for a new combination for future clinical trials. Clinical Trial Registration: https://www.clinicaltrials.gov/, identifier NCT03946358.

Tissue-resident memory T cells in gastrointestinal cancer immunology and immunotherapy: ready for prime time?

Tissue-resident memory T (TRM) cells have emerged as immune sentinels that patrol the tissue microenvironment and orchestrate localized antitumor immunity in various solid cancers. Recent studies have revealed that TRM cells are key players in cancer immunosurveillance, and their involvement has been linked to favorable responses to immunotherapy as well as general better clinical outcome in cancer patients. In this review, we provide an overview of the major advances and recent findings regarding TRM cells phenotype, transcriptional and epigenetic regulation in cancer with a special focus on gastrointestinal tumors. Finally, we highlight the exciting clinical implication of TRM cells in these types of tumors.

Interest of the Addition of Taxanes to Standard Treatment in First-Line Advanced HER2 Positive Gastroesophageal Adenocarcinoma in Selective Patients.

Background: Studies have reported a beneficial role of the addition of trastuzumab to platin-5-FU based chemotherapy in first-line advanced HER2 positive gastroesophageal adenocarcinoma (GEA). However, the effect of taxanes combined with platin-5FU + trastuzumab (PFT) is understudied. Methods: We performed a retrospective cohort study to evaluate the interest of taxanes among HER2-positive advanced GEA patients treated with PFT. We enrolled HER2-positive advanced GEA patients who underwent treatment between January 2009 to March 2021 in seven hospitals centers in France, treated with PFT alone (S group) or with taxanes + PFT regimen (T group). The primary outcome was progression-free survival (PFS). Also, overall survival (OS), response rate, conversion surgery rate, and safety were evaluated. Results: Overall, 65 patients received PFT-based therapy, 24 patients in the T group, and 41 patients in the S group. To avoid the selection bias, only those patients presenting an ECOG-PS of 0-1 and synchronous metastasis (21 patients in the T group and 19 patients in the S group) were included for analysis. The median PFS was 9.3 months (95%CI 7.0 to 17.2) in the T group and 5.9 months (95%CI 3.7 to 9.6) in the S group (log-rank p=0.038). Treatment by taxanes was significantly associated with a better PFS in univariate (HR 0.49; 95%CI 0.25 to 0.98, p=0.042) and multivariate Cox regression analysis (HR 0.44; 95%CI 0.21 to 0.94, p=0.033), and IPTW method (HR 0.56; 95% CI 0.34 to 0.91, p=0.019). OS was prolonged (19.0 months (95%CI 7.8 to 45.2) vs 13.0 months (95%CI 5.5 to 14.8), log-rank p=0.033) in favor of the T group. Treatment by taxanes was significantly associated with a better OS in univariate Cox regression analysis (HR 0.49; 95%CI 0.21 to 0.96, p=0.038) and IPTW method (HR 0.49; 95% CI 0.29 to 0.84, p=0.009). The response rate was higher in the T group, with conversion surgery in five patients. No treatment-related death was observed in both groups. Conclusions: Given the improvement in PFS and OS, the addition of taxanes to standard chemotherapy could be considered as a promising treatment for selected HER2-positive advanced GEA patients, with PS 0-1 and synchronous metastasis (NCT04920747).

Second-line treatment after docetaxel, cisplatin and 5-fluorouracil in metastatic squamous cell carcinomas of the anus. Pooled analysis of prospective Epitopes-HPV01 and Epitopes-HPV02 studies.

BACKGROUND: Squamous cell carcinoma of the anus (SCCA) is a rare disease often diagnosed at a localised stage. For locally advanced recurrence or metastatic disease, DCF (docetaxel, cisplatin, 5-fluorouracil) demonstrated high efficacy and became one of the standard regimens. However, there is no standard of care in the second line. PATIENTS AND METHODS: In the Epitopes-HPV01 and Epitopes-HPV02 prospective trials, 115 patients with advanced SCCA were treated with a DCF regimen in the first line. In these studies, second-line data were registered per protocol. RESULTS: After a median follow-up of >40 months, at progression, 73 patients received a second-line (L2) treatment. In this L2 population, median overall survival (mOS) was 13.5 months (95%CI 9.4-19.8), and median progression-free survival (mPFS) was 5.7 months (3.4-7.3) in L2. Fourteen patients presented an oligometastatic progression and were treated with an ablative treatment (surgery or radiotherapy); mOS was 48.3 months (NE-NE), and mPFS was 31.3 months (23.2-NE). Fifty-nine patients received a systemic treatment (chemotherapy or immunotherapy); mOS was 11 months (8.4-15.4) and mPFS was 4.9 months (3.3-7). The most frequent chemotherapy regimens were the reintroduction of DCF, paclitaxel, FOLFIRI and mitomycin plus fluoropyrimidine. No significant difference was observed between regimens (p = 0.26). Six patients received anti-PD1/L1-based immunotherapy. CONCLUSION: Second-line treatments are effective in patients with SCCA. Ablative treatment is feasible and is probably the best option for patients with oligometastatic progression. If this is not possible, systemic therapy by an anti-PD1/L1 immunotherapy or chemotherapy can be recommended. Reintroduction of DCF, paclitaxel, FOLFIRI or mitomycin-C plus fluoropyrimidine are possible options.

Present and Future Research on Anal Squamous Cell Carcinoma.

Squamous cell carcinoma of the anus is an orphan disease, and after more than three decades of no substantial advances in disease knowledge and treatment, it is finally gaining momentum with the arrival of a taxane-based chemotherapy and immunotherapy. Currently, about 20 combination clinical trials with an anti-PD1/L1 are ongoing in localized and advanced stages, in association with radiotherapy, chemotherapy, tumor vaccines, anti-CTLA4, anti-EGFR, or antiangiogenic molecules. Moreover, a new biomarker with high sensitivity and specificity such as HPV circulating tumor DNA (HPV ctDNA) by liquid biopsy, is improving not only the prognostic measurement but also the treatment strategy guidance for this disease. Finally, better understanding of potential targets is reshaping the present and future clinical research in this unique, HPV genotype-16-related disease in the great majority of patients.

Additive Value of Preoperative Sarcopenia and Lymphopenia for Prognosis Prediction in Localized Pancreatic Ductal Adenocarcinoma.

BACKGROUND: Surgical resection with adjuvant chemotherapy is the only treatment that can provide long term survival in localized pancreatic ductal adenocarcinoma (LPDAC). Notwithstanding, recurrence occurs in the vast majority of patients and a better stratification of preoperative therapies is required. This study aimed to investigate preoperative immunological and nutritional factors to predict relapse-free survival (RFS) in patients with LPDAC. METHODS: Analyses were derived from all consecutive LPDAC patients treated with surgical resection at Besancon University Hospital, France, between January 2006 and December 2014 (n=146). Biological and nutritional parameters were recorded before and after surgery. The association of 24 baseline parameters with RFS was evaluated using univariate and multivariate Cox analyses. Based on the final model, a prognostic score was developed. RESULTS: Lymphocyte count and body composition were available for 94 patients. In multivariate analysis, preoperative lymphopenia and sarcopenia (or a low muscle mass) were identified as independent prognostic factors for RFS. The score determined three groups with a median RFS of 5.6 months (95% confidence interval [CI] = 4.3 to 9.6 months) for high-risk group, corresponding to patients with lymphopenia; 11.5 months (95%CI = 9.8 to 13.9 months), and 21.2 months (95%CI = 9.9 to 55.3 months), for intermediate-(patient with sarcopenia without lymphopenia), and low-risk groups (no risk factor), respectively (p <0.001). Preoperative sarcopenia predicts the occurrence of postoperative lymphopenia in patients with a preoperative lymphocyte count above 1,000/mm3 (p = 0.0029). CONCLUSIONS: Preoperative lymphopenia and sarcopenia are pejorative prognostic factors in LPDAC and should be considered in the preoperative evaluation to stratify death risk in patients with LPDAC.

Study of the SARS-CoV-2-specific immune T-cell responses in COVID-19-positive cancer patients.

BACKGROUND: Cancer patients are considered highly vulnerable to the COVID-19 pandemic. However, delaying cancer-specific therapies could have a deleterious effect on survival. The potential suppressive effects of chemotherapies or cancer-related microenvironment raised the question on how cancer patients' immune system responds to SARS-CoV-2 virus. METHODS: We have started a prospective monocentric trial entitled COV-CREM (NCT04365322) in April 2020. The primary objective of the trial was to assess specific immune response's intensity and diversity to SARS-CoV-2 in infected patients. RESULTS: In this study, we showed that cancer patients (28 solid tumours, 11 haematological malignancies) exposed to SARS-CoV-2 produced a high rate of specific antibodies, as observed in patients without a cancer history (n = 29). However, our results highlight a lack in the generation of T-cell responses against CoV-N, M and S proteins from the SARS-CoV-2 virus, suggesting that cancer patients failed to mount a protective T-cell immunity. Nevertheless, SARS-CoV-2 infection did not impair established immune memory since specific responses against common viruses were not hampered in cancer patients. CONCLUSION: Given the severity and the unknown evolution of the ongoing COVID-19 pandemic, it is of fundamental importance to integrate cancer patients in vaccination programs.

Role of FOLFIRINOX and chemoradiotherapy in locally advanced and borderline resectable pancreatic adenocarcinoma: update of the AGEO cohort.

BACKGROUND: FOLFIRINOX has shown promising results in locally advanced (LAPA) or borderline resectable (BRPA) pancreatic adenocarcinoma. We report here a cohort of patients treated with this regimen from the AGEO group. METHODS: This is a retrospective multicentre study. We included all consecutive patients with non-pre-treated LAPA or BRPA treated with FOLFIRINOX. RESULTS: We included 330 patients (57.9% male, 65.4% <65 years, 96.4% PS <2). Disease was classified as BRPA in 31.1% or LAPA in 68.9%. Objective response rate with FOLFIRINOX was 29.5% and stable disease 51%. Subsequent CRT was performed in 46.4% of patients and 23.9% had curative intent surgery. Resection rates were 42.1% for BRPA and 15.5% for LAPA. Main G3/4 toxicities were fatigue (15%), neutropenia (12%) and neuropathy (G2/3 35%). After a median follow-up of 26.7 months, median OS (mOS) and PFS were 21.4 and 12.4 months, respectively. For patients treated by FOLFIRINOX alone, or FOLFIRINOX followed by CRT, or FOLFIRINOX + /- CRT + surgery, mOS was 16.8 months, 21.8 months and not reached, respectively (p < 0.0001). CONCLUSIONS: FOLFIRINOX for LAPA and BRPA seems to be effective with a manageable toxicity profile. These promising results in "real-life" patients now have to be confirmed in a Phase 3 randomised trial.

Feasibility of health-related quality of life (HRQoL) assessment for cancer patients using electronic patient-reported outcome (ePRO) in daily clinical practice.

INTRODUCTION: Routine Electronic Monitoring of Health-Related Quality of Life (HRQoL) (REMOQOL) in clinical care with real-time feedback to physicians could help to enhance patient-centered care. We evaluated the feasibility of REMOQOL in the French context in the QOLIBRY study. The primary objective was to assess the patients' compliance with REMOQOL. METHODS: The QOLIBRY study was a single-center, prospective study conducted in the University Hospital of Besançon (France). Eligible patients were those treated with systemic therapies for breast, lung or colorectal cancer at any stage. Patients were invited to complete the EORTC QLQ-C30 questionnaire and cancer-site-specific modules before each visit on tablets and/or computers in the hospital or at home. During the consultation, physicians had real-time access to visual summaries of HRQoL scores. Compliance was assessed as adequate if at least 66% of HRQoL assessments were completed during the 4 months of follow-up. RESULTS: Between March 2016 and October 2018, 177 patients were included in the QOLIBRY study. Median age was 64 years (IQR 54-71). The proportion of patients with an adequate compliance rate was 95.5% (n = 63) in the breast cancer cohort, 98.2% (n = 55) in the colorectal cancer cohort, and 90.9% (n = 50) in the lung cancer cohort. The physicians checked the HRQoL results in 73.1% of visits and prescribed supportive care and adapted patient management in 8.3% and 5.2% of visits, respectively. CONCLUSION & PERSPECTIVES: The results of QOLIBRY study suggest that REMOQOL is feasible in the French context. However, information about HRQoL monitoring, training of the physicians in the use of the software, and recommendations for using HRQoL results to guide care are essential and must be improved.