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

peer reviewedSquamous 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

Anti-Telomerase CD4+ Th1 Immunity and Monocytic-Myeloid-Derived-Suppressor Cells Are Associated with Long-Term Efficacy Achieved by Docetaxel, Cisplatin, and 5-Fluorouracil (DCF) in Advanced Anal Squamous Cell Carcinoma: Translational Study of Epitopes-HPV01 and 02 Trials

Docetaxel, cisplatin and 5-fluorouracil (DCF) chemotherapy regimen is highly effective in advanced anal squamous cell carcinoma (SCCA), as demonstrated by the Epitopes-HPV02 study results. Here, we analyzed the impact of DCF regimen and the prognostic value of adaptive immune responses and immunosuppressive cells in SCCA patients included in two prospective studies (Epitopes-HPV01 and HPV02). The presence of T-cell responses against Human papillomavirus (HPV)16-E6/E7 and anti-telomerase (hTERT)-antigens was measured by IFNᵧ-ELISpot. Here, we showed that HPV-adaptive immune responses are increased in SCCA patients. SCCA patients also displayed enhanced circulating TH1 T-cells restricted by hTERT. Exposition to DCF increased hTERT immunity but not HPV or common viruses immune responses. Notably, the correlation of hTERT immune responses with SCCA patients’ clinical outcomes highlights that hTERT is a relevant antigen in this HPV-related disease. The influence of peripheral immunosuppressive cells was investigated by flow cytometry. While both regulatory T-cells and monocytic-myeloid-derived suppressive cells (M-MDSC) accumulated in the peripheral blood of SCCA patients, only high levels of M-MDSC were negatively correlated with hTERT adaptive immune responses and predicted poor prognosis. Altogether, our results reveal that hTERT is a relevant antigen in HPV-driven SCCA disease and that M-MDSC levels influence TH1-adaptive immune responses and patients’ survival

FOLFIRINOX De-Escalationin Advanced Pancreatic Cancer: A MulticenterReal-LifeStudy

International audienceBackground - Our study describes the feasibility and efficacy of a first-line FOLFIRINOX (5-fluorouracil [5FU], folinic acid, irinotecan, and oxaliplatin) induction chemotherapy (CT) followed by de-escalation as a maintenance strategy for advanced pancreatic cancer. Materials and methods - This multicenter retrospective study was conducted from January 2011 to December 2018. FOLFIRINOX de-escalation was defined as stopping oxaliplatin and/or irinotecan after at least four cycles of FOLFIRINOX, without evidence of disease progression. Maintenance schedules were fluoropyrimidine monotherapy (intravenous or oral [capecitabine]), FOLFOX (5FU, oxaliplatin), or FOLFIRI (5FU, irinotecan). Primary endpoint was overall survival (OS). Secondary endpoints were first progression-free survival (PFS1), second progression-free survival (PFS2), and toxicity. Results - Among 321 patients treated with FOLFIRINOX, 147 (45.8%) were included. Median OS was 16.1 months (95% confidence interval [CI], 13.7-20.3) and median PFS1 was 9.4 months (95% CI, 8.5-10.4). The preferred maintenance regimen was FOLFIRI in 66 (45%) patients versus 5FU monotherapy in 52 (35%) and FOLFOX in 25 (17%) patients. Among 118 patients who received maintenance CT with FOLFIRI or 5FU, there was no difference in PFS1 (median, 9.0 vs. 10.1 months, respectively; p = .33) or OS (median, 16.6 vs. 18.7 months; p = .86) between the two maintenance regimens. Reintroduction of FOLFIRINOX was performed in 20.2% of patients, with a median PFS2 of 2.8 months (95% CI, 2.0-22.3). The rates of grade 3-4 toxicity were significantly higher with FOLFIRI maintenance CT than with 5FU (41% vs. 22%; p = .03), especially for neuropathy (73% vs. 9%). Conclusion - 5FU monotherapy maintenance appeared to be as effective as FOLFIRI, in a FOLFIRINOX de-escalation strategy, which is largely used in France. Implications for practice - FOLFIRINOX de-escalation and maintenance is a feasible strategy in advanced pancreatic cancer that decreases chemotherapy toxicity to improve both survival and quality of life. Survivals in patients with maintenance therapy are clinically meaningful. Fluoropyrimidine monotherapy maintenance seems to be as efficient as FOLFIRI and should be a reference arm in future pancreatic cancer maintenance trials

HPV16 Load Is a Potential Biomarker to Predict Risk of High-Grade Cervical Lesions in High-Risk HPV-Infected Women: A Large Longitudinal French Hospital-Based Cohort Study

High-risk HPV (hrHPV) testing has been implemented as a primary screening tool for cervical cancer in numerous countries. However, there is still a need for relevant triage strategies to manage hrHPV positive women to avoid excessive referral to colposcopy. The objective of this study was to assess, in women infected by hrHPV and presenting no or mild cytological abnormalities, HPV16 and HPV18 viral loads to predict the development of cervical high-grade lesion. Among 2102 women positive for hrHPV, 885 had no lesion or mild cytological abnormalities at baseline and had at least one follow-up (FU) visit. HPV16 and HPV18 prevalence was 25.9% and 8.4%, respectively. Of those women, 15% developed a high-grade lesion during the FU. An HPV16 viral load cut-off set at 3.2 log10GE/103 cells permitted to identify a subgroup of women at high risk of developing high-grade cervical lesion (HR = 2.67; 95% CI 1.80–3.97; p ≤ 0.0001). No specific HPV18 viral load threshold could have been defined in regard to the present study. In multivariate analysis, HPV16 load (absence/log10GE/103 cells < 3.2 vs. ≥3.2), RLU/PC 239 (1–100 pg/mL vs. >100 pg/mL) and cytology (normal vs abnormal) were independently associated with a significant increased risk of high-grade lesion development and were used to construct the prognostic score. In conclusion, HPV16 load is a relevant biomarker to identify women at high risk for developing cervical precancerous lesions

Prognostic value of CD4+ T lymphopenia in non-small cell lung Cancer

International audienceBackground: There is a paucity of data regarding the prognostic influence of peripheral blood CD4+ T lymphopenia in non-small cell lung cancer (NSCLC). Therefore, we investigated the prognostic value of T lymphopenia in NSCLC. Materials: Treatment-naive patients with a pathological diagnosis of NSCLC, at clinical stage I to IV were included in the prospective TELOCAP1 study. Lymphocytes count was evaluated in peripheral blood by flow cytometry. CD4+ and CD8+ T lymphopenia were defined as an absolute count of 500/ μL (median overall survival (OS) 16.1 versus 21.7 months, hazard ratio (HR): 1.616 [95% CI: 1.1-2.36], p = 0.012). This association with OS was especially marked in local/loco-regional NSCLC stages (median OS, 21.8 versus 72 months, respectively, HR: 1.88 [95% CI: 0.9-3.8], p = 0.035). Multivariate analysis confirmed the worse prognosis associated with CD4+ T lymphopenia in local/loco-regional NSCLC, but not in metastatic patients (HR 2.028 [95% CI = 1.065-3.817] p = 0.02). Restricted cubic spline analysis showed that patients with CD4+ T lymphocytes count ≤500/μL displayed a high risk of death regardless of NSCLC clinical stage. There was no obvious relationship between CD8+ T lymphopenia and clinical outcome. Conclusion: We identified CD4+ T lymphopenia as an independent prognostic factor in local/loco-regional stages of NSCLC and CD4+ T lymphopenia is also associated with a high risk of death, regardless of NSCLC clinical stage

RECIST and iRECIST criteria for the evaluation of nivolumab plus ipilimumab in patients with microsatellite instability-high/mismatch repair-deficient metastatic colorectal cancer: the GERCOR NIPICOL phase II study

International audienceBackground: Immune checkpoint inhibitors (ICIs) are highly effective in patients with microsatellite instability/mismatch repair-deficient (MSI/dMMR) metastatic colorectal cancer (mCRC). Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria may underestimate response to ICIs due to the pseudoprogression phenomenon. The GERCOR NIPICOL phase II study aimed to evaluate the frequency of pseudoprogressions in patients with MSI/dMMR mCRC treated with nivolumab and ipilimumab.Methods: Patients with MSI/dMMR mCRC previously treated with fluoropyrimidines, oxaliplatin, and irinotecan with/without targeted therapies received nivolumab 3 mg/kg plus ipilimumab 1 mg/kg every 3 weeks for four cycles then nivolumab 3 mg/kg every 2 weeks until progression or a maximum of 20 cycles. Computed tomography scan tumor assessments were done every 6 weeks for 24 weeks and then every 12 weeks. The primary endpoint was disease control rate at 12 weeks according to RECIST 1.1 and iRECIST by central review.Results: Of 57 patients included between December 2017 and November 2018, 48.0% received ≥3 prior lines of chemotherapy, 18.0% had BRAF V600E mutation, and 56.0% had Lynch syndrome-related cancer. Seven patients (12.0%) discontinued treatment due to adverse events; one died due to a treatment-related adverse event. The disease control rate (DCR) at 12 weeks was 86.0% with RECIST 1.1% and 87.7% with iRECIST. Two pseudoprogressions (3.5%) were observed, at week 6 and at week 36, representing 18% of patients with disease progression per RECIST 1.1 criteria. With a median follow-up of 18.4 months, median progression-free survival (PFS) and overall survival (OS) were not reached. The 12-month PFS rate was 72.9% with RECIST 1.1% and 76.5% with iRECIST. The 12-month OS rate was 84%. Overall response rate was 59.7% with both criteria. RAS/BRAF status, sidedness, Lynch syndrome, and other baseline parameters were not associated with PFS.Conclusion: Pseudoprogression is rare in patients with MSI/dMMR mCRC treated with nivolumab and ipilimumab. This combined ICI therapy confirms impressive DCR and survival outcomes in these patients

FOLFOXIRI vs FOLFIRINOX as first-line chemotherapy in patients with advanced pancreatic cancer: A population-based cohort study

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Is it safe to perform an anastomosis for rectal cancer after prostate cancer? A multicentre study of 126 patients from the GRECCAR group

International audienceAbstract Aim To determine the safety of performing an anastomosis after rectal cancer (RC) resection in patients with a previously treated prostate cancer (PC). Methods Patients with a previously treated PC who underwent rectal resection from 2008 to 2018 were retrospectively included. Outcomes were compared between patients who underwent rectal resection with anastomosis (restorative surgery, RS+ group) and those with a definitive stoma (RS− group). In the RS+ group, anastomotic leak (AL) rates were assessed according to the type of reconstruction. Results A total of 126 patients underwent rectal surgery for mid‐low RC after a previous PC treated by radiotherapy (RT) and/or radical prostatectomy. Overall, 80 patients (63%) underwent a RS and 46 patients (37%) underwent rectal surgery with a definitive stoma. There was no statistical difference between the two groups in terms of intraoperative data, except for the type of resection with more multivisceral resection in the RS‐ group ( p < 0.01). In the RS+group, a diverting stoma was performed in 74% of cases. No difference between the two groups in terms of overall morbidity was found. In the RS+group ( n = 80), 17 patients (21%) experienced AL. Of these, none was observed when delayed coloanal anastomosis was performed ( p = 0.16). Long‐term permanent stoma in the RS+ group was 16% ( n = 13). Conclusion Restorative surgery after resection for RC in patients with a previous history of RT and/or radical prostatectomy for PC is safe without additional morbidity. In selected patients for restorative surgery, performing delayed coloanal anastomosis may represent a promising option