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.

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.

In patients with metastatic colorectal cancer (mCRC), RAS and BRAF mutations are currently determined by tumor sample analysis. Here, we report BRAF mutation status analysis in paired tumor tissue and plasma samples of mCRC patients included in the AGEO RASANC prospective cohort study. Four hundred and twenty-five patients were enrolled. Plasma samples were analyzed by next-generation sequencing (NGS). When no mutation was identified, we used two methylated specific biomarkers (digital droplet PCR) to determine the presence or absence of circulating tumor DNA (ctDNA). Patients with conclusive ctDNA results were defined as those with at least one mutation or one methylated biomarker. The kappa coefficient and accuracy were 0.79 (95% CI: 0.67–0.91) and 97.3% (95% CI: 95.2–98.6%) between the BRAF status in plasma and tissue for patients with available paired samples (n = 405), and 0.89 (95% CI: 0.80–0.99) and 98.5% (95% CI: 96.4–99.5%) for those with conclusive ctDNA (n = 323). The absence of liver metastasis was the main factor associated to inconclusive ctDNA results. In patients with liver metastasis, the kappa coefficient was 0.91 (95% CI, 0.81–1.00) and accuracy was 98.6% (95% CI, 96.5–99.6%). We demonstrate satisfying concordance between tissue and plasma BRAF mutation detection, especially in patients with liver metastasis, arguing for plasma ctDNA testing for routine BRAF mutation analysis in these patients.

Two main therapies, pazopanib and sunitinib, are used in the first-line setting for metastatic renal cell carcinoma (mRCC). These two tyrosine kinase inhibitors (TKI) are equally effective in terms of survival; however, they frequently induce adverse events. In this setting, Health-Related Quality of life (HRQoL) is a key element in the choice between these two treatments and the evaluation of treatment effectiveness. It could be of interest to evaluate HRQoL in daily clinical practice to aid adequate therapy choice and management. Currently, the development of information and communication technology may allow HRQoL monitoring in routine practice. The objective of the QUANARIE study is to evaluate the use of HRQoL assessment in daily clinical practice for patients with mRCC treated with TKI using electronic patient-reported outcomes (e-PRO). The present article describes the key elements of the study protocol. The QUANARIE study is an interventional, prospective, multicentre trial. Patients diagnosed with mRCC initiating sunitinib or pazopanib treatment will be invited to complete the EORTC QLQ-C30 questionnaire, nine additional questions from the EORTC items library, and the EuroQoL EQ-5D, prior to each visit with the physician. Questionnaires will be completed by patients using tablets and/or computer terminals via the e-PRO software. The physician will have real-time access to a visual summary of the HRQoL evaluation. The primary objective is to assess the proportion of patients having good compliance with Routine Electronic Monitoring of HRQoL (REMOQOL) during the first 12 months. Physicians’ satisfaction with REMOQOL will be assessed as a secondary objective. We hypothesise that 80% of patients having good compliance with REMOQOL would be meaningful. A sample size of 56 patients would be needed. The results of this study will show whether REMOQOL is feasible on a large scale and whether patients are receptive to this new practice. This study will also determine how real-time multidimensional evaluation of patient perception can help physicians in their daily practice and how they used it in conjunction with other clinical information to manage patient care. ClinicalTrials.gov; Identifier: NCT03062410 ; First Posted: February 23, 2017; Last Update Posted: August 9, 2017.

Sunitinib is a tyrosine kinase inhibitor approved in the first-line metastatic renal cell carcinoma (MRCC) setting at the dose of 50 mg daily for 4 weeks followed by a pause of 2 weeks. Due to toxicity, this standard schedule (50 mg daily 4/2) can induce up to 50% of sunitinib dose modification (reduction and/or interruption). The current recommendation in such case is to reduce the dose to 37.5 mg per day (standard schedule 4/2). Recent data highlight an alternative schedule: 2 weeks of treatment followed by 1 week of pause (experimental schedule 2/1). The SURF trial is set up to evaluate prospectively experimental schedule 2/1 when toxicity occurs. This article displays the key elements of the study protocol. SURF [NCT02689167] is a prospective, randomized, open-label phase IIb study. Patients are included at sunitinib initiation while receiving standard schedule 4/2 (50 mg daily) according to the marketing authorization indication. When a dose adjustment of sunitinib is required, patients are randomized between standard schedule 4/2 (37.5 mg daily) and experimental schedule 2/1 (50 mg daily). Key eligibility criteria are the following: patients with locally advanced inoperable or MRCC who are starting first-line treatment with sunitinib, with histologically or cytologically confirmed renal cancer clear cell variant or with a clear cell component, and with Karnofsky performance status ≥70%. The primary objective is to assess the median duration of sunitinib treatment (DOT) in each group. The key secondary objectives are progression-free survival, overall survival, time to randomization, objective response rate, safety, sunitinib dose intensity, health-related quality of life, and the description of main drivers triggering randomization. We hypothesized that experimental schedule 2/1 would result in an improvement in median DOT from 6 to 8.5 months. It was estimated that 112 patients would be needed in each arm during 24 months. In order to take into account the possibility of treatment discontinuation before randomization, 248 patients are necessary. The SURF trial is asking a pragmatic question adapted to the current practice on what is the best way to adapt sunitinib when treatment-related adverse events occur. The results of the SURF trial will bring high-value data to support the use of an alternative schedule in sunitinib treatment. ClinicalTrials.gov, NCT02689167 . Registered on 26 February 2016.

Objectives: This study aimed to fill the data gap regarding the prevalence of germline (g) BRCA1/2 mutations in patients with metastatic breast cancer (mBC) in France. Methods: A prospective gBRCA1/BRCA2 mutation analysis was proposed to all patients with mBC treated in seven French centers between 19 February and 30 November 2015. The BRCA TrueTM test (Pathway Genomics^®, San Diego, CA, USA) analyzed the coding and flanking regions of BRCA1 and BRCA2 genes using next-generation sequencing, Sanger sequencing, and multiplex ligation-dependent probe amplification. Results: Among 407 included mBC patients, 11 (2.7%) carried pathogenic gBRCA1/2 mutations. Of these, five (45%) would not have met standard criteria for genetic screening. Compared with non-carriers, gBRCA1/2 carriers were significantly younger at mBC diagnosis (47.5 vs. 60.7 years, p = 0.0006), had higher-grade tumor histology (p = 0.044), and had a higher rate of contralateral recurrence (36.4% vs. 11.6%, p = 0.035), with comparable adjusted survival (median overall survival 74.9 vs. 100.1 months, p = 0.97). Variants of uncertain significance were identified in 17 (4.2%) patients. Conclusions: The 2.7% prevalence of gBRCA1/2 mutations in this prospective French mBC cohort was relatively low. Nearly half of the mutation carriers would not have been routinely referred for oncogenetic counseling, underscoring the potential value of broader genetic screening in this population.