FASTOCH: Feasibility of Electronic Patient-Reported Outcomes in Older Patients With Cancer-A Multicenter Prospective Study.

PURPOSE: Multiple studies have demonstrated that electronic patient-reported outcomes (ePROs) improve overall survival and quality of life in cancer care. However, there are no specific prospective data on remote ePRO monitoring in the older population, although they represent a significant proportion of patients with cancer. PATIENTS AND METHODS: From February 2021 to April 2022, patients age 75 years and older under active anticancer treatment were consecutively recruited in six institutions. Remote ePRO feasibility was determined in intention-to-test (ITT) on the basis of the number of active users in the overall population. Primary failure applied to patients who had no Internet access or declined to test ePROs, while the other patients were assigned to the ITT population. Feasibility was also determined per-protocol on the basis of the number of active patients in the ITT population. RESULTS: Of the 473 patients included, primary failure applied to 288 patients (233 of whom had no Internet access). Among the 185 patients in ITT, 122 used ePROs, leading to a 26% feasibility in ITT and a 66% feasibility per protocol. In a multivariate analysis, the intent to test population was from a higher socioprofessional category (P = .009) and felt in better general condition in the Geriatric 8-score evaluation (P = .002). Active patients significantly differed from the inactive on their self-assessment of a better general condition (P < .001) only. CONCLUSION: Our multicenter study showed a limited feasibility rate (26%) of remote ePROs monitoring for older patients with cancer, mainly because of technology barriers. Yet, among the patients who did have Internet access, most of them indeed used ePROs (66%). Given the expected benefit of ePROs, the technology barriers therefore need to be lifted to improve cancer care in older patients.

Pemigatinib for patients with previously treated, locally advanced or metastatic cholangiocarcinoma harboring FGFR2 fusions or rearrangements: A joint analysis of the French PEMI-BIL and Italian PEMI-REAL cohort studies.

BACKGROUND: Pemigatinib is approved for patients with pretreated, locally advanced or metastatic CCA harboring FGFR2 rearrangements or fusions. We aim to assess the effectiveness and safety of pemigatinib in real-world setting. MATERIAL AND METHODS: A joint analysis of two multicentre observational retrospective cohort studies independently conducted in France and Italy was performed. All consecutive FGFR2-positive patients affected by CCA and treated with pemigatinib as second- or further line of systemic treatment in clinical practice, within or outside the European Expanded Access Program, were included. RESULTS: Between July 2020 and September 2022, 72 patients were treated with pemigatinib in 14 Italian and 25 French Centres. Patients had a median age of 57 years, 76% were female, 81% had ECOG-PS 0-1, 99% had intrahepatic CCA, 74% had ≥ 2 metastatic sites, 67% had metastatic disease at diagnosis, while 38.8% received ≥ 2 previous lines of systemic treatment. At data cut-off analysis (April 2023), ORR and DCR were 45.8% and 84.7%, respectively. Median DoR was 7 months (IQR: 5.8-9.3). Over a median follow-up time of 19.5 months, median PFS and 1-year PFS rate were 8.7 months and 32.8%. Median OS and 1-year OS rate were 17.1 months and 60.6%. Fatigue (69.4%), ocular toxicity (68%), nail toxicities (61.1%), dermatologic toxicity (41.6%) hyperphosphataemia (55.6%), stomatitis (48.6%), and diarrhea (36.1%) were the most frequent, mainly G1-G2 AEs. Overall incidence of G3 AEs was 22.2%, while no patient experienced G4 AE. Dose reduction and temporary discontinuation were needed in 33.3% and 40.3% of cases, with 1 permanent discontinuation due to AEs. CONCLUSIONS: These results confirm the effectiveness and safety of pemigatinib in a real-world setting.

Case Report of Probable DRESS Syndrome Associated with Ribociclib.

Drug reaction with eosinophilia and systemic symptoms (DRESS) is a rare but known and potentially severe side effect of drugs. The recent development of cyclin-dependent kinase 4/6 (CDK4/6) inhibitors, such as ribociclib, has considerably improved the management of hormone receptor positive (HR+) and HER2 negative (HER2-) advanced breast cancer. Here, we present the case of an 83-year-old patient who developed a probable DRESS syndrome induced by ribociclib, presenting with fever, eosinophilia, rash, and hepatic cytolysis. The RegiSCAR score was 4. The symptomatology evolved favorably with topical and systemic corticosteroids, without any sequel. Another CDK4/6 inhibitor, palbociclib, was introduced later without any cross-toxicity and with an excellent therapeutic response for more than 3 years.

Cemiplimab for Locally Advanced and Metastatic Cutaneous Squamous-Cell Carcinomas: Real-Life Experience from the French CAREPI Study Group.

Although cemiplimab has been approved for locally advanced (la) and metastatic (m) cutaneous squamous-cell carcinomas (CSCCs), its real-life value has not yet been demonstrated. An early-access program enrolled patients with la/mCSCCs to receive cemiplimab. Endpoints were best overall response rate (BOR), progression-free survival (PFS), overall survival (OS), duration of response (DOR) and safety. The 245 patients (mean age 77 years, 73% male, 49% prior systemic treatment, 24% immunocompromised, 27% Eastern Cooperative Oncology Group performance status (PS) ≥ 2) had laCSCCs (35%) or mCSCCs (65%). For the 240 recipients of ≥1 infusion(s), the BOR was 50.4% (complete, 21%; partial, 29%). With median follow-up at 12.6 months, median PFS was 7.9 months, and median OS and DOR were not reached. One-year OS was 73% versus 36%, respectively, for patients with PS < 2 versus ≥ 2. Multivariate analysis retained PS ≥ 2 as being associated during the first 6 months with PFS and OS. Head-and-neck location was associated with longer PFS. Immune status had no impact. Severe treatment-related adverse events occurred in 9% of the patients, including one death from toxic epidermal necrolysis. Cemiplimab real-life safety and efficacy support its use for la/mCSCCs. Patients with PS ≥ 2 benefited less from cemiplimab, but it might represent an option for immunocompromised patients.

Predicting tumor response and outcome of second-look surgery with 18F-FDG PET/CT: insights from the GINECO CHIVA phase II trial of neoadjuvant chemotherapy plus nintedanib in stage IIIc-IV FIGO ovarian cancer.

BACKGROUND: This ancillary study aimed to evaluate 18F-FDG PET parameter changes after one cycle of treatment compared to baseline in patients receiving first-line neoadjuvant anti-angiogenic nintedanib combined to paclitaxel-carboplatin chemotherapy or chemotherapy plus placebo and to evaluate the ability of 18F-FDG PET parameters to predict progression-free survival (PFS), overall survival (OS), and success of second-look surgery. MATERIALS AND METHODS: Central review was performed by two readers blinded to the received treatment and to the patients' outcome, in consensus, by computing percentage change in PET metrics within a volume of interest encompassing the entire tumor burden. EORTC and PERCIST criteria were applied to classify patients as responders (partial metabolic response and complete metabolic response) or non-responders (stable metabolic disease and progressive metabolic disease). Also analyzed was the percentage change in metabolic active tumor volume (MATV) and total lesion glycolysis (TLG). RESULTS: Twenty-four patients were included in this ancillary study: 10 received chemotherapy + placebo and 14 chemotherapy + nintedanib. PERCIST and EORTC criteria showed similar discriminative power in predicting PSF and OS. Variation in MATV/TLG did not predict PFS or OS, and no optimal threshold could be found for MATV/TLG for predicting survival. Complete cytoreductive surgery (no residual disease versus residual disease < 0.25 cm/0.25-2.5 cm/> 2.5 cm) was more frequent in responders versus non-responders (P = 0.002 for PERCIST and P = 0.02 for EORTC criteria). No correlation was observed between the variation of PET data and the variation of CA-125 blood level between baseline sample and that performed contemporary to the interim PET, but a statistically significant correlation was observed between ΔSULpeak and ΔCA-125 between baseline sample and that performed after the second cycle. CONCLUSION: 18F-FDG PET using EORTC or PERCIST criteria appeared to be a useful tool in ovarian cancer trials to analyze early tumor response, and predict second-look surgery outcome and survival. An advantage of PERCIST is the correlation of ΔSULpeak and ΔCA-125, PET response preceding tumor markers response by 1 month. Neither MATV nor TLG was useful in predicting survival. TRIAL REGISTRATION: NCT01583322 ARCAGY/ GINECO GROUP GINECO-OV119, 24 April 2012.

Comparative analysis of predictive values of the kinetics of 11 circulating miRNAs and of CA125 in ovarian cancer during first line treatment (a GINECO study).

OBJECTIVE: MicroRNAs (miRNAs) are promising biomarkers in ovarian cancer. Their kinetics during treatment might be useful for monitoring disease burden, and guiding treatments in patients treated with peri-operative chemotherapy and interval debulking surgery (IDS). METHODS: Serial blood samples of patients enrolled in the randomized phase II CHIVA trial, comparing first line carboplatin-paclitaxel +/- nintedanib (NCT01583322) and IDS, were investigated to assess the kinetics of 11 relevant miRNAs. Their prognostic/predictive values regarding the likelihood of complete IDS, and the patient survival, were assessed and compared to those of CA125 kinetics. The selection of the miRNAs (miR-15b-5p, miR-16-5p, miR-20a-5p, miR-21-5p, miR-93-5p, miR-122-5p, miR-150-5p, miR-195-5p, miR-200b-3p, miR-148b-5p and miR-34a-5p) was based on the expression levels found with a large explorative panel, and on the literature data. RESULTS: 756 serial blood samples from 119 patients were analyzed for a total of 8172 miRNA assays, and 1299 CA125 values. The longitudinal kinetics of the miRNA expressions were highly inconsistent, and were not related to CA125 dynamics. The miRNA changes during neoadjuvant treatment were not found associated with RECIST tumor response or IDS outcomes. Decreases of miR-34a-5p and miR-93-5p were associated with PFS benefit (p = .009) and OS benefits (p < .001), respectively, using univariate tests. CONCLUSIONS: The longitudinal kinetics of miRNA expressions during neoadjuvant treatment in ovarian cancer patients were inconsistent, and were not found to be associated with tumor burden changes. Although some prognostic value could be discussed, no predictive value regarding tumor responses or IDS quality could be identified.

CA-125 ELIMination Rate Constant K (KELIM) Is a Marker of Chemosensitivity in Patients with Ovarian Cancer: Results from the Phase II CHIVA Trial.

PURPOSE: In patients with ovarian cancer receiving neoadjuvant chemotherapy, the first-line treatment success will depend on both the tumor-primary chemosensitivity and the completeness of interval debulking surgery (IDS). The modeled CA-125 ELIMination rate constant K (KELIM), calculated with the CA-125 longitudinal kinetics during the first 100 chemotherapy days, is a validated early marker of tumor chemosensitivity. The objective was to investigate the role of the chemosensitivity relative to the success of first-line medical-surgical treatment. EXPERIMENTAL DESIGN: The CA-125 concentrations were prospectively measured in the randomized phase II trial CHIVA (NCT01583322, carboplatin-paclitaxel regimen ± nintedanib, and IDS, n = 188 patients). The KELIM predictive value regarding the tumor response rate, likelihood of complete IDS, risk of subsequent platinum-resistant relapse (PtRR), progression-free survival (PFS), and overall survival (OS) was assessed using univariate and multivariate tests. RESULTS: The data from 134 patients were analyzed. KELIM was an independent and major predictor of subsequent PtRR risk, and of survivals. The final logistic regression model, including KELIM [OR = 0.13; 95% confidence interval (CI), 0.03-0.49] and complete IDS (no vs. yes, OR = 0.30; 95% CI, 0.11-0.76) highlights the preponderant role of chemosensitivity on the success of the first-line treatment. In patients with highly chemosensitive diseases, the patient prognosis was driven more by the chemotherapy-induced antitumor effects than by the surgery. CONCLUSIONS: The tumor-primary chemosensitivity, assessed by the modeled CA-125 KELIM calculated during neoadjuvant chemotherapy (http://www.biomarker-kinetics.org/CA-125-neo), may be a major parameter to consider for decision-making regarding IDS attempt, and selecting patients for treatments meant to reverse the primary chemoresistance.See related commentary by May and Oza, p. 4432.

Olaparib plus Bevacizumab as First-Line Maintenance in Ovarian Cancer.

BACKGROUND: Olaparib has shown significant clinical benefit as maintenance therapy in women with newly diagnosed advanced ovarian cancer with a BRCA mutation. The effect of combining maintenance olaparib and bevacizumab in patients regardless of BRCA mutation status is unknown. METHODS: We conducted a randomized, double-blind, international phase 3 trial. Eligible patients had newly diagnosed, advanced, high-grade ovarian cancer and were having a response after first-line platinum-taxane chemotherapy plus bevacizumab. Patients were eligible regardless of surgical outcome or BRCA mutation status. Patients were randomly assigned in a 2:1 ratio to receive olaparib tablets (300 mg twice daily) or placebo for up to 24 months; all the patients received bevacizumab at a dose of 15 mg per kilogram of body weight every 3 weeks for up to 15 months in total. The primary end point was the time from randomization until investigator-assessed disease progression or death. RESULTS: Of the 806 patients who underwent randomization, 537 were assigned to receive olaparib and 269 to receive placebo. After a median follow-up of 22.9 months, the median progression-free survival was 22.1 months with olaparib plus bevacizumab and 16.6 months with placebo plus bevacizumab (hazard ratio for disease progression or death, 0.59; 95% confidence interval [CI], 0.49 to 0.72; P<0.001). The hazard ratio (olaparib group vs. placebo group) for disease progression or death was 0.33 (95% CI, 0.25 to 0.45) in patients with tumors positive for homologous-recombination deficiency (HRD), including tumors that had BRCA mutations (median progression-free survival, 37.2 vs. 17.7 months), and 0.43 (95% CI, 0.28 to 0.66) in patients with HRD-positive tumors that did not have BRCA mutations (median progression-free survival, 28.1 vs. 16.6 months). Adverse events were consistent with the established safety profiles of olaparib and bevacizumab. CONCLUSIONS: In patients with advanced ovarian cancer receiving first-line standard therapy including bevacizumab, the addition of maintenance olaparib provided a significant progression-free survival benefit, which was substantial in patients with HRD-positive tumors, including those without a BRCA mutation. (Funded by ARCAGY Research and others; PAOLA-1 ClinicalTrials.gov number, NCT02477644.).

[Expectation about maintenance therapy among the GINECO French ovarian cancer cohort from the European NOGGO/ENGOT-ov22 Expression IV survey]. / Attentes des patientes suivies pour un cancer de l'ovaire concernant les traitements d'entretien : résultats de la cohorte française GINECO de l'enquête européenne NOGGO/ENGOT-ov22 (Expression IV).

BACKGROUND: Expression IV survey evaluated the patients' expectations to a maintenance therapy. METHODS: From January 2015 to March 2016, 401 French patients, in first line or recurrent disease, answered a 24-items anonymous questionnaire. The results were specifically analyzed according to the demographic characteristics and treatment lines. RESULTS: Among the patients, 62% had already been informed about maintenance therapy. Thirty-seven percent of patients received a maintenance treatment: 111 patients during first line and 39 patients in relapse. Expectations of patients were: 1) the chance of cure (73%), 2) the tumor shrinkage (36%), 3) quality of life improvement (35%) and 4) tumor growth reduction (27%). Among the responders, 42% were willing to take the treatment for 6-24 months, 20% for 24-60 months and 38% until tumor progression. 64% of patients expected more than a 6 months progression-free survival. Patients older than 70 years were less informed than their younger counterparts (48% vs 66%) and had lesser hope for cure with maintenance treatment (60% vs 77%). Patients in relapse had more expectation than patients in remission (tumor shrinkage: 47% vs 22%, slowing of tumor growth: 37% vs 15%, improving the progression-free survival of more than 6 months: 71% vs 53%, respectively). Among patients, 48% in relapse consented to take a treatment until progression vs 24% of patients in remission. CONCLUSION: This sub-analysis in French patients demonstrate a gap between the efficacy of maintenance therapy and the patients' expectations in ovarian cancer, particularly in relapsing disease justifying better information and explanations.

Cryopreserved arterial allografts for in situ reconstruction of abdominal aortic native or secondary graft infection.

OBJECTIVE: The objective of this study was to evaluate the early and long-term outcome of cryopreserved arterial allografts (CAAs) used for in situ reconstruction of abdominal aortic native or secondary graft infection and to identify predictors of mortality. METHODS: We retrospectively included 71 patients (mean age, 65.2 years [range, 41-84 years]; men, 91.5%) treated for abdominal aortic native or secondary graft infection (65 prosthetic graft infections; 16 of them had secondary aortoenteric fistula, 2 venous graft infections, and 4 mycotic aneurysms) by in situ reconstruction with CAA in the university hospitals of Clermont-Ferrand and Saint-Etienne from 2000 to 2016. The cryopreservation protocol was identical in both centers (-140°C). Early (<30 days) and late (>30 days) mortality and morbidity, reinfection, and CAA patency were assessed. Computed tomography was performed in all survivors. Survival was analyzed with the Kaplan-Meier method. Univariate analyses were performed with the log-rank test and multivariate analysis with the Cox regression model. RESULTS: Mean follow-up was 45 months (0-196 months). Early postoperative mortality rate was 16.9% (11/71). Early postoperative CAA-related mortality rate was 2.8% (2/71); both patients died of proximal anastomotic rupture on postoperative days 4 and 15. Early CAA-related reintervention rate was 5.6% (4/71); all had an anastomotic rupture, and two were lethal. Early postoperative reintervention rate was 15.5% (11/71). Intraoperative bacteriologic samples were positive in 56.3%, and 31% had a sole microorganism. Escherichia coli was more frequently identified in the secondary aortoenteric fistula and Staphylococcus epidermidis in the infected prosthesis. Late CAA-related mortality rate was 2.8%: septic shock at 2 months in one patient and proximal anastomosis rupture at 1 year in one patient. Survival at 1 year, 3 years, and 5 years was 75%, 64%, and 54%, respectively. Multivariate analysis identified type 1 diabetes (hazard ratio, 2.49; 95% confidence interval, 1.05-5.88; P = .04) and American Society of Anesthesiologists class 4 (hazard ratio, 2.65; 95% confidence interval, 1.07-6.53; P = .035) as predictors of mortality after in situ CAA reconstruction. Reinfection rate was 4% (3/71). Late CAA-related reintervention rate was 12.7% (9/71): proximal anastomotic rupture in one, CAA branch stenosis/thrombosis in five, ureteral-CAA branch fistula in one, and distal anastomosis false aneurysm in two. Primary patency at 1 year, 3 years, and 5 years was 100%, 93%, and 93%, respectively. Assisted primary patency at 1 year, 3 years, and 5 years was 100%, 96%, and 96%, respectively. No aneurysm or dilation was observed. CONCLUSIONS: The prognosis of native or secondary aortic graft infections is poor. Aortic in situ reconstruction with CAA offers acceptable early and late results. Patients with type 1 diabetes and American Society of Anesthesiologists class 4 are at higher risk of mortality.

Tim-3 Expression on Tumor-Infiltrating PD-1+CD8+ T Cells Correlates with Poor Clinical Outcome in Renal Cell Carcinoma.

Inhibitory receptors expressed by T cells mediate tolerance to tumor antigens, with coexpression of these receptors exacerbating this dysfunctional state. Using the VectraR automated multiparametric immunofluorescence technique, we quantified intratumoral CD8+ T cells coexpressing the inhibitory receptors PD-1 and Tim-3 from patients with renal cell carcinoma (RCC). A second validation cohort measured the same parameters by cytometry. The percentage of tumor-infiltrating CD8+ T cells coexpressing PD-1 and Tim-3 correlated with an aggressive phenotype and a larger tumor size at diagnosis. Coexpression of PD-1 and Tim-3 above the median conferred a higher risk of relapse and a poorer 36-month overall survival. Notably, other CD8+T-cell subsets did not exert a similar effect on overall survival. Moreover, only the PD-1+Tim-3+ subset of CD8+ T cells exhibited impaired function after stimulation. Our findings establish intratumoral Tim-3+PD1+CD8+ T cells as critical mediators of an aggressive phenotype in RCC. Use of the Vectra tool may be useful to identify similarly critical prognostic and predictive biomarkers in other tumor types and their response to immunotherapy. Cancer Res; 77(5); 1075-82. ©2016 AACR.

Prognostic Value of Baseline Neutrophil-to-Lymphocyte Ratio in Metastatic Urothelial Carcinoma Patients Treated With First-line Chemotherapy: A Large Multicenter Study.

BACKGROUND: A high neutrophil-to-lymphocyte ratio (NLR) is a marker of systemic inflammation and is associated with poor survival in localized or metastatic cancer. This study assessed the prognostic value of NLR after first-line chemotherapy (CT) in patients with metastatic urothelial carcinoma (mUC). PATIENTS AND METHODS: Two hundred eighty consecutive patients treated with first-line platinum-based CT at 4 centers in France and Turkey between 2002 and 2014 were included. The association of NLR and Memorial Sloan Kettering Cancer Center (MSKCC) scores with overall survival (OS) and progression-free survival (PFS) was determined by univariate Cox models. RESULTS: Median OS was 10.6 months (follow-up, 42.8 months). In univariate analysis, high NLR was associated with worse OS (hazard ratio [HR] for death = 1.36; 95% confidence interval [CI], 1.23-1.51; P < .0001); the result was similar after adjustment for MSKCC prognostic group (HR = 1.28; 95% CI, 1.14-1.43; P < .0001). Low NLR was associated with longer PFS (HR = 1.18; 95% CI, 1.05-1.33; P < .005). When NLR was divided in terciles, OS in the lowest tercile (NLR 0.6-2.78) was 12.4 to 16.6 (median, 13.4) months versus 5.3 to 9.9 (median, 7.3) months in the highest tercile (NLR 4.70-48.9) (P = .001). Similar trends were observed for PFS (5.6-8.9 [median, 7.6] months vs. 3.1-5.7 [median, 4.8] months) in patients with NLR values in the lowest versus highest tercile, respectively (P = .021). CONCLUSION: High pre-CT NLR was an independent prognostic factor for poor OS and PFS in mUC patients. The prognostic value of NLR, as either a continuous or categorical variable, compared favorably with MSKCC score but was easier to assess and monitor.

Base-Position Error Rate Analysis of Next-Generation Sequencing Applied to Circulating Tumor DNA in Non-Small Cell Lung Cancer: A Prospective Study.

BACKGROUND: Circulating tumor DNA (ctDNA) is an approved noninvasive biomarker to test for the presence of EGFR mutations at diagnosis or recurrence of lung cancer. However, studies evaluating ctDNA as a noninvasive "real-time" biomarker to provide prognostic and predictive information in treatment monitoring have given inconsistent results, mainly due to methodological differences. We have recently validated a next-generation sequencing (NGS) approach to detect ctDNA. Using this new approach, we evaluated the clinical usefulness of ctDNA monitoring in a prospective observational series of patients with non-small cell lung cancer (NSCLC). METHODS AND FINDINGS: We recruited 124 patients with newly diagnosed advanced NSCLC for ctDNA monitoring. The primary objective was to analyze the prognostic value of baseline ctDNA on overall survival. ctDNA was assessed by ultra-deep targeted NGS using our dedicated variant caller algorithm. Common mutations were validated by digital PCR. Out of the 109 patients with at least one follow-up marker mutation, plasma samples were contributive at baseline (n = 105), at first evaluation (n = 85), and at tumor progression (n = 66). We found that the presence of ctDNA at baseline was an independent marker of poor prognosis, with a median overall survival of 13.6 versus 21.5 mo (adjusted hazard ratio [HR] 1.82, 95% CI 1.01-3.55, p = 0.045) and a median progression-free survival of 4.9 versus 10.4 mo (adjusted HR 2.14, 95% CI 1.30-3.67, p = 0.002). It was also related to the presence of bone and liver metastasis. At first evaluation (E1) after treatment initiation, residual ctDNA was an early predictor of treatment benefit as judged by best radiological response and progression-free survival. Finally, negative ctDNA at E1 was associated with overall survival independently of Response Evaluation Criteria in Solid Tumors (RECIST) (HR 3.27, 95% CI 1.66-6.40, p < 0.001). Study population heterogeneity, over-representation of EGFR-mutated patients, and heterogeneous treatment types might limit the conclusions of this study, which require future validation in independent populations. CONCLUSIONS: In this study of patients with newly diagnosed NSCLC, we found that ctDNA detection using targeted NGS was associated with poor prognosis. The heterogeneity of lung cancer molecular alterations, particularly at time of progression, impairs the ability of individual gene testing to accurately detect ctDNA in unselected patients. Further investigations are needed to evaluate the clinical impact of earlier evaluation times at 1 or 2 wk. Supporting clinical decisions, such as early treatment switching based on ctDNA positivity at first evaluation, will require dedicated interventional studies.

Analysis of Base-Position Error Rate of Next-Generation Sequencing to Detect Tumor Mutations in Circulating DNA.

BACKGROUND: Detecting single-nucleotide variations and insertions/deletions in circulating tumor DNA is challenging because of their low allele frequency. The clinical use of circulating tumor DNA to characterize tumor genetic alterations requires new methods based on next-generation sequencing. METHODS: We developed a method based on quantification of error rate of each base position [position error rate (PER)]. To identify mutations, a binomial test was used to compare the minor-allele frequency to the measured PER at each base position. This process was validated in control samples and in 373 plasma samples from patients with lung or pancreatic cancer. RESULTS: Minimal mutated allele frequencies were 0.003 for single-nucleotide variations and 0.001 for insertions/deletions. Independent testing performed by droplet digital PCR (n = 231 plasma samples) showed strong agreement with the base-PER method (κ = 0.90). CONCLUSIONS: Targeted next-generation sequencing analyzed with the base-PER method represents a robust and low cost method to detect circulating tumor DNA in patients with cancer.

Sustained response to vemurafenib in a low grade serous ovarian cancer with a BRAF V600E mutation.

Low-grade serous ovarian adenocarcinomas (LGSOC) make up approximately 10 % of serous ovarian carcinomas. While rarely aggressive, this slow-growing tumor is well known to respond poorly to chemotherapy. Specific treatments for this ovarian subtype are lacking, with the same global approaches used for high grade cases being applied for LGSOC patients. LGSOCs have been reported to have a specific genetic profile, with notable implication of the MAPK pathway. This has opened up opportunities for novel therapeutic strategies, with in particular the use of targeted therapies. We report here the case of a heavily pretreated unresectable BRAF p.V600E-mutated LGSOC, which we treated vemurafenib, a BRAF inhibitor specific for V600E mutations. We saw impressive efficacy, with a long-term partial response along with CA125 reductions and symptom relief. Although this mutation is present in LGSOC at very a low incidence, we recommend routine testing for BRAF and other targetable mutations in this patient population, along with further evaluation in the increasingly popular basket trial approach.

Bleomycin-Induced Pneumonitis in the Treatment of Ovarian Sex Cord-Stromal Tumors: A Systematic Review and Meta-analysis.

OBJECTIVE: Adult ovarian sex cord-stromal tumors (SCSTs) are a rare histological subtype of ovarian cancer associated with a favorable prognosis. Bleomycin-containing regimens are standards of care, although pneumonitis may cause potentially fatal dose-limiting toxicity. We aimed to evaluate the safety of bleomycin in SCST treatment. METHODS: We performed a systematic literature review of all studies of bleomycin therapy for SCSTs that were referenced in MEDLINE (PubMed), EMBASE, and Cochrane Central Register of Controlled Trials and published from 1986 to 2014. RESULTS: Eight studies totaling 221 patients were included. Rates of pneumonitis (7.7%; 95% confidence interval, 4.2-11.2) and mortality (1.8%; 95% confidence interval, 0.1-3.6) related to bleomycin were significant. However, these results were very similar to those reported for men who were treated with bleomycin for a male germ cell tumor, suggesting that women with ovarian SCSTs are not particularly vulnerable to bleomycin lung toxicity. The main risk factors of bleomycin-induced pneumonitis are high cumulative bleomycin dose (>400 U or mg), age older than 40 years, and impaired renal function. Whether granulocyte colony-stimulating factor is a risk factor remains controversial. CONCLUSIONS: Bleomycin-induced pneumonitis frequently occurs in patients with SCSTs and lacks effective treatment. Prevention lies in limiting cumulative bleomycin dose, monitoring pulmonary function during treatment, discontinuing bleomycin at the onset of pulmonary symptoms or if pulmonary function is impaired, and avoiding bleomycin in older patients.

Trial Watch: Therapeutic vaccines in metastatic renal cell carcinoma.

Despite the renaissance of cancer immunotherapy, no novel immunotherapy has been approved for the treatment of renal cell cancer (RCC) since the availability of recombinant cytokines (interleukin-2, interferon-α). All vaccine trials have failed to meet their endpoints although they have highlighted potential predictive biomarkers (e.g., pre-existing immune response, hematological parameters, tumor burden). Recent advances in immunomodulatory therapies have prompted the study of combination treatments targeting the tumor immunosuppressive microenvironment consisting of regulatory T-cells (Treg), myeloid suppressor cells, and cytokines. Approaches under investigation are use of inhibitors to curb the overexpression of immune checkpoint ligands by tumor cells (e.g., anti-CTLA-4, anti-PD-1/PD-L1) and exploiting the immunomodulatory effects of anti-angiogenic agents that are the current standard of metastatic RCC care. Phase III trials are focusing on the possible synergy between therapeutic vaccines (e.g., IMA-901 and AGS-003) and anti-angiogenic agents.

[Olaparib in ovarian cancer with BRCA mutation]. / Olaparib dans les cancers de l'ovaire avec mutation BRCA.

With 4500 new cases and 3200 death each year, ovarian cancer is the first cause of mortality for gynecological cancer in France. Without any efficient screening, it is usually diagnosed around the age of 60 years at an advanced stage. The emergence of olaparib, a new targeted therapy, represents a major opportunity.

VEGF-A modulates expression of inhibitory checkpoints on CD8+ T cells in tumors.

Immune escape is a prerequisite for tumor development. To avoid the immune system, tumors develop different mechanisms, including T cell exhaustion, which is characterized by expression of immune inhibitory receptors, such as PD-1, CTLA-4, Tim-3, and a progressive loss of function. The recent development of therapies targeting PD-1 and CTLA-4 have raised great interest since they induced long-lasting objective responses in patients suffering from advanced metastatic tumors. However, the regulation of PD-1 expression, and thereby of exhaustion, is unclear. VEGF-A, a proangiogenic molecule produced by the tumors, plays a key role in the development of an immunosuppressive microenvironment. We report in the present work that VEGF-A produced in the tumor microenvironment enhances expression of PD-1 and other inhibitory checkpoints involved in CD8(+) T cell exhaustion, which could be reverted by anti-angiogenic agents targeting VEGF-A-VEGFR. In view of these results, association of anti-angiogenic molecules with immunomodulators of inhibitory checkpoints may be of particular interest in VEGF-A-producing tumors.