Usefulness of circulating tumor DNA from cerebrospinal fluid in recurrent high-grade glioma.

Molecular documentation at relapse of high-grade glioma is an urgent need for patient care. A prospective pilot study was conducted to assess the rate of mutation detection using targeted deep sequencing on circulating tumor DNA from cerebrospinal fluid (CSF) after chemo-radiotherapy based treatment. Fifteen patients were included: 13 patients with glioblastoma, 1 patient with gliosarcoma and 1 patient with anaplastic astrocytoma. At progression, 10/15 patients (67%) had detectable mutations in the CSF. Among them, 5/10 patients harbored at least one common mutation between initial tumor and ctDNA. CSF protein level and cfDNA concentration were higher, although not significant, in the ctDNA positive group versus ctDNA negative group (1.17g/L vs. 0.79g/L). Molecular documentation obtained from ctDNA in CSF at the time of relapse is informative in around two-thirds of the patients.

Port catheter versus peripherally inserted central catheter for postoperative chemotherapy in early breast cancer: a retrospective analysis of 448 patients.

PURPOSE: We aimed to compare the complication rate between port catheters (PC) and peripherally inserted central catheters (PICC) for the administration of postoperative chemotherapy for breast cancer. METHODS: All patients treated from January 2010 to August 2012 at the Centre Henri Becquerel for early breast cancer requiring postoperative chemotherapy were retrospectively screened. The primary endpoint was the occurrence of a major complication related to the central venous catheter. Major complications were defined as any grade 3 event according to CTCAE 4.0, delay in chemotherapy >7 days, change of the device, life-threatening event, event requiring a hospitalization, or a prolongation of hospitalization. RESULTS: A total of 448 patients were included; 290 had a PC and 158 a PICC. Overall, 31 major complications related to the central venous catheter were observed: 13 for patients with a PC (4.5%) and 18 for patients with a PICC (11.4%). In univariate analysis, having a PICC was the only factor significantly associated with a higher risk of major complications (HR = 2.83, p = 0.0027). We observed a trend for a higher risk of major complications for patients older than 60 years or with BMI >25 (p = 0.06). In multivariate analysis, having a PICC was the only predictive factor of major complications (HR = 2.89, p = 0.004). CONCLUSIONS: In univariate and multivariate analysis, having a PICC instead of a PC was the only predictive factor of device-related major complication. If confirmed prospectively by the NCT02095743 ongoing trial, this result might modify the management of adjuvant chemotherapy administration.

Impact of EGFRA289T/V mutation on relapse pattern in glioblastoma.

BACKGROUND: Molecular factors influence relapse patterns in glioblastoma. The hotspot mutation located at position 289 of the extracellular domain of the epidermal growth factor receptor (EGFRA289mut) is associated with a more infiltrative phenotype. The primary objective of this study was to explore the impact of the EGFRA289 mutation on the pattern of relapse after chemoradiotherapy-based treatment of patients suffering from newly diagnosed glioblastoma. PATIENTS AND METHODS: An ancillary study from a prospective cohort of patients suffering from glioblastoma was conducted. All patients received radiotherapy and concomitant temozolomide. The population was divided into two groups according to EGFRA289 status (mutated versus wild-type). The primary endpoint was the overlap score (varying from 0 to 1) between the initial irradiated tumor volume (Vinit) and the relapse volume (Vr). Secondary endpoints explored the impact of EGFRA289mut on survival. RESULTS: One hundred twenty-eight patients were included and analyzed: 11% had EGFRA289mut glioblastoma (n = 14/128). EGFRA289mut glioblastomas had a relapse pattern that was more marginal than EGFRA289wt glioblastomas: a median overlap score Vinit/Vr of 0.96 was observed in the EGFRA289mut group versus 1 in the EGFRA289wt group (P = 0.05). Half of the population with EGFRA289mut tumor (n = 7/14) had a marginal relapse (i.e. overlap scoreVr/Vinit ≤ 0.95) compared to 23.7% (n = 27/114) in the EGFRA289wt group, P = 0.035. EGFRA289mut did not influence survival. CONCLUSION: We highlighted a link between the EGFRA289 mutation and the relapse pattern in glioblastoma. The independent role of EGFRA289mut and its clinical implication should now be explored in further studies.

Evolution of overall survival and receipt of new therapies by subtype among 20 446 metastatic breast cancer patients in the 2008-2017 ESME cohort.

BACKGROUND: Treatment strategies for metastatic breast cancer (MBC) have made great strides over the past 10 years. Real-world data allow us to evaluate the actual benefit of new treatments. ESME (Epidemio-Strategy-Medico-Economical)-MBC, a nationwide observational cohort (NCT03275311), gathers data of all consecutive MBC patients who initiated their treatment in 18 French Cancer Centres since 2008. PATIENTS AND METHODS: We evaluated overall survival (OS) in the whole cohort (N = 20 446) and among subtypes: hormone receptor positive, human epidermal growth factor 2 negative (HR+/HER2-; N = 13 590), HER2+ (N = 3919), and triple-negative breast cancer (TNBC; N = 2937). We performed multivariable analyses including year of MBC diagnosis as one of the covariates, to assess the potential OS improvement over time, and we described exposure to newly released drugs at any time during MBC history by year of diagnosis (YOD). RESULTS: The median follow-up of the whole cohort was 65.5 months (95% CI 64.6-66.7). Year of metastatic diagnosis appears as a strong independent prognostic factor for OS [Year 2016 HR 0.89 (95% CI 0.82-0.97); P = 0.009, using 2008 as reference]. This effect is driven by the HER2+ subcohort, where it is dramatic [Year 2016 HR 0.52 (95% CI 0.42-0.66); P < 0.001, using 2008 as reference]. YOD had, however, no sustained impact on OS among patients with TNBC [Year 2016 HR 0.93 (95% CI 0.77-1.11); P = 0.41, using 2008 as reference] nor among those with HR+/HER2- MBC [Year 2016 HR 1.02 (95% CI 0.91-1.13); P = 0.41, using 2008 as reference]. While exposure to newly released anti-HER2 therapies appeared very high (e.g. >70% of patients received pertuzumab from 2016 onwards), use of everolimus or eribulin was recorded in less than one-third of HR+/HER2- and TNBC cohorts, respectively, whatever YOD. CONCLUSION: OS has dramatically improved among HER2+ MBC patients, probably in association with the release of several major HER2-directed therapies, whose penetrance was high. This trend was not observed in the other subtypes, but the impact of CDK4/6 inhibitors cannot yet be assessed.

Safety of assisted reproductive techniques in young women harboring germline pathogenic variants in BRCA1/2 with a pregnancy after prior history of breast cancer.

BACKGROUND: Knowledge is growing on the safety of assisted reproductive techniques (ART) in cancer survivors. No data exist, however, for the specific population of breast cancer patients harboring germline BRCA1/2 pathogenic variants. PATIENTS AND METHODS: This is a multicenter retrospective cohort study across 30 centers worldwide including women diagnosed at ≤40 years with stage I-III breast cancer, between January 2000 and December 2012, harboring known germline BRCA1/2 pathogenic variants. Patients included in this analysis had a post-treatment pregnancy either achieved through use of ART (ART group) or naturally (non-ART group). ART procedures included ovulation induction, ovarian stimulation for in vitro fertilization or intracytoplasmic sperm injection, and embryo transfer under hormonal replacement therapy. RESULTS: Among the 1424 patients registered in the study, 168 were eligible for inclusion in the present analysis, of whom 22 were in the ART group and 146 in the non-ART group. Survivors in the ART group conceived at an older age compared with those in the non-ART group (median age: 39.7 versus 35.4 years, respectively). Women in the ART group experienced more delivery complications compared with those in the non-ART group (22.1% versus 4.1%, respectively). No other apparent differences in obstetrical outcomes were observed between cohorts. The median follow-up from pregnancy was 3.4 years (range: 0.8-8.6 years) in the ART group and 5.0 years (range: 0.8-17.6 years) in the non-ART group. Two patients (9.1%) in the ART group experienced a disease-free survival event (specifically, a locoregional recurrence) compared with 40 patients (27.4%) in the non-ART group. In the ART group, no patients deceased compared with 10 patients (6.9%) in the non-ART group. CONCLUSION: This study provides encouraging safety data on the use of ART in breast cancer survivors harboring germline pathogenic variants in BRCA1/2, when natural conception fails or when they opt for ART in order to carry out preimplantation genetic testing.

Radiation therapy on primary tumour of synchronous metastatic head and neck squamous cell carcinomas.

PURPOSE: Patients with synchronous metastatic head and neck squamous cell carcinomas often present associated locoregional symptoms and a risk of life-threatening primary tumour progression. Few data have been published about the use of radiation therapy in the management of newly diagnosed metastatic disease associated with advanced locoregional disease. In this article, we aim to determine the role of radiation therapy of the primary tumour in the overall therapeutic strategy for these diseases. We further address radiation therapy modalities (technique, volumes, and fractionation) in such a context. MATERIAL AND METHODS: We conducted a literature survey on locoregional radiotherapy for newly diagnosed metastatic head and neck squamous cell carcinomas. RESULTS: Several retrospective studies have reported that locoregional radiotherapy is associated with improved overall survival of patients with synchronous metastatic head and neck squamous cell carcinomas. However, data about modalities such as timing of radiotherapy in the overall strategy, dose, fractionation and delineation volumes are scarce. Two schematic situations can be distinguished with respect to prognosis and treatment adaptations: polymetastatic/bulky or oligometastatic disease. In polymetastic/bulky disease associated with poor prognosis, standard-of-care is systemic therapy, but locoregional radiotherapy can be discussed either upfront, mainly for symptomatic palliation, or as consolidation after downsizing obtained by systemic therapy. As for oligometastatic disease, with the rise in use of efficacious and well-tolerated local ablative treatments of metastases, aggressive curative-intent locoregional radiotherapy can be considered with or without systemic therapy. CONCLUSION: Because locoregional disease is a major cause of disease failure in patients with synchronous metastatic head and neck squamous cell carcinomas, aggressive locoregional radiation therapy to the primary tumour may be discussed in the initial management of the disease where systemic therapy alone may not induce sufficient primary tumour reduction. With recent technological advances in radiotherapy, the delivery of radiotherapy is safe and feasible even in metastatic setting. Clinical trials assessing radiotherapy use for metastatic head and neck squamous cell carcinomas are warranted.

Impact of locoregional irradiation in patients with upfront metastatic head and neck squamous cell carcinoma.

OBJECTIVE: To evaluate the frequency of use, modalities and potential interest of locoregional irradiation (LRT) in patients with upfront metastatic head and neck squamous cell carcinoma (HNSCC). METHODS: Retrospective multicentric study. Were included all patients presenting an upfront metastatic HNSCC treated by platin-5FU- cetuximab based regimen, from 2008 to 2016. Patients with past history of cervical irradiation or HNSCC within the 5 years before metastasis diagnosis were excluded. RESULTS: 65 patients were included. 25 patients (38%) presented a response or stable disease with chemotherapy. Forty-one patients (63%) underwent a locoregional irradiation: 5 patients before chemotherapy (upfront RT), 13 patients with stable disease or response after chemotherapy (consolidation RT), and 23 patients with progressive disease. Median overall survival (OS) was 11.6 months, median progression free survival was 7.9 months. OS was significantly improved for patients who underwent LRT (median OS 16.1 vs 7.5 months, p < 0.01). Among patients who received LRT, OS trended to be better if LRT was performed as consolidation RT compared to upfront RT (median OS of 22.1 vs 15.5 months, p = 0.11). Among patients with stable disease or response after chemotherapy, there was a non-significant better OS for the 13 patients treated by LRT (median OS 22.1 vs 11.8 months, p = 0.21)). Radical dose was not associated with better locoregional control compared to palliative dose (p = 0.37). CONCLUSION: LRT is frequently performed during management of upfront metastatic HNSCC and associated with better OS. Non-progressive disease after firs-line chemotherapy seems a good way to select patients who would benefit from radical LRT.

[Nutritional management of patients with head and neck cancer treated with radiation]. / Prise en charge nutritionnelle des patients atteints de cancer de la tête et du cou traité par irradiation.

Radiotherapy and chemotherapy are standard treatment of head and neck cancer alone or associated to surgical treatment. Early (during treatment or the following weeks) and late side effects contribute to malnutrition in this population at risk. In this context, nutritional support adapted by dietary monitoring and enteral nutrition (nasogastric tube or gastrostomy) are often necessary. The early identification of the patients with high malnutrition risk and requiring enteral nutrition is necessary to improve the tolerance and efficacy of treatment.

Modification of chromosomal architecture in human spermatozoa with large vacuoles.

Human normal spermatozoa present a specific chromatin organization, illustrated particularly by the non-random chromosome positioning. Spermatozoa with large vacuoles, described using motile sperm organelle morphology organization (MSOME), are associated with nuclear alterations, such as abnormal chromatin condensation and aneuploidy. To question a probable association between large nuclear vacuoles and chromatin disorganization, we evaluated chromosomes X, Y and 18 topography in normal spermatozoa (NS) compared with spermatozoa with large vacuoles (SLV). After centrifugation on a gradient density system, 229 NS (spermatozoa presenting a normal nuclear shape and a vacuole area <6.5% of head area) from 10 normal semen samples and 221 SLV (spermatozoa presenting a vacuole area >13% of head area) from 10 semen samples with teratozoospermia were selected using MSOME. A three-colour FISH was carried out using α-satellite centromeric probes for chromosomes X, Y and 18. For each chromosome, longitudinal and spatial positioning of centromeres was analysed. Distribution of each chromosome was non-random in NS and in SLV, whatever the methodology used. Using longitudinal positioning, distribution of chromosome 18 and chromosome Y centromeres did not differ significantly between SLV and NS. On the contrary, chromosome X centromeres were more frequently positioned in the posterior region of sperm nucleus in SLV (p = 0.01). Considering spatial positioning, distributions differed significantly between SN and SLV for chromosome Y (p = 0.02) and chromosome 18 (p < 10(-4) ) and marginally for chromosome X (p = 0.08). Our study concluded to a modification in chromosomes X, Y and 18 centromere topography between NS and SLV, representing a novel and supplementary evidence to argue chromatin disorganization in SLV.

[Assessing the contribution of a standardized method in defining the tumor bed using surgical clips in breast cancer]. / Évaluation de l'apport d'une méthode standardisée dans la définition du lit tumoral à l'aide de clips chirurgicaux dans le cancer du sein.

PURPOSE OF THE STUDY: The objective of this study was to compare prospectively the delineations of tumour bed after breast conserving surgery from two techniques for defining the target volume. PATIENTS AND METHODS: Sixteen patients treated by lumpectomy with development of surgical clips were included. For each patient, four radiation oncologists delineated the clinical target volume (CTV boost) following its own method (technique 1) or using a predefined methodology (technique 2), the diameter to be applied around each clip relative to the risk of local recurrence. Factors taken into account to adjust the volume were tumour size, age, surgical margins and the presence of extensive ductal carcinoma. We then analyzed the factors varying the volume and variation of delineation for each method by calculating the concordance index: Kappa index and overlap. RESULTS: For all 16 patients, the volume delineated was nearly identical: 29.65 cm(3) with technique 1 and 33.54 cm(3) with technique 2 (P=0.6). The correlation was higher with technique 2 over technique 1, with KI from 0.146 to 0.285 (P=0.0001) and an OV of 0.302 to 0.458 (P=0.0002). CONCLUSION: Our study shows that within the same institute, there is a great variability in CTV delineation boost, even in the presence of surgical clips. A standardized approach to adjusting the volume of relapse risk factors has improved the consistency.

[Pneumocystis pneumonia in two breast cancer patients treated with docetaxel: an unusual adverse event of chemotherapy]. / Deux observations de pneumocystose chez des patientes traitées par docétaxel pour un cancer du sein : une complication inhabituelle de la chimiothérapie.

We report two cases of pneumocystis pneumonia in patients receiving chemotherapy for breast cancer. These case series emphasize the frailty of the patients as the causative role for occurrence of this uncommon complication of chemotherapy in breast cancer. We remind the importance of screening for unusual adverse events in frail patients receiving chemotherapy.