Early Locoregional Breast Surgery and Survival in de novo Metastatic Breast Cancer in the Multicenter National ESME Cohort.

OBJECTIVE: The aim was to evaluate the impact of local surgery performed during the year after MBC diagnosis on patients' outcomes from a large reallife cohort. SUMMARY BACKGROUND DATA: Locoregional treatment for patients with MBC at the time of diagnosis remains debated. METHODS: Women with newly diagnosed, de novo stage IV MBC and who started MBC treatment between January 2008 and December 2014 in one of the 18 French Comprehensive Cancer Centers were included (NCT03275311). The impact of local surgery performed during the first year on overall survival (OS) and progression-free survival (PFS) was evaluated by the Cox proportional hazards model in a 12 month-landmark analysis. RESULTS: Out of 16,703 patients in the ESME database, 1977 had stage IV MBC at diagnosis, were alive and progression-free at 12 months and eligible for this study. Among them, 530 (26.8%) had received primary breast cancer surgery within 12 months. A greater proportion of patients who received surgery had less than 3 metastatic sites than the no-surgery group (90.8% vs 78.2%, P < 0.0001). Surgery within 12 months was associated with treatment with chemotherapy, HER2-targeted therapy (89.1% vs 69.6%, P < 0.0001) and locoregional radiotherapy (81.7% vs 32.5%, P < 0.0001). Multivariable analyses showed that surgery performed within 12 months was associated with longer OS and PFS (adjusted HR [95%CI] = 0.75 [0.61-0.92] and 0.72 [0.63-0.83], respectively), which were also affected by pattern and number of metastatic sites, histological subtype, and age. CONCLUSIONS: In the large ESME cohort, surgery within 1 year after de novo MBC diagnosis was associated with a significantly better OS and PFS.

A NGS-based Blood Test For the Diagnosis of Invasive HPV-associated Carcinomas with Extensive Viral Genomic Characterization.

PURPOSE: Use of circulating tumor DNA (ctDNA) for diagnosis is limited regarding the low number of target molecules in early-stage tumors. Human papillomavirus (HPV)-associated carcinomas represent a privileged model using circulating viral DNA (ctHPV DNA) as a tumor marker. However, the plurality of HPV genotypes represents a challenge. The next-generation sequencing (NGS)-based CaptHPV approach is able to characterize any HPV DNA sequence. To assess the ability of this method to establish the diagnosis of HPV-associated cancer via a blood sample, we analyzed ctHPV DNA in HPV-positive or HPV-negative carcinomas. EXPERIMENTAL DESIGN: Patients (135) from France and Senegal with carcinoma developed in the uterine cervix (74), oropharynx (25), oral cavity (19), anus (12), and vulva (5) were prospectively registered. Matched tumor tissue and blood samples (10 mL) were taken before treatment and independently analyzed using the CaptHPV method. RESULTS: HPV prevalence in tumors was 60.0% (81/135; 15 different genotypes). Viral analysis of plasmas compared with tumors was available for 134 patients. In the group of 80 patients with HPV-positive tumors, 77 were also positive in plasma (sensitivity 95.0%); in the group of 54 patients with HPV-negative tumors, one was positive in plasma (specificity 98.1%). In most cases, the complete HPV pattern observed in tumors could be established from the analysis of ctHPV DNA. CONCLUSIONS: In patients with carcinoma associated with any HPV genotype, a complete viral genome characterization can be obtained via the analysis of a standard blood sample. This should favor the development of noninvasive diagnostic tests providing the identification of personalized tumor markers. See related commentary by Rostami et al., p. 5158.

Quality of life, anxiety, and postoperative complications of patients undergoing breast cancer surgery as ambulatory surgery compared to non-ambulatory surgery: A prospective non-randomized study.

PURPOSE: According to the latest recommendations a minimally invasive approach should be used to manage breast cancer and a global policy for minimizing costs encourages shorter periods of hospitalization. The aim of this study was to investigate the impact of length of hospitalization on quality of life, anxiety and depression and postoperative complications. METHODS: This is a prospective observational study of 412 female patients with breast cancer requiring a first mastectomy or lumpectomy to assess the impact of the length of hospitalization on quality of life (using the European Organization for Research and Treatment of Cancer Quality of Life QLQ30 and BR23 questionnaires) at postoperative day 14 (D+14), levels of anxiety at d-1 and D+1 (according to the Hospital Anxiety and Depression scale) and postoperative state at D+21. RESULTS: Our study included 244 patients that had ambulatory surgery and 124 that had non-ambulatory surgery. Global health status was significantly better for ambulatory surgery patients (adjusted p-value=0.014). There were no significant differences between the two groups for levels of anxiety, pain, lymphoceles and postoperative complications. No cases of nausea and vomiting requiring medical treatment were reported for either group. CONCLUSIONS: Breast cancer surgery can be performed using ambulatory surgery with no significant differences compared to non-ambulatory surgery in terms of quality of life, perioperative anxiety, and postoperative complications. Indeed, our study suggests that ambulatory surgery improves patient outcome. It should be determined whether the mode of hospitalization has any long-term impact on the patient, as a shorter hospitalization period would allow decreasing waiting times.

Evaluation of Pre-Therapeutic Assessment in Endometrial Cancer Staging.

OBJECTIVE: The aim of this retrospective cohort study is to evaluate the concordance between the preoperative MRI and histology data with the final histopathological examination. METHOD: This is a retrospective observational study of 183 patients operated for endometrioid cancer between January 2009 and December 2019 in the surgical oncology department of the Lorraine Cancer Institute (ICL) in Vandœuvre-lès-Nancy. The patients included are all women operated on for endometrioid-type endometrial cancer over this period. The exclusion criteria are patients for whom the pre-therapy check-up does not include pelvic MRI and those who have not had first-line surgery. The final anatomopathological results were compared with preoperative imaging data and with endometrial biopsy data. RESULTS: For the myometrial infiltration, the sensitivity of MRI was of 37% and the specificity of 54%. To detect nodal metastases, the sensitivity of MRI was of 21% and the specificity of 93%. We observed an under estimation of the FIGO classification (p = 0.001) with the MRI in 42.7% of cases (n = 76) and an overestimation in 24.2% of cases (n = 43). There was a concordance in 33.1% of cases (n = 59). We had a poor agreement between the MRI and final histopathological examination with an adjusted kappa (κ) of 0.12 [95% IC (0.02; 0.24)]. There was a moderate concordance on the grade between the pretherapeutic biopsy and the final histopathological examination on excised tissue with an adjusted kappa of 0.52 [95% IC 0.42-0.62)]. Endometrial biopsy underestimated the tumor grade in 28.9% of cases (n = 50) (p < 0.001), overestimated the tumor grade in 6.9% of cases (n = 12) and we observed a concordance in 64.2% of cases (n = 111). CONCLUSION: The pre-operative assessment of endometrial cancer is inconsistent with the results obtained on final histopathological examination. A study with a systematic review should be done to assess the performance of MRI, only in expert centers, in order to consider a a specific care management for endometrial cancer patients: patients who have had an MRI in an outpatient center should have their imaging systematically reviewed, with the possibility of a new examination in case of incomplete sequences, by expert radiologists, and discussed in multidisciplinary concertation meeting in expert centers, before any therapeutic decision. The sentinel node biopsy must be used for low and intermediate risk endometrial cancer.

Pre-operative axillary ultrasound with fine-needle aspiration cytology performance and predictive factors of false negatives in axillary lymph node involvement in early breast cancer.

PURPOSE: Breast cancer is the most common cancer among females worldwide. Axillary lymph node involvement is an important prognostic factor in pre-operative evaluation. The aim of this study was to evaluate the sensitivity and accuracy of AUS during the initial breast cancer diagnosis and the contribution of ultrasound with guided FNAC (AUS + FNAC) in cases of suspicious node. METHODS: A retrospective study was conducted at the Lorraine Cancer Institute between 1 January and 31 December 2015. It included patients with early breast cancer, all of whom received AUS. If axillary node involvement was suspected, FNAC was performed. Sentinel lymph node biopsy (SLNB) and/or axillary lymph node dissection (ALND) were performed depending on FNAC results. RESULTS: In total, 292 patients were included. 88 patients (30.1%) had a suspicious lymph node on ultrasound and had FNAC, of whom 53 tested positive for axillary node involvement (60.2%). Among the 35 patients who tested negative with FNAC, 15 had axillary metastatic involvement. Performance of AUS + FNAC was better than that of AUS alone, with sensitivity, specificity, positive predictive and negative predictive values of approximately 44.5%, 100%, 100% and 72.4%, respectively, and accuracy of approximately 77.4%. Luminal A subgroup, axillary involvement of less than two positive nodes or nodal tumor of less than 7 mm are independent factors of false negative rate. CONCLUSIONS: AUS performance would seem to be improved by FNAC, with a false negative rate of approximately 26%. It may be possible to reduce the false negative rate of AUS if its contributing factors are taken into consideration, along with the impact of specific echographic signs as revealed by experienced radiologists.

Identification of Specific Tumor Markers in Vulvar Carcinoma Through Extensive Human Papillomavirus DNA Characterization Using Next Generation Sequencing Method.

OBJECTIVES: A subset of vulvar carcinomas (VC) are associated with human papillomavirus (HPV) DNA. This trait can be used to identify tumor markers for patient's follow-up. A large diversity of HPV prevalence in VC has been reported, but no data are available concerning the insertional HPV status in this tumor type. Therefore, we have used an innovative next generation sequencing (NGS)-based CaptHPV method able to provide an extensive characterization of HPV DNA in tumors. MATERIAL AND METHODS: Tumor tissue specimens from 55 patients with VC were analyzed using p16 immunohistochemistry, in situ hybridization, polymerase chain reaction, and CaptHPV-NGS assays. RESULTS: Our analyses showed that 8 (14.5%) of 55 cases were associated with HPV 16 DNA. No other HPV genotypes were identified. The HPV genome was in a free episomal state only in one case and both episomal and integrated into the tumor cell genome in 7. There was a single insertion in 5 cases and multiple sites, scattered at different chromosomal loci in two. ISH data suggest that some of these might reflect tumor heterogeneity. Viral integration targeted cellular genes among which were TP63, CCDC148, LOC100133091, PKP1, and POLA2. Viral integration at the PKP1 locus was associated with partial gene deletion, and no PKP1 protein was detected in tumor tissue. CONCLUSIONS: Using the NGS-based innovative capture-HPV approach, we established a cartography of HPV 16 DNA in 8 VC cases and identified novel genes targeted by integration that may be used as specific tumor markers. In addition, we established a rationale strategy for optimal characterization of HPV status in VC.

Predictive factors of axillary positive sentinel lymph node biopsy in extended ductal carcinoma in situ treated by simple mastectomy at once.

BACKGROUND: The incidence of positive sentinel lymph node biopsy (SLNB) in ductal carcinoma in situ (DCIS) ranged from 0 to 14%. The main hypothesis would be the presence of an invasive contingent on the final histology. The objective was to identify predictive factors of sentinel lymph node positivity in the management of extended ductal carcinoma in situ treated by simple mastectomy. METHODS: This was a retrospective study carried out at the Lorraine Cancer Institute from January 2003 to December 2017. Women with DCIS on core-needle biopsy whose management consisted of simple mastectomy and SLNB procedure were included. RESULTS: 188 patients were analyzed. Preoperatively, 18 patients (9.6%) had DCIS with microinvasion, while the others had pure DCIS. Eight patients (4.2%) had positive sentinel lymph node biopsy, the majority of which were single micrometastases. Predictive factor of node invasion was microinvasion on biopsy (p<0.01). Only in cases of pure DCIS, the percentage of positive SLNB was reduced to 2.9%. Invasive carcinoma was found in the majority of patients with positive axillary SLNB procedure (75%, n=6), compared to 16.7% (n=30) without SLNB involvement (p<0.01). CONCLUSIONS: The low rate of positive sentinel node biopsy in pure ductal carcinoma in situ suggests that in the absence of microinvasion, the sentinel procedure would seem less appropriate. New techniques for identifying sentinel lymph node biopsy could report axillary staging after definitive histologic results.

[Factors limiting outpatient management in breast surgery]. / Facteurs limitant la prise en charge ambulatoire en chirurgie mammaire.

INTRODUCTION: Breast cancer surgery associates interventions of short duration and low morbidity, mostly accessible for outpatient management. METHODS: We performed a descriptive, retrospective, monocentric study involving 1735 patients operated between 1st of July 2015 and the 31st of December 2017 of a mammary or axillary lymph node procedure. A comparative study was carried out, involving 2 groups of patients treated either on an outpatient or conventional hospitalization mode, in order to find the main medico-social factors that could constitute barriers to this ambulatory modality. RESULTS: In total, 992 patients were treated in outpatient surgery and 743 in conventional surgery. The mean age of the ambulatory group was 56.9 years (±11.2), versus 65.9 years (±13.5) in the conventional hospitalization group. Thirteen stays (1.3%) had to be converted into conventional hospitalization. The main factors limiting outpatient management are age≥70 years, BMI≥25, isolation of the patient, total mastectomy, and drainage. CONCLUSION: Because of social, medical or psychological constraints, the rate of outpatient breast surgery remains in our practice, stable in recent years at 56%. Some ways of improvement can be envisaged, but it is likely that this rate will only increase in a very gradual manner in the years to come.

Photodynamic diagnosis with methyl-5-aminolevulinate in squamous intraepithelial lesions of the vulva: Experimental research.

The incidence of the High-grade Squamous Intraepithelial Lesion of the vulva, formerly vulvar intra-epithelial neoplasia is progressively increasing. Today, an early detection and a precise localization of vulvar lesions are still problematic issues, due to the lack of accuracy of the available diagnostic tool. A new approach is the photodynamic diagnosis based on the fluorescence detection of protoporphyrin IX (PpIX) in cancer cells after topical application of a cream of methyl amino-levulinic acid. This study aimed to evaluate the effectiveness of photodiagnosis in order to discriminate the intensity of PpIX fluorescence between vulvar tumor and healthy skin. After topical application of the cream, the fluorescence on xenografted A431 tumor and adjacent skin was non-invasively measured with optical fiber. The tumor to skin fluorescence ratios were 1.38 and 1.41 at respectively 3h and 6h after application, which were significantly higher compared to those observed before application. PpIX accumulation at different depths of the tumor was investigated by spectrofluorimetry after PpIX chemical extraction from tumor sections at 3h and 6h post-application. It was noticed at both application times that the concentration of PpIX within the tumor progressively decreased. However PpIX fluorescence was always detectable up to 2.5 mm, a depth equivalent to more than three quarters of the tumor. The tumor to exposed skin ratios of PpIX fluorescence showed a good selectivity up to1mm depth at 3h post-application and up to 1.5mm at 6h post-m-ALA. Thus, the photodynamic diagnosis using in vivo topical methyl amino-levulinic acid appears to be a promising way to detect the intraepithelial lesions of the vulva. Our results open the possibility for implementation of topical methyl amino-levulinic acid in clinical settings for recognition of vulvar high-grade squamous intraepithelial lesions.

Limited effectiveness of patent blue dye in addition to isotope scanning for identification of sentinel lymph nodes: Cross-sectional real-life study in 1024 breast cancer patients.

BACKGROUND: Although morbidity is reduced when sentinel lymph node (SLN) biopsy is performed with dual isotopic and blue dye identification, the effectiveness of adding blue dye to radioisotope remains debated because side effects including anaphylactic reactions. PATIENTS AND METHODS: Using data from a prospectively maintained database, 1884 lymph node-negative breast cancer patients who underwent partial mastectomy with SLN mapping by a dual-tracer using patent blue dye (PBD) and radioisotope were retrospectively studied between January 2000 and July 2013. Patients with tumors <3 cm and with >1 node detected by one of the two techniques (N = 1024) were included in this real-life cross-sectional study. RESULTS: Among the 1024 patients, 274 had positive SLN detected by isotopic and/or PBD staining. Only 4 patients having no detectable radioactivity in the axilla had SLN identified only by PBD staining (blue-only) while 26 patients had SLN only identified by isotopic detection (hot-only) illustrating failure rates of 9.5% (26/274) and 1.5% (4/274), respectively. Among these four patients, two had negative lymphoscintigraphy. Therefore, the contribution of PBD to metastatic nodes identification was relevant for only 2/274 patients (0.8%). Three patients (0.3%) had an allergic reaction with PBD, and anaphylactic shock occurred in two cases (0.2%). CONCLUSIONS: The added-value of PBD to reduce the false-negative rate of SLN mapping is only limited to the rare cases in which no radioactivity is detectable in the axilla (<1%). When a radioisotope mapping agent is available, the use of PBD should be avoided, because it can induce anaphylaxis.

Treatment of vulvar intraepithelial neoplasia with CO(2) laser vaporization and excision surgery.

OBJECTIVE: To evaluate the recurrence rate after a single treatment of vulvar intraepithelial neoplasia (VIN) with CO(2) laser vaporization. MATERIALS AND METHODS: Fifty women with usual-type or differentiated VIN (grades 2 and 3) treated with CO(2) laser vaporization or surgery excision (cold knife or CO(2) laser) were retrospectively evaluated. RESULTS: Of the 50 patients, 41 (82.0%) had usual-type VIN and 9 (18.0%) had differentiated VIN. Moreover, 24 (48.0%) were treated with surgery excision and 26 (52.0%) underwent CO(2) laser vaporization. Laser-treated patients were significantly younger (p < .01) with more multifocal (p < .05) and multicentric lesions (p < .01) than in the surgery group. Recurrence-free survival (RFS) rates at 1 year were 91.0% for the surgery and 65.2% for the laser vaporization groups (p < .01). At 5 years, RFS rates were unchanged for the surgery group and dropped to 51.3% (p < .01) for the laser group. On the univariate analysis, current smoker (p = .03), multicentric VIN (p = .02), and laser vaporization treatment (p < .01) had a statistically significant impact on RFS. One patient progressed to invasive cancer (2%). CONCLUSIONS: The recurrence rate after CO(2) laser vaporization requires regular, close, and extended monitoring.