Perioperative morbidity of radical trachelectomy with lymphadenectomy in early-stage cervical cancer: a French prospective multicentric cohort.

The aim of this study was to determine the predictive factors of postoperative morbidity of patients who have undergone a radical trachelectomy (RT) for early-stage cervical cancer and to assess the oncologic outcomes. We retrospectively analysed the data of 2 prospective trials on sentinel node biopsy for cervical cancer (SENTICOL I and II). Patients having a RT for early-stage cervical cancer with negative sentinel lymph node and safe margins, were included. Forty-nine patients met the inclusion criteria. Forty-five patients had a laparoscopic-assisted vaginal technique and 4 patients a total laparoscopic technique. The median age was 32 years (range, 22-46 years). 83.7% of patients had a stage IB1 disease. There were 63.3% squamous cell carcinomas and 34.7% adenocarcinomas. The median follow-up was 46 months (range, 1-85 months). Two patients (3.3%) had a severe postoperative complication (Clavien-Dindo ≥III and/or CTCAE ≥3). The main postoperative complications were urinary (28.6%), lymphovascular (26.5%) and neurologic (14.3%). On a multivariate analysis, postoperative complications were significantly associated with history of pelvic surgery and IB1 International Federation of Gynecology and Obstetrics stage. Inclusion in high surgical skills centers decrease the risk of postoperative complications. During the follow-up, 3 patients (6.1%) had a local recurrence and one patient died from a breast cancer. Between group with complications and group without any complications, overall survival and recurrence-free survival did not significantly differ at 5-year of follow-up. RT has few severe postoperative complications and appears as a safe alternative to spare fertility of young patients. To guarantee best surgical outcomes, patients should be referred to expert center

Biological network-driven gene selection identifies a stromal immune module as a key determinant of triple-negative breast carcinoma prognosis

Triple-negative breast cancer (TNBC) is a heterogeneous group of aggressive breast cancers for which no targeted treatment is available. Robust tools for TNBC classification are required, to improve the prediction of prognosis and to develop novel therapeutic interventions. We analyzed 3,247 primary human breast cancer samples from 21 publicly available datasets, using a five-step method: (1) selection of TNBC samples by bimodal filtering on ER-HER2 and PR, (2) normalization of the selected TNBC samples, (3) selection of the most variant genes, (4) identification of gene clusters and biological gene selection within gene clusters on the basis of String© database connections and gene-expression correlations, (5) summarization of each gene cluster in a metagene. We then assessed the ability of these metagenes to predict prognosis, on an external public dataset (METABRIC). Our analysis of gene expression (GE) in 557 TNBCs from 21 public datasets identified a six-metagene signature (167 genes) in which the metagenes were enriched in different gene ontologies. The gene clusters were named as follows: Immunity1, Immunity2, Proliferation/DNA damage, AR-like, Matrix/Invasion1 and Matrix2 clusters respectively. This signature was particularly robust for the identification of TNBC subtypes across many datasets (n = 1,125 samples), despite technology differences (Affymetrix© A, Plus2 and Illumina©). Weak Immunity two metagene expression was associated with a poor prognosis (disease-specific survival; HR = 2.68 [1.59–4.52], p = 0.0002). The six-metagene signature (167 genes) was validated over 1,125 TNBC samples. The Immunity two metagene had strong prognostic value. These findings open up interesting possibilities for the development of new therapeutic interventions

Biological network-driven gene selection identifies a stromal immune module as a key determinant of triple-negative breast carcinoma prognosis

International audienceTriple-negative breast cancer (TNBC) is a heterogeneous group of aggressive breast cancers for which no targeted treatment is available. Robust tools for TNBC classification are required, to improve the prediction of prognosis and to develop novel therapeutic interventions. We analyzed 3,247 primary human breast cancer samples from 21 publicly available datasets, using a five-step method: (1) selection of TNBC samples by bimodal filtering on ER-HER2 and PR, (2) normalization of the selected TNBC samples, (3) selection of the most variant genes, (4) identification of gene clusters and biological gene selection within gene clusters on the basis of String (c) database connections and gene-expression correlations, (5) summarization of each gene cluster in a metagene. We then assessed the ability of these metagenes to predict prognosis, on an external public dataset (METABRIC). Our analysis of gene expression (GE) in 557 TNBCs from 21 public datasets identified a six-metagene signature (167 genes) in which the metagenes were enriched in different gene ontologies. The gene clusters were named as follows: Immunity1, Immunity2, Proliferation/DNA damage, AR-like, Matrix/Invasion1 and Matrix2 clusters respectively. This signature was particularly robust for the identification of TNBC subtypes across many datasets (n = 1,125 samples), despite technology differences (Affymetrix (c) A, Plus2 and Illumina (c)). Weak Immunity two metagene expression was associated with a poor prognosis (disease-specific survival; HR = 2.68 [1.59-4.52], p = 0.0002). The six-metagene signature (167 genes) was validated over 1,125 TNBC samples. The Immunity two metagene had strong prognostic value. These findings open up interesting possibilities for the development of new therapeutic interventions

Sentinel lymph node in cervical cancer: time to move forward.

In early-stage cervical cancer, lymph node status is of paramount importance to determine the best therapeutic strategy and is one of the most important prognostic factors of survival. According to main international guidelines, pelvic full lymphadenectomy is recommended for lymph node staging. Sentinel lymph node (SLN) biopsy is an accurate method for the assessment of lymph nodal involvement and has been suggested instead of systematic pelvic lymph node dissection (PLND). The SLN technique requires a learning-curve to be well performed. Combined detection with technetium-99 and blue dye has been widely used but the recent introduction of indocyanine green (ICG) is of growing interest since it could improve SLN detection. SLN biopsy offers a more accurate anatomical staging by finding potential metastatic nodes outside of usual lymphadenectomy areas. SLN biopsy improves the diagnostic value of lymph node staging with ultrastaging and detection of low-volume nodal metastases [isolated tumor cells (ITCs) and micrometastases]. Appropriate selection of patient and minimal training combined with some simple rules may guarantee a low false negative rate. Several studies have shown that SLN mapping in these patients is feasible, with excellent detection rates and sensitivity. Less-radical lymph node dissection decreases the associated morbidity of PLND, especially the risk of lower-limb lymphoedema, which severely affects patient quality of life. Some points are still subject to debate such as the low accuracy of intraoperative SLN status assessment by frozen section and the impact of micrometastasis on prognosis. Although international guidelines consider SLN biopsy as an alternative to PLND, SLN biopsy alone is not the gold-standard yet due to lack of prospective evidence on long-term oncological safety. The 3 ongoing prospective trials SENTIX, PHENIX and SENTICOL III will most probably give an answer to these issues

Predictive factors of severe perioperative morbidity of radical hysterectomy with lymphadenectomy in early-stage cervical cancer: A French prospective multicentric cohort of 248 patients.

The purpose of this study was to assess the postoperative morbidity after radical hysterectomy (RH) for early-stage cervical cancer and to determine risk factors of severe perioperative morbidity. Data of two prospective trials on sentinel node biopsy for cervical cancer (SENTICOL I & II) were analysed. Patients having a radical hysterectomy were included between 2005 and 2012 from 25 French oncologic centers. Postoperative complications were prospectively recorded in a pre-specified analysis. 248 patients met the inclusion criteria. The median age was 44.5 years [25-85]. 88.7% of patients had a stage IB1 disease. There were 71.4% epidermoid carcinomas and 25% adenocarcinomas. 125 patients (50.4%) had a laparoscopic-assisted vaginal RH, 88 patients (35.5%) had a total laparoscopic RH, 26 patients (10.5%) had an open RH and 9 patients (3.6%) had a robotic-assisted RH. Sixteen patients (6.4%) had intraoperative complications. On a multivariate analysis, intraoperative complications were significantly associated with BMI >30 kg/m <sup>2</sup> . The urinary, lymphovascular and neurologic complications rates were respectively 34.3%, 20.6% and 19.8%. 31 patients (12.5%) had severe postoperative complications (Clavien-Dindo ≥ 3 or CTCAE ≥ 3). On multivariate analysis, severe postoperative complications were associated with parametrial involvement, preoperative brachytherapy and inclusion in low surgical skills center. This study based on prospective data showed that RH has low severe postoperative complications. The main complications were urinary infections and lower limb lymphedema. Patients with early-stage cervical cancer should be referred to expert center to ensure best surgical outcomes

The clinical implication of lymph nodes micrometastases and isolated tumor cells in patients with cervical cancer: A systematic review.

Lymph node macroscopic involvement in cervical cancer is a well-known prognostic factor, allows the gynecologic-oncologist to identify women at increased risk for recurrence. Since the development of sentinel node biopsy, micrometastases (MMs) and Isolated Tumor Cells (ICTs) have been increasingly identified in cervical cancer, however their prognostic value and treatment are still controversial. We reviewed the literature (MEDLINE and EMBASE database analysis) from inception up to January 2019, concerning the incidence of lymph nodes MMs and ITCs in cervical cancer, their controversial histologic and molecular biology definition, their anatomic distribution, the role of frozen section and the prognostic value and treatment options for women diagnosed with lymph nodes MMs/ITCs

Predictive factors of unexpected lymphatic drainage pathways in early-stage cervical cancer.

The purpose of this study was to describe sentinel lymph nodes (SLN) topography in patients with early-stage cervical cancer and to determine factors associated with atypical lymphatic drainage pathway (LDP). We analyzed the data of two prospective multicentric trials on SLN biopsy for cervical cancer (SENTICOL I and II) in women undergoing surgery for early-stage cervical cancer. SLN detection was realized with a combined labeling technique (Patent blue and radioactive tracer). Patients having bilateral SLN detection were included. Univariate and Multivariate analysis were performed by patients and by side to assess clinical and pathologic factors that may predict atypical LDP. Between January 2005 and July 2012, 326 patients with 1104 intraoperative detected SLNs fulfilled the inclusion criteria. The SLNs were mainly located in the interiliac or external iliac area in 83.2%. The other localizations were: 9.2% in the common iliac area, 3.9% in the parametrium, 1.6% in the promontory area, 1.5% in the paraaortic area and 0.5% in other areas. Thirty-five patients (10.7%) had atypical SLN without SLN in typical area on one or both sides. In multivariate analysis, tumor size ≥20 mm appeared as an independent factor of having at least one exclusive atypical LDP (ORa = 3.95 95%CI = [1.60-9.78], p = 0.003). Multiparity decreased significantly the probability of having at least one exclusive atypical LDP (ORa = 0.16 95%CI = [0.07-0.39], p < 0.0001). Tumor size larger than 20 mm and nulliparity increase the risk of having exclusive atypical LDP in early-stage cervical cancer

Diagnostic value of frozen section examination of sentinel lymph nodes in early-stage cervical cancer at the time of ultrastaging

We aimed to assess the diagnostic value of frozen-section pathologic examination (FSE) of sentinel lymph nodes (SLN) in patients with early-stage cervical cancer. Two French prospective multicentric database on SLN biopsy for cervical cancer (SENTICOL I and II) were analysed. Patients with IA to IIA1 2018 FIGO stage, who underwent SLN biopsy with both FSE and ultrastaging examination were included. Between 2005 and 2012, 313 patients from 25 centers fulfilled the inclusion criteria. Metastatic involvement of SLN was diagnosed in 52 patients (16.6%). Macrometastases, micrometastases and isolated tumor cells (ITCs) were found in 27, 12 and 13 patients respectively. Among the 928 SLNs analysed, FSE identified 23 SLNs with macrometastases in 20 patients and 5 SLNs with micrometastases in 2 patients whereas no ITCs were identified. Ultrastaging of negative SLNs by FSE found macrometastases, micrometastases and ITCs in additional 7, 11 and 17 SLNs. Ultrastaging increased significantly the rate of patients with positive SLN from 7% to 16.6% (p < 0.0001). The sensitivity and the negative predictive value of FSE were 42.3% and 89.7% respectively or 56.4% and 94.1% if ITCs were excluded. False-negative cases were more frequent with tumor size ≥ 20 mm (OR = 4.46, 95%IC = [1.45-13.66], p = 0.01) and preoperative brachytherapy (OR = 4.47, 95%IC = [1.37-14.63], p = 0.01) and less frequent with patients included in higher volume center (>5 patients/year) (OR = 0.09, 95%IC = [0.02-0.51], p = 0.01). FSE of SLN had a low sensitivity for detecting micrometastases and ITCs and a high negative predictive value for SLN status. Clinical impact of false-negative cases has to be assessed by further studies

Can Conization Specimens Predict Sentinel Lymph Node Status in Early-Stage Cervical Cancer? A SENTICOL Group Study.

The prognosis of patients with cervical cancer is significantly worsened in case of lymph node involvement. The goal of this study was to determine whether pathologic features in conization specimens can predict the sentinel lymph node (SLN) status in early-stage cervical cancer. An ancillary analysis of two prospective multicentric database on SLN biopsy for cervical cancer (SENTICOL I and II) was carried out. Patients with IA to IB2 2018 FIGO stage, who underwent preoperative conization before SLN biopsy were included. Between January 2005 and July 2012, 161 patients from 25 French centers fulfilled the inclusion criteria. Macrometastases, micrometastases and Isolated tumor cells (ITCs) were found in 4 (2.5%), 6 (3.7%) and 5 (3.1%) patients respectively. Compared to negative SLN patients, patients with micrometastatic and macrometastatic SLN were more likely to have lymphovascular space invasion (LVSI) (60% vs. 29.5%, p = 0.04) and deep stromal invasion (DSI) ≥ 10 mm (50% vs. 17.8%, p = 0.04). Among the 93 patients with DSI < 10 mm and absence of LVSI on conization specimens, three patients (3.2%) had ITCs and only one (1.1%) had micrometastases. Patients with DSI < 10 mm and no LVSI in conization specimens had lower risk of micro- and macrometastatic SLN. In this subpopulation, full node dissection may be questionable in case of SLN unilateral detection