Objective
The aim of this study is to compare robotic total mesorectal excision (R-TME) with laparoscopic TME (L-TME) in a series of consecutive rectal cancer patients.
Background
R-TME and L-TME ...have drawn contradictory reports. A recent phase III trial (ROLARR) concluded that R-TME performed by surgeons with varying experience did not confer an advantage in rectal cancer resection.
Patients and Methods
In this retrospective single-center cohort study (8/2008 to 4/2015), data were prospectively registered. A total of 200 L-TME and 200 R-TME were operated consecutively without selection. The primary outcome was the conversion rate to open laparotomy or transanal TME. The secondary endpoints were type of anastomosis, operative time, postoperative morbidity, circumferential radial (CRM) and distal margins, quality of life, bladder and sexual dysfunction, and oncological outcomes.
Results
Baseline characteristics were well balanced. Type of anastomosis colo-anal anastomosis (CAA) 40% vs 49%;
p
< 0.001, transanal TME (5% vs 13%;
p
= 0.005), and conversion rate (2% vs 9.5%; odd ratio (OR): 0.19 95% confidence interval (CI): 0.05–0.60) were significantly different. Intersphincteric resection (39% vs 47%), diverting stoma (66.5% vs 68%), CRM involvement, median operative time (243 vs 232 min), and R0 resection rate were similar. Conversion risk was lower for R-TME in male patients and those with small tumors (< 5 cm). The 3-year overall survival rate was 84.1% 77.3–88.9% and 88.4% 82.9–92.2% in the R-TME and L-TME group. No significant differences were reported in quality of life, and urinary or sexual function.
Conclusions
R-TME is less likely to be converted to open surgery than L-TME; operative time and curative pathologic criteria are equivalent. Future prospective trial should compare standardized procedures performed by experienced surgeons for subgroups of high-risk patients.
Geyer F C, Lacroix‐Triki M, Colombo P‐E, Patani N, Gauthier A, Natrajan R, Lambros M B K, Khalifeh I, Albarracin C, Orru S, Marchiò C, Sapino A, Mackay A, Weigelt B, Schmitt F C, Wesseling J, Sneige ...N & Reis‐Filho J S
(2012) Histopathology 60, E115–E130
Molecular evidence in support of the neoplastic and precursor nature of microglandular adenosis
Aims: Microglandular adenosis (MGA) is a proliferative breast lesion, which has been proposed to be a potential precursor of triple‐negative breast cancers. The aims of this study were to determine whether MGAs harbour genetic alterations and if any such genetic aberrations found in MGAs are similar to those found in matched invasive carcinomas.
Methods and results: Twelve cases of MGA and/or atypical MGA (AMGA), 10 of which were associated with invasive carcinoma, were evaluated. Immunohistochemical profiling revealed that all invasive carcinomas were of triple‐negative phenotype and expressed S100, cytokeratins 8/18 and ‘basal’ markers. The morphologically distinct components of each case (MGA, AMGA and/or invasive carcinoma) were microdissected and subjected to microarray comparative genomic hybridization. Apart from three typical MGAs, all samples harboured genetic alterations. The percentage of the genome affected by copy number aberrations in MGA/AMGA ranged from 0.5 to 61.9%, indicating varying levels of genetic instability. In three cases, MGA/AMGA displayed copy number aberrations similar to those found in matched invasive components, providing strong circumstantial evidence that MGA may constitute the substrate for the invasive carcinoma development.
Conclusions: Our results support the contention that MGA can be a clonal lesion and non‐obligate precursor of triple‐negative breast cancer.
Triple negative breast cancers (TNBC) are a more aggressive subset of breast cancer. A better understanding of its biology could allow the rational development of targeted therapies.
We extensively ...analyzed the EGFR/PI3K/PTEN axis in a large, homogeneous population of TNBC to help defining the putative role of anti-EGFR and -PI3K targeted therapies in this setting. EGFR gene amplification, EGFR protein expression, PIK3CA and PTEN gene alterations (two members of EGFR downstream pathways) and their clinicopathological and prognostic implications were analyzed in 204 TNBC samples from European patients.
EGFR amplification was detected in 18 of the 204 TNBC specimens (8.9 %) and was significantly associated with higher EGFR protein levels. Fourteen PIK3CA mutations were identified in exon 9 (6.7 %), and 17 in exon 20 (8.3 %). PIK3CA mutations, especially in exon 9, were significantly associated with grade I-II tumors. PTEN deletions were detected in 43 samples (21.50 %) and were significantly associated with grade III tumors (p < 0.001). Univariate analysis showed a significant association between relapse-free survival (RFS), T and N stage and exon 9 PIK3CA mutations. Overall survival was significantly associated with T stage, N stage and adjuvant chemotherapy, which was administered to 70.3 % of patients. In multivariate analyses, T stage, N stage, presence of exon 9 PIK3CA mutations and high EGFR protein level were independent poor prognostic factors for RFS, while adjuvant chemotherapy was associated with a better outcome.
High EGFR protein expression and exon 9 PIK3CA activating mutations are independent prognostic factors in TNBC. The efficacy of anti-PI3K targeted therapies needs to be evaluated in this setting.
In rectal surgery, some situations can be critical, such as anterior topography of locally advanced low tumors with a positive predictive radial margin, especially in a narrow pelvis of men who are ...obese. Transanal proctectomy is a new laparoscopic technique that uses the transanal endoscopic microsurgery device.
The aim of this study is to evaluate the technical feasibility of laparoscopic transanal proctectomy in patients with unfavorable features.
This is a single-center, prospective analysis of selected patients with rectal cancer operated on from January 2009 to June 2011.
Intraoperative details and short-term postoperative outcome were described.
Thirty men with advanced or recurrent low rectal tumors associated with unfavorable anatomical and/or tumor characteristics underwent a sphincter-sparing transanal endoscopic proctectomy. Twenty-nine patients had received preoperative treatment. We report a 6% conversion rate, no postoperative mortality, and a 30% morbidity rate. At the beginning of our experience, a urethral injury was diagnosed in 2 patients and easily sutured intraoperatively, without postoperative after-effect. The mesorectal resection was graded as "good" in all patients. R0 resection was achieved in 26 patients (87%). The short-term stoma closure rate was 85%. After a median follow-up of 21 months, 4 patients experienced locoregional recurrence alone. Overall survival rates at 12 and 24 months were 96.6% (95% CI, 78.0-99.5) and 80.5% (95% CI, 53.0-92.9). Relapse-free survival rates at 12 and 24 months were 93.3% (95% CI, 75.9-98.3) and 88.9% (95% CI, 69.0-96.3).
Although the transanal endoscopic proctectomy was performed by trained surgeons, we report a slight increase in early postoperative morbidity and relatively poor early outcome. There was a clear selection bias related to the study cohort exclusively composed of high-risk patients, but we need to be cautious before generalizing this technique.
The transanal endoscopic proctectomy is a feasible alternative surgical option to conventional laparoscopy for radical rectal resection in selected cases with unfavorable characteristics. Further investigations with larger cohorts are required to validate its safety and to clarify its best indication.
Hormone therapy (HT) is an effective treatment for metastatic endometrial carcinoma (mEC), with limited toxicity and low cost. We focused on molecular analysis of mECs treated by HT and, for the ...first time to date, we compared the genomic profiles of paired metastasis and primary ECs. The main objective was to identify predictive factors of the response to HT as well as specific altered signaling pathways driving mEC biology. From 1052 patients with EC treated by HT in two French cancer centers, 32 with endometrioid EC and 6 with high grade serous EC were included. We evaluated hormone receptors (HR) and mismatch repair proteins expression by immunohistochemistry and gene alterations by targeted next-generation sequencing and array-based comparative genomic hybridization. Several variables were tested in univariate and multivariate analyses to identify potential associations with (i) the clinical benefit of HT (CBHT) and (ii) a longer response (>18 months) (LRHT) and overall survival (OS). We compared the biological and genomic profiles of 11 primary/metastatic EC pairs. Thirty tumors (78.9%) were HR-positive and 6 (15.8%) showed microsatellite instability (MSI). The genomic profiles of 34 tumors showed an average altered genome of 3.26%, DNA repair homologous recombination deficiency in five tumors (14.7%), and 17 regions significantly targeted by amplification/deletion. Thirty-three tumors had 273 variants (158 genes, median of 7 mutations/sample), including 112 driver mutations. TP53, PTEN, PPP2R1A, ARID1A, FGFR2, and PIK3CA were the most frequently mutated. Based on the genomic status, nine oncogenic pathways were altered in more than 25% of primary EC. Clinically, 22 (57.9%) and 6 (15.8%) patients presented CBHT and LRHT, respectively. Neither oncogenic pathways alterations nor the variables tested were associated with CBHT and LRHT. Only patient’s age, mitotic index and the presence of at least one HR were associated with OS. Paired analysis of the primary/metastatic samples showed that among the 22 mutations acquired in the metastatic counterparts, the most frequently targeted genes were involved in pathways that might confer a selective advantage to cancer metastasis including hormone resistance. In conclusion, only patient’s age, mitotic index and the presence of at least one HR were associated with OS. The identification of gene mutations newly acquired in metastasis might help to better understand the formation of EC metastasis and select the best actionable candidates for HT-treated patients at the metastatic stage.
Abstract
Based on results of clinical trials, completion ALND (cALND) is frequently not performed for patients with breast conservation therapy and one or two involved sentinel nodes (SN) by micro- ...or macro-metastases. However, there were limitations despite a conclusion of non-inferiority for cALND omission. No trial had included patients with SN macro-metastases and total mastectomy or with >2 SN macro-metastases. The aim of the study was too analyze treatment delivered and pathologic results of patients included in SERC trial. SERC trial is a multicenter randomized non-inferiority phase-3 trial comparing no cALND with cALND in cT0-1-2, cN0 patients with SN ITC (isolated tumor cells) or micro-metastases or macro-metastases, mastectomy or breast conservative surgery. We randomized 1855 patients, 929 to receive cALND and 926 SLNB alone. No significant differences in patient’s and tumor characteristics, type of surgery, and adjuvant chemotherapy (AC) were observed between the two arms. Rates of involved SN nodes by ITC, micro-metastases, and macro-metastases were 5.91%, 28.12%, and 65.97%, respectively, without significant difference between two arms for all criteria. In multivariate analysis, two factors were associated with higher positive non-SN rate: no AC versus AC administered after ALND (OR = 3.32,
p
< 0.0001) and >2 involved SN versus ≤2 (OR = 3.45,
p
= 0.0258). Crude rates of positive NSN were 17.62% (74/420) and 26.45% (73/276) for patient’s eligible and non-eligible to ACOSOG-Z0011 trial. No significant differences in patient’s and tumor characteristics and treatment delivered were observed between the two arms. Higher positive-NSN rate was observed for patients with AC performed after ALND (17.65% for SN micro-metastases, 35.22% for SN macro-metastases) in comparison with AC administered before ALND.
Most High-Grade Ovarian Carcinomas (HGOCs) are sensitive to carboplatin (CBP)-based chemotherapy but frequently recur within 24 months. Recurrent tumors remain CBP-sensitive and acquire resistance ...only after several treatment rounds. Recurrences arise from a small number of residual tumor cells hardly amenable to investigation in patients. We developed Patient-Derived Xenografts (PDXs) that allow the study of these different stages of CBP-sensitive recurrence and acquisition of resistance. We generated PDX models from CBP-sensitive and intrinsically resistant HGOC. PDXs were CBP- or mock-treated and tumors were sampled, after treatment and at recurrence. We also isolated models with acquired-resistance from CBP-sensitive PDXs. All tumors were characterized at the histological and transcriptome levels. PDX models reproduced treatment response seen in the patients. CBP-sensitive residual tumors contained non-proliferating tumor cells clusters embedded in a fibrotic mesh. In non-treated PDX tumors and treated CBP-resistant tumors fibrotic tissue was not prevalent. Residual tumors had marked differences in gene expression when compared to naïve and recurrent tumors, indicating downregulation of cell cycle and proliferation and upregulation of interferon response and epithelial-mesenchymal transition. This gene expression pattern resembled that described in embryonal diapause and 'drug-tolerant persister' states. Residual and acquired-resistance tumors share the overexpression of three genes: CEACAM6, CRYAB, and SOX2.Immunostaining analysis showed strong CEACAM6, CRYAB, and SOX2 protein expression in CBP-sensitive residual and acquired resistance PDX, thus, confirming RNA profiling results. In HGOC PDX, CBP-sensitive recurrences arise from a small population of quiescent, drug-tolerant, residual cells embedded in a fibrotic mesh. These cells overexpress CEACAM6, CRYAB and SOX2, whose overexpression is also associated with acquired resistance and poor patient prognosis. CEACAM6, CRYAB and SOX2 may, thus, serve as a biomarker to predict recurrence and emergence of resistant disease in CBP-treated HGOC patients.
Neuregulin 1 (NRG1), a ligand for HER3 and HER4 receptors, is secreted by both pancreatic tumor cells (PC) and cancer-associated fibroblasts (CAFs), the latter representing the most abundant compound ...of pancreatic stroma. This desmoplastic stroma contributes to Pancreatic Ductal Adenocarcinoma (PDAC) aggressiveness and therapeutic failure by promoting tumor progression, invasion and resistance to chemotherapies. In the present work, we aimed at disrupting the complex crosstalk between PC and CAF in order to prevent tumor cell proliferation. To do so, we demonstrated the promising tumor growth inhibitory effect of the 7E3, an original antibody directed to NRG1. This antibody promotes antibody dependent cellular cytotoxicity in NRG1-positive PC and CAFs and inhibits NRG1-associated signaling pathway induction, by blocking NRG1-mediated HER3 activation. Moreover, 7E3 inhibits migration and growth of pancreatic cancer cells co-cultured with CAFs, both in vitro and in vivo using orthotopic pancreatic tumor xenografts. Our preclinical results demonstrate that the anti-NRG1 antibody 7E3 could represent a promising approach to target pancreatic stroma and cancer cells, thereby providing novel therapeutic options for PDAC.
•NRG1 is expressed in human pancreatic tumors and cancer-associated fibroblasts.•NRG1 promotes pancreatic cell growth.•NRG1 trapping by 7E3 antibody inhibits HER3 activation and downstream signaling.•Targeting NRG1 inhibits growth of orthotopic pancreatic tumor xenografts.
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