In high-grade ovarian carcinoma, platinum-sensitive tumor recurrence and acquired-resistance derive from quiescent residual cancer cells that overexpress CRYAB, CEACAM6, and SOX2.

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 not 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. Tumors were characterized at the histological and transcriptome levels. PDX models reproduced treatment response seen in the patients. CBP-sensitive residual tumors contained nonproliferating tumor cell clusters embedded in a fibrotic mesh. In nontreated 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 the cell cycle and proliferation and upregulation of interferon response and the 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 the 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. © 2022 The Pathological Society of Great Britain and Ireland.

Efficacy of chemotherapy according to BRCA status in patients with high-grade serous ovarian carcinoma at first platinum-sensitive relapse.

OBJECTIVE: Chemotherapy for high-grade serous ovarian cancers in platinum-sensitive relapse includes carboplatin/paclitaxel, carboplatin/gemcitabine, and carboplatin/pegylated liposomal doxorubicin. According to in vitro data, BRCA mutated patients are sensitive to replicative stress agents but BRCA status is not yet used for the choice of chemotherapy at relapse. Our aim was to assess these doublets according to BRCA status in first platinum-sensitive relapse. METHODS: The ESME ovarian cancer database comprises a multicenter retrospective cohort of patients with ovarian cancer treated in French cancer centers between January 2011 and December 2017. Patients with high-grade serous ovarian cancers at first platinum-sensitive relapse who received one of these doublets were included. The objective was to compare progression-free survival of each chemotherapy doublet according to BRCA status. RESULTS: Among the 10 263 patients in the database, 1539 patients had a first platinum-sensitive relapse: 825 BRCA wild type patients (53.6%) and 304 BRCA mutated patients (19.8%) (7 patients had a homologous recombination mutation and BRCA status was unkown for 403 patients). Median progression-free survival was longer in BRCA mutated patients than in BRCA wild type patients when receiving carboplatin/pegylated liposomal doxorubicin without maintenance treatment (15.8 vs 11.8 months; p<0.001). In contrast, we observed no difference in patients treated with carboplatin/paclitaxel (14.6 vs 14.3 months, respectively; p=0.70) or in those treated with carboplatin/gemcitabine (12.0 vs 9.8 months, respectively; p=0.18). In BRCA wild type patients without maintenance, better progression-free survival occurred with carboplatin/paclitaxel (median progression-free survival 14.3 months) than with carboplatin/gemcitabine and carboplatin/pegylated liposomal doxorubicin (9.8 and 11.8 months, respectively; p=0.017). In BRCA mutated patients without maintenance, there was no difference between the three doublets (median progression-free survival of 14.6, 12.0, and 15.8 months with carboplatin/paclitaxel, carboplatin/gemcitabine, and carboplatin/pegylated liposomal doxorubicin, respectively; p=0.40). CONCLUSION: While treatment with carboplatin/paclitaxel, carboplatin/gemcitabine, and carboplatin/pegylated liposomal doxorubicin shows comparable efficacy in BRCA mutated patients, treatment with carboplatin/paclitaxel appears to be more effective than carboplatin/gemcitabine and carboplatin/pegylated liposomal doxorubicin in BRCA wild type patients with high-grade serous ovarian cancers at first platinum-sensitive relapse.

Differential Sensitivity of Germline and Somatic BRCA Variants to PARP Inhibitor in High-Grade Serous Ovarian Cancer.

PURPOSE: The introduction of PARP inhibitors (PARPis) as a treatment option for patients with high-grade serous ovarian cancer (HGSOC) modified the approach of BRCA testing worldwide. In this study, we aim to evaluate the impact of BRCA1 and BRCA2 variants on treatment response and survival outcomes in patients diagnosed in our institution. METHODS: A total of 805 HGSOC samples underwent BRCA1 and BRCA2 variant detection by using next-generation sequencing (NGS). Among them, a pathogenic alteration was detected in 104 specimens. Clinicopathological features and germline status were recovered, and alteration types were further characterized. The clinical significance of variant type in terms of response to chemotherapy and to PARPis as well as overall survival were evaluated using univariate analysis. RESULTS: In our cohort, 13.2% of the HGSOC samples harbored a pathogenic BRCA1 or BRCA2 variant, among which 58.7% were inherited. No difference was observed between germline and somatic variants in terms of the gene altered. Interestingly, patients with somatic variants only (no germline) demonstrated better outcomes under PARPi treatment compared to those with germline ones. CONCLUSION: The determination of the inheritance or acquisition of BRCA1 and BRCA2 alterations could provide valuable information for improving management strategies and predicting the outcome of patients with HGSOC.

Tailored Management with Highly-Selective Diversion for Low Colorectal Anastomosis: Biochemical Postoperative Follow-Up and Long-Term Results from a Single-Institution Cohort.

BACKGROUND: Defunctioning stoma (DS) can decrease the rate of symptomatic anastomotic leakage (AL). Since 2010, we have used tailored, highly selective DS management for low colorectal anastomosis (LCRA). METHODS: In total, 433 rectal cancer patients underwent the same standardized procedure. Non-stoma (NS) management was used in patients with no surgical difficulties as well as good colonic preparation and quality of anastomoses. In all other cases, DS was used. C-reactive protein was measured during postoperative follow-up. Imbalance in the initial population was adjusted using propensity-score matching according to sex, age, body mass index, tumor location, and American Society of Anesthesiologists score. Rate of AL within 30 days, 5-year overall survival, local relapse-free survival, and disease-free survival were recorded. RESULTS: Anastomosis was mostly ultra-low and was performed equally by laparoscopy or robotic surgery. The overall rate of AL was 13.4%, with no significant differences between groups (DS, 12.2%; NS, 14.6%; p = 0.575). Operative time, blood loss, and hospital stay were significantly lower for NS patients. The rate of secondary stoma was 11.4% overall. Pathological results were similar, with a 98% R0 resection rate. With a median follow-up of 5.5 years for the NS and DS groups, the overall survival was 84.9% and 73.4%, respectively (p = 0.064), disease-free survival was 67.0% and 55.8%, respectively (p = 0.095), and local relapse-free survival was 95.2% and 88.7%, respectively (p = 0.084). The long-term, stoma-free rate was 89.1% overall. CONCLUSIONS: Tailoring DS for LCRA seems safe and could provide potential benefits in postoperative morbidity with the same long-term oncological results in NS patients. Prospective, multicentric studies should validate this approach.

Optimal timing of interval debulking surgery for advanced epithelial ovarian cancer: A retrospective study from the ESME national cohort.

OBJECTIVE: Interval debulking surgery is recommended after 3-4 cycles (standard IDS) of neoadjuvant chemotherapy (NACT) for epithelial ovarian cancer (EOC) not able to received upfront complete debulking surgery. However, real world practices frequently report performing IDS after ≥5 NAC cycles (delayed IDS). The aim of this work was to evaluate the impact on survival of the number of NACT cycles before IDS. METHODS: We identified from a French national database, women with newly diagnosed EOC who underwent IDS from January 2011 to December 2016. Progression free survival (PFS) and overall survival (OS) were compared using Cox model with adjustments for confounding factors provided by two propensity score methods: inverse probability of treatment weighting (IPTW) and matched-pair analysis. RESULTS: 928 patients treated by IDS for which our propensity score could be applied were identified. After a median follow-up of 49.0 months (95% CI [46.0;52.9]); from the IPTW analysis, median PFS was 17.6 months and 11.5 months (HR = 1.42; CI 95% [1.22-1.67]; p < 0.0001); median OS was 51.2 months and 44.3 months (HR = 1.29; CI 95% [1.06-1.56]; p = 0.0095) for the standard and delayed IDS groups. From the matched-pair analysis (comparing 352 patients for each group), standard IDS was associated with better PFS (HR = 0,77; CI 95% [0.65-0.90]; p = 0.018) but not significantly associated with better OS (HR = 0,84; CI 95% [0.68-1,03]; p = 0.0947). CONCLUSIONS: Carrying IDS after ≥5 NACT cycles seems to have a negative effect on patients survival. The goal of IDS surgery is complete resection and should not be performed after >3-4 NACT cycles.

Fusion Cell Markers in Circulating Tumor Cells from Patients with High-Grade Ovarian Serous Carcinoma.

Cancer is primarily a disease in which late diagnosis is linked to poor prognosis, and unfortunately, detection and management are still challenging. Circulating tumor cells (CTCs) are a potential resource to address this disease. Cell fusion, an event discovered recently in CTCs expressing carcinoma and leukocyte markers, occurs when ≥2 cells become a single entity (hybrid cell) after the merging of their plasma membranes. Cell fusion is still poorly understood despite continuous evaluations in in vitro/in vivo studies. Blood samples from 14 patients with high-grade serous ovarian cancer (A.C. Camargo Cancer Center, São Paulo, Brazil) were collected with the aim to analyze the CTCs/hybrid cells and their correlation to clinical outcome. The EDTA collected blood (6 mL) from patients was used to isolate/identify CTCs/hybrid cells by ISET. We used markers with possible correlation with the phenomenon of cell fusion, such as MC1-R, EpCAM and CD45, as well as CEN8 expression by CISH analysis. Samples were collected at three timepoints: baseline, after one month (first follow-up) and after three months (second follow-up) of treatment with olaparib (total sample = 38). Fourteen patients were included and in baseline and first follow-up all patients showed at least one CTC. We found expression of MC1-R, EpCAM and CD45 in cells (hybrid) in at least one of the collection moments. Membrane staining with CD45 was found in CTCs from the other cohort, from the other center, evaluated by the CellSearch® system. The presence of circulating tumor microemboli (CTM) in the first follow-up was associated with a poor recurrence-free survival (RFS) (5.2 vs. 12.2 months; p = 0.005). The MC1-R expression in CTM in the first and second follow-ups was associated with a shorter RFS (p = 0.005). CEN8 expression in CTCs was also related to shorter RFS (p = 0.035). Our study identified a high prevalence of CTCs in ovarian cancer patients, as well as hybrid cells. Both cell subtypes demonstrate utility in prognosis and in the assessment of response to treatment. In addition, the expression of MC1-R and EpCAM in hybrid cells brings new perspectives as a possible marker for this phenomenon in ovarian cancer.

Distal Pancreatectomy with Celiac Axis Resection (Modified Appleby Procedure) and Arterial Reconstruction for Locally Advanced Pancreatic Adenocarcinoma After FOLFIRINOX Chemotherapy and Chemoradiation Therapy.

BACKGROUND: Resectability of pancreatic carcinoma (PC) is directly linked to vascular extension (Tempero MA et al. in J Natl Compr Canc Netw 15(8):1028-1061, 2017. https://doi.org/10.6004/jnccn.2017.0131 ; Isaji S et al. in Pancreatology 18(1):2-11, 2018. https://doi.org/10.1016/j.pan.2017.11.011 ). Involvement of the celiac axis (CA) is typically a contraindication to surgery. High postoperative morbidity and subsequent poor prognosis have been observed in this case, especially for contact > 180° requiring arterial resection (Tempero MA et al. 2017). Recent medical advances in PC treatment, such as FOLFIRINOX-based chemotherapy eventually followed by chemoradiation therapy, offer the potential to select tumour for surgery and to obtain a negative-margin resection even in case of unresectable PC at diagnosis (Suker M et al. in Lancet Oncol 17(6):801-10, 2016. https://doi.org/10.1016/s1470-2045(16)00172-8 ; Pietrasz D et al. in Ann Surg Oncol 26(1):109-117, 2019. https://doi.org/10.1245/s10434-018-6931-6 ). A major pathologic response has been observed in more than 20% of patients after this treatment and is associated with an improved survival (Suker M et al. 2016; Pietrasz D et al. 2019). This evolution allows aggressive surgical strategies with the possibility of long-term disease control for patients showing a good response to induction treatment. PATIENT: This video presents the case of a 66-year-old man diagnosed with a locally advanced ductal adenocarcinoma of the pancreatic body with a 360° involvement of the CA and the hepatic artery. After eight courses of FOLFIRINOX chemotherapy and a capecitabin-based chemoradiation, a surgical exploration was planned for potential resection. TECHNIQUE: The key steps of the procedure are presented, i.e. surgical exposition, assessment of resectability with frozen sections of peri-arterial tissues, en bloc resection (Strasberg SM et al. in Surgery 133(5):521-527, 2003. https://doi.org/10.1067/msy.2003.146 ), and primary end-to-end arterial reconstruction. CONCLUSION: A modified Appleby operation for locally advanced PC is a technically challenging but feasible procedure in experienced teams. It offers the possibility of en bloc R0 resection of a locally advanced PC with the potential of long-term disease local control. This video may help surgeons to perform this complex intervention.

Clinicopathological characterization of a real-world multicenter cohort of endometrioid ovarian carcinoma: Analysis of the French national ESME-Unicancer database.

BACKGROUND: Prognostic significance of endometrioid epithelial ovarian cancer (EOC) is controversial. We compared clinical, pathological, and biological features of patients with endometrioid and serous EOC, and assessed the independent effect of histology on outcomes. METHODS: We conducted a multicenter retrospective analysis of patients with EOC selected from the French Epidemiological Strategy and Medical Economics OC database between 2011 and 2016. Our main objective was to compare overall survival (OS) in endometrioid and serous tumors of all grades. Our second objectives were progression-free survival (PFS) and prognostic features. RESULTS: Out of 10,263 patients included, 3180 cases with a confirmed diagnosis of serous (N = 2854) or endometrioid (N = 326) EOC were selected. Patients with endometrioid histology were younger, more often diagnosed at an early stage, with lower-grade tumors, more frequently dMMR/MSI-high, and presented more personal/familial histories of Lynch syndrome-associated cancers. BRCA1/2 mutations were more frequently identified in the serous population. Endometrioid patients were less likely to receive chemotherapy, with less bevacizumab. After median follow-up of 51.7 months (95CI[50.1-53.6]), five-year OS rate was 81% (95CI[74-85]) in the endometrioid subgroup vs. 55% (95CI[53-57] in the serous subset (p < 0.001, log-rank test). In multivariate analyses including [age, ECOG-PS, FIGO, grade, and histology], the endometrioid subtype was independently associated with better OS (HR = 0.38, 95CI[0.20-0.70], p= 0.002) and PFS (HR = 0.53, 95CI[0.37-0.75], p < 0.001). CONCLUSIONS: Clinicopathological features at diagnosis are not the same for endometrioid and serous EOC. Endometrioid histology is an independent prognosis factor in EOC. These observations suggest the endometrioid population requires dedicated clinical trials and management.

Robotic Radical Hysterectomy for Cervical Adenocarcinoma after Preoperative Brachytherapy in 10 Steps.

STUDY OBJECTIVE: Minimally invasive surgery decreases postoperative morbidity after radical hysterectomy (RH) for early-stage cervical cancer. However, a randomized trial and large retrospective data question its safety after observing lower rates of survival than open surgery [1,2]. The causes of this higher recurrence rate are not definitely established but may result from cancer exposure to the peritoneum during vaginal section and cancerous cells' spillage enhanced by pneumoperitoneum or a uterine manipulator. The aim of this surgical video was to present a standardized step-by-step approach for robotic RH according to the recent recommendations from the ARCAGY -Group of National Investigators for the Study of Ovarian and Breast Cancers surgeon's group [3]. DESIGN: Step-by-step video demonstration of the technique. SETTING: Tertiary center specialized in gynecologic oncology and minimally invasive surgery. INTERVENTIONS: A 48-year-old woman was diagnosed with a stage IB2 endocervical adenocarcinoma (International Federation of Gynecology and Obstetrics 2018) with a tumor size of 27 mm. Surgery was planned after preoperative pulsed dose rate uterovaginal brachytherapy. Surgery was performed following 10 reproducible steps: • Pelvic sentinel node identification according to the SENTICOL-III trial • Right infundibulopelvic and round ligaments transection • Right uterine vessels transection • Parametrectomy • Right uterosacral ligament transection • Bladder mobilization • Identical left dissection • Rectovaginal space development • Colpectomy by vaginal route after complete pneumoperitoneum exsufflation • Robotic vaginal cuff closure and pelvic inspection Thorough robotically assisted vaginal cuff closure was carried out as a comparative study suggesting that abdominal closure may decrease vaginal complications and dehiscence [3]. CONCLUSION: No international recommendations for the RH approach have yet been endorsed. Patients must be clearly informed about the benefit-risk ratio of the surgical route. If a minimally invasive RH is still decided, the patient should be referred to experienced centers, and precautionary measures must be implemented [4]. Colpotomy by vaginal route without pneumoperitoneum is recommended. Uterine manipulators have to be strictly avoided. Preoperative brachytherapy has been reported in experienced centers in France with favorable histologic response with high rates of pathologic complete response (near 70%) and seems particularly worthwhile for tumor sizes ranging from 2 to 4 cm or presenting with lymphovascular invasion [5].

Primary cytoreductive surgery with or without hyperthermic intraperitoneal chemotherapy (HIPEC) for FIGO stage III epithelial ovarian cancer: OVHIPEC-2, a phase III randomized clinical trial.

BACKGROUND: The addition of hyperthermic intraperitoneal chemotherapy (HIPEC) to interval cytoreductive surgery improves recurrence-free and overall survival in patients with FIGO stage III ovarian cancer who are ineligible for primary cytoreductive surgery. The effect of HIPEC remains undetermined in patients who are candidates for primary cytoreductive surgery. PRIMARY OBJECTIVE: The primary objective is to evaluate the effect of HIPEC on overall survival in patients with FIGO stage III epithelial ovarian cancer who are treated with primary cytoreductive surgery resulting in no residual disease, or residual disease up to 2.5 mm in maximum dimension. STUDY HYPOTHESIS: We hypothesize that the addition of HIPEC to primary cytoreductive surgery improves overall survival in patients with primary FIGO stage III epithelial ovarian cancer. TRIAL DESIGN: This international, randomized, open-label, phase III trial will enroll 538 patients with newly diagnosed FIGO stage III epithelial ovarian cancer. Following complete or near-complete (residual disease ≤2.5 mm) primary cytoreduction, patients are randomly allocated (1:1) to receive HIPEC or no HIPEC. All patients will receive six courses of platinum-paclitaxel chemotherapy, and maintenance PARP-inhibitor or bevacizumab according to current guidelines. MAJOR ELIGIBILITY CRITERIA: Patients with FIGO stage III primary epithelial ovarian, fallopian tube, or primary peritoneal cancer are eligible after complete or near-complete primary cytoreductive surgery. Patients with resectable umbilical, spleen, or local bowel lesions may be included. Enlarged extra-abdominal lymph nodes should be negative on FDG-PET or fine-needle aspiration/biopsy. PRIMARY ENDPOINT: The primary endpoint is overall survival. SAMPLE SIZE: To detect a HR of 0.67 in favor of HIPEC, 200 overall survival events are required. With an expected accrual period of 60 months and 12 months additional follow-up, 538 patients need to be randomized. ESTIMATED DATES FOR COMPLETING ACCRUAL AND PRESENTING RESULTS: The OVHIPEC-2 trial started in January 2020 and primary analyses are anticipated in 2026. TRIAL REGISTRATION: ClinicalTrials.gov:NCT03772028.

An auristatin-based antibody-drug conjugate targeting HER3 enhances the radiation response in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer characterized by poor response to chemotherapy and radiotherapy due to the lack of efficient therapeutic tools and early diagnostic markers. We previously generated the nonligand competing anti-HER3 antibody 9F7-F11 that binds to pancreatic tumor cells and induces tumor regression in vivo in experimental models. Here, we asked whether coupling 9F7-F11 with a radiosensitizer, such as monomethylauristatin E (MMAE), by using the antibody-drug conjugate (ADC) technology could improve radiation therapy efficacy in PDAC. We found that the MMAE-based HER3 antibody-drug conjugate (HER3-ADC) was efficiently internalized in tumor cells, increased the fraction of cells arrested in G2/M, which is the most radiosensitive phase of the cell cycle, and promoted programmed cell death of irradiated HER3-positive pancreatic cancer cells (BxPC3 and HPAC cell lines). HER3-ADC decreased the clonogenic survival of irradiated cells by increasing DNA double-strand break formation (based on γH2AX level), and by modulating DNA damage repair. Tumor radiosensitization with HER3-ADC favored the inhibition of the AKT-induced survival pathway, together with more efficient caspase 3/PARP-mediated apoptosis. Incubation with HER3-ADC before irradiation synergistically reduced the phosphorylation of STAT3, which is involved in chemoradiation resistance. In vivo, the combination of HER3-ADC with radiation therapy increased the overall survival of mice harboring BxPC3, HPAC cell xenografts or patient-derived xenografts, and reduced proliferation (KI67-positive cells). Combining auristatin radiosensitizer delivery via an HER3-ADC with radiotherapy is a new promising therapeutic strategy in PDAC.

Isolated ipsilateral local recurrence of breast cancer: predictive factors and prognostic impact.

BACKGROUND: Tumour features associated with isolated invasive breast cancer (BC) ipsilateral local recurrence (ILR) after breast conservative treatment (BCT) and consequences on overall survival (OS) are still debated. Our objective was to investigate these points. METHODS: Patients were retrospectively identified from a cohort of patients who underwent BCT for invasive BC in 16 cancer centres. End-points were ILR rate and OS. The impact of ILR on OS was assessed by multivariate analysis (MVA) for all patients and according to endocrine receptors (ERs) and grade or tumour subtypes. RESULTS: Of 15,570 patients, ILR rate was 3.1%. Cumulative ILR rates differed according to ERs/grade (ERs+/Grade2: HR 1.42, p = 0.010; ERs+/Grade3: HR 1.41, p = 0.067; ERs-: HR 2.14, p < 0.0001), endocrine therapy (HR 2.05, p < 0.0001) and age < 40-years old (HR 2.28, p = 0.005) in MVA. When MVA was adjusted on tumour subtype, the latter was the only independent factor. OS-after-ILR was significantly different according to ILR-free intervals (HR 4.96 for ILR-free interval between 2 and 5-years and HR 9.00 when < 2-years, in comparison with ≥ 5-years). CONCLUSION: ERs/Grade status, lack of endocrine therapy and tumour subtypes predict isolated ILR risk in patients treated with BCT. Short ILR-free-intervals represent a strong pejorative factor for OS. These results may help selecting initial treatment as well as tailoring ILR systemic chemotherapy.

Adjuvant chemotherapy in lobular carcinoma of the breast: a clinicopathological score identifies high-risk patient with survival benefit.

BACKGROUND: Invasive lobular carcinomas (ILCs) represent approximately 10% of all breast cancers. Despite this high frequency, benefit of adjuvant chemotherapy (CT) is still unclear. METHODS: Our objective was to investigate the impact of CT on survival in ILC. Patients were retrospectively identified from a cohort of 23,319 patients who underwent primary surgery in 15 French centers between 1990 and 2014. Only ILC, hormone-positive, human epidermal growth factor 2 (HER2)-negative patients who received adjuvant endocrine therapy (ET) were included. End-points were disease-free survival (DFS) and overall survival (OS). A propensity score for receiving CT, aiming to compensate for baseline characteristics, was used. RESULTS: Of a total of 2318 patients with ILC, 1485 patients (64%) received ET alone and 823 (36%) received ET + CT. We observed a beneficial effect of addition of CT to ET on DFS and OS in multivariate Cox model (HR = 0.61, 95% confidence interval, CI [0.41-0.90]; p = 0.01 and 0.52, 95% CI [0.31-0.87]; p = 0.01, respectively). This effect was even more pronounced when propensity score matching was used. Regarding subgroup analysis, low-risk patients without CT did not have significant differences in DFS or OS compared to low-risk patients with CT. CONCLUSION: ILC patients could derive significant DFS and OS benefits from CT, especially for high-risk patients.

Robotic Versus Laparoscopic Total Mesorectal Excision for Sphincter-Saving Surgery: Results of a Single-Center Series of 400 Consecutive Patients and Perspectives.

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.

Overview of the pathological results and treatment characteristics in the first 1000 patients randomized in the SERC trial: axillary dissection versus no axillary dissection in patients with involved sentinel node.

BACKGROUND: Three randomized trials have concluded at non inferiority of omission of complementary axillary lymph node dissection (cALND) for patients with involved sentinel node (SN). However, we can outline strong limitations of these trials to validate this attitude with a high scientific level. We designed the SERC randomized trial ( ClinicalTrials.gov , number NCT01717131) to compare outcomes in patients with SN involvement treated with ALND or no further axillary treatment. The aim of this study was to analyze results of the first 1000 patients included. METHODS: SERC trial is a multicenter non-inferiority phase 3 trial. Multivariate logistic regression analysis was used to identify independent factors associated with adjuvant chemotherapy administration and non-sentinel node (NSN) involvement. RESULTS: Of the 963 patients included in the analysis set, 478 were randomized to receive cALND and 485 SLNB alone. All patient demographics and tumor characteristics were balanced between the two arms. SN ITC was present in 6.3% patients (57/903), micro metastases in 33.0% (298), macro metastases in 60.7% (548) and 289 (34.2%) were non eligible to Z0011 trial criteria. Whole breast or chest wall irradiation was delivered in 95.9% (896/934) of patients, adjuvant chemotherapy in 69.5% (644/926), endocrine therapy in 89.6% (673/751) and the proportions were similar in the two arms. The overall rate of positive NSN was 19% (84/442) for patients with cALND. Crude rates of positive NSN according to SN status were 4.5% for ITC (1/22), 9.5% for micro metastases (13/137), 23.9% for macro metastases (61/255) and were respectively 29.36% (64/218), 9.33% (7/75) and 7.94% (10/126) when chemotherapy was administered after cALND, before cALND and for patients without chemotherapy. CONCLUSION: The main objective of SERC trial is to demonstrate non inferiority of cALND omission. A strong interaction between timing of cALND and chemotherapy with positive NSN rate was observed. TRIAL REGISTRATION: This study is registered with ClinicalTrials.gov , number NCT01717131 October 19, 2012.

Prognostic impact of the inclusion of uPA/PAI-1 for adjuvant treatment decision-making in ER+/Her2- pN0 early breast cancers.

PURPOSE: Intermediate-risk early breast cancer (EBC) is a heterogeneous group in which adjuvant chemotherapy decision proves to be difficult. Clinical and pathological criteria are sometimes insufficient to determine the best therapeutic options, and validated biomarkers such as uPA/PAI-1, are needed to contribute to the decision-making. The objective of this study was to evaluate the clinical outcome of an unselected ER+/HER2- pN0 EBC cohort of patients in whom the routine clinical decision process included a prospective uPA/PAI-1 determination. METHOD: This monocentric retrospective study included 520 patients who underwent curative surgery in our institute between 2006 and 2011. Adjuvant therapeutic strategy was decided based on clinical-pathological data, altogether with a routine prospective determination of uPA/PAI-1 tumor levels using fresh, extemporaneously sampled tissue. We evaluated the correlation between uPA/PAI-1 levels, clinical-pathological variables, and the patient's outcome (relapse-free survival, RFS, and overall survival, OS). RESULT: Median follow-up was 5.4 years. The 5- and 10-year RFS rates were ,respectively, 95 and 89%, and the five-year OS rate was 96.3%. Forty percent of tumors had low uPA/PAI-1 levels. Seventy-five percent of patients with low uPA/PAI-1 levels did not receive chemotherapy, when 25% did. Sixty percent of patients with high uPA and/or PAI-1 levels received chemotherapy, while 40% did not. No statistical significant correlation was found between the uPA/PAI-1 levels and RFS or OS. CONCLUSION: The personalization of the patients' treatment using uPA/PAI-1 tumor levels allows the reversion of the well-known poor prognostic impact of high uPA/PAI-1 levels and strongly supports the use of this biomarker in clinical practice.

Robotic Versus Laparoscopic Total Mesorectal Excision (TME) for Sphincter-Saving Surgery: Is There Any Difference in the Transanal TME Rectal Approach? : A Single-Center Series of 120 Consecutive Patients.

BACKGROUND: Robotic total mesorectal excision (R-TME), a novel way for minimally invasive treatment of rectal cancer, was shown in previous studies to be safe and effective. However, comparison with laparoscopic total mesorectal excision (L-TME) has drawn contradictory disputes, especially concerning operative high-risk patients. The aim of this study was to compare R-TME and L-TME on the rectal technical approach. METHODS: Between October 2009 and March 2013, a total of 120 consecutive rectal carcinomas, operated for sphincter-saving procedure, were enrolled. The patient population included the last 60 laparoscopic procedures and the first 60 robotic surgeries (six hybrid approaches, then 54 full robotic surgeries). There were no exclusions. RESULTS: Patients' baseline characteristics were similar in both the R-TME and L-TME groups. Outcomes were equivalent for blood loss (200 vs. 100 mL), postoperative hospital stay (12 vs. 11 days), conversion rate (3.2 vs. 4.8 %), lymph nodes yield (15 vs. 19), no positive distal margin (0 %), positive radial margin (6.4 vs. 9.3 %), diverting ileostomy (73 vs. 58 %) and severe morbidity (28 vs. 20 %). Significant differences were found for median operative time (274 vs. 228 min; p = 0.003) and proctectomy performed via transanal approach (1.7 vs. 16.7 %; p = 0.004). The R-TME operative time curve stabilized to 245 min after the first 25 procedures. CONCLUSIONS: For rectal cancer, R-TME may be as feasible and safe as L-TME in terms of technique. In our practice and for difficult cases, R-TME allows complete rectal dissection by an abdominal approach, while L-TME requires a transanal approach.

Resolving quandaries: basaloid adenoid cystic carcinoma or breast cylindroma? The role of massively parallel sequencing.

AIMS: The aims of this study were to perform a whole-exome sequencing analysis of a breast cylindroma and to investigate the role of molecular analyses in the differentiation between breast cylindroma, a benign tumour that displays MYB expression, and CYLD gene mutations, and its main differential diagnosis, the breast solid-basaloid adenoid cystic carcinoma, a malignant tumour that is characterized by the presence of the MYB-NFIB fusion gene and MYB overexpression. METHODS AND RESULTS: A 66-year-old female underwent quadrantectomy after an irregular dense shadow was discovered in the right breast at the screening mammogram. Histologically, the tumour displayed features suggestive of a solid-basaloid variant of adenoid cystic carcinoma with a differential diagnosis of cylindroma. Fluorescence in situ hybridization, reverse transcription-polymerase chain reaction, immunohistochemistry and whole-exome sequencing revealed absence of the MYB-NFIB fusion gene, low levels of MYB protein expression and a clonal somatic CYLD splice site mutation associated with loss of heterozygosity of the wild-type allele. CONCLUSIONS: The results of the histological, immunohistochemical and molecular analyses were consistent with a diagnosis of breast cylindroma, providing a proof-of-principle that the integration of histopathological and molecular approaches can help to differentiate between a low-malignant potential and a benign breast tumour of triple-negative phenotype.

Genomic landscape of adenoid cystic carcinoma of the breast.

Adenoid cystic carcinoma (AdCC) is a rare type of triple-negative breast cancer (TNBC) characterized by the presence of the MYB-NFIB fusion gene. The molecular underpinning of breast AdCCs other than the MYB-NFIB fusion gene remains largely unexplored. Here we sought to define the repertoire of somatic genetic alterations of breast AdCCs. We performed whole-exome sequencing, followed by orthogonal validation, of 12 breast AdCCs to determine the landscape of somatic mutations and gene copy number alterations. Fluorescence in situ hybridization and reverse-transcription PCR were used to define the presence of MYB gene rearrangements and MYB-NFIB chimeric transcripts. Unlike common forms of TNBC, we found that AdCCs have a low mutation rate (0.27 non-silent mutations/Mb), lack mutations in TP53 and PIK3CA and display a heterogeneous constellation of known cancer genes affected by somatic mutations, including MYB, BRAF, FBXW7, SMARCA5, SF3B1 and FGFR2. MYB and TLN2 were affected by somatic mutations in two cases each. Akin to salivary gland AdCCs, breast AdCCs were found to harbour mutations targeting chromatin remodelling, cell adhesion, RNA biology, ubiquitination and canonical signalling pathway genes. We observed that, although breast AdCCs had rather simple genomes, they likely display intra-tumour genetic heterogeneity at diagnosis. Taken together, these findings demonstrate that the mutational burden and mutational repertoire of breast AdCCs are more similar to those of salivary gland AdCCs than to those of other types of TNBCs, emphasizing the importance of histological subtyping of TNBCs. Furthermore, our data provide direct evidence that AdCCs harbour a distinctive mutational landscape and genomic structure, irrespective of the disease site of origin.