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PurposeNeurotensin receptor-1 (NTS1) is increasingly recognized as a potential target in diverse tumors including breast cancer, but factors associated with NTS1 expression have not been fully clarified.MethodsWe studied NTS1 expression using the Tissue MicroArray (TMA) of primary breast tumors from Institut Bergonié. We also studied association between NTS1 expression and clinical, pathological, and biological parameters, as well as patient outcomes.ResultsOut of 1419 primary breast tumors, moderate to strong positivity for NTS1 (≥ 10% of tumoral cells stained) was seen in 459 samples (32.4%). NTS1 staining was cytoplasmic in 304 tumors and nuclear in 155 tumors, a distribution which appeared mutually exclusive. Cytoplasmic overexpression of NTS1 was present in 21.5% of all breast tumors. In multivariate analysis, factors associated with cytoplasmic overexpression of NTS1 in breast cancer samples were higher tumor grade, Ki67 ≥ 20%, and higher pT stage. Cytoplasmic NTS1 was more frequent in tumors other than luminal A (30% versus 17.3%; p < 0.0001). Contrastingly, the main “correlates” of a nuclear location of NTS1 were estrogen receptor (ER) positivity, low E&E (Elston and Ellis) grade, Ki67 < 20%, and lower pT stage. In NTS1-positive samples, cytoplasmic expression of NTS1 was associated with shorter 10-year metastasis-free interval (p = 0.033) compared to NTS1 nuclear staining. Ancillary analysis showed NTS1 expression in 73% of invaded lymph nodes from NTS1-positive primaries.ConclusionNTS1 overexpression was found in about one-third of breast tumors from patients undergoing primary surgery with two distinct patterns of distribution, cytoplasmic distribution being more frequent in aggressive subtypes. These findings encourage the development of NTS1-targeting strategy, including radiopharmaceuticals for imaging and therapy.

Background The Cox model relies on the proportional hazards (PH) assumption, implying that the factors investigated have a constant impact on the hazard - or risk - over time. We emphasize the importance of this assumption and the misleading conclusions that can be inferred if it is violated; this is particularly essential in the presence of long follow-ups. Methods We illustrate our discussion by analyzing prognostic factors of metastases in 979 women treated for breast cancer with surgery. Age, tumour size and grade, lymph node involvement, peritumoral vascular invasion (PVI), status of hormone receptors (HRec), Her2, and Mib1 were considered. Results Median follow-up was 14 years; 264 women developed metastases. The conventional Cox model suggested that all factors but HRec, Her2, and Mib1 status were strong prognostic factors of metastases. Additional tests indicated that the PH assumption was not satisfied for some variables of the model. Tumour grade had a significant time-varying effect, but although its effect diminished over time, it remained strong. Interestingly, while the conventional Cox model did not show any significant effect of the HRec status, tests provided strong evidence that this variable had a non-constant effect over time. Negative HRec status increased the risk of metastases early but became protective thereafter. This reversal of effect may explain non-significant hazard ratios provided by previous conventional Cox analyses in studies with long follow-ups. Conclusions Investigating time-varying effects should be an integral part of Cox survival analyses. Detecting and accounting for time-varying effects provide insights on some specific time patterns, and on valuable biological information that could be missed otherwise.

Objectives To evaluate the diagnostic accuracy of breast MRI in identifying lesions requiring excision for patients with suspicious nipple discharge but normal mammograms and ultrasounds. Methods Between September 2013 and May 2019, 106 female participants (mean age 57.9 years) were consecutively included in this prospective multicenter study; 102 were retained for analysis. MRI was considered negative in the absence of suspicious enhancement and positive in cases of ipsilateral abnormal enhancement (BI-RADS 3 to 5). Final diagnoses were based on histological findings of surgical or percutaneous biopsies or at 1-year follow-up. We considered all lesions requiring excision found on pathology (papilloma, atypia, nipple adenomatosis, or cancer) as positive results. We considered spontaneous resolution of the discharge at 1 year as a negative result. Results MRI showed ipsilateral abnormal enhancement in 54 patients (53%) revealing 46 lesions requiring excision (31 benign papillomas, 5 papillomas with atypia, 2 nipple adenomatosis, and 8 cancers) and 8 benign lesions not requiring excision. No suspicious enhancement was found in the remaining 48 participants (47%). Forty-two were followed up at 1 year with spontaneous resolution of the discharge and six underwent surgery (revealing 2 benign papillomas). MRI diagnostic accuracy for the detection of a lesion requiring excision was as follows: sensitivity 96%, specificity 85%, positive predictive value 85%, and negative predictive value 96%. Conclusion In patients with suspicious nipple discharge and normal mammogram and ultrasound, MRI demonstrates excellent performance to identify lesions for which excision is required. Normal MRI indicates it is safe to propose follow-up only management, thus avoiding unnecessary duct excision. Trial registration ClinicalTrials.gov NCT02819362 Key Points • Breast MRI can be useful for the management of patients with suspicious nipple discharge and negative mammogram and ultrasound. • MRI detected a lesion requiring excision in 46 participants (45%) with unexplained discharge. • If breast MRI is negative, follow-up is a safe alternative for these patients.

A prognostic gene expression signature predicts metastasis in individuals with sarcomas and other tumor types more accurately than existing tools. Sarcomas are heterogeneous and aggressive mesenchymal tumors. Histological grading has so far been the best predictor for metastasis-free survival, but it has several limitations, such as moderate reproducibility and poor prognostic value for some histological types. To improve patient grading, we performed genomic and expression profiling in a training set of 183 sarcomas and established a prognostic gene expression signature, complexity index in sarcomas (CINSARC), composed of 67 genes related to mitosis and chromosome management. In a multivariate analysis, CINSARC predicts metastasis outcome in the training set and in an independent 127 sarcomas validation set. It is superior to the Fédération Francaise des Centres de Lutte Contre le Cancer grading system in determining metastatic outcome for sarcoma patients. Furthermore, it also predicts outcome for gastrointestinal stromal tumors (GISTs), breast carcinomas and lymphomas. Application of the signature will permit more selective use of adjuvant therapies for people with sarcomas, leading to decreased iatrogenic morbidity and improved outcomes for such individuals.

Purpose There is a need to refine the prognosis of triple-negative breast cancer (TNBC) patients after neoadjuvant chemotherapy (NAC) and to study the influence of the tumor microenvironment. We evaluated the prognostic value of pathological and immune markers in TNBC with residual disease (RD) after NAC. Methods In a series of 186 TNBC patients treated by NAC, we assessed the prognostic value of the Residual Cancer Burden (RCB) index. In 109 patients with RD, we studied the impact of clinicopathological features and tumor immune response in the residual tumor on overall survival (OS) and distant recurrence-free interval (DRFI). Results In the whole group, the OS and DRFI, at 3 years, were statistically different between the different classes of RCB ( P  = 0.0004 and P  < 0.0001, respectively). In univariate analysis of the RD group, low RCB index and high ratios of stromal tumor-infiltrating lymphocytes (TILs), CD3 + TILs, CD4 + TILs, CD8 + TILs, and IDO1-positive cells were significant favorable prognostic factors for DRFI at 3 years. In the final multivariate model, CD4 + TILs and RCB index showed a statistically independent prognostic significance for DRFI [Hazard Ratio (HR) 2.88 (95%CI 1.34–6.17), P  = 0.007 and HR 12.04 (95%CI 2.78–52.23, P  < 0.0001), respectively]. The CD4 + TIL levels influenced survival in the different RCB classes with a significant effect observed in RCB-II and RCB-III classes ( P  = 0.05 and P  = 0.05, respectively). Conclusions These results suggest that the combination of pathological (RCB index) and tumor micro-environmental features (CD4 + TILs) help refining the prognosis of TNBC patients with RD following NAC.

Background To determine safety and efficacy of radiofrequency ablation (RFA) for local treatment of lung metastases of renal cell carcinoma (RCC), sequenced or combined with systemic treatments. Methods Retrospectively, we studied 53 patients treated by RFA for a maximum of six lung metastases of RCC. The endpoints were local efficacy, overall (OS), disease-free (DFS), pulmonary progression-free (PPFS) and systemic treatment-free (STFS) survivals, complications graded by the CTCAE classification and factors associated with survivals. Potential factors analysed were: clinical and pathological data, tumoral staging of TNM classification, primary tumor histology, Fuhrman’s grade, age, number and size of lung metastases and extra-pulmonary metastases pre-RFA. Results One hundred metastases were treated by RFA. Median follow-up time was 61 months (interquartile range 90–34). Five-year OS was 62% (95% confidence interval (CI): 44–75). Median DFS was 9.9 months (95% CI: 6–16). PPFS at 1 and 3 years was 58.9% (95%CI: 44.1–70.9) and 35.2% (95%CI: 21.6–49.1), respectively. We observed 3% major complications (grade 3 and 4 of CTCAE classification). Local efficacy was 91%. Median STFS was 28.3 months. Thirteen patients (25%) with lung recurrence could be treated by another RFA. T3/T4 tumors had significantly worse OS, PPFS and STFS. Having two or more lung metastases increased the risk of pulmonary progression more than threefold. Conclusion Integrated to systemic treatment strategy, RFA is safe and effective for the treatment strategy of lung metastasis from RCC with good OS and long systemic treatment-free survival. RFA offers the possibility of repeat procedures, with low morbidity.

Combined intra-operative ablation and resection (CARe) is proposed to treat extensive colorectal liver metastases (CLM). This multicenter study was conducted to evaluate overall survival (OS), local recurrence-free survival (LRFS), hepatic recurrence-free survival (HRFS) and progression-free survival (PFS), to identify factors associated with survival, and to report complications. Four centers combined retropectively their clinical experiences regarding CLM treated by CARe. CLM characteristics, pre- and post-operative chemotherapy regimens, surgical procedures, complications and survivals were analyzed. Of the 288 patients who received CARe, 210 (73%) had synchronous and 255 (88%) had bilateral CLM. Twenty-two patients (8%) had extrahepatic disease. Median follow-up was 3.17 years (95%CI 2.83-4.08). Median OS was 3.33 years (95%CI 3.08-4.17) and 5-year OS was 37% (95%CI 29-45). One- and 5-year LRFS from ablated lesions were 87.9% (95%CI 83.3-91.2) and 78.0% (95%CI 71-83), respectively. Median HRFS and PFS were 14 months (95%CI 11-18) and 9 months (95%CI 8-11), respectively. One hundred patients experienced complications: 29 grade I, 68 grade II-III-IV, and three deaths. In the multivariate models adjusted for center, the occurrence of complications was confirmed as a major independent factor associated with 3-year OS (HR 1.80; P = 0.008). Five-year OS was 25.6% (95%CI 14.9-37.6) for patients with complications and 45% (95%CI 33.3-53.4) for patients without. Recent strategies facing advanced CLM include non-anatomic resections, portal-induced hypertrophy of the future remnant liver and aggressive medical preoperative treatments. CARe has the qualities of an approach that allows effective tumor clearance while maintaining good tolerance for the patient.

Purpose To evaluate the feasibility of pre-operative radiotherapy (54 Gy) with Helical Tomotherapy (HT) followed by surgery. Methods and materials Ten patients with non-metastatic resectable retroperitoneal liposarcomas were treated by pre-operative tomotherapy (54 Gy) and surgery. Clinical and biological toxicities were evaluated on the CTCAEV3.0 scale. For nine patients, delivered tomotherapy plans were compared with retrospectively-planned dynamic intensity-modulated radiotherapy (IMRT) dosimetric studies. Results No immediate or late Grade>2 toxicities were observed after radiotherapy. Post-operatively, one patient died and three patients experienced Grade 3 toxicity (two digestive and one metabolic). These toxicities disappeared and only two patients presented persistent Grade 1 paresthesia. R0 resection was obtained for four patients, R1 for four, and R2 resection for two. With a median follow-up of 26 months, no local or metastatic relapse was observed. Dosimetric comparisons between HT and retrospectively-planned IMRT demonstrate adequate target volume coverage for both techniques. Gastrointestinal sparing is higher with HT with a D200cc reduced by 5 Gy. Integral dose (ID) was increased in HT. Conclusions High dose pre-operative radiotherapy (54 Gy) for retroperitoneal liposarcoma is feasible and mostly well tolerated. Cumulative toxicity and tolerance depend mainly on patient’s general status. Image-guided radiation therapy (IGRT) is essential, irrespective of the IMRT technique used. Furthermore, HT offers the possibility of sparing selected areas in such complex volumes.

BackgroundChemotherapy (ct) is the preferred treatment option in metastatic colorectal cancer (mCRC). The objective of the study was to determine the overall survival (OS), disease-free survival (DFS) and ct-free survival (CFS) of pulmonary thermal ablation (TA) and its place in the treatment of mCRC.Patients and methodsAll consecutive patients treated (over 11 years) with percutaneous TA for lung metastasis of colorectal origin were reviewed. All sequences of treatments were considered. We determined the OS, DFS and CFS of pulmonary TA.ResultsTwo hundred and nine patients underwent 323 TA procedures for 630 lung metastases. Majority of the metastases (71.5%) were unilateral with a median diameter of 10 mm (2–46). A single metastasis was treated in 95 patients (45.5%), and 2–8 in 114 patients (54.5%). One hundred and thirty-two patients (63.2%) had only a single procedure, 77 patients (36.8%) had 2–5 procedures. Following the first TA (n = 209), 125 patients (59.8%) resumed ct. Sixty-four out of the 126 patients presenting lung progression were treated again with TA. The median CFS was 12.2 months (95% CI: 10.3–17.7). Patients with no extra-pulmonary metastases showed a statistically better CFS than those who had extra-pulmonary metastases with a median of 20.9 and 9.2 months, respectively (p < 0.001). Median follow-up and OS were 50 and 67.6 months, respectively.ConclusionThis study demonstrates, for the first time, that TA enables a CFS of 12.2 months that extended to 20.9 months in patients who presented with lung-only metastases. TA is a viable option for a pause in the therapy of mCRCs.

Cytoreductive peritoneal surgery (CRS) associated with hyperthermic peritoneal chemotherapy (HIPEC) has long been considered the standard treatment for colorectal peritoneal metastases (CPM). However, although efficacy of surgery has been demonstrated, evidence supporting HIPEC's role is less certain. Overall survival (OS), progression-free survival (PFS) and morbidity were analysed retrospectively for fifty consecutively included patients treated for colorectal CPM with complete CRS and systemic chemotherapy only. Median peritoneal cancer index (PCI) was 8 (range 1-24). 23 patients had liver or lung metastases (LLM). 22 patients had synchronous CPM. 27 complications occurred (12 Grade 1/2, 14 Grade 3, 1 Grade 4a, 0 Grade 5). Median follow-up was 62.5 months (95 %CI 45.4-81.3), median survival 32.4 months (21.5-41.7). Three- and 5-year OS were 45.5% (0.31-0.59) and 29.64% (0.17-0.44) respectively. Presence of LLMs associated with peritoneal carcinomatosis was significantly associated with poorer prognosis, with survival at 5 years of 13.95% (95 %CI 2.9-33.6) vs. 43.87% (22.2-63.7) when no metastases were present (P= 0.018). Median PFS was 9.5 months (95 %CI 6.2-11.1). With an equivalent PCI range and despite one of the highest rates of LLM in the literature, our survival data of CRS + systemic chemotherapy only compare well with results reported after additional HIPEC. Tolerance was better with acceptable morbidity without any mortality. Extra-hepatic metastasis (LLM) is a strong factor of poor prognosis. Awaiting the results of the randomized PRODIGE trial, these results indicate that CRS + systemic chemotherapy only is a robust hypothesis to treat colorectal CPM.