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Significant rational is available for specific targeting of PI3K/AKT/mTOR pathway in the treatment of non-small cell lung cancer (NSCLC). However, almost all clinical trials that have evaluated Pi3K pathway-based monotherapies/combinations did not observe an improvement of patient's outcome. The aim of our study was therefore to define combination of treatment based on the determination of predictive markers of resistance to the mTORC1 inhibitor RAD001/Everolimus. An in vivo study showed high efficacy of RAD001 in NSCLC Patient-Derived Xenografts (PDXs). When looking at biomarkers of resistance by RT-PCR study, three genes were found to be highly expressed in resistant tumors, i.e., PLK1, CXCR4, and AXL. We have then focused our study on the combination of RAD001 + Volasertib, a PLK1 inhibitor, and observed a high antitumor activity of the combination in comparison to each monotherapy; similarly, a clear synergistic effect between the two compounds was found in an in vitro study. Pharmacodynamics study demonstrated that this synergy was due to (1) tumor vascularization decrease, increase of the HIF1 protein expression and decrease of the intracellular pH, and (2) decrease of the Carbonic Anhydrase 9 (CAIX) protein that could not correct intracellular acidosis. In conclusion, all these preclinical data strongly suggest that the inhibition of mTORC1 and PLK1 proteins may be a promising therapeutic approach for NSCLC patients.

Count data is becoming more and more ubiquitous in a wide range of applications, with datasets growing both in size and in dimension. In this context, an increasing amount of work is dedicated to the construction of statistical models directly accounting for the discrete nature of the data. Moreover, it has been shown that integrating dimension reduction to clustering can drastically improve performance and stability. In this paper, we rely on the mixture of multinomial PCA, a mixture model for the clustering of count data, also known as the probabilistic clustering-projection model in the literature. Related to the latent Dirichlet allocation model, it offers the flexibility of topic modeling while being able to assign each observation to a unique cluster. We introduce a greedy clustering algorithm, where inference and clustering are jointly done by mixing a classification variational expectation maximization algorithm, with a branch & bound like strategy on a variational lower bound. An integrated classification likelihood criterion is derived for model selection, and a thorough study with numerical experiments is proposed to assess both the performance and robustness of the method. Finally, we illustrate the qualitative interest of the latter in a real-world application, for the clustering of anatomopathological medical reports, in partnership with expert practitioners from the Institut Curie hospital., 34 pages, 11 figures, published in : Computational Statistics

ObjectiveDescribe characteristics, treatment patterns and clinical outcomes of patients with small-cell lung cancer (SCLC).DesignRetrospective chart review study defining several cohorts: (1) limited-stage disease (LD) SCLC initiating 1L therapy (1 L LD-SCLC), (2) extensive-stage disease (ED) SCLC initiating 1L therapy (1L ED-SCLC) and (3) patients initiating 2L therapy.Setting39 physicians (medical oncologists, thoracic oncologists and/or pulmonologists) from France, Italy and the UK.ParticipantsPatients >18 years of age with a confirmed diagnosis of LD-SCLC or ED-SCLC and a full oncology medical history. Patients included initiated a 1L (2013–2015) or 2L (2013–2016) treatment (chemotherapy and/or radiotherapy—RT).Primary and secondary outcome measuresOverall survival (OS) and progression-free survival (PFS).Results231 patients in 1L LD-SCLC, 308 in 1L ED-SCLC and 225 with relapse/refractory SCLC initiating 2L treatment were included. The proportion of men was higher across all groups (56.8% to 68.5%) and mean age at time of diagnosis was 66.0 and 65.4 years in 1L LD-SCLC and 2L ED-SCLC cohorts. The majority of patients in LD-SCLC 1L group received chemotherapy with RT (76.2%). Patients initiating 2L therapy predominantly received chemotherapy alone (79.6%).Median OS in 1 L patients was 17.3 months in LD-SCLC and 8.8 months in ED-SCLC. Median PFS was 11.6 months in LD-SCLC and 6.1 months in ED-SCLC patients. Median OS in patients initiating 2L treatment was 6.6 months. OS from start of 2L treatment was lower in patients initially diagnosed with ED (5.1 months) than in patients initially diagnosed with LD (9.3 months) (pConclusionsDespite the availability of a high number of treatments and combinations, the prognosis of SCLC is still unsatisfactory, especially for those patients diagnosed with ED-SCLC, indicating high unmet need in this patient population.

1AbstractTriple-Negative Breast Cancer (TNBC) is a rare cancer, characterized by high metastatic potential and poor prognosis, and has limited treatment options compared to other breast cancers. The current standard of care in non-metastatic settings is neoadjuvant chemotherapy (NACT), with the goal of breast-conserving surgery and for an in vivo assessment of chemosensitivity. However, the efficacy of this treatment varies significantly across patients, and this histological response heterogeneity is still poorly understood partly due to the paucity of available curated TNBC data. Motivated by this problem, we investigate the use of machine learning (ML) to predict at diagnosis the histological response to NACT for early TNBC patients. To overcome the known biases of related small scale studies while respecting data privacy, we conduct, for the first time, a TNBC study in a multi-centric fashion behind hospitals’ firewalls using collaborative Federated Learning (FL). Thereby allowing access to enough TNBC data to sustain a complete response heterogeneity investigation. We show evidence that local ML models relying on Whole-Slide Images (WSIs) at diagnosis are able to predict the histological response to NACT as accurately as current clinical approaches, which rely on time-consuming expert annotations. We demonstrate that collaborative training further improves performance over single-center training outperforming clinical methods. Our ML model is interpretable by design, and we show that it is sensitive to specific histological patterns. While we identify known predictive biomarkers among them, this proof of concept for real-world collaborative FL paves the way for future biomarker discovery using unprecedently large datasets.

Significant rational is available for specific targeting of PI3K/AKT/mTOR pathway in the treatment of non-small cell lung cancer (NSCLC). However, almost all clinical trials that have evaluated Pi3K pathway-based monotherapies/combinations did not observe an improvement of patient’s outcome. The aim of our study was therefore to define combination of treatment based on the determination of predictive markers of resistance to the mTORC1 inhibitor RAD001/Everolimus. An in vivo study showed high efficacy of RAD001 in NSCLC Patient-Derived Xenografts (PDXs). When looking at biomarkers of resistance by RT-PCR study, three genes were found to be highly expressed in resistant tumors, i.e., PLK1, CXCR4, and AXL. We have then focused our study on the combination of RAD001 + Volasertib, a PLK1 inhibitor, and observed a high antitumor activity of the combination in comparison to each monotherapy; similarly, a clear synergistic effect between the two compounds was found in an in vitro study. Pharmacodynamics study demonstrated that this synergy was due to (1) tumor vascularization decrease, increase of the HIF1 protein expression and decrease of the intracellular pH, and (2) decrease of the Carbonic Anhydrase 9 (CAIX) protein that could not correct intracellular acidosis. In conclusion, all these preclinical data strongly suggest that the inhibition of mTORC1 and PLK1 proteins may be a promising therapeutic approach for NSCLC patients.

International audience; Cancers of unknown primary (CUP) are metastatic cancers for which the primary tumor is not found despite thorough diagnostic investigations. Multiple molecular assays have been proposed to identify the tissue of origin (TOO) and inform clinical care; however, none has been able to combine accuracy, interpretability, and easy access for routine use. We developed a classifier tool based on the training of a variational autoencoder to predict tissue of origin based on RNA-sequencing data. We used as training data 20,918 samples corresponding to 94 different categories, including 39 cancer types and 55 normal tissues. The TransCUPtomics classifier was applied to a retrospective cohort of 37 CUP patients and 11 prospective patients. TransCUPtomics exhibited an overall accuracy of 96% on reference data for TOO prediction. The TOO could be identified in 38 (79%) of 48 CUP patients. Eight of 11 prospective CUP patients (73%) could receive first-line therapy guided by TransCUPtomics prediction, with responses observed in most patients. The variational autoencoder added further utility by enabling prediction interpretability, and diagnostic predictions could be matched to detection of gene fusions and expressed variants. TransCUPtomics confidently predicted TOO for CUP and enabled tailored treatments leading to significant clinical responses. The interpretability of our approach is a powerful addition to improve the management of CUP patients. Copyright

International audience; Objectives: Most supervised learning approaches currently applied in radiomics consist in classifying patients in groups (eg, responder versus non-responder, short overall survival versus long overall survival). With these methods, individual information from each patient is used only to assign a patient to a group. To preserve detailed information of each patient, we are developing an alternative approach that consists in identifying a "twin patient" based on radiomic features and clinical parameters in a patient database, i.e. another patient with feature values similar to the ones observed in the tested patient. Here, we studied whether this approach could predict the response to neoadjuvant chemotherapy in breast cancer patients. Methods: 117 patients with a triple-negative breast cancer were included in this study. All patients underwent a baseline 18F-FDG PET/CT using Gemini GXL 16 (Philips, 41 patients) or Discovery 710 Elite (GE, 76 patients) with a standard imaging protocol, before a neo-adjuvant chemotherapy associating anthracycline and taxane. The pathological response was assessed on the surgical specimen after chemotherapy according to the Residual Cancer Burden (RCB score). Based on PET images, the primary lesion of each patient was segmented using a threshold set to 40% of SUVmax, and a 6 mm thick ring around the tumor region was also used to measure the peri-tumoral metabolic activity. In each resulting volume of interest, we computed 48 radiomic features using LIFEx software (intensity resampling: 128 gray-levels between 0 and 40 SUV; spatial resampling: 2x2x2 mm) [1]. Radiomic features were harmonized between the two PET devices using ComBat [2]. The profile of each patient included 96 radiomic features and 3 clinical variables (age, Ki-67 expression, body mass index), each expressed as z-score. Using a leave-one-out approach, we computed the Euclidian distance between the profile of the tested patient and the profiles of all patients of the database. The smallest distance was used to identify the twin of the tested patient. This procedure was repeated by defining profiles including only 2, 4 and 6 features using a systematic feature selection process. The performance was evaluated using the Youden Index (YI=Sensitity+Specificity-1) to predict the response to neoadjuvant chemotherapy. Results: In our cohort, 68 patients were identified as responders to therapy and 49 patients as non-responders. Without feature selection, YI was 0.13 (Se=45% ; Sp=68%). When using 2 features only, the best performance was obtained for the combination of Entropy_Tumor and LZE_Ring with YI=0.36 (Se=59% ; Sp=76%). With 4 features, the best YI (=0.50) was obtained by adding Energy_Ring and SRE_Ring to Entropy_Tumor and LZE_Ring (Se=73% ; Sp=76%). With 6 features, the best combination was obtained by adding LZE_Tumor and LZHGE_Ring, yielding a YI of 0.56 (Se=80% ; Sp=76%). When we selected features, clinical variables were never included in the best combination, and radiomic features extracted from the peri-tumoral regions (ring) improved the identification of relevant twins. Conclusion: We demonstrated that the so called "twin patients" defined as sharing a number of similar radiomic features were likely to present similar response to neo-adjuvant chemotherapy. Feature selection improved the performance by including only features relevant to the prediction task into the profile. Unlike the conventional group-based patient management, the twin approach uses the detailed individual information of each patient previously treated. Further studies involving an independent cohort and more features in the combination are underway to further explore the potential of this concept. The identification of patient similarities also acts as a discovery approach to formulate new biological hypotheses, for instance, highlighting here the association between peri-tumoral heterogeneity and response to therapy.

This abstract was withdrawn by the authors.

Recent clinical results support the use of new immune checkpoint blockers (ICB), such as anti-PD-1 (e.g. nivolumab and pembrolizumab) and anti-PD-L1 antibodies. Radiological evaluation of ICB efficacy during therapy is challenging due to tumor immune infiltration. Changes of circulating tumor DNA (ctDNA) levels during therapy could be a promising tool for very accurate monitoring of treatment efficacy, but data are lacking with ICB.This prospective pilot study was conducted in patients with nonsmall cell lung cancer, uveal melanoma, or microsatellite-instable colorectal cancer treated by nivolumab or pembrolizumab monotherapy at Institut Curie. ctDNA levels were assessed at baseline and after 8 weeks (w8) by bidirectional pyrophosphorolysis-activated polymerization, droplet digital PCR or next-generation sequencing depending on the mutation type. Radiological evaluation of efficacy of treatment was carried out by using immune-related response criteria.ctDNA was detected at baseline in 10 out of 15 patients. At w8, a significant correlation (r = 0.86; P = 0.002) was observed between synchronous changes in ctDNA levels and tumor size. Patients in whom ctDNA levels became undetectable at w8 presented a marked and lasting response to therapy. ctDNA detection at w8 was also a significant prognostic factor in terms of progression-free survival (hazard ratio = 10.2; 95% confidence interval 2.5-41, P 0.001) and overall survival (hazard ratio = 15; 95% confidence interval 2.5-94.9, P = 0.004).This proof-of-principle study is the first to demonstrate that quantitative ctDNA monitoring is a valuable tool to assess tumor response in patients treated with anti-PD-1 drugs.

Purpose : Lymphovascular invasion (LVI) is a poor prognosis factor in breast cancer (BC), but data on its value in the neoadjuvant setting is scarce. This study evaluates the relationships between post-NAC LVI and prognosis in BC. Methods: We identified 1197 patients with primary BC receiving NAC +/- trastuzumab between 2002 and 2011. Information on LVI in post-NAC surgical specimen was retrieved from review of medical charts. Univariate and multivariate analyses were performed to assess the association of clinical, pathological factors with disease free survival (DFS) and overall survival (OS) was assessed using a cox proportional hazard model. Results: On 1197 tumors, 528 were luminal (44.1%), 375 were triple negative breast cancer (TNBC) (31.3%) and 294 were HER2-positive (24.6%). On post-NAC surgical specimens, LVI was present in 302 (25.2%), absent in 531 (44.4%), and was not mentionned in 364 cases (30.4%). The presence of post-NAC LVI was associated with an impaired DFS (HR=2.17, 95 CI [1.65 - 2.86], p Table 1 Univariate analysis and multivariate analysis on DFS (whole population) Univariate Multivariate VariableClassHRClpHRCIpAge< 451 0.35 45-550.82[0.62 - 1.08] >550.87[0.64 - 1.19] Menopausal statuspremenopausal1.04[0.81 - 1.34]0.75 postmenopausal1 BMI class19-251 < 191.24[0.75 - 2.05]0.41 > 251.36[1.06 - 1.75]0.01 Tumor sizeT1-T21 T31.77[1.38 - 2.27]201.54[1.06 - 2.22]0.02 Mitotic index≤221 >221.18[0.9 - 1.53]0.23 DCIS componentno1 yes1.33[0.88 - 2.01]0.18 Pre-NAC LVIno1 yes1.35[0.88 - 2.01]0.09 ER statusnegative1 positive0.72[0.56 - 0.91] Post-NAC LVI was an independent predictor of poor DFS, that overwhelmed the prognostic impact of pathological complete response in all 3 BC subtypes. Post-NAC LVI was also an independent predictor of poor OS in the whole cohort and in all BC subtypes. Table 1 resumes univariate and multivariate analysis on DFS in whole population. Conclusion: Post-NAC LVI is a strong independent prognostic factor associated with poor DFS and OS, that (i) should be systematically mentioned in pathological reports following NAC and (ii) could be used to select high risk patients candidates to second line trials in the post-neoadjuvant window. Citation Format: Hamy-Petit A-S, Lam G-T, Laas E, Darrigues L, Balezeau T, Guerin J, Livartowski A, Sadacca B, Pierga J-Y, Vincent-Salomon A, Bidard F-C, Lerebours F, Brain E, Becette V, Rouzier R, Lae M, Reyal F. Lymphovascular invasion in breast carcinoma following neodjuvant chemotherapy is a strong prognosis factor [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P2-03-04.

Background: Few studies have evaluated the effects of adjuvant radiotherapy (RT)of breast cancer(BC). The relation between the risk of lung carcinoma and radiotherapy have been controversial. Methods and materials: We retrospectively studied 127 patients treated at the Institut Curie with non metastatic breast cancer and lung carcinoma between 2000 and 2011(2/3 of BC apperead befor lung). Confirmation Diagnosis bronchial cancer obtained by: biopsy: histological data:architecture, IHC (HR, HER 2, TTF1), EGFR, Kras statut clinical and radiological Correlation. Comparison with breast tumor Results: BC: median age at diagnosis 54 years, predominatly invasive ductual carcinoma(IDC), lumpectomy 78%, mastectomy 21%. Lung cancer: median age at diagnosis: 63 years, 67 smokers. histology: 52 % Adenocarcinoma, 18.1 % scamous cell carcinoma, 18.1% large cell carcinoma, 13.4 % small cell carcinoma. EGFR mutation in 4.3%. 109 patients underwent RT (3 cases of lung cancer befor BC):Region: internal mammary chain: 46, supracalvicular: 42, axillary: 21. Technique: lateral decubitus position: 44, dorsal decubitus position: 57. Interval between breast and lung cancer: 0–3 years: 24.4%, 3–5 years: 15%, 6–10years: 16.5%, 11–20 years: 28%, >20 years: peak of incidence of lung cancer in the 3 years of diagnosis of breast cancer: 24.4 %. There was no apparent relation between treatment of BC and relative risk of developing lung carcinoma. 2nd peak between 11–20 years: 32 % patients, suggest that RT may increase risk of lung carcinoma (latency period for radiation induced second malignancy). Conclusion: This study suggest that adjuvant RT is associated with a real but small risk of developing lung carcinoma. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P4-13-14.

Background: Breast cancer is the leading nonhematologic cause of meningeal carcinomatosis (MC). The aim of this study was to report the outcome of patients diagnosed with breast cancer MC and treated in single institution by a high-dose intrathecal methotrexate (MTX) regimen. Methods: Ninety-one patients were diagnosed with breast cancer MC from 2000 to 2007. Intrathecal treatment was MTX 15 mg/day (days 1-5), hydrocortisone acetate (day 1) and oral folinic acid (days 1-5), repeated every 2 weeks. Patients and tumor characteristics were associated with the early clinical and biological outcome and with the overall survival (OS). Results: The median survival was 4.5 months (range 0-53). In multivariate analysis, adverse prognostic factors at diagnosis were performance status >2 [P = 0.006, response rate (RR) = 0.33 (0.15-0.71)], more than three chemotherapy regimens before MC diagnosis [P = 0.03, RR = 0.40 (0.19-0.93)], negative hormone receptor status [P = 0.02, RR = 0.4 (0.19-0.90)] and high Cyfra 21-1 level [P = 0.048, RR = (0.09-0.99)]. Clinical progression after one cycle and biological response after two cycles were independently associated with OS [P < 0.001, RR = 0.09 (0.02-0.37) and P = 0.003, RR = 3.6 (1.5-8.5), respectively]. We propose a prognostic score in order to define three distinct groups of prognosis. Conclusions: MC presents a poor prognosis, but 1-year survival rate was 25%. This score may become a useful tool for treatment decision and clinical trials.

Purpose Malignant pleural effusion has a very poor prognosis, raises problems of medical management, and impairs quality of life. The authors report the first experience of a pleural implantable access system for the treatment of recurrent symptomatic malignant pleural effusion. Description Prospective follow-up of 29 patients between August 20, 2005 and August 1, 2007 in a single center. Thirty-four pleural implantable access systems were placed in 29 patients (23 patients with breast cancers, 4 patients with bilateral placements, and 1 patient with a replacement) under sedation after the decision of a multidisciplinary meeting. Evaluation Twenty-eight patients obtained partial or complete relief of their dyspnea. Six patients underwent pleurodesis after a maximum of 2 months. Fifteen patients were receiving chemotherapy at the time of placement. Seven patients died at the Institut Curie or in a palliative care unit without returning home. The other 22 patients presented a total of 280 days of hospitalization for 2,717 days of catheter implantation. No placement failures were observed in this series. Two infectious complications (infectious pneumonia and skin infection over the puncture site) and two mechanical complications (expulsion of the port and disconnection between the port and the catheter) were observed and easily treated. One patient had loculation of the pleural cavity develop after 16 thoracenteses making further thoracentesis ineffective. Conclusions The pleural implantable access system is an interesting alternative in terms of efficacy and safety for the outpatient management of malignant pleural effusion. It presents a number of advantages in terms of comfort and infectious risk compared with tunnelled pleural catheters.

STI571, or imatinib, selectively inhibits BCR/ABL, PDGFR and c-kit kinase activity. It has been reported that a large proportion of small cell lung cancer (SCLC) cell lines and tumors express c-kit and that STI571 inhibits tumor cell growth. We therefore investigated the therapeutic efficacy of STI571, alone or combined with chemotherapy, in human SCLC cells or tumors xenografted into nude mice. The level of c-kit mRNA expression was variable in SCLC tumors (positive for 2 of 4 xenografts), and c-kit protein was not detected by immunohistochemistry. On the 4 xenografted tumors, PDGFRalpha and PDGFRbeta were not detected by immunohistochemistry. STI571 induced inhibition of proliferation of the SCLC6 cell line without inducing apoptosis; in contrast, in combination with etoposide or topotecan, the growth inhibition of SCLC6 cells induced by STI571 was increased, with apoptotic DNA fragmentation. Four human SCLC xenografts (SCLC6, SCLC61, SCLC74 and SCLC108) were transplanted into mice. After intraperitoneal injection of STI571, we observed 80%, 40% and 78% growth inhibition of SCLC6, SCLC61 and SCLC108 tumors, respectively, without any significant inhibition of SCLC74 tumor growth. In mice bearing responsive SCLC tumors, we observed an increase of growth inhibition induced by chemotherapy (etoposide + ifosfamide or topotecan) by concomitant and continuous administration of STI571, associated with an increase of toxic deaths. In SCLC6-bearing mice receiving sequential treatments, we observed a reduction of toxic deaths but a decrease of synergistic antitumor efficacy. In conclusion, the efficacy of STI571 alone in SCLC xenografted tumors was variable and did not depend on c-kit expression. Moreover, a significant increase of chemotherapy-induced growth inhibition was obtained by concomitant administration of STI571 that should be carefully investigated in SCLC patients.

Percutaneous vertebroplasty (PV) is a therapeutic option in patients with vertebral metastases (VM). However its efficacy in pain relief, improvement in quality of life and safety in patients with VM from breast cancer has not been reported. We present a longitudinal retrospective study of 31 consecutively treated female patients with VM from breast cancer where 88 vertebrae were treated in 44 sessions of PV, in which osteolytic, osteoblastic and mixed lesions were recorded. The visual analogue pain scale (VAS) was used to evaluate pain pre-PV, at one, three, six and 12 months post-PV. The Eastern Cooperative Group (ECOG) performance status scale was used at the same time intervals to measure quality of life: 90.3% pain relief was identified with a VAS reduction from 5.7 ± 2.0 pre-PV to 2.9 ± 2.2 post-PV at one-month follow-up (p

Using the shell vial assay and sequence analysis of a variable region of the glycoprotein B (gB) gene, cytomegalovirus (CMV) excretion rates in urine and virus transmission were studied among 93 children from six day care centers (DCCs). During a 6-month period, excretion rates differed significantly between DCCs (P < .001). The 6 gB gene sequences, obtained from 24 CMV-infected children, were classified in four previously defined groups. In five DCCs, 2 or 3 strains cocirculated, and none was dominant. Infection could have been acquired outside the DCC for 2 children and inside it for 9. Two children from the same DCC had mixed infections. No differences in hygiene, child care practices, or experience and level of qualification of the staff could explain this wide variety of excretion rates between DCCs. The distribution of gB gene patterns observed does not suggest that 1 type was dominant or more efficiently transmitted.