Circulating tumour cells and pathological complete response: independent prognostic factors in inflammatory breast cancer in a pooled analysis of two multicentre phase II trials (BEVERLY-1 and -2) of neoadjuvant chemotherapy combined with bevacizumab.

Background: We present a pooled analysis of predictive and prognostic values of circulating tumour cells (CTC) and circulating endothelial cells (CEC) in two prospective trials of patients with inflammatory breast cancer (IBC) treated with neoadjuvant chemotherapy combined with neoadjuvant and adjuvant bevacizumab. Patients and methods: Nonmetastatic T4d patients were enrolled in two phase II multicentre trials, evaluating bevacizumab in combination with sequential neoadjuvant chemotherapy of four cycles of FEC followed by four cycles of docetaxel in HER2-negative tumour (BEVERLY-1) or docetaxel and trastuzumab in HER2-positive tumour (BEVERLY-2). CTC and CEC were detected in 7.5 and 4 ml of blood, respectively, with the CellSearch System. Results: From October 2008 to September 2010, 152 patients were included and 137 were evaluable for CTC and CEC. At baseline, 55 patients had detectable CTC (39%). After four cycles of chemotherapy, a dramatic drop in CTC to a rate of 9% was observed (P < 0.01). Pathological complete response (pCR) rate was 40%. No correlation was found between CTC or CEC levels and pCR rate. Median follow-up was 43 months. CTC detection (≥1 CTC/7.5 ml) at baseline was associated with shorter 3-year disease-free survival (39% versus 70% for patients without CTC, P < 0.01, HR 2.80) and shorter 3-year overall survival (OS) (P < 0.01). In multivariate analysis, independent prognostic parameters for shorter survival were absence of hormonal receptors, no pCR and CTC detection at baseline. CEC level at baseline or variations during treatment had no prognostic value. Conclusion: In this pooled analysis of two prospective trials in nonmetastatic IBC, detection rate of CTC was 39% with a strong and independent prognostic value for survival. Combination of pCR after neoadjuvant treatment with no CTC detection at baseline isolated a subgroup of IBC with excellent OS (94% 3-year OS), suggesting that CTC count could be part of IBC stratification in prospective trials.

Analysis of Arrestin Recruitment to Chemokine Receptors by Bioluminescence Resonance Energy Transfer.

Chemokine receptors recruit the multifunctional scaffolding protein beta arrestin in response to binding of their chemokine ligands. Given that arrestin recruitment represents a signaling axis that is in part independent from G-protein signaling, it has become a hallmark of G protein-coupled receptor functional selectivity. Therefore, quantification of arrestin recruitment has become a requirement for the delineation of chemokine and drug candidate activity along different signaling axes. Bioluminescence resonance energy transfer (BRET) techniques provide methodology for such quantification that can reveal differences between nonredundant chemokines binding the same receptor, and that can be upscaled for high-throughput testing. We here provide protocols for the careful setup of BRET-based arrestin recruitment assays, and examples for the application of such systems in dose-response or time-course experiments. Suggestions are given for troubleshooting, optimizing test systems, and the interpretation of results obtained with BRET-based assays, which indeed yield an intricate blend of quantitative and qualitative information.

[Systemic treatment of brain metastases from breast cancer]. / Métastases cérébrales de cancer du sein: traitements systémiques.

An increase in the incidence of breast cancer patients with brain metastases has been observed over the last years, mainly because the recent development of new drugs including therapies targeting HER2 (human epidermal growth factor receptor 2) resulted in an increased survival of these patients. With HER2+ patients living longer and the well-known neurotropism of HER2+ tumour cells, the resulting high incidence of brain metastases is not really surprising. Moreover, brain metastases more often occur within a context of existing extracranial metastases. These need to be treated at the same time in order to favourably impact patients' survival. Consequently, the management of breast cancer patients with brain metastases clearly relies on a multidisciplinary approach, including systemic treatment. A working group including neuro-oncologists, neurosurgeons, radiation oncologists and oncologists was created in order to provide French national guidelines for the management of brain metastases within the "Association des neuro-oncologues d'expression française" (ANOCEF). The recommendations regarding the systemic treatment in breast cancer patients are reported here including key features of their management.

A randomized controlled phase II trial of a novel composition of paclitaxel embedded into neutral and cationic lipids targeting tumor endothelial cells in advanced triple-negative breast cancer (TNBC).

BACKGROUND: EndoTAG-1, composed of paclitaxel embedded in liposomal membranes targeting tumor endothelial cells, was evaluated for safety and efficacy in advanced triple-negative breast cancer (TNBC). PATIENTS AND METHODS: One hundred and forty patients were treated with weekly EndoTAG-1 (22 mg/m(2)) plus paclitaxel (70 mg/m(2)), twice weekly EndoTAG-1 (2× 44 mg/m(2)), or weekly paclitaxel (90 mg/m(2)) for greater than or equal to four cycles (3-week treatment + 1-week rest) or until progression/toxicity. Primary end point was progression-free survival (PFS) rate evaluated centrally after four cycles of therapy (week 16). The study was not powered for intergroup comparisons. RESULTS: The PFS rate at week 16 was 59.1% [one-sided 95% CI: 45.6, ∞] on combination treatment, 34.2% [21.6, ∞] on EndoTAG-1, and 48.0% [30.5, ∞] on paclitaxel. Median PFS reached 4.2, 3.4, and 3.7 months, respectively. After complete treatment (week 41 analysis), median overall survival (OS) was 13.0, 11.9, and 13.1 months for the modified Intention-to-Treat (ITT) population and 15.1, 12.5, and 8.9 months for the per-protocol population, respectively. The clinical benefit rate was 53%, 31%, and 36% for the treatment groups. Safety analysis revealed known toxicities of the drugs with slight increases of grade 3/4 neutropenia on combination therapy. CONCLUSION: Treatment of advanced TNBC with a combination of EndoTAG-1 and standard paclitaxel [Taxol® (Bristol-Myers Squibb GmbH), or equivalent generic formulation] was well tolerated and showed antitumor efficacy. The positive trend needs to be confirmed in a randomized phase III trial. STUDY REGISTRATION: European Clinical Trials Database: EudraCT number 2006-002221-23. ClinicalTrials.gov identifier: NCT00448305.

[What do clinicians do with the results of the systematic staging imaging at the time of the breast cancer diagnosis?]. / Bilan d'extension des cancers du sein: résultats et conséquences cliniques.

INTRODUCTION: Asymptomatic distant metastasis is often looked for at the time of initial diagnosis of early breast cancer. However, there is no consensus on when to perform it and on the consequences on the treatment. PATIENTS AND METHODS: One hundred and twenty-three asymptomatic women receiving systemic neoadjuvant (32 patients) or adjuvant treatment (91 patients) for breast cancer at the Oscar-Lambret center in September 2011 were considered. The staging imaging was a PET scan for 59 patients (pts), a CT scan and a bone scan for 59 patients and both for 5 patients. The result for each procedure was considered normal, abnormal but typically benign or potentially malignant. In this case, another imaging technique was carried out to confirm the suspected diagnosis. The patient was considered metastatic if the results of two different procedures were concordant and eventually in case of response to chemotherapy. RESULTS: Nine pts were considered metastatic (9/125=7%). They were stage 1: 1, stage 2: 4 and stage 3: 4. The staging by CT, abdomen and pelvis scan coupled with bone scintigraphy discriminated five metastatic patients with overdiagnosis of 33 benign lesions and the need of 20 additional confirmatory tests. Similarly, the PET staging, more expensive, only discriminated two metastatic patients and 15 benign lesions requiring 20 confirmatory tests. CONCLUSION: These results support the international recommendations to make a staging from stage IIIA. The CT, abdominal and pelvic scan coupled with bone scintigraphy should be considered as a gold standard in breast cancer staging.

A retrospective case series of 103 consecutive patients with leptomeningeal metastasis and breast cancer.

Approximately 2-5 % of patients with breast cancer (BC) develop leptomeningeal metastasis (LM). 103 consecutive patients with BC were diagnosed with LM and initially treated with intra-CSF liposomal cytarabine from 2007 to 2011 at a single institution. Correlations were determined with respect to patient characteristics and BC subtype with regard to overall survival (OS). At LM diagnosis, 61 % of patients had a 0-2 performance status (PS), the remaining 39 % were severely neurologically impaired. Regardless of PS, all patients received intra-cerebrospinal fluid (CSF) liposomal cytarabine as first-line treatment. Systemic treatment and radiotherapy were also given in 58 and 17 % of patients respectively as clinically appropriate. Second- (intra-CSF thiotepa) and third-line (intra-CSF methotrexate) treatment was administered in 24 and 6 patients respectively. Median OS was 3.8 months (range 1 day-2.8 years). In multivariate analysis, an initial combined treatment, a second-line treatment with intra-CSF thiotepa, an initial clinical response, and a non-'ER/PR/HER2 negative' BC were significantly associated with a better OS. Median OS in this heterogeneous retrospective case series was similar to that of previously observed BC patients treated with intra-CSF methotrexate suggesting intra-CSF liposomal cytarabine is a reasonable first choice therapy of BC-related LM.

[Ki67 in young patients with breast cancer]. / Ki67 chez les patientes jeunes présentant un cancer du sein.

UNLABELLED: The aim of the study was to compare KI67 in young breast cancer patients (pts) (35 years or less), and in older ones. Forty-three young pts treated between January 1, 2006 and December 31, 2008 as well as pts more than 35 years treated in the same institution in 2006 were considered. Biomarker studies were carried out on a surgical specimen or on a biopsy before neoadjuvant chemotherapy if any. Young pts had a higher median value of KI67 (30% [3-95] versus 10% [0-90] P<0.0001) a higher rate of SBR3 (44 versus 28% P<04), of mitotic index 3 (35 versus 13% P<0.001). ER was less frequently positive (56 versus 87%, P<0.001) as well as PR (38 versus 68% P<0.001). HER2 was more frequently amplified in young pts (24 versus 10% P<0.007). Young pts more frequently had a triple negative breast cancer (TNBC) (31 versus 8% P<0.001). In TNBC pts, KI67 was higher in younger pts (70% [10-95] versus 38% [2-80] P=0.06). Among young pts, TNBC had a higher KI67 than non TNBC (70% [10-95 versus 20% [3-60] P<0.001). CONCLUSION: KI67 is significantly higher in young pts than in older ones. TNBC is significantly more frequent; among young pts, and KI67 is significantly higher in TNBC.

Plasma and tissue proteomic prognostic factors of response in primary breast cancer patients receiving neoadjuvant chemotherapy.

A pathological complete response (pCR) after neoadjuvant chemotherapy is observed in approximately 20% of breast cancer patients. A proteomic analysis was performed on plasma and tumor tissue before treatment to evaluate its potential impact on the prediction of response. One hundred and forty-nine breast cancer patients eligible for neoadjuvant chemotherapy were included in the study between February 2004 and January 2009 at three centers. The proteomic analysis was performed using SELDI Technology (ProteinChip CM10 pH4, IMAC-Cu and H50). Three acquisition protocols were used according to the mass range. Plasma and tumor proteomic signatures were generated using generalized ROC criteria and cross-validation. Twenty-eight (18.8%) patients out of 149 experienced a pCR according to Sataloff criteria. In the cytosol analysis, respectively 4, 2 and 8 proteins had significantly different levels of expression in the responders and non-responders using IMAC-Cu, H50 and CM10 pH4. Among the 8 proteins of interest on CM10 pH4, 2 (C1 and C7) were selected and were validated in 95.0 and 85.6% of the models. In the plasma analysis, respectively 12, 6 and 2 proteins had different levels of expression using the same proteinchips. Among the 12 plasma proteins of interest on IMAC-Cu, 2 (P1 and P7) were selected and were validated in 94.8 and 97.6% of the models. A combined proteomic signature was generated, which remained statistically significant when adjusted for hormone receptor status and Ki-67. Our results show that proteomic analysis can differentiate complete pathological responders in breast cancer patients after neoadjuvant chemotherapy.

The sequential use of endocrine treatment for advanced breast cancer: where are we?

BACKGROUND: Hormone receptor-positive advanced breast cancer is an increasing health burden. Although endocrine therapies are recognised as the most beneficial treatments for patients with hormone receptor-positive advanced breast cancer, the optimal sequence of these agents is currently undetermined. METHODS: We reviewed the available data on randomised controlled trials (RCTs) of endocrine therapies in this treatment setting with particular focus on RCTs reported over the last 15 years that were designed based on power calculations on primary end points. RESULTS: In this paper, data are reviewed in postmenopausal patients for the use of tamoxifen, aromatase inhibitors and fulvestrant. We also consider the available data on endocrine crossover studies and endocrine therapy in combination with chemotherapy or growth factor therapies. Treatment options for premenopausal patients and those with estrogen receptor-/human epidermal growth factor receptor 2-positive tumours are also evaluated. CONCLUSION: We present the level of evidence available for each endocrine agent based on its efficacy in advanced breast cancer and a diagram of possible treatment pathways.

Phase I study of lapatinib plus vinorelbine in patients with locally advanced or metastatic breast cancer overexpressing HER2.

BACKGROUND: To determine the recommended doses of lapatinib (LPT) combined with vinorelbine (VNR) in women with human epidermal growth factor receptor 2-overexpressing advanced breast cancer pretreated with trastuzumab. METHODS: In this phase I study, women were treated with oral daily LPT and i.v. VNR infused on days 1 and 8 every 3 weeks. Dose levels (DL) of LPT (mg)/VNR (mg m(-2)) ranged from 750/20 to 1250/30. The primary end point was feasibility based on maximal tolerated dose (MTD) and maximum administered dose (MAD). Pharmacokinetic interactions were investigated. RESULTS: Of 33 patients included, 29 were evaluable. Two DLT occurred at DL4 (1000/25) meeting the MAD criteria. Despite an additional intermediate DL3' (1250/22.5), MTD was reached at DL3 (1000/22.5). Grade 3-4 neutropenia was the most common toxicity (34% and 38% of patients, respectively). Other significant toxicities included grade 3-4 diarrhoea (3% each), and grade 3 asthenia (10%). Although not statistically significant, LPT (at 1000 or 1250 mg) decreased the VNR clearance by 30-40% compared with DL1. CONCLUSION: The MTD LPT 1000 mg/VNR 22.5 mg m(-2) (DL3) is recommended for additional development. Pharmacokinetic interactions might increase the exposure to VNR and consequently alter the hematological tolerance.

A phase I study of vinflunine in combination with capecitabine in patients with metastatic breast cancer previously treated with anthracyclines and taxanes.

PURPOSE: A phase I study was performed to determine the maximal tolerated dose (MTD), recommended dose (RD), safety and efficacy of vinflunine when combined with capecitabine in patients with metastatic breast cancer (MBC) previously treated with anthracyclines and taxanes, with pharmacokinetic blood sampling to test potential drug-drug interactions. PATIENTS AND METHODS: Sixteen patients with MBC who had received anthracyclines and taxanes in the neo/adjuvant setting, if progression occurred during or within 12 months of chemotherapy completion, and/or as first-line chemotherapy of MBC were enrolled. Vinflunine (VFL) was given on day 1 with capecitabine (CAPE) twice daily from days 1 to 14, every 3 weeks. Three dose levels (DL) were investigated (DL1: VFL 280 mg/m² and CAPE 1,650 mg/m²/day, DL2: VFL 320 mg/m² and CAPE 1,650 mg/m²/day and DL3: VFL 280 mg/m² and CAPE 2,000 mg/m²/day). RESULTS: The RD was established as vinflunine 280 mg/m² on day 1 plus capecitabine 1,650 mg/m²/day on days 1 to 14 given every 3 weeks. Dose-limiting toxicities were grade 4 neutropenia lasting at least 7 days for 2 patients, anorexia with fatigue for 1 patient and diarrhoea with fatigue, anorexia and febrile neutropenia for 1 patient. Neutropenia was the main toxicity of the combination, it was reported in 15 patients (93.8%) with grade 3 in 7 patients (43.8%) and 22.6% of cycles and grade 4 in 7 patients (43.8%) and 19.8% of cycles. Complications were rare with only one patient experiencing febrile neutropenia at DL exceeding the RD. The most frequent non-haematological toxicities were fatigue and gastrointestinal disorders; however, no grade 3 or 4 episode was observed at the RD. Hand-foot syndrome was reported in 5 patients (31.3%) and 22.6% of cycles, no episode of grade 3 was seen. Concerning pharmacokinetics, no modifications were detected for VFL, while slight accumulation between days 1 and 14 was observed for 5-FU formed from CAPE. The risk of clinical significant drug-drug interaction was considered weak. Objective partial responses were reported in 7 patients, yielding a response rate of 43.8% in the all-treated population according to the investigator assessment. CONCLUSIONS: The combination of vinflunine and capecitabine is safe and showed promising antitumour activity in MBC patients who have failed prior anthracyclines and taxanes. Further clinical development of this combination is warranted.

Pharmacokinetic evaluation of the vinorelbine-lapatinib combination in the treatment of breast cancer patients.

PURPOSE: The objectives of this study were to investigate the pharmacokinetics of intra-venous vinorelbine combined with lapatinib as well as the effect of covariates in breast cancer patients. METHODS: Women with HER2 + locally advanced or metastatic breast cancer progressing after ≤ 2 lines of trastuzumab-based treatment were treated with lapatinib per os starting 7 days (D) (D-7 to D0) before adding vinorelbine on a D1 & D8 every 3 weeks intravenous schedule. Lapatinib was given everyday. Dose levels [DL, lapatinib (mg)/vinorelbine (mg/m(2))] ranged from 750/20 to 1,250/25. A total of 29 patients, 37-76 years old, were treated with the combination of lapatinib + vinorelbine. For pharmacokinetic analysis, 7 time point samples were collected on D1 of cycle 1 for lapatinib and vinorelbine assays. For vinorelbine and lapatinib, respectively, whole blood and plasma concentrations were measured using ultra performance liquid chromatography with tandem mass spectrometry validated methods. Data analysis was performed using a non-linear mixed effect model program (Monolix version 3.1 s). RESULTS: A three-compartment open model adequately described vinorelbine pharmacokinetics. Body weight (BW) and platelet count significantly influenced blood vinorelbine clearance (CL). BW significantly influenced volume (V) and CL terms. Platelet count influenced vinorelbine elimination CL. The final parameter estimates were as follows: CL = 24.9 L/h, V1 = 8.48 L, Q2 = 50.7 L/h, V2 = 1,320 L, Q3 = 66.1 L/h, and V3 = 62.4 L (Qi and Vi denote inter-compartmental clearance and peripheral volume of distribution, respectively), normalized for a 70-kg patient according to BW allometric scaling (CL is normalized for a 250,000 platelet count). A one-compartment model with linear elimination adequately fitted the lapatinib plasma concentration-time data. The population pharmacokinetic parameters were CL = 27.7 L/h, V = 357 L, and the absorption constant, ka = 0.44 h(-1). The between-subject variabilities (BSV) could be well estimated for CL, V but not for ka. No covariate effect, including body surface area and vinorelbine dosage, could be identified for lapatinib. CONCLUSIONS: The pharmacokinetic modeling of vinorelbine and lapatinib was consistent with the results previously reported. BW and platelet count were confirmed as influencing blood CL of vinorelbine. A pharmacokinetic interaction occurred between vinorelbine and lapatinib probably due to lapatinib inhibition of CYP450-3A4. The combined lapatinib administration decreases statistically significant the vinorelbine CL. The maximal tolerated dose for the combination of lapatinib with vinorelbine on a q3w schedule is as follows: lapatinib 1,000 mg/day continuously and vinorelbine 22.5 mg/m(2) D1 & D8.

[Intraoperative molecular assessment of sentinel nodes in the breast cancer using the Gene Search BLN Assay technique: our experience about 126 patients]. / Évaluation de l'analyse peropératoire des ganglions "sentinelle" par biologie moléculaire (technique Gene Search BLN Assay) dans le cancer du sein: à propos de 126 patientes.

INTRODUCTION: Intraoperative molecular assay Gene Search BLN Assay (BLN) detects sentinel lymph node (SLN) metastasis in breast cancer. Our objective was to compare BLN to the definitive conventional histologic methods and to experiment the management of BLN in routine. MATERIAL AND METHODS: Each SLN was cut into alternate slabs. Half slabs were analysed with the intraoperative BLN molecular method, and the other slabs with the definitive histologic method. RESULTS: Two hundred and thirty four SLN have been analysed (124 patients). Thirty-five SLN had metastasis for 29 patients (23.4%). BLN correctly identified 28 patients. Two cases of discordance between BLN and standard method were found, probably explained by a sample bias. The sensibility of BLN is 96.4%, the sensitivity is 99%, the predictive positive value is 96.4%, the predictive negative value is 99% and the concordance is 98.4%. The surgery time increases and there is a need to adapt the theatre organization accordingly. CONCLUSION: The Gene Search BLN Assay gives a great interest for the patient, the surgeon and the pathologist because it increases the quality of the intraoperative analysis by comparison with the intraoperative conventional histology.

Nasal septum perforation: a side effect of bevacizumab chemotherapy in breast cancer patients.

BACKGROUND: Bevacizumab is an anti-vascular endothelial growth factor approved in association with paclitaxel or docetaxel as first line in patients (pts) with metastatic breast cancer. Rare cases of nasal septum perforations have been reported. We report our experience of nasal perforation in breast cancer pts receiving bevacizumab and chemotherapy either in the adjuvant or in the metastatic settings. METHODS: Between 1 January and 31 December 2009, 70 pts received bevacizumab together with chemotherapy. All the pts who had received bevacizumab were referred to the ENT specialist. Symptoms potentially related were looked for. Side effects were graded according to CTCAE. RESULTS: Five nasal septum perforations were diagnosed (5 out of 70; 7.14%). Bevacizumab dose was 15 mg kg(-1) 3 weekly. Three pts were metastatic. Bevacizumab was associated with docetaxel (100 mg m(-2) every 3 weeks) in two pts and with weekly paclitaxel in one. The last two pts received bevacizumab in combination with anthracyclin and then taxanes in the adjuvant setting. In these two cases, nasal septum perforation occurred at the time of docetaxel treatment. CONCLUSION: A high incidence of nasal septum perforation has been shown in pts with breast cancer receiving bevacizumab together with chemotherapy. Several mechanisms could be involved (mucositis, delayed tissue repair, antiangiogenic action of taxanes).

[Intraoperative determination of axillary node metastasis by RT-PCR]. / Utilisation d'une méthode PCR en temps réel pour l'étude des ganglions sentinelles dans les carcinomes mammaires : expérience des centres anticancéreux de Lille et de Clermont-Ferrand.

UNLABELLED: The intraoperative determination of axillary node micrometastasis according to the Rapid GeneSearch Breast Lymph Node (BLN) is based on RT-PCR (mRNA of mammaglobine and CK19) detects metastases > 0.2 mm. PATIENTS AND METHODS: Eighty-three pts between November 2007 and June 2008 were included (33 from Centre Jean-Perrin and 50 from Centre Oscar-Lambret). Lymph nodes were cut in 2 mm slices, and 1 out of 2 was examined with BLN; the others were examined by imprints then histological exam with immunohistochemistry. RESULTS: Forteen pts had micro- or macrometastasis. Seven were positive with intraoperative imprints including six macrometastasis and one micrometastasis; seven were positive with BLN and seven at histological exam with two cases of discordance. Sensitivity was 92%, specificity 98%. Positive predictive value 92%, and negative predictive value 98%. The median time for intraoperative determination was 40 minutes for 2 SLN. DISCUSSION: Half each lymph node is study by each method. This explains the discordances observed. Limit of BLN is the absence of CTI detection; however there is no consensus about the necessity of axillary clearance in such a case. CONCLUSION: In this series BLN reduces axillary clearance and improves comfort patients.

[Chemotherapy induced emesis: pathophysiology and prevention]. / Nausées et vomissements chimio-induits : physiopathologie, prophylaxie et recommandations.

Nausea and emesis are one of the most feared secondary effect of chemotherapy. The development of antiemetic therapies has increased after the introduction of cisplatin, a cytotoxin with the highest emetic potential. Chemotherapy-induced nausea and vomiting (CINV) have been classified into acute, delayed and anticipatory based on the time of onset. According to the percentage of nausea and emesis without any antiemetic treatment, chemotherapy is divised into highly, moderate, low and very low emetic potential. The discovery of emetics stimuli neurotransmitters and their receptors has led to the introduction of new molecules which associated with steroids have prevented nausea and vomiting chemotherapy-induced for 70 to 80% of the patients receiving chemotherapy with high emetic potential. Numerous studies have evaluated the various antiemetics and recommendations were issued by learned societies in US and Europe. This text discusses the physiopathology of nausea and vomiting, the development of anti-emetics and the new discovered antiemetics. Finally, a synthesis of the recommandations from the guidelines developed by the Multinational Association of Supportive Care in Cancer (MASCC), the American Society of Clinical Oncology (ASCO), the National Comprehensive Cancer Network (NCCN) and the European Society for Medical Oncology (ESMO) is presented.