17 TH ANNUAL BSMO MEETING 2015

17TH ANNUAL BSMO MEETING 2015 Breast Cancer Task Force Digestive Oncology BSMO Symposium

6 - 7 March 2015

Golden Tulip Brussels Airport www.BSMO.be BSMO.indd 1

04-03-15 14:05

INTRODUCTION Dear colleague, We wish to welcome you to the 17th Annual Meeting of the BSMO, a unique annual opportunity to gather as a community and exchange ideas and engage in cooperation’s. The Friday morning is dedicated to the BSMO Breast Cancer Task Force and the BSMO symposium is on Friday afternoon and Saturday morning. These are exciting but also challenging times for the medical oncologist, getting treatments in a timely fashion to the right patients. The Digestive Oncology symposium on Friday afternoon will help us sort out the current applicable strategies on Pancreatic Cancer and Gastric Cancer, allowing us to look forward to novel opportunities. The general BMSO symposium on Saturday morning follows the traditional format and relates to several aspects of our profession with an equilibrated clinical and scientific mix. It is these scientific insights combined with compassionate patient care that make us the medical oncologist. On behalf of the board, we would like to wish you a fruitful meeting!

Jacques De Grève BSMO President

PROGRAMME FRIDAY 6 MARCH 2015 BSMO BREAST CANCER TASK FORCE MEETING Chairs: Ahmad Awada, Institute Jules Bordet & Hans Wildiers, UZ Leuven 09.30

Adjuvant endocrine therapy in premenopausal breast cancer patients

10.00

Which patient needs tumor gene expression profiling for adjuvant systemic therapy

Hannelore Denys, UZ Gent

Christos Sotiriou, ULB, Brussel 10.30 Coffee break 11.00

Role of Carboplatin in TNBC and BSMO clinical trial status

Hans Wildiers, UZ Leuven and Christel Fontaine, UZ Brussel 11.30

Update of PEARL clinical trial in luminal diseases

Andrea Gombos, Jules Bordet Institute, Brussel 11.45

12.25

Zoledronic acid in the adjuvant setting Pros : François Duhoux, Cliniques Universitaires Saint-Luc Cons: Patrick Neven, UZ Leuven Initiatives from the members for the BSMO Breast Cancer Task Force

12.45 Lunch

BSMO-BGDO DIGESTIVE ONCOLOGY SYMPOSIUM Chairs: Eric Van Cutsem, UZ Leuven and Wim Demey, AZ Klina, Brasschaat Session I: Locally advanced/metastatic pancreatic cancer 14.00

Case: Locally advanced pancreatic cancer

14.15

Discussion: Operability criteria? Any role of neo-adjuvant therapy?

Alain Bols, AZ St. Jan, Brugge

Baki Topal, UZ Leuven Systemic therapies for locally advanced/metastatic pancreatic cancer

Jean-Luc Van Laethem, Hôpital Erasme and ULB, Brussel

PROGRAMME FRIDAY 6 MARCH 2015 Session II: Metastatic colorectal cancer 14.45

Case: Metastatic colorectal cancer

Joëlle Collignon, CHU Liège 15.00

Discussion: Is there a preferred regimen for first line treatment?

Marc Van den Eynde, UC Louvain Molecular understanding of colorectal cancer: therapeutic implications

Sabine Tejpar, UZ Leuven Screening for colorectal cancer Population based speaker from screening program

Marc Peeters, UZ Antwerpen High risk population

Kathleen Claes, UZ Gent 16.10 Coffee Break

Gastric cancer 16.30

New classifications, new therapies?

Karen Geboes, UZ Gent and UZ Brussel 16.50

New Drugs on the horizon

Ahmad Awada, Institut Jules Bordet, Brussel 17.15 Meeting closure

PROGRAMME SATURDAY 7 MARCH 2015 BSMO 17th Annual Meeting 08.55

Introduction

Jacques De Grève, BSMO President 09.00

Oncology Paper of the year 2015 presentation & award

Chair: Sylvie Rottey, UZ Gent Tumor-Infiltrating Lymphocytes*

Roberto Salgado, GZA, Antwerpen 09.30

What you should not have missed in the last year!

Chair: Lionel Duck, Clinique Saint-Pierre, Ottignies Speaker: Luc Dirix, GZA, Antwerpen

Proffered Papers Chair: Hans Wildiers, UZ Leuven 10.00

O.1 - Quantitative assessment of BRAF V600 mutant cell-free tumor DNA from plasma as a diagnostic and therapeutic biomarker in pts with BRAF V600 mutant melanoma.

Max Schreuer, Vrije Universiteit Brussel 10.08

O.2 - Investigation of non-V600 BRAF mutations commonly found in NSCLC for their sensitivity to Dabrafenib or Trametinib.

Amir Noeparast , UZ Brussel 10.16

O.3 - Whole exome sequencing of circulating and disseminated tumour cells in patients with metastatic breast cancer.

Anja Brouwer, University of Antwerp 10:24

O.4 - Impact of adjuvant chemotherapy on clinical and biological ageing in older breast cancer patients.

Barbara Brouwers, University Hospitals Leuven 10:32

O.5 - Clinical and genetic risk factors for epirubicin induced cardio toxicity in early breast cancer patients

Christof Vulsteke, AZ Maria Middelares 10:40

O.6 - Exploring the intra-patient PIK3CA mutational heterogeneity of circulating tumour cells by massive parallel sequencing in patients with metastatic hormone receptor-positive breast cancer.

Bram De Laere, University of Antwerp

PROGRAMME SATURDAY 7 MARCH 2015 10:48

O.7 - Low-level laser therapy as a tool for the management of radio dermatitis: a pilot study in breast cancer patients

Jolien Robijns, Jessa Ziekenhuis 10:56

O.8 - Correlation between circulating tumour cells and the haemostasis system in metastatic breast cancer.

Laure-Anne Teuwen, KU Leuven 11.00 Coffee Break 11.30 Heuson Memorial Lecture

Chair: Robert Paridaens, KU Leuven Some questions from a surgeon

Ivo de Wever, UZ Leuven 12.00 Lunch 13.00

Awards

13.15

Centralisation of Cancer Care: ignoring the expertise of the medical oncologists?

Chair: Jacques De Grève, VUB Speaker: Peter Vuylsteke, BSMO and Sabine Stordeur, KCE

14.15 BSMO General Assembly 2015 (members only)  Election of new BSMO Board  Precision Belgium, Philippe Aftimos and Lore Decoster  Finances: Robert Paridaens  Discharge of administrators  Varia 15.15 Meeting closure

GENERAL INFORMATION Accreditation Pending: erkenningsnummer / N agréation: 15003680 All delegates will receive an e-mail message as soon as the information is available.

Target audience

Medical oncologists and oncologists in training, other oncologists are also welcome to join the scientific sessions.

Website www.bsmo.be

Congress secretariat Congress Care PO Box 440 NL-5201 AK ‘s-Hertogenbosch T: +31 (0)73 690 1415 E: [email protected] W: www.congresscare.com

SPONSORS & EXHIBITORS Major Sponsor

Sponsors & Exhibitors

ABSTRACTS INVITED SPEAKERS [where available]

Gastric Cancer: New classifications, new therapies? Karen Geboes, UZ Gent & UZ Brussels Gastric cancer is one of the most common forms of cancer and the third-leading cause of cancer-related death worldwide. Clinical data shows that patients with advanced gastric cancer have a dismal prognosis. Anti-angiogenic molecules have been tested in several trials in gastric cancer. The Phase III AVAGAST trial of bevacizumab in gastric cancer demonstrated no significant overall survival benefit. Other trials with anti-VEGF agents, including TKI’s, failed to meet their endpoints. Recently however, ramucirumab has received CHMP recommendation in Europe based on positive clinical efficacy data from the REGARD trial and the RAINBOW study showing efficacy in second line (Wilke et al 2014). About 20% of patients will show Her2-overexpression and this biomarker is used to select patients eligible for treatment with the anti-HER2 drug trastuzumab (Bang Y, 2010). Not all anti-HER2 drugs have been clinically successful – lapatinib, an anti-EGFR/HER2 drug, failed to meet its endpoint of significantly improving overall survival in gastric cancer. Nevertheless, other anti-HER2 therapies, e.g. pertuzumab, are in late stage development. A comprehensive survey of genomic alterations in gastric cancer reveals demonstrates the existence of five distinct gastric cancer patient subgroups, defined by the signature genomic alterations FGFR2 (9% of tumours), KRAS (9%), EGFR (8%), ERBB2 (7%) and MET (4%). Collectively, these subgroups suggest that at least 37% of gastric cancer patients may be potentially treatable by RTK/RAS directed therapies (Deng, Gut 2012). The anti-EGFR Phase III trials, EXPAND and REAL-3, for cetuximab and panitumumab, failed to meet their primary endpoints. Later subgroup analysis of the EXPAND study showed that cetuximab may be effective in the subgroup of patients that highly express EGFR (Lordick et al 2013). A number of trials in gastric cancer are investigating c-Met as a potential biomarker. The c-Met inhibitor onartuzumab failed to show activity. The Phase III trial of the anti-c-Met drug, rilotumumab is evaluating efficacy in advanced gastric cancer patients preselected for c-Met overexpression by IHC. Early phase data for rilotumumab – but also for AMG 337, specifically in tumors showing

Met-amplification, looks promising and points towards a potentially effective new treatment option for a new subgroup of patients. Pembrolizumab is an anti-PD-1 antibody that to date has shown good antitumor activity, and good safety and tolerability in multiple tumor types (Ribas A, 2014; Rizvi NA, 2014). Data from the gastric cohort of the Phase Ib (KEYNOTE-012) trial evaluating pembrolizumab in PD-L1-positive advanced solid tumors were presented at ESMO 2014. In this study 40 percent of patients were defined as PD-L1-positive by IHC staining. Efficacy data presented showed that overall response rate (ORR) was 30.8 percent and disease control rate (DCR) 43.6 percent (Muro K et al, 2014).

Tumor-infiltrating lymphocytes Roberto Salgado, GZA, Antwerpen Breast cancer has not been considered as an immunogenic solid cancer type; however, recent studies demonstrate evidence of significant prognostic information that can be derived from immune cell infiltration via tumourinfiltrating lymphocytes (TILs) in patient tumours. The presence of TILs has been associated with increased response rates to cytotoxic chemotherapy as well as targeted therapies, leading to improved disease-free and overall survival in certain breast cancer subtypes. Accordingly, experts have developed a standardized methodology for evaluating TILs within clinical specimens in histopathological practice. An overview of a newly established practical guideline for TIL evaluation in breast cancer will be presented. Furthermore, this presentation discusses the predictive and prognostic significance of TILs, highlighting recent evidence linking TILs to prognosis in breast cancer. In addition, it summarizes the most current understanding of TIL composition as well as mechanisms of immunity generation and suppression. Overall, the current literature demonstrates that TILs are proving to be a promising target for the treatment of immunogenic breast cancers.

Heuson Memorial Lecture 2015 – Some questions from a surgeon Em. Prof Dr. Ivo De Wever This Heuson Memorial lecture gives me the opportunity to express some ideas living in the surgical community to our medical oncology colleagues. 1. How can you recognize a surgical oncologist ? He or she is al competent surgeon, present at the multidisciplinary meetings (MOCs) with an interest in the disease of the patient, its diagnosis and treatment. Should be able to explain reason for non-resectability, techniques

of biopsy and resection and possible complications. At surgery he or she will make great effort to avoid tumor spilling. 2. How to avoid a poor quality MOC ? The medical file should be complete and well known by the presenter. The surgeon has to see the patient before any final decision. The quality of the MOC depends on the quality of the participants and of the quality of the communication. 3. When is a biopsy not indicated ? In case of a potentially curable tumor, biopsy should be discussed with the surgeon. All transcoelomic biopsies are contra-indicated. 4. What is the aim of the neo-adjuvant therapy ? It should be clearly stated. Is it to obtain resectability or the avoid resection; to make the tumor smaller or to avoid useless surgical exploration. Is it to study the response of the tumor to systemic therapy ? 5. May response affect margin of resection ? Tumor response is a very complicated matter. We think the growth pattern of the tumor is important. If expansive, good response may lead to a smaller margin; if invasive probably not. 6. Is follow-up important for the surgical oncologist ? How can we learn without feedback ? How can we motivate ourselves and our patients without knowing the outcome ? 7. How should an oncologist ponder “inoperable” ? It is important to know the qualifications of who made the statement but even more to ask for the reason(s) and the circumstances. It might have to be reconsidered.

ABSTRACTS ORAL PRESENTATIONS O1 - Quantitative assessment of BRAF V600 mutant cell-free tumor DNA from plasma as a diagnostic and therapeutic biomarker in pts with BRAF V600 mutant melanoma.

Max Schreuer, Vrije Universiteit Brussel, Brussel Background: Analysis of BRAF V600 mutant cell-free tumor DNA (ctDNA) from plasma is under consideration as a biomarker in patients with advanced melanoma. Methods: Plasma samples were obtained from patients with advanced melanoma who participated in 3 prospective clinical trials. Quantitative allele-specific PCR analysis for BRAF V600 E/E2/D/K/R/M mutations was performed on cell-free DNA extracted from 1ml plasma (Idylla, Biocartis). Results: From 2/2014 to 12/2014, 232 plasma samples from 41 patients were analyzed. Detection of BRAF V600 mutant ctDNA at the time of diagnosis of metastatic disease was concordant with tumor tissue analysis in 100% of patients (BRAF-mutant 3/10, BRAF-wt 7/10). In the 3 BRAF-mutant patients, ctDNA results preceded tissue results with a median of 40 days (14-93). Therapeutic monitoring of BRAF-mutant ctDNA was performed in 33 patients (median of 7 analyses per patient [range 2-13]; median follow up of 4.8 months [0.5-9]). Treatment consisted of BRAF/MEK targeted therapy (n=26 patients), ipilimumab (n=5) or pembrolizumab (n=9). In the 6 patients who had a detectable BRAF-mutant ctDNA fraction (range 7-53%) at initiation of BRAF/MEK targeted therapy, the BRAF-mutant ctDNA fraction became undetectable (n=5) or <1% (n=1) after a median of 14 days (5-40) notwithstanding the absence of radiological CR. During BRAF/MEK targeted therapy, an increase in the BRAF-mutant ctDNA fraction was detected prior to PD on imaging in 7/12 patients (58%; median interval of 1.1 month [0.8-1.7]) and concomitantly with PD on imaging in 2/12 patients (17%). An increase in BRAF-mutant ctDNA fraction predicted PD during the following month in 67% of cases (n=14/21, p<0.001) and in 100% of cases within the following 2 months (n=21/21, p<0.001). Undetectable BRAF-mutant ctDNA predicted absence of PD in the following month in 91% of analyses (n=94/103; p<0.001) and in the following 2 months in 83% of analyses (n=77/93; p<0.001). Conclusions: Analysis of BRAF-mutant ctDNA from plasma allows for a rapid diagnosis of the BRAF status in patients with advanced melanoma. BRAF-mutant ctDNA likely reflects the BRAF-mutant proliferative tumor burden and holds promise as a therapeutic monitoring tool for patients with advanced BRAF V600 mutant melanoma.

O2 - Investigation of non-V600 BRAF mutations commonly found in NSCLC for their sensitivity to Dabrafenib or Trametinib.

Amir Noeparast, Gil Verschelden, Ijeoma Umelo, Sylvia De Brakeleer, Lore Decoster, E. Teugels, Jacques De Grève UZ Brussel, Brussels Background: The most common BRAF mutations in non-small cell lung cancer (NSCLC) are non-V600 in contrast to melanoma. BRAF pathway inhibitors have not been systematically investigated in non-V600 mutations in vitro and in the clinic. We tested the effect of two clinically available BRAF pathway inhibitors (Trametinib and Dabrafenib) on a subset of clinically identified BRAF mutations in a cohort of lung cancers enriched for adenocarcinoma in patients with no or limited smoking history. Methods: NSCLC tumor samples (FFPE) were tested for the presence of EGFR, KRAS, NRAS, HRAS and BRAF mutations by DGGE or NGS-based methods. We generated 15 BRAF expression plasmids, harboring the mutations found in the given cohort and others described in the literature. BRAF mutants were subjected to an in vitro kinase assay. BRAF constructs were also expressed in HEK293T cells (with and without wt-CRAF) to study their impact on ERK signaling and determine the effect of inhibitors. Results: Among 229 NSCLC patients, 12 patients (5.2%) were found to harbor a BRAF mutation in their tumor: V600 (25%), G469A (16.7%), G469V (8.3%), D594N (25%), D594E (8.3%), G596C (8.3%) and G466V (8.3%). Mutations were characterized as activating or kinase-impaired (in-vitro kinase assay) . Kinaseimpaired BRAF mutants could still activate the ERK pathway in a CRAF-dependent manner, more than wt-BRAF/wt-CRAF co-transfectant. A MEK inhibitor (Trametinib) and a selective BRAF-inhibitor (Dabrafenib) were tested at clinically relevant doses on HEK293T transfectants (either expressing BRAF mutant alone or together with CRAF). ERK signaling induced by activating mutations was reduced in response to both inhibitors separately. Trametinibinhibited the CRAFdependent ERK signaling induced by impaired-kinase BRAF mutations. Dabrafenib activated the ERK pathway in cells expressing only CRAF as well as cells co-expressing a kinase-impaired BRAF mutation and CRAF. Conclusions: This study predicts sensitivity of activating non-V600 BRAF mutations in lung cancer to Trametinib or Dabrafenib. Targeting kinase impaired BRAF mutations which signal through CRAF using Dabrafenib will require the addition of Trametinib.

O3 - Whole exome sequencing of circulating and disseminated tumour cells in patients with metastatic breast cancer.

Anja Brouwer, Dieter Peeters, Ken Op de Beeck, Geert Van de Weyer, Patrick Pauwels, Marc Peeters, Peter Vermeulen, Peter Van Dam, Steven Van Laere, Guy Van Camp, Luc Dirix University of Antwerp, Wilrijk Circulating tumor cells (CTC) offer the potential to provide a repeatedly accessible source of tumor cells for real-time assessment of tumor characteristics in patients with metastatic breast cancer (MBC). Questions remain to what extent CTCs are truly representative of the actually present tumor mass at a specific moment in time. Furthermore, the molecular heterogeneity within the CTC population is only now being explored. Here, we report on the first results of an ongoing comparative study of mutation profiles of CTC and synchronously isolated disseminated tumor cells (DTC) from metastatic effusions or biopsies of solid metastases of patients with clinically progressive MBC. CTCs were isolated from 7.5 ml blood using the CellSearch system. Enriched CTC samples were subsequently further purified and sorted into several batches of 1125 CTCs per patient using the DEPArray system. DNA was isolated and amplified using the Ampli1 kit and subjected to whole exome paired-end sequencing (WES). DTCs from metastatic effusions, fresh frozen tissue from solid metastases or the primary tumor, and bulk CTC (CellSearch Profile) were sequenced as a comparator for mutation profiles. DNA from the buffy coat of white blood cells are sequenced to enable somatic mutation analysis. Eight samples of 1-125 CTCs and a CellSearch Profile sample (30.000 CTC/7.5 ml) of one patient with MBC (patient 1) and four samples of 5-10 CTC, 2 temporally matched pleural effusion DTC samples and the primary tumor of a second patient (patient 2) have been sequenced so far. Average base coverages were 13.6x (patient 1) and 11.8x (patient 2) for CTC/DTC samples and 175x and 120x for the CellSearch Profile and the primary tumor respectively. 29.6-53.6% of the exomes of amplified products of CTC/DTC DNA were uncovered, probably due to technical limitations of the Ampli1 procedure. Overall, if adequately covered, good concordances were observed for variants identified with MuTect in 28 frequently mutated genes in breast cancer between samples of 1-125 CTC and the CellSearch Profile of patient 1. In patient 2, the same H1047R PIK3CA mutation was identified in the primary tumor and all CTC/DTC samples. In-depth analyses of the full exome data are being conducted.

O4 - Impact of adjuvant chemotherapy on clinical and biological ageing in older breast cancer patients.

Barbara Brouwers1, Sigrid Hatse2, Lissandra Dal Lago3, Patrick Neven2, Peter Vuylsteke4, Guy Debrock5, Heidi Van Den Bulck6, Ann Smeets2, Oliver Bechter2, Evalien Swerts7, Jithendra Kini8, Cindy Kenis2, Annouschka Laenen7, Bruna Dalmasso2, Patrick Schöffski2, Graham Pawelec8, Hans Wildiers2 1

University Hospitals Leuven, Leuven, 2University Hospitals Leuven - Catholic University Leuven, Leuven, 3Institut Jules Bordet, Brussels, 4Clinique Et Maternité Saint-Elisabeth, Namur, 5Ziekenhuis Oost-Limburg, Genk, 6Imelda Ziekenhuis Bonheiden, Bonheiden, 7Catholic University Leuven, Leuven, 8University Of Tübingen Medical School, Tübingen, Germany Background: This prospective observational study aimed to evaluate the impact of adjuvant chemotherapy on clinical and biological markers of ageing and frailty. Materials and methods: Eligible patients were females =70y with early invasive breast cancer for whom adjuvant chemotherapy was planned (ChemoG). The control group consisted of breast cancer patients for whom adjuvant chemotherapy was not indicated (ControlG). Patients underwent blood sampling, and received geriatric assessment (GA) and Quality of Life, (QoL) evaluation at baseline (after surgery), at 3 months (3m) and 1 year (1y). GA results were summarized in a single score, LOFS (Leuven Oncology Frailty Score), from 10 (very fit) to 0 (very frail). Primary endpoint was to assess whether chemotherapy induces accelerated telomere attrition at 1y. Secondary endpoints were evolution of other ageing biomarkers, LOFS and QoL during chemotherapy; correlations between ageing biomarkers, chronological age and LOFS at inclusion; the predictive value of ageing biomarkers for functional decline, QoL decline, and chemotherapy toxicity. Results. 57 patients were included (ChemoG), and 53 (ControlG). TL was similar in both groups at baseline, and decreased at 3m (p 0,05) and 1y (p 0,0009) in ChemoG, with a similar evolution in ControlG indicating no difference in evolution between both groups. 5 markers remained stable in ControlG while significantly changing in ChemoG: IL-6 decreased at 3m in the ChemoG (p 0,01) and returned to baseline values at 1y ; MCP-1 strongly decreased at 3m (p <0,0001) but increased above baseline value at 1y (p <0.0001) ; IGF-1 had a similar initial decline at 3m (p <0,0001) yet with only slight recovery at 1y (p 0,006). On the other hand, IL-10 increased at 3m (p 0,04) but decreased at 1y (p <0,0001), and TNF-alfa increased at 3m (p 0,001) and 1y (p <0,0001). LOFS declined in ChemoG at 3m (p 0,0007) but returned to baseline level at 1y (p 0,6) while remaining stable over time in ControlG. Conclusions. TL does not evolve differently over time in patients treated with or without chemotherapy. Chemotherapy has measurable impact on clinical frailty and other ageing biomarkers at 3 months, but these effects disappear at 1y follow-up.

O5 - Clinical and genetic risk factors for epirubicin induced cardiotoxicity in early breast cancer patients

Christof Vulsteke1, Hans Wildiers2, Alena Pfeil3, Charlotte Maggen2, Ruth Pettengell4 1

AZ Maria Middelares, Ghent, 2UZLeuven, Leuven, 3University of Basel, Basel, Switzerland, 4St George University, London, United Kingdom Introduction: Anthracycline-induced cardiotoxicity (ACT) is a well-known serious adverse drug reaction leading to substantial morbidity. The purpose of this study was to assess clinical and genetic risk factors for epirubicin-induced cardiac toxicity in early breast cancer patients. Methods: In 6 genes of interest (ABCC1, ABCC2, CYBA, NCF4, RAC2, SLC28A3), 10 single nucleotide polymorphisms (SNPs) involved in ACT were selected based on a literature search. Eight hundred and seventy seven patients treated between 2000 and 2010 with 3-6 cycles of (neo-) adjuvant 5-fluorouracil, epirubicin and cyclophosphamide (FEC) were genotyped for these SNPs using Sequenom MassARRAY. Main outcome measures were asymptomatic decrease of left ventricular ejection fraction (LVEF) >10% and cardiac failure grade 3-5 (CTCAE 4.0). To evaluate the impact of these 10 SNPs as well as clinical factors (age, relative dose intensity of epirubicin, occurrence of febrile neutropenia and planned and received cycles of epirubicin) on decrease of LVEF and cardiac failure, we performed uni-and multivariable logistic regression analysis. Secondary hematological malignanies were also studied because of the known link with long-term anthracycline toxicity. Additionally, exploratory analyses, including 11 additional SNPs related to FEC metabolism, were performed. Results: After a median (range) follow-up of 43.5 (4.8-115.2) months, LVEF decline of >10% occurred in 153 patients (17.5%) and cardiac failure in 16 patients (1.8%). In two patients a secondary hematological malignancy occurred (one acute myeloid leukemia and one chronic myeloid leukemia). In multivariable analysis, six cycles of FEC compared to three cycles received and heterozygous carriers of the rs246221 T-allele in ABCC1 relative to homozygous carriers of the T-allele were significantly associated with LVEF decline of >10% (OR 1.3, 95% CI 1.1-1.4, p<0.001 and OR 1.59, 95% CI 1.1-2.3, p =0.02). The other 9 SNPs and clinical factors tested were not significantly associated. In our exploratory analysis, no other SNPs related to FEC metabolism were retained in the multivariate model for prediction of LVEF decline Conclusion: In a large cohort of early breast cancer patients, number of received cycles of epirubicin was associated with ACT. We could also validate previous

reports regarding the impact of ABCC1 polymophisms in anthracycline-induced cardiotoxicity.

O6 - Exploring the intra-patient PIK3CA mutational heterogeneity of circulating tumour cells by massive parallel sequencing in patients with metastatic hormone receptor-positive breast cancer.

Bram De Laere, Dieter Peeters, Roberto Salgado, Peter Vermeulen, Peter Van Dam, Steven Van Laere, Luc Dirix University of Antwerp, Wilrijk Introduction: CTCs are a real-time reflection of the ad hoc relevant subpopulation in patients with progressive disease. The study comprises the clinical application of a methodology to determine the PIK3CA mutational status at a single CTC level. Methods: Using CellSearch and DEPArray we purified single and groups of CTCs from peripheral blood in 29 patients with metastatic ER+/PR+/HER2- breast cancer. Isolation of WBCs served as internal negative control. Circulating cell-free DNA was purified from CPT-collected plasma. Additionally, gDNA was extracted from archival FFPE tissue sections from primary tumour. Mutation analysis was performed via targeted amplicon sequencing of PIK3CA exons 9 and 20 on a GS Junior system. Results: WGA of CTC samples had a success rate of 86,3 19,7%(single) and 93,4 14,1%(group), respectively. NGS resulted in a mean fold coverage depth of 1257 703(Ex9) and 1494 897(Ex20) reads. Mutations were present at a high frequency in archival PT (16/27 (59,2%)) and showed poor and fair agreement with cfDNA (n=21; 42,8% disparity; kappa=0,113) and CTCs (n=22; 27,2% disparity; kappa=0,394), respectively. A concordant PIK3CA status across all compartments was observed in 10/18 (55,5%) samples. At the used sequencing depth, cfDNA failed to the detect PIK3CA mutations in 4 cases (22,2%), of which three were present in the respective PT and corresponding CTCs. Gain of mutation was observed in 4/18 patients (22,2%), with a wild type PT and mutant CTCs at progression (cfDNA confirmed the MT genotype in three cases). A wild-type PIK3CA sequence in recovered WBCs of evaluable patients (n=30) indicates a high specificity and tumorigenic nature of the picked up variants. In depth intra-CTC analysis reveals PIK3CA mutational heterogeneity with the presence of both mutant and wild-type CTCs. Additionally, unique double-mutated CTCs were detected as well. Conclusions: We report the frequent occurrence of PIK3CA hotspot mutations in metastatic HR+ breast cancer. Intra-patient heterogeneity was observed with

cases of concordance and discordance of the PIK3CA genotype in the intravascular compartment with comparison to the temporally unmatched PT. The study presents the utilization of a liquid biopsy, thereby paving the way towards the application of a more personalized medicine in the management of patients with metastatic cancer.

O7 - Low-level laser therapy as a tool for the management of radiodermatitis: a pilot study in breast cancer patients

Jolien Robijns, Sandrine Censabella, Stefan Claes, Paul Bulens, Jeroen Mebis Jessa Ziekenhuis, Hasselt Introduction: Radiodermatitis (RD) is a common and distressing side effect of radiotherapy. Objective: Investigate the efficacy of low-level laser therapy (LLLT) as a treatment for RD in breast cancer patients. Methods: For this prospective study two successive groups of breast cancer patients undergoing identical radiotherapy regime post-lumpectomy were compared. The control group (CTRL group, N=41) received the institutional skin care protocol, while the experimental group (LLLT group, N=38) was treated with this protocol plus biweekly with LLLT (6 sessions) starting at fraction 20 of radiotherapy. LLLT was delivered to the patients by a diode laser in the infrared range (808-905 nm) with a fixed energy density (4 J/cm2). There were no significant differences between the two groups with respect to patients' and treatment-related characteristics. The severity of RD was evaluated by trained nurses before the start of LLLT and at the end of radiotherapy according to the criteria of the Radiation Therapy Oncology Group (RTOG). Additionally, the patients were asked to rate their global treatment satisfaction, through a numerical rating scale (0, 'not at all' - 10, 'very much') at the end of radiotherapy. Results: Before the start of LLLT (i.e. fraction 20) the distribution of the RTOG grades was comparable between both groups (p= 0.352), with most of the patients presenting RTOG grade 1. At the end of radiotherapy, the severity of RD significantly differed between the two groups (p= 0.002), with a greater proportion of patients with grade 2 RD in the control group (29.3% vs. 2.6%, for the control and LLLT group, resp.): There was an intensification of the skin reactions in the CTRL group (p= 0.004), while it remained stable (p= 0.222) in the LLLT group. Furthermore, the patients' global satisfaction with LLLT was significantly higher than with the standard skin care (p= 0.001).

Conclusion: These results show that LLLT has a beneficial effect on RD by preventing the aggravation of the skin reactions. Moreover, the patients were more satisfied with LLLT than with the standard skin care. Further research is needed to investigate the efficacy of LLLT on the prevention and management of RD.

O8 - Correlation between circulating tumor cells and the hemostastis system in metastatic breast cancer.

Tom Van den Mooter1, Laure-Anne Teuwen2, Anja Brouwers3, Annemie Prové4, Annemie Rutten4, Jean Vandebroek4, Luc Dirix4 1

Univesity of Antwerp, Leuven, 2KU Leuven, Leuven, 3University of Antwerp, Antwerp, 4Oncology Center GZA Hospitals Sint-Augustinus, Antwerp Introduction: The interaction between tumor cells and the hemostasis system is an active area of research. Tumor cells interact with the coagulating cascade resulting in a potential benefit of survival and growth. Platelets directly or indirectly interact with tumor cells. Previous investigation has shown a correlation between circulating tumor cells (CTC) and the development of venous thromboembolism (VTE). The aim of this study is to search for a correlation between quantitatively measured circulating tumor cells and routine clotting tests and platelet counts in patients with metastatic breast cancer (MBC). Patients and methods: We retrospectively analyzed coagulation tests, platelet counts and circulating tumor cells of 292 patients with metastatic breast cancer from October 2007 until November 2014. Circulating tumor cells were quantitatively measured using the CellSearch system. Coagulation tests include d-dimers, prothrombin time (PT), activated partial thromboplastin time (aPTT) and fibrinogen level. We also looked for any major thrombotic events. Results: CTCs (this is = 1 CTC per 7.5 ml whole blood) are significantly correlated with d-dimers (Spearman's rank correlation coefficient (?): 0.348, p =0.008) compared with no CTC detected. Furthermore, fibrinogen is positively correlated with CTC count (?: 0.253, p < 0.001). A significant negative correlation was seen between CTC and PT (?: -0.183, p = 0.003). Conclusion: Elevated circulating tumor cells are correlated with increased ddimers and fibrinogen levels and with a decreased PT but not with aPTT or platelets. Few thrombotic events were seen. Further investigation is ongoing.

LIST OF SELECTED POSTERS P01 - Survival And Long Term Side Effects Of Treatment For Patients With Testicular Germ Cell Tumor. A single center 10-year retrospective study. Spyridon Sideris, Thierry Gil - Jules bordet institut, Brussels P02 - Neurone Specific Enolase, a biomarker for the breast cancer brain metastasis: a feasibility, two groups, non randomized, parallel study. Cristina Dumitrescu, Daniel Devriendt, Dominique Lossignol - Jules Bordet Institute, Brussels P03 - Tissue is the issue. Elien Dewaele, Jan Van den Brande, Pol Specenier - UZ Antwerpen, Edegem P04 - PD-L1/PD-1 staining of primary breast cancer using immuno-histochemistry. Cinzia

Solinas, Laurence Buisseret, Soizic Garaud, Anaïs Boisson, Celine Naveaux, Pushpamali De Silva, Ligia Craciun, Roland De Wind, Denis Larsimont, Karen Willard-Gallo - Institut Jules Bordet, Bruxelles

P05 - ARGX-111, a defucosylated antagonistic anti-MET antibody, displays potent anti-tumor activity through enhanced ADCC. Alain Thibault1, Natalie De Jonge1, Anna Hultberg1, Peter

Brouckaert2, Torsten Dreier1, Hans De Haard3, Philippe Aftimos4, Christian Rolfo5, Marc Peeters5, Ahmad Awada4 - 1Argen-X Bvba, Zwijnaarde, 2Ghent University, Zwijnaarde, 3Argern-X Bvba, Zwijnaarde, Institut Jules Bordet, Bruxelles, 5Universitair Ziekenhuis Antwerpen, Antwerpen

4

P06 - Retrospective study of Everolimus with fulvestrant in postmenopausal women with hormone receptor-positive metastatic breast cancer pretreated with aromatase inhibitors(AI's) and selective estrogen modifiers. L. Vanacker, L. Decoster, D. Schallier, C. Fontaine, Jacques De Grève - UZ Brussel, Brussels P07 - Pseudoprogression, complete response and late-onset auto-immunity in patient with NSCLC treated with anti-PD-L1. Tom Van den Mooter1, Lien Van Walle2, Laure-Anne Teuwen2, Annemie Prové3, Jean Vandebroek3, Annemie Rutten3, Luc Dirix3 - 1Univesity of Antwerp, Antwerp, 2KU Leuven, Leuven, 3Oncology Center GZA Hospitals Sint-Augustinus, Antwerp P08 - A phase II trial of oxaliplatin and 5-FU (mFOLFROX6) in patients with platinum-sensitive recurrent ovarian carcinoma. Sofiya Latifyan1, Veronique D'Hondt2, Fabienne Lebrun1, Thierry Gil1, Andrea Gombos1, Fanny Bustin1, Joseph Kerger1 - 1Institut Jules Bordet, Brussels, 2Institut Régional du Cancer, Montpellier, France P09 - Neoadjuvant chemotherapy in breast cancer patients induces miR-34a expression. Pierre

Freres, Claire Josse, Nicolas Bovy, Meriem Boukerroucha, Ingrid Struman, Vincent Bours, Guy Jerusalem - CHU de Liège, Liège

P10 - Evaluation of Abiraterone Acetate post-docetaxel in the Belgian compassionate use program. Charles Van Praet1, Tom Claeys1, Sylvie Rottey1, Gino Pelgrims2, Wim Demey3, Filip Van

Aelst4, Wim Wynendaele5, Thierry Gil6, Peter Schatteman7, Bertrand Filleul8, Denis Schallier9, Jean-Pascal Machiels8, Dirk Schrijvers10, Els Everaert11, Lionel D'Hondt8, Patrick Werbrouck12, Joanna Vermeij10, Jeroen Mebis13, Marylene Clausse14, Marika Rasschaert15, Joanna Van Erps16, Jolanda Verheezen17, Jan Van Haverbeke18, Jean-Charles Goeminne19, Nicolaas Lumen1 - 1Universitair Ziekenhuis Gent, Gent, 2Az Turnhout, Turnhout, 3az Klina, Antwerpen, 4az Delta, Roeselare, 5Universitair Ziekenhuis Leuven, Leuven, 6 Institut Jules Bordet, Brussel, 7Olv Aalst, Aalst, 8UCL, Brussel, 9Universitair Ziekenhuis Brussel, Brussel, 10 ZNA, Antwerpen, 11Az Nikolaas, Sint-Niklaas, 12Az Groeningen, Kortrijk, 13Jessa Ziekenhuis, Hasselt, 14Clinique Saint-Luc, Bouge, 15Az Monica, Antwerpen, 16Asz Aalst, Aalst, 17Sint-Trudo, Sint-Truiden, 18Sint-Andries Ziekenhuis, Tielt, 19Sainte-Elisabeth, Namur

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Zytiga

prijs ex-factory excl. BTW

NAAM VAN HET GENEESMIDDEL: ZYTIGA 250  mg tabletten. KWALITATIEVE EN KWANTITATIEVE SAMENSTELLING: Elke tablet bevat 250  mg 250 mg € 3.135,00 abirateronacetaat Hulpstoffen met bekend effect: Elke tablet bevat 189  mg lactose en 6,8  mg natrium. FARMACEUTISCHE VORM: Tablet. Witte tot x 120 tabs gebroken witte, ovale tabletten, waarop aan één kant AA250 werd aangebracht. Therapeutische indicaties: ZYTIGA is met prednison of prednisolon geïndiceerd voor: – de behandeling van gemetastaseerde castratieresistente prostaatkanker bij volwassen mannen die asymptomatisch of licht symptomatisch zijn na falen van androgeendeprivatietherapie en voor wie behandeling met chemotherapie nog niet klinisch geïndiceerd is; – de behandeling van gemetastaseerde castratieresistente prostaatkanker bij volwassen mannen bij wie de ziekte progressief was tijdens of na een chemotherapieschema op basis van docetaxel. Dosering en wijze van toediening: Dosering: De aanbevolen dosis is 1.000 mg (vier tabletten van 250 mg) als eenmalige dagelijkse dosis, niet met voedsel in te nemen (zie de informatie over de wijze van toediening). Als de tabletten met voedsel worden ingenomen, verhoogt dat de blootstelling aan abirateron. ZYTIGA moet worden gebruikt met een lage dosis prednison of prednisolon. De aanbevolen dosis prednison of prednisolon is 10 mg per dag. Bij patiënten die niet chirurgisch zijn gecastreerd, moet chemische castratie met een LHRH-analoog tijdens de behandeling worden voortgezet. Serumtransaminases moeten worden bepaald voordat de behandeling wordt gestart, elke twee weken in de eerste drie maanden van de behandeling en daarna maandelijks. De bloeddruk, het serumkalium en de vochtretentie moeten maandelijks worden gemeten. Patiënten met een aanzienlijk risico op congestief hartfalen dienen echter gedurende de eerste drie maanden van de behandeling elke twee weken gecontroleerd te worden en daarna maandelijks. Bij patiënten met reeds bestaande hypokaliëmie of degenen die hypokaliëmie ontwikkelen terwijl ze met ZYTIGA worden behandeld, dient overwogen te worden de kalium­concentratie bij de patiënt op ≥ 4,0 mM te houden. Voor patiënten die ≥ graad 3 toxiciteiten ontwikkelen, waaronder hyper­tensie, hypokaliëmie, oedeem en andere, non-mineralocorticoïde toxiciteiten, dient de behandeling te worden onderbroken en geschikte medische behandeling te worden ingesteld. Behandeling met ZYTIGA mag niet eerder worden hervat dan nadat de symptomen van de toxiciteit zijn afge­nomen tot graad  1 of tot baseline. In geval van een gemiste dagdosis van ZYTIGA, prednison of prednisolon, moet de behandeling de volgende dag worden hervat met de gebruikelijke dagdosis. Levertoxiciteit: Voor patiënten die tijdens de behandeling levertoxiciteit ontwikkelen (alanine­aminotransferase [ALAT] verhoogd of aspartaataminotransferase [ASAT] verhoogd tot meer dan 5 maal de bovengrens van de normaalwaarde [ULN]), moet de behandeling onmiddellijk worden onderbroken. Nadat de leverfunctietest­waarden weer op baseline van de patiënt zijn, kan de behandeling worden hervat in een verlaagde dosis van 500 mg (twee tabletten) eenmaal per dag. Bij patiënten bij wie de behandeling is hervat, moeten serumtransaminases minimaal elke twee weken gedurende drie maanden gecontro­leerd worden en daarna maandelijks. Als de levertoxiciteit bij de verlaagde dosis van 500 mg per dag opnieuw optreedt, moet de behandeling worden beëindigd. Als patiënten op enig moment tijdens de behandeling ernstige levertoxiciteit ont­wikkelen (ALAT of ASAT 20 maal de boven­grens van de normaalwaarde), moet de behandeling worden stopgezet en mogen patiënten niet opnieuw worden behandeld. Leverinsufficiëntie: Er is geen dosis­aanpassing nodig voor patiënten met reeds bestaande milde leverinsufficiëntie, Child‑Pugh Klasse A. Aangetoond is dat matige leverinsufficiëntie (Child-Pugh Klasse B) de systemische blootstelling aan abirateron met ongeveer een factor 4 verhoogt na eenmalige orale doses van 1.000 mg abirateronacetaat. Er zijn geen gegevens over de klinische veiligheid en werkzaamheid van meervoudige doses abirateronacetaat, toegediend aan patiënten met matige of ernstige lever­insufficiëntie (Child-Pugh Klasse B of C). Een dosisaanpassing kan niet voorspeld worden. Het gebruik van ZYTIGA moet zorgvuldig worden geëvalueerd bij patiënten met matige leverinsufficiëntie, bij wie het voordeel duidelijk moet opwegen tegen de mogelijke risico’s. ZYTIGA mag niet worden gebruikt bij patiënten met ernstige leverinsufficiënte (zie de rubriek Contra-indicaties). Nierinsufficiëntie: Bij patiënten met nierinsufficiëntie is geen dosis­aanpassing noodzakelijk. Er is echter geen klinische ervaring bij patiënten met prostaatkanker en ernstige nierinsuffi­ciëntie. Bij deze patiënten is voorzichtigheid geboden. Pediatrische patiënten Er is geen relevante toepassing van dit geneesmiddel bij pediatrische patiënten, aangezien prostaatkanker bij kinderen en adolescen­ten niet voorkomt. Wijze van toediening: ZYTIGA moet minstens twee uur na het eten worden ingenomen en na het innemen van de tabletten mag men minstens één uur niet eten. Deze tabletten moeten in hun geheel worden doorgeslikt met water. Contra-indicaties: – Overgevoeligheid voor de werkzame stof of voor één van de vermelde hulpstoffen. – Vrouwen die zwanger zijn of die zwanger zouden kunnen zijn. – Ernstige leverinsufficiëntie [Child‑Pugh-klasse  C]. Bijwerkingen: Samenvatting van het veiligheids­profiel: De meest voorkomende bijwerkingen die worden gezien, zijn perifeer oedeem, hypokaliëmie, hypertensie en urineweginfectie. Andere belangrijke bijwerkingen zijn onder andere hartaandoeningen, lever­toxiciteit, breuken en allergische longblaasjesontsteking. ZYTIGA kan hypertensie, hypokaliëmie en vochtretentie veroorzaken als farmacodynamisch gevolg van het werkingsmechanisme. In klinische studies werden verwachte mineralocorticoïde bijwerkingen vaker gezien bij patiënten die werden behandeld met abirateronacetaat dan bij patiënten die werden behandeld met placebo: hypokaliëmie bij 21% versus 11%, hypertensie bij 16% versus 11% en vochtretentie (perifeer oedeem) bij 26% versus 20%. Bij patiënten die werden behandeld met abirateronacetaat werden CTCAE (versie 3.0)-graad 3 en 4 hypokaliëmie en CTCAE (versie 3.0)-graad 3 en 4 hypertensie gezien bij respectievelijk 4% en 2% van de patiënten. Mineralocorticoïde reacties konden in het algemeen succesvol medisch worden behandeld. Gelijktijdig gebruik van een corticosteroïd verlaagt de incidentie en de ernst van deze bijwerkingen. Samenvatting van bijwerkingen in tabelvorm: In studies bij patiënten met gemetas­taseerde gevorderde prostaatkanker die een luteinising hormone‑­releasing hormone (LHRH)‑­analoog gebruikten of eerder een orchidectomie ondergingen, werd ZYTIGA toegediend in een dosis van 1.000 mg per dag in combinatie met een lage dosis prednison of prednisolon (10 mg per dag). Bijwerkingen die tijdens klinische studies en postmarketingervaring zijn waargenomen, staan hieronder vermeld naar frequentiecategorie. De frequentiecategorieën zijn als volgt gedefinieerd: zeer vaak (≥ 1/10), vaak (≥ 1/100 tot < 1/10), soms (≥ 1/1.000 tot < 1/100), zelden (≥ 1/10.000 tot < 1/1.000), zeer zelden (<1/10.000) en niet bekend (frequentie kan met de beschikbare gegevens niet worden bepaald). Binnen elke frequentie­categorie zijn de bijwerkingen weergegeven in afnemende mate van ernst. Tabel 1: Bijwerkingen vastgesteld in klinische studies en post­marketing: Infecties en parasitaire aan­doeningen: zeer vaak: urineweginfectie; vaak: sepsis. Endocriene aan­doeningen: soms: bijnier­insufficiëntie Voedings‑ en stof­wisselingsstoornissen: zeer vaak: hypokaliëmie; vaak: hypertriglyce­ridemie. Hartaandoeningen: vaak: hartfalen*, angina pectoris, aritmie, atriale fibrillatie, tachycardie; niet bekend: myocardinfarct. Bloedvat­ aandoeningen: zeer vaak: hypertensie. Ademhalingsstelsel-, borstkas- en mediastinumaan­doeningen: zelden: allergische longblaasjes­ontstekinga. Maag­darm­stelselaandoeningen: zeer vaak: diarree; vaak: dyspepsie. Lever‑ en galaandoeningen: vaak: alanineaminotransferase verhoogd, aspartaat­aminotransferase verhoogd. Huid‑ en onderhuid­aandoeningen: vaak: rash. Skeletspierstelsel- en bind­weefselaandoeningen: soms: myopathie, rabdomyolyse. Nier- en urinewegaandoeningen: vaak: hematurie. Algemene aandoeningen en toedieningsplaats­ stoornissen: zeer vaak: oedeem perifeer. Letsels, intoxicaties en verrichtings­complicaties: vaak: breuken**. *Hartfalen omvat ook congestief hartfalen, linkerventrikeldisfunctie en ejectiefractie verlaagd. **Breuken omvat alle breuken met uitzondering van pathologische breuk. a Spontane rapportage uit postmarketingervaring. De volgende CTCAE (versie 3.0)-graad 3 bijwerkingen traden op bij patiënten die met abirateronacetaat werden behandeld: hypokaliëmie 3%; urineweginfectie, alanineaminotransferase verhoogd, hypertensie, aspartaatamino­transferase verhoogd, breuken 2%; perifeer oedeem, hartfalen en atriale fibrillatie elk 1%. CTCAE (versie 3.0)-graad 3 hypertriglyceridemie en angina pectoris kwamen voor bij < 1% van de patiënten. CTCAE (versie 3.0)-graad 4 perifeer oedeem, hypokaliëmie, urineweginfectie, hartfalen en breuken kwamen voor bij < 1% van de patiënten. Beschrijving van bepaalde bijwerkingen: Cardiovasculaire reacties: Beide fase 3-studies sloten patiënten uit met ongecontroleerde hypertensie, klinisch relevante hartziekte blijkens een myocardinfarct of een manifestatie van arteriële trombose in de afgelopen 6 maanden, ernstige of onstabiele angina of hartfalen met NYHA klasse III of IV (studie 301) of hartfalen klasse II tot IV (studie 302) of een gemeten cardiale ejectiefractie van < 50%. Alle ingesloten patiënten (zowel behandeld met medicatie als met placebo) werden gelijktijdig behandeld met androgeendeprivatietherapie, voornamelijk door middel van LHRH‑analogen, hetgeen geassocieerd is met diabetes, myocard­ infarct, cerebrovasculair accident en plotse hartdood. De incidentie van cardiovasculaire bijwerkingen in de fase 3-studies bij patiënten die abirateronacetaat gebruikten, ten opzichte van patiënten die placebo innamen, waren als volgt: hypertensie 14,5% vs. 10,5%, atriale fibrillatie 3,4% vs. 3,4%, tachycardie 2,8% vs. 1,7%, angina pectoris 1,9% vs. 0,9%, hartfalen 1,9% vs. 0,6% en aritmie 1,1% vs. 0,4%. Levertoxiciteit: Levertoxiciteit met verhoogd ALAT, aspar­taattransaminase (ASAT) en totaal bilirubine, is gemeld bij patiënten die met abirateron­acetaat werden behandeld. In alle klinische studies werden verhoogde leverfunctie­testwaarden (ALAT‑ of ASAT‑verhoging >  5  x  ULN (upper limit of normal) of bilirubineverhoging >  1,5  x  ULN) gemeld bij ongeveer 4% van de patiënten die abirateronacetaat ontvingen, doorgaans tijdens de eerste 3 maanden na het starten van de behandeling. Patiënten met verhoogde ALAT‑ of ASAT‑waarden op baseline hadden in de klinische studie 301 een grotere kans op verhoogde leverfunctietestwaarden dan degenen met normale waarden op baseline. Wanneer verhogingen van ALAT of ASAT > 5 x ULN of verhogingen van bilirubine > 3 x ULN werden gezien, werd abirateronacetaat onder­broken of stopgezet. In twee gevallen trad er een aanzienlijke verhoging op van de lever­functietestwaarden. Deze twee patiënten, met normale leverfunctie op baseline, kregen ALAT‑ of ASAT‑verhogingen van 15 tot 40 x ULN en bilirubineverhogingen van 2 tot 6 x ULN. Na beëindiging van de behandeling normaliseerden bij beide patiënten de leverfunctietestwaarden en één patiënt werd opnieuw behandeld zonder dat de verhoogde waarden terug­keerden. In studie 302 werden verhogingen van ALAT of ASAT van graad 3 of 4 waar­ genomen bij 35 (6,5%) patiënten die met abirateronacetaat werden behandeld. De verhogingen van aminotransferases ver­dwenen bij alle patiënten op 3 na (2 met nieuwe multipele lever­metastases en 1 met ASAT-verhoging ongeveer 3 weken na de laatste dosis van abirateronacetaat). Staken van de behandeling wegens verhoging van ALAT en ASAT werd gemeld bij respec­tievelijk 1,7% en 1,3% van de patiënten behandeld met abirateronacetaat en bij respectievelijk 0,2% en 0% van de patiënten behandeld met placebo. Er werden geen overlijdensgevallen gemeld als gevolg van levertoxiciteit. In klinische studies werd het risico voor levertoxiciteit beperkt door uitsluiting van patiënten met hepatitis of significante afwijkingen van de leverfunctie­testen op baseline. In studie 301 werden patiënten met ALAT en ASAT ≥ 2,5 x ULN op baseline in afwezigheid van levermetastases en > 5 x ULN indien er wel levermetastases aanwezig waren uitgesloten van deelname. In studie 302 konden patiënten met levermetastasen niet worden geïncludeerd en werden patiënten met ALAT en ASAT ≥2,5 x ULN op baseline uitgesloten. Als zich bij patiënten die deelnamen aan klinische studies abnormale leverfunctietestwaarden ontwikkelden, werden deze op doortastende wijze behandeld door middel van een verplichte onderbreking van de behandeling en hernieuwde behandeling alleen toe te staan nadat de leverfunctietestwaarden waren gedaald tot de waarden zoals gemeten bij de patiënt op baseline. Patiënten met verhogingen van ALAT of ASAT > 20 x ULN werden niet opnieuw behandeld. De veiligheid van hervatting van de behandeling bij dergelijke patiënten is onbekend. Het mechanisme dat tot levertoxiciteit leidt, is niet duidelijk. Melding van vermoedelijke bijwerkingen: Het is belangrijk om na toelating van het geneesmiddel vermoedelijke bijwerkingen te melden. Op deze wijze kan de verhouding tussen voordelen en risico’s van het geneesmiddel voortdurend worden gevolgd. Beroepsbeoefenaren in de gezondheidszorg wordt verzocht alle vermoedelijke bijwerkingen te melden via: België: Federaal agentschap voor geneesmiddelen en gezondheidsproducten (www.fagg.be). Nederland: Nederlands Bijwerkingen Centrum Lareb. Website: www.lareb.nl. Aard en inhoud van de verpakking: Ronde witte HDPE flessen met een polypropyleen kindveilige dop, met 120  tabletten. Elke verpakking bevat 1  fles. HOUDER VAN DE VERGUNNING VOOR HET IN DE HANDEL BRENGEN: Janssen‑Cilag International NV, Turnhoutseweg 30, B‑2340 Beerse, België. NUMMER(S) VAN DE VERGUNNING VOOR HET IN DE HANDEL BRENGEN: EU/1/11/714/001. AFLEVERINGSWIJZE: Geneesmiddel op medisch voorschrift. DATUM VAN HERZIENING VAN DE TEKST: 20/11/2014. Meer informatie is beschikbaar op verzoek.

* Zytiga + prednison voor mannen met metastatische hormoonrefractaire prostaatkanker met pogressie tijdens of na behandeling met chemotherapie op basis van docetaxel 1. Logothetis CJ et al. Lancet Oncol 2012 – 2. Sternberg CN et al. Ann Oncol 2013

© Janssen-Cilag NV – PHBE/ZYT/0215/0005 – vu/er Erik Present, Antwerpseweg 15-17, 2340 Beerse

q Dit geneesmiddel is onderworpen aan aanvullende monitoring. Daardoor kan snel nieuwe veiligheids­informatie worden vastgesteld. Beroepsbeoefenaren in de gezondheidszorg wordt verzocht alle ver­moedelijke bijwerkingen te melden. Zie rubriek Bijwerkingen voor het rapporteren van bijwerkingen.

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ENJOY YOUR LIFE ENJOY YOUR PASSION

abirateronacetaat

Androgeen Deprivatie Therapie

* Docetaxel

Zytiga®

Verbetering van levenskwaliteit na Docetaxel

45

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ervaart een verbetering van pijnklachten1

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ervaart een verbetering van vermoeidheids‑ klachten2

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Roche Oncology

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R. E.: Dr. Chr. Lenaerts - Br 1363 - 12/01/2015