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From bench to clinical trials the EORTC experience in biology-based clinical cancer research
Journal of the Egyptian National Cancer Institute xxx (2017) xxx–xxx
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Review
From bench to clinical trials the EORTC experience in biology-based clinical cancer research Konstantinos Tryfonidis ⇑, Katherine Hartmann, Marie Morfouace, Denis Lacombe European Organization for Research and Treatment of Cancer (EORTC), Av. Mounier 83/11, 1200 Brussels, Belgium
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Article history: Received 24 July 2017 Accepted 6 September 2017 Available online xxxx Keywords: EORTC Biology Molecular profile Clinical research Clinical trials
a b s t r a c t For over 50 years the European Organization for Research and Treatment of Cancer (EORTC) has delivered major advances in cancer clinical research and cancer therapeutics. The introduction of molecularly targeted agents has led to significant improvements in outcome for patients with specific tumor types; however conventional chemotherapy remains the mainstay of treatment for the majority of patients. Due to increasing knowledge about the diversity of molecular pathways driving malignant progression, strategies to integrate biology into clinical research and development are continuously evolving. The challenges and the experience of the EORTC regarding how translational research is to be an indispensable component of the clinical research environment, which aims to deliver more sophisticated treatment approaches will be discussed in this perspective article. Ó 2017 National Cancer Institute, Cairo University. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Contents Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Cancer morphology or cancer biology? . . . . . . . . . . . The evolution of cancer therapy. . . . . . . . . . . . . . . . . The EORTC biology based clinical trials . . . . . . . . . . . Biobanking and data repositories in cancer research What the future is promising? . . . . . . . . . . . . . . . . . . Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Introduction Traditionally treatment of patients with cancer is based on certain clinical-pathological characteristics consisting of the organ in which the tumor originated as well as the extent of the disease, as captured by the size of the primary tumor, the nodal involvement and the presence or absence of distant metastases, as
Peer review under responsibility of The National Cancer Institute, Cairo University. ⇑ Corresponding author at: EORTC Headquarters, Av, Mounier, 83/11, 1200 Brussels, Belgium. E-mail address: [email protected] (K. Tryfonidis).
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reported by the TNM (tumor, node, and metastasis) classification. In some tumor types, certain biomarkers, expressed by the cancer cells such as the estrogen receptor (ER), the progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) status in breast cancer play an increasingly important role in therapeutic decision-making [1]. In recent years, further basic research in the field of cancer genomics has revolutionized cancer management by interpreting and assigning clinical significance to genomic alterations, e.g. Epidermal Growth Factor Receptor (EGFR) gene activating mutations are associated with response to tyrosine kinase inhibitors (gefitinib and erlotinib) for patients with non-small cell lung cancer (NSCLC) [2,3]. As the number of these potentially relevant genomic alterations is increasing, it becomes necessary for
https://doi.org/10.1016/j.jnci.2017.09.001 1110-0362/Ó 2017 National Cancer Institute, Cairo University. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Please cite this article in press as: Tryfonidis K et al. From bench to clinical trials the EORTC experience in biology-based clinical cancer research. J Egyptian Nat Cancer Inst (2017), https://doi.org/10.1016/j.jnci.2017.09.001
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them to be tested in a clinical research framework, where not only their prognostic but also their predictive value can be addressed. In this perspective article, we present the experience of the European Organization for Research and Treatment of Cancer (EORTC), a unique, pan-European academic clinical research organization with global reach for developing and conducting such biologically-driven clinical trials and we elaborate on the challenges and the impact that such studies may have. Cancer morphology or cancer biology? Histological evaluation of cancer by pathologists has revealed several subtypes which have been used for years to tailor treatment approaches. However, cancers are highly complex and are often driven by genetic aberrations that result in signaling pathways controlling proliferation and growth becoming constitutively active [4]. Recent advances in molecular biology technologies such as gene expression profiling analysis and next generation sequencing have resulted in a better understanding of the pathways, as well as their respective molecular components aberrations contributing to cancer development. Interrogating such genomic aberrations to identify those that influence genome stability, chromatin structure, differentiation, RNA processing and beyond, may improve our understanding of the molecular landscapes of cancer. Combining pathological and genomic data can provide a better understanding of the tumor and clinical response and help develop novel therapeutic strategies [5]. New WHO classifications for specific tumor types have already begun combining genomic alterations with ‘‘classical” pathology assessment to better stratify patients (e.g. medulloblastoma classification in the 2016 WHO classification, 4th revisited edition) [6]. However, genomic alterations identified in one tumor type cannot be broadly applied to others, due to extensive intertumor heterogeneity across different tumor entities; importantly, the same molecular aberration can have different relevance across different tumor types; for example, in patients with untreated metastatic melanoma with BRAF V600E mutation, Vemurafenib, a specific BRAF inhibitor showed an increase in 6-month overall survival (OS) compared to dacarbazine (84% vs 64%) [7]. On the contrary, the same inhibitor in colorectal cancer patients with the BRAF V600E mutation showed no clinical efficacy [8]. Functional molecular studies provided the mechanistic explanation for this discrepancy, emphasizing the need to couple clinical development of new targeted agents with rigorous basic and translational research [9,10]. The development of new drugs and new therapeutic strategies on the basis of the disease biology will constitute a critical step in implementing personalized medicine in cancer. It will ultimately involve connecting cancer genome events with their clinical significance in an evidence-based manner.
The evolution of cancer therapy The clinical management of cancer patients has traditionally relied on chemotherapeutic choices that are selected based on the underlying histology and are directed against all cells, cancerous or not, on the basis of rapid cellular division rates. In the recent years, improved understanding of the molecular biology of cancer coupled with advances in the medicinal chemistry shifted the focus to the clinical development of molecularly targeted agents. Despite the initial hope that such agents would target and therapeutically block some of the cancers ‘Achilles heels’, clinical reality indicates that even in success stories, resistance can occur, due to the plasticity of cancer cells and their ability to adapt to the selective pressures exerted by targeted agents [11,12]. Therapeutic resistance to targeted agents can be mediated by both pathwaydependent and -independent mechanisms [13]. Pathway dependent mechanisms include additional genetic alterations within the target oncogene itself, activation of a critical parallel mechanism that is not influenced by the targeted therapy, genomic alterations that deregulate signaling proteins acting either upstream or downstream of the target oncoprotein; while pathway independent resistance mechanisms include the tumor microenvironment and altered tumor angiogenesis. Pathway-dependent and pathway-independent mechanisms of drug resistance could of course develop simultaneously and this complicates more the development of effective clinical therapies to overcome resistant mechanisms of cancers [14]. Although we have already proceeded a step further by therapeutically harnessing the immune system against cancer, an approach, which is conceptually different from what has been described above, the integration of cancer biology in therapeutics remains critical in identifying the patient population, which can derive the utmost benefit from a specific treatment (Fig. 1). To take into consideration tumor heterogeneity, or overcome resistance to targeted therapies, combination studies are being developed. In the case of immune-therapies, understanding the role of the micro-environment in tumor development is important. For example, pre-clinical models of pancreatic tumors are showing that a so-called ‘‘cold” tumor can become infiltrated with activated tumor infiltrating lymphocytes (TILs) and respond better to standard therapy (e.g. Gemcitabine) when a combination of anti-PD-L1 and FAK inhibitors (targeting the Cancer-Associated Fibroblasts) is given [14]. Combining therapies that target different parts of the ‘‘Hallmark of Cancer” could help overcome low clinical efficacy or resistance to single agent therapies [4]. The EORTC biology based clinical trials During the last decades, EORTC has embraced the latest developments of cancer research, successfully developing biology-based
Disease of abnormal cells •Treatment with empirical chemotherapy
Disease of abnormal genes •Treatment with targeted agents Disease of abnormal genome and several interacons with complex mechanisms (immune system) •Treatment with targeted agents and disrupon of immune tolerance Fig. 1. Evolution of cancer treatment.
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clinical trials. Despite the regulatory and financial constraints, these trials have revealed meaningful outcomes for current therapeutic strategies and proved to be the newly adopted concept for subsequent clinical studies. Such biology-based trials have been characterized as complex studies; however their results echoed their need in order to achieve effectiveness in clinical practice. The advent of microarrays in the last 15 years has led to the development of the first-generation of multigene prognostic signatures, used in this case to tailor adjuvant treatment in patients with early breast cancer. EORTC tested the clinical utility of one of these signatures, MammaPrint, alternatively known as 70-gene signature (Agendia, Amsterdam, Netherlands) in a prospectively conducted randomized clinical trial[15]. The MINDACT study enrolled 6,693 patients with prior operated primary breast cancer and assessed their genomic risk per 70- gene signature and their clinical risk per modified Adjuvant! Online. Patients found to be both genomically and clinically low risk were spared adjuvant chemotherapy, whereas patients with both clinical and genomic high risk assessments were advised to receive chemotherapy. Patients found to be discordant in terms of genomic and clinical risk were randomized to use either genomic or the clinical risk classification to guide adjuvant chemotherapy administration. In total, 1550 patients who were clinical high risk but genomic low and followed the genomic assessment, thus they did not receive any adjuvant chemotherapy, achieved a 5-year distant- metastasis free survival of 95.7% which was significantly different than the predefined null hypothesis, confirming the initial hypothesis that 70-gene signature can identify a patient population at high clinical risk of recurrence that can safely forego cytotoxic chemotherapy [16]. Indeed, the study showed that among all patients at high clinical risk, the use of MammaPrint to guide adjuvant chemotherapy decisions resulted to a decrease in the use of chemotherapy in 46% of the participated patients [16]. Despite such success, this trial has been a clinical research ‘marathon’, due to the high costs supported by several grants, including a grant from the European Commission and the regulatory and the logistical complexities. MINDACT has been the first study that managed to prove de- escalation of treatment based on tumor specific biological characteristics (Fig. 2).
3
Liquid biopsies have become a true conceptual evolution over the last few years and constitute another important step towards personalized cancer care [17]. Circulating Tumor Cells (CTCs) have been proposed as a means to assess the minimal residual disease, a well- established practice in the management of hematologic malignancies [18]. In addition extensive research is ongoing regarding the circulating tumor DNA (ctDNA), specifically after the proof- of – concept analysis which showed that ctDNA as a highly sensitive biomarker for monitoring metastatic breast cancer [19]. Treat CTC is an EORTC-sponsored European trial screening HER2-negative patients who have completed (neo) adjuvant chemotherapy and surgery for the presence of CTCs. Those found positive were randomized to receive either six administrations of trastuzumab or only observation. After 18 weeks, another CTC test, with central confirmation in case there is at least one CTC-positive or CTC-doubtful CELLSEARCH image, was performed [20]. The results of this study are still awaited. Like the MINDACT study, Treat CTC is plagued by complexity; logistically, screening for CTCs is performed in national laboratories and confirmation of CTC positivity is to be performed in three central laboratories. Importantly, this will be the first prospectively designed clinical study in the adjuvant setting of breast cancer that attempts to inform treatment decisions based on minimal residual disease as defined by CTCs (Fig. 3). In this concept the under development 1613- LCG study (the APPLE study), evaluates feasibility and activity of AZD9291 (osimertinib) in patients with stage IV non- small cell lung cancer (NSCLC) and presence of T790M EGFR mutation detected in plasma ctDNA (NCT02856893) [21]. Another example of biomarker-driven clinical trial is the CREATE study. Indeed, the innovative prospective phase II CREATE study was designed to assess the efficacy and safety of crizotinib in patients with advanced stage of six rare tumor types, namely the Alveolar Soft Part Sarcoma (ASPS), clear cell sarcoma, anaplastic large cell lymphoma, inflammatory myelofibroblastic tumor, papillary renal cell carcinoma type 1 (PRCC1) and alveolar rhabdomyosarcoma all characterized and driven by MET and/ or ALK alterations. This study has been the first of its kind to establish treatment within a clinical trial on the basis of a molecular
Fig. 2. The MINDACT study.
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Fig. 3. The Treat- CTC study.
Fig. 4. The CREATE study.
alteration. Its complex logistical infrastructure and the rarity of the tumor types included required a long preparatory period before it could be officially opened as seen in the picture below. The study is currently ongoing and has already provided encouraging results for one of the tumor types the PRCC1 (Fig. 4) showing that among 4 patients with MET mutations, 2 patients achieved a confirmed partial response and one had stable disease; all 3 had long lasting disease control (14 treatment cycles). EORTC also has a long history of successes in the field of neurooncology, as shown by the pivotal trial combining temozolomide with radiotherapy for patients with glioblastoma [22]. This trial demonstrated that MGMT (methyl-guanine-methyl-transferase) gene promoter methylation can be used as a biomarker for identification of patients for whom increased activity of temozolomide is to be expected [22,23]. Also in anaplastic oligodendroglioma, deletion of both the short arm of chromosome 1 (1p) and the long arm of chromosome 19 (19q), known as 1p/19q co- deletion, is associated with increased sensitivity to chemotherapy [24,25]. In the recently presented CATNON study, patients with newly diagnosed non- co- deleted anaplastic glioma were randomized to radiotherapy alone, radiotherapy followed by adjuvant temozolomide, radiotherapy given concurrently with daily temozolomide or radiotherapy with both concurrent and adjuvant temozolomide. The study showed a significant benefit in the overall survival for patients that had received adjuvant temozolomide [26]. This study was designed approximately 10 years ago and is certainly an important step forward in the personalized treatment of glioblastoma and refinement of treatment based on molecular characteristics of the disease. Continuous progress in our understanding of the biologic profile for various malignancies, has led to an expanded list of molecular
alterations that can be used as targets for more ‘sophisticated’ drugs. The EORTC 1559-UPSTREAM in head and neck tumors is currently under development and will be the first pan- European study of biomarker based treatment strategy in patients with recurrent or metastatic squamous cell carcinoma. The study will include two cohorts of patients who will be treated with immunotherapy and three additional cohorts which will be treated with molecularly targeted agents based on specific molecular characteristics on their tumor tissue (e.g. p16, EGFR, PTEN, ERBB2, CCND1) (NCT03088059). A common characteristic of all the above- described clinical trials is the long period of time that they require to be implemented, conducted and concluded. It is surprising to realize that this can take even more than a decade before valid results are publically available. This reflects the evolution of the clinical research landscape leading to increased costs, scrutiny of pharma companies and funding bodies as well as heavy logistical burden especially regarding biologically based clinical trials (Table 1) [27,28]. All these factors highlight the need for combined efforts of multiple stakeholders with diverse expertise. It also emphasizes the need for research organizations, like the EORTC, with significant experience and operational capacity. Moreover, collaborations between the pre-clinical and clinical world are essential and can be facilitated by robust data sharing. Solutions like The Cancer Genome Atlas (TCGA) and the European Genome Archive (EGA) have been developed to share clinical and genomic data and should be promoted. Biobanking and data repositories in cancer research Biobanks are facilities that store biological samples from human donors, which have been collected under strict ethical
Please cite this article in press as: Tryfonidis K et al. From bench to clinical trials the EORTC experience in biology-based clinical cancer research. J Egyptian Nat Cancer Inst (2017), https://doi.org/10.1016/j.jnci.2017.09.001
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Table 1 EORTC- biologically driven clinical trials. Trial
Cancer Type
Molecular Target
Outcome
MINDACT Treat CTC
Breast Cancer Breast Cancer
De-escalation of adjuvant chemotherapy(16) Awaiting results(20)
CREATE
6 Rare Tumors: Alveolar Soft Part Sarcoma (ASPS), clear cell sarcoma, anaplastic large cell lymphoma, inflammatory myelofibroblastic tumor, papillary renal cell carcinoma type 1 and alveolar rhabdomyosarcoma GBM GBM GBM
MammaPrint – 70 gene expression signature Residual disease defined by presence of circulating tumor cells MET, ALK
Methylation of MGMT promoter 1p/19q co-deletion 1p/19q co-deletion PD-L1 expression
Increased activity of temozolomide(22) Sensitivity to chemotherapy Benefit of adjuvant temozolomide in overall survival Under development
EGFR T790 M ct- DNA
Under development(21)
Temozolomide + Radiation CATNON EORTC 1559UPSTREAM EORTC 1613APPLE
Head & Neck Tumors – recurrent/metastatic squamous cell carcinoma Stage IV- NSCLC
Awaiting results
Abbreviations: GBM – Glioblastoma, NSCLC – Non- small Cell lung Cancer, MGMT – methylguaninemethyltransferase.
international guidelines. They constitute a valuable resource for biomedical research, as human biological material is processed and stored using standardized procedures, and made available for future research. Indeed, centralization of the collection of clinical data in parallel with the sampling, processing and storage of biological samples according to well-defined standard operating procedures allows for development of well-designed translational research projects. The EORTC already has made this an integral part of its scientific strategy. Such a biobank can be used for translational research, for example retrospective validation of a biomarker prior to its inclusion in a prospective clinical trial. This can dramatically increase the speed of translational research and ultimately incorporation of biomarkers in clinical practice. Moreover storage of bio specimens is an opportunity to assess tumor relapse or progression on a patient by patient basis for example by evaluating drug resistance or determining potential alternative therapies. Additionally, serial evaluation of multiple tumor samples might inform tumor heterogeneity, a concept that has been addressed by numerous studies in several tumor types which has profound clinical consequences. Although this might not be an ideal way to address tumor heterogeneity as serial sampling has been unable to convincingly demonstrate that all mutations have been captured; it constitutes a first step to reveal the genetic diversity either between different regions of a primary tumor, between two different metastatic lesions or between the primary tumor and the metastatic lesion [29]. During the past several years, a number of biobanks have been developed to provide greater access to human tissue samples; however biobanking in cancer research still needs to be accompanied by universally established guidelines that will clarify existing technical and regulatory aspects. On this basis, recently the UK Breast cancer campaign tissue bank has implemented the policy of returning the data obtained from each sample processing back to the bank. This allows for correlative analysis across a whole series of studies investigating the same tissue set, avoids useless multiplications by different investigators and eventually spares wasting of tissue samples, all adding considerable value to the biobank resource [30]. Prospective biobanking of tissues has already been integrated into all EORTC trials to optimize testing of future biology-based questions. In addition to biobanks, public and controlled-access data repositories like TCGA and EGA serve as valuable resources in the development and ultimately clinical implementation of biomarkers. These repositories which include molecular and clinical data allow researchers to both identify novel associations and quickly
test biological hypotheses for specific biomarkers. As biologybased clinical trials can take more than a decade and millions of dollars to execute, it is essential that they are built on robust assumptions. Testing potential biomarkers in a retrospective fashion using publically available data can take on the order of days to weeks rather than years to complete and strengthens our understanding of these biomarkers prior to their use in prospective studies. However, these repositories are only as good as the studies they hold; it is essential for both pre-clinical and clinical researchers to deposit their data in order to maximize the results acquired from precious patient samples. What the future is promising? The implementation of high- throughput technologies nowadays for molecular profiling of tumors offers the advantage of detecting multiple events in a single sample with one experiment; this opens the possibility for simultaneous identification of multiple actionable mutations in a single patient and the subsequent enrollment in a combination therapy trial targeting each one of aberrations found. Such deep extensive molecular characterization of an individual patient sample also allows for identification of rare but potentially oncogenic molecular events. These scenarios are facilitated by several EORTC initiatives: building large databases of clinical data, collecting human biological material in a centralized biobank, establishing networks of multidisciplinary experts that can offer patients the opportunity to participate in large- scale clinical trials at their institution with the most up-to-date therapies. The concept of SPECTA (Screening Patients for Effective Clinical Trial Access) was initiated several years ago by EORTC using the significant experience gained from the previously described projects. This program is an effort at a European level to identify, earlier in the course of the disease, specific druggable molecular alterations via next generation sequencing with the ultimate goal of offering specific targeted treatments to patients within clinical trials [28]. Started as a platform initially to molecularly stratify patients with high- risk stage III and stage IV colorectal cancer (SPECTA color), it has now expanded to include several other tumor types including thoracic malignancies (SPECTA lung), brain, melanoma, prostate in addition to a rare disease component which aims to identify and collect molecular information for rare tumors irrespective of their histology of origin (SPECTA rare). With SPECTA, EORTC is taking the next step forward in the development and conduct of new generation, innovative biology-based clinical trials [31].
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Conclusions Molecular biology plays a pivotal role in the development of cancer. Biology based therapies are particularly attractive for their increased specificity and reduced toxicity as compared to traditional chemotherapies. Initial insights into the complex mechanisms behind cancer have led to the introduction of numerous novel targeted agents, the majority of which are currently investigational. However, there is still much we do not understand. Ultimately one of the biggest challenges in the design and implementation of biology based clinical trials will be in selecting the best biomarkers to test and determining how results on the population level translate to individual patients. Biology based clinical trials constitute an evolving area of clinical research where the EORTC has achieved promising results. These successes have been made possible by marrying the clinical and translational research divisions to promote cross-fertilization between basic and clinical research. The unique experience gained from such initiatives enables the EORTC to embark on more and more complex challenges in the field of clinical cancer research with the necessary infrastructure. In the end, a new model of clinical trial development is being promoted. The efficient integration of modern molecular technologies will ultimately result in next generation oncology research, delivering meaningful biological insights to the clinical care of cancer patients. Acknowledgment This publication was supported by Fonds Cancer (FOCA) from Belgium. References [1] Harbeck N, Gnant M. Breast cancer. Lancet 2017;389(10074):1134–50. [2] Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Brannigan BW, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 2004;350(21):2129–39. [3] Paez JG, Janne PA, Lee JC, Tracy S, Greulich H, Gabriel S, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 2004;304(5676):1497–500. [4] Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell 2011;144(5):646–74. [5] Collisson EA, Cho RJ, Gray JW. What are we learning from the cancer genome? Nat Rev Clin Oncol 2012;9:621–30. [6] Louis DN, Perry A, Reifenberger G, von DA, Figarella-Branger D, Cavenee WK, et al. The 2016 World Health Organization classification of tumors of the central nervous system: a summary. Acta Neuropathol 2016;131(6):803–20. [7] Chapman PB, Hauschild A, Robert C, Haanen JB, Ascierto P, Larkin J, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 2011;364(26):2507–16. [8] Kopetz S, Desai J, Chan E, Hecht JR, O’Dwyer PJ, Maru D, et al. Phase II pilot study of Vemurafenib in patients with metastatic BRAF-mutated colorectal cancer. J. Clin. Oncol. 2015;33(34):4032–8.
[9] Prahallad A, Sun C, Huang S, Di NF, Salazar R, Zecchin D, et al. Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR. Nature 2012;483(7387):100–3. [10] Ades F, Zardavas D, Aftimos P, Awada A. Anticancer drug development: moving away from the old habits. Curr Opin Oncol 2014;26(3):334–9. [11] Weinstein IB, Joe AK. Mechanisms of disease: oncogene addiction–a rationale for molecular targeting in cancer therapy. Nat Clin Pract Oncol 2006;3 (8):448–57. [12] Zardavas D, Baselga J, Piccart M. Emerging targeted agents in metastatic breast cancer. Nat Rev Clin Oncol 2013 April;10(4):191–210. [13] Holohan C, Van SS, Longley DB, Johnston PG. Cancer drug resistance: an evolving paradigm. Nat. Rev. Cancer 2013 October;13(10):714–26. [14] Garraway LA, Janne PA. Circumventing cancer drug resistance in the era of personalized medicine. Cancer Discov 2012;2(3):214–26. [15] van de Vijver MJ, He YD, van’t Veer LJ, Dai H, Hart AA, Voskuil DW, et al. A gene-expression signature as a predictor of survival in breast cancer. N Engl J Med 2002;347(25):1999–2009. [16] Cardoso F, van’t Veer LJ, Bogaerts J, Slaets L, Viale G, Delaloge S, et al. 70-Gene signature as an aid to treatment decisions in early-stage breast cancer. N Engl J Med 2016;375(8):717–29. [17] Bardelli A, Pantel K. Liquid Biopsies, what we do not know (yet). Cancer Cell 2017;31(2):172–9. [18] Paietta E. Assessing minimal residual disease (MRD) in leukemia: a changing definition and concept? Bone Marrow Transplant 2002;29(6):459–65. [19] Dawson SJ, Tsui DW, Murtaza M, Biggs H, Rueda OM, Chin SF, et al. Analysis of circulating tumor DNA to monitor metastatic breast cancer. N Engl J Med 2013;368(13):1199–209. [20] Ignatiadis M, Rack B, Rothe F, Riethdorf S, Decraene C, Bonnefoi H, et al. Liquid biopsy-based clinical research in early breast cancer: the EORTC 90091–10093 Treat CTC trial. Eur. J. Cancer 2016;63:97–104. [21] Remon J, Menis J, Hasan B, Peric A, De ME, Novello S et al. The APPLE Trial: Feasibility and Activity of AZD9291 (Osimertinib) Treatment on Positive PLasma T790M in EGFR-mutant NSCLC Patients. EORTC 1613. Clin Lung Cancer 2017 March 1. [22] Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 2005;352(10):987–96. [23] Hegi ME, Diserens AC, Gorlia T, Hamou MF, de TN, Weller M, et al. MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 2005;352(10):997–1003. [24] Cairncross JG, Ueki K, Zlatescu MC, Lisle DK, Finkelstein DM, Hammond RR, et al. Specific genetic predictors of chemotherapeutic response and survival in patients with anaplastic oligodendrogliomas. J Natl Cancer Inst 1998;90 (19):1473–9. [25] Jenkins RB, Curran W, Scott CB, Cairncross G. Pilot evaluation of 1p and 19q deletions in anaplastic oligodendrogliomas collected by a national cooperative cancer treatment group. Am J Clin Oncol 2001;24(5):506–8. [26] van Den Bent MJ, Erridge S, Vogelbaum MA, Nowak AK, Sanson M, Brandes AA, et al. Results of the interim analysis of the EORTC randomized phase III CATNON trial on concurrent and adjuvant temozolomide in anaplastic glioma without 1p/19q co-deletion: An Intergroup trial. J Clin Oncol 2016;34(Suppl. 18). [27] Lacombe D, Burock S, Meunier F. Academia-industry partnerships: are we ready for new models of partnership?: the point of view of the EORTC, an academic clinical cancer research organisation. Eur J Cancer 2013;49(1):1–7. [28] Lacombe D, Tejpar S, Salgado R, Cardoso F, Golfinopoulos V, Aust D, et al. European perspective for effective cancer drug development. Nat Rev Clin Oncol 2014;11(8):492–8. [29] Zardavas D, Irrthum A, Swanton C, Piccart M. Clinical management of breast cancer heterogeneity. Nat Rev Clin Oncol 2015;12(7):381–94. [30] Speirs V, Morgan A. Breast cancer: investment biobanking–increased returns from tissue samples. Nat Rev Clin Oncol 2013;10(3):128–9. [31] Sleijfer S, Bogaerts J, Siu LL. Designing transformative clinical trials in the cancer genome era. J Clin Oncol 2013;31(15):1834–41.
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Review
From bench to clinical trials the EORTC experience in biology-based clinical cancer research Konstantinos Tryfonidis ⇑, Katherine Hartmann, Marie Morfouace, Denis Lacombe European Organization for Research and Treatment of Cancer (EORTC), Av. Mounier 83/11, 1200 Brussels, Belgium
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Article history: Received 24 July 2017 Accepted 6 September 2017 Available online xxxx Keywords: EORTC Biology Molecular profile Clinical research Clinical trials
a b s t r a c t For over 50 years the European Organization for Research and Treatment of Cancer (EORTC) has delivered major advances in cancer clinical research and cancer therapeutics. The introduction of molecularly targeted agents has led to significant improvements in outcome for patients with specific tumor types; however conventional chemotherapy remains the mainstay of treatment for the majority of patients. Due to increasing knowledge about the diversity of molecular pathways driving malignant progression, strategies to integrate biology into clinical research and development are continuously evolving. The challenges and the experience of the EORTC regarding how translational research is to be an indispensable component of the clinical research environment, which aims to deliver more sophisticated treatment approaches will be discussed in this perspective article. Ó 2017 National Cancer Institute, Cairo University. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Contents Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Cancer morphology or cancer biology? . . . . . . . . . . . The evolution of cancer therapy. . . . . . . . . . . . . . . . . The EORTC biology based clinical trials . . . . . . . . . . . Biobanking and data repositories in cancer research What the future is promising? . . . . . . . . . . . . . . . . . . Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgment. . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Introduction Traditionally treatment of patients with cancer is based on certain clinical-pathological characteristics consisting of the organ in which the tumor originated as well as the extent of the disease, as captured by the size of the primary tumor, the nodal involvement and the presence or absence of distant metastases, as
Peer review under responsibility of The National Cancer Institute, Cairo University. ⇑ Corresponding author at: EORTC Headquarters, Av, Mounier, 83/11, 1200 Brussels, Belgium. E-mail address: [email protected] (K. Tryfonidis).
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reported by the TNM (tumor, node, and metastasis) classification. In some tumor types, certain biomarkers, expressed by the cancer cells such as the estrogen receptor (ER), the progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) status in breast cancer play an increasingly important role in therapeutic decision-making [1]. In recent years, further basic research in the field of cancer genomics has revolutionized cancer management by interpreting and assigning clinical significance to genomic alterations, e.g. Epidermal Growth Factor Receptor (EGFR) gene activating mutations are associated with response to tyrosine kinase inhibitors (gefitinib and erlotinib) for patients with non-small cell lung cancer (NSCLC) [2,3]. As the number of these potentially relevant genomic alterations is increasing, it becomes necessary for
https://doi.org/10.1016/j.jnci.2017.09.001 1110-0362/Ó 2017 National Cancer Institute, Cairo University. Production and hosting by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
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them to be tested in a clinical research framework, where not only their prognostic but also their predictive value can be addressed. In this perspective article, we present the experience of the European Organization for Research and Treatment of Cancer (EORTC), a unique, pan-European academic clinical research organization with global reach for developing and conducting such biologically-driven clinical trials and we elaborate on the challenges and the impact that such studies may have. Cancer morphology or cancer biology? Histological evaluation of cancer by pathologists has revealed several subtypes which have been used for years to tailor treatment approaches. However, cancers are highly complex and are often driven by genetic aberrations that result in signaling pathways controlling proliferation and growth becoming constitutively active [4]. Recent advances in molecular biology technologies such as gene expression profiling analysis and next generation sequencing have resulted in a better understanding of the pathways, as well as their respective molecular components aberrations contributing to cancer development. Interrogating such genomic aberrations to identify those that influence genome stability, chromatin structure, differentiation, RNA processing and beyond, may improve our understanding of the molecular landscapes of cancer. Combining pathological and genomic data can provide a better understanding of the tumor and clinical response and help develop novel therapeutic strategies [5]. New WHO classifications for specific tumor types have already begun combining genomic alterations with ‘‘classical” pathology assessment to better stratify patients (e.g. medulloblastoma classification in the 2016 WHO classification, 4th revisited edition) [6]. However, genomic alterations identified in one tumor type cannot be broadly applied to others, due to extensive intertumor heterogeneity across different tumor entities; importantly, the same molecular aberration can have different relevance across different tumor types; for example, in patients with untreated metastatic melanoma with BRAF V600E mutation, Vemurafenib, a specific BRAF inhibitor showed an increase in 6-month overall survival (OS) compared to dacarbazine (84% vs 64%) [7]. On the contrary, the same inhibitor in colorectal cancer patients with the BRAF V600E mutation showed no clinical efficacy [8]. Functional molecular studies provided the mechanistic explanation for this discrepancy, emphasizing the need to couple clinical development of new targeted agents with rigorous basic and translational research [9,10]. The development of new drugs and new therapeutic strategies on the basis of the disease biology will constitute a critical step in implementing personalized medicine in cancer. It will ultimately involve connecting cancer genome events with their clinical significance in an evidence-based manner.
The evolution of cancer therapy The clinical management of cancer patients has traditionally relied on chemotherapeutic choices that are selected based on the underlying histology and are directed against all cells, cancerous or not, on the basis of rapid cellular division rates. In the recent years, improved understanding of the molecular biology of cancer coupled with advances in the medicinal chemistry shifted the focus to the clinical development of molecularly targeted agents. Despite the initial hope that such agents would target and therapeutically block some of the cancers ‘Achilles heels’, clinical reality indicates that even in success stories, resistance can occur, due to the plasticity of cancer cells and their ability to adapt to the selective pressures exerted by targeted agents [11,12]. Therapeutic resistance to targeted agents can be mediated by both pathwaydependent and -independent mechanisms [13]. Pathway dependent mechanisms include additional genetic alterations within the target oncogene itself, activation of a critical parallel mechanism that is not influenced by the targeted therapy, genomic alterations that deregulate signaling proteins acting either upstream or downstream of the target oncoprotein; while pathway independent resistance mechanisms include the tumor microenvironment and altered tumor angiogenesis. Pathway-dependent and pathway-independent mechanisms of drug resistance could of course develop simultaneously and this complicates more the development of effective clinical therapies to overcome resistant mechanisms of cancers [14]. Although we have already proceeded a step further by therapeutically harnessing the immune system against cancer, an approach, which is conceptually different from what has been described above, the integration of cancer biology in therapeutics remains critical in identifying the patient population, which can derive the utmost benefit from a specific treatment (Fig. 1). To take into consideration tumor heterogeneity, or overcome resistance to targeted therapies, combination studies are being developed. In the case of immune-therapies, understanding the role of the micro-environment in tumor development is important. For example, pre-clinical models of pancreatic tumors are showing that a so-called ‘‘cold” tumor can become infiltrated with activated tumor infiltrating lymphocytes (TILs) and respond better to standard therapy (e.g. Gemcitabine) when a combination of anti-PD-L1 and FAK inhibitors (targeting the Cancer-Associated Fibroblasts) is given [14]. Combining therapies that target different parts of the ‘‘Hallmark of Cancer” could help overcome low clinical efficacy or resistance to single agent therapies [4]. The EORTC biology based clinical trials During the last decades, EORTC has embraced the latest developments of cancer research, successfully developing biology-based
Disease of abnormal cells •Treatment with empirical chemotherapy
Disease of abnormal genes •Treatment with targeted agents Disease of abnormal genome and several interacons with complex mechanisms (immune system) •Treatment with targeted agents and disrupon of immune tolerance Fig. 1. Evolution of cancer treatment.
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clinical trials. Despite the regulatory and financial constraints, these trials have revealed meaningful outcomes for current therapeutic strategies and proved to be the newly adopted concept for subsequent clinical studies. Such biology-based trials have been characterized as complex studies; however their results echoed their need in order to achieve effectiveness in clinical practice. The advent of microarrays in the last 15 years has led to the development of the first-generation of multigene prognostic signatures, used in this case to tailor adjuvant treatment in patients with early breast cancer. EORTC tested the clinical utility of one of these signatures, MammaPrint, alternatively known as 70-gene signature (Agendia, Amsterdam, Netherlands) in a prospectively conducted randomized clinical trial[15]. The MINDACT study enrolled 6,693 patients with prior operated primary breast cancer and assessed their genomic risk per 70- gene signature and their clinical risk per modified Adjuvant! Online. Patients found to be both genomically and clinically low risk were spared adjuvant chemotherapy, whereas patients with both clinical and genomic high risk assessments were advised to receive chemotherapy. Patients found to be discordant in terms of genomic and clinical risk were randomized to use either genomic or the clinical risk classification to guide adjuvant chemotherapy administration. In total, 1550 patients who were clinical high risk but genomic low and followed the genomic assessment, thus they did not receive any adjuvant chemotherapy, achieved a 5-year distant- metastasis free survival of 95.7% which was significantly different than the predefined null hypothesis, confirming the initial hypothesis that 70-gene signature can identify a patient population at high clinical risk of recurrence that can safely forego cytotoxic chemotherapy [16]. Indeed, the study showed that among all patients at high clinical risk, the use of MammaPrint to guide adjuvant chemotherapy decisions resulted to a decrease in the use of chemotherapy in 46% of the participated patients [16]. Despite such success, this trial has been a clinical research ‘marathon’, due to the high costs supported by several grants, including a grant from the European Commission and the regulatory and the logistical complexities. MINDACT has been the first study that managed to prove de- escalation of treatment based on tumor specific biological characteristics (Fig. 2).
3
Liquid biopsies have become a true conceptual evolution over the last few years and constitute another important step towards personalized cancer care [17]. Circulating Tumor Cells (CTCs) have been proposed as a means to assess the minimal residual disease, a well- established practice in the management of hematologic malignancies [18]. In addition extensive research is ongoing regarding the circulating tumor DNA (ctDNA), specifically after the proof- of – concept analysis which showed that ctDNA as a highly sensitive biomarker for monitoring metastatic breast cancer [19]. Treat CTC is an EORTC-sponsored European trial screening HER2-negative patients who have completed (neo) adjuvant chemotherapy and surgery for the presence of CTCs. Those found positive were randomized to receive either six administrations of trastuzumab or only observation. After 18 weeks, another CTC test, with central confirmation in case there is at least one CTC-positive or CTC-doubtful CELLSEARCH image, was performed [20]. The results of this study are still awaited. Like the MINDACT study, Treat CTC is plagued by complexity; logistically, screening for CTCs is performed in national laboratories and confirmation of CTC positivity is to be performed in three central laboratories. Importantly, this will be the first prospectively designed clinical study in the adjuvant setting of breast cancer that attempts to inform treatment decisions based on minimal residual disease as defined by CTCs (Fig. 3). In this concept the under development 1613- LCG study (the APPLE study), evaluates feasibility and activity of AZD9291 (osimertinib) in patients with stage IV non- small cell lung cancer (NSCLC) and presence of T790M EGFR mutation detected in plasma ctDNA (NCT02856893) [21]. Another example of biomarker-driven clinical trial is the CREATE study. Indeed, the innovative prospective phase II CREATE study was designed to assess the efficacy and safety of crizotinib in patients with advanced stage of six rare tumor types, namely the Alveolar Soft Part Sarcoma (ASPS), clear cell sarcoma, anaplastic large cell lymphoma, inflammatory myelofibroblastic tumor, papillary renal cell carcinoma type 1 (PRCC1) and alveolar rhabdomyosarcoma all characterized and driven by MET and/ or ALK alterations. This study has been the first of its kind to establish treatment within a clinical trial on the basis of a molecular
Fig. 2. The MINDACT study.
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Fig. 3. The Treat- CTC study.
Fig. 4. The CREATE study.
alteration. Its complex logistical infrastructure and the rarity of the tumor types included required a long preparatory period before it could be officially opened as seen in the picture below. The study is currently ongoing and has already provided encouraging results for one of the tumor types the PRCC1 (Fig. 4) showing that among 4 patients with MET mutations, 2 patients achieved a confirmed partial response and one had stable disease; all 3 had long lasting disease control (14 treatment cycles). EORTC also has a long history of successes in the field of neurooncology, as shown by the pivotal trial combining temozolomide with radiotherapy for patients with glioblastoma [22]. This trial demonstrated that MGMT (methyl-guanine-methyl-transferase) gene promoter methylation can be used as a biomarker for identification of patients for whom increased activity of temozolomide is to be expected [22,23]. Also in anaplastic oligodendroglioma, deletion of both the short arm of chromosome 1 (1p) and the long arm of chromosome 19 (19q), known as 1p/19q co- deletion, is associated with increased sensitivity to chemotherapy [24,25]. In the recently presented CATNON study, patients with newly diagnosed non- co- deleted anaplastic glioma were randomized to radiotherapy alone, radiotherapy followed by adjuvant temozolomide, radiotherapy given concurrently with daily temozolomide or radiotherapy with both concurrent and adjuvant temozolomide. The study showed a significant benefit in the overall survival for patients that had received adjuvant temozolomide [26]. This study was designed approximately 10 years ago and is certainly an important step forward in the personalized treatment of glioblastoma and refinement of treatment based on molecular characteristics of the disease. Continuous progress in our understanding of the biologic profile for various malignancies, has led to an expanded list of molecular
alterations that can be used as targets for more ‘sophisticated’ drugs. The EORTC 1559-UPSTREAM in head and neck tumors is currently under development and will be the first pan- European study of biomarker based treatment strategy in patients with recurrent or metastatic squamous cell carcinoma. The study will include two cohorts of patients who will be treated with immunotherapy and three additional cohorts which will be treated with molecularly targeted agents based on specific molecular characteristics on their tumor tissue (e.g. p16, EGFR, PTEN, ERBB2, CCND1) (NCT03088059). A common characteristic of all the above- described clinical trials is the long period of time that they require to be implemented, conducted and concluded. It is surprising to realize that this can take even more than a decade before valid results are publically available. This reflects the evolution of the clinical research landscape leading to increased costs, scrutiny of pharma companies and funding bodies as well as heavy logistical burden especially regarding biologically based clinical trials (Table 1) [27,28]. All these factors highlight the need for combined efforts of multiple stakeholders with diverse expertise. It also emphasizes the need for research organizations, like the EORTC, with significant experience and operational capacity. Moreover, collaborations between the pre-clinical and clinical world are essential and can be facilitated by robust data sharing. Solutions like The Cancer Genome Atlas (TCGA) and the European Genome Archive (EGA) have been developed to share clinical and genomic data and should be promoted. Biobanking and data repositories in cancer research Biobanks are facilities that store biological samples from human donors, which have been collected under strict ethical
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Table 1 EORTC- biologically driven clinical trials. Trial
Cancer Type
Molecular Target
Outcome
MINDACT Treat CTC
Breast Cancer Breast Cancer
De-escalation of adjuvant chemotherapy(16) Awaiting results(20)
CREATE
6 Rare Tumors: Alveolar Soft Part Sarcoma (ASPS), clear cell sarcoma, anaplastic large cell lymphoma, inflammatory myelofibroblastic tumor, papillary renal cell carcinoma type 1 and alveolar rhabdomyosarcoma GBM GBM GBM
MammaPrint – 70 gene expression signature Residual disease defined by presence of circulating tumor cells MET, ALK
Methylation of MGMT promoter 1p/19q co-deletion 1p/19q co-deletion PD-L1 expression
Increased activity of temozolomide(22) Sensitivity to chemotherapy Benefit of adjuvant temozolomide in overall survival Under development
EGFR T790 M ct- DNA
Under development(21)
Temozolomide + Radiation CATNON EORTC 1559UPSTREAM EORTC 1613APPLE
Head & Neck Tumors – recurrent/metastatic squamous cell carcinoma Stage IV- NSCLC
Awaiting results
Abbreviations: GBM – Glioblastoma, NSCLC – Non- small Cell lung Cancer, MGMT – methylguaninemethyltransferase.
international guidelines. They constitute a valuable resource for biomedical research, as human biological material is processed and stored using standardized procedures, and made available for future research. Indeed, centralization of the collection of clinical data in parallel with the sampling, processing and storage of biological samples according to well-defined standard operating procedures allows for development of well-designed translational research projects. The EORTC already has made this an integral part of its scientific strategy. Such a biobank can be used for translational research, for example retrospective validation of a biomarker prior to its inclusion in a prospective clinical trial. This can dramatically increase the speed of translational research and ultimately incorporation of biomarkers in clinical practice. Moreover storage of bio specimens is an opportunity to assess tumor relapse or progression on a patient by patient basis for example by evaluating drug resistance or determining potential alternative therapies. Additionally, serial evaluation of multiple tumor samples might inform tumor heterogeneity, a concept that has been addressed by numerous studies in several tumor types which has profound clinical consequences. Although this might not be an ideal way to address tumor heterogeneity as serial sampling has been unable to convincingly demonstrate that all mutations have been captured; it constitutes a first step to reveal the genetic diversity either between different regions of a primary tumor, between two different metastatic lesions or between the primary tumor and the metastatic lesion [29]. During the past several years, a number of biobanks have been developed to provide greater access to human tissue samples; however biobanking in cancer research still needs to be accompanied by universally established guidelines that will clarify existing technical and regulatory aspects. On this basis, recently the UK Breast cancer campaign tissue bank has implemented the policy of returning the data obtained from each sample processing back to the bank. This allows for correlative analysis across a whole series of studies investigating the same tissue set, avoids useless multiplications by different investigators and eventually spares wasting of tissue samples, all adding considerable value to the biobank resource [30]. Prospective biobanking of tissues has already been integrated into all EORTC trials to optimize testing of future biology-based questions. In addition to biobanks, public and controlled-access data repositories like TCGA and EGA serve as valuable resources in the development and ultimately clinical implementation of biomarkers. These repositories which include molecular and clinical data allow researchers to both identify novel associations and quickly
test biological hypotheses for specific biomarkers. As biologybased clinical trials can take more than a decade and millions of dollars to execute, it is essential that they are built on robust assumptions. Testing potential biomarkers in a retrospective fashion using publically available data can take on the order of days to weeks rather than years to complete and strengthens our understanding of these biomarkers prior to their use in prospective studies. However, these repositories are only as good as the studies they hold; it is essential for both pre-clinical and clinical researchers to deposit their data in order to maximize the results acquired from precious patient samples. What the future is promising? The implementation of high- throughput technologies nowadays for molecular profiling of tumors offers the advantage of detecting multiple events in a single sample with one experiment; this opens the possibility for simultaneous identification of multiple actionable mutations in a single patient and the subsequent enrollment in a combination therapy trial targeting each one of aberrations found. Such deep extensive molecular characterization of an individual patient sample also allows for identification of rare but potentially oncogenic molecular events. These scenarios are facilitated by several EORTC initiatives: building large databases of clinical data, collecting human biological material in a centralized biobank, establishing networks of multidisciplinary experts that can offer patients the opportunity to participate in large- scale clinical trials at their institution with the most up-to-date therapies. The concept of SPECTA (Screening Patients for Effective Clinical Trial Access) was initiated several years ago by EORTC using the significant experience gained from the previously described projects. This program is an effort at a European level to identify, earlier in the course of the disease, specific druggable molecular alterations via next generation sequencing with the ultimate goal of offering specific targeted treatments to patients within clinical trials [28]. Started as a platform initially to molecularly stratify patients with high- risk stage III and stage IV colorectal cancer (SPECTA color), it has now expanded to include several other tumor types including thoracic malignancies (SPECTA lung), brain, melanoma, prostate in addition to a rare disease component which aims to identify and collect molecular information for rare tumors irrespective of their histology of origin (SPECTA rare). With SPECTA, EORTC is taking the next step forward in the development and conduct of new generation, innovative biology-based clinical trials [31].
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Conclusions Molecular biology plays a pivotal role in the development of cancer. Biology based therapies are particularly attractive for their increased specificity and reduced toxicity as compared to traditional chemotherapies. Initial insights into the complex mechanisms behind cancer have led to the introduction of numerous novel targeted agents, the majority of which are currently investigational. However, there is still much we do not understand. Ultimately one of the biggest challenges in the design and implementation of biology based clinical trials will be in selecting the best biomarkers to test and determining how results on the population level translate to individual patients. Biology based clinical trials constitute an evolving area of clinical research where the EORTC has achieved promising results. These successes have been made possible by marrying the clinical and translational research divisions to promote cross-fertilization between basic and clinical research. The unique experience gained from such initiatives enables the EORTC to embark on more and more complex challenges in the field of clinical cancer research with the necessary infrastructure. In the end, a new model of clinical trial development is being promoted. The efficient integration of modern molecular technologies will ultimately result in next generation oncology research, delivering meaningful biological insights to the clinical care of cancer patients. Acknowledgment This publication was supported by Fonds Cancer (FOCA) from Belgium. References [1] Harbeck N, Gnant M. Breast cancer. Lancet 2017;389(10074):1134–50. [2] Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Brannigan BW, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 2004;350(21):2129–39. [3] Paez JG, Janne PA, Lee JC, Tracy S, Greulich H, Gabriel S, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 2004;304(5676):1497–500. [4] Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell 2011;144(5):646–74. [5] Collisson EA, Cho RJ, Gray JW. What are we learning from the cancer genome? Nat Rev Clin Oncol 2012;9:621–30. [6] Louis DN, Perry A, Reifenberger G, von DA, Figarella-Branger D, Cavenee WK, et al. The 2016 World Health Organization classification of tumors of the central nervous system: a summary. Acta Neuropathol 2016;131(6):803–20. [7] Chapman PB, Hauschild A, Robert C, Haanen JB, Ascierto P, Larkin J, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 2011;364(26):2507–16. [8] Kopetz S, Desai J, Chan E, Hecht JR, O’Dwyer PJ, Maru D, et al. Phase II pilot study of Vemurafenib in patients with metastatic BRAF-mutated colorectal cancer. J. Clin. Oncol. 2015;33(34):4032–8.
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Please cite this article in press as: Tryfonidis K et al. From bench to clinical trials the EORTC experience in biology-based clinical cancer research. J Egyptian Nat Cancer Inst (2017), https://doi.org/10.1016/j.jnci.2017.09.001