PERSPECTIVES VIEWPOINT

Clinical cancer research: the past, present and the future Vincent T. DeVita Jr, Alexander M. M. Eggermont, Samuel Hellman and David J. Kerr Abstract | In the past decade, we have witnessed unprecedented changes and some remarkable advances that have enabled true personalized medicine. Nevertheless, many challenges in clinical cancer research remain and need to be overcome if we are to witness similar progress in the next decade. Such hurdles include, but are not limited to, clinical development and testing of multiple agents in combination, design of clinical trials to best accommodate the ever increasing knowledge of heterogeneity of the disease, regulatory challenges relating to drug development and trial design, and funding for basic research. With this in mind, we asked four leading cancer researchers from around the world, and who have been associated with the journal since its launch in November 2004 what, in their opinion, we have learnt over the past 10 years and how we should progress in the next 10 years. DeVita, V. T. et al. Nat. Rev. Clin. Oncol. advance online publication 23 September 2014; doi:10.1038/nrclinonc.2014.153

Q

In your opinion what have been the most important findings in clinical cancer research in the past 10 years? Vincent T. DeVita Jr. In my view the most important clinical advances in cancer in the past decade have related to understanding how to harness the immune system in the treatment of advanced-stage cancer. The most striking example has occurred recently, and is the use of adoptive transfer of T cells reprogrammed to express chimeric antigen receptors (CARs) that recognize CD19 on the surface of malignant lymphocytes. These receptors are constructed of a portion of the antigen-recognizing site of a mono­ clonal antibody recognizing CD19, attached to a lymphocyte signalling moiety so when the target is attacked, the T lymphocyte is activated. First reported by Rosenberg and his group at the National Cancer Institute (NCI), the results in patients with previously treated leukaemias or lymphomas have been Competing interests A.M.M.E. is on the scientific advisory board and receives honoraria from Bristol–Myers Squibb and Merck Sharp & Dohme Limited. D.J.K. is Director of the Oxford University spin out company, Oxford Cancer Biomarkers. The other authors declare no competing interests.

startling. There have been complete and apparently durable remissions reported that would not have been possible at this stage with chemotherapy alone.1 This is an entirely new paradigm. Rosenberg and his group have extended this work in a way that may make it useful in any solid tumour. They have sequenced the DNA of tumours and searched for a unique mutation that can be the target of tailor-made CARs. They have reported a successfully treated case using this approach in a patient with cholangiocarcinoma—a n­otoriously difficult-to-treat tumour.2 With the discovery of the role of immune checkpoints in preventing the cellular immune response against cancer, inhibitors of these checkpoints have been developed that are effective in cancers that have generally been resistant to other therapies. Examples are melanoma treated with ipilimumab, an inhibitor of cytotoxic T‑lymphocyte antigen‑4 (CTLA-4),3 and anti-programmed death‑1 associated receptor (PD-1) and its ligand (PD-L1), both of which have been effective in lung cancer and melanoma.4 After decades of frustration trying to use the patient’s own immune system as therapy it was the understanding of how the immune system was blocked from

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responding to self-antigens that led to these advances. These are the fruits of the support of basic research in immunology, which has been a major part of NCI’s research effort since the passage of the Cancer Act in 1971. Close behind these advances in immuno­ logy has been the extension of the use of targeted therapy, first developed by Brian Druker in the 1990s for the treatment of chronic myeloid leukaemia, to targeting the mutated BRAF oncogene in melanoma, and mutated EGFR and the ALK gene in lung cancer.5–7 Alexander M. M. Eggermont. For me the concept of breaking immune tolerance and the sensational breakthrough in effectively manipulating the immune system is clearly the most important advance in clinical research in the past 10 years. This advance represents a major paradigm shift—we have now entered a new era. The impact of the first checkpoint inhibitors, that is, antibodies targeting CTLA‑4, PD‑1 and PD-L1, is unprecedented.8 In only 5 years, advanced-stage melanoma has been transformed from an incurable disease into a curable disease, and we are only at the beginning of discovering the transversal impact of this approach throughout solid tumour onco­logy. I think it is still largely under­estimated what the future will bring in this field, as the revolution was brought about by only two types of checkpoint blockers, and there are many immunomodulating candidate molecules that can further enhance on these impressive results.8 We now know that activating the immune system alone will not be sufficient and the old concept ‘activate the activator’, in general, is not effective because cytotoxic T lymphocytes (CTLs) can be shut down both centrally as well as peripherally: T‑cells can be downregulated by CTLA‑4 c­entrally at the lymph node immune response-priming site, as well as at the peripheral site (the primary tumour and tumour metastases), by the interaction between PD-1 on the CTL and PD-L1 on tumour cells or myeloid cells at the tumour site. The anti-CTLA‑4 agent ipilimumab was approved in 2010 because of its impact on survival in patients with advanced-stage melanoma, and both anti-PD-1 molecules (nivolumab and pembrolizumab) obtained breakthrough designated status and are ADVANCE ONLINE PUBLICATION  |  1

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PERSPECTIVES The contributors* Vincent T. DeVita Jr MD, FACP, FASCO, FAACR, is Amy and Joseph Perella Professor of Medicine and Professor of Epidemiology and Public Health, Yale University School of Medicine. In 1980 he was appointed by the President of the United States as Director of NCI and the National Cancer Program. In 1988 DeVita joined Memorial Sloan-Kettering Cancer Center as Physicianin-Chief, and incumbent of the Benno C. Schmidt Chair of Clinical Oncology. He served as Professor of Medicine at Cornell University School of Medicine until he returned to Yale in 1993. He served as the Director of Yale Cancer Center from 1993 to 2003. At the NCI, he developed combination chemotherapy programmes that ultimately led to an effective regimen (MOPP) of curative chemotherapy of Hodgkin’s disease and diffuse large B-cell lymphomas. In 1972, DeVita received the Albert and Mary Lasker Medical Research Award for his contribution to the cure of Hodgkin’s disease. He was elected to the Institute of Medicine of the National Academy of Sciences in 1974. The Commendatore of the Italian Republic order of merit was bestowed by the President of Italy in 1998. In 2002 DeVita was elected to the European Academy of Sciences for his outstanding and lasting contribution to cancer research and medical education. DeVita held the position of President of the American Cancer Society in 2012–2013. He is one of the three editors of Cancer: Principles & Practice of Oncology, a comprehensive textbook in the field of cancer medicine, now in its 10th edition. Alexander M. M. Eggermont is the Director General of Gustave Roussy Cancer Campus, Grand Paris, Villejuif/Paris-Sud, France. He is Professor of Oncology at the University Paris‑Sud, Professor of Surgical Oncology and Professor of International Networking in Cancer Research at the Erasmus University Medical Centre in Rotterdam, Netherlands. He obtained his PhD thesis entitled “Interferons in the Treatment of Cancer” at the Erasmus University. Professor Eggermont is a past President of ECCO and the EORTC and current Chair of the Adjuvant Therapy Committee of the EORTC Melanoma Group. He is acting President of the European Academy of Cancer Sciences (2010–2014) and is Chair of the Deutsche Krebshilfe International Jury for Comprehensive Cancer Centre Program. Samuel Hellman is the A. N. Pritzker Distinguished Service Professor Emeritus at the University of Chicago. He was formerly the Dean of Medicine at the University of Chicago, and before that Physician-in-Chief at Memorial Sloan-Kettering Cancer Center. He obtained his radiation oncology education at Yale University School of Medicine and the Royal Marsden Hospital. He subsequently became the founding Chairman of Radiation Oncology and Alvan T. and Viola D. American Cancer Society Professor at the Harvard Medical School before joining Memorial Sloan-Kettering Cancer Center. David J. Kerr contributes to the University of Oxford as Professor of Cancer Medicine, where he has worked with colleagues to build a new Institute for Cancer Medicine and Cancer Hospital. He has an international reputation for the treatment of and research into colorectal cancer and the quality of his work has been recognized by the award of several international prizes and the first NHS Nye-Bevan award for innovation. *The contributors are listed in alphabetical order.

expected to obtain approval for advancedstage melanoma in 2014.9–11 Their activity has also been demonstrated in renal cell carcinoma and lung cancer, and these agents are being evaluated in virtually all tumour types.12 One anti-PD-L1 antibodies, MPDL3280A, is also likely to be approved for melanoma, for lung cancer, and has been reported to have important activity in bladder cancer.13 The spectacular data reported on the activity of the combination of ipilimumab and nivolumab in patients with melanoma indicates that the future is bright future for immune combination thera­ pies.14 Breaking tolerance can be improved upon and it is the prerequisite. The door is now open to combine checkpoint inhibitors with activators such as OX40 and CD137 (co-­stimulatory T-cell molecules), and to re-explore the potential of combination approaches with cytokines.15

Samuel Hellman. Significant advances in systemically targeted treatments and physically-­targeted regional treatments have been made over the past decade. For both treatment advances, new disease paradigms have been postulated or have resulted from such advances. Molecularly-targeted agents that target specific genetic alterations in cancer cells have led to a class of agent with different characteristics and toxicities compared to standard systemic chemotherapy, as well as new ways of scheduling treatment. Some of these agents are monoclonal antibodies, while others are inhibitors of the protein products of genetic abnormalities. The recognition of immunological modification of host antitumour responses has provided a new avenue for treatment, with encouraging treatment results.16–18 Effective adoptive T‑cell therapies19 can now be incorporated with these modifications to enhance

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patient response. These methods of enhancing host antitumour responses have led to a renewed consider­ation of the abscopal effects of regional irradiation. Perhaps most surprising is the evidence that immunological mechanisms are critically important in determining radiation killing of tumour cells.20 Thus, both the local direct effects as well as in­direct effects of radiation are mediated by immune mechanisms. This situation calls for reconsideration of the volume and type of tissues (for example, regional draining lymph nodes) that should be irradiated within and outside the tumour volume in order to preserve and even augment the effects of radiation caused by immune‑mediated tumour ablation. Important changes in noninvasive regional treatment—often based on the improved ability to determine tumour location and dimensions—have improved radiation dose distribution. Intensity modulated radiation therapy (IMRT) has become an effective way to concentrate radiation within the target volume, while reducing some of the toxi­ city of other radiation treatment methods. Stereotactic body radiation therapy (SBRT) has had promising results, some of which may be due to entirely different mechanisms of radiation destruction of the tumour, such as those of an immunological nature, among others.21 Minimally invasive surgery (such as laparoscopy) has significantly advanced tumour removal with minimal morbidity. Image-guided robotic surgery offers moreprecise tumour removal. There are also newer, completely noninvasive methods of tumour destruction that use high-intensity focused ultrasound, often under direct MRI guidance. Finally, cancer management has been changed radically by newer imaging methods including rapid acquisition CT, PET and MRI, resulting in earlier diagnosis of the primary tumour or identification of formerly occult metastases. This advance has led to efforts to treat metastases that are limited in number and location (oligometastases) with curative intent by surgical excision or with radiation.22 David J. Kerr. The past decade has been domi­nated by the emergence of an ever lengthening list of companion diagnostics to guide a more-rational approach to cancer medicine.23 Agents that target hormone and growth factor receptor expression have been clinically accepted for two decades, but who could have foreseen the remarkable molecu­lar segmentation of lung and colorectal cancer (CRC), with quite profound therapeutic www.nature.com/nrclinonc

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PERSPECTIVES implications? The concerted application of modern molecu­lar genetic technology to tumour sample collections, allied to wellannotated clinical databases (usually as a component of clinical trials), has been a powerful discovery machine. This is not to say that this has been an industrial rather than intellectual exercise, data generation as if by assembly line, grinding inexorably through the gears. Biomarker discovery has involved novel screening techniques, structural biology solutions, adaptive bio­informatics, improvements and standardization in tissue collection and processing, and as always, a degree of seren­dipity. There is of course a chicken and egg debate about what came first—the biomarker and/or target or the drug? Rational drug designers will posit that discovery of an onco­genic driver preceded a logical programme of medicinal chemistry, pharmacology etc. (such as imati­nib that targets the BCR–ABL rearrange­ment), but there are examples where careful clinical observation has led ultimately to molecular character­ ization of a subset of chemoresponsive tumours (such as EGFR inhibitors for treating non‑small‑cell lung cancer [NSCLC]).

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This advance represents a major paradigm shift—we have now entered a new era

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Companion diagnostics can sometimes exclude patients who are inherently resistant to the drug. The best example of this is the use of tumour typing in patients with CRC and mutant KRAS who are being considered for treatment with the EGFR inhibitors cetuximab and panitu­mumab.24 Given that a KRAS mutation activates the signalling pathways downstream of EGFR, this effectively negates the inhibitory effects of the drug, which tallies with what is expected on a biochemical level. On the positive side, ROS1 is a receptor tyrosine kinase of the insulin receptor family, and chromosomal rearrange­ment can lead to driver mutations for NSCLC. Selection of patients with ROS1positive lung cancers for treatment with the inhibitor crizotinib yields a response rate of around 50%, which is also seen with a selection of tumours driven by the ALK fusion protein. Between them, these two molecularly defined subgroups account for approximately 8% of NSCLC cases, suggesting that it is practically possible to develop drugs whose activity is defined by relatively rare molecular subtypes.25

Q

What have been the most frustrating roadblocks and challenges to success in cancer research and treatment? V.T.D. There have been two that stand out in my mind. The most daunting is inconsistent funding for cancer research. When advocates pushed for a doubling of the NIH budget from 1997 to 2002, and succeeded, they didn’t take into account the pain this would cause when the doubling effort ended, as we knew it surely would. The NIH must spend allocated funds within the year the money is allocated. What was needed was approval to use ‘no year money’ that is, to spread the largess from doubling over 5 years to 10 years. Advocates ignored this. The result was panic and often wasteful spending of money during the 5‑year period, followed by drastic cuts when the doubling process ended abruptly. This situation ruined the careers of many young scientists whose work could not be continually supported and added a lot of instability to the field of cancer research. Since then funding has also been very lean and has slowed momentum in many fields of research. Another roadblock has been over regulation in both drug development and in conducting clinical trials. With the understandable desire to protect patients from research risks we have overshot the mark and are now ‘protecting’ patients from access to things they need. There was a landmark study that assessed the time it took from submission of a protocol for review to its approval and they came up with the amazing figure of 800 days and sometimes longer.26 The authors found that at cancer centres alone there were as many as 29 signatures required for approval of a treatment protocol. Furthermore, if amendments are made as they invariably must be, a protocol often goes back to the end of the line. These kinds of issues inhibit the flexibility clinical investi­ gators need to rapidly adjust to changing information, which is the hallmark of science these days. A.M.M.E. In clinical research the regulatory burden has again increased over the past 10 years and is a major roadblock in particular for the launching of academic trials. 90% of data collected in clinical trials are never looked at or used, but we maintain a culture of ‘overkill’ that spills over from drug development trials into all academic trials with or without drugs. This situation has led to a sharp decline, by more than 50%,

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in the number of academic clinical trials performed over the past decade. As a result, cooperative groups have had to cope with this burden. The average time to launch trials in this setting has increased to over 2 years. In addition, increased costs, fragmentation and redundancy between coopera­ tive groups have led to the creation of the National Clinical Trial Network (NCTN) in the USA and the decision to only fund four major groups. In Europe, we face similar challenges. The European Organisation for Research and Treatment of Cancer (EORTC) has recognized yet another roadblock: how to introduce molecular screening across tumour types for transversal clinical trial development in the academic setting. By creating collaborative molecular screening platforms (CMSPs) in the SPECTAprogramme, a new exciting initiative might indeed revive academic clinical trials across molecular targets.27

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The result was panic and often wasteful spending of money during the 5-year period…

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Another roadblock is excessive pricing of new drugs. If we are seriously committed to make progress and get better drugs to patients more rapidly it should be clear that excessive pricing of new drugs is yet another mechanism to prevent comparative e­ffectiveness trials in oncology. S.H. Unquestionably, one of the greatest frustrations is that, at a time of great opportunities for major saltations in cancer treatment, there has been a great reduction in cancer funding in the USA and a concomitant increase in required documentation. This is primarily due to a reduction in the grants being federally-funded. Although independent funding sources can be found, they cannot begin to replace federal financial support. Independent funding sources can be especially valuable in targeting specific areas of research for extended periods of time, without requiring extensive reporting, to enable a deeper study into basic cancer biology, which leads to great clinical promise. The best example of this has been the Ludwig Cancer Research efforts in tumour immunology and tumour-­ associated kinases. Private funding in the USA has often been disease-oriented, as evidenced by many organisations devoted to the study of breast or prostate cancer. ADVANCE ONLINE PUBLICATION  |  3

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PERSPECTIVES Increased stable cancer research funding is most needed to continue and expand the promising molecular, immunological and physically-targeted treatments, as well as continued strong basic science support. If the limited funding dilemma is not alleviated promptly, the recruitment and develop­ ment of new cancer researchers will be reduced and aspiring new scientists will be discouraged from cancer research, i­ronically at this most-promising time.

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…excessive pricing of new drugs is yet another mechanism to prevent comparative effectiveness trials in oncology

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As we learn more about individual cancers in individual patients, we must develop new types of investigation of treatments. Large clinical trials were meant to ensure statistical meaning from comparable heterogeneous groups of patients. Now this is often not the case, with detailed staging procedures and molecular characterization of tumours having identified smaller, more homogeneous groups. This makes large clini­cal trials more difficult and less necessary for comparing these more-­ uniform groups. The routine requirement of d­isproving the null hypothesis should be discontinued, and a Bayesian approach should be employed, especially when there are compelling background data. The fear of a false-positive might result in missing major new opportunities. D.J.K. There is a truism among pharmaceutical scientists that the only way to be confident that a protein is a suitable target for therapeutic intervention is in retrospect— after a successful drug has been developed. This situation underpins how poor we are as a community of drug developers at target validation. It is unusual nowadays for drugs to fail for medicinal chemical reasons, or unexpected toxicity that cannot be dealt with clinically, but we have failed repeatedly on validation, even by the increasingly clever molecular techniques that we employ for target discovery. The fact that most ‘novel’ drug-discovery targets are pursued simultaneously by multiple companies should not come as a surprise, because scientists from large and small companies attend the same meetings and read the same literature. Since the first product to market in a new area often reaps the most economic benefit,

there is a ‘first-past-the-post’ mentality that drives innovation in this sector. This secretive approach, in which targets are ‘validated’ in a relatively small number of laboratories, using relatively limited disease models, often provides the minimum information required in order to meet the competitive timelines that are perceived to be of prime importance in the race to be first. A few years ago, Aled Edwards, Chas Bountra, Tim Willson and I wrote an opin­ ion piece for Nature Chemical Biology 28 in which we urged adoption of an open access approach to anticancer drug development. If scientists in academia and industry were prepared to share and make freely available the reagents used to establish the biological and pharmacological basis of a novel drug target (such as chemical probes, antibodies, in vitro and in vivo models of disease, etc.) then, we argued, there would be an exponential rise in the number of labora­ tories engaged in target validation over a huge range of biological entities. Open access to such reagents is currently being promulgated by the Structural Genomics Consortium and partners who are generating protein structures and chemical probes for the regulators of epigenesis. The transition from a chemical to a clinical probe, in which public–private partnerships might take such a probe forward into phase I trials, allows all the clinical and pharmacodynamic data to be in the public domain so that biotechno­ logy and pharmaceutical companies could use this information to decide if the target is clinically relevant and, if so, whether they can compete to make a ‘best-in-class’ drug, rather than ‘first-in-class’. This requires a degree of cooperation between the pharma­ceutical industry, academ­ia, regulators and funders of research, which is unprece­dented, but which could hugely improve the e­fficiency of cancer drug development.

Q

Where should efforts and money be invested and what should we repeat and avoid? V.T.D. We need to increase the money devoted to basic research—un­differentiated basic research. Advocates for different diseases need to realize that most of the advances that have occurred in the clinic began in a lab somewhere with no relation­ ship to a disease. Compartmentalizing research support often leads to a waste of funds. So, we need to recommit to undifferentiated research and not repeat the mistake of too much disease advocacy.

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We also need to untangle the mess we have made of the clinical trials programme. The best way to do this, in my opinion, is to decentralize the decision-making process. This will require that NCI and the FDA delegate authorities to cancer centres. Neither organization is known for their propensity to give up authority so it will take a greater appreciation of this need by a wider a­udience to get it done. A.M.M.E. Money and efforts should be invested in tackling the roadblocks mentioned previously, and should be invested in clinical trials with a scientific rationale and scientific questions. Too many trials in the past were launched ‘because we could’ rather than ‘because we should’. Fragmentation and duplication are still common phenomena, also in the clinical trial world. Costs allocated to develop new clinical trials should request clear insight in the validity of the trial, the uniqueness or the complementarity value of the trial and full knowledge of existence of similar trials elsewhere. This can be simply done, but nonetheless is not consistent or common. Duplication of effort reflects a lack of collaborative effort and a lack of w­illingness to form consortia to do the job. We should avoid developing drugs with a marginal impact on outcome. With the current pricing system it will lead to both breaking the bank and ultimately destroying the drug development process. With the current formidable pipeline of new drugs we will fail if we don’t raise the bar and fight redundancy of pipelines and trials. The complex business of developing combi­ nations of new drugs will require flexi­ bility, such as only requesting the efficacy of the combination, and not the efficacy of each drug alone. A good example of that is the finding that BRAF-inhibitors fail in BRAF-mutant CRC because they upregulate the expression of EGFR on the surface of CRC cells. Interestingly, CRCs that did not respond to EGFR inhibitors become responsive, but only while being exposed to a BRAF inhibitor. Thus, only the dual drug combination (each by itself ineffective) led to disease regression and tumour control.29 This finding is a perfect example that molecular screening and genomics alone will not suffice, but that functional genomics are a prerequisite to understand and advance the oncology field. S.H. Most importantly, we should recognize that our knowledge of cancer causation, development, biochemistry and physiology www.nature.com/nrclinonc

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PERSPECTIVES is incomplete, and in some cases, wrong. Current paradigms must be tentative and open to change. Accepted notions of radi­ ation cell-killing do not consider the emerging studies of stromal and immuno­logical partici­p ation. 16–18 Studies of the tumour metaba­lome open a dormant field that might be a fertile base for new therapeutic strategies.30 The dichotomization of cancer as either local or widespread and the notion that all metastases at all locations are the same are false paradigms. Metastases comprise a continuum of increasing malignant capacity so that, early in the evolution of metastatic capacity, there may be deposits limited in site and malignant potential.31 Classic cancer chemotherapeutic agents are designed to be antiproliferative, but cell proliferation, although necessary for tumour growth, is not unique to cancer, and most of the limiting toxicity of these agents are due to damage to normal cell renewal tissues. The newer agents, based on tumour genetic abnormalities that are a variation of normal gene function, result in new types of host tissue damage. We need to study how these agents should be administered alone and in combination, but not based on the notion of exponential killing of cancer cells used in the development of both radiation and antiproliferative agent treatment. Because of the evidence of re-expression of developmentally expressed genes, another new class of agents may become available with their own set of toxicities. All these agents, and as yet unknown cancer characteristics, will require their own paradigms for treatment and evalu­ation, and should not rely on old methods of administration or of trial design.

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…how poor we are as a community of drug developers at target validation

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D.J.K. As I become more senior in the profession, I am leaning more towards a public health approach to cancer. In a career dominated by the intimacy of clinical consultation and research, I have come to see the enormous benefits that can be accrued by prevention compared to the sometimes meagre gains by treating established dis­ ease. In addition to public health measures around diet, lifestyle and tobacco control, noble attempts have been made to provide a rational basis for intervening to reduce the risk of cancer using quasi-­therapeutics such as vitamins and selenium. These have

involved considerable expenditure of time, money and energy, and have not really amounted to a hill of beans. I would like to see more invested in understanding the relationship between inflammation and cancer, 32 and through this, the development of tract­able therapeutic targets that could function in both primary and secon­ dary cancer prevention. Let us avoid the large, generic population-­based studies of the past and select indivi­duals who can be objectively, genetically identified at a significantly higher than general risk of developing cancer (primary prevention) or in the secondary situation, patients who harbour mutations or over­expressed pathways that render them sensitive to anti-inflammatory drugs, thus reducing the number of patients required for a trial, saving money and increasing the likelihood of success. In my own field, CRC is poised to be dissected in this way. We have identified germline DNA single nucleotide polymorphisms, which are associated with a threefold to fivefold higher risk of developing CRC;33 similarly, Charlie Fuchs, Andy Chan and colleagues have identi­fied a somatic tumoural mutation in PIK3C that sensitizes tumours to aspirin as a secondary preventive agent following surgical resection.34,35

Q

Where do you expect progress to be made in the future?

V.T.D. Regarding treatment, I expect that the continued use of genome sequencing in the clinics will identify additional ‘druggable’ molecular targets that can be targeted either by small molecules or through the use of adoptive cell therapy. However, it is very likely that to cure advanced malignancies we will need to use combinations of agents against multiple targets simultaneously as we did in the early days of successful combi­nation chemotherapy. In the current environ­ment of entangled regulations this will not be easy to achieve. I highly recommend that therapists read a paper by Hanahan and Weinberg entitled “The Hallmarks of Cancer”.36,37 This highly cited paper provides an organizing principle behind the development of cancer and identi­fies areas that are good targets, not only for treatment but also for the prevention of cancer. There are eight described hallmarks. Interestingly we have been focusing most of our treatment efforts on two or three of the hallmarks singly so the concept opens a wider horizon for clinical investigators in the use of ‘combination anti-hallmark therapy’.

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All these agents … will require their own paradigms for treatment and evaluation…

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A.M.M.E. We all know that in order to make progress in oncology, and in healthcare in general, we should do the following: first, fight tobacco use (by political will and by education); second, combat chronic infections (hepatitis by political programmes and reasonable vaccine pricing and educa­tion) and prevent cervical cancer by vaccination and education; third, educate the public on alcohol abuse; and finally, tackle obesity and stimulate mobility (via educational channels). In other words, there will be no progress without a massive investment in educating the people. If we become successful at the above four items, or even just the first item, we would achieve more in outcome benefit than we may reasonably expect from all the clinical trials we might conduct over the next 10 years. That being said, I think in clinical research outcomes we can expect a pipeline of reasonably effective drugs to become established; we will arrive at a better understanding of drug resistance by acquiring insight in cross-talk mechanisms and the role of epigenetics, and we will witness an increase in high-tech minimally invasive procedures in terms of radiotherapy and interventional radiology techniques that will reduce suffering and manage cancerdisease states more effectively. Ultimately, in this context, many cancers can become increasingly viewed and as chronic diseases that people live with. S.H. To answer this, I will summarize the progress and problems seen in the past decade. First, tumours evolve their malignant capabilities both before and during their clinical evolution. Second, there are many redundant pathways to the essential malignant phenotypes. Third, immunological mechanisms are very important in regional treatment and in modification of the tumour and host response, which provide avenues for improved therapies. Fourth, systemic and regional therapies used either alone or in combination need to overcome hurdles such as limited metasta­ses, resistant clones, tumour polyclonality and sanctuary sites. The past decade has seen much pro­gress and some surprises. I expect more of the same and cannot predict too specifically. Most predictable, I think there will be continued progress in tumour immunology ADVANCE ONLINE PUBLICATION  |  5

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PERSPECTIVES with increasing clinical relevance. The evidence that tumours can evoke significant immune responses that are suppressed by the tumour and the host stroma should provide many therapeutic opportunities. These findings are a validation of the importance and the relevance of tumour immunity.38 More unexpected perhaps are the data indicating the importance of the immune response in the direct radiation killing of tumours in vivo. Both of these immune effects can be related to the abscopal (distant) effects of localized irradiation and should lead to quite different methods of radiation designed to maximally elicit this tumour-targeted immune killing. Many of these findings might also apply to other physical mechanisms of tumour killing such as heat, UV radiation, and other non‑ionizing radiation.

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I don’t think we can emphasise enough the potential therapeutic benefits of patient stratification and selection…

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The recent advances in detecting tumour cells and tumour-specific nucleic acids in the blood should become important in early diagnosis, design of optimal therapy, and in monitoring patients for otherwise occult recurrence. Sequential studies of primary tumour evolution as well as recognizing the multiple stages of increasing metastatic capacity should, in the near future, cause a greater emphasis on diagnosing primary tumours and their metastases as early as p­ossible in their evolutionary progression. Another fruitful avenue will be the understanding of epigenetic mechanisms important in the malignant process and their modification for tumour therapy. There will be many surprises, especially if there are adequate resources and investigators to fully harvest the potential fruits of current and future research. D.J.K. Tony Blair—as prospective Prime Minister of the UK—was asked to des­ cribe his party’s top three policies, and he answer­ed: ‘Education, Education, Edu­cation.’ I would respond similarly to this question, ‘Biomarkers, Biomarkers, Biomarkers.’ I don’t think we can emphasise enough the potential therapeutic benefits of patient stratification and selection based on the cancer biology of their own tumour. I have emphasized the potential for companion diagnostics throughout this article, but we

must not forget the application of prognostic and toxgnostic markers to clinical decision making. How often are we faced as a clinical community with go/no-go decisions about whether we should offer a particular treatment or not in the absence of any useful biological data? For example, we have previously demonstrated a small (3–4%), but statistically significant overall survival benefit from adjuvant chemotherapy for stage II CRC. Rather than treat 100 patients to cure three, while inflicting significant adverse effects on 20% and a toxic death rate of 1/200, we believe that it would be possible to use prognostic markers to further segment this popu­ lation into those at low risk of recurrence (observation only) and relatively higher risk of recurrence, to whom one would be more inclined to offer chemotherapy.39 Of course that patient, informed by the relative biological risk of recurrence, would be the final arbiter of choice. There is growing recognition within the oncology community of the importance of safety and minimization of risk as part of the wider quality agenda. Although there is a dominant focus on discovering markers of efficacy, clearly risk:benefit ratios could be improved by reducing the toxicity of the drug regimens we employ, especially when  drug effectiveness is marginal. Toxgnostics is the application of genomewide association studies to find germline markers that identify those patients most at risk of treatment-associated adverse effects. These biomarkers would allow a priori selection of patients who need dose reductions or even drug avoidance if the risk of death is deemed too high.40 This biomarker-driven paradigm allows us to recast cancer medicine, selecting the right patients, the right drugs and the right doses by responding to the biology of the tumour and the genetic constitution of the patient. Yale Comprehensive Cancer Center, FMP 117, 333 Cedar Street, New Haven, CT 06519, USA (V.T.D.). Cancer Institute, Gustave Roussy Cancer Campus, Grand Paris, 114 rue Édouard Vaillant, 94805 Villejuif, France (A.M.M.E.). Department of Radiation and Cellular Oncology, The Ludwig Center for Metastasis Research, The University of Chicago Medical Center, 5758 South Maryland Avenue, Chicago, IL 60637, USA (S.H.). Radcliffe Department of Medicine, University of Oxford, Headley Way, Oxford OX3 9DU, UK (D.J.K.). Correspondence to: [email protected], [email protected], [email protected], [email protected]

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Clinical cancer research: the past, present and the future.

In the past decade, we have witnessed unprecedented changes and some remarkable advances that have enabled true personalized medicine. Nevertheless, m...
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