Download Research and the Changing Landscape of Oncology: Cancer Therapy

Research and the Changing Landscape
of Oncology: Cancer Therapy
Yiliang Zheng
Monash University, 5th Year
Cancer Council Australia 2015 Essay Competition
Yiliang Zheng, Monash University, 5th Year
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Essay Outline
Introduction………………………………………………………………..…………………....3
Past Highlights………………………………………………………………………………….4
Present Trends………….…………………………………………………………...………….5
Future Directions………………………………………………………………………………..7
Relevance of Research Advances and Novel Treatments to Australia Cancer Care…..……….8
Relevance of Research Advances and Novel Treatments to Medical Students – Our Future
Healthcare Professionals……………………………………………………………………...10
Conclusion………………………………...………………………………………………...…11
References………………………...…………………………………………………………..12
Yiliang Zheng, Monash University, 5th Year
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Introduction
In 2013, Science magazine, a leading American scientific journal, proclaimed cancer
immunotherapy as the ‘Breakthrough of the Year’ and went as far as claiming it the ‘turning
point in cancer’.1 The prominent leading example of immunotherapy, ipilimumab (Yervoy), an
anti-CTLA-4 antibody, has been touted as revolutionary in the treatment of metastatic
melanoma, resulting in significantly increased overall survival.2,3 Success of ipilimumab in
melanoma opened doors to the potential use of immune checkpoint inhibitors in other
malignancies, setting the stage for many current immunotherapy research and trials.4-6
Ipilimumab’s approval of use by the US FDA in 2011 arrived a mere decade after the
approval of imatinib (Glivec), a kinase inhibitor, in 2001 which transformed the treatment of
chronic myeloid leukaemia (CML), producing complete cytogenetic response rate of 76.2%
and progression-free survival of 96.7% at 18 months.7 With the advent of imatinib, a new
wave of small-molecule therapeutics, particularly the tyrosine-kinase inhibitors (TKIs),
redefined oncologic treatment, with a shift away from broadly-acting cytotoxic agents to
more tumour-specific targeted therapies.7-9
These paradigm shifts in the oncologic treatment landscape evolved from rapid advances in
global cancer research over recent decades which improved our understanding of cancer
biology. These research breakthroughs place us at an exciting, defining moment in the
oncology timeline as we enter an era of personalized cancer medicine with immunotherapy
and targeted therapy taking centre stage in cancer research and therapeutics today.10
This essay discusses past, present and future trends in cancer therapy, highlighting the pivotal
role research plays in their development. It delves into the implications of these research and
treatment advances in the context of Australia’s cancer care and health system. It also
explores the relevance of these therapeutic and research advances to medical students.
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Past Highlights
The early-to-mid 20th century saw the explosion of numerous chemotherapeutic discoveries,
such as antifolates, thiopurines, vinca alkaloids, which largely relied on large-scale screening
of plants, fungi and organisms for compounds with anti-cancer activity.11-13 It was the
landmark discovery of the effectiveness of nitrogen mustard against Hodgkin’s lymphoma
post-World War II which represented the dawn of oncology.14 Although many
chemotherapeutic agents were available, most were limited by narrow therapeutic index,
toxicities and acquired resistance.11,12 Little was known about cancer biology then, though
subsequent development of chemotherapy and radiotherapy regimens was guided by the
hypothesis of tumour cells’ sensitivity to DNA damage.15
Despite subsequent discoveries of the first proto-oncogenes and tumour suppressor genes in
1970s, the first mutated gene in human cancer in 1982, and tumour signalling pathways in
1990s, genetic understandings had minor impact on clinical efforts to control cancer.15-17 Drug
development continued with compound modifications and large-scale screening, without
learning from advances in cancer biology.
Surgery and radiotherapy had always been and are likely to remain the bulk of cancer
treatment.15 Improvements in technologies in recent decades, such as minimally-invasive
surgery, intensity-modulated radiation therapy (IMRT) and image-guided radiation therapy
(IGRT) that deliver precise radiation to the target in 3-dimensions and motion respectively,
make them more effective therapies, independent to molecular advances.15,18,19
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Present Trends
The progress of research in recent decades that brought increasing understanding of the
molecular mechanisms of cancer pathogenesis has translated to the discovery, development
and application of molecularly-targeted agents (MTAs).20 MTAs inhibit specific molecular
pathways enabling key capabilities or hallmarks in tumour cells (such as growth and
maintenance), activate apoptotic signaling and facilitate effector functions of immune cells,
effectuating rapid and profound tumour regression.12,15,21 Following successes of imatinib in
CML and rituximab in non-Hodgkin lymphoma, emergence of these mechanism-based
therapies has changed many metastatic solid tumours from diseases with nearly invariable,
early fatality, to chronic diseases with prolonged progression-free survival (PFS) and overall
survival.22 For instance, sunitinib, a multi-targeted TKI demonstrating longer PFS than
previously used interferon-α, became the most commonly used first-line agent in metastatic
renal cell carcinoma (RCC) which, with the use of other second-line agents including everolimus
and axitinib, improved overall survival from several months to years.22-25
Parallel to the development of MTAs is the advancement in genomics and proteomics. We are
only beginning to appreciate that chromosomal and genetic defects modify cellular signaling,
creating survival advantage for tumour cells.26 Following the footsteps of the Human Genome
Project which identified more than 290 cancer-related genes through collaborative research,
the Cancer Genome Atlas (CGA) and the International Cancer Genome Consortium (ICGC) are
monumental international efforts to provide a complete catalogue of all cancer genes in major
cancer types.27-29 Through genetic sequencing and molecular characterization of hundreds of
tumours, they aim to provide a comprehensive description of all genomic, transcriptomic and
epigenomic changes.29,30
Knowledge of oncogenic mutations and molecular changes holds promise to reveal potential
therapeutic targets and develop MTAs to treat specific patients’ tumours. Current research
identifies oncoproteins in various signaling pathways involved in tumour growth and
maintenance present in patient subpopulations, such as EGFR, HER2, BRAF, c-KIT – these act as
predictive biomarkers that predict response to specific MTAs.12,31-33 Molecular profiling of
patients’ tumours performed prior to treatment can determine their mutational status which can
be matched to particular therapeutic agents.31 For example, EGFR inhibitors cetuximab and
panitumumab are used for patients with KRAS mutation-negative colorectal carcinomas,
extending their PFS when combined with chemotherapy.15,22 Gefitinib, another EGFR inhibitor,
was used in lung adenocarcinoma expressing EGFR-activating mutation, demonstrating
significant PFS in the IPASS study in 2004.15,22,32,34 Trastuzumab, a HER2-inhibitor, is used as
part of the adjuvant therapy for HER2-overexpressing breast cancer.15,22 Presence of BRAF
V600E mutations in metastatic melanoma predicts favourable use of vemurafenib, an antiBRAF V600E antibody.15,22 With our shift towards precision medicine, molecular heterogeneity
of cancers means targeted therapies based on individual molecular aberrations will be
increasingly developed and applied in cancer therapy.35
The emergence of novel immune-based strategies came with an expansion in understanding of
immune controls and responses to tumours, particularly immune escape and checkpoint
blockade of inhibitory receptors and ligands, such as CTLA-4, PD1/PDL-1.36,37 Dr Jim Allison’s
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research in immune responses and T cells led to the discovery of ipilimumab and its subsequent
use in metastatic melanoma.37,38 By stimulating host immune responses, ipilimumab and other
immunotherapeutics, including cell vaccines, cytokines and anti-PD1 antibodies, have
demonstrated extraordinary clinical efficacy with durable tumour regression, especially in
diseases known to respond to immune-based therapies, like melanoma and RCC.37,39,40
Immunotherapy is showing promise in treating traditionally non-responding diseases and
current trials seek to further evaluate response rates.4-6,36,37,41 For example, pembrolizumab
and nivolumab, two anti-PD-1 antibodies approved for melanoma, are currently evaluated in
solid tumours such as non-small-cell lung cancers, breast and bladder cancers.41-43
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Future Directions
Targeted therapy and immunotherapy, with the emerging molecular and genetic
characterization of cancers, pose an alluring revolution in cancer treatment. However, much
work remains to be done before these novel therapeutics hold dominance in cancer treatment
of tomorrow.
Comprehensive catalogues of cancer genes in the CGA and ICGC need to be completed while
efficient, extensive methods of molecular characterization and genomic sequencing of tumours
have to be developed.30,31,35 We need to develop sensitive and specific predictive
biomarkers which match genomic abnormalities and predict response to MTAs; they will help
stratify patients that may benefit from specific MTAs.11,44 Clinical efficacy and safety of MTAs
need further evaluation.20,45 Drug resistance, especially with MTAs, is a pertinent problem and
novel strategies are required to overcome such resistance.15 We will need to deepen our
understanding of the immune system to uncover components that can be harnessed with
immunotherapy.46 We can optimize targeted therapies and immunotherapies, expand their
applications and evaluate their roles in adjuvant and neo-adjuvant settings.12,47-53 This allows
us to ultimately establish combined-multi-modal therapies for the individual patient to produce
rapid responses with durable remissions.12,47-53
These evaluations will require intensive research and trials to advance the roles these novel
therapies play in current and future mainstream cancer therapy. With the redefinition and
classification of cancers based on genomics, personalized, precise cancer therapy using
multimodal agents based on tumour-specific molecular profiles will likely be the standard
oncologic practice of tomorrow.
With emerging innovations in specialized fields, multiple treatment modalities and approaches
which may potentially be employed in future cancer therapy are being explored.
Investigations are underway in epigenomic engineering where cancer expression can be
modulated with precisely reversed epigenetic mutations through genomic editing and
reprogramming.54,55 Therapeutic radioisotopes with antibodies targeting tumour components
are developed in radioimmunotherapy while nanoparticles are explored as delivery vehicles
of therapeutics into tumour cells.56-61 Novel therapeutic targets such as miRNA, mitochondria
and cancer stem cells are investigated. Modulating miRNA expression may inhibit tumour
proliferation as miRNA are postulated to be involved in tumourigenic processes and regulating
resistance mechanisms.62-64 Mitochondrial-targeting agents can possibly suppress tumour
metastasis by modulating mitochondrial function and oxidation.65-68 Cancer stem cells are
increasingly recognized as potential treatment targets with strategies evaluated to inhibit their
pathways.69
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Relevance of Research Advances and Novel Treatments to Australia
Cancer Care
Australia is no stranger to the devastating impact of cancer which was estimated to be its
leading cause of burden of disease in 2012 with rising incidence rates.70,71 With the global
revolution in novel therapeutics and surge in genetic understanding of cancer, Australia has
both contributed to and benefited from these recent advances in research and therapy.
Australia’s scientific and medical communities actively contribute to the oncologic scene by
continually expanding knowledge of cancer biology and establishing trials for new drugs.
Pancreatic cancer is Australia’s major contribution to the ICGC through the Australian
Pancreatic Cancer Genome Initiative.72 By performing whole-genome sequencing and copy
number variation analysis of 100 pancreatic ductal adenocarcinomas, research teams
uncovered genetic drivers in tumourigenesis and highlighted 4 subtypes with potential clinical
utility.72-74 This allows investigators to match mutations to specific MTAs and test their efficacy
on patient subpopulations.73 The Australia and New Zealand Breast Cancer Trials Group
(ANZBCTG) continuously conducts trials that provided the most reliable evidence supporting
use of many treatment strategies in breast cancer, including tamoxifen and combination
therapy.75 In collaboration with other international research groups, such as the Breast Cancer
International Research Group, ANZBCTG seeks to further evaluate the use of specific targeted
therapies.75 The Melanoma Institute Australia similarly conducts various clinical trials to
evaluate efficacy of novel therapies in melanoma.76
While excitement mounts in Australia with the new wave of oncology medicines as prospective
therapies, their arrival poses challenges to regulatory and reimbursement processes that may
limit access to these medicines.
In Australia, drugs have to be approved for use by the Therapeutic Goods Administration
(TGA) and for subsidy on the Pharmaceutical Benefits Scheme (PBS) as recommended by the
Pharmaceutical Benefits Advisory Committee.77,78 The PBS is currently the only means of
providing Australians with broad and equitable access to cancer medicines.79 Unfortunately,
there is often a prolonged PBS approval process for new cancer medicines.79 Many Australian
patients cannot wait for the subsidy approval nor afford the full unsubsidized cost to access
new drugs.80 An illustrative example is in melanoma, with highest world-wide incidence in
Australia where the arrival of ipilimumab was highly anticipated.81 Ipilimumab was registered
by the TGA in 2011 for use in metastatic melanoma, but costs AUD$190,341.20 for 4
injections.82,83 Subsequent inclusion of ipilimumab on the PBS in 2013 allowed Australians to
only pay AUD$150.80.83,84
Subsidizing cancer medicines is costly. Expenditure on cancer medicines by the PBS has
substantially grown more than 60% in the five years to 2011, costing $587.5 million in
2012.85 Many stakeholders question the appropriateness of funding these expensive
medicines which may translate to marginal benefits for selected patients, diverting funds from
many other competing priorities.86
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Physical access to novel therapeutics is an additional issue in Australia. A third of Australians
with cancer live in rural-regional areas with poor access to cancer treatment and, consequently,
face significantly poorer survival outcomes, having up to 300% higher five-year mortality risk
for certain cancers.87,88 With the revolution of novel therapies, the gap of cancer burden in
Australia widens with patients in rural areas bearing a larger disproportionate part of the
burden as new therapies are primarily restricted to urban-based tertiary centres.
These challenging issues of timely, affordable and geographical access remain difficult to
resolve, expecting to worsen with the burgeoning surge in novel therapeutics. To date, the
Australian government remains supportive of continued listing of cancer drugs on the PBS,
recognizing their necessity in cancer treatment, while implementing measures to curb
expenditure growth.89 Establishment of the Rural Cancer Centres Initiative and patient-assisted
travel schemes may reduce geographical discrepancy in cancer care outcomes by improving
rural-regional access to cutting-edge therapies.88
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Relevance of Research Advances and Novel Treatments to Medical
Students – Our Future Healthcare Professionals
As cancer survival rates improve, more people are living with cancer today. On average, GPs
are said to encounter, annually, 4 new patients diagnosed with a potentially fatal cancer and
have, at any one time, 16 patients with cancer.90 Regardless of the discipline that medical
students eventually practice in, they will be expected to manage oncology patients to varying
degrees. It is hence important for students to have a firm and comprehensive understanding of
cancer management, as outlined in the Ideal Oncology Curriculum published by the Cancer
Council Australia, including established treatments of surgery, radiotherapy and
chemotherapy.91
Most common and several rare malignancies have at least a systemic therapy, such as an MTA
or immunotherapy, and doctors will encounter patients receiving these novel therapies.92 As
use of newer therapeutic agents become more widespread across disciplines, all healthcare
professionals will need to be familiar with them as they become the mainstay of treatment.92
Medical students today should ideally be aware of them and learn their side-effects as part
of medical school oncology education.
Medical students should also be equipped with knowledge in genetics and genome-wide
studies and skills in evidence-based medicine. This will allow them to effectively critically
appraise and contribute to cancer research.
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Conclusion
In over half a century, we have made great strides in cancer therapy with refined treatments
and improved five-year survival rates. As we witness the ever-changing landscape of
oncologic therapy, from surgery, radiotherapy and chemotherapy, to the advent of MTAs and
immunotherapy, it is easy to overlook the work of research that drives and inspires these
paradigm shifts to give us the armamentarium in cancer treatment of today. This progress is
due to the pooling of expertise of individuals with specialized skills working collaboratively in
multidisciplinary teams and convergence of different fields with independent research threads.
Each clinician and researcher contributes through small incremental advances to the lattice of
knowledge constructed over decades, allowing remarkable breakthroughs to produce novel
therapies. We need to maintain concerted international efforts in all aspects of modern
oncology – from research, drug development, and clinical application of novel agents – to
facilitate the effective translation of cancer biology to therapeutic benefits for cancer patients.
As we stand at the dawn of a new era of cancer research and therapy, we anticipate radical
changes to the future landscape. Each wave of discovery will bring new insights, challenges,
renewed hope and emerging, promising treatments. Our ceaseless hunt for ever-better
treatment will continuously push frontiers of research with ever-expanding understanding of
cancer biology and novel therapies.
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