21st century technology and rare cancer: A disconnect or a ripple of hope

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While there have been significant recent improvements seen for many patients with common cancer types, this has not been observed for the majority of patients with a rare cancer diagnosis. For the thousands of Australians diagnosed with a rare cancer each year, many will experience delays and frustrations in receiving a diagnosis and a management plan. Professor Clare Scott writes on the rare cancer challenge.

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“In the near future, it may be more efficient to perform molecular analysis on each rare cancer at the time of first diagnosis, in order for the best molecular match to guide a management plan.”

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Of the 43,000 Australians who die each year of cancer, around 14,000 die of a rare cancer, defined by the RARECARE group as a cancer type with an incidence rate of < 6/100,000 general population incidence¹. The majority of patients will not receive evidence-based care or treatment targeted to their specific cancer type. Very few will be eligible for PBS-funded 21st century targeted cancer treatments. Most tragically,the average age of those diagnosed with a rare cancer is younger, and perhaps not surprisingly, they are more likely to die of their cancer, than are those with a common cancer, with a devastating impact on their families and our community.
At the same time, the proportion of patients who are being diagnosed with a cancer that is classified as being rare is increasing, in part due to the realisation that even common cancers may in fact fall into the rare category once they are classified according to specific molecular changes.
What have we achieved?
Two categories of rare malignancy, childhood cancers and haematologic malignancies have been associated with notable improvements over the last three decades and serve as a guide as to how we may improve the outcome for rare cancers in general. The care of children with cancer is based on decades of highly organised and centralised clinical research that has focused on optimising dose, scheduling and combinations of conventional chemotherapeutics and supportive care. For haematologic malignancies, easy and safe access to malignant cells for analysis by flow cytometry has facilitated basic science research, allowing a greater understanding of their biology and hence how they may be treated. Despite accounting for only 10% of cancer burden and deaths, haematologic malignancies have received one third of PBS cancer expenditure,² reflecting the successful implementation of effective treatments arising from research, both basic and clinical.
The application of 21st century genomics technologies
The extraordinary potential of next generation sequencing (NGS) technology makes it possible for rare cancer types to be divided into molecular ‘subsets’ for more accurate study, rather than the current system based on histology and organ of origin. This may, paradoxically, reduce the ~200 rare cancer subtypes identified by RARECARE¹, to a more manageable number of ‘molecular’ groupings, providing some context as to prognosis and treatment direction for those patients for whom we currently have little in the way of evidence-based guidance. Many common cancers types may also become ‘rare’ by molecular association, as has been described above for molecular subsets of melanoma and lung cancer.
NGS technology allows analysis of DNA sequence, RNA sexpression, as well as regulation by the epigenome, microRNAs and other phenomena and will transform the way we think of rare cancers. NGS platforms are under local development for clinical analysis of tumour tissue and also have the potential to provide analysis of a liquid biopsy from the peripheral blood of circulating tumor DNA^3,4 and for less expensive analysis of tumour-derivatives (methylated DNA).^4,5 Utilising these molecular approaches, diagnosis will no longer be pigeon-holed in an organ or histologic subtype, but better ‘matched’ to molecularly similar tumour types, with direct therapeutic relevance. Just as studying a rare cancer, such as BRCA1/2-associated high-grade serous ovarian cancer (HGSC) can have relevance for related yet BRCA1/2 WT HGSC,⁵⁷ matching rare cancers to common cancers may allow their management path to be deduced by association. Context specific tailoring will likely be required, as BRAF mutations require different therapeuic approaches in colorectal cancer compared with melanoma.
However, plausible hypotheses may provide treatment options for patients who have no ‘standard of care’. An innovative approach, involving molecular analysis of cancer of unknown primary or CUP, is underway.^186771011 Indeed, many rare cancers could be seen as ‘cancers of unknown molecular primary’ (CUMP) and might be matched accordingly using NGS platforms. Most importantly, as by definition a rare cancer has arisen, often at a relatively young age, in a cell type of origin which does not commonly transform into a cancer, the likelihood of detecting a strong genetic driver in the tumour may be more likely than for a common cancer.
In the near future, it may be more efficient to perform molecular analysis on each rare cancer at the time of first diagnosis, in order for the best molecular match to guide a management plan. Likely prognosis and the most appropriate management and treatment may be better estimated than from our current anatomical and histological characterisation. While at present, molecular analysis of rare cancers is not funded, it is logical to think that within a relatively short number of years, that will become the priority, as it will become less acceptable to treat people based on histology and imaging alone. True evidence-based guidelines for each rare cancer type will take longer, however, as information from molecular profiling, leading to hypothesis-generated choice of treatment, will need to occur within research studies. Even these data will not reach the stringent requirements for regulatory approvals and funding decisions, heralding ongoing challenges for some time to come.
Clinical trials for rare cancer patients
Designing clinical trials for small numbers of patients is challenging. Approaches for studies limited by small patient numbers have been described, using Bayesian methods, optimising external controls, robust biomarker incorporation and adaptive designs e.g. ‘basket trials’.^197881112 International endeavours will be essential, suc has the International Rare Cancer Initiative (http://www.irci.info/);⁸ international clinical trial groups such as the Gynaecologic Cancer Intergroup, who have recently published consensus statements on the management of 20 rare gynaecologic cancers;⁹⁰ and at a more basic research level, the Cancer Genome Atlas rare cancer projects (http://cancergenome.nih.gov/cancersselected/RareTumorCharacterizationProjects).
National Co-ordination and Streamlining of Rare Cancer Management
Increased national coordination is required due to the rare nature of these diseases, as by definition it will be difficult to accumulate sufficient cases for statistically meaningful studies to be done without this. The aim of any such endeavours should be focused in several ways: i)to facilitate more accurate diagnosis, including molecular analysis, allowing focus on distinct rare cancer subsets; ii)review of novel tumour testing in a multidisciplinary team meeting, such as a Molecular Tumour Board, with a range of experts present; iii) participation in small, focused clinical trials and/or streamlining of management protocols with international collaboration; and iv) national and international data capture of patient management and outcomes.
In this era of significant genomic changes ahead of us, it is of great importance to involve Australian patients and their families, as all too often they feel they have to fight to find support and management options in our current system. Together, we can be more strategic, designing and harnessing new approaches, including innovative ways of accessing new treatments. The common themes recurring throughout are of the need for centralised coordination of management and research of rare cancer patients and of the potential utility of detailed molecular analysis. One approach to this has been to develop a website that allows individual rare cancer patients or their approved proxy to enter clinical data into a database. Details are available at CART-WHEEL.org and this program enables the community to work with researchers as a partnership.101 Additionally, support for consumers, patients and their families is provided by Rare Cancers Australia, a charity whose purpose is to improve awareness, support and treatment of Australians with rare and less common cancers http://www.rarecancers.org.au/.
Indeed, Rare Cancers Australia have highlighted the current disconnect between patients with rare cancers and access to PBS-funded therapies targeted directly to a person’s cancer¹¹. The advent of cancer care guided by novel tumour testing could be transformed with appropriate streamlining of infrastructure, a focus on rare cancer basic research and an overhaul of the regulatory and funding environment. The current disconnect between 21st century technology and rare cancer care could instead be transformed into a ripple of hope, for Australians with rare cancers who currently have very few treatment options.
Professor Clare Scott was recently Guest Editor for a forum on rare cancers in the open access journal Cancer Forum (www.cancerforum.org.au). She is a Medical Oncologist at the Royal Melbourne Hospital and a researcher with the Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria.
References
1. Gatta G, van der Zwan JM, Casali PG, et al. Rare cancers are not so rare: the rare cancer burden in Europe. Eur J Cancer.2011;47(17):2493-2511.
2. Australia RC. A Little More Time, Report. 2014.
3. Diaz LA, Jr., Bardelli A. Liquid biopsies: genotyping circulating tumor DNA. J Clin Oncol. 2014;32(6):579-586.
4. Chan KC, Jiang P, Chan CW, et al. Noninvasive detection of cancer-associated genome-wide hypomethylation and copy number aberrations by plasma DNA bisulfite sequencing. Proc Natl Acad Sci U S A. 2013;110(47):18761-18768.
5. Ledermann J, Harter P, Gourley C, et al. Olaparib maintenance therapy in patients with platinum-sensitive relapsed serous ovarian cancer: a preplanned retrospective analysis of outcomes by BRCA status in a randomised phase 2trial. Lancet Oncol. 2014;15(8):852-861.
6. Bowtell Ga. 2014.
7. Casali PG, Bruzzi P, Bogaerts J, Blay JY, on behalf of the Rare Cancers Europe Consensus P. Rare Cancers Europe (RCE) methodological recommendations for clinical studies in rare cancers: a European consensus position paper. Ann Oncol. 2014.
8. Keat N, Law K, McConnell A, et al. International Rare Cancers Initiative (IRCI). Ecancermedicalscience. 2013;7:ed20.
9. Harter P, Gershenson D, Lhomme C, et al. Gynecologic Cancer InterGroup (GCIG) Consensus Review for Ovarian Tumors of Low Malignant Potential (Borderline Ovarian Tumors). Int J Gynecol Cancer.2014;24(9 Suppl 3):S5-8.
10. Bae S, Friedlander M, Scott CL. CARTWHEEL. org can facilitate research into rare gynecological tumors. Int J Gynecol Cancer. 2011;21(9):1517-1519.
11. Australia RC: Funding for treatment of rare cancers in Australia. A report. 2015