FormalPara Key Points

  • There are many benefits to Indigenous Australians surrounding the use of cancer genomics and cell biology research, but also many risks.

  • Indigenous leadership and governance in both precision medicine and cell biology are necessary to produce equitable outcomes.

  • The ZERO Childhood Cancer program offers genomic analysis for every Australian child with cancer and has the potential to inform precision cancer treatments for Indigenous Australian children; however, the program must embed Indigenous engagement and governance into its clinical trial structure.

In Australia, cancer medicine is increasingly guided by our expanding knowledge of cancer genomics (the study of genetic information) and biology. Personalized treatments and targets are often defined by an individual’s genetic profile—known as precision cancer medicine. The translation of genomics-guided precision therapeutics from bench to bedside is beginning to produce real clinical benefits for Australians living with cancer. However, Indigenous Australians are disproportionately impacted by cancer [1] and simultaneously have limited access to cancer research and specialist genetic services [2, 3], meaning that the benefits offered by precision cancer medicine are currently limited. Improving access to culturally safe cancer genetics research and genetic health services for cancer has the potential to promote effective and safe precision cancer medicine for Indigenous Australians.

A combination of novel genomics technologies and functional cell biology research has enabled the discovery of new drug targets and treatment strategies for cancer over the last two decades. However, our knowledge of the human genome that enables new discoveries fails to capture the genomic diversity of human beings, particularly that of Indigenous peoples globally [4]. Importantly, the distinct actionable genomic alterations in cancer—to which targeted cancer therapies, treatment decisions, and risk stratifications are designed—can be over or underrepresented in populations of different ethnic backgrounds [4]. This may be particularly relevant in a childhood cancer context, where genetic factors are more likely to play a role in comparison to external cancer risk factors such as tobacco and alcohol consumption and sun exposure. Furthermore, the reference genome resources that are widely used in research and to identify clinically actionable genetic alterations are predominantly European in origin. Therefore, there is a need for Indigenous genomics to inform clinical practice and ensure equitable benefits for Indigenous peoples. In response, global efforts have begun to create Indigenous variant databases [5], and ongoing projects at the National Centre for Indigenous Genomics in Australia are focusing on assembling a suitable Indigenous Australian reference genome, in consultation and collaboration with Indigenous communities [6].

In addition to clinically relevant reference genomes, effective precision cancer research currently relies upon the use of patient-derived cell lines and xenograft models of human disease. Patient-derived cell lines may be created when patients with cancer donate some of their removed cancer tissue to researchers, with the cells then grown indefinitely in a dish in the laboratory. Donated cancer cells may also be grown in other animals, for example, mice, known as patient-derived xenograft models. These models serve as laboratory-based pre-clinical tools to understand cancer biology and identify novel therapeutic targets for patients. Indigenous-led precision medicine research initiatives will require ongoing, critical conversations around dynamic models of patient consent and the potential risks and benefits associated with the creation, use, and storage of Indigenous patient-derived tissue and models. This will include governance of data derived from these models and requires collaboration between Indigenous communities, researchers, and clinical practitioners.

Precision cancer research guided by cell biology and genomics can provide opportunities to refine treatment strategies, reduce side effects, and create novel targeted therapies that are fit-for-purpose for Indigenous Australians. Nonetheless, Indigenous Australians are largely yet to see personal benefits from these technological advances, owing to the general inaccessibility of personalized medicine services and infrastructure, perpetuated by systemic racism embedded within mainstream academic, medical research, and healthcare institutions. While there is much work to be done to ensure precision cancer medicine leads to improved health outcomes for Indigenous Australians, researchers must strike a balance between working at the pace of progress and working at the pace of trust. Exploring the opportunities for precision cancer medicine with Indigenous Australians should be Indigenous-led; centered around the priorities, needs, and interests of Indigenous communities; and ultimately maintain Indigenous governance from project planning to implementation and translation.

Risks and Ethical Considerations

Indigenous Australians have 60,000+ years of history as Australia’s first peoples and first scientists. However, since colonization, Indigenous Australians have been the subjects of much research, with very little perceived benefit received by communities [7]. Indigenous peoples globally share similar experiences, and in the context of genomics, large-scale open-access genomics projects such as the Human Genome Diversity Project (HGDP) and the 1000 Genomes project have disempowered Indigenous communities [8]. Concerns of exploitation led to the rejection of the HGDP by central Australian Aboriginal communities in the 1990s [9]. Their concerns were justified; open-access genomics projects ultimately enabled the generation of profits by pharmaceutical and ancestry testing companies, with no direct benefits provided back to the Indigenous communities involved [10].

These risks of exploitation must be managed through purposeful Indigenous-led design and governance. Australian Indigenous health research codes of conduct enshrine principles of respect, reciprocity, community partnership, and Indigenous data sovereignty. However, the unique ethical and cultural implications of precision cancer and genomics research remain poorly defined within these codes in Australia. Furthermore, Indigenous Australians must be consulted on the storage, scientific use, and governance of cancer samples for the creation of patient-derived models, as these samples and their use may be of great cultural significance. Currently, the onus is placed on researchers, Aboriginal health research ethics committees, and communities to ensure that Indigenous Australians are not exploited. Best-practice guidelines, such as those existing internationally, and importantly Indigenous Australian leadership in this research are essential to avoiding the perpetuation of past exploitation and ensuring Indigenous Australian communities reap the benefits of precision cancer medicine.

The ZERO Childhood Cancer Program

The ZERO Childhood Cancer program is a clinical trial (NCT05504772) that performs detailed genomic sequencing to identify precision cancer treatments for Australian children diagnosed with cancer. This trial began by focusing on children with high-risk cancers, with great success in improving health outcomes for children within this population through the provision of precision medicine [11]. The expansion of this initial trial aims to include every Australian child, which will incidentally include Aboriginal and Torres Strait Islander children. This trial should provide a rich data source for research into new population-specific treatments and may enable real-time recommendations for precision cancer treatments for Indigenous Australian children with cancer.

In addition to performing genomic testing on patient samples, where possible, the ZERO Childhood Cancer program will also create cell lines and PDX models [12]. This allows high-throughput drug screening to be carried out, which may contribute to treatment recommendations. The ZERO Childhood Cancer program must consider the ethical and cultural implications of generating the first known Indigenous Australian cancer cell lines and the Indigenous governance structures that are to be placed over these cell lines. The program must also contend with the global history of cancer cell line generation, which is fraught with the exploitation of people of color.

The ZERO Childhood Cancer program was designed iteratively, following input from pediatric oncologists, scientists, researchers, and consumers, including parents of children diagnosed with cancer. To ensure the existing clinical trial structure is adapted to one that also benefits Indigenous Australians, the ZERO Childhood Cancer team will need to engage with Indigenous Australian researchers, healthcare providers, community members, and families. The ZERO Childhood Cancer team is cognizant that potential benefits from the ZERO Childhood Cancer trial may be limited for Indigenous children involved in the study, owing to a paucity of pre-existing, clinically relevant knowledge regarding cancer biology and genetics. A study design that is Indigenous-led, informed by current Indigenous genomics research, and in line with health systems approaches to improving equitable access to cancer care for Indigenous Australians is, therefore, needed to achieve equitable health and wellbeing outcomes. To this end, the ZERO Childhood Cancer team has established a working group that includes Aboriginal precision cancer researchers to identify the potential risks of their program and a way forward to ensure equitable benefits for Indigenous Australian children with cancer.We acknowledge our Elders and the communities in which we live and write. We also acknowledge Indigenous people living with and passed from cancer, and their families. The authors would also like to acknowledge the contributions of the ZERO Childhood Cancer team to this chapter and to the progression of precision cancer research for Indigenous children with cancer.