The Power of Genomics

FormalPara Key Points

• The promise of genomics-guided precision oncology is highlighted by recent approvals of molecularly guided therapies coupled with companion diagnostic tests.

• A critical limitation of genomics-guided oncology is that it is unlikely to serve Indigenous cancer patients unless Indigenous rights-based approaches to genomics-guided cancer research and clinical care are prioritized.

• Relevant Indigenous datasets that can support precision oncology are needed.

• Indigenous access to and governance over key infrastructure are needed.

• We must grow and empower an Indigenous workforce with subject matter expertise and clinical acumen to ensure that genomics-guided precision oncology can sustainably benefit Indigenous cancer patients.

Due to an advanced understanding of cancer biology and the rapid development of genomic technologies,¹ cancer has shifted from 200 diseases based on pathology (i.e., what a tumor looks like under the microscope) to thousands of diseases based on molecular tumor profiles (i.e., what a tumor looks like when its altered genome² is interrogated) [1]. Most cancers arise from alterations to the genome, including changes in the number or structure of chromosomes and variations in a single building block of the genetic code (e.g., base pairs). Often, multiple changes need to occur, disrupting multiple checks and balances that prevent the uncontrolled proliferation and survival of abnormal, cancerous cells. While radiotherapy and surgery have focused on removing cells that have suffered irreparable damage to their DNA, and chemotherapy aims to disrupt cell growth by exploiting the subcellular machinery involved in cell proliferation, targeted therapy enabled by genomic profiling focuses on the molecular drivers and features of each condition, identifying and treating its “Achilles heel.” This chapter examines the current potential impact of genomics-guided oncology for Indigenous peoples and highlights potential solutions to possible future challenges.

The Potential Impact of Genomics in Oncology

Globally, oncologists are embracing the integration of molecular tumor profiles (i.e., the unique DNA changes in a person’s cancer) used in synergy with new and traditional tools, technologies, and multidisciplinary knowledge to inform clinical decision-making with patients (Fig. 77.1). This includes matching patients to the best treatment options available for their particular DNA profile. Highlighting the speed at which the field of genomics-guided precision oncology is moving, at least 20 biomarker-specific medicines or combinations received regulatory approval (including tissue-agnostic approvals)³ for treating solid tumors based on comprehensive genomic profiling in the United States and Europe between April 2019 and April 2021 [1]. Many of these biomarker-matched medicines are also approved or marketed in Canada and Australia for the same indications, while public access in Aotearoa New Zealand lags behind.

Fig. 77.1

Genomics-guided precision oncology promises to improve clinical decision-making between the patients and their attending physician (a). However, precision oncology widens inequities if introduced into existing health systems (b) without adequate attention to the needs of all populations. (Design: C Lourenco)

In cases in which a test result is matched to a readily available treatment, this process can be relatively straightforward. For others, where genomic test results and treatment options are less clear-cut, physicians may be able to present their case to a molecular tumor board (MTB)⁴ [2]. The MTB can provide expert guidance on the scientific and clinical significance of a gene variant⁵ identified from a genomic test, and on therapeutic options, including access to clinical trials, depending on available evidence. Emerging international evidence suggests that MTBs can improve patient outcomes. One study found that patients who receive MTB-recommended treatment are better matched to therapy and achieve better outcomes compared to those who receive treatment based on the physician’s choice alone [2]. In many countries, the MTB option is limited largely to academic centers with sufficient capacity, as it draws on the time and expertise of multidisciplinary teams of experts, including clinical variant curators, geneticists, bioinformaticians, and physicians [2]. Telehealth and streamlined virtual platforms [3] offer solutions that address access barriers to centers with MTB capability; however, limited research or involvement of Indigenous peoples limits our knowledge of the impact of MTBs on Indigenous populations. We are beginning to see the benefits of molecularly guided therapy in cancer patients, particularly those with tumors that have traditionally been difficult to treat. However, significant work remains to ensure this promise reaches Indigenous cancer patients [4, 5], beginning with overcoming crucial limitations.

Limitations of Genomics in Oncology

Historically, the deployment of new technological solutions has often served to widen inequalities between populations defined by socioeconomic position, ethnicity, gender, or geographical location. Simply implementing new technologies into current health systems does not achieve health equity in and of itself for several important reasons. First, our current health systems already underperform for Indigenous populations (Fig. 77.1b). Outcomes are often worse for Indigenous peoples as a result of cumulative inequities along the cancer care continuum. Second, access to medicines that target specific biomarkers is gatekept by access to relevant testing and technology. Geographically, this favors major metropolitan communities in wealthier countries, as comprehensive genomic profiling is mostly limited to well-resourced, research-capable facilities. Socioeconomically, this favors individuals/countries with the means to access testing and treatment. Moreover, Indigenous peoples around the world are disproportionately affected by inequities in the social determinants of health shaped by ongoing histories of colonization [6].

Third, Indigenous peoples remain poorly represented in genome-wide association studies (GWAS),⁶ despite improvements to the overall proportion of peoples of non-European ancestry within GWAS datasets globally [4]. Lack of Indigenous background variant databases (BVD)⁷ for the interpretation of targeted gene panels⁸ and genome sequencing poses problems with diagnostic accuracy for Indigenous patients, as current non-representative BVDs are used for diagnosis via clinical genomic variant analysis [4, 7].

As nations expand the use of comprehensive genomic profiling in oncology services and as new genomic research seeks to address the lack of representation in genomic databases, we must not follow the same pathway taken by previous genetic and genomic research, causing further harm to Indigenous communities [4, 7]. Indigenous peoples often choose to participate in research not for their own immediate or direct benefit, but to contribute to the health and wellbeing of future generations. However, such altruism must never come at the cost of exposure to unsafe research environments or harmful data-use practices. Genomic research involving Indigenous peoples needs to be rights-based and Indigenous-led, addressing Indigenous priorities, and with appropriate governance. What should this look like in the context of precision cancer research and clinical care?

Generating the Relevant Data to Support Precision Oncology

First, we need genomic data that serve Indigenous communities. To achieve this, relevant Indigenous BVDs need to be developed to support rapid and accurate interpretation of genomic tests, to avoid the needless pursuit of variants as potential disease candidates when those variants may simply be alternatives to currently available reference genomes. A comprehensive understanding of how genetics affects medicine safety and efficacy is essential. Pharmacogenomics focuses on gene variants involved in the metabolism of a wide range of medicines. Pharmacogenomic tests are crucial for ensuring that cancer medicines are given at doses that are safe (i.e., the medicine itself is not causing greater harm) and efficacious (i.e., the medicine achieves clinical benefit). We also need to understand the genomic profile of cancers impacting Indigenous patients in order to best inform the prioritization of cancer medications in the oncology “medicine cabinet” available to Indigenous communities. Many cancer-causing variants of key genes (e.g., TP53, KRAS, BRAF) have been identified across human cancers, but at the current rate, it seems unlikely that genomic research will identify any cancer-causing variants unique to Indigenous peoples at the population level. However, appropriate research platforms should also be capable of responding to variants of unknown significance (VUS)⁹ as they emerge from genomic tests involving Indigenous patients. Ethical frameworks for genomics research have already been developed and published by Indigenous scholars to inform best practice [8], including specific examples in cancer genomic research [5]. Indeed, Indigenous-led or co-designed clinical genomic research platforms and clinical tools are being developed for the purpose of better diagnostics and clinical decision-making for Indigenous peoples.

The Australian Alliance for Indigenous Genomics (ALIGN) is an Indigenous-led national alliance representing a commitment from academia, industry, government, and Indigenous communities to work collectively to develop a framework, designed by and for Indigenous people, to deliver the benefit of genomic medicine to all Australians. Core activities include establishing Indigenous governance over genomics research and clinical care, developing best practice data systems and data sovereignty, outlining key genomics policy, and growing capacity in Indigenous genomics. These represent key foundations for ensuring that Indigenous Australians benefit from genomics. Flagship programs will include focusing on pharmacogenomics, precision medicine, genome biology, and rare diseases.

The Rakeiora Project is a pathfinder project that seeks to identify the best means to enable national-scale genomic precision medicine research and practice in Aotearoa New Zealand. Rakeiora consists of two pathways, one for primary care and one for secondary care, with the latter taking place in oncology settings co-led by Dr Helen Wihongi (Ngāti Porou, Ngāpuhi, Te Whānau a Āpanui, Ngāti Hine) and Professor Cristin Print. Rakeiora has established a prototype cancer genomic medicine research information technology (IT) system co-designed and co-led with/by Māori, with tikanga Māori (Māori cultural protocols or principles) at its core. While Rakeiora currently focuses on translational research, it seeks to be scalable to clinical settings.

Access to and Governance over Key Research Infrastructure

Genomic research to address the clinically focused applications described above, including Indigenous background variant databases, pharmacogenomics, and targeted therapy, requires, as one key infrastructure pillar, the development and appropriate governance of biobanks. Tissues generously donated by participants to enable research have been instrumental in driving medical science, innovation, and clinical care. Often tissues are collected with consent to address defined questions. However, the rapid advancement of genomic and imaging technologies, biobanks, and, more importantly, the precious tissues and data stewarded within, will enable future investigations of cancer biology and novel treatments, including questions we have not yet thought to ask. However, this powerful research requires donors to consent to future unspecified use of their tissues, causing tension among Indigenous donors, which can be understood in the context of cultural understandings of the connection of bodily substances to place and ancestors, the information contained within, the beneficence of researchers, and concepts of ownership [9]. Another critical tension that requires attention is the power imbalance between institutions and Indigenous communities or Tribal authorities. Indigenous peoples are often asked to gift their tissues and their trust to institutions that may be resistant to suggestions of Indigenous data sovereignty or Tribal authority over how these tissues will be used [10]. By extension, Indigenous peoples require reassurance of the benefits that they and their communities will derive from the sharing of these materials.

From a rights-based perspective, Indigenous governance over Indigenous genomic resources can be asserted through the United Nations Declaration on the Rights of Indigenous Peoples (UNDRIP), but this requires nation-states to sufficiently and sustainably resource such endeavors as redress (in part) for land alienation, cultural subjugation, and the subsequent inequities borne out of colonization. However, existing complexities within legislative approaches to the protection of traditional knowledges and Indigenous cultural and intellectual property remain significant ongoing issues to the acknowledgment and protection of Indigenous peoples’ rights in genomics and biomedical research.

The Northern British Columbia (BC) First Nations Biobank is a project in development in partnership with the BC First Nations Health Authority and the 55 First Nations of Northern BC. First Nations biobank governance—founded on over 10 years of community discussions, First Nations–led consultations, and ongoing presentations to First Nations leaders—aims to create an independent First Nations biobank to enable communities to have the choice to participate in and benefit from future cancer-focused genomic research. At the core of this project are, inter alia, governance and Indigenous data sovereignty, and the implementation of cultural approaches to consent, stewardship, and research oversight.

Growing an Indigenous Workforce to Lead and Deliver Precision Oncology and Research

Building the infrastructure to support comprehensive genomic profiling in clinical services and research is only part of the solution. We need an Indigenous workforce to ensure that Indigenous populations benefit from benchtop to bedside, and beyond. From a healthcare delivery perspective, this includes Indigenous family physicians, surgeons, oncologists, radiation oncologists, nurses, pharmacists, geneticists, variant curators, and bioinformaticians to support the accurate interpretation of genomic data in clinical contexts. From a medical science perspective, in the delivery of relevant datasets and tools to support clinical decision-making and monitoring, this includes Indigenous researchers in key leadership roles in cancer genomic research, from basic science through to designing, steering, and running clinical trials, in addition to managing, maintaining, and governing established biobanks, cancer genome atlases, or BVDs containing Indigenous samples, DNA, or data. An increase in Indigenous capacity in clinical and research spaces would be further enhanced by an Indigenous presence on MTBs. Moreover, the sustainable inclusion of Indigenous voice and leadership within MTBs should be considered a vital addition to technical, scientific, and medical expertise when considering treatment for Indigenous patients, to ensure that the emerging benefits of MTBs [2] reach Indigenous patients.

The Summer Internship for Indigenous Peoples in Genomics (SING) Workshop is a week-long internship for Indigenous students and community members to learn the fundamental concepts of genomics and bioinformatics, as well as their cultural, ethical, legal, and social implications (CELSI) [4, 8]. SING is a “for Indigenous, by Indigenous” model of capability and leadership development that, since its inception in the United States in 2011, has expanded globally to include SING-Aotearoa (New Zealand) since 2016, SING-Canada since 2018, SING-Australia since 2019, and SING-Mexico since 2023. Given the application of genomic technologies to cancer research and treatment, Indigenous cancer clinicians and researchers contribute their expertise to SING as faculty members in their respective countries as well as reciprocally between countries, and a growing number of SING alumni are beginning careers or hold positions in cancer-related fields and careers around the world, or serve in community-based Indigenous leadership and advisory roles.

While such efforts are essential for Indigenous self-determination and must be prioritized if organizations are truly committed to achieving health equity globally, growing the Indigenous workforce is not enough. Given the demographic minority occupied by Indigenous peoples, it is critical that healthcare providers and researchers are called upon to adopt cultural safety and critical consciousness practices [11] to ensure the wellbeing of Indigenous patients and the families who accompany them on their cancer care journey, as well as the wellbeing of Indigenous students, colleagues, Elders, and communities involved in research. Healthcare systems must implement and enforce policies to demand such respect and cultural safety and have zero tolerance for the Indigenous-specific racism that has been highlighted in personal stories, media coverage, and formal inquiries [12]. The absence of cultural safety greatly impacts access to and utilization of all cancer care services and the research that can greatly impact those services. Such a task involves each one of us, with the concept of reconciliation increasingly emerging as a necessary step that we are still far from achieving.

Conclusion

Globally, oncology services embrace the power of genomics to inform precise cancer care for individual patients. Indigenous cancer patients have a right to the best standard of care, including molecularly guided therapy, while maintaining the right to self-determination about the best path forward for them. No matter how promising a new technology may be, implementation into existing health systems is not enough to achieve health equity. We must learn from the past, prioritize Indigenous-led cancer care (including genomics research infrastructure), and grow an Indigenous workforce to sustainably ensure that genomics-guided precision oncology reaches all who need it, while maintaining the Indigenous right to self-determination.