Think Globally, Act Locally: Globalizing Precision Oncology

Think globally, act locally. —Sir Patrick Geddes, Scottish biologist, sociologist, philanthropist, and pioneering town planner

The global cancer incidence is on the rise, and the global cancer burden is expected to reach 28.4 million cases in 2040, a 47% rise from 2020 (1). Precision medicine shifts the treatment model from a one-size-fits-all model to an individualized patient-centered strategy. Genome-driven precision oncology has been enabled by the rapid evolution of next-generation sequencing (NGS) technology, costing 3 billion dollars in 2003 to sequence the first human genome to less than $1,000 in 2022, contemporaneous with the exponential growth of genomically and immunologically targeted agents (2). Transformative therapies including HER2-targeted mAbs in breast cancers, BRAF inhibitors in melanoma, ALK/ROS/EGFR/RET inhibitors in lung cancer, and tissue agnostic therapies for NTRK fusions, microsatellite instability–high (MSI-H)/deficient mismatch repair (dMMR) tumors, and high tumor mutational burden (TMB-high) tumors have altered the landscape of treatment across multiple cancers. The precision oncologist aims to have a quiver of targeted therapies chosen for a patient's tumor biomarker to precisely hit the cancer's susceptible bullseye while sparing off-target effects, improving quality of life, providing unequivocal benefit, and increasing survival. Large-scale landmark genomics programs such as the Cancer Genome Atlas (TCGA) and the AACR Project Genomics Evidence Neoplasia Information Exchange (AACR Project GENIE) helped establish the importance of genomics. The Molecular Analysis for Therapy Choice (NCI-MATCH) and MOlecular Screening for CAncer Treatment Optimization-01 (MOSCATO-01) trials served as prototype for drug development in the precision medicine era. These trials implemented NGS-based large prospective basket/platform studies in advanced cancers, where patients were matched to treatments by their molecular characteristics rather than histology. Subsequently, NCI-COG MATCH and MOSCATO-01 demonstrated feasibility of genomics studies in pediatrics as well. It is now time to expand the reach of precision oncology globally beyond the Western nations.

In this issue of Cancer Discovery, Park and colleagues (3) present preliminary data from the Korean nationwide multi-institutional K-MASTER protocol. They present their experience utilizing NGS-based screening to match patients with advanced cancers to targeted therapies. This program is the latest effort in the broadening sphere of precision oncology. Although the majority of efforts stem from the United States and Europe, in the second decade of precision oncology, awareness of the need for global access is surfacing. Increasingly, sites in Asia and throughout the globe are coming up to the plate, increasing options for patients with advanced cancer who are left with few options when standard treatments fail (Fig. 1).

Globalization of precision oncology will require overcoming several key obstacles from multiple stakeholders for implementation, at the macro and microlevels, including education/training of clinicians, choosing the right molecular platform, addressing ethical and regulatory issues, addressing turnaround times, and most importantly funding and access to drugs. The K-MASTER program has addressed all of these issues in the East Asian context and has shed light on several differences.

First, racial and ethnic molecular divergence has caused frequencies of specific alterations to cause genomic diversity between populations (4). Park and colleagues illustrate this in K-MASTER. They compared the mutational frequencies of patients in K-MASTER with patients from TCGA. Druggable molecular targets were present at a similar frequency—31.8% of TCGA versus 28.7% of K-MASTER patients. They found tumors from K-master to have more frequent alterations in APC, AR, KRAS, TP53, ATRX, MAP2K7, ATM, and MMR genes, whereas TCGA patients had increased BRAF, FAT1, PTEN, GATA3, EPHB1, AKT2, DPHA2, and EGFR mutations among the total populations and within tumor types. To further investigate this potential difference at an ethnicity level, a curated comparison was done in cholangiocarcinoma in comparison with a cohort from the Eastern Hepatobiliary Surgery Hospital in Shanghai, China, and the Memorial Sloan Kettering (MSK)-IMPACT cohort from New York. Even within this population of a single tumor type, mutational frequencies varied, with chromatin-remodeling genes occurring more frequently in MSK-IMPACT. Therefore, choosing the right targets for a given population to drive the highest benefit may be important when bringing precision medicine to the global scale. Big data may be the answer for finding differences across populations. Large genomic databases have become a method for mining patient data pooled across institutions or countries to encourage discovery. Large multi-institutional databases, including TCGA and AACR Project Genie, are complemented by industry repositories from commercially available NGS platforms. Furthermore, the K-MASTER organizational efforts should be lauded for providing their data in a publicly available data set to be evaluated. However, the current genomic databases lack robust clinical treatment and response information, limiting the power to make treatment efficacy conclusions. As most of the databases have been developed independently, they reside in “silos” and lack interconnectivity (5). The utility of databases would be much improved when clinical information is added and if the data can be collated.

Second, increased patient diversity may highlight the role of addressing intrinsic patient pharmacogenomic factors for processing novel agents. Pharmacogenomic differences between populations may result in differential metabolism yielding varied efficacy, tolerated dose, and side-effect profiles.

Third, initial precision oncology trials such as NCI-MATCH, MOSCATO-01, SHIVA, and IMPACT1 were government-funded or major academic institution–based (6). It is both reasonable and necessary to develop capacity for the implementation of centrally funded precision medicine programs in many countries, such as Brazil, India, China, and Russia. In countries with single-payer care, one could envision a protocolized workflow to efficiently identify patients with advanced cancer for NGS testing and subsequent precision cancer treatment from a predetermined repository of targeted therapies. Beyond centrally funded programs, global programs should be designed as well. The source of sponsorship may become more difficult when efforts turn multinational. Perhaps, reflecting current clinical trial sponsorship, precision medicine clinical trials have become increasingly industry-sponsored. The Novartis Signature trial and Genentech MyPathway are both industry-sponsored platform of basket trials that have produced results for patients. For instance, the MyPathway study found clinically meaningful responses in targeted therapies against HER2, BRAF, EGFR, and hedgehog pathway alterations. One distinct advantage for industry-sponsored trials is their ability to enroll across borders. As an example, the industry-sponsored Hoffmann-LaRoche CUPISCO (NCT03498521) cancers of unknown primary trial has selected sites in Asia and South America in addition to Europe.

Last, the post-investigational price of drugs must be accessible to diverse populations. Although many international precision oncology trials include sites worldwide, patients from these areas are underrepresented, and “homegrown” studies designed and implemented in low- and middle-income countries (LMIC) are rare (Fig. 1). Although as many as two of three cancer-related deaths occur in LMIC, only 5% of previously estimated global oncology expenditures occur in those same locations (7). The World Health Organization's 22nd (2021) list of essential medicines includes only three targeted therapies for use in advanced solid tumors: imatinib, erlotinib, and trastuzumab (8). Access to drugs due to rising cost has limited many nations and health care systems from the widespread deployment of precision drugs and how to assess which drugs have the most value (9). Widespread use of precision drugs in LMICs is likely to occur only after they are obtained at affordable costs to patients.

Although patients should be the epicenter and ultimate beneficiary for precision medicine, the complexity, cost, byzantine regulatory policies, competing priorities, lack of infrastructure, and access limit this to a few major centers and geographies (Fig. 1). The COVID-19 pandemic has epitomized some of these challenges and exposed the logjams. Although innovation and unprecedented advances in basic and translational scientific machinery rapidly led to the development of vaccine and therapeutics, poor international coordination in distribution has led to a large inequity in access. A critical examination and lessons learned from the COVID-19 pandemic should be instructive and applied in the development and coordination of not only precision oncology programs but cancer care programs globally for both adults and children (10).

Ethically and equitably globalizing precision oncology should be a major priority in the upcoming decades. The K-MASTER cohort provides a framework for infrastructure building and serves as another example illustrating the widening global potential of precision oncology. Perhaps it is time to modify the precision oncology mantra: Give the right drug, to the right patient, at the right time in every country, to think globally and act locally.