Precision oncology: East meets West.

Abstract

Precision oncology aims to customize targeted cancer therapies to the patient's specific cancer molecular aberration(s). Evaluating a patient's tumor molecular profile with next generation sequencing and other modern technologies to identify actionable abnormalities for matching with targeted agents provides an opportunity to personalize and impact cancer medicine at an individual and population level.1 Since the discovery of imatinib (Gleevec®) for the treatment of BCR-ABL-driven chronic myelogenous leukemia and c-KIT mutant gastrointestinal stromal tumors, multiple monoclonal antibodies and small molecules have achieved regulatory approval and are now standard-of-care therapeutic options for patients, thus providing proof-of-concept for this approach. Trastuzumab for Her2/neu positive breast cancer, crizotinib for ALK and ROS1 rearranged non-small-cell lung cancer, as well as BRAF and MEK inhibitors for BRAF V600 mutant melanoma are a few examples, which have altered the therapeutic landscape of the oncology field. The development and incorporation of next generation sequencing clinical programs in academic institutions and commercial entities have permitted the conduct of multiple early studies of precision oncology in the western world. These clinical trials have specifically tested the precision medicine hypothesis by evaluating the clinical benefit of molecularly matched therapies in patients with different advanced cancers (Table 1). Collectively, these data have generally reflected the western population, as the studies have mainly been conducted in North America and Europe. A major issue that remains to be addressed is the likely geographical variability and prevalence of the varying actionable tumor molecular profiles in Asia compared to the West. This may impact the appropriate matching of patients with suitable therapies, trial accrual and the ultimate success of precision medicine programs. A prime example is that sensitizing EGFR mutations are much more prevalent in Asian populations compared to western ones. Another major challenge of precision oncology is that it may ultimately not be a feasible strategy to implement effectively and widely across Asia because of the current variability of established healthcare infrastructure, funding, critical mass of necessary expertise and political climate. In their Integrated Molecular Analysis of Cancers (IMAC) study, Heong et al.10 report their initial experience of developing a precision oncology screening program in the Asian context involving 396 tumor samples suitable for genomic analysis using targeted gene sequencing with a 50-gene panel from a total of 479 patients from 15 institutions in South East Asia. The investigators should be commended for their efforts in putting together a robust molecular screening program that mirrors that used in the West. The primary outcome was progression-free survival, while secondary endpoints included clinical benefit rate (complete or partial responses and stable disease at Week 8) and the turnaround time for molecular profiling reports. Importantly, the study included analysis of mutational data from the molecular profiling of collected tumors.10 What is impressive about the study is that the investigators were able to identify actionable targets for the matching of patients to appropriate antitumor agents. They have demonstrated that it is feasible to conduct a molecular screening program in South East Asia using clinical next generation sequencing and have shown early evidence that patients can potentially be matched with subsequent clinical benefit. Moreover, they have explored the preliminary spectrum of mutations in Asian patients with advanced cancers, albeit in a limited population size. The median turnaround time for the genomic results was 26 days, which is also reasonable given the context of this pilot study. The data reported in the IMAC study are similar in many respects to other precision oncology studies done in the western world (Table 1). In this report, 23 of 300 (8%) patients who had reportable molecular aberrations were matched to biomarker-driven targeted therapies. This 8% patient match rate is similar to the 5–11% match rates reported in other studies. A recent study evaluating a South Korean population from the Samsung Medical Center reported that a total of 55 of 418 (12.0%) patients harbored a biomarker that led to subsequent rational allocation to a clinical trial.11 The most commonly mutated oncogenes in the overall cohort included KRAS (19%), PIK3CA (16%), EGFR (5%), BRAF (3%) and KIT (3%) aberrations, while the most frequently mutated tumor suppressor genes included TP53 (40%), which again parallels other precision oncology studies. The expected higher prevalence of EGFR aberrations in Asian patients with lung cancer was confirmed in the IMAC study Specifically, 15 of 48 (31%) lung tumors harbored at least one mutation in the EGFR domain. Currently, most patients are often only referred for precision oncology studies when they do not have standard therapeutic options available for their metastatic cancer, and frequently have a declining performance status by this stage. It is unrealistic to expect major efficacy signals in such a patient population. Patients should therefore ideally undergo sequencing much earlier along their treatment journey, especially when there are promising active therapies available. Active molecular and immune profiling of tumors and surrogate tissue, such as circulating plasma DNA, should be sampled serially to minimize issues of tumor clonal evolution over time. The turnaround time of multiplex sequencing across many centers is now approximately 3–4 weeks, with the associated costs also falling, encouraging the contemporaneous practice of repeat molecular profiling. Ultimately, the success of precision oncology programs will depend heavily on a robust pipeline of clinical trials and standard-of-care drugs already availability to patients with different cancers across multiple large comprehensive cancer centers. There are several overarching precision oncology trials that are currently active, such as NCI-MATCH (NCT02465060), TAPUR (NCT02693535) driven by the American Society of Clinical Oncology (ASCO), Genentech's My Pathway (NCT02091141), and the Novartis Signature study. The combined data from these basket trials will no doubt provide us with greater insights into real world application of precision oncology. However, challenges continue to hinder the widespread implementation of precision oncology globally, dictated primarily by costs associated with molecular profiling and commercial pricing of antitumor agents. It still remains to be seen whether it will be the pharmaceutical industry or academia, which will support such initiatives globally, or whether it will be healthcare authorities, insurance companies or patients themselves who would bear the cost of such biomarker-driven approaches. Apart from dealing with the logistical and practical hurdles to implementing precision oncology, scientific challenges also need to be addressed. For example, multiplex profiling may lead to the detection of multiple actionable aberrations in the same patient tumor,12 such as cancers with both BRAFV600E and PIK3CAH1047R mutations. Should one target them individually, sequentially or concurrently? Furthermore, current precision oncology programs are centered primarily on genomically guided targeted therapies. This is however clearly insufficient in the era of immuno-oncology, and future programs should also include transcriptomic and immune profiling relevant to immunotherapeutic agents. In addition, it has been shown that high tumor mutation burden and mismatch repair defects predict sensitivity to immune checkpoint inhibition. The recent US Food and Drug Administration (FDA) approval of pembrolizumab in patients with mismatch repair defects represents the first tumor-agnostic approval of an agent using a genomic biomarker. The discovery of N-tropomyosin receptor kinase (TRK) fusions and the rapid clinical validation of a NTRK inhibitor, with deep and durable antitumor response rates of approximately 75% across 17 different cancers with TRK fusions is another watershed event in precision oncology. To conclude, the IMAC study together with the South Korean trial demonstrates the growing feasibility and impact of genomic screening programs in Asia. These results are greatly encouraging as their success now provides a springboard for future wide-reaching global collaborative trials in precision oncology. The initial positive experience gained with the IMAC study should encourage the investigators to continue their commendable efforts in sustaining and expanding their precision oncology program. Technologies for molecular prescreening, together with new knowledge, targets and biomarkers evolve quickly. All molecular prescreening programs should thus include a culture of constant review and redesigning of processes; for example, new genes or alterations should be added, and novel diagnostic platforms introduced. The current generation of precision oncology trials also needs a larger portfolio of active drugs, as well as a broad molecular testing panel that includes gene fusions, tumor mutation burden, mismatch repair, DNA damage response pathway and epigenetic aberrations, as well as the serial sampling of circulating plasma DNA to guide the matching with novel antitumor therapies. The clinical availability of such molecular profiles to evaluate the transcriptome, immunogenome, epigenome and methylome concurrently has the potential to widen therapeutic options and ultimately to impact patient benefit. The University of Texas MD Anderson Cancer Center is supported by the NIH Cancer Center Support grant CA016672.