In an Era of ctDNA, Is Metabolomics the New Kid on the Block?

In this issue of Clinical Cancer Research, Larkin and colleagues (1) harness metabolomics to prospectively identify cancer in the “low-risk, but not, no risk” patient group. This is the group of patients for which the probability of cancer is low on the clinical differential diagnosis, but where a delay in diagnosis may occur due to nonspecific symptoms. In managed healthcare, such as the UK National Health Service, cancer referral pathways have a two-week wait period for nonspecific symptoms such a fatigue or weight loss. To address this, Suspected CANcer (SCAN) pathway was established in Oxfordshire, United Kingdom to help identify patients with early stage cancers. Patients were evaluated with contrast enhanced computerized tomography (CT) scans of the chest, abdomen, and pelvis alongside blood tests to help establish a diagnosis. This allowed for a gold standard to be used to call malignancy versus non-malignancy. Nuclear Magnetic Resonance (NMR)-based biofluid metabolomic analysis was then used to determine if it could aid in the detection of cancer. The authors found that metabolomics demonstrated a relatively sensitive and specific test that could be used as a cost-effective screen prior to ordering CT scans. While in the United States efforts are being made to use modalities such as circulating tumor DNA (ctDNA) or low-dose CT scans to identify early stage cancers, these are not as of yet highly cost-effective for population-based screening.

The analysis of ctDNA is a rapidly advancing field used for disease monitoring, early detection, and genomic biomarker analysis hastened by the need for an accurate, rapid, and predictive test that can inform treatment decisions. Indeed, the use of ctDNA is making its way into clinical practice and being validated by clinical trials. For example, ctDNA-based molecular residual disease (MRD) has been used in non–small cell lung cancer perioperatively, where it was able to risk stratify MRD-positive and MRD-negative patients for the potential of relapse (2). In addition, pretreatment ctDNA was able to predict response of melanoma to first-line immunotherapy (3).

The promise of ctDNA is not without technical challenges. While ctDNA allows for the real-time genomic profiling without tumor biopsies, it is hindered by the low proportion of of ctDNA (%) in circulation and the sequencing requirements needed for accurate detection. Whole-genome sequencing or even whole-exon sequencing at a depth needed for detection is still prohibitively expensive for routine monitoring. In addition, the blood volumes required for detection are not trivial. For example, the Natera test requires 10 milliliters of blood per draw. Depending on the technology used, amplification with PCR may be needed prior to sequencing and this can lead to background errors which may masquerade as tumor-derived variants. As these technologies improve, there is the expectation that ctDNA detection and utilization will improve and become more cost-effective (4). In the meantime, there is a window of opportunity for alternative approaches to detect and monitor cancer.

One such opportunity comes from the paradigm shifting work of Rabinowitz group at Princeton University published in Nature Metabolism on circulating metabolite homeostasis (5). Using small animal in vivo carbon tracing of amino acids, glucose, and other metabolites, they found a linear relationship between consumption flux and circulating concentration of metabolites. This observation suggests that mass action kinetics drive the concentration of circulating metabolites. Extrapolation of this concept to cancers, posits that blood steam metabolites would be proportional to the mass produced and released into the blood stream by a tumor. Complications implementing these concepts undoubtedly exist, including the fasting/fed state and resultant endocrine biology. Nevertheless, the work illustrates that an opportunity may exist to use steady state of metabolites in the blood stream as a first screen for cancer.

This leads us to the current work by Larkin and colleagues (1). This current research describes a new minimally invasive and inexpensive blood test to identify cancer in patients with nonspecific symptoms in order to determine if the cancer has spread. The study analyzed samples from 304 patients with nonspecific symptoms of cancer, such as fatigue and weight loss, who were recruited through the Oxfordshire SCAN pathway. Unlike many blood-based tests for cancer, which use genetic material from tumors, this test measures the levels of small molecule metabolites NMR metabolomics. This rapid and inexpensive test has the possibility of identifying malignancy before conventional imaging, which could lead earlier cancer diagnosis, more appropriate treatment, and hopefully improve outcomes. Therefore, it is very exciting that the technology is showing promise in detecting cancer.

If metabolomics can be developed as a small blood volume test that can be rapidly turned over as a screen, this will be of high value to the primary care physician. However, in order to implement this methodology, it will be necessary to know the number of patients needed to find a true positive, as well as the positive and negative predictive values of the test. The likelihood that a patient will be missed by any one test is critical to making public health decisions. As the price for sequencing comes down, we may find complementary information in using both metabolomics and ctDNA testing. While one may have a higher sensitivity and require less volume, the ctDNA test can yield actionable information about point mutations and genetic predisposition. The clinical strengths of each test are demonstrated in Fig. 1.

As both tests are used mainly as screens, only a biopsy and formal pathologic diagnosis at this time can truly make a diagnosis of cancer. Therefore, while biopsies and CT scans will not be leaving the current practice of oncology in the foreseeable future, ctDNA and metabolomics may soon become paired companion diagnostic approaches. These tests have the potential to detect early treatment failures and prevent unneeded toxicities from ineffective therapies long before a CT scan can formally identify a difference. As such, let us welcome the development of metabolomics to the management of cancer as a potential new player on the block.

B.A. Van Tine reports grants from Pfizer, Merck, and Tracon Pharm; grants, nonfinancial support, and other support from GlaxoSmithKline; and personal fees from Epizyme, ADRx, Ayala Pharmaceuticals, Cytokinetics, Bayer, Targeted Oncology, Adaptimmune Limited, Bionest Partners (Healthcare/Education), Intellisphere LLC, Polaris, Deciphera Pharmaceuticals, Novartis, Lilly, Apexigen, and Daiichi Sankyo outside the submitted work; in addition, B.A. Van Tine has a patent for Accuronix Therapeutics issued. C.A. Lyssiotis reports personal fees from Astellas Pharmaceuticals, Odyssey Therapeutics, and T-knife Therapeutics outside the submitted work; in addition, C.A. Lyssiotis has a patent for targeting the GOT1-pathway as a therapeutic approach, US Patent No: 2015126580-A1; US Patent No: 20190136238; International Patent No: WO2013177426-A2 issued.