From the Tip to the Iceberg Below-Evolving Our Molecular Understanding of Thyroid Nodules.

In just over a decade, healthcare has witnessed amazing progress in understanding the molecular underpinnings of thyroid nodular disease and thyroid cancer—and equally as amazing, the initial translation of this understanding into the day-to-day clinical decisions made by afflicted patients together with their clinical team. No fewer than 7 different thyroid molecular diagnostic tests have been developed and investigated (1), most commonly applied to the clinical context of a cytologically indeterminate nodule. Into the near future, our ability to define molecular signatures will certainly provide prognostic insight that will modify treatment decisions or follow-up strategies (2). Even at present, the molecular analysis of advanced, metastatic thyroid cancer allows one to choose from uniquely targeted advanced therapeutics tailored to a patient’s specific oncogenic pathway. Though still in its early stages, from molecular diagnostics to molecular prognostics and therapeutics, the power of genomic medicine is transforming care for the benefit of health and survival.

As relates to thyroid nodule and cancer care, molecular breakthroughs could not be more opportune or in greater need, as we have witnessed a rapid increase in thyroid cancer detection over the last 3 decades primarily due to increased identification of smaller and more indolent disease. Despite this increased pool of detected disease, treatment appears to have minimally impacted overall thyroid cancer survival (3). Thus, while molecular diagnostic tests are already reducing unnecessary surgery, the next step for molecular thyroid care lies in its continued ability to further prognosticate and personalize medical decisions, targeting care only where most needed. Understanding who to treat, and who not to treat, will define the decades of thyroid nodules and cancer care ahead. Those who have already benefited from molecular testing understand its power, and nearly all those working in healthcare acknowledge its enormous untapped potential ahead.

It is with this background that the data by Dutta and colleagues (4) should be viewed with excitement. The authors apply a novel application of molecular testing to thyroid nodule care, analyzing the total quantity of circulating cell-free DNA (cfDNA) in affected patients with hopes of identifying which nodules are benign or cancerous. While similar technology has been previously described in relation to other diseases, its most common application has been to serve as a “liquid biopsy” thus defining the unique molecular signature from a tumor through a noninvasive approach (5). But in this unique study, published in The Journal of Clinical Endocrinology & Metabolism, the authors perform a simple quantitative measurement of total cfDNA, and analyze cfDNA as a novel diagnostic tool ahead. Though only an initial pilot study, the authors demonstrate the potential for this method to help differentiate benign from malignant thyroid disease. And while a large-scale, multi-institution validation study will be required, the initial discriminatory capacity shown by these data is exciting to ponder. Furthermore, study data demonstrate a significant reduction in cfDNA following surgical removal of the thyroid cancer, while also identifying within the cfDNA the common driver mutations known to be responsible for most thyroid cancer. These internal metrics of validity are notable and may lead to further clinical applications ahead.

Investigations such as this are exciting, both for their specific science, but even more so because they support the power of molecularly translating our genomic data into the world of clinical care. Indeed, most predict that physicians and healthcare workers will find their eyes and ears increasingly connected to this field of translational genomics ahead. And while many have gained comfort in understanding how a single DNA mutation can translate into a cancer diagnosis, the power and potential of genomics is much broader than just single base-pair changes—and much more complex. It is much less obvious, for example, how an RNA expression pattern portends prognosis when many of the expressed genes are not even hypothesized to be oncogenic a priori. Yet, these data remain powerful and clinical validation studies have proven their accuracy (6). Epigenetic markers may prove equally important. And, the relationship of the genome to the proteome to the metabolome has yet to be fully elucidated for most neoplasms. Equally exciting experiments investigating the single cell genomic evolution of cancer cells within a mass are beginning to inform us that understanding one somatic mutation simply doesn’t provide enough insight into the complexity of evolution ongoing within a neoplasm harboring millions of cells.

To be cautionary, there is little belief that molecular analysis can fully supplant the need for clinical evaluation or separate diagnostic testing. Rather, molecular analysis will prove its greatest power when intertwined as part of a synergistic partnership with above. But the data from the study by Dutta et al excite us through the power of thinking outside the box and viewing molecular diagnostics via a different lens. Indeed, a genetic mutation not only caused each thyroid nodule to form, but such signatures (it now seems) circulate through the plasma of each afflicted patient, providing hope for a novel way to understand this common disease.

Many novel ideas and pilot discoveries have fostered excitement yet led to little long-term benefit or sustained impact upon healthcare. That is the second great lesson—that discovery should be feverishly pursued but rapidly backed up by large-scale subsequent studies that define a finding’s true application in the diverse real world. And the final step must acknowledge and analyze the cost and value proposition to any new discovery. The use of cfDNA and many other genomic discoveries warrant close watching ahead. And while awaiting broad validation, these data nonetheless demonstrate the hopeful potential for genomic medicine and highlight its continual evolution from the tip down to the iceberg below.