The Prospective Incorporation of Molecular Profiling Will Transform Global Cancer Care

We began the new decade with the satisfying news of a palpable, praiseworthy decrease in cancer mortality in the United States. This success is a result of continued research and investment in the understanding of cancer biology, and it is reflective of improved screening, improvements in adjuvant therapy, and maybe most impactful, the dramatic breakthroughs that immuno-oncology has brought. These results could not be obtained without decades of hard work within our highly collaborative environment composed of academic researchers, industry innovation and investment, supportive regulatory policies, and the “all-in” engagement of our patient partners.

Although I always held out hope, I never thought I would see such dramatic advances in my lifetime. Significant progress has been made in many of our most recalcitrant cancers, including lung cancer, kidney cancer, melanoma, hematological malignancies, and many others. But as we celebrate these achievements, we must remember that the successes we have achieved do not reliably equate with cures, which are our patients’ fundamental expectation and our true goal. We must remember that we continue to practice “in the dark,” unsure of who should get which drugs, and who might not need any drugs, radiation, or even surgery. We practice trial-and-error medicine, full of waste and residual toxicity. Cancer care is far from optimized, and much work remains ahead.

The first year of a new decade is a perfect time to reflect on the bigger picture of cancer care around the world. While we in the United States and other richer regions of the
world have enjoyed many medical successes, most of our brothers and sisters coinhabiting our planet have not. Cancer care has become a luxury item, available only to those with either significant personal wealth or the good fortune to live in countries with strong economies. The difference between “the haves” and “the have-nots” is striking, and in no medical discipline is this more dramatic than in oncology.

Let’s face it—cancer care is complicated: It requires a large, highly trained, multidisciplinary team for it to be optimally delivered. The best teams must include experienced, specialized surgeons; medical oncologists; radiation oncologists; all of the affiliated professionals who assist in the diagnosis and management of patients, such as gastroenterologists, pulmonologists, and interventional radiologists; and, of course, nurses, nutritionists, and a building full of pieces of highly complex equipment, with skilled individuals who know how to run them.

Most of the world’s population faces a very different level of health care. They struggle to have clean water and clean air, and to have basic health needs met. Such people are forced to make hard choices, or have had the will and foresight to make strategic changes that we, in the United States, have not yet been bold enough to make. Here, unanswered questions include: Is health care a right or privilege? Should everyone have access to unlimited care? What is the value of medical services? If you had to buy these services yourself, with your own money, would you?

We know that the health care system in the United States is not sustainable for much longer, and cancer care—specifically, the widespread use of immunotherapy—is accelerating the oncoming economic crisis. Other nations have made the tough choices, in some cases limiting access to newer, expensive therapies that do not meet economically derived value metrics. How will we respond as a nation when we face the same social and economic decision points?

At a time when nations are building walls, we in the cancer community must deepen our commitments to each other through collaborative research and data sharing. Our only way forward is to work together, especially as we expand our understanding and the ability to measure the complexities of cancers. The next great frontier for cancer research is precision medicine; with it comes the expanded incorporation of complex molecular profiling, linked to artificial intelligence–based machine learning, into our therapies and decision-making.

While recognizing that basic molecular testing of tumors is part of everyday practice, we are just beginning to understand this rapidly evolving field. If we reflect back, even on the past decade, we have evolved from a culture where no molecular testing was done for most cancers, to a time when single or “oligo” testing was performed, to today, when broad molecular profiling is rapidly becoming the standard of care. In less than a decade, genetic sequencing has moved from being a research question with no insurance coverage, to garnering FDA approvals, to becoming accepted by insurance companies as the standard of care.

As our tests have become increasingly complicated, we have come to recognize the importance of tissue quality and of preanalytic management of the specimen. We see more clearly the need to understand the actual assays that are being run, and to appreciate how one type of assay compares with another—eg, tissue vs liquid samples. Also, as with any new technology, we have seen a widening knowledge gap among us clinicians. As the technology and complexity of precision medicine have changed, we have fallen behind in our ability to interpret our patients’ results. Some clinicians have become so frustrated and confused that they have stopped ordering molecular testing altogether. Others choose to order tests that yield a relatively low percentage of results that dramatically alter treatment decisions. Still others misinterpret results, causing additional medical expense and patient anxiety. And then, in many parts of the world, clinicians simply do not want to know the results of any tests they could theoretically order because, while they know that those results could indicate applicability of the latest promising treatment (eg, checkpoint inhibitors for microsatellite instability–high tumors), they do not have access to these therapies, leaving them only with regret over what might have been.

The rising cost of drug development is typically the first reason put forward to explain the rising cost of drugs, once they are approved. No doubt, drug development has become very expensive, and while the issue is multifactorial, a major reason is the rise of precision medicine. As we recognize that not all cancers are alike and subdivide them into smaller and smaller subgroups, trials become increasingly expensive. It costs more to find the patients, it takes longer to accrue the studies, and then, in the end, there is a smaller market of patients to purchase the therapy, limiting the return on investment.

At least within the United States, our government regulatory bodies have been keeping step with the rapid change in drug development and cancer technology. No longer is the only gold standard for drug approval a series of large phase 3 randomized trials. Don’t get me wrong; this is still a standard route for drug discovery and approval. However, as we have increasingly identified molecular targets in patients with fatal cancers that portend a very high benefit rate (<50%) with improved safety signals, our regulatory agencies have granted rapid approvals. So instead of “slogging” through large randomized trials in the hope of a hazard ratio of .8, trials are now being designed with target hazard ratios of .5 and lower, results that don’t actually require a statistician to confirm positivity. Given that our science is there, and our regulatory bodies are behind us, we need to play by new rules.

For the past several years, I have been fortunate to help build and lead a US-based collaborative group of investigators charged with studying the science of precision medicine, the Precision Oncology Alliance. It was only through coordinating our efforts and sharing our vast amounts of molecular and clinical data that we were able to uncover the many discoveries hidden within. Collectively, we understand the value in numbers, of the ability to characterize our patients into new subgroups, and of beginning to apply the latest therapies using prospective enrichment. As we move forward, increasingly complex molecular results are being analyzed using artificial intelligence/machine learning to provide us with more prognostic and predictive insights.

We are beginning to embrace tumor heterogeneity, and we continue to invest more in the practice of biomarker discovery. This work will uncover more targets and allow for better therapeutic decisions, meaning that we can all ultimately fight a smarter, more efficient war against cancer. Critical to our success will be global outreach and expansion of cancer care markets. We have well-established science showing us that cancers vary by global distribution, maybe secondary to differences in the microbiome. This suggests that results from trials performed in one region of the world may not be applicable in other regions.

As part of our current work, representatives from around the world are building a global precision network, the Oncology Alliance for Individualized Medicine (Onco AI-Med), that links cancer centers in 4 continents. By analyzing tumors optimized for tissue quality—limiting ischemia time—and performing extensive testing that includes whole-genome sequencing, whole RNA transcriptome, proteomics, and ultimately metabolomics on both the tumor and normal tissues, coupled with artificial intelligence learning, we expect to push the field of precision medicine to its next phase. We also hope that by having large populations of patients “profiled” prospectively, we will lower the cost of drug development through rapid patient identification.

Precision medicine, while still in its infancy, is accepted and here to stay. Rapid improvements in technology continue, which for all their benefits also create a widening knowledge gap, which we must close. To accomplish this, we must partner on a global scale, both because the science requires this and, more importantly, because we are morally compelled to share our success with our fellow global citizens. Cancer care can no longer be a luxury item, only for the rich. We must work toward wide access. Opening markets through collaborative science will secure the return on investment for our business partners, and secure our progress toward finding the cures for cancer.