The four fundamentals of early warning systems
A way to look at early cancer detection
A hurricane afflicts damage across Florida. Wildfires rage through California. A deadly typhoon afflicts central Japan after weeks of flooding. These natural disasters occur with disturbing regularity.
An individual's health can also suddenly and drastically decline through disease or accident. With cancer a leading cause of death, what can be learned from early warning systems established for natural disasters?
Four fundamental elements of early warning
The four fundamental elements of early warning systems are: risk knowledge, monitoring, response capability, and warning communication. These are 'means by which people receive relevant and timely information… in order to make informed decisions and take action'. (ref)
Awareness of the risk for a natural disaster is vitally important. Have you recently moved to Florida? Understand the history of hurricanes that have affected the state, learn from your neighbors their own stories and experiences, assess the particulars of your own living situation and emergency plans.
Awareness of risk for cancer is likewise vitally important. Are you at high risk for certain types of cancer? The American Cancer Society has put together this comprehensive set of guidelines for early cancer detection. by cancer type, sex and age.
There are environmental risks for cancer, such as cigarette smoking, HPV infection, even living near a source of environmental radiation called radon. In addition to the exposure to carcinogens, is the genetic background, of which a tremendous amount has been learned in the past twenty years. Risk genes, in particular for breast and ovarian cancer, have been identified and tests are routinely performed.
Here is where new cancer screening methods are urgently needed. As mentioned earlier in a blog post "Current screening approaches for early cancer detection", only mammography for breast cancer and Pap tests for cervical cancer in females, and colonoscopy or non-invasive stool or blood tests for colorectal cancer are the recommended screenings for average-risk individuals.
People who pay close attention to their health will visit a doctor once some symptom appears, and it is in symptomatic individuals where often cancer is detected too late. Detecting cancer in asymptomatic individuals is large (and expensive) undertaking, involving tens (or even hundreds) of thousands of individuals monitored for many years. For using tumor liquid biopsy for genotyping or monitoring those with advanced disease, this paper (Table 1, Aravanis and Klausner et al Cell 2017 NGS of ctDNA for early cancer detection) states only "100's" of individuals is the study-size to show clinical validity and clinical utility; "10,000 - 100,000s" are needed for early cancer detection.
The authors conclude low-cost sequencing combined with machine learning and population-scale screening trials will 'test the clinical utility of this approach'. The authors, employed by GRAIL Inc., are embarking on two major clinical trials, a prospective trial of 120,000 breast cancer patients (called The STRIVE Study: Breast Cancer Screening Cohort) and another 15,000 for The Circulating Cell-free Genome Atlas Study (CCGA).
Once the risk is known and the monitoring for a disaster is in place, an accurate assessment of the response capability is needed. In the case of cancer, much publicity and research funds pour into advances in treating late-stage disease. Individualized personalized medicine, whether therapy with CAR-T or novel checkpoint inhibitor combinations, are so expensive to produce reasonable questions are raised as to its benefit (or detriment) to society as a whole. When the QALY (Quality of Adjusted Life Year) exceeds a nominal $50,000 by fortyfour-fold (in this JAMA Dermatology illustration, the calculated QALY for talimogene laherparepvec plus ipilimumab combination immunotherapy is $2.2M), those costs are borne by everyone.
The armamentarium of cancer treatments is well-stocked, and five-year survival rates for many types of cancer diagnosed in its early, localized stages are typically in the 80%-90% range. As Kalinich and Haber point out in this Perspective in Science earlier this year, "Undoubtedly, effective screening for early invasive cancers represents the best hope for reducing cancer mortality and morbidity…Most importantly, the ongoing development of cost effective and accurate blood-based cancer screening strategies is poised to revolutionize clinical cancer care... The vision of effective earlier cancer detection and intervention warrants validation in appropriate populations through large-scale clinical trials that are likely to radically change the way we diagnose and treat cancer." ("Cancer Detection: Seeking Signals in the Blood", Science 23 Feb 2018)
This revolution in the way cancer is diagnosed and treated depends on the monitoring system, which is why the topic of liquid biopsy has attracted such intense interest, whether analysis of circulating tumor DNA, circulating tumor cells, or exosomes.
One item you can do is to look over the American Cancer Society's comprehensive set of guidelines for early cancer detection, and make sure you and your loved ones have the recommended screening tests performed. The worst thing you want to hear from a doctor is the phrase, "I wish you had the screening done years ago".
- Aravanis, A.M., Lee, M., and Klausner R.D. Cell 2017 "Next-Generation Sequencing of Circulating Tumor DNA for Early Cancer Detection", PMID:28187279 doi:10.1016/j.cell.2017.01.030.
- Kalinich, M., and Haber, D.A. Science 2018 "Cancer detection: Seeking signals in blood", PMID:29472467 doi:10.1126/science.aas9102.