Earlier this week, meta-analyses and commentary published in JAMA Internal Medicine ⎯ as part of a series on “Less is More” healthcare ⎯ asserted that most cancer screenings do not extend lifespan, thus implying little benefit to cancer screening. The authors suggest that together, previous cancer screening trials show no impact on all-cause mortality, even though none of these trials were specifically designed to look at this outcome. Whether or not cancer screening should be expected to change all-cause mortality is controversial. Leading experts with organizations like American Cancer Society have agreed that cancer screening was not designed to increase longevity, but rather to decrease premature suffering and death from cancer. The strategy behind regular cancer screening is to catch more cancers early enough so that doctors can take steps to improve a person’s chance of surviving cancer, prevent premature suffering and death, and improve quality of life. The issue of competing mortality risks further complicates assessing all-cause mortality, which is why it is so infrequently used in assessing medical interventions.
Since the start of United States Preventive Services Task Force (USPSTF) cancer screening recommendations, cancer screenings have added 12 million years to American lives over 25 years, according to a recent study. We are waging a new front in the war on cancer, because the status quo remains unacceptable. Dramatic advances in human genomics and artificial intelligence (AI) are resulting in the rewriting of textbooks about cancer biology, requiring new ways of thinking about cancer detection, pioneering science, and new ways of evaluating these tools that can change the paradigm of cancer screening.
Ongoing review of cancer screening technology is important to understanding the benefit and potential risks to patients. However, meta-analyses are by definition dependent on the included studies. As Yale’s Dr. F. Perry Wilson, points out, “Meeting the criteria to be included in a meta-analysis does not necessarily mean the study was a good one.” In this case, the authors admit they did not perform any assessments of the quality of the studies included in their analysis. This is hugely problematic. For example, one of the included randomized mammography trials was widely criticized for allegedly preferentially enrolling women with palpable breast masses in the mammography group, making those outcomes worse.
Even more problematic is the authors’ focus on the all-cause mortality outcome. Recommended cancer screenings only target three types of cancers for women, and two types for men, with an additional screening for those with a heavy smoking history. Most people are far more likely to have a cancer they are not being screened for, and most people will die of something other than the single cancer they are being screened for. As Queen Mary University of London’s Professor Peter Sasieni notes in BMJ, “All-cause mortality will generally be dominated by causes of death that are unrelated to the screening and any intervention that follows, so that any benefit (or harm) from screening will be concealed. This is not to say that a direct assessment of all-cause mortality should be ignored. It may indicate possible benefit or harm but failure to reveal either does not exclude the existence of clear and sufficient evidence of benefit or harm. It is the insensitivity (and lack of specificity) of all-cause mortality as an outcome that is the problem, not the outcome itself.”
We agree with data-driven and evidence-based clinical decision-making and policy approaches, but the status quo remains unacceptable. Where we and others in the medical and patient communities disagree with those waging a war against cancer screening, is that we need to focus on the bigger picture, our 50 year war on cancer itself – a war we are losing. What we need now is not “less is more” thinking, but rather the pioneers who challenge conventional thinking and bring new solutions to the table to change the status quo. We propose a new front in the war on cancer, multi-cancer early detection (MCED) testing, because we need to be screening more people for more types of cancer, not less. Patients and their physicians should not have to wait a decade or two for access to new technologies like MCED when we know that there is potential to reduce the overall burden of late stage cancer. That is why GRAIL unlocked the power of genomics and AI to validate the first MCED test based on a shared epigenetic cancer signal, and undertook one of the largest and most rigorous clinical programs in cancer research, with clinical studies that collectively include more than 300,000 participants.
Screening programs for breast, cervical, and colon cancer were implemented years – if not decades – before mortality studies were completed. The argument for requiring large trials with all-cause mortality endpoints for newer technologies like MCED tests is unprecedented, unrealistic, unnecessary, and not feasible. As MCED tests generally target a shared cancer signal to detect multiple cancer types, even in a relatively large trial several cancer types would each have too few participants and would include causes of death unrelated to the screening or intervention to produce reliable estimates of screening performance individually using cancer mortality as an endpoint.
Modern approaches for high-quality cancer screening trials with alternative endpoints can be used to establish efficacy at a fraction of the time and cost of trials powered for mortality. A recent paper includes reduction in late-stage cancer incidence (“stage shift”) as an example of a well-established endpoint in the field of early cancer detection to predict the mortality benefit of cancer screening based on the reduction in late stage cancers and the survival of early-stage cases in the absence of screening. To that end, we are conducting NHS-Galleri, an ongoing randomized controlled trial of 140,000 participants, in partnership with England’s National Health Service, with the primary objective of reducing late-stage cancer diagnoses, in-line with the UK’s overarching goal of finding more cancers earlier in its population.
This approach is supported by a recent study that showed that the potential for definitive intervention is highly dependent on stage at diagnosis—with a much higher rate of successful surgical intervention at early stages—and surgical resection is associated with better long-term outcomes consistently across cancer types. Further, these findings suggest that eligibility for surgery could also serve as a clinically meaningful endpoint for cancer screening trials.
Finally, the editorial authors also raised fears about the harms of one MCED blood test based on its reliance on the use of PET-CT imaging and the large amount of radiation exposure. But they failed to acknowledge that it is widely recognized that a prerequisite for an MCED test is the ability to predict the site of origin of the cancer signal to direct an efficient diagnostic evaluation. The test used to describe harms has not been validated, nor is it available for commercial use. They seemed to gloss over the facts about GRAIL’s MCED test, which has been validated and is commercially available, and has shown the ability to predict the origin of the cancer signal with high accuracy.
Currently, cancer types without screening recommendations represent approximately 70% of cancer deaths. The overall survival rate for cancer is four times higher when cancer is found before it spreads, but unfortunately most cancers which result in death are detected too late in part because they do not have effective screening tests. Despite the accepted risk of false positives and negatives, standard of care screenings remain recommended gold standards for finding cancer earlier. We believe making validated MCED tests available as a complement to recommended screening programs will help to dramatically increase cancer detection from screening in the population, and improve public health.
We are losing the war on cancer that we have been fighting for 50 years now, and this is largely because we are finding most cancers too late. Practicing clinicians and patients recognize this, the White House recognizes this, and the families of nearly 2,000 loved ones per day lost to cancer know this all too well. Finding cancers too late is costing us not just our family and friends. Within the next 10 years cancer costs are expected to be more than $245B annually with the highest costs among those with late stage diagnosis. What we need now to address this unacceptable situation are pioneering new technologies and innovative new approaches, such as validated MCED tests.