{"id":40358,"date":"2021-07-15T12:34:05","date_gmt":"2021-07-15T11:34:05","guid":{"rendered":"http:\/\/touchoncology.com\/?p=40358"},"modified":"2022-11-28T10:27:14","modified_gmt":"2022-11-28T10:27:14","slug":"criteria-for-evaluating-multi-cancer-early-detection-tests","status":"publish","type":"post","link":"https:\/\/touchoncology.com\/diagnostics-and-screening\/journal-articles\/criteria-for-evaluating-multi-cancer-early-detection-tests\/","title":{"rendered":"Criteria for Evaluating Multi-cancer Early Detection Tests"},"content":{"rendered":"
Somatic DNA mutational analysis has transformed how we characterize existing cancer and select treatments. For example, circulating tumour cell-free DNA (cfDNA) can be used to select targeted therapies, monitor treatment response and detect disease recurrence.1<\/span>\u00a0However, early attempts with targeted sequencing of circulating tumour cfDNA to screen for multiple cancers were unsuccessful because of low sensitivity and specificity.2,3<\/span><\/p>\n Currently, cancer screening is performed one organ at a time using imaging tests or histopathological analyses of biopsied tissue or other biospecimens. In the United States, only five types of cancer are recommended for screening in the general population: colon, breast, cervical, lung (in a high-risk population) and prostate (on an individualized basis).4\u20138<\/span>\u00a0There are several reasons why this single-cancer screening paradigm is failing the population and not detecting a sufficient number of cancers. First, unscreened cancers account for more than 60% of all cancer diagnoses and approximately 71% of cancer deaths (Figure 1A<\/span><\/em>).9<\/span>\u00a0(Data on file; calculated based on Surveillance, Epidemiology, and End Results Program and Cancer Statistics).10<\/span>\u00a0Second, single-cancer tests have optimized sensitivity, and accept high false-positive rates for each cancer. For an individual receiving all the recommended single-cancer screening tests in a single year, the cumulative false-positive rate for men is 31% (including colorectal, lung and prostate cancer) and for women is 43% (including breast, cervical, colorectal and lung cancer) (Figure 1B<\/span><\/em>).11\u201315<\/span>\u00a0Finally, any individual undergoing one of these single-cancer screening tests is much more likely to be diagnosed with a different cancer in that year (Figure 1C<\/span><\/em>).16<\/span>\u00a0For example, in the populations being screened for cervical, colorectal or breast cancer, the annual incidence rate of other cancers is 2\u201324-fold higher than that of the single cancer being screened.16<\/span><\/p>\n <\/p>\n For these reasons, the opportunity for early detection of multiple cancers with a single test is potentially transformational (Figure 2A<\/span><\/em>).9,17<\/span>\u00a0A conceptual shift is required, from screening only for guideline-recommended individual cancers to screening individuals for any cancer in combination with existing guideline recommendations. Because the occurrence of individual cancers in the general population is low, the number of people who need to be screened to find a single cancer is very large. However, this number decreases when multiple types of cancer are screened for in aggregate, thereby increasing the aggregate prevalence and resulting in a higher overall positive predictive value (PPV).18<\/span>\u00a0<\/a>The transformational idea of a multi-cancer early detection (MCED) test is the ability to detect multiple cancers and dramatically increase the cancer detection rate (CDR) in the population, i.e. the number of cancers detected divided by the number of cancers expected in the population monitored. In the United States, for example, there will be an estimated 1.2 million cases of cancer in 2021 in adults aged 50\u201379 years; mammography is expected to detect 114,000 of those cancers, for a CDR of approximately 9%.17<\/span>\u00a0Even when all five single-cancer screening tests are combined, the CDR is still only approximately 16%.17,19,20<\/span>\u00a0Although this is a notable accomplishment, by itself it is evident that it is not enough, as other cancers comprise approximately 51% of cancers diagnosed and 56% of cancer deaths.21<\/span>\u00a0<\/a>Importantly, MCED tests are intended to complement, not replace, single-cancer screening tests by being used in combination. Because an MCED test could maximize overall cancer detection in the population while minimizing harms with its low fixed false-positive rate, it could translate into higher value and a greater public health impact compared with single-cancer screening tests alone.<\/p>\n <\/p>\n As it relates to minimizing harms, a false-positive rate of <1% associated with a multi-cancer test, compared with a higher cumulative false-positive rate associated with multiple single-cancer tests, could result in reduced patient anxiety, fewer unnecessary diagnostic workups, and lower healthcare resource use and costs.\u00a0<\/a>In a health economic model comparing the clinical outcomes of adding an MCED test to current cancer screening with current screening alone, the addition of an annual MCED test was predicted to provide an incremental gain of 0.34 quality-adjusted life-years per person, and was a highly cost-effective intervention.23<\/span>\u00a0Of note, the current PATHFINDER study (ClinicalTrials.gov Identifier: NCT04241796) will provide patient-reported outcomes among patients who utilize a multi-cancer detection test in a clinical practice setting. Additionally, a multi-cancer test could offer the unique ability to detect any cancer, versus a traditional organ-specific test that only detects a single cancer. This could be especially valuable in detecting lethal cancers beyond the ones detected with traditional organ-specific screening paradigms.\u00a0<\/a>The inclusion of cancer signal origin (i.e. tissue of origin) analysis in a multi-cancer detection test is an important component to reducing patient anxiety and streamlining the diagnostic evaluation.24<\/span><\/p>\n In terms of estimating the potential public health impact, recent modelling efforts show that the implementation of an MCED test in addition to usual care (e.g. screening, incidental detection, symptomatic workup) may result in earlier cancer detection for 485 cancers per year per 100,000 individuals compared with usual care alone. For those with cancers detected earlier, this is expected to translate to a 78% reduction in late-stage cancer incidence, a 39% reduction in 5-year cancer mortality, and ultimately a 26% reduction of all cancer-related deaths.25<\/span>\u00a0It is well recognized that earlier stage-shifting of cancer diagnosis, one of the primary goals of an MCED, is strongly linked with higher rates of survival at 5 years.26<\/span>\u00a0The annual statistics published by the American Cancer Society also note that 5-year survival rates are highest for many cancers when diagnosis occurs at earlier stages.21<\/span><\/p>\n Indeed, a new generation of cfDNA-based MCED tests is being developed and will be available for clinical use in the near future.27<\/span>\u00a0Several analytical strategies have been proposed, including analysis of cfDNA and protein biomarkers,28<\/span>\u00a0cfDNA fragmentation patterns,29<\/span>\u00a0and DNA methylation patterns.22,30<\/span>\u00a0It should be noted that the tumour-type specific sensitivities of cfDNA-based MCED tests are dependent on the amount of tumour cfDNA shed into the blood, which varies for different tumour types and cancer stages.31<\/span>\u00a0These methods report simultaneous detection of signals from 7 to more than 50 types of cancer, with high specificity (each approach reports \u226595%) and moderate-to-high sensitivities (ranging from 44% to 98%, dependent upon cancer type and stage distribution), as well as prediction of the cancer signal origin with varying degrees of accuracy (61\u201393%).32<\/span>\u00a0In addition, a few large prospective studies, such as DETECT-A (~10,000 participants), STRIVE (ClinicalTrials.gov Identifier: NCT03085888; ~100,000 participants), SUMMIT (ClinicalTrials.gov Identifier: NCT03934866; ~25,000 participants), PATHFINDER (NCT04241796; ~6,200 participants) and ASCEND (ClinicalTrials.gov Identifier: NCT04213326; 3,000 participants), are completed or are under way to clinically validate MCED tests.27,33<\/span>\u00a0<\/a><\/a>Due to the novelty of genomic MCED tests, there is not an accepted framework for how such tests should be evaluated. Although some criteria have been suggested to evaluate the performance and safety, work needs to be done to clarify analytical and clinical validity, benefit\u2013risk, and clinical utility of MCED test.18,27,28<\/span>\u00a0As shown in\u00a0Figure 2B<\/span><\/em>, we propose that a cfDNA-based MCED test to be used alongside existing guideline-recommended screening should:<\/p>\n