Increased Early Cancer Diagnosis: Unveiling Immune-Cancer Biology to Explain Clinical “Overdiagnosis”

SIMPLE SUMMARY: Earlier diagnosis is often advocated to prevent advanced cancer morbidity and death. Compelling evidence exists where this occurs. A major conundrum is the lack of supportive evidence for some cancers where more sensitive screening and early detection may not translate into reduced morbidity and mortality. Some early cancers do not advance to metastases and death, and thus may not endanger the patient during life, nor require treatment. Biological variants that are non-metastatic and non-lethal may exist. Distinguishing potentially ‘fatal’ cancers from ‘non-fatal’ cancers is fundamental for screening to selectively benefit, while avoiding unnecessary treatment. Immune control of cancer has evidential support, and may explain why some cancers progress, while others stay quiescent. The extent of immune system modulation of malignant behaviour could decisively influence cancer outcomes, including lethality. We advance an evidence-based, immune model, worthy of further research, potentially explaining cancer “overdiagnosis” and the susceptibility to recurrence, regression, and lethality. ABSTRACT: Even though clinically small ‘early’ cancers represent many millions of cells biologically, when removed surgically, these often never recur or regrow, nor reduce the individual’s lifespan. However, some early cancers remain quiescent and indolent; while others grow and metastasize, threatening life. Distinguishing between these different clinical behaviours using clinical/pathological criteria is currently problematic. It is reported that many suspicious lesions and early cancers are being removed surgically that would not threaten the patient’s life. This has been termed ‘overdiagnosis’, especially in the sphere of cancer screening. Although a controversial and emotive topic, it poses clinical and public health policy challenges. The diagnostic differentiation between ‘non-lethal’ and ‘lethal’ tumor forms is generally impossible. One perspective gathering evidential support is that a dynamic balance exists between the immune response and malignant processes governing ‘lethality’, where many more cancers are produced than become clinically significant due to the immune system preventing their progression. Higher medical screening “diagnosis” rates may reflect lead-time effects, with more ‘non-progressing’ cancers detected when an early immune-cancer interaction is occurring. We present a model for this immune-cancer interaction and review ‘excess’ or ‘overdiagnosis’ claims that accompany increasingly sensitive diagnostic and screening technologies. We consider that immune tools should be incorporated into future research, with potential for immune system modulation for some early cancers.