The Evolution of Our Understanding of the Biology of Cancer Is the Key to Avoiding Overdiagnosis and Overtreatment

Abstract

There has been a tremendous evolution in our thinking about cancer since the 1880s. Breast cancer is a particularly good example to evaluate the progress that has been made and the new challenges that have arisen due to screening that inadvertently identifies indolent lesions. The degree to which overdiagnosis is a problem depends on the reservoir of indolent disease, the disease heterogeneity, and the fraction of the tumors that have aggressive biology. Cancers span the spectrum of biological behavior, and population-wide screening increases the detection of tumors that may not cause harm within the patient's lifetime or may never metastasize or result in death. Our approach to early detection will be vastly improved if we understand, address, and adjust to tumor heterogeneity. In this article, we use breast cancer as a case study to demonstrate how the approach to biological characterization, diagnostics, and therapeutics can inform our approach to screening, early detection, and prevention. Overdiagnosis can be mitigated by developing diagnostics to identify indolent disease, incorporating biology and risk assessment in screening strategies, changing the pathology rules for tumor classification, and refining the way we classify precancerous lesions. The more the patterns of cancers can be seen across other cancers, the more it is clear that our approach should transcend organ of origin. This will be particularly helpful in advancing the field by changing both our terminology for what is cancer and also by helping us to learn how best to mitigate the risk of the most aggressive cancers.See all articles in this CEBP Focus section, "NCI Early Detection Research Network: Making Cancer Detection Possible."

PolyG-DS: An ultrasensitive polyguanine tract–profiling method to detect clonal expansions and trace cell lineage

“…The analysis of the genetic relationships among histologically normal, dysplastic, and cancerous samples is critical to understanding the evolution of cancer in this disease and to identifying the specific dysplastic lesions that are cancer precursors, which is an unmet clinical need (49). Similar approaches could be employed to study the evolution of precancerous lesions in other cancer types in order to elucidate what lesions are genetically linked to cancer (aggressive) versus those that are unrelated to cancer (indolent) (50,51). In addition, we have demonstrated that PolyG-DS could be useful to characterize complex cancer evolutionary trajectories, such as the one identified in this study and in prior studies of HGSC evolution (40,45).…”

The Etiology and Pathophysiology Genesis of Benign Prostatic Hyperplasia and Prostate Cancer: A New Perspective

“…Nitric oxide is one of the most well studied and recognized female estrogen-induced vasodilators [258][259][260][261]. The key in preventive medicine is to prevent the disease from developing by catching or stopping it early; in this case between the fifth (40s) and before the seventh (60s) decade of life [228][229][230]. A potential three-pronged approach can be explored:…”

Supplemental screening using breast MRI in women with mammographically dense breasts

“…In other words: neither a woman diagnosed with breast cancer nor her physicians will be able to say whether her cancer is biologically relevant or not. While increasing recall thresholds may alleviate the problem somewhat, there is actually no data on how much overdiagnosis is a necessary by-product of diagnosing biologically aggressive cancers and how much of this side effect could be alleviated by improved classifications and individualized treatment strategies [27]. Why is overdiagnosis a problem at all?…”