1. Overdiagnosis as an extreme form of length-time bias Breast cancer screening as example Juan Gérvas, MD, PhD, Equipo CESCA, Madrid, Spain jjgervas@gmail.com @JuanGrvas jjgervas@gmail.com

2.  Overdiagnosis is an extreme form of length-time bias and occurs when screening detects indolent tumors that meet diagnostic criteria for cancer but would not otherwise have come to clinical attention during the lifetime of the individual. Reference: Failure of Researchers, Reviewers, Editors, and the Media to Understand Flaws in Cancer Screening Studies.Berry DA. Cancer. 2014;(Article first published online: 12 JUN 2014):1–8. doi: 10.1002/cncr.28795.  Overdiagnosis artificially inflates the case survival rate.  Overdiagnosed patients obtain no benefit while being subjected to all of the harms of treatment.

3. ABCD A = Tumor onset B = Beginning of the period in which breast cancer can be diagnosed with screening mammography C = Start of the clinical phase (signs-symptoms) of breast cancer D = Death because breast cancer, o for any cause BC = Latency (sojourn), period for early detection = Critical point of irreversibility S s SB = Lead time bias. BC = Length time bias when BC is longer than usual, or even close or equal to "n" (being "n" the number of years of health expectancy at the time of diagnosis). Overdiagnosis "stricto sensu" means that BC is equal to "n".

4. A = Tumor onset B = Beginning of the period in which breast cancer can be diagnosed with screening mammography C = Start of the clinical phase (signs-symptoms) of breast cancer D = Death because breast cancer, o for any cause BC = Latency (sojourn), period for early detection = Critical point of irreversibility s SB = Lead time bias. BC = Length time bias when BC is longer than usual, or even close or equal to "n" (being "n" the number of years of health expectancy at the time of diagnosis). Overdiagnosis "stricto sensu" means that BC is equal to "n". ABD S C In some cases C could be before B (and the latency period becomes negative)

5. 1. Lead-time bias. The increment in survival among screen-detected cases that equals the difference in time of detection and when the cancer would have been detected otherwise. Labeling individuals earlier as having cancer means they will live longer after having been so labeled. 2. Length bias. The increment in survival among screen-detected cases because of the over selection of slowly growing cancers. Cancers that are slowly growing have a longer period between the time a tumor can be detected on a mammogram and when it will become evident from symptoms. 3. Sojourn (latency) period. The time a tumor can be detected on a mammogram until when it will become evident from signs-symptoms. The distribution of sojourn time in breast cancer is unknown. Sojourn time varies, depending on factors such as age and breast density. Typical estimates range from 4 years to 7 years. 4. Critical point of irreversibility. Starting period of invasive cancer (metastasis or development of a clon which will "kill" the female without treatment). DEFINITIONS

6.  Overdiagnosis is an error of prognosis.  We do not know why overdiagnosis is so common and, worse, we cannot separate tumors that are overdiagnosis (we cannot at the time of diagnosis identify "overdiagnosis tumors“)  In the future, genetic intratumoral heterogeneity (the presence of multiple clones, intratumoral genetic chaos) might help CONCLUSIONS (I)  Overdiagnosis is not an error of diagnosis (overdiagnosis is not a false positive) References: Bewildering genetic intratumor heterogeneity: Evolution through space and time. Available in: http://cancerres.aacrjournals.org/content/72/19/4875.short http://cancerres.aacrjournals.org/content/72/19/4875.short Cancer intra-heterogeneity. Can the degree of genetic chaos accurately predict of tumour recurrence? Probably. Available in: http://scienceblog.cancerresearchuk.org/2014/10/09/lung-cancer-evolution-a-journey-through-space-and-time/ http://scienceblog.cancerresearchuk.org/2014/10/09/lung-cancer-evolution-a-journey-through-space-and-time/ Overdiagnosis. Tracking the clonal origin of lethal prostate cancer. Available in: http://www.jci.org/articles/view/70354http://www.jci.org/articles/view/70354

7.  In the future, genetic intratumoral heterogeneity (the presence of multiple clones, intratumoral genetic chaos) might help. At least in mice, mechanical properties of tumors differs substantially from normal cells and tissues so macroscopic stiffness of breast tumors predicts metastasis. CONCLUSIONS (II)  We don’t know why overdiagnosis is so common and, worse, we cannot separate tumors that are overdiagnosis (we cannot at the time of diagnosis identify "overdiagnosis tumors"). References: Macroscopic stiffness of breast tumors predicts metastasis. Available in: http://www.nature.com/srep/2014/140701/srep05512/pdf/srep05512.pdfhttp://www.nature.com/srep/2014/140701/srep05512/pdf/srep05512.pdf