Article

Rethinking Screening for Breast Cancer and Prostate Cancer

Department of Surgery and Radiology, University of California, San Francisco, San Francisco, CA 94115, USA.
JAMA The Journal of the American Medical Association (Impact Factor: 30.39). 10/2009; 302(15):1685-92. DOI: 10.1001/jama.2009.1498
Source: PubMed

ABSTRACT After 20 years of screening for breast and prostate cancer, several observations can be made. First, the incidence of these cancers increased after the introduction of screening but has never returned to prescreening levels. Second, the increase in the relative fraction of early stage cancers has increased. Third, the incidence of regional cancers has not decreased at a commensurate rate. One possible explanation is that screening may be increasing the burden of low-risk cancers without significantly reducing the burden of more aggressively growing cancers and therefore not resulting in the anticipated reduction in cancer mortality. To reduce morbidity and mortality from prostate cancer and breast cancer, new approaches for screening, early detection, and prevention for both diseases should be considered.

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    • "The effectiveness of breast cancer screening is extensively debated, particularly regarding the estimated proportion of overdiagnosed cancers [3, 22]. Identification of these overdiagnosed screen-detected cancers is challenging. "
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    ABSTRACT: Overdiagnosis of breast cancer, i.e. the detection of slow-growing tumors that would never have caused symptoms or death, became more prevalent with the implementation of population-based screening. Only rough estimates have been made of the proportion of patients that are overdiagnosed and identification of those patients is difficult. Therefore, the aim of this study is to evaluate whether tumor biology can help identify patients with screen-detected tumors at such a low risk of recurrence that they are likely to be overdiagnosed. Furthermore, we wish to evaluate the impact of the transition from film-screen mammography (FSM) to the more sensitive full-field digital mammography (FFDM) on the biology of the tumors detected by each screening-modality. All Dutch breast cancer patients enrolled in the MINDACT trial (EORTC-10041) accrued 2007–2011, who participated in the national screening program (biennial screening ages 50–75) were included (n = 1,165). We calculated the proportions of high-, low- and among those the ultralow-risk tumors according to the 70-gene signature for patients with screen-detected (n = 775) and interval (n = 390) cancers for FSM and FFDM. Screen-detected cancers had significantly more often a low-risk tumor biology (68 %) of which 54 % even an ultralow-risk compared to interval cancers (53 % low-, of which 45 % ultralow-risk (p = 0.001) with an OR of 2.33 (p < 0.0001; 95 % CI 1.73–3.15). FFDM detected significantly more high-risk tumors (35 %) compared to FSM (27 %) (p = 0.011). Aside from favorable clinico-pathological factors, screen-detected cancers were also more likely to have a biologically low-risk or even ultralow-risk tumor. Especially for patients with screen-detected cancers the use of tools, such as the 70-gene signature, to differentiate breast cancers by risk of recurrence may minimize overtreatment. The recent transition in screening-modalities led to an increase in the detection of biologically high-risk cancers using FFDM. Electronic supplementary material The online version of this article (doi:10.1007/s10549-013-2830-5) contains supplementary material, which is available to authorized users.
    Breast Cancer Research and Treatment 01/2014; 144(1). DOI:10.1007/s10549-013-2830-5 · 4.20 Impact Factor
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    • "Although both mammography and MRI demonstrate excellent sensitivity for detecting tissue abnormalities, they lack sufficient specificity to unequivocally distinguish malignant tissue from benign tissue (Esserman et al., 2009). The question remains as to whether premalignant molecular markers can be used noninvasively to detect aggressive cancers. "
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    ABSTRACT: Inhibitors of heat-shock protein 90 (Hsp90) have demonstrated an unusual selectivity for tumor cells despite its ubiquitous expression. This phenomenon has remained unexplained, but could be influenced by ectopically expressed Hsp90 in tumors. In this work, we synthesized Hsp90 inhibitors that can carry optical or radioiodinated probes via a polyethyleneglycol tether. We show that these tethered inhibitors selectively recognize cells expressing ectopic Hsp90 and become internalized. The internalization process is blocked by Hsp90 antibodies, suggesting that active cycling of the protein occurs at the plasma membrane. In mice, we observed exquisite accumulation of the fluor-tethered versions within breast tumors at very sensitive levels. Cell-based assays with the radiolabeled version showed picomolar detection in cells that express ectopic Hsp90. Our findings show that fluor-tethered or radiolabeled inhibitors that target ectopic Hsp90 can be used to detect breast cancer malignancies through noninvasive imaging.
    Chemistry & biology 09/2013; 20(9). DOI:10.1016/j.chembiol.2013.08.004 · 6.59 Impact Factor
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    • "Finally, if model-based estimates of lead time were correct, then it should prevent many metastases; however, screening does not prevent the occurrence of metastases (Esserman et al, 2009). Calculating overdiagnosis by adding cancers diagnosed many years after screening has stopped results in substantial underestimation as shown in Figure 2. "
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    ABSTRACT: Background: Published lead time estimates in breast cancer screening vary from 1 to 7 years and the percentages of overdiagnosis vary from 0 to 75%. The differences are usually explained as random variations. We study how much can be explained by using different definitions and methods. Methods: We estimated the clinically relevant lead time based on the observed incidence reduction after attending the last screening round in the Norwegian mammography screening programme. We compared this estimate with estimates based on models that do not take overdiagnosis into account (model-based lead times), for varying levels of overdiagnosis. Finally, we calculated overdiagnosis adjusted for clinical and model-based lead times and compared results. Results: Clinical lead time was about one year based on the reduction in incidence in women previously offered screening. When overdiagnosed tumours were included, the estimates increased to 4–9 years, depending on the age at which screening begins and the level of overdiagnosis. Including all breast cancers detected in women long after the end of the screening programme dilutes the level of overdiagnosis by a factor of 2–3. Conclusion: When overdiagnosis is not taken into account, lead time is substantially overestimated. Overdiagnosis adjusted for model-based lead time is a function tending to zero, with no simple interpretation. Furthermore, the estimates are not in general comparable, because they depend on both the duration of screening and duration of follow-up. In contrast, overdiagnosis adjusted for clinically relevant tumours is a point estimate (and interpreted as percentage), which we find is the most reasonable method.
    British Journal of Cancer 08/2013; 109(7). DOI:10.1038/bjc.2013.427 · 4.82 Impact Factor
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