A case–control study to estimate the impact on breast cancer death of the breast screening programme in Wales

Abstract

Twenty-five years after its first description the p53 protein has been shown to play a key role in both cancer and ageing. The p53 protein is activated by many different stress pathways, including oncogene action and DNA damage. The elucidation of the p53 response, which is aberrant in most cancers (including breast, lung, stomach and colorectal cancer), has provided many new targets for drug development and p53 gene therapy is now approved in China. In tumours where p53 is mutant small molecules may be able to restore its function. In many tumours the wild-type p53 gene remains intact but its function is compromised by loss of upstream signalling pathways or downstream effectors.A key regulator is Mdm2, an E3 ubiquitin ligase, that binds and ubiquitinates p53 and directs its degradation via the proteosome. Small potent peptides that can block the p53 Mdm2 interaction and activate the p53 response have been described. Growing selections of lead small molecules that mimic the action of these peptides have also been recently discovered. Cell-based screens have revealed that inhibitors of nuclear export and inhibitors of transcription (one of which is in clinical trial) can also activate the p53 response therapeutically. The pharmaceutical regulation of the p53 pathway offers great hope for improved treatment of human cancer. 2Mammographic screening with a breast cancer prevention programme Because of the heterogeneity of breast cancer from nodule to nodule, single findings cannot achieve the sensitivity or the negative predictive value necessary to identify a low-risk group that can be offered the option of follow-up (ACR Breast Imaging Reporting and Data System [BIRADS] 3 group). However, by using multiple findings in a strict algorithm, such a group can be identified. It is also important to keep in mind that breast cancer can be heterogeneous within an individual nodule. Part of the nodule may have circumscribed features that simulate a benign lesion, while another part may be spiculated and obviously malignant. Only by scanning the whole surface and substance of the nodule in two orthogonal planes (radial and anti-radial) can the presence of suspicious findings be excluded, and if there is a mixture of benign and suspicious findings, the benign findings should be ignored.These studies show that sonography is useful in the characterization of solid breast masses. Characterizing solid breast nodules into BIRADS categories defines carcinomas that might have been missed clinically or mammographically. It identifies a BIRADS 3 group that has far less than 2% risk of being malignant and can offer the patient the option of followup rather than biopsy. Currently, approximately 80% of patients with BIRADS 3 solid nodules are electing to be followed rather than to undergo biopsy. It improves the accuracy of the diagnosis of malignant breast lesions. Importantly, it also accurately defines a population of benign solid breast lesions that do not require biopsy when strict sonographic criteria of benignity are present.To a...

A remarkable reduction of breast cancer deaths in screened versus unscreened women: a case-referent study

“…Recent case-control studies used a correction factor for self-selection based on data from randomized controlled trials in Sweden and Canada [7,16,17]. This correction factor was 1.36, indicating a higher baseline mortality risk in the unscreened women.…”

“…For the IKL-region, the correction factor was 0.84 (95% CI: 0.58-1.21), indicating a lower baseline risk in women who do not attend screening. This factor was used in a formula developed by Duffy et al to correct the estimated odds ratio for self-selection bias [16,17].…”

Population screening and intensity of screening are associated with reduced breast cancer mortality: evidence of efficacy of mammography screening in Australia

“…We chose cases dying from 2002 onwards and breast cancers diagnosed from 1994 onwards to minimize potential biases that may occur in case-control studies, as identified by other researchers [11,12,15], and to optimize the chances of detecting a true effect. This was based on the following considerations: allowing sufficient time from screening commencement, since trial data indicate that effects of screening can take 7-10 years to emerge [11]; avoidance of the early phase of program implementation when screening coverage would have been low (the study aimed to evaluate the program in 'steady state'); and avoidance of the initial years of screening to reduce bias associated with overinclusion of prevalent screen-detected cancers [12].…”

“…This was based on the following considerations: allowing sufficient time from screening commencement, since trial data indicate that effects of screening can take 7-10 years to emerge [11]; avoidance of the early phase of program implementation when screening coverage would have been low (the study aimed to evaluate the program in 'steady state'); and avoidance of the initial years of screening to reduce bias associated with overinclusion of prevalent screen-detected cancers [12].…”

“…Because the potential mortality benefit from screening in practice (i.e., 'service screening') may differ from that expected from RCT evidence [11,12], emphasis has shifted to evaluating, and validly measuring the efficacy of contemporary population-based breast screening. A review of evaluation studies reported a relative risk of 0.57 for screening participants as opposed to non-participants, when pooling data from non-randomized studies [11].…”