Impact of screening mammography on breast cancer mortality.

The degree to which observed reductions in breast cancer mortality is attributable to screening mammography has become increasingly controversial. We examined this issue with three fundamentally different approaches: (i) Chronology--the temporal relationship of the onset of breast cancer mortality decline and the national implementation of screening mammography; (ii) Magnitude--the degree to which breast cancer mortality declined relative to the amount (penetration) of screening mammography; (iii) Analogy--the pattern of mortality rate reductions of other cancers for which population screening is not conducted. Chronology and magnitude were assessed with data from Europe and North America, with three methods applied to magnitude. A comparison of eight countries in Europe and North America does not demonstrate a correlation between the penetration of national screening and either the chronology or magnitude of national breast cancer mortality reduction. In the United States, the magnitude of the mortality decline is greater in the unscreened, younger women than in the screened population and regional variation in the rate of breast cancer mortality reduction is not correlated with screening penetrance, either as self-reported or by the magnitude of screening-induced increase in early-stage disease. Analogy analysis of United States data identifies 14 other cancers with a similar distinct onset of mortality reduction for which screening is not performed. These five lines of evidence from three different approaches and additional observations discussed do not support the hypothesis that mammography screening is a primary reason for the breast cancer mortality reduction in Europe and North America.

Revised estimates of overdiagnosis from the Canadian National Breast Screening Study.

We have re-estimated overdiagnosis of breast cancer from mammography screening by age group in the Canadian National Breast Screening Study (CNBSS), a randomized screening trial. In the CNBSS, participants were recruited in 15 centers. 89,835 women were randomized with informed consent, 50,430 age 40-49 and 39,405 age 50-59. Women aged 40-49 received annual mammography and physical examination (MA+PX) versus a single physical examination and usual care in the community (UC). Women aged 50-59 received (MA+PX) versus (PX-alone) annually. Individual randomization resulted in 44 almost identically distributed demographic and risk factors. Annual compliance over the five or four scheduled screens was 86-95%. The cumulative numbers of invasive and in situ breast cancers ascertained by year during screening and subsequent follow-up to 25 years post entry to the CNBSS in the mammography arm have been compared to those in the control arm. Estimates of overdiagnosis were derived using post-screening cessation cut-off points from 1 to 20years.⋯Overdiagnosis of invasive breast cancer at five years post cessation of screening for women aged 40-49 was estimated to be 32%, and 16% for women aged 50-59; 20years post cessation of screening 48% for women 40-49 and 5% for those 50-59. Including ductal carcinoma in situ with invasive cancer, estimates were 41%, 25%, 55% and 16%, respectively. We conclude that approximately 30% of invasive screen-detected breast cancers in women age 40-49 were overdiagnosed, and 20% of those screen-detected in women age 50-59. Including ductal carcinoma in situ, the estimates are 40% and 30%, respectively.

Is carcinoma in situ a precursor lesion of invasive breast cancer?

This study measures the probability of development of invasive breast cancer (BC) following the diagnosis of carcinomas in situ (CIS). A 25-year prospective follow-up was conducted by linking the Canadian National Breast Screening Study (CNBSS) to cancer registries and a national vital statistics database. Subsequent BC incidence was identified in CNBSS women who were diagnosed with CIS. CIS was classified into ductal (DCIS) and lobular carcinoma in situ (LCIS). Cumulative cancer incidence probabilities were calculated and a 1:5 matched nested case control study was conducted to estimate the odds of BC development. Of the 146 women diagnosed with CIS, 26 developed invasive BC (17.8%) and 12 died of BC (8.2%). The average time from the diagnosis of CIS to invasive BC was 6.3 years (± 5.6). The 20-year cumulative incidence probabilities for DCIS and LCIS were 19.0% (95%CI: 11.2, 26.8) and 21.3% (95%CI: 7.1, 35.4) respectively. The odds of development of BC in CIS women was significantly elevated compared with controls (OR = 2.6, 95% CI: 1.5, 4.5). While women with CIS had a higher odds of development of BC compared to those without CIS, at 20-year post CIS diagnosis, more than 80% of them remained free of invasive BC. This low probability of developing invasive BC post CIS diagnosis does not support the notion that CIS of the breast is an obligate precursor lesion of invasive BC.

The role of clinical breast examination and breast self-examination.

The efficacy of screening by clinical breast examination (CBE) and/or breast self-examination (BSE) is reviewed using indirect evidence from randomized breast screening trials and that from observational studies. In countries where breast cancer is diagnosed at an advanced stage, screening by CBE with the teaching of BSE as an integral component will probably be effective in reducing breast cancer mortality. However, in technically advanced countries where adequate treatment is given, no screening modality is likely to be sufficiently beneficial to outweigh the harms of screening, especially false positives and over-diagnosis.

Overview of guidelines on breast screening: Why recommendations differ and what to do about it.

Updated guidelines on breast cancer screening have been published by several major organisations over the past five years. Recommendations vary regarding both age range, screening interval, and even on whether breast screening should be offered at all. The variation between recommendations reflects substantial differences in estimates of the major benefit (breast cancer mortality reduction) and the major harm (overdiagnosis). Estimates vary considerably among randomised trials, as well as observational studies: from no benefit to large reductions, and from no overdiagnosis to substantial levels. The estimates vary according to the methodology of the randomised trials, and the design of the observational studies. Guideline recommendations reflect the choice of evidence informing them. While there are well-developed tools to deal with randomised trials in guideline work, these are not always used, or they may not be followed as recommended. Further, results of trials performed decades ago may no longer be applicable. For observational studies, the framework for inclusion in guidelines is not similarly well-developed and there are methodological concerns specific to screening interventions, such as small effects in absolute terms. There is a need for agreement on a hierarchy of observational study designs to quantify the major benefit and harm of cancer screening. This review provides a summary of recent guidelines on breast cancer screening and their major strengths and weaknesses, as well as a short overview of the major strengths and limitations of observational study designs. There is a need for agreement on a hierarchy of observational study designs in this field.

The Canadian National Breast Screening Study-1: breast cancer mortality after 11 to 16 years of follow-up. A randomized screening trial of mammography in women age 40 to 49 years.

BACKGROUND: The efficacy of breast cancer screening in women age 40 to 49 years remains controversial. OBJECTIVE: To compare breast cancer mortality in 40- to 49-year-old women who received either 1) screening with annual mammography, breast physical examination, and instruction on breast self-examination on 4 or 5 occasions or 2) community care after a single breast physical examination and instruction on breast self-examination. DESIGN: Individually randomized, controlled trial. SETTING: 15 Canadian centers. PARTICIPANTS: 50 430 volunteers age 40 to 49 years, recruited from January 1980 to March 1985, who were not pregnant, had no previous breast cancer diagnosis, and had not had mammography in the preceding 12 months. INTERVENTIONS: Breast physical examination and instruction on breast self-examination preceded random assignment of 25 214 women to receive mammography and annual mammography, breast physical examination, and breast self-examination and 25 216 women to receive usual community care with annual follow-up. MEASUREMENTS: Verified breast cancer incidence and cohort mortality through 31 December 1993 and deaths from breast cancer through 30 June 1996. RESULTS: The 105 breast cancer deaths in the mammography group and 108 breast cancer deaths in the usual care group yielded a cumulative rate ratio, adjusted for mammography done outside the study, of 1.06 (95% CI, 0.80 to 1.40). A total of 592 cases of invasive breast cancer and 71 cases of in situ breast cancer were diagnosed by 31 December 1993 in the mammography group compared with 552 and 29 cases, respectively, in the usual care group. The expected proportions of nonpalpable and small invasive tumors were detected on mammography. CONCLUSION: After 11 to 16 years of follow-up, four or five annual screenings with mammography, breast physical examination, and breast self-examination had not reduced breast cancer mortality compared with usual community care after a single breast physical examination and instruction on breast self-examination. The study data show that true effects of 20% or greater are unlikely.

Case-control study of genotypes in multiple chemical sensitivity: CYP2D6, NAT1, NAT2, PON1, PON2 and MTHFR.

BACKGROUND: Impaired metabolism of toxic chemicals is a postulated mechanism underlying multiple chemical sensitivity (MCS). Because genetic variation alters the rate of chemical metabolism, this study was designed to determine if MCS cases differed from controls for genetic polymorphisms in drug-metabolizing enzymes. METHODS: Female Caucasian participants (203 cases and 162 controls) were drawn from a larger case-control study based on a reproducible and validated case definition. Common polymorphisms for CYP2D6, NAT1, NAT2, PON1, and PON2 were genotyped. RESULTS: Comparing cases and controls, significant differences were found in genotype distributions for CYP2D6 (P = 0.02) and NAT2 (P = 0.03). Compared with the referent homozygous inactive (CYP2D6) or slow (NAT2) metabolizers, the odds for being CYP2D6 homozygous active (OR = 3.36, P = 0.01) and NAT2 rapid (OR = 4.14, P = 0.01) were significantly higher in cases than controls. The odds for being heterozygous for PON1-55 (OR = 2.05, P = 0.04) and PON1-192 (OR = 1.57, P = 0.04) were also significantly higher in cases. CONCLUSIONS: A genetic predisposition for MCS may involve altered biotransformation of environmental chemicals. The CYP2D6 enzyme activates and inactivates toxins; the NAT2 enzyme bioactivates arylamines to protein-binding metabolites. A gene-gene interaction between CYP2D6 and NAT2 suggested that rapid metabolism for both enzymes may confer substantially elevated risk (OR = 18.7, P = 0.002). Our finding parallels others' observation of a link between PON1 heterozygosity and neurological symptoms in Gulf War syndrome. This first demonstration of genetic variation in drug-metabolizing enzymes in association with MCS requires replication. However, it suggests new research directions on genetically variable toxin pathways that might be important in MCS.

Twenty five year follow-up for breast cancer incidence and mortality of the Canadian National Breast Screening Study: randomised screening trial.

OBJECTIVE: To compare breast cancer incidence and mortality up to 25 years in women aged 40-59 who did or did not undergo mammography screening. DESIGN: Follow-up of randomised screening trial by centre coordinators, the study's central office, and linkage to cancer registries and vital statistics databases. SETTING: 15 screening centres in six Canadian provinces,1980-85 (Nova Scotia, Quebec, Ontario, Manitoba, Alberta, and British Columbia). PARTICIPANTS: 89,835 women, aged 40-59, randomly assigned to mammography (five annual mammography screens) or control (no mammography). INTERVENTIONS: Women aged 40-49 in the mammography arm and all women aged 50-59 in both arms received annual physical breast examinations. Women aged 40-49 in the control arm received a single examination followed by usual care in the community. MAIN OUTCOME MEASURE: Deaths from breast cancer. RESULTS: During the five year screening period, 666 invasive breast cancers were diagnosed in the mammography arm (n=44,925 participants) and 524 in the controls (n=44,910), and of these, 180 women in the mammography arm and 171 women in the control arm died of breast cancer during the 25 year follow-up period. The overall hazard ratio for death from breast cancer diagnosed during the screening period associated with mammography was 1.05 (95% confidence interval 0.85 to 1.30). The findings for women aged 40-49 and 50-59 were almost identical. During the entire study period, 3250 women in the mammography arm and 3133 in the control arm had a diagnosis of breast cancer, and 500 and 505, respectively, died of breast cancer. Thus the cumulative mortality from breast cancer was similar between women in the mammography arm and in the control arm (hazard ratio 0.99, 95% confidence interval 0.88 to 1.12). After 15 years of follow-up a residual excess of 106 cancers was observed in the mammography arm, attributable to over-diagnosis. CONCLUSION: Annual mammography in women aged 40-59 does not reduce mortality from breast cancer beyond that of physical examination or usual care when adjuvant therapy for breast cancer is freely available. Overall, 22% (106/484) of screen detected invasive breast cancers were over-diagnosed, representing one over-diagnosed breast cancer for every 424 women who received mammography screening in the trial.

Rational and irrational issues in breast cancer screening.

Evidence on the efficacy of breast screening from randomized controlled trials conducted in the last decades of the 1900s is reviewed. For decades, controversy about their results has centered on the magnitude of benefit in terms of breast cancer mortality reduction that can be achieved. However more recently, several expert bodies have estimated the benefits to be smaller than initially expected and concerns have been raised about screening consequences such as over-diagnosis and unnecessary treatment. Trials with substantial mortality reduction have been lauded and others with null effects have been critiqued. Critiques of the Canadian National Breast Screening Study are refuted. Extreme responses by screening advocates to the United States Preventive Services Task Force 2009 guidelines are described. The role vested interests play in determining health policy is clearly revealed in the response to the guidelines and should be more generally known. A general reluctance to explore unexpected results or to accept new paradigms is briefly discussed.