Breast Cancer



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National Cancer Institute - Breast Cancer Risk Factors

  • Factors Associated with Increased Risk of Breast Cancer

  • Hormone replacement therapy/hormone therapy  - Based on solid evidence, combination hormone replacement therapy (HRT; estrogen-progestin), also called hormone therapy (HT), is associated with an increased risk of developing breast cancer. The evidence concerning the association between estrogen-only therapy and breast cancer incidence is mixed.                       

  •  Ionizing radiation -  Based on solid evidence, exposure of the breast to ionizing radiation is associated with an increased risk of developing breast cancer, starting 10 years after exposure and persisting lifelong. Risk depends on dose and age at exposure, with the highest risk occurring during puberty

  • Obesity - Based on solid evidence, obesity is associated with increased breast cancer risk in postmenopausal women who have not used HRT/HT.

  • Alcohol - Based on solid evidence, exposure to alcohol is associated with increased breast cancer risk in a dose-dependent fashion.

  • Factors Associated with Decreased Risk of Breast Cancer

  • Selective estrogen receptor modulators (SERMs) - benefits - Based on solid evidence for tamoxifen and fair evidence for raloxifene, treatment reduces the incidence of breast cancer in postmenopausal women. Tamoxifen also reduced the risk of breast cancer in high-risk premenopausal women.

  • Selective estrogen receptor modulators (SERMs) - harms - Based on solid evidence, tamoxifen treatment increases the risk of endometrial cancer, thrombotic vascular events (pulmonary embolism, stroke, deep venous thrombosis), and cataracts. Based on fair evidence, raloxifene also increases venous pulmonary embolism and deep venous thrombosis but not endometrial cancer.

  • Exercise - benefits - Based on solid evidence, strenuous exercising more than 4 hours per week is associated with reduced breast cancer risk.

  • Aromatase inhibitors or inactivators - benefits - Based on fair evidence, aromatase inhibitors or inactivators (AIs) reduce the incidence of new breast cancers in postmenopausal women who have a history of breast cancer.

  • Aromatase inhibitors or inactivators - harms - Based on fair evidence, AIs are associated with decreased bone mineral density, increased falls, and decreased cognitive function.

  • Prophylactic mastectomy - benefits - Based on solid evidence, bilateral prophylactic mastectomy reduces the risk of breast cancer in women with a strong family history.

  • Prophylactic mastectomy - harms - Based on fair evidence, physical and psychological effects include anxiety, depression, and impaired body image.

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National Cancer Institute - Breast Cancer Genetics 

  • Family History as a Risk Factor for Breast Cancer - In cross-sectional studies of adult populations, 5% to 10% of women have a mother or sister with breast cancer, and about twice as many have either a first-degree relative or a second-degree relative with breast cancer.[2-5] The risk conferred by a family history of breast cancer has been assessed in both case-control and cohort studies, using volunteer and population-based samples, with generally consistent results.[6] In a pooled analysis of 38 studies, the relative risk of breast cancer conferred by a first-degree relative with breast cancer was 2.1 (95% confidence interval [CI], 2.0-2.2).[6] Risk increases with the number of affected relatives and age at diagnosis.[3,4,6]

  • Autosomal Dominant Inheritance of Breast/Ovarian Cancer Predisposition - Autosomal dominant inheritance of breast/ovarian cancer is characterized by transmission of cancer predisposition from generation to generation, through either the mother’s or the father’s side of the family, with the following characteristics:

  • Inheritance risk of 50%. When a parent carries an autosomal dominant genetic predisposition, each child has a 50:50 chance of inheriting the predisposition. Although the risk of inheriting the predisposition is 50%, not everyone with the predisposition will develop cancer because of incomplete penetrance and/or gender-restricted or gender-related expression.
  • Both males and females can inherit and transmit an autosomal dominant cancer predisposition. A male who inherits a cancer predisposition and shows no evidence of it can still pass the altered gene on to his sons and daughters.
  • Difficulties in Identifying a Family History of Breast and Ovarian Cancer Risk  - When using family history to assess risk, the accuracy and completeness of family history data must be taken into account. A reported family history may be erroneous, or a person may be unaware of relatives affected with cancer. In addition, small family sizes and premature deaths may limit the information obtained from a family history. Breast or ovarian cancer on the paternal side of the family usually involves more distant relatives than on the maternal side and thus may be more difficult to obtain. When comparing self-reported information with independently verified cases, the sensitivity of a history of breast cancer is relatively high, at 83% to 97%, but lower for ovarian cancer, at 60%.[9,10]

  • Other Risk Factors for Breast Cancer

  • Age - Cumulative risk of breast cancer increases with age, with most breast cancers occurring after age 50 years.[13] In women with a genetic susceptibility, breast cancer, and to a lesser degree, ovarian cancer, tends to occur at an earlier age than in sporadic cases.

  • Reproductive and Menstrual History -  Breast cancer risk increases with early menarche and late menopause, and is reduced by early first full-term pregnancy. Although results have been complex and may be gene dependent, several studies have suggested that the influence of these factors on risk in BRCA1/BRCA2 mutation carriers appear to be similar to noncarriers.[12]

  • Oral Contraceptives  - Oral contraceptives may produce a slight increase in breast cancer risk among long-term users, but this appears to be a short-term effect. In a meta-analysis of data from 54 studies, the risk of breast cancer associated with oral contraceptive use did not vary according to a family history of breast cancer.[14]  Oral contraceptives are sometimes recommended for ovarian cancer prevention in BRCA1 and BRCA2 mutation carriers, but studies of their effect on breast cancer risk have been inconsistent.[15-17]

  • Benign Breast Disease and Mammographic Density  -  Benign breast disease (BBD) is a risk factor for breast cancer, independent of the effects of other major risk factors for breast cancer (age, age at menarche, age at first live birth, and family history of breast cancer).[41] There may also be an association between benign breast disease and family history of breast cancer.[42]  An increased risk of breast cancer has also been demonstrated for women who have increased density of breast tissue as assessed by mammogram,[41,43,44] and breast density may have a genetic component to its etiology.[45-47]

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National Cancer Institute - Breast Cancer Screening

  • Screening by Mammography -  Statement of Benefit  - Based on fair evidence, screening mammography in women aged 40 to 70 years decreases breast cancer mortality. The benefit is higher for older women, in part because their breast cancer risk is higher.

  • Table 1. Harms of Screening Mammography

    Harm  Study Design  Internal Validity  Consistency  Magnitude of Effects  External Validity 
    Treatment of insignificant cancers (overdiagnosis, true positives) can result in breast deformity, lymphedema, thromboembolic events, new cancers, or chemotherapy-induced toxicities. Descriptive population-based, autopsy series and series of mammary reduction specimens Good Good Approximately 33% of breast cancers detected by screening mammograms represent overdiagnosis.[5] Good
    Additional testing (false-positives) Descriptive population-based Good Good Estimated to occur in 50% of women screened annually for 10 years, 25% of whom will have biopsies.[6] Good
    False sense of security, delay in cancer diagnosis (false-negatives) Descriptive population-based Good Good 6% to 46% of women with invasive cancer will have negative mammograms, especially if young, with dense breasts,[7,8] or with mucinous, lobular, or fast-growing cancers.[9] Good
    Radiation-induced mutations can cause breast cancer, especially if exposed before age 30 years. Latency is more than 10 years, and the increased risk persists lifelong. Descriptive population-based Good Good Between 9.9 and 32 breast cancers per 10,000 women exposed to a cumulative dose of 1 Sv. Risk is higher for younger women. Good

     

  • Screening by Breast Self-Examination -  Statement of benefit 

    Based on fair evidence, teaching breast self-examination does not reduce breast cancer mortality.

  • Screening by Breast Self-Examination - Statement of harms   

    Based on solid evidence, formal instruction and encouragement to perform breast self-examination leads to more breast biopsies and to the diagnosis of more benign breast lesions.

  • Screening by Clinical Breast Examination -  Statement of benefits 

    Based on fair evidence, screening by clinical breast examination reduces breast cancer mortality.

  • Table 2. Harms of Screening Clinical Breast Examination
    Harms  Study Design  Internal Validity  Consistency  Magnitude of Effects  External Validity 
    Additional testing (false-positives) Descriptive population-based Good Good Specificity in women aged 50 to 59 years ranged between 88% and 96%.[10] Good
    False reassurance, delay in cancer diagnosis (false-negatives) Descriptive population-based Good Fair Of women with cancer, 17% to 43% had a negative clinical breast examination.[10] Poor

Fundamentals of Cancer Prevention (2006) - Dave S. Alberts, M.D., Lisa M. Hess



March 31, 2009

Benefits of Mammogram Under Debate in Britain

The conventional wisdom about breast cancer screening is coming under sharp attack in Britain, and health officials there are taking notice.

They have promised to rewrite informational fliers about mammography after advocates and experts complained in a letter to The Times of London that none of the handouts “comes close to telling the truth” — overstating the benefits of screening and leaving out critical information about the harms.

What women are not told, the letter said, is that for every woman whose life is saved by breast cancer screening, up to 10 healthy women are given diagnoses — and, often, surgery — for a cancer that is so slow-growing it would never have threatened a woman’s life.

“The culture is just that mammography is such a very sensible thing to do, so you chug along and have it done,” said one of the signers, Hazel Thornton, in a telephone interview.

Mrs. Thornton, 75, said she became disenchanted with routine screening more than 15 years ago, after a mammogram identified ductal carcinoma in situ, a noninvasive breast cancer that often does not progress. She had a lumpectomy, but was offered such a confusing array of treatment options that she realized doctors knew little about how aggressively to treat this kind of cancer.

“You don’t know about all the uncertainty until you’re one of the unlucky ones, and it happens to you,” she said.

The idea that mammography may do more harm than good may be alien to many American women. The prevention message has emphasized that screening protects women from breast cancer, and one survey of 479 women found that only 7 percent were aware that some cancers grow so slowly that even without treatment they will not affect a woman’s health.

A 2006 analysis by the Nordic Cochrane Center collaborative, an independent research and information center based in Copenhagen, found that for every 2,000 women age 50 to 70 who are screened for 10 years, one woman will be saved from dying of breast cancer, while 10 will have their lives disrupted unnecessarily by overtreatment. The figures were cited in the letter to The Times.

Julietta Patnick, the director of cancer screening programs for the British National Health Service, said the patient handout was being revised and added that information about overdiagnosis might be added.

But in a telephone interview, she dismissed the Cochrane figures as inaccurate. British studies, she said, show that the ratio of lives saved to lives unnecessarily disrupted is more like one to one.

“We know, from statistics, that there are cancers diagnosed through screening that wouldn’t otherwise have been diagnosed — because the woman dies of something else first, because she might get run over by a bus, or she might have a heart attack, or she might live to 90 and it would just sit there, and she wouldn’t have died of breast cancer,” Ms. Patnick said.

But the problem is, “You don’t know who that woman is,” she continued. “You just know that statistically, she exists.”

Experts agree that under a microscope, slow-growing cancers look no different from more aggressive ones, so it is impossible to know which ones can be left untouched.

The author of the Cochrane analysis, Dr. Peter C. Gotzsche, another signer of the British letter, has written an alternative version of a patient handout for women considering mammography. It starts off by saying, “It may be reasonable to attend breast cancer screening with mammography, but it may also be reasonable not to attend.”

Women in the United States are screened much more rigorously than women in Britain, with annual mammography starting at 40. British women start at 50, and get a mammogram once every three years.

Dr. Ned Calonge, chairman of the United States Preventive Services Task Force, says mammography has been oversold to American women.

“The expectation of women is that ‘If I get screened, I won’t get breast cancer,’ ” he said. “I hear that women will say: ‘How can I have breast cancer? I always get my mammogram.’ ”

In fact, Dr. Calonge went on, early detection may not make a difference in survival for many women.

“Some women would have the same outcomes, whether the cancer is detected clinically or by mammography,” he said. “And there are women whose cancer is so aggressive we cannot detect it early enough to make a difference in mortality.”

An expert panel that reviewed the evidence on annual mammography for the task force in 2002 downgraded the recommendation for annual screens to “recommended” from “strongly recommended.” That review raised some of the same concerns mentioned by the critics in Britain: the high incidence of false-positive scares that cause anxiety yet turn out to be nothing serious, and the potential overtreatment of ductal carcinoma in situ and other “indolent” cancers. The panel also expressed concern about the potential for harm from exposure to radiation during the scans.

Mammography is more effective in older women. But even among women 50 and over, the panel concluded, only one death would be prevented after 14 years of observing more than 800 women who had undergone screening.

“That’s a hefty number of women” who must be screened to derive a benefit, Dr. Calonge said.

Similarly, studies about prostate screening for men concluded this month that the P.S.A. blood tests save few lives while leading to unnecessary treatment with potentially serious complications.

Despite the task force’s reservations, most medical societies endorse annual mammography, as does the American Cancer Society. Robert Smith, director of cancer screening for the society, says he believes overdiagnosis is minimal at best, and only 10 percent of invasive cancers found through mammography are harmless and will never be life-threatening.

“I think this is another example of, ‘Here is something your doctor knows and isn’t telling you,’ ” Dr. Smith said. “This is a debate between people who see the glass half full or the glass half empty.”

Breast cancer screening is a good part of a preventive health care plan,” he continued. “It’s not perfect.”

Ultimately, women have to make their own decision about whether to be screened, said Dr. Lisa M. Schwartz, an associate professor at Dartmouth Medical School, who is co-author of “Know Your Chances” (University of California, 2008), a book about how to interpret health statistics and risk.

“You’re not crazy if you don’t get screened, and you’re not crazy if you do get screened,” said Dr. Schwartz, who also signed the letter to The Times. “People can make their own decision, and we don’t need to coerce people into doing this.

Breast Cancer Regression??

Or Disappearing Breast Cancer.

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NCI - Effects of Screening on Breast Cancer Survival --- "Screening for breast cancer does not affect overall mortality, and the absolute benefit for breast cancer mortality appears to be small."  See below.

  • Updated February 2010

       
    Effect of Screening on Breast Cancer Mortality

    The Randomized Controlled Trials
    Population-Based Screening Programs, Including Studies of Effectiveness of Screening



    The Randomized Controlled Trials

    Randomized controlled trials (RCTs), with participation by nearly half a million women from four countries, examined the breast cancer mortality of women who were offered regular screening. One trial (the Canadian National Breast Screening Study [NBSS]-2) compared mammogram plus clinical breast examination (CBE) with CBE alone, but the other eight compared screening mammogram (MMG) with or without CBE with a control consisting of usual care. The trials differed in design, recruitment of participants, interventions (both screening and treatment), management of the control group, compliance with assignment to screening and control groups, and analysis of outcomes. Some trials used individual randomization while others used cluster randomization in which cohorts were identified and then offered screening, and in one case, nonrandomized allocation by day-of-birth in any given month. Cluster randomization sometimes led to imbalances between the intervention and control groups. Age differences have been identified in several trials, although the differences were probably too small to have a major effect on the trial outcome.[1] In the Edinburgh Trial, socioeconomic status differed markedly between the intervention and control groups. Since socioeconomic status is associated with the risk of breast cancer mortality, this difference makes it difficult, if not impossible, to interpret the trial results.

    Since breast cancer mortality is the major outcome parameter for each of these trials, the methods used to determine cause of death is critically important. Efforts to reduce bias in the attribution of mortality cause have been made, including the use of a blinded monitoring committee (New York) and a linkage to independent data sources, such as national mortality registries (Swedish trials). Unfortunately, even these attempts may be unable to avoid prior knowledge of women’s assignment to screening or control arms. Evidence of possible misclassification of breast cancer deaths in the Two-County trial that could bias results in favor of screening has been reviewed.[2]

    Differences exist in the methodology used to analyze the results of these trials. Four of the five Swedish trials were designed to include a single screening mammogram in the control group, timed to correspond with the end of the series of screening mammograms in the study group. The initial analysis of these trials used an “evaluation” analysis, tallying only the breast cancer deaths that occurred in women whose cancer was discovered at or before the last study mammogram. In some of the trials a delay occurred in the performance of the end-of-study mammogram, resulting in more time for control group women to develop or be diagnosed with breast cancer. Other trials used a “follow-up” analysis, which counts all deaths attributed to breast cancer, regardless of the time of diagnosis. This type of analysis was used in a meta-analysis of four of the five Swedish trials in response to previously expressed concerns about the effect of a delay in control group mammograms upon evaluation analyses.

    The accessibility of the data for international audit and verification also varies, with formal audit having been undertaken only in the Canadian trials. In fact, the author of one trial (Kopparberg) refused to respond to queries about methodology or to submit raw data for independent review.[3]

    All of these studies are designed to study breast cancer mortality rather than all-cause mortality, because of the infrequency of breast cancer deaths relative to the total number of deaths. When all-cause mortality in these trials was examined retrospectively, only the Edinburgh trial showed a significant difference, which could be attributed to socioeconomic differences. The meta-analysis (follow-up methods) of the four Swedish trials also showed a small but significant improvement of all-cause mortality.

    The trials are listed chronologically.

    Health Insurance Plan, United States 1963 [4,5]

        Age at entry: 40 to 64 years.
        Randomization: Individual, but with significant imbalances in the distribution of women between assigned arms, as evidenced by menopausal status (P < .0001) and education (P = .05).
        Sample size: 30,000 to 31,092 in study group and 30,565 to 30,765 in control group.
        Consistency of reports: Variation in sample size reports.
        Intervention: Annual two-view MMG and CBE for 3 years.
        Control: Usual care.
        Compliance: Nonattenders to first screening (35% of the screened population) were not reinvited.
        Contamination: Screening mammography was not available outside the trial, but frequency of CBE performance among control women is unknown.
        Cause of death attribution: Women who died of breast cancer that had been diagnosed before entry into the study were excluded from the comparison between the screening and control groups. However, these exclusions were determined differently within the two groups. Women in the screening group were excluded based on determinations made during the study period at their initial screening visits. These women were dropped from all further consideration in the study. By design, controls did not have regular clinic visits, so the prestudy cancer status of control patients was not determined. When a control patient died and her cause of death was determined to be breast cancer, a retrospective examination was made to determine the date of diagnosis of her disease. If this was prior to the study period then she was excluded from the analysis. This difference in methodology has the potential for a substantial bias in comparing breast cancer mortality between the two groups, and this bias is likely to favor screening.
        Analysis: Follow-up.
        External audit: No.
        Follow-up duration: 18 years.
        Relative risk of breast cancer death, screening versus control (95% confidence interval [CI]): 0.71 (0.55–0.93) at 10 years and 0.77 (0.61–0.97) at 15 years.
        Comments: The mammograms were of poor quality compared with those of later trials, because of outdated equipment and techniques. One should remember that the intervention consisted of both MMG and CBE. Major concerns about trial performance are the validity of the initial randomization and the differential exclusion of women with a prior history of breast cancer.

    Malmo, Sweden 1976 [6,7]

        Age at entry: 45 to 69 years.
        Randomization: Individual, within each birth year cohort for the first phase, mammographic screening trial (MMST I). Individual for the entire birth cohort 1933 to 1945 for MMST II, but with variations imposed by limited resources. Validation by analysis of age in both groups shows no significant difference.
        Exclusions: In a Swedish meta-analysis, there were 393 women with pre-existing breast cancer excluded from the intervention group, and 412 from the control group. Overall however, there were 86 more women excluded from the intervention group than from the control group.
        Sample size: 21,088 study and 21,195 control.
        Consistency of reports: No variation in patient numbers.
        Intervention: Two-view MMG every 18 to 24 months × 5.
        Control: Usual care, with MMG at study end.
        Compliance: Participants migrating from Malmo (2% per year) were not followed. The participation rate of study women was 74% for the first round and 70% for subsequent rounds.
        Contamination: 24% of all control women had at least one MMG, as did 35% of the control women aged 45 to 49 years.
        Cause of death attribution: 76% autopsy rate in early report, lower rate later. Cause of death assessment blinded for women with a breast cancer diagnosis. Linked to Swedish Cause of Death Registry.
        Analysis: Evaluation, initially. Follow-up analysis, as part of the Swedish meta-analysis.[3]
        External audit: No.
        Follow-up duration: 12 years.
        Relative risk of breast cancer death, screening versus control (95% CI): 0.81 (0.62–1.07).
        Comments: Evaluation analysis required a correction factor for the delay in the performance of MMG in the control group. The two Malmo trials MMST I and MMST II have been combined for most analyses.

    Ostergotland (Part of Two County Trial), Sweden 1977 [8-10]

        Age at entry: 40 to 74 years.
        Randomization: Geographic cluster, with stratification for residence (urban or rural), socioeconomic factors and size. Baseline breast cancer incidence and mortality were comparable between the randomly assigned geographic clusters. The study women were older than the control women, P < .0001, but this should not have had a major effect on the outcome of the trial.
        Exclusions: Women with pre-existing breast cancer were excluded from both groups, but the numbers are reported differently in different publications. The Swedish meta-analysis excluded all women with a prior breast cancer diagnosis, regardless of group assignment.
        Sample size: Variably reported, ranging from 38,405 to 39,034 in study and from 37,145 to 37,936 in control.
        Consistency of reports: Variable.
        Intervention: Three single-view MMGs every 2 years for women younger than 50 years and every 33 months for women 50 years and older.
        Control: Usual care, with MMG at study end.
        Compliance: 89% screened.
        Contamination: 13% of women in the Two County trial had MMG as part of routine care, mostly in 1983 and 1984.
        Cause of death attribution: Determined by a team of local physicians. When results were recalculated in the Swedish meta-analysis, using data from the Swedish Cause of Death Registry, there was less benefit for screening than had been previously reported.
        Analysis: Evaluation initially, with correction for delay in control group MMG. Follow-up analysis, as part of the Swedish meta-analysis.[3]
        External audit: No.
        Follow-up duration: 12 years.
        Relative risk of breast cancer death, screening versus control (95% CI): 0.82 (0.64–1.05) Ostergotland.
        Comments: Concerns were raised about the randomization methodology and the evaluation analysis, which required a correction for late performance of the control group MMG. The Swedish meta-analysis resolved these questions appropriately.

    Kopparberg (Part of Two County Trial), Sweden 1977 [8-10]

        Age at entry: 40 to 74 years.
        Randomization: Geographic cluster, with stratification for residence (urban or rural), socioeconomic factors and size. The process for randomization has not been described. The study women were older than the control women, P < .0001, but this should not have had a major effect on the outcome of the trial.
        Exclusions: Women with pre-existing breast cancer were excluded from both groups, but the numbers are reported differently in different publications.
        Sample size: Variably reported, ranging from 38,562 to 39,051 in intervention and from 18,478 to 18,846 in control.
        Consistency of reports: Variable.
        Intervention: Three single-view MMGs every 2 years for women younger than 50 years and every 33 months for women aged 50 years and older.
        Control: Usual care, with MMG at study end.
        Compliance: 89% participation.
        Contamination: 13% of women in the Two County trial had MMG as part of routine care, mostly between 1983 and 1984.
        Cause of death attribution: Determined by a team of local physicians (see Ostergotland).
        Analysis: Evaluation.
        External audit: No. Primary author has refused to collaborate with several investigators, both internationally [11] and in Sweden.[3]
        Follow-up duration: 12 years.
        Relative risk of breast cancer death, screening versus control (95% CI): 0.68 (0.52–0.89).

    Edinburgh, United Kingdom 1976 [12]

        Age at entry: 45 to 64 years.
        Randomization: Cluster by physician practices, though many randomization assignments were changed after study start. Within each practice, there was inconsistent recruitment of women, according to the physician’s judgment about each woman’s suitability for the trial. Large differences in socioeconomic status between practices were not recognized until after the study end.
        Exclusions: More women (338) with pre-existing breast cancer were excluded from the intervention group than from the control group (177).
        Sample size: 23,226 study and 21,904 control.
        Consistency of reports: Good.
        Intervention: Initially, two-view MMG and CBE; then annual CBE, with single-view MMG in years 3, 5, and 7.
        Control: Usual care.
        Compliance: 61% screened.
        Contamination: None.
        Cause of death attribution: Cancer Registry Data.
        Analysis: Follow-up.
        External audit: No.
        Follow-up duration: 10 years.
        Relative risk of breast cancer death, screening versus control (95% CI): 0.84 (0.63–1.12).
        Comments: Randomization process was flawed. Socioeconomic differences between study and control groups probably account for the higher all-cause mortality in control women compared with screened women. This difference in all-cause mortality was four times greater than the breast cancer mortality in the control group, and therefore, may account for the higher breast cancer mortality in the control group compared with screened women. Although a correction factor was used in the final analysis, this may not adjust the analysis sufficiently.

    The study design and conduct make these results difficult to assess or combine with the results of other trials.

    NBSS-1, Canada 1980 [13]

        Age at entry: 40 to 49 years.
        Randomization: Individual volunteers, with names entered successively on allocation lists. Although criticisms of the randomization procedure have been made, a thorough independent review found no evidence of subversion and that subversion on a scale large enough to affect the results was unlikely.[14]
        Exclusions: Few, balanced between groups.
        Sample size: 25,214 study (100% screened after entry CBE) and 25,216 control.
        Consistency of reports: Good.
        Intervention: Annual two-view MMG and CBE for 4 to 5 years.
        Control: Usual care.
        Compliance: Initially 100%, decreased to 85.5% by screen five.
        Contamination: 26.4% in usual care group.
        Cause of death attribution: Death certificates, with review of questionable cases by a blinded review panel. Also linked with the Canadian Mortality Data Base, Statistics Canada.
        Analysis: Follow-up.
        External audit: Yes. Independent, with analysis of data by several reviewers.
        Follow-up duration: 13 years.
        Relative risk of breast cancer death, screening versus control (95% CI): 0.97 (0.74–1.27).
        Comments: This is the only trial specifically designed to study women aged 40 to 49 years. Cancers diagnosed at entry in both study and control groups were included. Concerns were expressed prior to completion of the trial about the technical adequacy of the MMGs, the training of the radiologists, and the standardization of the equipment, which prompted an independent external review. The primary deficiency identified by this review was the use of the mediolateral view from 1980 to 1985 instead of the mediolateral oblique view, which was used after 1985.[15] Subsequent analyses found the size and stage of the cancers detected mammographically in this trial to be equivalent to those of other trials.[16] This trial and NBSS-2 differ from the other RCTs in the consistent use of adjuvant hormone and chemotherapy following local breast cancer therapy in women with axillary node-positive disease.

    NBSS-2, Canada 1980 [17]

        Age at entry: 50 to 59 years.
        Randomization: Individual volunteer (see NBSS-1).
        Exclusions: Few, balanced between groups.
        Sample size: 19,711 study (100% screened after entry CBE) and 19,694 control.
        Intervention: Annual two-view MMG and CBE.
        Control: Annual CBE.
        Compliance: Initially 100%, decreased to 86.7% by screen five in the MMG and CBE group. Initially 100%, decreased to 85.4% by screen five in the CBE only group.
        Contamination: 16.9% of the CBE only group.
        Cause of death attribution: Death certificates, with review of questionable cases by a blinded review panel. Also linked with the Canadian Mortality Data Base, Statistics Canada.
        Analysis: Follow-up.
        External audit: Yes. Independent with analysis of data by several reviewers.
        Follow-up duration: 11 to 16 years (mean 13 years).
        Relative risk of breast cancer death, screening versus control (95% CI): 1.02 (0.78–1.33).
        Comments: This trial is unique in that it compares one screening modality to another, and does not include an unscreened control. Regarding criticisms and comments about this trial, see NBSS-1.

    Stockholm, Sweden 1981 [18]

        Age at entry: 40 to 64 years.
        Randomization: Cluster by birth date. There were two subtrials with balanced randomization in the first and a significant imbalance in the second with 508 more women in the screened group than the control.
        Exclusions: Inconsistently reported.
        Sample size: Declined from 40,318 to 38,525 in intervention group and rose from 19,943 to 20,978 in control, between published reports.
        Consistency of reports: Variable.
        Intervention: Single-view MMG every 28 months × 2.
        Control: MMG at year 5.
        Compliance: 82% screened.
        Contamination: 25% of women entering the study had MMG in the 3 years before entry.
        Cause of death attribution: Linked to Swedish Cause of Death Registry.
        Analysis: Evaluation, with 1-year delay in the posttrial MMG in control group. Follow-up analysis as part of the Swedish meta-analysis.[3]
        External audit: No.
        Follow-up duration: 8 years.
        Relative risk of breast cancer death, screening versus control (95% CI): 0.80 (0.53–1.22).
        Comments: There are concerns about randomization, especially in the second subtrial, about exclusions, and about the delay in control group MMG. Inclusion of these data in the Swedish meta-analysis resolves many of these questions.

    Gothenberg, Sweden 1982

        Age at entry: 39 to 59 years.
        Randomization: Complex; cluster randomly assigned within birth year by day of birth for older group (aged 50–59 years) and by individual for younger group (aged 39–49 years); ratio of study to control varied by year depending on mammography availability (randomization took place 1982–1984).
        Exclusions: A similar proportion of women were excluded from both groups for prior breast cancer diagnosis (1.2% each).
        Sample size: Most recent publication: 21,650 invited; 29,961 control.
        Consistency of reports: Variable.
        Intervention: Initial two-view MMG, then single-view MMG every 18 months × 4. Single-read first three rounds, then double-read.
        Control: Control group received one screening exam approximately 3 to 8 months after the final screen in study group.
        Cause of death attribution: Linked to Swedish Cause of Death Registry; also used an independent endpoint committee.
        Analysis: Both evaluation and follow-up methods.[3]
        External audit: No.
        Follow-up duration: 12 to14 years.
        Relative risk of breast cancer death, screening versus control (95% CI): Aged 39 to 59 years: 0.79 (0.58–1.08) [evaluation]; 0.77 (0.60–1.00) [follow-up].
        Comments: No reduction for women aged 50 to 54 years, but similar reductions for other 5-year age groups.
        Conclusions: Delay in the performance of MMG in the control group and unequal numbers of women in invited and control groups (complex randomization process) complicates interpretation.

    Screening for breast cancer does not affect overall mortality, and the absolute benefit for breast cancer mortality appears to be small.

    A way to view the potential benefit of breast cancer screening is to estimate the number of lives extended because of early breast cancer detection.[19,20] Harris [21] estimated the outcomes of 10,000 women aged 50 to 70 years who undergo a single screen. Mammograms will be normal (true negatives and false negatives) in 9,500 women. Of the 500 abnormal screens, between 466 and 479 will be false-positives, and 100 to 200 of these women will undergo invasive procedures. The remaining 21 to 34 abnormal screens will be true positives, indicating breast cancer. Some of these women will die of breast cancer in spite of mammographic detection and optimal therapy, and some may live long enough to die of other causes even if the cancer has not been screen detected. The number of extended lives attributable to mammographic detection is between two and six. Another expression of this analysis is that one life may be extended per 1,700 to 5,000 women screened and followed for 15 years. The same analysis for 10,000 women aged 40 to 49 years, assuming the same 500 abnormal examinations, results in an estimate that 488 of these will be false-positives, and 12 will be breast cancer. Of these 12, there will probably be only one to two lives extended. Thus, for women aged 40 to 49 years, it is estimated that one to two lives may be extended per 5,000 to 10,000 mammograms.
    Population-Based Screening Programs, Including Studies of Effectiveness of Screening

    Although the RCTs of screening have addressed the issue of the efficacy of screening (i.e., the extent to which screening reduces breast cancer mortality under the ideal conditions of an RCT), they do not provide information about the effectiveness of screening (i.e., the extent to which screening is reducing breast cancer mortality in the U.S. population). Studies that provide information on this issue include nonrandomized controlled studies of screened versus nonscreened populations, case-control studies of screening in real communities, and modeling studies that examine the impact of screening on large populations. An important issue in all of these studies is the extent to which they can control for additional effects on breast cancer mortality such as improved treatment and heightened awareness of breast cancer in the community.

    Two population-based, observational studies from Sweden compared breast cancer mortality in the presence and absence of screening mammography programs. One study compared two adjacent time periods within 7 of the 25 counties in Sweden and concluded a statistically significant breast cancer mortality reduction of 18% to 32% due to screening.[22] The most important bias in this study is that the advent of screening in these counties occurred over a period during which dramatic improvements were being made in the effectiveness of adjuvant breast cancer therapy. The authors do not present data on treatment received, nor do they address differences in treatment that could at least partially explain the observed reduction in breast cancer mortality. The second study considered an 11-year period and compared seven counties that had screening programs with five counties that did not.[23] It concluded that there was a statistically nonsignificant reduction of 16% to 20% in favor of screening. The most important bias in this study was similar to that in the first study. The counties in the control group were rural. Those in the screening group included some urban areas and in general they were largely in the southern, more densely populated part of the country in comparison with the control counties. Participants were accrued over a 7-year period (about 1980–1987) during which effective adjuvant hormonal therapy and chemotherapy were being introduced. The authors do not address differences in treatment in the various geographic areas that could explain the observed reduction in breast cancer mortality.

    In Nijmegen, the Netherlands, a population-based screening program was undertaken in 1975, and breast cancer mortality rates were compared with those in the neighboring town Arnhem and to all of the Netherlands. No difference in breast cancer mortality could be identified [24] despite the fact that case-cohort studies showed that screened women have decreased mortality. One such study was performed in Nijmegen itself, with an odds ratio of 0.48, for screened versus unscreened women.[25] Explanations for the lack of demonstrable benefit include earlier diagnosis of breast cancer in the general population (due to increased public awareness) and documented trends for the diagnosis of cancers with favorable prognostic indicators. Furthermore, adjuvant systemic therapy decreases breast cancer mortality, and its use may decrease the impact of early detection.

    A community-based case-control study of screening as practiced in excellent U.S. health care systems between 1983 and 1998 found no association between previous screening and reduced breast cancer mortality. Mammography screening rates, however, were generally low.[26]

    Since 1990, there has been a sustained reduction in age-adjusted breast cancer mortality in the United States of about 2% per year. Between 1990 and 2000, the cumulative reduction was 24%. To address the contribution of screening and adjuvant therapy to this decline, the National Cancer Institute formed a consortium of seven modeling groups.[27] These groups developed independent statistical models of female breast cancer incidence and breast cancer mortality in the United States. They used common inputs for the dissemination of screening mammography, chemotherapy, and hormonal therapy and for the benefits of treatment interventions. All seven models ascribed some benefit to both screening and adjuvant treatment, but their estimates of the relative and absolute contributions varied considerably. The estimated proportion of the total mortality reduction contributed by screening varied from 28% to 65%, with adjuvant treatment contributing the rest. The variability across models for the absolute contribution of screening was larger than it was for treatment, reflecting the greater uncertainty and higher complexity associated with estimating screening benefit.

    References

       1. Gøtzsche PC, Olsen O: Is screening for breast cancer with mammography justifiable? Lancet 355 (9198): 129-34, 2000.  [PUBMED Abstract]

       2. Gøtzsche PC, Nielsen M: Screening for breast cancer with mammography. Cochrane Database Syst Rev (4): CD001877, 2006.  [PUBMED Abstract]

       3. Nyström L, Andersson I, Bjurstam N, et al.: Long-term effects of mammography screening: updated overview of the Swedish randomised trials. Lancet 359 (9310): 909-19, 2002.  [PUBMED Abstract]

       4. Shapiro S, Venet W, Strax P, et al.: Ten- to fourteen-year effect of screening on breast cancer mortality. J Natl Cancer Inst 69 (2): 349-55, 1982.  [PUBMED Abstract]

       5. Shapiro S: Periodic screening for breast cancer: the Health Insurance Plan project and its sequelae, 1963-1986. Baltimore, Md: Johns Hopkins University Press, 1988.

       6. Andersson I, Aspegren K, Janzon L, et al.: Mammographic screening and mortality from breast cancer: the Malmö mammographic screening trial. BMJ 297 (6654): 943-8, 1988.  [PUBMED Abstract]

       7. Nyström L, Rutqvist LE, Wall S, et al.: Breast cancer screening with mammography: overview of Swedish randomised trials. Lancet 341 (8851): 973-8, 1993.  [PUBMED Abstract]

       8. Tabár L, Fagerberg CJ, Gad A, et al.: Reduction in mortality from breast cancer after mass screening with mammography. Randomised trial from the Breast Cancer Screening Working Group of the Swedish National Board of Health and Welfare. Lancet 1 (8433): 829-32, 1985.  [PUBMED Abstract]

       9. Tabàr L, Fagerberg G, Duffy SW, et al.: Update of the Swedish two-county program of mammographic screening for breast cancer. Radiol Clin North Am 30 (1): 187-210, 1992.  [PUBMED Abstract]

      10. Tabar L, Fagerberg G, Duffy SW, et al.: The Swedish two county trial of mammographic screening for breast cancer: recent results and calculation of benefit. J Epidemiol Community Health 43 (2): 107-14, 1989.  [PUBMED Abstract]

      11. Gotzsche PC, Olsen O: Correspondence. Authors' reply. Lancet 355(9205): 752, 2000.

      12. Roberts MM, Alexander FE, Anderson TJ, et al.: Edinburgh trial of screening for breast cancer: mortality at seven years. Lancet 335 (8684): 241-6, 1990.  [PUBMED Abstract]

      13. Miller AB, To T, Baines CJ, et al.: 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. Ann Intern Med 137 (5 Part 1): 305-12, 2002.  [PUBMED Abstract]

      14. Bailar JC 3rd, MacMahon B: Randomization in the Canadian National Breast Screening Study: a review for evidence of subversion. CMAJ 156 (2): 193-9, 1997.  [PUBMED Abstract]

      15. Baines CJ, Miller AB, Kopans DB, et al.: Canadian National Breast Screening Study: assessment of technical quality by external review. AJR Am J Roentgenol 155 (4): 743-7; discussion 748-9, 1990.  [PUBMED Abstract]

      16. Fletcher SW, Black W, Harris R, et al.: Report of the International Workshop on Screening for Breast Cancer. J Natl Cancer Inst 85 (20): 1644-56, 1993.  [PUBMED Abstract]

      17. Miller AB, Baines CJ, To T, et al.: Canadian National Breast Screening Study: 2. Breast cancer detection and death rates among women aged 50 to 59 years. CMAJ 147 (10): 1477-88, 1992.  [PUBMED Abstract]

      18. Frisell J, Eklund G, Hellström L, et al.: Randomized study of mammography screening--preliminary report on mortality in the Stockholm trial. Breast Cancer Res Treat 18 (1): 49-56, 1991.  [PUBMED Abstract]

      19. Kerlikowske K: Efficacy of screening mammography among women aged 40 to 49 years and 50 to 69 years: comparison of relative and absolute benefit. J Natl Cancer Inst Monogr (22): 79-86, 1997.  [PUBMED Abstract]

      20. Glasziou PP, Woodward AJ, Mahon CM: Mammographic screening trials for women aged under 50. A quality assessment and meta-analysis. Med J Aust 162 (12): 625-9, 1995.  [PUBMED Abstract]

      21. Harris R, Leininger L: Clinical strategies for breast cancer screening: weighing and using the evidence. Ann Intern Med 122 (7): 539-47, 1995.  [PUBMED Abstract]

      22. Duffy SW, Tabár L, Chen HH, et al.: The impact of organized mammography service screening on breast carcinoma mortality in seven Swedish counties. Cancer 95 (3): 458-69, 2002.  [PUBMED Abstract]

      23. Jonsson H, Nyström L, Törnberg S, et al.: Service screening with mammography of women aged 50-69 years in Sweden: effects on mortality from breast cancer. J Med Screen 8 (3): 152-60, 2001.  [PUBMED Abstract]

      24. Broeders MJ, Peer PG, Straatman H, et al.: Diverging breast cancer mortality rates in relation to screening? A comparison of Nijmegen to Arnhem and the Netherlands, 1969-1997. Int J Cancer 92 (2): 303-8, 2001.  [PUBMED Abstract]

      25. Verbeek AL, Hendriks JH, Holland R, et al.: Reduction of breast cancer mortality through mass screening with modern mammography. First results of the Nijmegen project, 1975-1981. Lancet 1 (8388): 1222-4, 1984.  [PUBMED Abstract]

      26. Elmore JG, Reisch LM, Barton MB, et al.: Efficacy of breast cancer screening in the community according to risk level. J Natl Cancer Inst 97 (14): 1035-43, 2005.  [PUBMED Abstract]

      27. Berry DA, Cronin KA, Plevritis SK, et al.: Effect of screening and adjuvant therapy on mortality from breast cancer. N Engl J Med 353 (17): 1784-92, 2005.  [PUBMED Abstract]

Rethinking Screening for Breast and Prostate Cancer - JAMA. 2009;302(15):1685-1692 (doi:10.1001/jama.2009.1498)

  • Breast and Prostate cancer screening is not working so maybe we should take another look for a better solution.  We are mainly detecting non-aggressive cancers, many of which will never harm the patient, while not detecting aggressive tumors in an early, curable stage.

Vanishing Cancer - 2009

Trouble with Mammograms - LA Times 2009

Mammograms - We need a new women's Health Movement - Ehrenreich

Actual Risk of dying from Breast Cancer

Truth Squad - Medical Reporting of Mammograms

Addicted to Mammograms

Screening for breast cancer with mammography - Cochrane Institute




Colloid Cancer

Estrogen Receptors

Specimen Mammogram