Age Trial

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Moss SM, et al. "Effect of mammographic screening from age 40 years on breast cancer mortality at 10 years' follow-up: A randomised controlled trial". The Lancet. 2006. 368(9552):2053-2060.
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Clinical Question

Among eligible women, does initiation of breast cancer screening with mammograms at age 40-41 reduce breast cancer mortality when compared to initiation at age 50?

Bottom Line

Among eligible women, initiation of mammographic screening at age 40 did not reduce breast cancer mortality when compared to initiation of screening at age 50.

Major Points

Screening mammography to reduce breast cancer mortality in women was demonstrated as effective in multiple trials including the 1971 HIP[1] and 1985 Swedish Two Counties[2] studies. Evidence supporting screening before the age of 50 years was lacking.[3] Publications addressing the utility of screening in women age 40-49 were were largely secondary analyses of larger population screening trials.[4] As mammography is associated with multiple potential harms including psychological distress from false-positives, pain, overdiagnosis, overtreatment,[5] and radiation exposure,[6] whether to screen women age 40-49 years old has been controversial.

The 2006 Age Trial randomized 160,840 women in the UK in a 1:2 ratio to annual mammograms starting at about age 40 or routine mammograms starting at about age 50. With mean follow-up of 10.7 years, there was no difference in the rates of breast cancer mortality between groups (0.18 vs. 0.22/1000 women-years; 95% CI 0.66-1.04). This trial is limited by its lack of reporting of crossover, limited baseline characteristics, and underpowering.

In 2009 the USPSTF reviewed the evidence for breast cancer screening and downgraded their recommendation for mammograms for women age 40-49 from a B[7] to a C.[8] The meta-analysis[4] informing the USPSTF recommendation included outcomes of 8 trials studying mammography in women aged 39-49 years (including the Age Trial). It found that mammographic screening was associated with a reduction in breast cancer mortality (RR of 0.85; credible interval 0.75-0.96). This was associated with a number needed to invite of 1,904 (credible interval 929-6,378) to prevent one death from breast cancer. The report was unable to explicitly quantify harm of screening but cited increased risk of radiation, mammogram-associated pain, and psychological responses associated with the procedures. The false positive rate among those age 40-49 years approached 56%. This age group had the lowest rate of biopsy of any age group at 9.3/1000 women/round of screening. Given these controversies, a 2013 Cochrane meta-analysis called into question the utility of universal mammography, especially in women <50 years of age.[5]

Guidelines

USPSTF breast cancer screening (2009, adapted)[8]

  • Women <50 years: Decision to start biennial screening should be individualized and incorporate potential benefits and harms to the patient (grade C)
  • Women 50-74 years: Biennial screening (grade B)
  • Women ≥75 years: Insufficient evidence to make recommendation for biennial screening (grade I)
  • Women ≥40 years: Insufficient evidence to make recommendations about clinical breast exam (grade I)
  • Women of all ages:
    • Recommend against teaching breast self-examination (grade D)
    • Insufficient evidence to compare digital mammography to MRI (grade I)

Design

Multiple details are reported elsewhere.[9][10]

  • Multicenter, open label randomized comparative trial
  • N=160,840 (goal: 195,000)
    • Intervention (n=53,914)
    • Control (n=107,007)
  • Setting: 23 centers in the UK
  • Enrollment: 1991-1997
  • Mean follow-up: 10.7 years
  • Analysis: Intention-to-treat
  • Primary outcome: Breast cancer mortality incidence rate

Population

Inclusion Criteria

  • Women age 39-41
  • Receiving care by a general practitioner associated with a study center

Exclusion Criteria

Not explicitly stated

Baseline Characteristics

  • Demographics: Age 40.4 years

Interventions

  • Women were randomized in a 1:2 ratio for intervention:control with stratification by referring practice
    • Intervention - Annual mammogram starting age 40-41 years until the calendar year of the 48th birthday then routine mammogram starting at age 50-52
    • Control - Routine mammogram starting at age 50-52

Outcomes

Presented as intervention vs. control.

Primary Outcome

Breast cancer mortality incidence rate
0.18 vs. 0.22/1000 women-years (IR 0.83; 95% CI 0.66-1.04)

Secondary Outcomes

All-cause mortality incidence rate
1.66 vs. 1.72/1000 women-years

Additional Analyses

Participation by screening in intervention group

Reported elsewhere[5]

Prevalence screen: 66%
8th screening: <50%

Criticisms

  • No concealment of allocation or blinding[11]
  • Underpowered as the power calculation required 195,000 participants (80% power was reduced to 73% power)[9]
  • An AHRQ-sponsored analysis deemed this trial to be of fair quality because crossover was not described and <70% of all women attended a screening in the trial[4]
  • A large amount of participants assigned to the intervention group had 7 mammograms[12]
  • Follow-up may not have been long enough[12]
  • Incomplete reporting of trial design

Funding

  • Medical Research Council and Cancer Research UK Department of Health
  • US National Cancer Research Institute

Further Reading

  1. Shapiro S, et al. "Periodic breast cancer screening in reducing mortality from breast cancer." JAMA. 1971;215(11):1777-1785.
  2. Tabar L, 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." The Lancet. 1985;1(8433):829-832.
  3. Forrest P, et al. "Breast cancer screening: Report to the Health ministers of England, Wales, Scotland & Northern Ireland by a working group chaired by Professor Sir Patrick Forrest." Department of Health and Social Security. Published 1986.
  4. 4.0 4.1 4.2 Nelson HD, et al. "Screening for breast cancer: An update for the U.S. Preventative Services Task Force." Annals of Internal Medicine. 2009;151(100):727-737.
  5. 5.0 5.1 5.2 Gotzsche PC and Jorgensen KG. "Screening for breast cancer with mammography." The Cochrane Database of Systematic Reviews. 2013;6:CD001877.
  6. Feig SA and Hendrick RE. "Radiation risk from screening mammography of women aged 40-49 years." JNCI Monographs. 1997 (22);119-124.
  7. USPSTF writers. "Screening for breast cancer: Recommendations and rationale." Annals of Internal Medicine. 2002;137:344-346.
  8. 8.0 8.1 USPSTF writers. "Screening for breast cancer: U.S. Preventative Services Task Force recommendation statement." Annals of Internal Medicine. 2009;151(10):716-726.
  9. 9.0 9.1 Moss S, et al. "Randomised controlled trial of mammographic screening in women from age 40: Results of screening in the first 10 years." British Journal of Cancer. 2005;92(5):949-954.
  10. Moss S. "A trial to study the effect on breast cancer mortality of annual mammographic screening in women starting at age 40." Journal of Medical Screening. 1999;6:144–148.
  11. Djulbegovic B and Lyman GH. "Screening mammography at 40-49 years: Regret or no regret?" The Lancet. 2006;368(9552):2035-2037.
  12. 12.0 12.1 Multiple authors. "Letters to the editor: Mammographic screening from age 40 years." The Lancet. 2007;369(9563):738-739.