Mammographic surveillance in women younger than 50 years who have a family history of breast cancer: tumour characteristics and projected effect on mortality in the prospective, single-arm, FH01 study

doi:10.1016/S1470-2045(10)70263-1

The Lancet Oncology

Volume 11, Issue 12, December 2010, Pages 1127-1134

https://doi.org/10.1016/S1470-2045(10)70263-1 Get rights and content

Summary

Background

Evidence supports a reduction in mortality from breast cancer with mammographic screening in the general population of women aged 40–49 years, but the effect of family history is not clear. We aimed to establish whether screening affects the disease stage and projected mortality of women younger than 50 years who have a clinically significant family history of breast cancer.

Methods

In the single-arm FH01 study, women at intermediate familial risk who were younger than 50 years were enrolled from 76 centres in the UK, and received yearly mammography. Women with BRCA mutations were not explicitly excluded, but would be rare in this group. To compare the FH01 cohort with women not receiving screening, two external comparison groups were used: the control group of the UK Age Trial (106 971 women aged 40–42 years at recruitment, from the general population [ie, average risk], followed up for 10 years), and a Dutch study of women with a family history of breast cancer (cancer cases aged 25–77 years, diagnosed 1980–2004). Study endpoints were size, node status, and histological grade of invasive tumours, and estimated mortality calculated from the Nottingham prognostic index (NPI) score, and adjusted for differences in underlying risk between the FH01 cohort and the control group of the UK Age Trial. This study is registered with the National Research Register, number N0484114809.

Findings

6710 women were enrolled between Jan 16, 2003, and Feb 28, 2007, and received yearly mammography for a mean of 4 years (SD 2) up until Nov 30, 2009; surveillance and reporting of cancers is still underway. 136 women were diagnosed with breast cancer: 105 (77%) at screening, 28 (21%) symptomatically in the interval between screening events, and three (2%) symptomatically after failing to attend their latest mammogram. Invasive tumours in the FH01 study were significantly smaller (p=0·0094), less likely to be node positive (p=0·0083), and of more favourable grade (p=0·0072) than were those in the control group of the UK Age Trial, and were significantly less likely to be node positive than were tumours in the Dutch study (p=0·012). Mean NPI score was significantly lower in the FH01 cohort than in the control group of the UK Age Trial (p=0·00079) or the Dutch study (p<0·0001). After adjustment for underlying risk, predicted 10-year mortality was significantly lower in the FH01 cohort (1·10%) than in the control group of the UK Age Trial (1·38%), with relative risk of 0·80 (95% CI 0·66–0·96; p=0·022).

Interpretation

Yearly mammography in women with a medium familial risk of breast cancer is likely to be effective in prevention of deaths from breast cancer.

Funding

UK National Health Service Health Technology Assessment.

Introduction

Women with a family history of breast cancer can be classified into three groups. At one extreme, the low-risk group have insufficient family history to raise absolute risk of breast cancer to a level which would justify intervention. At the other extreme, the high-risk group carry a BRCA1 or BRCA2 mutation, or have a strong family history indicating a high probability of such a mutation.1, 2 In this high-risk group, prophylactic surgery or MRI might be offered.3, 4, 5 Between these two groups is a population in which family history is sufficient to increase the risk of breast cancer substantially above that of the general population, but would not raise serious suspicion of a known high-risk gene mutation. For these women, a possible strategy would be to offer mammographic surveillance starting at an earlier age or more frequently than in the national screening programme.6, 7

In the UK, the National Health Service (NHS) Breast Screening Programme offers 3-yearly, two-view mammography to all women aged 50–70 years, and is in the process of being expanded to women aged 47–73 years in England. Findings of a feasibility study, including a survey of breast centres providing family history services, indicated that equipoise was insufficient to justify a randomised trial of mammographic surveillance compared with no surveillance in women younger than 50 years who have a clinically significant family history. The clinicians responsible for these services believed that withholding of mammography from women aged 40–49 years who had a significant family history of breast cancer would be imprudent. However, all clinicians agreed that the effect of such surveillance on breast cancer outcomes needed quantitative assessment. We therefore developed a single-arm study FH01 (Family History 01) in which women with a substantial familial risk of breast cancer were offered yearly mammography for 5 years. We aimed to assess the mammographic surveillance services provided in terms of their effect on disease stage at presentation, and to estimate the probable future effect on breast cancer mortality, by comparison with two external datasets.

Section snippets

Participants

Women were enrolled from 76 centres across 34 cancer research networks in the UK between Jan 16, 2003, and Feb 28, 2007. Women younger than 50 years were eligible for the study if their family history satisfied one of the following criteria: one first-degree female relative with breast cancer at 40 years or younger; one first-degree female relative with bilateral breast cancer at 50 years or younger; two first-degree or one first-degree and one second-degree female relatives on the same side of

Results

We recruited 6710 women, of whom 6132 (91%) were aged 40–44 years at enrolment (table 1); local variations in policy meant that a small number of participants were recruited outside this age range. Mean age at first screen was 42 years (SD 2). Data about affected relatives were missing for 224 women (3%). Of the remaining 6486 women, slightly less than half had a relative with breast cancer diagnosed at younger than 40 years.

4138 women (62%) attended four or more screening events by the closure

Discussion

Our data suggest that, in women younger than 50 years who are at medium or greater familial risk of breast cancer, mammographic surveillance could increase cancer detection, reduce the risk of advanced stage disease, and decrease predicted mortality (panel). We aimed to assess yearly surveillance in so far as this could be achieved: in most cases, the screening interval was 18 months or less. In women attending for yearly mammography, sensitivity of the screening programme was 79% for all

References (29)

A Maurice et al.
Screening younger women with a family history of breast cancer—does early detection improve outcome?
Eur J Cancer
(2006)
CTM Brekelmans et al.
Tumour characteristics, survival and prognostic factors of hereditary breast cancer from BRCA2-, BRCA1- and non-BRCA1/2 families as compared to sporadic breast cancer cases
Eur J Cancer
(2007)
L Tabar et al.
Update of the Swedish two-county program of mammographic screening for breast cancer
Radiol Clin North Am
(1992)
L Tabar et al.
The Swedish two-county trial twenty years later: updated mortality results and new insights from long term follow-up
Radiol Clin North Am
(2000)
RW Blamey et al.
Survival of invasive breast cancer according to the Nottingham prognostic index in cases diagnosed in 1990–99
Eur J Cancer
(2007)
SM Moss et al.
Effect of mammographic screening from age 40 years on breast cancer mortality at 10 years' follow-up: a randomised controlled trial
Lancet
(2006)
Y Miki et al.
A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1
Science
(1994)
R Wooster et al.
Identification of the breast cancer susceptibility gene BRCA2
Nature
(1995)
KA Metcalfe et al.
International variation in rates of uptake of preventive options in BRCA1 and BRCA2 mutation carriers
Int J Cancer
(2008)
Screening with magnetic resonance imaging and mammography of a UK population at high familial risk of breast cancer: a prospective multicentre cohort study (MARIBS)
Lancet
(2005)

A McIntosh et al.

Clinical guidelines and evidence review for the classification and care of women at risk of familial breast cancer

(2004)

The challenge of evaluating annual mammography screening for young women with a family history of breast cancer

J Med Screen

(2006)

S Moss et al.

Randomised controlled trial of mammographic screening in women from age 40: predicted mortality based on surrogate outcome measures

Br J Cancer

(2005)

S Tyndel et al.

Mammographic screening for young women with a family history of breast cancer: knowledge and views of those at risk

Br J Cancer

(2008)

Cited by (56)

A nationwide cross-sectional study investigating adherence to the Mediterranean diet, smoking, alcohol and work habits, hormonal dynamics between breast cancer cases and healthy subjects
2024, Clinical Nutrition Open Science
Despite substantial efforts in promoting prevention and the advancements in surgical and minimally invasive techniques, breast cancer remains a leading cause of mortality among women worldwide. Genetics and risk factors, including diet and lifestyle, play a critical role in determining the susceptibility to this neoplasm. The primary objective of this study is to investigate the pivotal role of adherence to the Mediterranean diet in breast cancer prevention. Additionally, we assessed differences in diet, Body Mass Index (BMI), smoking and alcohol habits, work shifts, exposure to environmental pollutants, and hormonal factors between patients with previously diagnosed breast cancer and healthy subjects.
The validated CREA questionnaire, alongside additional inquiries, was administered to the Italian population. Adherence to the Mediterranean diet was examined, and respondents were categorized into two groups: the general population and patients with a previous cancer diagnosis. Descriptive and inferential statistics were applied to assess all risk factors among these groups.
Results revealed low adherence to the Mediterranean diet, particularly among less educated individuals, those engaged in 24-hour shift work, smokers, and those with a high BMI. Furthermore, significant differences in working time distribution, consumption of meat, milk, and alcohol, as well as significant differences in hormonal factors such as age of menarche and menopause, age of first pregnancy, number of children and abortions, breastfeeding time, and contraceptive use were observed between these groups.
These findings underscore the importance of targeted interventions and personalized strategies to address specific risk factors and enhance preventive measures for individuals at risk.
Polygenic risk scores and breast cancer risk prediction
2023, Breast
Polygenic Risk Scores (PRS) are a major component of accurate breast cancer risk prediction and have the potential to improve screening and prevention strategies. PRS combine the risk from Single nucleotide polymorphisms (SNPs) associated with breast cancer in Genome Wide Association Studies (GWAS) and explain over 30% of breast cancer heritability. When incorporated into risk models, the more personalised risk assessment derived from PRS, help identify women at higher risk of breast cancer development and enables the implementation of stratified screening and prevention approaches. This review describes the role of PRS in breast cancer risk prediction including the development of PRS and their clinical application. We have also examined the role of PRS within more well-established risk prediction models which incorporate known classic risk factors and discuss the interaction of PRS with these factors and their capacity to predict breast cancer subtypes. Before PRS can be implemented on a population-wide scale, there are several challenges that must be addressed. Perhaps the most pressing of these is the use of PRS in women of non-White European origin, where PRS have been shown to have attenuated risk prediction both in discrimination and calibration. We discuss progress in developing and applying PRS in non-white European populations. PRS represent a significant advance in breast cancer risk prediction and their further development will undoubtedly enhance personalisation.
Breast cancer in neurofibromatosis 1: survival and risk of contralateral breast cancer in a five country cohort study
2020, Genetics in Medicine
In the original version of this Article, the affiliation details for Medical Oncology 1 Unit, Department of Oncology, Istituto Oncologico Veneto IOV - IRCCS, Padova, Italy were incorrectly given as IOV, Oncology, Padova, Italy. This has now been corrected in both the PDF and HTML versions of the Article.
We included 142 women with NF1 and breast cancer from five cohorts in Europe and 335 women without NF1 screened for other familial breast cancers. Risk of contralateral breast cancer and death were assessed by Kaplan–Meier analysis with delayed entry.
One hundred forty-two women with NF1 were diagnosed for breast cancer at a median age of 46.9 years (range 27.0–84.3 years) and then followed up for 1235 person-years (mean = 8.70 years). Twelve women had contralateral breast cancer with a rate of 10.5 per 1000 years. Cumulative risk for contralateral breast cancer was 26.5% in 20 years. Five and 10-year all-cause survival was 64.9% (95% confidence interval [CI] = 54.8–76.8) and 49.8% (95%CI = 39.3–63.0). Breast cancer–specific 10-year survival was 64.2% (95% CI = 53.5–77.0%) compared with 91.2% (95% CI = 87.3–95.2%) in the non-NF1 age-matched population at increased risk of breast cancer.
Women with NF1 have a substantial contralateral breast cancer incidence and poor survival. Early start of breast cancer screening may be a way to improve the survival.
Final Results of the Prospective FH02 Mammographic Surveillance Study of Women Aged 35–39 at Increased Familial Risk of Breast Cancer
2019, EClinicalMedicine
Citation Excerpt :
As a sensitivity analysis, assuming that due to lead time, length bias etc. the hazard of death for the FH02 cases is underestimated by 10%, this would give an expected 77% survival in the FH02 cases, and a RR of 0.79, a 21% reduction in mortality. The present study shows that programme and test sensitivity (72% and 93%) of mammography screening in women aged 35–39 years of age at moderate and high-risk of breast cancer are similar to those in women aged 40–49 years in the FH01 study [4]. The overall and projected survival is substantially better than in comparable women aged 35–40 in the POSH study who did not undergo screening [13].
Many women who are at increased risk of breast cancer due to a mother or sister diagnosed with breast cancer aged under 40 do not currently qualify for surveillance before 40 years of age. There are almost no available data to assess whether mammography screening aged 35–39 years would be effective in this group, in terms of detection of breast cancer at an early stage or cost effective.
A cohort screening study (FH02) with annual mammography was devised for women aged 35–39 to assess the sensitivity and screening performance and potential survival of women with identified tumours.
2899 women were recruited from 12/2006–12/2015. These women underwent 12,086 annual screening mammograms and were followed for 13,365.8 years. A total of 55 breast cancers in 54 women occurred during the study period (one bilateral) with 50 cancers (49 women) (15 CIS) adherent to the screening. Eighty percent (28/35) of invasive cancers were ≤ 2 cm and 80% also lymph node negative. Invasive cancers diagnosed in FH02 were significantly smaller than the comparable (POSH-unscreened prospective) study group (45% (131/293) ≤ 2 cm in POSH vs 80% (28/35) in FH02 p < 0.0001), and were less likely to be lymph-node positive (54% (158/290, 3 unknown) in POSH vs 20% (7/35) in FH02: p = 0.0002. Projected and actual survival were also better than POSH. Overall radiation dose was not higher than in an older screened population at mean dose on study per standard sized breast of 1.5 mGy.
Mammography screening aged 35–39 years detects breast cancer at an early stage and is likely to be as effective in reducing mortality as in women at increased breast cancer risk aged 40–49 years.
Translating genetics beyond bench and bedside: A comparative perspective on health care infrastructures for ‘familial’ breast cancer
2016, Applied and Translational Genomics
Developments in genomics research are considered to have great potential for improving health care – making genomics an urgent site for translational efforts. Yet while much emphasis is put on the technical challenges of translation, there is less scholarly attention for the social infrastructures through which novel medical interventions may be delivered to patient populations. Reflecting the idea that cancer is at the frontier of genomic applications in health care, this paper explores how the assessment of familial breast cancer risks was ‘translated’ into routine health care in Germany, the Netherlands and the United Kingdom. The paper identifies regulation, institutionalization and standardization as key mechanisms of translation that find distinct expression in particular sociocultural contexts and shape both the social and technical making of genomics into routine clinical practice. Translation is therefore an area of social as well as technical concern, and therefore requires collective decision-making.
Challenges and Opportunities in the Implementation of Risk-Based Screening for Breast Cancer
2016, Breast Cancer Screening: An Examination of Scientific Evidence
There is widespread interest in risk factor-based breast cancer screening because of the possibility that it may improve the effectiveness of breast cancer detection and possibly reduce the number of women who need to be screened and associated harms. Risk factors are already used to determine screening: for example, age is used to determine who is eligible for screening and age of onset of screening may be reduced and screening frequency maybe increased in women with a family history. Women with BRCA1 or BRCA2 mutations are screened using MRI in addition to mammography because of the potential for missing cancers and the high risk of interval cancers in mutation positive women. The question arises whether such risk-adapted screening can improve the sensitivity and specificity of screening for all women as well as in National programs. In general, incorporation of additional risk factors such as endocrine factors, mammographic density and genetic factors to age and family history improves the predictive accuracy of risk estimates. Additional screening modalities such as ultrasound, MRI, and digital breast tomosynthesis may increase detection rates and reduce interval cancers. However, it is not clear how these modalities and additional risk factors may be applied in breast screening and national programs, and whether this will be beneficial to the women screened. Here we discuss some of the challenges and potential opportunities of attempting to introduce risk-adapted screening.

View all citing articles on Scopus

^‡: Full list of authors at end of paper

View full text

Fast track — ArticlesMammographic surveillance in women younger than 50 years who have a family history of breast cancer: tumour characteristics and projected effect on mortality in the prospective, single-arm, FH01 study

Summary

Background

Methods

Findings

Interpretation

Funding

Introduction

Section snippets

Participants

Results

Discussion

Eur J Cancer

Eur J Cancer

Radiol Clin North Am

Radiol Clin North Am

Eur J Cancer

Lancet

A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1

Science

Identification of the breast cancer susceptibility gene BRCA2

Nature

International variation in rates of uptake of preventive options in BRCA1 and BRCA2 mutation carriers

Int J Cancer

Screening with magnetic resonance imaging and mammography of a UK population at high familial risk of breast cancer: a prospective multicentre cohort study (MARIBS)

Lancet

Clinical guidelines and evidence review for the classification and care of women at risk of familial breast cancer

The challenge of evaluating annual mammography screening for young women with a family history of breast cancer

J Med Screen

Randomised controlled trial of mammographic screening in women from age 40: predicted mortality based on surrogate outcome measures

Br J Cancer

Mammographic screening for young women with a family history of breast cancer: knowledge and views of those at risk

Br J Cancer

Fast track — Articles
Mammographic surveillance in women younger than 50 years who have a family history of breast cancer: tumour characteristics and projected effect on mortality in the prospective, single-arm, FH01 study