Keywords
breast cancer screening - mammography - ultrasound - magnetic resonance imaging
Palavras-chave
rastreamento de câncer de mama - mamografia - ultrassom - imagem de ressonância magnética
Introduction
In 2021, breast cancer became the most frequently diagnosed cancer in the world, and
the main cause of premature death in women.[1] In Brazil, 73,610 new cases of breast cancer were estimated for the year 2023, which
represents an adjusted incidence rate of 41.89 cases per 100,000 women.[1] Screening is an effective measure to detect the disease at an early stage and reduce
its mortality. In addition, the early diagnosis of breast cancer allows for a greater
range of therapeutic options and a reduction in treatment morbidity.[2]
[3]
[4]
In 2012 and 2017, the Brazilian College of Radiology and Diagnostic Imaging (CBR),
the Brazilian Society of Mastology (SBM) and the Brazilian Federation of Associations
of Gynecology and Obstetrics (Febrasgo), through the National Mammography Commission
(CNM), published recommendations for breast cancer screening.[5]
[6] The purpose of this update is to publish the available evidence on screening and
provide information for decision-making in women at different risks for developing
the disease.
Methods
Searches were performed in the Medline (via PubMed), EMBASE, Cochrane Library, EBSCO,
CINAHL and Lilacs (via Bireme) databases using as many keywords, descriptors and MeSH
terms as possible to find scientific evidence of breast cancer screening with mammography,
ultrasound (US), magnetic resonance imaging (MRI) and tomosynthesis (TS) in women
at usual, intermediate and high risk for breast cancer, published between January
2012 and July 2022 in Portuguese, English, French and Spanish. Complementary searches
were performed on Web sites, online tools and in the references of the analyzed studies.
The most recent, higher quality evidence processed (systematic reviews and meta-analyses)
that better answered the structured questions were selected for analysis. In the absence
of these, primary studies (clinical trials or cohorts) were included. The risk of
bias in the studies was assessed using the following tools: ROBIS (Risk of Bias in
Systematic Reviews), RoB 2.0 (Cochrane Risk of Bias Tools for Randomized Controlled
Trials version 2.0), QUADAS-C (Quality Assessment of Diagnostic Accuracy Studies –
Comparative) and ROBINS-I (Risk of Bias in Non-randomized Studies of Interventions).
The overall quality of the evidence set for each outcome was assessed using GRADE
(Grading of Recommendations Assessment, Development and Evaluation).
The recommendations were based on this evidence through consensus of the committee
of experts from the three entities (CBR, SBM and Febrasgo), defined when the members
reached at least 75% agreement with the recommendation. In the absence of an initial
agreement, in a second round of discussion and voting, a simple majority was needed
to define consensus. The recommendations were classified into five categories:
-
Category A – Strong recommendation in favor based on high-quality evidence.
-
Category B – Strong recommendation in favor based on moderate-quality evidence.
-
Category C – Weak recommendation in favor based on low-quality evidence.
-
Category D – Recommendation in favor, based only on expert consensus.
-
Category E – Recommendation against as there is insufficient evidence to support its use.
Screening Recommendations
Screening Recommendations
Screening of Women at Usual Population Risk
Screening of Women with Dense Breasts
Screening of Women with a Personal Biopsy History of Atypical Lobular Hyperplasia
(ALH), Classic Lobular Carcinoma in Situ (LCIS), and Atypical Ductal Hyperplasia (ADH)
Screening of Women with a Personal History of Treatment for Invasive Breast Cancer
or Ductal Carcinoma in Situ (DCIS)
Screening of Women with a Personal History of Chest Radiotherapy
Screening of Women with a Genetic Mutation or a Strong Family History of Breast Cancer
(Lifetime Risk ≥ 20%)
Rationale
The benefits of mammographic screening have been evaluated using cohort studies, systematic
reviews and randomized clinical trials, demonstrating a reduction of 22–30% in specific
mortality from breast cancer in women aged 40 to 74 years.[2]
[3]
[4]
[7] When other important outcomes were analyzed, a better quality of life measured using
the QALY (quality-adjusted life-years) was also observed, given the less aggressive
treatments,[2] in addition to a higher rate of initial tumors with better prognostic characteristics
and negative axilla,[3] and 28% fewer advanced tumors.[4]
Starting Age and Frequency of Screening
Starting Age and Frequency of Screening
Starting screening at age 40 reduces 10-year mortality from breast cancer by 25%,
but increases false-positive rates from 4.8% to 7%.[7] In Brazil, 41.1% of women diagnosed with breast cancer are younger than 50 years.[8] Regarding the screening interval, the two-year interval is related to a higher risk
of advanced tumors (RR: 1.28), larger than 15 mm and with worse prognostic factors.[7] Thus, the CNM recommends annual mammography screening starting at age 40.
Considerations for Women under 40
Considerations for Women under 40
Screening in this age group is not recommended given the lower incidence of breast
cancer (∼7% of cases). However, the AMAZONA III study showed this number is 17% in
Brazil, with larger tumors and worse prognosis at diagnosis compared with women over
40 years of age.[9] Therefore, in agreement with other international societies,[10]
[11] the CNM recommends that the attending physician performs an assessment of the estimated
risk of breast cancer for all women over 30 years of age using mathematical models
to better stratify those at high risk, who could benefit from differentiated screening.
When to Stop Screening
As prospective, controlled and randomized studies did not include women over 74 years
of age, direct data on screening in this age group are not available. However, the
life expectancy of women has increased, with an increasing incidence of breast cancer
in the age group above 75 years. Currently, 26% of deaths from breast cancer occur
in women diagnosed after the age of 74.[12]
[13] Considering these factors, many medical organizations recommend individualizing
the decision that should be discussed with the woman.
Adverse Effects of Screening
Adverse Effects of Screening
Although some adverse effects are reported, the quality of evidence for analyzing
them is low. Overdiagnosis is a debated effect, but its estimation is variable given
the difficulty in determining which tumor would or would not cause the patient's death.[14] The risk of carcinoma induced by the radiation used in mammographic screening is
low, although higher in women with large breasts, in whom the radiation dose is higher,
as well as in those undergoing supplemental incidences.[15] It was also associated with a 2.9% increase in the risk of biopsies with benign
lesions, which can cause anxiety.[14] However, the reduction in mortality of cancer detected early by screening outweighs
the risks of damage caused by exposure to radiation.
Considerations about Breast Tomosynthesis
Considerations about Breast Tomosynthesis
TS is an evolution of the digital mammography. Numerous studies confirm the effectiveness
of this technology in breast cancer screening, which increases the detection rate
by up to 50%,[16]
[17]
[18]
[19]
[20] and reduces the recall rate for additional images by 9% to 29%.[19]
[20] The detected tumors have histological and immunohistochemical characteristics similar
to those detected by mammography,[21]
[22]
[23] and results are maintained in subsequent rounds.[24] Therefore, TS is recommended by the CNM as a screening method when accessible and
available, as well as by various medical societies, including the American College of Radiology (ACR),[10] the American Cancer Society (ACS),[25] the European Society of Breast Imaging (EUSOBI),[26] the Société d'Imagerie de la Femme (SIFEM),[27] the National Comprehensive Cancer Network (NCCN)[11] and the European guidelines on breast cancer screening and diagnosis.[28]
Tomosynthesis should be used in combination with standard 2D mammography (combination
mode) or with synthesized 2D mammography (SM); the latter has the advantage of reducing
the radiation dose.[15]
[17]
[18] As the National Health Surveillance Agency (Anvisa) has not established the reference
and tolerance levels of the glandular dose for TS in Brazil yet, the recommendation
is that each service should carry out a survey of the mean glandular doses using a
sample of patients with breasts of different thickness, thereby establishing local
reference and tolerance levels.[29]
[30]
Screening Considerations for Women with Dense Breasts
Screening Considerations for Women with Dense Breasts
Dense breast is a risk factor for breast cancer and associated with reduced mammographic
sensitivity. For these reasons, supplementary methods have been proposed. All supplemental
modalities have improved sensitivity over mammography alone, allowing the detection
of early-stage cancers hidden in mammograms.[31]
[32]
[33]
[34]
[35]
[36]
[37]
[38]
Magnetic resonance imaging is the supplementary technique with the highest rate of
additional cancer detection.[31] This increases the likelihood of less invasive and curative treatments. Data on
critical outcomes such as mortality are not available. However, randomized trials
have shown that the supplemental use of US in dense breasts and MRI in extremely dense
breasts reduced the rate of interval cancer, an important patient-centered surrogate
outcome.[24]
[34]
[39] Regarding harm, the use of supplemental modalities is associated with increased
false positives and biopsies.[31]
[33]
[35]
[36]
[37]
[38] Thus, for women with dense breasts without other risk factors, the CNM recommends
annual mammography screening starting at age 40, with the option of using supplementary
methods such as US or MRI. For extremely dense breasts, there is scientific evidence
suggesting the superiority of MRI.
Screening Considerations for Women with a Personal History of ALH, LCIS, and ADH Diagnosis
Screening Considerations for Women with a Personal History of ALH, LCIS, and ADH Diagnosis
Atypical ductal hyperplasia, ALH and LCIS are considered non-obligate precursor lesions
for DCIS and invasive carcinomas,[40] and confer an increased relative risk for their subsequent development throughout
life, ranging from 2.6–5.0 times for ADH, 3.2–4.8 times for ALH and 6–10 times for
LICS.[41]
[42]
[43]
[44]
[45]
[46]
[47]
[48]
[49]
Studies evaluating screening in this group are scarce and based on retrospective series
that estimated the risk for in situ and subsequent invasive carcinomas. The current
strategy for defining screening in this subgroup is based on calculating the lifetime
risk for breast cancer.[11] Factors such as age at diagnosis and breast density directly impact the risk of
cancer, which can be estimated using risk calculation tools based on mathematical
models.[47] Currently, few models include this group in the risk calculation, namely the Breast
Cancer Risk Assessment Tool and the IBIS Breast Cancer Risk Evaluation Tool, and these
should be preferably used.[11]
[47]
Screening Considerations for Women with a Personal History of Treatment for Invasive
Breast Cancer and DCIS
Screening Considerations for Women with a Personal History of Treatment for Invasive
Breast Cancer and DCIS
Women with a personal history of breast cancer are seven times likelier to develop
a second malignant neoplasm in the ipsilateral or contralateral breast.[48] In patients treated with conservative surgery, mammography is less sensitive because
of the surgical alterations and higher incidence of interval carcinoma,[49] which explains the need for additional screening.
Complementary screening with MRI can detect 8.2–18.1 additional cancers to mammography
per 1,000 women.[50]
[51]
[52]
[53]
[54]
[55] The performance of MRI in this scenario has shown to be similar to that of patients
at high genetic risk, considering the sensitivity, detection rate, false positive
and positive predictive value (PPV) of biopsies.[56]
[57]
[58] However, the scientific evidence for MRI in this population is weak, based on predominantly
retrospective studies.[49]
[50]
[55]
[56]
[57]
[58]
[59] Among this heterogeneous group, the benefit of MRI is better established in young
patients (diagnostic age < 50 years) and with dense breasts.[49]
[50]
[51]
[52]
Few studies have evaluated the accuracy of US, with a detection rate of additional
cancers to mammography of 2.4 to 4.3/1,000 women, but with an increase in false positives
and lower PPV for biopsies. When performed in addition to MRI, US does not improve
sensitivity,[53]
[54] but it can be used as supplemental screening when MRI is not available.
In patients with a personal history of breast cancer treated with mastectomy, imaging
screening of the treated breast with or without reconstruction is not indicated given
the low detection rate of asymptomatic cancers by mammography, US or MRI.[59]
Screening Considerations for Women with a History of Thoracic Radiotherapy
Screening Considerations for Women with a History of Thoracic Radiotherapy
Women treated with thoracic radiotherapy before the age 30 have a 13.4 times higher
average risk of developing breast cancer than the general population, similar to those
carrying the BRCA1 gene mutation.[60] The increased incidence occurs ∼10 years after treatment, persisting 30 years later.
The highest incidence occurs when treatment is performed at 10–14 years of age (RR = 22.0)
and 15–19 years of age (RR = 14.3).[61] For this group, there is evidence of the importance of screening with mammography
and MRI starting at 25 years of age or eight years after radiotherapy, in accordance
with the recommendations of other medical entities, such as the Children's Oncology
Group and the International Guideline Group.[60]
Screening of Women with a Genetic Mutation or a Strong Family History of Breast Cancer
(Lifetime Risk ≥ 20%)
Screening of Women with a Genetic Mutation or a Strong Family History of Breast Cancer
(Lifetime Risk ≥ 20%)
Mutations in genes that predispose to breast cancer are classified as high risk, when
they cause an increase of five times or more in relation to non-carrier women (BRCA1,
BRCA2, TP53, PTEN, among others), or intermediate risk, when they increase 1.5–5 times
(ATM, CHECK2, BARD1, among others).[62]
[63]
[64] In Brazil, a study demonstrated that the most common mutation genes were BRCA1 (27.4%),
BRCA2 (20.3%), TP53 (10.5%), ATM (8.8%), CHEK2 (6.2%) and PALB2 (5.1%).[64] The Brazilian variant TP53 R337H was strongly associated with the risk of breast
cancer (OR = 17.4).[64] In the case of women with a strong family history of breast cancer but without known
mutation, those with an estimated ≥ 20% lifetime risk calculated by mathematical models were defined as high risk.[62] These women have the cancer at an early age, with peak incidence at 20–35 years
for the PT53 mutation, 30–39 years for the BRCA1 mutation, 30–49 years for BRCA2 mutations,
and 40–59 years for the high familial risk.[62]
[63]
[64]
[65]
For this risk group, there is strong scientific evidence of the importance of MRI
screening because of the reduction of interval cancers and the higher detection rate
of tumors in early stages, which may reduce the need for chemotherapy and mortality,
despite the higher number of false positives.[54]
[55]
[65]
[66]
[67] As for mammography, its role in patients with BRCA1 mutation has recently been questioned.
A meta-analysis[68] demonstrated that the addition of mammography to MRI in patients with BRCA1 mutation
modestly increased sensitivity (3.99%) and reduced specificity (4%). As for the BRCA2
mutation, the increase in sensitivity was greater (12.6%), with a small reduction
in specificity (5%). Thus, the CNM recommends screening with MRI, associated with
mammography, but not starting mammography before age 35 for BRCA1 and 30 for the other
groups. Additional US examinations do not yield additional detection of cancer if
MRI is performed and should be reserved for further evaluation or to guide biopsy
of findings identified on MRI.
As for the impact on mortality, an important study was published by Bae et al.[54] Even though this was a retrospective study, it was demonstrated that high-risk women
screened with mammography and MRI had better overall survival and tumors diagnosed
at stages of better prognosis than patients in the mammography-only group.
Conclusion
This guideline brought the consensus of recommendations based on current data for
breast cancer screening in Brazil, subdivided into sections according to the risk
for developing breast cancer, from women at usual risk, who represent ∼80% of patients
diagnosed with breast cancer, to women at higher risk.
