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Nearly half of American women aged 40 to 74 have dense breasts, which means that the proportion of fibrous and glandular tissue is greater than that of adipose tissue.
This common inherited trait is associated with a high risk of breast cancer and may also limit the effectiveness of breast cancer screening.
Adipose tissue appears almost black on mammograms. Dense breast tissue appears in white – the same color as breast tumors or masses – making it harder for radiologists to detect cancers and can lead to delayed diagnosis.
Nearly three dozen states have passed legislation requiring a certain level of notification to women, determined by mammography as having dense breasts.
However, the type of information contained in these notices varies greatly.
Some do not include the breast density category in women, which indicates the extent of dense tissue. Others do not explain the link between breast density and cancer risk or do not encourage women with dense breast tissue to discuss additional screening strategies with their primary care physician.
"All women who have a mammogram must know their breast density category so that they or their caregiver can calculate their risk of breast cancer. It's not helpful to tell a woman that she has dense breasts without knowing the breast density category, which determines the risk of breast cancer and forgotten cancer. " Karla Kerlikowske, MD, Professor at the Departments of Medicine and Epidemiology / Biostatistics at the University of California at San Francisco, said HemOnc today.
HemOnc today he's been talking to radiologists, epidemiologists and other experts about the biological link between breast density and cancer risk; research efforts to reduce the risk of cancer in women with dense breasts; the limitations of mammography for this population and the possibility that other screening modalities may be more effective; and the need for standardized reporting laws.
Classification and prevalence
The Breast Imaging and Reporting System (BI-RADS) – set up by the American College of Radiology in 1986 – classifies breast tissue into four broad density categories:
- Category A – almost entirely fat;
- Category B – scattered fibroglandular densities;
- Category c – heterogeneously dense; and
- Category D – extremely dense.
"Radiologists examine the results of screening and put women in one of these four categories," Jack Cuzick, PhD, FRS, CBE, Director of the Wolfson Institute of Preventive Medicine and the Center for Cancer Prevention at Queen Mary University in London, said HemOnc today. "The areas that appear white on the film are composed of both epithelial cells and fibrous tissue.
"The breast density measures these two cells, but it is thought that it is the best available, although indirect, measure of the number of epithelial cells," Cuzick added. "These are the cells that can divide and become cancer. The higher the number of dividing cells, the greater the chance that one of the cells will mutate and become cancer. "
According to a study by Sprague and his colleagues, more than 30 million Americans belong to the two most extreme breast density categories.
The researchers examined data from 1.51 million mammograms performed from 2007 to 2010 in Breast Cancer Surveillance Consortium facilities.
The results showed that 43.3% (95% CI, 43.1 to 43.4) of women aged 40 to 74 years had a heterogeneous or extremely dense chest. The proportion seemed inversely associated with age and BMI.
Investigators estimated that 27.6 million Americans aged 40 to 74 years had dense breasts. When researchers included women aged 75 and over in their analysis, this number reached 30.8 million.
Several factors – including young age, low BMI and hormone therapy for menopause – increase the risk of dense breasts. In contrast, two strategies to reduce the recurrence of breast cancer – tamoxifen in premenopausal women and aromatase inhibitors in postmenopausal women – have reduced breast density.
However, genetics can explain much of the risk.
In the Healthy Twin study, Sung and colleagues evaluated the role of genetic factors on mammographic density measurements in 730 Korean women. The analysis included 122 pairs of monozygotic twins, 28 pairs of dizygotic twins and 430 first degree relatives.
The researchers determined that the covariance between dense and non-dense areas had a significant genetic basis (correlation coefficient = -0.25, standard error = 0.06).
"The Healthy Twin study showed that, if an identical twin has a certain level of breast density, then the other twin has a very similar level," Kerlikowske said. "This is even true among fraternal twins, and we found the same thing between mothers and daughters."
Additional research has revealed genes associated with breast density.
For example, Lindström and colleagues identified common variants of ZNF365 associated with breast cancer density and risk. Later, the researchers identified significant genome-wide loci associated with breast density measurements, including a dense zone (AREG, ESR1, ZNF365, LSP1 / TNNT3, IGF1, TMEM184B, and SGSM3 / MKL1), a non-intense area (8p11.23) and a percentage density (PRDM6). , 8p11.23 and TMEM184B).
"Several studies have demonstrated a family aggregation of breast density and genes underlying breast density, and many of these genes are also associated with breast cancer," he says. Celine M. Vachon, PhD, Professor of Epidemiology and President of the Division of Epidemiology at the Mayo Clinic in Rochester, Minnesota, said HemOnc today.
The prevalence of breast density also varies by race and ethnicity.
McCarthy and her colleagues determined that black women had a higher prevalence of dense breasts than white women, even after adjusting for age, BMI and other risk factors of breast cancer.
The researchers evaluated data from 2,845 women (1,589 black and 1,256 white, mean age, 57 years old) with no history of breast cancer.
Researchers used a software algorithm developed in their facility to estimate absolute and percentage surface density. They used FDA-approved software (Quantra, Hologic) to calculate absolute and percentage volumetric absolute tissue estimates.
The results showed that black women had a significantly higher absolute breast area (40.1 cm).2 vs. 33.1 centimeters2; P <0.001) and the volume (187.2 cm3 vs. 181.6 cm3; P <0.001) than white women. However, white women had a higher surface area (23.5% vs. 19.6%; P <0.001) and volume density (13.4% vs. 11.6%; P <0.001).
When researchers adjusted age, BMI, and risk factors for cancer, black women showed significantly higher breast density in all categories, including absolute density in areas (P <0.001), surface density (P = 0.021), absolute density density (P <0.001) and density (P <0.001).
Cancer risk
Associations exist between breast density and established risk factors for breast cancer, suggesting that these risk factors may affect breast cancer because of their influence on breast density, according to Vachon.
"The strongest associations have been seen with age and IMC," Vachon said. "Reproductive factors such as nulliparity are associated with increased breast density and this density decreases with increasing numbers of children in a woman."
Boyd and his colleagues analyzed the link between mammographic density and breast cancer risk.
The researchers conducted three nested case-control studies in selected populations including 1,112 matched pairs. Investigators used Cumulus – a semi-automated method of measuring breast density – to examine the association of the measured percentage density in initial mammograms with the risk of breast cancer.
Their results revealed that women with at least 75% dense tissue had an almost five times greater risk of breast cancer than women with less than 10% dense tissue (OR = 4.7, 95% CI, 3%). -7.4), that the cancer was detected by screening (OR = 3.5, 95% CI, 2-6.2) or less one year after a negative screening test (OR = 17 , 8, 95% CI, 4.8-65.9).
Among women under the age of 56 – the median age of the cohort – 26% of all breast cancers and half of the cancers detected less than a year after negative screening were attributed to a mammographic density of 50% or more.
A study published this year showed that the high risk of cancer associated with breast density persisted in older women.
Braithwaite and colleagues analyzed data from 403,268 women aged 65 and over from the Breast Cancer Surveillance Consortium who underwent screening mammography in a community office between 1996 and 2012.
Women with BI-RADS Category C or Grade D breast density had an increased risk of breast cancer (65 to 74 years, HR = 1.39, 95% CI, 1.28 to 1.51). men 75 years and older, HR = 1.23, 95% CI, 1.1-1.37).
Conversely, women with BI-RADS Category A or Grade B breast density presented a reduced risk (65 to 74 years, HR = 0.66, 95% CI, 0.58-0.78; over 75 years, HR = 0.73, 95% CI, 0.62-0.87).
"Dense breast tissue is composed of an increased number of ductal and epithelial cells; thus, having more cells increases the risk of developing cancer, "said Kerlikowske. "There is also an increase in collagen and fibroblastic tissue.
"Some have hypothesized that it is the secreted or non-secreted proteins of the stroma that increase the risk of breast cancer," she added. "It is thought that the CD36 molecule is deactivated in women with dense breasts, so women with dense breasts are not as protected as individuals without dense breast tissue."
Despite the high risk, the evidence suggests that the high mammographic density of the breast does not increase the risk of death in people who develop breast cancer when other characteristics of the patient and tumor are taken into account.
Gierach and colleagues examined the association between mammographic density and breast and all-cause mortality in the Breast Cancer Surveillance Consortium.
Researchers used BI-RADS to evaluate the mammographic density of 9,232 women diagnosed with invasive primary breast cancer between 1996 and 2005.
After an average follow-up of 6.6 years, the investigators documented 1,795 deaths, of which 889 were due to breast cancer.
Site-specific multivariate analyzes, from age to diagnosis, stage of cancer, treatment, BMI and other factors have shown that a high breast tissue density (BI-RADS Category D) was not associated with breast cancer mortality risk (HR = 0.92, 95% CI). 0.71-1.19) or all-cause mortality (HR = 0.83, 95% CI, 0.68-1.02).
Risk reduction
Researchers are exploring approaches to reduce the risk of breast cancer in women with dense breasts.
"Studies have consistently shown a decrease in density with the use of oral tamoxifen," Vachon said. "It's not clear if a tamoxifen gel will have the same effects."
Researchers at the University of Southern California have launched a double-blind, randomized clinical trial to determine whether BHR-700 (Besins Healthcare), a proprietary gel containing 4-hydroxytamoxifene, with a strong Affinity for estrogen receptors in the breast, can effectively reduce breast density in healthy women aged 35 to 75 years.
4-Hydroxytamoxifene binds to estrogen receptors in the breast, disrupting the cell cycle of estradiol-induced breast tissue, according to the researcher. Pulin A. Sheth, MD, Assistant Professor of Clinical Radiology and Director of Breast Imaging at Norris Breast Center / Keck School of Medicine at USC. This interference can prevent cells from proliferating into cancer cells.
In the trial, 220 patients will receive two injections of gel per breast containing a total of 8 mg of BHR-700. The remaining 110 patients will receive a matching placebo.
Study participants will be treated for one year, after which they may elect to receive another year of active open treatment.
Breast density as determined by standard digital mammography will serve as a primary measure of results. Tolerability and safety will also be monitored and circulating blood levels of 4-hydroxy tamoxifen will be measured.
"We hope to see a statistically and clinically significant reduction in breast density in patients treated with BHR-700," said Sheth. HemOnc today. "Studies on tamoxifen have shown that an overall reduction of 4% to 5% was associated with a reduction in the onset of breast cancer. Since this study focuses on women with dense or very dense breasts, we hope that the effect could be considerably larger. "
Notification Laws
By the beginning of October, 36 states had passed laws requiring some type of notification of breast density to women after mammography screening.
These laws are meant to educate women who are having mammograms and their providers, Vachon said.
"As a result, women better understand the limitations of mammography for dense breasts, as well as the options that they offer to them," she said. "A negative mammogram does not mean that a woman should not see her doctor with new symptoms."
However, the laws on notifications vary enormously.
Some require that each person receive a notification letter, while others only require it for those whose breasts are heterogeneous or extremely dense. The degree of exploitable information – such as the effect of breast density on cancer risk or the importance of discussing additional screening with their primary care physician – differs significantly.
Federal legislators have begun to introduce legislation to Congress to standardize the notification process. The goal is to ensure that notifications inform people about breast density; explain how this can mask the presence of breast cancer in mammography; and encourage people who have dense breasts to talk to their health care providers about additional screening for breast cancer.
"Defenders have tried to pass a bill on the density of the chest, but after five years, the Congress has still not passed a bill," said Kerlikowske.
Most women want to know their breast density and are in favor of the concept of notification letters, according to Randy C. Miles, MD, MPH, radiologist in the breast imaging division of Massachusetts General Hospital.
Source: David Z. Chow.
"However, we must evaluate the best way to educate women and talk about this problem," he said. "The legislation varies widely by state."
Massachusetts passed a law in 2014 that requires mammography service providers to inform people in writing if the results show dense breast tissue.
Miles and her colleagues evaluated breast density knowledge and notification legislation in women who underwent routine mammography after the adoption of the Massachusetts Notification Act.
The researchers conducted surveys of women who underwent screening mammography at a university medical center over two periods of one week. The investigators conducted 1,000 investigations and 338 women responded.
The results showed that 61% of women were surprised to receive a breast density notification letter and 90% were not aware of recently adopted legislation.
More than half (54.7%, n = 185) of respondents reported having dense breasts; however, only 61% of this group (n = 113) correctly reported that dense breast tissue increased the risk of breast cancer.
"Despite the implementation of national breast density laws since 2009, confusion and misinformation about breast density persist in women undergoing mammography screening," Miles and colleagues wrote.
Christine M. Gunn, PhD, Assistant Professor of Research at the Faculty of Medicine at Boston University, and her colleagues analyzed the impact of breast density on women's perception and participation in follow-up care.
The researchers interviewed by telephone 30 English-speaking women aged 40 to 74 who had received a dense breast cancer notification at a Massachusetts hospital.
The results showed that 81% of the women interviewed recalled receiving the notification.
However, most did not remember specific content, and many said they had difficulty interpreting breast density. The majority of women planned or talked to their doctor about breast density following the notification.
An earlier analysis by Gunn and colleagues showed that the readability of breast density reports ranged from grade 7 to middle school.
"Notifications tend to be written at a very high level of literacy and some women have trouble understanding them," Gunn said. HemOnc today. "Women may not be ready to receive such communication and early research shows that notifications are not enough to explain enough what women need to do and what breast density is exactly. By associating this with providers who can not advise patients on the subject, this can create a lot of confusion. "
Additional screening
Mammography is the primary screening modality for US women aged 40 to 74, including those with dense breasts.
However, mammography is less accurate for women with dense breast tissue, which may result in neglected cancers or false positive results requiring additional follow-up.
Additional screening may offer benefits, but there are also disadvantages.
"The costs associated with additional screening for women with dense breasts are high, if we consider that 40% to 50% of women will have dense breasts," Vachon said. "In addition, additional imaging procedures are not without risks, including false positives, resulting in additional clinical assessment and anxiety. We need to do a better job of stratifying women according to the risks for systematic and complementary screening. "
Molecular imaging of the breast has shown the ability to detect missed breast cancers by conventional mammography, but the approach is only used by a few screening centers.
MRI is often used in addition to mammography in women at high risk of breast cancer; However, this approach is expensive.
Tomosynthesis, also known as 3-D mammography, increases the number of cancers detected in women with dense breasts compared to traditional 2-D mammography, while reducing unnecessary recall rates. According to Vachon, this modality is becoming the norm for breast cancer screening in the majority of US practices.
However, radiologists need a lot more time to interpret the results with this approach. In addition, screening costs more and women are exposed to high doses of radiation.
The guidelines of the US Working Group on Preventive Services on Breast Cancer Screening include a section for women with dense breasts, but there is no formal guidance on complementary screening.
"Current evidence is insufficient to evaluate the advantages and disadvantages of complementary screening for breast cancer by ultrasound, MRI, tomosynthesis or other methods. [for] women identified as having dense breasts on an otherwise negative screening mammogram, "says the guideline.
Complementary screening can improve cancer detection in women with dense breast tissue, but more fact-based research is needed, Miles said.
"Breast density is a rapidly evolving target in research," he said. "Not only are women confused about the density of their breasts, but they are also wondering if they should receive additional imaging with an ultrasound or breast MRI. This is largely due to the variability of additional screening recommendations being used across the country. At Massachusetts General Hospital, we recommend a high quality 3D tomosynthesis screening mammogram for women with dense breasts. Based on the existing evidence, we do not perform breast cancer screening ultrasound in these women. However, we recommend that women discuss with their doctor their personal risk of developing breast cancer to determine if they meet the criteria for an additional breast MRI.
"Some of the anxiety felt by women when they hear about breast density will subside as the breast imaging community develops consistent guidelines and recommendations regarding screening." complementary in women with dense breasts, "he added.
Considerable research is under way to compare screening modalities, many of which are still under development, Vachon said.
"Several groups are working on liquid-phase biopsy tests to detect the presence of tumors in the blood," she said. "This non-invasive test can complement the imaging modalities for early detection of breast cancer, especially in women with dense breasts."
Automated breast ultrasound – an imaging technique providing volumetric ultrasound data of the entire breast – associated with mammography, demonstrated the potential for improved detection breast cancer in women with dense breast tissue compared to mammography alone.
In South Korea, every woman of screening age undergoes breast ultrasound as a primary screening modality, tomosynthesis being a complementary test.
"There is resistance in the United States to provide additional ultrasound because it takes longer to run and interpret an ultrasound than for a mammogram," Kerlikowske said. "However, promising data is being released for automated ultrasound. This new technology will therefore likely continue to improve as it spreads in clinical practice. Automated ultrasound is potentially more reproducible than portable ultrasound. The additional ultrasound has three advantages: there is no radiation exposure, the breasts are not compressed and it is a relatively fast examination compared to MRI of the breast. "
Reese and colleagues have shown that Videssa Breast (Provista Diagnostics) – a combinatorial assay of proteomic biomarkers including serum protein biomarkers and tumor-associated autoantibodies, as well as patient-specific clinical data – allows for obtaining a Diagnostic score reliably detects breast cancer, making it a potential. additional viable screening tool for people with dense breast tissue.
The researchers evaluated the test in a study of 545 women aged 25 to 50 years.
Of the 454 women for whom information on breast density was available, the test showed a sensitivity of 88.9% and a specificity of 81.2% for dense breasts, as well as a sensitivity of 92.3%. % and a specificity of 86.6% for non-intensive breasts.
Negative predictive values were 99.1% in patients with dense breast tissue and 99.3% in those with non-dense breast tissue.
"Unlike imaging, Videssa Breast does not seem to be affected by breast density. It can effectively detect breast cancer in women with dense, nauseating breasts, "wrote Reese and his colleagues. "Thus, Videssa Breast is a powerful tool for health care providers when women with dense breasts exhibit difficult imaging results."
A personalized approach
Most experts with whom HemOnc today intervenes for a personalized screening approach.
"Decisions about additional imaging can not be based solely on age or breast density. A comprehensive risk assessment should be performed taking into account other risk factors, such as family history of breast cancer, breast biopsy history and body mass index, said Kerlikowske. .
Several tools take into account lifestyle and personal health factors, family history, and breast density to estimate breast cancer risk at age 5, 10 years, or lifetime, Gunn said.
"Although some women have dense breasts, their risk of breast cancer remains very low," Gunn said. "These women might not benefit from additional screening, which could come with its own set of costs. However, women with dense breasts and high risk of breast cancer may find additional screening beneficial. "
Cuzick also discussed the benefits of adaptive screening based on risk.
"If a woman is at high risk of breast cancer, she should consider screening more often, while low-risk women should do it less often," Cuzick said.
"Those most at risk should benefit from preventive treatment with tamoxifen if they are premenopausal and an aromatase inhibitor if they are menopausal," he added. "Incorporate the idea of renaming the breast cancer screening program to a breast cancer prevention program – through which we are not only trying to detect cancer at an early stage, but also to prevent cancer." identify ways to prevent it – is one of the exciting new areas in this area. field. "- by Jennifer Southall
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"Is automated full breast ultrasound a complementary screening modality for all women with dense breasts?"
References:
Boyd NF et al. N Engl J Med. 2007; doi: 10.1056 / NEJMoa062790.
Braithwaite D, et al. Epidemiological biomarkers of cancer Previous. 2018; doi: 10.1158 / 1055-9965.EPI-18-0044.
Ghosh K et al. J Clin Oncol. 2010; doi: 10.1200 / JCO.2009.23.4120.
Gierach GL et al. J Natl Cancer Inst. 2012; date of publication: 10.1093 / jnci / djs327.
Gunn CM et al. Patient Educ Counsel. 2018; doi: 10.1016 / j.pec.2018.01.017.
Lee CI et al. Med Clin North Am. 2017 date: 10.1016 / j.mcna.2017.03.005.
Lindström S, et al. Nat Common. 2014; doi: 10.1038 / ncomms6303.
Lindström S, et al. Nat Genet. 2011; Date: 10.1038 / ng.760.
McCarthy AM et al. Abstract 6580. Présenté à la réunion annuelle de l'American Association for Cancer Research; Du 18 au 22 avril 2015; Crême Philadelphia.
Miles RC et al. Acad Radiol. 2018; doi: 10.1016 / j.acra.2018.07.004.
Reese DE et al. PLoS One. 2017; doi: 10.1371 / journal.pone.0186198.
Siu AL et al. Ann Intern Med. 2016 doi: 10,7326 / M15-2886.
Sprague BL et al. J Natl Cancer Inst. 2014; date de publication: 10.1093 / jnci / dju255.
Sung J, et al. Traitement du cancer du sein. 2010; doi: 10.1007 / s10549-010-0852-9.
Zhang S et al. Traitement du cancer du sein. 2013; doi: 10.1007 / s10549-012-2310-3.
For more information:
Jack Cuzick, PhD, FRS, CBE, peut être contacté au Wolfson Institute of Preventive Medicine, Université Queen Mary de Londres, Charterhouse Square, Londres EC1M 6BQ, Royaume-Uni; email: [email protected].
Christine M. Gunn, PhD, peut être atteint à l'école de médecine de l'Université de Boston, 72 E. Concord St., Boston MA 02118; email: [email protected].
Karla Kerlikowske, MD, peut être atteint à l'Université de Californie, San Francisco, VAMC 111A1, San Francisco, CA 94143; email: [email protected].
Randy C. Miles, MD, MPH, peut être atteint à l'hôpital général du Massachusetts, 55 Fruit St., Boston, MA 2114; courriel: [email protected]; Twitter: @rmilesmd.
Pulin A. Sheth, MD, peut être atteint à la Keck School of Medicine de l'USC, 1975 Zonal Ave., Los Angeles, CA 90033; email: [email protected].
Celine M. Vachon, PhD, peut être atteint à la clinique Mayo, 200 1st St. SO, Rochester, MN 55905; email: [email protected].
Divulgations: Cuzick, Gunn, Kerlikowske, Miles et Vachon ne signalent aucune divulgation financière pertinente.
Près de la moitié des femmes américaines âgées de 40 à 74 ans ont des seins denses, ce qui signifie que la proportion de tissu fibreux et glandulaire est supérieure à celle de tissu adipeux.
Ce trait hérité commun est associé à un risque élevé de cancer du sein et peut également limiter l'efficacité du dépistage du cancer du sein.
Les tissus adipeux apparaissent presque noirs sur les mammographies. Les tissus mammaires denses apparaissent en blanc – de la même couleur que les tumeurs ou masses du sein – ce qui rend plus difficile la détection des cancers pour les radiologistes et peut conduire à un diagnostic retardé.
Près de trois douzaines d'États ont adopté une législation exigeant un certain niveau de notification aux femmes, déterminées par la mammographie comme ayant des seins denses.
Toutefois, le type d'informations contenues dans ces avis varie considérablement.
Certains n'incluent pas la catégorie de densité mammaire chez la femme, qui indique l'étendue des tissus denses. D'autres n'expliquent pas le lien entre la densité mammaire et le risque de cancer ou n'incitent pas les femmes ayant un tissu mammaire dense à discuter de stratégies de dépistage supplémentaires avec leur médecin de soins primaires.
«Toutes les femmes qui passent une mammographie doivent connaître leur catégorie de densité mammaire afin qu’elles-mêmes ou leur prestataire de soins puissent calculer leur risque de cancer du sein. Il n'est pas utile de dire à une femme qu'elle a des seins denses sans connaître la catégorie de densité mammaire, qui détermine le risque de cancer du sein et de cancer oublié. " Karla Kerlikowske, MD, professeur aux départements de médecine et d'épidémiologie / biostatistique de l'Université de Californie à San Francisco, a déclaré HemOnc today.
HemOnc today s'est entretenu avec des radiologues, des épidémiologistes et d'autres experts sur le lien biologique existant entre la densité mammaire et le risque de cancer; les efforts de recherche pour réduire le risque de cancer chez les femmes ayant des seins denses; les limites de la mammographie pour cette population et la possibilité que d'autres modalités de dépistage soient plus efficaces; et la nécessité de lois de notification normalisées.
Classification et prévalence
Le système de rapport et de données d'imagerie du sein (BI-RADS) – mis en place par l'American College of Radiology en 1986 – classe le tissu mammaire en quatre grandes catégories de densité:
- Catégorie A – presque entièrement gras;
- Catégorie B – densités fibroglandulaires dispersées;
- Catégorie c – dense de manière hétérogène; and
- Catégorie D – extrêmement dense.
«Les radiologistes examinent les résultats du dépistage et placent les femmes dans l’une de ces quatre catégories», Jack Cuzick, PhD, FRS, CBE, directeur du Wolfson Institute of Preventive Medicine et du Centre for Cancer Prevention à l’Université Queen Mary de Londres, a déclaré HemOnc today. «Les zones qui apparaissent en blanc sur le film sont composées à la fois de cellules épithéliales et de tissus fibreux.
"La densité du sein mesure ces deux cellules, mais on pense que c'est la meilleure mesure disponible, bien qu'indirecte, du nombre de cellules épithéliales", a ajouté Cuzick. «Ce sont les cellules qui peuvent se diviser et devenir un cancer. Plus le nombre de cellules pouvant se diviser est élevé, plus le risque que l'une des cellules soit mutée et devienne un cancer est grand ».
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Selon une étude de Sprague et ses collègues, plus de 30 millions d'Américaines appartiennent aux deux catégories de densité mammaire les plus extrêmes.
Les chercheurs ont examiné les données de 1,51 million de mammographies réalisées de 2007 à 2010 dans les établissements du Consortium de surveillance du cancer du sein.
Les résultats ont montré que 43,3% (IC à 95%, 43,1 à 43,4) des femmes âgées de 40 à 74 ans avaient une poitrine hétérogène ou extrêmement dense. La proportion semblait inversement associée à l'âge et à l'IMC.
Les enquêteurs ont estimé que 27,6 millions d'Américaines âgées de 40 à 74 ans avaient des seins denses. Lorsque les chercheurs ont inclus les femmes âgées de 75 ans et plus dans leur analyse, ce nombre a atteint 30,8 millions.
Plusieurs facteurs – notamment le jeune âge, un IMC bas et une hormonothérapie pour la ménopause – augmentent le risque de seins denses. Inversement, deux stratégies visant à réduire la récurrence du cancer du sein – le tamoxifène chez les femmes non ménopausées et les inhibiteurs de l’aromatase chez les femmes ménopausées – ont permis de réduire la densité mammaire.
Cependant, la génétique peut expliquer en grande partie le risque.
In the Healthy Twin study, Sung and colleagues assessed the role of genetic factors on mammographic density measurements among 730 Korean women. The analysis included 122 monozygotic twin pairs, 28 dizygotic twin pairs and 430 first-degree relatives.
The researchers determined the covariance between dense and nondense area had a significant genetic basis (correlation coefficient = – 0.25; standard error = .06).
“The Healthy Twin study showed that, if one identical twin has a certain level of breast density, then the other twin has a very similar level,” Kerlikowske said. “It is even true among fraternal twins, and the same has been found between mothers and daughters.”
Additional research has revealed genes associated with breast density.
For instance, Lindström and colleagues identified common variants in ZNF365 as associated with breast density and breast cancer risk. Later, researchers identified genome-wide significant loci associated with breast density measures, including dense area (AREG, ESR1, ZNF365, LSP1/TNNT3, IGF1, TMEM184B and SGSM3/MKL1), nondense area (8p11.23) and percent density (PRDM6, 8p11.23 and TMEM184B).
“Several studies have shown evidence for familial aggregation of breast density and genes underlying breast density, and several of these genes are also associated with breast cancer,” Celine M. Vachon, PhD, professor of epidemiology and chair of the division of epidemiology at Mayo Clinic in Rochester, Minnesota, told HemOnc today.
The prevalence of breast density also varies by race and ethnicity.
McCarthy and colleagues determined black women had a higher prevalence of dense breasts than white women, even after adjustments for age, BMI and other breast cancer risk factors.
The researchers evaluated data from 2,845 women (1,589 black and 1,256 white; mean age, 57 years) with no history of breast cancer.
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Investigators used a software algorithm developed at their institution to evaluate absolute and percent area density. They used FDA-approved software (Quantra, Hologic) to calculate volumetric estimates of absolute and percent dense tissue.
Results showed black women had significantly higher absolute breast area (40.1 cm2 vs. 33.1 cm2; P < .001) and volume (187.2 cm3 vs. 181.6 cm3; P < .001) than white women. However, white women had a higher area (23.5% vs. 19.6%; P < .001) and volume percent density (13.4% vs. 11.6%; P <0.001).
When researchers adjusted for age, BMI and cancer risk factors, black women demonstrated significantly higher breast density in all categories, including absolute area density (P < .001), area percent density (P = .021), absolute volume density (P < .001) and volume percent density (P <0.001).
Cancer risk
Associations exist between breast density and established breast cancer risk factors, suggesting these risk factors may influence breast cancer through their influence on breast density, according to Vachon.
“The strongest associations have been observed with age and BMI,” Vachon said. “Reproductive factors such as nulliparity are associated with increased breast density, and breast density decreases with the more children a woman has.”
Boyd and colleagues analyzed the association between mammographic density and breast cancer risk.
The researchers conducted three nested case-control studies in screened populations with 1,112 matched pairs. Investigators used Cumulus — a semiautomated method for measuring breast density — to examine the association of measured percentage of density in baseline mammogram with breast cancer risk.
Their findings revealed that women with at least 75% dense tissue had a nearly five times greater risk for breast cancer than women with less than 10% dense tissue (OR = 4.7; 95% CI, 3-7.4), regardless of whether the breast cancer was detected by screening (OR = 3.5; 95% CI, 2-6.2) or less than 1 year after a negative screening examination (OR = 17.8; 95% CI, 4.8-65.9).
Among women aged younger than 56 years — the median age of the cohort — 26% of all breast cancers and half of cancers detected less than 1 year after negative screening were attributed to mammographic density of 50% or more.
A study published this year showed elevated cancer risk linked to breast density persists among older women.
Braithwaite and colleagues analyzed data from 403,268 women aged 65 years and older in the Breast Cancer Surveillance Consortium who underwent screening mammography at a community practice between 1996 and 2012.
Women with BI-RADS category C or category D breast density demonstrated increased risk for breast cancer (ages 65 to 74 years, HR = 1.39; 95% CI, 1.28-1.51; ages 75 and older, HR = 1.23; 95% CI, 1.1-1.37).
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Conversely, women with BI-RADS category A or category B breast density demonstrated reduced risk (ages 65 to 74 years, HR = 0.66; 95% CI, 0.58-0.78; ages 75 years and older, HR = 0.73; 95% CI, 0.62-0.87).
“Dense breast tissue is composed of increased numbers of ductal and epithelial cells; thus, having more cells increases risk for cancer occurrence,” Kerlikowske said. “There also is an increase in collagen and fibroblast tissue.
“Some have hypothesized it is the proteins secreted or not secreted by the stroma that increases breast cancer risk,” she added. “The molecule CD36 is thought to get turned off in women with dense breasts, such that women with dense breasts are not as protected as individuals without dense breast tissue.”
Despite the elevated risk, evidence suggests high mammographic breast density does not increase mortality risk among those who develop breast cancer when other patient and tumor characteristics are taken into account.
Gierach and colleagues examined the association between mammographic density and breast cancer mortality or all-cause mortality within the Breast Cancer Surveillance Consortium.
The researchers used BI-RADS to assess mammographic density of 9,232 women diagnosed with primary invasive breast cancer between 1996 and 2005.
After mean follow-up of 6.6 years, investigators documented 1,795 deaths, of which 889 were due to breast cancer.
Multivariable analyses adjusted for site, age at diagnosis, cancer stage, treatment, BMI and other factors showed high breast tissue density (BI-RADS category D) was not associated with the risk for breast cancer mortality (HR = 0.92; 95% CI, 0.71-1.19) or all-cause mortality (HR = 0.83; 95% CI, 0.68-1.02).
Risk reduction
Researchers are examining approaches aimed at reducing breast cancer risk among women with dense breasts.
“Studies consistently have shown decreased density with oral tamoxifen use,” Vachon said. “It’s not clear whether a tamoxifen gel will have the same effects.”
Investigators at University of Southern California launched a randomized, double-blind clinical trial to assess whether BHR-700 (Besins Healthcare) — a proprietary gel that contains 4-hydroxytamoxifen, which has a strong affinity for estrogen receptors in the breast — can effectively reduce breast density among healthy women aged 35 to 75 years.
4-hydroxytamoxifen binds with estrogen receptors in the breast, stopping the cell cycle in breast tissue induced by estradiol, according to researcher Pulin A. Sheth, MD, assistant professor of clinical radiology and director of breast imaging at Norris Breast Center/Keck School of Medicine at USC. This interference may prevent cells from proliferating into cancer cells.
In the trial, 220 patients will receive two actuations of gel per breast containing a total of 8 mg BHR-700. The other 110 patients will receive matching placebo.
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Study participants will be treated for 1 year, after which they can choose to receive another year of active treatment in an open-label fashion.
Breast density as determined by standard digital mammogram will serve as the primary outcome measure. Tolerability and safety also will be monitored, and blood levels of circulating 4-hydroxytamoxifen will be measured.
“We hope to find that there is a statistically significant and clinically meaningful reduction in breast density among patients treated with BHR-700,” Sheth told HemOnc today. “It has been shown in studies with tamoxifen that an overall reduction between 4% and 5% is associated with a reduction in the occurrence of breast cancer. As this study focuses on women with dense or very dense breasts, we are hopeful that the effect could be significantly larger.”
Notification laws
As of early October, 36 states had adopted laws that require some type of breast density notification to women after screening mammograms.
These laws are meant to raise awareness among women receiving mammography and their providers, Vachon said.
“As a result, women have a better understanding of the limitations of mammography for dense breasts, as well as the options available to them,” she said. “A negative mammogram does not mean that a woman should not see her doctor with new symptoms.”
However, there is tremendous variation in notification laws.
Some require that everyone receive a notification letter, whereas others only require it for those found to have heterogeneously dense or extremely dense breasts. The degree of actionable information — such as the effect breast density has on cancer risk, or the importance of discussing supplemental screening with their primary care physician — differs greatly.
Federal lawmakers began introducing legislation in Congress in 2013 to standardize the notification process. The goal is to ensure the notifications educate individuals about breast density; explain how it may mask the presence of breast cancer on mammography; and encourage those who have dense breasts to talk to their health care providers about supplemental breast cancer screening.
“Advocates have tried to get a breast density bill passed but, after 5 years, Congress still has not passed a bill,” Kerlikowske said.
Most women want to know their breast density and favor the concept of notification letters, according to Randy C. Miles, MD, MPH, radiologist in the division of breast imaging at Massachusetts General Hospital.
Source: David Z. Chow.
“However, we need to evaluate how we can best educate women and talk about this issue,” he said. “Legislation is highly variable across states.”
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Massachusetts passed a law in 2014 that requires mammography providers to notify individuals in writing if results show dense breast tissue.
Miles and colleagues assessed knowledge of breast density and notification legislation among women who underwent routine mammography after passage of Massachusetts’ notification law.
Researchers administered surveys to women who underwent screening mammography at an academic medical center during two 1-week periods. Investigators administered 1,000 surveys, and 338 women responded.
The results showed 61% of women were surprised to receive a breast density notification letter and 90% were unaware of the newly enacted legislation.
More than half (54.7%; n = 185) of respondents reported having dense breasts; however, only 61% of that group (n = 113) correctly reported that dense breast tissue increased breast cancer risk.
“Despite implementation of state breast density laws since 2009, confusion and misinformation about breast density persists among women receiving mammography screening,” Miles and colleagues wrote.
Christine M. Gunn, PhD, research assistant professor at Boston University School of Medicine, and colleagues analyzed how dense breast notifications affected women’s perceptions and participation in follow-up care.
Researchers conducted phone interviews with 30 English-speaking women aged 40 to 74 years who received dense breast notification from a Massachusetts hospital.
The results showed 81% of women interviewed recalled receiving the notification.
However, most could not remember specific content, and many indicated they struggled to interpret what breast density meant. The majority of women planned to or did talk with their physicians about breast density as a result of receiving the notification.
A previous analysis by Gunn and colleagues showed readability of breast density notifications ranged from seventh-grade to college levels.
“Notifications tend to be written at a very high literacy level, and some women have difficulty understanding them,” Gunn told HemOnc today. “Women may not be prepared to receive such communication, and early research shows notifications alone do not sufficiently explain what women should do and what exactly breast density is. When coupling this with providers not being able to counsel patients on the topic, this can create a lot of confusion.”
Supplemental screening
Mammography is the primary screening modality for U.S. women aged 40 to 74 years, including those determined to have dense breasts.
However, mammography is less accurate for women with dense breast tissue, creating the potential for overlooked cancers or false-positive results that require additional follow-up.
Supplemental screening may offer benefits, but there are disadvantages, too.
“The costs associated with supplemental screening for women with dense breasts are high, if we consider 40% to 50% of women will have dense breasts,” Vachon said. “Also, the additional imaging procedures are not without their risks — including false positives, which result in additional clinical workup and anxiety. We have to do a better job of stratifying women by risk for both routine and supplemental screening.”
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Molecular breast imaging has shown the ability to detect breast cancers missed by conventional mammography, but the approach is used only by a few screening centers.
MRI often is used to complement mammography for women at high risk for breast cancer; however, that approach is costly.
Tomosynthesis — also called 3-D mammography — has been shown to increase the number of cancers detected among women with dense breasts compared with traditional 2-D mammography, while also reducing unnecessary recall rates. This modality is becoming standard for breast screening for a majority of U.S. practices, according to Vachon.
However, radiologists need significantly more time to interpret the results with this approach. Also, screening is costlier and women are exposed to high doses of radiation.
The U.S. Preventive Services Task Force guideline on breast cancer screening includes a section for women with dense breasts, but there is no formal guidance on supplemental screening.
“Current evidence is insufficient to assess the balance of benefits and harms of adjunctive screening for breast cancer using breast ultrasonography, MRI, tomosynthesis or other methods [for] women identified to have dense breasts on an otherwise negative screening mammogram,” the guideline states.
Supplemental screening can improve cancer detection among women with dense breast tissue, but more evidence-based research is necessary, Miles said.
“Breast density is a fast-moving target in research,” he said. “Not only are women confused about their breast density, but they are also confused about whether they should receive additional imaging with breast ultrasound or breast MRI. This is largely due to variability in supplemental screening recommendations used across the country. At Massachusetts General Hospital, we recommend high-quality screening mammography with 3-D tomosynthesis for women with dense breasts. Based on existing evidence, we do not perform whole-breast screening ultrasound in these women. We do, however, recommend that women discuss with their doctor about their personal risk for developing breast cancer to determine if they meet criteria for supplemental breast MRI.
“Some of the anxiety women feel when they hear about breast density will be calmed, as the breast imaging community develops consistent guidelines and recommendations about supplemental screening in women with dense breasts,” he added.
Considerable research is underway to compare screening modalities, many of which are still under development, Vachon said.
“Several groups are working on liquid biopsy tests that detect tumor shedding in the blood,” she said. “This noninvasive test may complement imaging modalities for early breast cancer detection, especially among women with dense breasts.”
Automated breast ultrasound — an imaging technique that provides volumetric ultrasound data of the entire breast — in combination with mammography has demonstrated the potential to improve breast cancer detection among women with dense breast tissue compared with mammography alone.
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In South Korea, every woman of screening age receives breast ultrasound as a primary screening modality, with tomosynthesis as an adjunct test.
“There is resistance in the United States to provide supplemental ultrasound because it takes more time to perform and interpret an ultrasound than mammography,” Kerlikowske said. “However, there are promising data being published for automated ultrasound, so maybe this new technology will continue to improve as it disseminates into clinical practice. Automated ultrasound has the potential to be more reproducible than handheld ultrasound. Supplemental ultrasound has three advantages: there is no radiation exposure, the breasts are not compressed and it is a relatively quick examination compared with breast MRI.”
Reese and colleagues showed Videssa Breast (Provista Diagnostics) — a combinatorial proteomic biomarker assay comprised of serum protein biomarkers and tumor-associated autoantibodies, as well as patient-specific clinical data — yields a diagnostic score that reliably detects breast cancer, making it a potentially viable supplemental screening tool for those with dense breast tissue.
The researchers evaluated the test in a study that included 545 women aged 25 to 50 years.
Among 454 women for whom breast density information was available, the test showed an 88.9% sensitivity and 81.2% specificity for dense breasts, and a 92.3% sensitivity and 86.6% specificity for nondense breasts.
Negative predictive values were 99.1% among those with dense breast tissue and 99.3% among those with nondense breast tissue.
“Unlike imaging, Videssa Breast does not appear to be impacted by breast density. It can effectively detect breast cancer in women with dense and nondense breasts alike,” Reese and colleagues wrote. “Thus, Videssa Breast provides a powerful tool for health care providers when women with dense breasts present with challenging imaging findings.”
A personalized approach
Most experts with whom HemOnc today spoke supported a personalized screening approach.
“Decisions about supplemental imaging cannot be based upon age or breast density alone. Full risk assessment needs to be performed accounting for other risk factors, such as family history of breast cancer, history of breast biopsy and body mass index,” Kerlikowske said.
Several tools take lifestyle and personal health factors, family history and breast density into account to estimate 5-year, 10-year or lifetime breast cancer risks, Gunn said.
“Although some women have dense breasts, overall they still may have a very low risk for breast cancer,” Gunn said. “These women may not benefit from additional screening, which can be accompanied by its own set of costs. However, women with dense breasts who do have an elevated risk for breast cancer may find additional screening beneficial.”
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Cuzick also addressed the benefits of risk-adaptive screening.
“If a woman is at high risk for breast cancer, she should consider screening more often, whereas those at low risk should be screened less often,” Cuzick said.
“Those at the highest risk should be considered for preventive therapy with tamoxifen if they are premenopausal and an aromatase inhibitor if they are postmenopausal,” he added. “Integrating the idea of renaming the breast cancer screening program to be considered a breast cancer prevention program — through which we not only try to detect cancer early but also identify ways in which we can prevent it — is one of the exciting new areas in this field.” – by Jennifer Southall
Click here to read the , “Is automated whole-breast ultrasound a valid supplemental screening modality for all women with dense breasts?”
References:
Boyd NF, et al. N Engl J Med. 2007;doi:10.1056/NEJMoa062790.
Braithwaite D, et al. Cancer Epidemiol Biomarkers Prev. 2018;doi:10.1158/1055-9965.EPI-18-0044.
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For more information:
Jack Cuzick, PhD, FRS, CBE, can be reached at Wolfson Institute of Preventive Medicine, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, United Kingdom; email: [email protected].
Christine M. Gunn, PhD, can be reached at Boston University School of Medicine, 72 E. Concord St., Boston MA 02118; email: [email protected].
Karla Kerlikowske, MD, can be reached at University of California, San Francisco, VAMC 111A1, San Francisco, CA 94143; email: [email protected].
Randy C. Miles, MD, MPH, can be reached at Massachusetts General Hospital, 55 Fruit St., Boston, MA 2114; email: [email protected]; Twitter: @rmilesmd.
Pulin A. Sheth, MD, can be reached at Keck School of Medicine of USC, 1975 Zonal Ave., Los Angeles, CA 90033; email: [email protected].
Celine M. Vachon, PhD, can be reached at Mayo Clinic, 200 1st St. SW, Rochester, MN 55905; email: [email protected].
Disclosures: Cuzick, Gunn, Kerlikowske, Miles and Vachon report no relevant financial disclosures.
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