Key steps for effective breast cancer prevention

Abstract

Despite decades of laboratory, epidemiological and clinical research, breast cancer incidence continues to rise. Breast cancer remains the leading cancer-related cause of disease burden for women, affecting one in 20 globally and as many as one in eight in high-income countries. Reducing breast cancer incidence will likely require both a population-based approach of reducing exposure to modifiable risk factors and a precision-prevention approach of identifying women at increased risk and targeting them for specific interventions, such as risk-reducing medication. We already have the capacity to estimate an individual woman’s breast cancer risk using validated risk assessment models, and the accuracy of these models is likely to continue to improve over time, particularly with inclusion of newer risk factors, such as polygenic risk and mammographic density. Evidence-based risk-reducing medications are cheap, widely available and recommended by professional health bodies; however, widespread implementation of these has proven challenging. The barriers to uptake of, and adherence to, current medications will need to be considered as we deepen our understanding of breast cancer initiation and begin developing and testing novel preventives.

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Fig. 1: Breast cancer risk modifiers and population frequency.
Fig. 2: Biological differences between high and low mammographic density.
Fig. 3: Developing novel preventives based on a deeper understanding of the early events in breast cancer development.

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Acknowledgements

K.L.B. is a Victorian Cancer Agency mid-career fellow and is also supported by the Peter MacCallum Research Foundation and Harold Homes Equity Trustees grant. K.-A.P is an Australian National Breast Cancer Foundation Fellow.

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Contributions

K.L.B and K.-A.P researched data for the article, made substantial contributions to discussions of the content and wrote the article. J.C. provided vital input to the article and insight into preventives that are currently being trialled. All authors reviewed and/or edited the manuscript before submission.

Corresponding author

Correspondence to Kara L. Britt.

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Competing interests

The authors wish to disclose that Cancer Research UK (CRUK) licences the International Breast Cancer Intervention Study (IBIS; also known as Tyrer–Cuzick) model for commercial use and J.C. receives some benefit. K.A.-P has a patent, System and Process of Cancer Risk Estimation (Australian Innovation Patent), issued regarding iPrevent. K.L.B has no competing interests.

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Nature Reviews Cancer thanks O. Olopade, S. Narod and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Related Links

Breast Cancer Surveillance Consortium: https://tools.bcsc-scc.org/BC5yearRisk/intro.htm

BOADICEA: https://ccge.medschl.cam.ac.uk/boadicea/

BCRAT: https://bcrisktool.cancer.gov/calculator.html

IBIS: http://www.ems-trials.org/riskevaluator/

Confluence project: https://dceg.cancer.gov/research/cancer-types/breast-cancer/confluence-project

Press release of results from Topical Endoxifen trial: https://www.globenewswire.com/news-release/2019/06/27/1875229/0/en/Atossa-Genetics-Preliminary-Phase-2-Study-Achieves-Primary-Endpoint-Topical-Endoxifen-Rapidly-Reduces-Breast-Density.html

Glossary

Mammographic density

(MD). The extent of white or radio-opaque tissue (dense area) shown on a mammogram. Per cent MD is used to represent this dense area as a proportion of the total tissue area of the breast on a mammogram.

Menopausal hormone therapy

(MHT). Sex hormones given to treat symptoms or prevent long-term morbidities associated with female menopause. Also known as hormone replacement therapy.

Menarche

The time in a girl’s life when her first menstrual bleeding or period begins.

Parity

The state of having borne offspring (liveborn or stillborn). Also used to indicate the number of pregnancies reaching viable gestational age (liveborn or stillborn — pregnancies resulting in multiple births, such as twins, count as one).

Homologous recombination

The exchange of nucleotide sequences between two similar or identical molecules of DNA. It is used by cells to accurately repair damage that occurs on both strands of DNA, such as double-strand breaks or inter-strand DNA cross-links.

Relative risk

(RR). The ratio of the probability of an event occurring in the group exposed to the modifier of interest versus the probability of the event occurring in the non-exposed group. A relative risk of 1.5 means people exposed to the risk modifier, on average, have a 50% higher risk than those not exposed.

Oral contraceptive pill

(OCP). A birth control pill taken orally. Most contain oestrogen and progesterone, which when given at certain times in the menstrual cycle at defined doses can prevent the ovary from releasing the egg for fertilization.

Post-partum involution process

A cell death-mediated process by which the lactating breast returns to the pre-pregnant state after weaning (or after childbirth if lactation is not initiated). It is characterized by robust tissue remodelling.

Mammary stem cells

(MaSCs). Cells within the mammary gland that have the capacity to form a new mammary tree when transplanted into a cleared mammary fat pad. MaSCs reside within the basal/myoepithelial compartment and can be identified with CD24/EpCAM and either CD29 or CD49f.

Odds ratio

(OR). A statistic that quantifies the strength of the association between an exposure and an outcome. OR = 1 means that the exposure does not affect the odds of outcome, OR >1 means that the exposure is associated with higher odds of outcome, and OR <1 means that the exposure is associated with lower odds of outcome.

Adipokine

A cell signalling protein secreted by adipose (fat) cells.

Klinefelter syndrome

A genetic condition, affecting about 1 in every 550 men, in which a male is born with an extra copy of the X chromosome. This results in higher levels of female hormones.

Gynaecomastia

Excessive enlargement of the male breast. May be unilateral (one side) or bilateral (both sides).

Absolute risk

The risk of developing a disease over a time period, for example, a person may have a one in ten risk (that is, a 10% risk) of a certain disease in their life. Absolute risk is one of the most easily understood ways of communicating health risks to the general public.

Hazards ratio

(HR). A measure of how often a particular event happens in one group compared with another group, over time. HR = 1.0 means that there is no difference in survival between the two groups. HR >1.0 or HR <1.0 means that survival was better in one of the groups.

Basal-like breast cancer

A breast cancer subtype that is more prevalent in African-American women, characterized by high histological grade, high mitotic indices and lack of oestrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) protein overexpression.

Polygenic disease

A genetic disorder that is caused by the combined action of more than one gene.

Breast cancer risk estimation models

Tools that estimate a person’s likelihood of developing breast cancer within a specific time frame.

Discriminatory accuracy

The ability of a risk model to separate individuals who will get breast cancer from those who will not. A value of 1.0 represents perfect discrimination, a value of 0.5 means that the model performance is no better than chance alone, values of 0.6–0.7 are considered good and values of 0.5–0.6 are considered sufficient.

Calibration

The ratio of the observed number of breast cancer cases to the expected number; values of one indicate optimal calibration.

Bilateral mastectomy

The removal of as much breast tissue as possible to reduce the breast cancer risk.

Bilateral salpingo-oophorectomy

A surgical procedure to remove both ovaries and fallopian tubes.

Transdermal therapy

A route of drug administration wherein the drug is delivered across the skin, via patches or creams, for systemic distribution.

Luminal progenitors

A type of luminal epithelial cell within the mammary epithelium that has both luminal differentiation markers and progenitor activity (colony-forming and repopulating activity in vivo).

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Britt, K.L., Cuzick, J. & Phillips, KA. Key steps for effective breast cancer prevention. Nat Rev Cancer 20, 417–436 (2020). https://doi.org/10.1038/s41568-020-0266-x

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