During the NCCN 2025 Annual Conference, Sagar Sardesai, MD, MPH, Associate Professor, Medical Oncology, and Medical Director, High-Risk Breast Cancer Prevention Program, The Ohio State University Comprehensive Cancer Center – James Cancer Hospital and Solove Research Institute, and Vice Chair of the NCCN Guidelines Panel for Breast Cancer Risk Reduction, highlighted methods to assess a woman’s risk for developing breast cancer, as well as strategies for risk-reduction.
Epidemiology and Risk Factors
Dr. Sardesai noted that each year in the United States, there are approximately 250,000 to 300,000 new diagnoses of breast cancer and about 40,000 related deaths. With a median age at diagnosis of 61 years, the chance of developing breast cancer in a woman’s lifetime is approximately 13%, or 1 in 8 women.1
“The incidence of breast cancer has been steadily increasing at approximately 1% per year—slightly higher in younger women in more recent times,” Dr. Sardesai commented. Risk factors for developing breast cancer include female sex, older age, family history of breast cancer, prolonged estrogen exposure, exposure to ionizing radiation, abnormal breast biopsies, postmenopausal obesity, and alcohol intake.
Known Genetic Predisposition
Several known pathogenic germline variants have been associated with a high risk of developing breast cancer,2 including those in BRCA1/2, which Dr. Sardesai noted account for most of the pathogenic genetic variants seen in the clinic. Other high-risk gene variants, associated with a ≥60% lifetime risk of developing breast cancer, include TP53, STK11, PTEN, PALB2, and CDH1. Pathogenic germline variants in ATM, CHEK2, NF1, RAD51C/RAD51D, and BARD1 are associated with a moderate lifetime risk of developing breast cancer. There is currently insufficient evidence to support an association between pathogenic variants in BRIP1 or the Lynch syndrome genes and an increased risk of developing breast cancer.2 “For those [variants] with insufficient evidence at this point, there is no clear benefit to recommending [patients undergo] risk-reducing mastectomies or enhanced cancer screening, especially in the absence of strong family history,” Dr. Sardesai said.
He noted that the routine use of polygenic risk scores (PRS), which evaluate multiple prespecified single nucleotide polymorphisms (SNPs) in breast cancer risk assessment, is currently discouraged. Further validation of PRS is required to better understand how SNPs interact with environmental, hormonal, and ancestry risk factors, as well as disease subtypes. Multiple ongoing studies will help guide the development of PRS in breast cancer risk assessment, aiding in the personalization of screening and risk-reducing therapies for appropriate individuals.
Dr. Sardesai highlighted the complexity of interpreting and disclosing genetic testing results to unaffected individuals, especially when there is insufficient context regarding the presence or absence of known cancer susceptibility pathogenic germline variants in affected family members (Table 1). He noted that results are often indeterminate or inconclusive, and that negative results do not necessarily rule out a genetic predisposition to cancer.
Genetic Test Results
| Result | Description |
|---|---|
| True-positive | The person is a carrier of an alteration in a known cancerpredisposing gene. |
| True-negative | The person is not a carrier of a known cancer-predisposing gene that has been positively identified in another family member. |
| Indeterminate (uninformative) | The person is not a carrier of a known cancer-predisposing gene, and the carrier status of other family members is either also negative or unknown. |
| Inconclusive (variants of unknown significance) | The person is a carrier of an alteration in a gene that currently has no known significance. |
Modifiable Risk Factors
The National Cancer Institute projects that obesity will become the most modifiable risk factor for developing cancer, ahead of tobacco use. Dr. Sardesai noted that obesity is following a similar epidemic model as smoking in the United States. Excess body weight is associated with an almost 2-fold increased risk of developing postmenopausal breast cancer (hazard ratio [HR], 1.86; 95% CI, 1.6–2.17).3 Alternatively, physical activity has been found to be protective against developing cancers irrespective of baseline body weight, with the protective effect increasing in line with the level of activity. Yet, the prevalence of physical inactivity globally is reported to be approximately 38% to 40%.4
The American Cancer Society (ACS) recommends either 150 minutes per week (or 30 minutes 5 times a week) of low- to moderate-intensity aerobic activity (moderate, 4–6 METs), or 75 minutes per week of vigorous-intensity aerobic activity (6–8 METs), or a combination of both, performed in intervals of at least 10 minutes. Furthermore, ACS encourages individuals to incorporate ≥2 strength training exercise sessions per week.5
Breast Cancer Risk Assessment Models
The most commonly used and validated breast cancer risk assessment models include the Gail model, IBIS (International Breast Cancer Intervention Study; also known as the Tyrer-Cuzick model), the Claus model, BRCAPro, and BOADICEA (Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm). “There is no one perfect model. Each of them has certain advantages or limitations. In day-to-day clinical practice, we often end up estimating a person’s breast cancer risk using many of these methods,” Dr. Sardesai said.
The Gail model, when estimating risk for breast cancer, takes into account personal history of breast cancer, current age, age at first period, age at first live birth, number of first-degree relatives with breast cancer, history of breast biopsy, and history of premalignant changes. However, this model does not consider family history beyond first-degree relatives or include a history of other cancer types.6 “As such, it’s not very useful in making recommendations for screening or risk reduction on an individual basis, especially if that patient has a family history in their second-degree relatives or on the paternal side,” Dr. Sardesai said.
He noted that specialty clinics for high-risk breast cancer are more likely to use the Tyrer-Cuzick (IBIS) or BOADICEA (CanRisk) model. The IBIS model takes into consideration nongenetic risk factors, including age at first period, age at first-term birth, biopsy history, height and weight, age at menopause, and family history of breast and ovarian cancers beyond first-degree relatives.7 Dr. Sardesai added that it may predict the presence of BRCA1/2 mutations. However, he cautioned that this model often overestimates breast cancer risk compared with other available methods.
In comparison, the Claus model considers first- and second-degree family histories as well as paternal family history, but it does not include lifestyle and hormonal factors nor family history of cancers other than breast and ovarian. Additionally, the Claus model is not validated in any independent dataset and often underestimates risk compared with other models.8
The BOADICEA (CanRisk) model is a comprehensive model that incorporates genetic, hormonal, and lifestyle factors and goes beyond standard germline variants to include BRCA1/2, PALB2, CHEK2, ATM, BARD1, RAD51C, and RAD51D. It does not, however, take into consideration personal risk factors such as breastfeeding and prior breast biopsy, and its use is more applicable to a White population.9
Recommendations for High-Risk Individuals
Patients with a potential high risk for developing breast cancer are often referred to a high-risk breast cancer clinic based on familial history of cancer. These patients then undergo risk assessment for pathogenic germline variants based on family history, and if deemed high risk, formal genetic testing can be performed using a germline multigene panel. If a pathogenic germline mutation associated with high or moderate lifetime breast cancer risk is identified, patients are counseled on risk-reducing options, including risk-reducing mastectomy or oophorectomy, risk-reducing agents, lifestyle modifications targeting modifiable risk factors, and close surveillance with enhanced cancer screenings.
The IBIS-I prevention trial showed that the use of prophylactic tamoxifen made a difference in reducing the cumulative incidence rate of developing breast cancer compared with placebo at 10 years of follow-up (6.4% vs 4.7%). The rate of invasive estrogen receptor (ER)–positive breast cancers was reduced from 4.3% with placebo to 2.9% with prophylactic tamoxifen at 10 years.10
“Use of 5 years of tamoxifen reduces the risk of developing breast cancer by almost 50%, and after 10 years of follow-up, most tamoxifen risk-reducing studies are still showing a relatively strong benefit of approximately 40% risk reduction in the risk of ER-positive tumors,” Dr. Sardesai said. However, he added, this population was exposed to a small risk of developing uterine cancer with prophylactic tamoxifen (0.5% vs 0.3% with placebo).
The STAR trial looked at the noninferiority of raloxifene in comparison with tamoxifen as prophylactic treatment. Compared with tamoxifen, raloxifene did not meet the noninferiority threshold (risk ratio, 1.02 [95% CI, 0.82–1.28]; P=.83), but it retained approximately 75% to 80% of the risk reduction benefit observed with tamoxifen. There were also fewer adverse events, namely invasive uterine cancer and thromboembolic events, reported with the use of raloxifene compared with tamoxifen.11
Aromatase inhibition with anastrozole was explored in the IBIS-II trial for the prevention of breast cancer in women at high-risk. Compared with placebo, anastrozole demonstrated a 50% reduction in the incidence of all breast cancers (P=.001).12 “One downside of aromatase inhibitors is the tolerance of these agents in the high-risk setting…Aromatase inhibitors are known to be associated with more musculoskeletal events, such as arthralgias,” Dr. Sardesai said. “My preference in the postmenopausal age group when possible is to go with [selective estrogen receptor modulators], such as raloxifene or low-dose tamoxifen.”
The TAM-01 trial investigated the use of low-dose tamoxifen (5 mg/day) in women aged <75 years with atypical ductal hyperplasia, lobular carcinoma in situ, or ductal carcinoma in situ, who were randomized to receive either tamoxifen or placebo for 3 years. Over a median follow-up of 5.1 years, there was a 52% reduction in the incidence of breast cancers with low-dose tamoxifen compared with placebo (log-rank P=.024).13
“There are several endocrine therapy agents that have been shown to reduce breast cancer incidence in high-risk individuals by almost 50% to 60%, with the greatest benefit in women with intraepithelial neoplasia,” Dr. Sardesai said. “However, the uptake of risk-reducing endocrine therapy remains low.” This is likely due to the lack of a demonstrated mortality benefit and an aversion to long-term endocrine therapy, which is associated with increased menopausal symptoms and potential serious adverse events. Additionally, many high-risk patients are either not aware of or not offered risk-reducing endocrine therapy.
Next Steps in Cancer Prevention Research
Dr. Sardesai noted that moving forward, more research is needed to identify agents that effectively reduce breast cancer risk in high-risk individuals while also improving postmenopausal symptoms or health issues such as osteoporosis—or at the very least, not worsening them. Currently, no effective risk-reducing strategies exist for ER-negative breast cancers. Additionally, measurable biomarkers that can be monitored for response are necessary, as is the precise identification of a cohort of patients to target, such as those with intraepithelial neoplasia or pathogenic germline variants.
Studies of particular interest include the A211102 trial, which is investigating metformin for breast cancer prevention and evaluating atypia on random periareolar fine-needle aspiration as a potential biomarker in patients receiving metformin or placebo for risk reduction (ClinicalTrials.gov identifier: NCT01905046). Another notable study, the ABCSG 50/BRCA-P trial, aims to determine the preventive effect of denosumab compared with placebo in women with a BRCA1 germline mutation (NCT04711109).
References
- 1.↑
American Cancer Society. Cancer Facts & Figures 2016. Accessed March 24, 2025. Available at: https://www.cancer.org/research/cancer-facts-statistics/all-cancer-facts-figures/cancer-facts-figures-2016.html
- 2.↑
Daly MB, Pal T, AlHilli Z, et al. NCCN Clinical Practice Guidelines in Oncology: Genetic/Familial High-Risk Assessment: Breast, Ovarian, Pancreatic, and Prostate. Version 3.2025. Accessed March 24, 2025. To view the most recent version, visit https://www.nccn.org
- 3.↑
Neuhouser ML, Aragaki AK, Prentice RL, et al. Overweight, obesity, and postmenopausal invasive breast cancer risk: a secondary analysis of the Women’s Health Initiative randomized clinical trials. JAMA Oncol 2015; 1:611–621.
- 4.↑
Wu Y, Zhang D, Kang S. Physical activity and risk of breast cancer: a meta-analysis of prospective studies. Breast Cancer Res Treat 2013;137:869–882.
- 5.↑
Rock CL, Thomson C, Gansler T, et al. American Cancer Society guideline for diet and physical activity for cancer prevention. CA Cancer J Clin 2020;70:245–271.
- 6.↑
Gail MH, Brinton LA, Byar DP, et al. Projecting individualized probabilities of developing breast cancer for white females who are being examined annually. J Natl Cancer Inst 1989;81:1879–1886.
- 7.↑
Boughey JC, Hartmann LC, Anderson SS, et al. Evaluation of the Tyrer-Cuzick (International Breast Cancer Intervention Study) model for breast cancer risk prediction in women with atypical hyperplasia. J Clin Oncol 2010;28:3591–3596.
- 8.↑
Claus EB, Risch N, Thompson WD. The calculation of breast cancer risk for women with a first degree family history of ovarian cancer. Breast Cancer Res Treat 1993;28:115–120.
- 9.↑
Lee A, Mavaddat N, Wilcox AN, et al. BOADICEA: a comprehensive breast cancer risk prediction model incorporating genetic and nongenetic risk factors. Genet Med 2019;21:1708–1718.
- 10.↑
Cuzick J, Forbes JF, Sestak I, et al. Long-term results of tamoxifen prophylaxis for breast cancer—96-month follow-up of the randomized IBIS-I trial. J Natl Cancer Inst 2007;99:272–282.
- 11.↑
Vogel VG, Costantino JP, Wickerham DL, et al. Effects of tamoxifen vs raloxifene on the risk of developing invasive breast cancer and other disease outcomes: the NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 trial. JAMA 2006;295:2727–2741.
- 12.↑
Cuzick J, Sestak I, Forbes JF, et al. Anastrozole for prevention of breast cancer in high-risk postmenopausal women (IBIS-II): an international, double-blind, randomised placebo-controlled trial. Lancet 2014;383:1041–1048.
- 13.↑
DeCensi A, Puntoni M, Guerrieri-Gonzaga A, et al. Randomized placebo controlled trial of low-dose tamoxifen to prevent local and contralateral recurrence in breast intraepithelial neoplasia. J Clin Oncol 2019;37:1629–1637.
