Changing Landscape in the Management of High-Risk Lesions for Breast Cancer

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As the population of women at increased risk for breast cancer grows, with an estimated 140,000 high-risk lesions diagnosed each year, “the landscape for surgical excision of high-risk lesions continues to evolve,” Melissa Pilewskie, MD, reported at the 2022 Lynn Sage Breast Cancer Symposium in Chicago.1 Data now support observation for some high-risk lesions, particularly atypical lobular hyperplasia and lobular carcinoma in situ.

Dr. Pilewskie is Associate Professor of Surgery and Director of the Breast Care Clinic, University of Michigan. The symposium was hosted by the Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago.

Among the 1 million benign breast biopsies performed in the United States each year, about 10% are atypical hyperplasia and about 4% are lobular carcinoma in situ. Studies showing low upgrade rates for lobular neoplasia have served as the impetus for changing clinical practice, suggesting observation, and treating these lesions as high-risk features instead of always recommending surgical excision, Dr. Pilewskie said. The data “support change in practice, allowing us to focus on the long-term cancer risk.”

Melissa Pilewskie, MD

Melissa Pilewskie, MD

Ongoing Risks

It is important to periodically review lifestyle factors associated with breast cancer, Dr. Pilewskie noted. “Standard recommendations for breast health (and overall well-being) should include consuming alcohol in moderation, maintaining a healthy [body mass index], and including moderate-intensity exercise. The data to back up these recommendations continue to grow.”

A recent study by Korn et al looked at 17 different cancers and their association with several factors, including body weight; physical activity; and consumption of plant-based foods, fast food, red and processed meat, sugar-sweetened drinks, and alcohol.2 Controlling for smoking status, the study found that all these factors “are likely important” and should be included in patient education.

“The data consistently showed that, on average, women who drink more than one drink per day have a small increase in relative risk—fairly modest but real and definitely something to discuss with patients,” Dr. Pilewskie noted. Exercise continues to be associated with a 20% to 30% reduction in breast cancer incidence, “with the greatest reduction being in women who spend 6 hours per week performing moderate-intensity activity.”

Chemoprevention Studies

“Risk calculators do not appear to be accurate for women with atypical hyperplasia and lobular carcinoma in situ,” said Dr. Pilewskie, who added that all patients with these lesions “meet criteria for chemoprevention and have significant benefit from risk-reducing medications.” An estimated 10 million U.S. women aged 35 to 79 may be eligible for chemoprevention based on an elevated 5-year predicted risk of 1.67%, she noted.

“There is a plethora of data from randomized controlled trials looking at both selective estrogen receptor modulators [SERMs] and aromatase inhibitors, including a large number of both average-risk and high-risk women,” Dr. Pilewskie noted. “The SERM trials overall [show a reduction of] breast cancer incidence by 38%, but that rate is even higher in studies that enrolled high-risk women alone.”

In the NSABP-P1 trial, comparing tamoxifen vs placebo in high-risk women, “the overall reduction in invasive cancer risk was 49%, and in certain populations, this benefit is even greater—a 56% risk reduction for women with lobular carcinoma in situ and a really impressive 87% risk reduction for women with atypical hyperplasia; and although the numbers were very small, a  62% risk reduction was seen in women with BRCA2 mutation. It highlights the importance of identifying patients at risk for estrogen receptor–positive disease. That’s who we should be talking with about these medications,” Dr. Pilewskie commented.

The STAR trial (NSABP P-2) compared tamoxifen with raloxifene and found “slightly improved efficacy with tamoxifen but lower toxicity with raloxifene,” Dr. Pilewskie said. “[Either of these agents] is often a nice option for patients. Aromatase inhibitors reduce the incidence rate by just over 50% and remain an alternative for postmenopausal women, but obviously they are associated with their own side-effect profiles.”

Low-Dose Tamoxifen

The Tam01 trial randomly assigned women to low-dose tamoxifen (5 mg daily) for 3 years or placebo. “For all breast events, the hazard ratio was 0.48, a significant benefit in outcomes,” Dr. Pilewskie said.

The SERM trials overall [show a reduction of] breast cancer incidence by 38%, but that rate is even higher in studies that enrolled high-risk women only.
— Melissa Pilewskie, MD

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“The take-home message of this study is really about the side-­effect profile.” She added, “Side effects are clearly one of the biggest limitations we have in getting acceptance of chemoprevention.”

Serious adverse events included one case of endometrial cancer in the tamoxifen group (vs none in the placebo group), one case of deep vein thrombosis in the tamoxifen group, and one pulmonary embolism in the placebo group. For nonserious events, there was a higher incidence of hot flashes with tamoxifen vs placebo (14% vs 7%), fewer headaches with tamoxifen (0.4% vs 5%), but no other significant differences.

Patient-reported outcomes showed that low-dose tamoxifen appears to be well tolerated, with “no significant difference in vaginal dryness or pain with intercourse, bladder control, musculoskeletal pain, or cognitive problems. The only significant difference was in hot flash frequency, which went from 1.5 per day in patients on placebo to 2.1 in those on low-dose tamoxifen, with no difference in intensity,” Dr. Pilewskie noted.3

“Another population of patients at risk are those who receive chest wall radiation therapy at a young age,” Dr. Pilewskie said. A study randomly assigning chest-irradiated cancer survivors to low-dose tamoxifen vs placebo for 2 years found “very similar changes to what are seen with full-dose tamoxifen,” in mammographic density as well as biomarkers for breast cancer, suggesting this is another population that could benefit from chemoprevention.”

NCCN/ASCO Recommendations

National Comprehensive Cancer Network (NCCN)/ASCO chemoprevention guidelines for tamoxifen therapy recommend 20 mg daily for 5 years for pre- or postmenopausal women who are 35 years or older, with a 5-year estimated breast cancer risk of at least 1.66%; and 5 mg of tamoxifen for women with lobular carcinoma in situ who are symptomatic on 20 mg or unwilling to take the standard dose for women with intraepithelial neoplasia.

“Importantly, the language we see now in NCCN and ASCO recommendations is strengthening,” Dr. Pilewskie said, “and ASCO is [specifying] the patients most likely to benefit, which includes those with atypical hyperplasia and lobular carcinoma in situ.”

Using and Refusing Chemoprevention

A study of 1,400 women at high risk found that overall chemoprevention use was 24%, “and that number is quite consistent with other single-institution data reported recently,” Dr. Pilewskie said. “There appears to be a difference in uptake based on risk factor, with women who have the highest risk factors being more likely to accept chemoprevention.”4

The number one reason given for refusing chemoprevention in this report was fear of side effects. Dr. Pilewskie remarked, “but in this study, over 60% of patients who started completed their therapy. So, once someone does agree to take chemoprevention, there is a high likelihood she will complete it.”

Topical Chemotherapy

The finding that only about one-quarter of women in the high-risk category accept chemoprevention highlights the need for novel strategies, Dr. Pilewskie said. “One strategy I have been very interested in is the use of topical chemoprevention, using drugs that we know work and applying them to the organ of interest to get benefit, but avoiding systemic side effects.”

A recent published study of topical chemoprevention in this setting randomly assigned patients to receive topical or oral telapristone acetate, an antiprogesterone agent. The concentration of drug in the breast tissue “was significantly lower with the topical delivery,”5 Dr. Pilewskie said. “However, the distribution throughout the breast was nearly identical, giving promise to finding additional agents that have improved skin penetration.”

Other studies are looking at different aspects of safety, tolerability, and efficacy of topical chemoprevention. 

DISCLOSURE: Dr. Pilewskie reported no conflicts of interest.


1. Pilewskie M: What’s new in non-genetic risk? Molecular biomarkers and genomic assays in breast cancer. 2022 Lynn Sage Breast Cancer Symposium. Presented September 23, 2022.

2. Korn A, Reedy J, Brockton NT, et al: The 2018 World Cancer Research Fund/American Institute for Cancer Research score and cancer risk: A longitudinal analysis in the NIH-AARP Diet and Health Study. Cancer Epidemiol Biomarkers Prev 31:1983-1992, 2022.

3. Buttiron Webber T, Marra D, Puntoni M, et al: Patient-versus physician-reported outcomes in a low-dose tamoxifen trial in noninvasive breast cancer. Breast J 27:817-823, 2021. 

4. Flanagan MR, Zabor EC, Stempel M, et al: Chemoprevention uptake in breast cancer risk reduction varies by risk factor. Ann Surg Oncol 26:2127-2135, 2019.

5. Lee O, Pilewskie M, Karlan S, et al: Local transdermal delivery of telapristone acetate through breast skin, compared with oral treatment: A randomized double-blind, placebo-controlled phase II trial. Clin Pharmacol Ther 109:728-738, 2021.