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Upgrade Rates and Breast Cancer Development Among Germline Pathogenic Variant Carriers with High-Risk Breast Lesions

  • Breast Oncology
  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

Background

High-risk lesions (HRL) of the breast are risk factors for future breast cancer development and may be associated with a concurrent underlying malignancy when identified on needle biopsy; however, there are few data evaluating HRLs in carriers of germline pathogenic variants (PVs) in breast cancer predisposition genes.

Methods

We identified patients from two institutions with germline PVs in high- and moderate-penetrance breast cancer predisposition genes and an HRL in an intact breast, including atypical ductal hyperplasia (ADH), flat epithelial atypia (FEA), and lobular neoplasia (LN). We calculated upgrade rates at surgical excision and used Kaplan–Meier methods to characterize 3-year breast cancer risk in patients without upgrade.

Results

Of 117 lesions in 105 patients, 65 (55.6%) were ADH, 48 (41.0%) were LN, and 4 (3.4%) were FEA. Most PVs (83.8%) were in the BRCA1/2, CHEK2 and ATM genes. ADH and FEA were excised in most cases (87.1%), with upgrade rates of 11.8% (95% confidence interval [CI] 5.5–23.4%) and 0%, respectively. LN was selectively excised (53.8%); upgrade rate in the excision group was 4.8% (95% CI 0.8–22.7%), and with 20 months of median follow-up, no same-site cancers developed in the observation group. Among those not upgraded, the 3-year risk of breast cancer development was 13.1% (95% CI 6.3–26.3%), mostly estrogen receptor-positive (ER +) disease (89.5%).

Conclusions

Upgrade rates for HRLs in patients with PVs in breast cancer predisposition genes appear similar to non-carriers. HRLs may be associated with increased short-term ER+ breast cancer risk in PV carriers, warranting strong consideration of surgical or chemoprevention therapies in this population.

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Acknowledgments

The authors would like to acknowledge Kevin S. Hughes, MD, and Kanhua Yin, MD, MPH, for their assistance with data collection.

Funding

Rebecca Winn Matchett, Christopher Matchett, and the Winn Family Foundation.

Author information

Authors and Affiliations

  1. Division of Breast Surgery, Department of Surgery, Brigham and Women’s Hospital, Boston, MA, USA

    Alison Laws MD, MPH, Saskia Leonard BS, Julie Vincuilla BS, MPH, Eshita Sharma BS & Tari A. King MD

  2. Breast Oncology Program, Dana-Farber Brigham Cancer Center, Boston, MA, USA

    Alison Laws MD, MPH, Judy E. Garber MD, MPH & Tari A. King MD

  3. Harvard Medical School, Boston, MA, USA

    Alison Laws MD, MPH, Judy E. Garber MD, MPH & Tari A. King MD

  4. John A. Burns School of Medicine, University of Hawaii, Honolulu, HI, USA

    Saskia Leonard BS

  5. Department of Surgery, Michigan Medicine, Ann Arbor, MI, USA

    Emma Hershey BS & Melissa L. Pilewskie MD

  6. Division of Cancer Genetics and Prevention, Dana-Farber Cancer Institute, Boston, MA, USA

    Samantha Stokes BS, MPA & Judy E. Garber MD, MPH

  7. Breast and Ovarian Cancer Risk Evaluation Program, Department of Internal Medicine, Michigan Medicine, Ann Arbor, MI, USA

    Kara Milliron MS, CGC & Sofia D. Merajver MD, PhD

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  1. Alison Laws MD, MPH
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Correspondence to Melissa L. Pilewskie MD.

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TAK reports speakers honoraria and advisory board participation for Exact Sciences. SM is Chief Scientific Officer and a founder of INHERET, LLC. The remaining authors report no conflicts of interest.

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Laws, A., Leonard, S., Hershey, E. et al. Upgrade Rates and Breast Cancer Development Among Germline Pathogenic Variant Carriers with High-Risk Breast Lesions. Ann Surg Oncol 31, 3120–3127 (2024). https://doi.org/10.1245/s10434-024-14947-0

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