Abstract P2-11-36: Osteopontin splice variants indicate prognosis in premalignant breast lesions
Authors: Weber Georg F. , Ziolkowski Piotr 
Published: March 2023

Abstract
BACKGROUND: Premalignant breast lesions pose variable risks for transformation, raising the question who should receive treatment to counteract the potential progression to breast cancer. Prognostic indicators will spare low-risk patients the burden of substantial treatment side effects and will enable high-risk patients to comfortably take preemptive action. Osteopontin (OPN) is a secreted mediator of breast cancer progression, which is subject to alternative splicing in transformed tissues and has been known to be a marker for breast cancer aggressiveness. Here, we test the variants OPN-a and OPN-c as potential prognosticators for the transformation of premalignant breast lesions. The presence of spliced Osteopontin-c in these lesions does reflect the risk for cancer development within 5 years. METHODS: By immunohistochemistry, we analyze the association of Osteopontin variant expression in healthy breasts, hyperplasias, radial scars, lobular and ductal carcinomas in situ from 434 women as well as papillomas from 114 women to assess a) staining for OPN exon 4 (present in OPN-a and OPNb) and OPN-c in low-risk to high-risk lesions b) correlations between staining and progression to cancer or survival. RESULTS: The staining intensity for OPN-c correlates with risk, and it is prognostic for ensuing invasive disease and survival. About 10% of OPN-c pathology score 0–1 (intensity), vs. 40% of score 3 experience cancer over 5 years. More than 90% of women, who progress, had pathology scores of 2–3 for OPN-c intensity at the time of initial diagnosis. When combining OPN-c and OPN exon 4 staining, all of the low intensity patients are alive after 5 years, whereas women in the high category have a close to 30% chance to die within 5 years. Of patients who succumb, close to 80% had a high combined score at the time of initial diagnosis. In the papilloma patients, fewer than 5% of OPN-c pathology score 0-1 (intensity), versus almost 18% of score 2-3 experienced cancer in follow-up. 9 of 12 women, who progressed, had pathology scores of 2-3 for OPN-c intensity at the time of initial diagnosis, none had a score of 0. When developing a combined risk score from intensity plus percent positivity for OPN-c, the progression risk for patients with low score was 3.2%, for intermediate score was 5.7%, and for high score was 18.8%. Papillomas in patients, who were later diagnosed with cancer in the contralateral breast, displayed stronger staining positivity than non-progressors. CONCLUSION: The information of OPN-c immunohistochemistry can provide a foundation for very reliable prognostication and has the potential to aid decision making in the treatment or watchful waiting of early breast lesions. The addition of OPN-a refines the prognostication of survival. The staining intensity for OPN variants may also inform on the cancer risk in the unaffected breast, which may reflect a genetic predisposition for Osteopontin expression and splicing. OPN splice variant immunohistochemistry on breast biopsies will allow counseling of the patients on their risk to develop breast cancer at a later time.
Citation Format: Georg F. Weber, Piotr Ziolkowski. Osteopontin splice variants indicate prognosis in premalignant breast lesions [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-11-36.