| Title: |
Progesterone receptor (PR) intra-tumor heterogeneity in premenopausal breast cancer: A secondary analysis of a randomized trial |
| Authors: |
Danielsson, Oscar; Dar, Huma; Perez-Tenorio, Gizeh; Nordenskjold, Anna; Yau, Christina; Benz, Christopher C.; Esserman, Laura J.; Nordenskjöld, Bo; Stål, Olle; Fornander, Tommy; Hartman, Johan; Tobin, Nicholas P.; Johansson, Annelie; Lindstrom, Linda S. |
| Publisher Information: |
Linköpings universitet, Avdelningen för kirurgi, ortopedi och onkologi; Linköpings universitet, Medicinska fakulteten; Region Östergötland, Onkologiska kliniken US; Karolinska Inst, Sweden; Karolinska Univ Hosp, Sweden; Gothenburg Univ, Sweden; Buck Inst Res Aging, CA USA; Univ Calif San Francisco, CA USA; Univ Calif San Francisco, CA USA; WILEY |
| Publication Year: |
2026 |
| Collection: |
Linköping University Electronic Press (LiU E-Press) |
| Subject Terms: |
breast cancer; immunohistochemistry; long-term risk; premenopausal; progesterone receptor heterogeneity; Surgery; Kirurgi |
| Description: |
Premenopausal breast cancer patients have an increased risk of distant recurrence, but their long-term risk remains unclear. Notably, over 90% of estrogen receptor (ER) positive tumors in premenopausal patients are also progesterone receptor (PR) positive, compared to 70% in postmenopausal patients. We aimed to determine whether PR intra-tumor heterogeneity influences long-term risk of distant recurrence and endocrine therapy benefit in premenopausal breast cancer patients. We conducted a secondary analysis of the Stockholm tamoxifen (STO-5) randomized controlled trial (1990-1997) with 20-year complete follow-up, including 924 premenopausal women with operable breast cancer in Stockholm, Sweden. Patients were randomized to 2 years of adjuvant endocrine therapy or control, with lymph node-positive patients receiving standard chemotherapy (CMF). Tumor blocks were available for 731 patients. PR intra-tumor heterogeneity was assessed by measuring variation in PR immunohistochemical staining intensity in whole tumor slides and was categorized as high or low for 520 ER-positive/PR-positive patients. Distant recurrence-free interval (DRFI) by PR heterogeneity was analyzed using Kaplan-Meier, multivariable Cox proportional-hazards regression, and multivariable time-varying flexible parametric modeling. We found PR intra-tumor heterogeneity significantly impacted 20-year DRFI (log-rank p = .002). Patients with high intra-tumor heterogeneity had a significantly increased risk of distant recurrence, compared to patients with low heterogeneity (hazard ratio [HR] = 1.42; 95% CI, 1.02-1.96). Similar results were observed in HER2-negative patients. Patients with high PR heterogeneity significantly benefited from endocrine therapy (HR = 0.41; 95% CI, 0.24-0.71). These findings suggest that premenopausal patients with high PR heterogeneity have increased long-term risk but significantly benefit from endocrine therapy. ; Funding Agencies|Cancerfreningen i Stockholm |
| Document Type: |
article in journal/newspaper |
| File Description: |
application/pdf |
| Language: |
English |
| Relation: |
International Journal of Cancer, 0020-7136, 2026, 158:4, s. 1106-1115; PMID 41137194; ISI:001599540800001 |
| DOI: |
10.1002/ijc.70209 |
| Availability: |
http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-219207; https://doi.org/10.1002/ijc.70209 |
| Rights: |
info:eu-repo/semantics/openAccess |
| Accession Number: |
edsbas.D50791C4 |
| Database: |
BASE |