Background <p>Diabetes is associated with impaired breast cancer prognosis; however, the effectiveness of glycosylated hemoglobin (HbA_1c) as a prognostic biomarker in breast cancer remains uncertain, especially for patients without diabetes. We aimed to determine whether elevated HbA_1c is associated with a worse prognosis in breast cancer patients without known diabetes.</p> Methods <p>The study population comprised women with primary invasive stage I-III breast cancer between 2010 and 2020 surgically treated at Aarhus University Hospital, Denmark, without a diabetes diagnosis at baseline. We assessed HbA_1c at breast cancer diagnosis as a categorical (quartiles; HbA_1c-Q1 = 21–33 mmol/mol, HbA_1c-Q2 = 34–36 mmol/mol, HbA_1c-Q3 = 37–38 mmol/mol, HbA_1c-Q4 = ≥ 39 mmol/mol) and log2-transformed continuous variable. Follow-up began at the date of primary breast cancer surgery and continued until the first occurrence of either a new breast cancer event (loco-regional or distant recurrence, or contralateral breast cancer), new primary cancer other than breast cancer, death, emigration, or end-of-follow-up (November 15th, 2021). Cox regression models estimated crude and adjusted hazard ratios and associated 95% confidence intervals (95% CIs) of a new breast cancer event and all-cause mortality, adjusting for patient characteristics based on a directed acyclic graph. The lowest HbA_1c quartile (HbA_1c-Q1) was used as reference.</p> Results <p>In total, 2514 women (median age 62 years) were included. During median 5.6 years follow-up for new breast cancer events, 230 (9.1%) events occurred. An escalating risk of new breast cancer events was observed with increasing HbA_1c quartiles (adjusted hazard ratios, HbA_1c-Q2: 1.09 [95% CI = 0.75–1.60]; HbA_1c-Q3: 1.35 [95% CI = 0.88–2.07]; HbA_1c-Q4: 1.69 [95% CI = 1.13–2.54]) compared to HbA_1c-Q1. During median 6.0 years follow-up for all-cause mortality, 267 deaths (10.6%) occurred. No apparent association was evident between increasing HbA_1c quartiles and all-cause mortality (adjusted hazard ratios, HbA_1c-Q2: 0.75 [95% CI = 0.52–1.07]; HbA_1c-Q3: 0.82 [95% CI = 0.55–1.21]; HbA_1c-Q4: 1.06 [95% CI = 0.74–1.53]). Similarly, a log2(HbA_1c) increase was associated with an increased risk of new breast cancer events, but not all-cause mortality.</p> Conclusions <p>For women with primary breast cancer and no known diagnosis of diabetes, higher levels of HbA_1c were associated with an increased risk of new breast cancer events, but not all-cause mortality. HbA_1c may serve as a prognostic metabolic biomarker for breast cancer patients without diabetes.</p>