In modern times, how important are breast cancer stage, grade and receptor subtype for survival: a population-based cohort study

Abstract

Background: In breast cancer, immunohistochemistry (IHC) subtypes, together with grade and stage, are well-known independent predictors of breast cancer death. Given the immense changes in breast cancer treatment and survival over time, we used recent population-based data to test the combined influence of IHC subtypes, grade and stage on breast cancer death.

Methods: We identified 24,137 women with invasive breast cancer aged 20 to 74 between 2005 and 2015 in the database of the Cancer Registry of Norway. Kaplan-Meier curves, mortality rates and adjusted hazard ratios for breast cancer death were estimated by IHC subtypes, grade, tumour size and nodal status during 13 years of follow-up.

Results: Within all IHC subtypes, grade, tumour size and nodal status were independent predictors of breast cancer death. When combining all prognostic factors, the risk of death was 20- to 40-fold higher in the worst groups compared to the group with the smallest size, low grade and ER+PR+HER2- status. Among node-negative ER+HER2- tumours, larger size conferred a significantly increased breast cancer mortality. ER+PR-HER2- tumours of high grade and advanced stage showed particularly high breast cancer mortality similar to TNBC. When examining early versus late mortality, grade, size and nodal status explained most of the late (> 5 years) mortality among ER+ subtypes.

Conclusions: There is a wide range of risks of dying from breast cancer, also across small breast tumours of low/intermediate grade, and among node-negative tumours. Thus, even with modern breast cancer treatment, stage, grade and molecular subtype (reflected by IHC subtypes) matter for prognosis.

Keywords: Breast cancer; ER; Grade; HER2; IHC subtype; Ki67; PR; Survival/death; TNM stage; pTN status.

Fig. 1

Breast cancer-specific survival proportions, hazard rates and adjusted hazard ratios by IHC subtype and grade. Legend: Survival proportions (panels a–f), hazard rates (panels g–l) and adjusted hazard ratios (panels m–r) including n = 19,220 women with known information on ER, PR, HER2, grade, TNM stage and surgery type. Numbers at risk at start: ER+PR+HER2− n = 3497 (grade I), n = 6605 (grade II), n = 1789 (grade III); ER+PR−HER2− n = 597 (grade I), n = 1399 (grade II), n = 717 (grade III); ER+PR+HER2+ n = 637 (grade II), n = 564 (grade III); ER+PR−HER2+ n = 318 (grade II), n = 369 (grade III); HER2pos n = 235 (grade II), n = 688 (grade III); TNBC n = 320 (grade II), n = 1485 (grade III). Logrank tests of survival differences by grade: ER+PR+HER2− p < 0.001, ER+PR−HER2− p < 0.001, ER+PR+HER2+ p = 0.7013, ER+PR−HER2+ p = 0.0836, HER2pos p = 0.1466, TNBC p = 0.6230. Hazard rate curves only plotted until last event in each group. Hazard ratios adjusted for age and year at diagnosis, subtype × grade interaction, TNM stage, surgery type and follow-up. N = 19,220. Estimates of HRs are given in Additional file 9

Fig. 2

Breast cancer-specific survival proportions, hazard rates and adjusted hazard ratios by IHC subtype and pTN. Legend: Survival proportions (panels a–f), hazard rates (panels g–l) and adjusted hazard ratios (panels m–r) including n = 16,809 women with known information on ER, PR, HER2, grade, TNM stage and surgery type, and restricted to T1-2, N any, M0. Numbers at risk at start: ER+PR+HER2− n = 6229 (pT1pN0), n = 1362 (pT2pN0), n = 3125 (pT1-2pN+); ER+PR−HER2− n = 1309 (pT1pN0), n = 361 (pT2pN0), n = 694 (pT1-2pN+); ER+PR+HER2+ n = 437 (pT1pN0), n = 171 (pT2pN0), n = 380 (pT1-2pN+); ER+PR−HER2+ n = 225 (pT1pN0), n = 92 (pT2pN0), n = 230 (pT1-2pN+); HER2pos n = 250 (pT1pN0), n = 131 (pT2pN0), n = 310 (pT1-2pN+); TNBC n = 638 (pT1pN0), n = 413 (pT2pN0), n = 452 (pT1-2pN+). Logrank tests of survival differences by grade: ER+PR+HER2− p < 0.001, ER+PR−HER2− p < 0.001, ER+PR+HER2+ p = 0.0001, ER+PR−HER2+ p = 0.6100, HER2pos p = 0.0099, TNBC p < 0.001. Hazard rate curves only plotted until the last event in each group. Hazard ratios adjusted for age and year at diagnosis, subtype × pTN interaction, grade, surgery type and follow-up. N = 16,809. Estimates of HRs are given in Additional file 9