Pattern of recurrence of early breast cancer is different according to intrinsic subtype and proliferation index

Abstract

Introduction: Recurrence risk in breast cancer varies throughout the follow-up time. We examined if these changes are related to the level of expression of the proliferation pathway and intrinsic subtypes.

Methods: Expression of estrogen and progesterone receptor, Ki-67, human epidermal growth factor receptor 2 (HER2), epidermal growth factor receptor (EGFR) and cytokeratin 5/6 (CK 5/6) was performed on tissue-microarrays constructed from a large and uniformly managed series of early breast cancer patients (N = 1,249). Subtype definitions by four biomarkers were as follows: luminal A (ER + and/or PR+, HER2−, Ki-67 <14), luminal B (ER + and/or PR+, HER2−, Ki-67 ≥14), HER2-enriched (any ER, any PR, HER2+, any Ki-67), triple-negative (ER−, PR−, HER2−, any Ki-67). Subtype definitions by six biomarkers were as follows: luminal A (ER + and/or PR+, HER2−, Ki-67 <14, any CK 5/6, any EGFR), luminal B (ER + and/or PR+, HER2−, Ki-67 ≥14, any CK 5/6, any EGFR), HER2-enriched (ER−, PR−, HER2+, any Ki-67, any CK 5/6, any EGFR), Luminal-HER2 (ER + and/or PR+, HER2+, any Ki-67, any CK 5/6, any EGFR), Basal-like (ER−, PR−, HER2−, any Ki-67, CK5/6+ and/or EGFR+), triple-negative nonbasal (ER−, PR−, HER2−, any Ki-67, CK 5/6−, EGFR−). Each four- or six-marker defined intrinsic subtype was divided in two groups, with Ki-67 <14% or with Ki-67 ≥14%. Recurrence hazard rate function was determined for each intrinsic subtype as a whole and according to Ki-67 value.

Results: Luminal A displayed a slow risk increase, reaching its maximum after three years and then remained steady. Luminal B presented most of its relapses during the first five years. HER2-enriched tumors show a peak of recurrence nearly twenty months post-surgery, with a greater risk in Ki-67 ≥14%. However a second peak occurred at 72 months but the risk magnitude was greater in Ki-67 <14%. Triple negative tumors with low proliferation rate display a smooth risk curve, but with Ki-67 ≥14% show sharp peak at nearly 18 months.

Conclusions: Each intrinsic subtype has a particular pattern of relapses over time which change depending on the level of activation of the proliferation pathway assessed by Ki-67. These findings could have clinical implications both on adjuvant treatment trial design and on the recommendations concerning the surveillance of patients.

Figure 1

Flow diagram of the patients through the study. DCIS, ductal carcinoma in situ.

Figure 2

Kaplan-Meier curves for breast cancer–free survival based on intrinsic subtypes (four markers) and proliferation rate. (A) Whole series according to the four intrinsic subtypes. (B) Luminal tumors according to Ki-67 value. (C) HER2-enriched tumors according to Ki-67 value. (D) Triple negative tumors according to Ki-67 value. HER2, human epidermal growth factor receptor 2; OR, odds ratio.

Figure 3

Kaplan-Meier curves for breast cancer–free survival based on intrinsic subtypes (six markers) and proliferation rate. (A) Whole series according to six intrinsic subtypes. TNP, triple-negative phenotype. (B) Luminal tumors according to Ki-67 value. OR, odds ratio. (C) Luminal human epidermal growth factor receptor 2 (HER2) tumors according to Ki-67 value. (D) HER2-enriched tumors according to Ki-67 value. (E) Triple-negative-nonbasal tumors according to Ki-67 value. (F) Basal-like tumors according to Ki-67 value.

Figure 4

Recurrence hazard rate functions for intrinsic subtypes (four markers) and proliferation rate. (A) Whole series according to Ki-67 value. (B) Luminal tumors as a whole and according to Ki-67 value. (C) Human epidermal growth factor 2 (HER2)-enriched tumors as a whole and according to Ki-67 value. (D) Triple-negative tumors as a whole and according to Ki-67 value. max(HR), maximum hazard rate.

Figure 5

Recurrence hazard rate functions for intrinsic subtypes (six markers). (A) Luminal A tumors. (B) Luminal B tumors. (C) Luminal human epidermal growth factor receptor 2 (HER2) tumors. (D) HER2-enriched tumors. (E) Triple-negative phenotype (TNP) nonbasal tumors. (F) Basal-like tumors. max(HR), maximum hazard rate.