Proliferation and estrogen signaling can distinguish patients at risk for early versus late relapse among estrogen receptor positive breast cancers

Abstract

Introduction: We examined if a combination of proliferation markers and estrogen receptor (ER) activity could predict early versus late relapses in ER-positive breast cancer and inform the choice and length of adjuvant endocrine therapy.

Methods: Baseline affymetrix gene-expression profiles from ER-positive patients who received no systemic therapy (n = 559), adjuvant tamoxifen for 5 years (cohort-1: n = 683, cohort-2: n = 282) and from 58 patients treated with neoadjuvant letrozole for 3 months (gene-expression available at baseline, 14 and 90 days) were analyzed. A proliferation score based on the expression of mitotic kinases (MKS) and an ER-related score (ERS) adopted from Oncotype DX® were calculated. The same analysis was performed using the Genomic Grade Index as proliferation marker and the luminal gene score from the PAM50 classifier as measure of estrogen-related genes. Median values were used to define low and high marker groups and four combinations were created. Relapses were grouped into time cohorts of 0-2.5, 0-5, 5-10 years.

Results: In the overall 10 years period, the proportional hazards assumption was violated for several biomarker groups indicating time-dependent effects. In tamoxifen-treated patients Low-MKS/Low-ERS cancers had continuously increasing risk of relapse that was higher after 5 years than Low-MKS/High-ERS cancers [0 to 10 year, HR 3.36; p = 0.013]. High-MKS/High-ERS cancers had low risk of early relapse [0-2.5 years HR 0.13; p = 0.0006], but high risk of late relapse which was higher than in the High-MKS/Low-ERS group [after 5 years HR 3.86; p = 0.007]. The High-MKS/Low-ERS subset had most of the early relapses [0 to 2.5 years, HR 6.53; p < 0.0001] especially in node negative tumors and showed minimal response to neoadjuvant letrozole. These findings were qualitatively confirmed in a smaller independent cohort of tamoxifen-treated patients. Using different biomarkers provided similar results.

Conclusions: Early relapses are highest in highly proliferative/low-ERS cancers, in particular in node negative tumors. Relapses occurring after 5 years of adjuvant tamoxifen are highest among the highly-proliferative/high-ERS tumors although their risk of recurrence is modest in the first 5 years on tamoxifen. These tumors could be the best candidates for extended endocrine therapy.

Figure 1

Kaplan-Meier estimates of distant event-free survival (DEFS) by marker groups in tamoxifen-treated and untreated patients. Kaplan-Meier estimates of 10-year DEFS of the four biomarker groups obtained by combining low and high MKS (mitosis kinome score) and ERS (estrogen-related score). Results are plotted separately for tamoxifen-treated (all patients) (A), tamoxifen-treated (node negative) (B), tamoxifen-treated (node positive) (C), and tamoxifen-untreated patients (D). loP, low MKS; hiP, high MKS; loER, low ERS; hiER, high ERS.

Figure 2

Time-dependent assessment of estrogen-related score (ERS) in the high mitosis kinase score (MKS)-group in both tamoxifen-treated and untreated patients. Landmark analyses of the Kaplan-Meier estimates of distant event-free survival (DEFS) for highly proliferative tumors (high-MKS) according to ERS groups (high and low) during the first 2.5 years (left side of each panel), from 2.5 to 5 years (center of each panel) and from 5 to 10 years (right side of each panel) are shown. Results are plotted separately for tamoxifen-treated, node-negative (A), tamoxifen-treated, node-positive (B) and tamoxifen-untreated, node-negative (C) patients.

Figure 3

Time-dependent assessment of combinations of different markers of proliferation and estrogen receptor (ER)-related genes. Landmark analyses of the Kaplan-Meier estimates of distant event-free survival (DEFS) during the first 5 years (left side of each panel) and from 5 to 10 years (right side of each panel) are shown for tamoxifen-treated patients according to four biomarker groups by combining mitosis kinase score (MKS) (low and high) and estrogen-related score (ERS) (high and low) in ER-positive/human epidermal growth factor (HER)2-negative low proliferation tumors (A) and high-proliferation tumors (B) by the three-gene model [21]; in Luminal A (C) and luminal B (D) by PAM50; and in low risk (E) and high risk (F) by Mammaprint. loP, low MKS; hiP, high MKS; loER, low ERS; hiER, high ERS.

Figure 4

Prognostic values of the four biomarker groups in the second cohort of tamoxifen-treated patients. Kaplan-Meier estimates of 10-year distant event-free survival (DEFS) of the four biomarker groups obtained by combining low and high mitosis kinase score (MKS) and estrogen-related score (ERS) in all patients (A) and node-negative patients (B). Annual hazard rates for distant recurrences by biomarker-group estimates using kernel-based methods for all patients (C). Landmark analyses of the Kaplan-Meier estimates of DEFS during the first 5 years (left side of the panel) and from 5 to 10 years (right side of the panel) is shown for the high-MKS groups by ERS (high and low) (D). loP, low MKS; hiP, high MKS; loER, low ERS; hiER, high ERS).

Figure 5

Predictive value of the estrogen-related score (ERS) in the high-proliferation group after neoadjuvant letrozole. The dynamic change of proliferation measured by mitosis kinase score (MKS) at baseline, 14 and 90 days in patients with baseline high proliferation treated with neoadjuvant letrozole in the high-ERS (A) and low-ERS (B) groups (red line = clinical response; blue line = non responder; green line = clinical information not available). (C) Box plot describing the proliferation at 14 and 90 days in the high-ERS and low-ERS groups. A comparison between MKS values in different groups was performed by Wilcoxon rank-sum test.