Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
, 110 (7), 726-733

Intratumor Heterogeneity of the Estrogen Receptor and the Long-term Risk of Fatal Breast Cancer

Affiliations

Intratumor Heterogeneity of the Estrogen Receptor and the Long-term Risk of Fatal Breast Cancer

Linda S Lindström et al. J Natl Cancer Inst.

Abstract

Background: Breast cancer patients with estrogen receptor (ER)-positive disease have a continuous long-term risk for fatal breast cancer, but the biological factors influencing this risk are unknown. We aimed to determine whether high intratumor heterogeneity of ER predicts an increased long-term risk (25 years) of fatal breast cancer.

Methods: The STO-3 trial enrolled 1780 postmenopausal lymph node-negative breast cancer patients randomly assigned to receive adjuvant tamoxifen vs not. The fraction of cancer cells for each ER intensity level was scored by breast cancer pathologists, and intratumor heterogeneity of ER was calculated using Rao's quadratic entropy and categorized into high and low heterogeneity using a predefined cutoff at the second tertile (67%). Long-term breast cancer-specific survival analyses by intra-tumor heterogeneity of ER were performed using Kaplan-Meier and multivariable Cox proportional hazard modeling adjusting for patient and tumor characteristics.

Results: A statistically significant difference in long-term survival by high vs low intratumor heterogeneity of ER was seen for all ER-positive patients (P < .001) and for patients with luminal A subtype tumors (P = .01). In multivariable analyses, patients with high intratumor heterogeneity of ER had a twofold increased long-term risk as compared with patients with low intratumor heterogeneity (ER-positive: hazard ratio [HR] = 1.98, 95% confidence interval [CI] = 1.31 to 3.00; luminal A subtype tumors: HR = 2.43, 95% CI = 1.18 to 4.99).

Conclusions: Patients with high intratumor heterogeneity of ER had an increased long-term risk of fatal breast cancer. Interestingly, a similar long-term risk increase was seen in patients with luminal A subtype tumors. Our findings suggest that intratumor heterogeneity of ER is an independent long-term prognosticator with potential to change clinical management, especially for patients with luminal A tumors.

Figures

Figure 1.
Figure 1.
Kernel density plot of the intratumor heterogeneity of the estrogen receptor (quadratic entropy QE, continuous score) for luminal A vs luminal B subtype tumors (PAM50). ER = estrogen receptor.
Figure 2.
Figure 2.
Kaplan-Meier analyses by intratumor heterogeneity of estrogen receptor (ER) and trial arm (four groups: low intratumor heterogeneity of ER/treated arm, low heterogeneity/untreated arm, high heterogeneity/treated arm, high heterogeneity/untreated arm). The P value is based on a two-sided log-rank test; numbers at risk are shown underneath each graph.

Similar articles

See all similar articles

Cited by 8 articles

See all "Cited by" articles

References

    1. Kamangar F, Dores GM, Anderson WF. Patterns of cancer incidence, mortality, and prevalence across five continents: Defining priorities to reduce cancer disparities in different geographic regions of the world. J Clin Oncol. 2006;2414:2137–2150.10.1200/JCO.2005.05.2308 - DOI - PubMed
    1. Pichon MF, Broet P, Magdelenat H et al. , . Prognostic value of steroid receptors after long-term follow-up of 2257 operable breast cancers. Br J Cancer. 1996;7312:1545–1551.10.1038/bjc.1996.291 - DOI - PMC - PubMed
    1. Early Breast Cancer Trialists' Collaborative Group, Davies C, Godwin J et al. , . Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: Patient-level meta-analysis of randomised trials. Lancet. 2011;3789793:771–784. - PMC - PubMed
    1. Colleoni M, Sun Z, Price KN et al. , . Annual hazard rates of recurrence for breast cancer during 24 years of follow-up: Results from the International Breast Cancer Study Group trials I to V. J Clin Oncol. 2016;349:927–935.10.1200/JCO.2015.62.3504 - DOI - PMC - PubMed
    1. Sheppard VB, Faul LA, Luta G et al. , . Frailty and adherence to adjuvant hormonal therapy in older women with breast cancer: CALGB protocol 369901. J Clin Oncol. 2014;3222:2318–2327.10.1200/JCO.2013.51.7367 - DOI - PMC - PubMed

Publication types

MeSH terms

Feedback