Factors Predicting Late Recurrence for Estrogen Receptor–Positive Breast Cancer

Ivana Sestak; Mitch Dowsett; Lila Zabaglo; Elena Lopez-Knowles; Sean Ferree; J. Wayne Cowens; Jack Cuzick


J Natl Cancer Inst. 2013;105(19):1504-1511. 

In This Article

Abstract and Introduction


Background Adjuvant endocrine therapy beyond 5 years reduces recurrence in patients with estrogen receptor–positive breast cancer. We have previously shown that immunohistochemical markers (IHC4) and two gene expression profile tests (recurrence score [RS] and PAM50 risk of recurrence [ROR]) are associated with time to distant recurrence, and we have now assessed the value of each of these scores and routine clinical variables for predicting outcome, specifically in years 5 to 10.

Methods We used univariate and multivariable proportional hazards models to determine the prognostic value of all variables and scores (IHC4, RS, ROR) for distant recurrence, separately in years 0 to 5 and specifically for years 5 to 10 for all patients. All statistical tests were two-sided.

Results Nodal status and tumor size were at least as strong in years 5 to 10 as in years 0 to 5 (nodal status, years 5–10: χ2 = 21.72 vs years 0–5: χ2 = 11.08, both P < .001; tumor size, years 5–10: χ2 = 10.52 vs years 0–5: χ2 = 10.82, both P = .001). Ki67 and the overall IHC4 score were the only statistically significant biomarkers related to distant recurrence univariablely in the 5 to 10 year period (χ2 = 8.67, χ2 = 13.22, respectively). The ROR score was the strongest molecular prognostic factor in the late follow-up period (χ2 = 16.29; P < .001), whereas IHC4 (χ2 = 7.41) and RS (χ2 = 5.55) were only weakly prognostic in this period. Similar results were seen for all subgroups and for all recurrences.

Conclusions None of the IHC4 markers provided statistically significant prognostic information in years 5 to 10, except for nodal status and tumor size. ROR gave the strongest prognostic information in years 5 to 10. These results may help select patients who could benefit most from hormonal therapy beyond 5 years of treatment.


Adjuvant chemotherapy and endocrine therapy for early breast cancer have had a considerable impact on outcomes,[1] but a substantial number of women, especially those with estrogen receptor (ER)–positive tumors, remain at risk for late recurrences. The annual rate is in excess of 2% for at least 15 years, even after 5 years of tamoxifen therapy,[2] and currently it is not possible to identify a group of such women who can be considered as cured.[3,4] This remains true for at least 10 years for women treated for 5 years with an aromatase inhibitor.[5]

Most of the studies of prevention of late relapse have been performed in women receiving tamoxifen as initial adjuvant endocrine therapy for early ER-positive breast cancer. The MA17 trial clearly showed that extended adjuvant therapy with letrozole after 5 years of tamoxifen prolongs disease-free survival and overall survival, regardless of the patient's nodal status involvement.[6] Brewster et al.[7] found that ER positivity, nodal involvement, and grade were all associated with increased risk of late recurrence. It is of importance to determine to what extent the newer immunohistochemical and molecular scores can help in predicting late recurrence.

Recent publications from the transATAC (Anastrozole, Tamozifen, Alone or in Combination) cohort have demonstrated that the Oncotype DX recurrence score (RS),[8] the immunohistochemical (IHC4) score[9] and the PAM50-based risk of recurrence (ROR) score[10] all provide additional information beyond that available for clinical variables, summarized in the clinical treatment score (CTS), about the risk of distant recurrence in postmenopausal women with hormone receptor–positive breast cancer treated with anastrozole or tamoxifen, but it is unknown how much of this effect extends beyond 5 years. Here, we investigate the relationship between clinical variables, immunohistochemical markers, and these scores for the prediction of distant recurrence separately in years 0 to 5 and years 5 to 10 after diagnosis for postmenopausal women with early hormone receptor–positive breast cancer.