Prediction of Late Disease Recurrence and Extended Adjuvant Letrozole Benefit by the HOXB13/IL17BR Biomarker

Abstract

BackgroundBiomarkers to optimize extended adjuvant endocrine therapy for women with estrogen receptor (ER)–positive breast cancer are limited. The HOXB13/IL17BR (H/I) biomarker predicts recurrence risk in ER-positive, lymph node–negative breast cancer patients. H/I was evaluated in MA.17 trial for prognostic performance for late recurrence and treatment benefit from extended adjuvant letrozole.MethodsA prospective–retrospective, nested case-control design of 83 recurrences matched to 166 nonrecurrences from letrozole- and placebo-treated patients within MA.17 was conducted. Expression of H/I within primary tumors was determined by reverse-transcription polymerase chain reaction with a prespecified cutpoint. The predictive ability of H/I for ascertaining benefit from letrozole was determined using multivariable conditional logistic regression including standard clinicopathological factors as covariates. All statistical tests were two-sided.ResultsHigh H/I was statistically significantly associated with a decrease in late recurrence in patients receiving extended letrozole therapy (odds ratio [OR] = 0.35; 95% confidence interval [CI] = 0.16 to 0.75; P = .007). In an adjusted model with standard clinicopathological factors, high H/I remained statistically significantly associated with patient benefit from letrozole (OR = 0.33; 95% CI = 0.15 to 0.73; P = .006). Reduction in the absolute risk of recurrence at 5 years was 16.5% for patients with high H/I (P = .007). The interaction between H/I and letrozole treatment was statistically significant (P = .03).ConclusionsIn the absence of extended letrozole therapy, high H/I identifies a subgroup of ER-positive patients disease-free after 5 years of tamoxifen who are at risk for late recurrence. When extended endocrine therapy with letrozole is prescribed, high H/I predicts benefit from therapy and a decreased probability of late disease recurrence.

Estrogen Receptor Expression in 21-Gene Recurrence Score Predicts Increased Late Recurrence for Estrogen-Positive/HER2-Negative Breast Cancer

“…This possibility should be assessed in correlative science studies associated with the relevant trials. Of note, the BCI has been found to predict benefit from letrozole in the MA.17 trial that randomized patients to receive the aromatase inhibitor for 5 years or no further endocrine treatment in women who had remained recurrence-free after 5 years' adjuvant tamoxifen treatment (22). It would be helpful to know the features of the 7 genes in BCI that contributed to the prediction.…”

Predictive Factors for Late (>5 Years) Distant Recurrences in Hormone Receptor (HR) Positive, Human Epidermal Growth Factor Receptor 2 (HER2) Negative Breast Cancer Patients: >20 Year Follow Up

“…There is growing evidence that tumor size at diagnosis and nodal status may be helpful in predicting the delayed recurrence in hormone positive patients [18][19][20]. In our study the tumor size, T-stage at diagnosis, and duration of adjuvant therapy were associated with late relapse (p≤0.025, p≤0.012, p≤0.037 respectively) however T-stage at diagnosis was the only independent predictor identified; with an estimated odds ratio of 2.62 (95% CI: 1.22, 5.64) and an estimated hazard ratio of 2.22 (95% CI: 1.32, 3.72).…”

Cross-Stratification and Differential Risk by Breast Cancer Index and Recurrence Score in Women with Hormone Receptor–Positive Lymph Node–Negative Early-Stage Breast Cancer

“…These findings suggest that a significant proportion of RS low risk patients are at an elevated risk of late recurrence and may benefit from extended endocrine therapy. Notably, the H/I component of the BCI test has been shown to be predictive of benefit from extended endocrine therapy in the MA.17 trial (11). BCI also recategorized women who were classified by RS into the high risk into a low risk group.…”

“…10). H/I is a biomarker that is associated with tumor responsiveness to endocrine therapy in breast cancer (10,11). MGI consists of the average expression of five cell cycle-associated genes and provides quantitative and objective molecular assessment of tumor grade and proliferative status (10,12).…”