Clinical and Genomic Risk to Guide the Use of Adjuvant Therapy for Breast Cancer

Abstract

BACKGROUND The use of adjuvant chemotherapy in patients with breast cancer may be guided by clinicopathological factors and a score based on a 21-gene assay to determine the risk of recurrence. Whether the level of clinical risk of breast cancer recurrence adds prognostic information to the recurrence score is not known. METHODS We performed a prospective trial involving 9427 women with hormone-receptor–positive, human epidermal growth factor receptor 2–negative, axillary node–negative breast cancer, in whom an assay of 21 genes had been performed, and we classified the clinical risk of recurrence of breast cancer as low or high on the basis of the tumor size and histologic grade. The effect of clinical risk was evaluated by calculating hazard ratios for distant recurrence with the use of Cox proportional-hazards models. The initial endocrine therapy was tamoxifen alone in the majority of the premenopausal women who were 50 years of age or younger. RESULTS The level of clinical risk was prognostic of distant recurrence in women with an intermediate 21-gene recurrence score of 11 to 25 (on a scale of 0 to 100, with higher scores indicating a worse prognosis or a greater potential benefit from chemotherapy) who were randomly assigned to endocrine therapy (hazard ratio for the comparison of high vs. low clinical risk, 2.73; 95% confidence interval [CI], 1.93 to 3.87) or to chemotherapy plus endocrine (chemoendocrine) therapy (hazard ratio, 2.41; 95% CI, 1.66 to 3.48) and in women with a high recurrence score (a score of 26 to 100), all of whom were assigned to chemoendocrine therapy (hazard ratio, 3.17; 95% CI, 1.94 to 5.19). Among women who were 50 years of age or younger who had received endocrine therapy alone, the estimated (±SE) rate of distant recurrence at 9 years was less than 5% (≤1.8±0.9%) with a low recurrence score (a score of 0 to 10), irrespective of clinical risk, and 4.7±1.0% with an intermediate recurrence score and low clinical risk. In this age group, the estimated distant recurrence at 9 years exceeded 10% among women with a high clinical risk and an intermediate recurrence score who received endocrine therapy alone (12.3±2.4%) and among those with a high recurrence score who received chemoendocrine therapy (15.2±3.3%). CONCLUSIONS Clinical-risk stratification provided prognostic information that, when added to the 21-gene recurrence score, could be used to identify premenopausal women who could benefit from more effective therapy. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, .)

Ki‐67 index, progesterone receptor expression, histologic grade and tumor size in predicting breast cancer recurrence risk: A consecutive cohort study

“…The 21‐gene RS provides prognostic information regarding the loco‐regional and distant recurrence risk and predicts chemotherapy benefit in EBC [9, 22, 23]. New results from the prospective TAILORx clinical trial showed that the combination of clinical risk stratification on the basis of tumor size, histologic grade, and 21‐gene RS could provide more accurate prognostic information about recurrence [20]. However, the 21‐gene RS assay is not available in most developing countries and is costly.…”

“…Tumor size and histologic grade were combined into a new variable, named the clinical risk, similar to the TAILORx clinical trial [20]. The clinical risk was referred to as low if the tumor diameter was ≤3 cm with a low histologic grade, ≤2 cm with an intermediate grade, or ≤1 cm with a high grade.…”

“…After removing samples with missing data, data from 389 patients (between May 2012 and December 2015; the development set) were used to develop the current predictive IHC3 model, and an additional 146 patients (between January 2016 and January 2017; the validation set) were used to validate the model. The patients were assigned into recurrence risk categories based on the Surexam ® 21‐gene RS and the TAILORx clinical trial criteria [20] (modeling reference standard/gold standard for IHC3 model). Recurrence risk was defined as high if patients were >50 years of age with an RS >25, ≤50 years of age with an RS of >20, or ≤50 years old with an RS of 16‐20 and had a high clinical risk.…”

“…For the 2 numeric variables, the best cutoff value was determined using CART, which was also used for the split point of a node when performing classification. The predicted variables were the risk categories according to the Surexam ® 21‐gene RS and the TAILORx prospective trial criteria [9, 20].…”

First person profile: Joseph Sparano, MD

“…This year, additional TAILORx results analyzing the combined use of Oncotype DX recurrence risk scores and clinical pathologic information to guide clinical decisions were published in NEJM . The findings indicated that clinical risk stratification when added to the genetic test could provide prognostic information for determining which premenopausal women might benefit from chemotherapy.…”