21-Gene assay as predictor of chemotherapy benefit in HER2-negative breast cancer

Abstract

The NSABP B-20 prospective-retrospective study of the 21-gene Oncotype DX Breast Cancer Recurrence Score® test predicted benefit from addition of chemotherapy to tamoxifen in node-negative, estrogen-receptor positive breast cancer when recurrence score (RS) was ≥31. HER2 is a component of the RS algorithm with a positive coefficient and contributes to higher RS values. Accrual to B-20 occurred prior to routine testing for HER2, so questions have arisen regarding assay performance if HER2-positive patients were identified and excluded. We report an exploratory reanalysis of the B-20, 21-gene study following exclusion of such patients. Patients were considered HER2 positive if quantitative RT-PCR for HER2 was ≥11.5 units, and excluded from re-analyses performed using the original cutoffs: <18, 18–30, ≥31, and the TAILORx cutoffs: <11, 11–25, >25. The endpoint remained distant recurrence-free interval (DRFI) as in the original study. Distribution was estimated via the Kaplan–Meier method and compared via log-rank test. Multivariate Cox proportional hazards models estimated chemotherapy benefit in each group. In the RS < 18 and 18–30 groups, 1.7 and 6.7% were HER2 positive. In the RS ≥ 31 group, 41% were HER2 positive. Exclusion resulted in fewer events, with loss of significance for benefit from chemotherapy in the overall HER2-negative cohort (log-rank P = 0.06), but substantial benefit from chemotherapy remained in the RS ≥ 31 cohort (HR = 0.18; 95% CI: 0.07–0.47) and the RS > 25 cohort (HR = 0.28; 95% CI: 0.12–0.64). No benefit from chemotherapy was evident in the other RS groups. Following exclusion of HER2-positive patients based on RT-PCR expression, substantial benefit of chemotherapy remained for RS ≥ 31 as originally employed, and with RS > 25 employed in TAILORx.

Clinical Outcomes in Early Breast Cancer With a High 21-Gene Recurrence Score of 26 to 100 Assigned to Adjuvant Chemotherapy Plus Endocrine Therapy

“…1 Outcomes were also similar in patients enrolled in TAILORx trial with an RS of 0 to 10 7 and 11 to 25 6 treated with endocrine therapy alone compared with the B20 cohort, 5 supporting the use of outcomes from the B20 trial in planning TAILORx. In addition, the projected rates of freedom from recurrence of breast cancer at a distant site in this population if treated with endocrine therapy alone was estimated to be 78.8% (SE, 14.0%) at 5 years and 65.4% (SE, 10.4%) at 9 years when simulating outcomes based on the treatment effect of chemotherapy noted in the ERBB2-negative cohort of the B20 trial, 4 providing additional evidence that the outcomes when treated with chemoendocrine therapy were better than expected with endocrine therapy alone in this population. For IDFS, an end point that also includes local-regional recurrences, contralateral breast cancer, other second primary cancers, and deaths from other causes, the estimated 5-and 9-year IDFS rates were 87.6% (SE, 1.0%) and 75.7% (SE, 2.2%).…”

“…The expected rate of distant recurrence through 5 and 9 years of patients with RS of 26 to 100 (referred to here as arm D of TAILORx) if treated with endocrine therapy alone was estimated by combining patient-specific distant recurrence risk information from TAILORx arm D with patient-specific chemotherapy benefit information from ERBB2-negative cohort derived from the NSABP B20 trial. 4 For each individual patient in TAILORx arm D, the log cumulative hazard of distant recurrence was estimated from a Cox model with effects for RS as a continuous covariate and age category (≤50 vs >50 years). The patient-specific log hazard ratio for chemotherapy effect was estimated from NSABP study B20 patients who were ERBB2-negative and hormone receptor-positive (by reverse transcription polymerase chain reaction) using a Cox model with effects for RS as a continuous covariate, age category (≤50 vs >50 years), randomized chemotherapy use, the 2-way interactions of RS with chemotherapy and age category with chemotherapy, and the 3-way interaction of RS with age category with chemotherapy.…”

“…2,3 Prediction of chemotherapy benefit was initially established in the prospective-retrospective validation study including primary tumor samples from 651 patients enrolled in the B20 trial with hormone receptorpositive, axillary node-negative breast cancer randomized to tamoxifen or chemotherapy plus tamoxifen, whether high RS was defined as 31 to 100 irrespective of ERBB2 RNA expression (n = 651), 2 or 26 to 100 in tumor samples that had a low ERBB2 RNA expression score (n = 569). 4 For the 122 (21%) patients with a high RS of 26 to 100 in the ERBB2negative cohort of the B20 validation cohort randomized to tamoxifen or tamoxifen plus an adjuvant chemotherapy regimen (including methotrexate and 5-fluorouracil with or without cyclophosphamide), 10-year distant recurrencefree survival rates were 62% (95% CI, 48%-81%) with tamoxifen alone, and 88% (95% CI, 81%-95%) with chemotherapy plus tamoxifen; there was a statistically significant interaction between chemotherapy treatment and high RS (likelihood ratio test on interaction, P = .01), indicating that high RS was not only prognostic for a high distant recurrence rate, but also predictive of chemotherapy benefit. 4 Distant recurrence-free survival rates were similar with endocrine therapy alone in other cohorts, including the prospective-retrospective validation study using primary tumor samples derived from 594 patients with hormone receptor-positive, ERBB2-negative axillary nodenegative breast cancer enrolled in the B14 trial who received adjuvant tamoxifen without chemotherapy; 157 (26%) with a high RS of 26 to 100 had an estimated 10-year distant recurrence-free survival rate of 70% (standard error [SE], 3.9%).…”

“…4 For the 122 (21%) patients with a high RS of 26 to 100 in the ERBB2negative cohort of the B20 validation cohort randomized to tamoxifen or tamoxifen plus an adjuvant chemotherapy regimen (including methotrexate and 5-fluorouracil with or without cyclophosphamide), 10-year distant recurrencefree survival rates were 62% (95% CI, 48%-81%) with tamoxifen alone, and 88% (95% CI, 81%-95%) with chemotherapy plus tamoxifen; there was a statistically significant interaction between chemotherapy treatment and high RS (likelihood ratio test on interaction, P = .01), indicating that high RS was not only prognostic for a high distant recurrence rate, but also predictive of chemotherapy benefit. 4 Distant recurrence-free survival rates were similar with endocrine therapy alone in other cohorts, including the prospective-retrospective validation study using primary tumor samples derived from 594 patients with hormone receptor-positive, ERBB2-negative axillary nodenegative breast cancer enrolled in the B14 trial who received adjuvant tamoxifen without chemotherapy; 157 (26%) with a high RS of 26 to 100 had an estimated 10-year distant recurrence-free survival rate of 70% (standard error [SE], 3.9%). 1 The Trial Assigning Individualized Options for Treatment (TAILORx) was a prospective trial designed to address gaps in our knowledge about the application of the 21-gene RS in hormone receptor-positive, ERBB2-negative, axillary node-negative breast cancer.…”

Use of Biomarkers to Guide Decisions on Adjuvant Systemic Therapy for Women With Early-Stage Invasive Breast Cancer: ASCO Clinical Practice Guideline Update—Integration of Results From TAILORx

“…In a recent exploratory reanalysis of B-20, the performance of the 21-gene assay in predicting chemotherapy benefit was assessed using the recurrence score cutoffs used in TAILORx. 6 The analysis demonstrated a statistically significant benefit from chemoendocrine therapy in women with a recurrence score of greater than 25 (hazard ratio, 0.27; 95% CI, 0.12 to 0.62; P , .001). Specifically, the 10-year distant recurrence-free estimate for women treated with tamoxifen alone was 62% (95% CI, 48% to 81%), compared with 88% (95% CI, 81% to 95%) in individuals treated with tamoxifen and chemotherapy.…”