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Simulation Modeling to Extend Clinical Trials of Adjuvant Chemotherapy Guided by a 21-Gene Expression Assay in Early Breast Cancer.

ABSTRACT:

Purpose

The Trial Assigning Individualized Options for Treatment (TAILORx) found chemotherapy could be omitted in many women with hormone receptor-positive, HER2-negative, node-negative breast cancer and 21-gene recurrence scores (RS) 11-25, but left unanswered questions. We used simulation modeling to fill these gaps.

Methods

We simulated women eligible for TAILORx using joint distributions of patient and tumor characteristics and RS from TAILORx data; treatment effects by RS from other trials; and competing mortality from the Surveillance, Epidemiology, and End Results program database. The model simulations replicated TAILORx design, and then tested treatment effects on 9-year distant recurrence-free survival (DRFS) in 14 new scenarios: eight subgroups defined by age (≤50 and >50 years) and 21-gene RS (11-25/16-25/16-20/21-25); six different RS cut points among women ages 18-75 years (16-25, 16-20, 21-25, 26-30, 26-100); and 20-year follow-up. Mean hazard ratios SD, and DRFS rates are reported from 1000 simulations.

Results

The simulation results closely replicated TAILORx findings, with 75% of simulated trials showing noninferiority for chemotherapy omission. There was a mean DRFS hazard ratio of 1.79 (0.94) for endocrine vs chemoendocrine therapy among women ages 50 years and younger with RS 16-25; the DFRS rates were 91.6% (0.04) for endocrine and 94.8% (0.01) for chemoendocrine therapy. When treatment was randomly assigned among women ages 18-75 years with RS 26-30, the mean DRFS hazard ratio for endocrine vs chemoendocrine therapy was 1.60 (0.83). The conclusions were unchanged at 20-year follow-up.

Conclusions

Our results confirmed a small benefit in chemotherapy among women aged 50 years and younger with RS 16-25. Simulation modeling is useful to extend clinical trials, indicate how uncertainty might affect results, and power decision tools to support broader practice discussions.

SUBMITTER: Jayasekera J

PROVIDER: S-EPMC7049983 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND:The recurrence score based on the 21-gene breast cancer assay predicts chemotherapy benefit if it is high and a low risk of recurrence in the absence of chemotherapy if it is low; however, there is uncertainty about the benefit of chemotherapy for most patients, who have a midrange score. METHODS:We performed a prospective trial involving 10,273 women with hormone-receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative, axillary node-negative breast cancer. Of the 9719 eligible patients with follow-up information, 6711 (69%) had a midrange recurrence score of 11 to 25 and were randomly assigned to receive either chemoendocrine therapy or endocrine therapy alone. The trial was designed to show noninferiority of endocrine therapy alone for invasive disease-free survival (defined as freedom from invasive disease recurrence, second primary cancer, or death). RESULTS:Endocrine therapy was noninferior to chemoendocrine therapy in the analysis of invasive disease-free survival (hazard ratio for invasive disease recurrence, second primary cancer, or death [endocrine vs. chemoendocrine therapy], 1.08; 95% confidence interval, 0.94 to 1.24; P=0.26). At 9 years, the two treatment groups had similar rates of invasive disease-free survival (83.3% in the endocrine-therapy group and 84.3% in the chemoendocrine-therapy group), freedom from disease recurrence at a distant site (94.5% and 95.0%) or at a distant or local-regional site (92.2% and 92.9%), and overall survival (93.9% and 93.8%). The chemotherapy benefit for invasive disease-free survival varied with the combination of recurrence score and age (P=0.004), with some benefit of chemotherapy found in women 50 years of age or younger with a recurrence score of 16 to 25. CONCLUSIONS:Adjuvant endocrine therapy and chemoendocrine therapy had similar efficacy in women with hormone-receptor-positive, HER2-negative, axillary node-negative breast cancer who had a midrange 21-gene recurrence score, although some benefit of chemotherapy was found in some women 50 years of age or younger. (Funded by the National Cancer Institute and others; TAILORx ClinicalTrials.gov number, NCT00310180 .).

Project description:BackgroundThe recurrence score based on the 21-gene breast-cancer assay has been clinically useful in predicting a chemotherapy benefit in hormone-receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative, axillary lymph-node-negative breast cancer. In women with positive lymph-node disease, the role of the recurrence score with respect to predicting a benefit of adjuvant chemotherapy is unclear.MethodsIn a prospective trial, we randomly assigned women with hormone-receptor-positive, HER2-negative breast cancer, one to three positive axillary lymph nodes, and a recurrence score of 25 or lower (scores range from 0 to 100, with higher scores indicating a worse prognosis) to endocrine therapy only or to chemotherapy plus endocrine (chemoendocrine) therapy. The primary objective was to determine the effect of chemotherapy on invasive disease-free survival and whether the effect was influenced by the recurrence score. Secondary end points included distant relapse-free survival.ResultsA total of 5083 women (33.2% premenopausal and 66.8% postmenopausal) underwent randomization, and 5018 participated in the trial. At the prespecified third interim analysis, the chemotherapy benefit with respect to increasing invasive disease-free survival differed according to menopausal status (P = 0.008 for the comparison of chemotherapy benefit in premenopausal and postmenopausal participants), and separate prespecified analyses were conducted. Among postmenopausal women, invasive disease-free survival at 5 years was 91.9% in the endocrine-only group and 91.3% in the chemoendocrine group, with no chemotherapy benefit (hazard ratio for invasive disease recurrence, new primary cancer [breast cancer or another type], or death, 1.02; 95% confidence interval [CI], 0.82 to 1.26; P = 0.89). Among premenopausal women, invasive disease-free survival at 5 years was 89.0% with endocrine-only therapy and 93.9% with chemoendocrine therapy (hazard ratio, 0.60; 95% CI, 0.43 to 0.83; P = 0.002), with a similar increase in distant relapse-free survival (hazard ratio, 0.58; 95% CI, 0.39 to 0.87; P = 0.009). The relative chemotherapy benefit did not increase as the recurrence score increased.ConclusionsAmong premenopausal women with one to three positive lymph nodes and a recurrence score of 25 or lower, those who received chemoendocrine therapy had longer invasive disease-free survival and distant relapse-free survival than those who received endocrine-only therapy, whereas postmenopausal women with similar characteristics did not benefit from adjuvant chemotherapy. (Funded by the National Cancer Institute and others; RxPONDER ClinicalTrials.gov number, NCT01272037.).