Validation of the 18-gene classifier as a prognostic biomarker of distant metastasis in breast cancer

Skye Hung-Chun Cheng, Tzu-Ting Huang, Yu-Hao Cheng, Tee Benita Kiat Tan, Chen-Fang Horng, Yong Alison Wang, Nicholas Shannon Brian, Li-Sun Shih, Ben-Long Yu, Skye Hung-Chun Cheng, Tzu-Ting Huang, Yu-Hao Cheng, Tee Benita Kiat Tan, Chen-Fang Horng, Yong Alison Wang, Nicholas Shannon Brian, Li-Sun Shih, Ben-Long Yu

Abstract

We validated an 18-gene classifier (GC) initially developed to predict local/regional recurrence after mastectomy in estimating distant metastasis risk. The 18-gene scoring algorithm defines scores as: <21, low risk; ≥21, high risk. Six hundred eighty-three patients with primary operable breast cancer and fresh frozen tumor tissues available were included. The primary outcome was the 5-year probability of freedom from distant metastasis (DMFP). Two external datasets were used to test the predictive accuracy of 18-GC. The 5-year rates of DMFP for patients classified as low-risk (n = 146, 21.7%) and high-risk (n = 537, 78.6%) were 96.2% (95% CI, 91.1%-98.8%) and 80.9% (74.6%-81.9%), respectively (median follow-up interval, 71.8 months). The 5-year rates of DMFP of the low-risk group in stage I (n = 62, 35.6%), stage II (n = 66, 20.1%), and stage III (n = 18, 10.3%) were 100%, 94.2% (78.5%-98.5%), and 90.9% (50.8%-98.7%), respectively. Multivariate analysis revealed that 18-GC is an independent prognostic factor of distant metastasis (adjusted hazard ratio, 5.1; 95% CI, 1.8-14.1; p = 0.0017) for scores of ≥21. External validation showed that the 5-year rate of DMFP in the low- and high-risk patients was 94.1% (82.9%-100%) and 80.3% (70.7%-89.9%, p = 0.06) in a Singapore dataset, and 89.5% (81.9%-94.1%) and 73.6% (67.2%-79.0%, p = 0.0039) in the GEO-GSE20685 dataset, respectively. In conclusion, 18-GC is a viable prognostic biomarker for breast cancer to estimate distant metastasis risk.

Conflict of interest statement

Competing Interests: The authors have read the journal's policy and the authors of this manuscript have the following competing interests: The author (SHC) owns a patent relating to the content of this manuscript (Taiwan patent number: 104115832). This does not alter our adherence to PLOS ONE policies on sharing data and materials. None of the authors has any conflicts of interests in this research, either financial or non-financial.

Figures

Fig 1. Flow of patient selection and…
Fig 1. Flow of patient selection and external validation.
Fig 2. DMFP rates of low- (scores…
Fig 2. DMFP rates of low- (scores of
(A) All patients (n = 683), (B) stage I (n = 175), (C) stage II (n = 328), (D) stage III (n = 174), (E) luminal A subtype (n = 216), (F) luminal B subtype (n = 85), (G) HER2 subtype (n = 259), and (H) triple-negative subtype (n = 123).
Fig 3. Hazard ratio forest plots for…
Fig 3. Hazard ratio forest plots for each subgroup.
18-GC as a continuous variable in the prediction of distant recurrence.
Fig 4. External validation of 18-GC.
Fig 4. External validation of 18-GC.
(A) Validation based on data of 327 patients included dataset from NCBI GSE20685, ID: 200020685. Time to distant metastasis by the 18-gene scores: The 5-year rate of DMFP in patients with scores of

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