Prediction of tumor mutation burden in breast cancer based on the expression of ER, PR, HER-2, and Ki-67
Received 14 December 2017
Accepted for publication 5 March 2018
Published 19 April 2018 Volume 2018:11 Pages 2269—2275
Checked for plagiarism Yes
Review by Single-blind
Peer reviewer comments 4
Editor who approved publication: Dr Ingrid Espinoza
Junnan Xu,1,2 Xiangyu Guo,1 Mingxi Jing,1 Tao Sun1
1Department of Medical Oncology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, Shenyang, Liaoning, People’s Republic of China; 2Department of Medical Oncology, Key Laboratory of Liaoning Breast Cancer Research, Shenyang, Liaoning, People’s Republic of China
Objective: Cancer immunoediting is the process of eliminating highly immunogenic tumor cells by somatic evolution and protecting the host from tumor development in the host immune system. Frequencies of somatic mutations or tumor mutation burden (TMB) were associated with immunogenicity of breast cancer. This study aimed to predict the level of TMB in patients with breast cancer by the expression of estrogen (ER), progesterone (PR), HER-2, and Ki-67, thereby anticipating the prognosis of patients and the possible response to immunotherapy.
Patients and methods: In 53 patients with breast cancer, the 453 multigenes panel based on NGS was used to determine the TMB value of breast cancer in the patient’s primary tumor tissues. The predicted TMB value was divided into 4 groups: A (0–3.33), B (3.33–5.56), C (5.56–8.89), and D (>8.89), according to the quartile method, with group A as reference level. Logistic regression was used to analyze the risk ratio of each molecule type, and the prediction model was established. Survival probabilities by covariates were assessed using Kaplan–Meier estimator survival analysis and Cox’s proportional hazards models.
Results: In 53 patients, the TMB value measured by the NGS polygenic panel was between 0 and 14.4/Mb. TMB distribution in 53 cases of breast cancer tissue: 18 cases in A group, 22 cases in B group, 10 cases in C group, and 3 cases in D group. HER-2 expression positivity was significantly associated with TMB (HER-2 positive vs HER-2 negative, odds ratio [OR] =34.81, 95% confidence interval [CI]: 3.711–821.689, P=0.0065). Higher TMB was distributed in the patients who were Ki-67 expression positive (>14%) than those who were Ki-67 expression negative (≤14%) (OR =0.217, 95% CI: 0.054–0.806, P=0.0242). However, no significant differences of TMB were found between ER-positive group and ER-negative group (OR =3.133, 95% CI: 0.124–127.687, P=0.4954) and between PR-positive group and PR-negative group in terms of TMB (OR =1.702, 95% CI: 0.162–20.335, P=0.6492). The predicted model is TMB = -1.14×ER +0.53×PR +3.55×HER-2-1.53×Ki-67+ CONSTANT (INTERCEPT). Patients with low TMB had a better disease-free survival (DFS) than those with high TMB (83 vs 59 m, P=0.002). In a multivariate analysis, high TMB (>5.56) was an independent predictive factor for decreased DFS (adjusted hazard ratio [HR], 5.594; 95% CI: 1.694–18.473; P=0.005).
Conclusion: The preliminary results suggest that the level of TMB value in patients with breast cancer can be predicted based on the expression levels of ER, PR, HER-2, and Ki-67, which may indicate the prognostic and predictive value of immunotherapy in patients with breast cancer.
Keywords: breast cancer, tumor mutation burden, estrogen receptor, HER-2
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