J Cancer 2021; 12(14):4408-4417. doi:10.7150/jca.52993 This issue Cite

Research Paper

Mutational Landscape of PI3K-AKT-mTOR Pathway in Breast Cancer: Implications for Targeted Therapeutics

Weikai Xiao1#, Guochun Zhang1#, Bo Chen1#, Xiaoqing Chen2, Lingzhu Wen1, Jianguo Lai1, Xuerui Li1, Min Li3, Hao Liu3, Jing Liu3, Han Han-Zhang3, Analyn Lizaso3, Ning Liao1✉

1. Department of Breast Cancer, Cancer Center, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.
2. Department of Breast, Foshan Women and Children Hospital, Foshan, China.
3. Burning Rock Biotech, Guangzhou, China.
# These authors made equal contributions.

Citation:
Xiao W, Zhang G, Chen B, Chen X, Wen L, Lai J, Li X, Li M, Liu H, Liu J, Han-Zhang H, Lizaso A, Liao N. Mutational Landscape of PI3K-AKT-mTOR Pathway in Breast Cancer: Implications for Targeted Therapeutics. J Cancer 2021; 12(14):4408-4417. doi:10.7150/jca.52993. https://www.jcancer.org/v12p4408.htm
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Abstract

Graphic abstract

Background: Comprehensive analysis of PI3K-AKT-mTOR pathway gene alterations in breast cancer may be helpful for targeted therapy.

Methods: We performed targeted sequencing using a panel of 520 cancer-related genes to investigate gene alterations in the PI3K-AKT-mTOR pathway from 589 consecutive Chinese women diagnosed with stage I-III breast cancer. Analyses of overall survival (OS) were performed using the publicly available clinical and genomic data from METABRIC.

Results: PI3K-AKT-mTOR pathway gene alterations were detected in 62.6% (369/589) of our cohort. The most commonly altered genes were PIK3CA (45%), PTEN (7.5%), AKT1 (5.9 %), PIK3R1 (2.7%), and PIK3CG (2%). Four PIK3CA mutations (E545K, H1047R, E542K, and H1047L) were detected in all the breast cancer molecular subtypes. Seven PIK3CA mutations (E545G, E418_L422delinsV, E726K, E110del, G1049R, G118D, and D350G) were only detected in HR+ subtypes. Two PIK3CA mutations (C420R and N345K) were only detected in non-triple-negative subtypes. Most cases with PTEN mutation were HR+/HER2- subtype (77.3%), followed by triple-negative subtype (18.2%). In the METABRIC breast cancer dataset, no significant OS difference was observed between the PIK3CA-mutant and wild-type groups. However, patients with multiple PIK3CA mutations (mOS: 131 vs. 159 months, P= 0.029), or PIK3CA mutations located in the C2 domain had significantly shorter OS (mOS, 130 vs. 154 months, P=0.020) than those without the mutations.

Conclusions: Our study reveals the heterogeneity in PI3K-AKT-mTOR pathway among the breast cancer molecular subtypes in our cohort. Moreover, the number and specific sites of PIK3CA mutations have distinct prognostic impact.

Keywords: Breast cancer, PI3K-AKT-mTOR pathway, gene alteration, molecular subtypes, prognosis


Citation styles

APA
Xiao, W., Zhang, G., Chen, B., Chen, X., Wen, L., Lai, J., Li, X., Li, M., Liu, H., Liu, J., Han-Zhang, H., Lizaso, A., Liao, N. (2021). Mutational Landscape of PI3K-AKT-mTOR Pathway in Breast Cancer: Implications for Targeted Therapeutics. Journal of Cancer, 12(14), 4408-4417. https://doi.org/10.7150/jca.52993.

ACS
Xiao, W.; Zhang, G.; Chen, B.; Chen, X.; Wen, L.; Lai, J.; Li, X.; Li, M.; Liu, H.; Liu, J.; Han-Zhang, H.; Lizaso, A.; Liao, N. Mutational Landscape of PI3K-AKT-mTOR Pathway in Breast Cancer: Implications for Targeted Therapeutics. J. Cancer 2021, 12 (14), 4408-4417. DOI: 10.7150/jca.52993.

NLM
Xiao W, Zhang G, Chen B, Chen X, Wen L, Lai J, Li X, Li M, Liu H, Liu J, Han-Zhang H, Lizaso A, Liao N. Mutational Landscape of PI3K-AKT-mTOR Pathway in Breast Cancer: Implications for Targeted Therapeutics. J Cancer 2021; 12(14):4408-4417. doi:10.7150/jca.52993. https://www.jcancer.org/v12p4408.htm

CSE
Xiao W, Zhang G, Chen B, Chen X, Wen L, Lai J, Li X, Li M, Liu H, Liu J, Han-Zhang H, Lizaso A, Liao N. 2021. Mutational Landscape of PI3K-AKT-mTOR Pathway in Breast Cancer: Implications for Targeted Therapeutics. J Cancer. 12(14):4408-4417.

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