Significance of PIK3CA Mutations in Patients with Early Breast Cancer Treated with Adjuvant Chemotherapy: A Hellenic Cooperative Oncology Group (HeCOG) Study

George Papaxoinis, Vassiliki Kotoula, Zoi Alexopoulou, Konstantine T Kalogeras, Flora Zagouri, Eleni Timotheadou, Helen Gogas, George Pentheroudakis, Christos Christodoulou, Angelos Koutras, Dimitrios Bafaloukos, Gerasimos Aravantinos, Pavlos Papakostas, Elpida Charalambous, Kyriaki Papadopoulou, Ioannis Varthalitis, Ioannis Efstratiou, Thomas Zaramboukas, Helen Patsea, Chrisoula D Scopa, Maria Skondra, Paris Kosmidis, Dimitrios Pectasides, George Fountzilas, George Papaxoinis, Vassiliki Kotoula, Zoi Alexopoulou, Konstantine T Kalogeras, Flora Zagouri, Eleni Timotheadou, Helen Gogas, George Pentheroudakis, Christos Christodoulou, Angelos Koutras, Dimitrios Bafaloukos, Gerasimos Aravantinos, Pavlos Papakostas, Elpida Charalambous, Kyriaki Papadopoulou, Ioannis Varthalitis, Ioannis Efstratiou, Thomas Zaramboukas, Helen Patsea, Chrisoula D Scopa, Maria Skondra, Paris Kosmidis, Dimitrios Pectasides, George Fountzilas

Abstract

Background: The PI3K-AKT pathway is frequently activated in breast cancer. PIK3CA mutations are most frequently found in the helical (exon 9) and kinase (exon 20) domains of this protein. The aim of the present study was to examine the role of different types of PIK3CA mutations in combination with molecular biomarkers related to PI3K-AKT signaling in patients with early breast cancer.

Methods: Tumor tissue samples from 1008 early breast cancer patients treated with adjuvant chemotherapy in two similar randomized trials of HeCOG were examined. Tumors were subtyped with immunohistochemistry (IHC) and FISH for ER, PgR, Ki67, HER2 and androgen receptor (AR). PIK3CA mutations were analyzed by Sanger sequencing (exon 20) and qPCR (exon 9) (Sanger/qPCR mutations). In 610 cases, next generation sequencing (NGS) PIK3CA mutation data were also available. PIK3CA mutations and PTEN protein expression (IHC) were analyzed in luminal tumors (ER and/or PgR positive), molecular apocrine carcinomas (MAC; ER/PgR negative / AR positive) and hormone receptor (ER/PgR/AR) negative tumors.

Results: PIK3CA mutations were detected in 235/1008 tumors (23%) with Sanger/qPCR and in 149/610 tumors (24%) with NGS. Concordance between the two methods was good with a Kappa coefficient of 0.76 (95% CI 0.69-0.82). Lobular histology, low tumor grade and luminal A tumors were associated with helical domain mutations (PIK3CAhel), while luminal B with kinase domain mutations (PIK3CAkin). The overall incidence of PIK3CA mutations was higher in luminal as compared to MAC and hormone receptor negative tumors (p = 0.004). Disease-free and overall survival did not significantly differ with respect to PIK3CA mutation presence and type. However, a statistically significant interaction between PIK3CA mutation status and PTEN low protein expression with regard to prognosis was identified.

Conclusions: The present study did not show any prognostic significance of specific PIK3CA mutations in a large group of predominantly lymph-node positive breast cancer women treated with adjuvant chemotherapy. Further analyses in larger cohorts are warranted to investigate possible differential effect of distinct PIK3CA mutations in small subgroups of patients.

Conflict of interest statement

Competing Interests: Author Zoi Alexopoulou is employed by Health Data Specialists Ltd. There are no patents, products in development or marketed products to declare. This does not alter the authors' adherence to all the PLoS ONE policies on sharing data and materials. The rest of the authors have declared that no competing interests exist.

Figures

Fig 1. REMARK diagram.
Fig 1. REMARK diagram.
Fig 2. Number of patients with different…
Fig 2. Number of patients with different types of PIK3CA mutations assessed by Sanger/qPCR in the entire population (N = 1008).
Fig 3. Disease-free survival (DFS) and overall…
Fig 3. Disease-free survival (DFS) and overall survival (OS) in the entire population, according to PIK3CA status (mutations in the helical [and kinase] or kinase only domain or wild-type [wt]).
No significant differences observed between the groups.
Fig 4. Multivariate Cox regression analysis presented…
Fig 4. Multivariate Cox regression analysis presented by forest plots.

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