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Clinical implications of routine genomic mutation sequencing in PIK3CA/AKT1 and KRAS/NRAS/BRAF in metastatic breast cancer

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Abstract

Background

There is increasing interest in the molecular profiling of tumour tissues in order to investigate alternative breast cancer (BC) therapies. However, the impact of genomic screening for druggable mutations with targeted gene panel sequencing (TGPS) in routine practice remains controversial.

Methods

This is a retrospective analysis of data from a genomic screening programme at our institution, in which we performed simplified TGPS for mutations in PIK3CA, AKT1, KRAS, NRAS, and BRAF in order to select patients for targeted therapy clinical trials. The genomes of archived samples of primary (PT) and/or metastatic (MT) tumours from advanced BC patients were analysed with MassARRAY technology (Sequenom MassARRAY, OncoCarta v1.0). The level of PTEN expression was assessed by immunohistochemistry. The primary endpoint was to identify the proportion of BC patients with PI3 K and MAPK alterations who were included in clinical trials using targeted therapies against these pathways.

Results

Two hundred and fifteen metastatic BC patients (65 PT and 168 MT) were included. Fifty-two patients (24.19 %) were enrolled in tailored clinical trials, of whom 29 (55.77, 13.49 % of all patients screened) harboured mutations targeted by the study drug. Moreover, 12 wild-type patients out of the 215 (5.58 %) were included in the clinical trials for which mutation analysis was an inclusion criteria. All the patients received drugs targeting the PI3K-AKT pathway and only two were given combinations directed against the PI3K and MAPK pathways. PI3KCA mutations were present in 33.7 % (61/181) of the patients, 45.83 % in PTs and 29.32 % in MTs. AKT1 mutations were detected in 5.48 % (8/146) of patients and PTEN loss in 34.67 % (52/150). KRAS, NRAS, and BRAF mutations were present in 12.06, 5.67, and 3.18 % of patients, respectively.

Conclusions

Genomic screening with a simplified TGPS is feasible, and was used to identify 13.49 % of patients who were included in clinical trials using targeted therapy against the mutations they harboured; PI3KCA mutations were the most frequent aberration in our series.

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Abbreviations

BC:

Breast cancer,

TGPS:

Targeted gene panel sequencing,

PT:

Primary tumour,

MT:

Metastatic tumour,

IHC:

Immunohistochemistry,

ER:

Oestrogen receptor

HER2:

Human epidermal growth factor receptor 2

NGS:

Next generation sequencing

PI3K:

Phosphoinositide 3-kinase

MAPK:

Mitogen-activated protein kinase

TNBC:

Triple-negative breast cancer

LBC:

Luminal breast cancer

FFPE:

Formalin-fixed paraffin-embedded

FISH:

Fluorescence in situ hybridisation

EGFR:

Epidermal growth factor receptor

HE:

Haematoxylin and eosin

PR:

Progesterone receptor

SAP:

Shrimp alkaline phosphatase

CGAN:

Cancer genome ATLAS network

FGFR:

Fibroblast growth factor receptor

AKT1:

V-akt murine thymoma viral oncogene homolog 1

KRAS:

Kirsten rat sarcoma viral oncogene homolog

NRAS:

Neuroblastoma ras viral (V-ras) oncogene homolog

BRAF:

B-raf proto-oncogene, serine/threonine kinase

PTEN:

Phosphatase and tensin homolog

PIK3CA:

Phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha

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Acknowledgments

This study was supported by grants from the Generalitat Valenciana (Prometeo 2015/005), the Ministerio de Salud Carlos III (PI12/02,767 and PI13/00606), and European FEDER Funds. MTM was funded by the Ministerio de Salud Carlos III on a Rio Hortega contract (CM12/00264). GR and MI-V were funded by the Ministerio de Salud Carlos III on a Miquel Servet II (CPII14-00013) and Sara Borell contract (CD15/00153), respectively. We would like to thank the expert personnel at the Genotyping and Epigenetics Laboratory at the Central Biomedical Research Unit (Unidad Central de Investigación de Medicina; UCIM) at the University of Valencia.

Author contributions

Study conception and design: ALL, AC, JAPF, and JMC. Data acquisition: OB, GR, and MI-V. Data analysis and interpretation: all authors. All the authors were also involved in drafting or critically revising the article for important intellectual content, and they approved the final version of the manuscript.

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Authors and Affiliations

  1. Department of Haematology and Medical Oncology. Hospital Clínico Universitario, Biomedical Research Institute INCLIVA, University of Valencia, AVD/Blasco Ibánez, 17, 46010, Valencia, Spain

    Juan Miguel Cejalvo, J. Alejandro Pérez-Fidalgo, Gloria Ribas, Octavio Burgués, Maider Ibarrola-Villava, Begoña Bermejo, María Teresa Martínez, Andrés Cervantes & Ana Lluch

  2. Department of Pathology. Hospital Clínico Universitario, Biomedical Research Institute INCLIVA, University of Valencia, Valencia, Spain

    Cristina Mongort & Elisa Alonso

Authors
  1. Juan Miguel Cejalvo
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  2. J. Alejandro Pérez-Fidalgo
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  3. Gloria Ribas
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  4. Octavio Burgués
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  8. Begoña Bermejo
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Corresponding authors

Correspondence to Juan Miguel Cejalvo or Ana Lluch.

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The authors state that they have no potential conflict of interest.

Ethics approval

This research was performed in accordance with the Declaration of Helsinki and was approved by the ethics committee at the Hospital Clinico Universitario, Valencia.

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Cejalvo, J.M., Pérez-Fidalgo, J.A., Ribas, G. et al. Clinical implications of routine genomic mutation sequencing in PIK3CA/AKT1 and KRAS/NRAS/BRAF in metastatic breast cancer. Breast Cancer Res Treat 160, 69–77 (2016). https://doi.org/10.1007/s10549-016-3980-z

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  • DOI: https://doi.org/10.1007/s10549-016-3980-z

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