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PIK3CA mutations early persistence in cell-free tumor DNA as a negative prognostic factor in metastatic breast cancer patients treated with hormonal therapy

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Abstract

Purpose

The identification of biomarkers of hormonal therapy (HT) failure would allow tailored monitoring in metastatic breast cancer (mBC) patients. PIK3CA gene mutation is one of the most frequent events in mBC and is associated with HT resistance. We evaluated the early prognostic value of cell-free DNA (cfDNA) PIK3CA detection in first-line HT-treated mBC patients.

Methods

Between June 2012 and January 2014, 39 patients were prospectively included in a dedicated clinical trial (NCT01612871). Blood sampling was performed before (M0) and 4 weeks (M1), 3 months (M3) and 6 months (M6) after HT initiation, and at tumor progression. Patients were followed until progression or until the end of the study (2 years). Mutation detection was performed using droplet-based digital PCR (ddPCR). Progression-free survival (PFS) was used as primary endpoint.

Results

Median age at inclusion was 63 years (range 40–86). Most patients (34/39) received an aromatase inhibitor and presented a non-measurable disease (71.8%). PIK3CA mutations were reported in 10 (27.8%) and 5 (14.3%) cases at M0 and M1, respectively. The persistence of a detectable circulating mutation at M1 was highly correlated with a worse progression-free survival (PFS), rate at 1 year: 40% versus 76.7%; p = 0.0053).

Conclusions

Four-week persistence of cfDNA PIK3CA mutation appears highly correlated with PFS.

Trial registration

NCT01612871, registered on June 6th, 2012; https://clinicaltrials.gov/ct2/show/NCT01612871.

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Data availability

The data that support the findings of this study are available from the Department of Biostatistics, Institut Claudius Regaud, IUCT-O Toulouse, France, upon reasonable request.

Abbreviations

BC:

Breast cancer

cfDNA:

Cell-free DNA

CDK:

Cyclin-dependent kinase

ER+:

Estrogen-receptor-positive

HT:

Hormonal therapy

mBC:

Metastatic breast cancer

mTOR:

Mammalian target of rapamycin

PI3K:

Phosphatidylinositol 3-kinase

PI3KCA:

PI3K catalytic subunit alpha

PFS:

Progression-free survival

RB:

Retinoblastoma

95% CI:

95% confidence interval

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Acknowledgements

The authors want to thank Dr. Hélène de Forges for her substantive writing and editing assistance.

Funding

This ancillary study was supported by the “Fond pour la Recherche Val d’Aurelle” grant. This research was supported by the SIRIC Montpellier Cancer Grant INCa_Inserm_DGOS_12553.

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Authors and Affiliations

  1. Department of Medical Oncology, Institut du Cancer de Montpellier (ICM), Univ. Montpellier, 208 rue des Apothicaires, 34298, Montpellier Cedex 5, France

    William Jacot, Anna Durigova, Stéphane Pouderoux & Gilles Romieu

  2. Department of Medical Oncology, Institut Claudius Regaud, IUCT-O, Toulouse, France

    Florence Dalenc, Jean-Louis Lacaze, Laurence Gladieff & Henri Roché

  3. Translational Research Unit, Institut du Cancer de Montpellier (ICM), Univ. Montpellier, Montpellier, France

    William Jacot, Evelyne Lopez-Crapez & Nathalie Gros

  4. INSERM, U1194, Montpellier, France

    William Jacot & Evelyne Lopez-Crapez

  5. Department of Biostatistics, Institut Claudius Regaud, IUCT-O, Toulouse, France

    Leonor Chaltiel & Thomas Filleron

  6. Institut d’Analyse Génomique, Imagenome-Inovie, Clinique BeauSoleil, Montpellier, France

    Nicolas Lozano & Pierre-Jean Lamy

Authors
  1. William Jacot
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  2. Florence Dalenc
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Contributions

Study concept/design/funding: WJ, P-JL, EL-C, FD, and AD. Reagents/materials/analysis tools contribution: NG, P-JL, NL, and EL-C. Patients’ inclusion and follow-up: WJ, FD, AD, J-LL, SP, LG, GR, and HR. Acquisition of data: NG, WJ, P-JL, and EL-C. Statistical analysis: LC and TF. Analysis and interpretation of data: WJ, P-JL, and EL-C. Drafting of the manuscript: NG, WJ, P-JL, EL-C, FD, LC, and TF. All the authors participated to the critical revision and validation of the final manuscript.

Corresponding author

Correspondence to William Jacot.

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Conflict of interest

The authors declare no conflict of interest.

Ethical approval

This study was approved by the CPP (Ethics Committee) Sud-Ouest et Outre-Mer III and registered under the reference No. 2012/25. This study was performed in accordance with the Declaration of Helsinki.

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Jacot, W., Dalenc, F., Lopez-Crapez, E. et al. PIK3CA mutations early persistence in cell-free tumor DNA as a negative prognostic factor in metastatic breast cancer patients treated with hormonal therapy. Breast Cancer Res Treat 177, 659–667 (2019). https://doi.org/10.1007/s10549-019-05349-y

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