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Induction of PIK3CA alterations during neoadjuvant letrozole may improve outcome in postmenopausal breast cancer patients

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Abstract

Purpose

Estrogen receptor positive (ER+) breast cancer constitutes almost 85% of all breast cancer patients and are a genetically highly heterogenic group. Data on the association of somatic alterations to outcome and prognosis are however sparse. In this neoadjuvant endocrine phase II trial including postmenopausal breast cancer patients with ER+, HER2 normal breast cancer, we investigated the rate of pathogenic mutations before and after treatment as well as the association with treatment response and survival.

Methods

Pretreatment and posttreatment tumour samples from 109 patients treated with neoadjuvant letrozole were collected and analysed with Next Generation Sequencing utilizing a panel of 12 genes (ALK, BRAF, EGFR, ERBB2, ERBB3, ESR1, KIT, KRAS, NRAS, PDGFRA, PIK3CA, and RAF1). Residual disease was assessed by a modified Miller Payne scale and the Residual Cancer Burden index. Survival data were collected prospectively.

Results

Among the 109 patients, 52 had at least one pathogenic mutation in the pretreatment sample and 60 in the posttreatment sample. The most frequently mutated gene was PIK3CA, followed by EGFR and KRAS. Twelve different pathogenic PIK3CA mutations were identified, primarily in exon 20 and exon 9. An altered PIK3CA mutation profile from the pre- to the posttreatment specimen was significantly associated to improved pathological outcome. Overall and Disease-Free Survival benefits in PIK3CA mutated patients was observed.

Conclusion

Considerable heterogeneity was identified both among patients and between pre- and posttreatment samples. PIK3CA has the potential to be a predictive biomarker. To further assess the implications of a treatment related altered PIK3CA mutation profile, more data are needed.

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Data availability

The data supporting all the figures, tables and supplementary tables in the published article, are not publicly available due to institutional restrictions. The dataset can be made available to qualified researchers through application to the Danish Breast Cancer Group. Please contact dbcg.rigshospitalet@regionh.dk.

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Funding

This study was funded by The Danish Cancer Society (Grant No. R146-A9562), The Harboe Foundation, University of Copenhagen’s Foundation for cancer research (Grant No. 2019-0018) and The Sejer Persson and Lis Klüver foundation. The founding sources are all non-commercial and had no role in the design or execution of the study and have not reviewed the data or manuscript.

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Authors and Affiliations

  1. Department of Oncology, Rigshospitalet, Copenhagen University Hospital, Section 5703 Rigshospitalet, Blegdamsvej 9, 2100, Copenhagen, Denmark

    Signe Korsgaard Skriver, Ann Soegaard Knoop & Bent Ejlertsen

  2. The Danish Breast Cancer Group, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark

    Maj-Britt Jensen & Bent Ejlertsen

  3. Department of Surgical Pathology, Zealand University Hospital, Roskilde, Denmark

    Jens-Ole Eriksen & Anne-Vibeke Laenkholm

  4. Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark

    Lise Barlebo Ahlborn & Maria Rossing

Authors
  1. Signe Korsgaard Skriver
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  2. Maj-Britt Jensen
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  3. Jens-Ole Eriksen
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  4. Lise Barlebo Ahlborn
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  5. Ann Soegaard Knoop
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  6. Maria Rossing
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  7. Bent Ejlertsen
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  8. Anne-Vibeke Laenkholm
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Corresponding author

Correspondence to Signe Korsgaard Skriver.

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Conflict of interest

SKS declares she has no conflict of interest. MBJ has received institutional grants from Nanostring Technologies Inc and Oncology Venture. JOE declares he has no conflict of interest none, LBA declares she has no conflict of interest, ASK has received an institutional grant from Roche and is on advisory board for: Novartis, Astra Zeneca, MDS, Roche, Pfizer and ELI LILLY DANMARK A/S. MR is on advisory board for Astra Zeneca, BE has received institutional grants from: Nanostring Technologies Inc, Novartis and Roche. AVL has received research grants from Nanostring Technologies Inc. and Roche.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. The study is registered on clinicaltrials.gov (NCT00908531). The Biomedical Research Ethics of the Danish Capital Region approved the protocol (H-15012740). The genomic investigations presented here were subsequently approved (H-16031391).

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Informed consent was obtained from all individual participants included in the study.

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Skriver, S.K., Jensen, MB., Eriksen, JO. et al. Induction of PIK3CA alterations during neoadjuvant letrozole may improve outcome in postmenopausal breast cancer patients. Breast Cancer Res Treat 184, 123–133 (2020). https://doi.org/10.1007/s10549-020-05833-w

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  • DOI: https://doi.org/10.1007/s10549-020-05833-w

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