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Original research
Increased PI3K pathway activity is associated with recurrent breast cancer in patients with low and intermediate 21-gene recurrence score
  1. Lawrence Hsu Lin1,
  2. Yvonne Wesseling-Rozendaal2,
  3. Varshini Vasudevaraja1,
  4. Guomiao Shen1,
  5. Margaret Black1,
  6. Dianne van Strijp2,
  7. Sigi Neerken2,
  8. Paul A van de Wiel2,
  9. George Jour1,
  10. Paolo Cotzia1,
  11. Farbod Darvishian1,
  12. Matija Snuderl1
  1. 1Department of Pathology, New York University Langone Health and Grossman School of Medicine, New York, New York, USA
  2. 2InnoSIGN, Eindhoven, The Netherlands
  1. Correspondence to Dr Matija Snuderl, Department of Pathology, New York University Grossman School of Medicine, New York, NY 10016, USA; Matija.Snuderl{at}nyulangone.org

Abstract

Aims We investigated key signalling pathways’ activity and mutational status of early-stage breast carcinomas with low and intermediate 21-gene recurrence score (RS) to identify molecular features that may predict recurrence.

Methods This is a retrospective case–control study of 18 patients with recurrent breast carcinoma with low and intermediate 21-gene RS (<25) and control group of 15 non-recurrent breast cancer patients. DNA and mRNA were extracted from tumour tissue. mRNA expression of genes involved in oestrogen receptor (ER), androgen receptor (AR), PI3K and MAPK signalling pathways was measured by real-time quantitative reverse transcription-qPCR (OncoSIGNal G4 test, InnoSIGN). Tumour mutational landscape was assessed by targeted DNA sequencing (Oncomine Precision Assay).

Results There were no statistical differences between the groups’ demographic and clinicopathological characteristics. PI3K pathway showed significantly higher activity in cases compared with controls (p=0.0014). Receiver operating characteristic curve analysis showed an area under the curve of 0.79 for PI3K pathway activity in the prediction of recurrent disease in low and intermediate 21-gene RS breast cancer. There was no difference in ER, AR and MAPK pathway activity. PIK3CA alterations were the most common driver mutations, but no difference was found between the groups (p=0.46) and no association with PI3K pathway activity (p=0.86). Higher Ki67 gene expression was associated with recurrences (p=0.042)

Conclusion Increased PI3K pathway activity, independent of PIK3CA mutations, may play a role in the recurrence of early-stage breast cancer with low and intermediate 21-gene RS. Pathway analysis can help to identify high-risk patients in this setting.

  • BREAST CANCER
  • Pathology, Molecular
  • MOLECULAR BIOLOGY
  • Biomarkers, Tumor
  • Breast Neoplasms

Data availability statement

Data are available on reasonable request. The data sets used and analysed during the current study are available from the corresponding author on reasonable request.

https://doi.org/10.1136/jcp-2023-209344

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    Data availability statement

    Data are available on reasonable request. The data sets used and analysed during the current study are available from the corresponding author on reasonable request.

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    Footnotes

    • Handling editor L C Collins.

    • Presented at This work’s preliminary results were previously presented as a poster in Association of Molecular Pathology Annual Meeting 2020 on 16 November 2020–20 November 2020.

    • Contributors Study concept and design: LHL, MB, DvS, SN, PAvdW, PC and MS; Acquisition of cases and data collection: LHL, MB and PC; Experiments: GS; Analysis of data: LHL, YW-R, VV, FD and MS; Manuscript review: LHL, YW-R, GS, MB, DvS, SN, PAvdW, FD, GJ, PC and MS; Wrote manuscript: LHL, YW-R, DvS, FD and MS. All authors read and approved the final paper. Study guarantor: MS.

    • Funding The study was in part supported by InnoSIGN (spin-off from Philips) with provision of the OncoSIGNal G4 pathway test and ThermoFisher with the Genexus instrument for mutational testing. NYULH Center for Biospecimen Research and Development, Histology and Immunohistochemistry Laboratory (RRID:SCR_018304) is supported in part by the Laura and Isaac Perlmutter Cancer Center Support Grant; National Institutes of Health/National Cancer Institute P30CA016087.

    • Competing interests YW-R, DvS, SN and PAvdW are employees or contractors of InnoSIGN and own InnoSIGN shares and/or options. MS is scientific advisor and shareholder of C2i Genomics, Heidelberg Epignostix and Halo Dx, and a scientific advisor of Arima Genomics, and InnoSIGN, and received research funding from Lilly USA.

    • Provenance and peer review Not commissioned; internally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.