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Original research
KIT genetic alterations in breast cancer
  1. Mahsa Vahdatinia1,
  2. Fatemeh Derakhshan1,
  3. Arnaud Da Cruz Paula2,
  4. Higinio Dopeso1,
  5. Antonio Marra1,
  6. Andrea M Gazzo1,
  7. David Brown1,
  8. Pier Selenica1,
  9. Dara S Ross1,
  10. Pedram Razavi3,
  11. Hong Zhang1,
  12. Britta Weigelt1,
  13. Hannah Y Wen1,
  14. Edi Brogi1,
  15. Jorge S Reis-Filho1,
  16. Fresia Pareja1
  1. 1Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA
  2. 2Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
  3. 3Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA
  1. Correspondence to Dr Fresia Pareja, Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; parejaf{at}mskcc.org; Dr Jorge S Reis-Filho, Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; reisfilj{at}mskcc.org

Abstract

Aims Activating somatic mutations or gene amplification of KIT result in constitutive activation of its receptor tyrosine kinase, which is targetable in various solid tumours. Here, we sought to investigate the presence of KIT genetic alterations in breast cancer (BC) and characterise the histological and genomic features of these tumours.

Methods A retrospective analysis of 5,575 BCs previously subjected to targeted sequencing using the FDA-authorised Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Targets (MSK-IMPACT) assay was performed to identify BCs with KIT alterations. A histological assessment of KIT-altered BCs was conducted, and their repertoire of genetic alterations was compared with that of BCs lacking KIT genetic alterations, matched for age, histological type, oestrogen receptor/HER2 status and sample type.

Results We identified 18 BCs (0.32%), including 9 primary and 9 metastatic BCs, with oncogenic/likely oncogenic genetic alterations affecting KIT, including activating somatic mutations (n=4) or gene amplification (n=14). All KIT-altered BCs were of high histological grade, although no distinctive histological features were observed. When compared with BCs lacking KIT genetic alterations, no distinctive genetic features were identified. In two metastatic KIT-altered BCs in which the matched primary BC had also been analysed by MSK-IMPACT, the KIT mutations were found to be restricted to the metastatic samples, suggesting that they were late events in the evolution of these cancers.

Conclusions KIT genetic alterations are vanishingly rare in BC. KIT-altered BCs are of high grade but lack distinctive histological features. Genetic alterations in KIT might be late events in the evolution and/or progression of BC.

  • BREAST CANCER
  • Breast Neoplasms
  • Proto-Oncogene Proteins c-kit
  • GENETICS

Data availability statement

Data are available on reasonable request. Data supporting the findings of this study are available from the corresponding authors on reasonable request.

http://dx.doi.org/10.1136/jcp-2022-208611

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    Data availability statement

    Data are available on reasonable request. Data supporting the findings of this study are available from the corresponding authors on reasonable request.

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    Footnotes

    • MV, FD and ADCP are joint first authors.

    • Handling editor Runjan Chetty.

    • Twitter @FresiaPareja

    • Contributors JSR-F and FP conceived and planned the study. MV, FD, JRS-F and FP reviewed the cases. MV, FD, ADCP, HD, AM, AMG, DB, PS, DSR, PR, HZ, BW, HYW, EB, JSR-F and FP analysed and interpreted the data. MV, FD and FP wrote the first manuscript, which was reviewed by all coauthors. MV, FD and ADCP contributed equally to this study. FP had access to the data and accepts full responsibility for the finished work.

    • Funding This study was partially funded by the Breast Cancer Research Foundation. Research reported in this article was supported in part by a Cancer Center Support Grant of the National Institutes of Health/ National Cancer Institute (grant no. P30CA008748). BW is funded in part by a Cycle for Survival grant. BW, JSRF and FP are funded in part by a National Institutes of Health/ National Cancer Institute P50 CA247749 01 grant. JSR-F is a Komen Scholar and a recipient of a Susan G Komen Scholarship grant.

    • Disclaimer The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

    • Competing interests JSR-F reports receiving personal/consultancy fees from Goldman Sachs, REPARE Therapeutics and Paige. AI, membership of the scientific advisory boards of VolitionRx, REPARE Therapeutics, Personalis, Bain Capital and Paige. AI, membership of the Board of Directors of Grupo Oncoclinicas, and ad hoc membership of the scientific advisory boards of Roche Tissue Diagnostics, Ventana Medical Systems, Merck, Daiichi Sankyo and Astrazeneca, outside the scope of this study. BW reports ad hoc membership of the scientific advisory board of REPARE Therapeutics, outside the scope of the submitted work. All other authors declare no conflicts of interest.

    • Provenance and peer review Not commissioned; externally 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.