Broad and deep tumour genome sequencing has shed new light on tumour heterogeneity and provided important insights into the evolution of metastases arising from different clones1,2. There is an additional layer of complexity, in that tumour evolution may be influenced by selective pressure provided by therapy, in a similar fashion to that occurring in infectious diseases. Here we studied tumour genomic evolution in a patient (index patient) with metastatic breast cancer bearing an activating PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha, PI(3)Kα) mutation. The patient was treated with the PI(3)Kα inhibitor BYL719, which achieved a lasting clinical response, but the patient eventually became resistant to this drug (emergence of lung metastases) and died shortly thereafter. A rapid autopsy was performed and material from a total of 14 metastatic sites was collected and sequenced. All metastatic lesions, when compared to the pre-treatment tumour, had a copy loss of PTEN (phosphatase and tensin homolog) and those lesions that became refractory to BYL719 had additional and different PTEN genetic alterations, resulting in the loss of PTEN expression. To put these results in context, we examined six other patients also treated with BYL719. Acquired bi-allelic loss of PTEN was found in one of these patients, whereas in two others PIK3CA mutations present in the primary tumour were no longer detected at the time of progression. To characterize our findings functionally, we examined the effects of PTEN knockdown in several preclinical models (both in cell lines intrinsically sensitive to BYL719 and in PTEN-null xenografts derived from our index patient), which we found resulted in resistance to BYL719, whereas simultaneous PI(3)K p110β blockade reverted this resistance phenotype. We conclude that parallel genetic evolution of separate metastatic sites with different PTEN genomic alterations leads to a convergent PTEN-null phenotype resistant to PI(3)Kα inhibition.

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Data deposits

DNA sequences have been deposited in the European Genome-phenome Archive with accession number EGAS00001000991.


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We thank members of the MSKCC Diagnostic Molecular Pathology Laboratory and the MSK Maria-Josée and Henry Kravis Center for Molecular Oncology for assistance with sequencing. We thank M. Asher and U. Bhanot from the MSKCC Pathology Core for assistance with tissue staining. This work was funded by a “Stand Up to Cancer” Dream Team Translational Research Grant, a Program of the Entertainment Industry Foundation (SU2C-AACR-DT0209), the Breast Cancer Research Foundation, the Geoffrey Beene Cancer Research Center, the Starr Cancer Consortium and an MMHCC grant (CA105388). D.J. is also funded by a National Institutes of Health Training Grant (T32 CA-71345-15) and by philanthropic support from Stephen and Kathleen Chubb.

Author information

Author notes

    • Dejan Juric
    •  & Pau Castel

    These authors contributed equally to this work.


  1. Massachusetts General Hospital Cancer Center, 55 Fruit Street, Boston, Massachusetts 02114, USA

    • Dejan Juric
    • , Tiffany Huynh
    • , Mari Mino-Kenudson
    • , Dennis Sgroi
    • , Steven Isakoff
    • , Ashraf Thabet
    •  & Leila Elamine
  2. Human Oncology and Pathogenesis Program (HOPP), Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 20, New York, New York 10065, USA

    • Pau Castel
    • , Helen H. Won
    • , Haley Ellis
    • , Gopa Iyer
    • , Ronak H. Shah
    • , David B. Solit
    • , Michael F. Berger
    • , José Baselga
    •  & Maurizio Scaltriti
  3. Department of Genetics, Washington University School of Medicine, 4566 Scott Avenue, St Louis, Missouri 63110, USA

    • Malachi Griffith
    •  & Elaine R. Mardis
  4. Siteman Cancer Center, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, Missouri 63110, USA

    • Malachi Griffith
    • , Obi L. Griffith
    •  & Elaine R. Mardis
  5. The Genome Institute, Washington University School of Medicine, 4444 Forest Park Avenue, St Louis, Missouri 63108, USA

    • Malachi Griffith
    • , Obi L. Griffith
    • , Benjamin J. Ainscough
    • , Avinash Ramu
    •  & Elaine R. Mardis
  6. Department of Medicine, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, Missouri 63110, USA

    • Obi L. Griffith
    •  & Elaine R. Mardis
  7. Department of Pathology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 20, New York, New York 10065, USA

    • Helen H. Won
    •  & Michael F. Berger
  8. Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 20, New York, New York 10065, USA

    • Saya H. Ebbesen
    •  & Scott W. Lowe
  9. Division of Genitourinary Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 20, New York, New York 10065, USA

    • Gopa Iyer
    •  & David B. Solit
  10. Howard Hughes Medical Institute, Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 20, New York, New York 10065, USA

    • Scott W. Lowe
  11. Novartis Pharma AG, Forum 1, Novartis Campus, CH-4056 Basel, Switzerland

    • Cornelia Quadt
    •  & Malte Peters
  12. Oncology Translational Medicine, Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, USA

    • Adnan Derti
    • , Robert Schegel
    •  & Alan Huang
  13. Breast Medicine Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Box 20, New York, New York 10065, USA

    • José Baselga


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D.J., P.C., M.F.B., J.B. and M.S. conceived the project, designed and analysed the experiments, and wrote the manuscript. M.G., O.L.G., B.J.A., A.R. and E.R.M. performed and analysed the WGS and WES data. T.H., M.M.-K., D.S., S.I., A.T., L.E., C.Q., M.P., A.D., R.B. and A.H. collected and analysed patients’ samples. P.C., H.E., S.H.E. and S.W.L. performed and supervised the laboratory experiments. H.H.W., G.I., R.H.S., D.B.S. and M.F.B. performed and supervised the IMPACT sequencing and analysis.

Competing interests

C.Q., M.P., A.D. and A.H. are Novartis employees. D.J., D.B.S. and J.B. consult for Novartis.

Corresponding authors

Correspondence to Michael F. Berger or José Baselga or Maurizio Scaltriti.

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