Incidence of peripheral edema in patients receiving PI3K/mTOR/CDK4/6 inhibitors for metastatic breast cancer

  • Kayla M. Daniell
  • Aditya Bardia
  • Fangdi Sun
  • Sacha A. Roberts
  • Cheryl L. Brunelle
  • Tessa C. Gillespie
  • Hoda E. Sayegh
  • George E. Naoum
  • Dejan Juric
  • Steven J. Isakoff
  • Donna M. Fitzgerald
  • Alphonse G. TaghianEmail author
Clinical trial



This study evaluated development of edema in patients receiving PI3K/mTOR/CDK4/6 targeted therapy for metastatic breast cancer (MBC).


We reviewed medical records of 160 patients receiving targeted therapy with PI3K/mTOR/CDK4/6 inhibitors to treat MBC (n = 160; 185 treatment occurrences). Clinicopathologic data, treatment details, and edema incidence were recorded.


Edema incidence was 43.1% (69/160) overall and 25.6% (41/160) in the upper extremity ipsilateral to the treated breast. In 185 therapy regimens administered, 6.8% of patients on a PI3K inhibitor, 8.8% of patients on an mTOR inhibitor, and 9.2% of patients on a CDK4/6 inhibitor experienced new onset or worsened preexisting upper extremity edema. Further, 9.1% of patients on a PI3K inhibitor, 18.8% of patients on an mTOR inhibitor, and 10.5% of patients on a CDK4/6 inhibitor experienced new onset or worsened preexisting edema elsewhere in the body. Multivariate logistic regression showed that, beyond the established breast cancer-related lymphedema (BCRL) risk factors [axillary lymph node dissection (Odds Ratio (OR) 2.69, p = 0.020), regional lymph node irradiation (OR 6.47, p < 0.001), and body-mass index ≥ 30 kg/m2 (OR 3.46, p = 0.006)], a relative decrease in serum albumin after 3 months of treatment increased risk of developing edema (OR 2.07, p = 0.062). Neither duration nor type of therapy were significant risk factors for edema.


PI3K/mTOR/CDK4/6 inhibitors may influence the development of edema, which may cause or exacerbate progression of BCRL in patients with MBC. The varied incidence of edema between therapeutic regimens warrants vigilant monitoring of patients treated with these therapies, especially those at high risk of developing BCRL.


Lymphedema Edema Breast cancer Metastatic breast cancer Targeted therapy 



This study was funded by Award Numbers R01CA139118 and P50CA089393, Granted to Alphonse G. Taghian from the NIH, and the Adele McKinnon Research Fund for Breast Cancer-Related Lymphedema.

Compliance with ethical standards

Conflict of interest

Aditya Bardia serves as a consultant for Genentech/Roche, Immunomedics, Novartis, Pfizer, Merck, Radius Health, Spectrum Pharma, and Taiho Pharmeceutical. Aditya Bardia reports institutional grants from Genentech/Roche, Immunomedics, Novartis, Pfizer, Merck, Radius Health, Mersana, and Innocrin, as well as personal funding from Biothernostics. Steven J. Isakoff serves as a consultant for Myriad, Puma, Immunomedics, and Mylan, and reports funding from Genentech, Pharmamar, Abbvie, OncoPep, Merck, AstraZeneca. Dejan Juric serves as a consultant for Novartis, Genentech, Eisai, Ipsen, and EMD Serono. Dejan Juric reports grants from Novartis, Genentech, Eisai, EMD Serono, Takeda, Celgene, and Placon Therpaeutics, as well as personal funding from Novartis, Genentech, Eisai, Ipsen, and EMD Serono. The remaining authors have no conflicts to disclose.

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.

Informed consent

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

Supplementary material

10549_2019_5206_MOESM1_ESM.docx (26 kb)
Supplementary material 1 (DOCX 26 KB)
10549_2019_5206_MOESM2_ESM.docx (27 kb)
Supplementary material 2 (DOCX 26 KB)


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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Kayla M. Daniell
    • 1
  • Aditya Bardia
    • 2
  • Fangdi Sun
    • 1
  • Sacha A. Roberts
    • 1
  • Cheryl L. Brunelle
    • 3
  • Tessa C. Gillespie
    • 1
  • Hoda E. Sayegh
    • 1
  • George E. Naoum
    • 1
  • Dejan Juric
    • 2
  • Steven J. Isakoff
    • 2
  • Donna M. Fitzgerald
    • 2
  • Alphonse G. Taghian
    • 1
    • 4
    Email author
  1. 1.Department of Radiation OncologyMassachusetts General Hospital, Harvard Medical SchoolBostonUSA
  2. 2.Division of Hematology and OncologyMassachusetts General Hospital, Harvard Medical SchoolBostonUSA
  3. 3.Department of Physical and Occupational TherapyMassachusetts General HospitalBostonUSA
  4. 4.Lymphedema Research ProgramMassachusetts General HospitalBostonUSA

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