Incidence of peripheral edema in patients receiving PI3K/mTOR/CDK4/6 inhibitors for metastatic breast cancer
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.
KeywordsLymphedema 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.
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 was obtained from all individual participants included in the study.
- 1.American Cancer Society: Breast Cancer Facts & Figs. 2017–2018 (2017) Breast Cancer Facts Fig: 1–44. https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/breast-cancer-facts-and-figures/breast-cancer-facts-and-figures-2017-2018.pdf
- 2.Berry D, Cronin K, Plevritis S, Fryback DG, Clarke L, Zelen M, Mandelblatt JS, Yakovlev AY, Habbema JD, Feuer EJ, Cancer Intervention and Surveillance Modeling Network (CISNET) Collaborators (2005) Effect of screening and adjuvant therapy on mortality from breast cancer. N Engl J Med 353(17):1784–1792. https://doi.org/10.1056/NEJMoa050518 CrossRefGoogle Scholar
- 5.Shaitelman SF, Chiang Y-J, Griffin KD, DeSnyder SM, Smith BD, Schaverien MV, Woodward WA, Cormier JN (2016) Radiation therapy targets and the risk of breast cancer-related lymphedema: a systematic review and network meta-analysis. Breast Cancer Res Treat 162(2):201–215. https://doi.org/10.1007/s10549-016-4089-0 CrossRefGoogle Scholar
- 6.McLaughlin SA, Wright MJ, Morris KT, Giron GL, Sampson MR, Brockway JP, Hurley KE, Riedel ER, Van Zee KJ (2008) Prevalence of lymphedema in women with breast cancer 5 years after sentinel lymph node biopsy or axillary dissection: objective measurements. J Clin Oncol 26(32):5213–5219. https://doi.org/10.1200/JCO.2008.16.3725 CrossRefPubMedCentralGoogle Scholar
- 8.Warren LEG, Miller CL, Horick N, Skolny MN, Jammallo LS, Sadek BT, Shenouda MN, O’Toole JA, MacDonald SM, Specht MC, Taghian AG (2014) The impact of radiation therapy on the risk of lymphedema after treatment for breast cancer: a prospective cohort study. Int J Radiat Oncol Biol Phys 88(3):565–571. https://doi.org/10.1016/j.ijrobp.2013.11.232 CrossRefPubMedCentralGoogle Scholar
- 12.Petrek JA, Senie RT, Peters M, Rosen PP (2001) Lymphedema in a cohort of breast carcinoma survivors 20 years after diagnosis. Cancer 92(6):1368–1377. https://doi.org/10.1002/1097-0142(20010915)92:6%3C1368::AID-CNCR1459%3E3.0.CO;2-9 CrossRefGoogle Scholar
- 14.Fu MR, Axelrod D, Guth AA, Fletcher J, Qiu JM, Scagliola J, Kleinman R, Ryan CE, Chan N, Haber J (2015) Patterns of obesity and lymph fluid level during the first year of breast cancer treatment: a prospective study. J Pers Med 5(3):326–340. https://doi.org/10.3390/jpm5030326 CrossRefPubMedCentralGoogle Scholar
- 16.Breastcancer.org: Metastatic Breast Cancer (2018). https://www.breastcancer.org/symptoms/types/recur_metast
- 18.Mayer I, Abramson V, Formisano L, Balko JM, Estrada MV, Sanders ME, Juric D, Solit D, Berger MF, Won HH, Li Y, Cantley LC6, Winer Arteaga E CL (2017) A phase Ib study of Alpelisib (BYL719), a PI3Kα-specific inhibitor, with letrozole in ER+/HER2– metastatic breast cancer. Clin Cancer Res 23(1):23–34. https://doi.org/10.1158/1078-0432.CCR-16-0134 CrossRefGoogle Scholar
- 19.Loi S, Haibe-Kains B, Majjaj S, Lallemand F, Durbecq V, Larsimont D, Gonzalez-Angulo AM, Pusztai L, Symmans WF, Bardelli A, Ellis P, Tutt AN, Gillett CE, Hennessy BT, Mills GB, Phillips WA, Piccart MJ, Speed TP, McArthur GA, Sotiriou C (2010) PIK3CA mutations associated with gene signature of low mTORC1 signaling and better outcomes in estrogen receptor–positive breast cancer. Proc Natl Acad Sci USA 107(22):10208–10213. https://doi.org/10.1073/pnas.0907011107 CrossRefGoogle Scholar
- 20.Stemke-Hale K, Gonzalez-Angulo A, Lluch A, Neve RM, Kuo WL, Davies M, Carey M, Hu Z, Guan Y, Sahin A, Symmans WF, Pusztai L, Nolden LK, Horlings H, Berns K, Hung MC, van de Vijver MJ, Valero V, Gray JW, Bernards R, Mills GB, Hennessy BT (2008) An integrative genomic and proteomic analysis of PIK3CA, PTEN, and AKT mutations in breast cancer. Cancer Res 68(15):6084–6091. https://doi.org/10.1158/0008-5472.CAN-07-6854 CrossRefPubMedCentralGoogle Scholar
- 22.United Stated Food and Drug Administration (2017) Highlights of prescribing information for KISQALI® (ribociclib). https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/209092s000lbl.pdf
- 23.Asdourian MS, Swaroop MN, Sayegh HE, Brunelle CL, Mina AI, Zheng H, Skolny MN, Taghian AG (2017) Association between precautionary behaviors and breast cancer-related lymphedema in patients undergoing bilateral surgery. J Clin Oncol 35(35):3934–3941. https://doi.org/10.1200/JCO.2017.73.7494 CrossRefPubMedCentralGoogle Scholar
- 25.McDuff SG, Mina AI, Brunelle CL, Salama L, Warren LEG, Abouegylah M, Swaroop M, Skolny MN, Asdourian M, Gillespie T, Daniell K, Sayegh HE, Naoum GE, Zheng H, Taghian AG (2018) Timing of lymphedema after treatment for breast cancer: when are patients most at risk? Int J Radiat Oncol Biol Phys 103(1):62–70. https://doi.org/10.1016/j.ijrobp.2018.08.036 CrossRefGoogle Scholar
- 26.Brunelle C, Skolny M, Ferguson C, Swaroop M, O’Toole J, Taghian AG (2015) Establishing and sustaining a prospective screening program for breast cancer-related lymphedema at the Massachusetts General Hospital: lessons learned. J Pers Med 5(2):153–164. https://doi.org/10.3390/jpm5020153 CrossRefPubMedCentralGoogle Scholar