Abstract P3-14-02: Upper extremity edema in the at-risk arm among patients receiving PI3K/mTOR/CDK4/6 inhibitors for metastatic breast cancer
Authors: Daniell KM , Bardia A , Sun F , Brunelle CL , Gillespie TC , Sayegh HE , Naoum GE , Isakoff SJ , Juric D , Taghian AG 
Published: May 2019

Background: Targeted therapies, including mTOR and CDK 4/6 inhibitors, have changed the landscape of management of hormone receptor-positive (HR+) metastatic breast cancer (MBC). These therapies have shown significant improvement in progression-free survival and are generally well-tolerated. In pre-clinical models, modulation of the PI3K/mTOR pathway can impede lymphoangiogenesis resulting in capillary leakage. In this study, we examined the impact of PI3K, mTOR, and CDK 4/6 inhibitors in the development of upper extremity edema (UEE) in the at-risk arm for breast cancer-related lymphedema (BCRL) in patients with MBC.

Methods: We conducted a retrospective chart review of patients treated with PI3K/mTOR/CDK4/6 inhibitors for MBC. Clinicopathologic data including age, body-mass index (BMI), specific pathway targeted, treatment duration, and presence of edema were recorded. Characteristics of treatment including surgery type and laterality, nodal surgery, radiation regimen, and tumor subtype were also collected.

Results: Among patients with MBC treated with PI3K, mTOR, and/or CDK 4/6 inhibitors (N = 160), the incidence of edema that developed after initiation of the targeted therapy was 11.3% (18/160) for UEE and 31.9% (51/160) for edema in any anatomical location. 50.0% (11/22) of patients treated with a PI3K-a inhibitor, 32.6% (14/43) of patients treated with an mTOR inhibitor, and 33.3% (8/24) of patients treated with a CDK4/6 inhibitor alone developed peripheral edema following initiation of the respective targeted therapy. Further, swelling developed in the at-risk upper extremity after C1D1 in 13.6% (3/22) patients treated with a PI3K-α inhibitor exclusively, 7.0% (3/43) treated with an mTOR inhibitor exclusively, and in 12.5% (3/24) treated with a CDK4/6 inhibitor exclusively. Of the 42 patients treated with a CDK4/6 inhibitor in combination with either an mTOR inhibitor, aromatase inhibitor, or an ER-binding promoter, the incidence of UEE in the at-risk upper extremity after C1D1 was 18.8% (6/32), 0.0% (0/7), and 0.0% (0/3) respectively. In multivariate logistic regression analysis, both therapy with PI3K-a inhibitors (OR: 3.22; p = 0.049) and a relative decrease in serum albumin after 3 months of treatment (OR: 3.35, p = 0.024) increased the risk of developing peripheral edema; however, duration of therapy, and nodal surgery were not significant risk factors. Upon stratification of this cohort by number of BCRL-related risk factors, the incidence of BCRL was 18.3%, 39.5%, and 83.3% in women with one, two, or three BCRL-related risk factors, respectively.

Conclusions: PI3K, mTOR, and CDK 4/6 inhibitors may influence the development of UEE, which may cause or exacerbate progression of BCRL in at-risk arm among patients with MBC. Further research is needed to prospectively evaluate these novel findings as well as elucidate physiologic and clinical impacts of these therapies on peripheral edema and BRCL. Moreover, it is crucial to understand the role of close monitoring for the development or progression of peripheral edema or BCRL to ensure early detection and treatment, thus potentially minimizing the negative impacts on the quality of life of patients with MBC.

Citation Format: Daniell KM, Bardia A, Sun F, Brunelle CL, Gillespie TC, Sayegh HE, Naoum GE, Isakoff SJ, Juric D, Taghian AG. Upper extremity edema in the at-risk arm among patients receiving PI3K/mTOR/CDK4/6 inhibitors for metastatic breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-14-02.