Abstract P1-10-12: Differential benefit of intra-operative administration of ketorolac on breast cancer disease recurrence according to baseline body mass index
Authors: Desmedt C , Demicheli R , Fornili M , Bachir I , Duca M , Viglietti G , Piccart M , Sotiriou C , Sosnowski M , Forget P , Biganzoli E 
Published: February 2018

Abstract
Background:
According to the last estimates, 63% of the women in the US are either overweight or obese. Increased body mass index (BMI) has been recognized as a risk factor for developing breast cancer (BC) and associated with adverse survival. So far, few treatment modalities focusing on the biological features of BC patients with increased adiposity have been evaluated. In cancer patients, elevated leptin levels have been found, among others, to stimulate the Rho GTPase pathway, involved in cell adhesion and motility. Here, using a unique retrospective institutional cohort including a total of 847 BC patients, we aimed at assessing whether the intra-operative administration of ketorolac, a Non-Steroidal Anti-Inflammatory Drug (NSAID), with a recently documented Rho GTPase inhibitory activity, would be associated with an improvement in distant disease recurrence according to BMI. We further assessed in an independent series of 1,009 patients, the effect of intra-operative diclofenac, another NSAID without Rho GTPase inhibitory activity.
Patients and methods:
In the institutional retrospective and consecutive 'ketorolac' series of patients with primary BC surgery, 538 were treated with and 309 without a single-dose (typically 20 mg in patients under 60 kg and 30 mg in patients ≥60 kg) of intra-operative ketorolac. In the 'diclofenac' series, 789 patients were treated with intra-operative diclofenac (75 mg) and 220 without. Competing risk analysis of distant recurrences was done by crude cumulative incidence curves to be interpreted as the cumulative probability of distant metastases as first event and consistently by Fine & Gray semi-parametric models on sub-distribution hazards. Subgroup analyses were conducted according to the Dixon&Simon approach. These analyses were adjusted for standard clinico-pathological variables: NSAID use, tumor size, age, nodal status, grade, ER status, and BMI. The median follow-up time of the ketorolac and diclofenac cohort was 5.7 and 8.0 years, respectively.
Results:
In both cohorts, the administration of the NSAID was associated with younger age at diagnosis, consistent with previous reports. The administration of ketorolac was associated with decreased incidence of distant recurrences both in the unadjusted and adjusted analysis (HRadj= 0.55, 95%CI: 0.35-0.86, p=0.01). Subgroup analyses in patients with BMI&lt;25 and ≥25 (overweight and obese) revealed that the effect was limited to the high BMI group of patients both in the unadjusted and adjusted analysis (HRadj= 0.58, 95%CI: 0.33-0.98). The administration of diclofenac was not associated with decreased incidence of distant recurrences, nor in the global population, neither in the BMI subgroups.
Conclusion:
The fact that only ketorolac but not diclofenac was associated with a significant reduction of distant recurrences in BC patients with elevated BMI could be explained by the specific Rho GTPase inhibitory effect of the R-enantiomer of ketorolac, absent in diclofenac. While this study is limited by its retrospective nature, it suggests a potentially important repositioning of ketorolac in the intra-operative treatment of BC patients with elevated BMI. A prospective study is on its way.
Citation Format: Desmedt C, Demicheli R, Fornili M, Bachir I, Duca M, Viglietti G, Piccart M, Sotiriou C, Sosnowski M, Forget P, Biganzoli E. Differential benefit of intra-operative administration of ketorolac on breast cancer disease recurrence according to baseline body mass index [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-10-12.