Abstract P1-19-42: Evaluation of mean corpuscular volume (MCV) as a pharmacodynamic predictive biomarker in patients receiving CDK4/6 inhibitors for metastatic breast cancer (MBC)
Authors: Choong Grace Mei Yee , Leon-Ferre Roberto A , O'Sullivan Ciara C , Ruddy Kathyrn J , Haddad Tufia C , Hobday Timothy J , Peethambaram Prema P , Loprinizi Charles L , Liu Minetta C , Suman Vera J , Goetz Matthew P , Giridhar Karthik V 
Published: March 2020

Introduction: CDK 4/6 inhibitors (CDK4/6i) are FDA approved for treatment of hormone receptor (HR) positive, HER2 negative metastatic breast cancer (MBC). Recent work demonstrated that a rise in MCV was correlated with longer median progression free survival (Anampa et al, Haemoatologica 2018). We performed a single-institution retrospective analysis to evaluate whether palbociclib induced early changes in MCV serve as a pharmacodynamic biomarker to predict response to CDK4/6i.

Methods: We identified a retrospective cohort of 81 patients with HR+, HER2- MBC treated with CDK4/6i as first line metastatic treatment at Mayo Clinic, Rochester. Hematologic indices were abstracted pretreatment and at the start of each cycle through the start of cycle 4 (C4). Wilcoxon signed test was used to examine the changes in MCV (ΔMCV) comparing pretreatment up to C4 and ΔMCV between cycles. Optimal cut points for ΔMCV were determined using Cutoff finder (Budczies et al., PLOS One 2012). Cox proportional hazard regression analysis was performed to evaluate associations of MCV and time to treatment failure (TTF), which was defined as the time from the start of the analyzed cycle to treatment discontinuation for any reason(in months). As eight comparisons were made, a Bonferroni correction established p-value &lt;0.00625 as the adequate cutoff for statistical significance. Statistical analyses were performed using JMP (SAS Institute Inc, Cary, NC).

Results: 60/81 patients had pretreatment and at least one subsequent lab data point that included MCV. The pretreatment mean hemoglobin (Hgb) was 12.8 [standard deviation (SD) 1.37 g/dL] and 6/60 (10.2%) patients with Hgb &lt;11.0 g/dL. Mean pretreatment MCV was 89.0 femtoliters/cell [fl (SD 4.63)] and no macrocytosis (defined as MCV &gt;100 fl) was observed. At C4, the mean Hgb was 12.1 g/dL (SD 1.11) with 4/49 (8.2%) with Hgb &lt;11.0 g/dL. The C4 mean MCV was 96.6 fl (SD 5.23) and 8/29 (16.3%) developed macrocytosis. Wilcoxon signed analysis showed a significant increase in ΔMCV pretreatment to C2 [n=51, median 1.5 with interquartile range (IQR) -0.1-3.2, p&lt;0.0001], C2 to C3 (n=44, median 2.9, IQR 1.4-5.2, p&lt;0.0001), and C3 to C4 (n=41, median 3.4, IQR 1.9-4.9, p&lt;0.0001). A rise in MCV≥8.15 from pretreatment to C4 was associated with a non-statistically significant improvement in TTF [n=49, hazard ratio (HR) 0.38, p = 0.06]. Between C2 and C3, a rise in MCV ≥2.9 was associated favorably with TTF (n=44, HR 0.36, p = 0.029). The estimated probability of remaining on treatment at 30 months was higher in those with C2-C3 ΔMCV ≥2.9 [44.1%; 95% Confidence Interval (CI) 17.3-68.2%] compared to those with a C2-C3 ΔMCV &lt;2.9 (10.1%; 95%CI 1.5-28.7%).

Discussion: We observed an increase in MCV in all patients receiving CDK4/6i by start of C4. The rise in MCV during CDK4/6i treatment may reflect drug induced cell-cycle arrest in hematopoietic cells. Evaluation in larger studies is needed to validate dynamic changes in MCV as a predictive biomarker of response to CDK4/6i therapy.

Citation Format: Grace Mei Yee Choong, Roberto A Leon-Ferre, Ciara C O'Sullivan, Kathyrn J Ruddy, Tufia C Haddad, Timothy J Hobday, Prema P Peethambaram, Charles L Loprinizi, Minetta C Liu, Vera J Suman, Matthew P Goetz, Karthik V Giridhar. Evaluation of mean corpuscular volume (MCV) as a pharmacodynamic predictive biomarker in patients receiving CDK4/6 inhibitors for metastatic breast cancer (MBC) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-19-42.