Abstract P6-07-06: Effect of serum biomarkers (activin A, CAIX, HER2, TIMP-1, and uPA) on outcome in HER2+ metastatic breast cancer patients treated in first line with lapatinib or trastuzumab combined with taxane: CCTG MA.31

Abstract

Background: In MA.31, the lapatinib-taxane combination led to shorter PFS than trastuzumab-taxane in HER2+ metastatic breast cancer. We investigated the prognostic and predictive effects of pretreatment serum biomarkers. Methods: MA.31 accrued 652 patients; 537 (82%) were centrally-confirmed HER2+. Biomarkers were categorized for univariate and multivariate predictive investigations with a median cut-point, ULN cut-points (15 ng/ml- HER2; 506 pg/ml- CAIX; 454 pg/ml- TIMP-1; 1940 pg/ml– uPA; 600 pg/ml- activin A), and custom cut-points (30 and 100 ng/ml for HER2). Stratified step-wise forward Cox multivariate analysis used continuous and categorical biomarkers for PFS in the ITT and central HER2+ populations; central HER2+ biomarker results are shown. Results: Serum was banked for 472 (72%) of 652 patients. Higher serum activin A (>median; >ULN; p<0.0001); higher CAIX (>median; >ULN; p=0.02; p=0.001); higher HER2 (>median; >15; >30; or >100 ng/ml; p=0.05-0.002) and higher TIMP-1 (>median; >ULN; p=0.001; p=0.02) had shorter univariate PFS. In multivariate analysis for PFS: higher continuous activin A (HR=6.75 with Box-Cox transformation, P<0.0001) was associated with significantly shorter PFS, along with treatment arm, prior adjuvant anthracyclines, and higher central EGFR status. In multivariate analysis for OS: higher continuous activin A (HR=85.9, with Box-Cox transformation, P<0.0001) was associated with significantly shorter OS, along with treatment arm and higher central EGFR status. The interaction terms of serum biomarkers with treatment were not significant. Elevated serum activin A was also significant at the median cutpoint for PFS (HR 1.79, p=0.0002) and OS (HR 2.39, p=0.006) in multivariate analysis. Conclusions: Higher serum activin A was a significant independent prognostic biomarker of shorter progression-free and overall survival. No serum biomarker was predictive of differential response to lapatinib vs. trastuzumab. Evaluation of activin A and CAIX-targeted therapy in addition to HER2-targeted therapy may be warranted in patients with elevated serum levels of these biomarkers. *AK, MH, DH, & JH contributed equally Grant: PA Breast Cancer Coalition. Citation Format: Kang A, Hupp M, Ho D, Huang J, Leitzel K, Ali S, Shepherd L, Parulekar WR, Ellis CE, Rocco CJ, Zhu L, Virk S, Nomikos D, Aparicio S, Gelmon KA, Truica C, Al-Marrawi Y, Rizvi S, Vasekar M, Nagabhairu V, Polimera H, Marks E, Richardson A, Ali AS, Krecko L, Carney WP, Downs S, Chen BE, Lipton A. Effect of serum biomarkers (activin A, CAIX, HER2, TIMP-1, and uPA) on outcome in HER2+ metastatic breast cancer patients treated in first line with lapatinib or trastuzumab combined with taxane: CCTG MA.31 [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-07-06.

Higher serum PD‐L1 level predicts increased overall survival with lapatinib versus trastuzumab in the CCTG MA.31 phase 3 trial

“…24 In summary, until now, there have been no predictive biomarkers identified in the MA.31 trial (ie, none predicting a differential benefit from lapatinib vs trastuzumab). 24 Biomarkers derived from tumor tissue have also been shown to have prognostic benefit in breast cancer. According to results from the FinHER trial of HER2positive early breast cancer, patients with high total tumor HER2 levels (based on VeraTag H2T) derived less benefit from trastuzumab therapy in comparison with those with moderate H2T levels.…”

“…23 Most recently, in this CCTG MA.31 trial, we reported that elevated serum levels of activin A, CA9, HER2, TIMP-1, and uPA were prognostic factors for shorter PFS and OS; however, none were predictive factors for differential outcomes with trastuzumab versus lapatinib. 24 In summary, until now, there have been no predictive biomarkers identified in the MA.31 trial (ie, none predicting a differential benefit from lapatinib vs trastuzumab). 24 Biomarkers derived from tumor tissue have also been shown to have prognostic benefit in breast cancer.…”

The prognostic relevance of urokinase-type plasminogen activator (uPA) in the blood of patients with metastatic breast cancer

“…Results from three studies are available as conference abstracts only [45][46][47] . Kang et al evaluated the prognostic and predictive effects of various serum biomarkers, among them uPA, in HER2-positive patients enrolled in the MA.31 trial (NCT00667251) treated by chemotherapy with lapatinib or trastuzumab 45 . Pretreatment serum samples were available for 472 patients; however, it is not clear in how many patients uPA was measured.…”