Abstract P6-09-15: Mechanism of drug resistance in relation to sites of metastases: Meta-analyses of randomized controlled trials in advanced breast cancer
Authors: Niraula S , Ocana A 
Published: March 2017

Background: Breast cancer is heterogeneous at different levels: biologic subtypes, intratumoral areas, and sites of metastases. In clinical studies, metastatic sites are usually classified as visceral or non-visceral, but this has little influence in treatment decisions particularly in the absence of clinical urgency. Indeed, it is unclear if response to new treatments differs among sites of metastatic lesions.

Methods: Randomized controlled trials (RCTs) investigating 3 different anticancer strategies in metastatic breast cancer were identified:

(1) Comparison of two endocrine strategies

(2) Endocrine therapy and targeted therapy compared with endocrine therapy alone

(3) New HER-2 targeted therapy compared with existing HER-2 targeted therapy

RCTs reporting hazard ratios (HR) for Progression Free Survival (PFS) and Overall Survival (OS) for sub-groups based on sites of metastases were weighted using generic inverse variance approach, and pooled in meta-analyses using Revman 5.3. Subgroup difference was tested with Chi2 and heterogeneity with I2 statistics.

Results: A total of 11 RCTs (6,701 pts) qualified. There was a significant difference in PFS between women with visceral Vs non-visceral metastases when two endocrine strategies were compared, with benefits limited to women with visceral metastases [Pooled HR 0.85; 95% CI, 0.77-0.95 Vs 1.02(0.88-1.18) for non-visceral; p(difference) 0.05]. However, combination of an endocrine therapy and a targeted therapy was associated with better PFS compared to endocrine therapy alone for both groups [HR 0.51(0.43-0.60) for visceral Vs 0.45(0.36-0.56) for non-visceral; p(difference) 0. 36]. Newer HER-2 targeted therapies were associated with significantly better PFS only in visceral but not in non-visceral metastases [HR 0.59 (0.52-0.66) Vs 0.71(0.44-1.13), p(difference) 0.45]. OS benefit with new HER-2 therapies was observed only for women with visceral metastases [HR 0.64 (0.56, 0.73) Vs 0.82 (0.57, 1.19), p(difference):0.20].

Summary of included studiesStudy/AuthorComparisonsN(Visceral)N(Non-Visceral)HR for PFS(Visceral))HR for PFS(Non-Visceral)Bergh et al.Endocrine Vs Endocrine2582560.81[0.63,1.04]1.10[0.86,1.41]Chia et al."3952980.88[0.74,1.05]1.01[0.81,1.26]Johnson et al."2811930.93[0.73,1.18]1.37[0.83,2.26]Mehta et al."3481950.79[0.63,0.99]0.84[0.62,1.14]BOLERO2Targeted + Endocrine Vs Endocrine4063180.45[0.35,0.58]0.42[0.28,0.63]PALOMA1"80850.55[0.32,0.95]0.29[0.09,0.93]PALOMA2"3243420.63[0.47,0.84]0.50[0.36,0.69]PALOMA3"3112100.47[0.34,0.65]0.55[0.45,0.67]CLEOPATRANew Vs Existing Anti-HER26301780.64[0.53,0.77]0.83[0.58,1.19]EMELIA"6693220.55[0.45,0.67]0.96[0.71,1.30]TH3RESA"4521500.56[0.44,0.71]0.41[0.26,0.65]

Conclusion: Targeted + endocrine therapy combination results in concordant, superior PFS suggesting similar mechanisms of targetable endocrine resistance between metastatic sites. Discordant responses with endocrine strategy alone support use of targeted therapy, rather than change in endocrine agent at disease progression. New HER2 therapies display continued challenge of drug penetration to areas of limited vascularization (eg. soft tissue, bone) with no PFS or OS benefit in that group despite impressive benefits in overall population.

Citation Format: Niraula S, Ocana A. Mechanism of drug resistance in relation to sites of metastases: Meta-analyses of randomized controlled trials in advanced breast cancer [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 P6-09-15.