Abstract CT141: Genetic landscape of premenopausal HR+/HER2- advanced breast cancer (ABC) based on comprehensive circulating tumor DNA analysis and association with clinical outcomes in the Phase III MONALEESA-7 trial
Authors: Bardia Aditya , Su Faye , Solovieff Nadia , Im Seock-Ah , Sohn Joohyuk , Lee Keun Seok , Campos-Gomez Saul , Jung Kyung Hae , Vazquez Rafael Villanueva , Lu Yen-Shen , Franke Fabio , Hurvitz Sara , Harbeck Nadia , Chow Louis , Lorenc Karen Rodriguez , Taran Tetiana , Babbar Naveen , Tripathy Debu 
Published: August 2019

Background: The genetic landscape of premenopausal hormone receptor-positive (HR+) ABC is not well understood. The Phase III MONALEESA-7 study (NCT02278120), the first trial of endocrine therapy ± a cyclin-dependent kinase 4/6 inhibitor for premenopausal patients (pts) with HR+/human epidermal growth factor receptor 2-negative (HER2-) ABC, demonstrated that the addition of ribociclib (RIB) to a nonsteroidal aromatase inhibitor (NSAI) or tamoxifen (TAM) + goserelin (GOS) significantly extended progression-free survival (PFS; Tripathy D, et al. Lancet Oncol. 2018). We conducted a comprehensive ctDNA genomic analysis from MONALEESA-7.

Methods: Premenopausal pts with HR+/HER2- ABC were randomized 1:1 to RIB or placebo (PBO) + NSAI (letrozole [LET] or anastrozole) or TAM + GOS. Plasma samples for ctDNA analysis were collected at baseline and end of treatment. ctDNA was analyzed using next-generation sequencing (targeted panel of 550 genes).

Results: Among the 489 pts with ctDNA analyzed at baseline, the most common alterations were in PIK3CA (28%), TP53 (19%), CCND1 (11%), MYC (8%), and GATA3 (8%). Poorer prognosis in both treatment groups was most evident in patients with TP53 and MYC alterations. A PFS treatment effect in favor of RIB was noted in all subsets, independent of biomarker status (Table). However, based on HR, a trend for more pronounced benefit with RIB + NSAI/TAM + GOS was observed in pts with altered CCND1, GATA3, and genes involved in receptor tyrosine kinase signaling.

Conclusions: RIB + NSAI/TAM + GOS provided PFS benefit irrespective of baseline biomarker alteration status and represents recommended first-line therapy for pts with premenopausal HR+/HER2- ABC. The genetic landscape of premenopausal ABC might modulate the magnitude of therapeutic benefit; these novel findings require confirmation in additional biomarker studies.

RIB + NSAI/TAM + GOSPBO + NSAI/TAM + GOSEvents, n/NPFS, median monthsEvents, n/NPFS, median, monthsHRa (95% CI)PIK3CAWT68/18024.6798/17012.190.45 (0.33-0.62)Alt38/6914.7546/7012.850.57(0.36-0.9)TP53WT78/20324.67109/19412.980.48(0.36-0.65)Alt28/469.2335/467.160.47(0.27-0.82)CCND1WT91/22122.11126/21712.880.52(0.39-0.68)Alt15/2811.2718/235.520.21(0.08-0.54)MYCWT90/22924.67125/22112.880.49(0.37-0.65)Alt16/207.3419/197.160.57(0.25-1.31)GATA3WT96/22622.11131/22212.850.52(0.39-0.68)Alt10/23NA13/185.520.18(0.05-0.62)Receptor tyrosine kinasesbWT76/19827.53114/20614.520.5(0.37-0.67)Alt30/5114.5530/345.650.26(0.14-0.47)8p11.23cWT84/21523.03124/21412.780.47(0.36-0.63)Alt22/3412.5220/269.130.51(0.26-1)8p11.23, chromosome 8, short arm, region 11.23; alt, alteration; CCND1, cyclin D1; CI, confidence interval; GATA3, GATA binding protein 3; GOS, goserelin; NA, not applicable; NSAI, nonsteroidal aromatase inhibitor; MYC, MYC proto-oncogene, bHLH transcription factor; PBO, placebo; PFS, progression-free survival; PIK3CA, phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit α; RIB, ribociclib; TAM, tamoxifen; TP53, tumor protein p53; WT, wild type.a HR for PFS of RIB vs PBO. b Receptor tyrosine kinase genes include EGFR, ERBB2, ERBB3, ERBB4, FGFR1, IGF1, IGF1R, KDR, KIT, PDGFRA, PDGFRB, and VEGFA. c Includes FGFR1, WHSC1L1, and ZNF703.

Citation Format: Aditya Bardia, Faye Su, Nadia Solovieff, Seock-Ah Im, Joohyuk Sohn, Keun Seok Lee, Saul Campos-Gomez, Kyung Hae Jung, Rafael Villanueva Vazquez, Yen-Shen Lu, Fabio Franke, Sara Hurvitz, Nadia Harbeck, Louis Chow, Karen Rodriguez Lorenc, Tetiana Taran, Naveen Babbar, Debu Tripathy. Genetic landscape of premenopausal HR+/HER2- advanced breast cancer (ABC) based on comprehensive circulating tumor DNA analysis and association with clinical outcomes in the Phase III MONALEESA-7 trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT141.