Abstract P4-06-05: Treatment of ESR1 mutant and PIK3CA mutant patient-derived breast cancer xenograft models reveals differential anti-tumor responses to estrogen receptor degraders and PI3K inhibitors in vivo
Authors: Young A , Crocker L , Cheng E , Lacap J , Hamilton P , Oeh J , Ingalla E , Arrazate A , Hager J , Nannini M , Friedman L , Daemen A , Giltnane J , Sampath D 
Published: March 2017

The phosphoinositide 3-kinase (PI3K) pathway is a key driver of hormone receptor (HR)–positive breast cancer growth and survival. It is estimated that 40-45% of HR+ breast cancers harbor oncogenic mutations in the PIK3CA gene, which encodes the p110α isoform of PI3K. Taselisib (GDC-0032) is a mutant-selective PI3K inhibitor that demonstrates enhanced potency in PIK3CA mutant breast cancer cells and is being developed as a treatment for metastatic breast cancer that targets PIK3CA-mutant, HR-positive, HER2-negative patients. Activating mutations in the ESR1 gene were recently described in metastatic breast cancer. These mutations confer hormone independent growth and may be associated with resistance to aromatase inhibitors. Drugs that selectively bind and antagonize the Estrogen Receptor alpha (ERα) protein and target it for degradation, such as fulvestrant, are referred to as selective estrogen receptor degraders (SERDs). Preclinical activity of the orally bioavailable SERD, GDC-0810, has not been well characterized in ESR1 mutant PDX models. Therefore, our aim was to evaluate the efficacy and pharmacodynamic responses to agents that target ERα and PI3K as monotherapies and in combination, in ESR1 and PIK3CA mutant HR+ breast cancer patient-derived xenograft (PDX) models. We hypothesized that mutational status of ESR1 and PIK3CA may predict the responsiveness of HR+ PDX models to SERDs and PI3K inhibitors in vivo. Characterization of seven PDX models included authentication of hormone receptor status by immunohistochemistry (IHC) and determination of ESR1 and PIK3CA genotype and allele frequency by exome sequencing. For a subset of models that utilize estrogen for growth, mice were supplemented with 17β-estradiol, and cells or tumor fragments were implanted into the fat pad of intact female NOD-SCID or NOD-SCID-IL2Rgamma null mice and treated with fulvestrant, GDC-0810, or taselisib. Both fulvestrant and GDC-0810 were efficacious in ESR1 wild type (WT) and mutant PDX models but to variable degrees ranging from tumor stasis to growth delay, with GDC-0810 resulting in superior single agent activity at relevant clinical exposure in the WHIM20 and WHIM43 ESR1 mutant models. PIK3CA mutations (E542K, E545K, M1004V, and H1047R) were confirmed in six PDX models and PI3K pathway activation verified by strong pS6RP IHC staining. Taselisib induced tumor growth inhibition and tumor regressions in models harboring PIK3CA mutations, and models with no detectable expression of WT p110α were the most sensitive. In the WHIM43 (ESR1 D538G, PIK3CA M1004V), HCI-011 (ESR1 WT, PIK3CA E545K) and HCI-013 (ESR1 Y537S, PIK3CA H1047R) PDX models, combining fulvestrant and taselisib treatment further enhanced tumor growth inhibition with respect to either treatment alone. Our studies demonstrate the diverse anti-tumor responses of HR+ PDX models to SERDs and the PI3K inhibitor taselisib in the context of clinically relevant ESR1 and PIK3CA mutations. Pharmacological and genomic characterization of additional PDX models may aid in strengthening associations between genotype, drug sensitivity and predictive biomarkers of response.

Citation Format: Young A, Crocker L, Cheng E, Lacap J, Hamilton P, Oeh J, Ingalla E, Arrazate A, Hager J, Nannini M, Friedman L, Daemen A, Giltnane J, Sampath D. Treatment of ESR1 mutant and PIK3CA mutant patient-derived breast cancer xenograft models reveals differential anti-tumor responses to estrogen receptor degraders and PI3K inhibitors in vivo [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 P4-06-05.