Abstract B106: Algorithmic basis for combination of PI3K pathway isoform-specific inhibitors: Navigating the genomic landscape in ER+ breast cancers
Authors: Dey Nandini , Williams Casey , Carlson Jennifer H. , Williams Kirstin , Klein Jessica , Krie Amy , De Pradip , Leyland-Jones Brian 
Published: May 2016

Introduction: Breast cancers are characterized by diverse genetic alterations. However, genetic alterations often affect a common oncogenic signal transduction pathway. Thus in tumor cells a specific molecular aberration(s) can have characteristic functional consequences which in turn can determine the therapeutic sensitivity of a particular drug.

Methods: We retrospectively analyzed data from nearly 150 consecutive BC patients (neoadjuvant, adjuvant and metastatic) which were seen in our center from February 2014 through August 2015. Patients were re-biopsied after consultation and samples were characterized (IHC for ER, PR, and HER2; FFPE samples for genomic [FoundationOne Medicine] and proteomic analyses [Theranostics]).

Results: A total of 100 genes were altered in 83 ER+ BC patients. PI3K pathway genes (PIK3CA, PIK3CAR1, PIK3C2B, AKT, PTEN, MDM2, MDM4, TSC2, mTOR, RPTOR) were altered in 77% of ER+ BC patients. The predominant alterations observed in this subtype were the amplification/mutation of PIK3CA gene (41%) followed by the loss of PTEN gene (12%) and the amplification of MDM2/4 genes (14%). The rarest alterations of genes observed in this subtype were the alterations of PIK3CAR1, PIK3C2B, mTOR and RPTOR genes (&gt;1%). Analyzing the composite alterations in individual patients within ER+ BC, we observed that 40% of patients had alterations in more than one node of the pathway. The most common combination (alterations) being the amplification/mutation of PIK3CA with the amplification of MDM2/4 genes. In contrast the percentage of patients belonging to other two subtypes of BC (HER2+ & TNBC) exhibiting a similar alterations in the PI3K pathway genes were significantly lower (∼ 40%). Among these patients only a negligible% exhibited alterations of more than one node of the pathway. In cell line based models, a combination of the pan-PI3K pathway inhibitor, GDC-0941 or isoform-specific inhibitors, GDC-0032 / AZD6482 were tested with AI which blocked proliferative signals and enhanced apoptosis in ER+/PIK3CA mutated and ER+/PTEN mutated cells. In PIK3CA helical domain mutated MCF7 and T47D cells GDC-0941 and GDC-0032 alone or in combination with AI were effective in blocking the direct proliferative signals of PI3K enzyme, including pAKT S473 and pAKT T308 as well as downstream signals of mTOR including pS6RP and p4EBP1 while treatment with AI alone was ineffective. In contrast, p110beta isoform specific inhibitor AZD6482 was effective in blocking the proliferative signals while GDC-0032 failed to abrogate any of proliferative signals in PTEN mutated MDA-MB415 cells. These mechanistic results were confirmed by apoptosis and 3D ON-TOP colony formation assays.

Significance: Genomic landscape forms the basis of the algorithm for the combination of PI3K pathway isoform-specific inhibitor(s) and anti-estrogen drug(s) towards precision medicine in ER+ BC. Applying cutting edge knowledge about how tumor cells signal to bring a particular phenotype on the landscape of genetic alterations from an individual patient is the best approach towards achieving success in precision medicine.

Citation Format: Nandini Dey, Casey Williams, Jennifer H. Carlson, Kirstin Williams, Jessica Klein, Amy Krie, Pradip De, Brian Leyland-Jones. Algorithmic basis for combination of PI3K pathway isoform-specific inhibitors: Navigating the genomic landscape in ER+ breast cancers. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B106.