Abstract 1911: Analysis of the pancreatic cancer (PC) genome by immunohistochemistry (IHC) and comparative genome hybridization (CGH) in patients with long term survival with metastatic disease (mPC) treated on a phase II molecular profiling trial.
Authors: Shahda Safi , Barrett Michael T. , Lenkiewicz Elizabeth , Evers Lisa , Posner Richard G. , Aziz Meraj , Weiss Glen J. , Jameson Gayle , Von Hoff Daniel D. , Ramanathan Ramesh K. 
Published: August 2014

Pancreatic cancer (PC) is a heterogeneous disease. Several mutations have been reported to develop along the path of PC evolution, and it is important to identify targets for potential therapy. CGH and IHC analysis of pancreatic tumor samples may reveal prognostic and predictive markers.

Methods: We evaluated tumor samples of patients (n=35) who were accrued to a phase II molecular profiling study (Ramanathan RK et al.12-LB-8953-AACR 2012). All subjects, with metastatic PC, with progression after 1st line of therapy had a core biopsy for CGH, IHC, and microarray analysis. Samples interrogated by CGH were flow sorted prior to analysis. Treatment recommendations were based on the IHC panel (Target Now®, Caris Life Sciences, Irving, TX).

Results: In 30 patients, adequate tumor was available for CGH. We identified 9 long term survivors, living &gt; 18 months from first diagnosis of mPC. Of the 9 patients, 5 had available CGH data.

(1) had two distinct aneuploid tumor cell populations. There was evidence suggestive of increased WNT signaling based on amplicon targeting FZD3;. IHC identified TS and SPARC as potential targets. Recommended treatment: Capecitabine and Nab-Paclitaxel

(2) had a focal amplicon targeting WNT6 and WNT10A suggestive of increased WNT signaling, and homozygous deletions targeting RB1 and PARD3B. An intragenic break within NOTCH2 was also observed. IHC identified TS and TOPO1 as potential targets. Recommended treatment: FOLFIRI

(3) was identified (and confirmed to be) KRAS wild-type, but had a homozygous deletion of RASA1, the gene that codes for p120-RasGAP a known negative regulator of KRAS signaling. Commonly seen deletions of CDKN2A and SMAD4 were not observed. IHC identified TS and ERCC1 as potential targets. Recommended treatment: FOLFOX

(4) had an amplification of a PARP gene (PARP8) and of a base excision enzyme (NEIL2), chromosomal copy number changes to genes involved in chromatin regulation (LCMT, EZH2, KLF13) and EMT with dedifferentiation (ZNF703). IHC identified MGMT as a potential target. Recommended treatment: Temazolamide.

(5) had amplifications of PIK3CA and of KRAS, and a homozygous deletion of CDKN2A. IHC identified TOPO2 as a potential target. Recommended treatment: Doxorubicin

Conclusion: Due to the heterogeneity of the genome, even in a select group with long term survival, each patient may require an individualized treatment plan. Pathway analysis of all patients treated in the study is ongoing. Treatment strategies to focus on the stroma and of methylation of the genome are being explored to circumvent the genetic heterogeneity. (Supported by a SU2C pancreatic dream team grant)

Citation Format: Safi Shahda, Michael T. Barrett, Elizabeth Lenkiewicz, Lisa Evers, Richard G. Posner, Meraj Aziz, Glen J. Weiss, Gayle Jameson, Daniel D. Von Hoff, Ramesh K. Ramanathan. Analysis of the pancreatic cancer (PC) genome by immunohistochemistry (IHC) and comparative genome hybridization (CGH) in patients with long term survival with metastatic disease (mPC) treated on a phase II molecular profiling trial. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1911. doi:10.1158/1538-7445.AM2013-1911