Abstract 1331: First results of the EIT PACMAN Study: OncoSignal pathway analysis to identify clinically actionable signal transduction pathway activity in a variety of cancer types
Authors: Martin-Romano Patricia , Neerken Sieglinde , Van de Stolpe Anja , Den Biezen-Timmerman Eveline , Ngo Maud , Nicotra Claudio , Akse Martijn , Eggermont Alexander , Van de Wiel Paul , Massard Christophe , Calvo Fabien 
Published: September 2020

Introduction: Precision medicine has shown to improve outcomes of cancer patients by identifying oncogenic alterations and actionable mutations. Yet, most tests perform DNA sequencing and are not able to discriminate which tumor driving signaling pathways (SP) are functionally active. OncoSignal pathway analysis tests quantitatively measure activity of SP such as estrogen receptor, androgen receptor, PI3K, MAPK, TGF-β, Notch on fresh frozen and formalin-fixed paraffin-embedded (FFPE) tissue samples, while mutation analysis provides complementary information related to the genomic alteration in the SP. Combined information is expected to improve choice of the optimal effective targeted therapy to improve patients' outcome and quality of life as well as to reduce unnecessary side effects/costs due to unnecessary therapy. In this study OncoSignal pathway analysis was performed on a series of samples from the Moscato trial (1), with the aim of assessing clinically actionable SP activity.

Methods: OncoSignal pathway analysis (ER, AR, PI3K, MAPK, HH, Notch, TGF-β) was performed blinded by Molecular Pathway Dx (Philips, Eindhoven) on tumor tissue samples from 5 breast and 31 prostate tumors, all proven to be hard to treat and obtained from the Moscato study. Results were sent back to Institut Gustave Roussy for clinical annotation and analysis. For breast and prostate cancer, pathway activity scores were determined for each SP in healthy breast (n=7) and prostate (n=9) tissues (GEO datasets: GSE17951 and GSE10780) and compared with pathway activity scores in cancer tissue samples (multiple GEO datasets: n=133 and n=1712). Increased activity of a pathway in cancer tissue (&gt;95th percentile of healthy tissue pathway activity) was considered as tumor-driver function for the respective pathway and thus clinically actionable. Subsequently, for each individual Moscato sample, alterations were considered as tumor driving pathways if the sample pathway activity score exceeded the 95th percentile of normal (primary) tissue pathway activity.

Results: Identified tumor driving SP in breast cancer were ER, AR, MAPK-AP1, HH, and PI3K pathway whereas in prostate cancer identified SP were the AR and PI3K pathway. Of the 5 breast cancer metastasis samples (lung, head/neck, skin, liver, lymph node; average tumor content 40%), all had at least one clinically actionable tumor driving pathway. Of the 30 prostate cancer metastasis samples (bone, liver, lymph nodes; average tumor content 62%), 29 (97%) had a clinically actionable tumor driving pathway.

Conclusion: OncoSignal pathway analysis enabled identification of clinically potentially actionable signaling pathway activity in 97-100% of analyzed breast and prostate cancer samples.

Citation Format: Patricia Martin-Romano, Sieglinde Neerken, Anja Van de Stolpe, Eveline Den Biezen-Timmerman, Maud Ngo, Claudio Nicotra, Martijn Akse, Alexander Eggermont, Paul Van de Wiel, Christophe Massard, Fabien Calvo. First results of the EIT PACMAN Study: OncoSignal pathway analysis to identify clinically actionable signal transduction pathway activity in a variety of cancer types [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1331.