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5583 Background: Elevated Glioma-associated Oncogene Homolog-1 (Gli1) protein expression is associated with Hedgehog (Hh) pathway activation in high-grade serous ovarian cancer (HGSOC). Inhibition of Hh signaling in Gli1-overexpressing HGSOC patient-derived xenograft (PDX) inhibited tumour growth, particularly in combination with chemotherapy. Early phase HGSOC clinical trials of vismodegib, a potent Hh inhibitor (SMO inhibitor), were disappointing. We identified a HGSOC PDX harboring both Indian Hh ligand-overexpression and bi-allelic deletion of TSC1, which latter event is reported to derepress the mTOR pathway, driving non-cannonical Gli1 expression. We explored the effect of vismodegib in combination with cisplatin or the mTOR inhibitor, everolimus, in this model. Methods: A cell-line was generated from the well-characterised PDX (identity confirmed by PDX-specific p53 mutation). In vitro response to vismodegib was assessed. qRT-PCR was performed to establish Hh-ligand and Gli1 expression with/without SMO inhibition. A PDX was generated from this cell-line and randomized to in vivo treatment with cisplatin, vismodegib, everolimus or vehicle alone, or vismodegib in combination with cisplatin or everolimus. Results: The HGSOC cell-line was sensitive to vismodegib in vitro (EC50 of 3.5µM) and qRT-PCR analysis revealed down-regulation of Hh-ligand and Gli1 expression following in vitro SMO inhibition, confirming on-target vismodegib activity. In vivo treatment with vismodegib or everolimus alone did not result in reproducible in vivo efficacy. The combination of vismodegib + everolimus caused short-lived responses in 3 of 6 mice. Strikingly, in vivo treatment with vismodegib in combination with cisplatin impaired median survival (19 days) when compared with cisplatin treatment alone (43 days; p = 0.039) due to rapid tumour progression. Conclusions: Combining chemotherapy with Hh inhibition in Hh ligand-overexpressing HGSOC PDX with mTOR pathway activation may be detrimental. These findings highlight the importance of an in-depth understanding of tumour biology in order to effectively combine therapeutic approaches.

e19598 Background: Cancer is highly prevalent in those above the age of 65 years. Elderly oncological patients are under-represented in clinical trials and there is a lack of clinical data to guide treatment decisions in this group of patients. We evaluated the cytotoxic treatment tolerability in this group of patients in a community hospital. Methods: Cytotoxic chemotherapies and tyrosine kinase inhibitors administered in Gold Coast Hospital to patients above 65 years of age between March 2010 and March 2011 were included. Data including number of comorbidities, concurrent medicines, ECOG status and treatment drug dose adjustment were obtained. The outcomes of treatment including treatment completion, early termination and its reason, toxicities and hospital admissions during treatment were also collected. Results: A total of 206 patients were identified. Majority had an ECOG score of 0 to 1 (89%) and number of co-morbidities between 0 and 3 (96%). Eighty percent of patients had initial or subsequent treatment dose reduction. Despite this, 53% of patients (n=109) did not complete the planned treatment; 68% had disease progression but 31% was due to treatment intolerance. There was a high number of reported grade 3 and 4 toxicities (n=84) and hospitalisations during treatment (n=154). Conclusions: There is a high rate of dose reduction and noncompletion of cytotoxic treatments even in a relatively healthy elderly population. We propose further prospective study incorporating in-depth geriatric assessment to evaluate elderly patients suitability for cytotoxic treatments. [Table: see text]