Takeda, Hiroyuki

3586 Background: HSP90 mediated chaperoning is a well-conserved biological mechanism for stabilization and activation of kinases. More than 60% of human kinases including VEGFR, CRAF, CSF1R, and FGFR are target of HSP90 (client kinases), whereas EGFR is non-client. CDC37 is a specific co-chaperone determining selectivity of client kinases recognized by HSP90. We hypothesized that gene expression levels of CDC37 have predictive values for anti-angiogenic therapies in mCRC. Methods: The subjects of this study were mCRC patients treated with regorafenib (REGO, Japanese retrospective cohort) and those treated with bevacizumab (BEV) or cetuximab (CET) in combination with first-line chemotherapy (CALGB/SWOG 80405 trial cohort). CDC37 expression levels were measured using RNA isolated from FFPE samples by nCounter gene expression profiling (Nanostring) and HiSeq 2500 (Illumina) in the Japanese and CALGB/SWOG 80405 cohorts, respectively. Overall survival (OS) and progression-free survival (PFS) were compared between patients with high CDC37 expression ( CDC37-H) and those with low expression ( CDC37-L), grouped by median cutoff value in each cohort. Results: In total, 484 patients were included (50 treated with REGO, 227 treated with BEV, and 207 treated with CET). In REGO-treated patients, CDC37-H showed significantly better OS (median 11.3 vs 6.0 months, adjusted hazard ratio [HR] 0.24, 95% confidence interval [CI] 0.11-0.54, p <0.01) and PFS (median 3.5 vs 1.9 months, adjusted HR 0.51, 95% CI 0.28-0.94, p = 0.03) compared to CDC37-L. Similarly, in BEV-treated patients, CDC37-H showed significantly better PFS (median 13.5 vs 9.6 months, adjusted HR 0.59, 95% CI 0.43-0.79, p <0.01) and numerically better OS (median 34.1 vs 29.4 months, adjusted HR 0.81, 95% CI 0.60-1.11, p = 0.20) compared to CDC37-L. However, in CET-treated patients, CDC37-H and CDC37-L patients showed similar OS (median 33.7 vs 26.1 months, adjusted HR 1.00, 95% CI 0.73-1.38, p = 0.98) and PFS (median 11.3 vs 11.0 months, adjusted HR 1.08, 95% CI 0.81-1.45, p = 0.60). Significant interaction was observed between CDC37 expression and treatment in terms of PFS in the CALGB/SWOG 80405 cohort ( p = 0.01). Conclusions: Our results suggest patients with CDC37-dependent ( CDC37-H) tumors may derive more benefit from REGO and BEV both of which target HSP90 client kinases or signaling pathways, but not from CET which target HSP90 non-client kinase. Further validation studies are warranted to develop a novel personalized approach for targeted therapies based on CDC37 expression in mCRC patients. Support: U10CA180821, U10CA180888; Pfizer, Genentech; https://acknowledgments.alliancefound.org. ClinicalTrials.gov Identifier: NCT00265850.

AbstractBackgroundHepatectomy is standard treatment for colorectal liver metastases; however, it is unclear whether liver metastases from other primary cancers should be resected or not. The Japanese Society of Hepato‐Biliary‐Pancreatic Surgery therefore created clinical practice guidelines for the management of metastatic liver tumors.MethodsEight primary diseases were selected based on the number of hepatectomies performed for each malignancy per year. Clinical questions were structured in the population, intervention, comparison, and outcomes (PICO) format. Systematic reviews were performed, and the strength of recommendations and the level of quality of evidence for each clinical question were discussed and determined. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to assess evidence and make recommendations.ResultsThe eight primary sites were grouped into five categories based on suggested indications for hepatectomy and consensus of the guidelines committee. Fourteen clinical questions were devised, covering five topics: (1) diagnosis, (2) operative treatment, (3) ablation therapy, (4) the eight primary diseases, and (5) systemic therapies. The grade of recommendation was strong for one clinical question and weak for the other 13 clinical questions. The quality of the evidence was moderate for two questions, low for 10, and very low for two.A flowchart was made to summarize the outcomes of the guidelines for the indications of hepatectomy and systemic therapy.ConclusionsThese guidelines were developed to provide useful information based on evidence in the published literature for the clinical management of liver metastases, and they could be helpful for conducting future clinical trials to provide higher‐quality evidence.