Alberts, Steven R.

Purpose This brief report describes a planned, interim, 6-patient toxicity analysis that confirms the safety of pemetrexed, carboplatin, radiation with subsequent surgery, as prescribed in the North Central Cancer Treatment Group trial N044E, in patients with locally advanced esophageal cancer. Methods Six patients with locally advanced, potentially resectable esophageal cancer received pemetrexed 500 mg/m 2 and carboplatin AUC = 6 on days 1 and 22 with 5040 centigray of concomitant radiation in 28 fractions over 5.5 weeks followed by esophagectomy as a prelude to a phase II multi-institutional trial. Results Only 1 of the 6 patients experienced a grade 4 adverse event (neutropenia). This patient also experienced a grade 3 depression. Of the remaining 5 patients, three experienced at least one grade 3 adverse event (neutropenia, nausea/vomiting, and esophagitis). There were no deaths. Incidentally, one patient manifested a complete pathologic response, three a partial pathologic response, and one stable disease. Conclusion These preliminary observations on safety suggest that this regimen can be further studied in this clinical setting.

Abstract Background: The paucity of effective therapeutic agents for hepatocellular cancer (HCC) underscores the critical need for more effective therapeutic strategies. Recent studies indicate lipid biosynthesis and desaturation is required for HCC survival. Targeting these may prove beneficial because such changes contribute to therapeutic resistance. Stearoyl CoA desaturase (SCD1), a key mediator of fatty acid (FA) biosynthesis and rate-limiting in conversion of saturated fatty acids (SFAs) to mono-unsaturated fatty acids (MUFAs), is upregulated in HCC and many other cancers. As such, we therapeutically targeted a novel lipogenic tumor survival mechanism mediated by SCD1 as a means to combat the chemoresistance associated with HCC. In so doing, we evaluated a novel lead SCD1 inhibitor in HCC. Methods: Paraffin embedded patient HCC tissues were examined for SCD1 expression. Using combined computational and synthetic chemistry approaches, we synthesized four novel specific SCD1 inhibitors with SSI-4 being the lead SCD1 inhibitor. HCC cell lines were examined using proliferation assays for response to SSI-4. IC50 concentrations for blocking SCD1 enzyme activity was determined. Blood half-life and bioavailability of single dose SSI-4 was determined. Mechanisms of action of SCD1 were examined that included Endoplasmic reticulum (ER) stress. In vivo, antitumor activity was determined using HCC patient derived xenograft (PDX) mouse models. Results: We identified elevated SCD1 mRNA and protein in HCCs tissues. SSI-4 dose-dependently inhibits cell proliferation in HCC cell lines with specificity demonstrated by oleic acid (MUFA) co-culture. Single dose oral gavage SSI-4 demonstrated a half-life of ~4 hours and excellent oral bioavailability. SSI-4 was well tolerated with long-term daily dosing. SSI-4 treatment of HCC cells and tumors led to endoplasmic reticulum (ER) stress followed by apoptotic cell death. Single agent SSI-4 demonstrated antitumor activity in HCC PDX mouse models with suppression of ER stress regulated proteins. Conclusions: Targeting a novel lipid metabolic pathway in HCC may provide effective therapy for aggressive HCC. Citation Format: John Alton Copland, Laura A. Marlow, Ilah Bok, James L. Miller, Matsuda Akiko, Yan W. Asmann, Vivekananda Sarangi, Steven R. Alberts, Kabir Mody, Lewis R. Roberts, Mark J. Truty, Tushar C. Patel. Targeting stearoyl CoA desaturase 1 (SCD1) in hepatobilliary carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 192. doi:10.1158/1538-7445.AM2017-192

420 Background: Advanced biliary cancers respond poorly to chemotherapy and have a dismal survival. Currently gemcitabine-cisplatin (GC) is the standard of care for patients with advanced disease. The efficacy of second line treatment options is not well-defined. We retrospectively evaluated outcomes of patients undergoing second line treatment for advanced biliary cancers at Mayo Clinic. Methods: After obtaining approval from the institutional board review (IRB), we identified 42 patients with advanced and metastatic biliary cancers that progressed after first line (GC) and received second line treatment from 2007-2014. All patients had adequate follow up data. JMP software was used for statistical analysis. Kaplan-Meier method and log-rank tests were used for survival analysis, and multivariate cox proportional hazards model was used to evaluate the prognostic effect of pertinent clinical variables. All tests were two sided and a P value of < 0.05 was considered significant. Results: The median age at diagnosis was 61.5 (range 26-87). The most common regimens used for second line settings were 5-FU-based (69%) followed by gemcitabine-based regimens (19%). The overall response rate (ORR) was 9.1%, while the disease control rate (DCR; stable disease and partial response) was 33%. The median overall survival (mOS) for the entire cohort from first line was 16.8 months (95% CI 12.7-21.7) and the progression-free survival (PFS) was 9.16 months (95% CI 7.3-14.7). From second line start the mOS was 10.4 months (95%; CI 7.3-23.7), and PFS was 2.8 months (95% CI 2.3-4.0). 73% of patients who received second line therapy were alive at 6 months and 50% at 12 months. 25 patients received third line treatment after progression. An univariate and multivariate analysis were performed including age, sex, stage at diagnosis, regimen used, CA19-9 and total body weight loss > 5%, but no significant prognostic factors were identified. Conclusions: Patients with biliary cancers who progress after first line treatment have poor prognosis, but may benefit from second line regimens. 5-FU based regimens were the most commonly used in the second line setting, and 73% of patients who received second line therapy were alive at 6 months.

396 Background: The 12-gene Oncotype DXColon Cancer Assay is clinically validated as a predictor of recurrence risk in stage II colon cancer patients following surgery. We previously reported that the 12-gene assay led to 45% change in physician treatment (Tx) recommendations in a prospective study in MMR-P stage IIA colon cancer patients. Here, from the same prospective study, we report the influence of the 12-gene assay on patient Tx decisions, physician confidence, concordance in Tx choice between physicians and patients, and patient decisional conflict. Methods: Consecutive patients with resected stage IIA colon cancer who were candidates for adjuvant chemotherapy were enrolled by 105 physicians from 17 sites. Patient's tumor specimens were assessed by the 12-gene assay (RT-PCR) and MMR (IHC). Prior to and after receiving these results, patients completed surveys including (1) their Tx decisions (observation (Obs) vs. 5FU-monotherapy (5FU) vs. 5FU + oxaliplatin (Oxal)) and (2) indicators of decisional conflict. Results: 190 of 221 patients enrolled were evaluable including 139 who were MMR-P. Pre-assay: 46% of patients chose Obs, 3% 5FU, 7% Oxal, 2% other and 41% were undecided. Post-assay: 75% chose Obs, 12% 5FU, 11% Oxal, 3% other (undecided was not a possible response). Post-assay 129 (96%) of 135 definitive Tx decisions (Obs, 5FU, or Oxal) were concordant between patients and physicians compared to 49 (66%) of 74 definitive decisions pre-assay. In the majority of cases, patients (85%) and physicians (69%) reported that the assay influenced their Tx decisions. Assay results increased physician confidence in Tx recommendations in 126 (84%) and provided additional clinically relevant information to physicians in 129 (86%) of cases. Patient decisional conflict was significantly lower after assay results (p<0.001). Conclusions: In this prospective study, quantitative recurrence risk information provided by the 12-gene assay influenced Tx decisions for a majority of patients and physicians, increased physician confidence, improved concordance in Tx choice between patients and physicians and decreased patient decisional conflict.