Alberts, Steven R.

Objectives: The aim of this was to determine survival after starting neoadjuvant therapy for patients who became ineligible for orthotopic liver transplantation (OLT). Methods and Materials: Since January 1993, 215 patients with unresectable cholangiocarcinoma began treatment with planned OLT. Treatment included external-beam radiation therapy (EBRT) with fluorouracil, bile duct brachytherapy, and postradiotherapy fluorouracil or capecitabine before OLT. Adverse findings at the staging operation, death, and other factors precluded OLT in 63 patients (29%), of whom 61 completed neoadjuvant chemoradiation. Results: By October 2012, 56 (89%) of the 63 patients unable to undergo OLT had died. Twenty-two patients (35%) became ineligible for OLT before the staging operation, 38 (60%) at the staging operation, and 3 (5%) after staging. From the date of diagnosis, median overall survival was 12.3 months. Survival was 17% at 18 months and 7% at 24 months. Median survival after fallout was 6.8 months. Median survival after the staging operation was 6 months. Two patients lived for 3.7 and 8.7 years before dying of cancer or liver failure caused by persistent biliary stricture at the site of the original cancer, respectively. Univariate analysis showed that time from diagnosis to fallout correlated with overall survival (P=0.04). Conclusions: In highly selected patients initially suitable for OLT, the mortality rate for cholangiocarcinoma was high in patients who became ineligible for OLT. Their survival, however, was comparable to expected survival for patients with locally advanced or metastatic disease treated with nontransplant therapies. The most common reason for patient fallout was adverse findings at the staging operation.

AbstractWe compiled and analyzed a database of cooperative group trials in advanced pancreatic cancer to develop historical benchmarks for overall survival (OS) and progression-free survival (PFS). Such benchmarks are essential for evaluating new therapies in a single-arm setting. The analysis included patients with untreated metastatic pancreatic cancer receiving regimens that included gemcitabine, between 1995 and 2005. Prognostic baseline factors were selected by their significance in Cox regression analysis. Outlier trial arms were identified by comparing individual 6-month OS and PFS rates against the entire group. The dataset selected for the generation of OS and PFS benchmarks was then tested for intertrial arm variability using a logistic-normal model with the selected baseline prognostic factors as fixed effects and the individual trial arm as a random effect. A total of 1,132 cases from eight trials qualified. Performance status and sex were independently significant for OS, and performance status was prognostic for PFS. Outcomes for one trial (NCCTG-034A) were significantly different from the other trial arms. When this trial was excluded, the remaining trial arms were homogeneous for OS and PFS outcomes after adjusting for performance status and sex. Benchmark values for 6-month OS and PFS are reported along with a method for using these values in future study design and analysis. The benchmark survival values were generated from a dataset that was homogeneous between trials. The benchmarks can be used to enable single-arm phase II trials using a gemcitabine platform, especially under certain circumstances. Such circumstances might be when a randomized control arm is not practically feasible, an early signal of activity of an experimental agent is being explored such as in expansion cohorts of phase I studies, and in patients who are not candidates for combination cytotoxic therapy. Clin Cancer Res; 20(16); 4176–85. ©2014 AACR.

AbstractPurpose: A let-7 microRNA-complementary site (LCS6) polymorphism in the 3′ untranslated region of the KRAS gene has been shown to disrupt let-7 binding and upregulate KRAS expression. We evaluated the LCS6 genotype and its association with KRAS mutation status, clinicopathologic features, and disease-free survival (DFS) in patients with stage III colon cancer who enrolled in a phase III clinical trial (NCCTG N0147).Experimental Design: The LCS6 genotype was assayed by real-time PCR in DNA extracted from whole blood (n = 2,834) and compared with paired tumor tissue (n = 977). χ2 and two-sample t tests were used to compare baseline factors and KRAS mutation status between patients defined by LCS6 variant status. Log-rank tests and multivariate Cox models assessed associations between LCS6 status and DFS, respectively.Results: We identified 432 (15.2%) blood samples and 143 (14.6%) tumor samples heterozygous or homozygous for the LCS6 G-allele, and 2,402 of 2,834 (84.8%) blood samples and 834 of 977 (85.4%) tumor samples homozygous for the LCS6 T-allele. Genotype results were highly concordant (99.8%) in cases with paired blood and tumor tissue (n = 977). G-allele carriers were significantly more frequent in Caucasians versus other races (χ2 test, P < 0.0001). The LCS6 genotype was not associated with KRAS mutation status, clinicopathologic features (all P > 0.2), or DFS (log-rank P = 0.49; HR, 0.929; 95% confidence interval, 0.76–1.14), even after combining LCS6 genotype with KRAS mutation status.Conclusions: In the largest association study investigating the LCS6 polymorphism in colon cancers, the germline LCS6 genotype was not associated with KRAS mutation status or with clinical outcome in patients with stage III tumors. Clin Cancer Res; 20(12); 3319–27. ©2014 AACR.

Abstract Purpose. The Oncotype DX colon cancer assay is a clinically validated predictor of recurrence risk in stage II colon cancer patients. This prospective study evaluated the impact of recurrence score (RS) results on physician recommendations regarding adjuvant chemotherapy in T3, mismatch repair-proficient (MMR-P) stage II colon cancer patients. Patients and Methods. Stage IIA colon cancer patients were enrolled in 17 centers. Patient tumor specimens were assessed by the RS test (quantitative reverse transcription-polymerase chain reaction) and mismatch repair (immunohistochemistry). For each patient, the physician's recommended postoperative treatment plan of observation, fluoropyrimidine monotherapy, or combination therapy with oxaliplatin was recorded before and after the RS and mismatch repair results were provided. Results. Of 221 enrolled patients, 141 patients had T3 MMR-P tumors and were eligible for the primary analysis. Treatment recommendations changed for 63 (45%; 95% confidence interval: 36%–53%) of these 141 T3 MMR-P patients, with intensity decreasing for 47 (33%) and increasing for 16 (11%). Recommendations for chemotherapy decreased from 73 patients (52%) to 42 (30%), following review of RS results by physician and patient. Increased treatment intensity was more often observed at higher RS values, and decreased intensity was observed at lower values (p = .011). Conclusion. Compared with traditional clinicopathological assessment, incorporation of the RS result into clinical decision making was associated with treatment recommendation changes for 45% of T3 MMR-P stage II colon cancer patients in this prospective multicenter study. Use of the RS assay may lead to overall reduction in adjuvant chemotherapy use in this subgroup of stage II colon cancer patients.

Abstract Purpose: We examined the prognostic impact of specific KRAS mutations in patients with stage III colon adenocarcinoma receiving adjuvant FOLFOX alone or combined with cetuximab in a phase III trial (N0147). Analysis was restricted to BRAF–wild-type tumors, because BRAF mutation was associated with poor prognosis, and BRAF and KRAS mutations are mutually exclusive. Experimental Design: The seven most common KRAS mutations in codon 12 and codon 13 were examined in 2,478 BRAF–wild-type tumors. Because KRAS mutations in codon 12 (n = 779) or 13 (n = 220) were not predictive of adjuvant cetuximab benefit, study arms were pooled for analysis. Disease-free survival (DFS) was evaluated by HRs using Cox models. Results: KRAS mutations in codon 12 (multivariate HR, 1.52; 95% confidence interval, CI, 1.28–1.80; P < 0.0001) or codon 13 (multivariate HR, 1.36; 95% CI, 1.04–1.77; P = 0.0248) were significantly associated with shorter DFS compared with patients with wild-type KRAS/BRAF tumors, independent of covariates. KRAS codon 12 mutations were independently associated with proficient mismatch repair (P < 0.0001), proximal tumor site (P < 0.0001), low grade, age, and sex, whereas codon 13 mutations were associated with proximal site (P < 0.0001). Conclusion: KRAS mutations in either codon 12 or 13 are associated with inferior survival in patients with resected stage III colon cancer. These data highlight the importance of accurate molecular characterization and the significant role of KRAS mutations in both codons in the progression of this malignancy in the adjuvant setting. Clin Cancer Res; 20(11); 3033–43. ©2014 AACR.

PurposeThe association of deficient DNA mismatch repair (dMMR) with prognosis in patients with colon cancer treated with adjuvant fluorouracil, leucovorin, and oxaliplatin (FOLFOX) chemotherapy remains unknown.Patients and MethodsResected, stage III colon carcinomas from patients (N = 2,686) randomly assigned to FOLFOX ± cetuximab (North Central Cancer Treatment Group N0147 trial) were analyzed for mismatch repair (MMR) protein expression and mutations in BRAFV600E(exon 15) and KRAS (codons 12 and 13). Association of biomarkers with disease-free survival (DFS) was determined using Cox models. A validation cohort (Cancer and Leukemia Group B 88903 trial) was used.ResultsdMMR was detected in 314 (12%) of 2,580 tumors, of which 49.3% and 10.6% had BRAFV600Eor KRAS mutations, respectively. MMR status was not prognostic overall (adjusted hazard ratio [HR], 0.82; 95% CI, 0.64 to 1.07; P = .14), yet significant interactions were found between MMR and primary tumor site (Pinteraction= .009) and lymph node category (N1 v N2; Pinteraction= .014). Favorable DFS was observed for dMMR versus proficient MMR proximal tumors (HR, 0.71; 95% CI, 0.53 to 0.94; P = .018) but not dMMR distal tumors (HR, 1.71; 95% CI, 0.99 to 2.95; P = .056), adjusting for mutations and covariates. Any survival benefit of dMMR was lost in N2 tumors. Mutations in BRAFV600E(HR, 1.37; 95% CI, 1.08 to 1.70; P = .009) or KRAS (HR, 1.44; 95% CI, 1.21 to 1.70; P < .001) were independently associated with worse DFS. The observed MMR by tumor site interaction was validated in an independent cohort of stage III colon cancers (Pinteraction= .037).ConclusionThe prognostic impact of MMR depended on tumor site, and this interaction was validated in an independent cohort. Among dMMR cancers, proximal tumors had favorable outcome, whereas distal or N2 tumors had poor outcome. BRAF or KRAS mutations were independently associated with adverse outcome.

BACKGROUNDA point mutation (V600E) in the BRAF oncogene is a prognostic biomarker and may predict for nonresponse to anti‐EGFR antibody therapy in patients with colorectal carcinoma. BRAFV600E mutations are frequently detected in tumors with microsatellite instability and indicate a sporadic origin. We used a mutation‐specific antibody to examine mutant BRAFV600E protein expression and its concordance with BRAFV600E mutation data.METHODSPrimary stage III colon carcinomas were analyzed for BRAFV600E mutations in exon 15, and 50 BRAFV600E mutation carriers and 25 wild‐type tumors were selected for analysis of BRAF proteins by immunohistochemistry (IHC). IHC was performed in archival tissue specimens using a pan‐BRAF antibody and a mutation‐specific antibody against BRAFV600E proteins. Staining was scored by 2 pathologists who were blinded to clinical and mutation data.RESULTSUsing a pan‐BRAF antibody, total BRAF protein expression was observed in the tumor cell cytoplasm in 74 of 75 colon carcinomas. A mutation‐specific antibody identified diffuse cytoplasmic staining of mutant BRAFV600E proteins in 49 of 74 cancers. Analysis using a polymerase chain reaction‐based assay revealed that all 49 of these cancers carried BRAFV600E mutations. In contrast, BRAFV600E staining was absent in all 25 tumors that carried wild‐type copies of BRAF.CONCLUSIONSA BRAF mutation‐specific (V600E) antibody detected tumors with BRAFV600E mutations and exhibited complete concordance with a DNA‐based method. These results support the use of IHC as a simplified strategy to screen colorectal cancers for BRAFV600E mutations in clinical practice. Cancer 2013;119:2765–2770. © 2013 American Cancer Society.

Purpose By using data from North Central Cancer Treatment Group Phase III Trial N0147, a randomized adjuvant trial of patients with stage III colon cancer, we assessed the relationship between smoking and cancer outcomes, disease-free survival (DFS), and time to recurrence (TTR), accounting for heterogeneity by patient and tumor characteristics. Patients and Methods Before random assignment to infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX) or FOLFOX plus cetuximab, 1,968 participants completed a questionnaire on smoking history and other risk factors. Cox models assessed the association between smoking history and the primary trial outcome of DFS (ie, time to recurrence or death), as well as TTR, adjusting for other clinical and patient factors. The median follow-up was 3.5 years among patients who did not experience events. Results Compared with never-smokers, ever smokers experienced significantly shorter DFS (3-year DFS proportion: 70% v 74%; hazard ratio [HR], 1.21; 95% CI, 1.02 to 1.42). This association persisted after multivariate adjustment (HR, 1.23; 95% CI, 1.02 to 1.49). There was significant interaction in this association by BRAF mutation status (P = .03): smoking was associated with shorter DFS in patients with BRAF wild-type (HR, 1.36; 95% CI, 1.11 to 1.66) but not BRAF mutated (HR, 0.80; 95% CI, 0.50 to 1.29) colon cancer. Smoking was more strongly associated with poorer DFS in those with KRAS mutated versus KRAS wild-type colon cancer (HR, 1.50 [95% CI, 1.12 to 2.00] v HR, 1.09 [95% CI, 0.85 to 1.39]), although interaction by KRAS mutation status was not statistically significant (P = .07). Associations were comparable in analyses of TTR. Conclusion Overall, smoking was significantly associated with shorter DFS and TTR in patients with colon cancer. These adverse relationships were most evident in patients with BRAF wild-type or KRAS mutated colon cancer.

Abstract Purpose: Surrogate biomarkers are lacking for predicting or monitoring response to anti-angiogenesis therapies. We investigated whether circulating biomarkers (CBMs) of angiogenesis (i.e., bFGF, SDF-1α, HGF, sKIT, Ang-2, and PlGF) correlated with treatment efficacy in a pooled analysis of metastatic colorectal cancer (mCRC) and recurrent glioblastoma multiforme (rGBM) patients (pts) treated with bevacizumab/sorafenib (BEV/SOR). Experimental procedures: Peripheral blood samples were obtained for CBM analyses from pts enrolled in the North Central Cancer Treatment Group (NCCTG) phase II studies N054C (mCRC, n=75, Grothey, ASCO 2010) and N0776 (rGBM, n=54, Galanis, ASCO 2010). Blood collection time points were: baseline (BL), cycle 1 day 3 (C1D3), prior to treatment cycles 2, 3, 5, 7, 9, 11, 13, and after the pt went off study. Plasma CBM levels were determined by commercially-available ELISAs (R&D Systems) and performed according to manufacturer's instructions. For each CBM, a linear regression model that adjusted for study was used to evaluate the correlation with either progression-free survival (PFS) success/failure or progression within 14 days of the last blood draw for the following measures: absolute BL levels, log2 BL levels; C1D3 log2-fold change (FC) from BL, prior to cycle 2 log2-FC from BL, last draw log2-FC from BL, and last draw log2-FC from prior draw. Results summary: There appears to be no significant difference in the PFS or overall survival (OS) between the pts on these two studies; therefore, we pooled the patients from both studies for a combined analyses. We found no difference in absolute or log2 levels for any of the CBMs during the course of BEV/SOR treatment. In these pooled analyses, we found increased absolute and increased log2 BL SDF-1α levels were significantly correlated with PFS success (p=0.023 and p=0.02, respectively). After correcting for multiple comparisons (method of Benjamini & Hochberg) the p-values &lt;0.05 had a false-discovery-rate of 41.4%. None of the other CBM measures were significantly correlated with either PFS success/failure or progression within 14 days of the last blood draw (all p&gt;0.10). Conclusions: This study provides preliminary evidence that SDF-1α may be a useful CBM for determining treatment efficacy in these pts treated with BEV/SOR. Further prospective validation of SDF-1α for predicting pt progression with this treatment combination in advanced disease (e.g., mCRC and rGBM) appears warranted. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5562. doi:1538-7445.AM2012-5562

Abstract Background: The hedgehog pathway is dysregulated in basal cell carcinoma, medulloblastoma, pancreatic, lung, gastric, and a variety of other cancers. BMS-833923 is a potent, oral, small molecule antagonist of hedgehog signaling. Methods: Subjects with advanced or metastatic solid tumors were enrolled into a multiple ascending dose study to identify a maximum tolerated dose and evaluate safety, tolerability, pharmacokinetics (PK), and pharmacodynamics of BMS-833923. All subjects receive a single dose one week prior to continuous daily dosing. The single dose window allows for single dose PK collection for one week. To identify the pharmacologically active dose range surrogate tissue was collected prior to Day 1 and again on Day 22 of the first cycle. Results: As of August 14, 2009 sixteen subjects have been treated at four dose levels: 30 mg (n=5), 60 mg (n=3), 120 mg (n=3), and 240 mg (n=5); with mean patient age of 56 (range 21–78) and ECOG performance 0–1. No subjects in the first three dose cohorts experienced drug-related CTCAE AEs greater than Grade 2. One subject with medulloblastoma in the 30 mg dose cohort continues on study for more than 10 months with stable disease. Treatment of patients in the fourth cohort at 240 mg continuous daily dosing is still on-going. In this cohort one subject experienced drug-related CTCAE Grade 2 lipase elevation and pancreatitis that quickly resolved when drug was withheld. This subject has a diagnosis of Gorlin Syndrome, which is caused by germline mutations in the hedgehog pathway genes Patched or Smoothened. This subject experienced a partial response (PR) that is still ongoing. BMS-833923 PK properties showed dose proportionality between the 30, 60, and 120 mg dose cohorts with a Cmax of 30 ng/ml, 56 ng/ml and 102 ng/ml respectively. The terminal half-life was greater than 7 days and drug accumulations were observed. Conclusion: BMS-833923 is generally well tolerated at daily doses of 30, 60, 120 mg. Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A55.