Purpose The purpose of this study was to examine the prognostic and oxaliplatin predictive value of mismatch repair (MMR) status and common hot spot mutations, which we previously identified in stage II and III colon cancer. Experimental Design Mutations in BRAF, KRAS, NRAS, MET, and PIK3CA were profiled in 2,299 stage II and III colon tumors from National Surgical Adjuvant Breast and Bowel Project (NSABP) clinical trials C-07 (n = 1,836) and C-08 (n = 463) with Type Plex chemistry and mass spectrometry. C-07 tested the worth of adding oxaliplatin to 5-fluorouracil plus leucovorin, and C-08 tested the worth of adding bevacizumab to FOLFOX. Cox proportional hazard models were used to assess prognostic or oxaliplatin predictive value of mutations for tumor recurrence, overall survival (OS), and survival after recurrence (SAR). Results BRAF mutations were associated with MMR-deficient tumors (P < 0.0001), poor OS [HR, 1.46; 95% confidence interval (CI), 1.20–1.79; P S: 0.0002], and poor SAR (HR, 2.31; 95% CI, 1.83–2.95; P < 0.0001). Mutations in KRAS, NRAS, MET, and PIK3CA were not associated with recurrence, OS, or SAR. MMR-deficient tumors were associated with an improved prognosis based on recurrence (HR, 0.48; 95% CI, 0.33–0.70; P < 0.0001). Mutations and MMR status were not predictive for oxaliplatin benefit. Conclusions This study shows that BRAF mutations profiled from stage II and III colon cancer tumors were associated with poor SAR and validates and explains, at least in part, previous observations associating it with poor OS. Profiling of all of these mutations is warranted for future clinical trials testing new targeted therapies that block relevant signaling pathways. Such clinical trials are under development at NSABP.
BackgroundPancreatic cancer is a deadly disease. Discovery of the mutated genes that cause the inherited form(s) of the disease may shed light on the mechanism(s) of oncogenesis. Previously we isolated a susceptibility locus for familial pancreatic cancer to chromosome location 4q32–34. In this study, our goal was to discover the identity of the familial pancreatic cancer gene on 4q32 and determine the function of that gene.Methods and FindingsA customized microarray of the candidate chromosomal region affecting pancreatic cancer susceptibility revealed the greatest expression change in palladin (PALLD), a gene that encodes a component of the cytoskeleton that controls cell shape and motility. A mutation causing a proline (hydrophobic) to serine (hydrophilic) amino acid change (P239S) in a highly conserved region tracked with all affected family members and was absent in the non-affected members. The mutational change is not a known single nucleotide polymorphism. Palladin RNA, measured by quantitative RT-PCR, was overexpressed in the tissues from precancerous dysplasia and pancreatic adenocarcinoma in both familial and sporadic disease. Transfection of wild-type and P239S mutant palladin gene constructs into HeLa cells revealed a clear phenotypic effect: cells expressing P239S palladin exhibited cytoskeletal changes, abnormal actin bundle assembly, and an increased ability to migrate.ConclusionsThese observations suggest that the presence of an abnormal palladin gene in familial pancreatic cancer and the overexpression of palladin protein in sporadic pancreatic cancer cause cytoskeletal changes in pancreatic cancer and may be responsible for or contribute to the tumor's strong invasive and migratory abilities.
We have isolated a cDNA clone encoding the human S3 ribosomal protein from a normal human colon cDNA library. The clone was identified as one of many that detected genes whose level of expression was increased in adenocarcinoma of the colon relative to normal colonic mucosa. Increased levels of the S3 transcript were present in the tumors of all eight patients examined. Moreover, the S3 mRNA was also more abundant in 7 of 10 adenomatous polyps, the presumed precursor of carcinoma. Additional studies demonstrated that increased levels of mRNAs encoding several other ribosomal proteins, including S6, S8, S12, L5, and P0, were present in colorectal tumors and polyps. These results suggest that there is increased synthesis of ribosomes in colorectal tumors and that this increase is an early event in colon neoplasia.
Importance The association of biomarkers with patient survival after recurrence (SAR) is poorly understood, yet may guide management and treatment. Objective To determine the association of DNA mismatch repair (MMR) status and somatic mutations in BRAFV600E or KRAS (exon 2) in the primary tumor with SAR in patients with stage III colon carcinomas treated with adjuvant FOLFOX-based chemotherapy. Design Tumor biomarkers were analyzed in relationship to SAR in participants in adjuvant chemotherapy trials. Intervention Patients with resected, stage III colon cancers who were randomized to adjuvant FOLFOX ± cetuximab (NCCTG N0147) or FOLFOX ± bevacizumab (NSABP C-08). Main Outcome Measure(s) Associations of biomarkers with SAR were analyzed using Cox proportional hazards models adjusted for clinicopathological features and time-to-recurrence. The interaction effect of primary tumor sidedness on the association of biomarkers with SAR was determined. Results Among patients with cancer recurrence [N0147 (N=871); C-08 (N= 524)], multivariable analysis revealed that those whose tumors had deficient (d) vs proficient (p) MMR had significantly better SAR (adjusted hazard ratio [HRadj.], 0.70, 95% CI, 0.52 - 0.96, adjusted P [Padj.] <.029). Patients whose tumors harbored mutant BRAFV600E (HRadj., 2.45, 95% CI, 1.85 - 3.25, Padj.<.0001) or mutant KRAS (HRadj., 1.21, 95% CI, 1.00 - 1.47, Padj.=0.052) had worse SAR compared to tumors that had wild-type copies of both genes, although only results for BRAFV600E achieved statistical significance. Significant interactions were found for MMR (Padj.=.029) and KRAS (Padj.=.025) by primary tumor site for SAR. Improved SAR was observed for patients with dMMR tumors of the proximal vs distal colon (HRadj., 0.57, 95% CI, 0.40 - 0.83, Padj. =.003), and worse SAR for mutant KRAS tumors of the distal colon (codon 12: HRadj., 1.76, 95% CI, 1.30 - 2.38, Padj. =.0003; codon 13: HRadj., 1.76, 95% CI, 1.08 - 2.86, Padj. =.022]. Conclusions and Relevance In patients with recurrence, dMMR was significantly associated with better SAR and this benefit was limited to primary tumors of the proximal colon. Mutations in BRAFV600E were significantly associated with worse SAR, and worse SAR for BRAFV600E or KRAS mutant tumors was more strongly associated with distal cancers. These biomarkers have implications for patient management at recurrence. Trial Registration NCCTG NO147, NCT00079274; NSABP C-08, NCT00096278
IMPORTANCE Preclinical models and studies in the metastatic and neoadjuvant settings suggest that single nucleotide polymorphisms in FCGR3A and FCGR2A may be associated with differential response to trastuzumab in the treatment of ERBB2/HER2–positive breast cancer, by modulating antibody-dependent cell-mediated cytotoxic effects. OBJECTIVE To evaluate the effect of FCGR2A and FCGR3A polymorphisms on trastuzumab efficacy in the adjuvant treatment of ERBB2/HER2–positive breast cancer. DESIGN, SETTING, AND PARTICIPANTS This is a retrospective analysis of patients enrolled in the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-31 trial, a phase 3 cooperative group study conducted between 2000 and 2005. The NSABP B-31 trial randomized 2119 women with surgically resected node-positive, ERBB2/HER2–positive breast cancer to treatment with doxorubicin and cyclophosphamide followed by paclitaxel or the same regimen with the addition of 1 year of weekly trastuzumab. Patients were accrued at cooperative group sites across the United States and Canada. This analysis was performed between 2013 and 2016. INTERVENTIONS Doxorubicin and cyclophosphamide followed by paclitaxel or the same regimen with the addition of 1 year of weekly trastuzumab. MAIN OUTCOMES AND MEASURES Disease-free survival. RESULTS The genotyped cohort (N = 1251) resembled the entire B-31 cohort based on clinical variables and the degree of benefit from trastuzumab. Median follow-up time was 8.2 years in the genotyped samples. The disease-free survival probability at 3, 5, and 8 years was 74% (95%CI, 71%–79%), 66%(95%CI, 62%–71%), and 58%(95%CI, 54%–63%) in patients who received ACT and 86%(95%CI, 83%–89%), 82%(95%CI, 79%–85%), and 78%(95%CI, 74%–81%) in patients who received ACTH. Addition of trastuzumab significantly improved patient outcome (hazard ratio [HR], 0.46; 95%CI, 0.37–0.57; P < .001). The expected trend for interaction between polymorphisms and trastuzumab was observed for both genes, but only FCGR3A-158 polymorphism reached statistical significance for interaction (P < .001). As hypothesized, patients with genotypes FCB3A-158V/V or FCB3A-158V/F received greater benefit from trastuzumab (HR, 0.31; 95%CI, 0.22–0.43; P < .001) than patients who were homozygous for the low-affinity allele (HR, 0.71; 95%CI, 0.51–1.01; P = .05). CONCLUSIONS AND RELEVANCE The FCGR3A-158 polymorphism is predictive of trastuzumab efficacy in this cohort of patients with early ERBB2/HER2–positive breast cancer. Patients who are homozygous for phenylalanine at this position represent a considerable proportion of the population and, in contrast to previously reported analyses from similarly designed trials, our results indicate that trastuzumab may be less efficacious in these patients. TRIAL REGISTRATION clinicaltrials.gov Identifier for NSABP B-31: NCT00004067
Pancreatic cancer is the fifth leading cause of cancer death in the United States. Nearly every person diagnosed with pancreatic cancer will die from it, usually in <6 mo. Familial clustering of pancreatic cancers is commonly recognized, with an autosomal dominant inheritance pattern in approximately 10% of all cases. However, the late age at disease onset and rapid demise of affected individuals markedly hamper collection of biological samples. We report a genetic linkage scan of family X with an autosomal dominant pancreatic cancer with early onset and high penetrance. For the study of this family, we have developed an endoscopic surveillance program that allows the early detection of cancer and its precursor, before family members have died of the disease. In a genomewide screening of 373 microsatellite markers, we found significant linkage (maximum LOD score 4.56 in two-point analysis and 5.36 in three-point analysis) on chromosome 4q32-34, providing evidence for a major locus for pancreatic cancer.
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