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PDF file - 77KB, Table 1: Up to 16 Week Assessments adjusting for treatment arm and sum of baseline tumor measurements. Table 2: Up to 24 Week Assessments adjusting for treatment arm and sum of baseline tumor measurements.

Purpose: The categorical definition of response assessed via the Response Evaluation Criteria in Solid Tumors has documented limitations. We sought to identify alternative metrics for tumor response that improve prediction of overall survival.Experimental Design: Individual patient data from three North Central Cancer Treatment Group trials (N0026, n = 117; N9741, n = 1,109; and N9841, n = 332) were used. Continuous metrics of tumor size based on longitudinal tumor measurements were considered in addition to a trichotomized response [TriTR: response (complete or partial) vs. stable disease vs. progression). Cox proportional hazards models, adjusted for treatment arm and baseline tumor burden, were used to assess the impact of the metrics on subsequent overall survival, using a landmark analysis approach at 12, 16, and 24 weeks postbaseline. Model discrimination was evaluated by the concordance (c) index.Results: The overall best response rates for the three trials were 26%, 45%, and 25%, respectively. Although nearly all metrics were statistically significantly associated with overall survival at the different landmark time points, the concordance indices (c-index) for the traditional response metrics ranged from 0.59 to 0.65; for the continuous metrics from 0.60 to 0.66; and for the TriTR metrics from 0.64 to 0.69. The c-indices for TriTR at 12 weeks were comparable with those at 16 and 24 weeks.Conclusions: Continuous tumor measurement–based metrics provided no predictive improvement over traditional response–based metrics or TriTR; TriTR had better predictive ability than best TriTR or confirmed response. If confirmed, TriTR represents a promising endpoint for future phase II trials. Clin Cancer Res; 17(20); 6592–9. ©2011 AACR.

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Purpose: To determine the frequency and prognostic association of molecular markers by anatomic tumor site in patients with stage III colon carcinomas.Experimental Design: In a randomized trial of adjuvant FOLFOX ± cetuximab, BRAFV600E and KRAS (exon 2) mutations and DNA mismatch repair (MMR) proteins were analyzed in tumors (N = 3,018) in relationship to tumor location, including subsite. Cox models were used to assess clinical outcome, including overall survival (OS).Results: KRAS codon 12 mutations were most frequent at the splenic flexure and cecum; codon 13 mutations were evenly distributed. BRAF mutation frequency sharply increased from transverse colon to cecum in parallel with deficient (d) MMR. Nonmutated BRAF and KRAS tumors progressively decreased from sigmoid to transverse (all P < 0.0001). Significantly, poorer OS was found for mutant KRAS in distal [HR, 1.98; 95% confidence interval (CI), 1.49–2.63; P < 0.0001] versus proximal (1.25; 95% CI, 0.97–1.60; P = 0.079) cancers. BRAF status and outcome were not significantly associated with tumor site. Proximal versus distal dMMR tumors had significantly better outcome. An interaction test was significant for tumor site by KRAS (Padjusted = 0.043) and MMR (Padjusted = 0.010) for OS. Significant prognostic differences for biomarkers by tumor site were maintained in the FOLFOX arm. Tumor site was independently prognostic with a stepwise improvement from cecum to sigmoid (OS: Padjusted = 0.001).Conclusions: Mutation in BRAF or KRAS codon 12 was enriched in proximal cancers whereas nonmutated BRAF/KRAS was increased in distal tumors. Significant differences in outcome for KRAS mutations and dMMR were found by tumor site, indicating that their interpretation should occur in the context of tumor location. Clin Cancer Res; 21(23); 5294–304. ©2015 AACR.

Supplemental Table 1. Univariate Cox Proportional Hazards Regression Models for Clinical Factors and Biomarkers (TTR, DFS, and OS)

Purpose: Assessing impact of poor accrual on premature trial closure requires a relevant metric. We propose defining accrual sufficiency on apparent ability to address primary endpoints (PE) rather than attaining accrual targets.Experimental Design: All phase III trials open January 1, 1993, to December 31, 2002, by five U.S. oncology Clinical Trials Cooperative Groups (CTCG) were evaluated for accrual sufficiency and scientific results. Sufficient accrual included meeting accrual target, CTCGs documentation attesting adequate accrual, or conclusive results at interim analysis; insufficient accrual included poor accrual as cited closure reason or other reasons rendering a trial unable to address its primary endpoints. Closure rates based on our accrual sufficiency definition are compared with rates of meeting accrual targets and addressing the primary endpoints. A percentage of target accrual above which trials commonly answer the intended scientific question was identified to serve as an alternative to meeting full target accrual in designating accrual success.Results: Of 238 eligible trials, 158 (66%) closed with sufficient accrual. Among 80 trials with insufficient accrual, 70 (29%) closed specifically because of poor accrual. Inadequate accrual rates are overemphasized when defining accrual success solely by meeting accrual targets. Nearly 75% of trials conclusively addressed the primary endpoints with positive results in 39% of trials. Exceeding 80% of target accrual serves as a reliable proxy for answering the intended scientific question.Conclusions: Approximately one third of phase III trials closed with insufficient accrual to address the primary endpoints, primarily due to poor accrual. Defining accrual sufficiency broader than meeting accrual targets represents a fairer account of trial closures. Clin Cancer Res; 18(1); 256–62. ©2011 AACR.

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.

PDF file - 108KB, Predictive value of specific KRAS mutations in patients with BRAF-wild type resected stage III colon cancer treated with adjuvant FOLFOX chemotherapy with vs without cetuximab. Unadjusted hazard ratios (HR) for disease-free survival by KRAS mutation strata are shown for patients who were randomized during the period when KRAS-mutated and -wild type tumors were eligible. HR < 1 indicates benefit from cetuximab. No estimates produced due to insufficient sample size in one subgroup.

Purpose: Recurrence risk assessment to make treatment decisions for early-stage colon cancer patients is a major unmet medical need. The aim of this retrospective multicenter study was to evaluate the clinical utility of guanylyl cyclase C (GCC) mRNA levels in lymph nodes on colon cancer recurrence.Methods: The proportion of lymph nodes with GCC-positive mRNA (LNR) was evaluated in 463 untreated T3N0 patients, blinded to clinical outcomes. One site's (n = 97) tissue grossing method precluded appropriate lymph node assessment resulting in post hoc exclusion. Cox regression models tested the relationship between GCC and the primary endpoint of time to recurrence. Assay methods, primary analyses, and cut points were all prespecified.Results: Final dataset contained 366 patients, 38 (10%) of whom had recurrence. Presence of four or more GCC-positive lymph nodes was significantly associated with risk of recurrence [hazard ratio (HR) = 2.46, 95% confidence interval (CI), 1.07–5.69, P = 0.035], whereas binary GCC LNR risk class (HR = 1.87, 95% CI, 0.99–3.54, P = 0.054) and mismatch repair (MMR) status (HR = 0.77, 95% CI, 0.36–1.62, P = 0.49) were not. In a secondary analysis using a 3-level GCC LNR risk group classification of high (LNR > 0.20), intermediate (0.10 < LNR ≤ 0.20), and low (LNR ≤ 0.10), high-risk patients had a 2.5 times higher recurrence risk compared with low-risk patients (HR = 2.53, 95% CI, 1.24–5.17, P = 0.011).Conclusions: GCC status is a promising prognostic factor independent of traditional histopathology risk factors in a contemporary population of patients with stage IIa colon cancer not treated with adjuvant therapy, but GCC determination must be performed with methodology adapted to the tissue procurement and fixation technique. Clin Cancer Res; 20(16); 4361–9. ©2014 AACR.

PDF file - 90K, Supplementary Table 1: Adjusted Association between LNR Status and Outcomes in Untreated T3N0 Colon Cancer Undergoing Molecular Staging; Supplementary Table 2: Unadjusted and adjusted association between LNR status and TTR, OS, and DFS within pMMR subgroup (N = 262).

PDF file - 12KB, Plots of observed versus expected 1-year survival probabilities for N9841 based on models for each metric and a model with no metric, adjusting for treatment arm and sum of baseline tumor measurements.

PDF file - 12KB, Plots of observed versus expected 1-year survival probabilities for N0026 based on models for each metric and a model with no metric, adjusting for treatment arm and sum of baseline tumor measurements.

PDF file - 81KB, Table S1. Multivariable logistic regression models showing the association of clinicopathologic and molecular characteristics with KRAS codon 12 or 13 mutation status in 2,478 BRAF-wild type stage III colon cancers.

CCR Translation for This Article from Achieving Sufficient Accrual to Address the Primary Endpoint in Phase III Clinical Trials from U.S. Cooperative Oncology Groups

Key message For genomic selection in clonally propagated crops with diploid (-like) meiotic behavior to be effective, crossing parents should be selected based on genomic predicted cross-performance unless dominance is negligible. Abstract For genomic selection (GS) in clonal breeding programs to be effective, parents should be selected based on genomic predicted cross-performance unless dominance is negligible. Genomic prediction of cross-performance enables efficient exploitation of the additive and dominance value simultaneously. Here, we compared different GS strategies for clonally propagated crops with diploid (-like) meiotic behavior, using strawberry as an example. We used stochastic simulation to evaluate six combinations of three breeding programs and two parent selection methods. The three breeding programs included (1) a breeding program that introduced GS in the first clonal stage, and (2) two variations of a two-part breeding program with one and three crossing cycles per year, respectively. The two parent selection methods were (1) parent selection based on genomic estimated breeding values (GEBVs) and (2) parent selection based on genomic predicted cross-performance (GPCP). Selection of parents based on GPCP produced faster genetic gain than selection of parents based on GEBVs because it reduced inbreeding when the dominance degree increased. The two-part breeding programs with one and three crossing cycles per year using GPCP always produced the most genetic gain unless dominance was negligible. We conclude that (1) in clonal breeding programs with GS, parents should be selected based on GPCP, and (2) a two-part breeding program with parent selection based on GPCP to rapidly drive population improvement has great potential to improve breeding clonally propagated crops.

Genotyping by sequencing approaches have been widely applied in major crops and are now being used in horticultural crops like berries and fruit trees. As the original and largest producer of cultivated blueberry, the United States maintains the most diverse blueberry germplasm resources comprised of many species of different ploidy levels. We previously constructed an interspecific mapping population of diploid blueberry by crossing the parent F1#10 (Vaccinium darrowiiFla4B × diploidV. corymbosumW85–20) with the parent W85–23 (diploidV. corymbosum). Employing the Capture-Seq technology developed by RAPiD Genomics, with an emphasis on probes designed in predicted gene regions, 117 F1progeny, the two parents, and two grandparents of this population were sequenced, yielding 131.7 Gbp clean sequenced reads. A total of 160,535 single nucleotide polymorphisms (SNPs), referenced to 4,522 blueberry genome sequence scaffolds, were identified and subjected to a parent-dependent sliding window approach to further genotype the population. Recombination breakpoints were determined and marker bins were deduced to construct a high density linkage map. Twelve blueberry linkage groups (LGs) consisting of 17,486 SNP markers were obtained, spanning a total genetic distance of 1,539.4 cM. Among 18 horticultural traits phenotyped in this population, quantitative trait loci (QTLs) that were significant over at least 2 years were identified for chilling requirement, cold hardiness, and fruit quality traits of color, scar size, and firmness. Interestingly, in 1 year, a QTL associated with timing of early bloom, full bloom, petal fall, and early green fruit was identified in the same region harboring the major QTL for chilling requirement. In summary, we report here the first high density bin map of a diploid blueberry mapping population and the identification of several horticulturally important QTLs.

Background: How can a clinician and patient incorporate survival and toxicity information into a single expression of comparative treatment benefit? Sloan et al. recently extended the ½ standard deviation concept for judging the clinical importance of findings from clinical trials to survival and tumor response endpoints. A new method using this approach to combine survival and toxicity effect sizes from clinical trials into a quality-adjusted effect size is presented. Methods: The quality-adjusted survival effect size (QASES) is calculated as survival effect size (ESS) minus the calibrated toxicity effect sizes (EST) (QASES=ESS-EST). This combined effect size can be weighted to adjust for the relative emphasis placed by the patient on survival and toxicity effects. Results: As an example, consider clinical trial NCCTG 89–20-52 which randomized patients to once-daily thoracic radiotherapy (ODTRT) versus twice-daily treatment of thoracic radiotherapy (TDRT) for the treatment of lung cancer. The ODTRT vs. TDRT arms had median survival time of 22 vs. 20 months (p=0.49) and toxicity rate of 39% vs. 54%, (p

Extreme cold and frost cause significant stress to plants which can potentially be lethal. Low temperature freezing stress can cause significant and irreversible damage to plant cells and can induce physiological and metabolic changes that impact on growth and development. Low temperatures cause physiological responses including winter dormancy and autumn cold hardening in strawberry (Fragaria) species, and some diploid F. vesca accessions have been shown to have adapted to low-temperature stresses. To study the genetics of freezing tolerance, a F. vesca mapping population of 143 seedlings segregating for differential responses to freezing stress was raised. The progeny was mapped using ‘Genotyping-by-Sequencing’ and a linkage map of 2,918 markers at 851 loci was resolved. The mapping population was phenotyped for freezing tolerance response under controlled and replicated laboratory conditions and subsequent quantitative trait loci analysis using interval mapping revealed a single significant quantitative trait locus on Fvb2 in the physical interval 10.6 Mb and 15.73 Mb on the F. vesca v4.0 genome sequence. This physical interval contained 896 predicted genes, several of which had putative roles associated with tolerance to abiotic stresses including freezing. Differential expression analysis of the 896 QTL-associated gene predictions in the leaves and crowns from ‘Alta’ and ‘NCGR1363’ parental genotypes revealed genotype-specific changes in transcript accumulation in response to low temperature treatment as well as expression differences between genotypes prior to treatment for many of the genes. The putative roles, and significant interparental differential expression levels of several of the genes reported here identified them as good candidates for the control of the effects of freezing tolerance at the QTL identified in this investigation and the possible role of these candidate genes in response to freezing stress is discussed.

Background Rosaceae include numerous economically important and morphologically diverse species. Comparative mapping between the member species in Rosaceae have indicated some level of synteny. Recently the whole genome of three crop species, peach, apple and strawberry, which belong to different genera of the Rosaceae family, have been sequenced, allowing in-depth comparison of these genomes. Results Our analysis using the whole genome sequences of peach, apple and strawberry identified 1399 orthologous regions between the three genomes, with a mean length of around 100 kb. Each peach chromosome showed major orthology mostly to one strawberry chromosome, but to more than two apple chromosomes, suggesting that the apple genome went through more chromosomal fissions in addition to the whole genome duplication after the divergence of the three genera. However, the distribution of contiguous ancestral regions, identified using the multiple genome rearrangements and ancestors (MGRA) algorithm, suggested that the Fragaria genome went through a greater number of small scale rearrangements compared to the other genomes since they diverged from a common ancestor. Using the contiguous ancestral regions, we reconstructed a hypothetical ancestral genome for the Rosaceae 7 composed of nine chromosomes and propose the evolutionary steps from the ancestral genome to the extant Fragaria, Prunus and Malus genomes. Conclusion Our analysis shows that different modes of evolution may have played major roles in different subfamilies of Rosaceae. The hypothetical ancestral genome of Rosaceae and the evolutionary steps that lead to three different lineages of Rosaceae will facilitate our understanding of plant genome evolution as well as have a practical impact on knowledge transfer among member species of Rosaceae., This project has been supported by the USDA NIFA SCRI grant # 2010-2010-03255. We acknowledge International Peach Genome Initiative for the permission to use the peach genome in this study

Strawberries are rich in polyphenols which impart health benefits when metabolized by the gut microbiome, including anti-inflammatory, neuroprotective, and antiproliferative effects. In addition, polyphenolic anthocyanins contribute to the attractive color of strawberry fruits. However, the genetic basis of polyphenol biosynthesis has not been extensively studied in strawberry. In this investigation, ripe fruits from three cultivated strawberry populations were characterized for polyphenol content using HPLC-DAD-MSnand genotyped using the iStraw35k array. GWAS and QTL analyses identified genetic loci controlling polyphenol biosynthesis. QTL were identified on four chromosomes for pelargonidin-3-O-malonylglucoside, pelargonidin-3-O-acetylglucoside, cinnamoyl glucose, and ellagic acid deoxyhexoside biosynthesis. Presence/absence of ellagic acid deoxyhexoside and pelargonidin-3-O-malonylglucoside was found to be under the control of major gene loci on LG1X2 and LG6b, respectively, on theF. × ananassalinkage maps. Interrogation of gene predictions in theF. vescareference genome sequence identified a single candidate gene for ellagic acid deoxyhexoside biosynthesis, while seven malonyltransferase genes were identified as candidates for pelargonidin-3-O-malonylglucoside biosynthesis. Homologous malonyltransferase genes were identified in theF. × ananassa‘Camarosa’ genome sequence but the candidate for ellagic acid deoxyhexoside biosynthesis was absent from the ‘Camarosa’ sequence. This study demonstrated that polyphenol biosynthesis in strawberry is, in some cases, under simple genetic control, supporting previous observations of the presence or absence of these compounds in strawberry fruits. It has also shed light on the mechanisms controlling polyphenol biosynthesis and enhanced the knowledge of these biosynthesis pathways in strawberry. The above findings will facilitate breeding for strawberries enriched in compounds with beneficial health effects.

PURPOSE The microsatellite instability (MSI) or deficient mismatch repair (dMMR) phenotype is usually regarded as a single biologic entity, given the absence of comparative analyses regarding prognosis and response to chemotherapy between sporadic and familial dMMR cancers. PATIENTS AND METHODS Patients with stage III colon cancers were randomly assigned to FOLFOX (leucovorin, fluorouracil, and oxaliplatin) with or without cetuximab in 2 large adjuvant phase III trials (N = 5,577). Among patients with MSI and KRAS exon 2 wild-type (WT) tumors, the prognostic and predictive impacts of sporadic versus familial dMMR cancers and BRAF V600E mutational status were determined. Multivariable Cox proportional hazards models were used to assess disease-free survival (DFS) by treatment arm, adjusting for age, sex, tumor grade, Eastern Cooperative Oncology Group performance status, pT/pN stage, and primary tumor location. RESULTS Among patients with MSI status with complete data for dMMR mechanism analysis (n = 354), 255 (72%) had sporadic ( BRAF mutation and/or MLH1 methylation) and 99 (28%) had familial tumors ( BRAF WT and unmethylated MLH1 or loss of MSH2/MSH6/PMS2 protein expression). A large proportion of dMMR sporadic tumors were mutated for BRAF (n = 200). In patients treated with FOLFOX, DFS did not differ statistically by dMMR mechanism, whereas in patients treated with FOLFOX plus cetuximab, those with sporadic tumors had worse DFS than those with familial cancers (multivariable hazard ratio, 2.69; 95% CI, 1.02 to 7.08; P = .04). Considering the predictive utility, the interaction between treatment and dMMR mechanism was significant ( P = .03). Furthermore, a nonsignificant trend toward a deleterious effect of adding cetuximab to FOLFOX was observed in patients with BRAF-mutant but not BRAF WT tumors. CONCLUSION The addition of cetuximab to adjuvant FOLFOX was associated with shorter DFS in patients with sporadic dMMR colon cancer. Additional studies are needed to validate these results in metastatic disease.

Background: Prior studies have supported an inverse association between physical activity and colon cancer risk and suggest that higher physical activity may also improve cancer survival. Among participants in a phase III adjuvant trial for stage III colon cancer, we assessed the association of physical activity around the time of cancer diagnosis with subsequent outcomes. Methods: Before treatment arm randomization (FOLFOX or FOLFOX + cetuximab), study participants completed a questionnaire including items regarding usual daily activity level and frequency of participation in recreational physical activity (N = 1,992). Using multivariable Cox models, we calculated HRs for associations of aspects of physical activity with disease-free (DFS) and overall survival (OS). Results: Over follow-up, 505 participants died and 541 experienced a recurrence. Overall, 75% of participants reported recreational physical activity at least several times a month; for participants who reported physical activity at least that often (vs. once a month or less), the HRs for DFS and OS were 0.82 [95% confidence interval (CI), 0.69–0.99] and 0.76 (95% CI, 0.63–0.93), respectively. There was no evidence of material effect modification in these associations by patient or tumor attributes, except that physical activity was more strongly inversely associated with OS in patients with stage T3 versus T4 tumors (Pinteraction = 0.03). Conclusions: These findings suggest that higher physical activity around the time of colon cancer diagnosis may be associated with more favorable colon cancer outcomes. Impact: Our findings support further research on whether colon cancer survival may be enhanced by physical activity. Cancer Epidemiol Biomarkers Prev; 27(6); 696–703. ©2018 AACR.

BACKGROUND\ud Since 2004, a regimen of 6 months of treatment with oxaliplatin plus a fluoropyrimidine has been standard adjuvant therapy in patients with stage III colon cancer. However, since oxaliplatin is associated with cumulative neurotoxicity, a shorter duration of therapy could spare toxic effects and health expenditures.\ud \ud METHODS\ud We performed a prospective, preplanned, pooled analysis of six randomized, phase 3 trials that were conducted concurrently to evaluate the noninferiority of adjuvant therapy with either FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CAPOX (capecitabine and oxaliplatin) administered for 3 months, as compared with 6 months. The primary end point was the rate of disease-free survival at 3 years. Noninferiority of 3 months versus 6 months of therapy could be claimed if the upper limit of the two-sided 95% confidence interval of the hazard ratio did not exceed 1.12.\ud \ud RESULTS\ud After 3263 events of disease recurrence or death had been reported in 12,834 patients, the noninferiority of 3 months of treatment versus 6 months was not confirmed in the overall study population (hazard ratio, 1.07; 95% confidence interval [CI], 1.00 to 1.15). Noninferiority of the shorter regimen was seen for CAPOX (hazard ratio, 0.95; 95% CI, 0.85 to 1.06) but not for FOLFOX (hazard ratio, 1.16; 95% CI, 1.06 to 1.26). In an exploratory analysis of the combined regimens, among the patients with T1, T2, or T3 and N1 cancers, 3 months of therapy was noninferior to 6 months, with a 3-year rate of disease-free survival of 83.1% and 83.3%, respectively (hazard ratio, 1.01; 95% CI, 0.90 to 1.12). Among patients with cancers that were classified as T4, N2, or both, the disease-free survival rate for a 6-month duration of therapy was superior to that for a 3-month duration (64.4% vs. 62.7%) for the combined treatments (hazard ratio, 1.12; 95% CI, 1.03 to 1.23; P=0.01 for superiority).\ud \ud CONCLUSIONS\ud Among patients with stage III colon cancer receiving adjuvant therapy with FOLFOX or CAPOX, noninferiority of 3 months of therapy, as compared with 6 months, was not confirmed in the overall population. However, in patients treated with CAPOX, 3 months of therapy was as effective as 6 months, particularly in the lower-risk subgroup. (Funded by the National Cancer Institute and others.)

Indication for primary tumour resection (PTR) in asymptomatic metastatic colorectal cancer (mCRC) patients is unclear. Previous retrospective analyses suggest a survival benefit for patients who underwent PTR. The aim was to evaluate the prognostic value of PTR in patients with synchronous mCRC by analysis of recent large RCTs including systemic therapy with modern targeted agents. Individual patient data (IPD) of 3423 patients enrolled into 8 randomised controlled trials (RCTs) with first-line systemic therapy in the ARCAD (Aide et Recherche en Cancerologie Digestive) database were analysed. The number of patients with unresected synchronous mCRC, resected synchronous mCRC and metachronous mCRC was 710 (21%), 1705 (50%) and 1008 (29%), respectively. Adjusting for age, gender, performance status (PS) and prior chemotherapy, the unresected group had a significantly worse median overall survival (16.4 m) compared with the synchronous resected (22.2 m; hazard ratio [HR] 1.60, 95% CI 1.43-1.78) and metachronous (22.4 m; HR 1.81, 95% CI 1.58-2.07) groups. Similarly, median progression-free survival was significantly worse for the unresected group compared with the synchronous resected (HR 1.31, 95% CI 1.19-1.44) and metachronous (HR 1.47, 95% CI 1.30-1.66) groups. In a multivariate analysis, the observed associations remained significant. This largest IPD analysis of mCRC trials to date demonstrates an improved survival in synchronous mCRC patients after PTR. These results may be subject to bias since reasons for (non) resection were not available. Until results of ongoing RCTs are available, both upfront PTR followed by systemic treatment and upfront systemic treatment are considered appropriate treatment strategies. (C) 2017 Elsevier Ltd. All rights reserved

Objectives While the risk of developing colorectal cancer increases with age, there are limited prospective data regarding best treatment in the older adult population. We launched a phase III trial to evaluate difference in treatment outcome for older adults (aged ≥ 70 years) with advanced colorectal cancer. Here we review the challenges faced and reasons for poor accrual to N0949. Materials and Methods We describe the conceptualization, development and limited results of N0949, a randomized phase III study of fluoropyrimidine/bevacizumab with or without oxaliplatin (mFOLFOX7 or XELOX) as first line chemotherapy for metastatic colorectal cancer. Fluoropyrimidine was physician choice (e.g., 5-FU/LV or capecitabine). Results Of the projected 380 patients, only 32 patients were enrolled between the study activation in January 2011 until its closure in September 2012. Reasons for poor accrual included eligibility criteria that were too stringent, discomfort with randomizing older patients to regimens of varying intensity without considering their physical fitness, and discomfort with the use of bevacizumab in the older patient population. Several efforts were mounted to design a rationale and age-appropriate study, consider toxicities and varying study practices, and be responsive to stakeholder feedback. Conclusions Challenges were experienced in conducting the first prospective phase III study evaluating progression-free survival of older adults with advanced colorectal cancer receiving palliative chemotherapy with fluoropyrimidine/bevacizumab with or without oxaliplatin in the USA. Future efforts to evaluate treatment outcomes in the older adult population should reflect on lessons learned in this large national effort.

This commentary describes the progress of the SEAL [Surrogate Endpoints for Aggressive Lymphoma] research group and invites collaboration in sharing data to continue building a large database of individual patient data from multiple clinical trials in DLBCL.

Enhanced knowledge of the biological and genetic basis of cancer is re-defining the target population for new treatments. In oncology, potential targets for a new therapeutic agent often include various solid and hematologic malignancies that share common signaling pathways. New agents are often tested in multiple tumor types across which information can be borrowed. We propose a hierarchical Bayesian design (HBD) to simultaneously test a novel agent in multiple groups for randomized Phase II clinical trials with binary endpoints. Compared to parallel design for individual tumor groups, the HBD has greatly reduced sample size. Therefore, this improves efficiency and decreases the financial cost of conducting randomized Phase II clinical trials. An R package hbdct has been developed to implement the HBD and streamline the sample size calibration.

Purpose Molecular testing of colorectal cancers (CRCs) to improve patient care and outcomes of targeted and conventional therapies has been the center of many recent studies, including clinical trials. Evidence-based recommendations for the molecular testing of CRC tissues to guide epidermal growth factor receptor (EGFR) –targeted therapies and conventional chemotherapy regimens are warranted in clinical practice. The purpose of this guideline is to develop evidence-based recommendations to help establish standard molecular biomarker testing for CRC through a systematic review of the literature. Methods The American Society for Clinical Pathology (ASCP), College of American Pathologists (CAP), Association for Molecular Pathology (AMP), and the American Society of Clinical Oncology (ASCO) convened an Expert Panel to develop an evidence-based guideline to help establish standard molecular biomarker testing, guide targeted therapies, and advance personalized care for patients with CRC. A comprehensive literature search that included over 4,000 articles was conducted to gather data to inform this guideline. Results Twenty-one guideline statements (eight recommendations, 10 expert consensus opinions and three no recommendations) were established. Recommendations Evidence supports mutational testing for genes in the EGFR signaling pathway, since they provide clinically actionable information as negative predictors of benefit to anti-EGFR monoclonal antibody therapies for targeted therapy of CRC. Mutations in several of the biomarkers have clear prognostic value. Laboratory approaches to operationalize molecular testing for predictive and prognostic molecular biomarkers involve selection of assays, type of specimens to be tested, timing of ordering of tests and turnaround time for testing results. Additional information is available at: www.asco.org/CRC-markers-guideline and www.asco.org/guidelineswiki

Background: Family history of colon cancer often portends increased risk of disease development; however, the prognostic significance of family history related to disease and survival outcomes is unclear. Methods: To investigate the relationship between family history of colorectal cancer and survival outcomes in stage III colon cancer patients, a prospective cohort of 1,935 patients with resected stage III colon cancer enrolled in a randomized controlled trial (N0147), comparing the standard of care FOLFOX to FOLFOX with cetuximab, was studied. Patients completed a baseline questionnaire on family history and were followed every 6 months until death or 5 years after randomization. Results: We examined the endpoints of disease-free survival (DFS), time to recurrence (TTR) and overall survival (OS), comparing patients with a positive versus negative family history of colorectal cancer. The adjusted hazard ratios (HRs) for patients with a positive family history were 0.95 [95% confidence interval (CI), 0.78–1.16] for DFS, 0.94 (95% CI, 0.76–1.16) for TTR, and 0.92 (95% CI, 0.74–1.15) for OS (all adjusted P>0.47). A non-significant trend toward improved DFS (P=0.17; adjusted P=0.34) was observed when 2 or more relatives were affected as compared to 0 relatives (multivariate HR: 0.72; 95% CI, 0.45–1.15), whereas subjects with histories of 0 or 1 affected relatives had similar DFS (multivariate HR for 1 vs. 0: 1.00; 95% CI, 0.81–1.24). Interactions of the molecular factors KRAS, BRAF, and MMR with family history were also explored. The only significant interaction was for deficient MMR (dMMR) and first-degree relatives with a family history of colorectal cancer (0 vs. 1 vs. 2+ relatives) for a benefit on OS (univariate P=0.001), which remained significant after adjusting for other factors (P=0.029). Conclusions: Among patients with stage III resected colon cancer treated with adjuvant FOLFOX, a family history of colorectal cancer did not significantly impact DFS, TTR, or OS outcomes, with the exception of patients with dMMR-expressing tumors.

The primary goal of this study was to evaluate the utility of progression‐free survival (PFS) as a surrogate endpoint for overall survival (OS) in mesothelioma based on clinical trials data. Given the short postprogression survival and moderate correlation between PFS and OS, the study found no evidence that PFS is a valid surrogate endpoint for OS in mesothelioma., Purpose. The aim of this study was to investigate whether progression‐free survival (PFS) can be considered a surrogate endpoint for overall survival (OS) in malignant mesothelioma. Materials and Methods. Individual data were collected from 15 Cancer and Leukemia Group B (615 patients) and 2 North Central Cancer Treatment Group (101 patients) phase II trials. The effects of 5 risk factors for OS and PFS, including age, histology, performance status (PS), white blood cell count, and European Organisation for Research and Treatment of Cancer (EORTC) risk score, were used in the analysis. Individual‐level surrogacy was assessed by Kendall's tau through a Clayton bivariate Copula survival (CBCS) model. Summary‐level surrogacy was evaluated via the association between logarithms of the hazard ratio (log HR)—log HROS and log HRPFS—measured in R2 from a weighted least‐square (WLS) regression model and the CBCS model. Results. The median PFS for all patients was 3.0 months (95% confidence interval [CI], 2.8–3.5 months) and the median OS was 7.2 months (95% CI, 6.5–8.0 months). Moderate correlations between PFS and OS were observed across all risk factors at the individual level, with Kendall's tau ranging from 0.46 to 0.47. The summary‐level surrogacy varied among risk factors. The Copula R2 ranged from 0.51 for PS to 0.78 for histology. The WLS R2 ranged from 0.26 for EORTC and PS to 0.67 for age. Conclusions. The analyses demonstrated low to moderate individual‐level surrogacy between PFS and OS. At the summary level, the surrogacy between PFS and OS varied significantly across different risk factors. With a short postprogression survival and a moderate correlation between PFS and OS, there is no evidence that PFS is a valid surrogate endpoint for OS in malignant mesothelioma. Implications for Practice. For better disease management and for more efficient clinical trial designs, it is important to know if progression‐free survival (PFS) is a good surrogate endpoint for overall survival in malignant mesothelioma. With a relatively large database of 17 phase II trials and 716 patients from Cancer and Leukemia Group B and North Central Cancer Treatment Group, we conducted statistical analyses and found that there is no evidence to suggest that PFS is a valid surrogate endpoint for OS for malignant mesothelioma. Future research work is needed to find alternative surrogate endpoints for OS.

Purpose Under-representation of elderly, women, and racial/ethnic minority patients with cancer in clinical trials is of national concern. The goal of this study was to characterize enrollment trends and disparities by age, sex, and race/ethnicity in lung cancer trials. Methods We analyzed data for 23,006 National Cancer Institute cooperative group lung cancer trial participants and 578,476 patients with lung cancer from the SEER registry from 1990 to 2012. The enrollment disparity difference (EDD) and enrollment disparity ratio (EDR) were calculated on the basis of the proportion of each subgroup in the trial population and the US lung cancer population. Annual percentage changes (APCs) in the subgroup proportions in each population were compared over time. Results Enrollment disparity for patients ≥ 70 years of age with non–small-cell lung cancer improved from 1990 to 2012 (test of parallelism, P = .020), with a remaining EDD of 0.22 (95% CI, 0.19 to 0.25) and EDR of 1.65 (95% CI, 1.51 to 1.82) in 2010 to 2012. No improvement was seen for elderly patients with small-cell lung cancer (SCLC), with an APC of 0.20 ( P = .714) among trial participants, despite a rising proportion of elderly patients with SCLC in the US population (APC, 0.32; P = .020). Enrollment disparity for women with lung cancer improved overall, with the gap closing by 2012 (EDD, 0.03 [95% CI, 0.00 to 0.06]; EDR, 1.07 [95% CI, 1.00 to 1.16]). Enrollment disparities persisted without significant improvement for elderly women, blacks, Asians/Pacific Islanders, and Hispanics. Conclusion Under-representation in lung cancer trials improved significantly from 1990 to 2012 for elderly patients with non–small-cell lung cancer and for women, but ongoing efforts to improve the enrollment of elderly patients with SCLC and minorities are needed. Our study highlights the importance of addressing enrollment disparities by demographic and disease subgroups to better target under-represented groups of patients with lung cancer.

Metformin might have antineoplastic properties against colon cancer (CC). Patients with stage III CC enrolled in the N0147 study completed a questionnaire regarding diabetes mellitus (DM) and metformin use. Patients with stage III CC undergoing adjuvant chemotherapy who used metformin before the diagnosis of CC experienced survival outcomes similar to those for non-DM patients and DM patients without metformin use., Background. Preclinical and epidemiological data suggest that metformin might have antineoplastic properties against colon cancer (CC). However, the effect of metformin use on patient survival in stage III CC after curative resection is unknown. The survival outcomes were comparable regardless of the duration of metformin use. Patients and Methods. Before randomization to FOLFOX (folinic acid, 5-fluorouracil, oxaliplatin) with or without cetuximab, 1,958 patients with stage III CC enrolled in the N0147 study completed a questionnaire with information on diabetes mellitus (DM) and metformin use. Cox models were used to assess the association between metformin use and disease-free survival (DFS), overall survival (OS), and the time to recurrence (TTR), adjusting for clinical and/or pathological factors. Results. Of the 1,958 patients, 1,691 (86%) reported no history of DM, 115 reported DM with metformin use (6%), and 152 reported DM without metformin use (8%). The adjuvant treatment arms were pooled, because metformin use showed homogeneous effects on outcomes across the two arms. Among the patients with DM (n = 267), DFS (adjusted hazard ratio [aHR], 0.90; 95% confidence interval [CI], 0.59–1.35; p = .60), OS (aHR, 0.99; 95% CI, 0.65–1.49; p = .95), and TTR (aHR, 0.87; 95% CI, 0.56–1.35; p = .53) were not different for the metformin users compared with the nonusers after adjusting for tumor and patient factors. The survival outcomes were comparable regardless of the duration of metformin use (

© 2019 Cockerton, Li, Vickerstaff, Eyre, Sargent, Armitage, Marina-Montes, Garcia-Cruz, Passey, Simpson and Harrison. Verticillium dahliae is a highly detrimental pathogen of soil cultivated strawberry (Fragaria x ananassa). Breeding of Verticillium wilt resistance into commercially viable strawberry cultivars can help mitigate the impact of the disease. In this study we describe novel sources of resistance identified in multiple strawberry populations, creating a wealth of data for breeders to exploit. Pathogen-informed experiments have allowed the differentiation of subclade-specific resistance responses, through studying V. dahliae subclade II-1 specific resistance in the cultivar “Redgauntlet” and subclade II-2 specific resistance in “Fenella” and “Chandler.” A large-scale low-cost phenotyping platform was developed utilizing automated unmanned vehicles and near infrared imaging cameras to assess field-based disease trials. The images were used to calculate disease susceptibility for infected plants through the normalized difference vegetation index score. The automated disease scores showed a strong correlation with the manual scores. A co-dominant resistant QTL; FaRVd3D, present in both “Redgauntlet” and “Hapil” cultivars exhibited a major effect of 18.3% when the two resistance alleles were combined. Another allele, FaRVd5D, identified in the “Emily” cultivar was associated with an increase in Verticillium wilt susceptibility of 17.2%, though whether this allele truly represents a susceptibility factor requires further research, due to the nature of the F1 mapping population. Markers identified in populations were validated across a set of 92 accessions to determine whether they remained closely linked to resistance genes in the wider germplasm. The resistant markers FaRVd2B from “Redgauntlet” and FaRVd6D from “Chandler” were associated with resistance across the wider germplasm. Furthermore, comparison of imaging versus manual phenotyping revealed the automated platform could identify three out of four disease resistance markers. As such, this automated wilt disease phenotyping platform is considered to be a good, time saving, substitute for manual assessment.

The cultivated almond exhibits self-incompatibility of the gametophytic type regulated by the S-locus, which is expressed in both the pistil (S-RNase) and pollen (SFB protein). Although almond cultivars are mostly self-incompatible, some cultivars have been found to be self-compatible. For a long time, self-compatibility was unequivocally associated only with the presence of the Sf haplotype. However, recent studies reported the existence of self-incompatible almond cultivars carrying the Sf genotype. This finding suggests the involvement of new, hitherto undiscovered components involved in the almond self-incompatibility system. The aim of this study was to clarify the transcription pattern of the S-genes and to look for additional components of the gametophytic self-incompatibility system in almond. Transcriptome analysis of un-pollinated pistils and incompatible and compatible pollinations of self-compatible and self-incompatible almonds carrying the Sf haplotype was performed using high-throughput RNA sequencing technologies. Among the unigenes, 1357 were shown to be differentially expressed, and gene ontology annotation revealed that they are mostly involved in metabolic processes and binding molecular functions. The expression trend of fourteen representative genes, some of which are putatively involved in the self-(in)compatible response, was confirmed by RT-qPCR. This transcriptomic analysis provides candidate genes for almond components of gametophytic self-incompatibility and could be used as reference for subsequent comparative transcriptomic analyses of pollen and pistil.

OBJECTIVE: To determine the disease free survival (DFS) and recurrence after the treatment of patients with rectal cancer with open (OPEN) or laparoscopic (LAP) resection. BACKGROUND: This randomized clinical trial (ACOSOG (Alliance) Z6051), performed between 2008–2013, compared LAP and OPEN resection of Stage II/III rectal cancer, within 12 cm of the anal verge (T1–3, N0–2, M0) in patients who received neoadjuvant chemoradiotherapy. The rectum and mesorectum were resected using open instruments for rectal dissection (included hybrid hand-assisted laparoscopic) or with laparoscopic instruments under pneumoperitoneum. The 2 year DFS and recurrence were secondary endpoints of Z6051. METHODS: The DFS and recurrence were not powered and are being assessed for superiority. Recurrence was determined at 3, 6, 9, 12 and every 6 months thereafter using carcinoembryonic antigen, physical exam, computed tomography and colonoscopy. 486 patients were randomized to LAP (243) or OPEN (243), with 462 eligible for analysis (LAP=240 and OPEN=222). Median follow up is 47.9 months. RESULTS: 2 year DFS was LAP 79.5% (95%CI, 74.4–84.9) and OPEN 83.2% (95% CI, 78.3–88.3). Local and regional recurrence was 4.6% LAP and 4.5% OPEN. Distant recurrence was 14.6% LAP and 16.7% OPEN. DFS was impacted by unsuccessful resection (HR 1.87, 95% CI, 1.21–2.91): (composite of incomplete specimen (HR 1.65, 95% CI, 0.85–3.18); positive circumferential resection margins (HR 2.31, 95% CI, 1.40–3.79); positive distal margin (HR 2.53, 95% CI, 1.30–3.77). CONCLUSION: Laparoscopic assisted resection of rectal cancer was not found to be significantly different to OPEN resection of rectal cancer based on the outcomes of DFS and recurrence. MINI-ABSTRACT: Reporting of the secondary endpoint of the disease free survival of a multi-center non-inferiority randomized clinical trial (ACOSOG (Alliance) Z6051) performed between 2008–2013 comparing LAP and OPEN low anterior and abdominoperineal radical resection for Stage II/III rectal cancer. Disease free survival two years after resection was found to be similar for patients treated with laparoscopic or open techniques for proctectomy.

Context: In planning oncology phase II and phase III clinical trials, the size of the expected effect for endpoints such as tumor response and overall survival are key parameters driving the sample size. We applied the empirical rule effect size approach, also known as the ½ standard deviation (SD) method, to define clinically significant effect sizes for overall survival and tumor response endpoints in a series of clinical trials. Methods: The observed effect size was calculated for 12 phase II and 27 phase III completed cancer clinical trials identified by experts as being notable. Results: The effect sizes of the phase II and phase III clinical trials ranged from -0.32 to 0.84 and 0.01 to 0.44 SDs respectively. Effect sizes for all but four of the phase II trials were less than a ½ SD. For phase III studies, the effect sizes for all but one study were below 0.4 SD and roughly 67% of them had an effect size smaller than 0.2 SDs. There were no differences across disease sites, although colorectal and breast trials did have slightly larger effect sizes. Conclusions: Even highly noteworthy existing phase II and phase III oncology clinical trials rarely achieve the ½ SD level of clinical significance. This method allows for more ready interpretation of the clinical significance of overall survival and tumor response endpoints. It allows for cross-study comparison across different endpoints. The method also facilitates study design as it directly builds clinical significance into the study.