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Introduction In this study (PRECISE), we assess the clinical utility of a germline DNA sequencing‐based test (ToxNav) for mutations in DPYD and ENOSF1 genes to alter clinician‐prescribed fluoropyrimidine doses and the use of a digital application (PROMinet) to record patient‐reported chemotherapy toxicity. Materials and methods Adult patients with a histological diagnosis of colorectal cancer (CRC) who consented to fluoropyrimidine‐based chemotherapy were recruited prospectively and given a digital application to monitor and record associated toxicities. Patient samples were analyzed for 18 germline coding variants in DPYD and 1 ENOSF1 variant. Results Genetic testing was performed for 60 patients and identified one patient at increased risk of fluoropyrimidine‐based toxicities. Uptake of genetic testing was high and results were available on average 17 days from initial clinical encounter. Patient‐reported chemotherapy toxicity identified differences in 5‐fluorouracil vs capecitabine regime profiles and identified profiles associated with subsequent need for chemotherapy dose reduction and hospital admission. Discussion The PRECISE clinical trial demonstrated that a germline DNA sequencing‐based test can provide clinically relevant information to alter clinicians' fluoropyrimidine prescription. The study also obtained high volume, high granularity patient‐reported toxicity data that might allow the improvement and personalization of chemotherapy management., In the PRECISE study, we assess the clinical utility of a germline DNA sequencing‐based test to alter clinician‐prescribed fluoropyrimidine doses and the use of a digital application to record patient‐reported chemotherapy toxicity. Genetic testing identified one patient at increased risk of fluoropyrimidine‐based toxicities and patient‐reported toxicity identified differences in chemotherapy regime profiles and association with subsequent need for chemotherapy dose reduction and hospital admission. The study demonstrated the clinical utility of a germline DNA sequencing‐based test for providing information to alter clinicians' fluoropyrimidine prescription and obtained high volume, high granularity patient‐reported toxicity data.

"The Integrity"of the human genome is under continual threat from endogenous and exogenous mutagens, and as a result of errors introduced during DNA replication. As the lesions generated by these processes, if left uncorrected, may lead to deleterious mutations, cells employ several sophisticated mechanisms to both prevent and repair such genomic damage. Failure of these repair mechanisms, leading to genomic instability, is common in cancer, and has even been suggested to be a universal characteristic of malignancy. This chapter outlines these cellular processes and reviews the both the mechanisms and consequences of their dysregulation in human cancer. It also highlights the emerging evidence suggesting that genomic instability is an important determinant of tumour behaviour. Finally, it discusses the possibility that targeting genomic instability may benefit patients with genomically unstable tumours in the clinic.

3542 Background: Right (R) vs left (L) sided colorectal cancers are clinically distinguishable based on prognosis and response to certain therapies, but as of yet, limited data have emerged to explain these differences. The science of molecular testing has evolved rapidly. Enabled by improved technologies and computing power, it is now feasible to obtain to systematic multi-omic datasets covering DNA, RNA, proteins, phospho-proteins and metabolomics on large numbers of patients. Multi-omic analysis can further define disease specific subgroups but pre-analytic quality of the tissues (ischemia time) and comparison to normal tissue controls is paramount to optimize results. Methods: Following informed consent, 450 colorectal cancer primary tumors and paired normal tissues were collected following an SOP to minimize ischemia time, and were analyzed using comprehensive genomics, transcriptomics, proteomics, phosphoproteomics, morphology and annual clinical information. Right (C18.0,2,3) and left (C18.6,7) CRC tumors, normal tissue were compared using machine learning tools to unravel the molecular mechanisms that underpin these clinically distinguishable phenotypes as well as correlating with known genomic metrics such MSI and KRAS mutation status. Results: Through leveraging the tumor and paired normal patient samples, systematic differences between left and right tumor samples were observed including specific molecular events associated with these anatomical differences. The detailed results will be presented at the meeting. Conclusions: Progress in precision medicine requires the inclusion of multi-omics which in turn requires changes to our current SOPs of tissue collection. The ability to define molecular distinctions such as between R and L colon cancer will permit the rapid discovery of clinically useful prognostic and predictive markers, dramatically adding to our fundamental understanding to colon cancer biology. Future work will focus on the discovery of novel targets and signatures, creating innovative tools that depict multi-omic results for clinicians.

Cancer predisposition syndromes are typically uncommon, monogenic, high-penetrance disorders. Despite their rarity, they have proven to be highly clinically relevant in directing cancer prevention strategies. As such, they share notable similarities with an expanding class of low-frequency somatic mutations that are associated with a striking prognostic or predictive effect in the tumours in which they occur. In this review, we highlight these commonalities, with particular reference to mutations in the proofreading domain of replicative DNA polymerases. These molecular phenotypes may occur as either germline or somatic events, and in the latter case, have been shown to confer a favourable prognosis and potential increased benefit from immune checkpoint inhibition. We note that incorporation of these variants into clinical management algorithms will help refine patient management, and that this will be further improved by the inclusion of other germline variants, such as those that determine the likelihood of benefit or toxicity from anti-neoplastic therapy. Finally, we propose that such integrated patient and tumour profiling will be essential if we are to deliver truly precision medicine for cancer patients, but in a similar way to rare germline mutations, we must ensure that we identify and utilize rare somatic mutations with strong predictive and prognostic effects. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

The molecular endometrial cancer (EC) classification defined by TCGA has improved both understanding of disease biology and clinical risk stratification. In my talk, I will review data for other biomarkers with proven or potential utility to further refine risk stratification in EC. I will also present results of analysis of whole genome sequence data from the large cohort of ECs recruited to the Genomics England 100,000 Genomes Project, and highlight the promise of this initiative to define new tumour subsets and therapeutic targets. Citation Format: David Church. Molecular stratification: Beyond TCGA [abstract]. In: Proceedings of the AACR Virtual Special Conference: Endometrial Cancer: New Biology Driving Research and Treatment; 2020 Nov 9-10. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(3_Suppl):Abstract nr IA015.

The chemokine CXCL13 mediates recruitment of B cells to tumors and is essential for the formation of tertiary lymphoid structures (TLSs). TLSs are thought to support antitumor immunity and are associated with improved prognosis. However, it remains unknown whether TLSs are formed in response to the general inflammatory character of the tumor microenvironment, or rather, are induced by (neo)antigen-specific adaptive immunity. We here report on the finding that the TGFβ-dependent CD103

Purpose: Pathogenic POLE proofreading domain mutations are found in many malignancies where they are associated with ultramutation and favorable prognosis. The extent to which this prognosis depends on their sensitivity to adjuvant treatment is unknown, as is the optimal therapy for advanced-staged or recurrent POLE-mutant cancers. Experimental Design: We examined the recurrence-free survival of women with POLE-mutant and POLE–wild-type endometrial cancers (EC) in the observation arm of the randomized PORTEC-1 endometrial cancer trial (N = 245 patients with stage I endometrial cancer for analysis). Sensitivity to radiotherapy and selected chemotherapeutics was compared between Pole-mutant mouse-derived embryonic stem (mES) cells, generated using CRISPR-Cas9 (Pole mutations D275A/E275A, and cancer-associated P286R, S297F, V411L) and isogenic wild-type cell lines. Results: In the observation arm of the PORTEC-1 trial (N = 245), women with POLE-mutant endometrial cancers (N = 16) had an improved recurrence-free survival (10-year recurrence-free survival 100% vs. 80.1% for POLE–wild-type; HR, 0.143; 95% confidence interval, 0.001–0.996; P = 0.049). Pole mutations did not increase sensitivity to radiotherapy nor to chemotherapeutics in mES cells. In contrast, Pole-mutant cells displayed significantly increased sensitivity to cytarabine and fludarabine (IC50 Pole P286R–mutant vs. wild-type: 0.05 vs. 0.17 μmol/L for cytarabine, 4.62 vs. 11.1 μmol/L for fludarabine; P < 0.001 for both comparisons). Conclusions: The favorable prognosis of POLE-mutant cancers cannot be explained by increased sensitivity to currently used adjuvant treatments. These results support studies exploring minimization of adjuvant therapy for early-stage POLE-mutant cancers, including endometrial and colorectal cancers. Conversely, POLE mutations result in hypersensitivity to nucleoside analogues, suggesting the use of these compounds as a potentially effective targeted treatment for advanced-stage POLE-mutant cancers. Clin Cancer Res; 24(13); 3197–203. ©2018 AACR.

Purpose: The elevated levels of somatic copy-number alterations (SCNAs) in a subset of high-risk endometrial cancers are suggestive of defects in pathways governing genome integrity. We sought to assess the prevalence of homologous recombination deficiency (HRD) in endometrial cancers and its association with histopathologic and molecular characteristics. Experimental Design: Fresh tumor tissue was prospectively collected from 36 endometrial cancers, and functional HRD was examined by the ability of replicating tumor cells to accumulate RAD51 protein at DNA double-strand breaks (RAD51 foci) induced by ionizing radiation. Genomic alterations were determined by next-generation sequencing and array comparative genomic hybridization/SNP array. The prevalence of BRCA-associated genomic scars, a surrogate marker for HRD, was determined in the The Cancer Genome Atlas (TCGA) endometrial cancer cohort. Results: Most endometrial cancers included in the final analysis (n = 25) were of non-endometrioid (52%), grade 3 (60%) histology, and FIGO stage I (72%). HRD was observed in 24% (n = 6) of cases and was restricted to non-endometrioid endometrial cancers (NEEC), with 46% of NEECs being HRD compared with none of the endometrioid endometrial cancers (EEC, P = 0.014). All but 1 of the HRD cases harbored either a pathogenic BRCA1 variant or high somatic copy-number (SCN) losses of HR genes. Analysis of TCGA cases supported these results, with BRCA-associated genomic scars present in up to 48% (63/132) of NEEC versus 12% (37/312) of EEC (P < 0.001). Conclusions: HRD occurs in endometrial cancers and is largely restricted to non-endometrioid, TP53-mutant endometrial cancers. Evaluation of HRD may help select patients that could benefit from treatments targeting this defect, including platinum compounds and PARP inhibitors.

Coordinated immune responses against human tumors are frequently characterized by tertiary lymphoid structures (TLS) which predict improved prognosis. The development of TLS is dependent on the chemokine CXCL13, reported to be secreted by dendritic cells and follicular helper T cells only. We report the unexpected finding that CXCL13 is also secreted by activated CD8+ T cells following stimulation by transforming growth factor beta (TGF-β). Using single cell RNA sequencing we found that expression ofCXCL13in CD8+ T cells was restricted to the intraepithelial CD103+ population. Accordingly, CD8+ T cells activated in the presence of TGF-β simultaneously upregulated CD103 and secreted CXCL13.CXCL13expression was strongly correlated with neo-antigen burden and cytolytic gene signatures in bulk tumors. In line with this, TLS were abundant in neo-antigen-high, CD103+ T cell-enriched tumors. TGF-β thus appears to play a role in coordinating immune responses against human tumors through CD8-dependent CXCL13-associated formation of TLS.

BACKGROUND: Precision cancer medicine depends on defining distinct tumour subgroups using biomarkers that may occur at very modest frequencies. One such subgroup comprises patients with exceptionally mutated (ultramutated) cancers caused by mutations that impair DNA polymerase epsilon (POLE) proofreading.METHODS: We examined the association of POLE proofreading domain mutation with clinicopathological variables and immune response in colorectal cancers from clinical trials (VICTOR, QUASAR2, and PETACC-3) and colorectal cancer cohorts (Leiden University Medical Centre 1 and 2, Oslo 1 and 2, Bern, AMC-AJCC-II, and Epicolon-1). We subsequently investigated its association with prognosis in stage II/III colorectal cancer by Cox regression of pooled individual patient data from more than 4500 cases from these studies.FINDINGS: Pathogenic somatic POLE mutations were detected in 66 (1·0%) of 6517 colorectal cancers, and were mutually exclusive with mismatch repair deficiency (MMR-D) in the 6277 cases for whom both markers were determined (none of 66 vs 833 [13·4%] of 6211; pINTERPRETATION: POLE proofreading domain mutations identify a subset of immunogenic colorectal cancers with excellent prognosis. This association underscores the importance of rare biomarkers in precision cancer medicine, but also raises important questions about how to identify and implement them in practice.FUNDING: Cancer Research UK, Academy of Medical Sciences, Health Foundation, EU, ERC, NIHR, Wellcome Trust, Dutch Cancer Society, Dutch Digestive Foundation.

Lynch syndrome (LS) accounts for around 3% of colorectal cancers (CRCs) and is caused by germline mutations in mismatch repair (MMR) genes. Recently, screening strategies to identify patients with LS have become popular. We audited CRCs screened with MMR immunohistochemistry (IHC) in 2013. 209 tumours had MMR IHC performed at a cost of £12 540. 47/209 (21%) cases showed IHC loss of expression in at least one MMR protein. 28/44 cases with loss of MLH1 had additional BRAF V600E testing, at a cost of £5040. MMR IHC reduced the number of potential clinical genetics referrals from 209 to 47. BRAF mutation testing, performed in a subset of cases with MLH1 loss, further reduced this to 21. At a cost of £1340 per referral, this model of LS screening for clinical genetics referral had significant potential savings (£234 340) and can be easily implemented in parallel with MMR IHC done for prognostication in CRCs.

Purpose: Recent studies have shown that 7% to 12% of endometrial cancers are ultramutated due to somatic mutation in the proofreading exonuclease domain of the DNA replicase POLE. Interestingly, these tumors have an excellent prognosis. In view of the emerging data linking mutation burden, immune response, and clinical outcome in cancer, we investigated whether POLE-mutant endometrial cancers showed evidence of increased immunogenicity. Experimental Design: We examined immune infiltration and activation according to tumor POLE proofreading mutation in a molecularly defined endometrial cancer cohort including 47 POLE-mutant tumors. We sought to confirm our results by analysis of RNAseq data from the TCGA endometrial cancer series and used the same series to examine whether differences in immune infiltration could be explained by an enrichment of immunogenic neoepitopes in POLE-mutant endometrial cancers. Results: Compared with other endometrial cancers, POLE mutants displayed an enhanced cytotoxic T-cell response, evidenced by increased numbers of CD8+ tumor-infiltrating lymphocytes and CD8A expression, enrichment for a tumor-infiltrating T-cell gene signature, and strong upregulation of the T-cell cytotoxic differentiation and effector markers T-bet, Eomes, IFNG, PRF, and granzyme B. This was accompanied by upregulation of T-cell exhaustion markers, consistent with chronic antigen exposure. In silico analysis confirmed that POLE-mutant cancers are predicted to display more antigenic neoepitopes than other endometrial cancers, providing a potential explanation for our findings. Conclusions: Ultramutated POLE proofreading-mutant endometrial cancers are characterized by a robust intratumoral T-cell response, which correlates with, and may be caused by an enrichment of antigenic neopeptides. Our study provides a plausible mechanism for the excellent prognosis of these cancers. Clin Cancer Res; 21(14); 3347–55. ©2015 AACR.

This study aimed to investigate whether molecular analysis can be used to refine risk assessment, direct adjuvant therapy, and identify actionable alterations in high-risk endometrial cancer. TransPORTEC, an international consortium related to the PORTEC3 trial, was established for translational research in high-risk endometrial cancer. In this explorative study, routine molecular analyses were used to detect prognostic subgroups: p53 immunohistochemistry, microsatellite instability and POLE proofreading mutation. Furthermore, DNA was analyzed for hotspot mutations in 13 additional genes (BRAF, CDKNA2, CTNNB1, FBXW7, FGFR2, FGFR3, FOXL2, HRAS, KRAS, NRAS, PIK3CA, PPP2R1A, and PTEN) and protein expression of ER, PR, PTEN, and ARID1a was analyzed. Rates of distant metastasis, recurrence-free, and overall survival were calculated using the Kaplan-Meier method and log-rank test. In total, samples of 116 high-risk endometrial cancer patients were included: 86 endometrioid; 12 serous; and 18 clear cell. For endometrioid, serous, and clear cell cancers, 5-year recurrence-free survival rates were 68%, 27%, and 50% (P=0.014) and distant metastasis rates 23%, 64%, and 50% (P=0.001), respectively. Four prognostic subgroups were identified: (1) a group of p53-mutant tumors; (2) microsatellite instable tumors; (3) POLE proofreading-mutant tumors; and (4) a group with no specific molecular profile (NSMP). In group 3 (POLE-mutant; n=14) and group 2 (microsatellite instable; n=19) patients, no distant metastasis occurred, compared with 50% distant metastasis rate in group 1 (p53-mutant; n=36) and 39% in group 4 (NSMP; P

Contains fulltext : 178711.pdf (Publisher’s version ) (Open Access) Human papilloma virus (HPV)-induced cervical cancer constitutively expresses viral E6/E7 oncoproteins and is an excellent target for T cell-based immunotherapy. However, not all tumor-infiltrating T cells confer equal benefit to patients, with epithelial T cells being superior to stromal T cells. To assess whether the epithelial T cell biomarker CD103 could specifically discriminate the beneficial antitumor T cells, association of CD103 with clinicopathological variables and outcome was analyzed in the TCGA cervical cancer data set (n = 304) and by immunohistochemistry (IHC) in an independent cohort (n = 460). Localization of CD103+ cells in the tumor was assessed by immunofluorescence. Furthermore, use of CD103 as a response biomarker was assessed in an in vivo E6/E7+ tumor model. Our results show that CD103 gene expression was strongly correlated with cytotoxic T cell markers (e.g. CD8/GZMB/PD1) in the TCGA series. In line with this, CD103+ cells in the IHC series co-expressed CD8 and were preferentially located in cervical tumor epithelium. High CD103+ cell infiltration was strongly associated with an improved prognosis in both series, and appeared to be a better predictor of outcome than CD8. Interestingly, the prognostic benefit of CD103 in both series seemed limited to patients receiving radiotherapy. In a preclinical mouse model, HPV E6/E7-targeted therapeutic vaccination in combination with radiotherapy increased the intratumoral number of CD103+ CD8+ T cells, providing a potential mechanistic basis for our results. In conclusion, CD103 is a promising marker for rapid assessment of tumor-reactive T cell infiltration of cervical cancers and a promising response biomarker for E6/E7-targeted immunotherapy.

205 Background: Histological phenotypic subtypes have been proposed that stratify survival in a discovery cohort of patients with stage I-III colorectal cancer (CRC). However, clinical utility has not been validated nor associations with recurrence and chemotherapy assessed. Therefore, this study assessed prognostic value in patients with stage I-III CRC as well as predictive value for recurrence and chemotherapy response. Methods: Two independent stage I-III CRC patient cohorts were utilized to assess associations between phenotypic subtypes, survival, and recurrence. Stage II-III patients, from the SCOT adjuvant chemotherapy trial, were utilized to assess associations between phenotypic subtypes and adjuvant chemotherapy response. Log rank analysis compared immune and stromal subtypes. Results: In an 867-patient internal cohort, phenotypic subtype stratified patients by disease-free survival (DFS) (HR 2.18 95% CI 2.26-4.47, p < 0.001); independent of stage and location. The stromal subtype also predicted increased local and distant recurrence (p < 0.001). In a 146-patient external validation cohort, phenotypic subtype significantly stratified patients by DFS (HR 3.43 95% CI 1.60-7.35, p = 0.001). In 1343 SCOT trial patients, phenotypic subtype significantly stratified patients by DFS (HR 1.59 95% CI 1.13-2.25, p = 0.010). Furthermore, there was evidence that the effect of regimen depended on phenotypic subtype (p = 0.048), only significantly stratifying DFS in patients receiving FOLFOX (HR 3.73 95% CI 1.58-8.81, p = 0.003) but not CAPOX (HR 0.84 95% CI 0.56-1.26, p = 0.396) adjuvant chemotherapy. Interestingly, the immune subtype associated with improved DFS in patients receiving FOLFOX compared to CAPOX adjuvant chemotherapy (HR 3.40 95% CI 1.41-8.19, p = 0.006). Whereas patients with a stromal subtype trended towards improved DFS in patients receiving CAPOX compared to FOLFOX adjuvant chemotherapy (HR 0.72 95% CI 0.50-1.05 p = 0.088). Conclusions: Histological phenotypic subtypes are an effective independent prognostic classification for patients with stage I-III CRC that can predict response to FOLFOX adjuvant chemotherapy as well as the presence of local and distant recurrence.

Intratumoural T-cell infiltrate intensity cortes wrelaith clinical outcome in stage II/III colorectal cancer (CRC). We aimed to determine whether this association varies across this heterogeneous group.We performed a pooled analysis of 1804 CRCs from the QUASAR2 and VICTOR trials. Intratumoural CD8In QUASAR2, intratumoural CD8The prognostic value of intratumoural CD8

TPS3615 Background: Colon cancer with deficient mismatch repair (dMMR) and POLE mutations are characterised by a high tumor mutational burden (TMB) and an immunogenic lymphocyte infiltrate. Approximately 12% of stage III colon cancer have dMMR. POLE mutations occur in 1% of colon cancers, but is enriched in patients

The ability of the immune system to regulate the growth and dissemination of human malignancies depends largely on the ability of its adaptive component to identify and target malignant cells. This process is in part driven by the presence of neoantigens, which are tumour specific novel epitopes generated from mutated peptides. Immune checkpoint inhibition – a treatment that effectively unleashes the host’s immune response – has been shown to be more effective in types of cancer that have a greater prevalence of neoantigens, which is in part a reflection of the tumour’s mutational burden. While, immune checkpoint inhibition therapy has not proven to be effective in unselected colorectal cancers, it has shown impressive efficacy in the subset of patients with microsatellite unstable tumours. These tumours have a high mutation burden, and consequently are predicted to possess a far greater number of neoantigens than microsatellite stable cancers. In this chapter we discuss the mutational landscape of colorectal cancer, and the mechanisms that give rise to a subset of tumours with a significantly higher mutation rate, specifically mismatch repair deficiency and DNA polymerase epsilon (POLE) proofreading domain mutations. We also describe how the neoantigen load in colorectal cancers is a product of the mutational burden, which provides a catalogue of possible novel epitopes, and the dynamic process of immunosurveillance, which serves to sculpt the immunogenic landscape. Finally, we outline the experimental methodologies by which it is possible to identify potential neoantigen targets and how these can be translated into clinical practice.

Cancer predisposition syndromes are typically uncommon, monogenic, high-penetrance disorders. Despite their rarity, they have proven to be highly clinically relevant in directing cancer prevention strategies. As such, they share notable similarities with an expanding class of low-frequency somatic mutations that are associated with a striking prognostic or predictive effect in the tumours in which they occur. In this review, we highlight these commonalities, with particular reference to mutations in the proofreading domain of replicative DNA polymerases. These molecular phenotypes may occur as either germline or somatic events, and in the latter case, have been shown to confer a favourable prognosis and potential increased benefit from immune checkpoint inhibition. We note that incorporation of these variants into clinical management algorithms will help refine patient management, and that this will be further improved by the inclusion of other germline variants, such as those that determine the likelihood of benefit or toxicity from anti-neoplastic therapy. Finally, we propose that such integrated patient and tumour profiling will be essential if we are to deliver truly precision medicine for cancer patients, but in a similar way to rare germline mutations, we must ensure that we identify and utilize rare somatic mutations with strong predictive and prognostic effects. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John WileySons, Ltd.

High-risk endometrial cancer (EC) is an aggressive disease for which new therapeutic options are needed. Aims of this study were to validate the enhanced immune response in highly mutated ECs and to explore immune profiles in other EC subgroups. We evaluated immune infiltration in 116 high-risk ECs from the TransPORTEC consortium, previously classified into four molecular subtypes: (i) ultramutated POLE exonuclease domain-mutant ECs (POLE-mutant); (ii) hypermutated microsatellite unstable (MSI); (iii) p53-mutant; and (iv) no specific molecular profile (NSMP). Within The Cancer Genome Atlas (TCGA) EC cohort, significantly higher numbers of predicted neoantigens were demonstrated in POLE-mutant and MSI tumors compared with NSMP and p53-mutants. This was reflected by enhanced immune expression and infiltration in POLE-mutant and MSI tumors in both the TCGA cohort (mRNA expression) and the TransPORTEC cohort (immunohistochemistry) with high infiltration of CD8+ (90% and 69%), PD-1+ (73% and 69%) and PD-L1+ immune cells (100% and 71%). Notably, a subset of p53-mutant and NSMP cancers was characterized by signs of an antitumor immune response (43% and 31% of tumors with high infiltration of CD8+ cells, respectively), despite a low number of predicted neoantigens. In conclusion, the presence of enhanced immune infiltration, particularly high numbers of PD-1 and PD-L1 positive cells, in highly mutated, neoantigen-rich POLE-mutant and MSI endometrial tumors suggests sensitivity to immune checkpoint inhibitors.

Background: Mismatch repair (MMR)-deficiency analysis is increasingly recommended for all endometrial cancers, as it identifies Lynch syndrome-patients, and is emerging as a prognostic classifier to guide adjuvant treatment. The aim of this study was to define the optimal approach for MMR-deficiency testing and to clarify discrepancies between microsatellite instability (MSI) analysis and immunohistochemical (IHC) analysis of MMR protein expression. Patients and Methods: 696 endometrial cancers were analyzed for MSI (pentaplex panel) and MMR protein expression (IHC). Agreement between methodologies was calculated using Cohen’s Kappa. MLH1 promoter hypermethylation, dinucleotide microsatellite markers and somatic MMR and POLE exonuclease domain (EDM) gene variants (using next-generation/Sanger sequencing) were analyzed in discordant cases. Results: MSI was found in 180 patients. Complete loss of expression of one or more MMR proteins was observed in 196 cases. A PMS2- and MSH6-antibody panel detected all cases with loss of MMR protein expression. The results of MSI and MMR protein expression were concordant in 655/696 cases (kappa=0.854, PConclusion: MSI and IHC analysis are highly concordant in endometrial cancer. This holds true for cases with subclonal loss of MMR protein expression. Discordant MMR-proficient/MSI-high cases (

Background Antiangiogenic agents have established efficacy in the treatment of metastatic colorectal cancer. We investigated whether bevacizumab could improve disease-free survival in the adjuvant setting after resection of the primary tumour. Methods For the open-label, randomised, controlled QUASAR 2 trial, which was done at 170 hospitals in seven countries, we recruited patients aged 18 years or older with WHO performance status scores of 0 or 1 who had undergone potentially curative surgery for histologically proven stage III or high-risk stage II colorectal cancer. Patients were randomly assigned (1:1) to receive eight 3-week cycles of oral capecitabine alone (1250 mg/m2 twice daily for 14 days followed by a break for 7 days) or the same regimen of oral capecitabine plus 16 cycles of 7·5 mg/kg bevacizumab by intravenous infusion over 90 min on day 1 of each cycle. Randomisation was done by a computer-generated schedule with use of minimisation with a random element stratified by age, disease stage, tumour site, and country. The study was open label and no-one was masked to treatment assignment. The primary endpoint was 3-year disease-free survival, assessed in the intention-to-treat population. Toxic effects were assessed in patients who received at least one dose of randomised treatment. This trial is registered with the ISRCTN registry, number ISRCTN45133151. Findings Between April 25, 2005, and Oct 12, 2010, 1952 eligible patients were enrolled, of whom 1941 had assessable data (968 in the capecitabine alone group and 973 in the capecitabine and bevacizumab group). Median follow-up was 4·92 years (IQR 4·00–5·16). Disease-free survival at 3 years did not differ between the groups (75·4%, 95% CI 72·5–78·0 in the capecitabine and bevacizumab group vs 78·4%, 75·7–80·9 in the capecitabine alone group; hazard ratio 1·06, 95% CI 0·89–1·25, p=0·54). The most common grade 3–4 adverse events were hand–foot syndrome (201 [21%] of 963 in the capecitabine alone group vs 257 [27%] of 959 in the capecitabine and bevacizumab group) and diarrhoea (102 [11%] vs 104 [11%]), and, with the addition of bevacizumab, expected increases were recorded in all-grade hypertension (320 [33%] vs 75 [8%]), proteinuria (197 [21%] vs 49 [5%]), and wound healing problems (30 [3%] vs 17 [2%]). 571 serious adverse events were reported (221 with capecitabine alone and 350 with capecitabine and bevacizumab). Most of these were gastrointestinal (n=245) or cardiovascular (n=169). 23 deaths within 6 months of randomisation were classified as being related to treatment, eight in the capecitabine alone group and 15 in the capecitabine and bevacizumab group. Interpretation The addition of bevacizumab to capecitabine in the adjuvant setting for colorectal cancer yielded no benefit in the treatment of an unselected population and should not be used.

Survivin is a 16.5 kDa protein that functions to inhibit apoptosis, promote proliferation, and enhance invasion. Absent in most adult tissues, survivin is selectively upregulated in many human tumors, where its overexpression correlates with poor outcome and treatment resistance. Consequently, survivin is a promising target for cancer therapy. Preclinical data demonstrate that survivin inhibition reduces cell proliferation, increases apoptosis, and sensitises cells to cytotoxic agents and radiotherapy. The pharmacological survivin inhibitors LY2181308 and YM155 have demonstrated acceptable toxicity and evidence of therapeutic efficacy as single agents in early-phase clinical trials. Current efforts seek to define the optimum use of survivin inhibitors in combination with cytotoxic therapies, where it is hoped that preclinical evidence of treatment synergy will translate into improved therapeutic efficacy. Results from these ongoing studies are keenly awaited.

The tumour suppressor PTEN is a key negative regulator of the PI3K-Akt pathway, and is frequently either reduced or lost in human tumours. Murine genetic studies have confirmed that reduction of Pten promotes tumourigenesis in multiple organs, and demonstrated dependency of tumour development on the activation of downstream components such as Akt. Insulin-like growth factors (IGFs) act via IGF1R to activate the PI3K-Akt pathway, and are commonly upregulated in cancer. A context-dependent interplay between IGFs and PTEN exists in normal tissue and tumours; increased IGF2 ligand supply induces Pten expression creating an autoregulatory negative feedback loop, whereas complete loss of PTEN may either cooperate with IGF overexpression in tumour promotion, or result in desensitisation to IGF ligand. However, it remains unknown whether neoplasia associated with Pten loss is dependent on upstream IGF ligand supply in vivo. We evaluated this by generation of Pten/mice with differing allelic dosage of Igf2, an imprinted gene encoding the potent embryonic and tumour growth factor Igf2. We show that biallelic Igf2 supply potentiates a previously unreported Pten/placental phenotype and results in strain-dependent cardiac hyperplasia and neonatal lethality. Importantly, we also show that the effects of Pten loss in vivo are modified by Igf2 supply, as lack of Igf2 results in extended survival and delayed tumour development while biallelic supply is associated with reduced lifespan and accelerated neoplasia in females. Furthermore, we demonstrate that reduction of PTEN protein to heterozygote levels in human MCF7 cells is associated with increased proliferation in response to IGF2, and does not result in desensitisation to IGF2 signalling. These data indicate that the effects of Pten loss at heterozygote levels commonly observed in human tumours are modified by Igf2 ligand, and emphasise the importance of the evaluation of upstream pathways in tumours with Pten loss. © 2012 Macmillan Publishers Limited All rights reserved.

PURPOSE OF REVIEW: The past couple of years have seen a flurry of publications detailing potential prognostic and predictive biomarkers for colorectal cancer. However, most studies have been underpowered and demonstrate elements of a statistical 'fishing exercise', that is the carrying out of a huge number of analyses to find a hint of importance for a particular marker. RECENT FINDINGS: Recently some well powered analyses using separate development and validation datasets and multivariate statistics have been published and these are starting to change attitudes towards such markers. SUMMARY: Although there are very limited markers in standard clinical practice, we feel that there are now some that are ready to be translated into routine use or that at least deserve some further attention and 'service assessment'.

Purpose Testicular cancers are an uncommon and highly curable group of tumors that are typically managed by specialist multidisciplinary teams (MDTs). Although recent guidelines have emphasized the importance of tumor prognostic factors in predicting recurrence and personalizing therapy in early-stage disease, the role of central pathology review in determining these factors is unclear. Patients and Methods We compared the referral histopathology reports with those obtained after expert central review for all cases reviewed by the UK Thames Valley Cancer Network testicular tumor MDT from August 2004 to September 2012. For cases in which the findings differed, we recorded the effect of the alteration on the estimates of patient prognosis and predicted clinical management using international (European Society of Medical Oncology [ESMO]) and local guidelines. Results The histopathology reports were altered after central review in 129 of 465 cases (27.7%) referred to the testicular tumor MDT during the study period. These resulted in changes in the estimation of prognosis for 42 patients (9.0% total), with a predicted affect on management according to the ESMO guidelines in 30 cases (6.5%). These proportions were broadly similar for both seminoma and nonseminoma, although the reasons for the discrepancies differed between the 2 (principally errors in categorization of rete testis invasion in seminoma and of lymphovascular invasion in nonseminoma). Changes to the tumor type were uncommon (2 cases). Conclusion Central MDT review results in frequent, clinically relevant alterations to testicular tumor histopathology reports for testicular tumors. The results of our study demonstrate the importance of specialist MDTs to inform patient-centered care and ensure best practice in the management of these uncommon cancers.

Advanced and metastatic endometrial cancer (EC) is associated with a poor prognosis, despite the availability of systemic treatments including endocrine therapy and combination cytotoxic chemotherapy. Response rates of systemic treatments are associated with high toxicity, have poor response rates and responses are genenrally short-lived. Recent findings on the molecular aberrations of the subtypes of EC have enabled in vitro and in vivo studies to exploit targeted treatment for this disease. One of the most common molecular aberrations in EC is the PI3K–AKT–mTOR pathway being activated through different mechanisms in both type I and type II ECs. The aim of this review is to summarize the numerous preclinical and clinical studies, and discuss the future directions.

3515Background: The intensity of the T cell anti-tumour response influences colorectal cancer (CRC) outcome, and may predict benefit from immunomodulatory therapies. However, previous studies have ...

Next-generation sequencing (NGS) efforts have established catalogs of mutations relevant to cancer development. However, the clinical utility of this information remains largely unexplored. Here, we present the results of the first eight patients recruited into a clinical whole-genome sequencing (WGS) program in the United Kingdom. We performed PCR-free WGS of fresh frozen tumors and germline DNA at 75× and 30×, respectively, using the HiSeq2500 HTv4. Subtracted tumor VCFs and paired germlines were subjected to comprehensive analysis of coding and noncoding regions, integration of germline with somatically acquired variants, and global mutation signatures and pathway analyses. Results were classified into tiers and presented to a multidisciplinary tumor board. WGS results helped to clarify an uncertain histopathological diagnosis in one case, led to informed or supported prognosis in two cases, leading to de-escalation of therapy in one, and indicated potential treatments in all eight. Overall 26 different tier 1 potentially clinically actionable findings were identified using WGS compared with six SNVs/indels using routine targeted NGS. These initial results demonstrate the potential of WGS to inform future diagnosis, prognosis, and treatment choice in cancer and justify the systematic evaluation of the clinical utility of WGS in larger cohorts of patients with cancer.

Brain metastases (BM) are a significant complication of metastatic breast cancer (MBC). The high incidence of BM in HER2 overexpressing MBC is now well recognized, however, the optimal management of such patients is not yet clearly defined. We aimed to analyze factors affecting survival after diagnosis of BM in patients treated in our center.Retrospective analysis of survival in all patients treated with antineoplastic therapy for BM from MBC in our institution between May 1st 2002 and April 30th 2005, according to HER2 expression and use of trastuzumab after diagnosis of BM.The median survival of the 26 patients with HER2 overexpressing disease after diagnosis of BM was significantly longer than that of the 60 patients with HER2 nonoverexpressing disease (6.2 vs. 3.8 months, P = 0.027). Further analysis revealed that this seems to be due to the favorable outcome of the 70% (n = 18) of HER2 overexpressing patients who received trastuzumab after BM were diagnosed. Median survival of this group was 11.9 months, compared with 3.8 months (HER2 nonoverexpressing disease, P = 0.002) and 3.0 months (HER2 overexpressing disease not treated with trastuzumab after development of BM, P = 0.05).Patients with HER2 overexpressing MBC who received trastuzumab after diagnosis of BM survived longer than expected. This finding justifies an active therapeutic approach: disease progression within central nervous system does not preclude benefit from trastuzumab treatment.

Studies in early-stage, predominantly low- and intermediate-risk endometrial cancer have demonstrated that L1 cell adhesion molecule (L1CAM) overexpression identifies patients at increased risk of recurrence, yet its prognostic significance in high-risk endometrial cancer is unclear. To evaluate this, its frequency, and the relationship of L1CAM with the established endometrial cancer biomarker p53, we analyzed the expression of both markers by immunohistochemistry in a pilot series of 116 endometrial cancers (86 endometrioid, 30 non-endometrioid subtype) with high-risk features (such as high tumor grade and deep myometrial invasion) and correlated results with clinical outcome. We used The Cancer Genome Atlas (TCGA) endometrial cancer series to validate our findings. Using the previously reported cutoff of 10% positive staining, 51/116 (44%) tumors were classified as L1CAM-positive, with no significant association between L1CAM positivity and the rate of distant metastasis (P=0.195). However, increasing the threshold for L1CAM positivity to 50% resulted in a reduction of the frequency of L1CAM-positive tumors to 24% (28/116), and a significant association with the rate of distant metastasis (P=0.018). L1CAM expression was strongly associated with mutant p53 in the high-risk and TCGA series (P0.001), although a substantial fraction (36% of endometrioid, 10% of non-endometrioid morphology) of p53-mutant endometrial cancers displayed10% L1CAM positivity. Moreover, 30% of p53-wild-type non-endometrioid endometrial cancers demonstrated diffuse L1CAM staining, suggesting p53-independent mechanisms of L1CAM overexpression. In conclusion, the previously proposed threshold for L1CAM positivity of10% does not predict prognosis in high-risk endometrial cancer, whereas an alternative threshold (50%) does. L1CAM expression is strongly, but not universally, associated with mutant p53, and may be strong enough for clinical implementation as prognostic marker in combination with p53. The high frequency of L1CAM expression in high-risk endometrial cancers suggests that it may also be a promising therapeutic target in this tumor subset.

Although it has long been recognized that the exonucleolytic proofreading activity intrinsic to the replicative DNA polymerases Pol δ and Pol ε is essential for faithful replication of DNA, evidence that defective DNA polymerase proofreading contributes to human malignancy has been limited. However, recent studies have shown that germline mutations in the proofreading domains of Pol δ and Pol ε predispose to cancer, and that somatic Pol ε proofreading domain mutations occur in multiple sporadic tumours, where they underlie a phenotype of 'ultramutation' and favourable prognosis. In this Review, we summarize the current understanding of the mechanisms and consequences of polymerase proofreading domain mutations in human malignancies, and highlight the potential utility of these variants as novel cancer biomarkers and therapeutic targets.

Over the last two decades, multidisciplinary team (MDT) working has become an integral part of cancer care in many healthcare systems in the Western world. MDT meetings were established as part of an effort to reduce the fragmented provision of cancer care, and to ensure that each patient receives a management plan based on expert consensus following consideration of all appropriate therapeutic options. Although limited, the available evidence indicates that MDT working is associated with improved patient outcomes, though the associated costs are significant. MDTs are likely to evolve over the coming years through the development of specific software tools to aid clinical decision-making, and through the incorporation of tumour genomics and the personalization of therapy this enables.

We read with interest the Brief Report “Association of Polymerase e-Mutated and microsatellite instable endometrial cancers with neoantigen load, number of tumor infiltrating lymphocytes, and expression of PD-1 and PD-L1” by Howitt and colleagues published online in JAMA Oncology on the 9th July. Over the last few years, we have also studied the interesting subgroup of endometrial cancers (ECs) with mutation in the POLE proofreading exonuclease domain and in particular their association with excellent prognosis not mentioned by Howitt et al in their report.

We conducted a meta-analysis of three endometrial cancer genome-wide association studies (GWAS) and two follow-up phases totaling 7,737 endometrial cancer cases and 37,144 controls of European ancestry. Genome-wide imputation and meta-analysis identified five new risk loci of genome-wide significance at likely regulatory regions on chromosomes 13q22.1 (rs11841589, near KLF5), 6q22.31 (rs13328298, in LOC643623 and near HEY2 and NCOA7), 8q24.21 (rs4733613, telomeric to MYC), 15q15.1 (rs937213, in EIF2AK4, near BMF) and 14q32.33 (rs2498796, in AKT1, near SIVA1). We also found a second independent 8q24.21 signal (rs17232730). Functional studies of the 13q22.1 locus showed that rs9600103 (pairwise r2 = 0.98 with rs11841589) is located in a region of active chromatin that interacts with the KLF5 promoter region. The rs9600103[T] allele that is protective in endometrial cancer suppressed gene expression in vitro, suggesting that regulation of the expression of KLF5, a gene linked to uterine development, is implicated in tumorigenesis. These findings provide enhanced insight into the genetic and biological basis of endometrial cancer.

Despite substantial morbidity and mortality of influenza and pneumococcal infections in cancer patients treated with chemotherapy, vaccination against both illnesses is infrequent. We evaluated the impact of implementation of clinical guidelines on vaccination of chemotherapy patients treated in our institute.We performed a prospective audit before (2012) and after (2013-2014) the introduction of immunisation guidelines for chemotherapy patients in a UK tertiary cancer centre.Guideline implementation was associated with a significant increase in the rate of pneumococcal vaccination compared to the 2012 baseline (47 vs. 25 %, P = 0.0018), though this was not sustained the following year (34 %, P = 0.13, vs. baseline). Influenza vaccine coverage was high (∼ 70 %) throughout. There was a marked disparity between patients aged ≤ 65 and those65 years in the rate of pneumococcal vaccination in both 2013 and 2014 (38 vs. 68 % and 17 vs. 53 %, respectively, both P0.001), and, to a lesser extent, in the rate of influenza vaccination in the same period (64 vs. 82 %, P0.1, and 63 vs. 85 %, P = 0.009, respectively).The implementation of clinical vaccine guidelines was associated with a significant increase in pneumococcal vaccination, though continued effort appears required to deliver persistent improvement. Initiatives to increase vaccination uptake in patients aged ≤ 65 are merited.

Malignant ovarian germ cell tumours (OGCT) comprise only 2–5% of all ovarian cancers but are significantly different to epithelial ovarian cancers. They affect women of child bearing age and are much more curable than their epithelial counterparts. In addition, the majority of patients will retain their fertility after multimodal treatment. The small numbers of patients mean that randomised controlled trials of chemotherapy, the gold standard test of treatment effectiveness in other malignancies, have proved impossible to perform. The different types of OGCT have variable degrees of chemosensitivity and differing prognoses. Treatment outcomes are also dependent on the stage of disease at diagnosis. In this article, dysgerminomas and non-dysgerminomas are analyzed separately, as there are notable differences in their behaviour and outcomes. It is difficult to think of many diseases in which prognosis has improved as greatly as ovarian germ cell tumours and this is due to modern combination chemotherapy. Like the treatment of testicular cancer, this represents one of the successes of modern medicine.

This review aims to summarize experimental evidence supporting the role of the insulin-like growth factor (IGF) signalling system in the progression, maintenance, and treatment of cancer. These data implicate the IGF system as an important modifier of cancer cell proliferation, survival, growth, and treatment sensitivity. The role of the IGF system in cancer should be examined in the context of the extra-cellular and intra-cellular signalling networks, in particular: phosphatidylinositol 3-kinase (PI3K), protein kinase B (Akt/PKB), mammalian target of rapamycin (mTOR), and forkhead transcription factors (FOXO). This review highlights evidence derived from molecular structure and functional genetics with respect to how the extra-cellular components of the IGF system function normally, and their subsequent modifications in cancer. The therapeutic relevance of the research evidence described is also addressed, as the challenge is to apply this knowledge to human health.

Despite adjuvant chemotherapy, between 20 and 50 % of patients with stage II/III colorectal cancer (CRC) will suffer recurrence, usually as incurable metastatic disease. Attempts to improve the efficacy of adjuvant regimens with addition of biologics have failed, and there is therefore a pressing need for novel therapeutic approaches. Inflammatory mediators, including the cyclooxygenase (COX) enzyme family, are commonly upregulated in CRC and known to promote tumour growth in preclinical models. COX inhibition by aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) may exert an antineoplastic effect. Despite considerable evidence in CRC prevention and emerging data demonstrating that regular aspirin reduces the frequency of metastases following CRC resection, its use has not become widespread due to concerns regarding toxicities. However, the recent identification of biomarkers that may predict aspirin benefit has renewed interest in the field. Large, randomised controlled trials underway/in set-up should provide definitive evidence of the efficacy of aspirin/NSAIDs as adjuvant therapy in CRC. This review examines the field to date, with focus on the biomarkers which may help refine the risk-benefit ratio. © 2014 Springer Science+Business Media New York.

Objectives Video-assisted thoracoscopic surgery (VATS) lobectomy for early stage non-small cell lung cancer (NSCLC) is a safe and effective alternative to open lobectomy. Adjuvant chemotherapy is part of the treatment recommended for patients with performance status (PS) 0-1 following resection of NSCLC of stages T1-3 N1-2 M0 and T2-3 N0 M0. If VATS reduces morbidity, does it help delivery of postoperative chemotherapy? We studied our data to compare the delivery and toxicity of chemotherapy in patients following VATS or open lung resections. Methods We performed a retrospective study of all patients who had resection of primary NSCLC in a single surgical centre between October 2008 and August 2013. Surgical and chemotherapy databases were reviewed to extract data on patient characteristics, operative details, pathological stage, chemotherapy delivery and toxicity. Results Three hundred and twenty-three resections were undertaken for NSCLC; 142 (44%) underwent VATS resection and 181 (56%) open thoracotomy; 16 (11.3%) and 28 (15.5%) of each group received adjuvant chemotherapy, respectively. Patient demographics and tumour stage were as follows: median age (range) was 65.5 (44-77) vs 67.5 (49-76); male: 43.8 vs 50% (P = 1.0); Stage I/II 75 vs 76.9%; Stage III 12.5 vs 30.8%; pre-chemotherapy PS 0 75 vs 78.2% for VATS and thoracotomy groups, respectively. All patients received platinum/vinorelbine therapy. Chemotherapy was initiated significantly earlier in the VATS group (mean 55.7 ± 3.1 vs 68.2 ± 4.3 days, P = 0.046); 68.8% of patients in the VATS group completed four cycles of chemotherapy compared with 60.1% in the open group (P = 0.75). There was a non-significant trend towards reduction in Grade 3/4 haematological toxicity in the VATS group compared with the open group (12.5 vs 39.3%, P = 0.09). Conclusions Adjuvant chemotherapy was started significantly earlier in patients following VATS lung resections for NSCLC compared with thoracotomy. There was also a trend towards improved tolerance with more complete courses and reduced haematological toxicity.

If we were to summarize the rationale that underpins medical oncology in a Latin aphorism, it might be 'veneno ergo sum'; that is, I poison, therefore I am. The burden of chemotherapy-associated toxicity is well recognized, but we have relatively few tools that increase the precision of anticancer drug prescribing. We propose a shift in emphasis from the focussed study of polymorphisms in drug metabolic pathways in small sets of patients to broader agnostic analyses to systematically correlate germline genetic variants with adverse events in large, well-defined cancer populations. Thus, we propose the new science of 'toxgnostics' (that is, the systematic, agnostic study of genetic predictors of toxicity from anticancer therapy). © 2014 Macmillan Publishers Limited.

Aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) protect against colorectal cancer (CRC) and are associated with reduced disease recurrence and improved outcome after primary treatment. However, toxicities of NSAIDs have limited their use as antineoplastic therapy. Recent data have suggested that the benefit of aspirin after CRC diagnosis is limited to patients with PIK3CA-mutant cancers. We sought to determine the predictive utility of PIK3CA mutation for benefit from both cyclooxygenase-2 inhibition and aspirin.We performed molecular analysis of tumors from 896 participants in the Vioxx in Colorectal Cancer Therapy: Definition of Optimal Regime (VICTOR) trial, a large randomized trial comparing rofecoxib with placebo after primary CRC resection. We compared relapse-free survival and overall survival between rofecoxib therapy and placebo and between the use and nonuse of low-dose aspirin, according to tumor PIK3CA mutation status.We found no evidence of a greater benefit from rofecoxib treatment compared with placebo in patients whose tumors had PIK3CA mutations (multivariate adjusted hazard ratio [HR], 1.2; 95% CI, 0.53 to 2.72; P = .66; (P)INTERACTION = .47) compared with patients with PIK3CA wild-type cancers (HR, 0.87; 95% CI, 0.64 to 1.16; P = .34). In contrast, regular aspirin use after CRC diagnosis was associated with a reduced rate of CRC recurrence in patients with PIK3CA-mutant cancers (HR, 0.11; 95% CI, 0.001 to 0.832; P = .027; (P)INTERACTION = .024) but not in patients lacking tumor PIK3CA mutation (HR, 0.92; 95% CI, 0.60 to 1.42; P = .71).Although tumor PIK3CA mutation does not predict benefit from rofecoxib treatment, it merits further evaluation as a predictive biomarker for aspirin therapy. Our findings are concordant with recent data and support the prospective investigation of adjuvant aspirin in PIK3CA-mutant CRC.

Colorectal cancer (CRC) is the third commonest cancer in the Western world. Approximately one-quarter of cases are classified as Stage II/Dukes' B, meaning that the disease has breached the bowel wall but not spread to draining lymph nodes or distant sites. Stage II colon cancer is a heterogeneous disease both biologically and in terms of outcome. Although pivotal data have confirmed the benefit of adjuvant 5-fluorouracil (FU) chemotherapy following resection of stage II tumours the absolute reduction in risk of recurrence is small - 3 to 4 percentage points - and so most patients treated fail to gain from therapy. In contrast to stage III disease, the addition of oxaliplatin to FU as adjuvant chemotherapy for stage II disease does not improve outcome. Much attention has focused on the identification of biomarkers that identify patients more or less likely to benefit from treatment. Recent data confirm that patients with T3 primary and tumour microsatellite instability (MSI) have excellent prognosis and do not require adjuvant chemotherapy. For patients with microsatellite-stable disease, a validated recurrence score based on gene expression provides greater prognostic information than conventional clinicopathological features alone and can be used to inform discussion on the benefits of adjuvant chemotherapy.

Background/Aims: During the last two decades, hundreds of reports have detailed putative prognostic and predictive biomarkers for colorectal cancer (CRC). However, the majority of these studies have been small and retrospective, reporting results that are highly likely to represent false positives. Consequently, their relevance to clinical practice requires definition. Methods: Review of published literature on CRC biomarkers, focusing on early-stage disease. Results: Although most putative biomarkers have failed to be validated in subsequent studies, level I evidence now indicates that tumour microsatellite instability can be used to identify a cohort of patients with stage IIA disease at low risk of relapse who can be spared adjuvant chemotherapy. Emerging data suggest that gene expression arrays may have a role in selecting patients with stage IIA disease and mismatch repair-proficient tumours for chemotherapy following tumour resection. Conclusion: Despite the profusion of biomarker literature, only mismatch repair status can be recommended as routine in current clinical practice. High-quality, adequately powered studies are essential to accurately define the utility of existing and putative biomarkers, and to support their rational application in the clinic.

Purpose. Ifosfamide is a drug commonly used in the management of sarcomas and other solid tumours. One potential toxicity of its use is renal tubular damage, which can lead to skeletal abnormalities; rickets in children and osteomalacia in adults. We aimed to characterise this rare complication in adults.Patients. Three illustrative patient cases treated in our institution are presented. All were treated for sarcoma, and received varying doses of ifosfamide during their therapy.Methods. We performed a review of the literature on the renal tubular and skeletal complications of ifosfamide in adults. Papers were identified by searches of PubMed using the terms “osteomalacia,” “nephrotoxicity,” “Fanconi syndrome,” “ifosfamide,” and “chemotherapy” for articles published between 1970 and 2006. Additional papers were identified from review of references of relevant articles.Results. There are only four case reports of skeletal toxicity secondary to ifosfamide in adults; the majority of data refer to children. Risk factors for development of renal tubular dysfunction and osteodystrophy include platinum chemotherapy, increasing cumulative ifosfamide dose, and reduced nephron mass. The natural history of ifosfamide-induced renal damage is variable, dysfunction may not become apparent until some months after treatment, and may improve or worsen with time.Discussion. Ifosfamide-induced osteomalacia is seldom described in adults. Clinicians should be vigilant for its development, as timely intervention may minimise complications.