Gene expression signatures for colorectal cancer microsatellite status and HNPCC

The majority of microsatellite instable (MSI) colorectal cancers are sporadic, but a subset belongs to the syndrome hereditary nonpolyposis colorectal cancer (HNPCC). Microsatellite instability is caused by dysfunction of the mismatch repair (MMR) system that leads to a mutator phenotype, and MSI is correlated to prognosis and response to chemotherapy. Gene expression signatures as predictive markers are being developed for many cancers, and the identification of a signature for MMR deficiency would be of interest both clinically and biologically. To address this issue, we profiled the gene expression of 101 stage II and III colorectal cancers (34 MSI, 67 microsatellite stable (MSS)) using high-density oligonucleotide microarrays. From these data, we constructed a nine-gene signature capable of separating the mismatch repair proficient and deficient tumours. Subsequently, we demonstrated the robustness of the signature by transferring it to a real-time RT-PCR platform. Using this platform, the signature was validated on an independent test set consisting of 47 tumours (10 MSI, 37 MSS), of which 45 were correctly classified. In a second step, we constructed a signature capable of separating MMR-deficient tumours into sporadic MSI and HNPCC cases, and validated this by a mathematical cross-validation approach. The demonstration that this two-step classification approach can identify MSI as well as HNPCC cases merits further gene expression studies to identify prognostic signatures

Induction chemotherapy followed by chemoradiotherapy versus chemoradiotherapy alone as neoadjuvant treatment for locally recurrent rectal cancer: study protocol of a multicentre, open-label, parallel-arms, randomized controlled study (PelvEx II)

Background A resection with clear margins (R0 resection) is the most important prognostic factor in patients with locally recurrent rectal cancer (LRRC). However, this is achieved in only 60 per cent of patients. The aim of this study is to investigate whether the addition of induction chemotherapy to neoadjuvant chemo(re)irradiation improves the R0 resection rate in LRRC. Methods This multicentre, international, open-label, phase III, parallel-arms study will enrol 364 patients with resectable LRRC after previous partial or total mesorectal resection without synchronous distant metastases or recent chemo- and/or radiotherapy treatment. Patients will be randomized to receive either induction chemotherapy (three 3-week cycles of CAPOX (capecitabine, oxaliplatin), four 2-week cycles of FOLFOX (5-fluorouracil, leucovorin, oxaliplatin) or FOLFORI (5-fluorouracil, leucovorin, irinotecan)) followed by neoadjuvant chemoradiotherapy and surgery (experimental arm) or neoadjuvant chemoradiotherapy and surgery alone (control arm). Tumours will be restaged using MRI and, in the experimental arm, a further cycle of CAPOX or two cycles of FOLFOX/FOLFIRI will be administered before chemoradiotherapy in case of stable or responsive disease. The radiotherapy dose will be 25 × 2.0 Gy or 28 × 1.8 Gy in radiotherapy-naive patients, and 15 × 2.0 Gy in previously irradiated patients. The concomitant chemotherapy agent will be capecitabine administered twice daily at a dose of 825 mg/m2 on radiotherapy days. The primary endpoint of the study is the R0 resection rate. Secondary endpoints are long-term oncological outcomes, radiological and pathological response, toxicity, postoperative complications, costs, and quality of life. Discussion This trial protocol describes the PelvEx II study. PelvEx II, designed as a multicentre, open-label, phase III, parallel-arms study, is the first randomized study to compare induction chemotherapy followed by neoadjuvant chemo(re)irradiation and surgery with neoadjuvant chemo(re)irradiation and surgery alone in patients with locally recurrent rectal cancer, with the aim of improving the number of R0 resections

One to 2-Year Surveillance Intervals Reduce Risk of Colorectal Cancer in Families With Lynch Syndrome

Contains fulltext : 87226.pdf (publisher's version ) (Closed access)BACKGROUND & AIMS: Two percent to 4% of all cases of colorectal cancer (CRC) are associated with Lynch syndrome. Dominant clustering of CRC (non-Lynch syndrome) accounts for 1%-3% of the cases. Because carcinogenesis is accelerated in Lynch syndrome, an intensive colonoscopic surveillance program has been recommended since 1995. The aim of the study was to evaluate the effectiveness of this program. METHODS: The study included 205 Lynch syndrome families with identified mutations in one of the mismatch repair genes (745 mutation carriers). We also analyzed data from non-Lynch syndrome families (46 families, 344 relatives). Patients were observed from January 1, 1995, until January 1, 2009. End points of the study were CRC or date of the last colonoscopy. RESULTS: After a mean follow-up of 7.2 years, 33 patients developed CRC under surveillance. The cumulative risk of CRC was 6% after the 10-year follow-up period. The risk of CRC was higher in carriers older than 40 years and in carriers of MLH1 and MSH2 mutations. After a mean follow-up of 7.0 years, 6 cases of CRC were detected among non-Lynch syndrome families. The risk of CRC was significantly higher among families with Lynch syndrome, compared with those without. CONCLUSIONS: With surveillance intervals of 1-2 years, members of families with Lynch syndrome have a lower risk of developing CRC than with surveillance intervals of 2-3 years. Because of the low risk of CRC in non-Lynch syndrome families, a less intensive surveillance protocol can be recommended.1 juni 201