[Oncogenetics]. / Oncogenetica.

Determining whether a hereditary cancer predisposition is present, is important for both the cancer patient and his family. It is relevant for surveillance and prevention or early detection of new tumours, treatment options and issues surrounding the desire to have children. For this reason, it must be ensured that for every patient with cancer (now or in the past) referral for genetic testing is considered. In this article we indicate how to take a family history and where to find and how to apply referral criteria if such a question arises in clinical practice. The consequences of a genetic diagnosis are illustrated by a breast cancer case.

Metastasis of colorectal carcinoma in the testis: first sign of peritoneal disease.

Metastases of colorectal carcinoma (CRC) in the testis are very rare and indicate an advanced stage of disease. In this case report, we present a patient with adenocarcinoma in the sigmoid colon with metastasis in the right testis. Testicular metastasis of CRC is mostly diagnosed late because of their low incidence rate. Patients with CRC and testicular metastasis have a poor prognosis. In this case, the patient turned out to have peritoneal metastasis and one should be aware that testicular metastasis could be the first sign of widespread disease.

Small Cell Carcinoma of the Esophagus: A Nationwide Analysis of Treatment and Outcome at Patient Level in Locoregional Disease.

BACKGROUND AND PURPOSE: Small cell carcinoma of the esophagus (SCEC) is a rare subtype of esophageal cancer for which optimal treatment is unknown. We analyzed the impact of treatment factors on outcome in patients with nonmetastasized SCEC. METHODS: Patients with a histologically confirmed SCEC without distant metastases were analyzed in a nationwide multicenter retrospective cohort. All patients received radiotherapy as part of curative treatment between January 2000 and December 2014. Details on treatment and outcome were retrieved from individual charts. Cox regression analysis was used to determine prognostic factors for survival. RESULTS: Fifty-eight patients were analyzed. Median survival was 16 months (95% confidence interval, 11-21 mo). Infield recurrences occurred in 25%, distant metastases in 45%, and brain metastases in 12%. In total, 63% of patients developed a recurrence. Most recurrences (67%) occurred within 1 year. In univariable analyses an increased number of chemotherapy cycles (>3) and lower radiotherapy doses (<45 Gy) were associated with improved survival. T-stage, N-stage, treatment period, type of chemotherapy, prophylactic cranial irradiation, and age were not associated with survival. In multivariable analyses, only the number of chemotherapy cycles was associated with better survival (hazard ratio, 0.78; P=0.006). CONCLUSIONS: SCEC recurs frequently at distant sites after definitive chemoradiotherapy and usually within 1 year after curative treatment. With a dose of 45 to 50 Gy, infield recurrence rate was low. We found a relationship between number of received chemotherapy cycles and survival with best results obtained after at least 4 cycles of chemotherapy.

Safety and efficacy of the addition of simvastatin to panitumumab in previously treated KRAS mutant metastatic colorectal cancer patients.

Panitumumab has proven efficacy in patients with metastatic or locally advanced colorectal cancer patients, provided that they have no activating KRAS mutation in their tumour. Simvastatin blocks the mevalonate pathway and thereby interferes with the post-translational modification of KRAS. We hypothesize that the activity of the RAS-induced pathway in patients with a KRAS mutation might be inhibited by simvastatin. This would theoretically result in increased sensitivity to panitumumab, potentially comparable with tumours with wild-type KRAS. A Simon two-stage design single-arm, phase II study was designed to test the safety and efficacy of the addition of simvastatin to panitumumab in colorectal cancer patients with a KRAS mutation after failing fluoropyrimidine-based, oxaliplatin-based and irinotecan-based therapy. The primary endpoint of this study was the proportion of patients alive and free from progression 11 weeks after the first administration of panitumumab, aiming for at least 40%, which is comparable with, although slightly lower than, that in KRAS wild-type patients in this setting. If this 40% was reached, then the study would continue into the second step up to 46 patients. Explorative correlative analysis for mutations in the KRAS and related pathways was carried out. One of 14 patients was free from progression at the primary endpoint time. The median progression-free survival was 8.4 weeks and the median overall survival status was 19.6 weeks. We conclude that the concept of mutant KRAS phenotype expression modulation with simvastatin was not applicable in the clinic.

Statin use is not associated with improved progression free survival in cetuximab treated KRAS mutant metastatic colorectal cancer patients: results from the CAIRO2 study.

Statins may inhibit the expression of the mutant KRAS phenotype by preventing the prenylation and thus the activation of the KRAS protein. This study was aimed at retrospectively evaluating the effect of statin use on outcome in KRAS mutant metastatic colorectal cancer patients (mCRC) treated with cetuximab. Treatment data were obtained from patients who were treated with capecitabine, oxaliplatin bevacizumab ± cetuximab in the phase III CAIRO2 study. A total of 529 patients were included in this study, of whom 78 patients were on statin therapy. In patients with a KRAS wild type tumor (n = 321) the median PFS was 10.3 vs. 11.4 months for non-users compared to statin users and in patients with a KRAS mutant tumor (n = 208) this was 7.6 vs. 6.2 months, respectively. The hazard ratio (HR) for PFS for statin users was 1.12 (95% confidence interval 0.78-1.61) and was not influenced by treatment arm, KRAS mutation status or the KRAS*statin interaction. Statin use adjusted for covariates was not associated with increased PFS (HR = 1.01, 95% confidence interval 0.71-1.54). In patients with a KRAS wild type tumor the median OS for non-users compared to statin users was 22.4 vs. 19.8 months and in the KRAS mutant tumor group the OS was 18.1 vs. 14.5 months. OS was significantly shorter in statin users versus non-users (HR = 1.54; 95% confidence interval 1.06-2.22). However, statin use, adjusted for covariates was not associated with increased OS (HR = 1.41, 95% confidence interval 0.95-2.10). In conclusion, the use of statins at time of diagnosis was not associated with an improved PFS in KRAS mutant mCRC patients treated with chemotherapy and bevacizumab plus cetuximab.

Concordance of predictive markers for EGFR inhibitors in primary tumors and metastases in colorectal cancer: a review.

BACKGROUND: Currently, only Kirsten rat sarcoma 2 viral oncogene homolog (KRAS) mutational status is used as a decisional marker for epidermal growth factor receptor (EGFR) inhibitor therapy in colorectal cancer (CRC) patients. Concordance of KRAS status between primary tumors and metastases has always been considered to be close to perfect; however, cases of discordance have been reported. The actual rate of concordance of KRAS status remains unclear, as is the same for v-raf murine sarcoma viral oncogene homolog B1 (BRAF), phosphatidylinositol 3-kinase CA subunit (PIK3CA), and loss of phosphatase and tensin homologue deleted on chromosome ten (PTEN). Therefore, it is unknown whether it is necessary to perform mutational analysis on metastases instead of on (or in addition to) primary tumors. DESIGN: A systematic literature search was conducted to collect all studies testing concordance of KRAS in CRC, and also of BRAF, PIK3CA, and loss of PTEN. RESULTS: Twenty-one studies have reported concordance of KRAS, with an overall concordance rate of 93% (range, 76%-100%). Overall concordance rates of studies testing concordance of BRAF status and loss of PTEN were 98% and 68%, respectively. Three studies reported concordance of PIK3CA status (range, 89%-94%). CONCLUSION: Though discordance of KRAS status does occur, it is uncommon. When considering the downsides of testing metastatic tissue in all patients along with the low incidence of discordance, we conclude that that testing the primary tumor (or whatever tissue available) is sufficient for clinical decision making on EGFR inhibitor therapy.

Therapeutic modulation of k-ras signaling in colorectal cancer.

KRAS has an important role in colorectal carcinogenesis and mutant KRAS leads to a permanently activated k-ras protein. To exert its biological activity, k-ras requires post-translational modification by prenylation. K-ras modulation has become a promising concept for new therapies, mostly by interference with the mevalonate pathway and subsequently by the prenylation of k-ras. Clinical data of agents interfering with the mevalonate pathway and the prenylation of ras are summarized and suggest that these agents might be effective when administered in combination with anticancer drugs that target k-ras. Here, we discuss the novel concept that modulation of k-ras might potentiate EGFR therapy by altering the KRAS phenotype.