Sigurdis Haraldsdottir

Colon and endometrial cancers with mismatch repair deficiency can arise from somatic, rather than germline, mutations.

BACKGROUND & AIMS Patients with Lynch syndrome carry germline mutations in single alleles of genes encoding the mismatch repair (MMR) proteins MLH1, MSH2, MSH6, and PMS2; when the second allele becomes mutated, cancer can develop. Increased screening for Lynch syndrome has identified patients with tumors that have deficiency in MMR, but no germline mutations in genes encoding MMR proteins. We investigated whether tumors with deficient MMR had acquired somatic mutations in patients without germline mutations in MMR genes using next-generation sequencing. METHODS We analyzed blood and tumor samples from 32 patients with colorectal or endometrial cancer who participated in Lynch syndrome screening studies in Ohio and were found to have tumors with MMR deficiency (based on microsatellite instability and/or absence of MMR proteins in immunohistochemical analysis, without hypermethylation of MLH1), but no germline mutations in MMR genes. Tumor DNA was sequenced for MLH1, MSH2, MSH6, PMS2, EPCAM, POLE, and POLD1 with ColoSeq and mutation frequencies were established. RESULTS Twenty-two of 32 patients (69%) were found to have 2 somatic (tumor) mutations in MMR genes encoding proteins that were lost from tumor samples, based on immunohistochemistry. Of the 10 remaining tumors 3 had one somatic mutation in a MMR gene, with possible loss of heterozygosity that could lead to MMR deficiency, 6 were found to be false-positive results (19%), and 1 had only one mutation in a MMR gene and remained unexplained. All of the tumors found to have somatic MMR mutations were of the hypermutated phenotype (>12 mutations/megabase); 6 had mutation frequencies >200/megabase, and 5 of these had somatic mutations in POLE, which encodes a DNA polymerase. CONCLUSIONS Some patients are found to have tumors with MMR defects during screening for Lynch syndrome, yet have no identifiable germline mutations in MMR genes. We found that almost 70% of these patients acquire somatic mutations in MMR genes, leading to a hypermutated phenotype of tumor cells. Patients with colon or endometrial cancers with MMR deficiency not explained by germline mutations might undergo analysis for tumor mutations in MMR genes to guide future surveillance guidelines.

Prostate cancer incidence in males with Lynch syndrome

Purpose:An increased risk of prostate cancer is currently not considered a part of the Lynch syndrome spectrum. The purpose of this study was to retrospectively examine prostate cancer incidence in the Lynch syndrome cohort at the Ohio State University in comparison with that in the general population.Methods:We included all males diagnosed with Lynch syndrome from June 1998 to June 2012 at the Ohio State University and obtained baseline information including cancer history. If patients had not been seen in the 12 months before June 2012, they were contacted to document changes in their cancer history. We compared prostate cancer incidence among the Lynch syndrome families with that of the general population by using the Surveillance, Epidemiology, and End Results registry 1999–2009.Results:Of the 188 males identified with Lynch syndrome, 11 males were diagnosed with prostate cancer during the study period. The ratio of observed to expected numbers of prostate cancer cases resulted in a standardized rate ratio of 4.87 (95% confidence interval: 2.43–8.71). Impaired mismatch repair expression and microsatellite instability were seen in one out of two prostate cancer specimens available for testing.Conclusion:Males with Lynch syndrome had a nearly fivefold increased risk of developing prostate cancer but did not appear to have earlier onset or a more aggressive phenotype.Genet Med 16 7, 553–557.

Diagnostic accuracy of 64-slice multidetector CT for detection of in-stent restenosis in an unselected, consecutive patient population

OBJECTIVES To investigate the diagnostic accuracy of 64-slice multidetector computed tomography (64-CT) for detection of in-stent restenosis (ISR) in an unselected, consecutive patient population. BACKGROUND Detection of in-stent restenosis by cardiac CT would be a major advance for the evaluation of patients suspected of having ISR. However, the diagnostic accuracy of current generation 64-CT in this context is not fully established. METHODS We conducted a prospective study on patients with stable angina or acute coronary syndrome with no prior history of coronary artery disease. Six months after percutaneous coronary intervention (PCI) with stent placement they underwent a 64-CT scan (Toshiba Multi-Slice Aquilion 64) and consequently a repeat coronary angiography for comparison. Cardiac CT data sets were analyzed for the presence of in-stent restenosis by two independent expert readers blinded to the coronary angiographic data. RESULTS Ninety-three patients with a total of 140 stents were evaluated. Males comprised 82% of the study group and the mean age was 63±10 years. The mean time from PCI to the repeat coronary angiography was 208±37 days and the mean time from 64-CT to repeat coronary angiography was 3.7±4.9 days. The restenosis rate according to coronary angiography was 26%. Stent diameter, strut thickness, heart rate and body mass index (BMI) significantly affected image quality. The sensitivity, specificity, positive and negative predictive values of 64-CT for detection of in-stent restenosis were 27%, 95%, 67% and 78%, respectively. CONCLUSIONS Current generation, 64-slice CT, remains limited in its ability to accurately detect in-stent restenosis.

An update on clinical trials of targeted therapies in thyroid cancer.

Purpose of review Several new targeted therapies with multikinase inhibitors targeting vascular endothelial growth factor (VEGF), rearranged during transfection and v-raf murine sarcoma viral oncogene homolog B1 pathways have been tested in clinical trials for radioiodine-refractory differentiated thyroid cancer (DTC) and medullary thyroid cancer (MTC) in the past 10 years. Recent findings Results of the first phase III trial of VEGF-targeted therapy (sorafenib) in DTC were presented in June 2013, and two phase III trials with VEGF and rearranged during transfection-targeted therapies (vandetanib and cabozantinib) in MTC have led to approval by US Food and Drug Administration in the past 2 years. Whereas such therapies increase median progression-free survival compared to placebo, there is no therapy proven to improve overall survival yet. Significant potential adverse event risks associated with such therapies need to be recognized. Dissemination of knowledge about targeted therapies is critical for various medical specialists as patient care for thyroid cancers is best delivered in a multidisciplinary setting. Summary Successful development of targeted systemic therapies in DTC and MTC in the past 5 years is incredibly exciting in the field and patients with advanced DTC/MTC now have new standard-of-care therapy options.

Effects of tenuiorin and methyl orsellinate from the lichen Peltigera leucophlebia on 5-/15-lipoxygenases and proliferation of malignant cell lines in vitro

The orcinol derivatives tenuiorin (1) and methyl orsellinate (2) were identified as active components of an extract from the lichen Peltigera leucophlebia (Nyl.) Gyeln. showing in vitro inhibitory activity against 15-lipoxygenase from soybeans. The compounds were subsequently tested for in vitro activity against 5-lipoxygenase from porcine leucocytes and proved to be moderately active, with IC50 values of 41.6 microM and 59.6 microM respectively. Tenuiorin is a known constituent of several Peltigera species but has not previously been isolated from P. leucophlebia. As correlation between 5-lipoxygenase inhibition and antiproliferative effects has earlier been witnessed for related lichen metabolites, tenuiorin and methyl orsellinate were further tested for antiproliferative activity on cultured human breast (T-47D)-, pancreatic (PANC-1)- and colon (WIDR) cancer cell lines. The monomeric methyl orsellinate exhibited no detectable antiproliferative activity whereas the trimeric tenuiorin caused moderate/weak reduction in [3H]-thymidine uptake of the pancreatic- and colon cancer cells, with ED50 values of 87.9 and 98.3 microM respectively.

Integrating anti-EGFR therapies in metastatic colorectal cancer.

Colorectal cancer remains one of the most common causes of cancer diagnoses and mortality in the United States. The treatment of metastatic colorectal cancer has evolved significantly over the last decade with near-tripling of patient survival rate. A significant contribution to this outcome was the advent of novel targeted agents, such as the epidermal growth factor (EGFR) inhibitors. In an era of emphasis on refining therapy, the presence of KRAS mutation will predict for resistance and limit exposure to patients who are more likely to benefit. In contrast, the presence of BRAF mutations does not seem to have a predictive value. Agents that are thought to reverse resistance to EGFR inhibitors such as those targeting PI3K, c-MET or IGF-1R are currently under study. EGFR inhibitors have exhibited single agent activity, and seem to synergize very well with standard chemotherapy except for cetuximab and 5-fluorouracil, leucovorin, oxaliplatin (FOLFOX). Preliminary data suggests that EGFR inhibitors have similar effectiveness to vascular endothelial growth factor (VEGF) inhibitors in the first line setting. Skin toxicity remains the main limiting factor for the utilization of EGFR inhibitors, but strategies including the use of agents such as minocycline or doxycycline added to topical care seem to limit the severity of the rash.

Comprehensive population-wide analysis of Lynch syndrome in Iceland reveals founder mutations in MSH6 and PMS2

Lynch syndrome, caused by germline mutations in the mismatch repair genes, is associated with increased cancer risk. Here using a large whole-genome sequencing data bank, cancer registry and colorectal tumour bank we determine the prevalence of Lynch syndrome, associated cancer risks and pathogenicity of several variants in the Icelandic population. We use colorectal cancer samples from 1,182 patients diagnosed between 2000–2009. One-hundred and thirty-two (11.2%) tumours are mismatch repair deficient per immunohistochemistry. Twenty-one (1.8%) have Lynch syndrome while 106 (9.0%) have somatic hypermethylation or mutations in the mismatch repair genes. The population prevalence of Lynch syndrome is 0.442%. We discover a translocation disrupting MLH1 and three mutations in MSH6 and PMS2 that increase endometrial, colorectal, brain and ovarian cancer risk. We find thirteen mismatch repair variants of uncertain significance that are not associated with cancer risk. We find that founder mutations in MSH6 and PMS2 prevail in Iceland unlike most other populations.

What is the optimal neo-adjuvant treatment for liver metastasis?

Colorectal cancer is the third most common cancer in the Western population and has a 5-year overall survival of 5–10% when metastatic. Approximately 30% of the patients with metastatic colorectal cancer have limited disease apparently isolated to the liver and, if this can be resected, the 5-year overall survival is improved to 30–60%. Therefore, it is important to identify patients who have both resectable disease and those with initially unresectable tumors who can potentially be downsized with chemotherapy to allow resection. First-line doublet chemotherapy regimens lead to response rates of 50–60%, triplet chemotherapy regimens may result in a response rate of up to 70%, and biological agents may add to responses or induce morphologic changes that facilitate disease resection. Surgical advances in recent years have also increased resectability rates and have challenged prior rules of resectability. Local therapies including ablation and radiation, often performed in conjunction with resection, may further aid in control of disease. The aim of this article is to focus on the role of neoadjuvant therapy in the treatment of colorectal liver metastases.

Patients with colorectal cancer associated with Lynch syndrome and MLH1 promoter hypermethylation have similar prognoses

Purpose:Mismatch repair–deficient (dMMR) colorectal cancer (CRC) is caused by Lynch syndrome (LS) in 3% and sporadic inactivation of MLH1 by hypermethylation (MLH1-hm) in 12% of cases. It is not clear whether outcomes between LS-associated and MLH1-hm CRC differ. The objective of this study was to explore differences in clinical factors and outcomes in these two groups.Methods:Patients with dMMR CRC identified by immunohistochemistry staining and treated at a single institution from 1998 to 2012 were included. MLH1-hm was established with BRAF mutational analysis or hypermethylation testing. Patients’ charts were accessed for information on pathology, germ-line MMR mutation testing, and clinical course.Results:A total of 143 patients had CRC associated with LS (37 patients, 26%) or MLH1-hm (106 patients, 74%). Patients with LS were younger, more often male, presented more often with stage III disease, and had more metachronous disease than patients with MLH1-hm tumors. There was no difference in cancer-specific survival (CSS) between the groups; overall survival was longer in patients with LS, but this difference was minimal after adjusting for age and stage at diagnosis.Conclusion:CSS did not differ in LS-associated CRC compared with MLH1-hm CRC, suggesting that they carry a similar prognosis.Genet Med 18 9, 863–868.

New era for treatment in differentiated thyroid cancer

Multikinase inhibitors were introduced into clinical trials for radioactive iodine-refractory diff erentiated thyroid cancer a decade ago. In The Lancet, Marcia Brose and colleagues report the results of DECISION, the fi rst phase 3 randomised, double-blind, placebo-controlled clinical trial with the multikinase inhibitor sorafenib in diff erentiated thyroid cancer. On the basis of this landmark trial, sorafenib received an orphan designation by the European Medicine Agency in diff erentiated thyroid cancer, and was approved by the US Food and Drug Administration (FDA) for treatment of radioactive iodine-refractory diff erentiated thyroid cancer in November, 2013. Sorafenib is only the fourth drug to be approved by the FDA for treatment of thyroid cancer. Several decades after doxorubicin was introduced for this indication in 1974, vandetanib (2011) and cabozantinib (2012) were approved for medullary thyroid cancer. It is now an exciting time for the specialty as strong collaborative research initiated by academia, industry, and governmental agencies has revolutionised treatment for thyroid cancer. Thyroid cancer has one of the fastest growing incidences of any cancer in high-income countries. Diff erentiated thyroid cancer accounts for about 90% of all thyroid cancers and includes papillary, follicular, poorly diff erentiated, and Hürthle cell histologies. Although the disease generally has a good prognosis, patients who develop metastatic radioactive iodine-refractory diff erentiated thyroid cancer have an overall survival of only 10–20% at 10 years. Cytotoxic chemotherapy including doxorubicin has yielded disappointing results. In 2003, discovery of oncogenic BRAF mutations in papillary thyroid cancer, with a frequency of approximately 45%, opened a new pathway for drug development. Sorafenib, a serine-threonine kinase inhibitor, designed to target BRAF and subsequently found to have several targets including RET and vascular endothelial growth factor receptor, was being tested at the time in early-phase clinical trials for various cancers. For our phase 2 clinical trial, the preliminary results showing anticancer activity of sorafenib in diff erentiated thyroid cancer were presented in August, 2005 and were received enthusiastically. Three additional prospective phase 2 trials of sorafenib showed encouraging effi cacy in diff erentiated thyroid cancer (table). Furthermore, several other multikinase inhibitors that target angiogenesis—eg, sunitinib, pazopanib, and lenvatinib—showed promising results in phase 2 trials in diff erentiated thyroid cancer. Consequently, placebo-controlled phase 3 trials of sorafenib and lenvatinib in diff erentiated thyroid cancer were initiated. Brose and colleagues’ trial is the fi rst to report results and is a crucial milestone in the development of targeted therapies in this disease. Brose and her team should be commended for undertaking their phase 3 trial of sorafenib that enrolled 417 patients (60% of whom were from Europe, 23% from Asia, and 17% from the USA) in less than 2 years. The accrual rate to this study is noteworthy because of the availability of sorafenib for off -label use for thyroid cancer in the USA during this period, the placebo-controlled nature of the trial, and the rigorous eligibility criteria used to identify patients with progressive forms of diff erentiated thyroid cancer. Overall survival is a primary endpoint for many phase 3 cancer trials, but in diff erentiated thyroid cancer even progression-free survival is a challenging endpoint because of the slow-growing nature of the cancer and the absence of well-established parameters to select patients with aggressive clinical course. Brose and colleagues’ fi ndings show a signifi cant increase in the trial’s primary endpoint, median progression-free survival, in the sorafenib group compared with the placebo group (10·8 vs 5·8 months, hazard ratio [HR] 0·59 [95% CI 0·45–0·76]) and a modest partial response in the sorafenib group (12%) compared with the placebo group (0·5%). However, overall survival did not diff er between the groups (HR 0·80, 95% CI 0·54–1·19). Since 71% of patients in the placebo group crossed over to open-label sorafenib upon disease progression, absence of a benefi t in overall survival is not surprising. The reported adverse events are similar to known safety data for sorafenib. Adverse events led to dose reductions in 64% and withdrawal from the study in 19% of patients. Although Brose and colleagues did not report rare serious adverse events (<2%) or all-grade adverse events occurring at a frequency below 10%, clinicians should be aware of the class eff ects of vascular endothelial growth factor receptor-targeted multikinase inhibitors, including Published Online April 24, 2014 http://dx.doi.org/10.1016/ S0140-6736(14)60663-2