Dr. Sigurdis Haraldsdottir, M.D., Ph.D. is an Assistant Professor of Medicine at Stanford University School of Medicine. She received her medical degree and master's degree in medical sciences from the University of Iceland. She did her Internal Medicine training at Boston University Medical Center and training in Medical Oncology at the Ohio State University, before joining the faculty at Stanford. Her clinical and research focus is in gastrointestinal malignancies with a focus on mismatch repair deficient cancers, particularly colorectal cancer. She is conducting population-based research on Lynch syndrome - an inherited cancer syndrome, and recently completed a nation-wide study on Lynch syndrome in Iceland. She received her Ph.D. in Medical Sciences in 2017 from the University of Iceland. Her interests also focus on investigating colorectal cancer genomics, and their effect on outcomes and treatment implications.
Member, Stanford Cancer Institute
Honors & Awards
Pelotonia Fellowship Award, Ohio State University (1/2013)
Workshop in Cancer Therapeutics and Drug Development, Leesburg, Virginia, Merrill J. Egorin (11/2014)
Obrine Weaver Award, Ohio State University (3/2014)
Graduated Top of Class, University of Iceland, Faculty of Medicine (6/2004)
Outstanding Achievement Award in Internal Medicine Residency, Landspitali University Hospital, Reykjavik, Iceland (6/2008)
Cancer Education Consortium Molecular and Translational Oncology Workshop, Fort Myers, Florida (6/2013)
Outstanding Clinical Care by Hematology & Oncology Fellow Award, Ohio State University Medical Center (6/2013)
Outstanding Research, Hematology & Oncology Fellow Award at Ohio State University Medical Center (6/2014)
Achievement Award, Assocation of Female Physicians in Iceland (7/2004)
Travel Grant Recipient, 2014 Colon Cancer Challenge Foundation (7/2014)
Vail Workshop, 2014 ASCO/AACR (7/2014)
Combination Chemotherapy With or Without Atezolizumab in Treating Patients With Stage III Colon Cancer and Deficient DNA Mismatch Repair
This phase III trial studies combination chemotherapy and atezolizumab to see how well it works compared with combination chemotherapy alone in treating patients with stage III colon cancer and deficient deoxyribonucleic acid (DNA) mismatch repair. Drugs used in combination chemotherapy, such as oxaliplatin, leucovorin calcium, and fluorouracil, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Immunotherapy with monoclonal antibodies, such as atezolizumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Giving combination chemotherapy with atezolizumab may work better than combination chemotherapy alone in treating patients with colon cancer.
Stanford is currently not accepting patients for this trial. For more information, please contact Sigurdis Haraldsdottir, 650-498-7061.
Irinotecan Hydrochloride and Cetuximab With or Without Ramucirumab in Treating Patients With Advanced Colorectal Cancer With Progressive Disease After Treatment With Bevacizumab-Containing Chemotherapy
RATIONALE: Drugs used in chemotherapy, such as irinotecan hydrochloride, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as cetuximab and ramucirumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Cetuximab and ramucirumab may also stop the growth of colorectal cancer by blocking blood flow to the tumor. It is not yet know whether giving cetuximab and irinotecan hydrochloride together is more effective with or without ramucirumab in treating colorectal cancer. PURPOSE: This randomized phase II trial is studying the side effects and how well giving cetuximab and irinotecan hydrochloride with or without ramucirumab work in treating patients with advanced colorectal cancer with progressive disease after treatment with bevacizumab-containing chemotherapy.
Stanford is currently not accepting patients for this trial. For more information, please contact Cancer Clinical Trials Office (CCTO), 650-498-7061.
Study of IDO Inhibitor in Combination With Gemcitabine and Nab-Paclitaxel in Patients With Metastatic Pancreatic Cancer
This phase I/II trial is designed to efficiently identify the regimen limiting toxicity (RLT) and recommended phase 2 dose (RP2D) for the combination of the immunotherapeutic agent indoximod when administered in combination with standard of care chemotherapy gemcitabine plus nab-paclitaxel in subjects with metastatic adenocarcinoma of the pancreas. All subjects will receive the same standard gemcitabine plus nab-paclitaxel regimen, plus indoximod in doses increasing from 600 mg twice daily to, potentially, 1200 mg twice daily.
Stanford is currently not accepting patients for this trial. For more information, please contact Melissa Worman, 650-725-0379.
Study of Pembrolizumab (MK-3475) vs Standard Therapy in Participants With Microsatellite Instability-High (MSI-H) or Mismatch Repair Deficient (dMMR) Stage IV Colorectal Carcinoma (MK-3475-177/KEYNOTE-177)
In this study, participants with stage IV Microsatellite Instability-High (MSI-H) or Mismatch Repair Deficient (dMMR) colorectal carcinoma (CRC) will be randomly assigned to receive either pembrolizumab or the Investigator's choice of 1 of 6 standard of care (SOC) chemotherapy regimens for the treatment of advanced colorectal carcinoma. The primary study hypothesis is that pembrolizumab will prolong progression-free survival (PFS) or overall survival (OS) compared to current SOC chemotherapy.
Stanford is currently not accepting patients for this trial. For more information, please contact Cancer Clinical Trials Office (CCTO), 650-498-7061.
Targeting BRAF Mutations in High-Grade Neuroendocrine Carcinoma of the Colon.
Journal of the National Comprehensive Cancer Network : JNCCN
2018; 16 (9): 1035–40
Mutations in the RAS/RAF/MEK/ERK pathway leading to constitutive activation and uncontrolled cellular growth have been identified in various human malignancies, making this pathway a target for potential therapeutics. The activating BRAFV600E mutation is one well-characterized oncogenic mutation that has been described and targeted with clinical success in various malignancies, including melanoma and hairy cell leukemia. Although BRAF-directed treatments have yielded clinical benefit in a subset of tumor types, such as melanoma, thyroid cancer, and lung cancer, BRAF inhibition fails to confer a clinical benefit in colon cancer. Identification of patients for whom BRAF inhibition may produce clinically meaningful outcomes is imperative. The incidence of BRAF mutations in neuroendocrine carcinoma (NEC) is estimated to be 5% to 10%. A recent case series demonstrated benefit in targeting the BRAFV600E mutation in metastatic high-grade rectal NECs. Combination BRAF and MEK inhibition is known to yield improved outcomes compared with BRAF inhibition alone in melanoma. This report presents 2 patients with high-grade colorectal NECs who had different responses to treatment with combined BRAF/MEK inhibition after experiencing disease progression through first-line platinum-based chemotherapy. One patient experienced an excellent initial response to therapy before ultimately experiencing progression, and in the other patient initially had stable disease before eventually experiencing progression. These cases highlight the complicated role BRAF mutations play in gastrointestinal NECs, and the need for further research to identify not only patients who may benefit from BRAF-directed therapies but also strategies to avoid development of resistance.
View details for PubMedID 30181415
Histology of colorectal adenocarcinoma with Check for double somatic mismatch-repair mutations is indistinguishable from those caused by Lynch syndrome
2018; 78: 125–30
Lynch syndrome (LS) is the most common form of hereditary colon cancer. Germline mutations in the mismatch-repair (MMR) genes MLH1, MSH2 (EPCAM), MSH6, and PMS2, followed by a second hit to the remaining allele, lead to cancer development. Universal tumor screening for LS is routinely performed on colon cancer, and screening has identified patients with unexplained MMR deficiency that lack MLH1 methylation and a germline mutation. Tumor sequencing has since identified double somatic (DS) mutations in the MMR gene corresponding with the absent protein in 69% of these patients. We assessed whether histomorphology could distinguish patients with DS mutations from those with LS. Colorectal cancer patients with DS mutations were identified from population-based cohorts from Iceland (2000-2009); Columbus, Ohio (1999-2005); and the state of Ohio (2013-2016). Next-generation sequencing was performed on tumors with unexplained MMR deficiency. Patients with LS from Ohio cohorts were the comparison group. The histologic features associated with MMR deficiency (tumor-infiltrating lymphocytes, Crohn-like reaction, histologic subtype, necrosis) were evaluated. We identified 43 tumors with DS mutations and 48 from patients with LS. There was no significant difference in histologic features between tumors in LS patients and tumors with DS mutations. Because histology of tumors with DS mutations is indistinguishable from those caused by LS, tumor sequencing for evaluation of DS mutations should be considered to help clarify sporadic versus hereditary causes of unexplained MMR deficiency.
View details for PubMedID 29723603
Promising New Agents for Colorectal Cancer
CURRENT TREATMENT OPTIONS IN ONCOLOGY
2018; 19 (6): 29
Choosing the optimal treatment approach for patients with metastatic colorectal cancer (mCRC) demands that oncologists assess both clinical and genomic variables and individualize care based upon the findings. Clinically, choices depend on assessing the side of the colon in which the primary tumor originates, the sites and burden of metastatic disease, the patient's performance status, and their individual comorbidities. Genomic assessment of the tumor to discern the mutational status of genes such as RAS/RAF, HER2, and TRK, as well as assessing whether tumors have defective mismatch repair (dMMR) or high microsatellite instability (MSI-H), all factor in to potential treatment options and can determine clinical trial eligibility. Metastasectomy may be an option for patients with a low burden of disease and accessible liver- or lung-limited metastases. In some unresectable cases, systemic therapy with a FOLFOX- or FOLFIRI-based regimen with or without a biologic agent can lead to sufficient disease reduction to make a patient eligible for resection of metastatic disease. Tumor sidedness and RAS mutational status guide which biologic we add to the initial chemotherapy backbone, with patients with left-sided, RAS wild-type (WT) tumors receiving anti-epidermal growth factor receptor (EGFR)-directed therapy and patients with right-sided tumors or those with RAS mutations receiving bevacizumab. In patients with tumors that manifest microsatellite instability or deficient mismatch repair, we typically administer checkpoint inhibitors such as pembrolizumab or nivolumab after progression on irinotecan- or oxaliplatin-based therapies. In patients with progressive disease, we routinely send tumor tissue for next generation sequencing (NGS) to assess for the presence of actionable genomic alterations such as HER2, BRAF, and TRK fusions and offer them the option of enrollment on clinical trials with agents targeting those or other identified alterations.
View details for PubMedID 29752549
Management of Borderline Resectable Pancreatic Cancer.
International journal of radiation oncology, biology, physics
2018; 100 (5): 1155–74
With the rapid development of imaging modalities and surgical techniques, the clinical entity representing tumors that are intermediate between resectable and unresectable pancreatic adenocarcinoma has been identified has been termed "borderline resectable" (BR). These tumors are generally amenable for resection but portend an increased risk for positive margins after surgery and commonly necessitate vascular resection and reconstruction. Although there is a lack of consensus regarding the appropriate definition of what constitutes a BR pancreatic tumor, it has been demonstrated that this intermediate category carries a particular prognosis that is in between resectable and unresectable disease. In order to downstage the tumor and increase the probability of clear surgical margins, neoadjuvant therapy is being increasingly utilized and studied. There is a lack of high-level evidence to establish the optimal treatment regimen for BR tumors. When resection with negative margins is achieved after neoadjuvant therapy, the prognosis for BR tumors approaches and even exceeds that for resectable disease. This review presents the current definitions, different treatment approaches, and the clinical outcomes of BR pancreatic cancer.
View details for PubMedID 29722658
The risk of developing a mismatch repair deficient colorectal cancer after undergoing cholecystectomy
SCANDINAVIAN JOURNAL OF GASTROENTEROLOGY
2018; 53 (8): 972–75
Mismatch repair deficient (dMMR) colorectal cancer (CRC) is caused by inactivation of the MMR DNA repair system, most commonly via epigenetic inactivation of the MLH1 gene, and these tumors occur most frequently in the right colon. The objective was to determine whether cholecystectomy (CCY) increases the risk of a dMMR CRC by comparing CCY incidence in patients with dMMR CRC and proficient MMR (pMMR) CRC to unaffected controls.All patients diagnosed with CRC in Iceland from 2000 to 2009 (n = 1171) were included. They had previously been screened for dMMR by immunohistochemistry (n = 129 were dMMR). Unaffected age- and sex-matched controls (n = 17,460) were obtained from large Icelandic cohort studies. Subjects were cross-referenced with all pathology databases in Iceland to establish who had undergone CCY. Odds ratios were calculated using unconditional logistic regression.Eighteen (13.7%) dMMR CRC cases and 90 (8.7%) pMMR CRC cases had undergone CCY compared to 1532 (8.8%) controls. CCY-related odds ratios (OR) were 1.06 (95% CI 0.90-1.26, p = .577) for all CRC, 1.16 (95% CI 0.66-2.05 p = .602) for dMMR CRCand 1.04 (95% CI 0.83-1.29, p = .744) for pMMR CRC. Furthermore, OR for dMMR CRC was 0.51 (95% CI 0.16-1.67, p = .266), 2.04 (95% CI 0.92-4.50, p = .080) and 1.08 (95% CI 0.40-2.89, p = .875) <10 years, 10-20 years and >20 years after a CCY, respectively.There was no evidence of increased risk of developing dMMR CRC after CCY although a borderline significantly increased 2-fold risk was observed 10-20 years after CCY. Larger studies are warranted to examine this further.
View details for PubMedID 30010450
Tumor Molecular Testing Guides Anti-PD-1 Therapy and Provides Evidence for Pathogenicity of Mismatch Repair Variants.
Lynch syndrome is characterized by germline abnormalities in mismatch repair (MMR) genes, leading to predisposition to multiple cancers . A second hit to the unaffected allele is required for tumorigenesis. MMR proteins repair incorrectly paired nucleotides and prevent generation of insertions and deletions at microsatellites . Aberrancies in these MMR proteins can be a result of germline mutations or somatic alterations. Defective MMR results in microsatellite instability (MSI) and a high mutational burden .The clinical implications of MSI are becoming readily apparent, as presence of MSI leads to the generation of neoantigens, stimulating tumor-associated lymphocytes [4,5]. This has led to the use of programmed cell death protein 1 blockade for MMR-deficient tumors . The U.S. Food and Drug Administration recently approved pembrolizumab for any advanced solid tumor demonstrating MSI and nivolumab for metastatic MSI colorectal cancer. However, the clinical significance of numerous MMR gene variants remains uncertain. The International Society for Gastrointestinal Hereditary Tumors classification system categorizes 2,360 MMR variants, which can be used to gauge pathogenicity . There are many variants of uncertain significance (VUS; or class 3) for which clinicians are unable to provide recommendations. In this study, we employed the combination of germline testing and tumor mutational assessment to help discern the clinical relevance of VUS and guide immunotherapeutic decisions.A clinical dilemma arises when genomic testing yields variants of uncertain significance (VUS).Germline VUS were identified in two patients with gastrointestinal malignancies, but only one patient had a second-hit mutation in a mismatch repair gene leading to mismatch repair deficiency that conferred response to immunotherapy.The combination of germline testing along with tumor mutational assessment can help discern the clinical relevance of VUS and can help guide therapeutic decision-making toward individualized patient care.
View details for PubMedID 30072391
- Conversion Therapy for Initially Borderline/Unresectable Metastases in Colon Cancer: What Is the Best Neoadjuvant Chemotherapy? CURRENT COLORECTAL CANCER REPORTS 2017; 13 (6): 419–28
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.
View details for DOI 10.1038/ncomms14755
View details for Web of Science ID 000400488000001
View details for PubMedID 28466842
Frequent PIK3CA Mutations in Colorectal and Endometrial Tumors With 2 or More Somatic Mutations in Mismatch Repair Genes.
2016; 151 (3): 440-447 e1
Some colorectal and endometrial tumors with microsatellite instability not attributable to MLH1 hypermethylation or germline mutations contain 2 or more somatic mutations in genes encoding mismatch repair (MMR) proteins. We sought to define the molecular phenotype of this newly recognized tumor subtype.From 2 prospective studies of the efficacy of screening for Lynch syndrome, we identified patients with colorectal and endometrial tumors who had 2 or more somatic (but not germline) mutations in genes encoding MMR proteins (double somatic). We determined the frequencies of tumor mutations in PIK3CA, BRAF, KRAS, NRAS, and PTEN by targeted next-generation sequencing and used logistic-regression models to compare them with those from patients with Lynch syndrome, MLH1-hypermethylated, or microsatellite-stable tumors. We validated our findings using independent datasets from The Cancer Genome Atlas.Among colorectal cancer cases, we found that 14/21 (67%) of patients with double somatic tumors also had PIK3CA mutations, compared to 4/18 (22%) of tumors from patients with Lynch syndrome, 2/10 (20%) tumors with MLH1 hypermethylation, and 12/78 (15%) tumors with microsatellite stability (P<.0001 for patients with double somatic tumors vs other subgroups). Mutations in PIK3CA were detected in all 13 patients with double somatic endometrial cancers (P=.04 compared to other subgroups). We did not detect BRAF mutations in patients with double somatic colorectal tumors or Lynch syndrome. We found highly similar results in a validation cohort from The Cancer Genome Atlas (113 patients with colorectal tumors, 178 endometrial tumors); 100% of double somatic cases carried a somatic mutation in PIK3CA (P<.0001 compared with other subgroups).Most patients with colorectal or endometrial tumors with 2 or more somatic (but not germline) mutations in MMR proteins also have mutations in PIK3CA; mutations in PIK3CA are detected at substantially higher frequencies in these double somatic tumors than in than other microsatellite instability subgroups. PIK3CA mutation status might be used to identify a specific group of colorectal tumors, and to select treatment or determine prognosis.
View details for DOI 10.1053/j.gastro.2016.06.004
View details for PubMedID 27302833
Patients with colorectal cancer associated with Lynch syndrome and MLH1 promoter hypermethylation have similar prognoses.
Genetics in medicine
2016; 18 (9): 863-868
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.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.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.CSS did not differ in LS-associated CRC compared with MLH1-hm CRC, suggesting that they carry a similar prognosis.Genet Med advance online publication 11 February 2016Genetics in Medicine (2016); doi:10.1038/gim.2015.184.
View details for DOI 10.1038/gim.2015.184
View details for PubMedID 26866578
Discordant Mismatch Repair Protein Immunoreactivity in Lynch Syndrome-Associated Neoplasms: ?A Recommendation for Screening Synchronous/Metachronous Neoplasms.
American journal of clinical pathology
2016; 146 (1): 50-56
Lynch syndrome (LS) predisposes individuals to developing synchronous and metachronous LS-associated neoplasms (LSANs). Mismatch repair protein (MMRP) immunohistochemistry (IHC) is widely used to identify LS, but its utility in patients with synchronous/metachronous lesions has not been studied. We studied MMRP IHC in patients with LS with more than one LSAN to provide screening recommendations in patients with synchronous/metachronous neoplasms.All patients with LS diagnosed at The Ohio State University Wexner Medical Center from 2009 through 2014 with more than one LSAN and available tumor tissue for immunostaining were identified. Tumors were stained for MLH1, MSH2, MSH6, and PMS-2 proteins, and immunoreactivity was scored as intact or lost.Thirteen patients with LS with 29 synchronous and/or metachronous primary LSANs were identified. Neoplasms involved large and small intestine (n = 19), ampulla (n = 1), endometrium (n = 1), and skin (sebaceous neoplasms, n = 8). Nine (69%) of 13 patients showed concordant MMRP results in all tumors, and four (31%) showed discordant MMRP results.LS diagnosis could have been missed in 31% of the study cases if only the LSAN exhibiting intact MMRP expression was screened. Accordingly, our findings support the recommendation to perform LS screening in all primary, synchronous, and metachronous intestinal and endometrial cancers if a previous tumor screened intact.
View details for DOI 10.1093/ajcp/aqw067
View details for PubMedID 27357288
- Radiation Recall Dermatitis With Concomitant Dabrafenib and Pazopanib Therapy. JAMA dermatology 2016; 152 (5): 587-9
Mismatch repair deficiency concordance between primary colorectal cancer and corresponding metastasis.
2016; 15 (2): 253-260
Universal screening for mismatch repair deficiency (dMMR) in cancer is increasingly being implemented to detect Lynch syndrome and aid in treatment decisions. The mismatch repair (MMR) immunohistochemistry (IHC) concordance rate between primary colorectal cancer (CRC) and metastasis is unknown. At times, only metastatic tumor is available for screening (lymph node, liver, lung etc.) rather than the primary tumor. Therefore, it is important to confirm that tissue from metastases can be used for screening for dMMR. We tested dMMR primary and metastatic tumor to assess concordance between the two. We identified dMMR CRC resected at Ohio State University from 1999 to 2013 and stained a corresponding metastasis for all four MMR proteins (MLH1, MSH2, MSH6, PMS2) with IHC. A total of 50 primary CRC with dMMR and available regional lymph nodes (LN; 26 cases) or other metastatic tissue (24 cases) were identified. Thirteen cases were explained by MLH1 hypermethylation and 10 cases had Lynch syndrome. Two cases had somatic MMR mutations and the etiology for dMMR was unknown in 25 cases. All cases showed concordance in IHC staining between the primary tumor and corresponding metastatic tissue. In 36 cases, metastatic LN/other site was resected at the same time as the primary tumor. In 14 cases, time lapsed [median 16.5 months; quartile (Q)1 8.0; Q3 25; range 3-69] from the primary resection until metastatic resection. Metastatic tissue can be used to screen for Lynch syndrome and dMMR.
View details for DOI 10.1007/s10689-015-9856-2
View details for PubMedID 26666765
How Can Next-Generation Sequencing (Genomics) Help Us in Treating Colorectal Cancer?
Current colorectal cancer reports
2014; 10 (4): 372-379
Next generation sequencing methods have exponentially increased the amount of genomic information available to scientists and clinicians. This review will explain the evolution of tumor gene sequencing and identify its potential to accelerate therapeutic progress by using colorectal cancer to illustrate the benefits of this type of analysis. A milestone in sequencing occurred when The Cancer Genome Atlas investigators characterized the genomes of 276 colorectal cancer samples, with the resulting information expected to provide future clinical applications and help to guide the treatment of colorectal cancer. Data regarding colorectal cancer mutational frequencies, prognostic and predictive biomarker usefulness, and signaling pathway alterations are emerging from various next generation sequencing platforms. Next generation sequencing methods are also enhancing our understanding of the causes and consequences of both the chromosomal instability and microsatellite instability pathways, as well as expanding our knowledge of the origins of familial colorectal cancer. Limitations to next generation sequencing methods include the need for storage and analysis of massive quantities of data, as well as assurance that the data is of the highest possible quality. However, this genomic technology carries with it the potential to revolutionize our treatment of colorectal cancer patients through better understanding of the underlying disease biology and subsequent development and application of therapeutic approaches targeting the genetic abnormalities specific to individual malignancies.
View details for DOI 10.1007/s11888-014-0244-3
View details for PubMedID 25395895
View details for PubMedCentralID PMC4226466
Colon and Endometrial Cancers With Mismatch Repair Deficiency Can Arise From Somatic, Rather Than Germline, Mutations
2014; 147 (6): 1308-?
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.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.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.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.
View details for DOI 10.1053/j.gastro.2014.08.041
View details for Web of Science ID 000345524800028
View details for PubMedID 25194673
- New era for treatment in differentiated thyroid cancer LANCET 2014; 384 (9940): 286-288
Prostate cancer incidence in males with Lynch syndrome
GENETICS IN MEDICINE
2014; 16 (7): 553-557
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.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.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.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.
View details for DOI 10.1038/gim.2013.193
View details for Web of Science ID 000338601400010
View details for PubMedID 24434690
An update on clinical trials of targeted therapies in thyroid cancer
CURRENT OPINION IN ONCOLOGY
2014; 26 (1): 36-44
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.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.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.
View details for DOI 10.1097/CCO.0000000000000029
View details for Web of Science ID 000327996500006
View details for PubMedID 24240178
- Adjuvant Chemotherapy Should Not Routinely Be Recommended to Patients with Stage II Colon Cancers that Manifest Microsatellite Instability. GI ASCO Educational Book 2014
Integrating anti-EGFR therapies in metastatic colorectal cancer.
Journal of gastrointestinal oncology
2013; 4 (3): 285-298
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.
View details for DOI 10.3978/j.issn.2078-6891.2013.028
View details for PubMedID 23997940
What is the optimal neo-adjuvant treatment for liver metastasis?
THERAPEUTIC ADVANCES IN MEDICAL ONCOLOGY
2013; 5 (4): 221-234
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.
View details for DOI 10.1177/1758834013485111
View details for Web of Science ID 000339342700002
View details for PubMedID 23858331
- Case of Sorafenib-Induced Thyroid Storm JOURNAL OF CLINICAL ONCOLOGY 2013; 31 (16): E262-E264
Advances in systemic therapy for advanced pancreatobiliary malignancies.
2013; 2: 105-?
Pancreatobiliary malignancies are relatively uncommon and the overall prognosis is poor. Treatment options for advanced disease are limited to systemic therapy for metastatic disease and a combination of systemic therapy and radiation therapy for locally advanced but unresectable tumors. There have been significant advances in the treatment of pancreatobiliary cancers in recent years but the prognosis for patient survival remains disappointingly poor. We review the current treatment options for locally advanced pancreatobiliary malignancies and highlight recent advances in systemic therapy, including novel approaches using targeted treatments.
View details for DOI 10.12688/f1000research.2-105.v1
View details for PubMedID 24358840
- Cancer of the Colon and Rectum: A Decade of Progress GI ASCO Educational Book 2013
- Clinical Indications for ziv-Aflibercept in Colorectal Cancer. International Journal of Targeted Therapies in Cancer 2013
- Recent advances in treatment of metastatic colorectal cancer. Clinical Investigation 2012
- A single institutional experience with panitumumab in metastatic colorectal cancer Journal of Cancer Therapy 2012
Diagnostic accuracy of 64-slice multidetector CT for detection of in-stent restenosis in an unselected, consecutive patient population
EUROPEAN JOURNAL OF RADIOLOGY
2010; 76 (2): 188-194
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.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.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.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.Current generation, 64-slice CT, remains limited in its ability to accurately detect in-stent restenosis.
View details for DOI 10.1016/j.ejrad.2009.05.030
View details for Web of Science ID 000283838200015
View details for PubMedID 19570632
Clinical evaluation and stress test have limited value in the diagnosis of in-stent restenosis
SCANDINAVIAN CARDIOVASCULAR JOURNAL
2009; 43 (6): 402-407
In-stent restenosis (ISR) is the main limitation of percutaneous coronary interventions (PCI), occurring in approximately 25% of cases. Although frequently asymptomatic, many PCI patients present with recurrent symptoms of chest pain at follow-up raising a clinical suspicion of ISR. The diagnosis of ISR can be challenging in these patients and difficult to rule out without repeat coronary angiography.We prospectively investigated the diagnostic accuracy of clinical evaluation and exercise stress testing to detect ISR as compared to coronary angiography, in a consecutive, unselected cohort of PCI patients.We studied 91 patients with a total of 143 stents. Clinical evaluation predicted ISR to be likely in 19% of cases and the exercise test was positive in 29%. The binary restenosis rate was 21%. Clinical evaluation had a positive predictive value of 29% and accuracy of 71%, while exercise stress testing had a positive predictive value of 19% and accuracy of 65%.In conclusion, we found the diagnostic accuracy of clinical evaluation to be low and not significantly improved by exercise stress testing when evaluating PCI patients for ISR.
View details for DOI 10.3109/14017430902926873
View details for Web of Science ID 000272974500008
View details for PubMedID 19412835
Diagnostic accuracy of 64-slice computed tomography compared with coronary angiography
2008; 94 (3): 199-205
The aim of this study was to evaluate the diagnostic accuracy (sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV)) of 64-slice multidetector computed tomography (MDCT) compared with quantitative coronary angiography (QCA) for detection of coronary artery disease (CAD).Sixty-nine patients participating in a study of coronary in-stent restenosis were investigated. After a 64-slice MDCT scan patients were evaluated by QCA. The coronary arteries were divided into 15 segments and stenosis was graded for each segment by both methods. The diagnostic accuracy of 64-slice MDCT was evaluated using the QCA as the gold standard.Among the 69 patients included in the study 13 (19%) were female and 56 male. The mean age was 63 (SD 10) years. The following risk factors were present: high blood pressure 67%, elevated blood cholesterol 54%, diabetes 12% and family history of CAD 71%. Current smokers were 22% and previous smokers were 48%. Altogether 663 segments were examined. Of those 221 (33%) segments were excluded; 103 because of stents, 48 because of heavy calcification, 41 because of motion artifacts and 29 because the segments were less than 1.5 mm in diameter. The mean time between MDCT and QCA was 6.3 (SD 12.1) days. The sensitivity of 64-slice MDCT for diagnosing significant stenosis (>or= 50% according to QCA) was 20%, the specificity was 94%, PPV was 16%, NPV was 95% and the accuracy was 89%.High NPV and specificity indicates that MDCT is useful for accurately excluding significant CAD but the low sensitivity and low PPV indicate that the method is not accurate in diagnosing coronary artery stenosis of 50% or more according to QCA.
View details for Web of Science ID 000257865200003
View details for PubMedID 18310782
Anti-proliferative effects of lichen-derived lipoxygenase inhibitors on twelve human cancer cell lines of different tissue origin in vitro
2004; 70 (11): 1098-1100
Lipoxygenases (LOXs) have been implicated in carcinogenesis in various cancer types. In the current study, three structurally different lichen metabolites, protolichesterinic acid (1), lobaric acid (2) and baeomycesic acid (3) were tested for anti-proliferative effects against 12 different human cancer cell lines. All compounds have known in vitro 5-LOX inhibitory activity, and 1 and 2 also inhibit 12-LOX. The activity of the lichen metabolites was compared to that of a specific 5-LOX inhibitor, zileuton (4). The following cancer cell lines were tested: Capan-1, Capan-2 and PANC-1 (all from pancreas), T47-D (breast), PC-3 (prostate), NCI-H1417 (small cell lung), NIH:OVCAR-3 (ovary), AGS (stomach), WiDr (colorectal), HL-60, K-562 and JURKAT (acute promyelocytic, erythro- and T-cell leukemia, respectively). Compound 1 showed the greatest inhibitory effect against all cell lines, with EC50 ranging from 2.4-18.1 microg mL(-1) (7.4-55.8 microM), followed by 2, with EC50 of 15.2 - 65.5 microg mL(-1) (33.2-143.6 microM). The effects of 3 and 4 were of similar orders of magnitude, with EC50 of 28.7 - >80 microg mL(-1) (76.8 - > 213.9 microM) and 12.9 - > 80 microg mL(-1) (50.4 - > 313.7 microM). The dual 5- and 12-LOX inhibitors 1 and to some extent 2 thus exert significant anti-proliferative effects against a variety of human cancer cell lines, while the selective 5-LOX inhibitors 3 and 4 are considerably less active.
View details for DOI 10.1055/s-2004-832657
View details for Web of Science ID 000225506000019
View details for PubMedID 15549672
Effects of tenuiorin and methyl orsellinate from the lichen Peltigera leucophlebia on 5-/15-lipoxygenases and proliferation of malignant cell lines in vitro
2002; 9 (7): 654-658
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.
View details for Web of Science ID 000179891300011
View details for PubMedID 12487331