Publications by authors named "Sigurdis Haraldsdottir"

38 Publications

Mismatch Repair (MMR) Gene Alteration and BRAF V600E Mutation Are Potential Predictive Biomarkers of Immune Checkpoint Inhibitors in MMR-Deficient Colorectal Cancer.

Oncologist 2021 Feb 25. Epub 2021 Feb 25.

Emory University School of Medicine, Winship Cancer Institute, Atlanta, Georgia, USA.

Background: Immune checkpoint inhibitor (ICI) therapy is highly effective in metastatic mismatch repair-deficient (MMR-D) colorectal cancer (CRC). In this study, we evaluated molecular and clinical predictors of ICI response in MMR-D CRC.

Materials And Methods: Patient databases at four cancer institutions were queried. The Fisher exact test was performed to test the association of clinical and molecular markers. The Kaplan-Meier method was used to estimate progression-free survival (PFS) and compared by the log-rank test. Twelve- and 24-month PFS rates were compared by the Z test.

Results: A total of 60 patients with CRC with MMR-D/microsatellite instability-high who previously received ICIs were identified. Patients with liver metastasis had a lower overall response rate as compared with other sites of metastasis (36.4% vs. 68.7%; p = .081). Patients with MLH1/PMS2 loss had worse 1-year and 2-year PFS rates compared with patients with MSH2/MSH6 loss (84.2% vs. 57.8% and 78.2% vs. 54.2%, respectively; p < .001). There were improved 1-year and 2-year PFS rates in patients with wild-type BRAF when compared with patients with BRAF V600E mutation (73.3% vs. 40%, and 73.3% vs. 26.7%; respectively; p < .001). Patients aged >65 had significantly worse PFS rates as compared with patients aged ≤65 (p < .001).

Conclusion: BRAF V600E mutation, MLH1 and/or PMS2 loss, as well as age >65 years and liver metastasis, may be predictive of duration of ICI response in patients with MMR-D CRC. Larger cohorts are needed to confirm our findings.

Implications For Practice: The results of this study reveal clinically important biomarkers that potentially predict immune checkpoint inhibitor response in patients with mismatch repair-deficient colorectal cancer.
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http://dx.doi.org/10.1002/onco.13741DOI Listing
February 2021

Implementing Systematic Genetic Counseling and Multigene Germline Testing for Individuals With Pancreatic Cancer.

JCO Oncol Pract 2021 Feb 13;17(2):e236-e247. Epub 2021 Jan 13.

Dana-Farber Cancer Institute, Boston, MA.

Purpose: National guidelines recommend genetic counseling and multigene germline testing (GC/MGT) for all patients with pancreatic ductal adenocarcinoma (PDAC). This study's aim was to assess real-world effectiveness of implementing systematic GC/MGT for all patients with PDAC at a high-volume academic institution.

Methods: An iterative process for systematizing GC/MGT was developed in which gastrointestinal oncology providers at the Dana-Farber Cancer Institute were recommended to refer all patients with PDAC for GC/MGT (clinician-directed referral). Workflows were subsequently changed such that patients with PDAC were automatically offered GC/MGT when scheduling their initial oncology consultation (automated referral). Clinical and germline data were collected on a consecutive cohort of patients with PDAC undergoing GC/MGT during a 25-month enrollment period (19-month clinician-directed referrals; 6-month automated referrals).

Results: One thousand two hundred fourteen patients with PDAC were seen for initial oncologic evaluation, 266 (21.9%) of whom underwent GC/MGT. Compared with baseline clinician-directed referrals, implementation of automated referrals led to a significant increase in patients with PDAC undergoing GC/MGT (16.5% 38.0%, < .001), including those undergoing multigene germline testing (MGT) ≤ 7 days of initial oncology evaluation (14.7% 60.3%, < .001), with preserved pathogenic variant detection rates (10.0% 11.2%, = 0.84). 16 of 28 (57.1%) pathogenic variant carriers had relatives who pursued cascade germline testing, and 13 of 26 (50.0%) carriers with incurable disease received targeted therapy based on MGT results.

Conclusion: Implementation of systematic GC/MGT in patients with PDAC is feasible and leads to management changes for patients with PDAC and their families. GC/MGT workflows that bypass the need for clinician referral result in superior uptake and time to testing. Further investigation is needed to identify other barriers and facilitators of universal GC/MGT.
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http://dx.doi.org/10.1200/OP.20.00678DOI Listing
February 2021

Universal Screening of Gastrointestinal Malignancies for Mismatch Repair Deficiency at Stanford.

JNCI Cancer Spectr 2020 Oct 19;4(5):pkaa054. Epub 2020 Jun 19.

Division of Medical Oncology, Department of Internal Medicine, Stanford University, Stanford, CA, USA.

Background: In light of recent Food and Drug Administration (FDA) approval of immune checkpoint inhibitors for mismatch repair deficient (dMMR) malignancies, identifying patients with dMMR malignancies has become increasingly important. Although screening for dMMR in colorectal cancer (CRC) is recommended, it is less common for extracolonic gastrointestinal (GI) malignancies. At Stanford Comprehensive Cancer Institute (SCCI), all GI malignancies have been screened for dMMR via immunohistochemistry since January 2016.

Methods: In this study, we conducted a retrospective review of all patients with GI malignancies screened for dMMR between January 2016 and December 2017. Tumor sequencing was performed on cases negative for germline pathogenic variants where tumor material was available.

Results: A total of 1425 consecutive GI malignancies were screened for dMMR at SCCI during the study period, and 1374 were included for analysis. dMMR was detected in 7.2% of all GI malignancies. We detected the highest prevalence of dMMR in gastric (15 of 150, 10.0%) followed by colorectal (63 of 694, 9.1%), pancreatic (13 of 244, 5.3%), and gastroesophageal malignancy (6 of 132, 4.5%) patients. Lynch syndrome was the most common etiology for dMMR in colorectal cancer (41.5%), double somatic (confirmed or possible) pathogenic variants the most common etiology in pancreatic cancer (44.4%), and somatic hypermethylation the most common etiology in gastric (73.3%) and gastroesophageal cancer (83.3%).

Conclusions: Given the relatively high incidence of dMMR in GI malignancies, we recommend screening all GI malignancies. Our results suggest that although a rare occurrence, double somatic pathogenic variants may be a biologically significant pathway causing dMMR in pancreatic cancer.
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http://dx.doi.org/10.1093/jncics/pkaa054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7667994PMC
October 2020

An amino-terminal deletion accounting for acquired resistance to RAF/EGFR inhibition in colorectal cancer.

Cold Spring Harb Mol Case Stud 2020 08 25;6(4). Epub 2020 Aug 25.

Department of Pathology, Stanford University School of Medicine, Stanford, California 94305, USA.

Although combination therapy with RAF and EGFR inhibitors has improved the survival outcomes of patients with -mutated colorectal cancer (CRC), acquired resistance invariably develops. The mechanisms of acquired resistance to RAF inhibitors have been largely attributed to activating mutations in genes, mutations, and amplifications in , genes, and In this report, we describe a patient with -mutated CRC who acquired an amino-terminal deletion involving the Ras-binding domain (RBD) after treatment with RAF/EGFR inhibitor therapy. Amino-terminal deletions involving the RBD are a rare mechanism of acquired resistance to RAF inhibitors, particularly in CRC for which there is only one prior report in the literature.
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http://dx.doi.org/10.1101/mcs.a005140DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7476412PMC
August 2020

Germline Testing for Patients With Mutations on Somatic Tumor Testing.

JNCI Cancer Spectr 2020 Feb 11;4(1):pkz095. Epub 2019 Nov 11.

See the Notes section for the full list of authors' affiliations.

Background: The National Comprehensive Cancer Network (NCCN) recommends germline testing for pathogenic mutations identified by somatic tumor sequencing. The aim of this study was to explore whether patients at Stanford with somatic mutations were recommended germline testing in accordance with NCCN guidelines.

Methods: We retrospectively collected all Stanford patients with mutations found by tumor sequencing. Medical records were reviewed for each patient to identify those recommended germline testing. A multivariable logistic regression model was fit associating baseline characteristics with whether or not a recommendation was made.

Results: Of 164 participants, 51 (31.1%) had no recommendation for germline testing. Of the 97 available germline-testing results, 54 (55.7%) were positive for pathogenic mutations. After adjusting for possible confounders, patients with genitourinary cancer (odds ratio [OR] = 0.03, 95% confidence interval [CI] = 0.00 to 0.03; =.003), lung cancer (OR = 0.04, 95% CI = 0.01 to 0.21; <.001), sarcoma (OR = 0.02, 95% CI = 0.00 to 0.14; <.001), skin cancer (OR = 0.01, 95% CI = 0.98 to 1.03; =.002), or "other" diagnoses (OR = 0.01, 95% CI = 0.00 to 0.16; <.001) were statistically significantly less likely to be recommended germline testing compared with patients with breast or gynecological cancers.

Conclusions: Our study highlights the importance of provider education outside of the oncologic specialties typically associated with -related cancers and continued exploration of referrals to genetics for germline testing on the basis of somatic findings.
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http://dx.doi.org/10.1093/jncics/pkz095DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7043298PMC
February 2020

Immune-Related Adverse Events and Immune Checkpoint Inhibitor Efficacy in Patients with Gastrointestinal Cancer with Food and Drug Administration-Approved Indications for Immunotherapy.

Oncologist 2020 08 14;25(8):669-679. Epub 2020 Jan 14.

Division of Hematology and Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.

Introduction: Immune-related adverse event (IRAE) onset may represent a clinical biomarker for anti-programmed cell death protein 1 (PD-1) antibody response based on emerging evidence from patients with various advanced malignancies. This phenomenon has not been previously reported in a multidisease cohort of patients with gastrointestinal (GI) cancer with Food and Drug Administration (FDA)-approved indications to receive immune checkpoint inhibitor therapy.

Materials And Methods: The study was a multicenter retrospective cohort analysis of 76 patients with GI cancer who had received anti-PD-1 antibodies for FDA-approved indications. The primary and secondary outcomes of the study were progression-free survival (PFS) and overall survival (OS) in patients based upon IRAE presence, respectively. PFS and OS were estimated by the Kaplan-Meier method; a Cox proportional-hazards model adjusted for IRAE onset, patient age, and enrolling institution was used to analyze outcomes.

Results: Median PFS and OS were prolonged in patients who experienced IRAEs compared with those who did not experience them (PFS: not reached [NR] vs. 3.9 months [hazard ratio (HR) 0.13, 95% confidence interval (CI) 0.05-0.3, p < .001]; OS: NR vs. 7.4 months [HR 0.11, 95% CI 0.03-0.36, p < .001]). Among patients who experienced IRAEs, there were no significant differences in PFS and OS by either initial IRAE severity, management, or time to onset.

Conclusion: Patients with gastrointestinal cancer who experienced IRAEs while on anti-PD-1 antibodies demonstrated significant improvements in PFS and OS compared with their counterparts who did not develop IRAEs. Although these findings add to results from studies in other tumor types, larger prospective studies are needed prior to clinical adoption of IRAE onset as a biomarker for immune checkpoint inhibitor response.

Implications For Practice: Predictive clinical biomarkers for immune checkpoint inhibitor response have been understudied in the field of immuno-oncology. Immune-related adverse event onset appears to be one such biomarker. Across tumor types, immune-related adverse event onset has been associated with response to anti-programmed cell death protein 1 (PD-1) antibodies. The results of this study demonstrate this for the first time in patients with gastrointestinal cancer receiving anti-PD-1 antibodies. Before immune-related adverse event onset can be adopted clinically as a predictive biomarker for immune checkpoint inhibitor response, however, larger prospective studies are needed to better understand the nuances between immune-related adverse event characteristics (severity, site, management, timing of onset) and immune checkpoint inhibitor effectiveness.
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http://dx.doi.org/10.1634/theoncologist.2019-0637DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7418359PMC
August 2020

NCCN Guidelines Insights: Genetic/Familial High-Risk Assessment: Colorectal, Version 2.2019.

J Natl Compr Canc Netw 2019 09;17(9):1032-1041

National Comprehensive Cancer Network.

Identifying individuals with hereditary syndromes allows for improved cancer surveillance, risk reduction, and optimized management. Establishing criteria for assessment allows for the identification of individuals who are carriers of pathogenic genetic variants. The NCCN Guidelines for Genetic/Familial High-Risk Assessment: Colorectal provide recommendations for the assessment and management of patients with high-risk colorectal cancer syndromes. These NCCN Guidelines Insights focus on criteria for the evaluation of Lynch syndrome and considerations for use of multigene testing in the assessment of hereditary colorectal cancer syndromes.
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http://dx.doi.org/10.6004/jnccn.2019.0044DOI Listing
September 2019

Comparison of definitive chemoradiation with 5-fluorouracil versus capecitabine in anal cancer.

J Gastrointest Oncol 2019 Aug;10(4):605-615

Division of Medical Oncology, Department of Internal Medicine, Stanford University, Stanford, CA, USA.

Background: Capecitabine (Cap) is an established treatment alternative to 5-fluorouracil (5-FU) for chemoradiation in rectal cancer. Few studies have compared the two agents in anal cancer. We compared outcomes and toxicities using Cap versus 5-FU in non-metastatic anal cancer patients at Stanford.

Methods: All non-metastatic anal cancer patients treated with definitive chemoradiation at Stanford from 1997-2016 were included. Fisher's exact and Mann-Whitney U tests were used to compare nominal and continuous variables. Gray's test was used to compare incidence of recurrence and colostomy, and Log-rank test was used to compare survival.

Results: Sixty-eight patients were included. Thirty-six patients received Cap and 32 received 5-FU (12 received standard 5-FU and 20 received low-dose continuous 5-FU). Patient characteristics were similar between the two groups. There was no difference in the 3-year overall and disease-specific survival between Cap and 5-FU (94% 80%, P=0.197; 100% 86%, P=0.051). Overall incidence of recurrence was equivalent between Cap and 5-FU (11% 13%, P=0.703), but incidence of locoregional recurrence was higher in the 5-FU group (0% 13%, P=0.042); patients treated with Cap had longer recurrence-free intervals (18 6 months, P=0.400), and all recurrences were distant. More colostomies were needed with 5-FU (3% 13%, P=0.133). Toxicities were similar between the two groups. The most common grade ≥2 toxicities were dermatitis (77%), anal pain (78%), and diarrhea (56%).

Conclusions: Overall survival (OS), cancer-specific survival and incidence of recurrence were equivalent between Cap and 5-FU in anal cancer. Patients treated with Cap had statistically significant lower incidence of loco-regional relapses.
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http://dx.doi.org/10.21037/jgo.2019.02.17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6657317PMC
August 2019

Methylated plasma test for colorectal cancer detection may be applicable to Lynch syndrome.

BMJ Open Gastroenterol 2019 28;6(1):e000299. Epub 2019 May 28.

Hereditary Cancer Center, Creighton University, Omaha, Nebraska, USA.

Objective: The plasma-based methylated (mSEPT9) is a colorectal cancer (CRC) screening test for adults aged 50-75 years who are at average risk for CRC and have refused colonoscopy or faecal-based screening tests. The applicability of mSEPT9 for high-risk persons with Lynch syndrome (LS), the most common hereditary CRC condition, has not been assessed. This study sought preliminary evidence for the utility of mSEPT9 for CRC detection in LS.

Design: Firstly, SEPT9 methylation was measured in LS-associated CRC, advanced adenoma, and subject-matched normal colorectal mucosa tissues by pyrosequencing. Secondly, to detect mSEPT9 as circulating tumor DNA, the plasma-based mSEPT9 test was retrospectively evaluated in LS subjects using the Epi proColon 2.0 CE assay adapted for 1mL plasma using the "1/1 algorithm". LS case groups included 20 peri-surgical cases with acolonoscopy-based diagnosis of CRC (stages I-IV), 13 post-surgical metastatic CRC, and 17 pre-diagnosis cases. The control group comprised 31 cancer-free LS subjects.

Results: Differential hypermethylation was found in 97.3% (36/37) of primary CRC and 90.0% (18/20) of advanced adenomas, showing LS-associated neoplasia frequently produce the mSEPT9 biomarker. Sensitivity of plasma mSEPT9 to detect CRC was 70.0% (95% CI, 48%-88%)in cases with a colonoscopy-based CRC diagnosis and 92.3% (95% CI, 64%-100%) inpost-surgical metastatic cases. In pre-diagnosis cases, plasma mSEPT9 was detected within two months prior to colonoscopy-based CRC diagnosis in 3/5 cases. Specificity in controls was 100% (95% CI 89%-100%).

Conclusion: These preliminary findings suggest mSEPT9 may demonstrate similar diagnostic performance characteristics in LS as in the average-risk population, warranting a well-powered prospective case-control study.
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http://dx.doi.org/10.1136/bmjgast-2019-000299DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6577308PMC
May 2019

Microsatellite Instability and Adjuvant Chemotherapy in Stage II Colon Cancer.

Am J Clin Oncol 2019 07;42(7):573-580

Department of Radiation Oncology, Stanford Cancer Institute.

Background: Randomized control trials and population-based studies do not demonstrate a definitive benefit for adjuvant chemotherapy (ACT) in stage II colon cancer (CC). Tumor sidedness and microsatellite instability (MSI) status may predict response to ACT, but previous studies have limited microsatellite data. We assessed the efficacy of ACT and possible interaction with MSI status and tumor sidedness in patients with resected stage II CC diagnosed between 2010 and 2013 using the National Cancer Database.

Materials And Methods: Overall survival was evaluated with the Kaplan-Meier method and multivariate and propensity score matched Cox proportional hazards models. The interaction between receipt of ACT, MSI status, and tumor sidedness was evaluated. The efficacy of ACT was assessed in patient subgroups by MSI status and tumor sidedness.

Results: Among 6964 stage II CC patients with known MSI status, 1497 (21.5%) received ACT, 843 had MSI tumors, and 6121 had microsatellite stable (MSS) tumors. In multivariate and propensity score matched analyses, ACT was associated with improved survival after adjusting for factors including high-risk features, MSI status, and tumor sidedness (multivariate hazard ratio, 0.52; P<0.001). There was no interaction between receipt of ACT and MSI status (P=0.25). Patients with MSS tumors benefitted from ACT (multivariate hazard ratio, 0.47; P<0.001), even without other high-risk features. Patients with MSI tumors did not (P=0.671). ACT was associated with improved survival regardless of tumor sidedness.

Conclusions: MSS alone may warrant ACT in stage II CC while patients with MSI tumors may not derive significant benefit from ACT.
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http://dx.doi.org/10.1097/COC.0000000000000554DOI Listing
July 2019

Clinical characteristics of patients with colorectal cancer with double somatic mismatch repair mutations compared with Lynch syndrome.

J Med Genet 2019 07 15;56(7):462-470. Epub 2019 Mar 15.

Internal Medicine, Ohio State University Wexner Medical Center, Columbus, Ohio, USA.

Background: Patients with colorectal cancer (CRC) with mismatch repair-deficient (dMMR) tumours without methylation or germline MMR pathogenic variants (PV) were previously thought to have Lynch syndrome (LS). It is now appreciated that they can have double somatic (DS) MMR PVs. We explored the clinical characteristics between patients with DS tumours and LS in two population-based cohorts.

Methods: We included patients with CRC from Ohio 2013-2016 and Iceland 2000-2009. All had microsatellite instability testing and/or immunohistochemistry (IHC) of MMR proteins, and methylation testing when indicated. Germline next-generation sequencing was performed for all with dMMR tumours; tumour sequencing followed for patients with unexplained dMMR. Clinical characteristics of DS patients and patients with LS were compared.

Results: Of the 232 and 51 patients with non-methylated dMMR tumours in the Ohio and Iceland cohorts, respectively, 57.8% (n=134) and 45.1% (n=23) had LS, 32.8% (n=76) and 31.4% (n=16) had DS PVs, 6% (n=14) and 9.8% (n=5) were unexplained and 4.3% (n=10) and 13.7% (n=7) had incorrect IHC. Age of diagnosis for DS patients was older than patients with LS (p=3.73×10) in the two cohorts. Patients with LS were more likely to meet Amsterdam II criteria (OR=15.81, p=8.47×10) and have multiple LS-associated tumours (OR=6.67, p=3.31×10). Absence of MLH1/PMS2 was predictive of DS PVs; isolated MSH6 and PMS2 absence was predictive of LS in both cohorts.

Conclusions: Individuals with LS are 15× more likely to meet Amsterdam II criteria and >5× more likely to have multiple cancers as compared with those with DS tumours. Furthermore, isolated loss of MSH6 or PMS2 protein predicts LS.
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http://dx.doi.org/10.1136/jmedgenet-2018-105698DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6748629PMC
July 2019

Targeting Mutations in High-Grade Neuroendocrine Carcinoma of the Colon.

J Natl Compr Canc Netw 2018 09;16(9):1035-1040

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 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 -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 mutations in neuroendocrine carcinoma (NEC) is estimated to be 5% to 10%. A recent case series demonstrated benefit in targeting the 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 mutations play in gastrointestinal NECs, and the need for further research to identify not only patients who may benefit from -directed therapies but also strategies to avoid development of resistance.
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http://dx.doi.org/10.6004/jnccn.2018.7043DOI Listing
September 2018

Tumor Molecular Testing Guides Anti-PD-1 Therapy and Provides Evidence for Pathogenicity of Mismatch Repair Variants.

Oncologist 2018 12 2;23(12):1395-1400. Epub 2018 Aug 2.

Division of Oncology, Department of Medicine, Stanford University School of Medicine, Stanford Cancer Institute, Stanford, California, USA.

Lynch syndrome is characterized by germline abnormalities in mismatch repair (MMR) genes, leading to predisposition to multiple cancers [1]. 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 [2]. 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 [3].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 [6]. 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 [7]. 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. KEY POINTS: 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.
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http://dx.doi.org/10.1634/theoncologist.2018-0108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6292542PMC
December 2018

The risk of developing a mismatch repair deficient colorectal cancer after undergoing cholecystectomy.

Scand J Gastroenterol 2018 Aug 16;53(8):972-975. Epub 2018 Jul 16.

h Department of Internal Medicine , Stanford University , Stanford , CA , USA.

Objectives: 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.

Materials And Methods: 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.

Results: 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.

Conclusions: 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.
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http://dx.doi.org/10.1080/00365521.2018.1481997DOI Listing
August 2018

Promising New Agents for Colorectal Cancer.

Curr Treat Options Oncol 2018 05 11;19(6):29. Epub 2018 May 11.

West Virginia University Cancer Institute, P.O. Box 9300, 1801 HSS, 1 Medical Center Drive, Morgantown, WV, 26506, USA.

Opinion Statement: 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.
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http://dx.doi.org/10.1007/s11864-018-0543-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6499928PMC
May 2018

Histology of colorectal adenocarcinoma with double somatic mismatch-repair mutations is indistinguishable from those caused by Lynch syndrome.

Hum Pathol 2018 08 1;78:125-130. Epub 2018 May 1.

Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH 43210, USA. Electronic address:

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.
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http://dx.doi.org/10.1016/j.humpath.2018.04.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6296362PMC
August 2018

Management of Borderline Resectable Pancreatic Cancer.

Int J Radiat Oncol Biol Phys 2018 04;100(5):1155-1174

Department of Radiation Oncology, Stanford Cancer Institute, Stanford, California. Electronic address:

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.
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http://dx.doi.org/10.1016/j.ijrobp.2017.12.287DOI Listing
April 2018

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

Nat Commun 2017 05 3;8:14755. Epub 2017 May 3.

University of Iceland, Sæmundargata 2, 101 Reykjavík, Iceland.

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.
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http://dx.doi.org/10.1038/ncomms14755DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5418568PMC
May 2017

Discordant Mismatch Repair Protein Immunoreactivity in Lynch Syndrome-Associated Neoplasms:  A Recommendation for Screening Synchronous/Metachronous Neoplasms.

Am J Clin Pathol 2016 Jul 29;146(1):50-6. Epub 2016 Jun 29.

From the Department of Pathology

Objectives: 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.

Methods: 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.

Results: 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.

Conclusions: 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.
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http://dx.doi.org/10.1093/ajcp/aqw067DOI Listing
July 2016

Frequent PIK3CA Mutations in Colorectal and Endometrial Tumors With 2 or More Somatic Mutations in Mismatch Repair Genes.

Gastroenterology 2016 09 11;151(3):440-447.e1. Epub 2016 Jun 11.

Department of Laboratory Medicine, University of Washington, Seattle, Washington. Electronic address:

Background & Aims: 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.

Methods: 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 data sets from The Cancer Genome Atlas.

Results: Among colorectal cancer cases, we found that 14 of 21 (67%) patients with double somatic tumors also had PIK3CA mutations, compared with 4 of 18 (22%) tumors from patients with Lynch syndrome, 2 of 10 (20%) tumors with MLH1 hypermethylation, and 12 of 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 with 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 had a somatic mutation in PIK3CA (P < .0001 compared with other subgroups).

Conclusions: 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 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.
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http://dx.doi.org/10.1053/j.gastro.2016.06.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5016834PMC
September 2016

Radiation Recall Dermatitis With Concomitant Dabrafenib and Pazopanib Therapy.

JAMA Dermatol 2016 05;152(5):587-9

Division of Medical Oncology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus.

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http://dx.doi.org/10.1001/jamadermatol.2015.5366DOI Listing
May 2016

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

Genet Med 2016 09 11;18(9):863-8. Epub 2016 Feb 11.

Division of Medical Oncology, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus, Ohio, USA.

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.
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http://dx.doi.org/10.1038/gim.2015.184DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5489337PMC
September 2016

Mismatch repair deficiency concordance between primary colorectal cancer and corresponding metastasis.

Fam Cancer 2016 Apr;15(2):253-60

Department of Pathology, Ohio State University Medical Center, Columbus, OH, USA.

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.
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http://dx.doi.org/10.1007/s10689-015-9856-2DOI Listing
April 2016

How Can Next-Generation Sequencing (Genomics) Help Us in Treating Colorectal Cancer?

Curr Colorectal Cancer Rep 2014 Dec;10(4):372-379

Division of Medical Oncology, Department of Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, OH.

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.
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http://dx.doi.org/10.1007/s11888-014-0244-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4226466PMC
December 2014

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

Gastroenterology 2014 Dec 3;147(6):1308-1316.e1. Epub 2014 Sep 3.

Department of Laboratory Medicine, University of Washington, Seattle, Washington.

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.
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http://dx.doi.org/10.1053/j.gastro.2014.08.041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4294551PMC
December 2014

New era for treatment in differentiated thyroid cancer.

Lancet 2014 Jul 24;384(9940):286-8. Epub 2014 Apr 24.

Department of Internal Medicine, Division of Medical Oncology, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA. Electronic address:

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http://dx.doi.org/10.1016/S0140-6736(14)60663-2DOI Listing
July 2014

[Colorectal cancer - review].

Laeknabladid 2014 02;100(2):75-82

Colorectal cancer is the third most common cancer in the Western hemisphere and the incidence increases with increasing age. Most colorectal cancers are localized with or without lymph node metastases. Up to 20% of patients present with metastatic disease, most commonly to the liver. Surgery is the only curative therapy for localized colorectal cancer and adjuvant chemotherapy is usually recommended for patients with lymph node metastases. Surgery, radiation therapy and chemotherapy are the key components of rectal cancer therapy. Selected patients with recurrent and metastatic disease can be salvaged with surgery but chemotherapy remains the mainstay of therapy for advanced colorectal cancer. Substantial progress has been observed in the treatment of metastatic colorectal cancer in recent years.
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http://dx.doi.org/10.17992/lbl.2014.02.531DOI Listing
February 2014

Prostate cancer incidence in males with Lynch syndrome.

Genet Med 2014 Jul 16;16(7):553-7. Epub 2014 Jan 16.

Division of Medical Oncology, Department of Internal Medicine, The Ohio State University Medical Center, Columbus, Ohio, USA.

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.
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http://dx.doi.org/10.1038/gim.2013.193DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4289599PMC
July 2014

Advances in systemic therapy for advanced pancreatobiliary malignancies.

F1000Res 2013 Apr 8;2:105. Epub 2013 Apr 8.

Division of Hematology and Medical Oncology, Mayo Clinic Arizona, Scottsdale, AZ, USA.

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.
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http://dx.doi.org/10.12688/f1000research.2-105.v1DOI Listing
April 2013

Advances in systemic therapy for advanced pancreatobiliary malignancies.

F1000Res 2013 8;2:105. Epub 2013 Apr 8.

Division of Hematology and Medical Oncology, Mayo Clinic Arizona, Scottsdale, AZ, USA.

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.
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http://dx.doi.org/10.12688/f1000research.2-105.v1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3752657PMC
April 2013