Personalized Cancer Research Articles

Clinical and Genetic Characteristics of Colorectal Cancer in Persons under 50 Years of Age: A Review.

The incidence of colorectal cancer (CRC) in persons under the age of 50years (EOCRC) is increasing even as the incidence of CRC in persons over age 50 is decreasing. This has led to recommendations to lower the age of CRC screening to age 45. It is not clear whether EOCRC is identical to CRCs in older patients or whether there are distinctive features between the two groups. We reviewed the literature on the clinical and genetic aspects of EOCRC. We found that there is an increased likelihood of a strong genetic basis for EOCRC, but that at least 80% of cases do not come from the known high-penetrance cancer syndromes. Early-onset CRCs tend to occur in the distal colon or rectum, are more likely to be detected due to cancer-related symptoms, appear to be increasing in whites more than non-whites on a population-wide analysis, and are more likely to present in an advanced stage of disease. There are some unique genetic features of EOCRC, including an increased proportion of tumors with LINE-1 hypomethylation, and combined chromosomal and microsatellite stability. EOCRC deserves additional attention because of the high number of life years at risk with EOCRC, and the implications for earlier CRC screening. Additional focus is needed on determining whether some cases of EOCRC have a unique mechanistic basis.

Sa1003 – Poor Knowledge of Personal and Familial Cancer Risk and Guideline-Based Screening Recommendations in Patients with Advanced Colorectal Polyps

Sa1003 – Poor Knowledge of Personal and Familial Cancer Risk and Guideline-Based Screening Recommendations in Patients with Advanced Colorectal Polyps

Porphyria cutanea tarda increases risk of hepatocellular carcinoma and premature death: a nationwide cohort study

BackgroundPorphyria cutanea tarda (PCT) is a skin disorder originating from a deficit of the liver enzyme uroporphyrinogen decarboxylase. PCT may be a risk factor for hepatocellular carcinoma (HCC) and other cancers, but the evidence is unclear. We aimed to investigate cancer and premature mortality risk in persons with PCT.MethodsThe cohort study consisted of all Norwegian residents from 18 years between 2000 and 2016 (n = 5.4 million). 612 persons with PCT, and all cancer diagnoses and causes of death were identified through record linkage between national registries. Hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) were adjusted for age, sex, education and calendar years. We additionally compared persons with PCT to persons with a history of chronic alcohol abuse (n = 30,468).ResultsPersons with PCT were more likely to be diagnosed with HCC [adjusted HR (aHR) = 19.7, CI = 8.8–44.0) and gallbladder and biliary tract cancer (aHR = 6.8, CI = 2.2–21.0) than the reference population. A moderate increased risk for HCC (aHR = 3.1, CI = 1.2–7.7) and gallbladder and biliary tract cancer (aHR = 4.0, CI = 1.1–14.4) remained when compared to persons with a history of chronic alcohol abuse. Additionally, compared to the reference population, persons with PCT had an increased risk of premature death (aHR = 1.5, CI = 1.2–1.7), due to the following causes of death: malignant neoplasms (aHR = 1.4, CI = 1.0–1.9), diseases of the liver (HR = 5.5, CI = 2.5–12.2), and drug and alcohol overdose (HR = 9.9, CI = 4.7–20.8).ConclusionsPersons with PCT had an increased risk of HCC and cancer of the gallbladder and biliary tract, as well as premature death. Although most of our findings can likely be explained by common lifestyle risk factors, something inherent in PCT may contribute to the development of HCC.

Abstract P2-14-20: Early locoregional breast surgery improves overall and progression-free survival in oligometastatic breast cancer

Abstract Background Four percent of patients have Metastatic Breast Cancer (MBC) at the time of diagnosis. Surgery in this context is generally not recommended. However, tumour resection may have an effect on tumour load influencing metastatic growth. Some studies have suggested an advantage of locoregional surgery in MBC. The objective was to evaluate the effectiveness of surgery in the year following diagnosis of metastatic disease. Methods Data were collected within the ESME breast cancer data platform. Stage IV patients diagnosed between 2008 and 2014 without further personal cancer were included. Patients who died or progressed in 1-year post-diagnosis were excluded. We compared patients operated within the first 12 months after diagnosis with the others. Results Among 1977 patients with MBC at diagnosis, alive and progression-free at 12 months, 530 (26.8%) had surgery within this interval. Patients operated in the year of diagnosis had less oligometastatic disease (less than 3 metastases; 9.2% vs 21.8%, p<0.01) compared to patients with no surgery. They had less bone metastasis (57.7% vs 74.4%, p<0.01), more lymph node (33.2% vs 27.8%, p=0.02), lung (19.8%, p<0.01) and less liver metastasis (17.9% vs 26.8%, p<0.01) sites. Other treatments included more chemotherapy and HER2-targeted therapy (89.1% vs 69.6%, p<0.01), locoregional radiotherapy (81.7% vs 32.5%, p<0.01) and the same frequency of hormone therapy (79.8% vs 78.6%, p=0.57). Multivariate survival analysis based on Cox model showed that surgery of primary breast lesion performed within 12 months (Hazard Ratio(HR)=0.75, p<0.01), HER2 positive status (HR=0.42, p<0.01) and the non-visceral metastases (HR=0.80, p=0.02) improved overall survival (OS) whereas an older age than 50 (HR=1.50, p<0.01) and 3 or more metastases (HR=1.45, p<0.01) were associated with poorer survival. Progression-Free Survival (PFS) was also improved for locoregional surgery (HR=0.70, p<0.001) after adjustment on HER2 positive status (HR=0.70, p<0.01), age greater than 50 (HR=1.18, p<0.01) and 3 or more metastases (HR=1.27, p<0.01). Propensity score matching analyses confirmed these results. Discussion We demonstrated that surgery of primary breast lesion had a benefit on OS (HR=0.75, p<0.01), and PFS (HR=0.70, p<0.01) in metastatic patient. Metastasis number less than 3 was a complementary protective factor to surgery. Studies have sought to evaluate the population that could benefit from surgery of primary breast lesion in the event of metastatic disease. They showed an increasing morbimortality in plurimetastatic patients. In our study, patients with more than 3 metastases had poorer OS and PFS (HR=1.45, p=0.01 and HR=1.27, p=0.03 respectively). Conclusion Results of our study show that surgical control of primary breast lesion could be considered as an option in the locoregional treatment of MBC, particularly in non-visceral oligometastastic breast cancer. Citation Format: Hotton J, Lusque A, Rauch P, Leufflen L, Buhler J, Pierret M, Salleron J, Marchal F. Early locoregional breast surgery improves overall and progression-free survival in oligometastatic breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-14-20.

Abstract P5-10-02: Development and validation of a polygenic score to predict breast cancer risk in unaffected Hispanic women negative for mutations on a multi-gene hereditary cancer panel

Abstract Background: Breast cancer (BC) is the most commonly diagnosed cancer and the leading cause of cancer-related death among Hispanic women in the United States. For women of European ancestry, genome-wide association studies (GWAS) have identified common variants, primarily single-nucleotide polymorphisms (SNPs), that individually confer modest risk but together explain a significant proportion of genetic BC predisposition. For Hispanic women, the genetic contribution of SNPs to BC risk is not well understood. In these studies, we aim to develop and validate a polygenic score to improve risk assessment for Hispanic women who test negative for mutations in known BC susceptibility genes. Methods: Genotypes and clinical histories were collected from consecutive development and validation cohorts of patients referred for hereditary cancer testing. Study subjects include women who report strictly Hispanic or Latin American ancestry, and who test negative for mutations in 11 genes associated with breast cancer (BRCA1, BRCA2, TP53, PTEN, STK11, CDH1, PALB2, CHEK2, ATM, NBN, BARD1). Based on a development cohort ascertained through June 2017, we evaluated an 86-SNP Residual Risk Score (RRS) that was previously developed and validated for women of European ancestry. In the same cohort we are developing a Hispanic Residual Risk Score (HRRS) optimized for women of Hispanic ancestry. BC associations of individual SNPs are being established through meta-analysis of the development cohort and published Hispanic studies. Multivariate logistic regression models were used to evaluate the 86-SNP RRS, and were the primary statistical tool for evaluation of individual SNPs and candidate polygenic scores. All models included personal/family cancer history and age as independent variables. P-values are based on likelihood ratio test statistics, and reported as two-sided. The development and validation studies are being conducted according to a protocol approved by the Quorum Institutional Review Board. Results: The development cohort included 5,454 Hispanic women, 24% of whom reported a personal history of BC. The 86-SNP RRS was significantly associated with a personal history of BC after accounting for personal and family cancer history (p<10-19) with odds ratio per unit standard deviation 1.39 (95% CI = 1.30-1.50). To date, more than 5,000 Hispanic women have been ascertained for inclusion in the validation cohort. Results comparing discriminatory accuracy of the RRS and the HRRS will be presented. Conclusions: The implementation of a clinically validated polygenic score may improve risk assessment and medical management of Hispanic women who test negative for monogenic BC mutations. The HRRS will be validated in an independent study population according to a pre-specified statistical analysis plan. Citation Format: Hughes ER, Wagner S, Pruss D, Gallagher SK, Swedlund B, Bulka K, Hoff R, Jammulapati S, Morris B, Perry T, Lanchbury JS, Gutin A. Development and validation of a polygenic score to predict breast cancer risk in unaffected Hispanic women negative for mutations on a multi-gene hereditary cancer panel [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-10-02.

Validation of a digital identification tool for individuals at risk for hereditary cancer syndromes

BackgroundThe number of individuals meeting criteria for genetic counseling and testing for hereditary cancer syndromes (HCS) is far less than the number that actually receive it. To facilitate identification of patients at risk for HCS, Counsyl developed a digital identification tool (digital ID tool) to match personal and family cancer history to National Comprehensive Cancer Network (NCCN) BRCA-related Hereditary Breast and Ovarian Cancer (HBOC), Lynch syndrome, and polyposis testing criteria in one-to-one, automated fashion. The purpose of this study was to validate the ability of the digital ID tool to accurately identify histories that do and do not meet NCCN testing criteria.MethodsThird-party recorded three-generation pedigrees were retrospectively reviewed by a certified genetic counselor (CGC) to determine if independent events included in pedigree histories met NCCN guidelines, and were then sorted into groups: high risk events (meets criteria) and low risk events (does not meet criteria). Events were entered into the digital ID tool to determine the extent of its concordance with events sorted by CGC review. Statistical tests of accuracy were calculated at a 95% confidence interval (CI).ResultsOne hundred ninety-seven pedigrees were reviewed consecutively representing 765 independent events for analysis across groups. 382/382 (100%) high risk events identified by the digital ID tool and 381/383 (99.47%) low risk events identified by the digital ID tool were concordant with CGC sorting. The digital ID tool had a sensitivity of 100% (99.04–100% CI) and specificity of 99.48% (98.13–99.94% CI). The overall accuracy of the digital ID tool was estimated to be 99.74% (99.06–99.97% CI), reflecting the rate at which the digital ID tool reached the same conclusion as that of CGC review of pedigree events for the recommendation of genetic testing for individuals at risk for HCS.ConclusionsThe digital ID tool accurately matches NCCN criteria in one-to-one fashion to identify at-risk individuals for HCS and may be useful in clinical practice, specifically for BRCA-related HBOC and Lynch Syndrome.

Feasibility of a patient-reported outcomes quality-of-life instrument to improve care in underserved, ethnic minority patients with cancer.

65 Background: We need better methods to understand the social determinants of health and integrate psychosocial and economic sequelae of cancer and its treatment into healthcare delivery for ethnoculturally diverse population. A Patient-Reported Outcomes Quality of Life (PROQOL) instrument has been developed to capture less commonly discussed patient concerns (Personal Relationships, Emotional health, Physical health, Cancer diagnosis and treatment, Money and Care planning) and improve patient-provider communication. We sought to adapt this instrument and pilot it in underserved, ethnically diverse solid tumor and hematological malignancies patients at Maricopa Integrated Health System (MIHS) in Phoenix, AZ. Methods: Two focus groups (FG) were conducted to understand patient perspectives of an adapted Spanish version of PROQOL. This version was then piloted among patients on active cancer treatment. Patients also completed a Linear Analog Scale Assessment (from 1-10) for quality of life (QOL) and its domains (higher scores indicate better QOL). Results: All participants in both FG (11/12 female) were Hispanics, with a median age of 53 years. Participants agreed that the domains covered in the PROQOL represented the most important psychosocial needs in their cancer continuum. No difficulty in understanding the individual domains or questions for delving deeper into each domain was noted. Median age of 34 pilot study participants (74% female) was 48 years, 79% were Hispanic, 10% were African Americans and median household income was $ 43,924 (range 23,002-98,382). 28/34 completed the Spanish version. Most common concerns were ‘Money’ (32%): difficulty paying medical bills and non-medical expenses and ‘Cancer Diagnosis, Treatment and Survivorship’ (32%): type of cancer and treatment concerns. Median overall QOL was 8 (range 3-10). Conclusions: PROQOL is feasible for systematic capture of patient concerns in underserved, ethnic minority cancer patients. A better understanding of these challenges can help design interventions to improve psychosocial and financial outcomes for the vulnerable groups and decrease disparities in care delivery.

Detection of PIK3/AKT pathway in Moroccan population with triple negative breast cancer

BackgroundTriple Negative Breast Cancer (TNBC) is an aggressive form of breast cancer, that represents 10–20% of all breast carcinomas and characterized by the lack of a specific cell surface marker compared to other breast cancer subtypes. Due to the absence of molecular markers for TNBC his treatment options remains limited, without proven targeted therapies, which emphasize the need for discovering molecular markers that could be targeted for patient treatment, An important number of TNBC cases harbor aberrations in the phosphoinositide 3-kinase (PI3K) pathway, leading to constitutive activation of the downstream signaling pathway. Among mechanisms of PI3K enhancement, PIK3CA mutations are most frequently (~ 30%) observed, along with protein loss of PTEN and AKT activation by phosphorylation (pAkt). Therefore, we propose to analyze clinocopathologic and molecular characteristics of PI3K/AKT/PTEN pathway in Moroccan triple negative breast cancer patients.MethodsWe conducted a retrospective study of 39 patients diagnosed with triple negative breast cancer between early 2013 and 2016. In this study, we used the Ion Personal Genome Machine (PGM) and Ion Torrent Ampliseq Cancer panel to sequence hotspot regions from PIK3CA, AKT and PTEN genes to identify genetic mutations in 39 samples of TNBC subtype from Moroccan patients and to correlate the results with clinical-pathologic data.ResultsAll patients were female with a median age of 46 years from (34–65). Most patients have had invasive ductal carcinoma (84.6%) and 69.2% of them were grade III SBR. Among the 39, 9 were right sided tumor patients and the remaining 30 were left-sided. Mutational analysis of PIK3CA gene was achieved in all TNBC patients. PIK3CA hotspot mutations were detected in 5/39 of TNBC (13%), in detail, among these 5 TNBC patients, one harbored mutation in exons 9 and four in exon 20.ConclusionThe PI3KCA gene is highly activated and plays a crucial role in the pathogenesis of TNBC more, therefore, may be a potential therapeutic target to improve outcomes in patients.

Abstract P265: Cancer Risk in Persons After a Diagnosis of Clinical Cardiovascular Disease: The Atherosclerosis Risk in Communities (ARIC) Study

Introduction: With improved survival of patients with cardiovascular disease (CVD), the risks of non-CVD outcomes is of increasing interest. We investigated the risk of subsequent cancer in persons with clinical CVD compared to those without using a matched cohort study nested in the ARIC study. Hypothesis: Persons with CVD may have higher risk of cancer compared to those without. Methods: In ARIC participants (aged 45-64 years) without prevalent CVD or cancer at the study baseline (1987-1989), we first identified every participant who developed clinical CVD (myocardial infarction [MI], heart failure, or stroke as a combined outcome and separately) during follow-up (through 2012). For each of them, applying incidence density sampling, we selected up to two participants without clinical CVD matched on key confounders (age, sex, race, diabetes, hypertension, lipid-lowering therapy, and smoking). Then, we used the Cox proportional hazards regression to estimate the risk of total and site-specific cancer comparing CVD to no CVD further adjusting for conventional risk factors for CVD or cancer, socioeconomic status, insurance, and routine physical examination. Results: We followed 2,565 with CVD and 4,622 without CVD from the date of sampling for a total of 62,772 person-years (mean of 9 years). The hazard ratio [HR] for total cancer risk was 1.13 (95% confidence interval, 1.00-1.32) for participants with CVD compared to those without. None of the HRs for site-specific cancers were statistically significant. When individual CVD subtypes were analyzed separately, participants with MI and heart failure had 2.1- and 1.3- folds significantly higher risk of total cancer compared to those without, respectively. Participants with MI had significantly increased HR in major types of cancer such as prostate, lung, and breast, with adjusted HR ranging from 2.5 to 3.5. Conclusion: Persons with clinical CVD, especially MI, had a modestly increased risk of total cancer following that event compared to those without. Future studies are warranted to better understand its potential reasons.

Risk of Oral and Upper Gastrointestinal Cancers in Persons With Positive Results From a Fecal Immunochemical Test in a Colorectal Cancer Screening Program

European guidelines recommend screening for colorectal cancer (CRC) using the fecal immunochemical test (FIT), with follow-up colonoscopies for individuals with positive test results. However, more than half of participants with positive results from the FIT are not found to have advanced neoplasia in the colonoscopy examination. Fecal occult blood might also come from the upper gastrointestinal (GI) tract, so perhaps we should consider esophagogastroduodenoscopy (EGD), to detect upper GI cancers. We aimed to determine how many individuals are found to haveoral or upper GI cancers (oral cavity, throat, esophageal, gastric, or small bowel cancer) within 3 years after a positive or negative result from a FIT in a CRC screening program. We performed a retrospective analysis of data from a pilot study of 3 rounds of biennial FIT-based screening for CRC in 2 regions in the west of the Netherlands, from 2006 through October 2012. Participants who developed oral or upper GI cancers were identified through linkage with the National Cancer Registry. We classified these cancers into 3 groups: those that developed in individuals with a positive result from a FIT but negative findings from colonoscopy (no advanced neoplasia), those that developed in individuals with a positive result from a FIT and a positive finding from colonoscopy (advanced neoplasia), and those that developed in individuals with negative results from a FIT. We compared oral and upper GI cancer incidence among groups. Among 16,165 screening participants, linkage identified 52 persons who developed an oral or upper GI cancer within 3 years after a FIT. We found no significant difference in incidence values between individuals with a positive vs a negative FIT result: 8 cancers developed in individuals with a positive result from a FIT (0.37%; 95% CI, 0.19-0.76) and 44 developed in individuals with a negative result from a FIT (0.31%; 95% CI, 0.23-0.42) (P= .65). Of the 8 individuals with a positive result from a FIT and an oral or upper GI cancer, 6 were diagnosed after negative findings from colonoscopy and 2 after positive findings from colonoscopy. We found that only 0.14% of all persons with a positive result from a FIT were diagnosed with a gastric or esophageal cancer within 3 years. In a study of individuals in the Netherlands undergoing screening for CRC by FIT, we found fewer than 1% of patients with a positive result from the FIT to receive a diagnosis of upper GI cancers within 3years. Routine EGD investigation of individuals with positive results from a FIT and negative findings from colonoscopy is therefore not recommended. TrialRegister.nl, Number: NTR5385.

PROBLEMS OF MEDICAL EXPERTISE FOR DISEASES THAT BRING TO DISABILITY AND DEATH AS A RESULT OF RADIATION EXPOSURE INFLUENCE IN CONDITIONS OF THE CHERNOBYL CATASTROPHE IN REMOTE POSTACCIDENTAL PERIOD.

The Chornobyl catastrophe (ChCt) resulted in radiation exposure of great quantity of people. Amongthem there were personnel of Chernobyl NPP (ChNPP) and workers of supporting enterprises, radiation protectionprofessionals, clean-up workers of different specialties including military personnel that were send for liquidationof its consequences, inhabitants of the Prypyat city and Chernobyl 30km exclusive zone (including children) thatwere evacuated during first days after accident and population of radioactive contaminated territories. Loss ofhealth, disability and death as a result of radiation exposure influence in conditions of the ChCt under discharge ofprofessional, military or official duties and/or living on radiation contaminated territories not by his own fault callfor developing of special form of medical expertise as part of medical social protective system for this contingents.The objective of the study was to analyze the state of medical and social expertise for the interdependence of thediseases that bring to the disability and death with the impact of the Chornobyl accident consequences for the adultpopulation and to determine the main directions for improvement of this system. The analysis of the medical expertise state for the interdependence of the diseases thatbring to the disability and death by the effect of the Chornobyl accident consequences for the adult population ina remote post-accidental period during 2013-2017 years (26142 personal medical expert investigations) was per-formed. It was determined that the total number of population suffered from ChCt during 2007-2018 years reduced for 26.05 % or by 657,988 persons. At the same time, there has been rapid increase in the num-ber of victims with disability who received positive medical expertize certificate about interdependence of diseasewith effect of ChCt (the 1st category according Ukrainian legislation) - from 40,106 in 1995 to 107,115 in 2018. Theincrease in the frequency of medical expertise cases of oncological diseases - 51,49 %, as well as cases concerningthe interdependence of diseases that caused the deaths of the victims - 34,99 % were shown. The outstandingissues of the medical expertise of diseases interdependence with ChCt effects for certain categories of victims (thy-roid cancer in persons who have lost their status after reaching adulthood, the definition of the legitimacy of thestatus of victims for inhabitants of territories that undergone radiation ecological control (the 4th-V category) thatrequire changes and additions to the legislative framework are discussed.

The ANDROMEDA prospective cohort study: predictive value of combined criteria to tailor breast cancer screening and new opportunities from circulating markers: study protocol

BackgroundIn recent years growing interest has been posed on alternative ways to screen women for breast cancer involving different imaging techniques or adjusting screening interval by breast cancer risk estimates. A new research area is studying circulating microRNAs as molecular biomarkers potentially useful for non invasive early detection together with the analysis of single-nucleotide polymorphisms (SNPs).The Andromeda study is a prospective cohort study on women attending breast cancer screening in a northern Italian area. The aims of the study are: 1) to define appropriate women risk-based stratifications for personalized screening considering different factors (reproductive, family and biopsy history, breast density, lifestyle habits); 2) to evaluate the diagnostic accuracy of selected circulating microRNAs in a case-control study nested within the above mentioned cohort.MethodsAbout 21,000 women aged 46–67 years compliant to screening mammography are expected to be enrolled. At enrolment, information on well-known breast cancer risk factors and life-styles habits are collected through self-admistered questionnaires. Information on breast density and anthropometric measurements (height, weight, body composition, and waist circumference) are recorded. In addition, women are requested to provide a blood sample for serum, plasma and buffy-coat storing for subsequent molecular analyses within the nested case-control study. This investigation will be performed on approximately 233 cases (screen-detected) and 699 matched controls to evaluate SNPs and circulating microRNAs. The whole study will last three years and the cohort will be followed up for ten years to observe the onset of new breast cancer cases.DiscussionNowadays women undergo the same screening protocol, independently of their breast density and their individual risk to develop breast cancer. New criteria to better stratify women in risk groups could enable the screening strategies to target high-risk women while reducing interventions in those at low-risk. In this frame the present study will contribute in identifying the feasibility and impact of implementing personalized breast cancer screening.Trial registrationNCT02618538 (retrospectively registered on 27–11-2015.)

Prognosis of cancer in persons with infrequent consultations in general practice: A population-based cohort study.

Cancer survival rates are lower in Denmark than in comparable European countries. This may partly be attributable to subgroups of cancer patients who seek medical attention at late disease stages. It is unknown if differences in usual (i.e. customary) consultation frequency in general practice are associated with cancer prognosis. We aimed to estimate the cancer prognosis of cancer patients stratified by their usual consultation frequency in general practice. We performed a population-based cohort study including 123,943 incident cancer patients aged 50 to 89 years diagnosed in Denmark in 2009 to 2013. We estimated associations between the patient's usual general practitioner (GP) consultation frequency 19 to 36 months before the cancer diagnosis and all-cause mortality by using hazard ratios (HR), estimated by Cox proportional hazards regression. We also estimated the associations between the patient's usual GP consultation frequency and tumour stage, by using logistic regression estimates of odds ratios (ORs). Patients who usually did not see their GP (non-consulters) had higher all-cause mortality [HR = 1.39 (95% CI: 1.33-1.44)] compared to patients who usually saw their GP three to five times during an 18 months period (average consulters). Non-consulters had higher odds of having distant tumour stage [OR = 1.46 (95% CI: 1.38-1.57)] than average consulters. Similar, yet less strong, patterns were seen among patients with low usual GP consultation frequency, yet not statistically significant for all cancer types. In conclusion, the association between usual GP non-consultation and cancer prognosis is a combination of at least two things: a mechanism through more advanced tumour stage and other independent factors.

Development and Validation of an Ultradeep Next-Generation Sequencing Assay for Testing of Plasma Cell-Free DNA from Patients with Advanced Cancer.

Purpose: Tumor-derived cell-free DNA (cfDNA) in plasma can be used for molecular testing and provide an attractive alternative to tumor tissue. Commonly used PCR-based technologies can test for limited number of alterations at the time. Therefore, novel ultrasensitive technologies capable of testing for a broad spectrum of molecular alterations are needed to further personalized cancer therapy.Experimental Design: We developed a highly sensitive ultradeep next-generation sequencing (NGS) assay using reagents from TruSeqNano library preparation and NexteraRapid Capture target enrichment kits to generate plasma cfDNA sequencing libraries for mutational analysis in 61 cancer-related genes using common bioinformatics tools. The results were retrospectively compared with molecular testing of archival primary or metastatic tumor tissue obtained at different points of clinical care.Results: In a study of 55 patients with advanced cancer, the ultradeep NGS assay detected 82% (complete detection) to 87% (complete and partial detection) of the aberrations identified in discordantly collected corresponding archival tumor tissue. Patients with a low variant allele frequency (VAF) of mutant cfDNA survived longer than those with a high VAF did (P = 0.018). In patients undergoing systemic therapy, radiological response was positively associated with changes in cfDNA VAF (P = 0.02), and compared with unchanged/increased mutant cfDNA VAF, decreased cfDNA VAF was associated with longer time to treatment failure (TTF; P = 0.03).Conclusions: Ultradeep NGS assay has good sensitivity compared with conventional clinical mutation testing of archival specimens. A high VAF in mutant cfDNA corresponded with shorter survival. Changes in VAF of mutated cfDNA were associated with TTF. Clin Cancer Res; 23(18); 5648-56. ©2017 AACR.

Acute hepatic porphyria and cancer risk: a nationwide cohort study.

Acute hepatic porphyria (AHP) is considered to be a risk factor for primary liver cancer (PLC), but varying risk estimates have been published. Our aim was to investigate the risk of PLC and other cancers in persons with AHP using a nationwide cohort design. Given that greater numbers of women than men tend to have manifest and more severe AHP, a further aim was to investigate sex differences in this risk. The study sample consisted of all Norwegian residents aged 18 years or older during the period 2000-2011. Persons with AHP (n = 251) were identified through the Norwegian Porphyria Centre, and patients with a cancer diagnosis were identified by linkage to the Cancer Registry of Norway. For persons with AHP, the annual incidence rate of PLC was 0.35%. PLC risk was substantially higher for individuals with an AHP diagnosis compared to the reference population [adjusted hazard ratio (aHR) 108, 95% confidence interval (CI) 56-207]. In a meta-analysis of published studies on PLC and AHP, including ours, women had a higher risk than men. In addition, our results suggested that persons with AHP may have increased risks of kidney (aHR 7.4, 95% CI 2.4-23.1) and endometrial cancers (aHR 6.2, 95% CI 2.0-19.3). Our findings confirmed a substantially higher risk of PLC associated with AHP compared to the general population. In a meta-analysis, the risk was shown to be greater for women than men. The novel findings of a moderate to substantial association between AHP and kidney and endometrial cancers should be investigated further.

MILD COGNITIVE IMPAIRMENT IS, IN CONTRAST TO DEMENTIA, ASSOCIATED WITH AN INCREASED RISK OF CANCER

Dementia and cancer are major public health concerns. Previous studies showed an inverse relation between dementia and cancer. However, it is uncertain whether this observation is based on biological mechanisms or if it is due to epidemiological limitations. Mild cognitive impairment (MCI) represents the earliest clinical features of dementia. We investigated the relation between MCI and cancer in addition to the association between dementia and cancer to better understand the nature of this finding. We assessed the relation between incident dementia and cancer in 13,207 participants of the prospective population-based Rotterdam Study. The association between MCI and cancer was studied in 5,181 persons of this cohort. Only solid and hematological cancer types were included. Cox proportional hazard models were used, adjusting for important confounding factors including age, sex, body mass index, education level, smoking status, and alcohol use. In addition, we excluded the first two and five years of follow-up time to limit the effect of reversed causality. In total 1,404 patients were diagnosed with dementia of whom 63 developed cancer. Dementia was associated with a decreased risk of cancer (hazard ratio (HR) 0·53; 95% CI 0·41–0·68). Seventy seven out of 501 persons with MCI were diagnosed with cancer. Persons with MCI had an increased risk of cancer (HR 1·21; 95% CI 0·95–1·53). The risk of cancer was increased after exclusion of the first two and five years of follow-up time (HR 1·28; 95% CI 0·97–1·68 and HR 1·75; 95% CI 1·21–2·53). The risk of cancer in persons with MCI was significantly higher compared to the risk in dementia patients (P <0.001).

Abstract 1745: Multifocal prostate cancer has high degree of genomic heterogeneity

Abstract Prostate cancer is the most common cancer type among men in the Western world. Most prostate cancers are multifocal with individual tumors harboring different aggressiveness. In recent genomics studies, the multifocal nature of prostate cancer has been investigated only in small sample cohorts. Here we have investigated the intra-organ mutational spectra of multiple tumors from a large cohort of prostate cancer patients. From radical prostatectomies performed between 2010 and 2012 at Oslo University Hospital, 43 prostatectomy specimens with multiple and clearly separated tumors were identified based on histology. From each of these prostatectomy specimens, DNA from frozen samples from 2-3 different tumor foci and corresponding normal tissue samples were analyzed by high-coverage whole-exome sequencing, adding up to a total of 159 samples. We identified 3093 somatic substitutions, insertions and deletions, with an average of 27 alterations per tumor sample. Both known and novel significantly mutated genes were identified and their distribution among different tumor foci from the same prostate was examined. Mutations in genes such as SPOP, MED12, and FOXA1 have previously been identified in prostate cancer and were also found to be frequently mutated in this cohort. However, the same mutations were rarely found in multiple tumor foci within the same prostate. In fact, for 13 out of the 43 examined patients there were no common mutations among tumors from the same prostate. For 12 patients, we found only one overlapping mutation among tumor foci. Whereas the overall list of mutated genes (n = 2101) overlap significantly with the 594 genes of the Cancer Gene Census (100/594; p=9.6e-06), this was not the case for 142 genes with overlapping mutations among different tumor foci (2/594; p=0.63). This indicates that the overlapping mutations are not typical cancer driving genes. To conclude, results from exome sequencing of multifocal prostate cancer show a large degree of heterogeneity in genomic alterations between different tumor foci within the same prostate. With very few common inter-foci mutations, an implementation of genome-based personalized prostate cancer medicine will require sampling of all tumor foci to tailor optimal treatment. Citation Format: Marthe Løvf, Sen Zhao, Ulrika Axcrona, Bjarne Johannesen, Andreas M. Hoff, Anne Cathrine Bakken, Kristina Totland Carm, Ola Myklebost, Leonardo A. Meza-Zepeda, Agnes K. Lie, Karol Axcrona, Ragnhild A. Lothe, Rolf I. Skotheim. Multifocal prostate cancer has high degree of genomic heterogeneity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1745. doi:10.1158/1538-7445.AM2017-1745

Abstract DPOC-006: mAGIC – CREATION OF A MOBILE APPLICATION TO INCREASE GENETIC COUNSELING FOR WOMEN WITH OVARIAN CANCER

Abstract PURPOSE: Current guidelines published by the National Comprehensive Cancer Network and the Society of Gynecologic Oncology recommend that all women with invasive ovarian, fallopian tube, or primary peritoneal cancers receive genetic risk evaluation by a genetic counselor. Despite recommendations, physicians continue to under–refer and women under–use genetic services. This study developed the Mobile Application for Genetic Information on Cancer (mAGIC) intervention to motivate ovarian cancer survivors to undergo genetic counseling. The overall study objective was to develop and assess the feasibility and effectiveness of a theory–based intervention aimed to encourage ovarian cancer survivors to receive genetic counseling. METHODS: Based on the Precaution Adoption Process Model and the Fogg Behavior Model for Persuasive Design, a multi–step process was used to design a 7–day mobile application intervention delivering daily text and video messaging. Content and formatting was developed by a multi–disciplinary expert team in conjunction with a Community Advisory Board and was based on focus groups with ovarian cancer patients. The final content covered the following topics: genetic counseling, genetic testing, cancer genetics and personal health, cancer genetics and my family, taking care of yourself, and preparing for a genetic counseling appointment. Usability testing was conducted to ensure the intervention was relevant and easy to use. To test the effectiveness of the intervention, a randomized control trial of 104 women with ovarian cancer, who have not previously received genetic counseling, was initiated. Participants were randomized to the mobile app intervention or control (usual care). Regardless of randomization assignment, participants received a phone call from a patient health navigator two weeks following enrollment to determine their intentions, self–efficacy, and communication with family regarding seeking genetic counseling. A three month follow–up survey of all participants measured genetic counseling uptake, stage of readiness, self–efficacy, knowledge, and distress. RESULTS: To date, 45 of 104 women have been randomized; 39 have completed the telephone survey and 10 have completed the three month survey. No interim analyses of the primary outcomes were planned; however participant feedback has been positive. CONCLUSIONS: Despite consensus guidelines recommending the referral of all ovarian, fallopian tube and primary peritoneal cancer patients to genetic counseling, not all patients receive the recommended genetic counseling. This mobile application provides a new tool for disseminating needed information about genetic counseling directly to women with ovarian cancer. Citation Format: Melissa A. Geller, MD, Sue Petzel, PhD, Hee Lee, PhD, Heewon Lee, BA, Kristen Niendorf, MS, Rachel Isaksson Vogel, PhD. mAGIC – CREATION OF A MOBILE APPLICATION TO INCREASE GENETIC COUNSELING FOR WOMEN WITH OVARIAN CANCER [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr DPOC-006.

Fear of progression in patients with low-risk malignant melanoma.

e21615 Fear of progression in patients with low-risk malignant melanoma Fear of cancer progression (FoP) is one of the problems most commonly reported by cancer patients and is among the most prevalent cancer-related worries in cancer survivors. FCR is highly variable in different cancer entities. Background: This study aimed to elicit the prevalence and significance of FCR in melanoma patients with low risk tumors and further to assess psychosocial and demographic factors predicting severity of FoP as well as to determine the impact of FoP on quality of life (QoL). Methods: In total, 133 patients with low-risk melanoma (pT1a) completed the short version of the Fear of Progression Questionnaire (FoP-Q-SF), the Hospital Anxiety and Depression Scale (HADS), and the EQ-5D questionnaire, as well as self-constructed questions on the socio-demographic background. Results: MeanFoP-Q-SF sum score was 30.1 points (± 8.4 points SD) and the median 29 points. Two thirds of patients deviated not more than 1 SD from the mean. Risk factors for elevated FoP were female gender (p &lt; 0.01), young age (p = 0.04) and working (p = 0.02) patients and patients with severe comorbidities (p = 0.03). Cancer in closely related persons predicted higher FoP (p &lt; 0.01). HADS anxiety scale (r = 0.49, p &lt; 0.01) and depression scale (r = 0.26, p &lt; 0.01) correlated with FoP. A negative correlation with the EQ-5D index was found (r = -0.34, p &lt; 0.01). Conclusions: As in many other malignancies,FoP is prevalent in low-risk melanoma patients and is associated with reduced QoL. Severe comorbidities, cancer in related persons, gender and income could be identified as predictors of FoP. Considerable high levels of FoP even in patients with low-risk malignancies underline the need of psychosocial support and intervention for special subgroups of melanoma patients to enable the patient to manage FoP more successfully.

Large germline next generation (NGS) sequencing panel of uterine serous carcinoma.

e13106 Background: Genetic predisposition to uterine serous carcinoma (USC) remains unclear and has been related to Lynch Syndrome (LS) and BRCA1/2 mutations. Wide NGS panels for this condition are starting to be implemented and data remain scarce. Methods: Consecutive USC were identified from a prospective endometrial cancer database (ECD) in a single institution. Clinical information including stage, follow-up, a three-generation pedigree, Microsatellite Instability (MSI) with 8 markers and the Mismatch Repair Protein (MMRPro) staining status, was retrieved from the ECD. Germline genetic testing was performed using a commercially available NGS panel including 80 familial cancer genes (Onco-GeneSGKit) on a MiSeq sequencer. Pathogenic or likely pathogenic variants were confirmed by Sanger sequencing. Results: Twenty-one women out of a total of 150 (14%) cases contained in the ECD were diagnosed with a USC. Median age was 65 (40-84 yo), median Body Mass Index of 26 (19-40), and histologically 18 were defined as pure and 3 as mixed USC. FIGO 2009 stages were I/II and III/IV in 42% and 58% of cases respectively. Adjuvant Chemotherapy (CT) was administered to 76%. MSI-High and MMRPro loss was described in 5%, 19% fulfilled Bethesda criteria, 23% had previous breast cancer and 5% personal Lynch related cancer history, 28% presented with pathological features of Lynch Syndrome such as dedifferentiation, Tumor Infiltrating Lymphocytes (14%), peritumoral lymphocytes or lower uterine location (14%). A median of 5 [range: 2-8] genetic alterations (pathogenic, variants of uncertain significance (VUS) and not described) per patient were observed, including 3 (14.3%) pathogenic mutations, 18 VUS and 43 not described. Among the three pathogenic mutations one was in MSH6 (p.Glu255Ter), another one in DKC1 (p.S280A) and the last one in the recessive gene MUTYH (p.Glu466del). VUS were detected in 57% of cases among 12 different genes: ATM (n = 3), AXIN2 (n = 2), BARD1 (N = 2), RAD50 (n = 2), RET (n = 2) and one case each of BMPR1A, BRIP1, CHEK2, MLH1, MSH6, SLX4 and TSC2. Conclusions: In our series 14% of USC harbored mutations in cancer predisposition genes.VUS are as high as 57% and represent a clinical challenge.