bluuebunny/crossref_metadata_2025_split huggingface dataset:
Risk of subsequent cancer diagnosis in patients treated with 3D conformal, intensity modulated, or proton beam radiation therapy.
Authors: Xiang Michael H. , Chang Daniel Tandel , Pollom Erqi L. 
Published: May 2019

1503 Background: Approximately half of cancer patients receive radiation therapy (RT). Modern RT modalities (3D conformal [3DCRT], intensity modulated [IMRT], proton beam [PBRT]) have been theorized to pose different risks of second cancers, but the relationship between RT modality and subsequent cancers has been unclear due to their rarity. Methods: Pediatric and adult patients with a first cancer diagnosis who received 3DCRT, IMRT, or PBRT were identified in the National Cancer Database. To analyze a more uniform population, cases were required to be non-metastatic and have at least 2 years of follow-up time. Ten cancer types were included: head/neck, upper gastrointestinal (GI), lower GI, gynecological, lymphoma, non-small cell lung, prostate, breast, bone/soft tissue, and brain/central nervous system. Diagnosis of a subsequent cancer was determined using a variable denoting the sequence of malignant neoplasms over the lifetime of the patient. The risk of subsequent cancer diagnosis was modeled using multivariable logistic regression adjusting for age, follow-up time, cancer type, RT dose, chemotherapy, and other factors. Propensity score matching was additionally used to balance baseline characteristics. Results: In total, 430,866 patients were included (33.4% 3DCRT, 65.1% IMRT, 1.5% PBRT) with median follow-up of 5.0 years and total follow-up period of 2.35 million person-years. In the comparison of IMRT relative to 3DCRT, there was no difference in the risk of subsequent cancer diagnosis (adjusted odds ratio [OR] 1.01; 95% confidence interval [CI] 0.98-1.03; p = 0.62). In contrast, recipients of PBRT had significantly lower risk of subsequent cancer diagnosis relative to IMRT (adjusted OR 0.31; 95% CI 0.26-0.37; p < 0.0001). The benefit associated with PBRT persisted in sensitivity analyses that excluded patients with prostate cancer (71.6% of the PBRT cases), receipt of chemotherapy, and/or follow-up time less than 5 years. Conclusions: Risk of subsequent cancer diagnosis was similar between IMRT and 3DCRT and significantly lower for PBRT. PBRT may be preferred in situations where avoidance of second cancers is paramount, such as pediatrics and young adults.
Ten-fold increase in genetic testing in pancreatic and metastatic prostate cancer with implementation of point of care (POC) testing.
Authors: Symecko Heather , Mueller Rebecca , Spielman Kelsey , Batson Melissa , Pundock Stacy , Hamilton Jada G. , Robson Mark E. , Domchek Susan M. 
Published: May 2019

1506 Background: Germline genetic testing (GT) for cancer susceptibility is recommended for pancreatic and advanced prostate cancer patients, due to potential implications for targeted therapies and risk assessment of family members. Traditional cancer GT programs may create barriers for certain patient populations. To more effectively integrate testing into standard oncology care POC GT was introduced in early 2018 in a joint protocol with Memorial Sloan Kettering Cancer Center. Here we report pre and post POC referral and testing numbers at the University of Pennsylvania. Methods: Patients with metastatic prostate or pancreatic cancer were ascertained through their GU/GI oncologist onto an IRB approved protocol and shown an educational video about GT by research staff who obtained informed consent and facilitated biospecimen collection. Genetic counselors returned results and provided post-test counseling by phone. To evaluate the impact of this model on the uptake of GT services, the number of patients who were referred to and proceeded with GT was compared before and after study initiation. Results: In 2017, 77 patients were referred to genetics of which 45 underwent genetic counseling and testing. Twenty-nine (38%) did not complete genetic counseling or testing, and 3 later underwent testing through the POC study. Since the study launched in 2018, 407 patients were referred and underwent testing through the study. This represents a ten-fold increase in patients who underwent GT. Conclusions: Comparing uptake of GT services before and after study initiation suggests that a POC model with abbreviated pre-test education and post-test genetic counseling by phone is a possible solution to barriers of traditional genetic counseling, increasing physician referrals and uptake of testing by patients. This approach allows for more timely access to genetic information that may impact treatment strategies and medical management of family members. Clinical trial information: pending. [Table: see text]
Characterization and clinical outcomes of mismatch repair deficient (dMMR) small bowel adenocarcinoma (SBA).
Authors: Latham Alicia , Reidy Diane Lauren , Segal Neil Howard , Yaeger Rona , Ganesh Karuna , Connell Louise Catherine , Kemeny Nancy E. , Shia Jinru , Hechtman Jaclyn Frances , Srinivasan Preethi , Patel Zalak , Tkachuk Kaitlyn , Berger Michael F. , Saltz Leonard B. , Cercek Andrea , Stadler Zsofia Kinga 
Published: May 2019

1511 Background: SBA is a rare cancer known to be associated with Lynch syndrome (LS). The prevalence, tumor characteristics, and clinical course of SBAs in the setting of LS is not well understood. We sought to characterize SBA according to mismatch repair and germline mutation status, comparing clinical outcomes. Methods: A retrospective review of SBAs at a single institution identified 74 SBAs that were assessed for dMMR either via immunohistochemical staining (IHC) or microsatellite instability status (MSI) using NGS. Germline DNA was analyzed for mutations in LS-associated mismatch repair genes ( MLH1, MSH2, MSH6, PMS2, EPCAM) and when available, clinical records were reviewed. Results: Of 74 individuals with SBA, 28.4% (21/74) of tumors exhibited dMMR and/or high-frequency MSI (MSI-H). The overall prevalence of LS in SBA was 9.5% (7/74), with all LS patients having dMMR/MSI-H tumors. 33.3% (7/21) of dMMR/MSI-H SBA patients had LS. The distribution of germline mutations among LS patients was 57.1% (4/7) in MLH1, 28.6% (2/7) in MSH2, and 14.3% (1/7) in PMS2. One patient with an dMMR/MSI-H tumor was found to have a high-penetrance APC mutation, diagnostic of familial adenomatous polyposis (FAP). In the 38 patients with available clinical follow-up, median age of onset was similar in the dMMR/MSI-H vs the pMMR/MSS group (62 vs 57, p = 0.8). The prevalence of synchronous/metachronous cancers was 5.9% (1/17) in the pMMR/MSS group and 38% (8/21) in the dMMR/MSI-H group (p = 0.02), with 62.5% (5/8) of these in LS (p = 0.001; synchronous/metachronous in LS (5/7) vs. non-LS (4/31)). In the pMMR/MSS group, 58.8% (10/17) of patients presented with metastatic disease at diagnosis, compared to 19% (4/21) in the dMMR/MSI-H group (p = 0.01). In dMMR/MSI-H SBA patients with early-stage disease, 11.8% (2/17) recurred, compared to 71.4% (5/7) in the pMMR/MSS group (p = 0.009). Conclusions: This preliminary evaluation suggests that SBA exhibiting dMMR/MSI-H status is more closely associated with early-stage disease and lower recurrence rates, similar to prior observations in colon cancer. LS was found in 9.5% of all SBA and in 33.3% of dMMR/MSI-H tumors, suggesting that germline assessment for LS in SBA is warranted.
New onset diabetes as a predictive factor of focal lesions in the pancreas in a high-risk screening program.
Authors: Montiel Maria Fernanda , Quesada Pompeyo Rafael , Dunseith Margaret , Cazacu Irina , Luzuriaga Alexandra , Dong Wenli , Bannon Sarah A. , Mork Maureen E , Feng Lei , You Y. Nancy , Vilar Sanchez Eduardo , Arun Banu , Brown Powel , Kim Michael Paul , Katz Matthew H. G. , Maitra Anirban , Bhutani Manoop S. , McAllister Florencia 
Published: May 2019

1512 Background: Genetic evolution studies have suggested the existence of a window of opportunity to improve clinical outcomes by intercepting pre-malignant lesions. This study reports the outcomes of Pancreatic Cancer (PC) surveillance in a high risk (HR) cohort followed at The University of Texas MD Anderson Cancer Center (MDA) between 2014 and 2018. Methods: The MDA PC High-Risk Clinic (MDA-PCHRC) performs surveillance based on risk stratification. This study reports 54 months of surveillance. The patients were stratified based on PC family history, personal history of other cancers, and germline mutations ( BRCA1/2, PALB2, STK11, CDKN2A, TP53) with high susceptibility to PC. Low risk patients were not offered surveillance while patients in the moderate or high-risk category were enrolled into a program which included annual screening with blood markers (CA 19-9, fasting glucose, HbA1C, amylase, and lipase) and magnetic resonance imaging/ cholangiopancreatography (MRI/MRCP). High risk patients also had a baseline endoscopic ultrasound (EUS). We evaluated the yield of premalignant lesions detection and our main goal was to detect predictive factors of focal pancreatic lesions and to validate our risk stratification strategy. Results: A total of 206 patients have been referred to our clinic during this time period. From this group, 126 (61%) patients completed at least one cycle of baseline surveillance, for the purposes of the analysis we only focus in the high risk (n=71) and moderate risk group (n=38). We have identified de novo pancreatic focal lesions in 22 patients, 20 from the high risk group (28%) and 2 from the moderate group (5%). Those lesions included 7 patients with simple cysts, 9 with side-branch IPMN, 3 with main duct IPMN, 1 with pseudocyst, 1 with mucinous cyst and 1 with a solid nodule (pancreatic neuroendocrine tumor). We compared demographic information (age, gender, and ethnicity) as well as family and personal medical history between patients with focal pancreatic lesions vs negative or diffuse findings. We found that new onset diabetes was significantly correlated with presence of focal pancreatic lesions 5 (22%) of patients with focal lesions versus patients without non focal lesion 2 (2%) ( P=0.003). Conclusions: Screening at the MDA-PCHRC detect pancreatic premalignant lesions in 20% of the patients in our cohort. We validated our risk stratification methodology and found that new-onset diabetes is predictive of pancreatic lesions, thus suggesting that this factor could be an important biomarker of focal lesions in a HR population.
Racial and ethnic differences in the results of multigene panel testing of inherited cancer predisposition genes in breast cancer patients.
Authors: Yadav Siddhartha , LaDuca Holly , Polley Eric , Shimelis Hermela , Niguidula Nancy , Hu Chunling , Lilyquist Jenna , Na Jie , Lee Kun , Gutierrez Stephanie , Yussuf Amal , Hart Steven , Tippin Davis Brigette , Chao Elizabeth , Pesaran Tina , Goldgar David , Dolinsky Jill S. , Couch Fergus 
Published: May 2019

1514 Background: The prevalence of germline mutations in non-white patients with breast cancer and the germline genetic drivers of breast cancer risk in non-white populations are largely unknown. Methods: The study population included 77,900 women with breast cancer (Non-Hispanic white: 57,003; Black: 6,722; Asian: 4,183; Hispanic: 5,194; Ashkenazi-Jewish: 4,798) who underwent germline multigene panel testing of cancer predisposition genes from March 2012 to December 2016. The prevalence of predisposition gene mutations in racial and ethnic populations relative to non-Hispanic Whites was assessed while accounting for age at diagnosis of breast cancer, family history of breast and ovarian cancer, and estrogen receptor status of breast tumors. Associations between mutations in each gene and breast cancer risk were evaluated using reference controls. Results: The overall frequency of pathogenic mutations in known breast cancer predisposition genes was 9.1% for non-Hispanic Whites, 9.8% for African Americans, 10.2% for Hispanics, 7.6% for Ashkenazi-Jewish, and 7.5% for Asians. BRCA1 mutations were enriched (p < 0.05) and CHEK2 mutations were under-represented in all racial and ethnic populations relative to non-Hispanic Whites. BRCA2 and BARD1 mutations were enriched in African Americans and Hispanics relative to non-Hispanic Whites, whereas PALB2 and RAD51C mutations were enriched in Hispanics. Among genes with mutation counts large enough for assessment, mutations in BARD1, BRCA1, BRCA2, PALB2 and TP53 were significantly associated with clinically relevant increased risks (odds ratio (OR) > 2) of breast cancer across all ethnicities and races. Rates of variants of uncertain significance were highest among Asians (29%), followed by blacks (27%), Hispanics (21%), non-Hispanic whites (16%) and Ashkenazi-Jews (14%). Conclusions: While there is some similarity across ethnic groups, substantial heterogeneity exists in the prevalence of mutations in breast cancer predisposition genes across major racial and ethnic groups in the US population. These findings contribute to our understanding of breast cancer risk and have significant implications for genetic testing, screening, and management of patients with an inherited predisposition to breast cancer, with a need for continued analysis with increased cohort size in ethnic minority groups.
Germline mutations and onset of lung adenocarcinoma in smokers and nonsmokers.
Authors: Reckamp Karen L. , Slavin Thomas Paul , Gray Stacy W. , Behrendt Carolyn E. , Castillo Danielle , Koczywas Marianna , Cristea Mihaela C. , Babski Kirsten , Stearns Donna , Marcum Catherine A , Rodriguez Yeny , Hass Amie , Vecchio Mary , Mora Alferez Analí Pamela , Cervantes Aleck , Sand Sharon , Mach Stephanie L , Tsou Terrence , Salgia Ravi , Weitzel Jeffrey N. 
Published: May 2019

1518 Background: Eligibility for lung cancer screening is based largely on pack-years of smoking, missing many cases. To propose additional groups for screening, this observational study evaluated whether germline mutations associated with cancer risk accelerate onset of lung adenocarcinoma (LA) in ever- and never-smokers. Methods: Patients with LA and family history of cancer were recruited from our oncology clinic and the Clinical Cancer Genomics Community Research Network. With consent, blood samples were screened by large multi-gene panel for 4 categories of germline mutation [lung cancer-associated genes ( TP53, EGFR); BRCA2; other genes in Fanconi anemia (FA) pathway; other DNA repair genes]. Accelerated failure-time models of age at LA diagnosis, adjusted for sex, ethnicity, and packs per day, were constructed for never-smokers and ever-smokers. Statistical significance, at p<0.05 limited the False Discovery Rate to 5% across 8 hypotheses. Results: In never-smokers with LA (n=104), mutated BRCA2, TP53 or EGFR were associated with younger age at diagnosis, while mutation in other FA or DNA repair gene was not. In ever-smokers with LA (n=65), mutated BRCA2 and other FA gene were associated with younger age at diagnosis, while other mutation categories were not (Table). Conclusions: Regardless of smoking history, BRCA2 mutation carriers experience accelerated onset of LA, as do never-smokers carrying TP53 or EGFR mutation and ever-smokers with mutation in FA gene other than BRCA2. With the exception of TP53 carriers (who merit whole body MRI), lung cancer screening with low-dose computed tomography, starting earlier in adulthood than usual, may be warranted for individuals with germline mutations in these genes. Age at Diagnosis of Lung Adenocarcinoma, by Germline Mutation and Smoking History, Adjusted for Sex, Ethnicity, and Packs per Day. [Table: see text]
Prevalence and clinical implications of mismatch repair (MMR) deficiency in unselected non-serous epithelial ovarian cancer (EOC) patients (pts).
Authors: Scaranti Mariana , Murali Krithika , Orbegoso Cecilia , Vroobel Katherine , Banerjee Susana N. , Gore Martin Eric , Attygalle Ayoma , George Angela 
Published: May 2019

1521 Background: It has previously been reported that 6-7% of clear cell (CC) and endometrioid (E) ovarian cancers are MMR deficient (MMRd). The prevalence of MMRd in other histological subtypes and correlation with germline (g) MMR (Lynch Syndrome) mutations in unselected non-serous EOC pts is less clear. MMRd in solid tumors has been associated with enhanced response to immunotherapy, hence knowledge of MMR status has therapeutic and familial implications. We aimed to study the prevalence and implications of MMRd and gMMRd in unselected pts with non-serous EOC. Methods: Routine immunohistochemistry (IHC) was performed for the MMR proteins MLH1, MSH2, MSH6 and PMS2 in all non-serous EOC pts from June 2016; retrospective MMR IHC testing in pts in follow-up was performed. Pts with MMRd tumors were referred for gMMR testing. Results: We analyzed 66 unselected pts with non-serous EOC. Median age was 56.4 years (yrs). The majority had E ovarian cancer (54.5%) followed by CC (25.8%), mixed histology (12.1%), mucinous (4.5%) and mullerian (3%) subtypes. Endometriosis was noted in 45.5% of pts, and 75% were FIGO stage I and II at diagnosis. Seventeen pts (25.8%) had concurrent endometrial cancer, all Grade I. On IHC, 15.2% were MMRd: 5 E, 2 CC, 2 mixed and 1 mullerian-type. Of these, 3 pts (30%) had gMMR mutation, 2/3 did not meet the Revised Bethesda criteria for testing. A lower average body mass index (Kg/m2) was noted in MMRd 25.9 versus 30.1 in MMR proficient (MMRp). Median age at diagnosis was 53.5 yrs in the MMRd and 57.7 yrs in MMRp. A higher frequency of concurrent endometrial cancer was observed on the MMRd group (60%) versus (20%) on MMRp (p = 0.007). No statistically significant difference in overall survival or disease-free survival was observed between the MMRd and MMRp population. Conclusions: Our study has shown a higher prevalence of somatic MMRd in non-serous EOC (15.2%) than in previously published literature with a significant proportion found to carry gMMR mutations (4.5%). These interim findings support the role of universal MMR IHC testing in non-serous EOC regardless of family history. [Table: see text]
Characterization of Lynch syndrome (LS) associated cancers in patients with immune dysfunction.
Authors: Bari Shahla , Wang Xia , Ajose Taiwo , Muzaffar Jameel 
Published: May 2019

1532 Background: LS is caused by a germline mutation in one of several DNA mismatch repair (MMR) genes: MLH1, MSH2, MSH6 or PMS2. Inappropriate immune responses as seen in chronic inflammatory conditions as well as immunodeficiency states confer increased risk of developing cancer. This aim of this study was to evaluate the effect of immune dysfunction on the characteristics of LS associated cancers. Methods: This was a retrospective analysis of LS patients and carriers at two institutions listed above. We evaluated mutational profiles, immune status, age of onset of first and subsequent cancers in this cohort. Results: 106 patients with mutations consistent with LS were included. 72 patients had at least one cancer while 34 were carriers. 44% patients were Caucasian female, 18% white males, 14% African American males, 11% African American females and 10% Hispanic females. Colon cancer (CRC) was the most common cancer (44%) and PMS2 was the most common mutation, noted in 35 patients (33%). Of the 72 patients with LS associated cancer, 18 patients were either immunosuppressed or had an autoimmune condition. Of the 10 patients who had an autoimmune condition ,7 had multiple cancers. Of the 9 patients who were immunosuppressed, 5 had multiple cancers. Out of a total of 18 out of 72 patients who had multiple cancers, 12 (66%) had either an autoimmune condition or were immunosuppressed. CRC was the index cancer in 42% and breast in 33% of patients with multiple cancers. Patients with MSH2 were most likely to have an immune related condition (32%) and accounted for 41% of patients with multiple cancers. The median age of first cancer in this group was 46 years while it was 48.5 years in the population without immune dysfunction (p = 0.2). There was a high prevalence of breast cancer (24%) as a LS associated cancer in our study population. 66% of the patients with PMS2 mutation had breast cancer with a median age of onset of 48 years (62 years for sporadic cancer). Conclusions: Our study is the first to look at the effect of immune dysfunction in LS patients. Immune dysfunction was associated with a higher rate of multiple cancers and was more commonly associated with the MSH2 mutation. It also highlights importance of aggressive screening for breast cancer in LS patients (especially with PMS2 mutation).
Risk of colon adenoma in patients with breast cancer.
Authors: Wang Yinghong , Abu-Sbeih Hamzah , Ali Faisal , Ge Phillip S. , Barcenas Carlos Hernando , Lum Phillip , Qiao Wei , Bresalier Robert , Bhutani Manoop S. , Gottumukkala Raju S. 
Published: May 2019

1541 Background: In our clinical practice at a tertiary cancer center, we have observed increased adenoma detection rate (ADR) in patients with breast cancer. Here, we describe ADR in patients with breast cancer to define the appropriate timing to initiate colonoscopy screening in these patients. Methods: We conducted a retrospective study of patients with breast cancer who underwent a colonoscopy after their diagnosis of breast cancer between 2000 and 2017. A control group ( n = 3295) comprised patients without any type of cancer who underwent their first screening colonoscopy between 2008 and 2017 was used in the logistic regression. Results: Of the 62,820 patients who had a diagnosis of breast cancer, 3304 were included. The mean age was 59 years. Regarding ADR, 1803 patients (55%) had adenomas. High-grade dysplasia was evident in 28% of polyps and invasive adenocarcinoma in 172 (5%). The median time from breast cancer diagnosis to adenoma detection was 3 years (IQR 1-6). The ADR was 21% in patients younger than 40 years ( n=63), 39% in patients between 40 and 50 years ( n=314), 54% in patients between 50 and 60 years ( n=1420), and 60% in patients older than 60 years ( n=1507). ADR in patients younger than 50 years of age who do not have a family history of colorectal cancer or a body mass index (BMI) higher than 30 kg/m2 was 26%. A subsequent colonoscopy was performed in 831 patients who had colonic adenoma in the initial colonoscopy. The ADR was 40% in patients who had a repeat colonoscopy within 3 years, 50% within 3-5 years, and 53% > 5 years. Multivariate logistic regression analyses revealed an increased risk of colon adenoma with older age, male sex, higher BMI, and personal history of breast cancer ( P<0.05). Conclusions: In patients with breast cancer, ADR was higher than that of patients without history of cancer. Notably, breast cancer was an independent risk factor for colon adenoma. In patients who are younger than 40 years of age, screening colonoscopy should be considered within five years of breast cancer diagnosis. Multivariate logistic regression: risk factors of adenoma. [Table: see text]