bluuebunny/crossref_metadata_2025 huggingface dataset:
A phase II study of pembrolizumab and capecitabine for triple-negative (TN) and hormone receptor-positive, HER2-negative endocrine-refractory metastatic breast cancer (MBC).
Authors: Shah Ami N. , Flaum Lisa E. , Rademaker Alfred , Santa-Maria Cesar Augusto , Jain Sarika , Helenowski Irene B. , Kindy Kelly , Dedic Tara , Uthe Regina , Nelson Valerie , Tsarwhas Dean , Cristofanilli Massimo , Gradishar William John
Published: May 2019

1096

Background: Response rates to single agent immune checkpoint blockade in unselected MBC are low; however, they may be augmented when combined with chemotherapy. Methods: We conducted a single-arm, phase II study of patients with TN or endocrine-refractory MBC who were candidates for capecitabine. Patients were treated with pembrolizumab 200 mg IV day 1 and capecitabine 1000 mg PO BID days 1-14 of a 21-day cycle. The primary endpoint was progression free survival (PFS) and secondary endpoints were overall response rate (ORR), safety and tolerability. The study had 80% power to detect a 2 month (mo) improvement in mPFS with the addition of pembrolizumab over historic controls treated with capecitabine alone. Results: Thirty patients, 16 with TN and 14 endocrine-refractory MBC, were enrolled from 2017-18. Patients had a median age of 51 years and received a median of 1 prior line of therapy for MBC. Of 29 evaluable patients, the mPFS was 4.1 mo (95% CI, 2.3-8.2 mo) and median overall survival was 15.4 mo (95% CI, 8.2-16.6 mo). ORR was 14% (n = 4), stable disease (SD) was 41% (n = 12), and clinical benefit rate (CBR = PR + SD > 6 mo) was 28% (n = 8). The ORR and CBR were similar between disease subtypes (ORR 13% and 14%, CBR 25% and 29% for TN and endocrine refractory, respectively). The 1-year PFS rate was 20.7% and 3 pts have ongoing responses. The most common adverse events were low grade and consistent with those seen in MBC patients receiving capecitabine, including hand-foot syndrome, gastrointestinal symptoms, fatigue, and cytopenias. Toxicities at least possibly from pembrolizumab included grade 3 or 4 liver test abnormalities (7%), rash (7%), and diarrhea (3%), as well as grade 5 hepatic failure in a pt with liver metastases. Conclusions: Compared to historical controls, pembrolizumab with capecitabine did not improve PFS in this biomarker unselected cohort; however, some patients had prolonged disease control. Future studies of chemo-immunotherapy in MBC with liver metastases require close safety monitoring. Clinical trial information: NCT03044730.
Measuring on-treatment genome-wide tumor copy number alterations in cell-free DNA (cfDNA) in plasma is highly prognostic in metastatic breast cancer.
Authors: Aguilar Adriana , Lafleur Josiane , Brousse Susie , Ferrario Cristiano , McLennan Graham , Jensen Taylor J. , Kimberly Kelly , Basik Mark
Published: May 2019

1097

Background: The clinical management of metastatic breast cancer depends on the measurement of tumor response to successive drugs by serial imaging and changes in blood tumor markers, which remain the standard of care despite poor sensitivity and specificity. Highly sensitive and specific cfDNA secreted from the tumor can detect the changes in tumor-specific aberrations that have been shown to be associated with patient response in the metastatic setting. However, most approaches require prior sequencing of the tumor to target specific known mutations. Methods: Using low coverage genomic sequencing, a genomic instability number (GIN) was measured in cfDNA based on the detection of genome-wide tumor-specific DNA copy number alterations for 27 patients with metastatic breast cancer. The GIN value and its variation from baseline before treatment, as well as within 10 days and 3 weeks after start of therapy were compared with tumor response, progression free survival (PFS) and overall survival (OS) of the patients. Patients were followed for a median of 22 months and we used a previously published GIN threshold at 170 for high vs low GIN values. Sequencing was performed blinded to the clinical results. Results: Baseline GIN values were not associated with tumor response at 3or 6 months, but showed a trend towards lower OS with higher GIN (p = 0.12). GIN values fell by an average of 28% in responders (stable disease or response) and 23% in those with progression (p = 0.85), but remained lower at 3 weeks only in the responders. High GIN values within 10 days and 3 weeks were associated with markedly worse OS (p = 0.014 and p = 0.009 respectively) and those at 3 weeks with worse PFS (p = 0.017). Hence the median survival of patients with high GIN at 10 days or 3 weeks was 12 months vs not reached for those with low GIN. The percentage drop of GIN at 10 days but not at 3 weeks was significantly associated with PFS (p = 0.016). Conclusions: These results demonstrate that GIN values of cfDNA measured at early on-treatment time points can predict PFS and OS with a high degree of accuracy. These findings deserve further study in a larger cohort but hold the promise of early prediction of clinical outcomes in a tumor-independent genome-wide approach.
Evaluation of pathologic and genomic characteristics in male breast cancer (MBC) patients.
Authors: Hansra Damien Mikael , Ahn Eugene R , McKnight John Edward , Pabbathi Haritha , Lynch Cynthia , Crilley Pamela A. , Parikh Ankur Rasik , Aithal Sramila , Moran Amber , Rollins Rebecca , Nixon Daniel W. , Markman Maurie , Alvarez Ricardo H.
Published: May 2019

1098

Background: MBC is a rare entity comprising less than 1% of breast cancers [Siegel RL 2017]. Due to the low incidence of MBC, information about the genomic landscape of MBC is lacking. Here we describe detailed pathologic and genomic characteristics of MBC patients. Methods: IRB approval was obtained for a retrospective analysis of archived pathology on patients treated at Cancer Treatment Centers of America. Comprehensive genomic profiling of tumors was derived from Foundation One next generation sequencing. Clinical information was derived from retrospective chart review. Inclusions: adult males with breast cancer with stage IV metastatic disease. Exclusions: Females, stage 0-IIIC disease, missing genomic and pathology information. Results of clinical, pathology and genomic data were summarized. Results: 10 patients met study criteria. Median age: 56 yrs., range 39-61 yrs. Race: 5/10 (50%) Caucasian, 5/10 (50%) African American. Number of prior treatment regimens: mean = 2.6 (range 0-6). Intrinsic subgroup: hormone receptor (HR)+/ HER2- 7/10 (70%), HR+/ HER2+ 2/10 (20%), HR-/ HER2+ 1/10 (10%), triple negative breast cancer (TNBC) 0/10 (0%). Tumor histology: invasive ductal carcinoma 10/10 (100%). Histology grade: poorly differentiated (diff.) 4/10 (40%), moderate diff. 4/10 (40%), well diff. 1/10 (10%), unknown 1/10 (10%). Biopsy site: primary tumor 4/10 (40%), metastatic site 4/10 (40%), liquid biopsy 1/10 (10%). Most frequent genomic alterations: PIK3CA 5/9 (56%), CCND1 4/9 (44%), ZNF703 3/9 (33%), FGF4 3/10 (33%), GATA3 3/9 (33%) FGF 19 3/9 (33%), FGF3 3/9 (33%) Alterations in FGF seen 14/38 (36.8%) of total genomic alterations. Most frequent alterations by primary tumor: ZNF703 3/4 (75%), FGF3 2/4 (50%), FGFR1 2/4 (50%), CCND1 2/4 (50%), FGF19 2/4 (50%), FGF4 2/4 (50%); by metastatic site: PIK3CA 4/5 (80%), GATA 3 2/5 (40%), CCND1 2/5 (40%), FGF3 1/5 (20%), FGF19 1/5 (20%), FGF4 1/5 (20%). Genomic alteration by histologic subgroup; HR+ HER2- PIK3CA 3/6 (50%), CCND1 3/6 (50%), FGF4 3/6 (50%), ZNF703 3/6 (50%), FGF19 3/6 (50%), FGF3 3/6 (50%); HR+/ HER2+: PIK3CA 2/2 (100%), CCND1 1/2 (50%), GATA3 1/2 (50%), MLL3 1/2 (50%); TNBC: BRCA2 1/1 (100%), BARD1 1/1 (100%). Microsatellite status was stable in 6/6 (100%) of patients. Conclusions: MBC patients display a heterogeneous variety of complex genomic alterations. Mutations in FGF genes were most commonly observed. Other common alterations seen in this series include PIK3CA, CCND1, ZNF703, and GATA3. Furthermore, the genomic profile of primary tumor site differed from the genomic profile of the metastatic site.
Outcomes after adjuvant radiotherapy in breast cancer patients with and without germline mutations: A large, single-institutional experience.
Authors: Chapman Bhavana Sree Vangara , Liu Diane D. , Stecklein Shane Richard , Gutierrez Barrera Angelica , Woodward Wendy A. , Sawakuchi Gabriel O , Arun Banu , Shaitelman Simona Flora
Published: May 2019

1502

Background: Women with germline mutations in DNA repair pathways are at an increased risk of developing breast cancer. We posit that tumors arising in these patients may be more sensitive to radiotherapy and, therefore, patients may experience improved locoregional control and survival outcomes following adjuvant radiotherapy as compared to patients without DNA repair pathway mutations. Methods: We evaluated the records of 2,221 women with stage 0-III de novo primary breast cancer treated with surgery and adjuvant radiotherapy who all underwent genetic testing at our institution from 1993 to 2018. Mutations were categorized as pathogenic variant, variant of unknown significance (VUS), or negative. The Kaplan-Meier method was used to estimate the locoregional recurrence rate (LRR), rate of distant metastasis (DM), disease-free survival (DSS), and overall survival (OS) from the time of surgery. Results: The median age at diagnosis was 45 years (range 19-84). Median follow-up time was 7 years (95% confidence interval 6.6-7.4). Among 1,960 patients with evaluable radiation records, 752 (38.4%) received breast only radiation, 12 (0.6%) received chest wall only radiation, and 1,196 (61.0%) received breast/chest wall and regional nodal radiation. A total of 255 (11.4%) and 162 (7.3%) patients had a pathogenic variant mutation and a VUS only, respectively. Pathogenic variant and VUS in BRCA1/2 mutations were detected in 216 (9.7%) and 82 (3.7%) patients, respectively. Perturbations in ATM, CHEK2, MLH, MSH2/6, MUTYH, PALB2, RAD50/51, and/or TP53 were detected in 71% (85/119) of patients who tested positive for a non- BRCA1/2 pathogenic variant or VUS. On univariate analysis, there was no significant association between BRCA1/2 mutation status or any genetic mutation and rate of LRR or DM, DSS, or OS ( p > 0.10 for all). Clinicopathological features including advanced stage and lymphovascular invasion were associated with higher cumulative incidence of LRR and DM as well as shorter DFS and OS ( p < 0.01 for all). Conclusions: Herein we report on the largest cohort of women with breast cancer treated with adjuvant radiotherapy at a single institution who have undergone germline testing. Our findings suggest that the overall prognosis of breast cancer treated with adjuvant radiotherapy in patients with germline BRCA1/2 or other genetic predisposition is similar to patients with sporadic breast cancer. Further investigation to evaluate acute or late toxicities and secondary cancers as a result of radiotherapy is warranted.
Breast radiotherapy among ATM-mutation carriers.
Authors: Modlin Leslie A. , Flynn Jessica , Zhang Zhigang , Mueller Boris , Khan Atif J. , Gillespie Erin F. , Cahlon Oren , McCormick Beryl , Robson Mark E. , Powell Simon N. , Braunstein Lior Zvi
Published: May 2019

1504

Background: Syndromes of DNA repair deficiency may confer both cancer predisposition and increased sensitivity to DNA damaging agents, such as ionizing radiation. Whereas homozygous deficiency of ATM causes the ataxia telangiectasia syndrome, heterozygous ATM mutation carriers exhibit increased rates of breast, pancreas and prostate cancers. ATM repairs DNA double-strand breaks; consequently, mutation carriers may exhibit excessive radiotherapeutic (RT) toxicity. We evaluated the tolerability of adjuvant breast radiation in ATM mutation carriers. Methods: We identified 167 ATM mutation carriers presenting to our institution with breast cancer; of these, 91 received RT and records were reviewed for RT-related morbidity. Toxicities were graded per CTCAE v5. Associations of clinicopathologic features with toxicity were evaluated by multivariate regression. Results: Of 91 ATM mutation carriers receiving breast RT, 31% (n = 28) harbored a pathogenic mutation whereas 69% (n = 63) harbored variants of uncertain significance (VUS). 71% (n = 65) underwent lumpectomy and adjuvant whole-breast RT; 29% (n = 26) had mastectomy and PMRT. Nine patients underwent bilateral RT for a total of 100 RT courses. 86% of RT courses comprised whole-breast/chest-wall tangents; 14% were VMAT or protons. Median tangent dose was 50Gy; 62% included an additional boost (median 10Gy) and 48% used a bolus (median thickness 0.3cm). Lymph nodes were treated in 43% (n = 39). At last on-treatment visit, 31% had grade 2 dermatitis, 4% had other grade 2 events (fatigue, seroma, decreased range of motion, or pain), and 1% had grade 3 dermatitis. At 1 year, 13% had grade ≥2 toxicity: grade 2a lymphedema (n = 3), and grade 2 (n = 1) or 3 (n = 2) capsular contracture. At last follow-up, 4 PMRT patients had capsular contracture (3 with grade 2, 1 with grade 3); 1 patient had grade 2b lymphedema. Overall, no patients had significant (grade ≥2) telangiectasias, fibrosis, or fat necrosis; no grade 4 or 5 toxicities were seen. Neither pathogenic ATM mutations nor VUS were associated with acute or late RT toxicities. Conclusions: We found no evidence of excess breast radiation toxicity among ATM mutation carriers, either pathogenic or VUS. Breast conserving therapy can be safely considered in this population.
Gliomas in the context of Li-Fraumeni syndrome: An international cohort.
Authors: Michaeli Orli , Tabori Uri , Schiffman Joshua David , Naumer Anne , Kohlmann Wendy , Evans D. Gareth , Forde Claire , Hoffman Lindsey Marie , Rednam Surya P , Maxwell Kara Noelle , Bornhorst Miriam , O'Neill Allison Frances , Nichols Kim , Villani Anita , Slavin Thomas Paul , Caspi Shani , Zelcer Shayna M. , Leary Sarah , Stasi Shannon M , Malkin David
Published: May 2019

1517

Background: Li-Fraumeni syndrome (LFS) is a cancer predisposition syndrome associated with germline mutation in the TP53 tumor suppressor gene. As a result of increased awareness and surveillance imaging, more asymptomatic low-grade brain lesions are being identified, raising important questions regarding the management of those patients. Sporadic low-grade gliomas (LGG) in the pediatric age rarely transform to malignant lesions, whereas the prognosis of high-grade gliomas (HGG) is grim in all age groups. Although HGG is a hallmark of LFS, little is known of the natural history of these lesions in this syndrome. Methods: For this multi-institutional retrospective study, anonymized clinicopathologic data from TP53 mutation carriers with gliomas were collected and analysed. Results: Our cohort included 61 patients, of whom 71% (n = 45) were children or young adults (age < 25 years). 39% of patients with known family history of cancer had a close relative with a brain tumor. Of 31 patients with low grade lesions at presentation, 83% (n = 26) were identified through surveillance. Five-year progression free survival (PFS) for these patients was 48%, though two patients progressed later. Furthermore, at 5 years 25% of these patients had biopsy proven malignant transformation to HGG. This “transformation free survival” rate did not plateau, as at 7 years 56% of patients transformed. When considering death from a brain tumor, the 5- and 10- year overall survival (OS) for the LGG group was 100% and 83%, respectively. Additional 3 patients succumbed to other LFS related malignancies. For the HGG group, consisting of 30 patients, the 5 year OS was 35% (median follow-up 19.5 months), comparing favorably with the sporadic HGG population as reported in the literature. Almost all of these patients presented with clinical symptoms. Notably, 12 (40%) of them had a prior malignancy. Conclusions: Our analysis suggests that the risk of transformation of LGG in the setting of LFS is high and warrants ongoing surveillance. Interestingly, there are a considerable number of long- term survivors in our HGG group, although the median follow up is still short. Further study to examine potential genotype- phenotype correlations in germline TP53 mutation carriers will inform strategies to identify those patients at highest risk of glioma progression.
Gaining insights into the DICER1 syndrome: An early report from the Italian DICER1 registry.
Authors: De Nicolo Arcangela , Turchetti Daniela , Brugnoletti Fulvia , Elefanti Lisa , Field Amanda , Innella Giovanni , Tita Rossella , Feroce Irene , Pomponi Maria Grazia , Zuntini Roberta , Renieri Alessandra , Bonanni Bernardo , Kanellopoulou Chrysi , Landi Maria Teresa , Hill D. Ashley , Menin Chiara , Genuardi Maurizio
Published: May 2019

1519

Background: DICER1 is a key endoribonuclease in the microRNA pathway that modulates gene expression. Germline loss of function variants in DICER1, first found in pleuropulmonary blastoma, have been subsequently linked to a variety of cancerous (and non) conditions referred to as DICER1 syndrome. In 2018, the Italian Society of Human Genetics launched an initiative aimed at establishing a national registry of DICER1 germline sequence variants. Methods: Centers involved in genetic testing for cancer predisposition were asked to report any identified DICER1 germline variants and related clinical information. Five University and/or research institutes filled-in the electronic survey. Informed consent was obtained from patients or their legal guardians prior to DNA testing by NGS and/or Sanger sequencing. Results: Six DICER1 sequence variants were identified in 11 individuals. Three missense variants are secondary results of NGS panels for cancer predisposition and lack definitive categorization in online databases. Three previously unreported variants are predicted to be protein truncating and, hence, likely pathogenic. Of these, DICER1 c.4844delA p.(Lys1615Argfs*5) and c.4886C > G p.(Ser1629*) result from ad hoc testing offered to probands based on a history of early onset follicular thyroid carcinoma and botryoid-type embryonal rhabdomyosarcoma of the cervix and of pleuropulmonary blastoma 2nd type, respectively. DICER1 c.4643T > A p.(Leu1548*), instead, results from whole exome sequencing in two siblings with malignant melanoma who tested non informative for alterations in the CDKN2A and CDK4 melanoma predisposing genes. Further investigation unearthed thyroid disease in the family and identified two other young carrier individuals, one unaffected and one thyroidectomized due to multinodular goiter. A DICER1 somatic hot spot sequence variant was detected in goiter specimens. Conclusions: Via the newly established national registry we uncovered novel DICER1 germline sequence variants and uncommon genotype-phenotype associations. Our joint effort will help us to refine our knowledge of the rare DICER1 syndrome , to inform research studies, and to improve testing and clinical management strategies.
Risk of cancer in first-degree relatives of childhood cancer patients: A linked longitudinal population-based registry study.
Authors: Madanat-Harjuoja Laura-Maria , Pitkäniemi Janne , Hirvonen Elli , Malila Nea , Diller Lisa
Published: May 2019

1522

Background: Population based data on risk of cancer in relatives of childhood cancer patients are sparse. Using linked population-based registries, we set out to evaluate risk of early onset cancer in first-degree relatives of childhood cancer patients. Methods: We queried the Finnish Cancer Registry and ascertained a cohort of 9135 individuals diagnosed with at least one cancer under the age of 21 years between 1970 and 2012. We then went on to identify a total of 58,211 unique first- and second-degree relatives by linking to the Central Population Registry. Relatives were then linked back to the annually updated Finnish Cancer Registry to identify cancer diagnoses in siblings, offspring and parents of childhood cancer patients, restricting to cancers occurring under the age of 40. Risk of cancer in relatives of the index case was estimated using standardized incidence ratios (SIRs) comparing cancer age and period specific incidence in relatives to that of the general population. Results: A total of 288 cancers were diagnosed in relatives during the 900,907 years of follow-up, while 266 cancers were expected. The overall risk of cancer in siblings of childhood cancer patients was elevated (SIR 1.18 95% CI 1.00-1.39). 144 of the childhood cancer patients were identified as having a sibling additional to index case with a diagnosis of cancer at age < 40; 44 of these 144 also had a parent with early onset cancer. The risk of early onset cancer was elevated in offspring overall (SIR 1.79 95%CI 1.05-2.81) and in offspring of retinoblastoma, malignant bone tumor and neuroblastoma patients. Siblings of lymphoma patients were at elevated risk of early cancer, and the mothers of 11 of 27 sibling pairs (lymphoma + cancer < 40 yo) also had cancer at age < 40. Conclusions: Linked registries allow family history of cancer to be evaluated across multiple relatives and to be longitudinally updated. Results are generally reassuring with regard to risk of cancer in relatives of childhood cancer patients. Elevated risk in relatives of retinoblastoma and malignant bone tumor patients are in line with the known cancer syndromes associated with these tumor types, and lymphoma and neuroblastoma families need further analysis.
Rare tumor with matched germline whole exome sequencing to identify somatic and inherited variants of clinical significance.
Authors: Perkins Bryce , Sprissler Ryan , Babiker Hani M. , Chalasani Pavani , Johnstone Laurel , Lau Brandon , Ramos Kenneth , Placencia Crystal , Gutenkunst Ryan , Hammer Michael , Mahadevan Daruka
Published: May 2019

1523

Background: Rare cancer incidence is defined as <6/100,000 cases. These cases are challenging due to delays in diagnosis, late stage at diagnosis, lack of standard of care and poor outcomes. We present molecular profiling of 28 rare tumor cases analyzed by whole exome sequencing (WES) seen in the Early Phase Therapeutics Program. Methods: We performed WES on 15 rare tumors with matched germline DNA, as well as tumor only on 2 additional cases. We sequenced a panel of 500 candidate cancer genes in 6 tumor/normal and 6 tumor only cases. Copy number alterations (CNAs) were assessed for the tumor-normal WES cases with SNVs and small indels for all cases. Caris (AZ) (tumor only) and liquid biopsy (Gaurdant360, CA) were also conducted in these patients for comparison. Results: Rare tumors affected 18 different tissues of the body with 1 case affecting tissue typical of common cancers. The rare tumor group contained 25% pathogenic or likely pathogenic germline variants compared to 7.1% for common tumors. This increased rate of inherited pathogenic variants met statistical significance: Fisher exact test (p = 0.0118). A total of 69 sequence variants and 8 CNAs were identified, 37 were actionable. For all but 3 patients, there was at least one variant associated with an actionable outcome given off-label use or clinical trial participation. There was excellent concordance with results from commercial sequencing; however, our tumor/germline sequencing identified additional germline variants of clinical significance, all were loss-of-function variants in tumor suppressors. Tumor vs. normal analysis showed that the majority of the commercially reported VUS were in fact germline VUS. In one case, a reported pathogenic variant we found to be an inherited pathogenic germline variant. 15 patients received at least 1 line of therapy indicated by genomic sequencing. For these patients the PFS ratio when compared to the most recent line of therapy prior to targeted therapy was 2.02, with 10/15 (67%) patients having a PFS ratio of >1.0, and 6/15 (40%) of patients having PFS ratio >1.3. Conclusions: We demonstrate the importance of tumor-normal analysis, especially in the context of rare tumors. Rare tumor patients may disproportionately benefit from tumor vs. normal WES at diagnosis to improve PFS within targeted therapy trials, guided by genomics.
Safety and efficacy of aspirin for primary prevention of cancer: A meta-analysis of randomized controlled trials.
Authors: Haykal Tarek , Barbarawi Mahmoud , Zayed Yazan , Kheiri Babikir , Yelangi Anitha , Dhillon Harsukh , Goranta Sowmya , Chahine Adam , Samji Varun , Bachuwa Ghassan , Katato Khalil
Published: May 2019

1533

Background: In the United States, cancer is the second leading cause of mortality, and millions more battle cancer worldwide. As such, primary prevention of cancer is a major interest globally. Aspirin has been studied as a primary prevention method for multiple diseases, mainly cardiovascular disease and various forms of cancer. The role of aspirin as a primary prevention of cancer is still controversial and may be more beneficial in certain cancers over others. With rapidly surfacing large randomized controlled trials (RCTs) studying this subject, we aimed to evaluate the efficacy and safety of aspirin as a primary prophylaxis for cancer. Methods: A comprehensive electronic database search was conducted for all RCTs that compared aspirin versus placebo for the prevention of any type of disease, and where cancer incidence or mortality was reported. The primary outcome was cancer-related mortality. Secondary outcomes were cancer incidence, all-cause mortality, major bleeding, any bleeding and gastrointestinal (GI) bleeding. We calculated risk ratios (RRs) and 95% confidence intervals (CIs) using a random-effects model at the longest follow-up period. Results: We included 16 RCTs with 104,018total patients, mean age of 60.51 years, mean follow-up of 5.48 years, and a male percentage of 38.72%. We found that aspirin was not associated with a significant reduction of cancer-related mortality compared with placebo (RR 0.99; 95% CI: 0.87-1.12; P = 0.85: I2= 41%). Compared with placebo, aspirin was not associated with significant reduction of all-cause mortality (RR 0.97; 95% CI: 0.92-1.02; P = 0.19; I2= 13%) or cancer incidence (RR: 0.98; 95% CI: 0.92-1.04; P = 0.43; I2= 16%). However, aspirin treatment was associated with significantly increased risks of any bleeding (RR 1.63; 95% CI: 1.31-2.03; P < 0.01), major bleeding (RR 1.41; 95% CI: 1.26-1.57; P < 0.01), and GI bleeding (RR 1.85; 95% CI: 1.38-2.48; P < 0.01) compared with placebo. Conclusions: Our study did not find any significant reductions in cancer-related mortality or cancer incidence when compared with placebo. Our study also highlights the dangers of aspirin for primary prevention of cancer as aspirin was found to cause higher rates of bleeding (any bleeding, major bleeding, and GI bleeding) compared to placebo at the longest follow-up period with no significant benefit in cancer primary prevention.
Role of vitamin D supplementation for primary prevention of cancer: Meta-analysis of randomized controlled trials.
Authors: Samji Varun , Haykal Tarek , Zayed Yazan , Gakhal Inderdeep , Veerapaneni Vijay , Obeid Michelle , Kheiri Babikir , Badami Sunil , Bachuwa Ghassan , Danish Rizwan
Published: May 2019

1534

Background: In the United States cancer is the second leading cause of mortality, as such, primary prevention of cancer is a major public health concern. Vitamin D supplementation has been studied as a primary prevention method for multiple diseases including cardiovascular disease, osteoporosis, diabetes mellitus and cancer. The role of aspirin as primary prevention of cancer is still controversial. With fast emergence of large randomized controlled trials (RCTs) in that regards, we aimed to evaluate the efficacy of Vitamin D supplementation as primary prophylaxis for cancer. Methods: A comprehensive electronic database search was conducted for all RCTs where comparison of Vitamin D supplementation versus placebo for the prevention of any type of disease with at least 3 years of Vitamin D supplementation was used and where cancer incidence or mortality was reported. The primary outcome was cancer-related mortality and cancer incidence. We calculated risk ratios (RRs) and 95% confidence intervals (CIs) using a random-effects model at the longest follow-up. Results: We included 10 RCTs with 79,055 total patients, mean age of 68.07 years, a female percentage of 78.02% and a minimum follow-up of 4 years and more. Vitamin D was associated with significant reduction of cancer-related mortality compared with placebo (RR 0.87; 95% CI: 0.79-0.96; P = 0.05: I2= 0%). Compared with placebo, Vitamin D was not associated with significant reduction of cancer incidence (RR: 0.96; 95% CI: 0.86-1.07; P = 0.46; I2= 31%). Conclusions: Our study highlights that the use of Vitamin D supplementation for primary prevention of cancer is important as it does decrease cancer-related mortality once cancer is diagnosed, however it has no role or effect on cancer incidence.
Opportunistic off-target cancer screening in organized programs: The EDIFICE 6 survey.
Authors: Morere Jean F. , Couraud Sebastien , Roupret Morgan , Touboul Chantal , Lhomel Christine , Eisinger Francois , Viguier Jerome , Greillier Laurent , De La Motte Rouge Thibault
Published: May 2019

1535

Background: The efficacy and benefit/risk ratio of organized nationwide cancer screening programs rely on the age range of eligible average-risk populations. We studied the characteristics of off-target populations who underwent opportunistic screening for colorectal (CRC), breast (BC) or cervical (CC) cancer, ≤5y prior to the recommended age. Methods: The French nationwide observational survey, EDIFICE 6, was conducted online (June 26-July 28, 2017) on a core sample of 12 046 individuals (18-69y). Representativeness was ensured by quota sampling on age, sex, profession, and stratification by geographical area/type of urban district. Opportunistic screening for BC (in 533 women, age 45-49y), CRC (in 1331 individuals, age 45-49y) or CC (in 633 women, age 20-24y) was assessed in terms of smoking status (current, former/never smoker), marital status (single, living with a partner), type of residential area (urban, rural), having a close relative with cancer, social vulnerability (EPICES score), and self-reporting own cancer risk (higher, identical/lower than average). Results: In the off-target populations, screening rates were 78% for BC (N = 418, mammogram), 13% for CRC (N = 172, fecal test or colonoscopy) and 42% for CC (N = 264, cervical Pap smear test). Premature BC screening rates were significantly higher (P < 0.05) in non-vulnerable than in vulnerable individuals (84% vs 69%), and among those self-reporting their own BC risk as higher than average (84% vs 76% reporting own BC risk as identical/lower than average). Premature CC screening rates were correlated with: smoking status (66% in current smokers vs 35% in former/never smokers), and marital status (63% in those living with a partner vs 34% single). Lastly, factors correlated with premature CRC screening were: type of residential area (urban, 15% vs rural, 8%), and believing own risk of CRC to be higher than average (27% vs 8% of those who self-reported their own CRC risk as identical/lower than average). Conclusions: This analysis reveals several factors related to premature screening for BC, CRC and CC, provides clear insight into off-target cancer screening uptake profiles, and hints at new strategies to ensure the optimal risk/benefit ratio of screening practices.
Low-fat dietary pattern and breast cancer mortality by metabolic syndrome degree: Secondary analyses of the Women’s Health Initiative (WHI) Dietary Modification randomized trial.
Authors: Pan Kathy , Aragaki Aaron K , Neuhouser Marian L , Simon Michael S. , Luo Juhua , Caan Bette , Linda Snetselaar , Mortimer Joanne E. , Manson JoAnn E , Kroenke Candyce , Lane Dorothy , Reding Kerryn , Rohan Thomas E , Chlebowski Rowan T.
Published: May 2019

1539

Background: The WHI Diet Modification (DM) trial randomized 48,835 postmenopausal women with no prior breast cancer to a low-fat dietary intervention or comparison group. After 16.1 years follow-up, the intervention was associated with an 18% reduction in risk of death after breast cancer (P =0.01), with greater reduction (29%) in those with waist circumference≥88 cm (J Clin Oncol 2017). To extend these findings, we examined the influence of the dietary intervention on breast cancer mortality in subgroups defined by number of metabolic syndrome (MS) components with 19.6 years median cumulative follow-up. Methods: WHI DM has been previously described. Four MS components were determined at entry: 1) waist circumference≥ 88 cm, 2) high blood pressure or anti-hypertensive use, 3) high cholesterol history and 4) diabetes history, with women categorized as having 0 (n=10,639), 1-2 (n=30,948), or 3-4 (n=4,246) MS components. Forest plots of hazard ratios (HRs) were generated with P-values for interaction between randomized group assignment and number of MS components. Results: Women with 3-4 MS components were more likely to be Black, be obese (BMI ≥30), and have diabetes (all P < 0.001). Breast cancers in women with 3-4 MS components were less likely to be local stage (P = 0.005) or well differentiated (P = 0.03). The magnitude of reduction in deaths from breast cancer in the dietary intervention vs comparison group increased as the number of MS components increased (interaction P = 0.01). Hazard ratios (HR) and 95% confidence intervals (CI) for death from breast cancer for intervention vs comparison groups for women with 0 MS components was 1.09 95% CI, 0.63-1.87, with risk low in both randomization groups (0.028% and 0.026%, respectively); for women with 1-2 MS components, HR 0.80 95% CI 0.62-1.02; and for women with 3-4 MS components, HR 0.31 95% CI, 0.14-0.69, with risk in the intervention group reduced to 0.026%. Conclusions: Adoption of a low-fat dietary pattern had a greater effect on reducing deaths from breast cancer in women with more MS components, suggesting that this is a high risk group more likely to benefit from the dietary intervention. Clinical trial information: NCT00000611.
Whole exome sequencing of germline DNA of individuals presenting extreme phenotypes of high and low risk to develop tobacco-induced lung adenocarcinoma (LUAD) according to KRAS status.
Authors: Perez-Gracia Jose Luis , Pita Guillermo , Segura Victor , Pajares Maria Jose , Fusco Juan Pablo , Andueza Maria Pilar , Sanchez-Bayona Rodrigo , Guruceaga Elisabet , Mora Maria Isabel , Gurpide Alfonso , de Torres Tajes Juan Pablo , Zulueta Javier , Pio Oses Ruben , Melero Bermejo Ignacio , Sanmamed Miguel F. , Rodriguez-Ruiz Maria E. , De Andrea Carlos E , Montuenga Luis M. , Gonzalez-Neira Anna , Patiño-García Ana
Published: May 2019

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Background: Individual susceptibility to carcinogens may depend on the genetic background. We characterized the constitutional exome of individuals presenting extreme phenotypes of high sensitivity and resistance to develop tobacco induced LUAD, correlating the results to KRAS status. Methods: From an identification cohort (n=3,631) we selected 100 caucasian heavy smokers that either developed LUAD at early age (cancer cohort, n=50) or did not develop LUAD or other tumors at advanced age (cancer free cohort, n=50). We sequenced their germline DNA with the Agilent Human Exome Capture v5 (21,522 genes, 357,999 exons). Using logistic regression we selected the most significant variants between both cohorts and correlated them with KRAS mutation status of LUAD patients. Results: mean ages for the cancer and cancer free cohorts were 50 (range 34-55) and 78 years (72-90). Mean tobacco consumptions were 44 (range 6-72) and 55 pack-years (20-124). Median coverage was 96% at >10X; median depth was 97X. Table shows the most significant variants. rs7240666 ( ALPK2) achieved top significance (p=8.14x10-5, OR 0.18). rs78898229 ( ANKRD36C) and rs74866537 ( PTPN4) were predominantly represented in patients with KRAS+ tumors, OR: 16 (3.3-78) and 11.9 (3.3-43); and rs12426243 (CCDC41) in KRAS- tumors (OR: 13 (3-53). Conclusions: Our study characterizes for the first time the genotype of individuals presenting extreme phenotypes of high and low risk to develop tobacco-induced LUAD according to KRAS status. Our results warrants further study to assess their value to screen these clinically relevant phenotypes; and to identify mechanisms of high susceptibility and resistance to carcinogens. [Table: see text]
Prognostic significance of blood-based cancer detection in plasma cell-free DNA (cfDNA): Evaluating risk of overdiagnosis.
Authors: Oxnard Geoffrey R. , Chen Xiaoji , Fung Eric T. , Ma Ting , Lipson Jafi , Hubbell Earl , Kurtzman Kathryn N. , Patel Shilpen , Shaknovich Rita , Dong Zhao , Liu Hai , Brooks Jacqueline D. , Spigel David R. , Seiden Michael , Aravanis Alex , Klein Eric A. , Hartman Anne-Renee , Liu Minetta C.
Published: May 2019

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Background: Screening tests for early cancer detection are often criticized due to risk of overdiagnosis—detection of good prognosis cancers which may not require immediate treatment. We recently reported development of cfDNA sequencing approaches for cancer detection; longitudinal follow-up (F/U) data were utilized here to evaluate prognostic significance of cancer detection using cfDNA. Methods: Plasma cfDNA samples were subjected to whole-genome bisulfite sequencing (WGBS, 30X) as part of a previously-reported Circulating Cell-free Genome Atlas (CCGA; NCT02889978) substudy. This exploratory analysis evaluated the overall survival (OS) of training and test set participants (pts) with cancer (20 cancer types, any stage I-IV). Combining train and test set pts, univariate and multivariate analyses (Cox proportional hazards) assessed OS association with WGBS result (cancer detected vs not detected, set at 98% specificity), clinical stage (IV vs I-III), diagnostic method (symptom- vs screen-detected), sex, age, and histologic grade. Results: Of 827 pts from the training set with F/U (median 12.2 mo), 334 (40.4%) had WGBS-detected cancer. Among 127 (15.4%) pts with cancer that died during F/U, cancer was detected in 104 (81.9%). Results were similar in the test set. In univariate analyses all variables were associated with prognosis, including WGBS result (HR 7.7 p<0.001). In multivariate analyses accounting for other covariates, the three variables that most significantly remained prognostic were WGBS (HR 3.0, p<0.001), clinical stage (HR 3.3, p<0.001), and diagnostic method (HR 3.0, p<0.001). Validation of these findings is ongoing in an independent cohort of ~5,000 cancer pts from CCGA using an optimized assay; updated performance results will be reported. Conclusions: Cancers detected using WGBS of cfDNA had a worse prognosis than cancers not detected. WGBS cancer detection carried comparable prognostic significance as clinical stage. By preferentially detecting higher risk cancers, cancer detection using plasma cfDNA may avoid some of the overdiagnosis that has been seen with some existing cancer screening methods. Clinical trial information: NCT02889978.
Characteristics of cancer patients with a history of solid organ transplantation: Analysis of a patient cohort reporting to a large cancer center.
Authors: Burock Susen , Nicklich Stefanie , Hartmann Leonie , Ulrich Claas , Keilholz Ulrich
Published: May 2019

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Background: Solid organ transplant recipients have a 2-4-fold elevated risk of developing cancer compared to the general population due to immunosuppressive therapy. Cancer patients with a history of organ transplantation (TPx) may or may not have a cancer attributed to immunosuppression. Here we report on a cohort of cancer patients of the Charité, diagnosed with the first occurrence of a solid cancer in 2010-2014 and a history of TPx. Methods: The cancer registry database of the Charité Comprehensive Cancer Center was queried for patients diagnosed with the first occurrence of solid cancer between 2010 and 2014 and a previous solid organ transplantation. General tumor and patient characteristics as well as outcome were analyzed. Results: A total of 226 patients (151 male, 75 female) were identified and included in the analysis. Transplanted organs included kidney in 148 patients, liver in 63, and heart, lung or a combination of both in 15. The median age at transplantation and initial tumor diagnosis was 54.7 years and 63.4 years respectively. Median interval between organ transplantation and diagnosis of the cancer was 8.1 years, range 0 - 39 years. 60.6% of cancers developed > 10 years after TPx. The interval between TPx and development of cancer inversely correlated to patient age at TPx, with a median of 17.9 years (age group 18-34), 13.0 years (35-49), 6.7 years, (50-64), and 5.3 years, (65+ years). The majority of cancers occurred within the first 10 years after TPx, however especially for the age group 35-49 cancer diagnoses peaked 20-25 years after transplantation. The most common cancer types where non-melanoma skin cancer (34%), followed by kidney (15%), lung (13%) prostate (8.61% of all male patients) and colorectal (4.87%). Median survival of all patients after tumor diagnosis was 4.6 years, with 1.0 years for lung cancer, 4.6 years for colorectal cancer, 5.7 years for prostate cancer respectively. The median OS was not yet reached for non-melanoma skin cancer and kidney cancer. Conclusions: Our data support the necessity of long- term follow up and cancer screening in patients after organ transplantation beyond the commonly practiced 10 years post transplantation screening.
Health insurance literacy, financial hardship and financial sacrifices among cancer survivors in the United States.
Authors: Zhao Jingxuan , Han Xuesong , Zheng Zhiyuan , Banegas Matthew P. , Ekwueme Donatus U. , Yabroff K. Robin
Published: May 2019

1560

Background: Rising costs of cancer care have imposed substantial financial burden on cancer survivors. To date, little is known about the associations between potentially modifiable patient characteristics, including health insurance literacy (HIL), on financial burden among cancer survivors. This study aimed to evaluate the associations between HIL and financial hardship and financial sacrifices among adult cancer survivors in the United States. Methods: We identified 914 adult cancer survivors from the 2016 Medical Expenditure Panel Survey Experiences with Cancer Questionnaire. HIL was measured based on the question “Did you ever have a problem understanding health insurance or medical bills related to your cancer, its treatment, or the lasting effects of that treatment?” Medical financial hardship was measured in three domains—1) material (e.g. problems paying medical bills); 2) psychological (e.g. worry about large medical bills); and 3) behavioral (e.g. delay or forego healthcare because of cost). Financial sacrifices were based on questions related to changes in spending on vacation or leisure activities. We used multivariable logistic regression modeling to separately evaluate the associations between HIL problems and 1) financial hardship and 2) financial sacrifices. Results: 18.9% cancer survivors aged 18-64 years and 14.6% survivors ≥65 years reported HIL problems. Regardless of age groups, cancer survivors with HIL problems were more likely to report any material (OR =3.2; 95% CI:1.9-5.2) or psychological (OR=7.2; 95% CI: 4.1-12.7) financial hardship than those without the problems, as well as more likely to delay or forgo multiple medical care due to cost, including prescription medicine (OR=3.6; 95% CI: 1.8-7.1), specialist visit (OR=2.6; 95% CI: 1.2-5.8), and follow-up care (OR=2.1, 95% CI 1.2-4.0). Higher likelihood of reporting all measures of financial sacrifices were observed among those with HIL problems in both age groups (all p<0.05). Conclusions: Cancer survivors with HIL problems were more likely to report financial hardship and financial sacrifices than those without the problems. Improving HIL may help mitigate financial hardship.
Contemporary changes in localized and metastatic prostate cancer incidence by geographic area following decreased PSA screening.
Authors: Yang Daniel X. , Makarov Danil V. , Gross Cary Philip , Yu James B.
Published: May 2019

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Background: In the setting of decreased PSA screening, the incidence of metastatic prostate cancer has been increasing in the United States. This was chronologically proceeded by decreasing localized prostate cancer incidence. While decreased detection of localized disease is hypothesized to increase likelihood of metastatic disease at diagnosis, it is unclear whether the two are geographically connected. Methods: Prostate cancer incidence was obtained from the of Surveillance, Epidemiology, and End Results (SEER) database for men 70 years or older. SEER Summary Stage 2000 was used to classify localized (local) and metastatic (distant) prostate cancers. Changes in incidence rates were calculated by health services areas (HSA), which each represents a relatively self-contained region of hospital care. We chose a priori to examine most recent years 2012-2015 for changes in metastatic disease, and proceeding years 2008-2011 for changes in localized disease. Population-weighted linear regression that was robust to outliers was performed. Results: A total of over 66,600 cases of localized and 6,400 cases of metastatic prostate cancer from 200 HSAs were included for analysis. From 2008 to 2011, localized incidence decreased from 613.6 to 534.2 per 100,000 men overall, and for each HSA on average decreased by 30.3 per 100,000 men for each year. From 2012 to 2015, metastatic incidence increased from 54.7 to 62.1 per 100,000 men overall, and for each HSA on average increased by 2.1 per 100,000 men for each year. Linear regression between HSA-level changes in localized and metastatic disease revealed a correlation coefficient of -0.023 (SE = 0.017, p = 0.16, 95% CI -0.056 to 0.009), representing lack of a statistically significant relationship between decreases in localized disease and later increases in metastatic disease within each health services region. Conclusions: Despite concerns of increasing metastatic prostate cancer incidence coinciding with decreases in PSA screening and localized cancer incidence, we do not observe a statistically significant geographic and temporal relationship between metastatic and localized disease at the HSA level. Our study is limited by short lead time and thus this trend warrants continued surveillance.