bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tumor subtype and other prognostic factors in breast cancer patients with brain metastases: The updated graded prognostic assessment (Breast-GPA).
Authors: Sperduto Paul W. , Mesko Shane , Cagney Daniel , Nesbit Eric , Chan Jason , Lee Jessica , Breen Will , Shi Diana , Soliman Hany , Shanley Ryan , Everett Ashlyn S. , Masucci Laura , Remick Jill , Plichta Kristin , Jain Supriya K. , Wu Cheng-Chia , Bryant John , Yu James B. , Nakano Toshimichi , Mehta Minesh P. 
Published: May 2019

1079 Background: Brain metastases (BM) are a common and fatal complication of breast cancer but survival varies widely based on various prognostic factors (PF). Hence, patient counseling and therapeutic decisions should be individualized. We previously published a prognostic index (Breast GPA) based on cohort A (1985-2007, n = 642), updated it with tumor subtype in cohort B (1993-2010, n = 400) and are now updating it with a larger contemporary cohort (C). Methods: A multi-institutional (19) multi-national (3) retrospective database of 2473 breast cancer patients with BM diagnosed from 1/1/2006-12/31/2017 was created and compared to our prior cohorts. Demographic, clinical, molecular factors, tumor subtype and treatment were correlated with survival. Kaplan-Meier survival estimates were calculated and compared with log-rank tests. Results: The median survival (MS) for cohorts A, B and C improved over time [12, 14 and 16 mo, respectively ( < 0.01)] despite the subtype distribution becoming less favorable: Luminal B (ER/PR/HER2+) decreased from 26% to 21%; HER2 (HER2+/ER/PR-) decreased from 31% to 17%, Luminal A (ER/PR+/HER2-) increased from 20% to 31%; Basal (ER/PR/HER2-) was unchanged at 24%.MS by subtype improved from 21 to 27 mo in Luminal B, 18 to 25 mo in HER2, 10 to 14 mo in Luminal A and 6 to 9 mo in Basal tumors. The number of BM was 1 in 35%, ≤4 in 67% and > 10 in 18%. PF significant for survival were tumor subtype, age, KPS, number of BM and extracranial metastases (ECM) (all < 0.01). Surprisingly, Hispanic women (7%) showed improved survival (p < 0.01). BRCA1 was mutated in 57/533 (11%) and those patients showed a trend (0.16) toward improved survival. Treatment patterns have changed: the use of whole brain radiation therapy decreased from 71% to 67% to 47% in cohorts A, B and C, respectively. Conclusions: Despite the shift to less favorable tumor subtypes, MS has improvedbut varies widely by diagnosis-specific PF. Compared to prior cohorts, number of BM and ECM were identified as new PF. Ethnic, genetic and treatment differences between the eras are apparent. The updated Breast GPA, based on these data, and the correlation between BRCA1 and tumor subtype will be presented.
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.