bluuebunny/crossref_metadata_2025_split huggingface dataset:
TAKTIC: A prospective, multicenter, uncontrolled, phase IB/II study of LY2780301 (LY) in combination with weekly paclitaxel (wP) in HER2-negative locally advanced (LA) or metastatic breast cancer (MBC) patients.
Authors: Vicier Cecile , Isambert Nicolas , Dalenc Florence , Campone Mario , Levy Christelle , Rezai Keyvan , Provansal Magali , Adelaide José , Garnier Séverine , Guille Arnaud , Chaffanet Max , Popovici Cornel , Charafe-Jauffret Emmanuelle , Pakradouni Jihane , Autret Aurelie , Goncalves Anthony 
Published: May 2019

1091 Background: Phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR)-pathway is frequently activated in HER2-negative breast cancer and may play a role in taxane-resistance. LY is a dual inhibitor of p70 S6 kinase and AKT. TAKTIC study aimed to determine the recommended phase II dose (RP2D) of the combination of LY with wP (phase Ib) and to estimate overall response rate (ORR) of this regimen (phase II) in HER2-negative LA or MBC patients, both in the overall patient population and in patients with activation of PI3K/AKT pathway (PI3KAKT+). Methods: HER2-negative inoperable LA or MBC patients (pts), with (phase Ib) or without (phase II) previous cytotoxic treatment for advanced disease were eligible. Oral LY (400 or 500mg) was administered daily in combination with intravenous wP (70 or 80mg/m2). A modified CRM using an adaptive Bayesian model guided the dose escalation of both agents. PI3KAKT+ was defined as activating mutation of PIK3CA and/or AKT by targeted NGS or homozygous loss of PTEN by array comparative genomic hybridization (aCGH) or loss of PTEN by immunohistochemistry, as evaluated on available fresh tumor tissue. Results: A total of 12 and 35 patients (pts) were included in the phase Ib and II, respectively. In phase Ib, only 1 dose-limiting toxicity (confusion) was observed at the last dose level (LY, 500 + wP, 80), which was determined as RP2D. Main drug-related adverse events (AE) in phase Ib were skin toxicity (92% of pts, G3-4 in 33%), and paresthesia (50% of pts, G3-4 in 8%). In the phase II study, ORR was 62.9 % [44.9,78.5] including 1 CR and 21 PR in the overall population and 55.6 % [30.8,78.5] in PI3KAKT+ pts (10 PR in 18 pts). Median progression-free survival was 12.4 months [7.9,17.9] and 6-month clinical benefit rate was 82.9% [66.4,93.4]. AEs in phase II were similar to phase I part, except that 17% of pts experienced pneumonia (G3-4 in 9%). Conclusions: Combining LY and wP in HER2-negative LA or MBC was feasible with preliminary evidences of efficacy, independently of PI3K/AKT activation. Clinical trial information: NCT01980277.
Development and validation of novel microenvironment-based immune molecular subtypes of breast cancer: Implications for immunotherapy.
Authors: Yu Yunfang , Zhang Wenda , Ou Qiyun , Li Anlin , Chen Yongjian , Wang Ying , Zhao Jianli , Tan Yujie , Yao Herui 
Published: May 2019

1094 Background: Breast cancer treatment with immunotherapy can improve clinical benefits, but the majority of patients did not respond to the treatment. To understand tumor–immune interactions in breast cancer, we identified novel microenvironment-based immune molecular subtypes. Methods: A training cohort of 1,394 breast cancer patients from the Molecular Taxonomy of Breast Cancer International Consortium profiled by RNA and DNA sequencing data were analyzed to calculate immune-related gene biomarkers and to assign prognostic categories using LASSO Cox regression model. Additionally, 969 patients from The Cancer Genome Atlas data set was used as an independent validation cohort. We further compared tumor mutation burden (TMB) and cytolytic activity (CYT) levels between different immune molecular subtypes. Results: Using the LASSO model, we established an immune molecular classifier based on following 5 features: IFN-γ signature, ICOSLG, TNFRSF14, Mast.cells.resting, and T.cells. CD4.memory.resting. Then we found that it contained two distinct microenvironment-based subtypes (immune class and non-immune class), characterized by significant differences in overall survival in the training cohort (hazard ratio [HR] 0.71; 95% confidence interval [CI] 0.61 to 0.81; P < 0.001) and in the validation cohort (HR 0.34; 95% CI 0.22 to 0.54; P < 0.001). We found an inverse association between immune gene expression and TMB levels (ρ = 0.096, P < 0.001). Immune class subtype patients with good prognosis had significantly lower TMB and higher CYT than did non-immune class subtype patients with poor prognosis (all, P < 0.05). The clinical use of the immune molecular subtypes showed a closer association with survival than did IFN-γ signature or PD-L1 expression (all, P < 0.05). The robustness of the immune molecular subtypes was confirmed in the validation cohort. Conclusions: We revealed novel immune molecular subtypes, which represented better utility in predicting breast cancer patients’ survival compared with IFN-γ signature or PD-L1, and could be an important guide for precision immunotherapy.
Clinical characteristics and outcome of metaplastic breast cancer: A retrospective tertiary care center experience.
Authors: Thapa Bicky , Arobelidze Salome , Jia Xuefei , Awada Hassan , Kewan Tariq Zuheir , Covut Fahrettin , Patel Mita , Daw Hamed , Spiro Timothy Peter , Haddad Abdo S. 
Published: May 2019

1095 Background: Metaplastic breast cancer (MBC) is a rare neoplasm which accounts for less than 1% of all breast cancers. MBC is associated with worse prognosis and there is a paucity of literature on management. We evaluated the clinical characteristic and outcomes of MBC patients at our institution. Methods: After IRB approval, 136 patients diagnosed with MBC were reviewed from the Cleveland Clinic tumor registry from 2000-2017. Patients were evaluated for overall survival (OS) and progression free survival (PFS) using univariable analysis. Time to event variables were estimated by Kaplan-Meier method. Results: A total of 136 pathologically proven MBC patients were included in the study. Median age at diagnosis was 60 years (27-92). Eighty two percent (n = 112) had nuclear grade III, 7% (n = 10) had high grade dysplasia, 2% (n = 3) had nuclear grade I, and 4% (n = 5) had nuclear grade II; 60% (n = 82) patients were diagnosed at stage II, 21% (n = 28) at stage I, 14% (n = 19) at stage III, and 5% (n = 7) at stage IV. Estrogen receptor, progesterone receptor and Her2 expression were positive in 16% (n = 22), 9% (n = 12), and 10% (n = 14) respectively. Only 37% (n = 50) patient had lumpectomy, 18% (n = 25) received hormonal therapy, 56% (n = 76) received radiation, 51% (n = 70) received anthracycline chemotherapy and 26% (n = 36) received non-anthracycline chemotherapy; 37% (n = 50) had chemotherapy after 4 weeks of surgery and 35% (n = 48) patients had chemotherapy within 4 weeks of surgery. On univariable analysis, the 5-year OS for stage III was 30% (14% - 64%), hazard ration (HR) of 4.53 (95% CI, 1.71 - 12.01) (p = 0.002), for stage IV HR of 43.26 (95% CI, 12.34 - 151.64) (p = 0.001); chemotherapy within 4 weeks of surgery was associated with a higher risk of death, HR of 0.30 (95% CI, 0.12 - 0.74) (p = 0.009). Hormonal therapy, radiation therapy, surgery and type of chemotherapy was not associated with significant change in OS and PFS. In our cohort, 2-year OS was 79 % (73 % - 87 %) and 5-year OS was 69 % (61 % - 77 %); 2-year PFS was 61 % (52 % - 70 %) and 5-year PFS was 72 % (65 % - 81 %). Conclusions: Stage of MBC and chemotherapy within 4 weeks of surgery was associated with statistically significant OS and PFS on univariable analysis. Randomized clinical trials are warranted to improve outcomes in MBC patients.
Effect of germline ATM mutations on clonal hematopoiesis.
Authors: Slavin Thomas Paul , Tsang Kar Wing Kevin , Longmate Jeffrey , Castillo Danielle , Herzog Josef , Qin Hanjun , Wang Jinhui , Neuhausen Susan L. , Mejia Rosa , King Elisabeth , Telatar Milhan , Marcum Catherine A , Hendricks Carolyn B. , Hake Christopher R. , Seewaldt Victoria Louise , Geradts Joseph , Stark Jeremy , Marcucci Guido , Weitzel Jeffrey N. 
Published: May 2019

1509 Background: Clonal hematopoiesis (CH) in myeloid related-genes is associated with development of primary and secondary leukemia and atherosclerotic disease, as well as, decreased overall survival. Identification of factors beyond age and cytotoxic exposures that predispose to CH may be useful to both recognize individuals at increased risk for CH and to better understand how CH develops. We have previously shown that germline mutations in the DNA repair gene ATM may predispose to CH. We hypothesized here that heterozygous ATM germline mutation carriers would have higher rates of CH in myeloid genes compared to controls. Methods: Germline DNA samples from 34 heterozygous ATM germline mutation carriers (cases) and 22 controls without ATM germline mutations were sequenced on an Illumina 2500 using a custom 79-gene-myeloid-CH-coding-exon-amplicon-based Qiaseq panel. Read depth averaged 130x. Pathogenic and likely pathogenic CH variants (PV) above an allele fraction of 2% were used for analyses. Cases and controls were compared using a rank-sum test. Results: Cases had a higher median age (56 years, range 30-82) than controls (48 years, range 5-72). Cases and controls were similar in solid tumor cancer history and known exposure to cancer cytotoxic therapy; 73.5% vs 86.4%, and 18.1 vs 20.6%, respectively. The number of CH PV was similarly associated with age in both cases and controls (cor = 0.31, p = 0.01). Cases displayed more CH PVs than controls (total 62 vs 3 PVs, median 2 PVs vs 0, p = 10-6). Of note, cases frequently had a concomitant second (n = 10; 29% of cases) or third (n = 4; 11.8% of cases) unique ATM CH PV, whereas no ATM CH PVs were seen in controls. Even after excluding ATM CH PVs, CH PVs were more frequent in cases (p = 0.00003). After ATM CH PVs, the most frequent CH PVs in cases were in NF1 (5 PVs), BCORL1 (4 PVs), and DMNT3A (4 PVs). Conclusions: Our study supports ATM as a strong predisposition locus for myeloid gene CH. CH in ATM germline mutation carriers frequently involved unique low allele fraction PVs in ATM, suggesting ATM germline PVs are driving production of likely bi-allelic ATM inactivation in white blood cells, or complete ATM loss. Complete ATM loss may be a nidus particularly for lymphocytic leukemia, as bi-allelic ATM inactivation is a frequent somatic finding.
Prevalence and penetrance of breast cancer-associated mutations identified by multiple-gene sequencing in the Women’s Health Initiative.
Authors: Kurian Allison W. , Hughes Elisha , Bernhisel Ryan , Larson Katie , Caswell-Jin Jennifer Lee , Shadyab Aladdin H. , Ochs-Balcom Heather , Pan Kathy , Qi Lihong , Reding Kerryn , Hartman Anne-Renee , Lancaster Johnathan M. , Tang Jean Y. , Stefanick Marcia L. 
Published: May 2019

1513 Background: Next-generation sequencing enables rapid analysis of many inherited cancer susceptibility genes. Little is known about the prevalence and penetrance of pathogenic variants (PVs) in such genes among post-menopausal women with breast cancer, who comprise the majority of all breast cancer patients. Methods: The Women’s Health Initiative enrolled post-menopausal women from 1993-1998. We conducted a nested case-control study using banked DNA samples of 2,195 women who subsequently developed invasive breast cancer (cases) and 2,322 cancer-free controls. Sequenced genes were APC, ATM, BARD1, BMPR1A, BRCA1, BRCA2, BRIP1, CDH1, CDK4, CDKN2A (p16INK4a and p14ARF) , CHEK2, EPCAM, GREM1, MLH1, MSH2, MSH6, MUTYH, NBN, PALB2, PMS2, POLD1, POLE, PTEN, RAD51C, RAD51D, SMAD4, STK11, and TP53. PV were defined using American College of Medical Genetics criteria. PV prevalence is reported as proportions and penetrance as the odds ratio (OR) and 95% confidence interval (CI) of PV versus none among cases versus controls. Results: Among cases, the median age at diagnosis was 73 years; 66% were White, 18% Black, 6% Hispanic, 6% Asian and 4% other. The prevalence of PVs in any gene was significantly higher in cases (6.61%, 95% CI 5.57-7.65%) versus controls (4.09%, 95% CI 3.29-4.90%). The prevalence of BRCA1/2 PVs was 1.2% in cases and 0.22% in controls. Among cases, the prevalence of PVs in other breast cancer-risk genes was 2.3% ( ATM, CDH1, BARD1, BRIP1, CHEK2, NBN, and PALB2 collectively), two-fold higher than PVs in BRCA1/2. Prevalence of BRCA1/2 PVs decreased with age among cases, while prevalence of ATM, CHEK2 and PALB2 PVs did not. Statistically significant ORs for breast cancer penetrance were observed for BRCA1 (5.43, 95% CI 1.19-51.52), BRCA2 (4.71, 95% CI 1.84-15.08), BARD1 (9.78, 95% CI 1.04-1295.87) and PALB2 (6.30, 95% CI 1.93-31.94). Conclusions: Approximately 7% of women diagnosed with post-menopausal breast cancer carry a PV in a cancer susceptibility gene. In contrast to studies of younger breast cancer patients, PVs in other breast cancer-related genes were two times more common than in BRCA1/2. Results may guide genetic testing of women with post-menopausal breast cancer.
Genome-wide association study using whole-genome sequencing to identify a novel locus associated with cardiomyopathy risk in adult survivors of childhood cancer: Utility of a two-stage analytic approach.
Authors: Sapkota Yadav , Liu Qi , Shelton Kyla C. , Wang Xuexia , Wilson Carmen Louise , Wang Zhaoming , Mulrooney Daniel A. , Jefferies John L , Oeffinger Kevin C. , Morton Lindsay M. , Zhang Jinghui , Armstrong Gregory T. , Bhatia Smita , Hudson Melissa M. , Robison Leslie L. , Yasui Yutaka 
Published: May 2019

1516 Background: Survivors of childhood cancer are at increased risk of treatment-related cardiomyopathy, found to be modified by genetic factors. To further investigate genetic risks of cardiomyopathy, we utilized whole-genome sequencing (WGS) in a clinically phenotyped cohort of long-term survivors of pediatric cancer. Methods: Utilizing a novel 2-stage analytic approach, we first performed association analysis for ejection fraction (EF) using WGS data in European-descent childhood cancer survivors from the St. Jude Lifetime Cohort (SJLIFE). EF was analyzed as a continuous variable to increase statistical power for genetic discovery. Common variants (minor allele frequency (MAF) > 0.05) were analyzed using linear regression, adjusting for age at diagnosis, sex, age at follow-up, doses of anthracycline and average radiation dose to the heart, and eigenvectors. Rare/low-frequency variants were aggregated by different functional annotations and agnostic 4-kb sliding windows, testing jointly using Burden/SKAT test. In the second stage, only the variant showing genome-wide significance with EF was tested for its association with cardiomyopathy risk. Results: Among the 2,015 SJLIFE survivors with WGS data, a locus on 6p21.2 near KCNK17achieved genome-wide significance with EF (rs2815063; MAF = 0.13; per allele beta = -0.016; P = 2.10´10-8), which replicated in 320 SJLIFE African survivors (MAF = 0.48; beta = -0.015; P = 0.004). In SJLIFE Europeans, 282 had a CTCAE Grade 2-5 cardiomyopathy. rs2815063 was significantly associated with increased risk of cardiomyopathy [per allele odds ratio (OR) = 1.38; P = 0.02], which replicated in 3,957 European survivors from the Childhood Cancer Survivor Study (163 CTCAE Grade 3-5 self-reported cases; per allele OR = 1.39; P = 0.038). rs2815063 alters DNA binding motif of EWSR1-FLI1, whose expression was found to lead to cardiomyopathy and death due to chronic cardiac failure in mice. Conclusions: Using a 2-stage approach, we report a novel locus for cardiomyopathy in childhood cancer survivors, which warrants additional work to gain mechanistic insights.
Preimplantation genetic diagnosis: What do BRCA mutation carriers think?
Authors: Khouri Olivia R , Gerber Deanna , Smith Julia Anne , Boyd Leslie R. 
Published: May 2019

1526 Background: The use of pre-implantation genetic diagnosis (PGD) to select against BRCA mutated embryos for in-vitro fertilization (IVF), introduces complex choices for patients with pathogenic BRCA mutations. We sought to describe the uptake of and attitudes toward this technology in this patient population. Methods: We conducted a prospective survey study at a single institution in New York City affiliated with both a Cancer Center and Fertility Center, to assess attitudes and utilization of PGD. Cancer Center staff distributed surveys to patients with known BRCA mutations between April and August 2018. Survey participation was voluntary and anonymous. Survey data were analyzed using descriptive statistics and two-tailed t tests. Results: 80 survey responses were collected. A majority of the patient population identified as Caucasian (87.5%, 70) and Jewish (52.5%, 42). The survey was distributed to all age groups; however 81% (65) were between 26 and 45 years of age. 63.8% (51) had heard of PGD prior to completing the survey, while 36.3% (29) had not. Only 40% of respondents (32) felt sufficiently educated regarding PGD. 35% (28) patients met with an REI, of whom 6.3% (5) utilized IVF with PGD, and 21.3% (17) plan to use IVF with PGD in the future. 11.3% (9) wish they had known about this technology prior to starting a family, 20% (16) would not have used PGD had they known about it prior to childbearing. Reasons respondents were unlikely to pursue PGD included: cost (38.8%, 31), completed childbearing (25%, 20), medical risk (18.8%, 15), and ethical concerns (16.2%, 13). Patients gave cost estimates for PGD ranging from $500 - $120,000. There was no statistically significant correlation between likelihood of pursuing PGD and parity (p = 0.45), religion (p = 0.78), education level (p = 0.13), number of family members affected by BRCA mutations (p = 0.20) or by cancer (p = 0.11). Conclusions: Overall, a small number of patients with pathogenic BRCA mutations utilize PGD. A minority of survey respondents felt adequately educated about PGD. Reported barriers to uptake were varied, and there was a wide range of cost estimates reported. Our results suggest that increased patient education regarding PGD in BRCA mutation carriers is warranted.
The PHACT Study: Population Health and Cancer Testing.
Authors: Dhawan Mallika Sachdev , Karipineni Silpa , Budge Jason , Mak Julie , Zhou Alicia , Williams Kelly , Cha Kyusun , Munster Pamela N. 
Published: May 2019

1531 Background: There is considerable uncertainty on cancer risk and recommendations for genetic testing in various populations. The purpose of this study is to test types and frequencies of cancer risk mutations in large, unaffected multiethnic populations, as well as feasibility and acceptance of general population germline testing. Methods: After consent, germline genetic testing via Color Genomics 30-gene Cancer Risk panel with personal and family cancer history assessment was offered to 500 participants residing in the San Francisco Bay Area. Participants were older than 21 and without a known family history of a cancer risk mutation. Recruitment occurred at random and through various, non-cancer related community events. Genetic counseling through a genetic counselor at UCSF was offered to all participants. Post-participation surveys were sent out to those who completed testing with 195 responses to assess attitudes towards genetic testing. Results: 500 participants completed testing; 35 were found to have a cancer risk mutation (7.0%). The majority of these have been in moderate risk cancer mutations including CHEK2 (1.0%), APC (0.8%), MUTYH (1.4%) and NBN (0.4%); higher risk mutations were found in BRCA1 (0.4%), BRCA2 (0.6%), BRIP1 (0.4%), PMS2 (0.2%) and PALB2 (0.2%). Data via self-reporting and SNP testing via the Color Genomics platform was collected to contextualize the racial, ethnic, and geographic association of these results. Rates of VUS (variants of uncertain significance) differed among the various ethnic groups (p = 0.027) with the lowest rates in Europeans vs. all other ethnicities (16.6% vs. 29%, p = 0.001). 37 (19.8%) out of 187 respondents reported that their genetic testing influenced testing in family members. In those 37 families, 8 additional people were positive for genetic mutations. Cost was the biggest barrier to pursuing prior genetic testing according to most individuals (20% of respondents); others were too busy (12%) or did not feel genetic testing was medically recommended (9%). Conclusions: The PHACT study demonstrates that large population screening of cancer risk mutations is feasible. The number of participants found to have mutations was greater than expected although the majority of these were in moderate risk genes. We found high rates of VUS in non-Europeans, which points to the complexity of population-based genetic testing.
Management of high, moderate, and low penetrance ovarian cancer susceptibility gene mutations: An assessment of current practice patterns.
Authors: Watson Catherine H. , Davidson Brittany Anne , Havrilesky Laura Jean , Lee Paula S. , McNally Leah , Moss Haley , Previs Rebecca A. , Puechl Allison , Secord Angeles Alvarez , Berchuck Andrew , Kauff Noah D. 
Published: May 2019

1536 Background: Limited information exists regarding appropriate risk-reduction strategies for women with moderate and low penetrance ovarian cancer (OVCA) susceptibility mutations. We sought to assess current practice patterns for women with these genetic changes through a survey of members of the Society of Gynecologic Oncology (SGO). Methods: All full SGO members were e-mailed a survey consisting of two vignettes: 1) a 35-year-old premenopausal woman who desires pregnancy; 2) a 55-year-old postmenopausal woman with multiple comorbidities. Each vignette contained sub-scenarios in which the patient had either a BRCA1 (RR = 30-60), RAD51C (RR = 5.0) or ATM (RR 1.5-2.0) OVCA susceptibility mutation. Respondents were queried about their preferred management approach. Chi-square test was used for statistical analysis. Results: 193 (15%) of 1284 SGO members responded. 58% were in academic practice. For the premenopausal woman, 52%, 13% and 6% would perform an RRSO prior to age 40 in the setting of a BRCA1, RAD51C and ATM mutation respectively. 47%, 68% and 9% would perform RRSO at 40-50; and 0%, 9% and 23% would perform RRSO at menopause, depending on the gene mutated. For the postmenopausal woman with comorbidities, 98%, 85% and 42% would proceed with RRSO in the setting of a BRCA1, RAD51C and ATM mutation respectively; 2%, 8% and 39% would observe (with/without screening); and 0%, 7% and 19% would do further research prior to proceeding. Distribution of responses for carriers of RAD51C and ATM mutations were different from BRCA1 in both vignettes [p < 0.001]. Conclusions: Respondents were more likely to perform RRSO earlier and more frequently in the setting of a BRCA1 mutation compared to either a RAD51C or ATM mutation. However, there was lack of consensus in management of the moderate and low penetrance OVCA susceptibility mutations. These patterns likely reflect the limited information available regarding the timing and magnitude of risk associated with these genes. Given the immediate and long-term morbidity of oophorectomy, more data regarding age-specific risks and appropriate risk-reduction strategies for moderate and low penetrance OVCA susceptibility mutations is needed.