bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hyperactivated mTOR and JAK2/STAT3 pathways: Crucial molecular drivers and potential therapeutic targets of inflammatory breast cancer (IBC).
Authors: Jhaveri Komal L. , Teplinsky Eleonora , Arju Rezina , Giashuddin Shah , Sarfraz Yasmeen , Alexander Melissa , Darvishian Farbod , Silvera Deborah , Levine Paul H , Hashmi Salman , Hoffman Heather J. , Singh Baljit , Goldberg Judith D , Hochman Tsivia , Valeta Amanda , Schneider Robert 
Published: March 2020

11106 Background: IBC is an aggressive form of breast cancer with poor prognosis. Combined multimodality Rx results in 5 year median OS of 30-50%, underscoring the unmet need for novel targeted strategies. Our preclinical research in cell lines and xenografts suggests a role for activated PI3K/AKT/mTOR pathway in IBC. IBC cells not only express high levels of IL-6 and IL-8 but can recruit tumor activated macrophages (TAMs), which can further induce IL-6, IL-8 and activate JAK2/STAT3 pathway. We therefore investigated independent and combined activity of these pathways. Methods: Archived tissue specimens of 42 IBC pts (1999 - 2009) and 13 controls (normal breast) were analyzed using IHC and scored by 3 independent pathologists. Results were defined as: 0, 1+ = neg; 2+ = pos for activated mTOR (phosphorylatedS6) and 0 = neg; 1+, 2+ = pos for activated nuclear JAK2/STAT3 (pJAK2; pSTAT3), cytokine (IL-6), macrophage infiltration (CD68) and TAMs (CD163). Proportion of IBC cases with pos expression were compared to proportion among controls (Fishers exact test). Clinical and survival data were obtained. Results: Median age at diagnosis - 44.5 yrs (29-64). 22 had HER2 overexpression (8 also ER+) and 9 were ER-/HER2-; ER & HER2 unknown for 1 and 2 pts respectively. Majority were Rxed with neoadjuvant anthracycline and/taxane without adjuvant trastuzumab. There were 24 deaths. Median OS: 67 mths (95% CI: lower 41). Proportions of IBC cases with pos expression when compared to controls are listed in the table (Fishers p value: <0.0001). Of the 31 pts with complete biomarker data who were PS6 pos, 97% had activated JAK2 & 58% had activated STAT3 (McNemar’s chi square, p <0.001). 24/31 (80%) showed strong infiltration of macrophages and TAMs. All cases had widespread IL6 staining. Conclusions: This study validates our preclinical findings and shows hyperactivation of mTOR and JAK2 signaling in vast majority of IBC specimens, with close association between mTOR, TAMs, cytokines and JAK2/STAT3 pathways. These findings support a role for dual blockade of mTOR and JAK/STAT pathways in clinical trials. [Table: see text]
A Ki-67 proliferation index cutoff value of 1% to predict 5-year RFS and OS in patients with pulmonary carcinoid tumors.
Authors: Reungwetwattana Thanyanan , Mandrekar Sumithra J. , Kroneman Trynda , Foster Nathan R. , Aubry Marie-Christine , Yi Eunhee S. , Kerr Sarah E , Yang Ping , Grothey Axel , Shridhar Vijayalakshmi , Voss Jesse S , Kipp Benjamin , Molina Julian R. 
Published: March 2020

11119 Background: Evaluation of prognostic factors in carcinoid tumors of the lung is limited due to the rarity of disease. This study assessed Ki-67 expression and other clinical variables as prognostic factors in 262 patients. Methods: A systematic search of Mayo Clinic lung cancer epidemiology and tumor registry databases from 1997 to 2009 identified 449 consecutive patients, with 262 having available tissue blocks [40 atypical carcinoids (AC) and 222 typical carcinoids (TC)]. Clinical data were collected by chart review. Tissue blocks were reviewed by 1/3 pathologists using WHO criteria. Tumors were tested for the Ki-67 index using digital image analysis (tumor tracing) by two operators. The association and predictive value of the factors with recurrence-free and overall survival (RFS and OS) were explored using univariable Cox proportional Hazards model and concordance (c) index. Results: Age, stage, smoking history, lymph node (LN) involvement and Ki-67 index were significant prognostic factors for RFS and OS. Median follow-up on alive-patients is 5 years (range: 0.006-5). Median percentage of Ki-67 index of AC and TC were 1.61% and 0.56% (P<0.0001), respectively. Patients with Ki-67 ≥ 1% had significantly worse RFS (HR=3.69, P<0.0001) and OS (HR=3.69, P=0.0007) compared with Ki-67 < 1% group. The c-index of Ki-67 (0.65) was comparable to the pathologic distinction between AC and TC (0.62 for original diagnosis and 0.63 for central-reviewed diagnosis). Conclusions: Ki-67 index cutoff value of 1% is a valuable prognostic biomarker for pulmonary carcinoids based on this large cohort. Our data also provide strong evidence for clinical variables such as age, stage, smoking history, and LN involvement as clinical prognostic factors in pulmonary carcinoids. A prognostic calculator incorporating Ki-67 and clinical variables is under development. [Table: see text]
Intraoperative versus external beam boost for breast cancer: A matched-pair analysis.
Authors: Sperk Elena , Astor Daniela , Welzel Grit , Gerhardt Axel , Suetterlin Marc , Wenz Frederik K. 
Published: March 2020

1120 Background: After breast conserving surgery, radiotherapy leads to a better overall survival. In addition to whole breast radiotherapy (WBRT) a boost to the tumor bed leads to a better local control. The tumor bed boost is usually added after WBRT or can be done intraoperative (IORT). Belletti et al. (Clin Cancer Res., 2008) described positive effects, an antitumoral effect and modulation of microenvironment after IORT with 50kV x-rays. A matched pair analysis was performed to investigate the impact of IORT boost on overall survival compared to standard external beam boost. Methods: Between 2002 – 2009, 370 patients were treated for breast cancer with WBRT + boost (external beam (EBRT) boost n = 146, IORT boost n =224). A matched pair analysis (1:1 propensity score matching for age, TNM, grading, hormonal treatment and chemotherapy) for overall survival and local recurrence free survival could be done for 53 pairs. All patients underwent breast conserving surgery and WBRT with 46-50Gy. 53 patients received an EBRT boost with 16Gy (2Gy/fraction, dedicated linear accelerator) and 53 patients received an IORT boost with 20Gy (INTRABEAM system, 50kV x-rays). Median follow-up was 6 months (range, 1-77 months) for the EBRT boost patients and 56 months (range, 2-97 months) for IORT boost patients. Kaplan Meier estimates were performed for overall survival and local recurrence free survival. Results: IORT boost patients had a longer follow-up than EBRT boost patients. Despite the difference in follow-up times, there was a strong trend towards better overall survival after IORT boost (90.2% vs. 62.3%, p = 0.375). One local recurrence was present in each group (EBRT boost after 15 months, local recurrence free survival 95%; IORT boost after 12 months, local recurrence free survival 98.1%). Conclusions: IORT given as a boost seems to have a positive impact on overall survival in breast cancer patients after breast conserving surgery. To identify such an effect a prospective randomized trial should be conducted.
Pregnancy outcome and survivorship in cancer patients.
Authors: Pillar Nir , Mazaki-Tovi Shali , Berger Raanan , Paluch-Shimon Shani , Symon Zvi , Lawrence Yaacov Richard 
Published: March 2020

1503 Background: Advances in cancer detection and treatment have resulted in increased prevalence of female cancer survivors at childbearing age. While the association between cancer treatment and fertility has been thoroughly investigated, data regarding pregnancy outcome of cancer survivor are scarce. The aim of this study is to determine whether cancer survivors and sufferers have increased risk of obstetric complications. Methods: A population-based cohort study using data from the NIS of the Healthcare Cost and Utilization Project, focusing on 2000-2006. The rate of maternal and fetal obstetric complications was determined in pregnant women with and without diagnosis of cancer. Results: A total of 6,732,293 births were included in the analysis, of these 15,191 had maternal cancer diagnosis (0.2%). Pregnant women with cancer diagnosis had increased risk for premature labor, ectopic pregnancy, and need for blood transfusion. Moreover, the rate of maternal (3.6/ 1000 births) and fetal (8.3/1000 births) mortality was higher amongst women with cancer compared to non-cancer bearing women- (0.12/ 1000 births) and (3.9/ 1000 births) respectively. Multivariate logistic regression revealed that both age and cancer diagnosis were significantly and independently associated with pregnancy complications. Conclusions: This is the first large-scale study to determine the prevalence of obstetric complications in cancer patients. Pregnant women with a diagnosis of cancer are at increased risk of major obstetric complications, including maternal and fetal death, although the absolute risk is relatively low. It may therefore be prudent to define such pregnancies as “high-risk” and advocate intense prenatal care for these patients. [Table: see text]
High-dose omega-3 fatty acid supplementation to modulate breast tissue biomarkers in premenopausal women at high risk for development of breast cancer.
Authors: Fabian Carol J. , Kimler Bruce F. , Petroff Brian K. , Zalles Carola Maria , Metheny Trina , Box Jessica A , Nydegger Jennifer L , Phillips Teresa A. , Hidaka Brandon H , Carlson Susan E , deGraffenried Linda A , Hursting Stephen D 
Published: March 2020

1515 Background: We conducted a pilot study of high dose omega-3 fatty acid (FA) supplementation in pre-menopausal women to determine if risk biomarkers for breast cancer in benign breast tissue sampled by random peri-areolar aspiration (RPFNA) could be favorably modulated and to acquire preliminary data on possible mechanism of action. Methods: 36 pre-menopausal women at increased risk for breast cancer were accrued to a trial of 6-month intervention with 4 g daily of omega-3-acid ethyl esters [1.86 g eicosapentaenoic acid (EPA), 1.5 g docosahexaenoic acid (DHA)]. To date, 31 subjects have completed study with RPFNA performed pre- and post-intervention in the follicular phase of the menstrual cycle and specimens evaluated for cytomorphology and proliferation (Ki-67). FA composition was determined in plasma, red blood cells, and RPFNA specimens. Additional specimens were frozen for assessment of hormones, a panel of 11 adipokines and cytokines, and gene expression. Results: The ratio of (EPA+DHA):Arachidonic Acid (AA) levels increased significantly in plasma and erythrocytes by a median of three-fold. There was a significant decrease in blood EPA+DHA between discontinuation at 6 months and 2 weeks later when RPFNA was performed. Despite that, there was favorable modulation for cytologic evidence of atypia (81% at baseline to 42% at off-study; p=0.003), Masood score (medians of 15 to 14; p=0.001), number of epithelial cells recovered (p=0.004) and Ki-67 expression (p=0.025 for 30 women with any Ki-67 at baseline, medians of 1.9% to 0.9%). Serum assays have been completed for 24 subjects. No statistically significant changes were observed for estradiol, testosterone, progesterone, SHBG, IGF-1, IGFBP-3. There was a trend (p=0.056) towards a decrease in resistin. To date, only two subjects have discontinued the study early; grade 2 or greater gastrointestinal side effects have been reported by only two subjects. Conclusions: Favorable modulation of tissue risk biomarkers, cytologic atypia and proliferation along with good tolerability suggests that high dose omega-3 FA esters should be tested further in a placebo controlled trial. Clinical trial information: NCT01252277.
Next-generation sequencing for genetic cancer risk assessment: Critical needs and perceptions of community clinicians.
Authors: Blazer Kathleen R. , Espenschied Carin , Weissman Benjamin , Sand Sharon , Weitzel Jeffrey N. 
Published: March 2020

1536 Background: Current standard-of-care practice for genetic cancer risk assessment (GCRA) focuses on single-gene testing for specific hereditary cancer syndromes. Next-generation sequencing (NGS) technologies recently became available for clinical applications. This study explored the perspectives and experiences of community-based clinicians regarding NGS testing for personalized GCRA. Methods: A 27-item survey was developed and administered online to 325 members of an interdisciplinary nationwide clinical cancer genetics community of practice. Results: Of 94 (29%) respondents, 25 (27%) have ordered at least one multi-gene panel and only 2 (2.1%) have ordered a whole exome or genome test from a commercial vendor for GCRA. Concerns about clinical utility, the challenge of interpreting and communicating results, lack of knowledge about and potential costs were most often cited as reasons for not pursuing NGS testing. Respondents were significantly more confident about their ability to interpret and counsel about single gene test results compared with multi-gene panels or whole exome/genome sequencing; and about multi-gene panels over whole exome/genome sequencing (p<.0001 for all comparisons). Conclusions: Findings suggest that while NGS tests are entering the realm of GCRA, multidisciplinary genomics education and clinical support resources are needed to address barriers to utilization and promote successful integration of NGS testing into community-based GCRA practice settings.
Screening of CHEK2 and TP53 p.R337H germ-line mutations in high-risk patients for hereditary breast and ovarian cancer from northeast of Brazil.
Authors: Nascimento Ivana Lucia Oliveira , Felix Gabriela Espirito Santo , Machado-Lopes Taisa Manuela Bonfim , Bomfim Thais , Romeo Maura , Toralles Betania , Garicochea Bernardo , Meyer Roberto , Abe-Sandes Kiyoko 
Published: March 2020

1539 Background: CHEK2 is a molecular messenger that interacts with a checkpoint network of other susceptibility genes like ATM, BRCA1, TP53, MDM2, Cdc25A and Cdc25C. The mission of these checkpoints is to preserve the genome integrity during the cell division by regulating the cellular response to DNA damages. The TP53 p.R337H germline mutation was studied in patients with Li-Fraumeni Syndrome, breast cancer and Choroid plexus carcinomas in Southern of Brazil, but never in the Northeast. In the hereditary breast cancer the mutation frequencies of susceptibility genes of low penetrance like CHEK2 is 1-10%, while for genes of high penetrance as TP53 is <1%. Thus, the aim of this study was to screening for CHEK2 and TP53 most common germline mutations in high-risk patients for hereditary breast and ovarian cancer (HBOC) from Northeast of Brazil. Methods: It was analyzed 100 high-risk patients for HBOC from Bahia, Brazil. The genomic DNA was extract from peripheral blood. The CHEK2 mutations, c.1100delC, c.444+1G>A and p.I157T, and TP53 p.R337H mutation were genotyped by Allelic Specific-PCR or PCR-RFLP. Results: Most of the subjects had only breast cancer (86.0%), followed by ovarian (7.0%) and both breast and ovarian cancer (7.0%). Among the breast cancer cases the most common histological type was the ductal (71.0%), while among the ovarian cancer cases were the serous (57.14%). The mean age at diagnostic was 42 yrs (± 9.99). Any of the patient presented c.1100delC, c.444+1G>A and p.I157T mutations. But, two have the p.R337H mutation. Conclusions: Though there is the hypothesis that mutations of low penetrance genes, such as CHEK2, are more likely to be found than high penetrance genes, such as TP53, here it was demonstrate that three of most predisposing variants of CHEK2, c.1100delC, c.444+1G>A and p.I157T, do not have major contribution in HBOC in the population studied. While, the p.R337H, though presented in low frequency compared with the Southern of Brazil (Ashton-Prolla et al., 2012), seems to have a significant contribution in HBOC.
Investigating parent of origin effects (POE) and anticipation in Irish Lynch syndrome kindreds.
Authors: Farrell Michael P. , Hughes David J. , Schmid Jasmin , Boonstra Philip S. , Mukherjee Bhramar , Walshe Margaret B. , Mac Mathuna Padraic M. , Green Andrew J , Gallagher David J. 
Published: March 2020

1542 Background: Genetic diseases associated with dynamic mutations often display parent-of-origin effects (POE) in which the risk of disease depends on the sex of the parent from whom the disease allele was inherited. Genetic anticipation describes the progessively earlier onset and increased severity of disease in successive generations of a family. Previous studies have provided limited evidence for and against both POE effect and anticipation in Lynch syndrome (LS). We sought evidence for a specific POE effect and anticipation in Irish LS families. Methods: Affected parent-child pairs (APCPs) (N = 53) were evaluated from LS kindreds (N = 20) from two hospital-based registries and one cancer genetic centre. POE were investigated by studying the ages at diagnosis in the offspring of affected parent-child pairs. Anticipation was assessed by a paired t-test, and bivariate Huang and Vieland model. Results: See Table. Paired t-test revealed anticipation with children developing cancer mean 11.8 years earlier than parents, and 12.7 years using the Huang and Vieland model (p < 0.001). Conclusions: These data demonstrate a similar age at diagnosis among all offspring of affected mothers that was indistinguishable from affected fathers. Affected sons of affected mothers were diagnosed with cancer almost 3 years younger than female offspring; however, this finding failed to reach statistical significance. Evidence of anticipation was suggested in this cohort, emphasizing the importance of early-onset screening. Addition LS families are under review and updated data will be presented at the meeting. [Table: see text]
Clinical experience with exemestane in postmenopausal women at increased risk of breast cancer.
Authors: Sorkin Mia , Lapolt Donna , Pusztai Lajos , Hofstatter Erin Wysong 
Published: March 2020

1565 Background: Exemestane has recently been identified as an effective breast cancer chemoprevention agent. This drug may be more appealing to patients than tamoxifen or raloxifene, since it does not increase the risks of thrombosis, cataracts and uterine cancer. Poor patient acceptance of tamoxifen and raloxifene as chemoprevention is well-documented but patient acceptance rates for exemestane have not been reported. The goal of this study was to assess exemestane use in a breast cancer prevention clinic. Methods: A retrospective chart review was conducted to capture patient characteristics, medical history and chemoprevention uptake of all postmenopausal women presenting to the Yale Breast Cancer Prevention Clinic from November 2011-November 2012. Descriptive statistics are presented. Results: Fifty-six postmenopausal women deemed eligible for initiation of chemoprevention were seen during the study timeframe, with a mean age of 58 (range 42-79). Risk categories included: 22 women (39%) diagnosed with breast atypia, 7 with LCIS (12%), 4 with prior DCIS (7%), 41 with family history of breast cancer (73%), and 8 women with a deleterious BRCA 1 or 2 mutation (14%). 22 (39%) of these women had osteopenia or osteoporosis. Of all eligible women, 13 opted to start a chemoprevention medication (23%); 8 of whom opted for raloxifene, 1 for tamoxifen and 4 for exemestane. While exemestane comprised 30.7% (4/13) of chemoprevention medication uptake, only 4 of 56 women eligible for chemoprevention decided to take exemestane (7%). Conclusions: Chemoprevention uptake rates of postmenopausal women in the setting of a breast cancer prevention clinic are higher (23%) than those reported in the general population, but remain low overall. Uptake of exemestane appears lower than that of raloxifene but higher than tamoxifen. A large proportion of postmenopausal women (39%) have osteopenia or osteoporosis which limits exemestane uptake in a breast cancer prevention setting.
Longitudinal comparison of body mass index (BMI) in breast cancer survivors to cancer-free women: A prospective study in high-risk women.
Authors: Gross Amy L , Davidovics Sarah A , Axilbund Jennifer E , Armstrong Deborah Kay , May Betty J , Visvanathan Kala 
Published: March 2020

1601 Background: Postdiagnosis weight gain in non-familial breast cancer (BC) survivors has been observed in a number of studies, with the reported prevalence and amount of weight gain being highly variable. Most studies did not include a cancer-free comparison group. Change in BMI has not been studied in BC survivors from high-risk populations. Methods: In an ongoing prospective cohort of women at Johns Hopkins with a family history of BC, ovarian cancer, and/or a BRCA1/2 mutation, we identified 249 survivors of stage 0-III BC and 400 cancer-free women who completed a baseline and at least one follow-up questionnaire and were age > 30 years (yrs) at enrollment. Linear regression was used to estimate % change in self-reported BMI from baseline to follow-up (median 3.7 yrs) for survivors compared to cancer-free women including the effects of time between BC diagnosis and baseline, and differing BC treatment. Results: Mean age at baseline was 54.6 yrs among for survivors and 50.2 yrs among for cancer-free women. Mean age at BC diagnosis was 48.7 yrs with > 50% diagnosed under 50 yrs, and 23% with ER- tumors. Baseline BMI did not differ between survivors and cancer-free women irrespective of tumor subtype. However, the average change in BMI was 1.79% (95% CI 0.32, 3.26) greater in survivors compared to cancer-free women in models adjusted for age, baseline BMI, menopausal status, physical activity, enrollment yr, and bilateral oophorectomy. The increase in BMI was highest (β = 4.22%; 95% CI 1.74, 6.70) in survivors diagnosed within 1 yr of baseline. Change in BMI in survivors diagnosed > 5 yrs prior to baseline did not significantly differ from cancer-free women. A significantly greater increase in BMI was also observed in survivors diagnosed at age > 50 yrs, and in those who received chemotherapy and not hormone therapy. Conclusions: In this study of BC survivors and cancer-free women enrolled from the same source population, we observed a greater percent increase in BMI over time among survivors, particularly those diagnosed within 5 yrs of baseline and/or treated with chemotherapy. Survivors in these categories may benefit from interventions aimed to reduce weight gain post diagnosis.