bluuebunny/crossref_metadata_2025 huggingface dataset:
Immediate tissue expander breast reconstruction following mastectomy in pregnancy-associated breast cancer.
Authors: Zabicki Calvillo Katherina , Caragacianu Diana L. , Chun Yoon S. , Caterson Stephanie , Bellon Jennifer Ruth , Wong Julia S. , Troyan Susan , Rhei Esther , Dominici Laura Stewart , Economy Katherine E. , Tung Nadine M. , Schapira Lidia , Meisel Jane L. , Partridge Ann , Mayer Erica L.
Published: March 2020

1133

Background: Management of pregnancy-associated breast cancer (PABC) requires balancing benefits of therapy with potential risks to the developing fetus. Surgical management can be influenced by gestational age of fetus and tumor stage. Minimal data describe surgical and obstetrical outcomes after mastectomy with immediate breast reconstruction (IR) in a pregnant patient (pt). Methods: Pts who underwent IR after mastectomy were identified within a multi-institutional PABC cohort. Retrospective chart review was performed for outcomes including adverse intraoperative events, immediate postoperative complications, gestational age at delivery and fetal weight. Other parameters evaluated included stage at presentation, duration of surgery, and use of delayed reconstruction in pts who did not receive IR. Results: Within a cohort of 79 PABC pts, 25 (32%) had mastectomy while pregnant, 8 (32%) of whom had IC; 17 (68%) did not undergo IR. Mean gestational age at time of IR was 16.6 weeks (range 10-30) and all IR utilized tissue expander (TE) placement followed by permanent implant placement in 7 pts. In the IR cohort, 1 (12.5%) pt was stage 0, 3 (37.5%) stage I and 4 (50%) stage IIB. There were no intraoperative or immediate postoperative surgical complications. The mean duration of surgery was 198 min with IR (7 pts) vs. 157 min without IR (available for 12 pts). All women who underwent IR delivered at, or close to, term infants of normal birthweight. One pt had pre-term labor after surgery at 29 weeks which resolved with tocolysis. Mean gestational age at delivery was 37.3 weeks in the IR cohort vs. 36.3 weeks in the non-IR cohort. No fetal abnormalities or major obstetrical complications were seen after IR. Post-mastectomy radiation (PMRT) was provided after pregnancy in 2 pts (25%) in the IR cohort and cosmetic outcome was not adversely affected. Conclusions: This report represents one of the largest series describing IR after mastectomy in PABC. Results suggest immediate tissue expander placement after mastectomy may increase duration of surgery but does not lead to adverse obstetrical or fetal outcomes. IR with tissue expanders may preserve reconstructive options when PMRT is indicated.
Preliminary analysis of risk factors associated with peritoneal carcinomatosis (PC) after prophylactic bilateral salpingoophorectomy (PBSO) in patients with a BRCA mutation.
Authors: Stjepanovic Neda , Carrasco Estela , Gadea Neus , Gil Antonio , Perez M. Assumpcio , Diaz Berta , Franco Silvia , Cabrera Silvia , Garcia Angel , Castellvi Josep , Díez Orland , Vilaro Marta , Balmaña Judith
Published: March 2020

1509

Background: Women with a BRCA1 or BRCA2 mutation are at high risk of developing ovarian carcinoma (OC) and a residual risk of PC after PBSO has been reported. We aimed to analyze the incidence of PC after PBSO and the clinical, pathological and molecular risk factors associated to PC in our series. Methods: Between April 2005 and December 2012, 100 patients with BRCA1 or BRCA2 mutation (50 each) underwent PBSO and were followed in the High Risk Clinics for the development of PC. PBSO pieces were submitted to pathological examination for presence of pathological and molecular risk factors like in situ or invasive Fallopian Tube Carcinoma (isFTC, inFTC) and p53 signature. Patients’ medical charts included in the High Risk Clinics Database were revised retrospectively for clinical, pathological and molecular characteristics. We analyzed the incidence of PC and the odds ratio (OR) for PC after PBSO in univariate analysis. Results: Overall, 2 patients (2%, 1 BRCA1, 1 BRCA2) were found to have isFTC, while 5 out 34 had a positive p53 signature (15%, 1 BRCA1, 4 BRCA2). With a median follow-up of 40 months (1-90) since PBSO, 2 patients developed PC (2%, both BRCA2). They underwent PBSO at age of 63 and 64 years and developed the PC 2 and 9 years after. One had a history of isFTC with p53 signature and 5 children, while the other had a prior history of bilateral breast cancer and no children. None had a family history of OC. Performing PBSO at an age older than 50 years was associated with an OR 8.56 (3.29-22.27) of PC. Conclusions: Fifteen and 2% percent of our patients had a positive p53 signature or an occult isFTC in the PBSO piece. Our analysis suggests that delaying PBSO to women older than 50 years may be associated with a higher risk of PC. Further analysis in a larger cohort is warranted.
Breast cancer mortality among users of cholesterol-lowering drugs.
Authors: Murtola Teemu Johannes , Visvanathan Kala , Artama Miia , Vainio Harri , Pukkala Eero
Published: March 2020

1514

Background: Breast cancer is a common malignancy and cause of cancer death. Recent studies have suggested that statins, an established cholesterol-lowering drug group used in the prevention of cardiovascular mortality, could have beneficial effects against recurrence and progression of breast cancer. We evaluated breast cancer-specific mortality among users of statins and other cholesterol-lowering drugs (fibrates and bile-acid binding resins) in a cohort of breast cancer patients. Methods: Our study cohort included all newly diagnosed breast cancer patients in Finland during 1995-2003 (31,236 cases), identified from the Finnish Cancer Registry. Information on cholesterol-lowering medication use was obtained from a national prescription database.We used Cox proportional hazards regression method to estimate mortality among medication users. Results: A total of 4,169 participants had used statins, while 313 had used fibrates or resins. Despite similar median age, tumor and treatment characteristics, only statin use was associated with decreased breast cancer mortality (participants with localized tumors: HR 0.33, 95% CI 0.24-0.42; metastatic tumors: HR 0.52, 95% CI 0.31-0.86). Fibrate and resin use were associated with increased overall mortality (HR 1.70, 95% CI 0.96-2.99 for participants with localized disease, HR 2.65, 95% CI 1.18-5.96 for participants with metastatic disease). Conclusions: Decreased breast cancer mortality among users of statins, but not other cholesterol-lowering drugs despite similar population characteristics suggests that this drug group may have benefit in prevention of cancer progression. Clinical trials testing statins’ efficacy in breast cancer patients are warranted.
Overview of meta-analyses and pooled analyses of nutrition and breast cancer risk.
Authors: Mullie Patrick , Autier Philippe , Boyle Peter
Published: March 2020

1519

Background: Twenty years ago, recommendations for prevention of breast cancer by dietary modification were based on decreased fat consumption, and increased consumption of dietary fibre, fruits, vegetables and vitamins. Subsequent literature is replete with reports of studies of diet and nutrition often containing widely varying advice for women regarding reducing their breast cancer risk. Methods: A systematic search in PubMed of the published literature was conducted to identify meta-analyses and pooled analyses relating breast cancer risk to a wide variety of nutritional components including intake of coffee, dairy, dietary fibre, eggs, fat components, fruits and vegetables, glycaemic index and load, meat components, minerals, seafood, soy, tea, and a variety of vitamins. Inclusion criteria were: published in English, time period 2000-2011, and restricted to studies with a prospective design. All published relative risks and confidence intervals were abstracted. Results: The search retrieved 2 pooled analyses and22 meta-analyses concerning alcohol (1), coffee (2), dairy (3), dietary fibre (2), eggs (1), fat components (3), fruits and vegetables (2), glycaemic index and load (3), meat (3), minerals (1), seafood (1), soyfood (1), tea (3), and vitamins (5). In total 256 relative risks were computed by meta- and pooled analyses, with 195 (76%) statistically not significant, 16 (6%) showing an increased risk and 45 (18%) showing a decreased risk of breast cancer. 18 relative risks were less than 0.90 and 5 were greater than 1.25. Of the 5 estimates for alcohol, 2 (40%) showed statistically significant increased risk for breast cancer. For other food items, proportions associated with non-significant risk were for dairy (85%), total fat consumption (83%), dietary fibre (56%), fruits and vegetables (96%), glycaemic index/load (77%), meat (95%) and vitamins (78%). Conclusions: Other than accepted dietary risk factors alcohol, obesity and physical activity, no individual nutritional item has been consistently related to breast cancer risk. Energy balance seems to be an essential element in breast cancer prevention.
Can microsatellite status of colorectal cancer (CRC) be reliably assessed after neoadjuvant therapy?
Authors: Vilar Sanchez Eduardo , Wu William , Bhatia Gita , Cuddy Amanda , Mork Maureen M. , Bannon Sarah A. , Lynch Patrick M. , Rodriguez-Bigas Miguel A. , Taggart Melissa W. , You Y. Nancy
Published: March 2020

1525

Background: Universal testing of resected CRC for Microsatellite Instability (MSI) status has been widely advocated. While PCR-based MSI analysis is the current gold standard test, immunohistochemistry (IHC) of mismatch repair (MMR) proteins is more commonly performed. At present, it remains un-established whether PCR-based MSI analysis remains reliable when performed on post-neoadjuvant treated specimens. Our goal was to examine the effect of neoadjuvant therapy on MSI analysis using both in vitro and clinical data. Methods: MSI analysis was performed using the standard panel of 7 markers. In vitro, MMR deficient (HCT116) and proficient (HCT116+Ch3) isogenic cell lines were exposed to 3 cycles of single agent 5-Fluorouracil, Oxaliplatin and Irinotecan and MSI analysis was tested after each cycle. To evaluate the induction of genomic instability, 3 additional coding microsatellite tracts in ATR, BLM and CHK1 were assessed by fragment analysis. In parallel, clinical data from 238 CRCs that were resected after neoadjuvant chemoradiation (n=191) or chemotherapy (n=47) between 9/2009 and 8/2011 were queried for MSI results. MSI analysis performed on paired pre-treatment and post-treatment resection tissues was compared. Results: No changes in MSI status were detected and there was no increase in genomic instability post-treatment in cell line models. In the clinical setting, pre-neoadjuvant MSI testing was limited by the availability of pre-treatment biopsy tissue. 3 patients found to be MMR proficient based on MSI analysis performed on pre-treatment biopsy remained microsatellite stable when analyzed on post-treatment resection tissue. 7 patients were MMR deficient based on MSI analysis performed on post-treatment resection tissue but most had strong clinical evidence to expect MMR deficiency. Conclusions: Based on both preclinical in vitro and clinical data, results of the MSI analysis does not appear to be affected by neoadjuvant therapy for both MMR proficient and deficient cases. In addition, preclinical results do not suggest that neoadjuvant chemoradiation induces an increase in genomic instability. Therefore, MSI analysis remains a reliable gold standard test on post-treatment specimens.
Imaging techniques in pancreatic cancer screening: Preliminary results from the PanGen-FAM registry.
Authors: Guillen-Ponce Carmen , Mocci Evelina , Earl Julie , Marquez Mirari , Milne Roger , Molina-Garrido MJ , Guerrero Carmen T , Real Francisco X , Malats Nuria , Carrato Alfredo
Published: March 2020

1529

Background: The incidence of pancreatic cancer (PC) is low, thus screening is recommended for individuals considered to be at high risk. These include members of families with ≥ 2 relatives with PC (FPC), Peutz Jegher syndrome, hereditary breast/ovarian cancer (HBOC), familial atypical multiple mole melanoma and Lynch syndrome. Previous studies have shown that non-invasive precursor lesions, such as intraductal papillary mucinous neoplasm (IPMN) and pancreatic intraepithelial neoplasia (PanIN) are more common and of a higher invasive grade in patients with a family history of PC. Methods: Baseline screening consisted of endoscopic ultrasound (EUS) and computed tomography (CT) and magnetic resonance imaging (MRI). FNA-EUS was performed when mass lesions or cysts ≥1 cm in size were encountered. The possibility of surgical intervention or ongoing clinical observation was discussed by a multidisciplinary team in the case of abnormal findings. Furthermore Circulating Tumor Cells (CTC) in peripheral blood as a diagnostic marker was assessed. Thirty-five individuals from FPC and HBOC families were screened between October 2011and December 2012. Results: The most frequent abnormal findings by EUS were parenchymal changes found in chronic pancreatitis (hyperechoic foci, echogenic strands, lobularity, cysts). Overall 13 (41%) patients showed at least 1 of these changes; of note, 7 patients were from the same FPC family. Four patients were diagnosed with cystic lesions by EUS; two lesions were confirmed by MRI but not by CT, one lesion was confirmed by both MRI and CT and was compatible with a mucinous tumor < 1cm in diameter and one lesion was detected only by EUS. One patient with cystic lesion >1 cm in size underwent EUS-FNA and the cytology showed benign celularity. One patient has a solid lesion, and it was a neuroendocrine tumor. The remaining patients with cystic lesions were proposed for ongoing close clinical observation. CTC have not been detected in 54 patients tested. Conclusions: A high prevalence of pancreatic abnormalities was found in patients from FPC families. Preliminary data suggest that EUS is the most sensitive method to detect small tumors and premalignant lesions.
Prevalence and differentiation of hereditary breast and ovarian cancer in Japan.
Authors: Nakamura Seigo , Iwase Takuji , Nishimura Seiichiro , Yamauchi Hideko , Nomizu Tadashi , Ohsumi Shozo , Takahashi Masato , Baba Shinichi , Shimizu Tadao
Published: March 2020

1534

Background: Breast cancer is the most common female cancer, according to the Center for Cancer Control and Information Service in Japan. However, the lifetime breast cancer risk in Japan is markedly lower (one in 16) than in the U.S. or Europe. We assembled needed data on the prevalence and characteristics of BRCA1/2 in Japan. Methods: Our study of BRCA 1 and 2 (BRCA1/2) collected data at 8 institutions in Japan on 320 individuals with a strong family history of breast cancer, according to the NCCN guidelines, by the end of March, 2012. Results: Among 260 proband cases, 46 (17.7%) were positive for BRCA1 and 35 (13.5%) were BRCA2 positive. Therefore, the total pathological mutation rate was 30.7%. Pathology data after breast surgery were obtained from 35 cases of BRCA1 mutation, 22 (62.9%) of which were triple negative and 10 (29.4%) were Luminal type. On the other hand, 24 cases (85.7%) of BRCA2 mutations were Luminal type. The most prevalent BRCA1 mutation site was L63X, found in 10 families. L63X was reported previously by studies in Japan, and it may be a founder mutation. We found 2 cases of large deletion detected by MLPA, comprising the first two reported cases in Japan. One was an entire deletion of exon 20 and the lacked exons 1-9. Eight cases of BRCA1 (3.1%) and 12 (4.6%) BRCA2 were uncertain variants. TN with a family history ovarian cancer were 14/20 (70%), TN under 40 y/o 17/23 (73.9%) and TN with one or more breast cancers in family history 19/32 (59.4%) showed higher incidences of BRCA1/2, especially BRCA1. Conclusions: HBOC may have nearly the same prevalence in Japan as in the U.S. or Europe. If TN cases are taken into account, the ratio of BRCA1 is higher. L63X may be one of the founder mutations in Japan. A nationwide database of HBOC is important to address these challenges: (1) To develop risk models for BRCA1/2 carriers in Japan (2) To identify the proper methods to detect cancer occurrence among Japanese BRCA1/2 carrier early (3) To differentiate whether uncertain mutation variants found in Japan are deleterious.
Timing of referral to genetic counseling among women with gynecologic or breast cancer.
Authors: Bregar Amy J , Febbraro Terri , Robison Katina , Scalia Wilbur Jennifer , Kent Laprise Jessica , Lopes Vrishali , Legare Robert Duffy , Stuckey Ashley
Published: March 2020

1545

Background: The National Comprehensive Cancer Network (NCCN) has established guidelines delineating appropriate candidates for genetic counseling. While genetic predisposition is responsible for a small percentage of cancer, genetic referral at diagnosis may effect treatment decisions. We aim to determine factors associated with timing of referral in women with breast and gynecologic cancers. Methods: Patients from an academic women’s oncology program were identified who met a subset of NCCN referral criteria for genetic evaluation between 2004-2010 (ovarian cancer at any age, breast cancer ≤ 50 years of age, or uterine cancer < 50 years of age). A retrospective chart review was conducted. Statistics were analyzed using SAS v. 9.2 (SAS Institute, Cary, NC); categorical variables were compared by chi-square or Fisher's exact test and continuous variables were compared by ANOVA. The study was approved by the hospital Institutional Review Board. Results: 820 women with cancer (26% uterine, 38% breast, 35% ovarian) were included. The overall referral rate was 22%; more breast than gynecologic cancer patients were referred (34% vs. 28%, p<0.0001). Breast cancer patients were more often referred at diagnosis compared to women with uterine (p<0.0001) and ovarian cancer (p=0.007). Early stage breast cancer patients were more often referred at diagnosis compared to women with late stages (p=0.03). Among ovarian cancer patients, those with late stages were more often referred at diagnosis compared to women with early stages (p=0.02). Age at diagnosis, family history, and parity were not associated with timing of referral. Among women with breast cancer, 26% of referred patients had a prophylactic contralateral mastectomy compared to 8% of those not referred (p<0.0001). Conclusions: Genetic counseling is underutilized in breast and gynecologic malignancies. The timing of referral varies widely and genetic counseling may impact treatment decisions. Breast cancer diagnosis, early stage breast cancer, and late stage ovarian cancer are associated with earlier referral for genetic evaluation. Further research is needed to determine additional factors that may increase referral rates and impact timing of referral.
Transcriptional regulation and prostate cancer risk loci.
Authors: Klein Robert J. , Xu Xing , Hussain Wasay , Farber James , Vaananen Riina-Minna , Taimen Pekka , Vijai Joseph , Hayes James E. , Lilja Hans , Pettersson Kim , Rubin Mark A. , Demichelis Francesca , Offit Kenneth
Published: March 2020

1554

Background: While genome-wide association studies (GWAS) have identified numerous loci at which common single nucleotide polymorphisms (SNPs) are clearly associated with the risk of developing prostate cancer, the mechanism by which these variants influence disease is not clear. Based on the observation that regions of the genome with marks of transcriptional regulatory elements harbor SNPs that are more likely to be under negative selective pressure, we hypothesized that many prostate cancer associated SNPs, or their correlated proxies in linkage disequilibrium, function by altering regulation of nearby genes through alteration of transcription factor binding sites. Two predictions of this hypothesis are that there will be an enrichment of prostate cancer risk SNPs or their proxies in regulatory elements in prostate tissue and that some of these SNPs will correlate with the expression levels of nearby genes. Methods: To test the first prediction, we compared the number of prostate cancer risk SNPs (or their proxies) that overlap with DNase hypersensitive sites in the LNCaP prostate cancer cell line with randomly selected SNPs matched for allele frequency, distance from nearby genes, and local gene density. To test the second prediction, we asked if any of the known prostate cancer risk SNPs are associated with mRNA expression levels of nearby genes. Results: We found a four-fold enrichment of real prostate cancer risk SNPs overlapping with DNase hypersensitive sites versus the random set (p=0.03) at an r2 threshold of 0.95. In both tumor and benign prostate tissue, we found that a recently identified prostate cancer risk SNP is associated with expression levels of IRX4, a transcription factor previously implicated only in cardiac development. Conclusions: These data support the hypothesis that many GWAS-identified risk SNPs alter transcriptional regulation of nearby genes.
Assessing breast cancer risk in primary care: What can we learn from cardiovascular disease?
Authors: Phillips Kelly-Anne , Keogh Louise A. , Steel Emma , Collins Ian M. , Emery Jon , Pirotta Marie , Mann Bruce , Butow Phyllis , Trainer Alison , Moreton Jane , Antoniou Antonis C. , Cuzick Jack M. , Hopper John L.
Published: March 2020

1559

Background: Routine assessment of breast cancer (BC) risk by primary care clinicians (PCCs) might improve uptake of BC prevention and screening interventions, thus reducing morbidity and mortality as has occurred for cardiovascular (CV) disease. Methods: Australian PCCs were recruited through local professional networks. Facilitated focus group discussions about current practice of assessing and managing BC risk were audiotaped, transcribed verbatim and managed using QSR NVivo qualitative data management software. A coding framework was developed based on the transcripts, data were coded and each code further analyzed to identify key themes. Results: 17 PCCs (12 doctors, 5 practice nurses) participated in 2 focus groups. 41% were male, median age 49 years, median number of years in practice was 15. Approaches to assessment and management of BC risk differed markedly from that of CV risk. PCCs see assessment and management of CV risk as an intrinsic, expected part of their role. Practice software prompts trigger CV risk assessment and PCCs often use an online tool (www.knowyournumbers.co.nz) to provide personalized risk estimates and to discuss management options for CV risk. Conversely, assessment of BC risk is not routine or prompted by practice software, is generally patient (not clinician) initiated, and management, beyond routine BC screening (e.g. chemoprevention), is considered outside the PCCs domain. Most PCCs are not familiar with, or using, BC risk assessment tools. PCCs suggested they could potentially routinely assess and manage BC risk. Such an approach would need to be widely endorsed as within the remit of primary care and would be enhanced by an online tool that is accessible, quick, visual (graphs and pictograms), evidence-based and regularly updated. Ideally, its use would be prompted by their practice software. Conclusions: There is a clear opportunity in primary care to enhance the capacity and motivation of clinicians to assess and manage BC risk. A risk assessment and decision aid tool, integrated into primary care software, might facilitate routine appropriate management of BC risk in the Australian primary care setting, modelling what has already been achieved for CV disease.
Risk-adapted screening in bladder cancer with the open-access tool RiskCheck Bladder Cancer: Proof of principle by the health service research foundation IQUO.
Authors: Geiges Goetz , Koenig Frank , Lüdecke Gerson ,   Interessensverband zur Qualitätssicherung der Arbeit niedergelassener Uro-Onkologen in Deutschland e.V. (IQUO)
Published: March 2020

1571

Background: The open-access questionnaire RiskCheck Bladder Cancer (RCBC) was proven in daily routine work from German urologists organized in the health services research foundation IQUO on asymptomatic patients to identify BC risk exposure and its relation to detectable tumors. Methods: The open-access RCBC questionnaire checked asymptomatic patients for their BC risk exposure in relation to personal-, smoking-, occupation- and medical induced risk. This resulted in a risk stratification with low- intermediate- and high risk. The intermediate and high risk subjects were checked for tumor presence by routine diagnostics. IBM-SPSS 20 was used for descriptive statistics and effectiveness was proven by classification tree analysis and cross-table analysis with Chi-square test. Results: Out of 303 checked asymptomatic persons 274 (90.4%) were negative for tumor and 29 (9.6%) had a detectable tumor. In the group of NED 176 (68.1%) persons were classified as low risk, and 98 (16.2%) with tumor risk. Out of the 29 detected tumors 20 were at intermediate or high risk (68.9%). This resulted in an over all detection rate of 6.6% and focused on the risk population of 16.9%. The RCBC risk assessment was significant (p < 0.01). Sensitivity 69.0%, specificity 64.2%, NPV 95.1%, PPV 16.9%, false positive cases 35.8%, false negative cases 31.0%, accuracy 64.7%. Compared to the common incidence (35/100,000) this is an increase in effectiveness of 188.6 in the screened population and 482.8 in relation to the risk population alone. Conclusions: Preventive medical care becomes effective because RCBC is able to condense a population with focusing investigations on people living under risk. A reasonable preventive care by a yearly recall control in urological offices for the risk population (32.3%) can be organized. In consequence the assessment is work effective, aim achieving and in result cost effective. The questionnaire RCBC integrates evidence based bladder cancer inductors, is easy in use and as a open-access tool available in 10 languages via internet to all medical services. www.riskcheck-bladder-cancer.info.
Effects of obesity and smoking on survival in non-small cell lung cancer.
Authors: Hansra Damien Mikael , Koru-Sengul Tulay , Zhao Wei , Miao Feng , Tannenbaum Stacey , Monedero Alicia P , Lee David J , Byrne Margaret M , Hurley Judith
Published: March 2020

1586

Background: Tobacco is the leading cause of preventable death in the US and is linked to many cancers most notably lung cancer. It is established that smoking not only causes lung cancer but is also associated with decreased survival. Obesity is an emerging leading cause of morbidity and mortality in the US and the relationship between obesity, tobacco, and survival in NSCLC is unclear. Methods: Data (n= 87,631) were obtained from linkage of the 1996-2007 Florida Cancer Data System, a population-based cancer registry, to the Agency for Health Care Administration database providing procedure and diagnoses codes. Survival time was calculated from date of diagnosis to date of death. Smoking status was categorized as never, current, and former. Obesity (yes/no) was determined by body mass index greater than 30. Cox proportional regression models were used to predict survival; demographic, clinical, treatment factors, and comorbidities were included in adjusted models with smoking status and obesity as the main factors. Results: The majority of patients were either former (49%) or current (40%) smokers, and non-obese (93%). There were significant differences between survival curves and median survival (months) for obese vs. non-obese patients (19.9 vs.9.8; P<.001). Former and current smokers had shorter median survival than never smokers (10.8 & 9.2 vs. 11.9; P<.001). Survival rates (%) at 1-yr (60.0 vs. 44.8; P<.001), 3-yr (38.4 vs. 22.1; P<.001) and 5-yr (30.2 vs. 15.0; P<.001) were better for obese vs. non-obese patients. Independent predictor of worse survival in the unadjusted model was former (HR 1.08; P<.001) and current (HR 1.20; P<.001) smokers compared to never. Obese patients had better survival vs. non-obese patients (HR 0.64; P<.001). In the adjusted model, controlling for extensive variables and comorbidities, former (HR 1.14; P<.001) and current (HR 1.22; P<.001) smokers still had significantly worse survival vs. never smokers. Obese patients still had better survival (HR 0.84; P<.001) vs. non-obese patients. Conclusions: Our results show that being a former or current smoker worsens survival while obesity improved survival regardless of smoking status when compared with non obese patients.
Correlation between anthropometric, pathologic data, and 21-gene recurrence score assay in early-stage breast cancer.
Authors: Quintyne Keith Ian , Woulfe Bernie , Coate Linda , Gupta Rajnish K.
Published: March 2020

1591

Background: Obesity or body mass index (BMI) > 30kg/m2 is a grave public health concern. Poorer outcome has been documented in obese breast cancer patients. We report the use of the Oncotype Dx Recurrence Score (RS) assay and its correlation with BMI and pathologic data. Methods: Study period: 01/09/08 – 31/05/12. Data was derived from: MWCC database; pathology reports; patient files; RS reports. Statistical analysis was carried out using R. Results: 89 patients were found. Median follow-up: 21.4 months. See Table for data. Conclusions: For this cohort: A skewed pattern in RS assay scores was observed in obese patients, where there were more intermediate and high scores, although this was not significant in multivariate model; tumour size and grade were shown to correlate with the RS assay results; these findings are thought-provoking and certainly can augment to the accruing energy balance data that has been increasingly of interest in oncological research. [Table: see text]
Effect of visual inspection with acetic acid (VIA) screening by primary health workers on cervical cancer mortality: A cluster randomized controlled trial in Mumbai, India.
Authors: Shastri Surendra Srinivas , Mittra Indraneel , Mishra Gauravi , Gupta Subhadra , Dikshit Rajesh , Badwe Rajendra A.
Published: March 2020

2

The full, final text of this abstract will be available at abstract.asco.org at 7:30 AM (EDT) on Sunday, June, 2, 2013, and in the Annual Meeting Proceedings online supplement to the June 20, 2013, issue of Journal of Clinical Oncology. Onsite at the Meeting, this abstract will be printed in the Sunday edition of ASCO Daily News.
Tumor pharmacokinetics (PK) and pharmacodynamics (PD) of SAR245409 (XL765) and SAR245408 (XL147) administered as single agents to patients with recurrent glioblastoma (GBM): An Ivy Foundation early-phase clinical trials consortium study.
Authors: Cloughesy Timothy Francis , Mischel Paul S. , Omuro Antonio Marcilio Padula , Prados Michael , Wen Patrick Y. , Wu Bin , Rockich Kevin , Xu Yi , Lager Joanne J. , Mellinghoff Ingo K.
Published: March 2020

2012

Background: XL765 is a potent pan PI3K inhibitor with activity against mTOR and XL147 is a potent pan-PI3K inhibitor. Inhibition of the PI3K/mTOR pathway may be beneficial in the treatment of GBM. Methods: Patients with GBM who were candidates for a surgical resection were eligible for this exploratory study. Cohorts of 6-10 patients were treated with one of three regimens: Cohort 1: XL765 50mg twice daily (BID), Cohort 2: XL147 200mg once daily (QD), Cohort 3: XL765 90mg QD for >10 days prior to undergoing tumor resection. Tumor tissue was obtained at ~12, 24 and 3 hours after the last dose, respectively. Frozen tumor tissue and blood were analyzed for drug concentration (PK) and pathway modulation was analyzed in post-dose frozen tumor tissue and compared to reference tumor samples from GBM patients not treated with XL765 or XL147. Pharmacodynamic impact (PD) on the pathway, apoptosis and proliferation was examined by immunohistochemistry (IHC) in an FFPE tumor sample from each patient and compared to an archived tumor sample from an earlier surgery. Results: Enrollment is complete with 21 patients enrolled; 6, 6 and 7 were evaluable for the PK/PD analysis in cohorts 1, 2 and 3, respectively. The toxicity profiles for both drugs were consistent with previous studies. PK analyses revealed a mean tumor to plasma ratio of 0.38 and 0.40 in cohorts 1 and 3 and 0.27 in cohort 2. PD analysis by IHC revealed reduction compared to archived tumor in pS6K1 in 4/6 and 7/7 patients in cohorts 1 and 3 and 6/6 patients in cohort 2. Reduction in Ki67 was observed in 6/6 and 5/7 patients in cohorts 1 and 3 and 4/6 patients in cohort 2. Conclusions: XL765 when given on a QD or BID schedule to patients with glioma yields moderately higher distribution of XL765 into CNS tumor compared to XL147 based on tumor to plasma ratios. Decreases in pS6K1, consistent with pathway inhibition, and decreases in Ki67, consistent with inhibition of proliferation, were observed following treatment with both XL147 and XL765. Clinical trial information: NCT01240460.
Phase II trial of the phosphatidyinositol-3 kinase (PI3K) inhibitor BKM120 in recurrent glioblastoma (GBM).
Authors: Wen Patrick Y. , Yung W. K. Alfred , Mellinghoff Ingo K. , Lamborn Kathleen , Ramkissoon Shakti , Cloughesy Timothy Francis , Rinne Mikael , Omuro Antonio Marcilio Padula , DeAngelis Lisa Marie , Gilbert Mark R. , Chi Andrew S. , Batchelor Tracy , Colman Howard , Chang Susan Marina , Massacesi Cristian , DiTomaso Emmanuelle , Prados Michael , Reardon David A. , Ligon Keith L.
Published: March 2020

2015

Background: The PI3K pathway is activated in most GBMs and represents a potential therapeutic target. BKM120 is an oral, pan-Class I PI3K inhibitor that enters the brain at therapeutic concentrations demonstrated to inhibit PI3K pathway, and potently inhibits the growth of U87 GBM tumors and human glioma tumor spheres in vitro and in vivo. Methods: The Ivy Foundation Early Phase Clinical Trials Consortium is conducting a phase II study of BKM120 in recurrent GBM patients with activation of the PI3K pathway (mutation, homozygous deletion or loss of IHC of PTEN, PIK3CA or PIK3RI mutations, or detectable pAKT). Additional eligibility criteria included radiologic progression, 1st or 2nd relapse, > 18 yrs, KPS > 60, adequate bone marrow and organ function, controlled blood glucose, and no enzyme-inducing antiepileptic drugs. Patients received BKM120 100mg daily. The study consisted of 2 parts conducted concurrently. Part 1 involved up to 15 patients who received BKM120 daily for 8-12 days prior to surgery for recurrent disease. Patients underwent FDG PET, pharmacokinetic (PK) studies, and tumor was obtained for drug concentrations and pharmacodynamic effects. Part 2 consisted of up to 50 patients with unresectable GBM treated with BKM120. The primary endpoint for Part 2 was 6-month progression-free survival (p0 =15%; p1= 32%). Results: To date 7 patients have been enrolled into Part 1, 33 into part 2. There were 5 women and 35 men. Median age was 54 yrs (29-68). Treatment was fairly well-tolerated. Major grades 3/4 toxicities were asymptomatic lipase elevation (5), fatigue (3), hyperglycemia (3), rash (3) elevated AST (1), and depression (1). Analysis of tumor from Part 1 showed reduction of pAkt by IHC. Genotyping of tumor specimens is ongoing. To date 33 patients had positive pAkt, 21 had PTEN loss by IHC. Of the first 19 patients who underwent whole exome sequencing, 3 had PIK3Ca mutations and 6 had PTEN mutations. Conclusions: BKM120 is generally well tolerated in patients with recurrent GBM and achieves adequate tumor concentration to inhibit pAkt. Updated PK and efficacy data and correlation of the latter with tumor genotype will be presented. Clinical trial information: NCT01339052.
A first-in-human study of neural stem cells (NSCs) expressing cytosine deaminase (CD) in combination with 5-fluorocytosine (5-FC) in patients with recurrent high-grade glioma.
Authors: Portnow Jana , Badie Behnam , Synold Timothy W. , Annala Alexander , Chen Bihong , Frank Joseph , Moats Rex A. , Wood John , D'Apuzzo Massimo , Bedell Victoria , Frankel Paul Henry , Aboody Karen S.
Published: March 2020

2018

Background: Human NSCs are inherently tumor-tropic, making them attractive drug delivery vehicles. This pilot-feasibility study assessed the safety of using genetically-modified NSCs for tumor selective enzyme/prodrug therapy. An immortalized, clonal NSC line was retrovirally-transduced to stably express CD, which converts the prodrug 5-FC to 5-fluorouracil (5-FU), producing chemotherapy locally at sites of tumor in the brain. Methods: Patients 18 years or older with recurrent high-grade glioma underwent intracranial administration of NSCs during tumor resection or biopsy. Four days later, 5-FC was administered orally every 6 hours for 7 days. Study treatment was given only once. A standard 3+3 dose escalation schema was used to increase doses of NSCs from 1 x 107 to 5 x 107 and 5-FC from 75 to 150 mg/kg/day. Intracerebral microdialysis was performed to measure brain levels of 5-FC and 5-FU; serial blood samples were obtained to assess systemic drug concentrations. Three patients received iron-labeled NSCs for MRI tracking. Brain autopsies were done on 2 patients. Results: Fifteen patients received study treatment. Three were inevaluable for toxicity and replaced. All patients tolerated the NSCs well. There was 1 dose-limiting toxicity (grade 3 transaminitis) possibly related to 5-FC. At the highest dose level of NSCs, the average steady-state concentration of 5-FU in the brain was 63.9±7.9 nM. The average maximum 5-FU level in brain was 104±88 nM compared to 24±36 nM in plasma, indicating local production of 5-FU in the brain by the NSCs. MR imaging of iron-labeled NSCs showed preliminary evidence of NSC migration. Autopsy data documented (by IHC, FISH, and PCR) NSCs at distant sites of tumor in the brain and no development of secondary tumors. Conclusions: This first-in-human study has demonstrated safety and proof-of-concept regarding NSC-mediated conversion of 5-FC to 5-FU and NSC tumor-tropism. NSCs have the potential to overcome obstacles of drug delivery that limit current gene therapy strategies. Results of this pilot study will serve as the foundation for future NSC studies. (Supported by NCI 1R21 CA137639-01A1, CIRM DR-01421). Clinical trial information: NCT01172964.
Biomarker (BM) evaluations in the phase III AVAglio study of bevacizumab (Bv) plus standard radiotherapy (RT) and temozolomide (T) for newly diagnosed glioblastoma (GBM).
Authors: Nishikawa Ryo , Saran Frank , Mason Warren , Wick Wolfgang , Cloughesy Timothy Francis , Henriksson Roger , Hilton Magalie , Garcia Josep , Vogt Tobias , Pallaud Celine , Chinot Oliver L.
Published: March 2020

2023^

Background: Bv plus 1st-line standard of care (SoC; T+RT) achieved a PFS benefit in the AVAglio phase III, randomized, double-blind, placebo [P]-controlled trial in patients (pts) with newly diagnosed GBM. AVAglio includes BM evaluation to identify pts benefiting most from Bv. Analysis of plasma VEGF-A and VEGFR-2 was prioritized based on encouraging findings in Bv trials in several tumor types. Methods: AVAglio includes an optional, exploratory correlative BM analysis; participating pts provided informed consent for BMs. Baseline (BL) plasma samples were analyzed using the Roche IMPACT platform, based on multiplex ELISA technology. Pts were dichotomized according to BM levels using either Q1, median or Q3 cut-offs. Potential interactions between BL BM levels and PFS were tested using Cox regression analyses. Results: Of 921 patients enrolled, 571 (62%) were evaluable in the BM study. Baseline characteristics and PFS outcome were comparable in the ITT and BM-evaluable populations. Median BL VEGF-A and VEGFR-2 levels were 77.0 pg/mL and 12.6 ng/mL, respectively. No significant interaction for PFS was seen at α=0.025. Conclusions: The potential predictive (VEGF-A, VEGFR-2) and prognostic (VEGF-A) value seen in breast, pancreatic and gastric cancers was not apparent in BL BM samples from AVAglio using a median, Q1 or Q3 cut-off. Additional plasma and tumor BM analyses are ongoing. Clinical trial information: NCT00943826. [Table: see text]
Impact of adjuvant temozolomide and IDH mutation status among patients with anaplastic astrocytoma.
Authors: Kizilbash Sani Haider , Giannini Caterina , Voss Jesse S , Decker Paul A. , Jenkins Robert B. , Laack Nadia N. , Parney Ian F , Uhm Joon H. , Buckner Jan C.
Published: March 2020

2025

Background: Although adjuvant radiation has demonstrated a clear survival benefit in anaplastic astrocytomas (AA), the role of concurrent temozolomide (TMZ) remains controversial. Methods: All adult patients diagnosed with AA from 2001 to 2011 and treated with standard doses of adjuvant radiation were identified retrospectively using the neuro-oncology database at the Mayo Clinic (Rochester, MN). Clinical data was extracted from the electronic medical record. IDH mutation status was also determined by obtaining either IDH1R132H immunostain on existing unstained slides or paraffin block sections, or by sequencing. Cumulative survival probabilities were estimated using the Kaplan-Meier method. Univariable and multivariable Cox proportional hazards regression models were fit to compare patients who did/did not receive TMZ. Results: 218 patients were identified that met inclusion criteria. 34 patients were excluded due to missing data on adjuvant chemotherapy. 146 patients had received adjuvant TMZ while 38 had not. Of these, IDH mutation status was determined on 124 patients who received TMZ and 33 of those who had not. The median duration of follow up was 36.4 months. On univariable analysis, adjuvant TMZ demonstrated a trend towards improved median survival from 35.2 to 53.1 months (p=0.06). As an independent variable, patients with IDH mutations had longer median survivals (111.7 months) when compared to IDH wild-type patients (23.3 months) (p<0.001). On multivariable analysis, five-year-survival was significantly impacted by receipt of adjuvant TMZ (HR = 0.56, p=0.03) and IDH mutation status remained a significant prognostic factor (HR = 0.19, p < 0.001) (see Table). Conclusions: IDH mutation strongly predicts a favorable outcome in patients with AA. Secondarily, concurrent TMZ is also associated with improved survival in patients with AA who are receiving adjuvant radiotherapy. [Table: see text]
Association of PIK3CA-activating mutations with more disseminated disease at presentation and earlier recurrence in glioblastoma.
Authors: Tanaka Shota , Batchelor Tracy , Iafrate Anthony John , Dias-Santagata Dora , Borger Darrell R. , Ellisen Leif William , Yang Daniel , Louis David N. , Cahill Daniel P. , Chi Andrew S.
Published: March 2020

2029

Background: The PI3K signaling pathway is a potent pro-survival pathway and associated with increased grade of malignancy in glioma. Activating mutations in PIK3CA are observed in 6% to 15% of glioblastomas, although their clinical significance is unknown. Our objective was to examine whether PIK3CA activating mutation is associated with a specific phenotype in newly diagnosed glioblastoma patients. Methods: We molecularly profiled 183 consecutive adult glioblastomas from December 2009 to June 2012. We included in our analysis all newly diagnosed primary glioblastoma patients with a KPS score of 60 or greater who were treated with standard chemoradiation. Molecular profiling consisted of SNaPshot genotyping, FISH for gene amplification (EGFR, MET, PDGFRA), and methylation-specific PCR for MGMT promoter methylation. Results: 158 patients were included in the study (median age: 58 years (range, 23-85), 90 males, median KPS: 90). With a median follow-up of 13.8 months, median progression-free survival (PFS) and overall survival (OS) were 11.6 and 26.2 months, respectively. Established molecular prognostic factors such as IDH1 mutation and MGMT promoter methylation were associated with longer PFS and OS (IDH1: PFS p=0.001, OS p=0.02; MGMT: PFS p=0.0005, OS p=0.0002). 12 patients (7.6%) harbored PIK3CA activating mutation by SNaPshot assay (4 at R88, 4 at hotspots 542-546, 4 at H1047). PIK3CA mutation was associated with younger age (p=0.02) and shorter PFS (6.8 vs. 11.8 months, p=0.0004). Shorter PFS for PIK3CA mutation remained significant after adjusting for age, KPS, gross total resection, IDH1 mutation, and MGMT promoter methylation (p=0.01). There was a significant association between PIK3CA mutation and more disseminated disease at diagnosis, as defined by gliomatosis, multicentric lesions, or distant leptomeningeal lesions. Eight of 12 (66.7%) PIK3CA mutant GBMs were disseminated versus 15.1% of PIK3CA wild-type tumors (p=0.0002). Conclusions: PIK3CA activating mutations are associated with younger age and early recurrence in primary glioblastoma. The aggressive behavior of these tumors may be related to their propensity to present with widespread disease.
Whole brain radiation therapy (WBRT) with or without oral topotecan (TPT) in patients (pts) with non-small cell lung cancer (NSCLC) with brain metastases: Final analysis of an open-label phase III study.
Authors: Ramlau Rodryg , Jassem Jacek , Papai-Szekely Zsolt , Chabot Pierre , Legenne Philippe , Levin Jeremey , Sherlock Jadwiga , Lane Stephen R. , Brennan John J , Sessa Tracey , Wissel Paul Stephen , Bonomi Philip
Published: March 2020

2031

Background: Brain metastases from NSCLC occur in ~ 20% of pts and if untreated are associated with a 1 to 2 month overall survival (OS). Pre-clinical studies show that TPT added to radiation results in a radiotherapy enhancement ratio of 1.4 to 1.6. This trial was designed to test the effect of TPT co-administered with WBRT on OS. Methods: Pts with NSCLC and at least one measurable brain lesion were eligible. 472 pts were randomized to WBRT (3 Gy/day x 10 days) or WBRT and TPT 1.1 mg/m2/day for 10 days. Stratification factors: number of brain metastases and recursive partitioning analysis (RPA) class. Two weeks following WBRT, systemic anti-cancer therapy could be restarted at the treating physician’s discretion. Results: 468 pts were in the modified ITT population; 235 pts (WBRT + TPT) and 233 pts (WBRT+ best supportive care [BSC]). Of the 235 pts administered WBRT + TPT, 91 also received TPT after WBRT. The treatment arms were balanced for gender, age and smoking history. Median daily TPT dose was 2.25 mg. The median OS in the TPT arm was not better than in the BSC alone arm; 4.0 months (95%CI 3.4,4.8) vs.3.6 months (95%CI 3.0, 4.0), respectively; HR 0.88 (0.73, 1.07), P=0.1862. In the ITT population analysis by stratification variables, RPA class (I vs. II/III) was significantly different (HR 0.59) whereas baseline brain lesions (1 vs >1) were not (HR 0.97). Complete response and overall response rates in the WBRT+ TPT were 10% and 27%, and with BSC 5% and 26%, respectively. There were no differences in time to response or neurologic signs and symptoms. All adverse events (AEs) were more frequent in the TPT arm (87% vs. 64%) as were AEs related to study treatment (57% vs. 21%), serious AEs (41% vs. 18%) and fatal AEs (5% vs. 0%). The AEs more frequently seen in the TPT arm were typical for TPT (hematologic toxicity, febrile neutropenia and diarrhea). Conclusions: The study did not achieve its primary objective. There was no difference in OS achieved by the addition of TPT to WBRT. AEs were more common in the TPT arm. Clinical trial information: NCT00390806.