bluuebunny/crossref_metadata_2025 huggingface dataset:
Cell-free DNA copy number variations as a marker for breast cancer in a large study cohort.
Authors: Beck Julia , Schütz Ekkehard , Urnovitz Howard B. , Tabchy Adel , Mitchell William M. , Mills Gordon B. , Meric-Bernstam Funda
Published: March 2020

11013

Background: Massive parallel sequencing provides high numbers of cell-free nucleic acid serum DNA sequences (cfDNA) that can detect trace amounts of tumor derived chromosomal imbalances and copy number variations (CNVs) in patients with cancer. The aim of this study was to determine if there is a difference between the cfDNA CNVs from patients with breast cancer (BrCa) compared to healthy controls. Methods: DNA extracted from serum samples of 225 BrCa (Stage 1 to 4) and 205 gender and age-matched healthy controls (HC) was amplified using random primers, tagged with a unique molecular identifier per sample, sequenced on an Illumina HiSeq system and aligned to the human genome (Build 37). Hits were counted in sliding 1Mbp interval regions and normalized. Using a Random-Resampling procedure, a model was established to distinguish BrCa from HC using the copy number variations (CNV) and cross validated. Results: From 1,100 rounds of random resampling (50/50), a set of 31 regions was selected, based on the frequency of occurrence in the models. Using 20 random sets of a 10-fold cross validation, the selected regions were found to be highly significant discriminators between BrCa and HC (p<10-5). When using a final linear model with 16 regions the AUC of a diagnostic ROC curve was found to be 0.895 for all samples, for Stage I and II the AUC was 0.86 compared to 0.93 for the higher stages. The final model included three regions from chromosome 8 and 1 and two regions from chromosome 15, the remaining regions were found as one per chromosome. Conclusions: Using comparative massive parallel sequencing of cfDNA from cancer patients vs. controls, we were able to show that a 16-region model based on CNV, is useful to distinguish patients with breast cancer from matched controls. Genomic instabilities that are shed into the circulation from breast cancer may play a role in screening, monitoring or as companion diagnostic tests in breast cancer.
Sensitivity for detecting PIK3CA mutations in early-stage breast cancer with droplet digital PCR.
Authors: Beaver Julia A. , Balukrishna Sasidharan , Jelovac Danijela , Higgins Michaela Jane , Jeter Stacie , Stearns Vered , Wolff Antonio C. , Kessler Jill , VanDenBerg Dustin , Valda Toro Patricia , Argani Pedram , Park Ben Ho
Published: March 2020

11019

Background: PIK3CA is mutated in up to 30% of breast cancers. Classically somatic mutations are identified by Sanger sequencing of the primary tumor specimen. However third generation droplet digital PCR technologies offer a novel platform for quantitative mutation detection with improved sensitivity. Methods: Thirty stage I-III breast cancer patients were consented on an IRB-approved prospective repository study at Johns Hopkins for collection of their primary breast tumor specimen. Formalin-fixed paraffin embedded (FFPE) samples were analyzed by standard sequencing for three PIK3CA hotspot mutations. The DNA from these samples was then analyzed using the RainDrop digital PCR platform with TaqMan probes in a triplex format to simultaneously detect and quantitate hotspot mutations and genome equivalents. Results are expressed as a percentage of mutant to wild-type PIK3CA molecules for each sample. Results: Standard sequencing of all tumors (n=30) identified seven PIK3CA Exon 20 mutations (H1047R) and three Exon 9 mutations (E545K). Samples were scored as PIK3CA mutation positive by digital PCR if the tumor DNA contained at least 5% mutant molecules. All ten mutations identified by sequencing were verified by digital PCR with quantities of mutant molecules ranging from 20.3-55.6% in a given sample. Digital PCR identified additional PIK3CA mutations that were wild type by standard sequencing including three mutant Exon 20 samples, two mutant Exon 9 samples and one sample with an Exon 20 and Exon 9 mutation. Quantities of mutant molecules in these additional samples ranged from 5-28.9%. Conclusions: RainDrop digital PCR offers improved sensitivity and quantification for detecting PIK3CA mutations in FFPE samples using nanograms of DNA. Additional mutations identified by digital PCR may reflect genetic heterogeneity or possibly tissue contamination. The clinical utility of identifying a small proportion of mutations is unknown but may impact eligibility for targeted therapies and clinical trials. Ongoing studies will also address whether the identification of solid tumor mutations in circulating cell-free plasma DNA by digital PCR can improve diagnostics and aid in therapeutic decisions.
mRNA expression profiles in circulating tumor cells (CTCs) of patients with metastatic breast cancer (MBC) treated with aromatase inhibitors (AI).
Authors: Reijm Esther Anneke , Sieuwerts Anieta M. , Bolt-de Vries Joan , Mostert Bianca , Onstenk Wendy , Peeters Dieter , Dirix Luc Yves , Seynaeve Caroline , Jager A. , de Jongh Felix E. , Hamberg Paul , van Galen Anne M. , Kraan Jaco , Jansen Maurice P. H. M. , Gratama Jan-Willem , Foekens John A. , Martens John W. M. , Berns Els M. J. J. , Sleijfer Stefan
Published: March 2020

11045

Background: Enumeration of CTCs can be used to assess prognosis in MBC and to evaluate treatment response. Besides enumeration, molecular CTC characterization is a promising tool to develop a more personalized treatment approach. Here, we evaluated the association between mRNA expression of currently known CTC-specific genes and response to first-line AI in MBC patients with estrogen receptor (ER)+ primary tumors. Methods: CTCs were isolated and enumerated from blood of 25 MBC patients before first-line therapy with an AI. Fourteen patients received a non-steroidal AI (8 letrozole, 6 anastrozole) and 11 patients were treated with exemestane. mRNA expression levels of 96 genes were measured by quantitative RT-PCR as previously described (Sieuwerts et al. Clin Cancer Res. 17:3600-3618, 2011). Expression levels of these genes were studied for their association with time to progression (TTP) after start first-line AI. Results: Median TTP was 338 (range 14–1,239) days. Median baseline CTC count for the 25 patients was 14 (range 0–753). In this relatively small cohort, the clinically relevant cut-off level of ≥5 CTCs in association with TTP did not reach statistical significance (Hazard Ratio [HR] 4.76, 95% Confidence Interval [CI]: 0.59–38.22, P=0.14). For type of AI, when comparing steroidal with non-steroidal AI, the measures in Cox univariate regression analysis were HR 2.54 (95% CI: 0.67–9.64), P=0.17. A 10-gene CTC profile was constructed based on the Wald statistics of the contribution of the individual genes in univariate Cox regression analysis of TTP. To identify patients with good and poor outcome, the Wald corrected sum of the 10 genes was used to dichotomize the continuous 10-gene predictor (HR 12.87 [95% CI: 1.60–103.56], P=0.016). In multivariate analysis, corrected for the clinically relevant variables type of AI and CTC count, only the 10-gene CTC profile was an independent factor associated with TTP (HR 12.46 [95% CI: 1.29-120.08], P=0.029). Conclusions: A 10-gene CTC predictor was constructed which distinguishes good and poor outcome to first-line AI in MBC patients. This profile is currently being validated in an independent group of patients.
Evaluation of UGT1A1 genotyping for predicting individual toxicity of irinotecan plus platinum analog regimens: Interim safety analysis of a prospective observational study.
Authors: Takano Masashi , Yamamoto Kaichiro , Tabata Tsutomu , Minegishi Yuji , Yokoyama Takuma , Hirata Eiji , Ikeda Takeshi , Kigawa Junzo , Yamada Kouzo , Morita Satoshi , Ando Yuichi , Okutani Yukihiro , Sugihara Masahiro , Sugiyama Toru , Ohashi Yasuo , Sakata Yuh
Published: March 2020

11049

Background: Irinotecan (IRI)+platinum (Pt) therapy works synergistically and is widely used for solid carcinomas. Although UGT1A1 genotyping has been implemented in daily practice since long, recommended doses of IRI+Pt therapy according to UGT1A1 genotyping remain undetermined. Risk factors for severe toxicities of IRI+Pt regimens remain uncertain. We conducted a prospective observational study to examine the correlation between UGT1A1 genotyping and toxicity/efficacy in IRI+Pt regimens (NCT 01040312). Methods: During October 2009 and March 2012, 321 patients were enrolled. Eligible patients had histologically confirmed SCLC, non-SCLC, cervical, ovarian, or gastric cancer; had PS 0-2; and were receiving IRI+Pt (cisplatin, carboplatin, and nedaplatin) regimen, following UGT1A1 genotyping: hetero (*1/*6, *1/*28) and homo (*6/*6, *6/*28, *28/*28). Primary endpoint was to evaluate overall toxicity profile during first 3 cycles of treatment. In this interim analysis, incidences of grade 3/4 toxicities were compared among UGT1A1 phenotypes, and logistic regression models were used to identify independent risk factors for these toxicities. Results: At the time of abstract writing, toxicity data from 137 patients were available. There were 110 (80%) hetero and 27 (20%) homo genotypes. Combination therapy of IRI (57.2 ± 12.2 mg/m2 for average initial dose) and Pt analogs (cisplatin, 63%; carboplatin, 20%; nedaplatin, 17%) was administered. Incidences of grade 3/4 toxicities during first 3 cycles of treatment in hetero and homo were as follows: leukocytopenia, 38% and 59%; neutropenia, 55% and 67%; thrombocytopenia, 7% and 22%; and diarrhea, 9% and 7%. Overall grade 3/4 hematological toxicity was 50% (55/110) in hetero and 78% (21/27) in homo; the adjusted odds ratio was 3.379 (p = 0.0185) in homo compared with hetero. Conclusions: A higher rate of grade 3/4 hematological toxicity in homo than in hetero was confirmed with IRI+Pt therapy. Thus, UGT1A1 genotyping could be a potential biomarker of toxicity with individualized chemotherapy using low-dose IRI regimens. At the presentation, analysis of >250 patients’ data will be shown. Clinical trial information: NCT01040312.
Impact of IVS14+1G>A and 2846A>T DPYD polymorphisms on toxicity outcome of patients treated with fluoropyrimidine-containing regimens.
Authors: Del Re Marzia , Loupakis Fotios , Barbara Cecilia , Latiano Tiziana , Vasile Enrico , Zafarana Elena , Cordio Stefano Sergio , Toffolatti Luisa , Ricasoli Miriam , Prestifilippo Angela , Venturini Filippo , Di Donato Samantha , Grifalchi Federico , Rinaldi Antonio , Butera Alfredo , Maiello Evaristo , Siena Salvatore , Falcone Alfredo , Cappuzzo Federico , Danesi Romano
Published: March 2020

11058

Background: DPD deficiency is an inherited syndrome resulting from loss-of-function mutations within the DPYD gene. The IVS14+1G>A variant is associated with DPD deficiency as a result of a 165-bp deletion in the DPD mRNA. A rare mutation, 2846A>T, is characterized by a change of the acidic aspartic acid to the aliphatic valine with potential impairment of enzyme activity (Amstutz et al., 2011). In this study, we describe the spectrum of toxicities of 5-FU and capecitabine in patients carrying the IVS14+1G>A and 2846A>T variants. Methods: Data were collected from 450 patients with gastrointestinal, breast and pancreas cancers. They were evaluated for DPD genotype upon development of grade ≥2 non-hematological and ≥3 hematological toxicities (CTCAE v. 4) secondary to standard fluoropyrimidine-containing regimens in combination with other cytotoxic agents and/or EGFR and VEGF antibodies. DNA was extracted from blood and IVS14+1G>A and 2846T>C DPD variants were screened on a Real-Time Life Sciences 7900 HT platform. The study was approved by the local Ethics Committee. Results: A total of 23 IVS14+1GA, four 2846AT, one IVS14+1AA and one 2846TT subjects were identified. Toxicities in all subjects were G3/4 diarrhea (100%), G3/4 mucositis (48%), febrile neutropenia (45%), G3/4 thrombocytopenia (38%), G3/4 anemia (24%), G2/3 hand-foot syndrome (14%), G3 dermatitis (7%) and G2/4 alopecia (7%). The homozygous IVS14+1AA patient survived because she was given a reduced 5-FU 250 mg/sqm test dose without folates, while the 2846TT patient deceased after the first cycle of FOLFOX4 treatment. Conclusions: Patients carrying the deleterious IVS14+1G>A and 2846T>C variant alleles display severe toxicities which is fatal in homozygous variant subjects. This finding suggests the usefulness of pre-treatment screening of DPD in patients candidates to fluoropyrimidine treatment. Acknowledgmnents. This study was supported by the Italian Association for Cancer Research (AIRC, Milano) and the Istituto Toscano Tumori (ITT, Firenze, Italy). Reference. Amstutz U, Froehlich TK, Largiadèr CR. Pharmacogenomics 2011;12:1321-36.
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.
Evaluation of a dedicated institutional tobacco cessation service for thoracic clinic cancer patients.
Authors: Dobson Amato Katharine Ann , Zevon Michael , Hysert Pat , Hysert Robert , Segal Stephanie , Reed Robert , Giovino Gary , Bansal-Travers Maansi , Ochs-Balcom Heather , Nwogu Chukwumere E. , Cummings K. Michael , Mahoney Martin , Hyland Andrew , Reid Mary E. , Warren Graham Walter
Published: March 2020

1603

Background: Tobacco use by cancer patients is associated with poor therapeutic outcomes including increased toxicity, decreased quality of life, and decreased survival. Though recommendations provide for tobacco assessment and cessation for cancer patients, few oncologists provide cessation support. Presented are data from universal tobacco assessment and cessation program for patients presenting at a thoracic oncology clinic in a NCI Designated Comprehensive Cancer Center. Methods: A standard set of evidence based tobacco assessment questions were incorporated into an automated electronic medical record based system delivered by nursing at initial consult and at follow-up. Patients eligible for tobacco cessation support (i.e. patients self-reporting tobacco use within 30 days) were automatically referred to a dedicated tobacco cessation service. All referred patients are sent a standardized packet of cessation materials with telephone-based follow-up by trained cessation counselors. Results: A total of 980 new thoracic clinic patients were referred to the cessation service from January 2011 and October 2012. Two-thirds of the patients referred (n=728) referred into the system were current smokers and the remainder had quit in the 30 days prior to assessment. Among the 788 patients with contact attempts by the cessation service, 81.2% (n=640) were successfully contacted and only 2.5% (n=20) refused the offer of cessation support. At first contact, 75.6% (n=484) of patients reported continued current tobacco use. Follow-up calls were placed for 53.1% (n=340) of those who participated in the first contact an average of 39 days after the first successful contact. The follow-up had a 93.2% (n=317) participation rate which revealed that 33.3% (n=106) reported not smoking, an 8.9% increase since the first cessation service telephone call. Conclusions: Data demonstrate that an automated tobacco assessment and cessation service for thoracic oncology patients can effectively generate a large mandatory referral base with high patient interest in cessation, and that cessation support can be implemented and maintained in high risk cancer patients.
Comparative impact of treatment on patient reported outcomes (PROs) in patients with glioblastoma (GBM) enrolled in RTOG 0825.
Authors: Armstrong Terri S. , Won Minhee , Wefel Jeffrey Scott , Gilbert Mark R. , Pugh Stephanie L. , Brachman David , Komaki Ritsuko , Crocker Ian R. , Robins H. Ian , Lee R. Jeffrey , Mehta Minesh P. , Wendland Merideth M
Published: March 2020

2003

Background: RTOG 0825 tested if adding bevicizumab (BEV) to standard chemoradiation improves survival (OS) or progression free survival (PFS) in newly diagnosed GBM. While OS was equivalent, PFS was longer with Bev (Arm 2) than with placebo (Arm 1). Patients completed quality of life and symptom PROs to evaluate clinical benefit. Methods: The M.D. Anderson Symptom Inventory-Brain Tumor Module (MDASI-BT) and the EORTC core Quality of life Questionnaire and brain tumor module (EORTC QLQ-C30/BN20), were completed by pts at baseline (B) and longitudinally (wk 6, 10, 22, 34, and 46) while on study. The difference between treatment arms were compared from B with evaluation in subsequent weeks in those pts without disease progression; and early change (EC) (baseline to wk 10) between those with and without progression as predictors for OS and PFS. Results: 542pts consented to participate on this trial, and 507 randomized pts participated, with completion of forms by 94% at baseline, 75% at wk 10, 61% at wk 22, and 58% at wk 34. There was a trend for all MDASI-BT symptom groupings to be worse in Arm 2, with significant findings in treatment symptoms at wk 22 and wk 34; both affective and generalized disease symptoms were also significantly worse. For EORTCQLQ30/BN20, differential effects varied at each time point, with no persistent differences. For the MDASI-BT, B neurologic symptom grouping and EC in cognitive symptoms were prognostic for both OS and PFS. For the EORTC QLQ30/BN20, global QOL and motor dysfunction at B as well as EC in communication and leg weakness were prognostic for OS; whereas physical function at B and EC in headaches, seizures, and weak legs were prognostic for PFS. Conclusions: The longitudinal collection of PROs in this phase III trial revealed important treatment-related differences as there was overall more deterioration in symptoms and QOL in Arm 2 as compared to Arm 1, with persistent significant differences in treatment associated symptoms. B and EC tumor associated symptoms on both PRO tools were prognostic for OS and PFS. Longitudinal modeling is ongoing to further assess for differential impact of treatment on symptoms and QOL. Support: U10 CA21661, U10 CA37422 and Genentech, Inc. Clinical trial information: NCT00884741.
Contrast-enhanced T1-weighted subtraction maps for response assessment in recurrent glioblastoma treated with bevacizumab.
Authors: Ellingson Benjamin M. , Kim Hyun J. , Woodworth Davis C. , Pope Whitney B. , Cloughesy Jonathan N. , Harris Robert J. , Lai Albert , Nghiemphu Phioanh L. , Cloughesy Timothy F.
Published: March 2020

2055

Background: Antiangiogenic therapy in glioblastoma (GBM) results in decreased enhancement on post-contrast T1w images, which complicates standard response assessment and is likely the reason no studies have found predictive value in enhancing tumor size or change in size. The current study examined whether contrast-enhanced T1-weighted subtraction maps (CE-ΔT1w) calculated from subtracting pre-contrast (T1) from post-contrast T1w images (T1+C) can improve quantification and predict response in GBM patients treated with bevacizumab. Methods: Recurrent GBM patients (n=160) from the BRAIN trial (AVF3708g), a multicenter Phase II trial evaluating bevacvizumab, were used in the current study. CE-ΔT1w maps were calculated 2 weeks before and 6 weeks after the first dose of bevacizumab by: 1) performing registration between T1 and T1+C images, 2) image intensity normalization of T1 and T1+C images, and 3) subtraction of T1 from T1+C images. The volume of tumor regions with positive contrast enhancement after subtraction was retained for analysis. Results: CE-ΔT1w maps greatly improved detectability of subtly enhancing lesions, particularly post-treatment. Results for PFS and OS are summarized in the table below. In all scenarios, CE-ΔT1w maps outperformed conventional tumor segmentation. Results show that size and change in size are both predictive of PFS and OS. Conclusions: CE-ΔT1w maps improve visualization and quantification of contrast enhancing tumor regions in recurrent GBM, allowing for more accurate response assessment. [Table: see text]
Safety analysis of bevacizumab plus NovoTTF-100A in patients with recurrent malignant gliomas.
Authors: Elzinga Grace , Chung Amy T , Wong Eric
Published: March 2020

2082

Background: Both bevacizumab and the NovoTTF-100A device are treatments approved by the FDA for recurrent glioblastoma. We examined our single-institution experience in using this combination for patients with recurrent malignant gliomas. Methods: We identified retrospectively the side effects experienced by patients while on both bevacizumab and NovoTTF-100A. Overall survival was also tabulated from initiation of this combined modality treatment. Results: There were 14 men and 6 women. Their median age was 54 (range 29-76). All had Karnofsky Performance Status of 60 or above. Fourteen patients received NovoTTF-100A after failure of bevacizumab treatment while the other 6 received both treatments concurrently. The median duration of bevacizumab plus NovoTTF-100A treatments was 2.3 (95% CI 1.8-4.7) months. There were 2 patients who experienced electric shock sensation on the scalp from a poorly-applied transducer array that resulted in minor scalp burns, 3 patients developed scalp rashes (2 moderate and 1 severe), 4 patients experienced liquefied hydrogel from the arrays as a result of high ambient temperature during summer months, 2 experienced vivid dreams of applying the arrays and 3 removed the arrays while periods of sleep or confusion. Only one patient required NovoTTF-100A treatment interruption because of severe scalp rash. No hemorrhage into the malignant glioma or thromboembolism was seen in this cohort. From the time of initiation of bevacizumab plus NovoTTF-100A treatments, the Kaplan-Meier median overall survival was 5.6 (95% CI 4.2-N/A) months. Conclusions: No additive or synergistic side effects were observed when patients were treated with both bevacizumab and NovoTTF-100A. Further evaluation in a prospective manner would be needed to evaluate both side effects and efficacy of this treatment combination.
A phase I study of the first-in-class mitochondrial metabolism inhibitor CPI-613 in patients with advanced hematologic malignancies.
Authors: Pardee Timothy S. , Levitan Denise A. , Hurd David Duane , Ellis Leslie R. , Isom Scott , Harrelson Robin , Manuel Megan , Dralle Sarah , Lyerly Susan , Powell Bayard L.
Published: March 2020

2516^

Background: Altered metabolism is a hallmark of cancer, including hematologic malignancies. This altered metabolism is a possible therapeutic target. The lipoate derivative CPI-613 is a first in class agent that targets pyruvate dehydrogenase complex.This trial was designed to determine the maximally tolerated dose (MTD), safety, and efficacy of CPI-613 given as a single agent by IV infusion. Methods: CPI-613 was given over a 2 hour infusion on days 1 and 4 for 3 weeks every 28 days with a starting dose of 420 mg/m2. The dose was escalated in 6 cohorts to a final dose of 3780 mg/m2. Treatment could be continued if the patient experienced clinical benefit. Results: A total of 26 patients with advanced relapsed or refractory hematologic malignancies were enrolled. Patients were heavily pretreated with a median of 3 previous therapies (range 1-11). CPI-613 was well tolerated when infused over 2 hours, with no worsening of cytopenias at any dose level. After the dose was escalated to 2940 mg/m2 the protocol was amended to a 1 hour infusion. When infused over 1 hour, 2 patients developed grade 3 renal failure. Infusion time was then returned to 2 hours and dose escalation resumed. At a dose of 3780 mg/m2, one patient experienced prolonged grade 3 nausea and one patient grade 3 renal failure, defining this dose as above the MTD. Renal failure resolved in all but one patient who opted for hospice care. A total of 6 patients were treated at a dose of 2940 mg/m2over 2 hours with no DLTs observed, establishing this as the MTD. Of the 21 patients evaluable for a response, eight achieved a response of stable disease or better for a response rate of 38%. Responses included a complete remission maintained over 27 cycles in one AML patient and clearance of marrow blasts in another, sustained partial response in both a Burkitt's and a cutaneous T cell lymphoma patient maintained over 17 and 8 cycles respectively, and stable disease in 2 multiple myeloma and 2 myelodysplasia patients. Conclusions: To our knowledge this is the first report of an agent with activity in aggressive hematological malignancies that is not myelosuppressive. The therapeutic index appears high suggesting CPI-613 should be further studied in phase II trials. Clinical trial information: NCT01034475.