bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact and correlation of mutational load (ML) and specific mutations (mts) assessed by limited targeted profiling (LTP) with PD-L1 tumour expression (exp) in resected non-small cell lung carcinoma (NSCLC).
Authors: Sui Jane Sze Yin , Teo MinYuen , Toomey Sinead , Rafee Shereen , McFadden Julia , Gately Kathy , Barr Martin P , Gray Steven G. , Hennessy Bryan , O'Byrne Ken , Cuffe Sinead , Finn Stephen P.
Published: September 2018

11587

Background: The advent of immunotherapy represents a paradigm shift in the treatment of NSCLC compared to conventional chemotherapy. Recent studies have shown higher mts burden assessed by exome sequencing are associated with improved objective response and clinical benefit. We performed this study to evaluate the impact of ML assessment by LTP, correlating with PD-L1 exp and clinicopathological variables in resected NSCLC. Methods: NSCLC patients(pts) who underwent curative resection between 1998 and 2006 at our institution were included. PD-L1 status was assessed using Ventana SP124 antibody on archival FFPE surgical tumour specimens cores. PD-L1 was scored positive if membranous staining was present in >1% of tumour cells aggregated across the replicate cores to address heterogeneity. In collaboration with the Lung Cancer Genomics Ireland Study a targeted panel of 49 genes were assessed by Sequenom MassArray including genes in MAPK and PI3K pathways. Clinical data was obtained from hospital electronic database. Results: Ninety-one pts were included, of which 51 (56.0%) were males, with a median age of 65 years (range: 42 – 82). 51.6%, n=47 with squamous histological subtypes, 46.2%, n=42 were ex-smoker and 49.5%, n=45 had Stage I disease. 23.1%, n=21 had PD-L1 positivity. 149 mts were identified of which, 32(21.5%) with PHLPP2, 31(20.9%) with PIK3R1 and 21(14.1%) with TP53. The presence of PI3K and TP53 mts are associated with positive PD-L1 status (see table). An inverse correlation of PD-L1 positivity with ML of (1 vs 2 vs 3: 53.8% vs 30.8% vs 15.4%) was noted. Conclusions: We did not identify higher PD-L1 exp with higher ML assessed by a LTP widely used in clincial practice. However, positive PD-L1 exp was correlated with PIK3R1 and TP53 mts , warranting further investigation as potential modulators or surrogates of positve PD-L1 expression. [Table: see text]
Genomic alterations in 670 patients with diverse cancers analyzed by next-generation sequencing (NGS) of circulating tumor DNA (ctDNA).
Authors: Schwaederle Maria Clemence , Chattopadhyay Ranajoy , Kato Shumei , Fanta Paul T. , Banks Kimberly , Piccioni David Eric , Ikeda Sadakatsu , Talasaz AmirAli , Lanman Richard B. , Bazhenova Lyudmila , Kurzrock Razelle
Published: September 2018

11593

Background: NGS of blood-derived ctDNA allows non-invasive tumor profiling. Liquid biopsy studies with clinical correlation have so far been mainly limited to small size cohorts. Methods: We performed comprehensive plasma genomic testing of ctDNA (NGS) in 670 patients (pts) (54-70 genes); Guardant Health, Inc.; (Clinical Laboratory Improvement Amendment certified and College of American Pathologists accredited). Results: The most represented cancers were gastrointestinal (31.8%), brain (22.7%), and lung (20.7%) (Table). Sixty-three percent of pts (N = 423) had ≥1 alteration. The most frequent alterations (characterized and variants of unknown significance (VUSs)) were in TP53 (32.5% of pts), followed by EGFR (13%), KRAS (12.5%), and PIK3CA (9.1%); for characterized alterations, the breakdown was 30.7% ( TP53), 7.6% ( EGFR), 12.2% ( KRAS), and 7.7% ( PIK3CA). Interestingly, 32% of brain tumors had ≥1 ctDNA alteration. Head and neck tumors were independently associated with a higher number of alterations (P=0.019). Forty-eight percent of pts (320/670) had potentially actionable alterations; in 241, (75% of 320), by an FDA-approved drug (mostly off label). Illustrative examples of clinical utility will be presented such as a patient with gastric cancer and EGFRamplification in ctDNA who received anti-EGFR treatment (60% regression), as well a patient with aggressive gynecologic malignancy who received immunotherapy based on a hypermutated ctDNA profile. Conclusions: Most pts, including a subset of those with brain tumors, demonstrated ctDNA alterations. Pts with head and neck tumors harbored higher numbers of alterations. Overall, three quarters of pts with alteration(s) had ≥1 aberration that could potentially be pharmacologically tractable, suggesting the need to further assess the utility of ctDNA in a therapeutic setting. [Table: see text]
Association of immune-related genes to neutrophil-lymphocyte ratio (NLR) with survival of cetuximab treatment for metastatic colorectal cancer (mCRC): JACCRO CC-05/06AR.
Authors: Sunakawa Yu , Yang Dongyun , LaFleur Bonnie , Luecke John , Thompson Debrah , Moran Miriana , Astrow Stephanie H. , Hsiang Jack , Zhang Wu , Tsuji Akihito , Takahashi Takehiro , Tanioka Hiroaki , Negoro Yuji , Takagane Akinori , Tani Satoshi , Yamaguchi Tatsuro , Eto Tetsuya , Fujii Masashi , Ichikawa Wataru , Lenz Heinz-Josef
Published: September 2018

11613

Background: The antitumor activity of cetuximab (cet) may be affected by extracellular immune mechanisms. We have reported that immune-related genes are associated with survival in mCRC patients (pts) treated with cet (ASCO 2016 abstract#11591). NLR reflects cancer-related inflammation and is a validated prognostic maker in many types of cancers; however, it is not currently used for treatment decision-making. The association between NLR and clinical outcome of cet treatment for mCRC is unknown, and which genes are affecting the NLR remain to be identified. Methods: We enrolled 77 pts (57% males and 15% right-colon cancer) with KRAS exon 2 wild-type from 2 phase II trials (JACCRO CC-05 or CC-06) of 1st-line therapy with FOLFOX or SOX plus cet. All patients’ tissues were measured for expression levels of 354 immune-related genes by HTG EdgeSeq Oncology Biomarker Panel using next generation sequencing for quantitative analysis of targeted RNAs. The association between the NLR and clinical outcome was evaluated using Spearman’s rank correlation coefficient. In addition, the two-sample t-test was performed to investigate which genes had significantly different expression level between NLR-low and high groups in top 100 genes associated with survival among all measured genes. Results: Seventy-one of 77 pts were available for NLR data. The NLR was associated with progression-free survival (PFS) and overall survival (OS) (r = 0.24; p= 0.04, r = 0.29; p= 0.01, respectively). When stratified by median value of NLR, the Kaplan-Meier curve of NLR-low (n = 36) vs. high (n = 35) had a significant difference in both PFS (median 11.8 vs. 9.1 m, p= 0.036) and OS (median 42.8 vs. 26.7 m, p= 0.029). The two-sample t-test revealed that LYZ, TYMP, and CD68 genes expressed significantly differently between NLR-low and high groups (t-test p-value < 0.005, FDR p-value < 0.150). Conclusions: NLR is significantly associated with survival of 1st-line cet treatment for mCRC. Genes encoding for activities on tissue macrophages and endothelial cells may affect the level of NLR associated with outcome of cet combination chemotherapy. Clinical trial information: UMIN000010635.
A randomized trial of selenium and vitamin E for primary prevention of non-melanoma skin cancer: Trial results and experience from a low-resource setting.
Authors: Argos Maria , Dignam James J. , Parvez Faruque , Rahman Mahfuzar , Hore Samar K , Shahriar Mohammad H , Sarwar Golam , Islam Tariqul , Slavkovich Vesna , Graziano Joseph , Gamble Mary , Harjes Judith , Anton Kristen , Kibriya Muhammad Ghulam , Jasmine Farzana , Kamal Mohammed , Shea Christopher R , Yunus Md , Baron John A. , Ahsan Habibul
Published: September 2018

1511

Background: Selenium and vitamin E supplementation previously have shown some evidence of a beneficial effect in the secondary prevention of non-melanoma skin cancer (NMSC). More than 100 million people worldwide are at increased risk of NMSC and other cancers due to arsenic exposure from drinking water and diet – a risk that persists for several decades even after the exposure has terminated. Here, we report on the design, methods and main results of the Bangladesh Vitamin E and Selenium Trial (BEST) – a population-based chemoprevention study conducted among 7,000 adults with visible arsenic toxicity. Methods: BEST is a 2 × 2 full factorial, double-blind, randomized placebo controlled trial of 7,000 adults having manifest arsenical skin lesions evaluating the efficacy of 6-year supplementation with alpha-tocopherol (100 mg daily) and L-selenomethionine (200 μg daily) for the prevention of NMSC incidence. Results: Excellent compliance was maintained through the course of the trial, based on data from pill counts, self-reported compliance, and bioadherence. Among participants on treatment through the end of the 6-year intervention period, > 85% were adherent to at least 80% of study supplements. More than 500 new NMSC cases were ascertained using a three-tiered biopsy protocol. No significant beneficial effects were observed on NMSC incidence during the study period for selenium or vitamin E. Among more than 500 observed deaths (including 182 cancer-related deaths), there were also no significant treatment effects on total mortality, cancer-related mortality or arsenical cancer-related mortality. Conclusions: This large population-based trial does not support any beneficial effect of vitamin E or selenium supplementation for the primary prevention of NMSC or mortality in an arsenic-exposed population. With the rapidly increasing burden of preventable cancers in low- and middle-income countries, efficient and feasible chemoprevention study designs and approaches, such as employed in Bangladesh, may prove impactful in conceiving large scale cancer chemoprevention trials in low-resource settings. Clinical trial information: NCT00392561.
Comparison of epigenetic aging in normal breast tissue from women with and without breast cancer.
Authors: Hofstatter Erin Wysong , Horvath Steven , Chagpar Anees B. , Wali Vikram , Bossuyt Veerle , Storniolo Anna Maria , Patwardhan Gauri , Von Wahlde Marie-Kristin , Pusztai Lajos
Published: September 2018

1522

Background: Age is one of the most important risk factors for developing breast cancer. However, why increasing age is associated with increasing incidence of breast cancer remains poorly understood. We hypothesize that accumulated epigenetic alterations in the breast contribute to the development of breast cancer, and that such changes accumulate more rapidly in the breast during the lifetime of women who develop breast cancer as compared to their healthy peers. We therefore sought to identify an epigenetic pattern of accelerated breast tissue “aging” in women with breast cancer. Methods: Samples of normal breast tissue were collected from four cohorts of women: age < 50 years with and without breast cancer, and age ≥50 years with and without breast cancer (BC). Samples were obtained from the Susan G. Komen Tissue Bank at IU Simon Cancer Center, reduction mammoplasties and adjuvant mastectomy specimens at Yale. The Illumina Human 450K BeadChip microarray was used to generate DNA methylation profiles. Data was analyzed using the “Epigenetic Clock”, a published biomarker of aging based on 353 specific CpGs in the human genome. Clinical data collected for each subject included: age, height, weight, ethnicity, medical and reproductive history, tobacco and alcohol use, family history of breast cancer, current medications, and tumor characteristics. Results: Normal breast tissue samples from 90 subjects were analyzed (age < 50 with BC = 22, age < 50 without BC = 30, age ≥50 with BC = 15, age ≥50 without BC = 23). Age range was 24-82 years and 18-82 years for cohorts with and without BC respectively. In the cohort with BC, 95% of tumors were estrogen receptor-positive. Overall, DNA methylation tissue age (DNAmAge) was strongly correlated with chronologic age (r = 0.88, p < 0.001). However, normal breast tissue from women with breast cancer demonstrated significantly accelerated DNAmAge as compared to healthy peers (p < 0.001). Conclusions: Normal breast tissue from women with breast cancer demonstrates evidence of an accelerated epigenetic "aging" process. DNAmAge of normal breast tissue may prove to be a useful tool in identifying those women at highest risk, and lend insight into novel mechanisms of breast cancer prevention.
The frequency of a novel KANK1 and NTRK3 translocation and BRAFV600E mutation in patients diagnosed with metanephric adenoma utilizing molecular mechanisms.
Authors: Catic Aida , Sophian Ardis , Mazur Lech , Rakheja Dinesh , Kozaric Amina Kurtovic , Beslija Semir , Kogan Jillene , Pins Michael
Published: September 2018

1537

Background: Renal metanephric adenoma (MA) is a very rare benign renal tumor, which is frequently misclassified when microscopic features alone are applied. Despite the classification of adenoma as a benign tumor, it is difficult to differentiate from other renal carcinomas such as malignant papillary renal cell carcinomas and in children it can be mistaken with Wilms tumor. The correct classification of a renal tumor is critical for diagnostic, prognostic, and therapeutic purposes. Despite the advancements in cancer genomics, there is limited data available regarding the genetic alterations critical to the metanephric adenoma development. Recent data suggest that 90% of MA have BRAFV600Emutations; the genetics of the remaining 10 % are unclear. Methods: This study was conducted on 13 FFPE specimens from patients who were diagnosed with renal metanephric adenoma. H&E stained slides from all cases were reviewed by study pathologist, and representative tissue blocks were further selected for BRAFV600E sequencing and fluorescent in situ hybridization was adapted to detect chromosomal rearrangement between KANK1 on chromosome 9 (9p24.3) and NTRK3 on chromosome 15 (15q25.3). Results: In this study, we identified a novel chromosomal translocation t(9;15)(p24;q24) between KANK1 and NTRK3, and provided new insights into molecular mechanisms which might identify a subset of metanephric adenomas. Such findings imply that recurrent cytogenetic aberrations may be of prognostic significance as well. Interestingly, our data suggested mutual exclusivity of BRAFV600Eand t(9;15) aberrations. Conclusions: Molecular and cytogenetic analyses have allowed us to elucidate a genetic aberration, which may be specific to metanephric adenoma. Aberrant expression of the KANK1-NTRK3 gene fusion may be one mechanism by which functionally relevant genes are altered in the development of metanephric adenoma, and thus mark a subgroup of metanephric adenomas with particular clinicopathological features. Also, our study adds KANK1 and NTRK3 to the list of candidate genes that may play a role in the 10% of renal metanephric adenomas that lack a BRAFV600E mutation.
Does the extent of therapy differ between breast cancers detected by screening mammogram and non-screening methods?
Authors: Den Brok Wendie-Lou D. , Speers Caroline , Gondara Lovedeep , Nichol Alan , Wilson Christine , Lohrisch Caroline A.
Published: September 2018

1544

Background: There is ongoing debate about the role of screening mammography and its impact on overall survival in breast cancer. We hypothesized that women with screen-detected breast cancers (SDBC) receive less surgery, regional radiotherapy (RRT), and chemotherapy (CH) than women with non-screen-detected breast cancers (NSDBC). Less therapy equates to less personal and societal burden, including less time away from work, fewer side effects, lower health care and disability costs, and reduced psychosocial distress. These may be adequate justification for screening programs even in the absence of an overall survival benefit. Methods: Women aged 40-79 years with stage 0-III breast cancers diagnosed between 2007-2012 and referred to the British Columbia Cancer Agency were identified using the Breast Cancer Outcomes Unit database. Clinical and tumor characteristics and type/extent of treatment were extracted. Linkage with the Screening Mammography Program of British Columbia segregated cases into SDBCs and NSDBCs. Interval breast cancers arising in regularly screened women (minimum 2-year interval) were excluded. Results: We identified 12,393 women; 7807 with SDBC and 4586 with NSDBC. Compared with NSDBCs, SDBCs were lower stage, less often treated with mastectomy and CH, and occurred in slightly older women (Table 1). SDBC received more radiation than NSDBC. Conclusions: Women with NSDBC are more likely to present with higher stage breast cancer. Rates of mastectomy and CH were 20% higher in NSDBC whereas SDBC had a modest 5% higher rate of RRT. These findings suggest that screening mammography decreases the extent of local and systemic treatment for breast cancer. [Table: see text]
Impact of patient-provider race/ethnicity and gender concordance on cancer screening: Findings from medical expenditure panel survey.
Authors: Malhotra Jyoti , Rotter David , Tsui Jennifer , Llanos Adana , Balasubramanian Bijal A , Demissie Kitaw
Published: September 2018

1547

Background: Racial/ethnic minority groups experience lower rates of cancer screening compared to non-Hispanic (NH) whites. Previous studies evaluating the role of patient-provider race/ethnicity and gender concordance in cancer screening have been inconclusive. Methods: We conducted a cross-sectional study of 18,690 patient-provider pairs using the 2003-2010 Medical Expenditure Panel Survey (MEPS) data. We assessed association between patient-provider race/ethnicity and gender concordance and, screening adherence for breast, cervical, and colorectal cancer using American Cancer Society guidelines. Separate multivariable logistic regression adjusting for demographics, self-reported health and MEPS survey year were conducted to examine relationships of interest. Results: Seventy percent of patients were NH-white, 15% were NH-black and 15% were Hispanic. Patients adherent to cancer screening were more likely to be non-Hispanic, better educated, married, wealthier, and privately insured. Among NH-black and NH-whites, patient-provider racial/ethnic concordance was not associated with screening adherence. Among Hispanics, patient-provider racial/ethnic discordant pairs had higher colorectal cancer screening rates as compared to concordant pairs (OR 1.48; 95% CI 1.28-1.71). This association was significant even on adjusting for gender concordance and survey language (English vs. Spanish). Conversely, patient-provider gender discordance was associated with lower rates of breast (OR 0.81; 95% CI 0.74-0.89), cervical (OR 0.79; 95% CI 0.72-0.87) and colorectal cancer (OR 0.86; 95% CI 0.80-0.93) screening adherence in all patients. This association was also significant on restricting analysis to racial/ethnic concordant pairs. Conclusions: Patient-provider gender concordance positively impacts adherence to cancer screening and this finding may guide future interventions. Patient-provider racial/ethnic concordance is not associated with screening adherence among whites and blacks but Hispanic patients seen by Hispanic providers have lower colorectal cancer screening rates. This counter-intuitive finding requires further study.
Breast cancer screening practices with high-risk women: A cross-sectional survey.
Authors: Blaes Anne Hudson , Vogel Rachel Isaksson , Raymond Nancy , Talley Kristine , Allen Alicia , Nagler Rebekah , Teoh Deanna Gek Koon , Mason Susan , Wyman Jean
Published: September 2018

1550

Background: Little literature exists on primary care providers’ knowledge and preferences towards breast cancer screening for high-risk women. While guidelines recommend MRI and mammography, it is unclear how frequently these recommendations are used. Methods: This web-based survey of providers licensed to practice in Minnesota was conducted. This analysis focuses on breast cancer screening practices for high-risk women. Data were summarized using descriptive statistics; professional characteristic comparisons were conducted using Chi-squared tests. Results: 805 of 10,392 (8%) invitees completed the survey. 72.2% were female. 43.9% were physicians (20.8% internists, 71.7% family medicine, 6.3% gynecology), 11.4% physician assistants (PAs), 44.8% advanced practice registered nurses (APRNs). 84.8% were in community practice, 38% > 20 years of experience and 27.1% < 10 years. When asked how effective screening was for reducing cancer mortality in high risk women, mammography was thought to be very effective (48.8%) or effective (46.8%) in women ages 40-49 years, for women ages 50+ years, 60.8% and 35.7%, respectively. 62.4% thought breast MRI was very effective in reducing cancer mortality in high risk women. There was no difference in breast MRI recommendation based on professional background, experience or practice setting. Female practitioners, less experience, and those working in gynecology or women’s health were more likely to recommend breast MRI. A case vignette for high risk screening cancer survivors is provided (Table). Conclusions: Most primary care providers believe mammography is helpful in women at high risk for developing breast cancer. Less than half of practitioners, however, are following guideline specific recommendations of both mammography and MRI for breast cancer screening in high-risk patients. [Table: see text]
Health4Families: An intervention to improve weight and health behaviors in families with hereditary breast/ovarian cancer or Lynch syndrome.
Authors: Peterson Susan K. , Strong Larkin , Schembre Susan , Cox Matthew , Li Liang , Karam Courtney , Song Jaejoon , Arun Banu , Pande Mala , You Y. Nancy , Rodriguez-Bigas Miguel A. , Lu Karen H. , Lynch Patrick M. , Basen-Engquist Karen
Published: September 2018

1555

Background: Physical activity, diet, and healthy weight may reduce cancer risk in hereditary breast and ovarian cancer (HBOC) and Lynch syndrome (LS) families. Evidence-based programs to help affected families make these behavioral changes are lacking. We evaluated data from a 16-week family-centered lifestyle intervention trial for individuals with HBOC or LS germline gene mutations and their relatives. Methods: Index cases with HBOC- or LS-associated mutations were recruited from an institutional registry and advocacy organizations, and identified relatives to participate with them in the study. Those eligible had BMI>25 and/or did not meet recommendations for exercise or fruit/vegetable consumption. Participants were randomized to multiple conditions including text messaging, online weight/diet monitoring, an online social network, and E-mail or telephone coaching. All monitored activity using Fitbits. Behavioral outcomes were assessed online at baseline and 8 weeks. Results: 65 HBOC index cases with 63 family members, and 35 LS index cases with 36 family members participated in the study. At 8 weeks, participants lost 3.2 pounds on average (p<.0001) and increased weekly physical activity from 126 to 172 minutes (p=.0012). LS participants decreased self-reported sedentary time (p=.0126). Program effects did not differ between index cases and family members. Participants reported high program satisfaction; 78% would recommend it to a family member. Conclusions: Hereditary cancer families can benefit from behavioral interventions to improve weight and physical activity. Data show that distance-based methods are effective, and are ideally suited for families with a hereditary predisposition to cancer but who are often geographically dispersed. Clinical trial information: NCT02194387. [Table: see text]
Effect of metformin chemoprevention on metabolomics profiles in Li-Fraumeni Syndrome (LFS).
Authors: Walcott Farzana L. , Annunziata Christina M. , Sotomayor Eduardo M. , Fojo Antonio Tito
Published: September 2018

1556

Background: LFS is a highly-penetrant, autosomal dominant, cancer predisposition disorder characterized by early onset cancer; germline mutations in TP53are present in 70% of LFS. We previously observed metformin inhibition on mitochondrial function in LFS patients. Metformin may reduce TCA cycle and glycolytic intermediates during cellular transformation, indicating inhibition of complex I of the mitochondria. To further explore this, we performed untargeted metabolomics profiling on stored serum of study participants. To our knowledge, there are no previous studies of metabolomics profiling in LFS patients treated with metformin. Methods: Adult LFS patients (≥18 years old) were enrolled for 20 weeks. Metformin was initiated at 500 mg per day and increased in 500 mg dose increments every two weeks to a maintenance dose of 2000 mg of metformin. Patients were taken off metformin for the last six weeks of the study (week 20). Global biochemical profiles were determined in human serum samples collected in 21 patients, each providing one sample at baseline, week 14 (on 2000 mg metformin) and week 20 (off metformin). Metabolomics analyses were performed by Metabolon, Inc. Results: Treatment with metformin induced a strong metabolic signature of increased fatty acid beta-oxidation in LFS patients. Acylcarnitines, long chain fatty acids, and 3-hydroxy fatty acids were significantly elevated following metformin treatment. TCA cycle intermediates, aconitate, malate, and fumarate were also increased as were levels of ketone body 3-hydroxybutyrate (BHBA)indicating robust β-oxidation, presumably to support increased energy production via the TCA cycle. Clearance of metformin results in normalization of levels to comparable baseline values, indicating a causal role of metformin in these changes. Conclusions: Global metabolomics profiling suggests an increase in TCA cycle intermediates and a strong signature of fatty acid oxidation with metformin treatment in LFS, suggesting metformin effect on the mitochondria and TCA cycle is more dynamic than previously shown. LFS patients may have distinct metabolic profiles which may be altered by treatment with metformin. Funding: ASCO Young Investigator’s Award 2016. Clinical trial information: NCT01981525.
Assessment of BRCA testing uptake in ovarian cancer patients during the implementation of an oncologist-led genetic counseling model at an urban and suburban teaching hospital.
Authors: Jorgensen Jennifer , Chiu Kimberley , Gotimer Kristin , Chalas Eva , Kuo Dennis Yi-Shin , Huang Gloria S.
Published: September 2018

1589

Background: BRCA testing has become an integral component of ovarian cancer management; however, low testing uptake remains an obstacle. This study evaluated the impact of an oncologist-led counseling and testing model on BRCA testing uptake. Methods: The ENGAGE study (NCT02406235) is a prospective study of an oncologist-led BRCA counseling and testing model in patients with epithelial ovarian, primary peritoneal and fallopian tube cancer (EOC). The United States lead accruing gynecologic oncology sites were Montefiore, an urban academic medical center; and Winthrop, a suburban teaching hospital. Oncologists were trained in BRCA counseling prior to site activation, and directly submitted patients’ samples for BRCA testing. Prior to the ENGAGE study, EOC patients were referred to genetics professionals for counseling and testing. We determined the number of BRCA tests performed, and simple descriptive statistics were used to summarize the data. Results: A combined total of 141 EOC patients underwent BRCA testing during the 20 consecutive months analyzed. In the 10 months pre-ENGAGE, 8 Montefiore patients had BRCA testing, all submitted through the genetics division. Nineteen Winthrop patients had BRCA testing, 16 from their oncologist’s office and 3 from an external genetics office. During the 10-month ENGAGE trial, 64 Montefiore patients and 50 Winthrop patients had BRCA testing. This represents a four-fold increase in BRCA testing uptake, with 114 patients tested during ENGAGE versus 27 patients tested pre-ENGAGE. Of these 114, 99 had BRCA counseling and testing through their oncologist’s office. Conclusions: Implementation of an oncologist-led genetic counseling and testing model was associated with increased BRCA testing among ovarian cancer patients in both the urban and suburban hospitals. Increased BRCA testing could be related to increased patient convenience and standardized training of the clinical team. These findings may guide other institutions as they implement streamlined genetic counseling and testing protocols.
Multicenter study to demonstrate radiomic texture features derived from MR perfusion images of pseudoprogression compared to true progression in glioblastoma patients.
Authors: Elshafeey Nabil , Kotrotsou Aikaterini , Giniebra Camejo Dunia , Abrol Srishti , Hassan Islam , El Salek Kamel , Hassan Ahmed , Shaaban Ahmed , Bergamaschi Samuel , Moron Fanny E , Law Meng , Zinn Pascal , Colen Rivka R.
Published: September 2018

2016

Background: To differentiate between pseudoprogression and true progression in patients with glioblastoma using MR perfusion radiomic texture analysis (TA). Methods: 98 patients with pathologically-proven diagnosis of GBM were retrospectively included in this IRB approved HIPAA compliant study. All patients underwent DSC and DCE Perfusion MRI as part of their routine clinical care. Images were analyzed using Nordic ICE 2.3 (NordicNeuroLab) ; rCBV and ktrans maps were obtained. Subsequently, 3D slicer 4.3.1(http://www.slicer.org) was used to segment the entire tumor on the different processed maps to create a volume of interest (VOI) for Radiomic TA. Multiple invariant texture features where then extracted from each VOI. 475 invariant texture features were applied to each map. Leave-one-out cross-validation (LOOCV), receiver operating characteristic (ROC), Kaplan Meier, and multivariate Cox proportional hazards regression analyses were used to assess the relationship between texture feature and pseudoprogression and true progression. Results: Variance and sum entropy were the two most significant radiomic features that discriminated between pseudoprogression and true progression. P value, AUC, specificity and sensitivity were 0.03, 89.26%, 81.82%, and 100% respectively. Conclusions: Radiomic TA derived from perfusion images can be helpful in determining true versus pseudoprogression in GBM. Further, this study illustrates successful application of radiomic TA as an advanced processing step for different MRI perfusion maps (DCE, DSC).
Overall survival (OS) by line of therapy (LOT) in Medicare-enrolled glioblastoma multiforme (GBM) patients (pts).
Authors: Aly Abdalla , Singh Prianka , Korytowsky Beata , Dastani Homa , Ling Lisa , Botteman Marc , Norden Andrew David
Published: September 2018

2039

Background: In clinical trials, the median OS of elderly GBM pts on standard treatment (tx) is ~9 months (mos) from diagnosis (dx), but has not been described in the real world (RW). This analysis describes RW OS for US Medicare GBM pts by LOT. Methods: GBM pts aged ≥66 years (y) were identified in SEER-Medicare (2007–2011). Pts were followed from dx to death, Medicare disenrollment or 12/31/2013. Systemic tx patterns were characterized as untreated (0L), ≥first line (1L+) and ≥second line (2L+). OS was estimated by the Kaplan-Meier method from dx for 0L, and from LOT start for 1L+ and 2L+. Results: Among 2533 eligible GBM pts (median age: 74 y; Charlson comorbidity index [CCI] ≥2: 13%), 49.9% received 1L+ and only 16.3% received 2L+. Median (1-year) OS for all pts was 5.3 mos (26%), range 1.6–10.7 mos (3–45%) depending on LOT, surgical resection (R) or Biopsy alone (B), tumor size, age, and CCI (Table). Conclusions: Receipt of tx has a significant impact on OS in Medicare GBM pts. This RW study shows that only 50% of pts receive tx, even though each LOT is associated with additional OS benefit. This suggests an unmet need for more efficacious therapies to allow additional treatment and improve outcomes. [Table: see text]
A novel MGMT methylation-based prognostic score in patients with glioblastoma.
Authors: Gerratana Lorenzo , Lombardi Giuseppe , De Carlo Elisa , Buoro Vanessa , De Maglio Giovanna , Marcato Raffaella , Isola Miriam , Cattaneo Monica , Bellu Luisa , Pelizzari Giacomo , Gurrieri Lorena , Follador Alessandro , Puglisi Fabio , Pizzolitto Stefano , Fasola Gianpiero , Zagonel Vittorina , Rizzato Simona
Published: September 2018

2048

Background: The methylation status of the O6-methylguanine-DNA methyltransferase (MGMT) promoter has been associated with improved outcome in glioblastoma (GBM) patients (pts). Pyrosequencing (PSQ) has been reported to be an accurate method for quantitative detection of CpG islands (CpGs) methylation, but the role of methylation heterogeneity among different CpGs sites is still unclear. Aim of this study was to evaluate on a large multicentric cohort a novel prognostic score based on the evaluation of the MGMT promoter methylation at 10 different CpGs sites. Methods: We retrospectively analyzed a series of 185 pts with GBM treated at the University Hospital of Udine and Istituto Oncologico Veneto in Padua between 2006 and 2015. The methylation level of 10 CpGs (74 – 83) was determined by PSQ. The cut-off point of 9% was used to define a CpG as methylated. One point was assigned to each methylated CpG, with a total score from 0 (all CpGs < 9%) to 10 (all CpGs ≥ 9%). A threshold capable to detect a favorable outcome (Overall Survival, OS > 24 months) has been identified through ROC analysis as 6 by a previous study conducted at our center. The prognostic impact was explored through Cox regression. Results: After a median follow-up of 59 months, the median OS and Progression Free Survival (PFS) in the whole population were 16.41 and 9.67 months, respectively. A score ≥ 6 identified pts with a considerably better median OS (24.85 vs 12.99 months, p < .0001) and PFS (11.44 vs 8.22 months, p < .0001). On multivariate analysis, it remained independently associated with a favorable prognosis (HR 0.38, 95% CI 0.27-0.55, p < 0.0001) after adjustment for IDH1 mutational status (HR 0.42, 95% CI 0.20-0.87, p = .02), age ( > 70 vs ≤ 70 years HR 2.20, 95% CI 1.48-3.28, p = .0001) and ECOG performance status (2-3 vs 0-1 HR 2.35, 95% CI 1.59-3.49, p < .0001). The score’s prognostic value was maintained in all the explored subgroups. Conclusions: Combining methylation data from multiple CpGs increases the prognostic value of the MGMT promoter methylation assessment. The study confirmed the independent prognostic value of a novel score system based on the evaluation of the MGMT promoter methylation at 10 different CpGi sites.
Number of tumor-infiltrating lymphocytes in breast cancer brain metastases compared to matched breast primaries.
Authors: Narloch Jessie , Luedke Catherine , Broadwater Gloria , Priedigkeit Nolan , Hall Allison , Hyslop Terry , Sammons Sarah LeNoir , Huggins-Puhalla Shannon Leigh , Leone Jose Pablo , Ramirez Juanita , Kirkpatrick John P , Ewend Matt G , Fecci Peter E , Brufsky Adam , Lee Adrian V. , Anders Carey K. , Blackwell Kimberly L.
Published: September 2018

2049

Background: Breast cancer brain metastasis (BCBM) is frequent in advanced disease, has limited therapies, and is associated with poor prognosis. Increased stromal tumor infiltrating lymphocytes (sTILs) are prognostic in triple-negative breast cancer (TNBC) and predictive of therapeutic response in early breast cancer (BC). However, little is known about sTILs in the metastatic setting. We compared %sTILs between the largest known cohort of matched primary tumors and BCBM and correlated the results with clinical endpoints. Methods: We retrospectively investigated 37 matched primary tumors and BCBM tissue from three institutions. In addition, we identified 29 primary tumors from patients later diagnosed with BCBM. H&E-stained sections were manually measured for %sTILs using standard criteria. Wilcoxon signed rank tests assessed for changes in %sTILs between primary and metastatic lesions. A Cox proportional hazards model was used to determine if %sTILs in the breast tissue predicts time from primary tumor biopsy to diagnosis of brain metastasis (TTDBM) while adjusting for clinicopathologic features. Results: Average age at time of BCBM diagnosis was 53.6 (SD 12.3). 52% (34/66) of primary tumors were hormone receptor (HR) positive. Of 60 patients with known HER2 status, 28% (17) were HER2 positive and 40% (24) TNBC. Median %sTILS was significantly different between all primary tumors (15, IQR 5-20) and brain metastases (10, IQR 5-10), p = 0.001. The TNBC subtype (n = 11) showed the largest decrease in %sTILs between primary tumors (20, IQR 10-20) and brain metastases (5, IQR 5-10), p = 0.022. Comparing primary tumors and brain metastases, there was a 5% decrease in %sTILs in HR-/HER2+ (n = 5, p = 0.13) and HR+/HER2- (n = 7, p = 0.13), and a 5% increase in %sTILs in the HR+/Her2+ subtype (n = 9, p = 0.69). Percent sTILs in the primary tumors was not a significant predictor of TTDBM, when adjusting for race, age, HR status, and HER2 status, p = 0.87. Conclusions: BCBM have a significantly decreased %sTILs compared to their primary tumors, most prominent in TNBC. These results suggest altered tumor immunogenicity in the metastatic setting which has broad implications for the development of immunotherapy.
Initial phase 1 study of WT2725 dosing emulsion in patients with advanced malignancies.
Authors: Fu Siqing , Piccioni D. E. , Liu Hongtao , Lukas Rimas Vincas , Aregawi Dawit , Yamaguchi Kenichiro , Whicher Kate , Chen Yu-Luan , Poola Nagaraju , Eddy John , Zhang Ian , Blum David
Published: September 2018

2066

Background: WT2725 is a Wilms’ tumor (WT1)-derived-oligopeptide vaccine intended to induce WT1 specific cytotoxic T-lymphocytes against WT1 positive tumors in HLA-A*0201+ or HLA-A*0206+. This first in human study of WT2725 was conducted to evaluate the safety, tolerability, and efficacy. Methods: Subjects with progressive or recurrent glioblastoma (GBM), acute myeloid leukemia (AML) (patients in morphologic remission with minimal residual disease determined by WT1 RT-PCR were allowed), non-small cell lung cancer (NSCLC), or ovarian cancer despite standard therapy were treated with 0.3, 0.9, 3, and 9 mg of WT2725 subcutaneously (s.c.) every week for 4 weeks, then every other week for 6 weeks, and every 4 weeks thereafter until progression or other discontinuation event (part 1); and with 18 mg and 27 mg of WT2725 s.c. every week for 8 weeks, then every other week for 10 weeks, and every 4 weeks thereafter until progression or other discontinuation event (part 2). Responses were evaluated by Immune-related Response Criteria (irRC) for solid tumors and modified International Working Group (IWG) for AML. Results: 62 subjects were dosed, the most frequent adverse events were grade 1 injection site reactions (no grade 3 injection site reactions or dose limiting toxicities observed). Of the 21 GBM subjects who were dosed, seven survived for ≥ 1 year (33%). Of these seven subjects, three survived for ≥18 months (14%), and two for ≥2 years (both in complete radiologic remission, 9.5%). One of the seven subjects with ≥1 year survival had previous treatment with bevacizumab. Two subjects continue dosing (1 complete response with no measurable disease >3 years and 1 partial response > 13 months on study). Results in subjects with non-GBM tumors (12 subjects with AML, 21 with ovarian CA, 7 with NSCLC, and 1 other cancer) are not presented here. WT1-specific CTLs and tumor burden was monitored. WT1 specific CTLs were associated with decrease of tumor burden in two patients with low tumor burden. Some patients with high disease burden did not respond. Conclusions: Preliminary data suggests WT2725 is well tolerated with potential antitumor activity in GBM patients, supporting future development of WT2725 for treatment of GBM in selected subjects. Clinical trial information: NCT01621542.
Examination and prognostic implications of the unique microenvironment of breast cancer brain metastases.
Authors: Prince Grace , Deal Allison Mary , McKee Megan Jean , Trembath Dimitri G. , Keith Kevin , Ramirez Juanita , Midkiff Bentley Randall , Blackwell Kimberly L. , Leone Jose Pablo , Hamilton Ronald L. , Brufsky Adam , Morikawa Aki , Brogi Edi , Seidman Andrew David , Ewend Matthew G. , Carey Lisa A. , Moschos Stergios J. , Vincent Benjamin Garrett , Anders Carey K.
Published: September 2018

2072

Background: Brain metastases (BM) are an increasingly common consequence of breast cancer (BC). Knowledge of the microenvironment in primary BC and its impact on prognosis is evolving. A similar understanding of the microenvironment of BC metastases is lacking, particularly for the brain, where unique immune regulation governs stroma composition. Such features of the peri-tumoral landscape, i.e. high immune infiltrate and low hemorrhage, offer prognostic value in BM from melanoma. This study reports on 4 biomarkers, gliosis (glio), immune infiltrate (immune), hemorrhage (hem) and necrosis (nec), and their prognostic significance in BCBM. Methods: A biobank of 203 patients (pts) who underwent craniotomy between 1989-2013 was created across 4 sites. Glio, immune, and hem (grouped 0 v 1-3) and nec (0-2 v 3) were scored via H&E stain (0-3). Overall survival (OS (years)) from craniotomy was estimated using the Kaplan-Meier method; log-rank tests compared OS. Cox proportional hazards regression was used to evaluate prognostic value of the 4 biomarkers. Results: Mean age at primary BC diagnosis was 48 years (range 26-77). BCBM subtype (n = 158) was 36% HER2+, 26% HR+/HER2-, 38% HR-/HER2- (TN). Across all samples, expression was 82% glio, 45% immune, 82% hem, and 13% nec. Subtype differences were seen for nec (higher in TN, p < 0.01). Across all pts, expression of glio, immune, and hem was associated with improved OS (years): 1.08 v 0.62 (p = 0.03), 1.31 v 0.93 (p = 0.03), 1.07 v 0.92 (p = 0.1), respectively. Nec was associated with inferior OS: 0.38 v 1.12 (p = 0.01). The association with improved OS was maintained for glio in TN (p = 0.02), and immune (p = 0.001) and hem (p = 0.07) in HER2+. In a multivariable model for OS, adding the 4 biomarkers to traditional clinical variables (age, race, subtype) significantly improved the model fit (p < 0.001). Conclusions: Nec is a poor prognostic finding in BCBM across all subtypes. Glio confers superior prognosis in TN, while immune and hem correlate with superior prognosis in HER2+. A deeper understanding of the rich BCBM microenvironment both refines prognostic considerations for this pt population and may lead to future investigations of targeted immunotherapies in select subtypes of BCBM.
Planned interim analysis of PATRICIA: An open-label, single-arm, phase II study of pertuzumab (P) with high-dose trastuzumab (H) for the treatment of central nervous system (CNS) progression post radiotherapy (RT) in patients (pts) with HER2-positive metastatic breast cancer (MBC).
Authors: Lin Nancy U. , Stein Alisha , Nicholas Alan , Fung Anita M. , Kumthekar Priya , Ibrahim Nuhad K. , Pegram Mark D.
Published: September 2018

2074

Background: There is currently no clear standard of care to address the management of recurring/multiple intracranial metastases post RT in HER2-positive MBC. The ongoing PATRICIA study (NCT02536339) is evaluating the safety and efficacy of P in combination with high-dose h for patients with HER2-positive MBC with CNS metastases who have CNS progression following RT. Reported herein are results from the protocol-specified interim analysis of PATRICIA. Methods: All eligible patients must have measurable (≥10 mm) CNS progression post RT, and stable non-CNS disease. Patients receive P (840-mg loading dose, then 420 mg every 3 weeks) and high-dose h (6 mg/kg weekly). The primary efficacy endpoint is objective response rate (ORR) in the CNS per Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) criteria. The interim analysis was planned after 15 patients were enrolled and had ≥2 left ventricular ejection fraction (LVEF) measurements, 2 cycles of study drugs, and 2 response measurements. The study would proceed to full enrollment (n=40) if objective response or stable disease in the CNS was observed in ≥1 of 15 patients and <2 of 15 patients develop congestive heart failure (CHF) related to P or H. Results: As of Sept 6, 2016, 15 patients had been enrolled across 9 sites. Median treatment duration was 4.4 (range 1.2−8.3) months. Six patients discontinued treatment (5 for disease progression; 1 for symptomatic deterioration). Range for duration of response was 1.4−3.3 months. There were no new safety signals for P combined with high-dose h treatment. No patients had CHF or a clinically significant drop in LVEF. Conclusions: Based on early evidence of clinical benefit (ORR 20%) and a lack of new safety signals, the safety and futility boundaries for PATRICIA have been passed and study enrollment continues. Clinical trial information: NCT02536339. [Table: see text]
Phase I first-in-man trial of a novel bromodomain and extra-terminal domain (BET) inhibitor (BI 894999) in patients (Pts) with advanced solid tumors.
Authors: Aftimos Philippe Georges , Bechter Oliver , Awada Ahmad , Jungels Christiane , Dumez Herlinde , Huyvaert Nathalie , Costermans Jo , Lee Chooi , Meeus Marie-Anne , Burkard Ute , Musa Hanny , Zhao Yihua , Schoffski Patrick
Published: September 2018

2504

Background: The BET family (BRD2, BRD3, BRD4) regulates transcription, epigenetic memory and cell growth, emerging as a novel therapeutic strategy. BI 894999 is a highly potent and selective orally available BET inhibitor. Methods: BI 894999 was given once a day, continuously (1 cycle = 3 weeks; Arm A). An intermittent schedule was explored: once a day, D1-14 Q21 days (1 cycle = 3 weeks; Arm B). Bayesian Logistic Regression Model was used to guide dose escalation. HEXIM1, HIST2H2BF and CCR2 gene expressions were used as pharmacodynamic (PD) markers. Results: 28 pts were treated: 21 in Arm A, 7 in Arm B. Median number of cycles was 2 (range: 1-12). Pts were treated at 6 dose levels in Arm A (0.2-5 mg) and 2 dose levels in Arm B (1.5 and 2 mg). The maximum tolerated dose (MTD) was exceeded at 2 mg in Arm A. In Arm B, dose escalation was halted due to the observation of ECG changes in 3 pts and raised serum troponin in 8 pts, pending cardiology review. MTD in Arm A was defined as 1.5 mg. The most frequent (≥10%) treatment-related adverse events were: fatigue (50%), thrombocytopenia (29%), decreased appetite (21%), diarrhea (18%), increased troponin T (18%), dysgeusia (14%), nausea (14%), stomatitis (14%), increased CK (11%), neutropenia (11%) and vomiting (11%). DLTs included: thrombocytopenia grade (G) 4 (n=3), increased troponin G3 (n=1), hypophosphatemia G3 (n=1), multiple G2 events in 1 pt preventing adequate dose intensity in cycle 1. Of 27 evaluable pts, 3 had partial response (PR; one was confirmed) and 1 had stable disease (SD) lasting >4 cycles. Cmax and AUC increased with dose in a greater than linear fashion particularly at higher dose levels. Mean terminal T1/2 was ~1 day with high interpatient variability. PD analyses showed target engagement in all 3 genes at doses ≥1 mg in both schedules. Conclusions: BI 894999 showed target engagement at doses ≥ 1 mg and demonstrated clinical activity (3 PRs and 1 SD lasting >4 cycles). Thrombocytopenia prevented continuous dosing and 1.5 mg was defined the MTD for Arm A, whilst dose escalation was halted in Arm B due to cardiac findings. Mitigating hematological toxicity of BI 894999 via synergistic drug combinations should be explored. Clinical trial information: NCT02516553.