bluuebunny/crossref_metadata_2025_split huggingface dataset:
A study on the prevalence of HER2 genetic heterogeneity and its impact on breast cancer survival.
Authors: Ho Jingshan , Chan Daniel Boon Yeow , Lee Soo-Chin , Koay Evelyn S. C. 
Published: March 2020

586 Background: HER2 heterogeneity (GH) has been described in breast cancer that has conventionally been labeled as HER2 negative (FISH score <2.2). We aimed to ascertain the prevalence of GH in HER2 negative breast cancers and to investigate for any impact on survival. Methods: We reviewed HER2 FISH (Vysis) data for 158 primary breast cancer specimens from 2006-2010 which were 0 – 2+ on immunohistochemistry. HER2:CEP17 ratios were calculated for each of the 60 cells scored and cases were classified as HER2 GH according to the ASCO/CAP guidelines (GH = 5-50% tumor cells with a ratio >2.2). Results: 67% (106/158), 7% (11/158) and 26% (41/158) were HER2 negative, equivocal (FISH ratio 1.8-2.2) and positive respectively. GH was found in 43% and 100% of Her2 negative and HER2 equivocal patients respectively. Of the 117 cases (with FISH score <2.2), HER 2 GH was associated with higher histologic grade (grade 3: 81.8%, 52.3% and 33.3% in HER2 equivocal, negative with GH and negative without GH (p = 0.007). There were no significant associations with ER status or the presence of lymphovascular invasion. The mean overall survival was 63 months (95% CI 43-87), 118 months (95% CI 96-141) and 148 months (95% CI 148-168) for HER 2 equivocal, negative with GH and negative without GH patients respectively (p=0.017). In a subset analysis of HER2 negative (with FISH score <2.2), non metastatic patients, with at least a 4 year follow up period (n=63), mean overall survival was 79 months (95% CI 60-98), 119 months (95% CI 96-143) and 159 months (95% CI 139-180) for HER2 equivocal, negative with GH and negative without GH patients (p=0.034). GH remained a significant factor in the multivariate analysis irrespective of grade, stage and ER status (p=0.046). Conclusions: HER2 GH occurs in 100% of HER2 equivocal and 43% of HER2 negative breast cancers and is associated with higher histologic grade and poorer overall survival, irrespective of grade, stage or hormonal status.
Breast cancer screening: Biology of tumors detected by analog and digital mammography.
Authors: Drukker Caroline , Schmidt Marjanka , Rutgers Emiel J. , Cardoso Fatima , Kerlikowske Karla , Esserman Laura , Slaets Leen , Bogaerts Jan , van 't Veer Laura J. 
Published: March 2020

587 Background: Population-based screening might be associated with a higher likelihood of a (ultra)low risk tumor assessed by the 70-gene signature (MammaPrint) (ultralow defined as indexscore >0.6, no distant metastasis observed at 5 years in the original 78 patients). The aim of this study is to determine the proportion of biologically (ultra)low risk tumors among the screen-detected tumors and to evaluate the impact of the analog versus digital screening technique. Methods: All Dutch breast cancer patients enrolled in the MINDACT trial (EORTC-10041), who were invited for the Dutch screening program (biennial, age 50-75), were included (n=1409). The proportions of 70-gene signature high, low and ultralow risk were calculated for patients with screen-detected (n=775), interval (n=390), and symptomatic, non-screening (n=244) carcinomas, taking into account analog vs. digital technology. Co-variants such as age, tumor size, grade, histological type, ER, HER2 and nodal status were included in the analyses. Results: Among the screen-detected tumors, 31.5% had a high risk, 31.2% a low risk and 37.3% an ultralow risk 70-gene signature result, compared to 47.4%, 28.5% and 24.1% among the interval carcinomas, respectively (p=0.001). Among the screen-detected carcinomas, 40.6% were detected using analog (n=315) and 59.4% using digital mammography (n=459). When using digital imaging a shift was seen among the screen-detected tumors in the proportions of high risk tumors from 27% to 35% and ultralow risk from 42% to 34%, low risk proportions remained the same (31%)(p=0.011). No such difference was seen for other tumor characteristics. Conclusions: Screen-detection was found to be associated with a higher likelihood of a biologically low risk tumor. The transition from analog to digital mammography resulted in a smaller proportion of ultralow risk and a larger proportion of high risk tumors among the screen-detected carcinomas.
Identification of the activated form of the progesterone receptor (PR) in breast cancer (BC).
Authors: Bosq Jacques , Caillaud Jean-Michel , Lange Carol A. , Fuqua Suzanne A. W. , O'Shaughnessy Joyce , Gilles Erard M. , Zukiwski Alexander A. , Bonneterre Jacques 
Published: March 2020

593 Background: Upon ligand binding, PRs dimerize and form a discrete focal subnuclear distribution pattern (FDP), which are associated with transcriptional activation of PR (APR). FDP and are observed in BC independently of menopausal status. The feasibility of using an IHC technique to characterize the PR functional status has previously been reported in BC and presence/absence of APR is hypothesized to predict anti-progestin activity. This study describes an immunohistochemistry (IHC) method, by which a biomarker could be developed to investigate this hypothesis. Methods: 303 paraffin embedded/formalin fixed archival BC samples were processed with PR-A or PR- B isotype specific antibodies. Nuclear morphology was analyzed with standard microscopy at x1000, interpretation of the IHC slides was done by an experienced pathologist. Standard PR, estrogen receptor (ER), and Ki67 testing were done. Tumor grading/stage was obtained from the patients’ records. Results: Histology was ductal 85%, lobular 13%, other 2%. Consistent with prior research observations, tumors had two PR nuclear morphologies: 1. Diffuse pattern (D) where the PR was distributed evenly in a fine granular pattern or, 2. Aggregate pattern (A) where the PR is distributed in discrete clumps or aggregates. This defined 3 tumor phenotypes: A cells only (A), D cells only (D), and a heterogenous mix of A+D cells (AD). The APRpos group is defined as the A and A+ D phenotypes. Tumors were PR positive in 76% for PRA and 80% for PRB. Tumors were APRpos for PRA in 23% and independent of PR intensity score, ER, Ki67, and HER2, but associated with higher PR % positivity and higher tumor grade. Tumors were APRpos for PRB in 22% and associated with lower PR intensity and higher tumor grade, independent of ERpos %, PRpos %, Ki67 and HER2. Conclusions: PR positive BC tumors can be grouped in two categories based on PR nuclear morphology: 1. a group with diffuse and homogenous nuclear staining, 2. a group with heterogeneous area of cells having a nuclear pattern consistent with a functional or activated PR (APR). The described IHC technique to identify APR has the potential to be developed as companion diagnostic as a potential predictor of anti-progestin efficacy in patients with BC.
Prediction of early and late distant recurrence in early-stage breast cancer with Breast Cancer Index.
Authors: Zhang Yi , Schnabel Catherine A. , Schroeder Brock , Jerevall Piiha-Lotta , Jankowitz Rachel Catherine , Stal Olle , Brufsky Adam , Sgroi Dennis , Erlander Mark G. 
Published: March 2020

594 Background: Breast Cancer Index (BCI) is a continuous risk index based on the combination of HOXB13:IL17BR (H:I) and the Molecular Grade Index (MGI) that estimates the individual risk of recurrence in ER+, LN- breast cancer patients. In the current study, a modified BCI model was developed using untreated breast cancer patients in order to evaluate its pure prognostic value, and to better optimize BCI for both early and late risk assessment. Methods: A model was built by linearly combining H:I and MGI weighted by their corresponding Cox regression coefficients using ER+ LN- patients from the untreated arm of the prospective Stockholm trial (N=283). Validation was performed in 2 independent ER+, LN- cohorts: the TAM arm of the Stockholm trial (N=317), and a multisite cohort of TAM-treated patients (N=358). Correlation of BCI with distant metastasis was evaluated by Kaplan-Meier analysis using the log rank test, and multivariate analysis adjusting for standard prognostic factors was performed using Cox proportional hazards. Results: The BCI linear model was significantly associated with risk of cumulative (0-10y), early (<5y) and late (≥5y) distant metastasis. Based on pre-specified cutpoints, BCI classified 64% and 55% patients as low-, 21% and 22% as intermediate-, and 16% and 23% as high-risk, with 10-y rates of distant recurrence (95% CI) of 4.8% (1.7-7.8%) and 6.6% (2.9–10.0%), 11.7% (3.1–19.5%) and 23.3% (12.3-33.0%), 21.1% (18.5–32.0%) and 35.8% (24.5–45.5%), in the Stockholm TAM and multisite cohort, respectively. Conclusions: BCI demonstrated significant prognostic performance beyond clinicopathological factors to predict cumulative, early and late risk of recurrence in early stage breast cancer patients. Use of BCI at diagnosis should enable clinicians to identify patients who are at high risk of late recurrence and may benefit from an additional 5y of hormonal therapy. [Table: see text]
Effect of PK-guided tamoxifen dose escalation on endoxifen serum concentrations in CYP2D6 intermediate and poor metabolizers.
Authors: Opdam Frans , Dezentje Vincent O. , den Hartigh Jan , Guchelaar Henk-jan , Hessing Trees , van der Straaten Tahar , Vree Robert , Batman Erdogan , Maartense Eduard , Smorenburg Carolien H. , Zeillemaker Anneke , Brakenhoff J. A. C. , Los Maartje , Kuijer Philomeen , Putter Hein , Dieudonné Anne-Sophie , Neven Patrick , Van De Velde Cornelis J. H. , Nortier J. W. R. , Gelderblom Hans 
Published: March 2020

595 Background: Breast cancer patients with absent or reduced CYP2D6 activity may benefit less from tamoxifen treatment because of impaired biotransformation to the active metabolite endoxifen. We investigated whether a temporary one-step dose escalation of tamoxifen in CYP2D6 poor (PM) and intermediate metabolizers (IM) could increase endoxifen serum concentration to a similar level observed in CYP2D6 extensive metabolizers (EM) without increasing toxicity. Methods: From a prospective study population of early breast cancer patients using tamoxifen, 12 CYP2D6 poor and 12 intermediate metabolizers were selected and included in a one-step tamoxifen dose escalation study during two months. The escalation dose (120 mg maximum) was calculated by multiplying the individual’s endoxifen level divided by the median endoxifen concentration (33.7 nM) observed in CYP2D6 extensive metabolizers by 20 mg. Toxicity was assessed and all patients returned to the standard dose of 20 mg after two months. Results: Tamoxifen dose escalation in CYP2D6 poor and intermediate metabolizers significantly increased endoxifen concentrations (PMs: from 8.0 nM to 27.3 nM, p<0.001; IMs: from 17.8 nM to 30.3 nM, p=0.002) without increasing side effects. In intermediate but not in poor metabolizers dose escalation increased endoxifen to levels comparable with those observed in extensive metabolizers using tamoxifen 20 mg once daily (33.7 nM). Conclusions: CYP2D6 genotype and endoxifen guided tamoxifen dose escalation increased endoxifen concentrations without increasing short term side effects. Whether such tamoxifen dose escalation is effective and safe in view of long term toxic effects is uncertain and needs to be explored. Clinical trial information: NTR1509.
A comparative analysis of distant recurrence risk assessments by Oncotype DX recurrence score alone and integrated with clinicopathologic factors in early-stage breast cancer.
Authors: Kelly Ciara Marie , Beamish Rose , McCaffrey John , SMITH Martina , Crown John , O'Connor Miriam , McGee Sharon F. , O'Reilly Seamus , Moylan Eugene J. , Gonzalez-Angulo Ana M. , Litton Jennifer Keating , Pusztai Lajos , Kelly Catherine Margaret 
Published: March 2020

598 Background: Treatment planning for patients with node negative, ER-positive, HER-2 negative breast cancer often incorporates the use of prognostic and predictive tools like Oncotype DX. Prior to the availabilty of Oncotype DX, clinicopathologic factors such as age, nodal status, tumour size and grade were used to determine risk of recurrence (ROR). RSPC represents a validated formal integration of oncotype DX recurrence score (RS) and clinicopathologic factors that further refines prognostic accuracy. RSPC does not improve the prediction of likelihood of chemotherapy benefit. The objective of this study was to compare distant recurrence risk assessment by RS and RSPC. Methods: We included patients with node negative, ER-positive, HER2-negative breast cancer who had Oncotype DX testing routinely or on clinical trial. We retrospectively reviewed patient charts and extracted clinicopathological and RS data. We calculated the RSPC using the RSPC educational tool. A comparative analysis was performed looking at the statification of patients into low (LR), intermediate (IR) and high (HR) ROR groups by RS and RSPC. The cut offs for low, intermediate and high risk by the RSPC were set to less than 12%, 12-20% and more than 20% risk of distant recurrence at 10yrs, corresponding to the risks of recurrence associated with the RS categories. Results: We identified 658 patients from 5 academic hospitals in Ireland and the US. Oncotype DX RS classified the following proportions of patients into three risk groups for distant recurrence: LR, n=334 (50.5%), IR, n=259 (39.4%), HR, n=67 (10.1%). RSPC classified the following proportion of patients into the three risk groups for recurrence: LR, n= 455 (69.1%), IR, n=110 (16.7%), HR, n=93 (14.1%). RSPC reclassified 72.6% (n=188) of the IR group (59.1% (n=153) from IR to LR and 13.5% (n=35) from IR to HR). RPSC reclassified 10.5% (n=35) of the LR group (8.1% (n=27) from LR to IR, and 2.4% (n=8) from LR to HR). RSPC reclassified 25.3% (n=17) of the HR group (17.9% (n=12) from HR to IR, and 7.4% (n=5) from HR to LR). Conclusions: RSPC reclassified 240 patients (36.5%) and was most helpful reassigning the IR group.
Genomic profiling of kinase genes in head and neck squamous cell carcinomas to identify potentially targetable genetic aberrations in FGFR1/2, DDR2, EPHA2, and PIK3CA.
Authors: Keck Michaela K. , Zuo Zhixiang , Khattri Arun , Brown Christopher D. , Stricker Thomas , Weichselbaum Ralph R. , Lingen Mark W. , Cohen Ezra E.W. , White Kevin P. , Vokes Everett E. , Hammerman Peter S. , Seiwert Tanguy Y. 
Published: March 2020

6010 Background: Development of targeted therapies in head and neck squamous cell carcinoma (HNSCC) has been limited due to the lack of validated, oncogenic genetic aberrations. We determined mutations and copy number (CN) events in kinases in a 120 patient cohort in order to identify new potential treatment targets. Methods: Fresh frozen tumor (≥70%) and matched normal tissue from 120 patients with treatment-naïve, locoregionally advanced HNSCC were evaluated using targeted, massively parallel sequencing (Illumina HiSeq) for 60 cancer-relevant, targetable kinases (as well as PI3K related tumor suppressors). CN analysis was performed on the NanoString nCounter for 40 cancer relevant kinases. Mutations were modeled bioinformatically using the CHASM oncogenic driver prediction algorithm and reviewed for prior occurrence in COSMIC. Results: We identified somatic mutations in three potentially targetable receptor tyrosine kinases: 7 (5.8%) mutations were identified in DDR2, 3 (2.5%) mutations in FGFR2, and 4 (3.3%) mutations in EPHA2. Furthermore we identified multiple mutations in several PI3K family members including PIK3CA (N=22 (18,3%)) as well as PI3K related tumor suppressors (PTEN N=3 (2.5%)), INPP4B N=7 (5.8%)). Several mutations showed low CHASM scores consistent with oncogenic driver characteristics. We identified recurrent copy number aberrations in two kinases – FGFR1 (N=15 (13%), median CN:3.27 (3.03-15.662)), and EGFR (N=13 (11%), median CN: 3.73 (2.93-17.75)). Interestingly similar mutations/copy number events have been described in other cancer types including endometrial, and lung squamous cell carcinomas. Conclusions: We identified multiple novel mutations and copy number events in 45% of tumors: genetic aberration in FGFR1, FGFR2, DDR2, EPHA2, and the PI3K pathway are candidate oncogenic drivers that are potentially targetable. Results are corroborated by similar aberrations in other cancer types e.g. lung squamous cell carcinomas that are already being explored as therapeutic targets. Further validation and initiation of focused clinical trials in mutation pre-selected patients is indicated.
Association of the 3'-untranslated region KRAS-variant with cisplatin resistance in patients with recurrent and/or metastatic head and neck squamous cell carcinoma.
Authors: Weidhaas Joanne B. , Lee Ju-Whei , Slebos Robbert , Howard Jason , Perez Jimena , Gilbert Jill , Nallur Sunitha , Paranjape Trupti , Garcia Joaquin J. , Burtness Barbara , Forastiere Arlene A. , Chung Christine H. 
Published: March 2020

6016 Background: A germline mutation in let-7 complementary site 6 (LCS6) within the KRAS 3'-untranslated region (rs61764370, the KRAS-variant: TG/GG) is known to associate with poor outcome and drug resistance in various cancers compared to the wild type allele (TT). We examine the prognostic significance of the KRAS-variant in recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC). Methods: The KRAS-variant was determined in 116 tumor DNA samples from HNSCC patients enrolled in 3 clinical trials and a tissue collection study using a previously validated PCR-based assay. Results: KRAS-variant status could be determined in 108/116 (93%) samples and an allele frequency of TG/GG was 28.7%. These results were correlated with patient demographics, p16/human papillomavirus (HPV) status and clinical outcome. There was no association between p16/HPV status and the KRAS-variant status (Fisher’s exact test, p=1.0). The KRAS-variant was associated with poor progression-free survival in patients treated with cisplatin+/-cetuximab (log-rank p=0.002) but this association was not observed in docetaxel/bortezomib treated patients (log-rank p=0.89). Conclusions: KRAS-variant is a potentially promising biomarker of poor prognosis and a predictive biomarker of cisplatin resistance in R/M HNSCC. Prospective validation is warranted. Clinical trial information: NCT00003809.
Radiographic extracapsular extension (ECE) and treatment outcomes in locally advanced oropharyngeal carcinoma (OPC).
Authors: Kann Benjamin H. , Buckstein Michael , Carpenter Todd J. , Golchin Ava , Bakst Richard Lorne , Misiukiewicz Krzysztof , Genden Eric Michael , Posner Marshall R. , Kostakoglu Lale , Som Peter M. , Gupta Vishal 
Published: March 2020

6019 Background: Pathologic ECE (pECE) of tumor through lymph node (LN) is a poor prognosticator for OPC and typically diagnosed upon surgical LN removal. At our institution, experienced radiologists routinely identify ECE on pretreatment CT. The prognostic value of radiographic ECE (rECE) is less clear and may prove clinically useful. In this study, we evaluate rECE as an independent prognosticator in OPC. Methods: Retrospective review of 185 patients with locally advanced OPC treated in our department from 2006-2012. 109 patients had accessible pretreatment CT reports clearly stating the presence or absence of rECE. Patients were treated with definitive concurrent chemoradiation therapy (CCRT) (30%), induction chemo then CCRT (47%), or surgery with adjuvant CCRT (14%) or RT (9%). Kaplan-Meier survival analysis compared these cohorts for locoregional control (LRC), distant control (DC), and progression-free (PFS) and overall survival (OS); log-rank tests were performed for significance. Multivariate analysis was conducted via cox-regression. Results: Median follow-up of the 109 patients was 31 months (range: 1-80 months). 61 patients had rECE(+) and 48 had rECE(-) scans. There was no significant difference between the cohorts in terms of median age, stage, treatment type, smoking history, or tumor HPV status. There was a difference in nodal stage with 83% of rECE(+) patients having N2-3 disease versus 67% of rECE(-) patients (p=0.02). On univariate analysis, there were differences between the rECE(-) versus rECE(+) cohorts in OS (4yr: 92% vs 72%, p=0.01), PFS (4yr: 92% vs 62%, p=0.002), and DC (4yr: 98% vs 76%, p=0.006), with no difference in LRC (4yr: 95% vs 91%, p=0.35). On multivariate analysis factoring in age, smoking history, stage, and treatment type, rECE presence was a negative predictor of OS (hazard ratio, 0.26; 95% CI, 0.07 to 0.95) and PFS (hazard ratio, 0.23; 95% CI, 0.06 to 0.81), with DC approaching significance (hazard ratio, 0.13; 95% CI, 0.02 to 1.05). Conclusions: While pECE is an established risk factor for locally advanced OPC, this study suggests that rECE may be an independent poor prognosticator of PFS, OS and DC with potential importance in guiding clinical management.
Phase II study of everolimus and sorafenib for the treatment of metastatic thyroid cancer.
Authors: Sherman Eric Jeffrey , Ho Alan Loh , Fury Matthew G. , Baxi Shrujal S. , Haque Sofia , Lipson Brynna Lane , Kurz Sarah , Fagin James A. , Pfister David G. 
Published: March 2020

6024 Background: Everolimus is an oral inhibitor of the mammalian target of rapamycin (mTOR). Unpublished work from the Fagin lab shows that mTORC1 is also required for the growth promoting effects of the oncoproteins RET/PTC, RAS and BRAF in rat thyroid PCCL3 cells. Further work shows synergy of mTORC inhibitors with RET kinase inhibitors in medullary thyroid cancer cell lines. Sorafenib is an oral kinase inhibitor with in vitro activity against multiple targets, including RAF, RET, VEGFR1, and VEGFR2 that is compendium approved for the treatment of radioactive iodine-refractory (RAIR) and medullary (MTC) thyroid cancer. Methods: The study was a single institution, two-stage phase II design. Primary objective was response rate initiated on 9/21/2010. Eligible patients (pts) had progressive, RAIR/fluorodeoxyglucose (18-F)-avid, recurrent/metastatic, non-anaplastic, thyroid cancer; RECIST measurable disease; and adequate organ/marrow function. Sorafenib was given at 400 mg orally twice a day and Everolimus at 5 mg orally once daily. 41 patients were enrolled; 36 were eligible for the primary endpoint of response and 3 were evaluable for toxicity only at the data cutoff date of 1/10/13. Seventeen patients are still actively on study. Mutational analyses of tissue is ongoing. Results: Of the 41 eligible pts, demographics: female- 44% (18); median age-61 years (35-79). Grade 4-5 adverse events at least possibly related to drug: grade 4- Alanine Aminotransferase Increase (1 pt): grade 4- Hyperglycemia (1 pt): grade 4-Pancreatitis (1 pt). Histology and response data by partial response, confirmed and unconfirmed, (PR), stable disease (SD) and progression of disease (POD) are in the table below. The median time on treatment is 167 days (range 1 to 797 days) at the cutoff date of 1/10/2013. Conclusions: The combination of sorafenib and everolimus shows promising results, especially in the Hurthle cell and medullary subgroups where data from studies at Ohio State have suggested very poor response to sorafenib alone. Clinical trial information: NCT01141309. [Table: see text]