bluuebunny/crossref_metadata_2025_split huggingface dataset:
Framingham risk score after risk-reducing salpingo-oophorectomy in women at risk for hereditary breast ovarian cancer: A controlled observational study
Authors: Michelsen T. M. , Tonstad S. , Dahl A. A. , Pripp A. H. , Tropé C. G. , Dørum A. 
Published: August 2020

11048 Background: Risk-reducing salpingo-oophorectomy (RRSO) effectively prevents ovarian cancer in BRCA mutation carriers and in women at risk for hereditary breast-ovarian cancer. RRSO induces immediate menopause, which may increase the risk of coronary heart disease (CHD). Our aim was to determine CHD risk using Framingham risk score and examine factors associated with this risk in women who had undergone RRSO compared to population-based controls. Methods: A sample of 326 (65% of invited) women who underwent RRSO after genetic counseling from 1980–2005 provided completed questionnaires, physical measures, and blood samples. Controls were 1,630 age-matched controls from the Norwegian Nord-Trøndelag Health Study (HUNT-2) (1995- 97). Results: Mean age in both the RRSO and control groups at survey was 54.4 years. Mean follow-up after surgery was 6.5 years (SD 4.4). The RRSO group had a more favorable CHD risk profile (higher education, more physical activity, less smoking, lower total cholesterol, higher HDL cholesterol, lower systolic blood pressure and lower BMI) and lower Framingham total score compared to controls (p<0.05). In multiple logistic regression analyses RRSO was inversely associated with Framingham 10-year risk ≥5% (Odds Ratio 0.49, 95% CI [0.34, 0.71] p<0.001). Conclusions: In contrast to expectation, women at increased risk of hereditary breast ovarian cancer had a favorable CHD risk profile after RRSO compared to age-matched controls from the general population, and RRSO was associated with lower Framingham risk score. Follow-up time, self-selection of women seeking genetic counseling, changes in lifestyle after surgery and survival bias are possible explanations of this finding. No significant financial relationships to disclose.
Value of preoperative staging of breast cancer patients using computed tomography to detect asymptomatic lung and liver metastasis
Authors: Han W. , Kim H. , Lee J. , Lee K. , Moon H. , Ko E. , Kim E. , Yu J. , Noh D. 
Published: August 2020

1105 Background: Preoperative clinical staging in breast cancer patients is important to determine the most appropriate treatment plans and to predict prognosis for individual patients. Identifying unexpected distant metastases in newly diagnosed breast cancer patients frequently alters initial treatment plans. Routine imaging studies to detect lung or liver metastasis is not indicated in patients with early and operable breast cancer. A recent study showed that routine use of chest radiograph and liver ultrasound does not provide much diagnostic benefit in early breast cancer patients. Methods: We aimed to investigate the value of preoperative computed tomography to detect asymptomatic liver and lung metastasis in breast cancer patients. We performed preoperative CT for 667 breast cancer patients to detect lung and liver metastasis among 1,636 primary breast cancer patients who had been diagnosed and treated between January 2006 and December 2007 at Seoul National University Hospital. Results: CT showed abnormal findings (suspicious of metastasis or indeterminate nodules) in 78 patients (10.5%). Among these, abnormal finding in 13 patients (1.7%) turned out to be true metastatic lesions. There was no CT-detected lung or liver metastasis in patients with T1 tumor and 4 metastases in patients with T2 tumor. There was no CT-detected lung or liver metastasis in patients with negative axillary lymph node metastasis. When patients were classified according to the AJCC staging, CT-detected true metastatic lesions were only present in stage III patients (13 out of 173 patients, 7.5%). The true metastatic lesions in lung or liver were all small sized nodules, ranging from 0.3cm to 1.2cm in largest diameters. In seven patients, the CT-detected metastatic lesions were less than 1cm which is in contrast with the previous studies. Conclusions: Our results demonstrated the lack of usefulness in performing routine CT exams to detect asymptomatic liver and lung metastasis in early breast cancer patients. Staging CT might be useful in stage III patients, since 13 (7.5%) patients were upstaged to stage IV by the use of CT. No significant financial relationships to disclose.
Cell-free circulating DNA as a promising marker of colorectal cancer detection and progression
Authors: Pucciarelli S. , Enzo M. , Agostini M. , Pizzini S. , Del Bianco P. , Lonardi S. , Friso M. , Mescoli C. , Urso E. , Nitti D. 
Published: August 2020

11059 Background: Since the pathologic stage is the most powerful prognostic factor for colorectal cancer (CRC), there is a strong need of non-invasive methods for early detection. Cell-free circulating DNA (cfDNA) released from cancer cells varies in size. It has been suggested that cfDNA (ALU repeats of 115 bp, representative of total DNA; ALU repeats of 247 DNA, representative of tumor DNA) may be associated with presence of tumor. Aim of this study was then to investigate whether the cfDNA may have a role as marker of CRC detection and progression. Methods: cfDNA was extracted from plasma samples from 136 patients with primary CRC at different stages [median age 64 yrs; male/female 78/58; stages I-II, 61; stages III-IV, 75], and from 24 patients with adenomas [median age 67 yrs; male/female 17/7)] and from 55 clean-colon healthy subjects [median age 56 yrs; male/female 13/43). cfDNA was assessed by quantitative real-time PCR (qPCR) of ALU repeats with 2 sets of primers (115 and 247 bp) amplifying different lengths of DNA. The levels of cfDNA (ALU-115, ALU-247) of CRC patients (stages I-II and stages III-IV) were compared with those of healthy subjects and patients with adenoma. Results: The median concentrations of total cfDNA (ALU115) in the plasma samples from patients with stages III-IV and stages I-II CRC, adenoma and normal controls were 52,4, 11.9; 1.9, and 1.7 ng/ml, respectively (p<.0001). The corresponding figures for tumor-related cfDNA (ALU247) were 48.8, 4.7, 2.2, and 0.7 ng/ml, respectively. (p<.0001). With a cut-off of 4.86 ng/ml, total DNA (ALU115) showed a sensitivity of 78.52 (95% CI 70.6–85.1) and a specificity of 86.08 (95% CI 76.4–92.8) in distinguishing patients with CRC from non-CRC [AUC: 0.860 (95% CI 0.81–0,90), p-value=.0001]. With a cut-off of 3.04, cfDNA tumor-related (ALU247) showed a sensitivity of 77.94 (95% CI 70.0–84.6) and a specificity of 82.28 (95% CI 72.1–90.0) in distinguishing patients with CRC from non-CRC [AUC: 0.864 (95% CI 0.81–0,91), p-value=.0001]. Conclusions: Both ALU115 and ALU 247 fragments of circulating cfDNA seem promising non-invasive molecular markers of detection and progression of CRC. The findings of the current study require to be confirmed on larger cohorts of patients with CRC and colonic adenoma. No significant financial relationships to disclose.
Correlation of quantitative total HER2 expression and HER2 homodimers with histopathologic characteristics of breast cancers in the FinHer study
Authors: Huang W. , Weidler J. , Lie Y. , Whitcomb J. , Leinonen M. , Bono P. , Isola J. , Kellokumpu-Lehtinen P. , Bates M. , Joensuu H. 
Published: August 2020

11061 Background: We recently reported that the HERmark assay (Monogram Biosciences) accurately measures continua of total HER2 expression (H2T) and HER2 homodimers (H2D) over a wide (∼3 logs) dynamic range, and that a higher concordance was observed between H2T and HER2 status with more stringent central tests as compared with IHC tests performed locally (Joensuu et al, 2008 SABCS,abstract 2071). H2D/H2T ratio was reported as a marker of activated HER2 and a prognosticator of disease progression in HER2+ patients not treated with trastuzumab in the adjuvant setting (Bates et al, 2008 SABCS,abstract 1074). In this follow-up analysis, H2T, H2D, and H2D/H2T ratio were correlated with histopathologic characteristics of breast cancers in the FinHer study. Methods: The HERmark assay was used to measure H2T and H2D in 899 formalin-fixed, paraffin-embedded FinHer specimens. The results were correlated with histopathologic characteristics of breast cancers in the FinHer study (Joensuu et al, N Engl J Med2006;354), including estrogen receptor/progesterone receptor (ER/PR), tumor grade, tumor size, lymph node metastasis, and stage. Results: Higher H2T and H2D levels correlated with ER/PR negativity and high tumor grade (P<0.0001). 42% (102/244) of ER- and 37% (137/374) of PR- cases were HERmark Positive; while 17% (110/655) of ER+ and 14% (75/524) of PR+ cases were HERmark Positive. 10% (13/136) of grade 1, 18% (65/353) of grade 2, and 35% (131/375) of grade 3 tumors were HERmark Positive. No significant association was found between H2T or H2D and tumor size, lymph node metastasis or stage. ER/PR negative and poorly differentiated cancers had higher H2D/H2T ratios (P=0.013), and H2D/H2T ratios >0.6 were associated with smaller primary tumor diameters at the time of cancer detection (P=0.009). Conclusions: The quantitative H2T measurement confirms the known correlations between HER2 expression and histopathologic characteristics of breast cancer. The novel H2D measurement and H2D/H2T ratio may provide further insights into HER2 activation and better diagnostic tests for targeted HER2 therapy. [Table: see text]
EGFR and KRAS mutation status of lung adenocarcinomas in African Americans
Authors: Reinersman M. , Riely G. J. , Nicastri A. , Soff G. A. , Getinet A. , Schwartz A. G. , Zakowski M. F. , Rusch V. W. , Kris M. G. , Ladanyi M. 
Published: August 2020

11065 Background: The 2004 discovery of the tyrosine kinase inhibitor-sensitizing mutations in the epidermal growth factor receptor (EGFR) represents a major advance in the study and management of non-small cell lung cancer. Conversely, KRAS mutations in these cancers confer resistance to the EGFR tyrosine kinase inhibitors gefitinib and erlotinib. EGFR mutations occur almost exclusively in adenocarcinoma, and are more common in never smokers, women, and people born in East Asian (compared to Whites). No comprehensive studies exist of EGFR and KRAS mutations in lung cancers from African-American patients. Methods: We collected formalin-fixed paraffin-embedded material from 121 resected lung adenocarcinomas from African-American patients for DNA extraction. EGFR exon 19 deletions and exon 21 L858R point mutations were detected by sensitive mutation-specific PCR-based methods. KRAS codon 12 and 13 mutation testing was performed by mass-spectrometry (Sequenom)-based genotyping and direct sequencing. These data were compared to Memorial Sloan-Kettering data for EGFR and KRAS mutations in all resected adenocarcinomas in white patients. Results: EGFR mutations were detected in 23 of 121 cases (19%), while KRAS mutations were found in 21 (17%). Exon 19 deletions accounted for 18 of 23 of the EGFR mutations compared to 5 EGFR L858R mutations. KRAS mutations were primarily the transversion type mutations (17 of 21). When compared to data from Memorial Sloan-Kettering for White patients (81/273, 30%), the 17% rate of KRAS mutations in lung adenocarcinomas from African-Americans was significantly lower (p=0.01). EGFR mutation status was similar between African-Americans and Whites (19% vs 18%, p=0.9) and the proportion of exon 19 deletions and L858R mutations was comparable as well. Conclusions: This is the first large series reporting results of mutation testing in lung adenocarcinoma specimens from African-Americans. African-American patients are less likely than Whites to harbor KRAS mutations in their lung adenocarcinomas. There was no significant difference in the prevalence of EGFR mutations. Since biological characteristics underlie clinical factors, these differences may help explain differences in outcomes comparing African-Americans to other groups. No significant financial relationships to disclose.
Characterization of AZD8931, a potent reversible small molecule inhibitor against epidermal growth factor receptor (EGFR), erythroblastic leukemia viral oncogene homolog 2 (HER2) and 3 (HER3) with a unique and balanced pharmacological profile
Authors: Speake G. , Klinowska T. , Hickinson M. , Marshall G. , Smith P. , Vincent J. , Anderton J. , Gray N. , Smith I. , Ogilvie D. 
Published: August 2020

11072 Background: Successful combined pharmacological inhibition of EGFR, HER2, and HER3 signaling is currently under investigation in the clinic. HERs (erbB receptors including EGFR, erbB2, erbB3, erbB4) undergo various types of alteration and in many cancers HER ligands are produced either by the tumor cells themselves or surrounding stromal cells. These mechanisms of receptor activation all lead to constitutive proliferative and/or survival signaling driven by homo- and/or heterodimerization of the HER family. Characterization of a novel tyrosine kinase inhibitor with a potent and balanced profile against EGFR, HER2 (erbB2), and HER3 (erbB3) has been carried out. Methods: A range of assays has been developed to assess the detailed pharmacology of AZD8931 and understand how the profile of AZD8931 compares with other HER family inhibitors, such as gefitinib and lapatinib. These assays have provided unique insights into the pharmacology of these drugs that result from the varying levels of HER and their associated ligands. Results: Across a number of cell systems, AZD8931 has been shown to be a potent inhibitor of tumor cell growth. This effect is through the ability of AZD8931 to inhibit potently the phosphorylation of EGFR (0.004 μM; 95% CIR: 1.377), HER2 (0.003 μM; 95% CIR: 1.817) and HER3 (0.004 μM; 95% CIR: 1.890) in a balanced manner. Furthermore, when compared to control AZD8931 has significant and dramatic effects on the downstream signaling pathways (pAKT [p=0.002] & pMAK [NS]), apoptotic (M30 [p=0.004]), and proliferative (Ki67 [p<0.0005]) endpoints. The novel agent AZD8931 displays a distinct pharmacological profile compared to both gefitinib and lapatinib. Conclusions: Based on our data as well as published literature, the combined pharmacological inhibition of EGFR, HER2, and HER3 signaling has not yet been tested in the clinic. AZD8931 offers an agent to test the hypothesis that combined inhibition of HER signaling could provide additional clinical benefit in cancer, particularly in the majority of solid tumors that do not overexpress HER2. [Table: see text]
Use of combined biomarkers analysis to predict response to chemotherapy in colorectal cancer: A single-institution feasibility study
Authors: Rodriguez-Pascual J. , Garcia E. , Lopez-Rios F. , Cubillo A. , Diaz-Padilla I. , Hernando O. , Ugidos L. , Calvo I. , Duran I. , Hidalgo M. 
Published: August 2020

11074 Background: Treatment options for patients (pts) with colorectal cancer (CRC) have increased in the last years. However, there are no validated prospective molecular markers in CRC to select which agents are better to treat any individual case. The aim of this study was to determine the feasibility of developing an implementing a biomarker panel to guide treatment selection in this setting. Methods: Colorectal cancer tumors were prospectively analyzed with a predefined set of 11 molecular targets, including: KRas and PI3K mutations, EGFR amplification (FISH), and ERCC-1, TS, TP expression by IHC. Clinical characteristics and response to chemotherapy were registered. To establish the utility of this panel, we determine as congruent-treatment if the panel predict the best treatment in patients with more of 1 chemotherapy line and no-congruent-treatment if do not. Results: A total of 84 patients were studied. Only 6 % required a repeated biopsy to obtain sufficient tumor for marker analysis. In 81 % of patients was feasible to study almost 8/11 targets. There were 29 pts (39%) with KRas mutant CRC; 3 pts with PI3K mutations (4%, all of them with KRas mutation); and 2 patients with EGFR amplification. ERCC-1 was positive in 5/78 (6.4%) and TS was positive in 47%. None of 54 pts had TP positivity. Clinical floow up was available in 66 pts (44 males, median age 59, 93% ECOG 0–1). Nineteen patients had early CRC; 23 with metastatic CRC treated with a first line chemotherapy and 24 with advanced CRC treated with 2 or more prior regimens. In this last group for whom the response to multiple agents is known, the panel predictive the most effective treatment in 14 of 24 cases. Conclusions: This targeted-therapy-panel is feasible to implement and should be explore to predict treatment response to CRC . No significant financial relationships to disclose.
SWOG S0342 and S0536: Expression of EGFR protein and markers of epithelial-mesenchymal transformation (EMT) in cetuximab/chemotherapy-treated non-small cell lung cancer (NSCLC)
Authors: Franklin W. A. , Gandara D. R. , Kim E. S. , Herbst R. S. , Moon J. , Redman M. W. , Olsen C. , Hirsch F. R. , Mack P. , Kelly K. 
Published: August 2020

11076 Background: High EGFR gene copy number is associated with efficacy in NSCLC patients (pts) receiving combined chemotherapy and cetuximab (S0342). EGFR protein is typically overexpressed in tumors with high copy number but no consistent association has yet been demonstrated between EGFR protein expression and outcome in pts treated with chemotherapy plus cetuximab. EMT is associated with aggressive biological behavior and resistance to anti-EGFR TKI therapy in NSCLC. Our objective was to identify any association between EGFR protein and EMT and to correlate findings with pt outcomes from cetuximab/chemotherapy in SWOG trials S0342 (paclitaxel [P]-carboplatin [CB] plus sequential or concurrent cetuximab [CX]) and S0536 (P-CB-CX + bevacizumab). Methods: Paraffin sections were stained by immunoperoxidase methods using monoclonal antibodies against EGFR and the EMT markers vimentin, E-cadherin and Zeb1. Sections were scored on continuous scale ranging from 0–300 based on the H score (sum of % positive at each intensity from 0–3). Results were compared to outcome by Kaplan-Meier plot. Results: 79 samples from S0342 were evaluated for EGFR and EMT markers. 67 samples from S0536 were assessed for EGFR only. Mean EGFR H score was 153 and 137 for S0342 and S0536 respectively. At all cut points tested (scores 0, <100, <300) no association between EGFR H score and response or progression-free survival (PFS) was detected in either trial. There was a trend for overall survival and EGFR level at each cutpoint in S0536 but the results did not achieve statistical significance (15 vs 11 mos, p=0.14; 15 vs 11 mos, p=0.20 and 14 mos vs not reached, p=0.10, respectively). Vimentin (6 positive pts) was associated with a shorter PFS, HR=2.60 (1.10–6.14), p=0.03. ECAD and Vimentin were significantly inversely correlated with one another (Spearman p-value<0.01) Conclusions: EGFR protein level by IHC does not significantly correlate with efficacy parameters in chemotherapy/cetuximab-treated NSCLC pts. Patients with vimentin producing tumors (and possible other EMT markers) had shorter PFS, suggesting possible relative resistance to EGFR blockade from cetuximab. [Table: see text]
Use of serum proteins identified by proteomics to predict prognosis in patients with metastatic renal cell cancer (mRCC) and comparison to the currently used MSKCC survival model
Authors: Vermaat J. , van der Tweel I. , Mehra N. , Sleijfer S. , Engwegen J. Y. , Korse C. M. , Schellens J. H. , Haanen J. B. , Beijnen J. H. , Voest E. E. 
Published: August 2020

11078 Background: In mRCC the Memorial Sloan-Kettering Cancer Center (MSKCC) risk model (Motzer et al.,JCO2002) is widely used for clinical trial design and patient management. To improve this model, we searched for serum proteins associated with overall survival (OS) using proteomics and determined their potential contribution to the composition of better prognostic models. Methods: Sera from 125 mRCC patients, mostly interferon-treated, collected between 2001–2006 in three Dutch Cancer Centers, were screened by SELDI-TOF mass spectrometry (MS). Identified proteins were analyzed for their association with OS by Cox regression analysis and Kaplan-Meier curves. Three proteins were subsequently validated with conventional ELISAs and immunoturbidimetry. Computed Cox PH regression models were individually compared with the Akaike's Information Criteria (AIC). The final model was statistically bootstrapped to strengthen its validity. Results: SELDI-TOF MS successfully detected eleven prognostic proteins associated with OS. The strongest prognostic proteins, apolipoprotein A-II (ApoA2), serum amyloid alpha (SAA), and transthyretin were validated by alternative methods and confirmed for their association with OS (p=7.4×10-9, p=3.2×10-8 and p=0.0002, respectively). Stepwise multivariable Cox regression analysis provided an optimal combination of prognostic factors; ApoA2, SAA, LDH, performance status and number of metastasis sites. Subsequent categorization of patients into three risk groups generated a novel survival model that robustly predicts patient prognosis (AIC=684 and p=5.8×10-15) with increased accuracy compared to the MSKCC model (AIC=719, p=2.0×10-7). Bootstrapping our model resulted in an optimism correction of 0.04 (R2=0.45). Initiating systemic therapy according to novel proposed model instead of the MSKCC model would result in a change of treatment in 14% of the patients. Conclusions: Using proteomics, serum proteins associated with OS in mRCC patients can be identified. Incorporating some of these factors together with traditional risk factors yields a prognostic model outperforming the MSKCC risk model thereby further improving patients’ management. No significant financial relationships to disclose.
Effect of pattern of lymphocyte infiltration in NSCLC on outcome
Authors: O'Callaghan D. , Rexhepaj E. , Gately K. , Gallagher W. M. , Delaney D. , Kay E. , O'Byrne K. 
Published: August 2020

11079 Background: The role played by the immune system in determining survival in non-small-cell lung cancer (NSCLC) is unclear. The aim of this study was to investigate the prognostic significance of T-lymphocyte infiltration in NSCLC focusing on CD3+, cytotoxic CD8+ and FOXP3+ T regulatory (Treg) cells. Methods: Immunohistochemistry was used to detect CD3+, CD8+ and FOXP3+ lymphocytes in the tumor islets and tumor stroma in 186 patients with surgically resected NSCLC with a minimum follow-up of 3 years. Quantification of immune infiltration was performed using the Aperio automated image analysis system incorporating the Genie software tool. The median of tumor:stroma CD3+, CD8+ and FOXP3+ infiltration ratios were used as thresholds to dichotomise patients to either high or low infiltration rates. Prognostic variables were identified using univariate and Cox multivariate analysis. Kaplan-Meier analysis and the log-rank test were used to illustrate differences in overall survival. Results: Patients with a higher intratumoral CD3+ and CD8+ lymphocyte infiltration ratio had significantly better survival compared to those with a low tumour/stroma infiltration ratio (p=0.023 & <0.001 respectively). Conversely high intratumoral T-regulatory FOXP3+ positive lymphocyte infiltration rates were associated with a particularly poor prognosis independent of surgical stage (p<0.001). Conclusions: Microlocalization of infiltrating T-lymphocytes, in particular Treg cells, is a powerful predictor of outcome for surgically resected NSCLC and compares favourably with recently published prognostic genomic approaches. Assessment of inflammatory cell infiltrates may help determine which patients should receive adjuvant chemotherapy and, in the future, in predicting benefit from novel adjuvant vaccine/immunotherapies. No significant financial relationships to disclose.