bluuebunny/crossref_metadata_2025_split huggingface dataset:
The functional MDM2 SNP309 polymorphism is associated with an earlier age of diagnosis in women with lung cancer
Authors: Sun S. , Xie X. , Schiller J. H. , Minna J. D. , Tomlinson G. 
Published: March 2020

10550 Background: MDM2 protein is a key negative regulator of p53 protein by targeting its destruction through the ubiquitin pathway. A single nucleotide polymorphism (SNP309 T→G) has been identified in the promoter of the MDM2 gene which results in higher levels of MDM2 protein, attenuation of the p53 pathway, and enhanced tumorigenesis. Estrogen signaling has also been shown to upregulate MDM2 expression. Recent studies have suggested that the MDM2 SNP309 polymorphism is associated with earlier age of onset of certain cancers, particularly in women. The purpose of this study was to determine whether the MDM2 SNP309 polymorphism is associated with lung cancer risk in a gender specific manner. Methods: MDM2 genotype analysis was performed on a cohort of 115 consecutive Caucasian patients with histologically confirmed lung cancer using a PCR-based nucleotide polymorphism discrimination test. Allele status was described as homozygous wild-type (TT), homozygous variant (GG) and heterozygous variant/wild-type (TG). Results: In total, 46 female and 69 male lung cancer patients were screened for the MDM2 SNP309 polymorphism ( Table 1 ). Females with the GG genotype were diagnosed at a significantly earlier age as compared to females with the TT genotype (p=0.038), while a similar comparison for males showed no significant difference. A trend towards an earlier age of onset in females as compared to males with the GG genotype was observed, although the sample size was small and this was not significant (p=0.47). Conclusions: In this study, we found that women, but not men, with the MDM2 SNP309 GG genotype were particularly susceptible to the development of lung cancer at an earlier age, supporting the hypothesis that the expression of this polymorphism is gender-specific and possibly regulated by estrogen. Women with the MDM2 polymorphism represent a potential high-risk group for the focus of lung cancer screening and chemoprevention efforts with anti-estrogen therapy. [Table: see text] No significant financial relationships to disclose.
The utility of an investigational real-time RT-PCR assay system for the detection of micrometastases in sentinel lymph nodes of breast cancer confirmed by 0.2 mm histological interval analysis
Authors: Kurozumi M. , Kobayashi Y. , Takei H. , Kitsugi K. , Ueno M. , Nishiguchi R. , Green G. , Vargo J. 
Published: March 2020

10560 Background: Comparison between real-time RT-PCR and histological analysis for the detection of lymph node metastasis in breast cancer patients is difficult because of the necessary use of different tissue for the two tests. In order to minimize this challenge this study used histology sections taken every 0.2 mm and all tissue between the sections was analyzed by real-time RT-PCR. Methods: 129 Lymph nodes (LNs) were obtained by Sentinel LN biopsy and/or axillary dissection from 80 breast cancer patients. All LNs were cut in half. One half of each LN was used for the routine intra-operative diagnosis. The other half was used for the 0.2mm histological interval analysis. All 10μm sections cut for histology at 0.2 mm intervals were analyzed using frozen section H&E under a light microscope. All remaining tissue between the sections used for histological analysis was assayed by real-time RT-PCR using the genetic markers mammaglobin and cytokeratin-19 (investigational GeneSearch Breast Lymph Node Assay, Veridex, LLC, Warren, NJ, USA). Cutoffs were pre- set for the real-time RT-PCR to detect only metastasis greater than 0.2 mm. Results: Compared to the histological diagnosis using 0.2 mm interval frozen sections, the real-time RT-PCR results were as follows; sensitivity of 100.0% (34/34), specificity of 93.7% (89/95) and overall accuracy of 95.3% (123/129). Conclusions: These data suggest by utilizing the 0.2 mm histological interval analysis, sampling discrepancies are minimized and a high level of sensitivity and overall accuracy is seen for the real-time RT-PCR assay. Assay specificity calculations may be less than 100% due to interpretation challenges in frozen section histology, especially in the cases of smaller metastases and/or lobular cancer, causing a small percentage of clinically relevant metastasis to be missed. [Table: see text]
Investigation of tumor biomarkers as response predictors in a monotherapy study with lapatinib (L) as a first line treatment in ErbB2 amplified women with breast cancer
Authors: Gomez H. L. , Chavez M. A. , Doval D. C. , Franco S. , Arbushites M. , Berger M. S. , Casey M. A. , Stein S. , Zaks T. , Martin A. M. 
Published: March 2020

10562 Background: Lapatinib is a potent inhibitor of both EGFR and HER2 tyrosine kinase activity. Results of the phase II trial EGF20009 in advanced or metastatic breast cancer (MBC) indicated an overall response rate of 24% to monotherapy L as first line (1L) treatment in 138 patients. In an effort to better define predictive biomarkers of response, we evaluated correlations between baseline tumor biomarker expression levels and clinical response to L. Methods: Response rate (RR) was defined as either complete response (CR) or partial response (PR). Tumor blocks were available on 118 patients from the time of most recent biopsy, and mRNA was extracted from 65 individual patient blocks for this preliminary analysis. Using qRT-PCR Taqman analysis, tumors were evaluated for expression of ERBB1- 4, PTEN, c-MYC, as well as two comparator genes for normalization. DecisionTree analysis using SpotFire software was performed to determine the genes most significantly associated with RR. Results: For the initial 65 patient samples analyzed, an elevation of ERBB2 expression was significantly associated with response to treatment with L (p=0.02) and a longer time to progression following treatment with L (p<0.0025). Furthermore, of the 17/65 responders in this preliminary study, SpotFire Decision Tree Analysis demonstrated that 16/17 (94%) who responded to L had a gene expression signature combining ERBB1, 2, and 3, which is currently being confirmed. No association was observed with ERBB4, PTEN and c-MYC in this preliminary analysis. Conclusion: This analysis suggests a correlation between elevated ERBB2 mRNA levels and both RR and TTP in patients treated with L as a 1L treatment. Analysis of the full set of samples (including genome-wide microarray analysis) is ongoing in an effort to determine biomarkers predictive of clinical activity beyond HER2. No significant financial relationships to disclose.
Insulin-like growth factor-1 receptor expression in invasive ductal breast carcinoma is related to tumor characteristics and prognosis
Authors: Hartog H. , Van der Vegt B. , Van der Graaf W. T. , Boezen H. M. , De Bock G. H. , Wesseling J. 
Published: March 2020

10563 Background: The role of the insulin-like growth factor-1 receptor (IGF-1R) in the outcome of breast cancer is poorly understood. Therefore, we analyzed the prognostic value of IGF-1R expression in relation to clinically relevant tumor characteristics. Methods: Expression of IGF-1R, insulin receptor, estrogen receptor (ER), progesterone receptor (PR), HER2 receptor, epidermal growth factor receptor and phosphorylated Akt (pAkt) was determined on tissue microarrays comprising primary invasive ductal breast carcinoma samples of a consecutive series of 221 patients. Patients presented at the University Medical Center Groningen between 1996 and 2001. Patient records were reviewed for clinical and tumor parameters. Cytoplasmic and membranous IGF-1R staining were scored separately, as the relevance of IGF-1R cellular localization is yet unknown. Associations were tested by Chi-square, Log Rank test and Cox regression analysis. Results: Overall, IGF-1R expression was present in 79% of the tumors. Cytoplasmic staining was present in 69%, membranous in 52%, staining was combined cytoplasmic and membranous in 42% of the tumors. Cytoplasmic, but not membranous, IGF-1R staining was associated with expression of ER (p<0.001), PR (p=0.001), pAkt (p=0.04), and increased relapse free and overall survival (RFS, p=0.01; OS, p=0.006). No correlations with other parameters were found. In ER/PR positive, HER2 negative tumors, but not in HER2 positive tumors, cytoplasmic IGF-1R expression correlated with increased RFS (p=0.002) and OS (p=0.001). In contrast, in triple negative tumors cytoplasmic and membranous expression of IGF-1R were both significantly associated with shorter RFS (p=0.02, p=0.04, resp.). In multivariate analysis, cytoplasmic IGF-1R expression was an independent prognostic factor for OS (HR 0.3, 95% CI 0.1–0.9, p=0.035). Conclusions: Cytoplasmic IGF-1R expression in invasive ductal breast carcinoma is associated with hormone receptor expression, phosphorylated Akt and good prognosis. Surprisingly, triple negative tumors expressing IGF-1R have a worse prognosis than those without. These results suggest that IGF-1R targeted therapy may have additional value in the treatment of triple negative tumors. No significant financial relationships to disclose.
Adrenomedullin and its receptors expression in renal tumors
Authors: Deville J. , Salas S. , Bartoli C. , Dupuis C. , Duffaud F. , Sebahoun G. , Figarella-Branger D. , Ouafik L. , Martin P. , Daniel L. 
Published: March 2020

10568 Background: Adrenomedullin (AM) is a 52 amino acid peptide that has an important role on tumor cell proliferation and neoangiogenesis through its receptors CRLR/RAMP2 and CRLR/RAMP3. AM gene expression is stimulated by Hypoxia Inductible Factor-1 (HIF- 1) and 60–80% of the human conventional renal carcinomas (cRCC) display mutations in the tumor suppressor protein von Hippel-Lindau, which leads to constitutively elevated HIF-1. Methods: Tumors and non-malignant kidney tissues were obtained from patients who underwent unilateral nephrectomy. We studied VEGFA, AM and its receptors expression by quantitative RT-PCR in 62 frozen renal tumors including: 40 cRCC; 5 cRCC metastasis; 5 chromophobe carcinomas; 5 Papillary carcinomas; 2 oncocytomas; 2 collecting duct carcinomas; 2 normal adjacent renal tissue; 1 unclassified renal tumor. AM and AM-receptors expression was studied in 42 paraffin-embedded renal tumors by immunohistochemistry using rabbit anti-AM, anti-CRLR, anti-RAMP2 and anti-RAMP3 polyclonal antibodies. Effects of these anti AM or anti AM- receptors antibodies on cell proliferation were examined in vitro on BIZ cell line (cRCC cells). Results: VEGFA, AM and AM-receptors genes were overexpressed in cRCC compared to other renal tumors (Except AM gene in chromophobe carcinoma). Their expressions were independent of classical prognostic factors (such as Fuhrman Grade and pT status). In cRCC, there was a strong positive correlation between VEGF-A gene expression and AM (r=0.7; p=0.01) and AM-receptors genes expressions (RAMP2 r=0.61; p= 0.01 and RAMP3 r=0.58; p= 0.01). Immunohistochemistry confirmed a tumor expression of CRLR, RAMP2 and AM in more than 80% cRCC. RAMP3 was expressed by inflammatory cells but not by tumoral cells. The cell proliferation assay showed a significant inhibition of BIZ cell proliferation by AM antibody or AM-receptors antibodies. Conclusion: AM and its receptor CRLR/RAMP2 are overexpressed in cRCC. In vitro cell proliferation assay results support that AM inhibition may suppress cRCC growth, independently of potential antiangiogenic effects. Further studies on animal models are needed but AM pathway may be a potential therapeutic target in cRCC. No significant financial relationships to disclose.
Outcome prediction to cetuximab in advanced colorectal cancer: Analysis of EGFR and HER2 gene copy number by fluorescence in situ hybridization
Authors: Personeni N. , De Hertogh G. , Störkel S. , Debiec-Rychter M. , Geboes K. , De Roock W. , Humblet Y. , Piessevaux H. , Van Cutsem E. , Tejpar S. 
Published: March 2020

10569 Background: Recent studies suggest that increased epidermal growth factor receptor (EGFR) gene copy number assessed by in situ hybridization predicts response to cetuximab in patients (pts) with advanced colorectal cancer (mCRC). Additionally, preclinical data indicate that HER2, a member of the EGFR family, can modulate the efficacy of anti-EGFR monoclonal antibodies. Methods: We assessed EGFR and HER2 gene copies by fluorescent in situ hybridization (FISH) on paraffin-embedded samples from 70 pts with mCRC treated with cetuximab alone or with irinotecan. FISH was assessed either on primary tumors (55 pts) or on metastases (15 pts) according to two parameters: the absolute copy number of genes and chromosome (chr) centromeres, and their frequencies in 100 tumor cells. A sensitivity analysis was performed and fitted to outcome data in an attempt to define relevant cutoffs. EGFR protein expression by immunohistochemistry was deemed positive with =10% tumor cells being stained. Multiple paired samples originating from different tumor sources were analyzed whenever available (27 pts). Results: The overall response rate was 25%. Prevalent FISH patterns were disomy (8%) and balanced polysomy (90%) for EGFR gene and chr 7. EGFR amplification was seen in two pts (2%), of which only one responded. HER2 amplification was seen in two of 54 pts (3%), both experiencing stable disease. Average EGFR copies and frequency of tumor cells with >2 copies respectively ranged from 1.6 to 4.0 and from 10% to 90%, thus reflecting a substantial tumor heterogeneity. Despite assessing multiple centile cutoffs of gene copy numbers and their frequencies in tumor cells, we found no association between EGFR and HER2 copy numbers and objective response, time to progression, and overall survival. Analysis of paired samples did not improve the predictive value of EGFR copies by FISH. Excluding EGFR amplification, associated to a strong (3+) EGFR staining, we found no correlation between EGFR copy number and protein expression. Conclusions: Neither EGFR nor HER2 copies by FISH, nor EGFR expression, are predictors of outcome in mCRC pts treated with cetuximab. FISH might still play a role in screening EGFR and HER2 amplification, but cost-effectiveness is debatable. [Table: see text]
The combination of the HER2 antibody trastuzumab, the EGFR tyrosine kinase inhibitor gefitinib, and docetaxel as first-line therapy in patients with HER2 overexpressing stage IV breast carcinoma
Authors: Somlo G. , Koczywas M. , Luu T. , McNamara M. , Bedell V. , Slovak M. L. , Wilczynski S. , Morgan R. , Russell C. , Frankel P. 
Published: March 2020

1057 Background: Interference with both HER2 and epidermal growth factor (EGFR) dependent pathways may improve therapeutic efficacy of docetaxel (doc) in pts with HER2 overexpressing (+) BC. Methods: Patients (pts) without prior chemotherapy (Rx) exposure for stage IV HER-2 + BC were enrolled. Prior hormonal or adjuvant Rx inclusive of taxane or trastuzumab (tras) were allowed. A left ventricular ejection fraction of > 45% and ECOG performance status of ≥ 2 were required. Pts were to receive doc 75 m2, tras every 3 weeks, and gefitinib (gef) 250 mg daily. BC samples from 12 pts were analyzed by FISH for HER2 and EGFR amplification (amp), and topoisomerase II (topo II) amp or loss. IHC was to be performed to examine p-Src, p-STAT3, Ki67 and survivin expression. Results: The median age was 49 (range, 34–67) and ECOG performance status 0.5 (0–1). The first 9 patients received gef 250 mg daily; 2 pts received dox 75 mg/m2 and developed grade 3 febrile neutropenia (neu), hence, additional pts received doc at 60 mg/m2: 3 more episodes of grade 3 neu were seen. Gef was held due to grade 3 dermatitis (2 pts) and diarrhea (2 pts). Pts received a median of 6 cycles (3–10). Gef schedule then was changed, and was prescribed on days 2–14, only. Three of the next 9 pts experienced grades 3 or 4 neu, and we observed 3 cases of grade 3 gastrointestinal toxicities; pts were able to receive 11 + (range; 5–25+) cycles on this schedule (p<0.04). There were 4 complete (CR)and 6 partial R (23 % CR, 59 % overall R), and 3 pts had stable disease (SD; all R and SD confirmed); 3 pts progressed at 4, 4, and 5 mos, 1 pt was inevaluable. The median time to progression is 12 + mos. Samples from 3 pts revealed topo II amplification and one pt sample showed loss of one topo II allele; none were amplified for EGFR. Outcome will be correlated with IHC defined signal trasduction status and proliferation rates. Conclusions: The combination of doc, tras, and short course of gef is feasible, with encouraging R and SD rates and time to progression. Further exploration of simultaneous blockage of multiple signal transduction pathways is indicated in combination with chemoRx. Supported by NCI CA33572 and by a grant from AstraZeneca. No significant financial relationships to disclose.
Pathological response rates in 710 operable breast cancer (BC) patients treated by neoadjuvant chemotherapy (NCT), according to immunohistochemichal subtypes of tumours
Authors: Chollet P. J. , Abrial C. , Tacca O. , Raoelfils I. , Leheurteur M. , Mouret-Reynier M. , Amat S. , Durando X. , Dauplat J. , Penault-Llorca F. 
Published: March 2020

10579 Background: Pathological responses rates were studied in 710 women with stage II-III operable BC treated between 1982 and 2004. A pathological review was conducted to assess the residual disease in breast and nodes according to Chevallier's classification (Am J Clin Oncol 1993) and patients repartited according to 3 tumour phenotypes: Her2+ (Her2+ phenotype), Her2-HR+ (Hormonal Receptor; luminal phenotype) and Her2-HR- (triple negative phenotype). Methods: Median diameter of the invasive tumour was 40 mm [10–130]. 555 (78%) patients had a canalar, 90 (13%) a lobular, 18 (2.5%) a mixed or invasive carcinoma, 36 (5%) neoplasic cells only and 11 (1.5%) another carcinoma. 25.6% of the tumours were grade III SBR. The median number of NCT courses was 6 [1–9] followed by a surgery for 92%, a radiotherapy for 95%, an adjuvant chemotherapy for 17% and/or an hormonotherapy for 52%. A breast evaluation was realized before, during and after NCT. Results: Overall response rate was 68% (16% complete). The complete pathological response (pCR) rate was 14.2% according to Chevallier's classification. On 656 patients operated, 470 (72%) had a conservative surgery. On 520 patients with an axillary dissection, 272 (52.3%) had involved nodes. After a median follow-up of 93 months, Disease-Free Survival (DFS) and Overall Survival (OS) at 120 months were 54.9% and 66.5%, respectively. According to tumour's phenotype, the pCR rate (Chevallier's classes 1+2) was: 24.5% in Her2+ phenotype, 14.8% in triple negative phenotype and 4.4% in luminal phenotype. These results showed that: -the pCR was three-fold more frequent in Her-2+ phenotype than in luminal one (p = 3.5.10-5) -the pCR was two-fold more frequent in triple negative phenotype than in luminal one (p = 3.10-3) -no significant pCR difference was found between Her2+ phenotype and triple negative one Furthermore, a significantly better DFS was found for luminal phenotype; DFS was intermediate for triple negative phenotype, and lower for Her2+ phenotype. Conclusions: The pCR rates were higher in Her2+ phenotype and in triple negative one. It is important to note that, in this series, most Her2+ patients did not receive any Herceptin treatment. No significant financial relationships to disclose.
The role of BRCA1 in DNA repair and chemosensitivity
Authors: Sharma V. B. , Kurian A. W. , Feldman A. , Ford J. M. 
Published: March 2020

10606 Introduction: The BRCA1 tumor suppressor protein has been implicated in many cellular processes, including several different DNA repair pathways. Inherited mutations in the BRCA1 gene result in an increased risk for developing breast and ovarian cancer. BRCA1 associated tumors are frequently estrogen receptor negative thus rendering them ineffective targets of hormonal manipulations. Therefore chemotherapy is the only treatment option available to patients with metastatic disease. Methods: Global genomic repair activity was detected by an immunoslotblot assay. UV-C and chemosensitivity was determined by the MTT assay. The comet assay was used to measure oxidative DNA damage (ODD). Results: Brca1 deficient cells demonstrate decreased global genomic repair independent of p53 expression. These cells are 3-fold more sensitive to UV-C radiation, 5-fold more sensitive to cisplatin, and 25-fold more sensitive to gemcitabine than Brca1 positive cells. The combination of cisplatin and gemcitabine is synergistic. This synergy is independent of Brca1 protein expression. In addition, the cholesterol lowering drug lovastatin is able mitigate the ODD caused by hydrogen peroxide. Reduced ODD is also observed in breast epithelial cells from high risk patients after 6 months of oral lovastatin use. Discussion: These results confirm our earlier findings that BRCA1 is involved in the nucleotide excision repair pathway. In addition, we demonstrate that this effect is independent of p53 expression. We also find that Brca1 deficient MMECs are more sensitive to UV-C, and the cytotoxic drugs cisplatin and gemcitabine. Cisplatin is known to cause DNA intra- and inter-strand crosslinks whereas gemcitabine is a nucleoside analog. The increased sensitivity of Brca1 deficient MMEC's to these agents supports the role of Brca1 in the different molecular pathways involved in their repair. In addition, we demonstrate that lovastatin can overcome ODD in vitro and in vivo and may be an effective agent to modify breast cancer risk for individuals at increased risk. No significant financial relationships to disclose.