bluuebunny/crossref_metadata_2025_split huggingface dataset:
Increased HER2 expression in women with recurrent ER positive breast cancer
Authors: Kaklamani V. G. , Cicconi J. , Gradishar W. , Willey E. , Diaz L. , Rademaker A. , O'Regan R. 
Published: March 2020

10516 Introduction: Tamoxifen (TAM) remains widely used in the treatment of all stages of breast cancer. Although the majority of hormone receptor (HR) positive tumors respond to TAM, many of these breast cancers will develop resistance resulting in disease recurrence or progression. Over-expression of HER2 appears to play a role in de novo tamoxifen-resistance. We have demonstrated previously that HR-positive breast cancers exposed to selective estrogen receptor modulators (SERMs), such as tamoxifen, in vivo continue to express HR but have an increase in the expression of HER2 (O'Regan Clin Cancer Res 2006). However the above finding has not been confirmed in patient samples. Materials and Methods: We evaluated 30 paired tissue samples from patients with HR positive tumors whose cancers recurred. The first tissue sample is from diagnosis and the paired sample comes from metachronous metastatic disease. Results: The median age of diagnosis was 56 (29–96). Seven patients presented with stage I disease, 11 with stage II and nine with stage III3, and three patients had missing staging information. The median time to recurrence was three years. The expression of ER decreased from diagnosis to recurrence from 79% to 59% (p=0.035). PR also decreased between diagnosis and recurrence from 34% to 22% (p=0.13). HER2 score was 2 or 3 in 27% of samples at diagnosis and in 53% at time of recurrence (p=0.01). These cancers did not have HER2 gene amplification. Conclusions: These results confirm our in vivo findings that over-expression of HER2 plays a significant role in acquired TAM- resistance. We have previously demonstrated that trastuzumab inhibits growth of SERM-resistant breast cancers in vivo despite the fact that these cancers did not have HER2 gene amplification. Taken together, our findings suggest that trastuzumab should be examined clinically in patients with TAM-resistant metastatic breast cancer, as they may be particularly sensitive to inhibition of HER2-driven pathways. No significant financial relationships to disclose.
p63/p73 expression mediates cisplatin sensitivity in a subset of triple-negative primary breast cancer: Implications for a new clinical trial
Authors: Isakoff S. J. , Leong C. , Vidnovic N. , DeYoung M. P. , Sgroi D. , Goss P. E. , Ryan P. D. , Ellisen L. W. 
Published: March 2020

10522 Background: Triple-negative breast cancer (ER-, PgR- and HER2-negative) has a poor prognosis relative to other subtypes, even with the best available chemotherapy. We recently reported that in squamous cell cancers, p63 promotes survival by direct interaction with and inhibition of p73-dependent apoptosis. We now report on the role of p63/p73 in triple-negative breast cancer. Methods: We performed quantitative RT-PCR on primary breast cancer specimens to determine the expression of specific p63 and p73 isoforms. Cell culture experiments used MCF7, HCC-1937, MDA-MB-468, T47D, and MCF10A cell lines. Lentiviral p63 and p73 shRNA were used for knockdown experiments. Chemotherapy dose-response curves were generated using MTT assay. Results: In primary tumors, ΔNp63 and TAp73 isoforms are expressed exclusively within a subset of triple-negative tumors in which p53 mutations are commonly found. Knockdown of p63 in triple-negative cell lines, but not the ER-positive MCF7 line, induced apoptosis which was specifically dependent on p73 expression. Breast cancer cell lines expressing p63/p73 exhibited p73-dependent sensitivity to cisplatin. Knockdown of p73 resulted in a 10–100 fold increase in the IC50 of cisplatin, but no change in doxorubicin or paclitaxel sensitivity. Exogenous p73 expression in MCF10A cells, which have high levels of p63 but no p73, confers increased sensitivity to cisplatin. Conclusion: These results show that p63/p73expression promotes survival in a subset of breast cancers, and they provide a mechanism for cisplatin sensitivity. These findings suggest that p63/p73 expression may serve as a biomarker to predict cisplatin sensitivity in triple-negative breast cancer. Based on these results, we are conducting a phase II study of 39 patients evaluating cisplatin as first line therapy for metastatic triple-negative breast cancer. The primary endpoints are overall objective response rate and response rate in low versus high p63/p73 expressing subgroups. No significant financial relationships to disclose.
FLT3 D835/I836 mutations predict worse disease-free survival (DFS) in younger adults with cytogenetically normal acute myeloid leukemia (CN AML) without FLT3 internal tandem duplications (ITD): A Cancer and Leukemia Group B (CALGB) study
Authors: Whitman S. P. , Ruppert A. S. , Radmacher M. D. , Mrozek K. , Paschka P. , Kolitz J. E. , Larson R. A. , Caligiuri M. A. , Marcucci G. , Bloomfield C. D. 
Published: March 2020

10532 Background: The adverse prognostic impact of FLT3 ITD is well-recognized in younger adults with CN AML, whereas the clinical relevance of D835/I836 mutations in the second tyrosine kinase domain of FLT3 (FLT3 TKD), that occur in 5%-14% of patients (pts), remains controversial. We evaluated the prognostic impact of FLT3 TKD, alone and with other prognostic markers, in 139 de novo CN AML adults, aged <60 years, without FLT3 ITD, and treated on similar CALGB protocols (9621 and 19808). Methods: FLT3 TKD was detected by RT-PCR/EcoRV digestion. Affymetrix U133 plus 2.0 gene expression profiles derived from FLT3 TKD+ and FLT3 wild-type (FLT3 WT) pts with available RNA were compared. Results: Relative to FLT3 WT pts, FLT3 TKD+ pts [n=16 (11.5%)] presented with higher white blood cell counts (WBC) (median: 57.2 v 14.6 × 109/L; P<.001), % bone marrow (BM) blasts (median: 75.5 v 63; P=.001), and % blood blasts (median: 62.5 v 46; P=.03). All 16 FLT3 TKD+ pts achieved complete remission versus 85% of FLT3 WT pts (P=.13). With a median follow-up of 4.6 years, FLT3 TKD+ pts had worse DFS (P=.01; 3-year DFS rates: 31% v 60%) and a trend for worse overall survival (OS) (P=.17, 3-year OS rates: 40% v 65%) compared to FLT3 WT pts. Other variables moderately associated with a worse DFS (P<.10) included higher % BM blasts and NPM1 WT. Adjusting for these two variables, FLT3 TKD remained significantly associated with adverse DFS (P=.02; hazard ratio=2.3). A gene expression signature consisting of 333 probe sets (P<.001) differentiated FLT3 TKD+ (n=9) from FLT3 WT (n=50) pts. Genes represented in this signature include those involved in cell motility (e.g., C3AR1, VNN1, VNN2, ADAM8; all over-expressed in FLT3 TKD+), development (e.g., HOXB5, HOXB6; both over-expressed in FLT3 TKD+) and stress response (e.g., MPO; under-expressed in FLT3 TKD+). Conclusions: FLT3 TKD appears to be an independent predictor for DFS among younger CN AML adult pts without FLT3 ITD. Gene expression profiling provides additional insight into the biology of FLT3 TKD+ AML and may lead to identification of additional targets for improved therapy. No significant financial relationships to disclose.
Clinical implications of the molecular relationship between HER2 and BRCA1
Authors: Ellsworth R. E. , Deyarmin B. , Hooke J. A. , Shriver C. D. 
Published: March 2020

10536 Background: While HER2 status is used prognostically, the effects of HER2 can be influenced by other genes; co- amplification of TOP2A modulates the effectiveness of treatment with Herceptin. BRCA1, deleted in >50% of sporadic breast tumors, is located distal to HER2 on chromosome 17q and is marked by structural instability. To determine how alterations at the BRCA1 locus may modify amplification of HER2, FISH analysis of BRCA1 was performed in breast tumors with HER2 amplification and/or allelic imbalance on chromosome 17q12. Methods: HER2 status (n=68) was determined using the PathVysion HER2 kit. For BRCA1 analysis, DNA probes were generated by nick translation from a BAC clone containing the entire BRCA1 gene in conjunction with a CEP 17 probe. Copy number gains and deletions were defined as BRCA1:CEP17 >1.3 and <0.8, respectively; aneusomy was defined when >10% of tumor cells had copy numbers > (polysomy) or < (monosomy) than two. Results: Amplification of the HER2 gene was detected in 57% of tumors; an additional 16% of tumor were polysomic for chromosome 17q. The remaining 27% of tumors had previously detected allelic imbalance at the 17q12 region. The majority of samples (47%) were characterized by an amplification of HER2 with a downstream deletion of BRCA1, while HER2 and BRCA1 were amplified concomitantly in 21% of tumors, including those with polysomy of 17q. Fifteen percent of samples were monosomic for chromosome 17q; using current clinical scoring criteria, each of those samples were reported as having, despite the altered copy number, negative HER2 status. Levels of overall genomic instability, which were previously measured at 26 chromosomal regions, were significantly higher (P<0.05) in tumors with deletion of BRCA1 compared to those without loss of BRCA1 (38% and 24%, respectively). Conclusions: Alterations, especially deletions, of BRCA1 are highly correlated with copy number changes in HER2. Because deletion of BRCA1 has been associated with overall genomic instability, patients with amplification of HER2 and deletion of BRCA1 may prove unresponsive treatment with Herceptin. Loss of BRCA1 should, therefore, be considered as a genetic modifier to HER2 amplification and the status of BRCA1 should be considered in selecting treatment options for patients with HER2 amplified tumors. No significant financial relationships to disclose.
Genotype and phenotype in hereditary and sporadic breast cancers
Authors: Giorgetti G. , Galizia E. , Bianchi F. , Ferretti C. , Corradini F. , Belvederesi L. , Piccinini G. , Loretelli C. , Santinelli A. , Cellerino R. 
Published: March 2020

10538 Background: BRCA1 protein is involved in distinct DNA-repair processes. Germline mutations in BRCA1 gene confer cancer susceptibility. A frequent mechanism for epigenetic inactivation is hypermethylation of the CpG island in promoters of tumours suppressor genes. BRCA1 promoter hypermethylation has been found in a variable percentage of breast cancers (15–30%). BRCA1-associated breast cancers are usually high-grade, poorly differentiated and stain negative for HER2/neu, oestrogen and progesterone receptors (ER, PgR). Many studies have shown that hereditary BRCA1 and basal-like sporadic breast tumours have a similar phenotype and gene expression signature. Methods: By clinical criteria, 223 patients were selected and, for each patient, the probability to carry a BRCA1 mutation was calculated using the software BRCAPRO and Manchester Score System. All patients were studied by direct sequencing and MLPA of BRCA1 Open Reading Frames (ORFs). Thirty sporadic breast carcinomas, from women undergone surgery for primary invasive breast carcinoma between 1995 and 2001, were selected on the basis of negative staining for ER, PgR and HER2/neu (“BRCA-like”). In these patients, Methylation Specific-PCR and Bisulfite Sequencing on genomic DNA (obtained from sections of paraffin-embedded tissues and modified with sodium bisulfite) were used to assess the methylation pattern of BRCA1 promoter. BRCA1 immunohystochemical analysis (IHC) was performed in all patients. Results: We identified 17 patients with deleterious germline mutations in BRCA1. In “BRCA-like” patients, 13 methylated and 17 unmethylated cases were found by methylation analysis of BRCA1 promoter. The BRCA1 IHC was performed in all available samples ( table 1 ). Conclusions: Hypermethylation of BRCA1 promoter was found in 43% of “BRCA- like” patients. Expression of BRCA1 seems to correlate with hypermethylation of its promoter. Further studies are in progress to better understand the possible role of BRCA1 promoter hypermethylation in sporadic breast cancers. [Table: see text] No significant financial relationships to disclose.
Screening an Irish cohort with colorectal cancer for Lynch Syndrome using immunohistochemistry for mismatch repair proteins
Authors: Power D. G. , Farrell M. P. , Muldoon C. B. , Fitzpatrick E. , Stuart C. , Flannery D. , Kennedy M. J. , Stephens R. B. , Daly P. A. 
Published: March 2020

10547 Background: Large-scale screening for germ-line mutations that lead to the onset of disease in adulthood is possible owing to recent technical advances. The care of those with inherited predisposition to breast and ovarian cancer is now becoming a mainstream component of medical care. It is more difficult to identify those with Lynch Syndrome (LS) as various criteria (Amsterdam and Bethesda) have not proved definitive. An important development is the examination of tumor tissue to detect mismatch repair (MMR) protein loss using immunohistochemical (IHC) techniques. When coupled with family history those at risk of harbouring a mutation for LS can be identified. Once a mutation is identified predictive testing can be offered to family members, risk-reduction measures applied and mortality from colorectal cancer reduced. Methods: Screening for MMR protein expression (MLH1, MSH2, MSH6, PMS2) was planned on all colorectal cancer (CRC) cases using IHC on formalin-fixed tumor tissue from January 1st 2002. Local ethics committee approval was obtained and then written informed-consent from patients. Family history data was gathered from the index case or an appropriate relative. An aliquot of blood was stored from index cases for subsequent genetic screening if indicated by IHC analysis and genetic counseling. Results: 108 cases with CRC (62 male, 46 female, median age 59 years) from a potential total of 612 have been screened for MMR protein expression by a gastrointestinal pathologist and independently validated. Turn-around time for IHC analysis was 9 weeks. 5 patients (4.6%) had loss of MMR proteins, MSH2/MSH6- 2 cases, MSH6 alone- 1 case and MLH1/PMS2- 2 cases. All 5 have opted for genetic counselling and sequencing of relevant genes. Conclusion: These early results in an Irish cohort with CRC showing MMR loss in 4–5% of cases is consistent with other population findings. Microsatellite instability analysis is difficult, expensive and relatively unavailable. IHC, however, is an established technique in pathology departments and can be the cheapest and most reproducible approach to identify LS cases. IHC results along with robust family data can guide the genetic counseling process towards preventing deaths from CRC and other LS-associated cancers. No significant financial relationships to disclose.
The 8.1 ancestral MHC haplotype is strongly associatied with colorectal cancer
Authors: Kocsis J. , Toth K. E. , Madaras B. , Biro A. , Füst G. , Blaskó B. , Pocsai Z. , Ádány R. , Laki J. 
Published: March 2020

10548 Background: The immune system is believed to play an important role in sufficiently or insufficiently inhibiting the multistep process of tumour development. The so-called 8.1 ancestral haplotype (8.1AH) in the main histocompatibility complex is associated with alterations of the immune response characterized by an increase in antibodies, circulating immune complexes and TNF-a, and lack of a complement protein component (C4A). Methods: To study the possible association of the 8.1AH with colorectal cancer the DNA samples of 183 hungarian patients (average age 67.99 ys; 63–74 ys) with colorectal cancer and 129 healthy hungarian controls (average age 66.5 ys; 60–73.5 ys) were genotyped for member alleles of the 8.1 AH: AGER -429C, HSP70–2 -1267G (HSP70–2G), TNF- a -308A (TNF2) and LTA+252G by SSP-PCR and PCR-RFLP. Simultaneous carriage of the four member alleles was considered carriage of the 8.1AH. Results: We found the frequency of the 8.1AH to be significantly higher in patients with colorectal cancer than in healthy controls (19.1% vs. 7%, P=0.002). After adjustment to age and gender individuals carrying the 8.1AH had a 2.81 (1.23–6.22, P=0.011) fold risk to develop colorectal cancer compared with non-carriers of the haplotype. None of the member alleles alone showed association with colorectal cancer (PAGER-429C=0.486; PHSP70–2G=0.898; PTNF2=0.140; PLTA=0.376.) Conclusions: The 8.1AH by the genetically encoded alterations of the immune response may affect the development of colorectal cancer. The frequency of the 8.1AH is 5–10% in Hungary/Central Europe but, for instance, approx. 20–25% in the populations with Celtic origin. Our novel observation might contribute to cancer research and therapy when more information is available on which key components of the altered immune response encoded by the 8.1AH are not effective enough against tumor development. No significant financial relationships to disclose.
Breast cancer survival in carriers of BRCA1 and BRCA2 mutations
Authors: Rennert G. , Bisland S. , Bar Joseph N. , Zhang S. , Rennert H. S. , Barnett-Griness O. , Narod S. A. 
Published: March 2020

10552 Background: The characteristic pathologic features of breast cancers in women with a BRCA1 mutation suggest that women with hereditary breast cancer might have a worse than expected prognosis, but the results of clinical studies have been inconsistent. The current study is a national population-based study of Israeli women aimed at evaluating the impact of the inheritance of a BRCA1 or a BRCA2 mutation on breast cancer prognosis. Methods: All incident cases of invasive breast cancer diagnosed in Israel from January 1, 1987 to December 31, 1988 were identified. Paraffin-embedded tumor blocks or unstained slides and pathology and oncology records were requested for all patients. DNA was extracted from each paraffin block and was analyzed for three founder Jewish mutations in BRCA1 and BRCA2. Of 2,514 diagnosed cases, a pathology sample was retrieved from 1,794 (71.4%) and the medical record was retrieved for 1,545 of these (86.1%). Results: A BRCA1 or BRCA2 mutation was identified in 10% of Ashkenazi women with breast cancer, including 18% of women diagnosed below the age of 50. The adjusted hazard ratio for breast cancer-specific survival was not different for non-carriers and carriers of a BRCA1 (HR = 0.8, 95% CI: 0.5 - 1.3, p = 0.3) or BRCA2 (HR = 1.3, 95% CI: 0.8 - 2.2, p = 0.3) mutation. Among women who were treated with CMF/CAF chemotherapy, BRCA1 carriers experienced better survival than non-carriers (HR = 0.5; 95% CI 0.2–1.2) but the difference did not reach statistical significance (p = 0.1). Tumor size (>2 cm) was a significant predictor of breast cancer specific mortality in non-carriers (HR = 2.8; 95%CI: 2.2 to 3.5) but not in BRCA1 carriers (HR = 1.1; 95% CI 0.5 to 2.8). ER status also did not play a significant predictive role in survival of carriers. Conclusions: Compared to non-carriers, women with breast cancer who carry a founder Jewish mutation in one of the BRCA genes experience similar or possibly even lower breast cancer-specific mortality rate, in spite of a bad profile of prognostic factors. No significant financial relationships to disclose.
MMP1 1G/2G promoter polymorphism and risk of esophageal adenocarcinoma
Authors: Singh S. , Asomaning K. , Kulke M. H. , Zhou W. , Zhai R. , Su L. , Heist R. S. , Lynch T. J. , Christiani D. C. , Liu G. 
Published: March 2020

10555 Background: The 2G allele of the MMP1 -1607 1G/2G promoter polymorphism creates an Ets binding site that leads to increased transcriptional and enzyme activity, particularly in the presence of growth factors and cytokines. This polymorphism has been associated with greater risk of cancer (e.g., renal cell, lung and oral cancers, glioblastomas) and cancer invasiveness (e.g., melanoma, cervical, lung and colorectal cancer). The aim of the current study was to evaluate the role of this MMP 1G/2G polymorphism in the risk of esophageal adenocarcinoma (EA). Methods: We evaluated 323 histologically confirmed EA cases and 464 healthy controls frequency-matched for age and gender. Genotyping of the MMP1 1G/2G promoter polymorphism involved a Taqman approach. All EAs had endoscopic evidence showing that the center of the tumors were located at or above the gastroesophageal junction. Odds Ratios (OR) were calculated using multivariate logistic regression, adjusted for age, gender, smoking status, and body-mass index (BMI) at the age of 18 years (to represent a healthy adult BMI). Results: Genotype frequencies were: 33% (1G/1G), 47% (1G/2G) & 20% (2G/2G) in controls; in cases, 26% (1G/1G), 50% (1G/2G) & 24% (2G/2G). 88% of cases were male. The MMP1 2G/2G and 1G/2G genotypes conferred a greater risk of EA, with adjusted ORs of 1.50 (95%CI=1.0–2.3) and 1.34 (95%CI=0.9–1.9), respectively, when compared with the wildtype 1G/1G genotype. The 2G allele (2G/2G + 1G/2G) conferred an adjusted OR of 1.38 (95%CI=1.0–1.9). By stage, the adjusted ORs for the 2G allele were 1.26 (95%CI=0.8–2.1), 1.45 (95%CI=0.9–2.3), & 1.54 (95%CI=0.9–2.7) for node negative, node-positive, and metastatic disease, respectively. Conclusions: The 2G allele of the MMP1 -1607 1G/2G polymorphism was associated with an increased risk of EA in this analysis. In addition, there was a non-significant trend towards conferring greater risk in the more advanced stages of EA, suggesting a possible role of this polymorphism in the invasiveness of this cancer. No significant financial relationships to disclose.
Application of serum proteomic patterns by ProteinChip SELDI system in diagnosis of gastric cancer
Authors: Lim J. , Cho J. , Paik Y. , Chang Y. , Kim H. 
Published: March 2020

10559 Background: Gastric cancer is one of the most common malignancy in the world and one of the leading causes of cancer related death in Korea. Most treatments for advanced gastric cancer have limited efficacy. So early detection of gastric cancer could have profound impact on the successful treatment. Application of multiple biomarkers may improve the diagnostic prediction to distinguish cancer from non-cancer. ProteinChip Surface-Enhanced Laser Desorption/Ionization Time-of-flight Mass Spectrometry (SELDI-TOF-MS) system is one of the currently used techniques to identify biomarkers for cancers. In this study, we have explored whether the serum proteomic patterns by ProteinChip SELDI system can differentiate gastric cancers from non-cancer cohorts. Methods: We have screened protein profiles of 100 serum samples obtained from 60 gastric cancer patients and 40 healthy individuals. Protein expression profiles were expressed on ProteinChip Array and analyzed by PreoteinChip Reader. Peak intensities were normalized by total ion currency and analyzed by the Biomarker Wizard Software to identify the peaks showing significantly different intensities between normal and cancer groups. Classification analysis and construction of decision trees were done with the Biomarker Pattern Software. Results: SELDI -TOF-MS by averaging 50 laser spots collected at a laser intensity setting of 160, a detector sensitivity of 6, and mean mass range of 30 kDa. Seventeen protein peaks shown significant differences between two groups were chosen to make a protein biomarker pattern. The decision tree which gives the highest discrimination included four peaks at 5,919, 8,583, 10,286, and 13,758 as splitters. The sensitivity and the specificity for classification of with the decision tree giving the highest discrimination were 96.7% (58/60) and 97.5% (39/40), respectively. When the protein biomarker pattern was tested with the blinded test set including 30 gastric cancer patients and 20 healthy individuals and, it yielded a sensitivity of 93.3% (28/30) and a specificity of 90% (18/20). Conclusions: These results suggest that serum-protein profiling pattern by SELDI system may distinguish gastric cancer patients from normal counterparts with relatively high sensitivity and specificity. No significant financial relationships to disclose.