bluuebunny/crossref_metadata_2025_split huggingface dataset:
Gene expression profiling can predict pathological complete response (pCR) to anthracycline-based therapy in estrogen- receptor (ER) negative breast cancer (BC) patients
Authors: Desmedt C. , André F. , Azambuja E. , Haibe-Kains B. , Larsimont D. , D'Hondt V. , Di Leo A. , Piccart M. , Pusztai L. , Sotiriou C. 
Published: March 2020

10564 Background: Breast cancers show variable sensitivity to anthracycline (A)-based therapy. Here we aimed to identify gene expression profiles associated with pCR to this treatment. As it has repeatedly and consistently been shown that ER is the most dominant factor influencing the molecular composition of breast cancer, defining different types of BC disease and because we wanted to eliminate the confounding effect of indirect ovarian suppression in ER+ BC, we focused in this study on ER-negative patients only. Methods: We analyzed Affymetrix gene expression profiles generated from 132 ER- pre-treatment samples, constituting the largest series of ER- preoperatively A-treated BC (n=132/35 pCR). Sixty-two samples derived from the prospective multicentric TOP trial (epirubicin single-agent), 41 from Institut G. Roussy (retrospective selection/ FEC) and 27 from MD Anderson (prospective study/ FAC). Results: A student t- test analysis on the combined population of A-treated pts was performed identifying 102 genes that were significantly associated with pCR (p<.01). These genes were mainly involved in cell death, DNA replication and recombination, molecular transport, cell cycle and morphology. Interestingly, 14 of these genes were located on the topoIIa amplicon. Of interest, none of these 14 genes seem to carry any prognostic value in untreated ER- pts (N=161). When we considered gene expression indices for specific A-targets such as topoIIa and helicase, we found that both were associated with pCR. However, subgroup analysis revealed that topoIIa index was predictive in ERBB2+ but not in ERBB2- subgroup. None of the genes from the adriamycin predictor (Potti et al.) or the p53 signature (Miller et al.) were significantly associated with pCR. Conclusions: This study suggests that a group of genes associated with topoIIa can identify ER-negative BC pts likely to respond to A-based therapy. These promising results are currently being validated in a larger series. No significant financial relationships to disclose.
Prospective phase II study of neo-adjuvant doxorubicin followed by cisplatin /docetaxel in locally advanced breast cancer—5 years of follow up
Authors: Ajarim D. S. , Rahal M. , Al-Sayed A. , Alshabana M. , Tulbah A. , AlMalik O. , El-Husseiny G. , Ezzat A. , Al-Tweigeri T. 
Published: March 2020

10574 Background: Neoadjuvant (primary) chemotherapy as part of multimodality treatment is increasingly used as standard of care for patients (pts) with locally advanced breast cancer and firmly established. We conducted a prospective study using doxorubicin 75 mg/m2 q 3 weeks × 3 cycles followed sequentially by docetaxel 75 mg /m2 and cisplatin 75 mg/m2 q 3 weeks × 3cycles. All pts had definitive surgery followed by radiation therapy, ± tamoxifen. Primary end points were pathologic complete response (pCR), secondary endpoints were, safety, rate of conservative surgery and overall survival. Material: Eligible pts included biopsy proven invasive breast cancer, T2-T4 (primary = 4–10 cm) N0-N2, M0. 59 of 60 enrolled pts completed treatment one patient refused surgery after the completion of 6 cycles of chemotherapy were excluded from the analysis, median age:41yrs (24- 60), Premenopausal: 68%, median tumor size: 6.0cm (4 - 10), Stage IIB:32% and IIIA / IIIB: 68%, both ER / PR positive: 53%, Her2/neu (3+) by IHC staining and /or Fish positive: 29%. All patients had negative metastatic workup. Results: 59 pts are evaluable for analysis: clinical complete response was seen in: 44%, clinical partial response in: 56 %. Breast conserving surgery was performed in: 44 %, and MRM in: 56%. Pathological complete response (pCR) in the breast was: 31 %, in axilla were: 37 %. Grade3–4 Toxicities: Febrile Neutropenia: (13%), Nausea vomiting: (12%), Mucositis: (10%), weakness/asthenia/weight loss: 12%. Overall at follow up of 60 months the DFS & OS (67% and 74%).Patients who achieved complete pathologic response in breast and/or axilla the DFS and OS were (91%), 13 patients relapsed 46% were Her2 positive. Conclusion: Sequential combination of doxorubicin followed by docetaxel/cisplatin is a safe, feasible and active combination, that offer the possibility of conservative surgery and associated with high clinical and pathologic response, further investigation of this combinations are warranted. No significant financial relationships to disclose.
Breast cancer growth rates in BRCA1/2 mutation carriers
Authors: Bosse K. , Goβmann A. , Rhiem K. , Warm M. , Schmutzler R. K. 
Published: March 2020

10575 Background: 1. Recent investigations suggest an accelerated growth rate in BRCA1/2-associated breast cancer. 2. This characteristic may have influence on screening policy. Patients and Methods: BRCA1/2 mutation carriers are regularly observed in a structured surveillance program that comprises annual mammography and MRI-scan in addition to sonography undertaken every six months. We performed a prospective study in approx. 2035 women participating in a breast cancer screening program from 01/1997 until 12/2006. In 9 carriers 10 BRCA-associated breast cancer cases were diagnosed of whom at least one previous examination was available. A calculation of the tumor volume doubling time was performed according to the following algorithm: VDT= log2 × (t2-t1)/logm2 - logm1 (VDT= Volume doubling time; t1 and t2 at the beginning and at the end of the observation period; m1 and m2 size of the tumor at point in time t1 and t2). Results: The 10 cases shown in table 1 prove both high growth rates with VDTs measuring on average 48 days and benign morphologic criteria in early stage disease by all 3 imaging procedures. The VDT for BRCA1-associated tumors was in average 42 days, while the single BRCA2 associated case had a VDT of 102 days. Conclusions: Our data demonstrate a short VDT of 48 days in BRCA1/2 mutation carriers. This is in line with another observational study which identified a tumor doubling time of 45 days for familial tumors in comparison to sporadic tumors with 82 days (Tilanus-Linthorst et al., 2005). These data underline the necessity for a closely meshed screening interval of 6 months. Lit: Tilanus- Linthorst et al., Eur J Cancer. 2005. Jul.41(11):1610–17 [Table: see text] No significant financial relationships to disclose.
High prognostic potential of glioblastoma stem cell analysis
Authors: Banna G. L. , Pallini R. , Ricci-Vitiani L. , Signore M. , Lombardi D. , Martini M. , Maira G. , Giuffrida D. , Larocca L. M. , De Maria R. 
Published: March 2020

10580 Background: Cancer stem cells (CSCs) are a rare cell population responsible for tumor development and maintenance. Recent studies have shown that glioblastoma stem cells express the CD133 marker and are resistant to radiotherapy and chemotherapy. However, clinical data based on the study of CSCs in patients with glioblastoma are not available yet. Methods: Glioblastoma samples from 44 patients treated with complete or partial tumorectomy, followed by radiotherapy and temozolomide were prospectively analyzed. Immunohistochemistry was performed to evaluate the prognostic value of the number of CD133+ cells present in tumors. Moreover, the relationship between the ability to generate long-term culture of tumorigenic cells in vitro and the clinical outcome of glioblastoma patients was tested. Results: CD133 expression did not show an overall prognostic value. CSC cultures were obtained from 14 of the 44 tumors (32%). The generation of CSCs emerged as significant independent prognostic factor by the Cox multivariate analyses, with an adjusted hazard ratio of 2.50 (95% CI, 1.04 to 6.06; P=0.004). The median overall survival among patients with tumors generating CSCs was 8.0 months (95% CI, 4.0 to 11.5), as compared with 15 months (95% CI, 11.0 to 19.0) among those without generation of CSCs (P=0.0002). The median progression-free survival was 3.5 months (95% CI, 2.0 to 6.0) for glioblastoma generating CSCs and 9.0 months (95% CI, 7.0 to 12.0) for glioblastoma not generating CSCs (P=0.0001). A higher CD133 expression significantly associated with tumors generating CSCs (P=0.006), and correlated with a higher risk of death in patients with tumors generating CSCs in vitro (hazard ratio of 1.65, 95% CI, 1.05 to 2.60; P=0.0285). Conclusions: Generation of long-term culture of tumorigenic CSCs in vitro from glioblastoma predicts a poor clinical outcome for patients, in terms of both overall and progression-free survival. In tumors generating CSCs, CD133 expression may have a prognostic value. No significant financial relationships to disclose.
Can we identify a group of breast cancer patients with a good prognosis despite four or more positive (4+) axillary nodes using a tissue microarray (TMA)?
Authors: Crabb S. J. , Bajdik C. D. , Speers C. H. , Huntsman D. G. , Gelmon K. A. 
Published: March 2020

10582 Background: Although breast cancer with 4+ axillary lymph nodes generally carries a poor prognosis, we hypothesized that a good prognostic subgroup of such patients would be identifiable by immunohistochemical (IHC) biomarkers. Methods: Patients with primary breast cancer with 4+ axillary nodes and no metastatic disease at diagnosis were identified from a large clinically annotated TMA of formalin-fixed paraffin-embedded archival breast cancers and analyzed for eight IHC based biomarkers: estrogen receptor, HER2, carbonic anhydrase IX, EGFR, CK 5/6, progesterone receptor, p53 and Ki67. Expression of each biomarker was scored 0 or 1 to indicate good or bad prognosis based on univariate analysis of relapse free survival (RFS). Patients were banded as having a total score of 0 (i.e. each biomarker predicted a good outcome), 1–4 or 5–8. Kaplan Meier and Cox regression analysis of RFS outcomes was performed. 10 year RFS for each band was compared to the mean of predicted outcomes based on the prognostic tool Adjuvant! ( www.adjuvantonline.com ). Results: 313 eligible patients were identified and complete data were available for 228. The subset of 228 was similar to the larger group of 313 with respect to RFS and conventional prognostic factors. 10 year RFS for the 228 patients was 39.5% (standard error, SE 3.4%). The subgroup of 37 (16%) scoring zero for all 8 biomarkers had a mean 10 year RFS of 77.6% (SE 7.0). Mean 10 year RFS for the bands scoring 1–4 (154 patients, 68%) and 5–8 (37 patients, 16%) were 34.9% (SE 4.1) and 19.0% (SE 6.9) respectively. Mean 10 year RFS predictions by Adjuvant! were 35.9% (SE 2.6), 34.5% (SE 1.2) and 34.3% (SE 2.3) respectively. In multivariate analysis with conventional prognostic factors, the banded biomarker score retained statistical significance for predicting RFS (p=0.0007) along with estrogen receptor status (p=0.03) and tumour size (p=0.01). Conclusions: This TMA biomarker panel identified a breast cancer subgroup with good prognosis despite extensive axillary node involvement. Long term outcome was markedly better than that predicted by conventional prognostic factors. If validated, treatment decisions and clinical trial stratification might be modified using this new score. No significant financial relationships to disclose.
A twenty eight-gene signature and survival in completely-resected non-small cell lung cancer (NSCLC)
Authors: Van Zandwijk N. 
Published: March 2020

10583 Background: Current staging methods are imprecise for predicting the outcome of treatment of non-small-cell lung cancer (NSCLC). We have developed a 28-gene signature that is closely associated with recurrence-free and overall survival. Methods: We used whole-genome gene expression microarrays to analyze frozen-tumor samples from 174 patients (pT1&2, N0&1, MO), who had undergone complete surgical resection in 5 European institutions. Randomly generated numbers were used to assign 2/3 of the samples to an algorithm training group with the remaining 1/3 set aside for independent validation. Cox proportional hazards models were used to evaluate the association between the level of expression and patient survival. We used risk scores and nearest centroid analysis to develop a gene-expression model for the prediction of treatment outcome. Leave-one-out cross validation was used to prevent model over-training. Results: 28 genes that correlated with survival were identified by analyzing microarray data and risk scores. Based on the expression of these genes, patients in training and validation groups were classified as either high (48%) or low (52%) risk. Analysis of predicted risk groups revealed significantly different survival distributions for patients in both the training set (p<0.001) and independent validation set (p=0.006). Genes in our prognostic signature encode for several membrane-bound proteins with previously demonstrated involvement in cell cycle regulation and cell proliferation processes. Conclusions: Our 28-gene signature is closely associated with time to recurrence and overall survival of completely-resected NSCLC patients. [Table: see text]
Edi-3, a new independent prognostic factor in ovarian cancer
Authors: Mustea A. , Koensgen D. , Lichtenegger W. , Pirvulescu C. , Sun P. M. , Thomas A. , Lausch E. , Steiner E. , Hengstler J. G. , Sehouli J. 
Published: March 2020

10585 Background: Recently, we have identified for the first time a new putative phosphodiesterase named edi-3 that correlates with tumorigenesis in endometrial cancer. In the present study we analyzed the prognostic relevance of edi-3 in ovarian cancer. Methods: Edi-3 mRNA expression was measured by quantitative RT-PCR (TaqMan) in 62 patients with primary ovarian cancer. All patients signed informed consent, approved by the Clinical Review Board and Ethics Committee of the Medical University Berlin, Charité, Germany. The tumor specimens were collected according to the Tumor Bank Ovarian Cancer standard operating procedures. A validated systematic intraoperative documentation tool was used for the detailed documentation of all surgical procedures. Using the multivariate proportional hazard model we analyzed whether edi-3 predicts survival independent from FIGO-stage, grading, postoperative residual disease and histological type. Results: Edi-3 expression is associated with survival in the univariate Cox model (hazards ratio [HR]: 1.488, 95% confidence interval [CI]: 1.131 - 1.959, P=0.005). Interestingly, edi-3 was also predictive in the multivariate proportional hazard model adjusted for the conventional clinical factors (HR: 1.521, CI: 1.107 - 2.090, P=0.010). Conclusions: Edi-3 is a new independent prognostic factor in primary ovarian cancer with HR=1.5 (P=0.010). Its function, a possible role in inositol phosphate metabolism, will be further explored in a multi-instutional setting. No significant financial relationships to disclose.
A phase II clinical trial of ZD1839 (gefitinib) in combination with docetaxel as first-line treatment in patients with advanced breast cancer
Authors: Dennison S. K. , Jacobs S. A. , Wilson J. , Seeger J. , Cescon T. , Raymond J. M. , Geyer C. E. , Wolmark N. , Swain S. M. 
Published: March 2020

1059 Background: We conducted a phase II multi-institutional trial of gefitinib and docetaxel as first-line treatment in patients with metastatic breast cancer. The primary objectives were to determine the clinical benefit rate (defined as the proportion of patients who experienced confirmed complete response or partial response or who had stable disease for at least 24 weeks) and the toxicity profile of the combination treatment. Methods: All patients had histologically confirmed breast cancer with metastatic disease. They may have received adjuvant chemotherapy, but no prior docetaxel or prior chemotherapy for metastatic disease. Patients received gefitinib 250 mg once daily and docetaxel 75 mg/m2 every 3 weeks, until tumor progression, toxicity or other reasons for discontinuation. Results: Between April 2003 and September 2004, 33 patients were enrolled at 11 participating institutions. Patients received a median of 5 cycles of treatment. The clinical benefit rate was 51.5% (95% CI: 33.5% - 69.2%). There was 1 confirmed complete response and 12 confirmed partial responses, and the overall objective response rate was 39.4% (95% CI: 22.9% - 57.9%). Four patients had stable disease for = 24 weeks. The median duration of clinical benefit was 10.9 months (95% CI: 6.0 - 17.6 months). The most common reason for study discontinuation was disease progression (16 patients), followed by toxicity (10 patients). Toxicities were mainly attributable to docetaxel, including = grade 3 neutropenia in 43% of patients. Conclusion: The combination of gefitinib and docetaxel is an active regimen in patients with previously untreated metastatic breast cancer. Further work is needed to determine which subset of patients with breast cancer will benefit from gefitinib. No significant financial relationships to disclose.
Prognostic impact of angiogenic markers in tumor and stromal cells in non-small cell lung cancer (NSCLC)
Authors: Donnem T. , Al-Saad S. , Al-Shibli K. , Delghandi M. P. , Persson M. , Nilsen M. , Busund L. T. , Bremnes R. M. 
Published: March 2020

10596 Background: The vascular endothelial growth factors (VEGFs) -A, -C, -D and the vascular endothelial growth factor Receptors (VEGFRs) -1, -2 and -3 are important molecular markers in angiogenesis and lymphangiogenesis. This study elucidates the prognostic significance of these molecular markers in tumor cells as well as in the tumor stroma of resected NSCLC tumors. Methods: Tumor tissue samples from 335 resected patients with stage I to IIIA were obtained and tissue microarrays were constructed from duplicate cores of tumor cells and surrounding stromal tissue from each resected specimen. Immunohistochemistry was used to evaluate the expression of each molecular marker. Results: In univariate analyses, high tumor cell expression of VEGF-A (P = .0005), VEGFR-1 (P = .013), VEGFR-2 (P = .006) and VEGFR-3 (P = .0003), were negative prognostic indicators for disease-specific survival (DSS). The most significant correlations between angiogenic marker expression and DSS were observed in patients with T2 stage and/or with sqamous cell carcinomas. In tumor stroma, however, high expression of VEGF-A (P = .017), VEGF-C (P = .003), VEGF-D (P = .009), VEGFR-1 (P = .01) and VEGFR-2 (P = .019), correlated with good prognosis. In multivariate analyses, high expression in tumor cells of VEGFR-3 (P = .007) was an independent negative prognostic factor for DSS, whereas high VEGF-C (P = .004) expression in stromal cells had an independent positive impact on survival. Conclusions: While high tumor cell expression of VEGFR-3 is an independent predictor of reduced survival in primary NSCLC, high VEGF-C expression in stromal cells is, in contrast, a favorable independent prognostic indicator. No significant financial relationships to disclose.
Haploinsufficiency of CDK4 prevents hepatocarcinogenesis in mice deficient in ELF, a mediator of TGF-beta signaling
Authors: Pishvaian M. J. , Blake T. M. , Kitisin K. , Kim S. S. , Kang A. , Rashid A. , Tang Y. , Mishra B. , Reddy E. P. , Mishra L. 
Published: March 2020

10608 Background: The transforming growth factor-β (TGF-β) has a dual role in cancer, but in the prevention of tumorigenesis, TGF-β signaling inhibits cell cycle progression through an increase in cell cycle inhibitors and decrease in cell cycle activators. The adaptor protein embryonic liver fodrin (ELF) is crucial for normal TGF-β signaling. ELF facilitates the association and nuclear translocation of the TGF-β signaling proteins, Smad3 and Smad4. We have demonstrated that elf± mice develop hepatocellular cancers (HCC) spontaneously within 12 months. We have also shown that most human HCCs demonstrate a decreased expression of ELF. Our goal was to assess the interaction between ELF and cyclin dependent kinase 4 (CDK4), which is overexpressed in most human cancers. Methods: We compared the expression of CDK4 and ELF by immunohistochemistry and analyzed the interaction between CDK4 and ELF, in vitro by immunoprecitpitation and western blot. Finally, we assessed the development of HCC in intercrossed elf± and CDK4+/neo mice. Results: CDK4 and ELF expression are inversely correlated in HCCs from elf± mice. Furthermore, ELF interacts with CDK4 by forming a complex that includes Smad3 in COS-7 and HepG2 cells. ELF is phosphorylated upon overexpression of CDK4, revealing a possible mechanism by which CDK4 may inhibit ELF-dependent TGF-β signaling. To further assess whether the development of HCC in elf± mice is dependent upon CDK4 expression, we have intercrossed elf± and CDK4+/neo mice. At 12 months, only 17% of the elf±/CDK4+/neo mice developed HCC, compared to 40% of our historical control elf± mice. This initial data strongly suggests that haploinsufficiency of CDK4 can prevent the HCCs seen in elf± mice, and provides the genetic foundation for further exploring the benefits of specific inhibitors of CDK4 in the treatment of HCC. Conclusions: These results demonstrate the molecular interactions between ELF and CDK4, and suggest a mechanism by which CDK4 may render cells unresponsive to the growth inhibitory effects of TGF-β signaling. Furthermore, haploinsufficiency of CDK4 prevents the formation of HCC, and thus targeted-inhibition of CDK4 activity may be a logical treatment for HCC in humans. No significant financial relationships to disclose.
Improvement in survival of breast cancer patients with synchronous metastases
Authors: Salmon A. Y. , Uziely B. , Meirowitz A. , Sharon N. , Peretz T. 
Published: March 2020

1063 Background: Less than 10% of breast cancer patients are diagnosed with metastatic disease upon initial diagnosis. Once metastases are detected, median survival ranges between 18 and 24 months. Many new chemotherapy agents, hormonal therapy, monoclonal antibodies and supportive care options were presented during the last decade. Although a few randomized trials have demonstrated improvement in survival for various agents, it has not been clear whether the overall survival of these patients has improved. In this study, we analyzed the survival of patients diagnosed with metastatic breast cancer in during the 1990’s Methods: We have analyzed 874 patients diagnosed with breast cancer at our Institute in the years 1991–1994 and 1102 patients in 1996–1999. Tumor characteristics, treatments, and the outcomes of these patients were compared. We used Kaplan-Meier, Wilcoxon test and Cox proportional hazard in order to investigate variants between the 2 groups. Results: After excluding all women with no evidence of metastatic disease at diagnosis, we analyzed 96 patients. No major difference in tumor characteristics was found between the group of patients diagnosed in the early 1990’s and the group diagnosed in the late 1990’s. We found a significant relationship between the period of diagnosis of metastatic breast cancer and survival: median survival was 19 months for the first group and 35 months for the second group (p=0.0398, 95% C.I), with 5-year overall survival rates 8% for patients diagnosed in the early 1990’s and 25% for patients diagnosed in the late 1990’s, p=0.0497. Two years survival was 25% and 60% respectively, although insignificant, p = 0.0941. Although there was no significant difference in number of chemotherapy courses given in the 2 groups, many more new generation treatments were used for the late 90th group. The Hazard of death within 5 years for patients treated with at least one new generation protocol was 0.53, p= 0.004. Conclusions: This study suggests that there has been significant survival improvement in breast cancer patients diagnosed with synchronous metastasis during the second half of the 1990’s. This improvement can be explained by the introduction of new treatments agents and strategies during the last decade No significant financial relationships to disclose.