bluuebunny/crossref_metadata_2025 huggingface dataset:
Topoisomerase II-alpha (TOP2A) gene co-amplification does not predict response to therapy and survival in Her-2 neu positive metastatic breast cancer
Authors: Kapoor A. , Chow S. , Bhargava R. , Surti U. , Rosenzweig M. , Vuga M. , Brufsky A.
Published: March 2020

21108

Background: Preliminary data from a phase III trial of adjuvant traztuzumab (BCIRG, SABCS 2005, abstract 1045) suggested that co-amplification of the genes for HER2 and topisomerase II alpha (TOP2A) on chromosome 17 resulted in improved disease free survival with chemotherapy regimens containing both and anthracycline and traztuzumab. We sought to determine if co-amplification of HER2 and TOP2A was a predictor of response and benefit (or lack thereof) to herceptin containing chemotherapy in the metastatic setting, since few women receive both therapies concurrently for MBC. Methods: A tissue mircoarray (TMA) with 3-fold redundancy was constructed using 0.6mm cores from primary or metatstatic paraffin embedded tumor from 124 cases from Magee-Women's Hospital which were Her2 2+ or 3+ by IHC, or amplified by FISH, on pathology report. Four micron thick TMA sections were used for HER2 immunohistochemical (CB11 monoclonal antibody, Ventana Medical Systems, Tucson, AZ) and HER2 and TOP2A FISH analysis (HER2/CEP 17 and TOP2A/CEP 17 dual color probes from Vysis Inc. Downers Grove, IL). HER2 (or TOP2A) gene to chromosome 17 ratios of 2.0 or more was considered as amplification. Results: Tissue blocks from 52 tumors delivered clearly interpretable amplification for Her2 by FISH on reanalysis. The remaining 72 tumors are undergoing further reanalysis. Of the 52 tumors with Her2 amplification, 15 (29%) had co- amplification of TOP2A. Median survival was 44 months (95% CI, 31–69) for women with TOP2A coamplified tumors and 35 months (95% CI, 29- 63) for women with non-coamplified tumors (p=0.448, NS). Median time to progression on first therapy was 17 months (95% CI, 14–20) for women with TOP2A coamplified tumors and 15 months (95% CI, 12–17) for women with non-coamplified tumors (p=0.939, NS) Conclusions: In this analysis, TOP2A and HER2 gene co-amplification did not correlate with worse TTP on first metatstatic therapy or worse OS from metatstatic disease.

No significant financial relationships to disclose.
Somatic mutations of EGFR and KRAS in pure bronchioloalveolar carcinomas and adenocarcinomas of the lung with bronchioloalveolar features
Authors: Dahabreh I. J. , Murray S. , Spiliadi H. T. , Karagiani E. A. , Stamatelopoulos A. , Vassilikos K. , Zanos G. , Janinis J. , Dahabreh J.
Published: March 2020

21111

Background: EGFR mutations are more common in lung cancers from female, non-smoking patients of Asian ethnicity with adenocarcinoma histology. We investigated the relationship between clinicopathologic parameters and mutations of EGFR and KRAS in patients with pure bronchioloalveolar carcinomas (BACs) and adenocarcinomas (ADCs) with BAC features, not previously treated with EGFR inhibitors. Methods: We retrospectively reviewed the files of patients who were diagnosed with pure BACs or ADCs with BAC features between February 2001 and May 2005. Demographics, stage and smoking histories were recorded. Paraffin embedded tissue blocks were retrieved and re-examined using the WHO 1999/2004 histological criteria for lung cancers. EGFR expression, detected by immunohistochemistry, was scored from 0 to +3. Expression was considered positive when the score was +1, or higher. DNA was isolated from paraffin blocks (containing at least 75% tumor cell content) and exons 18–21 of the EGFR gene and exon 2 of the KRAS gene were amplified by PCR and bi-directionally sequenced. The chi-squared test and regression analysis were used to identify parameters correlating with EGFR or KRAS mutations. Results: A total of 46 patients were eligible for this study. Tissue was available from 43 patients, 19 with pure BAC and 24 with ADC with BAC features. There were 27 (62.8%) males and 16 (37.2%) females, all of Greek descent. Mean age was 62.7 years (range, 41–79). There were 34 smokers and former smokers (79%) and 9 never-smokers (21%). Tumors were classified as mucinous (20), non- mucinous (19) or mixed (4). We detected somatic EGFR mutations in 7 patients (including common mutations, delEx19, L858R, G719C), and KRAS codon 12 mutations in 13 patients. EGFR and KRAS mutations were mutually exclusive. No clinicopathologic parameters correlated with the presence of EGFR or KRAS mutations. Conclusions: Among Greek lung cancer patients with pure BACs or ADCs with BAC features, unselected for response to EGFR inhibitors, the incidence of KRAS or EGFR mutations was 30.2% and 16.3% respectively. EGFR and KRAS mutations were mutually exclusive but no clinicopathologic factor predicted the presence of mutations in either gene. Further molecular analysis is ongoing.

No significant financial relationships to disclose.
High KI67 expression is associated, in a multi-variate model, with lower risk of biochemical recurrence in prostate cancer patients following radical prostatectomy
Authors: Gannon P. O. , Koumakpayi I. H. , Le Page C. , Alam Fahmy M. , Mes-Masson A. , Saad F.
Published: March 2020

21112

Background: The prediction of disease progression in prostate cancer patients following radical prostatectomy (RP) remains problematic. The use of molecular markers could offer a better stratification of patients more at risk of progression. As such, we recently reported that nuclear ErbB3 was associated with Gleason score and hormone-refractory status. The objective of this study was to evaluate whether ErbB3 could predict overall biochemical recurrence (BCR). In addition, we evaluated if three nuclear markers known to be associated with progression (Cyclin D1, Ki67 and androgen receptor) were more significant predictors of BCR than ErbB3 alone or in combination. Methods: Using immunohistochemistry, we analyzed a tissue microarray containing 373 cores from 63 RP specimens. No patient had received hormone therapy prior to surgery and prior to BCR. The quantitative analysis of nuclear staining was measured by two independent observers (ErbB3, Cyclin D1 and AR) or with the ImagePro Plus softwareTM (Ki67). Marker expressions were categorized as either positive or negative according to the median expression. Results: Of the four markers analyzed, Ki67 alone was the strongest predictor of overall BCR. In a multi-variate Cox regression model (backward conditional), while controlling for the pre-operative PSA, Gleason score and lymph node invasion at time of surgery, KI67 was found to be an independent predictor of BCR with a KI67+ patients having lower risk of BCR (HR=-2.51, p=0.015, CI 95%: 1.19–5.29). We then analyzed if different marker combinations could predict BCR. Patients positive for nuclear AR or AR+/Cyclin D1+ double positive were found to have lower risk of BCR (Kaplan-Meier, p=0.047 and p=0.026, respectively). However, in the multi- variate model, the combinations of Cyclin D1+/AR+ (HR=-2.28, p=0.053, CI 95%: 0.94–5.49), ErbB3+/Ki67+ (HR=-2.43, p=0.034, CI 95%: 1.07- 5.52) and AR+/Ki67+ (HR=-2.32, p=0.049, CI 95%: 1.01–5.35) could not improve on the predictive value of KI67 alone. Conclusions: The major new finding of the study is that patients positive for KI67 expression were at a lower risk of developing BCR, which contrast previously published results, and warrants further investigations.

No significant financial relationships to disclose.
Pattern of estrogen receptor positivity in breast cancer among the elderly
Authors: Cheung K. , Morgan D. A. , Wong A. W. , Parker H. , Ellis I. O.
Published: March 2020

21122

Background: It is known that oestrogen receptor (ER) positivity in breast cancer increases with increasing age. Some clinical data show that radiotherapy can be safely avoided to achieve similar local control following lumpectomy in elderly patients taking tamoxifen; and that there is negligible benefit of adjuvant chemotherapy for patients approaching the age of 70. We postulate that biological differences (with ER being an important one) may be contributory. This study aimed to analyse the pattern of ER positivity in the elderly population. Methods: Among 2,061 patients >70 years who had operable primary breast cancer (<5cm) managed in a dedicated clinic from 1987, there were 1,557 tumours which had ER data available. Their pattern was studied and compared with that in 2,674 tumours from younger (= 70 years) counterparts treated during the same period in the same centre. Histochemical (H) score was measured using standard ER immunohistochemical assay and reported by the same team of dedicated breast pathologists. Results: The patterns of ER in different age groups are shown below. Conclusion: In all age groups there is a marked biphasal distribution of ER positivity, but in patients >70 years this biphasal distribution is more marked than in other age groups , with a great preponderance of highly ER-positive tumours, and a substantial minority being ER-negative (H=0), with very few in intermediate groups. Endocrine therapy is clearly appropriate for the highly ER-positive majority, but management of those ER-negative ones (H = 0) is a challenge.

[Table: see text]

No significant financial relationships to disclose.
Glutathione-S-transferase genes polymorphisms predict response and progression free survival in head and neck cancer patients treated with cisplatin based chemoradiotherapy
Authors: Federico M. H. , Brunialti K. C. , Castro G. , Pasini F. S. , Maistro S. , Mangone F. R. , Villar R. C. , Snitcovsky I.
Published: March 2020

21127

Background: Alterations in the function of DNA repair genes and detoxification genes may influence response to cisplatin based chemoradiotherapy in patients (pts) with head and neck cancer. Our purpose was to evaluate the prognostic ability of polymorphisms of three genes glutathione S-transferase (GST), ERCC1 and XPD in patients with head and neck squamous cell carcinoma (HNSCC). Methods: A polymerase chain reaction-restriction fragment length polymorphism (RFLP-PCR) or multiplex PCR approach was used to determine the frequency of the XPD Lys751Gln (n=29), ERCC1 Asn118 (n=50), GSTP1 Ile105Val (n=22) and GSTT1/GSTM1 (n=66), in DNA of peripheral lymphocytes. A total of 50 pts were treated with platinum based chemoradiotherapy exclusively and 16 pts received the same regimen in the adjuvant setting. Median follow-up was 6.4 months and 17 pts had tumor progression and 2 died, with a progression free survival (PFS) of 18 months. Results: The frequencies (%) of the distinct genotypes were, respectively, for the homozygous common allele and heterozygous plus homozygous polymorphic variant: 40 and 60 for ERCC1; 48 and 52 for XPD; 36 and 64 for GSTT/GSTM1, 41 and 59 for GSTP1. We did not observe any association between ERCC1, XPD, GSTM1/GSTT1 polymorphisms and response, but for GSTP1, the polymorphic variant was associated with tumor response, as compared to wild type (p=0.069 χ2 test). In relation to PFS, no associations were found between XPD, ERCC1 and GSTP1, however, for GSTM1/GSTT1, the null or heterozygous genotype (median survival: not reached, n=43) was associated with a better PFS, as compared to the wild type (18 months, n=23; p=0.087, Log-rank). Conclusions: Among the polymorphic variants studied here, our impression is that GST is the most powerful prognostic factor of favorable response and PFS to cisplatin based chemoradiotherapy in HNSCC. Supported by CAPES.

No significant financial relationships to disclose.
Triple-negative phenotype is a strong predictor of sensitivity to epirubicin-cyclophosphamide (EC) then docetaxel (D) (ECD) primary chemotherapy (PCT) for localized breast cancer
Authors: Marty M. E. , Guinebretiere J. , Mathieu M. , Sigal-Zafrani B. , De Roquancourt A. , Spielmann M. , Giacchetti S. , De Cremoux P. , Spyratos F. , Asselain B.
Published: March 2020

21128

Background: Molecular markers (GEP, p53 mutations,) could overcome usual predictors (size, pathology, Hormone receptors, HER2) in identifying patients (pts) experiencing complete pathological response (pCR) with anthracyclin based chemotherapy (Clin.Cancer Res., 2004, 10 6789). We aimed at validating and refining these finding in pts treated with ECD. Methods: From 05/2004 to 04/2006 170 pts not amenable to Breast Conserving Therapy and/or with high evolutive potential were randomly allocated to EC (75/750mg/sqm)x4 then D (100 mg/sqm)x 4 (with or without celecoxib in HER2-ve or trastuzumab (T) in HER2+ve. The primary endpoint - absence of residual invasive breast carcinoma and of nodal involvement (pCR)- was to be correlated with usual predictors , phenotype, GEP and p53 mutations assessed from core biopsies. pCR ranged from 13 to 14% in the arms without T thus without suggestion of a difference between these arms. pCR in the 30 HER2+ve pts having received ECD + T was 30% (NS). Results in 135 fully evaluable pts not allocated to T and having undergone secondary surgery are analyzed. Results: Main predictors and related pCR are shown in the table below Results of ongoing molecular analysis will be reported. Conclusions: Expression of ER appears to be the major prognosticator for ECD induced pCR. Triple negative breast cancers experience the highest pCR rate (p< 0.0001) (chi2 test with Yates correction). Molecular studies to be presented will show if GEP and/or p53 mutations could allow to improve such prediction.

[Table: see text]

No significant financial relationships to disclose.
Socioeconomic status as an independent prognostic factor in node negative, stage I-II breast cancer patients
Authors: Zeichner-Gancz I. , Munoz-Gonzalez D. E. , Pérez Sánchez V. M. , Castillero C. , Ramirez-Ugalde M.
Published: March 2020

21129

Background: Many prognostic factors for breast cancer are known, of those, clinical , histological, genetical and the socioeconomic status are considered important for the outcome of these patients. The objective of our study vas to evaluate the Socioeconomic status as an independent factor for survival Methods: Clinical records of node negative clinical stage I- II patients treated at the institution from 1980 to 1996 were reviewed . We included those initially treated with surgery, available paraphine blocks, follow up of at five years (the ones that had no recurrence). They were divided in two groups: 1: Lower socioeconomic status, economically deprived and 2: medium low to high status. The slides were reviewed s and the blocks were processed for immuno-histochemistry: steroid receptors, Her-2, p 53 and CD 34. The analysis was performed with X2, , t test and log rank for difference in survival Results: A total of 81 patients were studied, 35 in group 1, and 46 in group 2. Mean age for groups 1 and 2 was of 52 (28–74) and 52.9 (28–83) years respectively (p=0.39). Were stage I in group 1 8, II-28. In Group 2 were stage I, 12, II-34 (p=0.87). Patients in both groups were treated with surgery alone, with radiotherapy, chemotherapy and/or hormone therapy, without statistical significance for treatment.Vascular or lymphatic permeation was observed in 20 and 22 patients from groups 1 and 2 respectively (p=0.40). Mean SBR was of 7.2 and 7.1 respectively for groups 1 and 2 (p=0.54) Estrogen receptor was present in 10 and 11 patients (p=0.63) and progesterone receptor in 8 and 6 (p0.25) for each group. Her-2 was over expressed in 12 and 17 patients from group 1 and 2, p53 in 6 and 14 respectively (p=0.17)and CD34 in 7 and 6 for both groups respectively ( p=0.40). Median survival was of 225 months for group 1 and not reached at 243 months for group 2, with 90.22% alive, p= 0.005 Conclusions: According to our results, in this group of well studied patients, the only significant factor observed that had an impact over survival was the socioeconomic status. None of the clinical, histological or genetical variables showed significance. We think that prospective studies with special emphasis on the socioeconomic status have to be carried out in order to try to explain the differences that we observed.

No significant financial relationships to disclose.
The diagnostic value of serum levels of VEGF, bFGF and endostatin in patients with liver cancer
Authors: Nikopoulou A. , Makrantonakis P. , Karamouzis M. , Nikolaidis P. , Agorastos J. , Nikopoulos A. , Giannoulis E.
Published: March 2020

21133

Background: : Aim of this study is to evaluate the diagnostic value of serum levels of vascular endothelial growth factor ( VEGF ), basic fibroblast growth factor ( bFGF ) and Endostatin in patients with primary hepatocellular carcinoma ( PHC ) and in patients with metastatic liver disease ( MLD ). Methods: Eighty participants were included in this study and divided into three groups. Exclusion criteria were history of myocardial infraction, stroke, diabetic retinopathy, rheumatoid arthritis, psoriatic arthritis, pregnancy, trauma and recent surgical treatment. In group A were included 20 normal controls (NC), in group B 30 patients with PHC and in group C 30 patients with MLD. The concentrations of VEGF, bFGF and Endostatin in serum were measured by using enzyme like immunosorbent assay kits (Quantikine R&D systems Inc., Mineapolis.MN). Results: Results are shown in table . In patients with PHC there was a positive correlation between the serum level of VEGF and tumor size (r=0.517, p=0.08), between the serum level of VEGF and platelets number (r=0.573, p=0.003) and between the serum level of VEGF and the serum level of a-fetoprotein (r=0.478, p=0.029). In patients with PHC sensitivity of VEGF, bFGF and Endostatin was found 60%, 54% and 23% respectively. In patients with MLD sensitivity of VEGF, bFGF and Endostatin was found 73%, 73% and 27.5% respectively. However, both in patients with PHC and with MLD specificity of VEGF, bFGF and Endostatin were found 95%, 95% and 100% respectively. Conclusions: Angiogenic factors VEGF, bFGF and Endostatin can distinguish normal controls from patients with liver cancer. Serum levels of VEGF are related to the size of the tumor in patients with PHC. Serum VEGF, bFGF and Endostatin could be useful tumor markers in the diagnosis of PHC and MLD because of their high specificity. The significant correlation of VEGF with a- fetoprotein indicates its importance as a marker in diagnosis of PHC.

[Table: see text]

No significant financial relationships to disclose.
Immature vessel percentage (IVP) as a potential predictive factor for anti-angiogenic therapeutics
Authors: Eid A. A. , Hennings L. , Caradine K. , Hodges A. , Safar A. M.
Published: March 2020

21137

Background: As opposed to mature blood vessels, the early sprouts (lacking the pericyte coverage) are selectively obliterated after Vascular Endothelial Growth Factor (VEGF) antagonists (e.g. Bevacizumab BV). Microvessel density (MVD) has been widely used to assess tumor vasculature however; it does not give an indication of the degree of vessel maturity since it assesses endothelial cells irrespective to the pericyte coverage. With the introduction of BV for treatment of metastatic colon, lung and breast cancers, predictive markers to guide patient selection are desirable but lacking. Methods: To assess the maturity of tumor vascular beds we used double-labeling immunohistochemistry to colocalize endothelial cells (CD31+) and pericytes (aSMA+) in archived material from colorectal liver metastasis (n=13). None of these subjects received BV or chemotherapy prior to sampling. To represent various regions within a section, counts were performed in designated-low, and -high vascular regions. IVP, the main study endpoint, was estimated in both regions, and then averaged by two independent pathologists without particular training in angiogenesis. Results: There was a considerable degree of heterogeneity in the IVP within this group (SD 12.5, mean 26.6). However, the agreement between the 2 pathologists was relatively high with an intra-class correlation coefficient of 0.655. Conclusions: Considerable tumoral vascular heterogeneity exists in colorectal liver metastasis. IVP may predict therapeutic benefits from BV. In this era of anti-angiogenic therapy and in view of the toxicity and the financial burden of these agents, better patient selection using biologically relevant techniques such as the one described here need to be considered. IVP is a candidate tool with multiple advantages; it utilizes abundantly available material (subject to reconfirmation or testing in different settings), does not require particular training and appears reproducible.

No significant financial relationships to disclose.
Prognostic and predictive value of vascular endothelial growth factor and soluble flt-1 and kdr levels in the sera of small cell lung cancer patients
Authors: Ustuner Z. , Saip P. , Yasasever V. , Ozturk B. , Vural B. , Ozbek U. , Topuz E.
Published: March 2020

21152

Background: Small cell lung cancer (SCLC) has a rapid growth rate, and is characterized by early metastases. Tumor growth is dependent on angiogenesis. Vascular endothelial growth factor (VEGF) is an important regulator of angiogenesis. Whether surveillance of pre and post treatment serum VEGF and its receptors Flt-1 and Kdr levels in SCLC patients have impact on clinical outcome is unknown. Methods: From February 2001- January 2003, 39 consecutive patients (34 male, 5 female) with histologically proven SCLC were enrolled into the study. The patients were staged as limited and extensive according to the Veterans Administration Lung Group (VALSG). Pre treatment (n:39) and post treatment (n:25) serum samples of the same patients after 3 months of treatment were collected. The levels of VEGF and its receptors Flt-1 and kdr are measured in the serum by quantitative sandwich enzyme immunoassay technique. Statistical analysis was performed using the SPSS 10.0 pocket program. Results: The median pretreatment serum VEGF, Flt-1, and Kdr levels were 1,200 pg/ml (range, 1,414.3±956.2 pg/ml), 85 pg/ml (range, 97.8±70.7 pg/ml), and 11,550 pg/ml (range, 14,481±6,267 pg/ml) respectively. The pretreatment serum VEGF, Flt-1, and Kdr concentrations were not different in limited and extensive stages. We detected a poor but positive correlation between VEGF and Kdr (r=0.46, p=0.003). Pretreatment low serum VEGF value (<728.5 pg/ml) and good response to treatment were found as good prognostic factors in multivariate analysis. Surveillance of serum VEGF and Flt-1, Kdr values did not correlate with clinical parameters. Conclusions: Serum VEGF was found to be a significant and independent prognostic factor in SCLC patients. We showed a limited association between serum levels of VEGF and Kdr. Whether the levels of serum VEGF and its receptors Flt-1 and kdr have value in detecting treatment modalities of SCLC needs further studies.

No significant financial relationships to disclose.
Bone morphogenic proteins 1 to 7 in human breast carcinoma
Authors: Davies S. R. , Watkins G. , Douglas-Jones A. , Mansel R. E. , Jiang W. G.
Published: March 2020

21154

Background: Bone morphological proteins (BMPs) have a diverse role and they act in a time, concentration and cell type specific manner. They have been shown to regulate cellular motility and the cells ability to invade and recently BMP molecules have been shown to have an impact on the biological behaviour of breast cancer cells. In this study we looked, for the first time, at the expression of a panel of BMPs in breast carcinomas. Methods: Fresh frozen primary breast cancer tissues (n =120) and non-neoplastic mammary tissue (n = 32) were used. The distribution and location of BMPs was assessed using immunohistochemical methods and the levels of BMPs (BMP-1, -2, -3, -4, -5, -6, and -7) were determined using quantitative RT-PCR. The results were analysed against the clinical, pathological and follow-up (10 years) data. Results: BMP-2 and BMP-7 had a contrast pattern of expression in normal and tumour tissues, in that BMP-2 transcript level was lower and BMP-7 was higher in breast tumours than normal tissues. BMP-2 transcript was also significantly lower in tumours from patients with a moderate and poor prognosis than from those with a good prognosis (p=0.04). Also both BMP-2 and BMP-7 showed a significant difference between node positive and node negative tumours (p=0.033 and p=0.031 respectively). BMPs 1, 3, 4, 5 and 6 showed an inconsistent variation in transcript levels within the cancer subgroups with no statistically significant results. Conclusions: This study has demonstrated the differential expression pattern of BMP molecules in breast cancer and reveals a potential prognostic value of BMP-2 and BMP-7 for the patients. The findings may also suggest that these BMPs may be potential therapeutic targets.

No significant financial relationships to disclose.
CXCR4/SDF-1 expression in early breast cancer (BC) is not influenced by circulating estrogens serum levels
Authors: Marini G. , Grisanti S. , Ruggeri G. , Ardighieri L. , Simoncini E. , Amoroso V. , Rangoni G. , Valcamonico F. , Lucini L. , Facchetti F.
Published: March 2020

21159

Background: The chemokine SDF-1 and its receptor CXCR4 have been found to enhance the metastatic potential of BC cells and correlate with a poorer prognosis of BC patients. Estradiol is a known mitogenic factor for BC cells. SDF-1 has been reported to be an estradiol (E2)-inducible autocrine growth factor that supports the growth of breast cancer cell lines in vitro. The aim of this study was to verify whether estrogens serum levels may influence SDF-1 and CXCR4 expression in vivo, in a series of patients with early stage BC. Methods: 68 patients sequentially observed at the Spedali Civili di Brescia from 2001 to 2002, with a diagnosis of T1a,b,c, N0 breast cancer were retrospectively analysed. CXCR4 and SDF-1 expression was determined by immunohistochemistry with anti-human CXCR4 (Clone 44716) and anti-human SDF-1 (Clone 79018) monoclonal antibodies (R&D Systems, Minneapolis, USA) followed by incubation with the EnVision peroxidase kit (Dakocytomation, Glostrup, Denmark). A serum sample was obtained from all patients at baseline before surgery. Serum estrone (E1) and estradiol (E2) were measured by radioimmunoassay by using commercial kits (Alifax, Padua, IT and Ortho-Clinical Diagnostics, Amersham, UK, respectively). Results: Estrogens serum levels analysis revealed elevated levels of E1 in 9/54 (16%) post-menopausal patients, while E2 levels were in the normal ranges. SDF-1 was expressed in 68/68 (100%) patients with a diffuse and intense cytoplasmatic pattern of staining and CXCR4 was coexpressed in 15/68 (22%) patients with a predominant faint nuclear distibution (p 0,06). No significant correlations were found between CXCR4, SDF-1 and E1 or E2, respectively, as well as with other clinico-pathological characteristics. After a median follow-up of 48 months, 3/68 (4%) patients which all resulted CXC4/SDF1-positive, relapsed and are dead for metastatic disease. Conclusions: This study demonstrates that in T1N0 BC patients: 1) SDF-1 is high levels in the majority of cases; 2) CXCR4 is expressed in approximately 20% of cases with restriction to the nucleus and 3) serum levels of circulating E2 and E1 in pre- or post-menopausal patients, respectively, do not influence CXCR4/SDF-1 expression on breast cancer cells.

No significant financial relationships to disclose.
Immune response after high-intensity focused ultrasound ablation for H22 tumor
Authors: Zhou P. , Fu M. , Bai J. , Wang Z. , Wu F.
Published: March 2020

21169

Background: Previous results have shown that high intensity focused ultrasound (HIFU) ablation can potentially activate a host anti-tumor immunity. This study was to investigate whether acoustic cavitaion may enhance host immune responses after HIFU treatment for solid malignancy, and to explore the potential mechanisms regarding the enhanced anti-tumor immunity. Methods: (1) Tumor cell vaccine preparation: H22 cells were irradiated with HIFU (0.8MHz, 1050W/cm2, 90s); H22 cells were heated for one hour in 65°C water bath. (2) Animal study: 150 KM mice were randomly divided into three groups: control group, thermal group, and HIFU group. Each group had 50 mice for immune experiments. By using hypodermic injection, the mice in thermal group and HIFU group received either 0.2ml heat-treated H22 vaccine or 0.2ml HIFU-treated H22 vaccine in the left flank of each mouse. Those in control group received only injection with same amount of saline solution. The vaccination times were 4 sessions, once a week for 4 consecutive weeks. One week after last vaccination, each mouse was challenged with H22 tumor cells. All mice were followed up to observe the long-term survival in each group, and peripheral blood was collected to detect changes in T lymphocytes and their subsets by flow cytometry technique. Results: The tumor incidences and 6-week survival rates were observed 100% and 88% of mice in control group, 72.5% and 40% in thermal group, and 42.5% and 14% in HIFU group respectively. Compared to the values in either control group or thermal group, there was a significant decrease of tumor incidences and 6-week survival rates in HIFU group. The volume of tumor was obviously lower in HIFU group, and a significant difference was observed between HIFU group and thermal group or control group. Compared to the values in control group, there were a significant increase of CD4+ levels and CD4+/CD8+ ratio, and a significant decrease of CD8+ level in both HIFU group and thermal group. Conclusions: Antitumor immune response could be enhanced after HIFU ablation for H22 implanted tumor in mice, and acoustic cavitation could play an important role to stimulate host antitumor immune system.

No significant financial relationships to disclose.
Pharmacogenetic analysis of toxicity after 5-fluorouracil (5FU) or 5FU/oxaliplatin therapy for metastatic colorectal cancer: Preliminary results in FFCD 2000–05 trial
Authors: Castaing M. , Loriot M. A. , Barrois M. , Miran I. , Mulot C. , Laurent-Puig P. , Pignon J. P. , Ducreux M. , Boige V.
Published: March 2020

2508

Background: The FFCD 2000–05 randomized trial compared simplified LV5FU2 followed by FOLFOX6 (arm 1) to FOLFOX6 followed by FOLFIRI (arm 2) in the treatment of metastatic colorectal cancer. The aim was predicting the toxicity profile of oxaliplatin after the first line treatment using pharmacogenetic data. Methods: Patients (pts) with available blood samples were compared to the other pts for clinical prognostic factors (chi2 test). A logistic model was computed to test the association between polymorphisms and toxicity in each arm. An interaction test was used to assess a differential effect according to treatment (predictive effect), in order to identify a predictive effect of oxaliplatin. Grade 3–4 hematological and non-hematological toxicities (H-tox and NH-tox) at 4 months and grade 2–4 neurological at 6 months were the endpoints of the study. Thirteen genetic variants in 10 candidate genes were selected for pharmacogenetic analysis: ERCC1_04 (rs3212961), ERCC1_05 (rs11615), ERCC1_06 (rs3212948), ERCC1_24 (rs3212955), ERCC2_02 (rs1799793), ERCC2_03 (rs13181), ERCC2_06 ( rs238406 ), ERCC2_09 (rs1799787), GSTM1 (null/present), GSTT1 (null/present), TS (TSER, Ins/del6bp) and UGT1A1 (rs8175347). Genotyping was performed using Taqman probes, QMPSF and fragment analysis. Results: 327 pts (156/171) out of 410 were included (61 had no blood samples, 16 had less than 2 cycles, 3 had incomplete data on toxicity, 3 had insufficient DNA). No difference was found between included and excluded pts in the analysis for gender, age, OMS, number of metastatic organs and adjuvant chemotherapy. Pts received similar 5FU doses in both arms. Number of patients with at least one toxicity in arms 1/2 were as followed: 5/54 grade 3–4 H-tox, 28/47 grade 3–4 NH-tox, and 0/103 grade 2–4 neurological. The genotype CC of ERCC2_02 correlated with higher NH-tox at 4 months in arm 2 (p=0.0008, OR=0.31, 95%CI=[0.15–0.62] versus p=0.87, OR=0.93, CI=[0.39–2.21] in arm 1) compared to genotypes CT and TT, with borderline interaction (p=0.05). Conclusions: These preliminary results on early toxicity in first-line are in favour of an effect of ERCC2_02 on NH-tox of FOLFOX6 and a predictive effect on NH-tox of oxaliplatin.

[Table: see text]
Pharmacogenetic prediction of clinical outcome in advanced colorectal cancer patients receiving 5-fluorouracil (FU)/oxaliplatin (OX) as first-line chemotherapy
Authors: Marcuello E. , Pare L. , Altes A. , Rio E. Del , Sedano L. , Barnadas A. , Baiget M.
Published: March 2020

2509

Background: Chemotherapy using oxaliplatin, 5-fluorouracil is known to be effective in the treatment of CRC patients. Optimization of this therapy is complicated due to wide variability in drug response that may be due to functional genomic polymorphisms in genes related to the drug target, to the metabolizing or to the DNA repair. We report the evaluation of polymorphisms in the TS, MTHFR (drug target) ERCC1, XPD and GSTP1 (repair enzymes) genes. Methods: We treated 109 CRC patients with a first line oxaliplatin/5-FU chemotherapeutic regimen. Genetic polymorphisms were determined by PCR based RFLP or by Real-Time PCR on an ABI PRISM 7000, using DNA from peripheral blood. The investigated polymorphisms were: TS (VNTR in the 5’ UTR, the 3R G>C SNP and the 1494del6), ERCC1 (Asn118Asn, 8092C>A, 19716 G>C), GSTP1 (Ile105Val) and XPD (Lys751Gln). Clinical response (CR), progression free survival (PFS) and overall survival (OS) were evaluated according to each genotype. Results: The patients were classified according to the clinical risk assessment (CRA) defined by EORTC in three groups with different DFS (12, 9, 7 months; P= 0.008) and different OS (41,19,11 months; P= 0.0002). In the univariate analysis for CR, ERCC1 and XPD polymorphisms were significant (P=0.03, P= 0.047, respectively). After adjustment for the mentioned clinical risk assessment, only ERCC1 retained significance (P=0.037; HR: 4.2, C/C vs T/T). In the univariate analysis for PFS, only ERCC1 polymorphism was significant (P=0.034). After adjustment for the clinical risk, this genotype did not retained its significance (P=0.37). Finally, TS, ERCC1 and XPD polymorphisms were significant in the univariate analysis for overall survival, (P=0.032, P=0.003, P=0.016 respectively). Following the adjustement for the clinical risk, all three genotype variables retained significance (P=0.019, P=0.002, P= 0.024, respectively). Conclusions: i) The EORTC risk assessment classification was a very useful predictor of DFS and OS in our group of patients; ii) Germline genetic polymorphism of ERCC1 predicted response to FU/OX in CRC patients and iii) Polymorphisms in the TS, ERCC1 and XPD genes were good predictors of overall survival.

No significant financial relationships to disclose.
Analysis of renal function in patients entered onto CTEP-sponsored phase I studies since 1979
Authors: McHayleh W. M. , Sehgal R. , Potter D. M. , Royds R. B. , Nekrassova T. G. , Ivy S. P. , Ramalingam S. , Belani C. P. , Naret C. L. , Egorin M. J.
Published: March 2020

2519

Background: The NCI and FDA utilize different criteria for classifying renal dysfunction. We analyzed renal function in all patients entered onto CTEP-sponsored phase I clinical trials since 1979 to evaluate the percentage of patients with acceptable renal function according to criteria utilized by the National Cancer Institute, as compared with those advocated by the Food and Drug Administration. Methods: Data from 12575 patients entered onto CTEP-sponsored phase I studies since 1979 were evaluated. Renal function was characterized by calculating creatinine clearance (CrCl) by three different formulae (Cockroft-Gault, Jelliffe, and Levey), as well as GFR according to MDRD. Results: Of the 12,575 patients, data were available to calculate renal function with all the 4 formulae in 5,177. Distributions of CrCl and GFR were defined, and patients were classified as having normal renal function or severe, moderate, or mild renal dysfunction according to FDA or NCI criteria. The resulting distributions are indicated in the table below. Conclusions: Approximately 40% of patients entered into CTEP-sponsored phase I trials have mild renal dysfunction according to FDA criteria and approximately 95% have CrCls > 50 ml/min. These data imply that moderate and severe are the only renal dysfunction categories that need to be evaluated in renal dysfunction studies of novel antineoplastic agents and that FDA guidelines should be applicable. Whether patients in the NCI database with CrCls of 50–80 ml/min experience more toxicities than those with creatinine clearances > 80 ml/min is undergoing evaluation.

[Table: see text]

[Table: see text]
Pharmacokinetics of lenalidomide in subjects with various degrees of renal function
Authors: Chen N. , Lau H. , Kong L. , Zeldis J. , Knight R. , Laskin O.
Published: March 2020

2520

Background: Lenalidomide is a novel oral immunomodulatory drug approved for treating myelodysplastic syndrome (MDS) and multiple myeloma (MM). As unchanged lenalidomide is eliminated predominantly by urinary excretion, the present study investigated the effect of renal impairment (RI) on pharmacokinetics (PK) of lenalidomide. Results were used to refine initial dosing recommendations based on a subject’s estimated creatinine clearance. Methods: The study was conducted at 3 clinical centers. Thirty male and female subjects aged 39–76 years were stratified into 5 groups based on their creatinine clearance (CLCr) values: normal renal function (NRF) (CLCr > 80 mL/min; N = 7), mild RI (50 = CLCr = 80 mL/min; N = 5), moderate RI (30 = CLCr < 50 mL/min; N = 6), severe RI (CLCr < 30 mL/min, but not on dialysis; N = 6), and end stage renal disease (ESRD, requiring dialysis; N = 6). Subjects with NRF, mild, moderate or severe RI received a single 25-mg oral dose of lenalidomide. Subjects with ESRD received 2 single 25 mg doses which were separated by 7–10 days: one dose on a non-dialysis day and the other dose 3 hours before a 4-hour haemodialysis. Assessments included PK and safety parameters. Results: All subjects completed the study. Total and renal clearance of lenalidomide were strongly correlated with CLCr (R > 0.9, p < 0.01). As a result, AUC8 increased with decreasing CLCr. The mean difference in AUC8 between NRF and mild RI was < 20%. Compared with the pooled data from NRF and mild RI groups, mean AUC8 increased approximately 140% in moderate RI, 240% in severe RI, and 360% in ESRD (off dialysis). There was no correlation between Cmax or Tmax and CLCr. Approximately 10% of the dose was recovered in the dialysate of subjects with ESRD. Protein binding of lenalidomide was not markedly affected by RI (∼35 - 44%). The drug was well tolerated. On the basis of these data, recommendations for initial starting doses were made ( Table below). Conclusions: Lenalidomide dosage adjustment should be considered for patients with CLCr < 50 mL/min.

[Table: see text]

No significant financial relationships to disclose.
Phase I and pharmacokinetic (PK) dose-adjusted study of IV vinflunine (VFL) in cancer patients with liver dysfunction (LD): Pharmacokinetic results
Authors: Paule B. , Saliba F. , Gil-Delgado M. , Puozzo C. , Favrel S. , Ravaud A. , Delord J. , Fumoleau P.
Published: March 2020

2523

Background: VFL is a novel microtubule inhibitor of the vinca alkaloid class that has shown high antitumour activity in several in vivo tumour models and in clinical trials. VFL is mainly eliminated through metabolism and bile excretion. Therefore this trial was designed to determine if LD could increase exposure and toxicity of VFL and require a dose-adjustment. Methods: This trial had a sequential design with the objective of determining the maximal tolerated dose (MTD) and the recommended dose (RD) in three groups of LD based on clinical and biological criteria: mild (PT > 70% and UNL < serum bilirubin = 1.5xUNL), moderate (Child-Pugh A) and severe (Child-Pugh B). VFL and 4-O-deacetylvinflunine (DVFL), its only active metabolite, were quantified in whole blood during cycle 1. PK parameters (AUCinf, Cltot) were estimated using a non-compartmental analysis and were compared using a one-way ANOVA with group factor either between groups or between groups and a control group of 49 patients without LD enrolled in phase I trials). Results: Three VFL doses were investigated: The inter-individual variability (CV) in AUCinf was approximately 30% for all groups. Even if AUCinf increased between mild and moderate groups, no difference was demonstrated between moderate and severe LD groups. All individual values were within the range of control values. Cltot were also similar between groups and the control group. Statistical analysis did not evidence any significant difference between groups. No difference was observed in blood concentrations of DVFL compared to the control group. No relationship between dose limiting toxicity and blood exposure was evidenced. Conclusions: The results showed that vinflunine and DVFL pharmacokinetic parameters do not appear to be affected by the degree of LD. However, the dose of VFL has to be adjusted to the level of LD for safety reasons.

[Table: see text]

No significant financial relationships to disclose.
Population PKPD of paclitaxel and carboplatin in ovarian cancer patients: A study by the EORTC-PAMM-NDDG
Authors: Joerger M.
Published: March 2020

2529

Background: Paclitaxel (P) and carboplatin (C) are considered standard first-line treatment in advanced ovarian cancer following cytoreductive surgery. Threshold-models have been used to predict P PKPD, whereas the time above P plasma concentration of 0.05- 0.2 μmol/L (P tC>0.05–0.2) predicts neutropenia. The objectives of this study was to build a population PKPD-model of PC in ovarian cancer patients. Methods: 139 ovarian cancer patients received P 175 mg/m2 over three hours followed by C AUC 5 over 30 min. Plasma concentration-time data of PC were measured, and data processed using nonlinear mixed-effect modelling. Semiphysiological models with linear or sigmoidal maximum response, and threshold models were adapted to the data. Results: 105 patients had complete PK and toxicity data. In 34 patients with measurable disease, objective response rate was 76%. Neutrophil and thrombocyte counts were adequately described by an inhibitory linear response model. Mean P tC>0.05 was 61.4 hrs. P tC>0.05 was significantly higher in patients with a complete (91.8 hrs) or partial response (76.3 hrs) compared to patients with progressive disease (31.5 hrs) (p=0.02 and 0.05, respectively). Patients with P tC>0.05 > 61.4 hrs had a longer time to disease- progression compared to patients with P tC>0.05 < 61.4 hours (89.0 vs 61.9 weeks, p=0.05). P tC>0.05 was a good predictor for severe neutropenia (p=0.01), while carboplatin exposure (Cmax and AUC) was the best predictor for thrombocytopenia (p<10-4). Conclusions: In this group of patients, P tC>0.05 is a good predictive marker for severe neutropenia and clinical outcome, while C exposure is a good predictive marker for thrombocytopenia. (Biomed grant PL96–2333, JHM Schellens coordinator)

No significant financial relationships to disclose.
Prospective analysis of mRNA expression signatures as predictive tests in primary breast cancer
Authors: Hannemann J. , Halfwerk H. , Velds A. , Loo C. , Rutgers E. J. , Rodenhuis S. , van de Vijver M. J.
Published: March 2020

2531

Background: Preoperative chemotherapy is increasingly employed to treat primary breast cancer, allowing an ‘in vivo chemosensitivity test’. Markers which predict a pathological complete response are urgently needed to refine this strategy. This study was conducted to evaluate the use of gene expression profiling to predict response to neoadjuvant anthracycline- or taxane-based chemotherapy. Methods: Patients with operable or locally advanced HER2-negative breast cancer received preoperative chemotherapy: either dose- dense doxorubicin and cyclophosphamide (ddAC) or capecitabine and docetaxel (CD). Core needle biopsies were taken before treatment and gene expression profiling was performed using 35k oligo microarrays. Results: Gene expression profiles were obtained from pretreatment biopsies of 63 tumors. 27% of the patients achieved a (near) pathologic complete remission (pCR), 40% of the patients had a partial remission and 33% of the patients did not respond to chemotherapy. Based on the gene expression profiles, tumors were assigned to the previously identified “molecular subtypes” luminal, basal-like or ERBB2-like (Sorlie et al., PNAS 98: 10869, 2001). 13 out of 25 patients with a basal-like tumor (52%) achieved a complete remission, whereas for the luminal tumors a pCR was only obtained in 2 out of 29 patients. Using four published gene expression classifiers of response to chemotherapy, a reasonable separation between responders and non-responders could be observed for two of these. We also performed exploratory supervised classification analyses on our dataset to identify a novel classifier. This resulted in a classifier for response to therapy irrespective of the chemotherapy regimen used and a second classifier specifically associated with response to ddAC chemotherapy. We will perform validation of these classifiers in samples from patients that are currently being enrolled in the study. Conclusions: Basal-like tumors have a better response to neoadjuvant chemotherapy as compared to other tumor types. The identification of robust gene expression signatures for better response prediction may require larger patient groups and should probably be established separately for each of the molecular subtypes of breast cancer.

No significant financial relationships to disclose.
Pharmacogenomic (PG) analysis for prediction of individual response to paclitaxel in 5-FU-refractory metastatic gastric cancer: Prediction formula of tumor response using novel marker genes and genotypes associated with the toxicity
Authors: Ikeda R. , Yoshida K. , Takagane A. , Tsuburaya A. , Kobayashi O. , Sunouchi H. , Matsukawa M. , Tanimoto K. , Hiyama K. , Nishiyama M.
Published: March 2020

2538

Background: Taxanes offer hope for improving outcomes of metastatic gastric cancer patients including 5-FU failure cases, but the response remarkably varies among patients. We conducted this prospective PG study for paclitaxel monotherapy to develop a prediction formula of efficacy and to identify potent genetic markers of toxicity. Methods: Paclitaxel was intravenously given on Days 1, 8, and 15, every 4 weeks in 5-FU failure metastatic gastric cancer patients with typical eligibility criteria. Tumor and blood samples were collected before the initial paclitaxel administration for PG. PK analysis was done on day 1 of cycle 1. Tumor response and toxicity were evaluated by RECIST and CTCAE, respectively. Results: Forty-nine pts were enrolled, and up to date, 48 and 44 pts have been determined for worst toxicity and best tumor response, respectively. Observed response rate was 27.3% (12/44), and common grade 3/4 toxicities were neutropenia (31.3%) and leucopenia (20.8%). PG analysis demonstrated that CYP2C8*1C (w/v=27, v/v=5) and CYP2C8 -411T>C (w/v=24, v/v=10) were weakly associated with grade 3/4 leucopenia (p=0.087 and 0.092), and CYP2C8 IVS7+49T> A (w/v=9, v/v=6) might correlate with grade 3/4 anemia (p=0.039), although none of them correlated with any PK parameter. We identified 4 novel potent marker genes (SEPT5, MARN2, PER3, and PISA3) for paclitaxel efficacy in vitro through microarray expression analysis, and then successfully developed the best linear models, which converted the quantified expression data into objective clinical response, in terms of best tumor response (r=0.985, AICS=-5.269) and overall survival (r=0.980, AICS=6.953), using 15 and 13 data sets of gene expression and clinical response, respectively. At present, utility-confirmation analyses using other clinical samples appeared to show that the formulae could accurately predict tumor response. Conclusions: Polygenetic strategies using several known polymorphisms for toxicity and a prediction formula using 4 novel genes for efficacy would be of predictive value for individual response to paclitaxel.

No significant financial relationships to disclose.