bluuebunny/crossref_metadata_2025_split huggingface dataset:
Intragenic expression profile in tissue and plasma for the detection of TMPRSS2 rearrangements associated with prostate cancer
Authors: Sanders H. R. , Li H. , Qu K. Z. , Zhang Z. J. , Sferruzza A. D. , Albitar M. 
Published: August 2020

5162 Background: TMPRSS2 gene rearrangements have been reported in 40%-85% of prostate cancer (PCa) patients and have not been found in normal individuals or those with benign prostate hyperplasia (BPH). However, multiple partner genes, including ETS transcription genes, and breakpoints have been reported. We developed an assay based on TMPRSS2 5′ and 3′ intragenic differential expression (IDE) to potentially serve as a diagnostic or prognostic marker for PCa. Methods: We analyzed TMPRSS2 in FFPE tissue from 20 patients (9 PCa and 11 BPH) and plasma from 42 patients (32 PCa and 10 BPH). IDE was expressed as a ratio of 3′:5′ transcript levels which were determined by real-time RT-PCR using distinct primer/probe sets. A normal 3′:5′ ratio (≥30) was established by comparing nonmalignant cells to tumor cells from FFPE tissue. This cutoff was subsequently used to identify abnormal ratios in plasma specimens. Results: In FFPE tissue, 100% of PCa samples had a 3′:5′ratio <30 and 91% of BPH samples were ≥30 ( Table ). RNA in 48% of plasma samples passed our QC criteria for acceptability. The 3′:5′ ratios were <30 in 47% and ≥30 in 6.7% PCa plasma. Conclusions: By measuring IDE, we are not limited to screening for known TMPRSS2/ETS gene translocations. In tissue, this approach enabled us to identify patients with PCa vs. BPH with high specificity. Although work is needed to improve plasma RNA quality, IDE of plasma TMPRSS2 may be a useful non-invasive diagnostic or prognostic tool. [Table: see text] No significant financial relationships to disclose.
Anthracyclines in basal breast cancer: The NCIC-CTG trial MA5 comparing adjuvant CMF to CEF
Authors: Cheang M. , Chia S. K. , Tu D. , Jiang S. , Shepherd L. E. , Pritchard K. I. , Nielsen T. O. 
Published: August 2020

519 Background: MA5 randomized premenopausal women with node-positive early breast cancers to cyclophosphamide- methotrexate-fluorouracil (CMF) or cyclophosphamide-epirubicin-fluorouracil (CEF) adjuvant chemotherapy. This and other trials have shown that adjuvant regimens containing anthracyclines confer significant survival benefit to breast cancer patients. Meta-analyses have revealed most benefit in women with HER2(+) or TOPO2 (+) tumors. Population-based data suggest that patients with a core basal phenotype (negative for hormone receptors and HER2, positive for CK5/6 or EGFR) conversely have worse survival on anthracycline containing vs. CMF regimens. Here we test the hypothesis specified a priori that for basal breast cancers anthracyclines may be inferior, using data from MA5. Methods: From 710 patients in MA5, blocks suitable for tissue microarray construction were recovered for 549. Immunohistochemistry for ER, PR, HER2, Ki67, CK5/6 and EGFR was obtained, allowing stratification of 511 cases into intrinsic biological subtypes by published methods (Cheang MC et al. Clin Cancer Res 2008;14:1368–76). Prespecified analyses were conducted independently by the NCIC- CTG statistical centre. Results: In the CEF arm, patients with core basal tumors had a hazard ratio of 1.8 (log rank p=0.02) for overall survival (OS) relative to the other biological subtypes. In the CMF arm, there was no significant difference (HR 0.9, p = 0.7). The interaction between core basal status and treatment was borderline significant (p=0.06). Relapse free survival differences did not reach significance. Conclusions: Data from this randomized trial supports the hypothesis that anthracycline containing adjuvant chemotherapy regimens are inferior to adjuvant CMF in women with basal breast cancer. [Table: see text] No significant financial relationships to disclose.
Neo-tAnGo: A neoadjuvant randomized phase III trial of epirubicin/cyclophosphamide and paclitaxel ± gemcitabine in the treatment of women with high-risk early breast cancer (EBC): First report of the primary endpoint, pathological complete response (pCR)
Authors: Earl H. M. , Vallier A. , Hiller L. , Fenwick N. , Iddawela M. , Hughes-Davies L. , Provenzano E. , McAdam K. , Hickish T. , Caldas C. 
Published: August 2020

522 Background: Neo-tAnGo used a 2-by-2 factorial design, addressing: (i) gemcitabine (G) in a sequential neoadjuvant chemotherapy (CT) regimen of epirubicin/cyclophosphamide (EC) and paclitaxel (T); and (ii) the sequencing of these treatment components (EC then T ± G versus T ± G then EC). Methods: Patients (Pts) with early breast cancer (T2 tumours or above) were randomised to EC then T, T then EC, EC then TG or TG then EC. All components were given x 4 cycles. (E= 90 mg/m2 day (d)1 every (q) 21d; C = 600 mg/m2 d1 q21d; T = 175 mg/m2 d1 q14d; G = 2,000 mg/m2 d1 q14d.) The primary endpoint was pCR, defined as absence of invasive disease in the breast and axillary lymph nodes. 800 pts were required to detect 10% differences in the primary endpoint pCR rates, at the 5% (2-sided) significance level with 85% power. Stratification was by age, inflammatory/locally advanced disease, tumour size, clinical involvement of axillary nodes and oestrogen receptor (ER) status. Results: Between January 2005 and September 2007, 831 pts were randomised by 88 consultants from 57 UK centres. Characteristics were balanced across groups: 63% <50 years old, 25% had inflammatory and/or locally advanced disease, 79% of tumours <50 mm, 50% node positive and 34% ER negative. Two-reader review of 813 (98%) eligible pts'. pathology reports, blinded to treatment arm, were carried out. pCR rates were 17% (95% CI 14–21) for EC&T pts and 17% (95% CI 14–21) for EC&TG pts (p = 0.98). However the sequence T±G then EC, showed pCR of 20% (95% CI 16–24) compared with 15% (95% CI 11–18) for EC then T±G pts (p = 0.03). Adjustment by stratification did not alter results. Conclusions: The Neo-tAnGo results confirm those of the adjuvant tAnGo trial in terms of gemcitabine effect (ASCO 2008). The sequence of T±G-first has demonstrated a significant advantage in pCR compared with the more conventional anthracycline-first sequencing. [Table: see text]
Neoadjuvant chemotherapy in operable breast cancer with docetaxel, doxorubicin, and cyclophosphamide (TAC) or TAC followed by vinorelbine and capecitabine (NX): Final results and analysis of markers predicting response to treatment
Authors: Huober J. , von Minckwitz G. , Denkert C. , Kleine-Tebbe A. , Weiss E. , Zahm D. , Köhler G. , Mehta K. , Loib S. 
Published: August 2020

524 Background: The aim of this analysis was to determine the pathological complete remission rate (pCR) for the entire Gepartrio study population and to identify markers predicting response to NACT. Methods: The design of the Gepartrio study was described elsewhere (von Minckwitz et al.). Age at diagnosis, tumor size, lymph node status, estrogen (ER), progesterone (PgR), HER-2 status, histological type, and grade were assessed in uni- and multivariate analysis. Clinical response after 2 cycles TAC and pCR at surgery were used as efficacy endpoints. Results: 2072 pts were randomized depending on response after 2 cycles TAC. 1122 pts (54.2%) had a clinical response after 2 cycles and 385 (18.6 %) pCR. The highest pCR rate (60%) was observed in pts with triple neg tumors and < 40 years. In the HR pos/HER-2 pos pts the pCR rates were 17.6% vs. 9% for HR pos/HER-2 neg pts (p<0.001). In the HR neg subset absence of HER-2 overexpression (“triple neg tumors”) resulted in significantly improved pCR rates compared to the HR neg HER-2 pos subset (40.7% versus 31.6%, p=0.041). In univariate analysis predictors for both an early response and a pCR at surgery were age < 40 years, non T4 tumor, grade 3, neg hormone receptors (HR) and a triple neg status. Non lobular histology was only predictive for a pCR in univariate analysis. In multivariate analysis independent factors for early response were non T4 tu, tumors ≥ 40 mm, poor grading and neg HRs. Independent predictors for a pCR remained age < 40 years, poor grading, a non lobular subtype and triple neg tumors. Conclusions: The pCR rate for the whole study population of the Gepartrio trial was comparable to other neoadjuvant regimens. Markers identified as independent predictors may help in decision making for pts being considered for neoadjuvant chemotherapy. [Table: see text]
Molecular characterization of male breast cancer by standardized quantitative RT-PCR analysis: First large genomic study of 347 male breast cancers compared to 82,434 female breast cancers
Authors: Shak S. , Palmer G. , Baehner F. L. , Millward C. , Watson D. , Sledge G. W. 
Published: August 2020

549 Background: Because male breast cancer (BC) is rare, there is little known about the disease and treatment is extrapolated from female BC. Newer molecular technologies have not been used to profile male BC. We report here a study of quantitative gene expression by gender status in tumor specimens submitted for Recurrence Score testing. Methods: All estrogen receptor positive tumor specimens successfully examined in the Genomic Health laboratory from June 2004 through December 2008 were included. Quantitative expression for each gene was measured by the 21 gene oncotype DX assay on a scale from 0 to 15 (relative to reference genes), where a one unit increment is associated with a 2-fold change in expression. Results: There were 347 male and 82,434 female BCs. The males were older (mean age 63.8 vs 57.4 yrs). Standard histopathology was similar, although slightly more male BCs were ductal (83% vs 78%). Like female BC, there was a wide variation in gene expression in male BC. The distribution of RS in males and females was similar - RS mean (±SD) 18.1 (±11.2) in males and 19.1 (±10.2) in females (p = NS). The proportion of tumors with RS <18, 18 - 30, and ≥ 31 was 53.6%, 35.2%, and 11.2% in males and 53.4%, 36.3%, and 10.3% in females. Although the patterns of expression of the Oncotype DX genes were more similar than different in males and females some differences were notable. Mean expression of ER, PR, and SCUBE2 were 0.5 units higher in males. Mean expression of the proliferation genes, Ki-67, MYBL2, Survivin, Cyclin B1, and STK15, were 0.5 units higher in males. Mean expression of STMY3 was 0.9 units higher in males. Of note, whereas the level of quantitative ER significantly increased with increasing patient age in females (0.4 units per decade), little increase was observed in males (<0.1 units per decade). Conclusions: This large genomic study of male BC reveals a heterogeneous biology as measured by the standardized quantitative oncotype DX breast cancer assay, similar to that observed in female BC. Some differences, which may reflect the differences in hormone biology between males and females, were noted and deserve further study. [Table: see text]
Systematic review of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for ovarian peritoneal carcinomatosis: A more efficacious way of delivering intraperitoneal chemotherapy
Authors: Chua T. C. , Robertson G. , Farrell R. , Liauw W. , Yan T. D. , Morris D. L. 
Published: August 2020

5524 Background: Advanced and recurrent ovarian cancer results in extensive dissemination of tumor within the peritoneal cavity. The current evidence suggests that cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (HIPEC) may be a feasible option with potential benefits compared to the current standard of care in the treatment of peritoneal carcinomatosis from ovarian cancer. Methods: A systematic review of relevant studies before August 2008 was undertaken to document and report its efficacy. Each study was appraised using a predetermined protocol. The quality of studies was assessed. The patient characteristics, protocol of treatment, perioperative morbidity and mortality, and treatment outcomes were synthesized through a narrative review with full tabulation of results of all included studies. Results: In total, 15 non-randomized, observational studies were reviewed, comprising of 512 patients. All patients received HIPEC as part of the combined treatment with cytoreductive surgery. Cisplatin was the most common chemoperfusate. The mortality associated with the treatment ranged from 0 to 10%. The rates of severe morbidity ranged from 0 to 40%. The median time of follow up ranged from 14 to 64 months, the median disease-free survival ranged from 10 to 57 months and the overall median survival ranged from 22 to 64 months. In patients who had an optimal cytoreduction, the median survival ranged from 29 to 66 months, with a 3- and 5-year survival rate that ranged from 35 to 63% and 12 to 66%, respectively. Conclusions: The future for cytoreductive surgery and HIPEC in ovarian cancer is promising. More studies are called for to validate the efficacy of this treatment. For it to become generally accepted, the oncology community must commit to a randomized trial. Before this, the current treatment of cytoreductive surgery combined with adjuvant intraperitoneal and intravenous chemotherapy should remain the mainstay of treatment. No significant financial relationships to disclose.
Comprehensive CYP2D6 genotyping in a multiracial U.S. breast cancer population
Authors: Irvin W. J. , Carey L. A. , Olajide O. , Dees E. C. , Peppercorn J. , Chiu W. K. , Walko C. M. , McLeod H. L. , Evans J. P. , Weck K. E. 
Published: August 2020

553 Background: CYP2D6 genotyping has been suggested to avoid suboptimal responses to tamoxifen (T). Most studies to date are in white patients (pts) and focus on a limited number of genetic variants. In this clinical trial, we comprehensively examined CYP2D6 allele frequencies in women of heterogenous ethnicity taking tamoxifen (T). Methods: In LCCC 0801, pts on T ≥ 4 months and not on potent CYP2D6 inhibiting medications were genotyped using the CYP450 AmpliChip for 2D6 alleles: *1-*11, *15, *17, *19, *20, *29, *35, *36, *40, *41, *1XN, *2XN, *4XN, *10XN, *17XN, *35XN and *41XN. T dose was increased in pts with any intermediate or poor metabolizing (IM or PM) alleles [but not in pts homozygous for extensive metabolizing (EM) alleles]. Serial T metabolite levels are being assessed. Here we report the allele frequency data from this study compared to previously published cohorts. Results: 108 pts participated in the study: 24 (22%) African-Americans (AA), 76 (70%) non-Hispanic whites, 4 Asians, 3 Hispanics and 1 Spanish European. Genotyping revealed 28 (26%) EM/EM, 1 EM/UM (ultra-rapid), 29 (27%) EM/IM, 22 (20%) EM/PM, 8 (7%) IM/IM, 10 (9%) IM/PM, 9 (8%) PM/PM and 1 unknown. Conclusions: Pts in this trial had a similar frequency of PM alleles to previous reports, however a high proportion of pts have IM alleles. In particular, the majority (79%) of AA pts possess at least one variant allele. Since PM and IM genotypes have been associated with reduced T metabolism, this may have implications for T efficacy and emphasizes the importance of trials examining CYP2D6 genotyping as a determinant of T use. (Supported by Laboratory Corporation of America, Roche Diagnostics, NC UCRF, NCI SPORE.) [Table: see text] [Table: see text]
Association of ERCC1 protein expression to platinum resistance in epithelial ovarian cancer
Authors: Steffensen K. D. , Waldstrøm M. , Jakobsen A. 
Published: August 2020

5530 Background: Although platinum-based chemotherapy remains the cornerstone for treatment of ovarian cancer, some patients are resistant to the treatment and will therefore not benefit from the standard platinum-based chemotherapy. Preclinical and clinical data have suggested a potential use of ERCC1 (excision repair cross-complementation group 1 enzyme) as a molecular predictor of clinical resistance to platinum-based chemotherapy. ERCC1 is a key enzyme in the nucleotide excision repair pathway which is involved in the DNA repair mechanisms in tumor cells. The primary aim of the present study was to investigate if immunohistochemical expression of ERCC1 protein was associated with resistance to standard combination carboplatin and paclitaxel chemotherapy in newly diagnosed ovarian cancer patients. Methods: Formalin-fixed, paraffin-embedded tissue sections from 101 patients with newly diagnosed ovarian cancer were used for immunohistochemical staining for the ERCC1 protein. The percentage of positive tumor cells in each slide were scored as 0 if 0 % of the tumor cells were positive, 0.1 if 1 %-9 %; 0.5 if 10 %-49 %; and 1.0 if 50 % or more were positive. A semi quantitative H-score was calculated by multiplying the staining intensity (0–3) with the percentage score. The tumor was considered positive when the H-score was > 1.0. All patients received carboplatin-paclitaxel combination chemotherapy. Results: ERCC1 protein overexpression was found in 13.9 % of the tumors. Platinum resistance were found in 75 % of the tumors with positive ERCC1 protein expression compared to 27 % among the patients with negative tumor staining for ERCC1 (p = 0.0013). These findings translated into a significant difference in progression free survival in both univariate (p = 0.0012) and in multivariate analysis (p = 0.006). Conclusions: The data presented suggests a positive association between positive ERCC1 protein expression and clinical resistance to platinum-based chemotherapy. No significant financial relationships to disclose.
Randomized phase III study of canfosfamide (C, TLK286) plus pegylated liposomal doxorubicin (PLD) versus PLD as second-line therapy in platinum (P) refractory or resistant ovarian cancer (OC)
Authors: Vergote I. , Finkler N. J. , Hall J. B. , Melnyk O. , Edwards R. P. , Jones M. , Meng L. , Brown G. L. , Rankin E. M. , Burke J. J. , Rose P. G. 
Published: August 2020

5552 Background: Canfosfamide (C) is a glutathione analog prodrug activated by glutathione S-transferase P1–1. C is synergistic with PLD and PLD increases the expression of GST P1–1 and sensitivity to C in OC cells. Methods: 244 pts were planned with P refractory or resistant (progression within 6 mos. after P) OC following ≤ 2 P regimens, and measurable disease (RECIST). Pts received C at 1,000 mg/m2 and PLD at 50 mg/m2 IV or PLD at 50mg/m2 q4wks until tumor progression. Randomization was stratified by ECOG PS, best prior P response and bulky disease (≥ 5cm). Results: This multinational study randomized 125 pts until June 4, 2007 when the study was temporarily placed on clinical hold to review another C trial. The 65/60 pts were well-balanced for disease characteristics and received a median 3/3.5 cycles per patient (range 1–11/0–17) of C + PLD/PLD, 35 pts (21/14) discontinued study treatment(s) due to the hold, respectively. Most common adverse events (AEs) for C + PLD were hematologic at 66% vs. 44% for PLD and were manageable with dose reductions. Non-hematologic AEs were similar for both arms, except the incidence of Grade 2–3 Palmar-Plantar Erythrodysesthesia (PPE) (9% vs. 21%) and stomatitis (17% vs. 23%) was lower and less severe with C+PLD vs. PLD. Grade 4 PPE (2%) was only observed on the PLD arm. Overall median PFS, the primary endpoint, was 5.6 mos. for C + PLD and 3.7 mos. for PLD (p = 0.7243, HR = 0.92). Objective response rate (ORR) by RECIST was 12.3% for C + PLD vs. 8.3% for PLD. In a planned analysis, 75 pts (40 /35) who were P refractory or primary P resistant observed a median PFS of 5.6 mos. for C + PLD vs. 2.9 mos. for PLD (p = 0.0425, HR = 0.55). ORR for C + PLD was 15.0% (with 1 CR) vs. 5.7% for PLD. Stable disease was observed 42.5% on C + PLD and 37.1% on PLD; median duration of SD was 7.4 mos. and 4.1 mos., respectively (p = 0.0439, HR = 0.49). The median time to response was 2.8 mos. on C + PLD vs. 4.8 mos. on PLD. Conclusions: The overall PFS showed a positive but not statistically significant trend for C +PLD vs. PLD. In the P refractory or primary P resistant population, the median PFS was significantly longer for C+PLD than PLD alone. C may ameliorate the AEs of stomatitis and PPE known to be associated with PLD. [Table: see text]
Combined topotecan and lapatinib in patients with early recurrent ovarian or peritoneal cancer after first line of platinum-based chemotherapy: A French FEDEGYN-FNCLCC phase II trial
Authors: Joly F. , Weber B. , Pautier P. , Fabbro M. , Selle F. , Krieger S. , Leconte A. , Bourgeois H. , Henry-Amar M. 
Published: August 2020

5555 Background: High HER1 expression is associated with poor prognosis. Preliminary data have shown links between HER1 expression and topotecan efficacy. The objective of the trial was to evaluate the efficacy of the association of topotecan and lapatinib in non-HER screened patients who failed first line platinum-based chemotherapy within 12 months. Methods: Chemotherapy consisted of 4-week course of topotecan (d1, d8, d15, 3.2 mg/m2 IV) and lapatinib (1250 mg/d PO). Response was assessed using RECIST or RUSTIN criteria. The primary objective was global response (GR, i.e. CR, PR, and SD). Biomarker profiles were evaluated according treatment response. A two-step phase II trial was designed to include 54 patients assuming a GR rate of 75% for the combination compared to 55% for topotecan alone. Results: From March to September 2008, 39 patients (37 ovarian and 2 peritoneal carcinomas), median age 60 (18 to 80), were included in 16 institutions. Patients presented with FIGO stage I (n = 1), II (n = 2), III (n = 29), and IV (n = 7) disease. Twenty and 19 patients had disease relapse occurring < 6 and 6–12 months after initial chemotherapy respectively. 2 patients were non evaluable. After 1 to 8 cycles (median 2) of topotecan-lapatinib there were 0/2 PR, 7/9 SD, 12/7 progressions in patients who failed <6 or 6–12 months respectively. The GR rate was 46% (35 and 58%; 95% confidence limits, 30–63%) and the trial was prematurely stopped. Three patients developed toxicity leading to treatment discontinuation after 3 cycles. Biological data will be presented at meeting. Conclusions: Combined topotecan and lapatinib is associated with modest GR rate. Biological profiles of responders are pending. No significant financial relationships to disclose.