bluuebunny/crossref_metadata_2025_split huggingface dataset:
Principal factor analysis of predictive markers of response and resistance to primary chemo-endocrine treatment in elderly breast cancer (BC) patients
Authors: Generali D. G. , Fox S. , Buffa F. M. , Berruti A. , Brizzi M. , Allevi G. , Bonardi S. , Dogliotti L. , Bottini A. , Harris A. 
Published: March 2020

618 Background: This study was undertaken to identify protein expression patterns able to predict response and resistance to chemo-endocrine therapy in elderly BC patients enrolled in a randomised phase II study. Methods: 114 women with T2–4 N0–1, estrogen receptor positive BC were randomly assigned to 6 months of primary Letrozole (L) (2,5 mg/daily) or L plus oral “metronomic” cyclophosphamide (50 mg/daily) (LC). Expression of 24 markers was assessed before treatment on TMAs. Markers were involved in signalling and angiogenic/hypoxia pathways as follow; erbB2, T regulatory cells, caspase3, BNIP3, phosphorylated ERaplha, CCDN1, mTor, Hif-1α, phd1, phd2, phd3, CA9, COX2, p38, p44, EGFr, PI3k, pAkt, CD31, VEGF, Ki67, p53, bcl2, herb2. Principal factor (PF) analysis attempts to identify underlying factors that explain the correlation patterns within a set of observed variables; here, PF analysis was used to reduce the marker expression data by identifying a small number of PFs that explained most of the variance observed. These PFs were introduced in a multivariate logistic regression (MLR) to study basal protein expression profiles with response to chemo-endocrine treatment. Clinical variables such as treatment, age, tumor size, nodal status, grading and histotype were also included in MLR. Results: 91 out of 113 evaluable patients (80.5%) attained a disease response, 48 patients a complete response (CR) (42.5%) whereas 22 did not respond (19.5%). The first 12 extracted PFs from PF analysis explained 80% of the expression data variance; these were considered in a MLR together with clinical variables. The 4th PF, mainly representing Hif-1α and p44 expression, and at lower degree EGFr expression, was the only independent predictor of disease response (OD=0.22, p=0.003). The 6th PF, mainly representing phosphorylated ERalpha expression, was the only independent factor associated with CR (OD=2.036, p=0.023). There was no interaction between these PFs and treatment randomisation. Conclusion: The activated form of ERalpha is with complete response, whereas Hif-1α and p44 were able to discriminate patients resistant to chemo-endocrine treatment. In this latter cohort, specific target therapies can be recommended. No significant financial relationships to disclose.
FGFR4 Arg388 allele is associated with resistance to adjuvant therapy in primary breast cancer
Authors: Thussbas C. , Nahrig J. , Streit S. , Bange J. , Kates R. , Ulm K. , Kiechle M. , Hoefler H. , Ullrich A. , Harbeck N. 
Published: March 2020

625 Background: Bange et al. recently found that a single-nucleotide polymorphism (SNP) at codon 388 of fibroblast growth factor receptor 4 (FGFR4) gene, causing a transmembrane domain missense mutation (Gly388Arg), is associated with outcome in node-positive breast cancer. Methods: This study addresses clinical relevance of this SNP, FGFR4 genotype, phenotype, and HER2 regarding patient outcome and influence of adjuvant systemic therapy in a substantial primary breast cancer collective (n=372; 1987–2002), median follow-up 94.5 months. Treatment was administered according to consensus recommendations at the time: 73 patients (all N0) received no adjuvant systemic therapy; 114 received adjuvant chemotherapy (87% CMF-based), 164 tamoxifen, 10 combined chemo-endocrine therapy, 11 unknown. 128 (36%) patients experienced disease recurrence, 104 (81%) distant relapses; 140 (38%) died. PCR-RFLP-analysis of germ-line polymorphism was performed in uninvolved lymph nodes; FGFR4 and HER2 expression were assessed immunohistochemically in tumor tissue arrays. Primary endpoint was DFS, since it best reflects impact of adjuvant systemic therapy. Results: In 51% of patients, homo- or heterozygous Arg388 allele was present. No correlation existed between FGFR4 genotype and expression or HER2 status. In N0 patients, FGFR4 genotype was not correlated with disease outcome. In N+ patients, however, FGFR4 Arg388 was significantly associated with poor DFS (p=0.02) and OS (p=0.04). Notably, this association seems to be attributable to relatively poor therapy response in Arg388 carriers, reflected in their significantly shorter DFS (p=0.02) and OS (p=0.045) among patients receiving adjuvant systemic therapy. It is also seen as a significant interaction term in a multivariate proportional hazards model with Arg388 carriers having only about half as much benefit from adjuvant systemic therapy as wild-type carriers. Conclusions: Our results show that the previously found association of FGFR4 Arg388 genotype with breast cancer progression is strongest in patients with adjuvant systemic therapy, particularly chemotherapy, and thus may reflect therapy resistance. No significant financial relationships to disclose.
Randomized phase II trial evaluating the efficacy of adding sequential half body irradiation (SHBI) to adjuvant chemotherapy in high-risk breast cancer patients with >10 positive lymph nodes
Authors: Barsoum M. S. , Gafar R. M. , Nazmy M. M. , Niazy A. 
Published: March 2020

627 Background: Adjuvant sequential half body irradiation (SHBI) is both interesting as well as scientifically sound approach with proven efficacy in many tumors. Methods: Patients with node positive (≥10) breast cancer were randomized in this phase II trial to receive either 6 cycles of adjuvant cyclophosphamide 500 mg/m2, 5FU 500 mg/m2 and epirubicin 100 mg/m2 followed by postoperative local irradiation (Arm A) versus the same adjuvant treatment plus consolidation SHBI staring 3 weeks after end of adjuvant treatment with upper half 750cGy /5 fractions /1week then one month gap followed by the lower half for the same dose (Arm B) Results: Between November 1999 and November 2000 a total of 70 patients who met the eligibility criteria were enrolled. Arm A (n=35) and arm B (n=35) were almost comparable with the respect to different prognostic factors. There was significant improvement in the disease free survival (DFS) at 5 years in arm B. The DFS was 65±8% in arm B while it was 33±8% in arm A (log-rank test: P =0.0036). In subset analysis the difference is apparent in subgroups of patients with less potential metastatic burden, which are T2 cases and ER positive cases. The DFS at 5 years was 83% in arm B and it was 35% in arm A (P=0.0008) in T2 cases. In the subgroup of patients with ER positive tumors (n=51), the DFS at 4 years was 58% in arm B and it was 25% in arm A (P=0.0072). The complications of the addition of SHBI were mild (grades 2 and 3) and mainly gastrointestinal (vomiting, diarrhea and colic). In both arms of the study there were no life-threatening complications or treatment-related mortality. Conclusions: SHBI was found to be a well-tolerated consolidation regimen with acceptable side effects and it showed significant improvement of the DFS in breast cancer patients with ≥ 10 positive lymph nodes especially in the relative cases with good prognosis (T2-ER positive). This makes it worthy of testing in a phase III trial. No significant financial relationships to disclose.
CYP2D6 genotypes in association with steady state plasma concentrations of active metabolites of tamoxifen in patients with breast cancer
Authors: Lim H. , Lee H. , Lee K. , Lee E. , Jang I. , Ro J. 
Published: March 2020

634 Background: Tamoxifen is a prodrug that is metabolized to active metabolites, Z-4-hydroxy-N-desmethyltamoxifen (BX) and Z-4-hydroxy-tamoxifen (4OH) where CYP2D6 plays a major role in the conversion. Genetic polymorphisms of CYP2D6 by ethnicities are well known with CYP2D6*10 in Asians (up to 50% in Koreans), and CYP2D6 *2 and *4 in American Whites as major variant alleles. We analyzed the steady state plasma concentrations of tamoxifen and its metabolites in patients (pts) with breast cancer to evaluate their associations with various CYP2D6 genotypes. Methods: Blood samples were collected from 219 pts on tamoxifen, 20 mg daily as adjuvant therapy for more than 3 months at National Cancer Center, Korea. Plasma tamoxifen, N-desmethyltamoxifen, BX, 4OH were measured by validated HPLC with fluorescence detector, and analyzed according to CYP2D6 genotype groups by Wilcoxon rank sum test. CYP2D6*10, CYP2D6*5 and CYP2D6*2×2 were identified by PCR-RFLP methods, and the rests were classified as CYP2D6*1 (wild type). This study was approved by IRB at National Cancer Center Hospital (NCCNHS04–033) and conducted after informed consent obtained by the patients. Results: Thus far, we measured plasma concentration of tamoxifen and its metabolites for 158 pts among 198 pts genotyped. 59 pts (29.8%) carried CYP2D6*1/*1, 84 pts (42.4%) *1/*10 and 49 pts (24.7%) *10/*10. Other types were CYP2D6*1/*5 (8.6%), *5/*5 (1.0%), *1/*2×2 (2.5%). Pts with CYP2D6 *10/*10 (n=40) demonstrated significantly lower steady state plasma concentrations of BX and 4OH than those with other genotypes (n=118) (BX: 7.9 vs.19.2. ng/ml [95 % CI; 5.5–10.4 vs. 15.8–22.7 ng/ml] p<0.0001; 4OH: 1.5 vs. 2.8 ng/ml [95 % CI; 1.1–2.0 vs. 2.3–3.3 ng/ml] p<0.0001), whereas there were no differences with *1/*10 (n=64) vs. without *10 allele (n=54) (BX: 20.6 vs. 18.1 ng/ml; 4OH: 2.9 vs. 2.7 ng/ml). Basically no significant differences in BX/4OH or other compounds by various CYP2D6*2 ×2 and *5 alleles were observed. Conclusions: The steady state plasma concentrations of BX and 4OH were significantly low with CYP2D6 *10/*10 genotype, and their clinical implications need to be explored.(Supported by a grant NCC-0410590). No significant financial relationships to disclose.
Randomized, multicenter, crossover phase II trial to compare exemestane (E) vs. anastrozole (A) in postmenopausal patients (pt) with advanced breast cancer (ABC) and positive hormone receptors (HR). Final efficacy analysis of GEICAM 2001–03 study
Authors: Mayordomo J. , Llombart A. , Martín M. , Antón A. , Barnadas A. , Antolín S. , Alés-Martínez J. , Álvarez I. 
Published: March 2020

638 Background: Head-to-head comparison of a steroidal aromatase inhibitor (AI) (E) vs. a non-steroidal AI (A) with crossover at the time of progression to evaluate the sequence of administration. Principal and secondary objectives were overall response rate (ORR), clinical benefit (CB) and time to progression (TTP). Methods: Postmenopausal pt with measurable ABC and positive HR, were stratified [previous tamoxifen (tam) (yes vs. no), previous chemotherapy (ct) (yes vs. no) and stage (IIIb vs. IV)], and randomized to E (25mg/day), or A (1mg/day) until progression. As per Simon’s test, with a p1 of 25% ORR and a p0 of 10% ORR, α and β errors 0.05 and 10%, 50 pt per arm were needed. Results: 103 (51 vs. 52) pt were recruited between 2002 and 2004. Main pt characteristics: median age 70 and 73 years, 82 vs. 88% stage IV, 12 vs. 17% previous ct, 51 vs. 50% previous tam, median size of lesions of 5 vs. 4 cm, mean number of lesions of 1.4 in both arms. Most frequent site of lesions were breast (33 vs. 35%), lymph nodes (22% vs. 25%) and connective tissue (27% vs. 23%). Efficacy: For initial treatment ORR was 37% (CI95% 24–51) in arm E vs. 52% (CI95% 38–66) in arm A (p= 0.151). 47% of pt in E vs. 60% in A presented CB (p=0.202). Mean TTP for arm E was 8.1 months (m) (1.1–15.2) and for arm A was 12.1 m (6.6–17.6) (p=0.4716). 11 pt (arm E) and 12 (arm A) crossed-over after progression. Following crossover mean TTP for E was 4.4 m (3.7–5.1) and for second line A was 1.9 m (0.1–3.7) (p=0.0172). Conclusions: E and A seem to be equivalent in terms of efficacy as first treatment for postmenopausal pt with ABC and positive HR. We suggest a possible advantage of the steroidal AI, exemestane, following disease progression on the non-steroid AI anastrozole. [Table: see text]
A multi-center study of the effects of toremifene (TOR) and anastrozole (ANA) on serum lipids and bone metabolism in postmenopausal patients with estrogen receptor (ER) positive breast cancer: Interim report
Authors: Mitsuyama S. , Yanagida Y. , Doihara H. , Komaki K. , Kusama M. , Ikeda T. , Kimura M. , Sano M. , Miyauchi K. 
Published: March 2020

645 Background: We have already reported the data that the antiestrogen TOR has better effects than tamoxifen on serum lipid metabolism (ASCO 2003, Breast Cancer Res. Treat 2004). In this study, we evaluated the time course effects of TOR and ANA on serum lipids profile and bone metabolism in ER positive, postmenopausal breast cancer patients with adjuvant hormone therapy. This is the first study to compare TOR and ANA. Methods: Patients were randomly allocated to a TOR40mg/day group (36 cases) or an ANA1mg/day group (33 cases). Serum lipids were measured at before, and 6 and 12 months after the initiation of administration. Changes in the serum lipids and bone markers were compared. Results: Results of lipids: In the TOR group, total cholesterol (TC), LDL, ApoB and Triglyceride (TG) significantly decreased at 6 and/or 12 months compared with the values before the start of administration (p<0.05). HDL and ApoA1 significantly increased at 6 and 12 months in the TOR group (p<0.0002), but ApoA1 at 12 months also significantly increased in the ANA group (p=0.02). Between the TOR and ANA groups, the changes in the percentage of the values of TC, HDL, LDL, ApoA1 and ApoB were significantly different at 6 and/or 12 months (p<0.05). Results of bone markers: BAP significantly increased in the ANA group (p<0.0001); in contrast, NTx significantly decreased in the TOR group (p<0.0001). Between the TOR and ANA groups, the changes in the percentage of the values of BAP and NTx were significantly different at 6 and 12 months (p<0.005). Conclusions: TOR and ANA have different profiles. These findings indicate that TOR has beneficial effects on both lipids and bone metabolism in postmenopausal patients with breast cancer. No significant financial relationships to disclose.
Pilot trial of a synthetic breakpoint peptide vaccine in patients with chronic myeloid leukemia (CML) and minimal disease
Authors: Maslak P. G. , Dao T. , Gupta S. , Gomez M. , Chanel S. , Korontsvit T. , Zakhaleva V. , Ashraf S. , Berman E. , Scheinberg D. 
Published: March 2020

6514 Background: CML is characterized by a tumor-specific fusion oncoprotein, BCR-ABL. Peptides spanning the B3A2 breakpoint of BCR-ABL can elicit MHC restricted T cell responses and clinical responses. No such data have previously been reported for vaccines targeting B2A2. Methods: We initiated a clinical trial administering synthetic analog breakpoint specific peptide vaccines for either B3A2 or B2A2 breakpoints to CML patients with major or complete cytogenetic remission. Measurable minimal disease was determined by either quantitative polymerase chain reaction (RQ-PCR) or nested PCR for BCR-ABL. Vaccine was administered with GM-CSF and Montanide ISA 51 subcutaneously. Eleven vaccinations were planned over the course of 1 year with the first 5 doses administered bi-weekly. Results: Eleven of 20 planned patients have been accrued to the study. Eight had documented cytogenetic remission and 3 were BCR-ABL positive via FISH analysis. Seven of the 11 patients had measurable BCR-ABL transcript levels as determined by RQ-PCR and all 11 were positive using the nested technique. Of the 5 patients positive for BCR-ABL (by RQ-PCR) before vaccination, 3 converted from RQ-PCR positive to negative while the transcript levels in the other patients decreased by approximately 1 log after 5 doses. All 5 of these patients remained positive using the nested PCR technique. Vaccination was well tolerated with local skin reactions at the injection sites. Immunologic reactivity was assessed ex vivo by CD4 autologous proliferation assay and T cell interferon (IFN) secretion (ELISPOT) assay. Ten of 11 patients were immunologically unreactive to the peptides prior to the vaccinations. Following the 5th dose of vaccine, 8/8 patients (including 2 with B2A2) tested showed significant immunologic responses by one of the above assays. Conclusions: These preliminary results suggest vaccination with synthetic analog peptides derived from CML proteins results in immunologic responses and may be associated with molecular improvement. Clinical efficacy of these vaccines in reducing/ eliminating minimal disease has yet to be established. [Table: see text]
Select high risk genetic features predict earlier progression following chemotherapy in chronic lymphocytic leukemia: Prospective randomized trial (Intergroup E2997) to evaluate justification for risk-adapted therapy
Authors: Grever M. R. , Dewald G. W. , Neuberg D. S. , Reed J. C. , Kitada S. , Flinn I. W. , Appelbaum F. R. , Larson R. A. , Tallman M. S. , Gribben J. G. , Byrd J. C. 
Published: March 2020

6521 Background: Genomic features including lack of IgVH mutations, del(11q), del(17p), and p53 mutations have been reported to predict clinical course and overall survival in CLL patients (pts). Bcl-2 family proteins and ZAP-70 have also been explored as predictors in CLL. Methods: We prospectively evaluated the prognostic significance of clinical features and laboratory variables on response and progression-free survival (PFS) following treatment with fludarabine (F, n=132) or fludarabine plus cyclophosphamide (FC, n=137) as part of the US Intergroup Trial E2997 for previously untreated CLL. Results: FC therapy had higher complete response (CR) (23.4% versus 4.6%), overall response (OR) (74.3% versus 59%), and median PFS (31.6 mos versus 19.2 mos) compared to F. CR and OR were not significantly different based on interphase cytogenetics, IgVH status, or p53 mutation. IgVH status or levels of ZAP-70, Bcl-2, Bax, Mcl-1, XIAP, Caspase-3, and Traf-1 proteins were not associated with clinical response or PFS. IgVH status and ZAP-70 levels were associated with time from diagnosis to treatment. Using a model including treatment arm, pts with del(17p) or (11q) had significantly shorter PFS (hazard ratios 3.54 and 2.05 respectively). In pts with a p53 mutation without del(17p) there was no enhancement of the model predicting poorer outcome, nor did IgVH status enter the model for predicting PFS. Conclusions: Combination chemotherapy is associated with a higher CR, OR, and PFS. Also, initiation of therapy for pts with Rai stages 0/1 resulted in a higher response rate. Del(17p) and del(11q) are highly predictive of shortened PFS with fludarabine-based chemotherapy. IgVH and p53 mutational status, as well as expression of ZAP-70, Bcl-2 family proteins, and CD38, did not predict response or PFS. ZAP-70 expression is associated with cytogenetic subsets predicted to have a worse overall prognosis, but did not identify pts who will do poorly with therapy. A combination of clinical staging and cytogenetics provide support for future risk-stratified treatment of CLL. Pts with a projected short response duration can be identified for future investigational strategies. No significant financial relationships to disclose.
Prognostic significance of WT-1 levels in patients with myelodysplastic syndrome and leukemia after reduced-intensity allogeneic transplantation
Authors: Michaelis L. C. , Sher D. , Myers M. , Siddiqui M. , Collins-Jones D. , Ulaszek J. , Huo D. , Wickrema A. , Van Besien K. , Stock W. 
Published: March 2020

6524 Background: Expression of WT-1, a zinc-finger transcription factor, is elevated at diagnosis in many kinds of leukemia. The prognostic significance of the WT-1 transcript level before and after stem cell transplant is controversial. We performed real-time quantitative PCR (RQ-PCR) on samples from pts with leukemia and MDS undergoing allo stem-cell transplant (SCT) to determine if WT-1 expression correlates with survival (OS) and/or disease-free survival (DFS). Methods: Pts were conditioned with fludarabine, melphalan and alemtuzumab. cDNA was synthesized for RQ-PCR, which was performed on bone marrow (BM) and peripheral blood (PB) samples drawn prior to transplant admission and at day 28 (D28) post transplantation. All samples were analyzed using LightCycler technology and reported as a normalized ratio of WT-1 copy number to ABL copy number. Results: Data on 48 patients who underwent allo SCT are reported here. During a median follow up of 17 months, 24 patients died and the OS rate at one year was 52%. The DFS rate at one year was 34%. There was a statistically significant association between pretransplant WT-1 levels measured in PB and OS, with increase in risk of death by 36% for every 10 fold increase in WT-1 levels (p=0.048). Pretransplant WT-1 levels in both PB and BM also predicted DFS: the risk of relapse or death was increased by 44% (PB) and 71% (BM) for every 10 fold increase in WT-1 levels (p=0.012; p=0.048). However, after controlling for disease status at transplantation using a Cox model, pretransplant WT-1 levels were no longer a significant predictor because these levels were highly correlated with disease status at transplantation. We did not find any significant correlation between WT-1 levels 28 days post-transplantation and outcome. Conclusions: Our preliminary results differ from several published studies demonstrating prognostic significance of WT-1 RQ-PCR after allo SCT. Although elevated WT-1 levels prior to transplantation correlate with higher risk of post-transplant relapse and death from any cause, these preliminary data fail to establish an independent prognostic role for WT-1 RQ-PCR in the setting of reduced intensity allo SCT. Analysis of additional post-transplant time points is proceeding. No significant financial relationships to disclose.
Graft-versus-tumor effect following reduced-intensity allogeneic stem cell transplantation in prostate cancer
Authors: Bregni M. , Bernardi M. , Ciceri F. , Rigatti P. , Peccatori J. 
Published: March 2020

6551 Background: Allogeneic transplantation has been utilized as adoptive immunotherapy for patients with solid tumors resistant to conventional therapy. Methods: In 2001 we started a pilot study of allogeneic hematopoietic cell transplantation after a reduced-intensity regimen in patients with metastatic, androgen-independent prostate cancer, aged 18–70, ECOG PS 0–1. Planned sample size was 10 patients. Primary endpoint was feasibility of the procedure. The conditioning regimen included thiotepa, fludarabine, and cyclophosphamide. Patients received allogeneic peripheral blood cells from an HLA-identical sibling. A median of 6.9×10e6 CD34+ cells/kg were infused (range 4.8–11.8). Graft-versus-Host Disease (GvHD) prophylaxis consisted of cyclosporine A and short-course methotrexate. All the patients were evaluable for engraftment and chimerism. Results: Six patients have been enrolled. The median age was 61 years (range 51–66). The median time to reach an absolute neutrophil count of 1.0×10e9/l and a platelet count of 20×10e9/l was 11 and 12 days respectively (range 10–14 and 11–16). All patients achieved complete lymphoid- and myeloid-chimerism at day +90 by cytogenetics or by VNTR polymorphism analysis. Median day of cyclosporine A withdrawal was +85. Three patients developed acute GvHD grade ≥2, usually soon after cyclosporine withdrawal. At a median follow-up of 401 days (range 93–682), 2 patients are alive and 4 died, 2 for disease progression (+214 and +275), one for CMV disease (+93) and one for hemorrhagic cystitis (+527). This last patient achieved an almost complete response confirmed on choline-PET scan after cyclosporine withdrawal and limited chronic GvHD. In other 4 patients we observed a PSA reduction, concurrently with cyclosporine withdrawal or development of GvHD. Conclusions: The close association between GvHD and/or cyclosporine withdrawal and tumor responses strongly suggests that tumor regression was associated with an immune-mediated reaction related to allografting. Future strategies will aim at enhancing the anti-tumor effect and at decreasing GvHD and transplant-related mortality. No significant financial relationships to disclose.