bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cxcr4 expression and risk of bone metastasis in patients with early breast cancer
Authors: Conforti R. , Xia W. , Boulet T. , Michiels S. , Delaloge S. , Spielmann M. , Hortobagyi G. N. , Pustzai L. , Andre F. , Cristofanilli M. 
Published: March 2020

10610 Background: CXCR4, a receptor for SDF1, has been reported to be involved in early metastatic process. This study aimed at evaluating i. prognostic value of CXCR4, ii. correlation between CXCR4 expression in primary tumors and occurrence of metastases in SDF1- expressing organs. Patients and Methods: CXCR4 expression in the primary tumor was analyzed by immunohistochemistry (Human CXCR4 MAb 170, R& D System, MN, USA) in 823 patients included in two randomized trials evaluating efficacy of anthracyclines-based chemotherapy over a no-chemotherapy arm. The prognostic value of CXCR4 expression was assessed by the Cox regression model adjusted for tumour grade, stage, estrogen-receptor (ER) status and age. Distant metastasis rates for a specific site (either as first event or as subsequent metastases) were calculated by time untill occurrence of metastasis or death. We predefined 4 recurrence sites of interest: liver, brain, lung and bone that are organs expressing SDF1. Results: CXCR4 was expressed in 92 of 794 assessable primary tumors (12%). There was no significant association between CXCR4 expression and clinical characteristics, except a trend for a higher rate of ER- positive disease in CXCR4+ tumors (p=0.05). CXCR4 was not prognostic for neither overall survival (Hazard Ratio (HR) = 1.03 CI95%=[0.63 - 1.67], p=0.90), disease-free survival (HR = 0.93 CI95%=[0.63 - 1.37] , p=0.93), nor incidence of overall metastases (HR= 1.36 CI95%=[0.87–2.12], p=0.17). We next assessed the incidence of metastases in SDF1-producing organs according to CXCR4 staining. While CXCR4 was not associated with an increased risk of liver (HR=0.67 [0.27–1.70] p=0.40), lung (HR=0.89 [0.20–3.87] p=0.87) or brain metastases (HR=1.04 [0.40–2.70] p=0.94), CXCR4+ tumors presented a higher risk of bone metastases (HR=2.17 [1.30–3.65] p<0.01). The 10 year incidence of bone metastases were 23% [14–33%] and 12% (10–15%] in CXCR4+ and CXCR4- tumors respectively. Conclusions: This study suggests that expression of CXCR4 in breast cancer is associated with higher rate of bone metastases, a finding concordant with data from mouse models (Kang et al, Cancer Cell). This finding might lead to further development of adjuvant strategies using bone-targeting agents (e.g. biphosphonates, CXCR4 inhibitors). No significant financial relationships to disclose.
Prominent vascular endothelial proliferation in clinically aggressive neuroblastoma
Authors: Peddinti R. , Zeine R. , Luca D. , Seshadri R. , Chlenski A. , Cole K. , Pawel B. , Salwen H. , Maris J. , Cohn S. L. 
Published: March 2020

10611 Background: Tumor blood vessels are disorganized and vascular endothelial cell proliferation (VEP) has been identified as a poor prognosticator in many adult cancers. To determine the clinical significance of VEP in neuroblastoma (NB), we evaluated blood vessel architecture in tumor sections from 51 children diagnosed at Children's Memorial Hospital, Chicago (CMH) and in 154 NB tumors on a Tissue Microarray (TMA) constructed at Children's Hospital of Philadelphia (CHOP). Methods: H&E-stained tumor sections were examined for the presence of structurally abnormal vessels and further characterized by immunostaining with anti-CD31 and von Willebrand factor (vWF) antibody to highlight endothelial cells. Tumors that contained vessels with disorganized walls and more than one endothelial cell layer were classified as VEP positive. Tumor sections that contained only thin walled vessels with no more than one layer of endothelial cells were classified as VEP negative. Associations between VEP and established clinico-pathologic features and outcome were assessed. Results: In the CHOP series, VEP was associated with high-risk group classification and MYCN amplification (p<0.001 and p=0.006). In the CMH series only 5 of the 10 children with MYCN amplification had VEP but 4 of these 5 patients have died, while there were no deaths in the subset of patients with MYCN amplified tumors that lacked VEP (n=5). In both study groups, VEP was significantly associated with Schwannian stroma-poor histology (CMH series: p=0.008; CHOP series: p<0.001) and decreased survival probability (CMH series: p=0.017; CHOP series: p= 0.014). Conclusions: The association between structurally abnormal vessels and poor outcome provides further support for the concept that angiogenesis plays an important role in determining the biologic behavior of NB tumors. Our results also indicate that angiogenesis is regulated differently in Schwannian stroma-rich versus stroma-poor NB tumors. Further studies investigating the activity of angiogenic inhibitors in children with clinically aggressive stroma-poor NB are warranted. No significant financial relationships to disclose.
Survival benefit of gefitinib treated non-small-cell lung cancer patients with exon 19 deletion mutations in epidermal growth factor receptor (EGFR), detected by a new sensitive PCR-based method
Authors: Nakajima E. , Sugita M. , Dziadziuszko R. , Tsuboi M. , Kato H. , Bunn P. A. , Franklin W. A. , Hirsch F. R. 
Published: March 2020

10614 Background: As for two common types of EGFR mutations, patients with exon 19 deletion mutations have longer survival than those with the L858R point mutations in exon 21 after treatment with EGFR inhibitors. We have developed a simple, polymerase chain reaction (PCR)-based method to detect exon 19 deletion mutations, and evaluated survival benefit of gefitinib treated patients with exon 19 deletion mutations versus patients without these mutations. Patients and methods: Tumor tissue was microdissected under stereoscopic microscopy from formalin-fixed paraffin-embedded sections, and DNA was extracted from tumor cells with DNeasy (Qiagen). Our method consisted of two different semi-nested PCRs with the deletion screening PCR and the common deletion specific PCR. All of the known deletions present in cell lines were detected by this method without direct sequencing. The result was validated by sequencing of exon 19. 73 non-small-cell lung cancer (NSCLC) Japanese patients treated with gefitinib were analyzed with this method. Study group consisted of 28 females (38%), 29 never smokers (40%) and 57 patients with adenocarcinoma (78%). Results: The PCR-based method detected mutations at mutant to wild type DNA copy ratio of 1/600, and in samples as small as 30 ng of purified DNA. Exon 19 deletion mutations were found in 25 (34%) patients. This method was more sensitive than conventional sequencing. The sequencing was performed in 19 patients with mutations and could not detect 3 deletions. Among 60 assessable patients 14 had overall response (23%). Objective response rates to gefitinib were observed in 7/21 patients with exon 19 deletion mutations (33%), and 7/39 patients without exon 19 deletion mutations (17%) (P = .211). Patients with exon 19 deletion mutations survived significantly longer than those without exon 19 deletion mutations (P = .017). Conclusions: The PCR-based method to detect exon 19 deletion mutations is cost effective and very sensitive, compared to previously described methods. We demonstrated survival benefit in NSCLC patients with exon 19 deletion mutations treated with gefitinib, and our PCR-based method is easily applicable for clinical use. No significant financial relationships to disclose.
Gemcitabine oxaliplatin (GEMOX) is an active combination in heavily pretreated metastatic breast cancer (MBC)
Authors: Penault-Llorca F. M. , Nayl B. , Mouret-Reynier M. , Leheurteur M. , Van Praagh I. , Durando X. , Ferriere J. , Cure H. , Chollet P. 
Published: March 2020

1082 Background: This study was performed to evaluate retrospectively the efficacy and tolerance of gemcitabine plus oxaliplatin (GEMOX) as salvage chemotherapy in patients with metastatic breast cancer (MBC) in a mono-institutional series. Methods: From January 2003 to March 2005, 38 MBC patients were treated at disease progression according to three schedules: (a) gemcitabine 1000 mg/m2 on day 1 and 8 and oxaliplatin 100 mg/m2 on day 1 every three weeks (n=30); (b) gemcitabine 1,000 mg/m2 on day 1, followed same day by oxaliplatin 100 mg/m2 every two weeks (n=7); (c) gemcitabine 1250 mg/m2 on days 1 and 8 and oxaliplatin 100 mg/m2 on day 1 every four weeks (n=1). Results: All patients (median age, 58 years) received prior chemotherapy for metastatic disease (median of four lines). Radiological response was assessed in 36 patients: 12 patients (33%) experienced a partial response and 11 patients (31%) had a stable disease. The median times to progression and survival were 4 months (range, 0–21 months) and 10 months (range, 2–24 months), respectively. A total of 233 cycles were administered with a median of 5.5 cycles per patient (range, 1–21 cycles). Grade 3/4 toxicity consisted of myelotoxicity in 26% of patients and neurotoxicity in 8%. Conclusions: This retrospective study suggests that GEMOX is an effective combination with a good tolerance profile in heavily pretreated MBC. Further evaluation of this regimen is warranted in this tumor indication. No significant financial relationships to disclose.
Cost-effectiveness of HER2 testing and trastuzumab therapy for metastatic breast cancer (MBC) patients in Sweden
Authors: Lidgren M. , Rehnberg C. , Wilking N. , Jönsson B. 
Published: March 2020

1088 Background: Trastuzumab is a monoclonal antibody that together with chemotherapy significantly improves time to progression and overall survival for MBC patients with tumours overexpressing HER2. The aim of this study was to analyse the cost- effectiveness of HER2 testing and trastuzumab in combination with chemotherapy compared with chemotherapy alone from a societal perspective in a Swedish setting. Methods: We used a Markov state transition model to simulate HER2 testing and subsequent treatment in a hypothetical cohort of 65 year old metastatic breast cancer patients based on the study by Marty et al (Marty et al, J Clin Oncol. Jul 1 2005;23(19):4265–4274). Outcomes included life-time costs, quality adjusted life years (QALY), and cost per QALY gained. Five different testing and treatment strategies were evaluated. Results: We estimated the cost per QALY gained to be about 485,000 SEK (approximately 70,000 USD) and the cost per life year (LY) gained to be about 332,000 SEK (approximately 47,000 USD) for the strategy of IHC testing for all patients, with FISH confirmation of 2+ and 3+, and trastuzumab and chemotherapy treatment for FISH positive patients. For the strategy of FISH testing for all patients, with trastuzumab and chemotherapy for FISH positive patients, we estimated the cost per QALY gained to about 561,000 SEK (approximately 80,000 USD) and the cost per LY gained to be 384,000 SEK (approximately 55,000 USD). The remaining testing and treatment strategies were dominated. Results were sensitive to changes in the quality adjustment of life years with metastatic disease, the risk of breast cancer related death, and test characteristics. Conclusions: Our analysis indicate that the present Swedish guidelines of IHC testing for all patients with metastatic breast cancer, with FISH confirmation of 2+ and 3+, followed by trastuzumab and chemotherapy treatment for FISH positive patients is a cost-effective treatment option. However, further research on budget impact of trastuzumab treatment and patient accessibility to trastuzumab treatment is needed. No significant financial relationships to disclose.
NEAT-A: Accelerated sequential epirubicin followed by CMF using pegfilgrastim is a feasible regimen for delivering dose dense chemotherapy in early breast cancer
Authors: Rea D. , Bowden S. J. , Gross L. , Poole C. J. , Hiller L. , Agrawal R. K. , McAdam K. F. , Earl H. M. , Anwar S. 
Published: March 2020

11001 Background: E-CMF [epirubicin (E) x 4 cycles every (q) 21 days (d), followed by classical CMF x 4 cycles q 28d] is established as highly effective adjuvant chemotherapy for early breast cancer (BC), reducing mortality by 30% compared with CMF alone [Poole NEJM 2006]. However, dose dense anthracycline-taxane schedules, accelerated with GCSF support, have been shown to be superior to conventional regimens [Citron JCO 2003, Burnell SABCS 2006]. Exploration of accelerated E-CMF is therefore of considerable interest. Methods: A non-randomised, multicenter trial was designed to explore the feasibility and tolerability of accelerated E-CMF chemotherapy for women with early BC. The primary endpoint was delivered dose intensity (DDI). The accrual target was 40 patients (pts). Pts were treated with 4 cycles E (100mg/m2) q 14d, with Pegfilgrastim (PF) (6mg sc) d2, followed by 4 cycles of Cyclophosphamide, Methotrexate, and 5-Fluorouracil (600/40/600mg/m2) administered intravenously d1 + 8, with PF d9, q 21d. Results: 44 pts were enrolled. Complete dose information from 40 pts and toxicity data from 336 cycles (44 pts) has been analysed. Median DDI was 96.7% of target. Delays of >2 d were recorded for 8% of cycles. Dose reductions were recorded in 4% of cycles. 90% of pts received >85% intended total dose and 85% of pts received >85% intended DDI. Percentage grade 2 and 3/4 toxicity reported per cycle were respectively: fatigue 34/12; all infections 7/4; emesis 19/4; bone pain 18/4; diarrhoea 7/3; dyspnoea 20/3; febrile neutropenia not applicable (na)/2; mucositis 12/0.3; and phlebitis 29/na. Hospitalisation occurred in 10% of cycles. One pt developed endocarditis in association with repeated line infections, and a further pt experienced severe delayed phlebitis requiring surgical intervention. Conclusions: Accelerated E-CMF with PF is feasible achieving high DDI in a majority of pts. Non-haematological toxicity was responsible for the majority of hospital admissions which were more frequent than anticipated. Relative efficacy of this regimen requires phase III evaluation. We have also completed a second study of accelerated E-CMF where 6 cycles of intensified CMF (800/50/600mg/m2) was delivered at 14 d intervals. No significant financial relationships to disclose.
Relationships between clinical and biochemical predictors of chemotherapy-related amenorrhea in premenopausal adjuvant breast cancer patients
Authors: Su I. , Alton J. , Sherman L. , Stankiewicz C. , Ratcliffe S. , DeMichele A. 
Published: March 2020

11011 Background: Premature ovarian failure (POF) is a major side effect of breast cancer adjuvant therapy. Predicting post- chemotherapy POF and reproductive status impacts decisions about fertility, contraception, menopausal issues and breast cancer treatment. We examined clinical and biochemical predictors of chemotherapy related amenorrhea (CRA) in premenopausal adjuvant breast cancer patients. Methods: We conducted a cohort study of 121 breast cancer patients with stages I-III disease, premenopausal at diagnosis, enrolled 1 to 4 years from chemotherapy. All patients received 4 cycles of doxorubicin and cyclophosphomide with or without 4 cycles of paclitaxel or docetaxel, at q2 (dose-dense) or q3 week intervals. The primary endpoint was CRA (amenorrhea > 12 months from chemotherapy start). Pretreatment menstrual status and clinical factors were collected prospectively; subjects were recontacted for additional information and venipuncture. Regression models were used to examine risk factors for CRA and log FSH. Results: Mean age was 43.2 years (range 26.7–57.8). Mean follow up from chemotherapy start to enrollment was 2.1 years (range 1.0–4.1). 68 subjects developed CRA, while 53 continued menstruating. In a model including age, tamoxifen use, dose density, chemotherapy regimen, ovarian suppression during chemotherapy, smoking, body mass index and race, only age (OR 1.57[CI 1.29–1.89], p<0.001), tamoxifen use (OR 7.25 [CI 5.89–34.87], p=0.01), and dose density (OR 3.38 [CI 1.16–16.50], p=0.03) had independent associations with CRA. Serum FSH at enrollment (n=112) was higher in CRA than in non-CRA (11.8 vs 45.8, p< 0.001). However, 39% (25/65) of CRA subjects had FSH < 40 mIU/mL, the biochemical threshold for menopause (mean 26.4, range 10.1–39.9). FSH was not associated with chemotherapy regimen (p=0.51) or schedule (p=0.21). Conclusions: Age, tamoxifen use, dose density and subsequent FSH were independently associated with CRA. Clinically, amenorrhea for more than 12 months did not always represent biochemical menopause. Better methods are needed to characterize ovarian function in patients after adjuvant chemotherapy. No significant financial relationships to disclose.
Mechanisms of bone metastasis (BM) growth in patients with metastatic breast cancer (MBC): An exploratory study
Authors: Ooi W. S. , Popovic S. , Kalina M. , Harriette K. , Singh G. , Gainford M. C. , Clemons M. 
Published: March 2020

1102 Background: The benefits of bisphosphonates (BPs) in reducing or delaying skeletal related events (SREs) in patients with BM have been attributed to their potent osteoclast (OC) inhibiting effect. However, despite the use of modern systemic anti-cancer therapy including potent BPs, many patients with BM continue to suffer from the consequences of their bone disease. An improved understanding of the basic mechanisms of bone destruction would allow further appropriate targeted treatment strategies to be developed. Methods: Archival paraffin embedded BM specimens from patients with MBC were examined for expression of OCs, receptor activator of nuclear factor kappa B (RANK), RANK Ligand (RANKL) and Osteoprotegerin (OPG). Histological specimens were also available for primary breast cancer, lymph node (LN) metastasis, normal breast and bone tissues for comparison. Results: BM specimens were available for 20 BP naïve pts and 2 pts treated with BP. OCs were significantly increased in the BM of the BP naive group compared to controls. There were no OCs seen in the BP treated group. RANK was expressed on tumor cells (TCs) in the both bone and nodal metastases but not on the primary cancer cells. It is also expressed on the OCs which were present in both BM and normal bone. While RANKL was absent in TCs, it was strongly expressed in all stromal cells (SCs) in all specimens and in osteoblasts. The OPG, while present in TCs of the BM and LN metastases, is not detected in the primary cancer. Conclusion: The mechanism of bone destruction in MBC are not fully understood and are clearly multifactorial. OCs may not be the singular obligatory factor for osteolysis in BM. Further investigation of various inhibitors of the RANK/RANKL/OPG pathways, may allow novel treatment strategies to be developed. No significant financial relationships to disclose.
Results of first-line weekly paclitaxel (P) + gemcitabine (G) in metastatic breast cancer (MBC): An AERO phase II trial
Authors: Mousseau M. , Serin D. , Petit T. , Priou F. , Zelek L. 
Published: March 2020

1103 Background: Three weekly paclitaxel and gemcitabine (PG) combination is recognised as an efficient treatment of metastatic breast cancer. Weekly paclitaxel has shown improved results comparatively with the three weekly administration. We conducted a study to evaluate a weekly schedule of PG combination in fist line treatment of metastatic breast cancer (MBC). Patients and methods: Patients with MBC were enrolled in this study to evaluate the feasibility and efficacy of P 80mg/m2 D1, 8, 15 and G 1,250 mg/m2 D1, 8 (at fixed dose rate of 10mg/m2 /min) and cycles were repeated every 21 days. This phase II trial had a 2 stages design. Overall response rate was the primary end point. Results: In the first step of the trial 19 pts were enrolled with a median age of 59.5 (range 40 - 74). Baseline ECOG < 2 in 89% of pts. Main metastatic sites were: bone (36 %), lung (36%), liver (36%) and lymph nodes (32%). 52 % of pts had only one metastatic site. Previous treatments included surgery (89%), radiotherapy (73%), anthracycline based chemotherapy (74%) and adjuvant hormontherapy (52%). 18 pts were evaluable for efficacy and toxicity. 6 achieved PR, 5 SD and 6 PD resulting in an ORR of 33%. All patients were evaluable for toxicity. Main grade 3–4 toxicities per patient were neutropenia (67%), febrile neutropenia (5%), anemia (17%), thrombocytopenia (33%), trasnsaminases leveations (11%) and dyspnia (5%). Chemotherapy was delayed frequently for toxicity reasons (delays or arrest for toxicity in 15 pts). Conclusion: This weekly PG regimen has some activity in MBC. Although life-threatening toxicities were uncommon, delays in haematological recovery are frequent, making the investigated schedule unsuitable for further studies. [Table: see text]
The statistical distribution of involved axillary lymph nodes in breast cancer: A SEER population-based study
Authors: Vinh-Hung V. , Guern A. , Storme G. 
Published: March 2020

11031 Background: The number of involved lymph nodes in patients with breast cancer is highly variable. It might be important to examine the frequency distribution (FD) of these numbers in order to characterize their variability. This study examines the FD’s statistical properties and determines what they imply in terms of statistical analyses. Methods: The data was based on the National Cancer Institute’s Surveillance, Epidemiology and Ends Results (SEER). It covered 109618 patients, in whom axillary dissection had been performed between 1973 and 2002, in 9 states or towns of the USA. The involved lymph nodes were fitted to different statistical distributions adapted to count data using the maximum likelihood method (ML). The fittings were evaluated with the Kolmogorov-Smirnov (KS) statistic (KS close to 1 indicates lack of fit and KS close to 0 indicates good fit) and with the chi2 statistic (large chi2 indicates lack of fit). Results: The FD showed a logarithmically decreasing frequency, i.e. log-concave type. The mean number of involved nodes was 1.1465 and the variance was 9.54. The fit with a Poisson distribution gave a chi2=7.18*106 and the KS was 0.389. The fit with a negative binomial distribution using the ML gave a chi2=291.7, and the KS was 0.0086, i.e. 45-fold improved fit. Discussion: The FD’s variance 9-fold larger than the mean number of involved nodes indicates important overdispersion, i.e. the variability increases when the number of involved nodes increase. The Poisson distribution is inappropriate as was shown by the chi2 and KS. Overdispersion implies that nodal metastases are not independent random events. Overdispersion might be explained by 1) subsets of patients had a higher than expected propensity of nodal involvement, and/or 2) nodal involvement is a cascade process in which the likelihood of involvement increases when more nodes are involved. The implication for further analyses is that building predictive models of nodal involvement should take into account overdispersion and use appropriate modeling distributions such as the negative binomial. Conclusion: The FD characterization indicated a log-concave type with overdispersion. This might be important to gain an insight into the mechanisms of nodal involvement and to improve their analyses. No significant financial relationships to disclose.