bluuebunny/crossref_metadata_2025_split huggingface dataset:
The impact of epoetin-alpha on anemia, red blood cell (RBC) transfusions, and survival in breast cancer patients (pts) treated with dose-dense sequential chemotherapy: Mature results of an AGO phase III study (ETC trial)
Authors: Moebus V. , Lueck H. , Thomssen C. , Harbeck N. , Nitz U. , Kreienberg R. , Jackisch C. , Schneeweiss A. , Huober J. , du Bois A. , Untch M. 
Published: March 2020

569 Background: Dose-dense chemotherapy has been shown to have a significant advantage in disease-free survival (DFS) and overall survival (OS) in high risk breast cancer pts, but leads to a higher number of RBC transfusions (CALGB C9741, AGO-ETC). Controversial results have been reported regarding the influence of Epoetin-alpha on DFS and OS in cancer pts. Methods: From 12/98 until 4/03, 1,284 pts were recruited into a multi-center phase-III trial. Breast cancer pts with at least 4 involved lymph nodes and below 65 years of age were randomized between a standard regimen (4 × EC followed by 4 × Paclitaxel) and a dose-dense arm consisting of three courses each of epirubicin (150 mg/m2), paclitaxel (225 mg/m2) and cyclophosphamide (2,500 mg/m2) at 2 weeks interval (ETC). A second randomization ± Epoetin-alpha was performed in the ETC arm only (150 IU/kg/sc three times weekly). Results: In 10/06, 1255 (98%) pts were evaluable. 658 pts were randomized in the dose-dense ETC arm, of whom 333 received Epoetin-alpha. Median follow- up is 62 months. Anemia was seen significantly more often in the ETC-arm alone compared to treatment with Epoetin-alpha (p<0.0001). Altogether, 11% of all patients were treated with RBC transfusions. Standard EC->T treatment resulted in 1% RBC transfusions, but 28% in the ETC arm alone vs. 13% in the ETC + Epoetin-alpha-arm (p<0.0001) received RBC transfusions. Despite this significantly higher transfusion rate the median Hb-value dropped from 12,8g/dl at cycle 1 to 10,7g/dl at cycle 9 in the ETC arm alone. In contrast the same value remained stable with Epoetin-alpha (12,4g/dl at cycle 1 and 9 each). At a median follow-up of 62 months, there is no difference between the ETC-arm alone and the ETC + Epoetin-alpha-arm concerning 5-year DFS and OS ((71% vs. 72% (p=0.86) and 83% vs. 81% (p=0.89)). Conclusions: The dose-dense adjuvant ETC-regimen significantly improves DFS and OS but is combined with relevant hematological toxicity. Epoetin-alpha significantly reduces the number of RBC transfusions and prevents anemia. However, the prevention of anemia has no influence on DFS and OS in the adjuvant treatment with dose-dense ETC. [Table: see text]
Nijmegen breakage syndrome 1 (NBS1) gene polymorphism and chemotherapy-induced neutropenic fever in breast cancer patients
Authors: Sun A. , Yu T. , Wang L. , Lu J. , Gonzales G. , Pusztai L. , Singletary S. , Ross M. I. , Wei Q. , Buchholz T. A. 
Published: March 2020

574 Background: Neutropenic fever (NF) is a serious complication of the chemotherapies given to breast cancer patients and often limits their use. Hence, identifying which patients are at increased risk to develop NF is very important. The NBS1 gene product is important for the repair of double-strand DNA breaks and is activated by chemotherapy. The objective of this study was to determine if genetic variations of NBS1 polymorphisms predict the risk of chemotherapy-induced NF in breast cancer patients. Methods: Blood from 306 newly diagnosed breast cancer patients treated with chemotherapy were prospectively collected on a study approved by the institutional review board. The relationship of chemotherapy administration (e.g. dose, timing) and growth factor use were correlated with the absolute neutrophil count (ANC) and NF development. For each patient, we assessed three polymorphisms (924T>C, 8360G>C, and 30537G>C) of NBS1 gene using polymerase chain reaction-restriction fragment length polymorphism method. Two-sided Chi-square test was used for univariate analysis and a multivariable logistical regression analysis was used to calculate odds ratios. Results: In total, 167 (55%) patients experienced ANC less than 1,000 cells/microliter (CIN1000) and 30 (10%) patients developed NF. For 8360G>C polymorphism, 9.7% of patients had a 8360CC variant genotype and these patients had increased risk of NF than the other genotypes (NF in CC 20.7% vs. in others 8.1%; Odds Ratio [OR] = 3.0; 95% confidence interval [CI] = 1.1 - 8.0, p = 0.034). In multivariable logistic regression model, 8360CC genotype (OR = 5.0, 95% CI = 1.6 - 16.1, p = 0.007) and growth factor support (OR = 19.6, 95% CI = 4.4 - 87.6, p < 0.001) were significantly associated with NF development. No genotypes of 924T>C and 30537G>C polymorphisms increased the risk of NF and there was no statistical association between the three NBS1 gene polymorphisms and CIN1000. Conclusions: Breast cancer patients with 8360CC variant polymorphism in NBS1 gene have increased risk in developing NF with systemic chemotherapy. Analysis of polymorphisms of NBS1 and other DNA repair genes could potentially help identify who will develop chemotherapy-induced bone marrow toxicities. No significant financial relationships to disclose.
Toxicity of concurrent radiotherapy with CMF chemotherapy in the E-CMF adjuvant breast carcinoma regimen
Authors: Church D. N. , Flubacher M. , Cameron A. , Bahl A. , Braybrooke J. 
Published: March 2020

582 Background: In the adjuvant management of breast cancer although delivery of radiotherapy (RT) concurrently with anthracyclines is contraindicated, toxicities are acceptable when the chemotherapy regimen used is CMF. The NEAT trial (NEJM 2006; 355:1851- 1862), presented at ASCO in 2003 demonstrated a significant survival advantage for sequential 4x epirubicin and 4x CMF chemotherapy (E- CMF) compared with 6x CMF and was adopted in the UK as a standard regimen. In order to limit treatment duration, RT may be given concurrently with chemotherapy during the CMF phase of treatment. We have reviewed the toxicity associated with this approach. Methods: Retrospective review of all patients treated with concurrent breast RT and CMF chemotherapy as part of the E-CMF regimen in our institution. Toxicities were graded according to the Radiation Therapy Oncology Group (RTOG) toxicity criteria. Confidence intervals were calculated by the binomial method using Stata version 9. Results: 77 patients received concurrent therapy between March 2004 and May 2006. Baseline characteristics; median age: 48, ER positive: 63.5%, HER2 positive: 11.7%, node positive disease: 85.7%. Type of surgery; lumpectomy: 61.0%, mastectomy: 39.0%, nodal dissection: 100%. Chemotherapy delivery; completed without delay: 35.1%, completed therapy with dose reduction/delay: 48.1%, discontinued therapy prematurely due to toxicity 16.8%. Sites of RT; breast: 62.3%, chest wall: 35.1%, axillary nodes: 45.5%, supraclavicular fossa: 36.4%. Schedule of RT; 50Gy/25#: 18.2%, 46/45Gy/20#: 67.6%, 45Gy/15#: 14.3%. Median interval between final dose of epirubicin and start of RT: 55 days. Toxicity; cutaneous grade 3–4 acute radiotherapy toxicity: 31.2% (95%CI 21.1–42.7%); cutaneous infective cellulitis: 14.3% (95%CI 7.4–21.1%); grade 3–4 neutropenia: 54.4% (95%CI 42.8–65.9%); febrile neutropenia requiring hospitalisation: 22.1% (95% CI 13.4–33.0%). The median duration of stay in hospitalised patients was 8 days (range 3–23 days). Conclusions: Toxicities were significantly greater than documented previously for concurrent therapy. RT should not be given concurrently with CMF chemotherapy as part of the E-CMF regimen. No significant financial relationships to disclose.
Three-year disease-free survival (DFS) as surrogate end-point for predicting five-year overall survival (OS) benefit in adjuvant taxane-based chemotherapy for breast cancer (BC): Analysis of 10 randomized clinical trials (RCTs)
Authors: Giannarelli D. , Bria E. , Cuppone F. , Ciccarese M. , Nisticò C. , Carlini P. , Milella M. , Lorusso V. , Terzoli E. , Cognetti F. 
Published: March 2020

584 Background: The issue regarding the eventual correlation between DFS at earlier follow-up (i.e. 3-yrs) with 5-yrs OS has not actually been explored in trials addressing the role of taxanes in BC. All RCTs in which patients were randomized to receive a standard or a taxane-based regimen for early BC were analyzed to evaluate this topic. Methods: All phase III trials with at least 60 month follow-up were considered eligible. The correlation has been explored according to a linear regression model considering both each single outcome pair (DFS/OS) for all arms (extracted by curves), their differences, and each outcome Hazard Ratio (HR) or calculated Relative Risk (RRs), following 2 steps: 1) correlation between 5-yrs DFS and OS (to confirm the evidence); 2) correlation between 3-yrs DFS and 5-yrs OS (predictive role). The correlation was estimated according to Pearson (r) and R2 coefficients (parametric) and Spearman (Rho) coefficient (non- parametric). A model to calculate the target sample size to determine 5-yrs OS benefit of 3%, 5% and 7%, respectively, was calculated as well. Results: Ten RCTs (17,067 patients) with available data for outcomes were gathered. For 5-yrs DFS/OS, a linear correlation was found between rates (r=0.74, R2=0.55; p<0.0001; Rho=0.83; p<0.0001), and HRs (r=0.90, R2=0.81; p<0.0001; Rho=0.91; p<0.0001). Three-yrs DFS correlates with 5-yrs OS, with both rates (r=0.81, R2=0.66; p<0.0001; Rho=0.92; p<0.0001), and RRs (r=0.84, R2=0.71; p=0.002; Rho=0.85; p=0.002). Three-yrs DFS and 5-yrs OS absolute differences strongly correlate (r=0.86, R2=0.74; p=0.001; Rho=0.84; p=0.002). The sample size model (on the basis of the r-coefficient=0.81), calculates 2,733, 863, and 389 pts to improve 3-yrs DFS of 4%, 7% and 10%, which means to improve 5-yrs OS of 3.2%, 5.7% and 8.1%, respectively. Conclusions: By these data, 3-yrs DFS is a reliable surrogate end-point for OS when testing new drugs in early BC, and is able to predict a late survival benefit. Thanks to the smaller patient sample size, RCTs with this design will provide early results in a shorter time period, allowing a faster data transfer to clinical practice. No significant financial relationships to disclose.
CYP2D6*4 polymorphism as blood predictive biomarker of breast cancer relapse in patients receiving adjuvant tamoxifen
Authors: Gonzalez-Santiago S. , Zárate R. , Haba-Rodríguez J. , Gómez A. , Bandrés E. , Moreno S. , Borrega P. , García-Foncillas J. , Aranda E. 
Published: March 2020

590 Background: Polymorphisms in cytochrome P450 2D6 gene affect the plasma concentration of tamoxifen active metabolites (endoxifen). Some drugs are known to be CYP2D6 inhibitors. We aim to determine the relationship between CYP2D6*4 polymorphisms, concomitant CYP2D6 inhibitors use and clinical outcomes of breast cancer patients receiving adjuvant tamoxifen (TAM). Patients and Methods: CYP2D6*4 (1934 G>A+1) genotype was determinated from DNA of blood samples using PCR-RFLP technique and Taqman Allelic Discrimination Assay in a series of 84 breast cancer patients receiving adjuvant TAM. CYP2D6 inhibitors were recorded. Chi-square test and logistic regression models were used to determinate association between genotype, use of concomitant CYP2D6 inhibitors and disease relapse rate. Results: In our 84 patients series mean age was 51.5y. (33–71). 14.8% were stage I, 58.0% stage II and 27.2% stage III. 61.4% were nodes positive and 98.7% tumors had positive hormonal receptors. We observed disease recurrence in 36.9% of cases. The mean following-up was 5.5 y. Genotype frequency was: wt/wt (57.1%), wt/*4 (40.5%) and *4/*4 (2.4%). 50% (18 of 36) of patients with the wt/*4 + *4/*4 genotypes had disease relapse compared with 27% (13 of 48) with wt/wt genotype (P= 0.041). Only 6 patients received concomitants CYP2D6 inhibitors, mainly antidepressants, all of them with the wt/*4 genotype. 50% presented disease relapse. Clinical pathological variables were evaluated and significant relation was found between stage and disease relapse by univariate analysis (P= 0.001). We investigated whether CYP2D6*4 genotype and stage to diagnosis could influence in disease relapse. For these analyses we use as reference group the genotype wt/wt. We observed that combined genotype wt/*4 + *4/*4 was more strongly associated with disease recurrence than wt/wt genotype (adjusted hazard ratio [HR], 2.82, 95% confidence interval [CI] 1.0- 7.9) P= 0.049. Conclusions: Breast cancer patients with the CYP2D6 *4/*4 or wt/*4 genotype could have lower benefit of TAM adjuvant treatment and tend to have a higher risk of disease relapse. Pre-treatment CYP2D6 genotype determination from blood sample could predicts TAM clinical outcomes and help to oncologist in treatment decision. No significant financial relationships to disclose.
Neoadjuvant chemotherapy with a dose-dense sequential combination of epirubicin and cyclophosphamide followed by paclitaxel and gemcitabine ± trastuzumab in stage II and III breast cancer. Correlation between pathologic complete response (pCR) and biologic markers
Authors: Sanchez A. , Dueñas-García R. , Jaén-Morago A. , Chacón I. , García-Tapiador A. , Martínez-Ortega E. , de la Torre-Cabrera C. , Dueñas B. , Ribelles N. , Sánchez-Rovira P. 
Published: March 2020

595 Background: To evaluate the efficacy, measured as pCR, and safety of a noncross-resistant sequential and dose- dense schedule as neoadjuvant treatment for early breast cancer patients (pts). To correlate pCR with gene expression. Methods: Histologically confirmed stage II-III breast cancer pts, including inflammatory tumors, were treated first with epirubicin and cyclophosphamide (90/600 mg/m2) for 3 cycles and then with paclitaxel and gemcitabine (150/2,500 mg/m2) for 6 cycles. All drugs were administered on day 1, every 2 weeks with growth factor support. Weekly trastuzumab (2 mg/kg with a loading dose 4 mg/kg) was given concomitantly with paclitaxel and gemcitabine in Her2 positive pts. A biopsy was performed before treatment for the gene expression study. Pts underwent surgery, radiotherapy and adjuvant hormonal therapy according to institutional practice. Results: 73 pts with a median age of 45.3 (range 28.6–73.6) were enrolled; 42 (57.5%) T2, 12 (16.5%) T3 and 19 (26%) T4 (13 inflammatory). Median tumor size was 4 cm (1–10). 30 pts (41.1%) were hormonal receptor negative, 32 (43.8%) ki-67 positive, 10 (13.7%) p53 positive, 31 (42.5%) GIII and 20 (27.3%) Her2 positive. All pts responded; 27 (36.9%) achieved a pCR (absence of invasive tumor in the breast); 32.1% in Her2 negative pts and 50% in Her2 positive pts. 47 pts (64,4%) underwent conservative surgery. G3/4 hematologic toxicities were leukopenia in 6 pts (9%), neutropenia in 8 pts (12%) and anemia in 1 (2%). Most frequent G3/4 nonhematologic toxicities were nausea (13%) and vomiting (15%). Asymptomatic decrease in cardiac ejection fraction was observed in 1 pt treated with trastuzumab with subsequent normalization. Conclusions: These results show a highly effective regimen in terms of pCR with a good toxicity profile. The addition of trastuzumab increased the pCR rate in Her2 positive pts. Updated results, including correlation between pCR and biological markers and disease-free survival will be presented at the meeting. No significant financial relationships to disclose.
The effect of margin status on local recurrence following breast conservation and radiation therapy for DCIS
Authors: Kell M. R. , Dunne C. , Canning C. , Morrow M. 
Published: March 2020

597 Background: There is no consensus on what constitutes an adequate surgical margin in patients receiving breast conserving surgery (BCS) and postoperative irradiation (RT) for ductal carcinoma in situ (DCIS). Inadequate margins may result in high local recurrence, and excessively large resections may lead to poor cosmetic outcome without oncological benefit. Methods: A comprehensive search for published trials which examined outcomes after adjuvant RT following BCS for DCIS was performed using medline and cross referencing available data. Reviews of each study were conducted, and data were extracted. Fixed and random effects methods were used to combine data. Primary outcomes were in breast tumour recurrence (IBTR) related to surgical margins. Results: Analysis of 3,606 patients from randomized trials confirms that patients with negative margins are significantly less likely to recur than those with positive margins after RT (RR 0.53, 95% CI= 0.42 to 0.66, p<0.01). Combined data from randomized and non randomized trials, of 5,500 patients, demonstrates that where the margin status is close or unknown there is significant risk of IBTR compared to a negative margin (RR=1.68, 95% CI= 1.22–2.33, p<0.01). When specific margin thresholds are examined a 2 mm margin is superior to less than 2 mm (OR=0.67, 95% CI 0.51 -0.89, p<0.01), however we saw no significant difference in the rate of IBTR between a 2 mm margin and >5 mm (OR=1.49, 95% CI 0.54 to 4.9, p>0.05). Conclusions: Surgical margins negative for DCIS should be obtained following BCS for DCIS. A margin threshold of 2mm appears be as good as a larger margin when BCS for DCIS is combined with RT. No significant financial relationships to disclose.
Prognostic significance of human papillomavirus (HPV) tumor status for patients with head and neck squamous cell carcinoma (HNSCC) in a prospective, multi-center phase II clinical trial
Authors: Fakhry C. , Westra W. , Li S. , Cmelak A. , Ridge J. , Pinto H. , Forastiere A. , Gillison M. 
Published: March 2020

6000 Background: Retrospective, single-institution studies suggest that patients with HPV- positive (HPV+) HNSCC may have a better prognosis than patients with HPV-negative (HPV-) tumors. Methods: The effect of tumor HPV status on treatment response and survival outcomes was prospectively evaluated in a multi-center, phase II clinical trial conducted by the Eastern Cooperative Oncology Group. Patients with newly diagnosed, resectable, stage III or IV HNSCC of the oropharynx or larynx were uniformly treated with two cycles of induction chemotherapy (IC; paclitaxel 175 mg/m2 and carboplatin AUC 6) followed by chemoradiation (CRT; weekly paclitaxel 30 mg/m2 administered concurrently with standard fractionation external beam radiation therapy, total dose of 70 Gy in 35 fractions over 7 weeks). Tumor HPV status was determined by in situ hybridization on formalin-fixed, paraffin-embedded tumors. The independent effect of tumor HPV status on survival was evaluated by Cox-proportional hazards models. Results: Genomic DNA of oncogenic HPV type 16, 33, or 35 was specifically located within tumor cell nuclei of 40% (95%CI 29.7- 50.1) of evaluable cases. Factors associated with HPV+ tumor in univariate analysis included Caucasian race (p=0.02), improved ECOG performance status (p=0.01), an oropharyngeal primary (p<0.001), early tumor stage (p=0.02), and basaloid histology (P<0.001). Response rates assessed after IC (81.6% vs. 55.2%, p=0.01) and CRT (84.2% vs. 56.9%, p=0.07) were higher in patients with HPV+ than HPV- tumors. After a median follow-up time of 39.1 months, patients with HPV+ tumors had a risk of progression that was 72% lower (HR=0.28, 95% CI: 0.07–1.0) and a risk of death that was 79% lower (HR=0.21, 95% CI: 0.06–0.74) than patients with HPV- tumors, after adjustment. Conclusion: The improved prognosis of HPV+ HNSCC has been confirmed in a prospective clinical trial and may be explained in part by enhanced sensitivity to chemotherapy and radiation. No significant financial relationships to disclose.
Incidence of human papillomavirus (HPV)-related head and neck cancers in the U.S. from 1998–2003: Pre-HPV vaccine licensure
Authors: Saraiya M. , Kawaoka K. 
Published: March 2020

6003 Background: While smoking and alcohol are implicated in the majority of head and neck cancers, human papillomavirus (HPV) has been responsible for 15–35% of head and neck cancers worldwide. In head and neck sites such as the oropharynx, tonsil, and tongue, HPV is associated with 50–90% of squamous cell cancers. Recent recommendation of an HPV vaccine, protecting against infection with HPV types 16 and 18 have prompted this current assessment of the burden of squamous cell cancers (SCC) at these sites. Methods: Using data from CDC’s National Program of Cancer Registries and/or NCI’s SEER Program for cases diagnosed from 1998–2003, covering 83% of the U.S. population, we assessed the squamous cell cancers (SCC) of the base of tongue, oropharynx, and tonsil in the U.S. population on the basis of age group, gender, race/ethnicity, stage, US region, and year of diagnosis. Incidence rates were age- adjusted to the 2000 U.S. standard population and are expressed per 100,000 individuals. Results: The average annual incidence rates per 100,000 individuals during 1998–2003 are: base of tongue, 1.16 (95% confidence interval 1.14–1.18); oropharyngeal, 0.90 (95% CI 0.89–0.92); and tonsillar, 1.35 (95% CI 1.34–1.37). Blacks have the highest incidence of base of tongue, oropharyngeal, and tonsillar SCC (1.25, 1.61, and 1.47, respectively) while Asian/Pacific Islanders have the lowest incidence (0.37, 0.25, and 0.49, respectively). The South has the highest incidence of base of tongue, oropharyngeal, and tonsillar SCC (1.24, 1.06, and 1.52 respectively). Tonsillar cancer had the highest incidence rates for Whites, Asian/Pacific Islanders, American Indians/Alaska Natives, and Hispanics (1.37, 0.49, 0.85, and 0.89, respectively), but oropharyngeal cancer was the highest in Blacks (1.47). Both base of tongue and tonsillar SCC show a significant annual increase (2.68%, 2.96%, respectively). Conclusions: Increasing incidence rates among those head and neck cancers that are HPV- associated such as tonsillar and base of tongue suggest that the HPV vaccine may have a significant impact on these cancers. No significant financial relationships to disclose.
The impact of previous tracheostomy in patients with locally advanced squamous cell carcinoma of the larynx submitted to concurrent chemotherapy and radiation
Authors: Dias F. L. , Herchenhorn D. , Small I. A. , Araújo C. M. , Ferreira C. G. , Kligerman J. 
Published: March 2020

6004 Background: The combination of chemotherapy and radiotherapy is a standard treatment for locally advanced larynx cancer. Patients presenting with previous tracheostomy due to aiway obstruction have a worse clinical outcome when submitted to a total laryngectomy or radiotherapy; the impact of previous tracheostomy is not clear in patients submitted to chemotherapy combined with radiation. Methods: A single-institutional study, patients with stage III and IV laryngeal carcinoma were prospectively selected from 2000 to 2003. Treatment consisted of Cisplatin 100 mg/m2 every three weeks for 3 cycles concurrent with radiotherapy to a total dose of 70.2 Gy. Prognostic factors like stage, age, performance status, chemotherapy completion, treatment response and previous tracheostomy were correlated on univariate and multivariate analysis with treatment response, progression-free and overall survival. Results: Forty-nine patients were selected, previous tracheostomy was performed in 12 (24,5%) before chemo/radiation therapy. Patients with tracheostomy had an inferior median overall cancer-specific survival (12 months versus 56 months), HR 2.37 (CI 95% 1.43–3.93) p=0.001, progression free-survival HR 2.8 (CI 95% 1.61–4.89) p<0.001 and lower rates of complete responses (40 versus 75%). The impact of previous tracheostomy was not altered when adjusted by number of chemotherapy cycles, tumor stage, performance status, age or treatment response. On a cox regression analysis for overall cancer-specific survival it was the strongest prognostic factor HR 7.75 (CI 95% 2.75–21.84) p<0.001. Conclusions: Previous tracheostomy is an independent negative prognostic factor for patients submitted to chemotherapy combined with radiation. Tracheostomty should be considered in the design of future studies and to select patients to different treatment strategies. No significant financial relationships to disclose.