bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evaluation of circulating biomarkers of bone metastasis in early-stage breast cancer.
Authors: Dean-Colomb Windy Marie , Hess Kenneth R. , Young Elliana J. , Gornet Terrie , Handy Beverly Carol , Moulder Stacy L. , Ibrahim Nuhad K. , Pusztai Lajos , Booser Daniel J. , Valero Vicente , Hortobagyi Gabriel N. , Esteva Francisco J. 
Published: March 2020

10613 Background: Bone is the preferred site for metastasis of breast cancer, affecting approximately 70% of women with advanced disease. N-terminal of procollagen type 1 (P1NP), c-terminal peptide crosslinks (CTX), Osteocalcin (OC) and interleukin-6 (IL-6) are markers of bone turnover that may have clinical utility as predictors of breast cancer recurrence in the bone. Methods: Serum was collected from 168 patients with stage I/II/III breast cancer prior to treatment from 09/2001 to 12/2008 and stored at -80 C. Serum levels of P1NP, CTX, OC and IL-6 were determined using the Roche’s Elecsys 2010 automated immunoassay system. Correlations of biomarker levels with time to bone metastasis (BM) development were assessed with Cox proportional hazards regression analysis and the Kaplan-Meier method. Results: Among the 168 patients analyzed, 60 patients subsequently developed BM. The biomarkers all had skewed distributions with long right tails and thus were all analyzed on the log scale. Residual analysis suggested non-linear relationships between each biomarker and risk of developing BM during follow-up. Thus, we fit Cox proportional hazards regression models for each biomarker with quadratic polynomials (on the log scale). On univariate analysis, these analyses generated p = 0.33 for IL-6, 0.26 for osteocalcin, 0.40 for CTX, and 0.032 for P1NP. Adjusting for clinical factors (stage, age, race, post menopausal, ER/PR status, HER2 status, nuclear grade) yielded p = 0.0035 for the quadratic polynomial for log P1NP. A cut-point of 75 ng/mL identified patients with a short time to development of BM. The 1, 3, and 5-year freedom-from-BM probabilities were 96%, 77% and 66% for the 150 patients with P1NP values ≤ 75 ng/mL and 88%, 45%, and 36% for the 16 patients with P1NP values > 75 ng/mL. The hazard ratio comparing patients with P1NP values ≤ 75 ng/mL to patients with P1NP values > 75 ng/mL was 3.0 (95% CI, 1.5 - 6.2) and p = 0.0075 ng/mL. After adjustment for clinical factors, the hazard ratio was 3.4 (1.5, 7.6) with p = 0.0026. Conclusions: Serum P1NP levels >75 ng/mL correlate with a shorter time to development of BM in patients with stage I-III breast cancer.
Predictive impact of RRM1 protein expression on vinorelbine efficacy in NSCLC patients randomized in a chemotherapy phase III trial.
Authors: Vilmar Adam , Santoni-Rugiu Eric , Sorensen Jens Benn 
Published: March 2020

10617 Background: Platinum based doublets remain the cornerstone of treatment in non-small cell lung cancer (NSCLC) and often includes gemcitabine. A biomarker predicting sensitivity to this antimetabolite would represent a major step forward in the management of advanced disease. Ribonucleotide reductase subunit M1 (RRM1) has been of some value in NSCLC but evidence is not uniform. Accordingly, we explored the predictive role of RRM1 in patients with advanced NSCLC. Methods: 443 patients with advanced NSCLC were randomized in a phase III trial to regimen A (paclitaxel and cisplatin with gemcitabine) or regimen B (cisplatin and vinorelbine). Immunohistochemical evaluation of RRM1 was performed on mainly bioptic material and correlated to response rates, progression free survival (PFS) and overall survival (OS). Results: 261 (58.9%) patients had representative tissue samples for RRM1 evaluation. Disease control rate, PFS and OS were significantly improved in patients with RRM-negative tumors receiving regimen B as compared to patients with RRM-positive tumors (68.8% vs. 31.2%, P = 0.046 , 6.90 months (mths) (95% CI 5.83-7.96) vs. 3.93 mths (95% CI 3.11-4.76), P = 0.000 and 11.57 mths (95% CI 9.65-13.48) vs. 7.4 mths (95% CI 5.37-9.43), P = 0.002, respectively). However, this was not the case for patients receiving regimen A (67.6% vs. 32.4%, P = 0.366, 6.73 mths vs. 7.6 mths, P = 0.207, 11.07 mths vs. 12.37 mths, P = 0.103, respectively ). Together with histological subtype, RRM1-positivity emerged as the only other significant prognostic variable with a hazard ratio of 1.56 (95% CI 1.38-2.35, P = 0.033) in multivariate analysis for patients treated with regimen B. Conclusions: RRM1 protein expression was without predictive impact in patients treated with cisplatin, paclitaxel and gemcitabine. Surprisingly, the predictive power proved robust in the cisplatin and vinorelbine arm across classic endpoints confirmed by multivariate analysis. These findings may suggest that RRM1 is involved in vinorelbine sensitivity and warrant further research which will be presented shortly.
Synthetic lethality of EGFR blockade in the context of tumor hypoxia.
Authors: Makino Haruhiko , Javvadi Prashanthi , Tomimatsu Nozomi , Saha Debabrata , Burma Sandeep , Nirodi Chaitanya 
Published: March 2020

10624 Background: Hypoxia induces a wide spectrum of biological responses in tumors that alter tumor radio-sensitivity. In several tumors, including non-small cell lung carcinoma (NSCLC), the epidermal growth factor receptor (EGFR) is frequently over-expressed and activated in response to hypoxia, although the precise role of EGFR in hypoxia-associated radioresitance is unclear. Activating mutations in EGFR have been clinically linked to dramatic responses to EGFR tyrosine kinase inhibitors. We previously demonstrated that NSCLCs harboring activating EGFR mutations are radiosensitive with severe deficits in the non homologous end-joining (NHEJ) repair of DNA damage. Methods: We investigated hypoxia associated radiation responses in a panel of NSCLC cell lines and immortalized human bronchial epithelial cells expressing wild type EGFR (WT) or expressed EGFR forms with somatic activating L858R or DE746-E750 mutations (MT). Results: (1) Relative to WT EGFR, MT EGFR expression is associated with significantly higher radiosensitivity under chronic hypoxia (2) Under hypoxic conditions, MT EGFR expression is associated with a unique spectrum of DNA damage responses (DDR) that significantly deviated from canonical response of WT EGFR expressing NSCLCs (3) Genome wide gene expression analysis identified a dramatic hypoxia-associated DDR shift to selective down-regulation of homologous recombination (HR). Moreover, MT EGFR deficits in NHEJ caused a synthetic lethality effect in the context of hypoxia through a simultaneous blockade of HR and NHEJ. (4) Blockade of WT EGFR by the anti-EGFR monoclonal antibody, cetuximab perfectly recapitulated the contextual synthetic lethality of MT EGFR expression. (5) Cetuximab had a dramatic synergistic effect on survival of rat lung orthotopic tumors where hypo-fractionated radiotherapy or cetuximab alone had marginally controlled tumors. Conclusions: The data support a critical role for EGFR-mediated DNA repair in hypoxia associated tumor radio-resistance. Furthermore, this role could be a target for refractory hypoxic EGFR-WT tumor especially in the context of hypo-fractionated radiotherapy which, in its current form, is potentially counter-productive for hypoxic tumors.
Intestinal HIF-2 to protect against radiation-induced gastrointestinal syndrome.
Authors: Taniguchi Cullen M , Wu Colleen , Atwood Todd , Maxim Peter , Giaccia Amato 
Published: March 2020

10629 Background: Gastrointestinal (GI) toxicity accounts for significant morbidity during systemic chemotherapy or abdominopelvic radiation therapy. Unfortunately, there are no effective preventative treatments. Hypoxic signaling through hypoxia-inducible factor-1 (HIF-1) and -2 (HIF-2) is critical for intestinal homeostasis during inflammatory challenges and was posited to play a role in radioprotection. Methods: We stabilized both HIF-1 and HIF-2 pharmacologically with the prolyl hydroxylase inhibitor DMOG and with transgenic mice. Male C57/Bl6 mice eight weeks of age were pretreated with saline or 8mg DMOG 16hrs and 4hrs prior to being irradiated with a single fraction of 20Gy to the abdomen using a modified TLI jig that shields the upper body of the mouse to reduce hematopoietic toxicity. After XRT, the mice got daily doses of saline or DMOG for 5 days. Results: Mice treated with DMOG had a 1.5-fold enrichment of crypt regeneration in the colon as determined by microcolony assay (13.3±3.4 vs 21.2±1.7 crypts/section, saline vs DMOG, n=10/group, p=0.005). Death from GI radiotoxicity can result from compromised epithelial integrity. We tested epithelial and barrier function by gavaging irradiated mice with FITC-dextran, which undetectable in the blood unless the GI epithelia is compromised. Treatment with DMOG decreased FITC-dextran uptake by 4-fold over controls (52.6±14.7 vs 12.4±3.4 mcg/ml, n=6/group, p=0.02). These physiologic improvements translated to improved overall survival with DMOG treatment after being exposed to 20Gy of abdominal radiation (p=0.03). To determine if the radioprotective effect of DMOG was specific to HIF-1 or HIF-2, we overexpressed stabilized HIF1 or HIF2 in the intestinal epithelia using a lox-stop-lox (LSL) system and Villin-Cre. The overexpression of HIF1 had no effect on survival (p=0.22), while mice with intestinal-specific HIF2-overexpression had significantly improved survival after receiving 20Gy of abdominal radiation (p=0.001). Conclusions: Activation of HIF-2 is sufficient to protect mice from lethal doses of abdominal radiation may provide a novel class of treatments to protect the GI epithelium from the deleterious side effects of chemotherapy and radiation.
Molecular profiling of uveal melanoma patients.
Authors: Gatalica Zoran , Danenberg Kathleen D , McGinniss Matthew Jerome , Ghazalpour Anatole , Bender Ryan P , Ashfaq Raheela , Arguello David , Wright Brian , Griffin Nicole , Basu Gargi D. 
Published: March 2020

10630 Background: Although uveal melanoma represents only 5% of all melanomas, it is the most common primary intraocular malignancy of the adult eye. Approximately 50% of patients will develop metastases which are resistant to medical interventions. There is a great need for improved therapy as the prognosis is poor for advanced stages. Our study was undertaken to investigate the presence of novel therapeutic targets. Methods: We analyzed 49 uveal melanoma patients with immunohistochemistry for 16 markers including cKIT, PDGFR, cMET, PTEN and IGF1R. Further, microarray analysis was performed on 29 samples using the Illumina platform. We also investigated amplification of EGFR and mutational analysis of cKIT, BRAF, KRAS and NRAS on a smaller patient subset. Results: Overexpression of KIT at the protein and RNA level was 74% (28 out of 38) and 45% (13 out of 29), respectively. Expression of cKIT did not correlate with gain-of-function cKIT mutations in any of the 34 samples tested. In our study, MET was overexpressed in 15 out of 17 cases at the RNA level and IGF1R was high in 4 out of 6 patients indicating poor prognosis. PTEN expression by IHC was present in 90% (36 out of 40) patients indicating the PI3K pathway is not activated in the majority of uveal melanoma patients. BRAF was wildtype in all 42 patients tested. Similarly, no KRAS or NRAS mutations were detected. Protein and RNA expression of PDGFR were low in our patients. MGMT was lost in 16 out of 40 patients at the protein level and 10 out of 29 patients at the RNA level. EGFR expression, copy number and protein levels were low in the patients tested. Conclusions: Our data on cKIT suggests that it is a promising target in uveal melanoma. Low expression of MGMT in about a third of our patients may indicate the likelihood of favorable response to dacarbazine and temozolomide. There are currently several clinical trials investigating various cKIT inhibitors, as well as temozolomide in advanced uveal melanoma patients. Our findings highlight the importance of molecular profiling uveal melanoma patients.
Accuracy of MRI, mammography (MG), and 2D and 3D ultrasound (2DUS/3DUS) in determining the pathologic tumor response after neoadjuvant chemotherapy (NACT) in breast cancer patients.
Authors: Hahn Markus , Siegmann Katja C. , Meisner Christoph , Steinhoff Ann-Katrin , Hattermann Valerie , Fehm Tanja N. , Hartkopf Andreas D. , Wallwiener Markus , Vogel Ulrich , Wallwiener Diethelm 
Published: March 2020

1067 Background: The pathological tumor response in patients with locally advanced breast cancer to NACT is essential for survival and for surgical strategies. Therapy monitoring based on German recommendations is routinely performed by clinical examination, MG and 2DUS. The clinical value of MRI and 3DUS has not been established yet. The aim of the study was to determine the accuracy, sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) between the different imaging techniques in predicting postoperative histological tumor response after NACT. Methods: Patients with primary breast cancer (cT1-T4, cN0-1, M0) undergoing neoadjuvant chemotherapy between 2005 and 2010 were eligible for this prospective trial. The response was measured by MRI, MG, 2DUS and 3DUS for complete or partial remission versus stable disease after the last cycle of treatment and compared with the final pathological response. Patients with progressive disease were excluded from the study. Statistical analysis was done by calculating the accuracy of each imaging technique and the size difference between imaging and histological tumor size. Sensitivity, specificity, PPV and NPV were calculated for complete or partial pathological response. The study was approved by the local ethic committee (BCD001 194/2004). Results: 103 patients with the mean age of 47.7 (range 24.5 – 71.4) years were evaluated. The accuracy was 0.680 (95%CI: 0.580 -0.768) for MRI, 0.563 (95%CI: 0.453-0.669) for MG, 0.724 (95%CI: 0.618 -0.815) for 2DUS and 0.710 (95%CI: 0.588-0.813) for 3DUS. Sensitivity, specificity, PPV and NPV were 78%, 47%, 75% and 52% for MRI, 61%, 45%, 69% and 36% for MG, 93%, 23%, 74% and 60% for 2DUS, 94%, 19%, 73% and 57% for 3DUS. The mean (standard deviation) size difference was -1.8 mm (14.8) on MRI, 1.5 mm (26.0) on MG, -9.1mm (19.1) on 2DUS and for the volume difference -6916mm3 (15831) on 3DUS. Conclusions: The data suggest that 2DUS is sufficient in predicting tumor response between NACT treatment. MRI and MG are more accurate the 2DUS in predicting the tumor size for surgical planning.
Prognostic impact of weight change during chemotherapy.
Authors: Kasprowicz Nikola S. , Hepp Philip Gm , Andergassen Ulrich , Scholz Christoph , Annecke Katja , Wischnik Arthur , Simon Wolfgang , Forstbauer Helmut , Augustin Doris , Zwingers Thomas , Harbeck Nadia , Sommer Harald Leo , Friese Klaus , Kiechle Marion , Janni Wolfgang , Rack Brigitte Kathrin 
Published: March 2020

1072 Background: Besides established prognostic factors such as tumor size or nodal status, individual host factors of the patient such as obesity, physical activity and diet seem to modulate the course of breast cancer (BC) as well. However, the specific impact of weight change during adjuvant chemotherapy remains unclear. The aim of this analysis was to evaluate the influence of weight change during chemotherapy on BC survival in a large, multi-center prospectively randomized trial. Methods: The ADEBAR trial compares two anthracycline based adjuvant chemotherapy regimen in patients (pts) with lymph node positive ( > 3 positive) early BC: 4 x epirubicin (E) 90 mg/m2 + cyclophosphamide (C) 600 mg/m2 q3w followed by 4 x docetaxel 100 mg/m2 q3w versus 6 x E 60 mg/m2 + 5-FU 500 mg/m2 d1+d8 and C 75 mg/m2 d1-14 q4w. Weight was measured before each cycle. The weight before the 1st and the 6th cycle was assessed. Significant weight change was defined as increase or decrease of > 5% of the initial weight. Overall survival (OS), disease free survival (DFS), and BC specific survival (BCSS) were assessed by Kaplan-Meier analysis. Results: In total, 1502 pts were included in the study. 1177 of them completed 6 cycles of chemotherapy. Out of the 350 pts (29.7%) who changed weight 142 pts (12.1%) lost and 208 pts (17.7 %) gained weight. There was a significant correlation between weight change and menopausal status (p<0.0001), indicating that more premenopausal pts gained and postmenopausal pts lost weight. All other tumor characteristics were similarly distributed across the groups. Pts with weight change > 5% showed a significantly worse outcome with respect to OS (p = 0.0028) and BCSS (p = 0.0258). A difference in DFS was not observed (p = 0.1917). The difference in OS was limited to pts who lost weight (p = 0.0008), whereas pts with weight gain have no significant different OS (p = 0.1246) in comparison to pts with constant weight. Conclusions: Our results suggest that weight loss during anthracycline-based treatment of early stage BC is associated with poorer OS. While weight normalization has shown beneficial effects in lifestyle intervention trials, patients should be advised not to lose weight during chemotherapy.
Phase III trial of first-line treatment with gemcitabine plus docetaxel versus gemcitabine plus paclitaxel in women with metastatic breast cancer (MBC): A comparison of different schedules and treatment.
Authors: Del Mastro Lucia , Fabi Alessandra , Mansutti Mauro , De Laurentiis Michele , Durando Antonio , Colantuoni Giuseppe , Zaniboni Alberto , Barni Sandro , Merlo Domenico Franco , Bruzzi Paolo , La Torre Ignazia , Ceccarelli Matteo , Kazeem Gbenga , Marchi Paolo , Boy Davide , Venturini Marco , De Placido Sabino , Cognetti Francesco 
Published: March 2020

1073 Background: Weekly (W) administration of Gemcitabine+Docetaxel (G+D) or Gemcitabine+Paclitaxel (G+P) at low doses may be associated with greater efficacy and/or lower toxicity compared to the standard 3-weekly (3W) schedule. Methods: Patients (pts) (360) with MBC, that relapsed after one adjuvant/neoadjuvant regimen containing an anthracycline (unless contraindicated) that was completed for at least 12 months, were to be randomized equally to a) D 75mg/m2 on Day1 + G 1000mg/m2 on Days1/8 q3W ; b) P 175mg/m2 on Day1 + G 1250mg/m2 on Days1/8 q3W ; c) D 30mg/m2 + G 800mg/m2 on Days1/8/15 qW; or d) P 80mg/m2 + G 800mg/m2 on Days1/8/15 qW. Primary endpoint was time to progression (TTP). Secondary endpoints were overall survival (OS), overall response rate (ORR) and overall toxicity (T). Results: Due to slow accrual rate, a futility analysis was performed to evaluate the chance of observing a significant result in favour of the alternative hypothesis. The results from this led to early study termination. 241 pts [median age (range) 57.0(31-77) years] were enrolled and randomized to: 3W G+D 60(24.9%); 3W G+P 64(26.6%); W G+D 58(24.1%); W G+P 59(24.5%), of which 18(30.0%), 24(37.5%), 14(24.1%) and 19(32.2%) pts respectively completed the study protocol (i.e. received 6 cycles, extended up to 10 for partial/complete responders). Median TTP [months(95%CIs)] was 8.33 (6.19-10.16) in W and 7.51 (5.93-8.33) in 3W, with 86.3% of pts progressed in each schedule. OS did not significantly differ between treatments and schedules. ORR was comparable between D and P, while it was higher in W than in 3W (50.4% vs. 33.1%; odds ratio 0.44 [95%CI: 0.26-0.75], p=0.003). Grade 3/4 Ts were 69.2% and 71.9% of pts in D and P and showed a higher trend in 3W (75.2%) than in W (65.8%). Neutropenia was the most frequent grade 3/4 T (51.7% and 44.7% in D and P; 39.3% and 56.5% in W and 3W). Conclusions: No substantial differences between treatments were observed in safety and efficacy. W might be associated with lower grade 3/4 Ts and possibly with a better tumour response compared to 3W. These results should be interpreted with caution due to early termination of the study.
Baseline comprehensive geriatric assessment to predict for toxicity of single-agent chemotherapy in elderly metastatic breast cancer patients: Results from the OMEGA study of the Dutch Breast Cancer Trialists’ Group.
Authors: Hamaker Marije , Seynaeve Caroline M. , Wymenga Machteld , van Tinteren Harm , Nortier J. W. R. , Maartense Eduard , de Groot Steffen , Smorenburg Carolien H. 
Published: March 2020

1080 Background: A comprehensive geriatric assessment (CGA) systematically appraises the somatic, psychosocial and functional health status of elderly patients. If CGA can predict toxicity of chemotherapy in elderly cancer patients, this assessment could be useful in deciding on optimal treatment. In this analysis, we evaluated the association between frailty on CGA or Groningen Frailty Index (GFI), and grade 3/4 toxicity in metastatic breast cancer (MBC) patients treated with first-line chemotherapy. Methods: In the OMEGA study, MBC patients (≥ 65 years) were randomized between PEGdoxo 45mg/m2every 4 weeks or capecitabine 2000 mg/m2 on days 1-14 every 3 weeks. Baseline geriatric assessment included functional status (ECOG performance status (PS), IADL), cognition (MMSE), mood (GDS), comorbidity (Charlson), polypharmacy and undernutrition (BMI) and GFI. Frailty on CGA was defined as one or more of the following: IADL≤13, MMSE ≤23, GDS ≥5, BMI ≤20, ≥5 medications or Charlson ≥2. GFI score for frailty was ≥4. Results: In total, 78 patients were randomized (PEGdoxo 38, capecitabine 40), median age 75 years (range 65-86). ECOG PS was 0-1 in 78% of patients and 2-3 in 22%. So far, 72 patients were evaluable for toxicity and baseline CGA. Overall, 50 patients (70%) were frail on CGA, and 40 (55%) according to GFI. Grade 3/4 toxicity related to chemotherapy was reported in 30 patients (42%) and 50% of CGA-frail patients experienced grade 3/4 toxicity, compared to 20% of CGA-fit patients (p=0.02). Grade 3/4 toxicity was experienced by 44% of GFI-frail patients, compared to 38% of GFI-fit patients (p=0.39). After correcting for type of chemotherapy and age, toxicity was associated with CGA-frailty (odds ratio (OR) 4.00, 95% confidence interval (CI) 1.77-13.59, p=0.03) while GFI-frailty was not associated with toxicity (OR 1.11, 95% CI 0.85-1.46, p=0.43). Conclusions: In this randomized study on first-line single-agent chemotherapy in elderly MBC patients, baseline CGA demonstrated a good predictive value for grade 3/4 toxicity of chemotherapy but GFI did not.