bluuebunny/crossref_metadata_2025_split huggingface dataset:
The haplotype of three polymorphisms in the SATB1 promoter-region and impact on survival in breast cancer patients.
Authors: Heubner Martin Leonhard , Kimmig Rainer , Siffert Winfried , Ulrich Frey 
Published: March 2020

584 Background: Special AT-rich sequence binding protein 1 (SATB1) has regulatory effects on gene expression and appears to play an important role in tumor progression. We screened the promoter region of the SATB1 gene for polymorphisms, evaluated the corresponding haplotypes regarding alterations in promoter activity in vitro and analyzed the impact of these haplotypes on the clinical course of breast cancer patients. Methods: 241 caucasian breast cancer patients who had been treated were enrolled in this retrospective analysis. The median follow up time was 93 months (4-155 months). PCR products from DNA of 10 healthy unrelated volunteers were analyzed to identify new polymorphisms within the promoter region. Genotyping was conducted using restriction length polymorphism and pyrosequencing. PCR constructs with the respective alleles from the four most frequent haplotypes were cloned into the vector pGEM-Teasy (Promega Corporation, Madison, WI, USA) and then transferred into the luc2-containing reporter vector pGl 4.10 Vector (Promega) for transfection of HEK293 cells. The pGl 4.73 Vector (Promega), containing hRluc, was used for norming the transfection rates. Results: Sequencing the region -3807bp to -2828 upstream from ATG of ten healthy blood donors, we found three single nucleotide polymorphisms SNPs consisting of base exchanges, -3600T>C, -3363A>G and -2984C>T.The SATB1 -3600T/-3363A/-2984C haplotype had a lower promoter activity than all other constructs in vitro and showed a significant association with the nodal status (p=0.049). Kaplan-Meier survival analysis revealed a significantly better survival for homozygous SATB1 -3600T/-3363A/-2984C haplotype carriers compared with heterozygous or the other haplotypes (p=0.033). Conclusions: The SATB1 -3600T/-3363A/-2984C haplotype is associated with lower promoter activity and appears to impact upon survival in breast cancer patients.
Predictive value of tumor infiltrating lymphocytes (TIL) for response to breast cancer neoadjuvant chemotherapy (NCT).
Authors: Garcia-Martinez Elena , Luengo-Gil Gines , Chaves Asuncion , Velazquez Lorena , Gonzalez-Billalabeitia Enrique , Vicente-Conesa Maria Angeles , Garcia Teresa , Garcia-Garre Elisa , Vicente Vicente , Ayala Francisco 
Published: March 2020

585 Background: The association of tumor microenvironment immune response with outcome after breast cancer (BC) NCT has been suggested by several studies. However, the relevance of each TIL subpopulation is still controversial. The objective of this study was to evaluate the predictive and prognostic value of TIL before and after NCT in patients with BC. Methods: We analyzed TIL and CD68 cells in pre- and post-chemotherapy biopsies of BC patients treated with NCT (80.4% sequential AC-docetaxel). A tissue microarray with paired pre- and post-NCT biopsies was built, and stained with immunohistochemistry (IHC) for CD3, CD4, CD8, CD20, FOXP3 and CD68. Morphometric analysis (TIL count/mm2) was performed after slide scanning and digitalization. Results: We included 121 consecutive patients with invasive BC, most of them with stages IIB (28%) or IIIA-C (56.4%). IHC phenotype: 50.4% Her2- hormone-sensitive (HS), 13.2% Her2+ HS, 10.7% Her2+ non-HS, and 21.5% triple negative. Pathologic complete response (pCR): 17.4%. Median overall survival (OS) and disease free survival (DFS) has not been reached (median follow-up: 60 months). Higher than median pre-NCT TIL infiltration was predictive of pCR to NCT: CD3 > 172/mm2 (p=0.001; Hazard Ratio [HR]: 9,61, 95% confidence interval [95%CI] 2.49–37.02); CD4 > 67/mm2 (p=0.001; HR: 8.82, 95%CI 2.43–31.96); CD20 > 42/mm2 (p=0.001; HR: 8.71, 95%CI 2.31–32.74). Logistic regression multivariate models including grade and IHC phenotype confirmed the independent predictive value of higher pre-NCT CD3, CD4, and CD20 for pCR. In the group of patients with HS Her2- BC without pCR (n=44), higher infiltration (cut-point: median value) by some TIL subpopulations and by CD68 cells in post-NCT residual tumor associated to lower DFS: CD8 > 37/mm2 (log-rank; p=0.04), CD20 > 14/mm2 (p=0.07) and CD68> 39/mm2 (p=0.06). Conclusions: Higher pre-treatment CD3, CD4 and CD20 TIL predicted pRC in patients with invasive BC receiving anthracyclines and taxanes NCT, while higher infiltration of residual tumor by CD8 associated to worse DFS in patients with HS Her2- BC without pCR after NCT. TIL might be useful as predictive factors in the setting of NCT for BC [Supported by GEICAM-Beca Ana Balil].
Management of breast cancer during pregnancy: Results of a large registry from a single institution.
Authors: Peccatori Fedro , Sarno Maria Anna , Azim Hatem Abdel , Gentilini Oreste Davide , Galimberti Viviana , Martella Stefano , Pruneri Giancarlo , Renne Giuseppe , Scarfone Giovanna , Fumagalli Monica , Sangalli Claudia , Locatelli Marzia Adelia , Rotmensz Nicole , Lambertini Matteo , Colleoni Marco , Goldhirsch Aron 
Published: March 2020

589 Background: Given the rising trend of delaying pregnancy to later in life, more women are diagnosed with breast cancer during pregnancy. Management is still controversial and relies on expert guidelines. Thus the experience of single centres with high patients’ volume remains of interest. Methods: All breast cancer patients (pts) diagnosed at the European Institute of Oncology (IEO) in Milan were included in a specific registry since 1995. Results: Out of 8340 patients < 47 y/o registered up to Dec 2012, 167 were diagnosed during pregnancy (2%). Median age was 36 years (24-47y). Median gestational age was 18 weeks (1-38 w). 73 % pts had a pT1-2 tumor, with positive nodes in 48%. 9,6% had luminal A, 38% luminal B, 26% basal like and 16% HER2+ tumors, according to St Gallen criteria. 29/167 pts (17%) opted for an induced abortion. Of the remaining 97 pts, 81 (84%) underwent definitive surgery during pregnancy; 58 (72%) and 23 pts (28%) had quadrantectomy and mastectomy, respectively. Immediate breast reconstruction was performed in 13 cases. Sentinel node procedure (SLN) was performed in 42 pts (52%), with positive axilla in 10 pts. 41 pts (51%) received chemotherapy during pregnancy. Regimens included weekly epirubicin (24 pts), EC/AC (12 pts), FAC/FEC (3 pts), q21 epirubicin (2 pts). No G3-G4 toxicities were reported. No pregnancy complications were observed, with the exception of 1 case of premature delivery at 28 weeks. Median gestational age at delivery was 36 weeks (29-40 w). No major malformations were observed. Gestational age at birth and birth-weight were similar in babies who received chemotherapy in-utero (36 w and 2555g) and in babies who did not receive gestational chemotherapy (37w and 2600g). At a median follow-up of 42 months (range: 1-178 m), all children had normal neurological and physical development with no late adverse effects observed. Conclusions: Managing breast cancer during pregnancy should follow standard practice as in non-pregnant pts. Surgeries like SLN and breast reconstruction were performed with no serious complications. Our results further emphasize the safety of anthracycline-based gestational chemotherapy without major effects on pregnancy course or fetal health.
ER as a predictor of early breast cancer (EBC) outcomes in patients.
Authors: O'Shaughnessy Joyce , Loesch David M. , Paul Devchand , Stokoe Christopher T. , Pippen John E. , Blum Joanne Lorraine , Krekow Lea , Holmes Frankie Ann , Vukelja Svetislava J. , Lindquist Deborah , Sandbach John F. , Sedlacek Scot M. , Wang Yunfei , Jones Stephen E. 
Published: March 2020

590 Background: Some ER-negative (ER-) breast cancers express low levels of estrogen receptors and approximately 12% express androgen receptors (Traina, T, et al. ASCO, 2012). Whether young premenopausal women (age <40) with ER- breast cancer (BC) who are more likely to retain ovarian function after adjuvant chemotherapy have a worse outcome than older women with ER- disease has not been widely investigated. Methods: We analyzed 2 adjuvant US Oncology BC studies: 99-016, 1830 BC patients randomized to doxorubicin/cyclophosphamide (AC)→Paclitaxel (P) (AC/P) vs AP→weekly P (no cyclophosphamide [C]) (AP/wP); and 01-062, 2611 patients randomized to AC→docetaxel (T) vs AC→T plus capecitabine (XT). ER+ patients received standard endocrine therapy following chemotherapy. Five-year DFS results did not show significant differences between the treatment arms on either study. The outcomes were analyzed for 5-year DFS by age ≤40yrs and >40yrs and by ER status. Results: In the two studies combined, ER- patients ≤40 had a superior DFS (84%) than ER- patients >40 (80%), while ER+ patients ≤40 had a worse 5-yr DFS (83%) than ER+ patients >40 (89%), although these findings were of borderline significance (see Table below). In 99-016, omitting C did not adversely affect outcomes in either age group, regardless of ER status. Conclusions: We did not observe worse outcomes in ER- patients ≤40 years compared to those >40 years in 2 US Oncology adjuvant chemotherapy trials, suggesting no adverse impact of assumed greater ovarian function following adjuvant chemotherapy in patients ≤40yrs. ER+ patients ≤40 had a worse DFS than ER+ patients >40. Omitting C in ER- patients ≤40 or >40 did not adversely affect outcome. [Table: see text]
4EVER: Assessment of circulating tumor cells with a novel, filtration-based method, in a phase IIIb multicenter study for postmenopausal, HER2- negative, estrogen receptor-positive, advanced breast cancer patients.
Authors: Fasching Peter A. , Gumbrecht Walter , Fehm Tanja N , Haeberle Lothar , Muth Mathias , Sickert Daniel , Pugia Michael , Friedrich Katja , Matzas Mark , Lueftner Diana , Beckmann Matthias W. , Hadji Peyman , Kreuzeder Julia , Lux Michael P , Janni Wolfgang , Schneeweiss Andreas , Belleville Erik , Decker Thomas , Grischke Eva-Maria , Tesch Hans 
Published: March 2020

591 Background: The presence of circulating tumor cells (CTCs) has been shown to be of prognostic relevance for patients with early and advanced breast cancer (BC). The usefulness of CTC assessments depends on accurate cell counts and corresponding analysis of molecular targets. The aim of this sub study was to assess the feasibility of a novel, integrated CTC platform for automated cellular protein and nucleic acid analysis in a prospective multi-center study. Methods: The German 4EVER study included patients with postmenopausal, metastastic, ER positive, HER2 negative BC, who progressed after therapy with a non-steroidal aromatase inhibitor and were treated with exemestane and the mTOR inhibitor everolimus. Baseline blood samples (TransFix vaccum tubes, Cytomark, Caltag Medsystems Ltd.) were used for CTC analysis and processed on the modified Versant kPCR Sample Prep system using 8µm pore size Whatman Nuclepore track-etched membranes (GE Healthcare Piscataway, NJ). After CTC capture, immunostaining was performed for Cytokeratin 8/18/19 and CD45. CTCs were detected by image analytics after fluorescence scanning microscopy using a dedicated software solution implemented by Siemens. The data is summarized and correlated with baseline clinical characteristics. Results: CTC counts and clinical data were available for 111 blood samples (91.7%). CTCs were found in 75 patients (67,6%), 13 patients having 1 CTC, 38 having 2-9 CTCs and 24 patients having 10 or more CTCs. In an exploratory analysis the presence of CTCs was correlated with baseline patient and tumor characteristics. There were no associations with primary TNM stage, hormone receptor status or tumor type. Conclusions: CTC assessment with this novel filtration based method was feasible in a multi-center study setting. The CTC positivity rate was within the expected range. The follow-up of this study will give first insights, how the CTC measures of this platform can be used as a prognostic tool. As this CTC assessment platform was developed to perform additional automated cellular protein and nucleic acid analysis, the usefulness might derive from these analytic tools as well. Clinical trial information: NCT01626222.
Efficacy of cabozantinib (Cabo) in medullary thyroid cancer (MTC) patients with RAS or RET mutations: Results from a phase III study.
Authors: Sherman Steven I. , Cohen Ezra E.W. , Schoffski Patrick , Elisei Rossella , Schlumberger Martin , Wirth Lori J. , Mangeshkar Milan , Aftab Dana T. , Clary Douglas O. , Brose Marcia S. 
Published: March 2020

6000 Background: Cabo extends progression-free survival (PFS) in patients (pts) with progressive, metastatic MTC (Schöffski, J Clin Oncol 30, 2012). Mutations in the RET oncogene are associated with most hereditary cases and ~half of sporadic cases of MTC. RAS gene mutations have recently been identified in subsets of RET wild type (wt) cases. Therefore, we investigated the association of RET (a prospectively defined endpoint) and RAS mutations (a post hoc analysis) with efficacy outcomes in the phase 3 study of cabo in MTC. Methods: Pts enrolled into the double-blind, placebo-controlled phase III trial were evaluated for the presence of somatic and germline RET mutations using Sanger and next generation methods. A subset of pts determined to be RET wt (44 pts) or RET unknown (41 pts) were then evaluated for tumor-associated mutations in KRAS, NRAS, and HRAS in codons 12, 13, and 61 by next generation sequencing. Impact of RET and RAS gene mutation status was evaluated with respect to PFS and tumor response rate (RR) according to RECIST. Results: RET status was determined in 65% of the study pts (215/330), of which 79% harbored an activating mutation, and 21% were RET wt. All RET mutational subgroups (RET mutated, RET wt, and RET unknown) showed hazard ratios indicating PFS benefit from cabo treatment, and demonstrated RRs between 22% and 32%. However pts harboring a RET mutation had longer median PFS on cabo (60 wks) than pts with wt RET (25 wks, PFS difference p=0.0001). Also, pts with the poor prognosis mutation RET M918T showed a longer median PFS on cabo treatment (61 wks) than pts with any other RET mutation (36 wks, PFS difference p=0.009). Patients with hereditary MTC had similar PFS to those with sporadic disease, and the presence of the common RET polymorphism G691S had no effect on either PFS or RR. Sixteen of 85 tested pts (5% of total study pts) with wt or unknown RET status were found to harbor a RAS gene mutation. The RAS-mutated pts showed a similar RR (31%) and PFS (47 wks) as RET mutated pts (32% and 60 wks). Conclusions: While hazard ratios indicate PFS improvement for all RET subgroups on cabo, the extent of benefit may depend in part on RET genotype. Cabo treatment benefit is also seen in pts harboring a RAS mutation. Clinical trial information: NCT00704730.
A randomized, open-label, phase II study of afatinib versus cetuximab in patients (pts) with recurrent or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC): Analysis of stage 2 (S2) following crossover.
Authors: Cupissol Didier , Seiwert Tanguy Y. , Fayette Jérôme , Ehrnrooth Eva , Blackman Alice Sarah , Cong Xiuyu Julie , Cohen Ezra E.W. 
Published: March 2020

6001 Background: This open-label trial assessed the efficacy of the irreversible ErbB Family Blocker afatinib (A) vs cetuximab (C) in R/M HNSCC pts following failure of platinum-containing therapy. In Stage 1 (S1), A and C had confirmed objective response rates (RECIST 1.0) of 16.1% vs 6.5% by investigator review (8.1% vs 9.7% independent central review [ICR]; Seiwert TY, et al. MHNCS 2012. Abs 235). S2 data after crossover are presented. Methods: In S1, pts were randomized 1:1 to oral A 50 mg/day or IV C 250 mg/m2/wk (400 mg/m2 IV loading dose) until progressive disease (PD) or intolerable drug-related adverse events (DRAEs). Pts could then crossover to the other treatment arm (S2), with treatment given until further PD or intolerable DRAEs. Tumor response in S2 (RECIST 1.0) was evaluated at 4 wks after crossover and every 8 wks thereafter. Results: 56% of pts crossed over into S2: 32 from A to C and 36 from C to A. Of these, 88% crossed over after PD and 12% after intolerable DRAEs. Baseline characteristics of S2 pts were similar in the A and C groups and treatment duration in S1 prior to crossover was comparable (A: 3.7 [0.2–15.7] months; C: 3.5 [0.0–12.5] months). Median treatment duration in S2 was 2.1 (0.0–7.6) months for A and 1.2 (0.0–9.9) months for C. Tumor size decreases of ≥30% were observed in 1 pt in each treatment group (ICR). The disease control rate (DCR) for A was 33% vs 19% for C and the median progression-free survival time was 9.3 wks for A and 5.7 wks for C (ICR). The most frequently reported DRAEs (≥20%) for A were rash/acne (56%), diarrhea (53%) and stomatitis (22%), and for C was rash/acne (44%). DRAEs of ≥Grade 3 were seen in 47% of pts treated with A and 16% of pts treated with C. 12 A-treated patients had dose reductions to 40 mg and 1 pt had a further dose reduction to 30 mg; no C-treated pts had dose reductions. Conclusions: R/M HNSCC pts seem to benefit from sequential therapy with A/C or C/A, especially when using A treatment after C failure. Cross resistance is not universally present and further investigation of sequential treatment is warranted. Clinical trial information: NCT00514943.
Analysis of HPV and ERCC1 in recurrent or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN).
Authors: Mehra Ranee , Egloff Ann Marie , Li Shuli , Yang Donghua , Wang Lin , Zhu Fang , Forastiere Arlene A. , Burtness Barbara , Argiris Athanassios ,   Eastern Cooperative Oncology Group
Published: March 2020

6006 Background: We studied the association of human papillomavirus (HPV) and excision repair cross-complementation group 1 (ERCC1) tumor expression with clinical outcomes in patients (pts) with R/M SCCHN. Methods: Archival baseline specimens were obtained from pts on ECOG trials: E1395, phase III trial of cisplatin/paclitaxel (CP) vs. cisplatin/5-FU (CF), and E3301, phase II trial of docetaxel/irinotecan. HPV DNA was detected by in situ hybridization (ISH) with a wide spectrum HPV probe. Tumor p16 status was defined as positive if immunohistochemical staining for p16 was strong and present in >80% of tumor cells. ERCC1 expression was measured (HistoRx PM-2000) and data analyzed using AQUA algorithms, after tissue was stained with ERCC1 ab (1:5000 HPA0297731, Sigma), and a wide-spectrum cytokeratin ab (Dako Z0622) for tumor mask. A prior determined cut point for nuclear staining was utilized. Fisher's exact test and log-rank test were used to compare categorical variables and survival. Stratified logistic regression and Cox regression model were used to estimate odds ratio (OR) and hazard ratio (HR), respectively, adjusting for potential confounding factors. p-values were two-sided. Results: Tissue was evaluable from 65 tumors (T) for HPV, 66 for p16 (E1395 and E3301), and 43 for ERCC1 expression (E1395). 11 T were HPV+ (12 p16+), and 54 were HPV-/p16-. HPV+ tumors were similarly represented in all treatment groups (p=0.58). Objective response rates (RR): 67% for HPV+, 22% for HPV- (p=0.013); 60% p16+, 22% p16- (p=0.05). RR rates were calculated excluding cases with unevaluable/unknown responses. HR for OS was 2.66 (HPV, p=0.02) and 2.27 (p16, p=0.04), favoring HPV+/p16+ pts. 18 T were ERCC1 high (H) and 25 ERCC1 low (L). HR for OS (H vs. L) was 1.96 (p=.11) RR: CF, 58% (L), 29% (H); CP, 33% (L), 56% (H). A test of ERCC1 by treatment interaction (p=0.12) suggested the effect of ERCC1 may be different for taxane vs. non-taxane regimens. Conclusions: This is the first study to show that HPV+/p16+ status is associated with a significant improvement in RR and OS among pts treated for R/M SCCHN. ERCC1 L was associated with a trend towards a better OS.
p16 expression as a human papillomavirus (HPV)-independent prognostic biomarker in non-oropharyngeal squamous cell carcinoma (non-OPSCC).
Authors: Chung Christine H. , Zhang Qiang , Kong Christina , Harris Jonathan , Ang K. Kian , Harari Paul M. , Wang Dian , Redmond Kevin P. , Shenouda George , Trotti Andy , Raben David , Gillison Maura L. , Jordan Richard , Le Quynh-Thu 
Published: March 2020

6007 Background: p16 is an important tumor suppressor and cell cycle regulator that is commonly lost in HPV-negative (-) and upregulated in HPV-positive (+) OPSCC. While the role of p16 expression in OPSCC as a surrogate marker of HPV infection and its association with prognosis are well established, its significance has not been studied in non-OPSCC including oral cavity, hypopharynx and larynx, where HPV infection is rare. We hypothesize that p16 expression is a prognostic biomarker of favorable outcome (progression-free and overall survival) in non-OPSCC. Methods: p16 expression in non-OPSCC from RTOG 0129, 0234 and 0522 was determined by immunohistochemistry (p16 mouse monoclonal antibody, prediluted, MTM-CINtech, 9518) and considered positive if >70% of the tumor cells demonstrated diffuse staining. The high risk HPV status in non-OPSCC from RTOG 0129 and 0522 was determined by in situ hybridization using a cocktail probe including HPV16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58 and 66. Hazard ratios from Cox models were expressed as positive/negative, stratified by trial, and adjusted for age, gender, T, and N stage. Results: p16 expression was positive in 14.1% (12/85), 24.2% (23/95) and 19.0% (27/142) of non-OPSCC from RTOG 0129, RTOG 0234, and RTOG 0522, respectively. HPV ISH was positive in 6.5% (6/93) and 6.9% (7/101) of non-OPSCC from RTOG 0129 and RTOG 0522, respectively. There was moderate agreement between p16 and HPV status (kappa=0.53). The hazard ratios for p16 expression are 0.63 (p=0.03) and 0.56 (p=0.01) for PFS and OS, respectively. In 0522, there was no interaction between p16 status and two treatment arms (RT+cisplatin+/-cetuximab). In comparison of OPSCC and non-OPSCC, patients with p16(+) OPSCC have better PFS and OS than patients with p16(+) non-OPSCC, but patients with p16(-) OPSCC and non-OPSCC have similar outcomes. Conclusions: Similar to results in patients with OPSCC, patients with p16(+) non-OPSCC have better outcomes than patients with p16(-); however, the differential appears smaller than has been observed in HPV(+) OPSCC. Further studies are warranted to delineate the role of p16 expression as a prognostic biomarker in non-OPSCC and OPSCC. Clinical trial information: NCT00265941, NCT00047008, NCT00084318.