bluuebunny/crossref_metadata_2025_split huggingface dataset:
Breast cancer treatment according to pathogenic variants in cancer susceptibility genes in a population-based cohort.
Authors: Kurian Allison W. , Ward Kevin C. , Abrahamse Paul , Hamilton Ann S , Deapen Dennis , Morrow Monica , Katz Steven J. 
Published: May 2019

560 Background: Increasing use of germline genetic testing may have unintended consequences on breast cancer treatment. We do not know whether treatment deviates from guidelines for women with pathogenic variants (PV) in cancer susceptibility genes. Methods: SEER data for all women aged ≥20 years, diagnosed with breast cancer in 2014-15 and reported to Georgia and California registries (N = 77,588) by December 1, 2016 were linked to germline genetic testing results from 4 laboratories that did nearly all clinical testing. We examined first course of therapy (before recurrence or progression) of stage < IV patients who linked to a genetic test: bilateral mastectomy (BLM) in candidates for surgery (unilateral, stages 0-III); post-lumpectomy radiation in those with an indication (all but age ≥70, stage I, hormone receptor (HR)-positive and HER2-negative); and chemotherapy in those without a definitive indication (stage I-II, HR-positive, HER2-negative and 21-gene recurrence score < 30). We report the percent treated based on multivariable modeling, adjusted for age, race, stage, grade, insurance and socioeconomic status. Results: The table shows that 9% of patients who linked to a genetic test result had a PV (N = 1,283). Compared to women with negative results,women with BRCA1/2 PVs were more likely to receive BLM, more likely to receive chemotherapy without definitive indication, and less likely to receive indicated radiation in their first course of therapy. Lower-magnitude effects were seen with other PVs but not variants of uncertain significance (VUS). Conclusions: In a population-based setting, women with PVs in BRCA1/2 or other cancer susceptibility genes may have a higher risk of receiving locoregional and systemic treatment that does not follow guidelines. [Table: see text]
No relationship of axillary total tumor load (TTL) by PCR (OSNA) in early breast cancer and local and distant clinical outcomes.
Authors: Ales-Martinez Jose , Tur Raquel , Parra Juan , Ceballos Jaime , Filipovich Elena , Segovia Beatriz , Revestido Rafael , De Castro ANA , Blanco Paz , Velasco María José , Martin Maria Rocio 
Published: May 2019

564 Background: The study of sentinel lymph nodes (SLN) assessed by One Step Nucleic Acid Amplification (OSNA, Sysmex, Kobe, Japan) creates a new variable, Total Tumor Load (TTL). This variable is defined as the total number of CK19 mRNA copies in all positive SLN (copies/microL). The latest edition of the Spanish Oncological Gynecology Society (SEGO) Guideline (2017) proposes a complete axillary lymph node dissection (ALND) when TTL is 15,000 copies or more in early breast cancer. In our center we are using OSNA to ascertain if there is axillary node involvement but the decision to proceed to ALND is based on Z0011 criteria. We want to determine if there is a correlation between clinical outcomes and TTL values, between TTL and pathological variables and if TTL is a useful tool to decide when to complete an ALND. Methods: Clinicopathological and follow up data were obtained from all patients with invasive breast cancer and SLN assessed by OSNA between 2011 and 2017 at our center. Results: A total of 321 patients underwent SNB assessed by OSNA with an average follow-up of 56 months. 320 were female and 1 male. Age range 27-89 years (mean 58.9). 85 % were ductal, 10 % lobular and 5 % other. 53.5% were luminal A, 28.66% luminal B, 7.78%, triple negative, 4.3%, Her2 positive and 4.3%. luminal B-Her2 positive.TTL was equal to 0 in 183 cases and greater than zero in 138 cases.71 cases showed a TTL higher than 15,000 copies. Only 21 cases met Z0011 criteria and had ALND. As of now, 3 patients have had locoregional relapse and 8 metastatic disease. 12 have died, only two from metastatic breast cancer. Conclusions: Using Z0011 criteria, we have adequate clinical outcomes with a low rate of ALND; If we had based the axillary management on TTL values we would have multiplied the number of ALND by a factor of 3.3 (from 21 to 71); We have observed a tendency to higher TTL in luminal phenotypes and to lower TTL in HER2 positive and triple negative subtypes; Work is in progress to increase our sample size.
Gene expression comparison between primary triple-negative breast cancer and matched axillary lymph node metastasis.
Authors: Srour Marissa K. , Gao Bowen , Dadmanesh Farnaz , Qu Ying , Cui Xiaojiang , Giuliano Armando E. 
Published: May 2019

565 Background: Sentinel lymph node (SLN) biopsy guides breast cancer treatment and prognostication. To date, there have been few studies examining the genetics of SLN metastasis in triple negative breast cancer (TNBC). The aim of this study is to characterize and compare gene expression patterns of primary breast cancers and autologous matched SLN metastases. Methods: Patients with stage 2-3 ER/PR negative, HER2 negative TNBC with macrometastasis to the SLN who did not have neoadjuvant therapy were selected. The tumor-specific area was isolated from breast and SLN paraffin embedded tissue sections. Gene expression of a panel of 2567 cancer-associated genes was analyzed with the HTG EdgeSeq system coupled with the Illumina Next Generation Sequencing (NGS) platform. Results were validated with RNA-scope assays for RNA in situ detection. Results: 18 pairs of TNBC and matched SLN metastasis were analyzed for 2567 genes. Compared with the primary TNBC, SLN metastasis had 34 statistically significant upregulated genes and 31 downregulated genes. SLN metastasis had at least a 5-fold change (FC) in upregulation in 3 genes and downregulation in 3 genes, compared to primary TNBC [Table]. Notably, there was an upregulation of anti-apoptosis and survival signaling genes (i.e. BIRC3) in the SLN metastasis. There was also an upregulation of chemotaxis genes (CCL13, CXCL19, CXCL21, CXCR5, TNFSF11, p<0.001). The most striking feature is the downregulation of genes known to regulate cell microenvironment interaction (MMP2, MMP14, COL1A1, COL1A2, COL5A2, COL6A6, COL11A1, COL17A1). Conclusions: In TNBC, SLN metastasis has a distinct gene expression profile. Genes associated with anti-apoptosis, survival responses, and chemotaxis are upregulated, and genes associated with regulation of extracellular matrix are downregulated. Upregulated and downregulated genes with at least a 5-fold change in gene expression in lymph node metastasis compared with TNBC.[Table: see text]
Risk stratification in earl- stage luminal breast cancer patients treated with and without RT.
Authors: Wadsten Charlotta , Whitworth Pat W. , Patel Rakesh , Savala Jess , Warnberg Fredrik , Bremer Troy 
Published: May 2019

568 Background: The goal was to develop and validate a biologic signature for 10-year ipsilateral invasive breast event (IBE) risk in luminal Stage 1 breast cancer (BC) patients treated surgically and either with or without radiation therapy (RT). Methods: This cohort was from Uppsala University and Västerås Hospitals diagnosed with Stage 1 BC and treated surgically between 1987 and 2004. Treatment was neither randomized nor strictly rules based, including adjuvant RT, Hormone Therapy (HT), and Chemotherapy (CT). Biomarkers (HER2, PR, Ki67, COX2, p16/INK4A, FOXA1 and SIAH2) were assessed on tissue microarrays in PreludeDx’s CLIA lab by board-certified pathologists. Risk groups were calculated using biomarkers and clinical factors age and size. A multivariate Cox proportional hazards analysis was used to determine hazard ratio for biologic signature. 10-year IBE risk was assessed using Kaplan-Meier survival analysis. Results: There were 423 luminal cases with biomarker data having 54 IBEs, and a median follow-up of 11.8 years. There were 372 patients treated with BCS and 51 with Mastectomy, and 325 received RT, 169 received HT, and 47 received CT. In a multivariate analysis, the biologic signature (HR = 1.6, p = 0.019) and RT (HR = 0.51, p = 0.027) were associated with IBE risk adjusting for other treatments (HT and CT) and Luminal A status (p = 0.37). For patients over 50 yrs of age with luminal A disease and treated without CT (n = 205), an elevated biologic signature identified a subset of patients with a 15% (+/- 14%) 10-year IBE risk without RT (n = 38) compared to a 4% (+/-6%) IBE risk with RT (n = 72), while patients with a low biologic signature had a 10-year IBE risk of 4% (+/- 4%) without RT (n = 26) and 3% (+/-5%) IBE risk with RT (n = 69). Conclusions: With further prospective validation, the biologic signature identified herein may provide a tool enabling improved management for women diagnosed with early luminal BC.
Beyond TILs: Predictors of pathologic complete response (pCR) in triple-negative breast cancer (TNBC) patients with moderate tumor-infiltrating lymphocytes (TIL) receiving neoadjuvant therapy.
Authors: Abuhadra Nour , Hess Kenneth R. , Litton Jennifer Keating , Rauch Gaiane M , Thompson Alastair Mark , Lim Bora , Adrada Beatriz E , Mittendorf Elizabeth A. , Damodaran Senthil , Candelaria Rosalind P , Arun Banu , Yang Wei Tse , Ueno Naoto T. , Santiago Lumarie , Murthy Rashmi Krishna , Ibrahim Nuhad K. , Sahin Aysegul A. , Symmans William Fraser , Moulder Stacy L. , Huo Lei 
Published: May 2019

572 Background: Increased TIL in TNBC is associated with higher rates of pCR. High TIL is also associated with improved disease free survival and overall survival. The aim of this study is to identify data cut-points of pre-treatment low, moderate and high TIL count based on pCR and to identify clinical and pathological predictors of pCR in patients with moderate TIL. Methods: We evaluated the relationship between pCR and TIL in 180 patients with stage I-III TNBC enrolled in the ARTEMIS trial (NCT02276443). Recursive portioning was used to identify cut-points. Clinical and pathological variables such as age at diagnosis, stage, race, histology as well as Ki-67, vimentin, and androgen receptor (AR) by immunohistochemistry, were evaluated in pts with moderate TIL. A multivariable logistic regression model identified variables independently, significantly associated with pCR. Results: Four TIL groups were identified with pCR rates of 23%, 31%, 48% and 78% respectively (p < 0.0001) (Table A). In the two combined moderate TIL groups, 90 (97%) pts were evaluable for the multivariate model. Stage I-II disease, high Ki-67 and low AR were associated with increased probability of pCR (Table B). The multivariable logistic regression model area under the ROC curve was 0.78 (95% CI=0.68-0.88; p<0.0001). A model of computed risk score [ Stage I-II (score 2)+Ki-67≥ 50% (score 1)+AR<10% (score 1)] predicted a probability of 67% for pCR when all three variables were favorable (Table). Conclusions: Four TIL groups were identified. In pts with moderate TIL levels, early stage disease, high Ki-67 and low AR were associated with increased probability of pCR with neoadjuvant therapy. [Table: see text]
Prognostic value of PAM50 in residual breast cancer following neoadjuvant endocrine therapy (NET): A retrospective analysis with long follow-up.
Authors: Gil Gil Miguel J. , Perez Francisco Javier , Soler Monso Teresa , Pascual Tomas , Galván Patricia , Pare Laia , Petit Anna , Falo Catalina , Stradella Agostina , Pla María Jesús , Salazar Ramon , Prat Aleix 
Published: May 2019

575 Background: NET is gaining more acceptances for the management of hormonal receptors (HR)-positive breast cancer (BC). To date, the decrease of Ki-67 and PEPI score are the only prognostic factors associated with relapse-free survival after NET. PAM50 is a validated prognostic test in newly diagnosed BC; however, its value in residual tumors after NET is currently unknown. Methods: We took tumor tissues from patients of a retrospective study of 119 postmenopausal women with HR-positive stage II-III BC. Patients were diagnosed from 1997 to 2009 and were treated with NET for a median duration of 8.5 months . Median age was 74 (63-88). After NET all patients underwent surgery (73% conservative). Adjuvant treatment were endocrine therapy in 100%, radiotherapy in 76.5% and chemotherapy 7%. Median follow-up from surgery was 112 months. Median follow-up from surgery was 112 months. We observed 26 (24%) of distant relapses and 75 deaths (44 without cancer). Median overall survival was 134.8 months. RNA was extracted from FFPE tumor tissues of surgical specimens. A panel of 55 BC-related genes, including the research-based PAM50 assay (subtypes, ROR-S and ROR-P pre-defined cutpoints), androgen receptor (AR), immune genes (CD8A, CD4, PDL1 and PD1). Uni- and multi-variable Cox models were used to evaluate the association of each variable with distance recurrence free interval (DRFI). Results: PAM50 subtype distribution: Luminal A 54.3%, Normal-like 24.3%; HER2-enriched 16,5%, Luminal B 1% and basal 1%. Distribution of ROR-S groups was Low 64%, medium 30%and high 6%. Distribution of PEPI score was: 0 in 43%, 3 in 37% and 6 in 20%. Among the different variables explored, PEPI score 0 (HR 0.27 [95%IC 0.09-0.79] p=0.001), low ROR-S (HR 0.39 [95%CI 0.17-0.91] p=0.001) and high AR expression (HR 0.71 [95CI 0.53-0.96] p=0.007) were significantly associated with lower DRFI in univariate analyses. After adjusting for PEPI (with or without Normal-like tumors), ROR-S and AR remained significantly associated with outcome. Conclusions: PAM50 ROR-S and AR expression in residual tumors after NET provide independent prognostic information beyond PEPI. With further validation, these biomarkers could help clinicians in the decision-making of adjuvant chemotherapy.
Heterogeneity in signaling pathway activity within primary breast cancer and between primary and metastases.
Authors: Verhaegh Wim , van Brussel Anne , Moelans Cathy , Alves de Inda Marcia , Gil Julie , Bikker Jan Willem , den Biezen-Timmermans Eveline , Van De Stolpe Anja , van Diest Paul J. 
Published: May 2019

589 Background: Treatment with targeted drugs aims to block tumor driving signaling pathway(s). Drug choice is often based on a single preoperative primary breast cancer biopsy. It is important that biopsied cancer tissue is representative for the primary tumor (PT) or metastases to treat. Little is known about pathway heterogeneity within the PT, and between PT and metastatic tumors. A novel analysis method was developed to identify and quantify activity of signal transduction pathways in cancer tissue, based on Bayesian models that infer a pathway activity score from transcription factor target gene mRNA levels (Cancer Res 2014;74:2936-45). Methods: Pathway analysis, originally developed for AffymetrixU133Plus2.0, was adapted to RT-qPCR for use on formalin fixed paraffin embedded tissue. Estrogen (ER) and androgen (AR) receptor, PI3K, Hedgehog (HH), TGFβ and Wnt pathway activities were analyzed. Samples were from multiple locations (“quadrants”) in 15 luminal A, 9 luminal B, and 8 ER-negative primary breast cancers; from subdivided quadrant samples (4 “subquadrants”) of respectively 9, 4, and 4 PTs; and from 13 distant and 24 lymph node (LN) metastases of respectively 9 and 7 matched luminal PTs. Analysis of pathway activity score (PAS) variance was performed with linear mixed models with subgroup-dependent standard deviations. Results: In primary breast cancer intra-tumor PAS variance was not larger at macroscale (“quadrant”) than at microscale (“subquadrant”). For ER, AR, HH, and Wnt pathways, PAS variation was higher between distant metastases and PT than within the PT (p < 0.0002). For HH and Wnt pathways, PAS variation was higher between LN metastases than within the PT (p < 0.002). Correlation between primary and metastatic pathway activities ranged from -0.34 for ER to 0.47/0.50 for TGFβ/HH pathways. Conclusions: A single location tissue sample was representative for the whole primary tumor with respect to signaling pathway activity, suggesting one biopsy as generally sufficient for (neo)adjuvant therapy choice. Pathway activities varied between primary cancer and metastases, indicating the necessity of metastatic sample analysis (biopsies or liquid biopsy) to improve therapy choice.
Circulating tumor DNA (ctDNA) during and after neoadjuvant chemotherapy and prior to surgery is a powerful prognostic factor in triple-negative breast cancer (TNBC).
Authors: Cavallone Luca , Aguilar Adriana , Aldamry Mohammed , Lafleur Josiane , Brousse Susie , Lan Cathy , Alirezaie Najmeh , Bareke Eric , Majewski Jacek , Pelmus Manuela , Ferrario Cristiano , Marcus Elizabeth A. , Robidoux Andre , Discepola Federico , Basik Mark 
Published: May 2019

594 Background: TNBC, the most aggressive form of breast cancer, is treated primarily with chemotherapy, even before surgery (neoadjuvant chemotherapy or NAC). The prognosis and need for adjuvant therapy depends greatly on the tumor response assessed by pathology (pCR). Highly sensitive and specific ctDNA assays have been shown to be of prognostic value in the metastatic settingbut not yet in earlier settings. Methods: Tissue was collected from 26 Q-CROC-03 clinical trial TNBC patients before, during and after NAC, prior to surgery. Whole exome sequencing on tumor tissues was used to select single nucleotide variants with high allele frequency (VAF), prioritizing TP53, to generateindividual digital droplet PCR (ddPCR) assays. An average of 5 variants (range 1-12) per patient were tested, for a total of 121 variants. A detection threshold was defined for each variant from a pool of normal controls. Median follow-up was 55 months. Results: ctDNA was detectable in 96% of patients at baseline, but 20% of the 121 variants were not detectable at any time point. At baseline, the mean VAF of all analyzed variants, but not of TP53 variants alone, was significantly correlated (p < 0.05) with tumor factors (tumor size, stage, grade, nodal status before and at surgery, RCB score) but not with patient age or BRCA1/2 mutation status. 87 variants (74%) were detected at baseline and their VAF fell by 86% after 1 cycle of chemotherapy (T1). The detection of ctDNA at T1 was associated with DFS (p = 0.027) while the detection of ctDNA at the last post-chemotherapy pre-surgery time point (T4) was strongly associated with pathological complete response (pCR) and both DFS (p = 0.013) and OS(p = 0.006). At this time point, 5 of 41 variants (12%) were detected in pCR patients vs 42 of 80 (53%) in non-pCR, while only 6 of the 15 (40%) non-pCR patients had detectable TP53 variants. Interestingly, for variants detected at baseline, the positive predictive value of T4 ctDNA for disease recurrence was 69%, similar to that of non-pCR, while the negative predictive value of no ctDNA at T4 was 89% for disease recurrence vs 80% for pCR. Conclusions: ctDNA detection after NAC prior to surgery is strongly predictive of disease-free survival and overall survival and is comparable to pCR as a prognostic factor in our cohort (NCT01276899).
A multicenter prospective observational study of nutritional status on survival in locally advanced nasopharynx cancer treated by induction chemotherapy and chemoradiotherapy.
Authors: Miao Jingjing , Wang Lin , Hu Chaosu , Lin Shaojun , Tan Sze Huey , Ong Enya , Chen Xiaozhong , Chen Yuan yuan , Zhong Yahua , Jin Feng , Lin Qin , Lin Shaomin , Hu Xuefeng , Zhang Ning , Wang Rensheng , Wang Cong , Shi Hanping , Chua Melvin Lee Kiang , Xie Conghua , Zhao Chong 
Published: May 2019

6036 Background: We conducted a multicenter prospective study (NCT02575547) to investigate the association between longitudinal nutritional status and survival in locally advanced nasopharynx cancer (LA-NPC) treated with induction chemotherapy and concurrent chemoradiotherapy (IC-CCRT). Methods: All patients with biopsy-proven LA-NPC and planned for IC-CCRT were recruited from ten institutions. IC entailed 2 cycles of docetaxel 75mg/m2/3w and cisplatin 75mg/m2/3w; CCRT entailed 2-3 cycles cisplatin 100mg/m2/3w and IMRT (70-72Gy/30-32fr). Study parameters included weight loss (WL), % of ideal body weight (%IBW), body mass index (BMI), nutrition risk screening 2002 (NRS2002), patient-generated subjective global assessment (PG-SGA), and EORTC QLQ-C30 that were collected at the following time-points: baseline (T1), 1 w pre-2nd IC (T2), 1 w pre-CCRT (T3), 4 w mid-CCRT (T4), end-CCRT (T5), 3 mo post-CCRT (T6), 1 y post-CCRT (T7), 2 y post-CCRT (T8). Results: 186 patients were recruited; 171 were eligible for analysis. Median follow-up was 35.8 mo (range 12.3-46.1 mo). Compliance rates were 97.7% (167/171) and 87.7% (150/171) for IC and CCRT, respectively; all except one completed RT. Longitudinal assessment indicated the worst nutritional status at T5, followed by recovery at T8: 27.1% with %IBW <90%; 69.2% with WL ≥5%, which was also associated with a worsened QOL (OR = 6.23 for QOL change ≥25.0, P = 0.012). Interestingly, T1 nutritional status was not associated with prognosis (P >0.05 for all). However, nutritional parameters at T5 were significantly associated with survival; %IBW <90% was the strongest predictor for inferior DMFS (HR = 2.669) and OS (HR = 4.661) among all parameters (multivariable-adjusted P <0.05). Subgroup analyses revealed that %IBW <90%, WL ≥10% at T5 represented the most adverse subset of patients (Table). Conclusions: Here, we show that poor nutrition despite systemic intensification leads to inferior QOL and disease control in LA-NPC patients. This is counter-intuitive and highlights the crucial importance of paracrine factors in optimising treatment efficacy. Clinical trial information: NCT02575547. [Table: see text]
High-dose, short-duration, intra-arterial cisplatin therapy for oral cancer.
Authors: Ohmae Masatoshi , Kato Itsuro , Fujita Yusei , Meshii Noritoshi , Motoki Ayako , Nakazawa Mitsuhiro , Uzawa Narikazu 
Published: May 2019

6038 Background: We developed a superselective intra-arterial chemotherapy (iaCT) approach for oral cancer wherein an intra-arterial catheter is retrogradely inserted via the superficial temporal artery (STA) and/or occipital artery (OA). In most iaCT cases, high-dose anticancer agents are administrated via the intra-arterial catheter weekly or biweekly with daily irradiation. This approach remarkably improves curative efficiency, but some adverse events, e.g., severe mucositis, dysphagia, dysgeusia, dry mouth, and radiation osteonecrosis, mainly because of irradiation, decrease the quality of life. Methods: Thirty-two patients with stage II, III, or IV oral squamous cell carcinoma were treated using this new iaCT approach. The catheter was superselectively placed in the tumor-feeding arteries by cut-down of STA or OA. The catheter was completely placed under the skin and was connected to an infusion reservoir that was subcutaneously implanted around the mastoid process via the subcutaneous tunnel, ensuring little possibility of catheter-related issues such as infection and displacement of catheter. Anticancer agents (30 mg/m2of cisplatin with/without 10 mg/m2of docetaxel) were intra-arterially administered via the reservoir twice a week for 3 weeks, 180 mg/m2/6 times in total, without irradiation. The treatment effect was assessed using computed tomography, positron emission tomography, and biopsy. Results: The response rate of this approach was 100%, with 31 and 1 case having complete response (CR) and partial response (PR), respectively. Five patients with delayed regional lymph node metastasis or PR underwent salvage surgery; 28 patients (87.5%) had disease-free survival, while 2 (6.2%) died due to local recurrence and 2 due to distant metastasis. All patients developed CTCAE v4.0 Grade 2 oral mucositis in the flow area of the intended artery, most of which disappeared in half a year. No dry mouth, dysgeusia, and eating disorder were observed because the patients did not receive radiotherapy. No systemic adverse events such as hematologic toxicity and renal and/or hepatic injuries occurred. Conclusions: This method improved the adverse event of iaCT with radiotherapy, and the main advantage of superselective iaCT was not lost.