tbuckley/cabot-search huggingface dataset:
Effect of mutant TP53 genotypes on the outcome of breast cancer (BC) patients in different clinical tumor subtypes.
Authors: George Fountzilas, Meletios A. Dimopoulos, George Kouvatseas, Eleni Timotheadou, George E. Pentheroudakis, Helen Gogas, Dimitrios G. Pectasides, Christos Christodoulou, Elpida Charalambous, Aggeliki Lyberopoulou, Helena Linardou, Christos Papandreou, Amanda Psyrri, Gerasimos Aravantinos, Christos Markopoulos, Vasileios Venizelos, Ioannis Efstratiou, Konstantine T. Kalogeras, Sotiris Lakis, Vassiliki Kotoula
Journal: Journal of Clinical Oncology (2015)

11041 Background: Comprehending the clinical utility of the massively produced BC genomic data remains a challenge. Here, we examined the impact of BC genotypes on patient outcome with respect to clinical (immunohistochemical) tumor subtypes and treatment. Methods: Paraffin DNA from 1664 tumors (556 Luminal A, 439 Luminal B, 291 Luminal-HER2, 157 HER2-enriched and 221 triple-negative [TNBC]) yielded informative results upon targeted parallel sequencing for 58 genes. Patients had operable BC and had been treated in 4 prospective trials with adjuvant anthracycline-based chemotherapy in the pre- and post-trastuzumab (T) era. Analysis was performed in training and validation sets and in the entire cohort. Results: Eligible mutations (mut, n = 3086) were observed in 56 genes and were distributed in various combinations (1 to > 20 mutant genes) in 1043 tumors (63%). PIK3CA mut were found in 466 (44%); TP53 in 420 (40%); GATA3 in 128 (12%); and, CDH1 in 121 (11.5%) tumors. PIK3CA mut were more common in Luminal A/B tumors (49%), while TP53 in HER2-positive (57%) and TNBC (73%) (all p < 0.001). Both PIK3CA and TP53 mut were observed in 7% of all tumors. TP53 mut conferred increased risk for relapse in patients with Luminal A/B (HR = 2.00; 95% CI 1.42-2.82; Wald p < 0.001) and TNBC (HR = 1.82; 95% CI 1.04-3.20; Wald p = 0.037). In the same context, PIK3CA mut were associated with favorable prognosis in the absence of TP53 mut; this effect disappeared in tumors with mut in both genes. In HER2-positive patients in the pre-T era, TP53 mut alone or in combination with PIK3CA mut did not interfere with outcome. By contrast, these mutant genotypes tended to confer decreased risk for relapse in patients treated with T (HR = 0.51; 95% CI 0.23-1.14; Wald p = 0.101). All described effects were equally significant in the training and validation sets. Conclusions: TP53 mutant genotypes are unfavorable prognosticators in Luminal A/B and TNBC patients, but may predict benefit in HER2-positive patients with operable BC treated with T. PIK3CA mut do not seem to interfere with patient outcome in the latter context. If validated in independent large studies, these findings may have important clinical implications.
Role of the pulmonary and critical care medicine physician in the American health care system
Authors: E. D. Crandall, R. K. Albert, J. R. Balmes, D. S. Dark, M. G. Lykens, J. J. Marini, G. J. Redding, R. M. Rogers, R. M. Strieter, D. F. Tierney, G. Turino, J. S. Wagener, C. M. Wiener
Journal: American Journal of Respiratory and Critical Care Medicine (1995)
Renal cell carcinoma (RCC) presenting as cancer of unknown primary (CUP): Diagnosis by molecular tumor profiling (MTP).
Authors: John D. Hainsworth, David R. Spigel, F Anthony Greco
Journal: Journal of Clinical Oncology (2013)

e15501 Background: CUP is a heterogeneous clinicopathologic syndrome representing many types of occult clinically undetectable primary neoplasms. With the advent of MTP, the tissue of origin in CUP is frequently identified when used in concert with immunohistochemistry (IHC) and clinical features. Histopathology alone is usually not specific, and diagnostic IHC is often limited. Diagnosis of the RCC subset of CUP has important therapeutic potential given the availability of multiple approved biologic therapies, and the use of MTP may facilitate the correct diagnosis. Methods: 488 CUP patients (pts) seen between 2008 – 2012 had MTP (RT-PCR 92-gene assay, CancerTYPE ID, bioTheranostics, Inc.) of their archived tumor specimens. The clinicopathologic features were reviewed and, where feasible, subsequent additional IHC stains were obtained to support the MTP diagnosis. The response and survival to first-line RCC site-specific therapy were evaluated. Results: RCC was the MTP diagnosis in 22 pts (4.5%), including papillary in 8, clear cell in 7, and unknown subtype in 7. Histology included poorly differentiated carcinoma in 15 and adenocarcinoma in 7 (4 with papillary features, 1 with clear cell features). None had evidence of a primary renal lesion detectable by abdominal computed tomography, and the sites of metastasis most often included retroperitoneal nodes (63%), mediastinal nodes (31%), lung (22%), and bone (18%). Diagnostic RCC IHC stains were performed initially in only 3 tumors (14%), but RCC IHC stains (RCC, PAX 8, others) performed later supported the MTP diagnosis in 7 of 9 tumors where remaining tissue was available. 16 pts received first-line RCC targeted therapies (objective response rate was 18%, median survival of 13.4). Conclusions: RCC is a subset of CUP which can be diagnosed by MTP. RCC is usually not suspected in the absence of clear cell features, and occult RCC appears to commonly be the papillary subtype. RCC IHC may be diagnostic in some CUP tumors, but may be omitted in the initial pathologic evaluation. CUP-RCC pts are important to identify as they may benefit from standard RCC targeted therapies, and respond poorly to empiric chemotherapy.
Neuroendocrine carcinoma of the cervix: A single institution’s experience.
Authors: Megan Preston, Georgia Anne-Lee McCann, David M. O'Malley, Christina Boutsicaris, Larry J. Copeland, David E. Cohn, Jeffrey Fowler, Ritu Salani, Eric Lawernce Eisenhauer
Journal: Journal of Clinical Oncology (2012)

e15585 Background: Neuroendocrine carcinomas (NEC) of the cervix comprise only 2% of all cervical cancers. As a result, prospective data is limited and treatment guidelines rely on literature from lung NEC. The objective of this study was to examine and report on our experience in the management of this rare, aggressive disease. Methods: This was an IRB-approved, single-institution, retrospective review. Study criteria included patients with cervical NEC diagnosed between 1990-2011. Demographic, treatment and survival data was collected. Progression-free survival (PFS) and overall survival (OS) was defined as the time from date of initial treatment until progression or death respectively, or date of last contact. Results: A total of 24 patients met inclusion criteria. The median age at diagnosis was 43. Median PFS was 13.6 months and median OS was 16.4 months. The majority of patients had advanced-stage disease (61% stage II-IV, 39% stage I). Of the 9 patients with stage I disease, 4 were treated with platinum + etoposide-based neoadjuvant chemotherapy and 5 were treated with initial radical surgery. Seven of the 9 patients had post-operative adjuvant therapy consisting of chemotherapy, chemo-radiation or radiation only. Seven of the 9 patients (78%) were alive at last follow-up. Of the two patients who were deceased, one had metastatic disease found at surgery and the other declined adjuvant therapy and died of recurrence. Patients with stage II-IV disease (n=15) had a median PFS and OS of 11.5 and 12.1 months, respectively. Only 2 had no evidence of disease at last encounter. The remainder died without achieving remission. Patients with metastatic disease had significantly worse survival when compared to those with loco-regional disease with a median OS of 8 vs. 28 months (p = .03), respectively. Conclusions: We report one of the largest single-institution experiences of neuroendocrine cervical cancer. Advanced-stage patients had a poor prognosis regardless of therapy. However, multi-modality therapy in early-stage disease resulted in an excellent prognosis (78% survival) for these rare, highly aggressive tumors. These findings support the goal of curative intent for early-stage disease using multi-modality therapy.
Gene expression markers of resistance to capecitabine-oxaliplatin-bevacizumab treatment in metastatic colorectal cancer (mCRC).
Authors: Nuria Rodriguez, Paloma Cejas, Juan Moreno, Marta Mendiola, Antonieta Salud, Maria Jose Safont, Carlos Garcia-Giron, Jorge Aparicio, Ruth Vera, Mónica Jorge Fernández, Pilar Escudero, Juan Maurel, Jaime Feliu
Journal: Journal of Clinical Oncology (2015)

e14555 Background: First-line bevacizumab and capecitabine-oxaliplatin (B-CAPOX) was examined in 69 elderly patients with mCRC in the prospective BECOX study. This trial included a biomarker substudy aiming to identify predictive markers for response to this therapy in the primary tumor tissue. Methods: Formalin-fixed, paraffin-embedded (FFPE) tumor samples patients were analyzed to identify predictive biomarkers for response to B-CAPOX treatment. RT-PCR analyses were conducted on tissues from 48 patients at baseline to measure gene expression levels of MMP-7, Neuropilin-1, Neuropilin-2, HIF-1-alfa, HIF-2, VEGFR-1, VEGFR-2, VEGF-A, COX-2, TGFβF-beta, TCF-4, IGFBP3, ICAR-1R, RAC-1b , RAC-1b, Aurora kinase A and Aurora kinase B. Inmmunohistochemistry expression of p53, pAKT, pERK and PTEN was also performed in these tissue samples. The relationship of expression levels and clinical variables (overall response rate (ORR), progression-free survival (PFS) and overall survival (OS)) was modeled using multiplicative Cox proportional hazards models. Results: Low IGFBP3 expression was associated with a higher ORR (OR 10.5; p = 0.001) in both univariate and multivariate analysis. No gene expression analyzed could be associated with PFS. In the univariate analysis VEGF-A (p = 0.009), TGFβbeta (p = 0.002), ICAR-1R (p = 0.033) and pAKT (p = 0.038) were associated with OS. In the multivariate analysis only the low TGFβ-beta expression was associated with longer OS. Conclusions: Gene expression of IGFBP3 was identified as potential predictive marker for response to B-CAPOX. These data show that IGFBP3 may have an important role in the intrinsic resistance to antitumoral treatment.
Minimally invasive surgery to improve time to chemotherapy in colon cancer: Compliance to the American College of Surgeons Commission on Cancer quality metrics.
Authors: Sinziana Dumitra, Rebecca A. Nelson, Vasilena Zheleva, Mustafa Raoof, Lily L. Lai
Journal: Journal of Clinical Oncology (2017)

712 Background: One of the American College of Surgeons Commission on Cancer (ACS CoC) quality measures in colon cancer is receipt of chemotherapy (CT) in Stage III disease within 120 days of diagnosis. Minimally invasive surgery (MIS) has been associated with faster recovery times. The aim of this study is to assess whether MIS improves compliance to this metric. Methods: Stage III colon cancer patients 80 years old and younger from 2010 to 2012 were identified in the National Cancer Database. Demographic, tumor and treatment characteristics were evaluated including receipt of CT and surgical approach. Uni- and multi-variate logistic regression was used to assess factors associated with CT compliance. Results: Of the 19,963 patients identified, 14,901(74.6%) were compliant while 5,062 (25.3%) were not. Of the patients who were non-compliant, 956 (4.8%) received CT after 120 days. Surgical approach was significantly different between CT compliant and non-compliant groups (MIS 28% vs 32%,p &lt; 0.000). Uni- and multi-variate analyses identified MIS as a significant factor associated with improved compliance to CT with an OR of 1.31 (95%CI 1.22-1.41). Other factors associated with CT compliance were nodal and tumor stage and treatment in an academic program. Non-compliance was associated with age 50-64 (OR 0.76; 95%CI 0.68-0.86), age 65-79 (OR 0.49; 95%CI 0.43-0.56) and increased co-morbidities (OR 0.60; 95%CI 0.53-0.67). Lack of insurance (OR 0.69; 95%CI 0.58-0.81) or Medicaid (OR 0.54; 95%CI 0.47-0.62) and Medicare (OR 0.69; 95%CI 0.63-0.77) as well as distance to hospital of more than 44 miles were also associated with non-compliance to CT (OR 0.86; 95%CI 0.76-0.97). Conclusions: This is the first study to demonstrate that MIS for Stage III colon cancer improves compliance to receipt of CT within the 120 days. Given the potential survival benefits as a result of adherence to ACS CoC cancer care quality metrics, MIS may benefit patients not only in faster return to recovery but also in improved cancer outcomes.
Next-generation sequencing (NGS) in pancreatic neuroendocrine tumors (panNETs): Defining differentiation and grade genetically.
Authors: Nitya Prabhakar Raj, David Klimstra, Ronak Shah, Muyinat Osoba, Derek Alexander, Diane Lauren Reidy
Journal: Journal of Clinical Oncology (2017)

291 Background: Advances in tumor sequencing technology have improved our understanding of the genetic basis of panNETs. Whole exome sequencing of well differentiated (WD) panNETs demonstrated changes in chromatin remodeling genes; in poorly differentiated (PD) neuroendocrine carcinomas, changes along the TP53/RB signaling pathways have been observed. We sought to validate these observations in clinical practice. Methods: This prospective study (NCT01775072) used the MSK-IMPACT (Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets) assay to do NGS on panNETs in the routine practice setting. MSK-IMPACT is an assay providing full exon coverage of 410 cancer related genes, detecting base substitutions, small indels, copy number changes, and select gene rearrangements. Results: Results are available in 89 tumor samples from 78 patients (mean patient age 53, 58% female); 31 tumors (35%) low grade, 35 tumors (39%) intermediate grade, and 23 tumors (26%) high grade; 5 patients (6%) with PD tumors and 73 patients (94%) with WD tumors. Changes in chromatin remodeling genes were observed only in WD tumors; DAXX alterations in 24 tumors (27%), ATRX alterations in 15 tumors (17%), and SETD2 alterations in 10 tumors (11%). RB1 alterations were identified in 3 tumors (3%); all of these tumors were PD/high grade. TP53 alterations were seen in 9 tumors (10%); 4/9 tumors (44%) PD/high grade, 3/9 tumors (33%) WD/intermediate grade, 2/9 tumors (22%) WD/low grade. All WD, TP53-altered tumors also had DAXX/ATRX changes. Conclusions: In line with prior work, using an institutional NGS assay, we demonstrated tumor differentiation and grade genetically. Changes in chromatin remodeling genes were exclusive to WD tumors. Only PD tumors had RB1 changes. While TP53 was altered in both WD and PD tumors, TP53-altered WD tumors also harbored changes in the chromatin remodeling genes.
Supportive care in cancer organization in France: State of the art.
Authors: Florian Scotte, Christian Herve, Roland Bugat, Fadila Farsi, Moise Namer, Jean-Marc Tourani, Christophe Tournigand, Gabriel Yazbek, Sandrine Richard, Stephane Oudard, Ivan Krakowski
Journal: Journal of Clinical Oncology (2012)

e19640 Background: Second Cancer Act was defined in France in December 2009 including enhancement of supportive care in Cancer (SCC). How are supportive care organized in France? Are patients informed about supportive treatment side effects? Methods: The AFSOS (French Speaking Association for Supportive Care in Cancer) conducted this observational study to evaluate practices, organizations and informations given to patients (pts) about SCC. Among 1621 french medical doctors (MD) caring cancer pts who were sent an adhoc questionnaire, 20% (330 MD including 44% medical oncologists) answered. Results: Three different organizations were described: Single MD, transversal team and specific structure specialized in global care (specifically developed in comprehensive cancer centers-CCC). Psycho-oncology, palliative care, nutrition and pain care were the four main items considered as supportive care. During their disease, 68% of pts are receiving SCC, presented by their MD (88%) or nurse devoted to announcement of disease and SCC information (57%). Supportive care is more dispensed during palliative period (90%) than at diagnosis (44%). Patients information is rather supplied during palliative care (85%) than at diagnosis (52%) using a specific questionnaire for outpatient (20%) or specific supportive care session (17%). 71% of cancer department have a cross team to provide supportive care, with specific SCC team particularly in CCC (62%; p=0.01)). 37% have inpatient specific units. Only 40% have a specific organization in home care connection, more in CCC than in public or private centers (respectively 69%, 45%, 20%; p=0.01). 73% use specific financial valorization of CSC activity. Adverse events information is dispensed to 54% of the pts for erythropoiesis stimulating agents (ASE), 74% for biphosphonates and 94% for opioids treatments, rather by medical oncologist than other specialists (p=0.01). Conclusions: Specific organization developed especially in comprehensive cancer centers seems to facilitate SCC organization and information to pts. In the mean time, recommendations include this information, involvement in supportive care team and methods have to be enhanced. Further results compared with patient point of views are expected.
Versatile Polymer Nanoparticles as Two‐Photon‐Triggered Photosensitizers for Simultaneous Cellular, Deep‐Tissue Imaging, and Photodynamic Therapy
Authors: Liang Guo, Jiechao Ge, Qian Liu, Qingyan Jia, Hongyan Zhang, Weimin Liu, Guangle Niu, Sha Liu, Jianru Gong, Steffen Hackbarth, Pengfei Wang
Journal: Advanced Healthcare Materials (2017)

Clinical applications of current photodynamic therapy (PDT) photosensitizers (PSs) are often limited by their absorption in the UV–vis range that possesses limited tissue penetration ability, leading to ineffective therapeutic response for deep‐seated tumors. Alternatively, two‐photon excited PS (TPE‐PS) using NIR light triggered is one the most promising candidates for PDT improvement. Herein, multimodal polymer nanoparticles (PNPs) from polythiophene derivative as two‐photon fluorescence imaging as well as two‐photon‐excited PDT agent are developed. The prepared PNPs exhibit excellent water dispersibility, high photostability and pH stability, strong fluorescence brightness, and low dark toxicity. More importantly, the PNPs also possess other outstanding features including: (1) the high 1 O 2 quantum yield; (2) the strong two‐photon‐induced fluorescence and efficient 1 O 2 generation; (3) the specific accumulation in lysosomes of HeLa cells; and (4) the imaging detection depth up to 2100 µm in the mock tissue under two‐photon. The multifunctional PNPs are promising candidates as TPE‐PDT agent for simultaneous cellular, deep‐tissue imaging, and highly efficient in vivo PDT of cancer.
Cancer yield of mammography, MRI, and ultrasound in high-risk women enrolled in a prospective multi-institution breast cancer screening trial
Authors: C. Lehman, C. Gatsonis, C. Isaacs, E. Pisano, S. Ascher, P. Weatherall, D. Bluemke, M. Schnall
Journal: Journal of Clinical Oncology (2004)

9626 Background: Several single institution trials suggest MRI and US may be beneficial in detecting clinically and mammographically occult cancer in women at high risk for breast cancer. However, few prior studies include both US and MRI in patient evaluation, and the range of added cancer yield of both modalities varies widely from <1% to >10%. This is the first North American, multi institution study of MRI, mammography and US. Methods: We conducted a prospective study of screening mammography, MRI and ultrasound in women ≥ 25 years of age who were genetically high risk, defined as BRCA1 or BRCA2 carriers or with at least a 20% probability of carrying a BRCA1/BRCA2 mutation as determined by BRCAPRO. In order to be eligible, women had to have a normal breast examination. All three imaging modalities were performed within 90 days of each other. Women were eligible if they were unaffected with cancer or had breast cancer but had completed adjuvant chemotherapy and radiation therapy at least six months prior to study entry. Results: A total of 195 women were enrolled in this study over a six month period and 171 completed all study exams (mammography, ultrasound and MRI). Sixteen biopsies were performed and six cancers were detected for an overall 3.5% cancer yield. MRI detected all six cancers while mammography detected two and US detected one. The diagnostic yields for each test were: MRI 3.5%, US 0.6%, and mammography 1.2%. MRI, US, and mammography resulted in biopsies being performed in 8.2%, 2.3%, and 2.3% patients, respectively. Conclusions: Screening high risk women with mammography, MRI and US produced a 3.5% cancer yield. Screening MRI was associated with a higher biopsy rate, but was the only modality that detected all six cancers in our study. No significant financial relationships to disclose.
Identification of glioblastoma patients who stand to benefit from PARP inhibitor therapy.
Authors: Kerrie Leanne McDonald, Mustafa Khasraw, David M. Ashley
Journal: Journal of Clinical Oncology (2015)

2071 Background: The development of effective targeted drugs for the treatment of glioblastoma (GBM) represents a major unmet need. Veliparib (ABT-888; Abbvie) inhibits both PARP1 and PARP2 (poly[ADP-ribose] polymerase). The successful clinical application of veliparib and other PARP inhibitors (PARPi) will be assisted by the identification of predictive biomarkers. Methods: Efficacy of veliparib in combination with radiotherapy (RT) was tested on a panel of primary and recurrent GBM patient-derived cell lines (PDCLs). In order to screen for potential biomarkers for PARPi we performed whole genome sequencing (WGS) on sensitive and resistant PDCLs and also measured the expression of 96 candidate DNA repair pathway genes using the RT2 Profiler PCR Array (Human DNA Repair; Qiagen) Results: Differential sensitivity to veliparib and RT were observed amongst the panel of PDCLs. Three out of sixteen PDCLs showed hypersensitivity to veliparib/RT. PDCLs sensitive to treatment exhibited a large number of structural variation (SV) events ( > 200). The average SV events identified in the resistant PDCLs were < 50. We detected mutations in genes involved in mismatch repair (MMR): MLH1, MSH2, MSH6 and PMS2. We also detected mutations in other genes involved in DNA maintenance such as XRCC4, FANCA, FANCD2, ATR, RPA1, REV3L and PARP1 only in the sensitive PDCLs. Conclusions: Mutations in DNA maintenance pathways may be a method for selecting patients for therapies involving the combination of DNA damaging agents such as radiotherapy, and PARP inhibitors. Additionally, the signature associated with genomically unstable GBM may be a method of identifying potential responders to PARP inhibitor therapy.