tbuckley/cabot-search huggingface dataset:
Correlation of ERCC1 mRNA expression with KRAS mutation status in colorectal, pancreatic, and lung adenocarcinoma.
Authors: Diana L. Hanna, Martin K. H. Maus, Craig Stephens, Peter Philipp Grimminger, Stephanie H. Astrow, Dongyun Yang, Fotios Loupakis, Jack Hsiang, Gary Zeger, Afsaneh Barzi, Heinz-Josef Lenz
Journal: Journal of Clinical Oncology (2013)

11062 Background: KRAS is mutated in about 40% of colorectal cancers; it is the only validated predictive marker used in patients with metastatic disease. ERCC1 is a critical enzyme in nucleotide excision repair and is associated with response, progression free and overall survival in patients with NSCLC, colorectal, and gastric cancer treated with platinum based chemotherapy. We tested whether ERCC1 mRNA expression correlates with KRAS and BRAF mutation status in patients with colorectal, pancreatic, and lung cancer. Methods: Formalin fixed paraffin embedded tumor specimens from 1,514 patients (573 colorectal; 91 pancreatic; 850 lung) were microdissected; DNA and RNA were extracted. Specifically designed primers and probes were used to detect 7 different base substitutions in codons 12 and 13 of KRAS and the V600E BRAF mutation. ERCC1 mRNA expression levels were measured by quantitative RT-PCR in a CLIA approved laboratory. Results: Mt KRAS tumors had significantly lower ERCC1 mRNA levels relative to wt KRAS tumors in both colorectal (0.89 vs. 1.06; p&lt;0.001) and pancreatic (1.20 vs. 1.80; p=0.006) groups. While mt KRAS lung tumors showed decreased ERCC1 expression (1.25 vs. 1.39), the trend did not meet significance (p=0.069). Within the colorectal subset, mt BRAF cancers trended towards less ERCC1 expression than tumors harboring both wt KRAS/BRAF genes (0.96 vs. 1.06; p=0.25). Conclusions: This is one of the first reports linking KRAS mutation status with ERCC1 gene expression in colon, pancreatic and lung cancer. KRAS mutation status may predict sensitivity to platinum based therapy in colon and pancreatic cancer. Colorectal tumors with either the BRAF or KRAS mutation have decreased ERCC1 expression, relative to those that carry both wildtype genes. This may explain the poor sensitivity to oxaliplatin based regimens in these patients. Furthermore, this suggests that ERCC1 expression may be driven by MAPK activation given the uniform ERCC1 downregulation amongst mt KRAS and mt BRAF cancers. Thus, MEK inhibitors may improve the efficacy of oxaliplatin based chemotherapy. Prospective biomarker driven studies should validate these principles, guide clinical decision making and improve outcomes.
Features of familiality in a cohort of patients (pts) with sarcoma.
Authors: Georgios Lypas, Elizabeth J. Root, Suzanne George, Andrew J. Wagner, James E. Butrynski, Jeffrey A. Morgan, George D. Demetri, Lisa DiGianni, Serena Masciari, Michelle Genevieve Rath, Judy Ellen Garber, Chandrajit P. Raut
Journal: Journal of Clinical Oncology (2012)

1547 Background: Sarcomas occur in a number of cancer predisposition syndromes, yet genetic evaluation is rarely recommended for sarcoma pts. We broadly reviewed the family cancer histories of unselected pts in a tertiary center sarcoma clinic to explore the potential relevance of genetic assessment. Methods: Between 2005 and 2008, 397 pts (median age 52 years) with documented sarcoma who consented to research use of medical records and tissues also completed a family history questionnaire. Patient and family histories were reviewed for features suggesting hereditary risk (e.g. early age at diagnosis or familial clustering of certain associated diagnoses). Results: A family history of malignancy was noted in 301 of 397 pts (76%). Seventy-six pts (19%) were diagnosed with 99 additional malignancies, most frequently breast cancer (n=23), prostate cancer (12), melanoma (12), thyroid cancer (6) or a second sarcoma (10). Sarcoma was diagnosed prior to or synchronously (within 6 months) with another malignancy in 20 pts and metachronously in 56 pts. In 18 pts, sarcoma arose within a prior radiation field. Thirty-seven pts (9%) had a sarcoma subtype associated with a recognized syndrome: desmoid fibromatosis (n=16), malignant peripheral nerve sheath tumor (11), PEComa/angiomyolipoma (6), retinoblastoma (3), and GIST with paraganglioma (1). Based on additional features, the associated syndromes were confirmed in 6 of them (1.5% of the cohort): familial adenomatous polyposis (n=1), neurofibromatosis type 1 (2), familial retinoblastoma (2), and Carney-Stratakis dyad (1). Thirty-three pts (8% of the cohort, or 16% of pts age &lt;50) fulfilled TP53 testing criteria (Chompret, Birch or classical Li-Fraumeni Syndrome [LFS] criteria). Another 147 pts (37% of the entire cohort) did not fulfill LFS testing criteria, but were diagnosed with sarcoma before age 50 and had at least one first or second degree relative with a diagnosis of malignancy before age 50. Conclusions: Sarcomas are rare and diverse cancers. Given the potential association with cancer predisposition syndromes, genetic evaluation should be strongly considered in sarcoma pts based on age at diagnosis, histology, and family cancer history.
Loss of Heterozygosity Drives Adaptation in Hybrid Yeast
Authors: Caiti S. Smukowski Heil, Christopher G. DeSevo, Dave A. Pai, Cheryl M. Tucker, Margaret L. Hoang, Maitreya J. Dunham
Journal: Molecular Biology and Evolution (2017)

Hybridization is often considered maladaptive, but sometimes hybrids can invade new ecological niches and adapt to novel or stressful environments better than their parents. The genomic changes that occur following hybridization that facilitate genome resolution and/or adaptation are not well understood. Here, we examine hybrid genome evolution using experimental evolution of de novo interspecific hybrid yeast Saccharomyces cerevisiae × Saccharomyces uvarum and their parentals. We evolved these strains in nutrient-limited conditions for hundreds of generations and sequenced the resulting cultures identifying numerous point mutations, copy number changes, and loss of heterozygosity (LOH) events, including species-biased amplification of nutrient transporters. We focused on a particularly interesting example, in which we saw repeated LOH at the high-affinity phosphate transporter gene PHO84 in both intra- and interspecific hybrids. Using allele replacement methods, we tested the fitness of different alleles in hybrid and S. cerevisiae strain backgrounds and found that the LOH is indeed the result of selection on one allele over the other in both S. cerevisiae and the hybrids. This is an example where hybrid genome resolution is driven by positive selection on existing heterozygosity and demonstrates that even infrequent outcrossing may have lasting impacts on adaptation.
Quality of life in cancer survivors compared with the general population.
Authors: Anne Hudson Blaes, Kevin Scott Baker, Brad Benson, Robin L. Bliss, Jill Lunsford Lee, Joseph Philip Neglia, Daniel A. Mulrooney
Journal: Journal of Clinical Oncology (2012)

e16502 Background: Assessments of quality of life (QOL) among cancer survivors have had mixed results. Literature suggests that those treated with cranial irradiation (CNS) or stem cell transplantation (SCT) have a poorer quality of life. Methods: 309 cancer survivors (37 adult and 241 childhood malignancies, 31 SCT survivors) completed the Medical Outcomes Study 36-Item Short Form Healthy Survey (MOS SF-36). Demographic, disease and treatment characteristics were assessed and inter-group heterogeneity tested across three survivor groups (F-test for age; chi-square for disease and treatment characteristics). Aggregate data analysis for SF-36 composite and norm-based scoring measures was undertaken by using the mixed effect model with unequal random effect variances across studies. Treatment characteristics included age at diagnosis, current age, site of disease [cranial (y/n)], chemotherapy (y/n), radiation therapy (y/n), SCT with/without total body irradiation (TBI). All statistical tests were two-sided, P-values &lt; 0.05 considered statistically significant. Results: The mean age at assessment was 33.4 years. 255 (83.9%) received chemotherapy, 187 (60.7%) radiation, 49 (15.9%) underwent SCT. Among those irradiated, 28 (9.1%) had TBI and 62 (20.1%) had CNS irradiation. The MOS SF-36 physical composite score was 50.5 (9.5-73.3) and mental health composite score was 50.2 (9.2-55.9). Pooled results for the MOS SF-36 included: bodily pain 51.9 (19.9-62.1), general health perceptions 46.7 18.6-63.9), mental health 50.6 (16.2-64.1, physical functioning 51.0 (14.9-57.0), role emotion 50.2 (9.2-55.9), role physical 50.2 (17.7-56.9), social functioning 49.5 (13.2-56.9) and vitality 51.9 (20.9-70.8). No significant variation from the general population median normative values (50.0) was identified, including those treated with CNS and SCT. There was no difference in QOL amongst those treated as children, young adults (ages 15-30 years) or adults. Role physical declined significantly with advancing age (p=0.02). Conclusions: In spite of the chronic conditions prevalent among cancer survivors, the overall QOL of most cancer survivors, including those who have received CNS or SCT, is comparable to that of the general population.
Patterns of acquired resistance to anti-PD-1 antibodies in patients with metastatic melanoma (MM).
Authors: Jenny HJ Lee, Adam James Cooper, Megan Kate Lyle, Elizabeth Liniker, Alexander M. Menzies, Richard Kefford, Georgina V. Long, Matteo S. Carlino
Journal: Journal of Clinical Oncology (2015)

e20005 Background: PD-1 antibodies demonstrate impressive clinical activity in MM. Much effort is focused on determining predictors of response and innate resistance, but little is known about the patterns and mechanisms of acquired resistance, nor disease behaviour and survival after PD-1 failure. We sought to describe the patterns of disease progression (DP) and post DP survival in pts treated with PD-1 antibodies after initial treatment response. Methods: Pts with MM treated with nivolumab or pembrolizumab with initial RECIST clinical benefit (complete response [CR], partial response [PR], or durable stable disease [durSD] for > 6 months) who then progressed were included. Perpendicular measurements of all metastases ≥ 5mm (lymph nodes ≥ 15mm in short axis) visible on CT scan were measured at baseline and until DP, and the nature of DP and subsequent survival were analysed. Results: 14 eligible pts had progressed; 3 with prior CR, 8 with PR and 3 with SD. Median follow-up of this cohort of pts was 22 months (range 14-35), and median PFS was 12 months (95% CI). 7/14 (50%) pts had asymptomatic radiological progression. All 3 patients with CR progressed in new lesions only, 2 pts with solitary mets amendable to surgical resection, and 1 pt with multiple lymph node recurrence. Pathology from one resected progressing lung lesion was inflammatory, not malignant, and was excluded from the post progression follow-up analysis. The remaining 11 pts with PR or durSD had 124 measured mets at baseline, and demonstrated a heterogeneous pattern of progression. 20 of 41 (49%) progressing lesions were new. 8 pts had DP in baseline lesions (med 19%, range 8-50%) and 3 pts had DP in new sites only. Only 1 pt developed brain metastases, with a post DP survival of 5 months. The remaining 13 patients are alive with a median post DP follow up of 8 months (range 2-14months). Conclusions: Acquired resistance to anti-PD1 agents often represents only a fraction of the burden of disease, with the development of brain mets uncommon. Survival after progression can be prolonged, which has the potential to affect subsequent therapeutic options. The selection of progressing lesions for translational analyses may poorly reflect overall tumour behaviour in an individual.
Clinicopathologic predictors (CP) of survival in patients with endometrial stromal sarcomas (ESS) treated with multi-modality therapy.
Authors: Samir Dalia, Anthony Paul Conley, Kate Fisher, Ji-Hyun Lee, Robert Michael Wenham, Sachin Apte, Ricardo Jorge Gonzalez
Journal: Journal of Clinical Oncology (2013)

10556 Background: ESS is a rare uterine neoplasm in which there is minimal data about CP prognostic markers. Our study aims to determine the association of CP variables on overall survival (OS). Methods: Patients at Moffitt Cancer Center between January 1, 1990 and April 30, 2012 with the diagnosis of ESS were identified using our institutional database. Vital status, demographics, and therapeutic information were recorded. Survival time was estimated using the Kaplan-Meier method, and Cox proportional hazard model was used to identify potential risk factors for the time to event data. A p value &lt; 0.05 was significant. Results: 64 patients were identified. 11 were excluded for incomplete records or inaccurate pathology, and 53 patients were analyzed. Median OS was 214 months (95% Confidence Interval (CI) 60-338). Median follow up was 133 months (95% CI 84-182). Mean age was 53±14 years, 45 (85%) underwent oophorectomy at or prior to diagnosis, 12 (23%) were diagnosed with metastatic disease, 37 (70%) were low grade, 19 (36%) were FIGO stage III-IV. Mean BMI was 29±8 kg/m 2 , 23 (43%) received adjuvant therapy (adjT) of any type (hormonal, chemotherapy, or radiation) and 16 (30%) received hormonal therapy at any time (HRT). 27 (51%) patients had ER or PR testing and 19 (70%) were ER(+), 20 (74%) were PR (+). The sample size was too small for multi-variable analysis. The Table shows the results of select univariable analysis and OS. Conclusions: Age, initial tumor size, ER and PR status had the greatest impact on survival while BMI, FIGO stage, AdjT or HRT did not. The association between survival and ER or PR status was seen independent of if a patient received HRT. Multicenter collaborative efforts are needed in order to further study the effects of ER and PR status on survival in ESS. [Table: see text]
The risk and clinical outcome of candidemia depending on underlying malignancy
Authors: Olivier Lortholary, Charlotte Renaudat, Karine Sitbon, Marie Desnos-Ollivier, Stéphane Bretagne, Françoise Dromer
Journal: Intensive Care Medicine (2017)

To assess the risk factors and outcomes associated with fungemia caused by the six most commonly occurring Candida species in patients with and without malignancies.Analysis of the episodes of fungemia due to common Candida species in adults, based on an active hospital-based surveillance program (Paris area, France, 2002 to 2014).Of the 3417 patients (3666 isolates), 1164 (34.1%) had a solid tumor (45.7% digestive tract) and 586 (17.1%) a hematological malignancy (41.8% lymphoma, 33.5% acute leukemia). The hematology patients were significantly younger, more often pre-exposed to antifungals, more often infected by C. tropicalis, C. krusei, or C. kefyr, and more often treated in the first instance with an echinocandin. Compared with inpatients who were not in ICU at the time of fungemia, those in ICU were less frequently infected by C. parapsilosis (p < 0.02), had more recent surgery (p < 0.03), and died more frequently before day 8 and day 30 (p < 0.0001). An increase in crude mortality over time in ICU was observed only in oncology patients (p < 0.04). For all patients, lack of prescription of antifungals despite knowledge of positive blood culture increased the risk of death. The odds of being infected by a given Candida species compared with C. albicans were uneven regarding age, gender, type of malignancy, hospitalization in ICU, central venous catheter, HIV status, intravenous drug addiction, and previous exposure to antifungal drugs. Compared with C. albicans, C. glabrata (OR = 0.69 [0.54-0.89]) and C. parapsilosis (OR = 0.49 [0.35-0.67]) were associated with a decreased risk of death by day 8 and day 30.The clinical context of underlying malignancy and hospitalization in ICU may be relevant to the initial management of candidemia.
Single-dose, four-way crossover, open-label, relative bioavailability (BA) studies of a novel formulation of abiraterone acetate (AA) versus the reference formulation under fasted conditions in healthy male subjects.
Authors: Ronald Goldwater, Azra Hussaini, Yuxin Zhang, Bill Bosch, Paul Nemeth
Journal: Journal of Clinical Oncology (2017)

e605 Background: AA is approved for treatment of metastatic castration-resistant prostate cancer. The originator AA (OAA) formulation is poorly absorbed and exhibits large pharmacokinetic variability in abiraterone exposure in healthy subjects. AA fine particle (AAFP) is a proprietary formulation (utilizing SoluMatrix Fine-Particle Technology) that was designed to provide improved BA versus the OAA formulation. Methods: In Study 1, 20 subjects were randomized in a crossover design to single doses of AAFP 100, 200, or 400 mg or OAA 1000 mg. To further expand the AAFP dose range, 36 subjects were randomized in a crossover design to AAFP 125, 500, or 625 mg or OAA 1000 mg in Study 2. Both studies included a 7-day washout period prior to crossover. Results: AAFP 500 mg BA relative to OAA 1000 mg measured by the ratio of test-to-reference geometric means was AUC 0-t 93.4% (90% CI: 85.3–102.4%), AUC 0-∞ 91.0% (90% CI: 83.3–99.4%), and C max 99.8% (90% CI: 86.3–115.5%). Dose proportionality was seen across all AAFP dose levels (see table). Between-subject variability for AAFP 500 and 625 mg was similar to OAA 1000 mg. No significant AAFP-related adverse events (AEs), serious AEs, or deaths occurred. Treatment-emergent AEs were mostly Grade 1. Conclusions: AAFP demonstrated improved BA and AAFP 500 mg was bioequivalent to OAA 1000 mg in healthy male volunteers under single dose and fasted conditions. AAFP showed dose proportionality across all doses studied (100–625 mg). Clinical trial information: NCT02737332. [Table: see text]
Final results of a phase II trial of stereotactic body radiotherapy (SBRT) in patients with hepatocellular carcinoma (HCC) with Child-Pugh class A (CPC-A).
Authors: Foster D Lasley, Paul Kwo, Sandra Althouse, Susan M. Perkins, Mary A. Maluccio, Higinia Rosa Cardenes
Journal: Journal of Clinical Oncology (2014)

4103 Background: After confirming the safety and appropriate radiation dose in phase I dose escalation trial, a phase II trial was completed to evaluate the efficacy of SBRT for HCC in CPC-A patients. Methods: Thirty-eight patients with HCC in the context of liver cirrhosis, CPC-A, were treated with SBRT in a Phase II trial at Indiana University. All patients received three fractions, 1,600 cGy per fraction (total dose 4800 cGy), 1-2 fractions per week. Dose was prescribed to the 80-90% isodose line covering the planning target volume (PTV). Demographics, clinical variables, treatment –related toxicities within 90 days of end of treatment, and local control at 6 months were tabulated and 95% exact binomial confidence intervals for local control (LC) at 6 months was calculated. A modified RECIST criteria was used to determine local failure. Progression Free Survival (PFS), and Overall Survival (OS) estimates were calculated using Kaplan-Meier methodology. Results: Median follow-up time was 31.0 months (2.8-64.4 months). There were 28 males and 10 female; median age of 61 years (range 24-86). Thirty-six (94.7%) patients had stage T1 disease and one patient each (2.6%) with T2 and T3 disease. Pre-treatment AFP ng/ml median (range): 8.3 (1.5-2931.9). All patients had 1 treated lesion. Median (range) for gross tumor volume (cc) was 30.9 (2.0-79.1); PTV volume (cc) was 99.1 (20.8-196.0); and uninvolved liver volume (cc) was 1607.3 (939.0-3214.0). There was 1 grade 4 toxicity of elevated GGT and 3 grade 3 toxicities including, 1 each of GGT, increased INR, and thrombycytopenia. Of the 38 patients enrolled, 1 did not return for their 6 month follow-up. Of the 37 evaluable patients, 35 (94.6%), 95% C.I. (81.8%, 99.3%) had LC at 6 months. Median PFS was 30.9 months (95% CI: 13.9 months, 64.4 months). Median OS is 38.3 months (95% CI: 28.2 months, 64.4 months). OS at 1, 2 and 3 years was 94%, 77% and 52% respectively. Conclusions: In selected patients with hepatocellular carcinoma in the context of CPC-A liver cirrhosis, SBRT is an effective therapy with good toxicity profile. Clinical trial information: NCT00243841.
Early assessment of PSA response in patients with mCRPC treated with enzalutamide and abiraterone.
Authors: Allison H. Feibus, Jeffrey R. Guccione, Ashwin Vasudevamurthy, Elisa M. Ledet, Patrick Cotogno, Charlotte Manogue, Emma M. Ernst, Brian E. Lewis, Jonathan L. Silberstein, A. Oliver Sartor
Journal: Journal of Clinical Oncology (2017)

e574 Background: Abiraterone (Abi) and enzaleutamide (Enza) are first-line agents for the treatment of metastatic castrate-resistant prostate cancer (mCRPC). Primary resistance is well-documented, but little data exists for rapid treatment responders. This study intended to further characterize patients with early prostate-specific antigen (PSA) decline. Methods: A single-institution retrospective review was performed on 123 mCRPC patients treated with Abi and/or Enza. PSA was recorded every 4 weeks for the duration of treatment. The primary endpoint was to describe PSA response, including sensitivities and specificities, as a predictor of later treatment response (defined as ≥50% decrease in PSA from baseline). Additional clinical covariates were also evaluated as treatment-response predictors. Results: A PSA response to Abi was achieved in 52/123 (42%) of patients. Median time to PSA nadir was 37 days. 30/52 (58%) patients responded to the drug within 4 weeks. Median length of time on drug was 110 days. A PSA response to Enza was achieved in 21/123 (17%) of patients. Median time to PSA nadir was 140 days. 18/21 (86%) of patients responded to the drug within 4 weeks. Median length of time on drug was 161 days. Conclusions: Percentage of PSA decline and time to drug response for Enza and Abi are important variables that can serve as reliable way for clinicians to predict long-term PSA response. It is vital to make appropriate treatment modifications for patients that do not display early PSA response. [Table: see text]