tbuckley/cabot-search huggingface dataset:
Next-generation sequencing mutational analysis of triple-negative breast cancer patients from matched FFPE and fresh frozen samples.
Authors: Mark Landers, Rhonda Meredith, Jerry Lee, Yipeng Wang, Byung-In Lee, Joseph Monforte
Journal: Journal of Clinical Oncology (2012)

1058 Background: TNBC is an aggressive subtype of breast cancer accounting for 10-15% of all cases. TNBC tumors (ER-/PR-/HER-) are more common in patients with BRCA mutations. BRCA mutations leading to homologous DNA repair deficient tumors enhance the efficacy of chemotherapy and PARP inhibitors. BRCA mutations have been identified in 20% of patients without family history. Identification of germline and somatic BRCA mutations in unselected patients could increase the number of patients who benefit from these therapies. Determining BRCA mutational status from FFPE and fresh frozen specimens may enable clinical studies in these patient populations.We describe the development of an NGS BRCA mutational assay compatible with FFPE and fresh frozen samples using tumor/adjacent normal matched tissues. Methods: Matched samples were purchased from Cureline. gDNA was isolated by lysis/column purification (Qiagen) and enriched for BRCA exons/flanking regions (Halogenomics Selector). Fragment libraries were constructed (Ion Torrent frag express) and prepared for sequencing by emPCR (Ion Torrent Template Xpress). Libraries were sequenced for 65 cycles (Ion Torrent PGM) yielding 2-4M reads/sample. Variants were called from tMAP aligned reads by GATK and VarScan. Overlapped exonic variants were filtered by p-value (&lt;0.0001) from VarScan. Results: In the first patient set normalized average depth of BRCA exon coverage was 64X and 72X per 150K reads in FFPE and fresh frozen tissues respectively covering 95-100% of target. hg19 alignment rates varied between 97-99% across all samples. Similar numbers of variants were called in both FFPE (12) vs. fresh frozen (13) with a corresponding mean duplicate removed depth of coverage of 23.3X and 42.4X at the called positions. 10/13 calls in fresh frozen overlapped with those in FFPE. A tumor specific somatic frameshift insertion in BRCA2 was detected in both FFPE and fresh frozen tissues. Conclusions: Results indicate that NGS mediated BRCA mutational analysis demonstrates equivalent utility in both FFPE and fresh frozen tumor samples although more sequencing reads are required to produce equivalent depth of coverage starting from FFPE samples.
BRCA1/BRCA2 predictive genetic testing in an Irish population: A missed opportunity.
Authors: David Edward O Reilly, Lucy Dooley, Geoffrey Alan Watson, M. P. Farrell, R. M. Clarke, Amy Nolan, Carmel Nolan, Eileen Berkeley, Emily O'Donovan, David James Gallagher
Journal: Journal of Clinical Oncology (2018)

e13530 Background: The diagnosis of a BRCA1/2 mutation has significant implications for both probands and their families, with both screening and prophylactic surgical interventions available. Underutilisation of genetic testing services has been reported in other jurisdictions. BRCA1/2 testing is requested in only 29-53% of eligible women and 11-12% of eligible men, representing a missed cancer prevention opportunity. Possible explanations include lack of family disclosure, poor access or lack of awareness of genetic counselling services, or patient preference. We investigated the rates of BRCA1/2 predictive testing in an Irish population. Methods: We performed a multicentre, retrospective analysis of 63 pedigrees from two Irish tertiary hospitals over a five-year period (2012-2017). By manually examining pedigrees, we identified eligible family members who should receive BRCA1/2 mutation testing as per national guidelines. Results: A total of 1048 candidates for predictive BRCA1/2 mutation testing were identified. 318 (30.4%) proceeded to BRCA1/2 mutation testing including 215 (37.5%) females and 99 males (21.5%). Uptake of testing favouring womIrish population, particularly among Irish males. Predictive BRCA1/2 testing and subsequent screening/surveillaen was statistically significant (T = 3.7, p < .0002). Conclusions: We demonstrate suboptimal uptake of BRCA1/2 mutation testing in the nce/prophylactic intervention in mutation carriers can meaningfully impact breast cancer survival. This represents a missed cancer prevention opportunity for Irish society.
Outcomes of systemic therapy for patients with metastatic undifferentiated pleomorphic sarcoma (UPS).
Authors: Diego Andres Adrianzen Herrera, Deborah Kuk, Mary Louise Keohan, Mark Andrew Dickson, Sandra P. D'Angelo, Ping Chi, Narasimhan P Agaram, Cristina R. Antonescu, M Hameed, William D. Tap, Li-Xuan Qin, Mrinal M. Gounder
Journal: Journal of Clinical Oncology (2016)

11066 Background: UPS, formerly termed malignant fibrous histiocytoma (MFH) are high grade sarcomas where the cell of origin is unkown. Although they represent 15% of sarcomas, there is sparse data on the effectiveness of systemic therapies in advanced setting. Methods: We retrospectively reviewed patients (pts) with complete medical records and pathology confirmation at Memorial Sloan Kettering Cancer Center who met ICD-O code M8830/3 and were treated for metastatic disease between 1984 - 2012. Results: We included 246 pts with median age at metastasis of 62 yrs (24 - 91), 60% male and median ECOG 1. Primary site was predominantly lower extremity (56%); median primary tumor size was 10 cm (1.5 - 40); initial stage was localized in 78%. Median number of metastatic sites was 1 (1-4), with the most common site as the lungs (87%), alone or combined with extrapulmonary metastasis (18%). At the time of analysis, 211 had died and median overall survival (mOS) was 15.5 months from time of metastases. In univariate analysis, OS was associated with KPS (p < 0.001) but not age, primary site, stage at presentation and number of metastasis sites. Median number of treatment lines was 2 (1 - 13). First line regimens included single or combinations of anthracycline (doxorubin [A] with ifosfamide and/or dacarbazine) (61%) or gemcitabine [G] with docetaxel (24%). Median time to treatment progression (mTTP) was 2.8 and 2.5 (1st line), 2.9 and 2.9 (2nd line) and 2.8 and 2.7 (3rd line) mo for [A] and [G] based regimens, respectively. No differences in mTTP were seen in any line between combination and single agent [A] regimens (p = 0.38, 0.71, and 0.52; 1st, 2nd and 3rd line respectively) or between [A] and [G] based regimens (p = 0.49, 0.57, and 0.73; 1st, 2nd and 3rd line respectively). For 1stline, tumor response, stable disease and progression were noted in [A] and [G] based regimens at a rate of 26, 23, 50% and 22, 38, 34%, respectively. Conclusions: This is the largest series evaluating the efficacy of chemotherapy in metastatic UPS. KPS was the only factor that impacted OS. Responses were marginally higher in regimens with anthracycline plus two alkylating agents. Benefit of chemotherapy was 2.5 – 2.9 mo and there were no difference in mTTP between regimens.
The application of next-generation sequencing in the community clinical oncology setting.
Authors: Pavan S. Reddy, Ahmad Khalil Rahal, K. James Kallail, Dennis Frederic Moore, Phu Van Truong, Bassam Ibrahim Mattar, Michael W. Cannon, Nassim H. Nabbout, Seth Joel Page, Quoc Van Truong, Christopher Dakhil, Jeremy Michael Deutsch, Shaker R. Dakhil
Journal: Journal of Clinical Oncology (2016)

e23145 Background: The advent of next-generation sequencing (NGS) for cancer holds promise for targeted therapy, but the practical issues surrounding integration of this testing into the community oncology setting have not been well addressed. This retrospective observational study describes the clinical utility of NGS panels in a single community cancer center. Methods: A retrospective chart review was conducted on patients seen at a single community cancer center whose tumors were tested with NGS for actionable mutations. Under IRB approval, data were collected on date of testing, stage at testing, mutational results, type of cancer, treatment decisions and survival. A total of 58 NGS panels were ordered in patients with advanced cancer after failure of standard therapy between March 2014 and September 2015. Results: The most common actionable mutations found were KRAS and TP53. Of the 58 NGS panels, 52 (90%) had sufficient tumor tissue for NGS. At least one mutation was identified in 39 pts (75%). Forty-four of the 52 patients (85%) were not involved in clinical trials or started on targeted therapy. Fifteen of the 44 patients (35%) had no mutations identified or non-actionable mutations; 29 of the 44 patients (65%) had actionable mutations. Eight of the 52 patients (15%) were enrolled to at least one targeted agent that matched their mutation or onto clinical trials that matched their genetic alterations. Conclusions: Although a majority of patients with advanced cancers whose tumors underwent NGS profiling demonstrated genetic alterations, only 15% were enrolled to a matched trial or a targeted therapy. This low impact of NGS testing on treatment decisions could be due to lack of guidelines on interpretation of results of NGS diagnostic tests. Randomized clinical trials and/or genomic databases are needed to guide physicians in the community practice setting on how to best utilize NGS results. Actionable mutation (s) Total patients identified (n) AKT;BRAF;CCND3;CEBPA;CTTNB1;DNMT3A;GNAS; HRAS;JAK3;KDR;MAP2K1;NPM1;NRAS;PTEN; STK11;U2AF1;VHL;WT1 1 CDKN2A;CREBBP;ERBB2;FGFR1/3;NTRK1/3; PIK3R1;TET2 2 PIK3CA 3 RUNX1L56S 4 MET 5 KRAS;TP53 16
24-month overall survival from KEYNOTE-021 cohort G: Pemetrexed-carboplatin plus pembrolizumab as first-line therapy for advanced nonsquamous NSCLC.
Authors: Ryan D. Gentzler, Corey J. Langer, Hossein Borghaei, Shirish M. Gadgeel, Vassiliki Papadimitrakopoulou, Amita Patnaik, Steven Francis Powell, Renato G. Martins, James Stevenson, Shadia Ibrahim Jalal, Amit W. Panwalkar, James Chih-Hsin Yang, Matthew A. Gubens, Lecia V. Sequist, Mark M. Awad, Joseph Fiore, Sanatan Saraf, Steven M. Keller, Leena Gandhi
Journal: Journal of Clinical Oncology (2018)

9026 Background: Cohort G of the phase 1/2 KEYNOTE-021 study (NCT02039674) evaluated pembrolizumab (pembro) + pemetrexed and carboplatin (PC) vs PC in first-line advanced nonsquamous NSCLC. With median follow-up of 10.6 mo, ORR (estimated treatment difference, 26%; P = 0.0016) and PFS (HR, 0.53; P = 0.010) significantly improved with pembro + PC vs PC. The HR for OS was 0.90 (95% CI, 0.42‒1.91). We present results after approximately 2 y of follow-up. Methods: Pts with previously untreated stage IIIB/IV nonsquamous NSCLC without EGFR mutations/ALK translocations were randomized 1:1 to 4 cycles of carboplatin AUC 5 mg/mL/min + pemetrexed 500 mg/m2 Q3W with or without pembro 200 mg Q3W for 2 y (maintenance pemetrexed permitted in both arms). Eligible pts with radiologic disease progression could cross over from PC to pembro. Response was assessed by BICR per RECIST v1.1. Primary endpoint was ORR; PFS and OS were secondary endpoints. P values are nominal. Results: 123 pts were randomized. As of Dec 1, 2017, median follow up was 23.9 mo (range, 0.8‒35.1 mo). 11 pts in the pembro + PC arm and 2 in the PC arm completed randomized treatment. Among pts in the PC arm who discontinued/completed, 41/56 (73%) subsequently received anti–PD-(L)1 agents, including 26 who crossed over to pembro on study. ORR was 57% with pembro + PC vs 30% with PC (P = 0.0016). PFS was significantly improved with pembro + PC vs PC (HR, 0.53; 95% CI, 0.33‒0.86; P = 0.0049). Median (95% CI) PFS was 24.0 (8.5‒NR) mo for pembro + PC vs 9.3 (6.2‒14.9) mo for PC. HR for OS was 0.56 (95% CI, 0.32‒0.95; P = 0.0151). Median (95% CI) OS was not reached (24.5 mo‒NR) for pembro + PC and 21.1 (14.9‒NR) mo for PC; 24-mo OS rates were 67% and 48%, respectively. Grade 3–5 treatment-related AE incidence was 41% with pembro + PC vs 27% with PC. 3 pts had treatment-related fatal AEs (pembro + PC, n = 1; PC, n = 2). Conclusions: After median follow-up of approximately 24 mo, the risk of death for pembro + PC vs PC was reduced by nearly half (HR, 0.56; nominal P = 0.0151) despite a high crossover rate among patients in the PC arm. Improvements in PFS and ORR persisted, and median PFS in the pembro + PC arm was 24.0 mo compared to 9.3 mo in the PC alone arm. Clinical trial information: NCT02039674.
Immunogenomic analyses associate immunological alterations with mismatch repair defects in prostate cancer
Authors: Daniel Nava Rodrigues, Pasquale Rescigno, David Liu, Wei Yuan, Suzanne Carreira, Maryou B. Lambros, George Seed, Joaquin Mateo, Ruth Riisnaes, Stephanie Mullane, Claire Margolis, Diana Miao, Susana Miranda, David Dolling, Matthew Clarke, Claudia Bertan, Mateus Crespo, Gunther Boysen, Ana Ferreira, Adam Sharp, Ines Figueiredo, Daniel Keliher, Saud Aldubayan, Kelly P. Burke, Semini Sumanasuriya, Mariane Sousa Fontes, Diletta Bianchini, Zafeiris Zafeiriou, Larissa Sena Teixeira Mendes, Kent Mouw, Michael T. Schweizer, Colin C. Pritchard, Stephen Salipante, Mary-Ellen Taplin, Himisha Beltran, Mark A. Rubin, Marcin Cieslik, Dan Robinson, Elizabeth Heath, Nikolaus Schultz, Joshua Armenia, Wassim Abida, Howard Scher, Christopher Lord, Alan D’Andrea, Charles L. Sawyers, Arul M. Chinnaiyan, Andrea Alimonti, Peter S. Nelson, Charles G. Drake, Eliezer M. Van Allen, Johann S. de Bono
Journal: Journal of Clinical Investigation (2018)

BACKGROUND. Understanding the integrated immunogenomic landscape of advanced prostate cancer (APC) could impact stratified treatment selection.
Tackling the youth mental health crisis across adolescence and young adulthood
Authors: Patrick D McGorry, Cristina Mei
Journal: BMJ (2018)

We agree with Gunnell and colleagues on the need for better understanding of risk factors influencing the mental health of adolescents (12-18 years).1 We would like to extend this focus to emerging adults (18-25 years) because the extended period of transition to adulthood is so critical for the development of potentially chronic adult mental disorders.

Three quarters of mental disorders begin …
“PRIME Study": Searching for immune biomarkers in advanced castration resistant prostate cancer (CRPC) patients treated with standard therapy
Authors: N. Romero-Laorden, A. Zapatero, L. San Jose, R. Lozano Mejorada, M.I. Pacheco, L. Rivera, I. Hernandez, I. Aragon, T. González, R. Colomer Bosch
Journal: Annals of Oncology (2018)

Background: CRPC is the lethal manifestation of the most frequent tumour in men. Despite of new target therapies emerged in last years patients will finally develop resistances that My be related to immune system alterations and it will lead to their death. Recent studies have shown that immunotherapy can be a critical therapeutic strategy. To identify how drugs that we use conventionally can modify the immune system at a microenvironment level is important to understand the biology of CRPC and the association with response/resistance to standard therapy, but also critical to the next future application of new immune therapeutic strategies in this setting. Trial design: This study is part of a multicentric National Biomarker Platform integrated by 56 centres initiated with the support of a Young Investigator Award from SOGUG and promoted by the Prostate Cancer Unit led by Dr. David Olmos at CNIO, that has enroled >900 patients. We establish a new prognostic factors explicative study using two prospective cohorts: CRPC patients treated with docetaxel (PROSTAC cohort) and abiraterone (AA, PROSABI cohort). Key inclusion criteria: a) histological confirmation of prostate cancer; b) documented criteria (PCWG) for CRPC; c) availability of tumour tissue; d) candidate for standard treatment with docetaxel or AA. Primary endpoint: to validate the prognostic value for overall survival (OS) of the expression signature (ES) in peripheral blood of 9 genes (Olmos et al, Lancet Oncol 2012) related to lymphocites B/T immunodeficiency in a 496 CRPC patients population treated with first line chemotherapy and AA. Secondary endpoints: a) to study the prognostic role for PFS of the ES; b) to compare its prognostic/predictive utility with other ES. Exploratory endpoints: a) to analyse an immunoprofile antibodies panel in peripheral blood in a subgroup of patients from this population and correlate those findings with the expression data in the primary tumour and the metastasis; b) explore new therapeutic strategies in TRAMP prostate cancer mouse models with different immune characteristics, with the global objective of identifying new clusters of patients candidates to immunotherapy that it is still a challenge. Clinical trial identification: PROSTAC study: NCT02362620; PROSABI study: NCT02787837. Legal entity responsible for the study: Hospital Univesitario La Princesa - CNIO Spanish National Cancer Research Centre. Funding: This work was supported by an unrestricted grant from "Fundación CRIS contra el cancer", grants from "Fondo de Investigación Sanitaria, Instituto de Salud Carlos IIII" (PI17/008). Disclosure: N. Romero-Laorden, R. Lozano Mejorada: During this work, NRL and RL were supported by grants from "Instituto de Salud Carlos III" (JR17/00007 to NRL and CM17-00221 to RL). All authors have declared no conflicts of interest.
TCT-605 Sex Based Differences in In-Hospital Outcomes of Patients With Cardiogenic Shock Treated With Percutaneous Mechanical Circulatory Support in the United States
Authors: Pedro Villablanca, Oluwole Adegbala, Tomo Ando, Divyanshu Mohananey, Tanush Gupta, Sagar Ranka, Vicky Chiang, Nathaniel Smilowitz, Mir Basir, Adam Greenbaum, Marvin Eng, Harish Ramakrishna, None mark menegus, Binita Shah, Deepak Bhatt, William O'Neill
Journal: Journal of the American College of Cardiology (2018)
Safety analysis of an open label, randomized phase 2 study of osimertinib alone versus osimertinib plus carboplatin-pemetrexed for patients with non–small cell lung cancer (NSCLC) that progressed during prior epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapy and which harbors a T790M mutation of EGFR.
Authors: Morihito Okada, Kentaro Tanaka, Hajime Asahina, Taishi Harada, Kosuke Hamai, Kana Watanabe, Kunihiko Kobayashi, Kenji Sugio, Satoshi Oizumi, Isamu Okamoto
Journal: Journal of Clinical Oncology (2018)

e21073 Background: Osimertinib is a standard treatment for patients with NSCLC positive for activating and T790M mutations of EGFR after failure of prior EGFR-TKI treatment. The efficacy and safety of osimertinib combined with platinum-based chemotherapy has been unknown. Methods: This open label, randomized phase 2 study enrolls adults with clinical stage IIIB or IV or postoperative recurrent NSCLC harboring activating and T790M mutations of EGFR after prior EGFR-TKI treatment failure. Patients are randomly assigned to receive osimertinib (80 mg/day) alone or in combination with carboplatin-pemetrexed (area under the curve of 5 and 500 mg/m2, respectively, on day 1 every 3 weeks). The primary end point is progression-free survival. A safety review of the first treatment course by an independent data monitoring committee was planned after enrollment of 12 patients in each arm. Results: As of 27 November 2017, 24 patients (median age, 67 years [range, 46–80]; 58.3% male; 83.3% stage IV; 100% adenocarcinoma; 58.3% exon-19 deletion and 41.7% L858R mutations of EGFR; 54.2% never-smokers) had been assigned equally to the two arms and received the protocol treatment at least once. Treatment-emergent adverse events were reported in all patients. One such event of grade (G) ≥3 (decreased neutrophil count of G3) occurred in the osimertinib arm, whereas four episodes each of decreased white blood cell count, decreased neutrophil count, decreased platelet count, and anemia of G3 or G4; two episodes of skin rash of G3; and one episode each of bronchial infection, oral mucositis, hypertension, and hypokalemia of G3 occurred in the combination arm. The event frequency in the combination arm was similar to that in previous studies of carboplatin-pemetrexed. Exaggeration of adverse events by osimertinib or previously unobserved events were not apparent in the combination arm. Conclusions: The combination treatment was safe in the selected patient population. Clinical trial information: 000024438.
Role of ERBB receptor feedback inhibitor 1 (ERRFI1) downregulation in progression of premalignant oral lesions to cancer.
Authors: Prajwal A, Anurag Kumar, Shyam Chauhan
Journal: Journal of Clinical Oncology (2018)

e18045 Background: Oral cancer is the second most common cancer in India and often preceded by premalignant lesions. EGFR aberration is one of the earliest and most common event in development of Oral cancer. ERBB receptor feedback inhibitor 1 (ERRFI1) negatively regulates EGFR by decreasing its tyrosine kinase activity and enhancing its internalization and degradation Methods: This study was conducted on patients who underwent elective surgery for oral cancer (n = 20) and diagnostic biopsy for oral premalignancy (n = 20). Normal oral mucosal tissue (n = 20) was obtained from distant normal site of oral cancer patients during surgery. Expression levels of ERRFI1 in these tissues was assessed by immunohistochemistry and quantitative real time PCR Results: Immunohistochemical analysis demonstrated significant decrease in the expression of ERRFI1 in oral cancer tissue compared to oral premalignant tissue(p = 0.014). However, expression of ERRFI1 was higher in premalignant lesions than normal oral tissue (p = 0.038). Similar change in the mRNA levels of this gene was observed by quantitative real time PCR analysis of these tissues (p < 0.005). Conclusions: Our study demonstrates the involvement of ERRFI1 downregulation in the pathogenesis of oral cancer. Significant decrease in its levels suggests its potential utility as a predictor of cancer progression from premalignant to malignant lesions.
Prevalence of high risk acute lymphoblastic leukemia (ALL) in Mexico, a possible explanation for outcome disparities.
Authors: Leonardo Verduzco-Rodriguez
Journal: Journal of Clinical Oncology (2018)

e22501 Background: ALL is the most frequent cancer in Mexican children. In developed regions 5-year overall survival (OS) is > 90% and cure rate is 85%. 5 year OS in Mexico is only 50-65%. Hispanic pts treated for ALL have a lower OS than non-Hispanic pts in the US. While different disease biology could explain outcome disparities, non-biologic mechanisms such as quality of care and lower therapeutic adherence may also be important contributing factors. In Mexico the 1993 National Cancer Institute (NCI) criteria continue to be used for the classification of risk as standard risk (SR, defined as age 1-9 and WBC at diagnosis < 50,000/ µL) or high risk (HR, all other pts). In Mexican literature the prevalence of HR pts is 50-60%, in sharp contrast with resource-rich settings such as the US, with 25% of pts being HR. Methods: We reviewed the open database for Mexico Popular Insurance Health Services (which covers 50% of Mexican population) for cases of pediatric ALL in 2016. This is a public database with information on demographic data, clinical stage and risk assessment. Our objective was to determine the frequency of HR and SR cases. Results: 883 pts were diagnosed with ALL in 2016, 471 male (53.3%) and 412 female (46.6%). Annual incidence was 2.25 new cases per 100,000 children (age 0-18). Mean age was 7.6 years (range 1-18). 45 (5%) were less than 2 years old, 535 (61%) were between 2 and 9 years old and 303 (34%) were more than 10 years old. 686 (78%) of pts were classified as HR and 197 (22%) of cases were classified as SR. Conclusions: HR pediatric ALL is highly prevalent in Mexican patients, which can partly explain their worse prognosis. Further investigation is needed to understand the drivers of poor cancer outcomes in our population. NCI risk classification is historically important and useful for comparing results, but it is insufficient. It is necessary to use flow cytometry, DNA analysis and determination of minimum residual disease in the determination of risk.