tbuckley/cabot-search huggingface dataset:
A comparison of internet-based models assessing the likelihood of a <i>BRCA</i> mutation
Authors: L. J. Bordeleau, M. Ennis, S. Canon, S. Panchal
Journal: Journal of Clinical Oncology (2008)

22051 Background: Mutations in the BRCA1 and BRCA2 genes account for the majority of hereditary breast and ovarian cancer. Various risk assessment models are available to calculate the risk of a BRCA mutation, and a greater than 10% risk is often used to identify an eligible candidate for genetic testing. Of these models, the Penn II (http://www.afcri.upenn.edu/itacc/penn2/) and BOADICEA (https://pluto.srl.cam.ac.uk/cgi-bin/bd1/v1/bd.cgi) are the only models available on the internet. Here, we compare these models to determine their utility in patients from a large breast cancer program in our tertiary referral center. Methods: Risk assessments were done using the Penn II and BOADICEA models for 200 consecutively tested non-BRCA carriers, and 100 consecutively tested BRCA carriers from Mount Sinai Hospital, Toronto (Canada) from August 1995 and March 2006. Sensitivity and specificity were calculated at the 10% testing threshold. Receiver operating curves were constructed by plotting sensitivity over the false positive rate (1-specificity) and area under the curves (AUCs) were calculated. Testing thresholds were established at 90% sensitivity. Results: 100 carriers (91% female, 58% BRCA1 mutation positive, 39% Ashkenazi Jewish, mean age: 50.7 years, 79% affected with breast cancer) and 200 non-carriers (97.5% female, 39.5% Ashkenazi Jewish, mean age: 52 years, 73% affected with breast cancer) were included. The AUC was 0.74 for both models. The sensitivity and specificity at the 10% testing threshold were: Penn II (0.93, 0.32); BOADICEA (0.70, 0.65). The testing threshold to achieve 90% sensitivity was 10.9% and 2.8% respectively. Conclusions: Both the Penn II and BOADICEA risk assessment models identify those at highest risk of carrying a BRCA mutation, and have been used to determine eligibility for publicly and privately funded genetic testing. A major advantage of both models is that they are available on the internet and thus easily accessible. In our patient population, substantially higher sensitivity was achieved with the Penn II model at the 10% testing threshold. A much lower testing threshold (2.8%) would be required to achieve a similar sensitivity with the BOADICEA model. An additional benefit of the Penn II model is the ease of data entry when compared to the BOADICEA model. No significant financial relationships to disclose.
Evaluation of microsatellite instability (MSI) status in gastrointestinal (GI) tumor samples tested with comprehensive genomic profiling (CGP).
Authors: Michael J. Hall, Kyle Gowen, Eric M. Sanford, Siraj Mahamed Ali, John Kaczmar, Vincent A. Miller, Phil Stephens, Roman Yelensky, Mary Beryl Daly, James Sun
Journal: Journal of Clinical Oncology (2016)

528 Background: PD-1 inhibitor therapy (pembrolizumab) has demonstrated promising activity in MSI-H (MSI-High) colorectal cancer (CRC) and MSI-H non-CRC compared to MSS tumors, supporting MSI as predictive of anti-PD-1/L1 therapy independent of tumor histology. We developed and validated a novel computational method to assess MSI status using next generation sequencing (NGS) data generated from CGP of clinical cases. We then sought to determine the frequency of MSI in a diverse sample of clinical cases of GI tumors previously assayed with CGP (FoundationOne). Methods: To determine MSI status, 114 intronic homopolymer repeat loci (10-20bp long in the human reference genome) with adequate coverage on the CGP panel were analyzed for length variability and compiled into an overall MSI score via principal components analysis. Translation of the MSI score to MSI-H or MSS (MSI-Stable) was established using a training data set. Results: Our methodology was validated in 69 samples with MSI status (20 MSI-H, 49 MSS) previously determined by standard clinical testing, either PCR or immunohistochemistry staining. Our concordance was 97% (65/67). We then applied our method to 2545 GI cancers assayed with CGP in the course of clinical care, with small bowel carcinoma having the highest rate of MSI-H (Table). The 3.5% frequency of MSI-H in CRC is lower than expected, possibly attributed to sampling bias against MSI-H CRC in the cohort. In CRC, we discovered significant differences in mutational profile: histone methyltransferase MLL2/3 mutations were enriched in MSI-H CRC (P&lt;0.0001, Fisher’s Exact test), while TP53mutations were enriched in MSS CRC (P&lt;0.0001, Fisher’s). Conclusions: CGP can be used to detect MSI with high accuracy. In addition, application of this approach to the 2545 GI cancers demonstrates the use of CGP to identify differences in mutational profiles between MSI-H and MSS cancers. Broadened application of these methods to more tumor types may provide target enrichment for emerging immunotherapies. [Table: see text]
Gene expression and breast cancer mortality in Northern California Kaiser Permanente Patients: A large population-based case control study
Authors: L. A. Habel, C. P. Quesenberry, M. Jacobs, D. Greenberg, L. Fehrenbacher, C. Alexander, J. Baker, D. Watson, J. Hackett, S. Shak
Journal: Journal of Clinical Oncology (2005)

603 Background: The 21 gene Recurrence Score (RS) assay (Oncotype DX) has been validated to quantify the risk of distant recurrence in tamoxifen-treated (tam+) pts with N-, ER+ breast cancer (BC) (Paik et al, NEJM, 2004). The relation between gene expression and BC mortality in a community hospital setting for ER+ tam+ pts, as well as for tam- and ER- pts, was not known. Methods: We conducted a nested case-control study in BC pts diagnosed from 1985–94 at 14 Kaiser hospitals. Eligibility included negative nodes, age < 75 yrs, and no chemotherapy. Cases died of BC prior to 2002. Up to 3 controls were matched to each case on age, race, tam treatment, facility, diagnosis yr, and follow-up time. Using pre-specified methods, archived tumor tissue was analyzed using the RT-PCR 21 gene expression assay and RS algorithm. Pre-specified primary and secondary endpoints were analyzed by conditional logistic regression to estimate the association between gene expression (for RS, proliferation gene group score, and individual genes, including ER and PR) and BC death, while controlling for tumor size, grade, and confounding variables. Results: Among 4964 potentially eligible BC pts, we identified 220 cases and 570 matched controls. Median age was 59 yr (range 28–74); 30.9% were tam+ (mostly after 1988). Median follow-up time was 4.9 yrs for cases (time to death) and 12.9 yrs for controls. RS was significantly associated with BC death in ER+ pts treated with or without tam (p=0.002). Gene expression for ER and PR had different associations–ER expression was associated with mortality in the ER+ tam+ pts (p = 0.003), but not the ER+ tam- pts (p=0.26), and was predictive of tam benefit but not of prognosis. PR was associated with mortality in the ER+ tam- pts (0.004), and was strongly prognostic. Among both ER+ tam- pts and ER- pts, those with high proliferation gene group scores had over 6 times the risk of BC death compared to those with low scores (p=0.001). Conclusion: A large population-based study from 14 Northern California hospitals demonstrates the Recurrence Score is independently associated with breast cancer mortality, and is both prognostic and predictive. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genomic Health Genomic Health Genomic Health
Outcome of patients with clinically node-positive bladder cancer who undergo consolidative surgery after preoperative chemotherapy: MD Anderson Cancer Center experience.
Authors: Philip Levy Ho, Daniel Levi Willis, Jeevitha Patil, Karen Tart, Sahil Parikh, Jay Bakul Shah, Scott Edward Delacroix, Arlene O. Siefker-Radtke, Colin P. N. Dinney, Louis L. Pisters, Ashish M. Kamat
Journal: Journal of Clinical Oncology (2014)

318 Background: We previously reported results of our phase II study in patients with retroperitoneal lymph node (RPLN) metastasis from bladder cancer (BC) undergoing consolidative surgery after preoperative chemotherapy. Here we present an expanded cohort of patients who underwent consolidative surgery after chemotherapy for clinically node-positive BC. Methods: We reviewed results of patients from our IRB approved protocol including those with clinical evidence of nodal metastasis in the pelvis or retroperitoneum (M1), without visceral metastasis, from 1995-2010. Endpoint of the study was cancer-specific survival (CSS) calculated from time of surgery. Results: 55 patients with either clinical pelvic lymph node (PLN) metastasis (n=29) or PLN and RPLN metastasis (n=26) were identified. Median CSS was 19 months for all patients; 21 for PLN alone and 16 for PLN and RPLN disease. Kaplan-Meier estimate of 5-year CSS was 31% with no difference between PLN alone and PLN with RPLN disease. Clinical nodal stage was N1: 16, N2: 5, N3: 8, and M1 (RPLN): 26. Majority (94%) of patients received cisplatinum-based chemotherapy. At cystectomy, all patients underwent a PLN dissection with 12 patients (all clinical M1 RPLN) undergoing concurrent RPLN dissection (RPLND). In all, 30 of 55 (55%) patients were pN0 at the time of surgical extirpation while 26% (5 of 19) were pN+ despite radiologic complete response after chemotherapy. 5-year CSS was 57% for pN0 and 9% for pN+ disease (p&lt;0.0001). Median survival in patients with residual tumor in PLN (n=17) was 10.5 months vs. 7 months for RPLN (n=8) (median survival not reached in pN0 patients, p&lt; 0.001). 17 patients developed recurrences outside the surgical field after a median of 8 months. While no recurrences occurred within the lymphadenectomy template, 14% of patients with clinical M1 RPLN disease who did not undergo RPLND had recurrences in RPLN basin. Conclusions: Post-chemotherapy consolidative surgical resection may result in 5-year disease-free survival in patients with clinical evidence of node-positive disease, including those with RPLN positive disease, who have major response to chemotherapy.
Actionable biomarkers in a non-small cell lung cancer (NSCLC) clinical pathway (CP).
Authors: Peter G. Ellis
Journal: Journal of Clinical Oncology (2016)

155 Background: Oncologists use Via Pathways (VP) to drive standardization to best evidence-based cancer care. VP include guidance for biomarker testing and associated treatments. Practices collaborated to analyze the first line non squamous carcinoma NSCLC VP. An unexpectedly large percentage of treatment decisions captured by oncologists in the VP portal had unknown ALK translocation or EGFR mutation test results. The VP was modified to require input of whether or not the test was ordered. This analysis examines the impact of this change. Methods: ALK and EGFR testing responses from the VP database were analyzed pre and post implementation of the change. Treatment decisions were reviewed to analyze prescribing patterns. Results: From 1/1/2014 to 1/29/2015, ~40% of EGFR or ALK testing responses were unknown. Post-implementation (1/30/2015 to 5/31/2015), 29.8% were charted as awaiting ALK results and 9.4% did not order the test; 29.5% were charted as awaiting EGFR results and 7.6% did not order the test. For the combined period, appropriate targeted agents were selected for 91.9% (n = 37) and 86.5% (n = 133) of patients who were ALK translocation positive and EGFR sensitizing mutation positive, respectively. Conclusions: Results demonstrate the ability of CP to promote testing of key biomarkers and use of appropriate targeted agents. Frequent evaluation and modification of pathway content is needed to ensure practice patterns are accurately captured. [Table: see text]
Prognostic impact for different sites of extranodal involvement in patients with diffuse large B-cell lymphoma in the rituximab era.
Authors: H. Takahashi, N. Tomita, M. Yokoyama, S. Tsunoda, T. Yano, K. Murayama, C. Hashimoto, K. Tamura, K. Sato, H. Fujita, Y. Ishigatsubo
Journal: Journal of Clinical Oncology (2011)

e18505 Background: Extranodal involvement is considered poor prognostic factor for patients with diffuse large B-cell lymphoma (DLBCL); however, the prognostic impact of each involvement site has not yet been fully elucidated. Methods: We retrospectively analyzed data for 1,221 patients with DLBCL uniformly treated by R-CHOP therapy between 2003 and 2006. Patients with distinct forms of DLBCL, such as intravascular lymphoma, primary effusion lymphoma, and pyothorax-associated lymphoma, were excluded from the study. Primary CNS lymphoma and intraocular lymphoma were also excluded. We evaluated 26 extranodal involvement sites (orbita, nasal cavity, paranasal sinus, Waldeyer ring, salivary gland, thyroid gland, breast, thymus, lungs, pleura, stomach, small intestine, colon, peritoneum, liver, pancreas, kidney, spleen, adrenal gland, testes, ovary/uterus, bones, bone marrow, peripheral blood, skin, and subcutaneous tissue) with respect to prognostic impact. Results: The median age was 64 years (range, 15–91 years). Nine hundred and ten patients (74.6%) were treated with 6-8 cycles of therapy. Local irradiation was added in 297 patients (24.4%). Univariate analysis revealed that the patients with certain extranodal involvement had significantly worse overall survival (OS) than did the patients without the extranodal involvement; these sites included nasal cavity, paranasal sinus, lungs, pleura, small intestine, peritoneum, liver, pancreas, stomach, spleen, adrenal gland, testes, bones, bone marrow, peripheral blood, skin, and subcutaneous tissue. Patients with Waldeyer ring involvement had significantly better OS. Multivariate analysis revealed that patients with involvement of pleura (P < 0.001), small intestine (P = 0.015), peritoneum (P = 0.002), adrenal gland (P < 0.001), testes (P = 0.005), bone marrow (P < 0.001), and peripheral blood (P = 0.002) had significantly worse, but Waldeyer ring had significantly better OS (P = 0.038). Conclusions: Extranodal involvement affects the prognosis of patients undergoing R-CHOP therapy for DLBCL. Waldeyer ring involvement may be a better prognosis factor.
Evaluation of hyponatraemia in lung cancer patients: A U.K. teaching hospital experience.
Authors: Ankit Jain, Mariam Jafri, Sophie Mascall, Salma Moona Alam, Rhian Thomas, James Kendrick, Joyce Thompson
Journal: Journal of Clinical Oncology (2015)

197 Background: Hyponatraemia, defined as a serum Na &lt; 135mEq/L, is the commonest electrolyte abnormality in oncology practice. We describe the demographics, oncological management and response of hyponatraemia to oncological treatment modalities in our patient group. Methods: We retrospectively analysed serum sodium levels in lung cancer patients admitted to a teaching hospital in the UK between 2007 and 2013. Data was collected on baseline demographics, histology, tumour stage and grade of hyponatraemia. Mild hyponatraemia was defined as a serum sodium between 130-135mEq/L, moderate 125-129mEq/L and severe as &lt; 124mEq/L. Results: 182 (108 male; 74 female) patients with lung cancer and documented hyponatraemia were hospitalised between 2007 and 2013. The median age of patients on admission was 69.2 years (range 33-92 years). 119(65%) had mild, 58(32%) moderate and 5(3%) severe hyponatraemia. 74(40%) were adenocarcinomas, 58(32%) squamous carcinomas, 43(24%)SCLC and 7(4%) had unspecified NSCLC. 89(49%) had metastatic disease on diagnosis. 18/43(42%)small-cell, 14/58(33%) squamous, 23/74 (31%)adenocarcinoma patients had moderate to severe hyponatraemia. 132(74%) of this cohort had active oncological treatment: 93(51%) chemotherapy, 25(14%) radiotherapy, 17(9%) surgery whilst 47(26%) had best supportive care. 28(15%) had a biochemical response to their treatment, 11(39%) of these patients were adenocarcinomas, 10(36%) squamous carcinomas and 7(25%) SCLC. Conclusions: Hyponatraemia in lung cancer patients is widely distributed in various age groups and histological subtypes. Among those admitted with hyponatraemia, severe cases were rare. Higher rates of SIADH are seen in SCLC than in any other malignancy and proportionately more SCLC patients had moderate - severe hyponatremia than NSCLC. Hyponatraemia responds to active oncological treatment including chemotherapy, radiotherapy and surgery. Although historically, hyponatraemia is considered a poor prognostic marker and has been associated with shorter survival duration, this should not preclude active oncological management. Further studies are needed to evaluate the prognostic value of hyponatraemia and its treatment in cancer patients.
KIT hyperactivation in imatinib-resistant GIST: Implications for salvage therapies
Authors: S. Bauer, C. Hubert, M. C. Heinrich, P. Cohen, M. Bertagnolli, G. D. Demetri, J. Fletcher
Journal: Journal of Clinical Oncology (2005)

9034 Background: Many GIST pts respond to KIT inhibition with imatinib (IM), yet eventually develop resistance. IM resistance mechanisms are heterogeneous, and little is known about KIT functional roles in IM-resistant GIST. Methods: GIST cell lines were established from biopsy specimens. Biological consequences of KIT, PI3-K, PLCgamma, MEK/MAPK and mTOR inhibition were determined by immunoblotting for protein activation, and by cell proliferation and apoptosis assays. Results: Novel cell lines, GIST430 and GIST48, were developed from GISTs progressing clinically on IM. These lines contain primary IM-sensitive KIT juxtamembrane mutations and secondary IM-resistance mutations in the ATP-binding (GIST430) and catalytic (GIST48) portions of the KIT kinase domain. Kinase activation was compared with GIST882 cells, which contain only a primary IM-sensitive mutation. KIT expression was equally strong in the 3 GIST cell lines, whereas KIT activation was 3-to-6 fold higher in GIST430 and GIST48 than in GIST882. In addition to the higher set point for KIT activation, GIST430 and GIST48 had intrinsic IM-resistance: IM IC50s for KIT activation were 1.0, .2 and .1 μM in GIST430, GIST48 and GIST882, respectively. After treatment with 1 μM IM, residual KIT activation was 6 and 2.8-fold higher in GIST430 and GIST48, respectively, compared to GIST882. Both GIST430 and GIST48 were sensitive to the alternate KIT inhibitor, PKC412. PKC412 IC50s for KIT activation were .1, .1, and >1.0 μM, and for proliferation were .4, .25, and 1.0 μM, in GIST430, GIST48 and GIST882, respectively. In all GIST lines, cell growth arrest resulted from PI3-K inhibition, and - to a lesser extent - from MEK/MAPK and mTOR inhibition (Table). Conclusions: GIST secondary KIT mutations can be associated with KIT hyperactivation and IM resistance. IM resistance may be overcome with alternate KIT inhibitors, or by targeting critical downstream signaling proteins. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis Novartis Novartis Novartis
Long-term survival after multidisciplinary treatment of small-bowel neuroendocrine tumors with synchronous liver metastases: A single-institute experience.
Authors: Emilio Bertani, Nicola Fazio, Antonio Chiappa, Edoardo Botteri, Francesca Spada, Chiara Grana, Davide Ravizza, Laura Cossu, Guido Bonomo, Bruno Andreoni
Journal: Journal of Clinical Oncology (2013)

e15147 Background: Neuroendocrine tumors (NETs) that originate in the distal jejunum and ileum are commonly diagnosed in stage IV, with liver metastases in 50%-75% of cases. The aim of this study was to ascertain the impact of surgery in a consecutive series of patients with small bowel NET and synchronous liver metastases treated at a single institute. Methods: Ninety-one patients managed between 1995 and 2011 were extracted from the institutional tumor registry. All patients had diagnosis by histology of small bowel NET and synchronous liver metastases. Results: Among the 91 patients 28 (30.8%) underwent primary tumor removal and liver metastases resection or intraoperative termal ablation (Group 1), 54 (59.3%) underwent resection of only the primary tumor (Group 2), and the remaining 9 (9.9%) did not receive any surgery (Group 3). After a median follow-up of 64 months an overall survival (OS) of 93.1%, 81.8% and 76.2% at 3, 5 and 8 years was registered for the whole group. Cancer-specific survival (CSS) was 93.1%, 83.3% and 77.6% at 3, 5 and 8 years, respectively. Five-years OS differed significantly according to the surgical approach (96.0% for Group 1 vs 79.8% for Group 2 vs 48.6% for Group 3, p=0.02). During the course of the illness octreotide was administered in 78 patients (85.7%), peptide receptor radiotherapy in 61 (67.0%), systemic chemotherapy in 21 (23.1%), hepatic artery embolization in 17 (18.7%), interferon in 11 (12.1%), molecular targeted agents in 2 (2.2%). For patients who underwent any surgery (Group 1 and Group 2) the multidisciplinary approach was associated with a better OS (85.7% vs 77.2% 5-years OS, p=0.04). In the multivariate analysis only age was associated with OS, HR: 1.05 (C. I.: 1.01-1.10). The results of CSS were comparable to those of OS. Conclusions: In this metastatic setting of small bowel NETs the 5 year OS was as high as 82% with a maximum benefit achievable for patients who had primary tumor resection and liver disease amenable to surgical or thermal ablation. However, the potential impact of age in prognosis should be carefully considered when choosing the treatment to be delivered in such patients.
CMV Infection Alone Does Not Affect The Survival In Patients After Umbilical Cord Blood Transplantation: Can We Put Off The Time Of Preemptive Therapy?
Authors: Juan Tong, Zimin Sun, Huilan Liu, Kaiyang Ding, Liangquan Geng, Changcheng Zheng, Baolin Tang, Xin Liu
Journal: Blood (2013)