tbuckley/cabot-search huggingface dataset:
Second malignant neoplasms (SMN) in Cowden syndrome patients with underlying germline PTEN mutations.
Authors: Joanne YY Ngeow, Jessica Mester, Haider Mahdi, Lamis Yehia, Jill Barnholtz-Sloan, Charis Eng
Journal: Journal of Clinical Oncology (2013)

1527 Background: Cowden syndrome (CS) patients with underlying germline PTEN mutations are at significantly increased risks of breast, thyroid, endometrial and renal cancers. Current estimates of lifetime cancer risks do not provide the majority of patients who present after their first cancer a meaningful gauge of their risk of a SMN. Quantification of the risk of a SMN will allow patients to be better informed and provide clinicians a much needed guide to finally address patients’ question of “how likely am I to have a second cancer and will it likely be the same primary?” Methods: We conducted a 5-year, multi-center prospective study of CS and CS-like patients, all of whom had comprehensive PTEN analysis done. Patients’ records were reviewed for prior history of invasive cancers. Invasive SMNs were confirmed by pathology reports or physician reports where possible. All metastatic disease, synchronous primary cancer at the same site and non-melanoma skin cancers were excluded. Incidences of SMNs were compared between patients with pathogenic PTEN mutations (PTEN mut+ ) and wildtype PTEN (PTEN wt ). Standardized incidence ratios (SIR), cumulative incidences and excess absolute risks for SMNs were calculated comparing against SEER-derived data. Results: Of 2,792 CS/CS-like patients who present with 1 or more cancers, there were 100 (4%) PTEN mut+ patients. Compared with PTEN wt CS/CS-like patients with SMNs (223/2039; 11%), PTEN mut+ cases (42/100; 42%) were more likely to develop SMNs (p&lt;0.0001). PTEN mut+ cases were also younger at median age of SMN diagnosis (48yrs vs 54 yrs; p=0.30). PTEN mut+ patients were 56-fold more likely to develop any SMN compared with the general population (95%CI 41-55); corresponding to an excess absolute risk of 731/10000 person years. Breast cancer was the most common SMN encountered in PTEN mut+ CS/CS-like patients (SIR 73; 95%CI 45-122) followed by endometrial (SIR 44; 95% CI 18-92), renal (SIR 47; 95% CI 15-113) and thyroid cancers (SIR 222; 95% CI 37-734). Conclusions: Our study shows that PTEN mut+ CS/CS-like patients are significantly more likely to present with a SMN compared to PTEN wt CS/CS-like patients and the general population, and should be advised and surveillanced accordingly.
Clinical utility of a 17-gene genomic prostate score (GPS) for treatment selection in men with newly diagnosed prostate cancer (PCa).
Authors: Marc A. Dall'Era, Bela Denes, H. Jeffrey Lawrence, Athanasios C. Tsiatis, Megan Rothney, Tara Maddala, Phillip G. Febbo, Ketan Badani
Journal: Journal of Clinical Oncology (2015)

e16124 Background: The 17-gene prostate cancer assay is clinically validated as a biopsy-based gene expression assay that, combined with clinical features, provides an estimate of PCa disease aggressiveness. We report two clinical utility studies that assess the impact of incorporating the GPS on treatment recommendations (TR) and decisions in men with very-low to intermediate risk PCa. Methods: In the first study, community-based urologists ordering at least 4 assays from 5/2013 to 1/2014 participated. Clinicopathologic data, the GPS and treatment were abstracted from medical records of GPS patients and a clinically similar baseline group. The proportion of men recommended and pursuing active surveillance (AS) immediately before and after the availability of the GPS were computed. In the second prospective study, urologists at 3 centers (academic and community) recorded TR on pre- and post-GPS questionnaires, including changes in treatment intensity. Results: 15 urologists completed the chart review study on 211 men (124 GPS; 87 baseline). The relative increase in TR for AS was 22%, (50% baseline, 61% GPS; absolute difference of 11%). GPS pts chose AS more than baseline pts (67% GPS; 43% baseline, absolute increase of 24%, relative increase of 56%). Of men recommended AS, 96% of GPS and 80% of baseline pts chose it. In 158 men in the prospective study, the relative increase in recommendation for AS was 24% and absolute TR increase for AS was also 10% (41% to 51%). 18% of TR changed post-GPS and TR modality and/or intensity occurred in 26% of men (25 decreased; 14 increased; 2 equivocal). Conclusions: Both studies, conducted with different methodologies, demonstrate that use of GPS provides meaningful change in TR and decisions in men with newly diagnosed PCa and results in a net increase in recommendation and/or adoption of AS. In the chart review study, TR changes appear to underestimate changes in actual treatment received and more GPS patients than baseline patients were assigned to AS supporting the clinical utility of GPS in the initial assessment and management of men with low risk PCa.
Expression of the multidrug transporter genes ABCC1/MRP1, ABCC3/MRP3, and ABCC4/MRP4 are powerful predictors of clinical outcome in childhood neuroblastoma
Authors: M. D. Norris, J. Smith, A. Kwek, C. Flemming, S. L. Cohn, W. B. London, A. Buxton, G. M. Marshall, M. Haber
Journal: Journal of Clinical Oncology (2007)

9524 Background: We have previously shown, both retrospectively and prospectively, that high-level expression of the multidrug transporter gene ABCC1/MRP1, is strongly predictive of poor outcome in the childhood cancer neuroblastoma (NEJM, 334:231–8, 1996; JCO, 24:1546–53, 2006), and that ABCC1/MRP1 can be regulated by the MYCN oncogene. The contribution of other ABCC family genes to clinical outcome in this disease has now been examined. Methods: Real-time quantitative PCR was used to determine ABCC gene expression in a large prospectively accrued cohort (n=209) of primary untreated neuroblastomas from patients enrolled on POG biology protocol 9047. Results: Older age, advanced stage, and MYCN amplification were all predictive of poor outcome in the cohort. Amongst the ABCC family, high levels of ABCC1 and ABCC4, but low levels of ABCC3, were strongly associated with reduced survival and event-free survival (P&lt;0.005) in the overall study population, and also in subgroups of patients lacking MYCN amplification. Following adjustment for the effect of MYCN gene amplification and other prognostic indicators by multivariate analysis, expression of ABCC1 (HR=2.3; p=0.03), ABCC3 (HR=2.7; p=0.0141), ABCC4 (HR=3.4; p=0.002) retained significant prognostic value for outcome, whereas age and MYCN amplification lost all prognostic significance. By combining the expression of these three transporter genes, patients could be stratified into groups having excellent, intermediate or poor outcome (EFS=84%, 59%, 17%, respectively). Conclusions: These data, suggest that ABCC1, 3 and 4 are amongst the most powerful prognostic markers yet identified for childhood neuroblastoma and as such represent important targets for potential therapeutic intervention. No significant financial relationships to disclose.
The role of sidedness, EGFR gene copy number (GCN) and EGFR promoter methylation in RAS/BRAF wild type (WT) colorectal cancer (CRC) patients receiving irinotecan/cetuximab.
Authors: Marco Puzzoni, Riccardo Giampieri, Laura Demurtas, Valeria Pusceddu, Alessandra Mandolesi, Luca Faloppi, Cristian Loretelli, Alberto Zaniboni, Alfredo Falcone, Stefano Cascinu, Mario Scartozzi
Journal: Journal of Clinical Oncology (2017)

628 Background: Data from randomized trials suggested that tumour sidedness could represent a prognostic and predictive factor in CRC patients. Distinctive molecular and clinical features are related to tumour sidedness, however their predictive role has not yet been clearly defined. Methods: Tumour samples from RAS/BRAF WT metastatic CRC patients treated with second-third line irinotecan-cetuximab were analised for EGFR GCN and promoter methylation. Study objective was to evaluate the correlation of tumour sidedness, EGFR promoter methylation and EGFR GCN with clinical outcome. Results: Eighty-eightpatients were included in the study, 24/88 (27.3%) had right sided CRC(RSCC), 64/88 (72.7%) had left sided CRC(LSCC); 32/88 (36.4%) had EGFR GCN &lt; 2.12 tumour, 56/88 (63.6%) had EGFR GCN ≥ 2.12 tumour; 44/88 (50%) had EGFR promoter methylated tumour. RSCC were associated with reduced ORR (4.2% for RSCC vs 35.9% for LSCC, p:0.0030), with shorter PFS (3.0 vs 10.29 months, HR:2.74, p &lt; 0.0001) and shorter OS (8.0 vs 13.6 months, HR:2.83, p &lt; 0.0001). EGFR GCN &lt; 2.12 tumours were associated with reduced ORR (6.2% for EGFR GCN &lt; 2.12 vs 39.3% for ≥ 2.12 tumours, p:0.0009), with shorter PFS (3.8 vs 7.0 months HR:2.15, p = 0.0010) and shorter OS (8.5 vs 14.0 months HR:2.59, p &lt; 0.0001). EGFR methylated tumours were associated with reduced ORR (9.1% for methylated vs 45.5% for unmethylated, p = 0.0001), with shorter PFS (3.0 vs 7.67 months HR:3.23, p &lt; 0.0001) and shorter OS (8.0 vs 17.0 months HR:3.57, p &lt; 0.0001). At multivariate analysis EGFR GCN and EGFR promoter methylation mantained their independent role for ORR (respectively p:0.0082 and p:0.0025), PFS (respectively Exp(b):0.40, p:0.0048 and Exp(b):4.52, p &lt; 0.0001) and OS (respectively Exp(b):0.23, p:0.0001 and Exp(b):5.58, p &lt; 0.0001). Conclusions: In our study an accurate molecular selection based on an all RAS and BRAF analisys along with EGFR GCN and EGFR promoter methylation status resulted more relevant than tumour sidedness for the prediction of clinical outcome during cetuximab/irinotecan. We then suggest that molecular selection might overcome the importance of tumour sidedness in this setting.
First-in-human phase I “basket” study of Debio1347 (CH5183284), a novel FGFR inhibitor, in patients with FGFR genomically activated advanced solid tumors.
Authors: Martin Henner Voss, Barbara Adamo, Rebecca Suk Heist, Leena Gandhi, Corinne Moulon, Hiroaki Tanaka, Nobuya Ishii, Anne Vaslin, Yuko Aoki, Valerie Nicolas-Metral, Silvano Brienza, Claudio Zanna, Keith Flaherty, Josep Tabernero, Jose Baselga
Journal: Journal of Clinical Oncology (2014)

TPS2629^ Background: Deregulated fibroblast growth factor receptor (FGFR) signalling is associated with tumorigenesis. Debio 1347 is an orally-available ATP competitive inhibitor of FGFR 1, 2 and 3 with preclinical data showing high target-specificity and antitumor activity across models of FGFR amplified, mutated or translocated tumors for various human malignancies. Methods: This first-in-human, phase I dose-escalation multiple tumor type “basket” study enrols patients with advanced solid malignancies harbouring defined activating alterations of FGFR 1, 2, or 3. These include amplifications and translocation events with known activating effect as well as somatic mutations previously reported as activating or located in genomic regions of relevance for kinase activity. The dose-escalation part of the trial enrols patients with advanced solid tumour malignancies and presence of any such alteration. Genetic screening is performed independently at each site with post-hoc centralised confirmation of molecular status by Next Generation Sequencing (NGS). The primary endpoint is determination of maximum tolerated dose (MTD). Patients receive Debio 1347 orally once daily and are assessed for dose-limiting toxicities (DLT) during the first 4 weeks. With a starting dose-level of 10 mg the study follows a 3+3 algorithm with dose-escalation on a modified Fibonacci sequence. The MTD is defined as the level where ≥ 2/6 patients suffer a DLT. All the patients receive dietary phosphate restriction.The secondary objective is exploration of antitumor effect in the various tumor types enrolled on trial. Pharmacokinetics is evaluated after single and repeated administration. Pharmacodynamics biomarkers including phosphate and FGF23 are explored in plasma samples. Pre- and post-treatment skin and tumor biopsies are used for pharmacodynamics analyses. Recruitment started in September 2013. Cohort 1 has been completed. Cohort 2 began in January 2014. Subsequent dose expansion is planned at the final recommended dose across pre-defined disease-specific baskets to evaluate safety and efficacy in the setting of specific FGFR alterations of relevance to each disease. Clinical trial information: NCT01948297.
Explanatory analysis of advance care planning for stage IV non-small cell lung cancer.
Authors: Takaaki Tokito, Haruyasu Murakami, Keita Mori, Iwao Osaka, Toshiaki Takahashi
Journal: Journal of Clinical Oncology (2014)

e20547 Background: The American Society of Clinical Oncology published the goals of individualized care including advance care planning (ACP) for advanced cancer patients in 2011, but there are no data on the ACP implementation status. Methods: We retrospectively reviewed the electronic medical records and informed consent forms of consecutive stage IV non-small cell lung cancer (NSCLC) patients treated with chemotherapy between January 2010 and December 2012 at our institution. Two outcomes were defined to investigate the ACP implementation status: C-D, the duration from the last day of chemotherapy to death, and D-D, that from the day of confirming DNAR to death. We used the Kaplan-Meier method to estimate the endpoints and Cox regression models to analyze explanatory factors associated with the endpoints. Results: In total, 136 patients were eligible (median age, 67 years; 89 men; 105 current/ever smokers). Of 103 patients with adenocarcinoma, 30 had epidermal growth factor receptor mutations, and 110 patients had performance status 0–1. Of the 136 patients, 71 received 1 regimen, 39 received 2 regimens, and 26 received ≧3 regimens. The ACP implementation status is shown in the table. The median C-D was 64 days. Receipt of ≤2 chemotherapy regimens and provision of prognosis information to patients were significantly associated with C-D in multivariate analysis. The median D-D was 25 days. Provision of information regarding supportive care before first-line chemotherapy and provision of prognosis information to the patient were significantly associated with D-D in multivariate analysis. Conclusions: Investigation of the ACP implementation status in NSCLC patients at our institution showed that providing information on supportive care before first-line chemotherapy and informing the patient about prognosis is beneficial in prolonging supportive care. Yes (%) No Information provided Incurable disease, before first-line chemotherapy 96 (70) 40 Supportive care, before chemotherapy 69 (50) 67 Chemotherapy risks and benefits 116 (85) 20 Chemotherapy expenses 16 (12) 120 Prognosis 43 (32) 93 Clinical trial Informed 48 (35) 88 Participated 23 (17) 113 Confirmed DNAR 133 (98) 3 From the patient 12 (9) - Living will 25 (18) 111
Racial disparities in cervical cancer mortality over time.
Authors: Jose Alejandro Rauh-Hain, Marcela G del Carmen, John O. Schorge, David M. Boruta, Whitfield Board Growdon, Annekathryn Goodman, Rachel Marie Clark, Leslie Siriya Bradford, Joel Clemmer
Journal: Journal of Clinical Oncology (2013)

5604 Background: The aim of this study is to examine changes over time in survival for African-American (AA) and white women diagnosed with cervical cancer (CeCa). Methods: Surveillance, Epidemiology, and End Results (SEER) Program data 9 for 1983-2007 were used for this analysis. Kaplan–Meier and Cox proportional hazards survival methods were used to assess differences in survival by race at 5-year intervals. Results: The study included 23,722 women; including 19,777 whites and 3,945 AA. AAs were older (51.4 vs. 49 years; p&lt;0.001), had a higher rate of regional (38.3% vs. 31.7; p&lt;0.001) and distant metastasis (10.5% vs. 8.5; p&lt;0.001). AAs received less frequently cancer-directed surgery (53.1% vs. 65.7%; p&lt;0.001), and more frequently radiotherapy (56.9% vs. 47.3%; p&lt;0.001). AAs had a hazard ratio (HR) of 1.40 (95% CI, 1.31-1.49) of CeCa mortality compared to whites. Adjusting for SEER registry, marital status, stage, age, surgery, radiotherapy, grade and histology, AA women had a HR of 1.15 (95% CI, 1.07-1.24) of CeCa related mortality. AAs had a higher HR of all cause mortality and CeCa related mortality for all the five-year diagnosis cohorts (Table). After adjusting for the same variables, there was a significant difference in survival in the 1988-1992 group (HR 1.26; 95% CI 1.09-1.47). Conclusions: The present data indicates significant survival differences by race for women with invasive CeCa. After adjusting for SEER registry, marital status, stage, age, surgery, radiotherapy, grade and histology, only between 1988-1992 there was a difference in survival between the groups. [Table: see text]
The impact of cigarette smoking on treatment outcome in metastatic pancreatic cancer patients.
Authors: Sofia Ghani, Potjana Jitawatanarat, Kaweesak Chittawatanarat, Sandeep Samuel, Renuka V. Iyer, Wen Wee Ma
Journal: Journal of Clinical Oncology (2014)

e15183 Background: Cigarette smoking is a known risk factor for pancreatic cancer. However, the impact of cigarette smoking on survival in patients with metastatic pancreatic cancer (mPCa) is unknown. Here, we hypothesized that cigarette smoking adversely affected the survival of mPCa patients (pts) who received chemotherapy. Methods: We conducted a retrospective review on pts with mPCa between 2000-2012 managed at our institution. We analyzed 1 year overall survival (OS) comparing patients who were ‘current smokers’ that included pts who quit within ≤ 2 yr of diagnosis vs. ‘non-smokers’ that included pts who never smoked and those who quit > 2 yr prior to diagnosis. Results: 445 patients were identified (“non-smoker” = 311, “current smokers” = 134). The majority of deaths were identified as cancer related deaths (91.9%). “Current smokers” were younger, with a better ECOG performance status and less cardiac history. Among pts who received chemotherapy (CTX) (n=343), the survival of “current smokers” was shorter than “non-smokers” (median OS 230 days (95%CI: 202-261) vs 192 days (95%CI:175-231) though the difference did not reach statistical significance (HR 1.26, 95% CI 0.98-1.63; p=0.069). Adverse 1 yr OS outcome was more evident in “current smokers” age <60 (HR 1.41, 95% CI 0.98-2.04; p=0.06) but not in age ≥ 60 (HR 1.1, 95% CI 0.81-1.49; p=0.55). The survival of pts who did not receive CTX was significantly worse than those who did (median OS: 66 days (12-735) vs 219 days (27-1233)). After adjustment for Charlson comorbidity index (CCI), CA 19-9 ≥ 35 (HR 1.14, 95% CI 0.88-1.48;p=0.33) and age ≥ 60 (HR 1.07, 95% CI 0.79-1.46; p=0.63) did not adversely effect 1 yr OS comparing between “current smokers” and “non-smokers”. Conclusions: Our retrospective study showed that cigarette smoking may be associated with worse survival among mPCa pts treated with CTX. The adverse association seemed to be more pronounced in younger pts (age<60) and was independent of CA19-9 level. The findings were hypothesis-generating, suggesting that cigarette smoking may attenuate the efficacy of CTX in mPCa, pointing to the importance of smoking cessation in PCa pts. Further studies should be conducted to confirm the relationship.
Conventional-dose (CDCT) versus high-dose chemotherapy (HDCT) in the salvage management of relapsed pure seminoma: Results from an international database.
Authors: Andrea Necchi, Salvatore Lo Vullo, Patrizia Giannatempo, Luigi Mariani, Daniele Raggi, Kathrin Schumacher, Christophe Massard, Edward Kanfer, Karin Oechsle, Daniele Laszlo, Mariagrazia Michieli, Karl-Heinz Pflueger, Norbert Ifrah, Martina Margrit Crysandt, Patrick Wuchter, Arnon Nagler, Anders Wahlin, Manuela Badoglio, Paolo Pedrazzoli, Francesco Lanza
Journal: Journal of Clinical Oncology (2015)

e15559 Background: The optimal management of relapsed seminoma is still unknown. We retrospectively analyzed the outcomes of CDCT versus HDCT in the salvage treatment strategy of patients (pts) failing ≥ 1 CT regimens. Methods: Eligibility included adult male pts with pure seminomatous histology, and treatment with salvage CT. Pts with elevated alfa-fetoprotein were excluded. Consecutive pts who received CDCT were identified in the database of Fondazione INT Milano, while the transplantation registry of EBMT (from 13 European Centers) was used to retrieve all cases of salvage HDCT. Multivariable Cox analyses (MVA) evaluated the association of prespecified factors (type of CT, line of CT, prior radiotherapy [RT], and chemosensitivity according to standard definition), with progression-free (PFS) and overall survival (OS). Interaction models between treatment and singly taken covariates were also undertaken. Results: From 05/1990 to 12/2012, 73 cases were identified, 27 received CDCT and 46 HDCT. Median age was 37 years (IQR: 34-44), 5 pts has a retroperitoneal primary and 11 had an intermediate prognosis. HDCT was given in second line (n = 14) and third line or beyond (n = 20, 12 had missing information). 25 had received paraortic±iliac RT, 13 were cisplatin refractory/absolutely refractory. Median follow up was 42 months (IQR: 13-71). 5-y OS was 36.2% (95%CI, 21.5-60.9) and 61.2% (95%CI, 44.6-83.9) for CDCT and HDCT, respectively. On MVA for PFS, refractory disease (HR: 2.49, 95%CI: 1.14-5.46) and HDCT (HR: 0.19, 95%CI: 0.06-0.67, p = 0.009) were significant predictors. For OS, prior RT (HR: 2.13, 95%CI: 1.00-4.52, p = 0.048) and refractoriness (HR: 3.48, 95%CI: 1.41-8.62, p = 0.007) were significantly prognostic, while HDCT trended to significance (HR: 0.29, 95%CI: 0.07-1.25, p = 0.098), as it was confirmed in the subgroup analysis for second line only (HR: 0.18, 95%CI: 0.02-1.38. p = 0.099). Conclusions: Despite the limited numbers, our retrospective analysis suggests that HDCT may represent the first therapeutic option in pts with a pure seminoma after failure of one or multiple lines of CT. Our observation requires validation through a prospective study.
Exploratory study of histopathological characteristics of cervical cancer in an African (Tanzania) population.
Authors: Sara Bravaccini, Elisa Chiadini, Maurizio Puccetti, Patrizia Serra, Nestory Andrew Masalu, Maria Maddalena Tumedei, Claudia Rengucci, Paola Ulivi, Andrea Rocca, Wainer Zoli, Dino Amadori
Journal: Journal of Clinical Oncology (2013)

e16530 Background: In Tanzania, cervical cancer is the leading cause of death after breast cancer, with the majority of tumors diagnosed at a very advanced stage. Little information is available on the characteristics of cervical cancer in Sub-Saharan African women. We aimed to evaluate histopathological features of cervical cancers and relative margins in a group of African women and to characterize HPV infection. Methods: Tissue samples from32 Tanzanian women with invasive cervical cancer were evaluated in the Biosciences Laboratory of our Institute (IRCCS IRST, Meldola, Italy) as part of a global cancer control project currently ongoing in close cooperation with the Bugando Medical Center of Mwanza, Tanzania. Results: 24/32 (75%) women had squamous carcinoma and 4/32 (12.5%) had adenocarcinoma of the cervix. The HPV test was performed in the entire series but DNA amplification by pyrosequencing was only possible in 27/32 (84.4%). The presence of HPV infection was confirmed in 26/27 (96.3%) cases in both tumor and relative margins. Typization of the virus revealed that a high percentage of the women had HPV 16 virus of whom 12 (46.2 %) had African type 1 and 4 (15.4%) African type 2. Conclusions: A major problem in the cancer tissue samples from the Tanzanian patients was the poor evaluability of DNA amplification due to suboptimal fixation which compromised tissue morphology. Our preliminary study shows that cervical cancer in Tanzanian women is characterized by a very high frequency of HPV-positive tumors, with a high prevalence of HPV 16 African type 1 and 2 infections. The substantial number of HPV infections could explain the high rate of cervical cancer and subsequent mortality in this African population. [Table: see text]