tbuckley/cabot-search huggingface dataset:
Survival trends for advanced colorectal cancer (CRC): Are improvements only for patients in clinical trials?
Authors: T. J. Price, D. Roder, K. Pittman, K. Patterson, N. Rieger, P. Hewett, D. Rodda, M. Colbeck, G. Maddern, C. Luke
Journal: Journal of Clinical Oncology (2006)

6124 Background: Significant improvements in the outcome for patients with advanced CRC have been achieved. We have reviewed the prospective CRC database at our institution from 1992 to 2004 to explore whether the availability of new chemotherapy drugs (irinotecan &amp; oxaliplatin) and surgical advances has impacted on survival in the normal population. Earlier results had suggested a trend to improved survival (1). Methods: In Australia the first of these drugs became available at the end of 1997 thus we have taken this as the time point to compare outcomes pre and post. Disease-specific survivals were analysed from the date of diagnosis for stage D, and from the date of distant recurrence for stages A, B and C, with a date of censoring of live cases at December 31st, 2004. The Kaplan-Meier product-limit estimate was used for univariate analyses and Cox proportional hazards regression for multivariable analyses. Results: The current analysis is of 744 patients; 92–97 n=313, 98–04 n=431. Survival for the respective time periods were 47.6% and 54.9% 12 mths; 28.0% and 34.8% 24 mths; 18.9% and 23.0% 36 mths; 12.6% and 17.2% 48 mths; and 10.4% and 14.9% 60 mths. Cox proportional hazards regression indicated a lower risk of case fatality for 1998–2004 than 1992–1997 cases (p=0.048) after adjusting for age measured in years. The key predictors of case fatality in a multivariate analysis were found to be period (i.e., 1992–97/1998–04), age, and stage of disease at time of initial diagnosis. While an upward trend in survival was recorded for all ages, it was most pronounced for 70–79 year olds (n=272), where the increase in 24 mth survival was from 21.1% for 1992–97 to 36.1% for 1998–2004 (p=0.015). For patients aged 80 years and over (1992–97 n=40 &amp; 1998–2004 n=67) the 24mth survivals were 18.6% (6.7%) and 26.4% (6.9%) respectively (p&gt;0.200). Conclusions: Clinical trials have shown improvements in survival for highly selected patients. This current analysis confirms an improvement in survival over time for advanced CRC and this is seen in unselected patients including the elderly. Preliminary data has suggested that a number of factors have contributed to the trend of improved survival. Final analysis, including updated chemotherapy trends, will be presented at the meeting. (1) Proc ASCO 2004, #3707 No significant financial relationships to disclose.
Combined immunophenotyping of tumor-infiltrating lymphocytes as a prognostic factor in resected patients with non-small cell lung cancer.
Authors: Ross A. Soo, Bernadette Reyna Asuncion, Marie Loh, Zul Fazreen, Braxton Sim, Min En Nga, Yin Huei Pang, Brendan Pang, Barry Iacopetta, Richie Chuan Teck Soong
Journal: Journal of Clinical Oncology (2014)

11125 Background: Current evidence has highlighted the potential role for tumor infiltrating lymphocytes (TILs) in determining the survival of non-small cell lung cancer (NSCLC) patients. Whilst multiple studies have investigated the prognostic role of various subtypes of TILs, data is limited on the co-expression of TILs subpopulations and its clinical relevance. Identifying immune prognostic markers may help select postoperative NSCLC patients with a poorer prognosis for treatment with immunotherapy. We aim to identify NSCLC subgroups according to combined immunophenotypes and investigate their clinical relevance. Methods: A tissue microarray was constructed from 105 cases of resected NSCLC. Immunohistochemistry for TILs with CD3, CD8, FoxP3 and Granzyme B (GZMB) Ab was performed with an autostainer. TILs were quantified using the Vectra Automated Multispectral Imaging System. Low (-) and high (+) densities of TILs were dichotomised by the medians. EGFR and KRAS mutations were determined with Sanger sequencing. Clustering was performed using the heatmap function of R v3.0.2. Associations with clinicopathological variables were assessed by Chi-square analysis, and association with disease-specific survival (DSS) was performed using Cox proportional hazards model analysis. Results: The median age of patients was 64 years, 70% were male, 59% were stage I, and 57% of tumors were adenocarcinoma. Unsupervised clustering revealed 4 major subgroups based on the co-occurrence of high and low densities: FOXP3+/CD3+ (29% of cases), FOXP3+/CD3- (11%), FOXP3-/GZMB+ (28%) and FOXP3-/GZMB- (31%). The FOXP3+/CD3+ phenotype was significantly associated with squamous cell histology (p=0.047). There was no association with other features, including EGFR or KRAS mutation status. Patients with FOXP3+/CD3+ phenotype had a worse DSS (HR 2.17, 95% confidence interval [1.08-4.36], p=0.034) compared to those in other subgroups. Conclusions: Combined immunophenotyping suggests NSCLC may be comprised of four major subgroups. The FOXP3+/CD3+ phenotype may indicate a worse prognosis for patients with resected NSCLC and thus identify patients for immune directed adjuvant therapy.
Final follow-up (f/u) results from RADIANT: A randomized double blind phase 3 trial of adjuvant erlotinib (E) versus placebo (P) following complete tumor resection in patients (pts) with stage IB–IIIA <i>EGFR</i> positive (IHC/FISH) non-small cell lung cancer (NSCLC).
Authors: Mary E.R. O'Brien, Karen Kelly, Nasser K. Altorki, Wilfried Ernst Erich Eberhardt, David R. Spigel, Lucio Crino, Chun-Ming Tsai, Joo-Hang Kim, Eun Kyung Cho, Philip C. Hoffman, Shaf Keshavjee, Sergey Orlov, Piotr Serwatowski, Joe Wang, Margaret A. Foley, Julie D. Horan, Frances A. Shepherd
Journal: Journal of Clinical Oncology (2015)

7540 Background: Adjuvant chemotherapy for NSCLC has reached a plateau. The use of the tyrosine kinase inhibitor (TKI), E, was explored in the adjuvant setting given success in advanced setting.We report final f/u from RADIANT. Methods: Completely resected IB–IIIA NSCLC pts were randomized 2:1 to receive E 150 mg daily or P for 2 years. The primary endpoint was disease free survival (DFS) in the full analysis set (FAS). Secondary endpoints included overall survival (OS) in the FAS and DFS and OS in EGFR mutation (M+) subset (del19/L858R). 973 pts were randomized and the planned final analysis was performed after 410 DFS events (April 2013 data cutoff, ASCO14 #7501). A subsequent exploratory analysis occurred after final f/u (June 2014 cutoff). Results: The median f/u is 59.6m (95% CI 56.7–61.2). There was no statistically significant difference in DFS or OS overall or in the EGFR M+ group. The OS data remain immature with 33.5% deaths in the E arm and 31.4% in the P arm. The most common site of relapse (>15% pts) overall and in EGFR M+ were lung and brain in E treated pts and lung, bone and brain in P pts. Among the 13 pts in the EGFRM+ subgroup with brain as site of relapse, 11 of these patients relapsed after E cessation. There were no new safety concerns. Conclusions: Overall adjuvant E did not prolong DFS; a trend for E benefit previously observed (ASCO14 #7513) in EGFR M+ subgroup is no longer apparent. EGFR mutation status was not a stratification factor in this trial and was not a prognostic factor (ESMO14 #1177PD). Further results from ongoing trials are awaited to determine the role of TKI in EGFR M+ early stage lung cancer. Clinical trial information: NCT00373425. Full Analysis Set HR (95% CI) P-Value E (N=623) P (N=350) DFS Median 55 56.2 0.94 (0.78–1.144) 0.5620 # Events (%) 280 (44.9) 168 (48.0) OS Median NR NR 1.12 (0.890–1.413) 0.3306 # Events (%) 209 (33.5) 110 (31.4) EGFR M+ Subset HR (95% CI) P-Value E (N=102) P (N=59) DFS Median 47.8 28.5 0.75 (0.482–1.158) 0.1906 # Events (%) 49 (48.0) 34 (57.6) OS Median NR NR 1.19 (0.609–2.310) 0.6142 # Events (%) 26 (25.5) 13 (22.0) HR: Hazard Ratio; NR: Not Reached.
OPTIMA prelim: Optimal personalized treatment of early breast cancer using multiparameter analysis: Preliminary study.
Authors: Rob Stein, Andreas Makris, Luke Hughes-Davies, Janet A Dunn, John M. S. Bartlett, Jenny Donovan, Christopher McCabe, David A. Cameron, Peter Canney, Helena Margaret Earl, Adele Francis, Adrienne Morgan, Sarah Pinder, Daniel Rea, Christopher John Poole, Peter Hall, Louise Hiller, Nigel Stallard, Helen B Higgins
Journal: Journal of Clinical Oncology (2012)

TPS665 Background: “Multi-parameter” prognostic tests such as Oncotype DX are increasingly used to identify women with ER +ve HER2 -ve breast cancer treated with endocrine therapy who are unlikely to benefit meaningfully from adjuvant chemotherapy. The supporting evidence for predictive testing is retrospective and is strongest for women with negative nodes. Randomised trials to validate testing are in progress but more evidence is needed, especially for node positive disease. There is early evidence that other multi-parameter tests which are in development have a predictive utility. Methods: OPTIMA will assess the value of multi-parameter tests in a UK population. OPTIMA prelim, the feasibility phase, will recruit 300 patients from May 2012 (with a 200 patient bridging extension to the main study). Eligible patients will have ER +ve HER2 -ve tumours with involved nodes (pN1-2). Patients will be randomised to the standard arm of both chemotherapy and endocrine therapy, or to the “test-directed treatment” arm in which patients will be assigned either the same chemotherapy and endocrine therapy or endocrine therapy only according to the result of an Oncotype DX test. OPTIMA prelim has 3 objectives. (1) To establish whether randomisation to test-directed treatment is acceptable to patients and clinicians. This will be done through qualitative research with in-depth interviews with OPTIMA researchers and by recording and analysing consultations when the trial is discussed with potential participants. (2) Alternative multi-parameter tests will be evaluated on all patients’ tumours and their performance will be compared to Oncotype DX using statistical and cost-effectiveness analysis to select a candidate test(s) appropriate for NHS use to be evaluated in the main trial. (3) The success of the main trial depends on efficient tumour sample collection and analysis to avoid treatment delays. The obstacles to this will be analysed in detail using a sample tracking database. The main study is an efficacy trial of 2-3 arms with the same design but uses tests selected in OPTIMA prelim. It will compare 5-year relapse free survival of test-directed vs. conventional treatment with a non-inferiority hypothesis.
FINESSE: An open, three-cohort, phase II trial testing oral administration of lucitanib in patients with FGFR1-amplified or nonamplified estrogen receptor-positive metastatic breast cancer.
Authors: Fabrice Andre, Fergus Daly, Hatem Abdel Azim, Valerie Agrapart, Theodora Goulioti, Ana Catarina Da Costa Pereira Pinto, Chadi Saba, Marc Guitart, Nicholas C. Turner, Marie Jeanne Pierrat, Sibylle Loibl, Thibault Chesnel, Giuseppe Curigliano, Sherene Loi, Martine J. Piccart-Gebhart, Javier Cortes
Journal: Journal of Clinical Oncology (2014)

TPS1134 Background: FGF aberrancy is observed in approximately 25% of breast cancer (BC) patients. Preclinical studies demonstrated that targeting FGFR could lead to antitumor effects. Lucitanib is a multikinase inhibitor targeting FGFR1-2, VEGFR1-3 and PDGFRA/B. In the phase I trial testing lucitanib continuous dosing, 6 objective responses were observed in 12 evaluable patients presenting with FGFR1 and/or FGF3-4-19 (11q) amplification. Based on this, a phase II trial has been initiated. Methods: This is a phase II trial testing the efficacy of lucitanib 15 mg daily in patients with ER+/HER2- metastatic BC who have received at least first line endocrine therapy in the metastatic setting. After informed consent, a biopsy of metastatic site is required to assess the presence of FGFR1- and/or 11q- amplification, which will be centrally evaluated using FISH. Testing could be also performed on archived metastatic biopsies. The primary objective is to evaluate the ORR of single agent lucitanib in metastatic BC patients with FGFR1-amplified, FGFR1-non-amplified with neither FGFR1- amplification nor 11q- amplification. Secondary objectives include clinical benefit rate, PFS, safety, pharmacokinetics and exploratory biomarker analyses. A Simon two-stage design will be used for each of the cohorts to test the null hypothesis that the ORR is 5% or less vs 20% using a one-sided test with 5% level of significance and 90% power. In each cohort separately, an initial 21 patients with measurable disease at baseline will be assessed at the end of stage 1. If at least 2 patients respond per the pre-specified criteria, this cohort will accrue additional 20 patients. The null hypothesis will be rejected if there are at least 5 responders among all 41 patients. The trial started in December 2013. It is planned to open in 9 countries and 30 centers. As of January 24, 5 patients have been screened, 1 of them in the FGFR1-amplified arm. Conclusion: FINESSE is a phase II trial testing lucitanib, a multikinase inhibitor, in three selected populations in order to define the efficacy of the drug and the predictive value of FGFR1 or 11q amplifications. Clinical trial information: 2013-000288-10.
Location of colon cancer (right-sided [RC] versus left-sided [LC]) as a predictor of benefit from cetuximab (CET): NCIC CTG CO.17.
Authors: Stephanie Yasmin Brule, Derek J. Jonker, Christos Stelios Karapetis, Christopher J. O'Callaghan, Malcolm J. Moore, Ralph Wong, Niall C. Tebbutt, Craig Underhill, Desmond Yip, John Raymond Zalcberg, Dongsheng Tu, Rachel Anne Goodwin
Journal: Journal of Clinical Oncology (2013)

3528 Background: RC and LC differ with respect to biology, pathology, and epidemiology. Further, recent SEER data suggests a mortality difference between RC and LC that varies by stage: stage II and III RC having lower and higher mortality, respectively. We examined if the primary tumour site can also predict for outcome in pre-treated, chemotherapy refractory, metastatic colon cancer (MCC). We compared RC vs. LC as a predictor for efficacy of EGFR inhibition with CET. Methods: Using CO.17 (CET vs. BSC), we coded the primary tumour site for 399 pts as RC (cecum to transverse colon) or LC (splenic flexure to rectosigmoid). Fisher’s exact test assessed the association between site of cancer and baseline characteristics. Univariate and multivariate analyses of overall survival (OS) and progression free survival (PFS) by site of cancer were performed using Cox regression models. Results: Pts with RC (150/399) had more poorly differentiated tumours, mutant KRAS status, and peritoneal rather than liver and lung metastases, and they more often entered the study less than two years after initial diagnosis. Among pts receiving BSC, tumour location (RC vs. LC) was not prognostic for PFS (HR 1.07 [0.79, 1.44], p=0.67) or OS (HR 0.96 [0.70, 1.31], p=0.78). Among pts with KRAS wild type tumour status, site of cancer was a predictor of benefit from CET, with much greater PFS observed for LC (interaction p=0.002). Conclusions: In refractory MCC, tumour location within the colon (RC vs. LC) is not a prognostic factor, but is a strong predictor of PFS benefit from CET therapy. Additional research is needed to understand the molecular differences between RC and LC and their interaction with EGFR inhibition. [Table: see text]
Oncotype DX scores in BRCA1 and BRCA2 associated breast cancer.
Authors: Nicholas Patrick McAndrew, Kara Noelle Maxwell, Jill Stopfer, Jacquelyn Powers, Amanda C. Brandt, Jessica M. Long, Katherine L. Nathanson, Susan M. Domchek
Journal: Journal of Clinical Oncology (2015)

541 Background: The Oncotype DX score is widely used to evaluate recurrence risk and potential benefit of chemotherapy in stage 1, estrogen receptor (ER) positive, Her2 negative tumors. Oncotype DX was developed and validated in sporadic breast cancer patients. No data are available regarding Oncotype DX results in BRCA1/2 mutation carriers. The purpose of this study is to determine the distribution of Oncotype DX scores in patients with BRCA1/2 associated cancers, as well as subsequent therapy and disease course for this population. Methods: 18 patients were identified between 2006-2013 who had deleterious BRCA1/2 mutations and stage 1, ER positive, Her2 negative, node negative invasive breast cancer. Data regarding Oncotype DX scores, subsequent therapy (including local, prophylactic, hormonal, and chemotherapy), and length of follow-up was collected. Results: The distribution of Oncotype DX scores was similar in this population as compared to prior published data on patients with sporadic tumors, with approximately 41% of patients having a “low” score, 47% having an “intermediate” score, and 12% having a “high” score. While none of the patients with “low” risk scores had a recurrence of disease at an average of 44.1 months in follow-up, one patient with “intermediate” risk disease had a recurrence 48 months after initial diagnosis. Further molecular analysis of one of the
Next-generation sequencing (NGS) in metastatic colorectal cancer (CRC) patients (pts) in Israel.
Authors: Ayala Hubert, Ravit Geva, Amiel Segal, Baruch Brenner, Ronen M. Brenner, Sharon Pelles-Avraham, Alexander Beny, David Sarid, Shoshana P. Keren-Rosenberg, Salomon M. Stemmer, Alberto Gabizon, Ofer Purim, Esther Tahover, Moshe J. Inbar, Ido Wolf, Addie Dvir, Lior Soussan-Gutman, Jeffrey S. Ross, Phil Stephens, Vincent A. Miller
Journal: Journal of Clinical Oncology (2014)

e14548 Background: Many metastatic CRC pts progress after exhausting all approved standard therapies but maintain a good performance status and could be candidates for further therapy. We hypothesized that a comprehensive NGS assay (FoundationOne) could identify novel therapy targets not routinely considered for CRC pts. Methods: Hybridization capture of 3,769 exons from 236 cancer-related genes and 47 introns of 19 genes commonly rearranged in cancer was applied to ≥ 50 ng of DNA extracted from CRC FFPE specimens and sequenced to high, uniform coverage. Genomic alterations (GA) including base substitutions, small indels, copy number alterations, and select gene fusions, were characterized and reported for each pt sample. Actionable GAs were defined as those identifying anti-cancer targeted therapies on the market or in registered clinical trials. Results: Thirty three CRC pts were included in the analysis(mean age, 54.2 years; range, 28-81; 52% male). Clinical samples used for NGS originated from colon (14, 42%), liver (10, 33%), lung (4, 9%), abdominal wall (2, 6%), and lymph nodes (2, 6%). At the time of NGS testing, 24 pts (73%) were pre-tested for KRAS (5 positive, 19 wild type [WT]). Thirty two cases harbored ≥1 GA, with a total of 117 GAs and a mean of 3.54 GAs per tumor. The most frequent currently non-actionable GAs were identified in TP53 (28, 85%), APC (19, 58%), and MYC (5, 15%). Twenty four (72%) of cases harbored ≥1 actionable GA; most commonly, KRAS (11, 33%), BRAF (7, 21%), PIK3CA (5, 15%), and FBXW7 (3, 9%). Actionable GAs characterized by gene amplifications were detected in FGFR1 (2, 6%), EGFR (1, 3%), and MET (1, 3%). An activating ERBB2 point mutation not detectable by IHC or FISH, potentially targetable with anti-HER2 therapies was identified in 1 pt (3%). KRAS, BRAF, ERBB2, MET, and EGFR were the only actionable GAs that were mutually exclusive. Four pts identified as KRAS WT by hotspot analysis were KRAS mutants by the more comprehensive NGS assay. Conclusions: For metastatic CRC, comprehensive genomic profiling can identify actionable GAs not currently tested for in routine practice. Results point to the potential of MTOR, BRAF, ERBB2 and EGFR targeted therapies for a significant subset of pts.
Tumor assessments according to RECIST versus volumetry: Impact on early changes in tumor size in metastatic colorectal cancer (mCRC).
Authors: Ruediger Paul Laubender, Ute Sartorius, Michael Schlichting, Dominik Paul Modest, Ulrich Robert Mansmann, Anno Graser, Volker Heinemann
Journal: Journal of Clinical Oncology (2012)

e14043 Background: We previously proposed an algorithm for reconstructing the true volume of a tumor lesion by using the longest diameter (LD) and the longest orthogonal diameter (LOD). The following analyses aimed to replicate the previous findings, and evaluate the agreement between RECIST-based tumor assessments (TA) and volumetry in the quantification of early changes in tumor size. Methods: mCRC patients (pts) from the FIRE-3 trial (FOLFIRI + cetuximab vs FOLFIRI + bevacizumab) underwent routine staging using contrast-enhanced CT scans. At least 2 hepatic target lesions per pt were defined for 2 raters at baseline and measured every 8 weeks using semi-automated volumetry (Siemens Syngo Via Oncology, Siemens Healthcare) and manual measurement of the LD according to RECIST 1.1, and the LOD. Agreement between the tumor volume algorithm and volumetry for each rater and the corresponding inter rater agreement (IA) were investigated using Bland-Altman (BA) plots with limits of agreement (LOA). Agreement between the RECIST-based TAs and volumetry was quantified by intraclass correlation (ICC). Both raters and the statisticians were blinded to the treatment given. Results: 222 target lesions from 25 pts were measured at 99 TAs. BA plots indicate that the volume algorithm showed negligible constant bias for both raters (0.09 with p=0.25 and 3 observations outside LOA, and -0.05 with p=0.41 and 6 observations outside LOA). IA with regard to the volumetry showed a smaller constant bias (-0.16 with p=0.17, no observation outside LOA) compared with the volume algorithm (-0.31 with p=0.04, one observation outside LOA). The relative change in tumor size between baseline and first TA was investigated. The ICCs between RECIST-based TAs and volumetry for the 2 raters were 0.79 and 0.73. Data in relation to treatment efficacy will be presented. Conclusions: The algorithm for estimating the tumor volume was validated as shown by the negligible bias and low number of measurements outside the LOA in the BA plots. The moderate ICCs for early changes in tumor size indicate differences between RECIST- and volume-based TAs and suggest that volume measurements discern early changes in tumor size more precisely.