tbuckley/cabot-search huggingface dataset:
DNA repair functionality modulates the clinical outcome of patients with advanced sarcoma treated with trabectedin (ET-743)
Authors: P. Schöffski, P. G. Casali, M. Taron, A. T. Van Oosterom, I. R. Judson, F. Grosso, J. Y. Blay, R. G. Maki, J. C. Tercero, J. M. Jimeno, R. Rosell
Journal: Journal of Clinical Oncology (2006)

9522 Background and Methods: The sensitivity to trabectedin (Yondelis, ET-743) in experimental cancer models correlates with functional transcription-coupled nucleotide excision repair (TC-NER) and with deficient homologous recombination repair (HRR) activity. In order to assess the clinical relevance of this observation we have characterized the mRNA expression levels of ERCC1, XPD, BRCA1 and BRCA2 by RT-PCR in historical tumor samples from 92 sarcoma patients (pts) treated with the agent. Results: The overall objective response (CR+PR) rate to Yondelis in this group was 9%, which confirms the previous clinical experience with the compound in unselected, pre-treated patients with sarcoma. The Kaplan-Meier estimates for progression-free survival at 6 months (PFS6) was 23% and for median survival 8 months (mo). 26% of pts were alive at 24 mo. Correlative Study: Pts with high expression levels (&gt; median) of ERCC1 had better PFS6 (32% vs 15%, p = 0.07) and better median survival (12 vs 7 mo) as compared to pts with low expression ( ≤ to median). Pts with low expression levels of BRCA1 had better PFS6 (33 vs 11%, p = 0.02) and superior median survival (15 vs 5 mo, p = 0.0003) than pts with high expression. Expression levels of XPD and BRCA2 (58 pts) had no significant impact on PFS and survival. The analysis of co-expression of ERCC1-BRCA1 identified a highly sensitive group of pts, characterized by high ERCC1 and low BRCA1 expression levels, with a PFS6 of 50% (p=0.0003) and median survival of 20.4 mo (p = 0.0005). A Cox regression analysis demonstrated that ERCC1 (HR=0.52, p = 0.02) and BRCA1 (HR=2.73, p = 0.0006) are independent variables for PFS, while BRCA1 (HR= 2.57, p = 0.0005) is also an independent variable for survival. Conclusion: This exploratory retrospective study supports the hypothesis that the sensitivity to Yondelis in pts with sarcoma correlates with a functional TC-NER and with deficient HRR. Prospective studies in sarcoma and other potentially sensitive tumor types are required to confirm and validate these findings. [Table: see text]
Survival prolongation after treatment failure in patients with advanced gastric cancer (AGC): Results from combined analysis of JCOG9205 and JCOG9912.
Authors: A. Takashima, N. Boku, K. Kato, J. Mizusawa, K. Nakamura, H. Fukuda, K. Shirao, Y. Shimada, A. Ohtsu
Journal: Journal of Clinical Oncology (2010)

4061 Background: Japan Clinical Oncology Group (JCOG) conducted two phase III trials (JCOG9205, Ohtsu et al, JCO 2003, and JCOG9912, Boku et al, Lancet Oncol 2009) of first-line chemotherapy (Cx) for AGC. Patient accrual was from 1992 to 1997 in JCOG9205 and from 2000 to 2006 in JCOG9912. Median overall survivals (OS) in 5-fluorouracil continuous infusion (5FUci) arm, the standard arm in both trials, were 7.1 months in JCOG9205 and 10.8 months in JCOG9912. We assumed that second-line Cx improved the survival because those were used much more in the period of JCOG 9912; however, survivals were possibly influenced by the baseline factors. Methods: To harmonize the inclusion criteria in both studies, pts with intestinal stenosis in JCOG9205 and pts with adjuvant Cx in JCOG9912 were excluded. OS, time to treatment failure (TTF), and OS minus TTF (OS-TTF) were compared under adjusting baseline factors using Cox proportional hazard model. The covariates were sex, age, PS, macroscopic type, histological type, gastrectomy, target lesion, peritoneal metastasis, and number of metastatic sites. Results: 94 of 105 pts in JCOG9205 and 233 of 244 pts in JCOG9912 were included. The secon-line Cx was given in 52% (49/94) of pts in JCOG9205 and 83% (193/233) in JCOG9912. Irinotecan or taxane containing regimen was given in 9% (8/94) and in 67% (157/233) respectively. 88 pts of JCOG9205 and 231 pts of JCOG9912 were used for Cox regression analysis. Even after adjusting baseline factors, TTF were similar; however, both OS and OS-TTF were longer in JCOG9912 than in JCOG9205 as is shown in the Table. Conclusions: Longer survival after treatment failure of 5FUci for AGC was observed in JCOG9912 even when some potential confounding factors were adjusted. Although there has been no phase III results showing a survival benefit of second-line Cx for AGC, these results well suggest the survival benefit of the second-line Cx with irinotecan or taxane. TTF HR (95% CI) OS HR (95% CI) OS-TTF HR (95% CI) Unadjusted analysis 0.84 (0.65-1.08) 0.62 (0.48-0.81) 0.63 (0.49- 0.82) Adjusted analysis 0.95 (0.72-1.25) 0.71 (0.53-0.94) 0.72 (0.54-0.96) No significant financial relationships to disclose.
Immune self-tuning in renal cell carcinoma patients
Authors: A. Busse, A. Asemissen, A. Schmittel, K. Zimmermann, K. Miller, A. Rietz, S. Ochsenreither, A. Fusi, E. Thiel, U. Keilholz
Journal: Journal of Clinical Oncology (2009)

e22069 Background: Renal cell carcinoma (RCC) cells can inhibit protective antitumor immunity by secretion of immunosuppressive factors leading to the induction of regulatory T cells. The objective of this study was to investigate the prognostic impact of mRNA expression levels of IL10, TGFβ and forkhead box transcription factor (FoxP3) mRNA in peripheral blood mononuclear cells (PBMCs) of metastatic RCC patients before receiving treatment with sorafenib. Methods: PBMCs of 46 patients were assessed for their expression levels of TGFβ, IL10 and FoxP3 by quantitative RT-PCR. Clinical features considered included ECOG performance status, hemoglobin, alkaline phosphatase, and calcium concentrations. Disease evaluation was performed every 8 weeks following RECIST criteria. Relationship between pre-treatment factors and survival were examined in univariate analyses and subsequently by multivariate analysis using a stepwise Cox regression model. Results: In contrast to FoxP3, mRNA expression levels of IL10 and TGFβ were significantly higher in the 46 RCC patients compared to healthy volunteers: Median expression levels [ratio marker /housekeeping gene PBGD] were 5.56E-05 vs 2.05E-04 (P=0.034) for IL10 and 7.38E-02 vs 3.04E- 01 (P=0.023) for TGFβ. Univariate analysis revealed a negative prognostic influence of IL10 on progression free survival (p=0.04) and on overall survival, although not significant (P= 0.063). Surprisingly, high TGFβ and FoxP3 expression levels had a positive influence on progression free (P&lt;0.001 and P=0.047, respectively) and overall survival (P&lt;0.001 and P= 0.031, respectively). In the multivariate analysis low ECOG performance status and high TGFβ mRNA expression levels were independently associated with worse progression free (P=0.001 and P=0.054,) and worse overall survival (P=0. 006 and P&lt; 0.001, respectively). Conclusions: RCC caused an immune-suppressive phenotype in PBMC characterized by increased mRNA expression levels of IL10 and TGFβ. Surprisingly, in contrast to IL10, a high TGFβ mRNA expression level was an independent good prognostic factor. Whether this observation can be attributed to recently described immune promoting functions of TGFβ needs to be determined. No significant financial relationships to disclose.
Safety of erlotinib in TRUST, a phase IV trial in patients with advanced non-small cell lung cancer (NSCLC): Initial results from the East/South East (E/SE) Asian subgroup
Authors: Y. Wu, L. Zhang, J. Siu-Kie Au, A. Cheng, K. Park, H. Kim, V. Srimuninnimit, V. Sriuranpong, M. Lin, H. Kuo
Journal: Journal of Clinical Oncology (2007)

18018 Background: Erlotinib significantly improved survival versus placebo and was well tolerated in patients (pts) with previously treated advanced NSCLC in the phase III BR.21 study (Shepherd et al. N Engl J Med 2005;353;123–32). TRUST, an open-label, multicenter study was initiated to provide erlotinib access to pts with advanced NSCLC. Here we report data for E/SE Asian pts. Methods: Eligible pts had failed 1–2 prior standard chemotherapy (CT) regimens, or were unsuitable for CT. Erlotinib 150 mg/day p.o. was given until disease progression/unacceptable toxicity. NCI CTC v3.0 was used to grade toxicities. Results: At data cut-off of 20/11/06, 885 pts were included in the analysis: n= Taiwan 297, mainland China 248, Hong Kong 160, South Korea 146, Thailand 30, Indonesia 2, Malaysia 2. Median age was 61yrs (range 22–95). Pt characteristics (%): male/female 55/45, ECOG PS 0/1/2/3 15/67/14/4, stage IIIb/IV 20/79, adenocarcinoma/other 68/32, erlotinib as 1st/2nd/3rd/other line therapy 11/55/33/&lt;1, never/ever smoker 52/47 (no data &lt;1). 83% pts experienced rash, of which 9% was grade (gr)3/4. Safety data forms were available for 598 pts; 54% had at least one adverse event (AE).104 pts (17%) had a treatment (tx)-related unexpected adverse event (AE) but no single AE occurred in &gt;3% pts and only 3% were ≥gr3. Serious tx-related AEs were experienced by 19 pts (3%); 17 were gr3/4, most commonly gastrointestinal (n=6). One pt had suspected tx-related interstitial lung disease (gr2); the patient continued tx. 18 pts (3%) withdrew due to a tx-related event; 11 were gr3/4, most commonly gastrointestinal (n=4) and respiratory (idiopathic pulmonary fibrosis n=1, pneumonitis n=2). 76 pts (13%) required dose reduction due to a tx-related event (13%), mainly due to rash (n=57). 83% pts received erlotinib for &gt;4 weeks. Efficacy will be presented. Conclusions: The results reported here for E/SE Asian pts in the TRUST study confirm in a community setting the good tolerability observed with erlotinib in clinical trials. Importantly, erlotinib was generally well tolerated and so could be administered at full tx dose to most pts. [Table: see text]
MicroRNA signatures from FFPE tissue distinguish patients with colorectal cancer of UICC stage I from those with metastatic disease of stage IV.
Authors: T. Mayr, P. Pechanska, K. Ridwelski, R. Mantke, M. Pross, J. Pertschy, T. Manger, F. Marusch, B. Hinzmann, H. Adams, A. Rosenthal
Journal: Journal of Clinical Oncology (2011)

e14055 Background: miRNAs have a length of 21-23 bp. They are more stable than mRNAs, especially in formalin-fixed paraffin embedded (FFPE) tumor tissue. The increased stability of miRNA makes them attractive as potential biomarkers. Methods: In the frame work of a prospective, multicenter, IRB approved study we recruited more than 4.000 patients (pts) with colorectal cancer in all four UICC stages from 33 primary care und university hospitals in Germany. Informed consent was obtained from all pts. For this study we used a set of 357 FFPE tissues from stage I (n=179) and stage IV (n=178). All FFPE tissues were quality controlled by an in-house pathologist. Total RNA including miRNA was isolated using miRNeasy FFPE kits and QiaCube robots (Qiagen). 250ng total RNA was labeled using the FlashTag kit (Genisphere) and then hybridized onto GenChip miRNA arrays (Affymetrix). Results: After all QC, 311 array data sets remained. A training set (N=114, stage I=58, stage IV=56) and an test set (N= 197, stage I=103, stage IV=94) were formed. miRNA signatures with a length of 2 to 1.000 probesets were identified using FARMS condensation followed by a nested bootstrap approach with random forest and SVM for feature selection. The best signature (1.000 probesets) showed a sensitivity (S+) of 73% and a specificity (S-) of 71%. This signature was validated in the test set and achieved a S+ of 71% (95% CI: 0.610-0.801) and a S- of 66% (95% CI: 0.560-0.751). Furthermore, the potential of randomly drawn training sets of different sizes was examined in a bootstrap approach by which training sets of size 20, 40, 80, 114, 180, and 280 were repeatedly sampled. A discovery pipeline was then applied which also used a double-nested bootstrap approach. Resulting classifiers were cross-validated on all samples outside of its training set, adding validation performance to the prospective estimates of the discovery pipeline. Training sets of 180-280 samples yielded better results than the original 114 sample set, and outperformed all small sets of 20-80 samples. Conclusions: We will apply the best miRNA signatures to identify pts with stage II and stage III disease who are at high risk of metastasis.
An Internet-based survey evaluating attitudes of cancer patients towards pain intervention
Authors: C. B. Simone, N. Vapiwala, M. K. Hampshire, J. M. Metz
Journal: Journal of Clinical Oncology (2006)

18540 Background: Pain is a common symptom among cancer patients (pts), but many pts experience inadequate medical management for pain. There are little data quantifying reasons that cancer pts fail to receive optimal analgesic treatment. This study evaluated those reasons and investigated the causes of pain in cancer pts. Methods: An Internet-based questionnaire assessing pt demographics and pain symptoms was piloted with pts and healthcare providers and posted on the OncoLink (http://www.oncolink.org) website. The questionnaire included 22 queries evaluating medication utilization, pain control and attitudes regarding pain medications. The questionnaire was IRB approved and held on a secure server. Between 11/05–1/06, 99 pts responded to the questionnaire. They were predominantly Caucasian (76%), female (78%) and pursued education beyond high school (66%). The most common diseases included cancer of the breast (51%), lung (8%) and brain (6%). Cancer treatment included surgery (75%), chemotherapy (63%) and radiation (45%). Results: Half (49%) of the respondents reported pain directly from their cancer and 42% complained of pain due to cancer treatment. This pain was primarily intermittent (42%) or chronic (35%). Most (77%) pts did not use medication specifically to help manage their pain. Analgesic usage trended less in women (19% vs. 36%, p = 0.10), Caucasians (19% vs. 38%, p = 0.06), and pts with higher education levels (17% vs. 26%, p = 0.29) but did not reach statistical significance. Reasons most commonly cited for not taking analgesics included the healthcare provider not recommending medications (86%), fear of becoming addicted or dependent (80%) and an inability to pay for medication (75%). Participants experiencing pain, but not taking analgesics, sought alternative measures for pain control such as physical therapy (84%), massage (7%) and acupuncture (4%). Conclusions: Although many cancer pts experience pain regularly, both from their cancer and cancer treatment, most pts in this study did not seek out analgesics. Pts do seek complementary therapies for pain control. Healthcare providers should regularly have open discussions with pts regarding pain symptoms. Further study will be needed to evaluate attitudes of pts towards pain based on disease condition. No significant financial relationships to disclose.
Prognostic value of positron emission tomography for non-small cell lung cancer survival; analysis of 268 cases
Authors: H. Kramer, W. J. Post, H. J. M. Groen
Journal: Journal of Clinical Oncology (2004)

7227 Background: Positron emission tomography (PET) is more accurate than computed tomography (CT) in the staging of non-small cell lung cancer (NSCLC). We analyzed the prognostic value of PET for survival in NSCLC patients. Methods: Consecutive patients with proven NSCLC who had PET for staging were selected. All patients had been evaluated by laboratory tests, bronchoscopy, chest X-ray, and CT of the chest and upper abdomen. A clinical stage (c-TNM) was determined prior to PET. A pet-TNM was obtained by observers blinded to clinical data. We used the McNemar test to compare c-TNM and pet-TNM. Univariate survival analyses were performed with the Kaplan-Meier method and log rank test, for performance score, sex, weight loss, comorbidity, histology, hilar and paramediastinal tumor location, c-TNM, and pet-TNM. Cox regression analysis was performed with the significant variables of the univariate analyses, together with age and interaction variables. Results: From 1996 until 2001, 268 patients were included, 206 men and 62 women. Median age was 63 years (range, 29–88), ECOG performance score was 0/1/2 in 114/135/19 patients, 37% had squamous and 30% had adenocarcinoma. c-TNM and pet-TNM were identical in 150 (56%) patients, 68 were upstaged and 48 were downstaged by PET, and 2 without c-TNM had stage IB/IV. c-TNM did not overlap with pet-TNM (p = 0.024). At analysis, 212 (79%) patients had died. Median survival in months was not reached for stage IA (pet-TNM), 45 for stage IB, 21 for IIA, 29 for IIB, 13 for IIIA, 14 for IIIB, and 9 for stage IV. At univariate analysis, survival difference between the arms was significant for performance score (0 vs. 1/2), weight loss (< 10% vs. ≥ 10%), pulmonary comorbidity and paramediastinal location (no vs. yes), c-TNM and pet-TNM (stage I vs. II vs. IIIA vs. IIIB vs. IV). At Cox regression analysis, pet-TNM was the only significant (p < 0.001) predictor of poor survival, while c-TNM, performance score, and weight loss were not significant. Conclusion: Tumor stage as determined by PET is the best prognostic factor for survival in patients with NSCLC. No significant financial relationships to disclose.
Importance of lifestyle modification in cervical cancer survivors.
Authors: M. P. Schlumbrecht, C. C. Sun, S. N. Westin, F. Zandstra, K. Denton, H. Rhodes, D. A. Gonzales, E. A. Garcia, C. Levenback, D. C. Bodurka
Journal: Journal of Clinical Oncology (2010)

e15521 Background: With the introduction of multimodality therapy for cervical cancer many women will be long-term survivors in need of comprehensive postsurveillance care. Lifestyle modifications are critical components of such care. Our goal was to evaluate patterns of obesity and smoking in a cohort of cervical cancer survivors. Methods: We reviewed the records of patients treated for invasive cervical cancer at our institution from 2000-2003 who were NED ≥ 3 years. Demographic and clinical information was collected, including smoking history and anthropometric measurements. BMI was categorized according to WHO criteria. Logistic regression, Wilcoxon-signed rank test, and chi-square analyses were performed. Results: Of the101 women with complete follow-up data at 3 years, median age at diagnosis was 44.4 yrs (mean 45.2; range, 23.9-75.7). 68% were White; 16% were Hispanic; 14% were Black. At diagnosis, 38% had a normal BMI, 22% were overweight, and 41% were obese compared with 35%, 20%, and 46% at 3 years, respectively. Of the 21 women whose BMI categorization changed, only 15 had weight gain, and 6 lost weight. By paired analysis, increase in BMI was significant over the 3-year interval (n = 65) (p < 0.01). There was a trend for more psychiatric consults in obese women (p = 0.1), and only 7 had nutrition consults. 50 patients were nonsmokers; 25 formerly smoked, and 26 actively smoked at diagnosis. Smoking cessation was discussed with 15 patients and 1 patient accepted referral. Compared with nonsmokers, ever smokers were more likely to experience treatment complications (OR 2.6; 95%CI [1.2, 5.8]) and have consults by the pain service (p = 0.01). Current smokers also appeared to be at greater risk for radiation cystitis (OR 3.2, p = 0.1). Median time to GU consult for ever smokers was less than never smokers (11 vs. 51 mos). Conclusions: Obesity and smoking may significantly complicate care in cervical cancer patients during the survivorship phase of the cancer continuum. It is crucial for oncologists and primary care physicians to reinforce healthy lifestyle changes in these women. In 2008, our institution began offering comprehensive services in the GYN Survivorship Clinic, a major aim of which is to provide patients with lifestyle management strategies. No significant financial relationships to disclose.
Phase II study of capecitabine and radiotherapy (RT) plus concomitant boost in patients (pts) with locally advanced rectal cancer (LARC)
Authors: G. G. Shi, E. Lin, C. Eng, M. Delcos, C. Crane, C. B. Amos, T. Brown, J. L. Abbruzzese, J. Skibber, N. Janjan
Journal: Journal of Clinical Oncology (2004)

3775 Rationale: Preoperative RT with continuous infusional 5-fluorouracil (CI-5FU) improves sphincter preservation and produces pathological complete remissions (pCR) in 10–30% of pts with LARC. Capecitabine (Xeloda) mimics CI-5-FU via daily oral administration and is preferentially converted to 5-FU by high intra-tumor thymidine phosphorylase, which is further activated by RT. Design: Based on the promising phase I data (Dunst et al JCO 20:3983:2002), we initiated a phase II study of capecitabine 825 mg/m2 orally twice-daily plus RT (52.5 Gy/30 fractions to the primary and perirectal nodes) in 54 pts with T3 or greater LARC. All eligible pts will receive 4 cycles of adjuvant capecitabine (1250 mg/m2 orally twice daily for 2 wks every 3 wks). Results: Of the 31 pts enrolled (median age: 56, performance status: 0–1, 24 males, 7 females, 14 T3N0, 15 T3N1, 1 TXN1, 1 T4N1), all had completed chemoradiation and 12 pts also had completed adjuvant capecitabine with additional 5 pts still on adjuvant therapy to date. Toxicities during chemoradiation and adjuvant therapy were summarized below. There were no grade 4 events except in 1 pt with ileus possibly related to treatment. The grade 3 events consisted of diarrhea (13%), and radiation dermatitis (6%) and mostly clustered in pts who are > 65 yr of age. Grade 2 events were: diarrhea (26%), fatigue (19%), HFS (16%), anemia (16%), radiation dermatitis (13%), rectal pain (6%) and neutropenia (3%). Transient non-complicating lymphocytopenia were also noted in 58% of pts. Of 28 pts evaluable for tumor response, 20 pts (71.4%) achieved pathological down-staging (5 pathological complete remissions, 15 partial remissions, 7 stable disease). Conclusions: RT with capecitabine and adjuvant capecitabine for LARC appeared to be very well tolerated and produced comparable results to that with RT plus CI-5FU and could replace inconvenient CI-5FU. Updated results will be presented at the meeting. *Study supported by Roche Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Roche Roche; Pfizer; Novartis