tbuckley/cabot-search huggingface dataset:
Pemetrexed as second-line treatment for patients with advanced non-small cell lung cancer (NSCLC): Efficacy and correlation with molecular markers
Authors: A. Blasco, R. Sirera, J. Terrasa, M. Provencio, C. Guillén, I. Maestu, R. de las Peñas, I. Bover, M. Berdiel, I. de Aguirre
Journal: Journal of Clinical Oncology (2008)

8095 Background: Pemetrexed is approved as second-line therapy in advanced NSCLC. In this study, we evaluate the efficacy and safety of pemetrexed in patients with Advanced NSCLC previously treated and we also perform a pharmacogenomic analysis to determine if biologic characteristics could be related to any clinical benefit. Methods: 195 patients with NSCLC stage IIIB (malignant pleural effusion) or IV were selected to receive pemetrexed (500 mg/m2, IV infusion) supplemented with vitamin B12, folic acid and dexamethasone prophylaxis. DNA was extracted from peripheral lymphocytes and Taqman assays for allelic discrimination were used for the following single- nucleotide polymorphism (SNP) typing: Methylene-Tetra-Hydro-Folate-Reductase (MTHFR), methionine synthase (MTR), thymidylate synthase (TS) and reduced folate carrier 1 (RFC1). Results: Median age 63 years (37–82); males: 88%; never-smokers: 9%; performance status (PS) 0: 23%; adenocarcinoma: 34%, squamous: 45%; stage IIIB: 20%, IV: 80%. The responses rates: PR 9%, SD 21%, PD 61% (9.7% pending of evaluation). Median TTP was 2.1 months (95% CI 1.9–2.3) and non statistical differences between smoking status or histology were found. Median OS was 6.7 months (m) (95% CI 5.3–8.1) and non-smokers had better OS 15.7 m (95% CI 5.3–26.1) vs 4.1 m (95% CI 3.0–5.3), p= 0.003. OS was also different by PS, PS0 9.9 m (95% CI 7.5–12.3), PS1 5.9 m (95% CI 4.5–7.2), PS2 3.1 m (95% CI 2.2–3.9) p<0.0001. Patients with adenocarcinoma presented better OS that squamous: 8.4 m (95% CI 3.5–13.7) vs 5.7m (95% CI 4.2–7.2), p= 0.22. There were no differences in clinical characteristics among the different SNP types, except TS and smoking history. No differences in response were observed according to any of the SNPs. Conclusions: More pharmacogenomic analysis will be performed to determine predictors of chemosensitivity in NSCLC, to optimize response rates and survival benefit. EGFR mutational status is being analyzed to study differences in survival for those patients with adenocarcinomas or those receiving EGFR inhibitors as third-line therapy. No significant financial relationships to disclose.
Acute leukemia (AL) following Hodgkin’s lymphoma (HL): A population-based study of over 38,000 patients
Authors: S. J. Schonfeld, E. S. Gilbert, G. M. Dores, C. F. Lynch, E. Holowaty, P. Hall, H. Storm, E. Pukkala, A. Andersen, L. B. Travis
Journal: Journal of Clinical Oncology (2005)

6510 Background: Treatments for HL are associated with large increased relative risks of secondary leukemia, but there are few estimates of the excess absolute risk (EAR), the optimal measure of disease burden in a population. Further, the influence of age and calendar year of HL diagnosis on EAR has not been well characterized. Methods: Among 38,642 one-year survivors of HL reported to 13 population-based cancer registries in North America and Europe (1943–2001), 231 AL (215 acute nonlymphocytic leukemias; 16 acute lymphocytic leukemias) subsequently developed. Poisson regression analysis was used to estimate EAR of AL as a function of age and calendar year of HL diagnosis, gender, latency, and initial treatment. EAR (excess cases per 100,000 person-years) is presented for patients diagnosed with HL at age 35 years (average cohort age), unless noted otherwise. Results: EAR increased with increasing age at HL diagnosis (P <.001). For patients diagnosed with HL at age ≥35, EAR was 72 whereas it was 30 for those diagnosed at a younger age (P<.001). Risk was higher for men than women (50 and 37 at age 35, respectively). EAR was 64 during the first 15 years after HL diagnosis and decreased sharply to 11 thereafter (P trend <.001). EAR was significantly larger (P< .001) among patients treated with any chemotherapy (CT) than with radiotherapy (RT) alone (50 and 26, respectively). Among HL patients given CT, AL risk was significantly lower for those treated after 1984 than between 1970–1984 (33 and 57, respectively) (P = .024), but remained elevated. Conclusions: A strong effect of increasing EAR of AL with increasing age at HL diagnosis is apparent. Risk remains elevated for ≥15 years after HL diagnosis. Population-based data suggest a reduction, but not an elimination, in the EAR of leukemia among HL patients given CT after 1984; analytic studies are required to correlate these decreases with specific chemotherapeutic regimens and to examine any role of RT. No significant financial relationships to disclose.
Lymph node retrieval rates affect adjuvant chemotherapy (AC) utilization for stage II colon cancer at the National Comprehensive Cancer Network (NCCN) institutions
Authors: C. C. Earle, M. R. Weiser, S. Shibata, J. M. Skibber, J. Wilson, A. Rajput, Y. Wong, D. K. Romanus, A. TerVeer, D. Schrag
Journal: Journal of Clinical Oncology (2008)

4046 Background: The decision to take AC in stage II colon cancer requires weighing uncertain benefits with the potential for acute and, increasingly, long-term toxicity. Methods: The NCCN Colon/Rectal Cancer Outcomes Database records practice patterns on all eligible patients receiving treatment at 8 NCI-designated comprehensive cancer centers in order to monitor quality of care. Among all patients diagnosed with stage II colon cancer between Sept 1, 2005 and October 9, 2007, we analyzed receipt of chemotherapy within 120 days of diagnosis and prior to any recurrence (AC), as the dependent variable, and age, comorbidity, lymph nodes (LN) removed, T stage, perforation, obstruction, lymphovascular invasion (LVI) and institution as independent variables in a stepwise logistic regression model. Results: Among 196 patients, 88 (45%) received AC a median 52 days after surgery. An oxaliplatin-containing regimen was used 67% of the time, and 67 (76%) completed at least 4 months of AC. The table shows that younger age and the presence of lymphovascular invasion (LVI) were associated with receipt of AC. There was a trend toward AC use with higher T stage. Perforation, obstruction, and histological grade were not associated with AC use. Higher comorbidity was a determinant of not receiving AC on univariable analysis but not after adjustment. Notably, the presence of less than 12 lymph nodes (LN) in the surgical specimen was a strong predictor of AC use. There were no differences in practices by institution. Conclusions: The discretionary choice to give AC is influenced by many of the expected patient and tumor characteristics. However, more attention to examining the recommended benchmarks for lymph node dissection may spare patients unnecessary exposure to AC and decrease the potential for long-term toxicity. Receipt of AC in stage II colon cancer Variable Category N %AC OR 95% CI p-value Age < 50 46 83 50 - 64 59 51 0.13 (0.04, 0.40) <0.0001 65 - 74 49 37 0.06 (0.02, 0.20) 75+ 42 5 0.003 (0.001, 0.02) LN Examined 12+ 172 42 <12 24 67 3.52 (1.08, 11.52) 0.04 LVI No 150 42 Yes 46 54 4.04 (1.43, 11.40) 0.008 No significant financial relationships to disclose.
A phase I pharmacokinetic study of PR-104, a hypoxia-activated nitrogen mustard prodrug administered on a weekly schedule in patients with solid tumors
Authors: T. J. Melink, M. B. Jameson, M. J. McKeage, J. C. Gutheil
Journal: Journal of Clinical Oncology (2008)

14543 Background: PR-104 is a prodrug which, in the presence of hypoxia, forms a nitrogen mustard that exerts cytotoxic activity through DNA crosslinking. In a prior phase I study using a q21 day schedule, the maximum tolerated dose (MTD) was 1100 mg/m2; neutropenia was dose-limiting. This dose escalation study defines the toxicity profile, MTD and pharmacokinetics (PK) of PR-104 and its alcohol metabolite. Methods: Patients (pts) with advanced solid tumors received PR-104 as a 1-hour IV infusion on days 1, 8 and 15 every 28 days with PK sampling on days 1–2 of cycle 1. Cohorts of ≥3 pts were dosed starting with cohort 1 at 135 mg/m2. Dose-limiting toxicity (DLT) was assessed with cycle 1. Results: 13 pts have been dosed: median age 53 years (range 31–70); 7 male; melanoma (4 pts) and 1 pt each with other tumors; median of 2 (range 1–3) prior chemotherapy regimens. Three dose levels (135, 270, 540 mg/m2) have been evaluated. Pts have received a median of 2 cycles (range 1–5). DLT resulted in cohort expansion to 6 pts at 270 mg/m2 (1 pt with grade 3 anemia) and 540 mg/m2 (1 pt with grade 4 thrombocytopenia/cerebral hemorrhage). At 540 mg/m2, predominately grade 1 hematologic toxicity (3 of 4 pts) has been observed with cycle 1; more severe (grades 2/3) and delayed myelosuppression (2 pts) has been observed following cycle 2. The most common non-hematological adverse events were grades 1/2 fatigue (6 pts), constipation, nausea and abdominal pain (3 pts each). Stable disease was seen in 2 pts: head and neck cancer and melanoma (5 cycles each). PR-104 PK are reported in the table below. Conclusions: With a weekly schedule, the primary toxicity of PR-104 has been dose dependent myelosuppression which is similar to that seen with an every 3 week schedule. The MTD is at least 270 mg/m2. Overall, PR-104 has shown manageable toxicities. It remains to be determined if weekly administration has therapeutic advantages over an every 3 week administration. The PK of PR-104 on a weekly or every 3 weeks schedule appears similar. PR-104 Dose (mg/m2) Number of pts PR-104 Cmax (ug/mL) PR-104 AUC (ug.min/mL) PR-104A Cmax (ug/mL) PR-104A AUC (ug.min/mL) 135 2 2.8±2.2 114±102 1.5±0.6 46±20 270 6 4.5±1.6 145±55 3.2±2.0 99±58 540 2 8.2±3.2 284±33 7.5±2.6 293±131 Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Proacta, Inc. Proacta, Inc.
A phase IB, open-label, parallel design study of PTK787/ZK 222584 in combination with irinotecan in patients (Pts) with metastatic colorectal cancer (CRC) to investigate the interaction between the agents
Authors: S. Tejpar, E. Lin, P. Bono, Y. Humblet, T. Jalava, A. Kay, E. Masson, D. Laurent, H. Joensuu, E. van Cutsem
Journal: Journal of Clinical Oncology (2005)

3594 Background: PTK787/ZK 222584 (PTK/ZK) is a novel, oral, anti-angiogenesis compound that blocks tyrosine kinase activity from all known vascular endothelial growth factor (VEGF) receptors. Preliminary PK data from another trial suggested a reduction in systemic exposure for irinotecan and its metabolite SN-38 with PTK/ZK. The purpose of this study is to evaluate any significant PK interaction between PTK/ZK and irinotecan and, if so, elucidate the mechanism. Methods: This 2-arm study characterizes the PK profile, safety, tolerability, and anti-tumor activity of oral PTK/ZK in combination with irinotecan in Pts with first or second line metastatic CRC. Pts were randomized 1:1 to receive irinotecan at a dose of 250 mg/m2 over a 90 min infusion q21 days without PTK/ZK (arm 1) or with PTK/ZK (1250 mg/d; arm 2). Cross-over from arm 1 to arm 2 was allowed after cycle 2. Pts had histologically documented metastatic CRC, WHO Performance Status of 0–2 and adequate hematologic and organ function. Results: 44 Pts were randomized (21 to arm 1, 23 to arm 2). 27 had received one treatment (12 in arm 1, 15 in arm 2) prior to the study. 13 from arm 1 crossed over to arm 2. At steady state, PK of PTK/ZK was not affected by irinotecan. However, PTK/ZK reduced the exposure of irinotecan by 27% and SN-38 by 49%. The most frequently observed grade 3/4 toxicities were vomiting (21.7%) diarrhea (17.4%) neutropenia (13%) and hypertension (13%). PTK/ZK did not aggravate irinotecan related AEs. Median TTP for all Pts is 211 days. A 24% ORR was observed and is in the range reported earlier for Pts who received the same irinotecan dose. Conclusion: Because most Pts crossed over from arm 1 to arm 2 after 2 treatment cycles a formal comparison of the efficacy is not feasible. The AUC decrease of irinotecan and SN-38 did not seem to be clinically significant. The combination of PTK/ZK with irinotecan showed promising activity with a safety profile comparable to irinotecan combinations with another anti-angiogenisis agent. A randomized phase II trial to study PTK/ZK in irinotecan containing regimens is needed to fully explore potential combination benefits. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis, Schering AG
Chromosome 17 polysomy and Her-2/neu status in metastatic breast cancer patients indicated to trastuzumab therapy
Authors: M. Hajduch, R. Trojanec, K. Bouchalova, Z. Kolar, K. Petrakova, K. Cwiertka, M. Svoboda
Journal: Journal of Clinical Oncology (2005)

9584 Background: Numeric and structural aberrations of chromosome 17 (C17) are common findings in breast cancer patients. Aneusomy of C17 is often correlated with bad prognosis. Polysomy of C17 may explain the immunohistochemical (IHC) positivity in fluorescent in situ hybridization (FISH) negative cases. Although polysomic cases represent only 10–20% of breast cancer, at least 5–7% of them are not indicated to trastuzumab treatment because they do not fill criteria of Her-2/neu: C17 ratio >2,0 and efficacy of trastuzumab in polysomic patients has not been confirmed yet. In Czech Republic, such patients are indicated for trastuzumab treatment only when they are IHC 3+ positive (high positivity). Methods: In the Czech National Centre for Her-2/neu evaluation at Palacky University, 541 samples of breast cancer tumours were tested by FISH assay (PathVision) with locus specified probes for detection of Her-2/neu gene (LSI Her-2/neu; 17q11.2-q12) and centromeric region of C17 (CEP 17; 17p11.1-q11.1). In tumors with polysomy of C17 (>2.5 centromeric signals/nucleus), numeric aberrations of C17 were further confirmed using FISH probes covering p-arm of C17: 17p11.2, 17p12 and 17p13. Results: Her-2/neu gene (H) amplification was found in 44% cases (H/C17>2.0) and 6.3% patients showed borderline amplification (H/C17=1.5–2.0). Polysomy of C17 (C17/nucleus>2,5) was found in 15.3% of cases. In these polysomic cases, 70.2% had amplification (H/C17>2.0), 11.7% borderline amplification (H/C17=1.5–2.0) and 15.6% showed normal status (H/C17 <1,50) of Her-2/neu. However, only 58% of polysomic tumors were true polysomic when examined by probes covering p-arm of C17. Further investigations showed that false polysomic tumors were partially due to cross-hybridization of C17 centromeric probes to centromeres of other chromosomes, but also due to amplification and/or translocation of C17 centromeric signals. Conclusions: Re-examination of polysomic tumors with FISH probes covering p-arm of C17 better reflects status of C17 versus Her-2/neu in breast cancers and increases percentage of patients who may profit from trastuzumab based therapies. This work was supported by grants IGA MZCR 7495- 3 and 7506–3. No significant financial relationships to disclose.
Prognostic significance of HER-2/neu over-expression on the incidence of brain metastasis in newly diagnosed breast cancer
Authors: B. S. Abdulkarim, Z. Gabos, R. Sinha, J. Hanson, N. Chauhan, J. Hugh, J. Mackey
Journal: Journal of Clinical Oncology (2006)

649 Background: As systemic therapy improves, brain metastases (BM) from breast cancer are becoming increasingly evident. An increased risk of BM in HER-2/neu over-expressing metastatic breast cancer patients has been suggested. However, the relationship between HER-2/neu over-expression and the risk of BM in newly diagnosed breast cancer patients is unknown. Methods: To determine incidence of BM in HER-2/neu over-expressing breast cancer patients, a cohort of patients between 01/1998 and 12/2003 with uniform HER-2/neu testing were identified from a cancer registry. A total of 460 patients with HER-2/neu over-expression and 500 patients with HER-2/neu negative disease were reviewed. Patients were excluded if there was breast cancer diagnosed before 01/1998 or others cancer. A total of 301 HER-2/neu over-expressing and 363 HER-2/neu negative patients were included for this analysis. The association between histological features and the occurrence of BM were evaluated with univariate and multivariate analyses. Results: BM were identified in 8% (24 patients) of HER-2/neu over-expressing breast cancer patients compared to only 1.7% (6 patients) in the HER-2/neu negative patients (hazard ratio 5.15 [2.079–12.78], p=0.0001). In patients with recurrent disease, the proportion of BM for HER-2/neu over-expressing patients was 24% compared to 10% in HER-2/neu negative patients. HER-2/neu over-expression, tumor size &gt;2cm, ≥ 4 nodes positive and grade 2/3 were predictors of BM in univariate analysis. In multivariate analysis, HER-2/neu over-expression and tumor size&gt;2cm were an independent prognostic factors for the development of BM, while hormone receptors expressions was protective (p=0.02). Conclusions: Our population based study show that newly diagnosed HER-2/neu over-expressing breast cancer patients are at significantly increased risk for BM. As most BM occur in HER-2/neu over-expressing patients with systemic metastatic disease, these findings could prompt consideration of brain prophylaxis strategies and/or serial radiologic screening to detect asymptomatic BM. No significant financial relationships to disclose.
Impact of a cancer of unknown primary (CUP) service on end-of-life planning for patients with metastatic cancer.
Authors: Katie Weatherstone, James Stewart, Jackie Marshall, Roopinder Gillmore
Journal: Journal of Clinical Oncology (2014)

66 Background: Cancer of Unknown Primary (CUP) is the 4th most common cause of cancer death in England and Wales. [(Office for National Statistics, Mortality Statistics: Deaths registered in England and Wales. http://www.ons.gov.uk/ons/search/index.html?newquery=series+dr (accessed 1/7/14).] Patients with CUP have poor outcomes secondary to delayed, inappropriate investigations and poor treatment response. In line with NICE guidance [(NICE guidelines: CG 104 (July 2010).]. Metastatic malignant disease of unknown primary: diagnosis and management of metastatic malignant disease of unknown primary.) a CUP service was set-up at the Royal Free in June 2012. This analysis assessed its impact on patients diagnosed with metastatic cancer who were not fit for active treatment. Methods: Clinical notes were reviewed for all admissions with an imaging-based diagnosis of metastatic cancer. A retrospective analysis (January-April 2009) was compared to prospective data following the launch of the CUP service (June-December 2012). Results: The notes of 9 patients (2009) and 15 patients (2012) were compared (see table). Age and length of stay (LOS) were analysed using t-test, other data were compared using chi-squared test. All patients were reviewed by Oncology and Palliative Care teams. There was a significant reduction in mean LOS (6.7 days, 18.6 days p&lt;0.004) and the number who died in hospital (7%, 67% p&lt;0.002) with only one patient not dying in his preferred place. Conclusions: Prompt assessment by the CUP service facilitates early input from Oncology and Palliative Care teams resulting in reduced LOS and fewer deaths in hospital in keeping with the agenda of the End of Life Care Strategy [(End of Life Care Strategy: Promoting high quality care for all adults at the end of life (July 2008). DOH (England).]. [Table: see text]
cMet: Results in papillary renal cell carcinoma of a phase I study of AZD6094/volitinib leading to a phase 2 clinical trial with AZD6094/volitinib in patients with advanced papillary renal cell cancer (PRCC).
Authors: Hui Kong Gan, Jason Lickliter, Michael Millward, Yi Gu, SU Weiguo, Chuan Qi, Hua MU, Melanie Frigault, Shethah Morgan, Humphrey Athelstan Gardner, Laurence Albiges, Sumanta Kumar Pal, Howard A. Burris, Toni K. Choueiri
Journal: Journal of Clinical Oncology (2015)

487 Background: Met is a receptor tyrosine kinase that is deregulated across multiple cancer types, leading to uncontrolled tumor cell growth, invasion and survival. MET is frequently dysregulated in PRCC. Activating Met mutations are present in hereditary and a subset of sporadic PRCC cases (up to 21% of type I PRCC, Albiges et al, 2014). Trisomy of chromosome 7 (containing both MET and HGF genes) has been reported in 45-75% of sporadic PRCC cases; 81% of type I and 46% of type II PRCC have copy number alterations of MET (Albiges et al, 2014). Methods: AZD6094 (HMPL-504/volitinib) is a potent, selective Met inhibitor. Preclinically, AZD6094 inhibits in vitro growth of MET-amplified gastric and lung cell lines. In vivo AZD6094 induces regressions in PRCC explant models. Results: In phase I, AZD6094 was well tolerated, with good exposure and low accumulation (Gan et al, 2014). Two PRCC pts in the 600 mg QD cohort (one with ongoing treatment at 19 months) and 1 PRCC in the 1,000 mg QD cohort (ongoing treatment at 13 months) achieved PR. A fourth patient, on 300 mg BD, showed a best tumor response of 25% decrease from baseline. Analysis of tumor samples showed that all the responders had MET copy number increase. Conclusions: These encouraging findings have triggered a phase II trial. This is an open label non-randomised multi-centre study to assess the efficacy of AZD6094 monotherapy in treatment naive and previously treated PRCC patients. Eligibility includes PRCC histopathology, ECOG status 0 or 1, ability to comply with the collection of tumor samples, adequate haematological, liver, and kidney function, and measurable disease (RECIST 1.1). The study is ongoing in collaboration with Sarah Cannon Research Institute in the United States, Canadian, EU centres. This study is sponsored by AstraZeneca, clinical trial information: NCT02127710. Clinical trial information: NCT01773018.