tbuckley/cabot-search huggingface dataset:
High-resolution melting analysis (HRMA) for KRAS mutational study in patients with metastatic colorectal cancer (mCRC pts).
Authors: Alfonso De Stefano, Umberto Malapelle, Chiara Carlomagno, Roberto Bianco, Roberta Marciano, Carolina Cimminiello, Maria Colantuoni, Sabino De Placido, Giancarlo Troncone
Journal: Journal of Clinical Oncology (2012)

515 Background: The use of anti EGFR monoclonal antibodies cetuximab and panitumumab is restricted to KRAS wild-type (WT) mCRC pts. Standard method for KRAS testing is direct sequencing. To overcome its limited sensitivity, novel techniques have been developed. However there is little concordance on the clinical significance of more sensitive tests. HRMA is very sensitive and economic and allows rapid detection of DNA sequence variations based on specific sequence-related melting profile. Here we report the evaluation of therapeutic effects of cetuximab in direct sequencing tested WT pts, according to their HRMA mutational status. Methods: We retrospectively evaluated 50 (35 males, 15 females) mCRC pts with WT KRAS status by direct sequencing. Median age was 61 years (range 29 – 77). Most (40%) pts had liver metastases and 24% had multi-organ disease. They received second- or third-line cetuximab-containing chemotherapy, with irinotecan (n=25) or with combination regimen (22 FOLFIRI and 3 FOLFOX). Twenty-eight pts were treated in second-line and 22 in third-line. KRAS mutation status was reassessed in all pts using HRMA. Results: All 50 pts were evaluated for tumor response, PFS and OS. In 4 (8%) pts, KRAS mutations were only identified by HRMA. The response rate of HRMA KRAS WT pts was 28.3%, with 1 complete (2.2%) and 12 partial (26.1%). No response was observed in HRMA KRAS MT (3/4 with a progression as best response). Stable disease rates were 30.4% (14/46 pts) and 25% (1/4 pts) in HRMA WT and MT cases respectively. Disease control rate (objective responses plus stable disease) was 58.7% in HRMA KRAS WT pts and 25% in HRMA KRAS MT. No significant correlation was found between HRMA-KRAS status and response rate (p=0.287) or disease control rate (p=0.219). However, median PFS (5.1 versus 2.5 months; HR=0.34, p=0.04) and median OS (11.3 versus 3.2 months; HR=0.11, p=0.03) were significantly longer for HRMA KRAS WT pts compared to HRMA KRAS MT. Conclusions: These data show a significant difference in clinical outcome between HRMA KRAS WT and MT pts receiving a cetuximab-containing second- or third-line treatment, suggesting that techniques more sensitive than direct sequencing could better select pts for cetuximab-based treatment.
A restrospective analysis of toxicities encountered with palliative epirubicin, oxaliplatin, and capecitabine (EOX) chemotherapy for advanced esophagogastric cancer.
Authors: Shelize Sadrudin Khakoo, Alexandros Georgiou, Justin S. Waters
Journal: Journal of Clinical Oncology (2014)

162 Background: Palliative chemotherapy for advanced gastric and gastro-oesophageal junctional (GEJ) carcinoma improves tumour related symptoms and overall survival compared to best supportive care alone. EOX has been established as one of the most effective regimens in randomised clinical trials, but produced significant toxicity. We wished to examine the tolerability of EOX in everyday practice. Methods: A retrospective search was conducted to identify patients with advanced gastric or GEJ cancer, treated at our institution with at least one cycle of first line palliative EOX between 2009 and 2012. Patient baseline characteristics, toxicities (graded according to CTCAEv.4), dose reductions, treatment interruptions and discontinuations were analysed. Results: We identified 60 patients, 83% were male, and the median age was 64 years (age range18-82 years). 85% had a baseline performance status (PS) of 1, 10% PS of 2 and 5% PS of 0. 75% had GEJ cancer and the remainder had gastric cancer. 82% were commenced on standard EOX (1250mg/m 2 capecitabine, 130mg/m 2 oxaliplatin and 50mg/m 2 ). 80% of patients experienced grade 3 or worse toxicity. 27% discontinued treatment due to excessive toxicity and 37% due to progressive disease. Significant toxicities (at least grade 3) were: 28% neutropenia, 27% diarrhoea, 23% fatigue, 10% vomiting, 10% anaemia, 8% neutropenic sepsis, 8% nausea, 5% thrombocytopenia, 5% peripheral neuropathy, 3% mucositis and 3% chest pain. 47% of patients required a dose reduction of at least 1 drug. 66% of patients completed 3 cycles, 35% completed 6 cycles and 18% completed 8 cycles. The mean progression free survival for patients completing 8 cycles was 4.6 months. Conclusions: EOX improves tumour related symptoms and overall survival but the benefits are often short-lived and in some patients it is associated with unacceptable toxicity, given their limited life expectancy. More thought needs to be given to prophylactic measures and modification of the EOX regimen to improve tolerability without compromising efficacy.
Phase II trial evaluating addition of fulvestrant to erlotinib in patients with stage IIIb/IV non-small cell lung cancer (NSCLC) who are stable on erlotinib and exhibit immunohistochemical (IHC) or PCR positivity for estrogen or progesterone receptor (PR).
Authors: L. Bazhenova, R. Quintana, R. H. Hastings, K. Messer
Journal: Journal of Clinical Oncology (2010)

TPS294 Background: In NSCLCestrogen receptors (ER) α and β are expressed independent of sex and histology. Estrogen regulates gene expression and promotes growth of NSCLC cell lines and tumor xenografts. Epidermal growth factor receptor (EGFR) and ER pathways share and interact through downstream signaling molecules. Activation of EGFR results in phosphorylation of ERα via MAPK and ERK. In cell lines and xenographic models, the combination of an ER antagonist fulvestrant and an EGFR inhibitor gefitinib is additive in decreasing growth. This trial will determine a progression-free survival (PFS) rate of ER or PR positive NSCLC patients who are stable after 2 months of erlotinib monotherapy, and receiving fulvestrant + erlotinib. Methods: This is a single center, open-label, single-arm study. Eligible patients have measurable, stable disease as described, and ER a, ERb, and/or PR-positive tumors determined by IHC and PCR on paraffin-embedded tissue. Fulvestrant is added to daily eroltinib at 500 mg, based on pharmacokinetic studies in breast cancer, followed by two QOW doses of 250 mg, followed by 250 mg monthly till progression. Response is determined by RECIST every 8 weeks. Our hypothesis is that the combination of fulvestrant and erlotinib will increase PFS rate over historical efficacy of erlotinib alone. The sample size of 30 patients is based on a two- stage design incorporating stopping rules for lack of efficacy and toxicity with significance level 10% and power 85%. The study is powered to detect an improvement in PFS rate at 14 weeks from the start of fulvestrant from 50% to 73%. 27 patients were screened, 3 enrolled. 15 of 27 had ER and PR status measured (13 by IHC and 14 by PCR). By IHC ERα was positive in 9, ERβ in 3 pts, PR in 1. All 3 were negative in 3. By PCR ERα was positive in 5, ERβ in 12, PR in 3, all negative in 1 pt. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca
Response to erlotinib after failure of gefitinib in non-small cell lung cancer with EGFR mutation
Authors: H. Kim, Y. Kim, S. Oh, M. Seo, S. Lee, D. Kim, D. Heo
Journal: Journal of Clinical Oncology (2008)

19072 Background: Non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutation show excellent response to gefitinib, but eventually develop resistance. The selection of subsequent treatment has yet to be defined. We retrospectively analyzed the efficacy of erlotinib in non-small cell lung cancer with EGFR mutation after failure of gefitinib. Methods: We have identified 10 patients with advanced NSCLC who had documented EGFR mutation and were treated with erlotinib after failure of gefitinib at Seoul National University Hospital between 2002 and 2007. Clinical characteristics and response to erlotinib was analyzed. EGFR mutations (exon 18 to 21) were studied by direct DNA sequencing. Results: Of the 10 patients with EGFR mutation (exon 19 deletion: L858R: G719 = 4: 5: 1), the median age was 55 years (range, 39–67), 7 (70%) were female and 8 (80%) were never-smoker. All patients had adenocarcinoma except for 1 patient with adenosquamous carcinoma. Nine patients had initial disease control with gefitinib and median time to progression for gefitinib was 8.3 months (95% CI 5.41–11.19). Five of the patients received cytotoxic chemotherapy after failure of gefitinib before receiving erlotinib. At the time of starting erlotinib, major site of disease progression to previous treatment was leptomeninges in 5 (50%, combined with brain metastasis in 2), lung in 3 (30%) and bone in 2 (20%). There were 1 complete response, 1 partial response, 5 stable disease to erlotinib yielding a disease control rate of 70%. All patients with leptomeningeal carcinomatosis showed disease control with erlotinib. With a median follow-up of 19.5 months, the median time to progression for erlotinib was 4.1 months (95% CI 2.06–6.14) and median overall survival was 8.5 months (95% CI 1.68–15.31). Conclusions: Treatment with erlotinib after failure of gefitinib in advanced non-small cell lung cancer patients with EGFR mutations might be a reasonable bridging treatment. Apparently high incidence of leptomeningeal failure with gefitinib and high disease control rate with erlotinib in these patients warrants further investigation. No significant financial relationships to disclose.
Adjuvant chemotherapy for colorectal cancer in the over 75 age group: A 10-year experience.
Authors: R. M. Bambury, N. H. Coleman, M. M. Tharmabala, D. Gough, W. Grogan, O. S. Breathnach
Journal: Journal of Clinical Oncology (2010)

3605 Background: One third of patients diagnosed with colorectal cancer in Ireland are over 75 years of age at diagnosis. Colorectal cancer is the most frequently diagnosed malignancy and the second leading cause of cancer death in this age group. Adjuvant 5-fluorouracil (5-FU) based chemotherapy for stage III and selected stage II patients with colorectal cancer has been shown to decrease mortality. Retrospective analyses suggest that this survival benefit is maintained in elderly patients. However, many elderly patients do not receive adjuvant chemotherapy because its tolerability in this population in the community setting is uncertain. Methods: In a retrospective analysis of colorectal cancer cases in our hospital we assessed adjuvant chemotherapy use, tolerability and survival outcomes in the over 75 age group in the Irish community setting. Results: 175 patients aged 75 or over were diagnosed with Stage II (n=112) or III (n=63) colorectal cancer between 2000 and 2009 in our hospital. 29% of stage III and 6% of stage II patients received adjuvant chemotherapy. Patients aged ≥80 were less likely to receive chemotherapy when compared with patients aged 75- 79 (5% vs. 25% p < 0.005). In total 34 patients received adjuvant chemotherapy. Age ranged from 75 to 82 years. Mean age was 77. Where recorded, ECOG performance status was 0 or 1 in all patients. 91% of patients were prescribed the 6 month Roswell Park regimen (weekly 5-FU/leucovorin for 4-6 weeks followed by a 2 week break). 53% completed chemotherapy at full dose. 74% received >85% of the planned dose. The main reason for early discontinuation of treatment was gastrointestinal toxicity. 25% of patients required hospital admission while on chemotherapy. There were no chemotherapy related deaths. After a median follow-up of 5 years 50% of patients remain alive. Conclusions: A recent review of the colon cancer cases in the USA SEER database reported that 33% of stage III patients in the over-75 age group received adjuvant chemotherapy. Our data shows a similar treatment rate. Chemotherapy was reasonably well tolerated in our cohort of very elderly patients. Biological age alone should not be considered a contraindication to adjuvant chemotherapy. No significant financial relationships to disclose.
Updated results of a phase I study of pasireotide (SOM230) in combination with everolimus (RAD001) in patients (pts) with advanced neuroendocrine tumors (NET).
Authors: J. A. Chan, D. P. Ryan, C. S. Fuchs, A. X. Zhu, T. A. Abrams, B. M. Wolpin, P. Malinowski, E. Regan, M. Kulke
Journal: Journal of Clinical Oncology (2011)

4120 Background: Octreotide and the mTOR inhibitor everolimus have antitumor activity in NETs. Pasireotide is a novel somatostatin analog with binding affinity to a broader range of somatostatin receptor subtypes than octreotide. We performed a phase I study to evaluate safety and feasibility of combining pasireotide and everolimus in patients with advanced NETs. Methods: Pts received escalating doses of pasireotide and everolimus. Treatment was continued until tumor progression, unacceptable toxicity, or withdrawal of consent. Dose-limiting toxicity (DLT) was defined within the first 56 days of therapy. Results: Among 22 enrolled pts, 21 were evaluable for toxicity. Enrolled pts had the following characteristics: M:F = 14:8; median age 60 (range 35-76); ECOG PS 0/1/2 = 16/5/1; carcinoid/pancreatic NET = 18/4. Pts received a median of 4 cycles of treatment (range 1-26). No pts at dose level (DL) 1 and DL 2 experienced DLT. DLT was experienced by 1 pt at DL 3 (gr 3 rash) and 1 pt at DL 4 (gr 3 diarrhea). Dose escalation was halted at DL 4 to further assess safety and toxicity at DL 3; no further DLT was observed in 6 additional patients treated at DL3. Other gr 3 or higher treatment-related adverse events across all cycles included hyperglycemia (n=1 at DL1, 1 at DL2, 4 at DL3, 2 at DL4), hypophosphatemia (n=4; 1 at each DL), thrombocytopenia (n=2 at DL3, 1 at DL4), lymphopenia (n=1 at DL1, 1 at DL3), elevated alkaline phosphatase (n=1 at DL2, 1 at DL3), mucositis (n=1 at DL3), prolonged QTc (n=1 at DL3), and joint pain (n=1 at DL4). Independently-reviewed best objective responses in 21 evaluable pts revealed partial response in 1 pt, stable disease in 19 pts, and progressive disease in 1 pt. Conclusions: Combination therapy with pasireotide and everolimus is safe and feasible and is associated with preliminary evidence of antitumor activity in NET. Pasireotide 60 mg IM monthly combined with everolimus 10 mg daily should be further investigated in future NET studies. Dose level No. of evaluable pts Pasireotide sc (mcg, twice daily, days 1-42) Pasireotide LAR, intramuscularly (mg, day 29 and q 4 weeks thereafter) Everolimus (mg, daily beginning day 1) 1 3 600 40 5 2 3 900 60 5 3 6 + 6 900 60 10 4 3 1,200 80 10
A retrospective comparison study of docetaxel and paclitaxel for patients with advanced or recurrent esophageal cancer who previously received fluoropyrimidine and platinum-based chemotherapy.
Authors: Tsuyoshi Shirakawa, Ken Kato, Naoki Takahashi, Hirokazu Shoji, Tetsuji Terazawa, Yoshitaka Honma, Satoru Iwasa, Atsuo Takashima, Natsuko Okita, Tetsuya Hamaguchi, Yasuhide Yamada, Yasuhiro Shimada
Journal: Journal of Clinical Oncology (2013)

112 Background: Fluoropyrimidine plus platinum (FP)-based chemotherapy has been widely used as a first-line regimen for advanced or recurrent esophageal cancer (EC). Although the taxanes have shown efficacy in esophageal cancer after FP-based chemotherapy, there is no standard regimen for second-line chemotherapy (SLC). We conducted a retrospective study to investigate the clinical features of taxane therapy in SLC of EC. Methods: The selection criteria were pathologically proven EC; advanced or recurrent disease that had previously been treated with FP at our hospital; performance status 0-2; and adequate organ functions. The FP regimens used included 5-FU or S-1 and cisplatin or nedaplatin. Docetaxel (DTX) was administerd at 70mg/m2 triweekly for 6 weeks with 1 week’s rest. Paclitaxel (PTX) was administered at 100mg/m2 weekly with the same schedule. Overall survival of PTX was compared to DTX with baseline prognostic factors adjusted, using Cox proportional hazard model. Results: The analysis covered 110 patients over the period from August 2006 to June 2012. The median age was 64 years (range 39-83); 97 males and 13 females; 108 squamous cell carcinomas and 2 adenocarcinomas; 34 advanced and 76 recurrent; cStage I/II/III/IV at diagnosis 8/21/49/32; PS 0/1/2 score 20/81/9; DTX treatment 82 patients and PTX treatment 28. Progression-free survival and overall survival were 2.3 &amp; 6.1 months with PTX and 2.8 and 6.9 months with DTX (no significant difference). The response rates were PTX/DTX/Total 11.1%/3.7%/5.5%. Hazard ratio of overall survival between DTX and PTX was 1.054 with adjusted by PS, sex and number of metastasis. The rate of grade 3-4 neutropenia was higher with DTX (28%) than with PTX (7%). Grade 3 febrile neutropenia was seen in 3.7% of DTX-treated patients but in no PTX patients. Grade 2 or more fatigue was seen in 16% of DTX patients and 10% of PTX ones, and grade 2 or more neuropathy was seen in 1.2% of DTX patients and 32% of PTX ones. Conclusions: PTX and DTX were both effective in SLC of EC, but the toxicity profiles of the two regimens differed. In terms of febrile neutropenia or fatigue, PTX seems more appropriate for SLC of EC.
Combination of paclitaxel, cisplatin, and fluorouracil in patients with advanced and metastatic gastric cancer as first- or second-line therapy: A multicenter prospective study.
Authors: X. Zhang, S. Yongqian, F. Zhang, J. Liang, X. Ma, L. Chen, J. J. Huang, G. Shi, W. Cao, L. Shen, M. Jin
Journal: Journal of Clinical Oncology (2011)

e14561 Background: We conducted this multicenter prospective study to evaluate the efficacy, toxicity, and feasibility of PCF (paclitaxel, cisplatin [DDP] and fluoruouracil [5-FU]) regimen as first-line and the second-line therapy in patients with advanced gastric cancer (AGC, locally advanced unresectable and metastatic gastric adenocarcinoma) in China. Methods: The patients with histologically confirmed AGC were treated with Paclitaxel 150 mg/m2 introvenously on day 1; DDP 15 mg/m2 introvenously on days 1-5 and 5-FU 600mg/m2/day continuously intravenous infusion on days 1-5 every 3 weeks until disease progression or unacceptable toxicities. Results: Between June 2005 and Sep 2007, a total of 75 patients were treated with the combination: 41 patients as first-line therapy (group A) and 34 patients second-line (group B) with the median age of 59 years old and performance status of KPS ≥ 90. Toxicities were analized in all enrolled 75 patients. Sixty seven patients were evaluable for efficacy. The median overall survival (mOS) were 14.2 months (95% CI, 8.2-20.2 months) in the group A and 9.2 months (95% CI, 5-13.4 months) in the group B. The median progression-free survival (mPFS) in two groups were 5.3 months (95% CI, 4-6.6 months) and 4.7 months (95% CI, 4-5.3 months) respectively. The total response rate of all patients was 32.4% (23/71). The response rates of the two groups were 40% (16/40) and 22.6% (7/31) respectively. Major grade 3 or 4 adverse events include neutropaenic 41.3%, febrile neutropenia 9.3%, nausea/anorexia 10.7%, and vomiting 5.3% . There was no treatment-related deaths. Conclusions: The combination of paclitxel, lower doses of cisplatin and 5-FU (PCF) is active and tolerable as a first-line therapy and second-line for patients with AGC.
VeriStrat predicts survival in patients with non-small cell lung cancer (NSCLC) treated with erlotinib and bevacizumab
Authors: J. S. Salmon, T. P. Dang, D. Billheimer, H. Roder, J. Grigorieva, M. Tsypin, R. S. Herbst, A. S. Tsao, H. Tran, D. P. Carbone
Journal: Journal of Clinical Oncology (2008)

8008 Background: We previously developed a serum Matrix-Assisted Laser Desorption/Ionization- Time of Flight Mass Spectrometry (MALDI-TOF MS) proteomic algorithm (VeriStrat) that can reliably predict survival outcome in patients treated with erlotinib or gefitinib (Taguchi, JNCI 2007). We wanted to determine if the VeriStrat model could also also identify those patients with improved time to progression and overall survival in a separate data set of NSCLC patients treated with the combination of erlotinib plus bevacizumab on a Phase I/II multicenter study (Herbst, et al JCO 2005). Methods: Pretreatment serum was available for 35 of 40 patients with advanced NSCLC treated with bevacizumab and erlotinib. MALDI-TOF mass spectra were obtained with a Voyager-DE STR instrument (PerSeptive Biosystems) and the raw spectra were calibrated, corrected for baseline, and normalized prior to analysis. Results: The reproducibility and variability were tested in total of 276 spectra from 35 patient samples. Of these, 26 patients were classified as having a “good” outcome and 9 were classified as “bad”. We found that VeriStrat accurately predicts both OS and PFS when applied in a blinded fashion to this cohort of patients using the log-rank test (p=0.004 and p=0.003, respectively). Conclusions: MALDI-TOF MS proteomic analysis of pretreatment serum was able to identify protein/peptide expression patterns that independently predicted survival in patients treated with erlotinib with or without bevacizumab, confirming our the previously published results and extending them to patients treated with erlotinib and bevacizumab. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Biodesix Biodesix Biodesix
Effect of diferuloyl methane (curcumin) on radiation-induced inhibition of proliferation and cytotoxicity of pancreatic cancer cells.
Authors: R. Tuli, A. Surmak, J. M. Herman
Journal: Journal of Clinical Oncology (2011)

222 Background: Pancreatic ductal adenocarcinoma carries a dismal prognosis. Unfortunately, the majority of patients present with locally advanced or metastatic disease unamenable to resection, and the benefit of radiation therapy (RT) in this population is not well substantiated. Diferuloyl methane (curcumin) is a naturally occurring polyphenol derived from the spice turmeric. Although it has been shown to have anticancer properties, it has not been well studied with radiation, particularly for pancreatic cancer. Herein, we attempt to determine whether curcumin can sensitize pancreatic cancer cells to radiation. Methods: The pancreatic carcinoma cell lines, MiaPaCa-2 and Panc02, were utilized for studies. Cells were treated with curcumin (10 nM to 1 mM), RT (1 to 9 Gy), or combinations thereof and compared to untreated controls. Cells were irradiated using a 137-Cs GammaCell in a single fraction. If applicable, cells were pretreated with curcumin one hour prior to RT. Cell viability was assessed through reduction of resazurin into fluorescent resorufin. Levels of apoptosis were determined by measuring caspase-3 and -7 activities using a luminescent assay. Results: Treatment with curcumin alone led to minimal inhibition of proliferation until concentrations exceeded 10 uM. The half maximal inhibitory concentration (IC50) was 40 uM and the IC20 was 10 uM. Cells experienced a dose- dependent inhibition of proliferation with increasing RT doses (IC20 of 5 Gy). Combined treatment with IC20 of curcumin and RT led to a synergistic increase in inhibition of proliferation (70%). The RT dose enhancement factor was 2.5 with 100 uM curcumin and 5 Gy. Caspase 3/7 activity was not significantly enhanced by treatment with curcumin alone (10 uM), but increased significantly when RT was added (5 Gy; p&lt;.01). Conclusions: Curcumin is a potent radiosensitizer of pancreatic cancer cells that synergistically enhances the effects of RT. It has minimal effects on proliferation and apoptosis when used as a single agent at lower doses. Curcumin also potentiates RT-induced cytotoxicity through induction of apoptosis. These data are currently being validated in an orthotopic pancreatic cancer model. No significant financial relationships to disclose.