bluuebunny/crossref_metadata_2025 huggingface dataset:
Distance-to-care: Stage at diagnosis for New Mexico (NM) residents with colorectal cancer (CRC).
Authors: Mason Meredith C. , Bruner Andrew , Meisner Angela W. , Morris Katherine T. , Nir Itzhak , Rajput Ashwani , Wiggins Charles
Published: February 2017

421

Background: CRC is a leading cause of morbidity and mortality among NM’s American Indians, Hispanics, and non-Hispanic whites. Previous studies have shown that rural residents are more likely than urban dwellers to be diagnosed with late stage disease. Geographically New Mexico is the 5th largest state with a population of 2 million, many of whom reside in rural regions. This study was designed to characterize the association between distance-to-care and stage of disease at diagnosis in NM.

Methods: The population-based NM Tumor Registry was used to identify records for all incident cases of CRC between 2001-2008. Latitude and longitude were determined for the place of residence for cancer cases and for the facility where each case was diagnosed. The “Great Circles” algorithm was used to estimate the distance from place of residence to the diagnosing facility. The percentage of cases diagnosed with early stage vs. other stages (i.e., regional, distant, and unknown stages-combined) was assessed by quartile of distance-to-care with the use of the chi-squared test for trend. Multiple logistic regression was used to characterize the association between stage and quartile of distance-to-care while controlling for other factors know to be associated with stage at diagnosis.

Results: Analysis was based on 6,291 incident cases of CRC that were diagnosed among NM residents. Latitude and longitude for both place of residence at diagnosis and location of diagnosing facility were available for 4,385 (69.7%) of all incident cases. The percentage of cases diagnosed at early stage was inversely related to the distance between the place of residence at diagnosis and the facility where the cancer was diagnosed, as follows: 41.4% of cases in Quartile 1 (shortest distance-to-care); 39.9% in Quartile 2; 37.8% in Quartile 3; and 35.3% in Quartile 4 (p=0.002).By multiple logistic regression, distance-to-care was a significant predictor of stage at diagnosis after adjustment of sex, age and race/ethnicity.

Conclusions: Rural residents of NM who must travel relatively long distances to receive medical care are at increased risk of being diagnosed at late stage colorectal cancer.
Is PET/CT useful in the staging of anal cancer?
Authors: Bhuva Neel , Glynne-Jones Robert , Harrison Mark
Published: February 2017

422

Background: The use of 18flurodeoxyglucose PET or PET/CT in staging of anal cancer is becoming increasingly fashionable. However, evidence endorsing it as a definitive staging modality it is still emerging. The largest published series to date from the UK found sensitivity of PET to be superior for detection of regional nodal metastases and overall PET changed stage in 23% and management in 16% of cases [de Winton E et al. The impact of 18-fluorodeoxyglucose positron emission tomography on the staging, management and outcome of anal cancer. BJR 2009; 100: 693-700]. We initially performed a retrospective pilot feasibility study for the period 2009-2010 and found that PET/CT altered staging in 42% of the 43 patients included, predominantly upstaging nodal status. We continue our analysis and report this prospective series - to assess the usefulness of PET/CT in the staging of anal cancer.

Methods: 47 patients were treated radically for anal cancer at Mount Vernon Cancer Centre (UK) between January 2010 and July 2011, of which 27 had PET/CT scans. Staging was compared following conventional modalities and PET/CT. The TNM clinical staging system was used.

Results: In 9 patients the PET/CT stage differed from MRI staging. In total, there were 4 ‘T stage’ changes and 8 ‘N stage’ changes. Of these, 1 case showed a difference in ‘T’ staging alone 5 showed a change in ‘N’ staging alone and 3 showed a change in ‘T’ and ‘N’ staging. PET/CT altered staging in 33% of patients.

Conclusions: We conclude that PET/CT alters staging in a significant number of cases correlating with the literature and our own retrospective analysis. Furthermore there is agreement that PET/CT shows greater sensitivity for detection of lymph nodes. Although PET/CT cannot replace CT/MRI as the optimal modality for planning, it can reveal useful information regarding tumour extent, nodal involvement and distal metastases. PET/CT can account for greater definition of dose delivery, and more accurately ascertain the need to include/exclude pelvic lymph nodes. With more precise staging, acute and late toxicity profiles will be greatly influenced, especially with more advanced radiotherapy techniques such as Intensity Modulated Radiotherapy (IMRT), whilst maintaining satisfactory outcomes.
Measurements of 5-FU levels in plasma of patients with gastrointestinal cancer.
Authors: Blaschke Martina , Cameron Silke , Blumberg Jutta , Wegner Ulrike , Ramadori Giuliano
Published: February 2017

437

Background: 5-fluorouracil (5-FU) 50 years after its first introduction into therapy of gastrointestinal tumors is still one of the most effective anticancer drugs. Due to large interindividual metabolism optimal dosing has not yet been established. As 5-FU is mostly used in combination with other drugs elevated serum levels could be responsible for severe side effects. The aim of this study was to analyse intra- and interindividual variability of 5-FU levels in patients with 5-FU infusional therapy.

Methods: 230 blood samples were obtained from 31 gastrointestinal cancer patients (esophagus (8), stomach (10), ileum (1), colorectum (12)) treated with 5-FU-infusional regimens, based on a 24 or 48 hour AIO treatment schedule. 5-FU was delivered using a Baxter pump. Intra- and interindividual differences in 5-FU plasma concentrations were analysed before (0h; n=115), at 2-3 hours after start of infusional 5-FU treatment (n=19) (early sampling) and towards the end of the infusion (n=96) (late sampling). 5-FU plasma concentrations were measured using an immunolinked Elisa assay (Saladax 5-FU PCM).

Results: Early blood sampling resulted in lower 5-FU plasma concentrations (541±126,9 ng/ml) due to NaCl prefilling (4,5 ml) of the 5-FU tubing, as the Baxter pump delivers 4ml/h. Blood sampling at the later time-point resulted in reliable values (971±81,1 ng/ml). 5-FU concentrations did increase with elevated 5-FU doses. Measurements of 5-FU plasma concentrations lead to reproducible results. 5-FU concentrations were dose-dependent with low intra- and interindividual variability. However, care has to be taken, as the results can be influenced by inaccurate blood sampling (e.g at the port), early blood sampling (steady state-levels not reached), too late sampling (folfusor-pump already empty, i.e. in summer with elevated temperature), delayed centrifugation or hemolysis. Critical analysis of the measurements and correct performance of the sampling is therefore necessary.

Conclusions: Measurement of 5-FU plasma concentrations may in the future allow to optimize the 5-FU dosing and to identify the cause of toxicity. Changes of 5-FU clearance in long-term therapy have to be studied.
Obturator canal lymph node metastasis from rectal carcinoid tumor.
Authors: Wang Yi-Zarn , Hall Michael Anthony
Published: February 2017

440

Background: The optimal treatment option for rectal carcinoid tumor remains unsettled. Trans-anal excision has been accepted for small tumors (< 1-2 cm in size) without lymph node involvement. Larger tumors, and those with lymph node metastasis, however, are usually treated via low anterior resection (LAR) with total mesorectal excision (TME). Midgut carcinoid tumors have been found to have the tendency to obstruct lymphatic flow and create a detour in lymphatic passage. We hypothesize that rectal carcinoid may have similar potential to develop alternative lymphatic pathways outside of the mesorectal envelope, thus escaping surgical removal with traditional TME.

Methods: A retrospective chart review of rectal carcinoid patients who underwent radical LAR with TME between 2006 and 2011 was conducted to determine if any extra-mesorectal metastasis had occurred.

Results: 19 patients who underwent LAR with TME for rectal carcinoid were identified. 14 patients had radio-guided surgery (RGS). 12 of which, were injected with TC-99 intra-operatively and 2 had a preoperative injection of In-111 for octreotide scan. 6 of the 19 patients (31.5%) were found to have obturator canal lymph node metastasis, confirmed by final pathologic review. 5 of these 6 patients had the nodal metastasis to the right obturator canal. Of note, 4 of the 6 patients complained of debilitating foot and medial thigh pain on the affected side, with complete symptom resolution after surgical excision.

Conclusions: Up to 31.5% of rectal carcinoid patients can have extra-mesorectal lymph node metastasis that could easily be missed by the traditional TME. Preoperative octreotide scanning with In-111 injection or intra-operative Tc-99 peri-tumor injection, with concomitant RGS can easily identify and remove such metastasis. Symptomatic improvement can be accomplished with its removal. The effect of such extra-mesorectal metastasis on patients’ long term or disease free survival is yet to be determined.
KRAS mutation as a prognostic factor in patients undergoing hepatic resection for metastatic colorectal cancer.
Authors: Baker Justin John , Aufforth Rachel , Auman James Todd , Eil Robert , McLeod Howard L. , Kim Hong Jin , Meyers Michael O. , Calvo Benjamin F. , Yeh Jen Jen
Published: February 2017

444

Background: It is well known that KRAS mutations limit the efficacy of anti-EGFR therapy in patients with metastatic colorectal cancer (mCRC). However the role of KRAS mutations in patients who undergo a curative liver resection for mCRC is less clear. The purpose of our study was to evaluate the relationship between KRAS mutation status and survival in this patient population.

Methods: We examined an IRB approved tissue repository and retrospective database of 129 patients from 1998-2010 who underwent curative liver resection for mCRC. Tumors were sequenced for KRAS codons 12, 13, and 61 mutations using pyrosequencing. Overall survival (OS) and disease-free survival (DFS) were analyzed using the Kaplan-Meier method and compared using the log-rank test. Multivariate analysis was performed using the Cox proportional hazards regression method.

Results: The median follow-up for our cohort was 20.4mo (0.4-112). Mean age was 61.4±12.3. Prior to surgical resection 55 (43%) patients received chemotherapy. 35 (27%) tumors were KRAS mutant (mt), 83 (64%) were wild-type (wt), and 11 (9%) were not characterized. Median OS for KRAS wt patients was 40.3mo vs. 27.1mo for KRAS mt patients (p=0.046). Median DFS for KRAS wt was 13.6mo vs. 7.7mo for KRAS mt patients (p=0.037). 8 patients received cetuximab post–operatively. Cetuximab status was unknown in 50 patients. When we excluded those treated with cetuximab, the median OS was 40mo for KRAS wt vs. 25mo for KRAS mt patients (p=0.007). There were no differences in OS or DFS in patients who received cetuximab (p=0.7). In a multivariable model with pre-operative chemotherapy (p=0.2), extent of resection (p=0.053), and cetuximab therapy (p=0.7), the presence of KRAS mutation was independently associated with poor prognosis (HR=2.7 [1.3-5.5]).

Conclusions: In patients undergoing curative liver resection for mCRC, KRAS mutation status is independently predictive of a worse outcome regardless of cetuximab therapy. KRAS status may be associated with more aggressive tumor biology. Our data supports the critical need to define KRAS mutation status and to develop therapies against KRAS and its downstream effectors.
Use of FoxP3+ and cytotoxic CD8+ T lymphocytes to identify a patient subgroup with a favorable prognosis similar to colon cancers with deficient DNA mismatch (dMMR) repair.
Authors: Yoon Harry H. , Orrock Jared M , Foster Nathan R. , Sargent Daniel J. , Smyrk Thomas C. , Sinicrope Frank
Published: February 2017

460

Background: The immune response has emerged as a strong prognostic factor in colon cancer. Whereas CD8+ T cells mediate antitumor response, regulatory T cells expressing FoxP3+ can antagonize this effect, though prognostic data conflict. These markers have yet to be analyzed with MMR status, which is important since dMMR tumors show enhanced immune response.

Methods: CD8+ and FoxP3+ density were analyzed by immunohistochemistry (IHC) in resected stage II and III colon carcinomas (N = 216) from participants in phase III adjuvant 5-fluorouracil-based trials. High vs low immune density was dichotomized at the median. MMR status, determined by IHC or analysis of microsatellite instability, was categorized as dMMR (12%) or proficient MMR (pMMR). Cox models, stratified by study, were adjusted for age, stage, grade and, where noted, MMR.

Results: The association of FoxP3+ density with overall survival (OS) differed by CD8+ density (P for interaction = .040). By multivariable analysis, FoxP3+high was significantly associated with improved OS in CD8+low tumors (hazard ratio 0.43 [95% confidence interval 0.19 – 0.95]; P = .030], but not in CD8+high tumors (P = .91). Results were consistent after MMR adjustment. We then determined their prognostic impact in the larger pMMR subset (N = 119). Tumors with high FoxP3+ were associated with improved OS in cases with low, but not high, CD8+ density ( Table ). These patients (FoxP3+high, CD8+low) had similar 5-year OS rates as 107 dMMR cases from parent studies (89% vs 80%; P = .74), despite having distinct clinicopathologic features.

Conclusions: The prognostic impact of FoxP3+ T cells depends on CD8+, indicating the importance of analyzing both in combination. High FoxP3+ exerts a paradoxically favorable survival impact, but only when CD8+ is low. Survival in pMMR tumors with high FoxP3+ and low CD8+ was similar to that of dMMR tumors, indicating that a favorable pMMR subset can be identified.

[Table: see text]
LMTK3 polymorphism in patients with metastatic colon cancer.
Authors: Loupakis Fotios , Zhang Wu , Gerger Armin , Yang Dongyun , Bohanes Pierre Oliver , Labonte Melissa Janae , Benhaim Leonor , Wakatsuki Takeru , Ning Yan , Wilson Peter M.D. , El-Khoueiry Rita , El-Khoueiry Anthony B. , Iqbal Syma , Barzi Afsaneh , Giamas Georgios , Stebbing Justin , Lenz Heinz-Josef
Published: February 2017

471

Background: LMTKs are a family of serine-threonine-tyrosine kinases. LMTK3 isoform is a potent regulator of estrogen receptor activity LMTK3 gene polymorphisms affect DFS and OS of breast cancer patients. Cumulative evidence implies that estrogen receptor signalling plays a role in colon carcinoma development and progression. We investigated whether the LMTK3 rs9989661 SNP is a prognostic factor in patients with advanced colon cancer.

Methods: 318 patients with metastatic colon cancer treated at the USC/Norris Comprehensive Cancer Center or the LA County/USC Medical Center were included in this study. Genomic DNA was extracted from white blood cells of peripheral blood samples using the QiaAmp kit (Qiagen, Valencia, CA). The LMTK3 polymorphism was genotyped by PCR-RFLP. The association between the LMTK3 polymorphism and overall survival was examined using the log-rank test and multivariate Cox-model.

Results: There were 141 females and 177 males, with a median age of 58 years (range 25-86). The cohort comprised 234 whites, 43 Asians, 15 Blacks, 24 Hispanics, and 2 Native Americans. The median survival was 13.7 months with a median follow-up of 2.3 years. The median overall survival was 16.6 vs. 12.8 months for patients with C/- vs. patients with T/T (HR=0.78; 95% CI: 0.56-1.08; p=0.055). At a multivariate analysis restricted to subjects with left-sided disease (n=126) the median OS for patients with C/- genotype was 23.8 months compared to 14.9 months of T/T patients (HR=0.51; 95%CI: 0.28-0.91; p=0.014).

Conclusions: This study suggests that LMTK3 may be an independent prognostic factor for patients with metastatic colon cancer and raise the issue of possible disparities according to primary tumor location. Our group produced similar results also in the adjuvant setting. Functional correlative preclinical analyses and external clinical validation studies are currently ongoing.
Role of polymorphic fc gamma receptor II/III in the efficacy of cetuximab in KRAS-NRAS-BRAF-PI3K mutated.
Authors: Garcia-Foncillas Jesus , Rodriguez Javier , Boni Valentina , Sola Iosu , Honorato Beatriz , Zarate Ruth , Bandres Eva
Published: February 2017

477

Background: The immunoglobulin G1 (IgG1) monoclonal antibody (MoAb) cetuximab is active in metastatic colorectal cancer (mCRC) as first or subsequent lines of therapy. Efficacy seems restricted to KRAS wild-type tumors. IgG1 may also induce antibody dependent cell mediated citotoxicity (ADCC) by recruitment of immune effector cells. ADCC is influenced by FcγR polymorphisms. We investigated the association of FcγR polymorphisms and disease control rate (DCR) in mCRC patients treated with chemotherapy plus cetuximab.

Methods: Tumor tissues from 106 patients were screened for KRAS codon 12 and 13 mutations using a sensitive multiplex assay (DxS, Manchester. UK). NRAS (codons: 12, 13 and 61), PI3K (exon 20) and BRAF (exon 15) were analysed by direct sequencing. Fcγ RIIa and Fcγ RIIIa polymorphisms were genotyped by TaqMan assays.

Results: DCR was significantly higher in KRAS wild-type tumors (61% vs 39%, p=0.049). In EGFR downstream-mutated mCRC patients, those harbouring a FcγRIIa H/H genotype had a higher DCR than alternative genotypes (67% vs 33%, p=0.017). By multivariate analysis, FcγRIIa-131H/H remained significantly correlated with DCR (p=0.008).

Conclusions: FcγR polymorphisms may play a role in the clinical efficacy of cetuximab in EGFR downstream mutated mCRC patients. Further research into cetuximab immune-based mechanisms in KRAS-mutated patients seems warranted.
Association of the expression of CD133 in locally advanced rectal cancer with tumor regression and survival after neoadjuvant radiochemotherapy.
Authors: Sprenger Thilo , Conradi Lena , Beissbarth Tim , Rüschoff Josef , Ghadimi B. Michael , Rödel Claus , Becker Heinz , Rödel Franz , Liersch Torsten
Published: February 2017

479

Background: CD133 has been described as a stem cell marker in colorectal cancer and is associated with higher tumorigenic potential and resistance to radiochemotherapy (RCT). In this study the expression of CD133 was evaluated in pre-treatment tumor biopsies and corresponding post-treatment surgical specimens of locally advanced rectal cancer patients undergoing multimodal therapy and was correlated to histopathological features and clinical follow-up.

Methods: 97 patients with UICC II/III rectal cancer treated with preoperative 5-FU based RCT within the German Rectal Cancer Trials were investigated. Pre- and post-treatment CD133 expression levels were determined using immunhistochemistry and correlated with histopathologic parameters, tumor regression, tumor recurrence and disease-free survival (DFS).

Results: As compared to pre-treatment biopsies we observed a significantly higher CD133 expression in post-treatment tumor specimens (p=0.01). There was, however, no correlation for both biopsies and tumor specimens between CD133 expression levels, pathological characteristics and survival. In matched analyses of corresponding biopsy/tumor pairs, patients with a decreased number of CD133 positive cells after preoperative RCT showed significantly lower post-treatment tumor stages (p=0.03) and higher histopathological tumor regression (p<0.01). Moreover, these patients had a significantly improved DFS in uni- (p<0.001) and multivariate analyses (p=0.001).

Conclusions: CD133 expression displays a marker with prognostic and monitoring validity in rectal cancer patients. A decrease of the CD133 positive cell fraction in post-treatment tumor tissue is associated with a more favorable outcome after preoperative RCT.
Efficacy of vemurafenib, a selective BRAFV600E inhibitor, in combination with a MEK inhibitor in BRAFV600E colorectal cancer models.
Authors: Higgins Brian , Kolinsky Kenneth Daniel , Yang Hong , Kim Min Jung , Li Jia Kui , Go Zenaida , Packman Kathryn , Bollag Gideon , Su Fei
Published: February 2017

488

Background: BRAF mutations occur in about 10% of colorectal cancer (CRC). Most BRAF mutations involve the V600E amino acid substitution, resulting in constitutive activation of the MAPK signaling pathway. Vemurafenib (RG7204, PLX4032) is a first-in-class, BRAFV600E-specific small molecule inhibitor that dose-dependently inhibits tumor growth in V600E CRC xenografts. However, unlike responses observed in melanoma, single agent vemurafenib in a Phase I extension trial of 20 patients with previously treated metastatic CRC, resulted in only 5% response rate. The goal here was to explore in vitro and in vivo if addition of a MEK inhibitor (MEKi) could increase effects of vemurafenib on anti-proliferation and anti-tumor activity in BRAFV600E CRC cell lines.

Methods: Combo of vemurafenib with a MEKi was tested in MTT assay for antiproliferative effect and combination effect was determined by combination index (CI) calculated by the CalcySyn software. Western analysis and Annexin V staining were utilized to evaluate combo effects on pathway inhibition and apoptosis induction. Optimal doses of both vemurafenib and MEKi were tested as single agent and in combination in the Colo205 and LS411N CRC xenograft models in nude mice.

Results: Synergistic anti-proliferative effect was observed with the combo of vemurafenib and a MEKi in the V600E positive CRC cell lines tested. More effective pathway inhibition and apoptosis induction were observed with combo than either agent alone. Combination of vemurafenib and a MEKi delivered greater anti-tumor activity and increased life span of animals in the Colo205 and LS411N CRC xenograft models.

Conclusions: These in vitro and in vivo data suggest that combined pharmacologic blockade within the RAS/RAF/MEK/ERK pathway is more effective than either agent alone and may be a way to exploit greater antitumor activity CRC patients in clinic.
Cetuximab-related skin toxicity in metastatic colorectal cancer (mCRC) patients and its correlation with molecular markers: Results from the German AIO CRC 0104 trial.
Authors: Stintzing Sebastian , Kapaun Christine , Laubender Ruediger P. , Jung Andreas , Neumann Jens , Modest Dominik Paul , Giessen Clemens Albrecht , Moosmann Nicolas , Wollenberg Andreas , Kirchner Thomas , Heinemann Volker
Published: February 2017

491

Background: Skin toxicity is a frequent adverse event of EGFR targeting agents. The role of cetuximab induced skin toxicity (Cet-ST), for the most acneiform skin rash, as a prognostic or a predictive factor of treatment efficacy is currently under discussion.

Methods: The prognostic and predictive value of Cet-ST in relation to treatment response and survival of patients of a randomized trial investigating CAPIRI plus cetuximab versus CAPOX plus cetuximab as first-line treatment of mCRC was analyzed. Cet-ST was grouped into clinically relevant (grade 2-3) and non relevant (grade 0-1) toxicity (NCI-CTCAE 3.0). KRAS mutations in codons 12 and 13, EGFR-FISH, EGFR-IHC and EGFR intron-1 polymorphism were evaluated in tumor specimens.

Results: A total of 149 patients got cetuximab until the first tumor assessment (6 weeks) and were used for this analysis. Overall response rate was higher in patients with grade 2-3 Cet-ST when compared to grade 0-1 (62.1% vs. 41.3%). Patients without Cet-ST (grade 0) had a short PFS (1.9 months) and OS (11.0 months). PFS (7.8 months vs. 5.2 months) and OS (30.3 months vs. 18.0 months) were longer in patients with Cet-ST grade 2-3 than in patients with grade 0-1 Cet-ST. Almost 90% of Cet-ST occurred during the first two cycles of treatment. When only KRAS codon-12 mutated tumors which are thought not to be sensitive to cetuximab were investigated, Kaplan-Meier differences in PFS and OS times between patients with grade 0-1 Cet-ST and grade 2-3 Cet-ST became statistically significant. In a multivariate analysis, male gender, age and EGFR intron-1 polymorphism were significantly correlated with Cet-ST.

Conclusions: Cetuximab related skin toxicity is a strong predictor of outcome. It is proposed that Cet-ST is rather a prognostic than a predictive factor since this effect is most evident in patients with KRAS codon-12 mutated tumors. EGFR intron-1 polymorphism appears to be a predictor of Cet-ST.
Colorectal cancer (CRC) KRAS mutational status and response to chemotherapy in absence of influence of epidermal growth factor receptor (EGFR) monoclonal antibody (MAb) therapy.
Authors: Yarom Nirit , Boame Nana , Gresham Gillian , Hill David , Jonker Derek J.
Published: February 2017

504

Background: KRAS mutations (MUT), present in ~40% of CRC, predict benefit from EGFR MAb treatment. The effect of mutation status on benefit from chemotherapy alone is less clear.

Methods: Following ethics approval, 223 CRC patients with known KRAS status treated at a single institution were retrospectively analyzed for response to chemotherapy prior to initiation of EGFR MAb therapy. Tumour response rate and progression-free survival (PFS) were determined retrospectively. Given chemotherapy sequencing variability, a measure of the time to chemotherapy-refractory state (TTCR) was defined as time from start of first line therapy to progression on all drugs; ie fluoropyrimidines (F), irinotecan (I), and oxaliplatin (O), +/- bevacizumab (B).

Results: Patients were median age 60 years (25-86), 58/42% male/female, 38% rectal or rectosigmoid, 18% liver-only metastases, 45.6% stage I-III and 54.4% stage IV at initial diagnosis, 43% prior adjuvant chemotherapy, 43/57% KRAS MUT/wild-type(WT) status. With a median follow-up of 27 months, 64 (29%) are alive. TTCR did not vary by KRAS status, with median 16.7 vs 14.8 months in WT vs MUT status patients, respectively, HR 0.85 [0.65-1.12], p=0.26. Overall survival (which now includes influence of any subsequent EGFR MAb therapy, received by 76/126 (60%) of KRAS WT status patients) did not differ significantly by KRAS status, with median survival 34.3 vs 29.2 months for WT vs MUT status, respectively, 0.79 [0.58-1.08], p=0.14.

Conclusions: For most treatment strategies KRAS status did not affect 1st line PFS or time to chemotherapy-refractory state. However, for patients who received triple combination therapy, MUT status was associated with early progression. Small sample size, chance or some yet-to-be-elucidated molecular interaction may account for this finding.

[Table: see text]
Alternative sequencing of FOLFIRI or mFOLFOX6 with erlotinib in the second-line treatment of metastatic colorectal cancer (mCRC): An ongoing phase II trial.
Authors: Lopez Charles D. , Vaccaro Gina M. , Kampa-Schittenhelm Kerstin M , Strother John M. , Burt Andrea , Masterson Jeff
Published: February 2017

507

Background: Despite 1st-line response rates (RR) in mCRC of > 50% with FOLFOX or FOLFIRI, 2nd-line RRs are less (FOLFOX ~ 15%; FOLFIRI ~ 4%). Thus, there is a critical need for better 2nd-line strategies. Although use of anti-EGFR antibodies with chemotherapy has validated EGFR as a target in wt-KRAS mCRC, combining anti-EGFR tyrosine-kinase-inhibitors (TKIs) with chemotherapy has not shown consistent activity/tolerability. In vitro, anti-EGFR TKIs can induce a G0/G1 cell cycle arrest that attenuates chemo-induced apoptosis. However, when we alternately sequenced chemotherapy with erlotinib in HCT116p53+/+ CRC cells (mut-KRAS), we found markedly enhanced apoptosis (compared to chemotherapy alone or concurrent chemo/erlotinib). Based on these results, we initiated a clinical trial to alternately sequence 2nd-line chemotherapy with erlotinib in mCRC.

Methods: Non-randomized, parallel Simon’s two-stage phase II (optimum design) using 2nd-line (opposite of 1st-line) mFOLFOX6 or FOLFIRI (d1,2; d14,15) alternating with erlotinib (E) 100 mgs qd (d3-8; d16-21). Primary objective: radiographic RRs by RECIST criteria. Secondary objectives: time to progression (TTP), 2nd progression free survival (PFS), toxicity and tolerability. 1st stage analysis at 10 pts/arm: mFOLFOX6/E or FOLFIRI/E arms will continue if >2/10 pts, or >1/10 pts, respectively with CR/PRs. 2nd-stage analysis at 29 pts/arm: mFOLFOX6/E or FOLFIRI/E will be considered promising if > 4/29 pts, or > 6/29 pts, respectively demonstrate CR/PRs.

Results: n=15 pts to date. Of evaluable pts: 2 PR, 4 SD, 3 PD were observed in the FOLFIRI/E arm (n=9) and 1 SD in mFOLFOX6/E arm (n=1). Gr3/4 toxicities (n=10 evaluable pts): neutropenia (7), rash (1), nausea (1), oral pain (1), diarrhea (1), elevated LFTs (1), hyponatremia (1), elevated INR (1), GI bleed (1), abd pain (1). Dose reductions/treatment delays in evaluable pts: FOLFIRI/E (n=4/9); mFOLFOX6/E (n=0/1).

Conclusions: The FOLFIRI/E arm demonstrates sufficient responses to expand accrual into the 2nd-stage. The mFOLFOX6/E arm continues 1st-stage accrual. Toxicities were generally manageable. Molecular correlates are ongoing.
CD133 status influences in prognosis of patients with metastatic colorectal cancer receiving cetuximab.
Authors: Inoue Dai , Matsusaka Satoshi , Yamamoto Noriko , Suenaga Mitsukuni , Mishima Yuji , Shinozaki Eiji , Terui Yasuhito , Mizunuma Nobuyuki , Ishikawa Yuichi , Hatake Kiyohiko
Published: February 2017

509

Background: Recently, the cancer stem cell (CSC) theory has been proposed, and CD133 has been suggested as a potential marker of CSCs in metastatic colorectal cancer (mCRC). Cetuximab, an IgG1 anti-EGFR chimeric mouse/human monoclonal antibody, has been approved for the treatment of mCRC. The purpose of this study is to evaluate the prognostic significance of CD133 expression in mCRC treated with cetuximab in combination with chemotherapy.

Methods: We evaluated the prognosis of pts with mCRC treated with cetuximab retrospectively, and performed immunohistochemical staining to analyze the CD133 status. Non-parametric statistics, univariate and multivariate analysis were used.

Results: From October 2008 to June 2009, 56 pts with measurable metastatic colorectal cancer were received cetuximab and 43 were evaluable. Patients characteristics were as follows : median age : 59.6 years (range 28-80) , PS 0/1 : 30/13 , colon/rectum : 28/15 , metastatic site (liver +/- : 35/8 , lung +/- : 32/11 , bone +/- : 6/37 , peritoneum +/- : 6/37 , lymph node +/- : 11/32 , local +/- : 3/40), best response rate was 9.3% (CR/PR/SD/PD : 1/3/19/11). Compared with CD133- pts with colorectal cancer , the progression-free survival (PFS) of CD133+ pts was significantly better (5.5 month; 95% CI, 4.4-6.7,p=0.026), and median overall survival (OS) was also significantly better (11.0 month; 95% CI, 5.4-16.5, p=0.002). In univariate analysis, liver metastasis, lung metastasis, peritoneal metastasis, lymph node metastasis, age, and CD133 at the baseline predicted PFS, and age, gender, liver metastasis, lung metastasis, bone metastasis, peritoneal metastasis, lymph node metastasis at the baseline, the presence of skin rash, and CD133 predicted OS. In order to evaluate the independent predictive effect of chemotherapy, multivariate Cox regression analysis was carried out. It showed that CD133 was the strongest predictor.

Conclusions: CD133 status at the baseline was correlated with the prognosis of patients treated with cetuximab, suggesting that CD133 status might play a role to estimate the prognosis.
Use of the intensity of membranous EGFR staining by immunohistochemistry to predict the efficacy of chemotherapy containing cetuximab in KRAS wild-type patients with metastatic colorectal cancer: A retrospective analysis.
Authors: Takahashi Naoki , Yamada Yasuhide , Taniguchi Hirokazu , Akiyoshi Kohei , Honma Yoshitaka , Iwasa Satoru , Kato Ken , Hamaguchi Tetsuya , Shimada Yasuhiro
Published: February 2017

516

Background: KRAS mutation status is a strong predictive factor for anti-EGFR monoclonal antibody therapy efficacy in metastatic colorectal cancer (mCRC). In the BOND trial, objective response rates to cetuximab in irinotecan-refractory mCRC were not significantly different based on the intensity of EGFR staining by immunohistrochemistry (IHC). However, this result was not evaluated by KRAS mutation status, so we retrospectively evaluated the relationship between the efficacy of chemotherapy containing cetuximab and the intensity of membranous EGFR staining in KRAS wild type (KRAS-WT) patients.

Methods: Between August 2008 and July 2011, specimens of 391 CRC patients were collected by endoscopic biopsy or surgical resection. EGFR staining by IHC and genetic screening for KRAS status were performed and intensity of EGFR staining was scored by the Guidelines for Interpreting EGFR pharmDx, DAKO. We analyzed 94 KRAS-WT patients who received combination chemotherapy with an irinotecan-regimen plus cetuximab or cetuximab monotherapy and met the following criteria: histologically proven mCRC adenocarcinoma , at least 1 previous regimen of standard fluoropyrimidine - containing chemotherapy , ECOG PS score 0-2, and adequate hepatic and renal function. Patients were classified into 2 groups by intensity of EGFR staining: (A) absence of staining and weakly to moderately positive (IHC 1+ and IHC 2+), (B) strongly positive (IHC 3+). Progression-free survival (PFS) and overall survival (OS) were estimated by the Kaplan-Meier method, and compared in Groups A and B by the log-rank test.

Results: There was no significant difference in patient characteristics between the 2 groups except for primary site. The median PFS of Groups A (n=76) and B (n=18) were 5.4 months and 9.1 months (p= 0.029), the median OS was 8.1 months and 13.2 months (p=0.054) and response rate was 20.1% and 33.3%, respectively.

Conclusions: In KRAS-WT patients with fluoropyrimidine-containing chemotherapy-refractory mCRC, strong intensity of EGFR staining by IHC might be predictive for efficacy of chemotherapy containing cetuximab.
Role of presurgery circulating cancer cells (CTCs) as a potential pronostic factor in patients (pts) with liver surgery (LS) of colorectal cancer (CRC) metastases (M).
Authors: Teijeira Lucia , Viúdez Antonio , Antelo Maria L. , Tarifa Antonio , Zazpe Cruz , Herrera Javier , Hernandez Irene , Vera Ruth
Published: February 2017

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Background: Kinetic behavior of perioperative CTCs in pts with liver CRC M has been little explored. The aim of this study was to quantified CTCs performance before, just performed and 3 months after radical LS in pts with CRC M and analyzed the surrogate role of CTCs determinations in DFS and OS.

Methods: 7.5 ml of blood were drawn in CellSave tubes. CTCs were enumerated before, just performed and 3 months after radical LS. CTCs were immunomagnetically separated and fluorescently labeled using the CellSearch System (Veridex/Immunicon Corp.)

Results: From February 2009 to August 2011, 30 pts with LS of CRC M were included. Median age was 59 (45-75); 63.3 % men. Kras status: 63.2% wild-type and 36.8% mutated; 46.7% with synchronous disease. Fong-Criteria (FC) distribution: 30% pts with 1 FC, 36.7% pts with 2 FC and 33.3% pts with 3 FC, of whom 56.7% received neoadjuvant (76.4% fluoropirimidines-based; 29% cetuximab-based; 47% bevacizumab-based) and 73.3% adjuvant treatment. PR and SD were observed in 68.8% and 31.3% of pts, respectively (100% DCR). In 83% of cases, limited LS were done (79.3% R0, median M resected: 2), 20% of pts with synchronous surgery of primary tumour. Of the 15 pts analysed, pCR were observed in 2 (13.3%) with 6 other pts (40%) with major pathological response. With a median of follow-up of 21 months, progression disease occurred in 9 pts (55.6% with liver progression), and 4 pts died. Median CTCs was 0 before (0-2: 85%; ≥3: 14.8%), just performed (0-2: 78%; ≥3: 21%) and 3 months after surgery (0-2: 94.1%; ≥3: 5.9%). DFS for pts with pre-surgery CTCs ≥3 was 10 months, and not reached for 0-2 CTCs group. OS has not been achieved in any CTCs group. In the multivariate analysis, with FC and pre-surgery CTCs, pre-surgery CTCs ≥3 tends to be an independent predictor of outcome (HR: 2.83; CI:0.53-15).

Conclusions: Independently of neoadjuvant treatment, pre-surgery CTCs levels ≥3 could be a surrogate of short DFS in pts with LS of CRC M. Our study shown a slight increase in CTCs quantification after LS, instead a significant CTCs decrease was observed after adjuvant therapy. Role of radical LS in kinetic of CTCs should continue to be analysed in future studies.
Growth patterns of liver metastases as compared to resected tumors of the same colorectal cancer patients.
Authors: Eefsen Rikke Loevendahl , Van den Eynden Gert G. , Brodt Pnina , Burnier Julia V. , Hoyer-Hansen Gunilla , Christensen Ib Jarle , Metrakos Peter , Laerum Ole Didrik , Federspiel Birgitte , Willemoe Gro , Osterlind Kell , Illemann Martin
Published: February 2017

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Background: Colorectal cancer (CRC) affects one million people a year. 25% of the patients have metastatic disease at the time of diagnosis. Metastatic disease is one of the major challenges in the treatment of cancer. Even though the TNM staging system is a good prognostic marker, tumours have a biological diversity that cannot be evaluated by the TNM system. Recently three different growth patterns of CRC liver metastases were identified. The aim of this study was to determine the growth patterns of CRC liver metastases from patients with more than one metastasis.

Methods: A pilot study was conducted including 34 patients resected for CRC liver metastases, 28 patients selected from a database of 200 patients, operated in Copenhagen between 2007-2010 and 6 patients, operated in Montreal. From these 34 patients, 15 patients were resected for two or more liver metastases. All paraffin embedded tissue sections were stained for reticulin and haematoxylin and eosin at the Finsen Laboratory. Evaluation of the growth pattern was done by three different observers from Antwerp and Copenhagen. Reproducibility was >90%.

Results: In the fifteen patients, 9 from Copenhagen and 6 from Montreal, that had multiple hepatic metastases, there was uniformity in the growth pattern of the individual metastases. 40% had a desmoplastic, 33% a pushing and 20% a replacement growth pattern and 7% had a mix pattern. Of the 9 patients from Copenhagen 33% were synchronous and 67% metachronous metastases. Within patients, all patterns were identical.

Conclusions: The uniformity of growth patterns seen in each patient suggests that these patterns are not random. The identical growth pattern may be determined by specific interactions between the tumor and the host microenvironment, as postulated by Paget’s seed and soil theory. This could represent three different stromal and cytokine responses or oncogenic pathway responses and could represent metastatic tumour growth in different microenvironments.
Changes in expression levels of excision repair cross-complementing group 1 (ERCC1) and dihydropyrimidine dehydrogenase (DPD) during first-line oxaliplatin-based treatment of advanced metastatic colorectal cancer (mCRC).
Authors: Baba Hideo , Watanabe Masayuki , Okabe Hirohisa , Miyamoto Yuji , Sakamoto Yasuo , Baba Yoshifumi , Iwatsuki Masaaki , Chikamoto Akira , Beppu Toru
Published: February 2017

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Background: We previously reported the updated results of the FIRIS study, reconfirming the non-inferiority of IRIS (irinotecan/S-1) to FOLFIRI with progression-free survival (PFS) as the primary endpoint (ASCO2011 #3562). Moreover, in patients who had received prior oxaliplatin-based chemotherapy, median OS was significantly longer in the IRIS group than in the FOLFIRI group (adjusted HR=0.755, 95% CI: 0.580–0.987). The aim of this retrospective study was to elucidate molecular mechanisms underlying the better survival in the IRIS group among patients who had previously received oxaliplatin.

Methods: Irinotecan-naive mCRC patients (ECOG PS 0–1, adequate organ function, resectable liver metastases) were enrolled. Resected liver metastases were available for 17 patients who had received FOLFOX and 21 patients who had received no prior oxaliplatin-based chemotherapy. Using laser captured microdissection and real-time RT-PCR, we analyzed mRNA expression of excision repair cross complementing group 1 (ERCC1) and dihydropyrimidine dehydrogenase (DPD), factors related to drug resistance and metabolism.

Results: Baseline factors (sex, age, histology) of the subjects were similar in the two groups. Expression levels of nucleotide excision repair pathway gene ERCC1 and pyrimidine catabolic pathway gene DPD differed significantly between the FOLFOX group and non-oxaliplatin group. Mean expression levels of ERCC1 and DPD were respectively 1.9 and 7.4 times higher in the FOLFOX group than in the non-oxaliplatin group (ERCC1: 1.58 vs. 0.85, P=0.0005; DPD: 0.580 vs. 0.078, P=0.01).

Conclusions: Increased expression of ERCC1 and DPD after first-line oxaliplatin-based chemotherapy is probably related to chemosensitivity to subsequent therapy. Tumor heterogeneity and clonal selection of tumor cells resistant to oxaliplatin may also be involved.
Prognostic and predictive effect of COX-2 expression in appendiceal adenocarcinomas.
Authors: Raghav Kanwal Pratap Singh , Kazmi Syed Mohammad Ali , Shetty Aditya V. , Taggart Melissa W. , Fournier Keith F. , Royal Richard E. , Mansfield Paul F. , Eng Cathy , Wolff Robert A. , Overman Michael J.
Published: February 2017

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Background: Cyclooxygenase-2 (COX-2), an inducible isoenzyme, is upregulated in inflammation and involved in cancer progression by promoting angiogenesis, cell proliferation and migration and by inhibiting apoptosis. COX-2 is implicated in colorectal tumorigenesis and by extension COX-2 expression testing and therapeutic inhibition has been considered in appendiceal adenocarcinomas (AAs). However, its role in this setting has never been well studied. The purpose of our study was to investigate COX-2 expression in AAs and to evaluate its prognostic and predictive significance.

Methods: We performed a retrospective review of 607 patients with AAs treated at MD Anderson Cancer Center between 2002 and 2010. Immunohistochemistry was performed for COX-2 expression (COX2 mAb Clone CX229, Cayman Chemical) in 49 (8%) patients. Thirty (61%) stained positive and 19 (39%) showed no staining. Kaplan-Meier product limit method and log-rank test were used to estimate overall survival (OS) and to determine association between OS, COX-2 expression and other characteristics.

Results: Median age at diagnosis was 47 yrs (range 34-78 yrs). Grade (P = 0.003), completeness of cytoreduction score (P = 0.010) and stage (P = 0.023) were significantly associated with OS. Median OS for patients with COX-2 positive and COX-2 negative tumors was 58.3 and 42.8 months, respectively (P = 0.232). Nine COX-2 positive patients received celecoxib (selective COX-2 inhibitor) in combination with other chemotherapy. Mean treatment duration was 5.5 months with best radiographic response being stable disease in 7 patients. Reduction in tumor markers (CEA or CA19-9) was seen in 7 cases (median reduction of 30%). Similar treatment duration (6.6 months), rate of stable disease (6/8 pts) and tumor marker reduction (7/8 pts) was seen on the preceding non-celecoxib containing chemotherapy in these patients. Median OS, with and without COX-2 inhibition, was 55.7 and 57.6 months respectively (P = 0.57).

Conclusions: In this cohort, COX-2 expression is not a significant prognostic factor in AAs. Benefit from COX-2 inhibition in COX-2 expressing AAs is unclear. Current data does not support the routine use of either COX-2 testing or COX-2 inhibition therapy in AAs.
Survival with cetuximab/FOLFOX or cetuximab/FOLFIRI of patients with nonresectable colorectal liver metastases in the CELIM study.
Authors: Folprecht Gunnar , Gruenberger Thomas , Bechstein Wolf , Lordick Florian , Lang Hauke , Weitz Jürgen , Suedhoff Thomas , Hartmann Joerg Thomas , Liersch Torsten , Kohne Claus-Henning
Published: February 2017

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Background: Non-resectable liver metastases (mets) can be resected if they responded to systemic treatment. Cetuximab increases response rates in patients with k-ras wild type (wt) tumours.

Methods: Patients (pts) with non-resectable liver mets (defined as technically non-resectable or ≥ 5 liver mets) were randomized to cetuximab/FOLFOX (arm A) or cetuximab/FOLFIRI (arm B). Resectability was re-evaluated after four and then every 2 months. Resection was offered to pts who became resectable during treatment. (Folprecht et al, Lancet Oncol 2010) Progression free survival (PFS) and overall survival (OS) were analysed in June 2011.

Results: One hundred nine pts were randomized to cetuximab/FOLFOX or cetuximab/FOLFIRI, 106 evaluable for response. The median OS in all pts was 33.1 months [95% CI: 25.8-40.4], 35.7 [29.9-41.6] mo. in arm A and 29.0 [18.1-39.8] mo. in arm B (HR 1.09 [0.69-1.72]). The 4-year OS was 28% in all pts. The PFS was 11.2 [7.2-15.3] and 10.5 [8.9-12.2] mo. in arm A and B, respectively (HR 1.15 [0.77-1.70]). According to the k-ras mutational status, the OS and PFS was 36.1 [24.4-47.8] and 11.9 [8.25-15.6] in k-ras wt, 27.4 [15.7-39.1] and 9.9 [4.5-15.2] in k-ras mutant pts. In the k-ras wt subset, the OS was 35.8 [30.2-41.4] and 41.6 [24.8-58.5] mo. in arm A and B (HR 1.01 [0.55-1.86]), the PFS 12.1 [5.2-19.1] and 11.5 [8.8-14.1] mo. in arm A and B (HR 1.09 [0.66-1.79]). Pts with R0 resection had a significantly longer OS (median 46.7 [30.7-62.7] mo.) than pts without (median OS: 27.3 [21.2-33.3] mo, p=0.002). In R0 resected pts, the 3- and 4 year OS was 64% and 49%. The median disease free survival (DFS) was 9.9 mo after R0 resection, the 2 year DFS 19%. According to a review of CT/MRI scans which was performed by surgeons blinded to all clinical data, there was no survival difference between “resectable” pts and pts not categorized as “resectable” at baseline (HR 0.81 [0.44-1.50]), but a significantly better OS was observed for pts regarded as “resectable” after treatment vs. other categories (HR 0.47 [0.27-0.83], p=0.007).

Conclusions: Pts had a favourable overall survival which was longer in R0 resected pts. Resectability after treatment seems to be important for the pts outcome.