bluuebunny/crossref_metadata_2025 huggingface dataset:
Microdosing imaging pharmacokinetic (PK) study of the antisense oligonucleotide (ASO) to survivin (LY2181308) using positron emission tomography (PET): A novel paradigm in clinical drug development
Authors: Saleem A. , Ranson M. , Callies S. , Lahn M. , Prenant C. , Brown G. , Matthews J. C. , Dence C. S. , McMahon A. , Price P.
Published: August 2020

3578

Background: Survivin, an inhibitor of an apoptosis protein, widely overexpressed in cancer is associated with poor clinical outcome. We performed the first worldwide human microdosing imaging PK study of an ASO with LY2181308, a specific, second generation antisense inhibitor of Survivin using carbon-11 radiolabelled LY2181308 ([11C]LY2181308). Methods: LY2181308 was administered at the recommended phase II dose (750 mg over 3 hours IV daily x 3, then once weekly). [11C]LY2181308 was manufactured to GMP standard by random [11C]methylation with [11C]methyl iodide of LY2181308 using a GE Tracerlab FXc molecule. [11C]LY2181308-PET scans were performed at baseline and during treatment infusion. [11C]LY2181308 uptake in normal tissue and tumour was quantified. Results: Three pts (2 female Caucasian/1 male Asian) were scanned after administering [11C]LY2181308 which delivered (135–376 μg) of LY2181308. Despite its large size (6778 amu), [11C]LY2181308 rapidly distributed to tissues, with maximal uptake in kidney followed by liver, spleen, vertebral body, tumour, spinal cord, lung, and muscle at baseline. Although renal uptake was high, urinary elimination (bladder activity) was low suggesting renal trapping of [11C]LY2181308 at baseline. For a normalised injected dose of 1 mg, mean (range) tumour concentrations of 31 (4–41) ng/ml were observed at baseline, consistent with that predicted from the preclinical PK/PD model. In a pt with mesothelioma who also had a second [11C]LY2181308-PET scan during LY2181308 treatment infusion, there was about 2-fold increase in [11C]LY2181308 tumour uptake, in contrast to markedly reduced uptake in kidneys, liver, and spleen and similar aortic (circulatory) [11C]LY2181308 levels. In this patient, tumour [18F]FDG- PET uptake at 28 days was reduced by up to 40% after treatment, suggesting drug activity. Conclusions: [11C]LY2181308 pharmacokinetics suggest biologically active human tumour drug concentrations can be attained. LY2181308 therapy saturated normal tissue kinetics and increased tumour uptake of [11C]LY2181308. Data uniquely obtained from fully regulated microdosing studies may rationalise and hasten drug development.

[Table: see text]
Clinical trial of NPI-0052 in advanced malignancies including lymphoma and leukemia (advanced malignancies arm)
Authors: Townsend A. R. , Millward M. , Price T. , Mainwaring P. , Spencer A. , Longenecker A. , Palladino M. A. , Lloyd G. K. , Spear M. A. , Padrik P.
Published: August 2020

3582

Background: The novel structure (non-peptide based) of NPI-0052 (NPI) appears to lead to unique proteasome inhibition (PI), toxicology and signal transduction profiles. Preclinical research suggests improvements in therapeutic ratio and activity in hematologic and solid tumor models, leading to clinical trials in patients with myeloma, lymphomas, leukemias, and solid tumors. Methods: Patients with solid tumor, lymphoma or leukemia diagnoses without standard treatment options were treated with IV NPI on Days 1, 8 and 15 of 28-day cycles in a 3+3 design dose escalation to a Recommended Phase 2 Dose (RP2D). Enrollment then began in 10 patient lymphoma and CLL RP2D cohorts. PI (D1 and D15) and PK (D1 and D15) were assayed. Results: 30 patients were treated at doses ranging from 0.1 mg/m2 to 0.9 mg/m2. 0.7 mg/m2 was selected as the RP2D secondary to DLT of transient “hallucinations” (visual imprints when eyes closed) and dizziness/unsteady gait at 0.9 mg/m2. At the RP2D fatigue, parosmia/dysgeusia, transient peri-infusion site pain and lymphopenia were commonly ascribed to NPI. At the RP2D PK data showed: half-life = 31 ± 28 min; AUCtotal = 270 ± 219 ng/mL*min; Cmax = 33.4 ± 34.2 ng/mL; clearance = 7.17 ± 0.40 L/min; volume of distribution (Vz) = 223.3 ± 229.7 L. PI was assayed in blood, indicating a dose:response relationship with mean inhibition of chymotrypsin-like activity up to of 88% Day 1 and 100% Day 15, and inhibition of caspase-like and trypsin-like activity of up to 51% and 72%. PI remained between doses in whole blood (RBC), but recovered between doses in PBMC. Stable disease was induced in 31% of patients, including one each with mantle cell, Hodgkin's lymphoma, follicular lymphoma, sarcoma, prostate carcinoma, and two with melanoma. Conclusions: NPI-0052 produces dose-dependent pharmacologic effects through the predicted efficacious range to an MTD, while producing a toxicity profile that is tolerable and dissimilar to bortezomib in spite of reaching higher PI levels. These data indicate potential for a greater range of uses than other proteasome inhibitors and lead to additional studies being initiated in hematologic malignancies and solid tumors alone and in combination.

[Table: see text]
High β-III tubulin expression in triple-negative (TN) breast cancer (BC) subtype and correlation to ixabepilone response: A retrospective analysis
Authors: Horak C. E. , Lee F. Y. , Xu L. , Galbraith S. , Baselga J.
Published: August 2020

3587

Background: High βIII-tubulin (βIII) expression confers resistance to many anti-microtubule agents (Sève, Lancet 2008; 9: 168). The anti-microtubule agent ixabepilone (Ixa) demonstrates efficacy in βIII over-expressing tumor models resistant to taxanes and has clinical activity in patients with TN BC. The incidence and expression of βIII by BC subtype have not been delineated. Methods: Retrospective analyses of βIII mRNA expression were conducted in two microarray datasets of BC cohorts. Using intrinsic gene clustering, BC tumors from the Ixa neoadjuvant study CA163–080 (080) and the International Genome Consortium (IGC) were defined as basal-like (BL), luminal-like, Her2-overexpressing (Her2+) or normal-like subtypes. For study 080, IHC status subtyping defined TN, Her2+ and Her2-ER+PR+ patients. Mean expression of TUBB3, the gene encoding for βIII, was determined for each subtype. Clinical responses for 080 patients were compared to βIII expression levels. Results: For both cohorts, mean expression of TUBB3 was higher in BL and Her2+ tumors (one-way ANOVA and Tukey's HSD test; both p < 0.001). TUBB3 expression was rank-ordered: low, medium and high. In 080 and IGC cohorts, high expressors represent >50% of patients in BL and Her2+ subtypes and ∼20% of other BC subtypes. Subtyping 080 patients by receptor expression status demonstrated mean TUBB3 expression was higher for TN compared to Her2+ and Her2-ER+PR+ patients (t-test; p = 0.009). TN patients (n = 11/46) in study 080 had a trend to higher pCR rate than the overall population (n = 29/161), 26 vs. 18%. Receiver operating characteristics (ROC) analysis with AUC=0.66 demonstrates that high TUBB3 expression may predict for Ixa response in the overall 080 population. Conclusions: BC patients with TN, BL and Her2+ tumors have higher βIII expression. For the 080 study, responses to Ixa were higher for TN BC patients, and ROC analysis correlated response to βIII levels in the overall population. These data suggest high βIII in BL and TN BC may contribute to the aggressiveness of these subtypes and predict for Ixa clinical response. Additional studies are needed to address the activity of taxanes relative to βIII expression in TN BC.

[Table: see text]
Use of peripheral blood genomic markers whose expression levels reflect that of breast tumor genomic markers to predict drug treatment and sensitivity
Authors: Lee S. , Xu X. , Tan P. , Lee J. , Iau P. , Sukri N. , Tan S. , Lim S. , Chuah B. , Goh B.
Published: August 2020

3588

Background: Tumor gene expression signatures have been used to predict drug response, and we have previously reported drug-induced signatures to be more informative than the untreated baseline signatures. However, repeated tumor sampling during treatment is not feasible for most patients. We studied peripheral mononuclear cell (PBMC) gene expression levels in association with tumor gene expression levels in an attempt to identify peripheral blood markers that may serve as more accessible surrogates to predict drug treatment and response. Methods: Chemonaive breast cancer patients were treated with an alternating sequential regimen of doxorubicin and docetaxel and randomized to start with either drug. RNA from primary tumor before and 3 weeks, and from PBMC before and 24 hours after the first cycle of each drug was hybridized on the Affymetrix HG-U133+2 array containing 54,675 probe sets. Results: Pre- and post-treatment tumors from 47 patients were studied, including 35 with paired PBMC samples. 230 pre- and 85 posttreatment PBMC probe sets showed strong correlation in expression level (Pearson correlation coefficient >0.9) with the corresponding pre- and posttreatment tumor probe set, and included genes involved in transcription regulation and binding. Of the 975 tumor probe sets whose changes distinguished doxorubicin from docetaxel treatment, 12 corresponding PBMC probe sets were identified (p < 0.001) whose changes at 24 hours distinguished the two treatments with 77% accuracy. Of the 1,081 and 1,526 tumor probe sets whose changes predicted treatment response to doxorubicin and docetaxel, 19 and 15 informative PBMC probe sets predicted response to each drug with 100% and 80% accuracy, and included TNF receptor associated protein 1 and trefoil factor 1 for doxorubicin-, and folliculin and dynein for docetaxel-response. When the PBMC probe sets were validated in an independent test set treated with docetaxel (n = 23), 87% was correctly classified as docetaxel-treated, while 89% of non-responders clustered together. Conclusions: Peripheral blood contains genomic markers whose expression levels closely reflect that of breast tumor markers, and may be promising as surrogates to predict drug treatment and sensitivity.

No significant financial relationships to disclose.
Use of two-year disease-free survival (DFS) as a primary endpoint in stage III adjuvant colon cancer trials with fluoropyrimidines with or without oxaliplatin or irinotecan: New data from 12,676 patients from MOSAIC, X-ACT, PETACC-3, NSAPB C-06 and C-07, and C89803
Authors: Sargent D. J. , Yothers G. , Van Cutsem E. , Cassidy J. , Saltz L. , Wolmark N. , Shi Q. , Buyse M. , de Gramont A. ,   The Adjuvant Colon Cancer Endpoints (ACCENT) Group
Published: August 2020

4011

Background: The ACCENT group previously validated DFS with 3 years (yr) median follow-up (f-up) based on 20,898 pts from trials testing 5-FU based regimens (rx) (3yr DFS) as an endpoint to predict overall survival with 5 yr median f-up (5yr OS) (Sargent, JCO 2005). ACCENT further proposed (1) 2yr DFS predicts 5yr OS, (2) a stronger relationship between DFS and OS in stage III pts (Sargent JCO 2007) and (3) 6 or 7 yrs are necessary to demonstrate DFS and OS association in future trials due to extended survival following recurrence (de Gramont ASCO 2008). The relationship between endpoints in more recent trials with oral fluoropyrimidines, oxaliplatin, and irinotecan is unknown. Methods: Concordance between 2 and 3yr DFS, and 5 and 6yr OS was examined in 6 randomized phase III trials from 1997–2002. Individual data for 12,676 pts was analyzed; 2 trials tested oxaliplatin, 2 irinotecan, and 2 oral rx vs 5-FU/LV control. Association between DFS and OS hazard ratios (HRs) via weighted least squares (WLS), and concordance between predicted and actual within-trial HRs, were calculated overall and for stage III pts. Results: Overall association between 3 yr DFS and 5 yr OS HRs was reduced compared to the prior ACCENT analysis (Table). In stage III pts, the association between DFS and OS HRs remained strong. Observed 5 and 6yr OS HRs were predicted accurately by 2yr DFS overall and in stage III pts (within 95% prediction limits in all trials). In all pts, DFS HRs were more highly associated with 6 vs 5yr OS HRs. Conclusions: In recent trials in stage III pts, DFS HRs based on 2yr median f-up are highly predictive of 5 and 6yr OS HRs. In all pts the association between DFS and OS HRs is stronger for 6yr OS, but 7yr follow-up may be required. These data support 3yr DFS as a primary endpoint for modern stage III trials, and indicate that 2yr DFS would also be an appropriate primary endpoint.

[Table: see text]

[Table: see text]
Presence of 18q loss of heterozygosity (LOH) and disease-free and overall survival in stage II colon cancer: CALGB Protocol 9581
Authors: Bertagnolli M. M. , Niedzwiecki D. , Hall M. , Jewell S. D. , Mayer R. J. , Goldberg R. M. , Colacchio T. A. , Warren R. S. , Redston M.
Published: August 2020

4012

Background: LOH at 18q is associated with poorer overall survival in patients with colon cancer; however available studies are retrospective and vary in analysis methods. We recently completed an 18qLOH assay method validation study, and after standardizing technique, this prospective study investigated the role of 18qLOH among patients with low-risk stage II colon cancer. Methods: In Cancer and Leukemia Group B (CALGB) protocol 9581, we randomized 1738 stage II patients to post-operative treatment with a 500 mg loading dose of monoclonal antibody 17–1A followed by four infusions of 100 mg every 28 days or observation. The primary endpoint was overall survival (OS); disease free survival (DFS) was a secondary endpoint. Status of 18qLOH was assessed in patients with available tissue and interpretable PCR results. Patients were excluded if their tumors were uninformative for 18qLOH or if their tumors displayed microsatellite instability. Results: We report 18qLOH data on 156 patients. Patient characteristics including treatment, age, gender, performance status, site and grade of tumor, were similar between all patients enrolled and the subset of patients with tumor samples analyzed. The DFS and OS for treated and observed patients were no different (5-yr DFS: 0.81 and 0.80, p= 0.96; 5-yr OS: 0.88 and 0.86, p=0.44 at a median of 6.8 yrs of follow-up) and the data were pooled across the study's arms. Of the tumors examined, 101 (65%) were positive for 18qLOH. A significantly lower proportion of patients with 18qLOH-positive tumors had proximal tumors (46.5% vs 65.5%; p=0.02). Significantly decreased DFS and OS were observed in patients with 18qLOH-positive tumors. Five-year DFS among patients with 18qLOH-positive tumors was 0.78 vs 0.93 among patients with 18qLOH-negative tumors [HR 0.39; 95% CI (0.16, 0.94); logrank p=0.03 based on 33 events]. Five-year OS among patients with 18qLOH-positive tumors was 0.85 vs 0.98 among patients with 18qLOH-negative tumors [HR 0.25; 95% CI (0.07, 0.83); logrank p=0.01 based on 24 events]. Conclusions LOH at 18q was prognostic for DFS and OS among patients with available tissue for analysis after resection of low-risk stage II colon cancer who were not treated with chemotherapy in the adjuvant setting.

[Table: see text]
Capecitabine (Cape) versus 5-fluorouracil (5-FU)-based (neo-)adjuvant chemoradiotherapy (CRT) for locally advanced rectal cancer (LARC): Safety results of a randomized, phase III trial
Authors: Hofheinz R. , Wenz F. , Post S. , Matzdorff A. , Laechelt S. , Mueller L. , Link H. , Moehler M. , Burkholder I. , Hochhaus A.
Published: August 2020

4014

Background: 5-FU based CRT is regarded standard perioperative treatment in LARC. Here we report safety data of a non-inferiority phase III trial investigating (neo-)adjuvant CRT with Cape in comparison with 5-FU. Methods: Patients (pts) aged ≥18 years with LARC UICC stages II or III were recruited in this two-arm, two-strata randomized phase-III trial (arm A: Cape, arm B: 5-FU; stratum [S] I: adjuvant, S II: neoadjuvant). Regimens: Arm A: CRT: 50.4 Gy + Cape 1,650 mg/m2 days 1–38 plus five cycles of Cape 2,500 mg/m2 d 1–14, rep. d 22 (S I: 2 x Cape, CRT, 3 x Cape; S II: CRT, TME surgery followed by Cape x 5). Arm B: CRT: 50.4 Gy + 5-FU 225 mg/m2 c.i. daily [S I] or 5-FU 1,000 mg/m2 c.i. d 1–5 and 29–33 [S II] plus 4 cycles of bolus 5-FU 500mg/m2 d 1–5, rep. d 29 (S I: 2 x 5-FU, CRT, 2 x 5-FU; S II: CRT, TME surgery followed by 5-FU x 4). Primary endpoint was survival, secondary endpoints comprised safety and disease-free survival. Results: Of 401 randomized pts a total of 392 are evaluable (Arm A n=197, arm B n=195; S I n=231, S II n=161). Both arms were well balanced with respect to age, sex, WHO status, T- and N- stages. Regarding duration of treatment, 78% (Cape) and 80% (5-FU) completed all scheduled treatment cycles in S I, and 46% (Cape) and 40% (5-FU) in neoadjuvant stratum S II. In S II a total of 38% (Cape) and 43% (5-FU) did not continue chemotherapy after tumour resection. Concerning early efficacy endpoints in S II, pts treated with Cape (evaluable thus far n=121) exhibited a higher rate of T-downstaging (defined as ypT0–2; 52 vs 39%; p=0.16) and N0 (71 vs 56%; p=0.09). Regarding overall safety (NCI-CTC), pts receiving Cape experienced significantly less leukopenia (25 vs 35%; p=0.04), but more hand-foot syndrome (31 vs. 2%; p<0.001). Stomatitis/mucositis, diarrhea, nausea/vomiting, and radiodermatitis were not significantly different between both arms. Conclusions: Given the observed safety profile and the trend in improved downstaging in neoadjuvant stratum, Cape exhibits a potential to replace 5-FU as perioperative treatment of LARC. Efficacy results on the primary endpoint are expected for 2010.

[Table: see text]
Impact of age and comorbidities on treatment effect, tolerance, and toxicity in metastatic colorectal cancer (mCRC) patients treated on CALGB 80203
Authors: Meyerhardt J. A. , Jackson McCleary N. , Niedzwiecki D. , Hollis D. , Venook A. , Mayer R. , Goldberg R.
Published: August 2020

4038

Background: Little is known regarding the interaction of comorbid conditions (CC) and age when treating pts for mCRC. We sought to determine the impact of CC and age (<70 and ≥70 yrs) on survival and toxicity in these pts. Methods: We utilized a cohort of 238 pts with mCRC enrolled in CALGB 80203, a curtailed, multicenter 2x2 phase III trial of fluorouracil/leucovorin + oxaliplatin (FOLFOX) or irinotecan (FOLFIRI) ± cetuximab. Endpoints were overall survival (OS; time to death), progression-free survival (PFS; time to recurrence or death), and grade 3/4 toxicity. Pts completed a self-administered questionnaire on diet and lifestyle that included a modified Charlson's comorbidity survey. Cox models were adjusted for treatment (rx) arm, gender, and prior rx. Results: In CALGB 80203, 77% were < 70 and 23% ≥70. Thirty-five percent of pts had at least one CC (34% < 70 yrs; 41% ≥ 70 yrs). At least one grade 3/4 toxicity was experienced by 87% of pts ≥70 v 66% <70 (p=0.002), primarily hematologic (56% v 31%, p=0.003). Amongst 238 pts, 94% and 84% experienced a PFS event and OS event, respectively. No pts are censored prior to 3 yrs. Median follow-up was 23 mos. The adjusted hazard ratio (HR) for ≥70 v <70 of PFS was 1.0 (0.7–1.4) and of OS was 1.1 (0.8–1.6). Similarly, there were no significant differences in HR for PFS and OS by # CC. The table demonstrates no evidence of interaction between CC and age. Conclusions: While the early closure of CALGB 80203 presents sample size limitations for subset analyses, we did not observe an impact on PFS or OS by age and/or CC. Older pts did experience more toxicity from rx. Further studies with larger datasets are warranted.

[Table: see text]

[Table: see text]
Modifiable factors that influence colorectal cancer lymph nodes sampling and examination
Authors: Valsecchi M. E. , Leighton J. , Tester W.
Published: August 2020

4047

Background: Colorectal cancer is the fourth most common malignancy in the United States. The single most important prognostic factor is lymph node involvement. Multiple guidelines recommend a minimum of 12 nodes should be sampled in order to insure accurate staging and treatment. However this standard of care requirement is not always achieved. The objective of this study is to identify potential modifiable factors that may explain this inadequacy between the optimal approach and routine practice. Methods: The medical charts of all patients treated for colorectal cancer stage I-III between 1999–2007 at Albert Einstein Medical Center were reviewed. The association between multiple variables and the presence of ≥12 lymph nodes reported were examined using logistic regression models. Results: A total of 337 patients were included; 173 (51%) had ≥12 lymph nodes retrieved with a mean of 12.7 (SD±7.6). Demographic characteristics: 78% older than 60 years old; 161 patients (47.8%) male; white (27%), black (67%) and other race (6%). Using a univariate analysis the following variables were statistically associated with ≥12 lymph nodes reported: Colon size (20.6±14.7 vs. 29.9±23.1 cm, P<.001); Mesocolon thickness (3.8±0.9 vs. 4.2±0.9 cm, P<.001); Tumor size (4.14±2.3 vs. 4.6±2.1, P=.03); Site of tumor (Right vs. Left, P<.001); Pathologist (P=.06); Pathologist's Assistant (P=.006); Type of surgery (Right or Sub-Total Colectomy vs. Others, P<.001), Individual Surgeon (P=.009). The results of the multivariate logistic regression analysis, adjusting for age, sex and race, are presented in the Table . Conclusions: This studied showed that multiple factors influence the number of lymph nodes sampled. The role of the surgeon, the pathologist and specially the pathologist's assistant are potentially improvable factors with appropriate education.

[Table: see text]

No significant financial relationships to disclose.
Interlaboratory assay reproducibility study for loss of heterozygosity on chromosome 18 (18q LOH) in colon cancer
Authors: Jessup J. M. , Dobbin K. , Hamilton S. , Thibodeau S. , Redston M. , Taube S. , Wang Z. , Benedetti J. ,   Program for the Assessment of Clinical Cancer Tests (PACCT) 18q LOH Team
Published: August 2020

4052

Background: 18q LOH may be a useful marker in stage II colon carcinoma to assess who needs adjuvant chemotherapy. The objective of this study was to evaluate the intra- and inter-laboratory reproducibility of an assay for 18q LOH that is similar to the integral assay used in E5202, the current Intergroup phase III stage II colon carcinoma clinical trial. Methods: Specimens from 130 stage II/III colon cancer patients were obtained from the Cooperative Human Tissue Network and evaluated at three different laboratories. Samples were divided into subsamples, coded and distributed. Each laboratory used similar equipment in an established PCR protocol with 5 dinucleotide repeats. Starting materials used both histologic sections and extracted DNA samples of tumor and non-neoplastic tissue obtained only by scalpel microdissection. LOH was defined as tumor/normal peak ratio that was >1.35 or <0.67 without microsatellite instability (MSI). Tumors were categorized as either MSI+, LOH + or -, uninformative/monoallelic, or unevaluable (DNA not amplifiable). Standard tests assessed reproducibility of both the numerical ratios and the tumor 18q LOH status. Results: Sample quality issues prevented analysis of 13 tumors (10%). The frequency of 18q LOH was 64%. The probability of agreement on the same tumor evaluated twice was 92% (Cohen's kappa 0.83). Intra-class correlation coefficients for individual markers were consistently over 0.90. Tissue specimens must have high (>85%) tumor cell content for reproducibility. Differences among patients affected reproducibility much more than effects of laboratory and sample type (DNA vs. histologic section). Conclusions: This study validates reproducibility of the 18q LOH assay for both clinical categorization of status and numerical ratios if samples are high quality and appropriate for scalpel microdissection.

[Table: see text]
Clinical usefulness of mtTFA expression as a predictive marker in colorectal cancer patients treated with FOLFOX
Authors: Yoshida Y. , Hasegawa J. , Nezu R. , Kim Y. , Hirota M. , Yoshikawa K. , Kawano K. , Izumi H. , Kohno K.
Published: August 2020

4059

Background: We previously reported that mitochondrial transcription factor A (mtTFA; also designated Tfam) preferentially recognizes cisplatin-damaged DNA via physical interaction with p53 and is upregulated by the treatment with cisplatin and 5-FU (Yoshida et al, Cancer Res. 2003). The aim of this study was to evaluate whether expression of mtTFA predicts clinical outcome in patients with metastatic colorectal cancer treated with modified FOLFOX6 (mFOLFOX6). Methods: From January 2006 to April 2008, 59 patients who had metastatic lesions from colorectal cancer treated with mFOLFOX6 at the Osaka Rosai Hospital were included in this study. They consisted of 25 women (42.4%) and 34 men (57.6%), with a median age of 62 years (29–84). Patients were treated with oxaliplatin 85mg/m2 plus leucovorin 200mg/m2 as a 2-h infusion at day 1, followed by 5-FU bolus 400mg/m2 and 46-h continuous infusion of 2400 mg/m2. Treatment was repeated in 2-week intervals for at least 4 cycles. The expressions of mtTFA and p53 of resected primary tumors were examined by immunohistochemistry. Results: Among 59 patients, one complete response and 32 partial responses were observed (response rate, 55.9%) . The positive rates was 44.1% (26/59; CR 1, PR 7, SD/PD 18) for mtTFA and 59.3% (35/59; CR 1, PR 19, SD/PD 15) for p53, respectively. Strong expression of mtTFA was detected in 8 of 33 CR/PR (24.2%) and in 18 of 26 SD/PD (69.2%), indicating that the expression of mtTFA correlated significantly with response to chemotherapy (P<0.01). On the other hand, there was no significant correlation between response to chemotherapy and p53 expression (P=0.82). mtTFA expression was significantly associated with overall survival (P=0.036) and progression free survival (P=0.037). Multivariate analysis revealed that mtTFA expression significantly impacted on OS (Hazard ratio 2.10, P=0.036). Conclusions: Immunohistochemical study of mtTFA may be useful in prediction of the clinical outcome of metastatic colorectal cancer patients treated with FOLFOX.

No significant financial relationships to disclose.
Association of a germ-line variant in the K-ras 3’ untranslated region with response and progression-free survival in patients with mCRC treated with single-agent cetuximab (IMCL-0144) or in combination with cetuximab (EPIC) independent of K-ras mutation status
Authors: Winder T. , Zhang W. , El-Khoueiry A. , Yang D. , Pohl A. , Lurje G. , Rowinsky E. , Khambata-Ford S. , Langer C. , Awad M. , Lenz H.
Published: August 2020

4061

Background: Recent studies have found K-ras mutation status predicts response to EGFR inhibitors in mCRC. An in vitro study demonstrated let-7 microRNA family can regulate RAS expression by binding to the 3’UTR of RAS gene. Chin et al found a SNP in a let-7 microRNA complementary site (LCS) in the K-ras 3’ UTR increases cancer risk in NSCLC. We tested the hypothesis whether this SNP may be associated with clinical outcome in 130 mCRC patients enrolled in IMCL-0144 trial and in 186 pts enrolled in EPIC trial independent of K-Ras mutation status in the tumor. Methods: K-ras lcs 6 SNP was tested in 130 mCRC patients enrolled in IMC-0144 phase II clinical trial (single agent cetuximab) and in 186 mCRC patients enrolled in a second line phase III trial of cetuximab plus irinotecan versus irinotecan alone (EPIC). Genomic DNA was extracted from dissected formalin fixed paraffin embedded tumor tissue and K-ras mutation status and the polymorphism were analyzed using direct sequencing and PCR-RFLP technique. Results: The G harboring allele frequency in K-ras lcs6 was 8% in IMC-0144 and 11% in EPIC. K-ras lcs6 polymorphism was significantly associated with tumor response in patients with wild type K-ras in IMC-0144. The 12 pts harboring a G allele (TG+GG) had a 42% partial response (PR) rate compared to 55 pts with TT genotype with only 9% PR.(p=0.02, Fisher's-exact test). However, pts with TT genotype enrolled in EPIC treated with CPT-11 and cetuximab with mutant K-ras had a significantly better PFS of 12 weeks (95% CI 6.4–18) compared to those harboring the a G allele with median PFS of 6.4 weeks (95% 5.7–7) (p=0.037. log-rank test). There was no association between this polymorphism and clinical outcome in patients with wild type K-ras enrolled in EPIC. In a multivariate analysis the polymorphism remained independently associated with PFS in EPIC. Conclusions: Our data suggest for the first time that the functional germline polymorphism in K-ras lcs6 may be a potential predictive marker in mCRC patients treated with cetuximab-based chemotherapy independent of K-ras mutation status. This finding warranted further confirmative clinical trials.

[Table: see text]
Association of CD133 polymorphisms and clinical outcome in metastatic colorectal cancer (mCRC) patients (pts) treated with either first-line 5-FU + bevacizumab (BV) or second-line irinotecan (IR)/cetuximab (CB) or IR alone
Authors: Pohl A. , Zhang W. , Yang D. , Lurje G. , Ning Y. , Khambata-Ford S. , Langer C. , Kahn M. , Teo J. L. , Lenz H. J.
Published: August 2020

4062

Background: CD133 has been routinely used to identify colon cancer stem cells. A recent study indicated that elevated levels of CD133 plasma mRNA correlated with colon cancer recurrence. Furthermore plasma levels of CD133+ progenitor cells have been found to be decreased after treatment with BV. We tested whether potentially functional frequently occurring germline variations in the 3’UTR-region of the CD133 gene (rs2240688, rs3130 and rs2286455), might be associated with clinical outcome in first- and second-line treated mCRC pts. Methods: Genomic DNA was extracted either from peripheral blood (79 pts, who were enrolled in a phase-II clinical trial with FOLFOX/BV or XELOX/BV) or formalin-fixed paraffin-embedded tumor samples (186 pts, who were enrolled in the EPIC phase III clinical trial, US-sites only) of mCRC pts. Pts received either first-line treatment with FOLFOX/ BV (33 pts) or XELOX/BV (46 pts) or second-line treatment with CB/IR (84 pts, arm A) or IR (102 pts, arm B) alone. Genotyping was performed using PCR-RFLP assays. Results: 79 pts (47 men, 32 women) received FOLFOX/BV or XELOX/BV. Radiologic response: 43 pts (54%) CR/PR, 35 pts (45%) SD/PD. Median PFS was 10.8 months (95%CI: 8.1–14.9). The second cohort consisted of 186 pts (103 men, 83 women). Radiologic response: Arm A 11 pts (13%) CR/PR, 73 pts (87%) SD/PD. Arm B 6 pts (6%) CR/PR, 96 pts (94%) SD/PD. Median PFS (arm A) was 3.0 months (95%CI: 2.4–4.1) vs. 2.7 months (arm B,95%CI: 2.2–2.9). Combined analysis of rs2286455 and rs3130 showed a significant association with PFS (p= 0.010, log-rank test) in pts receiving FOLFOX/BV or XELOX/BV. In pts receiving IR alone rs2240688 was significantly associated with OS (p=0.0128, log-rank test). Multivariate analysis showed a significant association with PFS in first-line setting for rs2286455 and rs3130 (adjusted p=0.012) and a trend in second-line setting for rs2240688 (adjusted p=0.086). Conclusions: These are the first data to show that polymorphisms in CD133 predict outcome in mCRC pts in first- and second- line setting, suggesting that CD133 may be a potential predictive marker. These results need to be confirmed in larger prospective studies.

[Table: see text]
Coexpression of matrix metalloproteinase-7 (MMP7) and phosphorylated insulin growth factor receptor I (pIGF-IR) as predictors of resistance to anti-EGFR therapy in advanced colorectal cancer (ACRC): A GEMCAD study
Authors: Horndler C. , Gallego R. , Alonso V. , Alonso V. , Escudero P. , Jimeno M. , Garcia-Albeniz X. , Fernandez-Martos C. , Castellví-Bel S. , Maurel J.
Published: August 2020

4063

Background: IGF-IR is supposed to have anti-apoptotic and mitogenic properties in colorectal cancer and by transactivation can promote EGFR phosphorylation. MMP-7 is produced by colorectal cancer cells and by degrading IGFBP-3 can activate IGF-IR. Methods: We retrospectively investigated the role of pIGF-IR immunoreactivity (IHC) (Rubini) and MMP-7 IHC in primary CRC or metastases, to predict response rate (RR), progression free survival (PFS) and overall survival (OS) in ACRC patients (pts) treated with either cetuximab or panitumumab as second or third line therapy. RAS mutational status of codons 12/13 was determined using quantitative PCR-based assay. CT scans were done every 1.5–2 months (m) until progressive disease. Results: A total of 99 pts with available tissue from 168 pts with ACRC treated with anti-EGFR therapy in 4 Spanish Institutions, were analysed for RAS mutational status, pIGF-1R and MMP-7. There were no major differences in RR (18.8 vs 16%), PFS [3.3 vs. 3.1 months (m)] and OS (7.7 vs. 7m) between the whole and selected cohort. Fifty-seven (57.6%) pts were male, the median age was 62 (range 34–79) years, the median number of previous chemotherapy lines was 2 (range 1–3) and PS was distributed as follow: PS0, 17 (17.2 %) pts; PS1, 66 (66.7%) pts and PS2, 16 (16.2%) pts. Expression of MMP-7 and pIGF-1R were observed in 48 (48.5%) and 52 (52.5%) pts respectively. Co-expression of MMP-7 and pIGF-1R [Double Positive (DP)] was observed in 26 (26.3 %) pts and in 16 (24%) out of 66 RAS wild-type (WTRAS) pts. There was no association between RAS mutational status and DP (p=0.52). DP progressed more than non-DP pts both in the overall sample (73 vs. 43%, p=0.028) and in WTRAS pts (75 vs. 32%, p=0.011). In the subset of WTRAS pts, DP pts also have a poorer OS: 6.4 (95% CI 5.8–7.1) m vs. 8.6 (95%CI 6.0–11.3) m (p=0.005), and a trend for worse PFS 2.7 vs 4.0 m (p=0.11). Conclusions: Co-expression of pIGF-1R and MMP7 is associated with resistance to anti- EGFR therapy in WTRAS pts. Our study suggests that pts with WTRAS and DP could be a target population to assay new anti-IGF-1R compounds.

No significant financial relationships to disclose.
Circulating endothelial cell (CEC) monitoring in metastatic colorectal cancer (mCRC) patients (pts) treated with first-line bevacizumab (BEV)-based combination regimens: Results of the randomized phase II FNCLCC-ACCORD 13/0503 trial
Authors: Farace F. , Mendiboure J. , Adenis A. , Boucher E. , Pierga J. , Conroy T. , Montoto-Grillot C. , Pignon J. , Ducreux M. , Malka D. ,   FNCLCC
Published: August 2020

4071

Background: There is no validated biomarker to predict the efficacy of BEV, an anti-VEGF monoclonal antibody. Rare cell subpopulations such as CEC are good candidates. Methods: Pts with mCRC, aged 18–75 yrs, ECOG performance status (PS) 0–2, and no prior palliative chemotherapy were randomized to either BEV (5 mg/kg) + FOLFIRI every 2 weeks (arm A, 12 cycles) or BEV (7,5 mg/kg) + XELIRI every 3 weeks (arm B, 8 cycles). BEV was continued until disease progression [PD]. The primary endpoint was crude 6-month progression-free survival (PFS) rate. In consenting pts, CEC (CD45-CD31+CD146+7- amino-actinomycin- cells) were measured at baseline (Day [D]1, before treatment), D8, and at the end of cycle 1 (D15 or 22) in 1-mL whole blood by four-color flow cytometry according to a method we established previously (J Immunol Methods 2008). Results were correlated to pts’ characteristics and primary endpoint (Wilcoxon's, Fisher's, and trend tests). Results: From 03/06 to 01/08, we enrolled 145 pts (male, 56%; median age, 61 yrs; PS 0–1, 91%; number of metastatic sites [1/2/>2], 45/48/8%). Pts with at least one CEC measurement (n=99; arm A, 51; arm B, 48) did not differ from the 46 other pts regarding sex, age, PS, and number of metastatic sites. Baseline CEC levels (n=97; median, 16/mL) were higher in PS 1–2 pts (n=42) than in PS 0 pts (n=55) (17 vs. 12/mL, p=0.02) (age, sex, number of metastatic sites: NS) and in pts with PD (n=17) than in pts with non- PD (n=80) at 6 months (30 vs. 15/mL, p=0.004). CEC levels were higher at the end of cycle 1 in the PD group (n=17) than in the non-PD group (n=74) (34 vs. 14/mL, p=0.01). The 6-month PFS rate varied from 0% to 32% in the 4 groups defined by baseline and end-of-cycle- 1 CEC values (cutoff: baseline median) (trend test, p=0.006) ( table ). Conclusions: Baseline and end-of-cycle-1 CEC levels may predict tumor control in patients with mCRC starting first-line BEV + chemotherapy.

[Table: see text]

[Table: see text]
The impact of young age on outcome in colon cancer
Authors: Truong C. , Kempton S. , Lum S. , Morgan J. W. , Wong J. H. , Roy-Chowdhury S.
Published: August 2020

4075

Background: The early age of diagnosis (<40 years) of colon cancer (CC) is generally considered to be associated with a particularly grave prognosis. Our objective was to determine the prognostic relevance of young age on outcome in CC. Methods: Retrospective cohort study from Region 5 of the California Cancer Registry (R5 CCR). Survival by Kaplan- Meier with significance assessed by log-rank test, T-test and Chi Square where appropriate. Results: Between January 1,1994 and December 31, 2003 10,730 patients with CC were diagnosed in R5 CCR. The patients ranged in age from 18–103 years (mean 71.1 years). Two hundred fourteen patients (2%) were 40 years of age or younger. The mean age of young patients was 34.6 years (range 18–40) and for old patients 71.3 years (range 41–103). The mean number of nodes examined were 18.5 in the young CC patient and 18.4 in the remainder of CC patients. There was no significant difference in the anatomic sub-site of the primary between younger and older CC patients (p=0.43). Young patients presented with more advanced primary tumors (T4 18.7% vs. 11.6%, p=0.03), more frequently with more extensive nodal involvement (N+ (54.4% vs. 40.2%, p<0.0001), and more frequently with distant metastatic disease (M1 25.7% vs. 18.3%, p=0.005). Despite these adverse characteristics, young patients had a significantly better disease specific survival (DSS) compared to their older counterparts (5 year survival 70.1% vs. 62.3%, p=0.02). Young patients had a suggestion of improved DSS compared to older patients in Stage I disease (5 yr DSS 96.0% vs. 90.5%, p=0.34) with more certain evidence of improved DSS in Stage II (5 yr DSS 94.8% vs. 79.9%, p=0.02), Stage III (5 yr DSS 73.4% vs. 57.2%, p=0.01) and most profoundly in Stage IV (5 yr DSS 20.1% vs. 0.08%, p=0.002). Conclusions: Despite adverse characteristics at diagnosis, young CC patients have a better DSS than their older counterparts. This is in contrast to the generally held opinion that young CC patients fare worse. This may reflect the ability of young CC patients to accept and tolerate more intense and aggressive therapies.

No significant financial relationships to disclose.
Cetuximab plus FOLFIRI first line in patients (pts) with metastatic colorectal cancer (mCRC): A quality-of-life (QoL) analysis of the CRYSTAL trial
Authors: Folprecht G. , Nowacki M. , Lang I. , Cascinu S. , Shchepotin I. , Maurel J. , Rougier P. , Cunningham D. , Zubel A. , Van Cutsem E.
Published: August 2020

4076

Background: Assessing QoL is important to evaluate the impact of treatment on pts with mCRC. The phase III CRYSTAL trial compared cetuximab plus FOLFIRI with FOLFIRI alone in the first-line treatment of patients with EGFR-expressing mCRC. Primary endpoint was progression-free survival (PFS); QoL was a secondary endpoint. Methods: Pts were randomised 1:1 to cetuximab (400 mg/m2 initial dose then 250 mg/m2/wk) plus FOLFIRI q2w (irinotecan 180 mg/m2, folinic acid 400 mg/m2, 5-FU bolus 400 mg/m2, 5-FU infusion 2400 mg/m2 over 46 h) (Group A, n=599) or FOLFIRI alone (Group B, n=599). QoL was assessed with the EORTC QLQ-C30 (v3.0) questionnaire. Pts were to complete the questionnaire at baseline, every 4 cycles, and at final tumor assessment. The primary QoL analysis focused on Global Health Status and Social Functioning scales and employed a pattern-mixture model that included the drop-out pattern. Descriptive statistics were provided for each multi-item scale considering QoL changes over time. Results: Risk of disease progression was significantly reduced by 15% (HR=0.85) in favor of Group A (p=0.0479); pts with KRAS wild-type (wt) tumors in Group A had a 32% (HR=0.68) reduced risk of progressing. Questionnaire completion compliance rates were similar between treatment groups. Pattern-mixture analyses showed no statistically significant differences between the two treatment groups for changes from baseline on the Global Health Status (p=0.29) and Social Functioning (p=0.39) scales. Comparing treatment groups in terms of QoL scores over time resulted in no statistically significant differences, apart from nausea/vomiting in favor of the cetuximab group at week 16 (10.2 vs 13.3; p=0.0129), week 32 (9.3 vs 12.5; p=0.0488) and week 40 (7.6 vs 12.5; p=0.0194). Conclusions: In pts with mCRC, cetuximab plus FOLFIRI first-line significantly prolongs PFS compared with FOLFIRI alone while preserving QoL. The PFS benefit is even more pronounced for pts with KRAS wt tumors. The EORTC QLQ-C30 Social Functioning scale was expected to reflect skin reactions related to cetuximab, but there was neither a clinically meaningful nor statistically significant difference between groups.

[Table: see text]
Phase III study of standard triweekly versus dose-dense biweekly capecitabine (C) + oxaliplatin (O) + bevacizumab (B) as first-line treatment for metastatic colorectal cancer (mCRC): XELOX-A-DVS (dense versus standard): Interim analysis
Authors: Hurwitz H. , Patt Y. Z. , Henry D. , Garbo L. , Mitchell E. P. , Kohles J. , Spigel D.
Published: August 2020

4078

Background: Every 3 week (Q3W) COB has been shown to be highly active and non-inferior to FOLFOX+B in first-line mCRC. Phase II data suggest that dose-dense every 2 week (Q2W) COB may be significantly more active and better tolerated than Q3W COB. Methods: XELOXA-DVS was a phase III, open-label study of 435 patients with chemonaive mCRC who met standard eligibility criteria. Patients were randomized to Q3W: C 850 mg/m2 BID d1–14 + O 130 mg/m2 d1 + B 7.5 mg/kg d1 or Q2W: C 1500 mg/m2 BID d1–7 + O 85 mg/m2 d1 + B 5 mg/kg d1 for up to 72 weeks. Complete surgical resection was allowed using pre-defined criteria. The primary endpoint, progression-free survival (PFS), was estimated using the Kaplan- Meier method, while the hazard ratio and 95% CI were estimated using Cox regression analysis, based on the intent-to-treat population. No formal statistical testing was conducted. Results: The median PFS was 8.4 months (Q2W) and 9.7 months (Q3W) (hazard ratio [HR]=0.84; 95% CI=0.62–1.13). The median PFS (on-treatment) was 9.1 months and 10.2 months, respectively (HR=0.81). Of the 72 and 73 patients with disease progression (DP), the median time to DP was 9.4 and 10.8 months, respectively (HR=0.86). The objective response rates were 21.7% vs 29.4%, respectively (HR=1.05). Patients in the Q2W vs Q3W group experienced higher rates of grade 3/4 diarrhea (29% vs 24%), hand-foot syndrome (12% vs 8%), and treatment discontinuation rates (40% vs 20%), respectively. Other grade 3/4 toxicities (>5%, Q2W vs Q3W) included fatigue (13% vs 13%), dehydration (12% vs 10%), nausea (8% vs 9%), peripheral neuropathy (5% vs 9%), anorexia (5% vs 7%), and abdominal pain (5% vs 7%). Conclusions: At the dose and schedule used, dose-dense Q2W COB was not superior to standard Q3W COB. These data further confirm the activity and tolerability of Q3W COB. The activity and tolerability of a lower C dose Q2W, with more aggressive dose reduction, combined with B and O or irinotecan is currently being evaluated (X-BIO).

[Table: see text]
Bevacizumab (B) plus everolimus (E) in refractory metastatic colorectal cancer (mCRC)
Authors: Bullock K. E. , Hurwitz H. I. , Uronis H. E. , Morse M. A. , Blobe G. C. , Hsu S. D. , Zafar S. Y. , Nixon A. B. , Howard L. A. , Bendell J. C.
Published: August 2020

4080

Background: For patients (pts) with mCRC, no standard therapy exists after progression on 5-FU, oxaliplatin, irinotecan, bevacizumab, and/or cetuximab/panitumumab. Preclinical data demonstrate combined VEGF and mTOR inhibition has greater anti-angiogenic and anti-tumor activity than either monotherapy. B inhibits VEGF; E inhibits mTOR. Phase I data in patients demonstrated B + E was safe and activity was seen in several pts with refractory mCRC. Methods: 25 pts with refractory mCRC were enrolled in an expanded cohort of B + E. Doses: B 10 mg/kg q2 wks; E 10 mg PO QD. Blood, skin, and tumor biopsies pre- and on-treatment were collected for markers of response and resistance. Results: At this time, 19 pts (10M: 9F) are evaluable for toxicity; 17 for efficacy. Median age 57 years (range 35–78). Median number prior regimens 3. All pts had prior B exposure; 17 pts had progressive disease on prior B-based therapy. There was one Grade (Gr) 4 adverse event (AE) of hypokalemia. Grade 3 AE related to treatment were bowel perforation/fistula, (n=2), hyperglycemia (3), hypokalemia (3), hypertension (2), fatigue (1), alk phos elevation (1; lab only), hypoalbuminemia (1), and volume depletion (1). Other events of interest were: Gr1–2 mucositis (n=10), Gr1 hyperlipidemia (11). Of 17 pts evaluable for response, 4 pts had SD as best response (median 24 wks, range 17–31+ wks); there were 3 minor responses in pts who had progressed on B (median 16 wks, range 16–27 wks). No CR or PR were seen. Biomarker data is pending. Conclusions: B+E has activity in refractory mCRC in pts who had progressed on a B-based regimen, suggesting B+E may overcome resistance to B. Patient accrual is continuing and updated data will be presented.

[Table: see text]
Randomized phase II study of perifosine in combination with capecitabine versus capecitabine alone in patients with second- or third-line metastatic colon cancer
Authors: Vukelja S. , Richards D. , Campos L. T. , Bedell C. , Hagenstad C. , Hyman W. , Letzer J. , Gardner L. , Sportelli P. , Nemunaitis J.
Published: August 2020

4081

Background: Perifosine (Peri), a synthetic alkylphospholipid, inhibits or modifies a number of different signal transduction pathways (AKT, MAPK and JNK). Peri as a single agent or in combination with other cytotoxic agents, has shown clinical benefit with a manageable safety profile. In a phase I solid tumor trial, Peri was safely combined with capecitabine (Cap) and demonstrated interesting activity in patients (pts) with metastatic colorectal cancer (mCRC), with one patient progression-free for 49 weeks (wks). To assess the true effect of Peri, a phase II was initiated as an exploratory randomized double-blind, placebo controlled study where mCRC pts received Cap in combination with Peri or placebo. Methods: Pts with 2nd or 3rd line mCRC, not previously treated with single agent Cap. ECOG PS 0–1, normal organ/marrow function required. Dose for Cap was 825 mg/m2 BID d 1–14 q 3 weeks. Dose for Peri or placebo was 50 mg qd. Primary outcome analyses included median time to progression (TTP) and response rate (CR+PR). Results: 37 pts have been randomized. Median age 68 (range 32–83) and 57% were male. Median prior Rx was 2 (range 1 - 5). For the analyses, 25 pts were unblinded (12 too early) with 22/25 pts evaluable for response (2 pts off for toxicity at d 14, 46 and 1 patient off at d 4 for other disease; all 3 pts were on Cap + placebo). Results in table below. The log-rank p-value comparing active to placebo for TTP is 0.01. As of 12/08, all unblinded pts are off treatment and 11/12 that were too early remain on treatment with enrollment ongoing. Most frequent (>5%) grade 3 /4 adverse events for Cap + Peri was hand/foot syndrome (16%) and anemia (8%); for Cap + placebo was fatigue (8%). Conclusions: Perifosine in combination with capecitabine was well tolerated, clinically active and more than doubled median TTP over capecitabine alone in pts with advanced, metastatic CRC.

[Table: see text]

[Table: see text]