bluuebunny/crossref_metadata_2025 huggingface dataset:
Use of HER2 gene amplification to identify patients with metastatic colorectal cancer resistant to anti-EGFR monoclonal antibodies.
Authors: Barbara Cecilia , Martin Vittoria , Molinari Francesca , Landi Lorenza , Riva Alice , Saletti Piercarlo , de Dosso Sara , Geva Ravit , Tejpar Sabine , Fountzilas George , Kalogeras Konstantine T. , Frattini Milo , Cappuzzo Federico
Published: February 2017

474

Background: KRAS mutation represents the only validated biomarker used in clinical practice for selection of metastatic colorectal cancer (mCRC) candidates for therapy with the anti-Epidermal Growth Factor Receptor (EGFR) monoclonal antibodies. Previous studies conducted in small cohorts of patients suggested that HER2, the major EGFR partner, could modify the sensitivity to anti-EGFR agents. Aim of the present study was to investigate the role of HER2 gene status in a cohort of mCRC patients treated with cetuximab or panitumumab.

Methods: 266 chemorefractory mCRC patients treated with cetuximab or panitumumab alone or in combination with chemotherapy were collected in an international consortium effort. HER2 gene status was analyzed using the dual-color FISH assay LSI HER2/neu-CEP17 (PATHVYSION, Abbott) in one central lab, whereas KRAS/BRAF mutations were investigated locally. HER2 gene amplification was defined as the presence of a ratio between HER2 gene and chromosome 17 centromere > 2.

Results: An objective response to anti-EGFR therapy (complete or partial response according to RECIST criteria) was observed in 79/266 (29%) of patients. Twelve cases (4.5%) showed the classical pattern of HER2 gene amplification (R>2) in the whole tissue (>80% of tumor cells). By matching HER2 gene status with clinical response we observed that HER2 gene amplification was significantly related to therapy resistance (p<0.0001). Moreover, analysis of follow-up data indicated that HER2 gene amplification was significantly associated with a worse progression free survival (PFS, p=0.0025) and with a trend for a worse overall survival (p=0.062). Similar associations were also observed in the KRAS/BRAF wild-type patients.

Conclusions: Data from this large retrospective study suggest that HER2 gene status evaluated by FISH may represent an additional marker useful for the prediction of mCRC patients’ response to EGFR-targeted therapies, in line with very recent evidence. In particular, patients with HER2 gene amplification seem to be resistant and show a shorter PFS. Future studies are needed to deeply investigate the clinical and biological meaning of HER2 gene status deregulation in mCRC.
Circulating tumor cells as a surrogate marker for determining response to chemotherapy in Japanese patients with metastatic colorectal cancer.
Authors: Matsusaka Satoshi , Suenaga Mitsukuni , Mishima Yuji , Terui Yasuhito , Shinozaki Eiji , Mizunuma Nobuyuki , Hatake Kiyohiko
Published: February 2017

486

Background: The purpose of this study was to investigate the potential of circulating tumor cells (CTCs) as a surrogate marker of clinical outcome in metastatic colorectal cancer (mCRC) patients in order to identify Japanese patients responsive to oxaliplatin-based chemotherapy.

Methods: The treatment regimen was oxaliplatin-based chemotherapy. Collection of CTCs from whole blood was performed at baseline and at 2 and 8-12 weeks after initiation of chemotherapy. Isolation and enumeration of CTCs was performed using immunomagnetics.

Results: Between January 2007 and April 2008, 64 patients with mCRC were enrolled in this prospective study.Patients with ≥3 CTCs at baseline and at 2 and 8-12 weeks had a shorter median progression-free survival (8.5, 7.3, and 1.9 months, respectively) than those with <3 CTCs (9.7, 10.4 and 9.1 months, respectively) (log-rank test: p=0.047, p<0.001, and p<0.001, respectively). Patients with ≥3 CTCs at 2 and 8-12 weeks had a shorter median overall survival (10.2 and 4.1 months, respectively) than those with <3 CTCs (29.1 and 29.1 months, respectively) (p<0.001 and p=0.001, respectively). A spurious early rise in CEA level was observed in 11 patients showing a partial response. On the other hand, no rise in early CTC level was observed among responders.

Conclusions: The clinical utility of CTC enumeration in improving our ability to accurately assess treatment benefit and in expediting the identification of effective treatment regimens for individual Japanese patients.
Genetic polymorphisms by race/ethnicity among colon cancer patients in Los Angeles County.
Authors: Lee Wendy , Duldulao Marjun Philip , Nelson Rebecca A. , Shen Xiaoming , Li Wenyan , Lu Jianming , Garcia-Aguilar Julio , Kim Joseph
Published: February 2017

492

Background: Though disparate outcomes in colon cancer may be multifactorial, racial/ethnic disparities persist despite adjusting for these factors. Genetic alterations, including single-nucleotide polymorphisms (SNPs), have been shown to predict treatment response in colorectal cancer. Here, we evaluate the variability of genetic alterations in colon cancer patients by examining SNPs in major racial/ethnic groups.

Methods: We obtained 76 normal tissue specimens from colon cancer patients of different race/ethnicity at our institution. DNA was extracted and analyzed for 6 SNPs (MTHFR 677C>T, XRCC1 685C>T, XRCC1 1301G>A, XPD 2282A>C, TP53 215G>C, and CCND1 870G>A) by polymerase chain reaction and direct sequencing. Prevalence of each allelic combination was compared between groups by the chi-square test.

Results: Archived colon cancer tissues were obtained from whites, blacks, Hispanics and Asians (n=19 per group). From genotyping, we identified statistically significant differences in prevalence of CCND1 870G>A between groups ( Table , p=0.0428). Specifically, whites and Asians had significantly higher prevalence of CCND1 870G>A than blacks and Hispanics (100% and 94%, vs. 68% and 79%, respectively). Furthermore, whites and Asians were more frequently heterozygous (G/A) for the SNP (89% in both), whereas Hispanics comprised the largest proportion (16%) of patients homozygous for CCND1 870G>A. Overall, the allelic frequency of CCND1 870G>A varied among the racial/ethnic groups. Other SNPs in treatment-related pathways were evaluated, but there was no difference in prevalence of the other 5 SNPs between groups.

Conclusions: Our findings demonstrate that detection of specific genetic polymorphisms differs between the major racial/ethnic groups with colon cancer. Differences in the prevalence of CCND1 870G>A, which affects cell-cycle progression, suggests a potential mechanism for disparities in cancer susceptibility and progression. Therefore, identification of such genetic variability may support a genetic basis for racial disparities in cancer outcomes.

[Table: see text]
Predictors of primary and distant site surgery in patients with stage IV colorectal cancer.
Authors: Uyeno Lori , Nelson Rebecca A. , Singh Gagandeep , Garcia-Aguilar Julio , Kim Joseph
Published: February 2017

499

Background: Operative management of primary tumor and distant metastases in stage IV colorectal cancer is highly variable and removal of asymptomatic primary tumors in the setting of distant disease remains controversial. The purpose of our study was to describe the patterns of surgery in stage IV colorectal cancer patients in a US population-based cohort and explore patient and tumor characteristics associated with treatment selection and survival.

Methods: Stage IV colorectal cancer patients in Los Angeles County from 2000 to 2006 were identified using the LA County Cancer Surveillance Program registry. The cohort included 2,956 patients (2,211 stage IV colon and 745 stage IV rectal cancers). Cox proportional hazard models were used to estimate survival. Treatment was categorized as primary surgery, distant site surgery, or chemotherapy only. Multivariate logistic regression was used to identify patient and tumor variables associated with treatment.

Results: Greater than 65% of the stage IV colorectal cohort had primary tumor surgery of which 51% had chemotherapy. Only 4.5% had surgery to remove distant disease. Patients who had chemotherapy only and no surgery was 15%. Median survival of primary surgery, distant surgery, or chemo only was 14, 21, and 11 months. Multivariate Cox regression revealed that primary surgery and distant surgery had a decreased risk of death compared to no surgery (HR= 0.4 p<.0001, HR=0.7 p<.004). Multivariate logistic regression was used to identify predictors associated with treatment selection. Patients >65 years (p<.003); low socioeconomic status (p<0.05); and rectal tumors (p<.0001) were less likely to have surgery of the primary tumor. Female gender (p<.0001) and primary tumor surgery (p<.0001) were predictors for distant site surgery whereas age>65 years (p<.0001) had a negative association.

Conclusions: Our population-based study of stage IV colorectal cancer patients suggests that the majority of stage IV patients with distant disease have surgery, but less than 5% have surgery for distant disease. Although survival of stage IV colorectal patients is improved with surgery, increasing age, low socioeconomic status, and rectal tumors are negative predictors for undergoing surgery.
Establishment of primary gastric and gastroesophageal (GE) junction xenografts: A model for characterizing disease heterogeneity.
Authors: Janjigian Yelena Yuriy , Mazgaj Robert , Carbonetti Gregory , Tang Laura H. , Hefter Blake , Kelsen David Paul , de Stanchina Elisa , Strong Vivian E.
Published: February 2017

51

Background: Gastric cancer is a heterogeneous disease that may be subdivided into distinct subtypes—proximal/gastroesophageal (GE) junction, diffuse/signet ring type, and distal gastric cancers—based on histopathologic and anatomic criteria. Each subtype is associated with unique epidemiology and gene expression. Human epidermal growth factor receptor (HER2) is a validated treatment target in gastric cancer. For patients with metastatic disease, the available cytotoxic agents are applied indiscriminately to all disease subtypes, and with only modest success. The purpose of this study is to establish xenograft models from gastric cancer subtypes to improve our understanding of disease heterogeneity and develop therapies geared for each subtype of gastric cancer.

Methods: Fresh specimens obtained from resected primary or metastatic tumors under aseptic conditions. 1 g tumor samples injected SQ into flanks of NOD/SCID mice. Xenografts established after 5 passages and maintained by serial transplantation into new mice. Cell cultures established after 5 in vitro passages; cell lines after 15 passages.

Results: To date 26 tumor samples have been implanted from which 8 xenografts have been established. Table below summarizes the results. Cell line established from HER2-positive, trastuzumab refractory tumor resected from brain metastasis.

Conclusions: HER2-positive tumors have a favorable xenograft yield. Prior chemo or radiation therapy does not impact engraftment. Standard and experimental therapies are being tested on these xenografts to further validate difference in their biology and guide rational design of clinical trials.

[Table: see text]
Impact of the gene expressions of thymidylate synthase and dihydropyrimidine dehydrogenase on survival in patients enrolled in the ACTS-GC study.
Authors: Sasako Mitsuru , Terashima Masanori , Ichikawa Wataru , Ochiai Atsushi , Kitada Koji , Kurahashi Issei , Sakuramoto Shinichi , Katai Hitoshi , Sano Takeshi , Imamura Hiroshi
Published: February 2017

52

Background: The efficacy of 5-FU-based therapy is basically related to the expression of enzymes involved in pyrimidine metabolism, such as thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), thymidine phosphorylase (TP) and orotate phosphoribosyltransferase (OPRT). Biomarker analysis was conducted to evaluate the influence of these expressions on the outcomes of patients enrolled in the ACTS-GC study, a randomized phase III trial, which demonstrated the efficacy of adjuvant treatment with S-1 after D2 dissection for stage II and III gastric cancer (Sakuramoto et al., NEJM 2007)

Methods: Formalin-fixed paraffin-embedded specimens were available for 829 of a total of 1,059 (78.3%) patients. Expressions of TS, DPD, TP and OPRT were measured by RT-PCR in macrodissected tumor specimens and normalized to β-actin expression as the reference gene. The expression levels of each gene were categorized as low or high at the 33.3rd or 66.7th percentile. If the p-value of the interaction was less than 0.1, statistical significance was assumed.

Results: Expressions of the 4 genes were quantifiable in 97% of the 829 specimens and the distributions were balanced across the arms. The hazard ratio (HR) for overall survival (OS) of S-1 to surgery alone was smaller in the high-TS (highest one-third) (HR, 0.370; 95%CI, 0.221-0.619) than in the low-TS group (lower two-thirds) (HR, 0.757; 95%CI, 0.563-1.018). This interaction between TS expression and OS was statistically significant (p=0.015). Similarly, the HR for OS of S-1 to surgery alone was smaller in the high-DPD (higher two-thirds) (HR, 0.520; 95%CI, 0.376-0.720) than in the low-DPD group (lowest one-third) (HR, 0.848; 95%CI, 0.563-1.276). This interaction (p=0.065) was also statistically significant. There was no interaction between the TP or OPRT expression and OS.

Conclusions: This large biomarker study showed that intratumoral TS and DPD gene expressions may be predictive markers of the efficacy of S-1 in gastric cancer patients receiving postoperative adjuvant chemotherapy with S-1.
Systematic survey of therapeutic trials for metastatic colorectal cancer.
Authors: Chen Zhiyu , Overman Michael J. , Garrett Chris R. , Jiang Zhi-Qin , Wolff Robert A. , Abbruzzese James L. , Eng Cathy , Kopetz Scott
Published: February 2017

523

Background: The FDA’s 2004 “Critical Path Initiative” encouraged novel clinical trials and incorporation of biomarker-based enrichment studies to improve drug development. A survey of metastatic colorectal cancer (mCRC) trials from 2006 (Kopetz et al. JCO) demonstrated a very low utilization of novel therapies and minimal biomarker integration. The extent of change of mCRC clinical trials 5 years later is unknown.

Methods: The NIH clinical trials database was searched for enrolling phase II or III treatment trials in mCRC, using previously published search strategies. Enrichment studies were defined by the presence of a tumor-based biomarker in the eligibility criteria. Trials were categorized according to FDA approval status and mechanism of action of the included agents, with novel agents being defined as ones not targeting the same protein or cellular mechanism as an existing agent that is FDA-approved for mCRC.

Results: 162 trials were identified for mCRC pts with planned enrollment of 31,050 mCRC patients, representing a 58% and 45% increase from the 2006 survey, respectively. Fewer studies used only agents already FDA-approved for mCRC in 2011 compared to 2006 (39% vs 54%, respectively, P=0.02), with a substantial increase in the number of trials that included agents against novel therapeutic targets (n=49 vs 13, P=0.001). Enrichment trial designs were identified in 64 studies, compared with 13 in 2006 (P=0.0001). While the majority of these designs were for KRAS-wild type tumors and EGFR monoclonal antibodies, there has been a 5-fold increase in novel biomarker-directed trials (n=3 vs 15). However, 101 trials (62%) with an anticipated enrollment of over 21,000 mCRC pts, neither incorporate a novel agent nor biomarker in their trial design.

Conclusions: Compared with trial in 2006, current mCRC trials are more likely to evaluate novel agents and incorporate enrichment designs with tumor-based biomarkers. Yet despite the rapid development of biomarker technology for pt enrichment and wider acceptance of innovative trial designs, most clinical trials are empiric in design and fail to integrate recommendations from the FDA Critical Path Initiative.
HLA-cw polypmorphism and killer cell immunoglobulin-like receptor (KIR) gene analysis in Korean patients with colorectal cancer.
Authors: Kim Hyung Jin , Lee In Kyu , Kang Won-Kyung , Kwon Jung Hyun , Oh Seong-Taek
Published: February 2017

525

Background: Many kinds of genetic and environment factors are involved in colorectal cancer development. Natural killer cells (NK cells) play important roles to protect from viral infections and the early development of cancers, and it is activated or inhibited by killer cell immunoglobulin-like receptors (KIR) which bind to HLA class I. KIR genes are encoded on chromosome 19q13.4. And there are 7 kinds of activating KIRs, and another 7 kinds of inhibiting KIRs. The genetic polymorphisms of KIR genes effect the expression of KIR on NK cells, and there are ethnic differences. In this study, we were trying to investigate the KIR genotype of Korean colorectal cancer patients.

Methods: DNAs were extracted from the peripheral bloods from normal populations and Korean colorectal cancer patients. KIR genes were amplified using PCR-SSP methods, and HLA-Cw genes were characterized using PCR methods. The results were analyzed between cancer patients and normal control group.

Results: KIR2DL2 and KIR2DS2 were found at low rate and KIR2DL3 were found at high rate compare to the Eastern studies, but the rates were similar with Japan study. In this study, KIR2DS5 (33.2% vs. 20.8%, p-value<0.007) was increased in colorectal cancer group, and in rectal cancer subgroup, KIR3DL1 (93.2%, vs. 98.1%, p-value<0.05), KIR2DS2 (7.8% vs. 19.5%, p-value<0.01), KIR2DS4 (93.2% vs. 98.1%, p-value<0.05) were decreased significantly. HLA-Cw6 (9.1% vs. 15.7%, p-value<0.05) and HLA-Cw7 (17.4% vs. 27.7%, p-value<0.02) were decreased in colorectal cancer group, but no difference was found when they were classified to HLA-C1 and HLA-C2 group. Among the patients with HLA-C1 homozygote, KIR2DS2 was decreased significantly (5.8% vs. 14.5%, p-value<0.004).

Conclusions: There are ethnic differences of KIR genotypes. KIR2DS5 is increased in Korean colorectal cancer patients, and in rectal cancer subgroup, KIR3DL1, KIR2DS2 and KIR2DS4 are decreased, so there are immunologic differences between colon and rectal cancers. And among the patients with HLA-C1 homozygote, KIR2DS2 is decreased. Therefore KIR2DS2 in presence of their ligand (HLA-C1 group) may have protective effect against colorectal cancer.
A phase II open-label trial of dacomitinib monotherapy in patients with HER2-positive advanced gastric cancer after failure of at least one prior chemotherapy regimen.
Authors: Oh Do-Youn , Lee Keun-Wook , Cho Jae Yong , Kang Won Ki , Rha Sun Young , Bang Yung-Jue
Published: February 2017

54

Background: HER2 is a clinically relevant therapeutic target in gastric cancer. Trastuzumab plus chemotherapy has improved patients’ survival in HER2 (+) advanced gastric cancer (AGC). Pan-HER inhibitor shows significant antitumor effects in in vitro and xenograft model of HER2 (+) gastric cancer. The aim of this study was to find the efficacy/safety of dacomitinib, a irreversible pan-HER tyrosine kinase inhibitor by Pfizer, in HER2 (+) AGC patients.

Methods: We enrolled AGC patients with HER2 FISH (+) or HER2 IHC 3+ who were treated with at least one prior palliative chemotherapy regimen and with ECOG PS 0-2, normal cardiac ejection fraction. Patients were treated with dacomitinib 45 mg once daily continuously every 4 weeks. Response was evaluated every 8 weeks using RECIST v1.1 and safety was assessed with CTCAE v4.0. The primary endpoint was 4 month-progression free survival rate (4m-PFS). PK and PD study were also conducted.

Results: A total of 27 patients were enrolled. The median age was 61 (range: 43-80). Twenty two patients were male. The ECOG PS was 0 in 9 patients, 1 in 16, and 2 in 2. The number of prior palliative chemotherapy regimen was 1 in 7 patients (25.9%), 2 in 9 (33.3%), more than 3 in 11 (40.7%). Six patients received prior anti-HER2 therapy (trastuzumab 2, lapatinib 2, lapatinib or placebo in clinical trial 2) A total of 80 cycles were delivered (median 2 cycles per patient, range: 1-6). The 4m-PFS was 22.2 % and median progression-free survival was 2.1 months (95% CI: 2.3-3.4) There was 2 PR, 9 SD and 16 PD, resulting in 7.4 % response rate (95% CI: 0-17.5%) and 40.7 % disease control rate (95% CI: 21.9-59.6%). Median overall survival was 7.1 months (95% CI: 4.4-9.8). The most common toxicities were skin rash, diarrhea, and fatigue, but most of them were grade ½. Grade 3 skin rash was observed in 3 patients. There was no treatment-related death.

Conclusions: Considering the heavily pretreated nature of enrolled patients, the dacomitinib is active and safe treatment option in HER2 (+) AGC patients. The results of PK and PD studies will be also presented at the meeting. (ClinicalTrials.gov: NCT01152853 )
A single-institution phase II trial of five fractions of radiotherapy followed by four courses of FOLFOX chemotherapy as preoperative therapy for rectal adenocarcinoma.
Authors: Myerson Robert J. , Parikh Parag J , Tan Benjamin , Hunt Steven , Fleshman James W , Birnbaum Elisa H , Mutch Matthew G , Kodner Ira J , Safar Bashar , Naughton Michael , Picus Joel , Sorscher Steven , Lockhart Albert Craig , Rigden Caron , Suresh Rama , Wang-Gillam Andrea , Hall Lannis
Published: February 2017

553

Background: Preoperative radiotherapy (RT) with 5FU chemotherapy (CT) is a standard of care for cT3-4 rectal cancer. Studies incorporating additional cytotoxic agents have resulted in increased morbidity with little benefit. We evaluate a template that seeks to (1) include the known benefits of preoperative RT on local response/control, (2) provide for preoperative multi-drug CT, (3) avoid the morbidity of concurrent RT and multi-drug CT.

Methods: Patients with cT3-4, any N, any M rectal cancer were eligible. Patients were confirmed to be candidates for surgery, provided the response was sufficient. Preoperative treatment was 5 fractions RT (25 Gy to involved mesorectum, 20 Gy to elective nodes), followed by 4 cycles of mFOLFOX6. Postoperative CT was at the discretion of the medical oncologist. The principal objectives are to demonstrate that this regimen can achieve T stage down staging (ypT < cT) and acute grade 3+ gastrointestinal (GI) morbidity equal to or better than historical controls.

Results: Accrual opened late 2009, with 60 patients enrolled through 8/2011. Forty-six have had sufficient time to proceed to surgery with 4 having grade 3 preoperative GI morbidity. Two cases are inevaluable for response: one withdrew consent prior to CT and one received no surgery due to progression of cM1 disease (with local response). The 44 evaluable cases included 4 cT4 and 40 cT3; 32 (73%) cN+, 4 cM1. At surgery 33 (75%) had ypT0-2 residual disease including 13 (30%) ypT0, 14 (32%) were ypN+. Cases were sub-analyzed by whether disease was too advanced for the upcoming ACOSOG preoperative FOLFOX vs. 5FU-RT trial. By ACOSOG eligibility, response rates were (eligible first, ineligible second) ypT0: 10/22 (45%) vs. 3/22 (14%) (p = 0.05), ypT0-2: 19/22 (86%) vs. 14/22 (64%) (p = NS).

Conclusions: This regimen achieves high response rates with acceptable morbidity. The response for ACOSOG eligible cases meets pre-determined stopping criteria for proceeding to a randomized trial. Our successor study will randomize to this regimen vs. FOLFOX alone for ACOSOG eligible cases, while initially continuing as a single arm trial for ACOSOG ineligible cases.
A phase I/II trial of the multipeptide cancer vaccine IMA910 in patients with advanced colorectal cancer (CRC).
Authors: Mayer Frank , Mayer-Mokler Andrea , Nowara Elzbieta , Torday Laszlo , Ludwig Joerg , Kuttruff Sabrina , Weinschenk Toni , Walter Steffen , Singh Harpreet , Reinhardt Carsten
Published: February 2017

555

Background: Treatment interruption after 12 weeks of oxaliplatin-based therapy followed by re-introduction upon signs of progression results in better overall tolerability and quality of life compared to continuous therapy while survival rates are only modestly impaired. Specific immunotherapy may provide a safe and tolerable intervention to prolong time to re-introduction and eventually overall survival. IMA910 is a novel peptide-based cancer vaccine consisting of 13 tumor-associated peptides (TUMAPs), which are naturally presented on MHC molecules of colorectal tumors.

Methods: HLA-A*02+ advanced CRC patients being at least clinically stable after 12 weeks of first-line oxaliplatin-based therapy were enrolled. After immunomodulation with a single low dose of cyclophosphamide (300 mg/m2), patients were immunized intradermally (up to 16 vaccinations) with IMA910 in combination with GM-CSF (cohort 1; n=66) or IMA910 with GM-CSF plus topically applied imiquimod (cohort 2; n=26). T-cell responses to individual IMA910 peptides were analyzed by HLA-multimer and intra-cellular cytokine assay. Analysis of disease control rates (DCR) and progression-free survival (PFS) was based on RECIST-centrally reviewed CT/ MRI scans.

Results: IMA910 was overall well tolerated with most AEs being mild and transient local site reactions. Three patients presented with systemic hypersensitivity reactions, all of which were observed after ≥10 vaccinations and were confirmed to have an in vitro reaction against GM-CSF in all cases. IMA910 induced immune responses in 71% and 72% of patients in the two cohorts, respectively. Interestingly, patients developing CD8 T-cell responses against multiple TUMAPs had a better clinical outcome compared to others, in terms of DCR (18% vs. 2% at 6 months; p=0.012) and PFS (HR: 0.652; p=0.039). OS data will be shown at the meeting.

Conclusions: Vaccination with IMA910 is safe, well tolerated, and immunogenic. Significantly better clinical outcome of multi-TUMAP responders in comparison to patients with one/no TUMAP response indicates clinical activity of IMA910 in 1st line advanced CRC patients.
Adjuvant chemoradiation therapy with 5-FU/LV (INT-0116) versus S-1 chemotherapy in completely resected gastric cancer: Practice pattern and feasibility at a single institution.
Authors: Hwang Deok Won , Lee Su Jin , Lee Jeeyun , Park Se Hoon , Park Joonoh , Park YoungSuk , Lim Hoyeong , Kang WonKi
Published: February 2017

57

Background: Considering the high incidence of gastric cancer worldwide, large-scaled phase III adjuvant trials have been relatively scarcely reported. Until 2010, there have been two large-scaled adjuvant trials in gastric cancer that showed survival benefit from adjuvant chemotherapy +/- radiotherapy: S-1 monotherapy and chemoradiation therapy (CRT) with 5-FU/LV. There has been no direct comparison between S-1 monotherapy and CRT. We analyzed the practice pattern of adjuvant treatment at single institution in Korea in terms of patient’s preference, compliance rate, adverse events between CRT and S-1.

Methods: From January 2008 to July 2009, 405 gastric cancer patients who had received adjuvant therapy after curative resection were included for the study. The CRT regimen was INT 0116 protocol. The S-1 monotherapy was to administer 40-60 mg bid, for 28 days, every 6 weeks (8 cycles).

Results: Of the total 405 patients, 244 (60.3%) patients had CRT and 161 (39.7%) patients had S-1 monotherapy. The median age was 54 years (range, 24-80) and most of the patients were ECOG PS 0-1. S-1 group was more common than CRT group in Stage II (52.2% for S-1 vs. 47.8% for CCRT) and CRT group was more common in stage III-IV (72.4% for CCRT vs. 27.6% for S-1, p<0.001). The patients’ compliance for the planned treatment was significantly higher in CRT group (95.1% vs. 72.8%, p<0.001). Most common reason for cessation of S-1 therapy was patients’ refusal. For severe adverse events, grade 3-4 neutropenia was substantially more frequent in CRT group (40.2% vs. 8.7%, p<0.001) and GI toxicities of nausea and mucositis were frequent in CRT group when compared with S-1 group (CRT vs S-1; nausea, 5.7% vs <1%; p=0.002; mucositis, 7.4% vs 2.5%; p=0.034).

Conclusions: Patients with advanced stage (III–IV) preferred CRT to S-1. The compliance was significantly higher for the CRT group despite of higher incidence of adverse events.
MRI-based selection of patients with metastatic extramesorectal rectal cancer nodes for preoperative chemoradation.
Authors: Maas Monique , Lambregts Doenja MJ , Gillissen Freek , Engelen Sanne ME , Lahaye Max J , Buijsen Jeroen , Beets-Tan Regina GH , Beets Geerard L
Published: February 2017

570

Background: 20% of rectal cancer patients have metastatic lymph nodes outside the mesorectum (EMRs). These EMR node positives are associated with poor prognosis. Accurate selection would help to tailor treatment and improve prognosis for these patients.

Methods: Rectal cancer patients were included in a study in which treatment was based on (contrast-enhanced) MRI. EMR-status was predicted by an expert radiologist. Based on this prediction patients underwent chemoradiation (CRT) of the EMRs. 6-8 weeks after CRT EMRs were restaged. If still involved, the EMRs were resected. When the EMRs were sterilised by the CRT, they were not resected. Patients were followed 3 to 6-monthly after surgery by a combination of modalities. 3-year outcome was estimated with Kaplan-Meier curves.

Results: 50 patients with suspected EMRs were included. Median follow-up was 26(0-50) months. In 13 patients EMRs were resected after CRT and in only 2/13 positive nodes were found. Of the remaining 37 patients 5 had a local recurrence (LR). In total 32+11=43 patients (86%) had no involved EMRs after CRT. Five patients had metastasis of whom 2 also had a LR. 3-year LR was 2.3%, 3-year DFS was 86% and 3-year OS was 90%.

Conclusions: MRI-based selection of patients with EMRs for CRT provides adequate local control. Distant metastasis is the main cause of poor prognosis in these patients. When MRI is used for EMR identification and thus for identification of patients who need CRT also on the obturator regions, patients can be spared an extensive resection with associated morbidity.
Microsatellite high colorectal cancer: Does the underlying mechanism for instability matter?
Authors: Hyngstrom John Robert , Rodriguez-Bigas Miguel A. , Chang George J. , Taggart Melissa W. , Skibber John Michael , Feig Barry W. , You Y. Nancy
Published: February 2017

575

Background: Microsatellite instability (MSI) testing in colorectal cancer (CRC) provides prognosis, predicts chemotherapy response, and guides diagnosis of hereditary nonpolyposis colorectal cancer (HNPCC) syndrome. MSI can be sporadic or hereditary, arising from somatic or germline mutations in DNA mismatch repair (MMR) genes respectively. The clinical implications of these distinct mechanisms are uncertain.

Methods: Patients who underwent MSI testing for CRC between 2000 and 2011 were identified. MSI-high (MSH) CRCs were defined by: pathogenic mutation in MMR genes; >30% of markers with allelic shift in PCR-based MSI testing; or loss of expression in at least 1 MMR protein on immunohistochemistry. The subset with MLH1 gene promoter methylation, BRAF mutation, or EPCAM mutation was considered sporadic. Clinicopathologic features and disease-free survival (DFS) were examined in reference to microsatellite stable (MSS) CRCs.

Results: MSH CRC’s, 92 germline and 49 sporadic, were compared with 105 MSS CRCs. Compared to MSS CRCs, both germline and sporadic MSH CRCs more commonly arose in the proximal colon (63% and 92%, vs. 30%; p<.001), exhibited mucinous/signet ring histology (40% and 47%, vs. 16%; p<.001) and lymphocytic infiltrate/Crohn’s like reaction (15% and 49%, vs. 8%; p<.001). Further comparison between germline vs. sporadic MSH CRCs revealed significant differences in median age (44 yrs. vs. 66; p<.001), proximal colon tumor location (63% vs. 91%; p<.001), AJCC stage (33% vs. 51% Stage III or IV; p<.025) and presence of lymphocytic/Crohn’s like reaction (49% vs. 15%, p<.001). Moreover, sporadic MSH CRCs more often had poor prognostic features including poor differentiation (51% vs. 28% in germline, p<.025) and lymphovascular invasion (57% vs. 34% in germline, p<.007). No difference was observed in stage-stratified DFS between germline vs sporadic MSH CRCs.

Conclusions: Patients with sporadic MSH CRCs exhibit distinct clinicopathologic features compared to those with germline MSH tumors. Despite poor prognostic features, no apparent survival difference was observed. Further characterization of these distinct groups is warranted to explain the discordance between risk factors and outcomes.
Cetuximab (C225) in the first-line treatment of advanced colorectal cancer (CRC) patients (Pts) with K-ras wild-type (WT) tumors: Does the choice and schedule of fluoropyrimidine (Fp) matter?
Authors: Ku Geoffrey Yuyat , Haaland Benjamin , Lopes Gilberto de Lima
Published: February 2017

576

Background: C225, a monoclonal antibody against the epidermal growth factor receptor, has been shown to inconsistently improve response rates (RR), progression-free survival (PFS) and overall survival (OS) in the first-line treatment of advanced CRC Pts with K-ras WT tumors.

Methods: We performed a meta-analysis of four trials where K-ras WT Pts received a Fp (capecitabine (C) or bolus (b) or infusional (CI) 5-fluorouracil (5-FU)) and oxaliplatin (oxali) or irinotecan (CPT) ± C225 (CRYSTAL, OPUS, COIN and NORDIC VII trials) and one trial, where K-ras WT and mutant Pts received C225 with capecitabine (C) and oxali or CPT (AIO study). We sought to determine if the choice of Fp affects the response to C225. A mixed effects model similar to that of DerSimonian and Laird was fit by restricted maximum likelihood and used to obtain an overall estimate of the effect of C225 in the presence of CI 5-FU, an indirect estimate of the decrease in the effect of C225 in the presence of C/b5-FU relative to CI 5-FU, and an estimate of the study-to-study variability.

Results: Only Pts treated with CI 5-FU based chemo derived benefit from C225. Relative to CI 5-FU, Pts treated with C or b5-FU based doublet chemo had a decrease in RR, PFS and OS. The choice of oxali or CPT did not affect responses to C225.

Conclusions: The lack of benefit for C225 with C or b5-FU chemo is unexpected. A possible explanation is increased toxicity with C225, which led to dose reduction of C only in the C225-arm of the COIN study; however, increased toxicity was not seen in the NORDIC VII study. Pending further study, only CI 5-FU regimens should be used with C225.

[Table: see text]
Evaluation of relapse-free survival in T3N0 colon cancer: The role of chemotherapy—A multicentric retrospective analysis.
Authors: Grande Roberta , Cosimelli Maurizio , Gemma Donatello , Ciancola Fabrizio , Corsi Domenico C. , Rossi Lorena , Sperduti Isabella , Fabbri Maria Agnese , Mancini Raffaello , Ruggeri Enzo , Zampa Germano , Bianchetti Sara , Gamucci Teresa
Published: February 2017

578

Background: Use of adjuvant chemotherapy (AC) in stage II colon cancer (CC) is still under debate. Choice should be based on patients (pts) and disease characteristics. According to worldwide guidelines AC should be considered in high-risk (H) T3N0 pts. No data are available for better option in low-risk (L) pts. Aim of the study is to evaluate relapse-free survival (RFS) and disease-free survival (DFS) retrospectively in T3N0 CC pts related to treatment.

Methods: RFS and DFS are evaluated with Kaplan Meier method. In order to find the optimal cut off for node number the receiver operating characteristics curve analysis and maximally selected rank statistics were performed. Multivariate Cox proportional hazard model was developed using stepwise regression, enter limit and remove limit were p = 0.10 and p = 0.15 respectively.

Results: 1,000 pts with T3N0 CC were recruited. To date, data of 764 pts are available. Median age was 68 (29-93), M/F 42/344, grading 1/2/3 40/561/132; 303 L (40%), 356 H (46%), 105 unknown (14%); 121 (16%) pts showed symptoms (S) at diagnosis: 43 pts had perforation (P) or bowel obstruction (BO). Median sampled lymph nodes (LN) were 15 (1-76); 339 (44%) pts were treated with AC. Median follow up (fu) was 5 years (yr) (range 3-24). Survival analysis analysis was performed only for pts with a minimum fu of 3 yr and younger than 80 (79%). 5 yr RFS was 79% and 5 yr DFS was 77%. At multivariate analysis S, LN and AC were prognostic factors for RFS. AC is prognostic factor for all endpoints (Table). In L group 5 yr RFS was 88% in treated pts and 71% in non-treated pts (p 0.004); in H group was respectively 84% and 70% (p 0.002).

Conclusions: Preliminary data confirmed the role of known prognostic factors and suggest the relevance of AC also in L stage II T3N0 CC pts. However, the highest risk in L subgroup should be identified to be submitted to AC. Data collection is ongoing.

[Table: see text]
Are we getting better at treating patients with rectal cancer? A 15-year trend analysis.
Authors: Guller Ulrich , Koeberle Dieter , Warschkow Rene , Schmied Bruno , Cerny Thomas , Tarantino Ignazio
Published: February 2017

589

Background: The objective of this trend analysis was to assess whether clinical outcomes following rectal cancer resection have improved over a 15-year time period.

Methods: The present study is based on the colorectal database of the authors` hospital, one of the largest tertiary care centers of Switzerland. All patients undergoing a rectal cancer resection for stage I - IV disease were consecutively included between 1991 and 2005. The 15-year time period was subdivided into five 3-year periods, among which different outcomes were compared. All tests were two-sided, the level of statistical significance was set at 0.05.

Results: Overall, 682 consecutive patients undergoing a rectal cancer resection for stage I - IV disease were included. Mean age was 65 years (range: 24 to 93 years), 62.1% of patients were male, median ASA physical status was 2 (range 1 – 4). Among the various time periods, there were no significant differences regarding patients` demographics as well as tumor stage. All following outcomes significantly decreased over time: operating room time (max. 217minutes to 164 minutes, P-trend: <0.001), rate of abdomino-perineal resections (from 20.5% to 7.6%; P-trend < 0.001), rate of R1/2 resections (from 16.9% to 8.6%; P-trend: 0.008), rate of intraoperative complications (from 16.9% to 4.9%; P-trend: 0.018), rate of general postoperative complications (from 59% to 35.1%; P-trend <0.001), and rate of local recurrence (8.4% to 4.9%; P-trend:0.033). 5-year overall survival did not significantly change over time, neither in the overall patient cohort (P-trend: 0.476), nor in the subsets of stage I-III (P-trend: 0.675) and stage IV patients (P-trend: 0.486).

Conclusions: This first study in the literature based on a large cohort of consecutive stage I – IV rectal cancer patients provides compelling evidence that that operating room time as well as rates of abdomino-perineal resections, R1/2 resections, intra- and postoperative complications, as well as rates of local recurrence have significantly decreased from 1991 – 2005. However, there was no significant improvement of overall survival, neither in the overall cohort nor in the subsets of stage I-III versus stage IV rectal cancer patients.
Twenty years of chemotherapy for colorectal cancer (CRC): Progress made, insights gleaned.
Authors: Jawed Irfan , Wilkerson Julia , Duffy Austin G. , Fojo Antonio Tito
Published: February 2017

596

Background: The past 20 years have seen progress in CRC therapy with more effective agents and better medical, surgical and supportive care.

Methods: We conducted a systematic review of 101 phase III and large phase II trials in CRC to quantify benefit over time with first-line and subsequent therapies. Outcomes examined in the experimental (EA) and control arms (CA) included progression-free survival (PFS), overall response rate (ORR), stable disease (SD), overall survival (OS) and post-treatment survival (PTS). Data were analyzed according to dates of publication and median enrollment.

Results: Significant outcomes are reported; most had R2 values > 0.6. OS of EA improved 0.83 mos/yr. Importantly the OS of CA improved 0.58 mos/yr likely reflecting use of experimental therapies in CA in subsequent studies and improvement in CRC care over time as suggested by: (1) modest improvements of PFS: 0.33 [EA] and 0.26 [CA] mos/yr; (2) PTS gains of 0.48 [EA] and 0.29 [CA] mos/yr, accounting for majority of OS gains; and (3) lack of OS improvement in 14 second/subsequent line trials. Using logistic regression to examine all drugs as class predictors of increasing OS, oxaliplatin [OX], bevacizumab [BEV], and irinotecan [IRI] were significant in the EA, but only OX and BEV were significant in the CA. Capecitabine [CAP] and cetuximab/panitumumab [CET/PAN] were not significant in EA or CA, with CAP odds ratio towards null and CET/PAN odds ratio away from null. The lack of IRI effect in CA concurs with observation that only IRI regimens had worse OS in CA compared with EA. The CET/PAN results likely reflect lack of efficacy/harm in patients with WT KRAS tumors. As expected PFS and PTS correlate highly with OS, but importantly ORR had very high correlations with both PFS and OS. SD emerged as an “adverse” outcome, OS decreasing as SD rates increase.

Conclusions: OS of CRC patients has improved gradually over past two decades, with gains from chemotherapy but also other factors, such as lead-time bias, more loco-regional approaches and improved supportive care. IRI performed better in EA than in CA. CET/PAN had negative effects in the entire population. In CRC, ORR correlates highly with OS, while SD portends a poor outcome.
Factors associated with use of chemoradiation for rectal cancer.
Authors: Charlton Mary E. , Lin Chi , Pendergast Jane F , Chrischilles Elizabeth A. , Wallace Robert B
Published: February 2017

607

Background: Adjuvant or neoadjuvant chemotherapy (chemo) and radiation therapy (RT) have been the standard of care for virtually all patients with stages II/III rectal cancer for 20 years. However, recent analyses of the SEER database have demonstrated variation in treatment. Leveraging the clinical characteristics and patient beliefs available in the Cancer Care Outcomes Research and Surveillance Consortium (CanCORS) cohort, we determined the proportion and associated characteristics of those who received chemo and RT.

Methods: We identified CanCORS patients with stage II/III rectal cancer with primary site resection, and used data from patient surveys and abstracted medical records to construct variables (age, gender, marital status, race, education, income, insurance status, stage, comorbidity, patient treatment beliefs, staging procedures, tumor location/size, types of providers seen).

Results: Of the 310 eligible patients, 14% received neither chemo nor RT, 13% received chemo or RT, and 73% received both. Receipt of chemo and RT was associated with younger age, stage III, rectosigmoid junction (vs. rectum NOS) tumor, receipt of staging PET, and patient beliefs that chemo/RT would help them live longer, cure their cancer and help with symptoms. In a logistic model, age (<55 vs >65; OR=2.2, 95% CI: 1.31, 3.46), stage (III vs. II; OR=1.52, 95% CI: 1.06, 2.17), PET (OR=2.41, 95% CI: 1.15, 5.03) and rectosigmoid junction tumor (OR=1.59, 95% CI: 1.10, 2.29) were associated with receipt of chemo; similarly, age and rectosigmoid junction tumor were associated with RT. Of those who did not receive chemo or RT, 35% reported they did not think chemo/RT would help, 65% reported their doctor said chemo/RT would not help and 18% were worried about side effects; 65% reported they never saw a medical or radiation oncologist and 26% reported that no doctor ever discussed the possibility of chemo or RT.

Conclusions: A significant proportion of patients with stage II/III rectal cancer did not receive chemo and RT, and a number of those reported that no doctor ever discussed the possibility of chemo or RT with them. While deviation from guidelines may be warranted and/or patient driven, further analyses should determine reasons for lack of recommended treatments.
Addition of bevacizumab to first-line FOLFOX4 and overall survival in patients with metastatic colorectal cancer.
Authors: Suenaga Mitsukuni , Matsusaka Satoshi , Mizunuma Nobuyuki , Shinozaki Eiji , Ogura Mariko , Ozaka Masato , Takagi Koichi , Yamaguchi Toshiharu , Hatake Kiyohiko
Published: February 2017

610

Background: In our previous report, addition of bevacizumab (BV) to the FOLFOX4 regimen appeared to significantly improve response rate, progression-free survival and overall survival in first-line treatment for patients with metastatic colorectal cancer (mCRC) (Suenaga M, et al. ASCO-GI 2011 [abstr 588]). Update results met median overall survival, and statistical analysis of survival was performed.

Methods: An observational cohort study was carried out on all eligible patients scheduled to receive FOLFOX4 (n = 128) or FOLFOX4+BV (n = 85) between 2005 and 2007, 2007 and 2009, with a median follow-up time of 20.4 months vs. 30.2 months, respectively. Predefined efficacy endpoints were treatment characteristics, response rates, progression-free survival, and overall survival in the periods of time observed.

Results: Median progression-free survival was 9.9 months (95% CI, 8.4-11.4) in the FOLFOX4- and 17 months (95% CI, 11.8-22.3) in the FOLFOX4+BV-treated patients (p=0.002). Median overall survival times were 20.5 months (95% CI, 16.9-24) and 38.8 months (95% CI, 32.9-44.8) in the two groups, respectively (p<0.001). In the ECOG PS 0 population, progression-free survival in the FOLFOX4 and FOLFOX4+BV groups was 11 months and 17 months with a hazard ratio of 0.63 (95% CI, 0.44-0.89) in favour of FOLFOX4+BV, similarly in OS with a hazard ratio of 0.53 (95% CI, 0.36-0.77). Subgroup population received 5-FU plus leucovorin (FL) as maintenance during oxaliplatin discontinuation due to adverse events had longer PFS or OS in both groups, though no significance. PFS were 14.7 and 21.6 months, and OS were 29 and 45.9 months, respectively. Secondary resection was performed more in FOLFOX4+BV (11.8%) than FOLFOX4 (3.9%) patients.

Conclusions: These data indicate potential survival benefits from the addition of BV to the FOLFOX4 regimen as first-line treatment for mCRC. Maintenance using FL after discontinuation of oxaliplatin due to adverse events appeared to be an essential factor for better survival.