bluuebunny/crossref_metadata_2025 huggingface dataset:
The prevalence RAS and BRAF mutations among patients in the Middle East and Northern Africa with metastatic colorectal cancer.
Authors: Garawin Tamer , Lowe Kimberly , Kafatos George , Murray Samuel
Published: February 2017

598

Background: Anti-EGFR therapies are recommended for metastatic colorectal cancer (mCRC) patients with confirmed wild-type RAS (exons 2, 3, 4 of KRAS and NRAS) status. There is limited published information on the prevalence of RAS mutations using real world data. The objective of this study was estimate the prevalence of RAS and BRAF mutations among patients with mCRC in the Middle East and Northern Africa (MENA) in an effort to inform the rationale for biomarker testing and treatment choice. Methods: The study included 1,669 patients from August 2013 to July 2015 with mCRC from Algeria, Bahrain, Egypt, Jordan, Kuwait, Lebanon, Libya, Morocco, Oman, Qatar, Saudi Arabia, and the United Arab Emeritus. Information on RAS mutation status was obtained from one pathology lab using High Resolution Melting Analysis. Extended RAS analysis was conducted in a subset of patients, including: overall RAS (exon 2, 3, 4 of KRAS and NRAS; n = 750), KRAS exon 2 (n = 750), KRAS exon 3 and 4 (n = 507), NRAS exon 2, 3, and 4 (n = 507), and BRAF exon 15 (n = 78). The proportion of patients with each mutation was summarized. Results: The overall RAS mutation in the full sample was 35.3% (n = 589/1669). The observed mutation for KRAS exon 2 in a subset of patients with extended RAS analysis (n = 750) was 32.4% (243/750). Out of the subjects with wild-type exon 2 (n = 507), the observed mutations rates were as follows: KRAS exon 4 (20/507 = 3.9%), KRAS exon 3 (13/507 = 2.6%), NRAS exon 2 (7/507 = 1.4%), NRAS exon 3 (6/507 = 1.2%), and NRAS exon 4 (0%). The prevalence of BRAF exon 15 was 3.8% (3/78). The most robust data on specific RAS mutations was obtained from Algeria, Egypt, and Saudi Arabia. The prevalence of KRAS exon 2 mutations in these countries was as follows: Algeria (n = 33/86 = 38.4%), Egypt (n = 83/303 = 27.4%), Saudi Arabia (n = 85/245 = 34.7%). Conclusions: To our knowledge, this is the first study to evaluate the prevalence of RAS and BRAF mutations in the Middle East using real world data. The results of this descriptive study illustrate that there is variation in the prevalence of RAS and BRAF mutations in MENA.
Liquid biopsy leads to a paradigm shift in cancer treatment.
Authors: Suzuki Koichi , Takayama Yuji , Ichida Kosuke , Fukui Taro , Kakizawa Nao , Muto Yuta , Watanabe Fumiaki , Hasegawa Fumi , Tsujinaka Shingo , Kaneda Yuji , Miyakura Yasuyuki , Noda Hiroshi , Kiyozaki Hirokazu , Konishi Fumio , Rikiyama Toshiki
Published: February 2017

602

Background: Liquid biopsy represents an ideal non-invasive tool allowing multiple testing over time, monitoring real time changes occurring within the tumor and evaluation of therapeutic response. Here we show monitoring of KRAS mutation in detection of circulating tumor DNA (ctDNA) during treatments for metastatic colorectal cancer patients (pts). Methods: 238 plasma samples were collected from 57 pts who underwent chemotherapy. KRAS mutant ctDNA (MctDNA) was determined by digital PCR as a tool of Liquid biopsy, detecting rare mutant clones in blood. Results: KRAS assessment in tumor tissues showed 19 pts with mutation (M) and 38 without mutation (W). Among 19 pts with M, 12 pts displayed MctDNA at the initial assessment and 7 pts showed no MctDNA. Then, one (M*) of 7 pts exhibited MctDNA during treatments. While 38 pts with W showed no MctDNA before chemotherapy except one pt (M**), 4 pts exhibited MctDNA after treatments with different regimens. MctDNA was detectable in the blood of these 4 pts prior to radiographic detection of disease progression. Regardless of KRAS status in tumor tissues, poor response was seen in pts with MctDNA. Conclusions: Liquid biopsy provides us a circulating biomarker for monitoring treatment response and choice of optimal regimens. [Table: see text]
Perioperative chemotherapy with S-1 plus oxaliplatin (SOX) for stage III colorectal cancer patients.
Authors: Aisu Naoya , Yoshida Yoichiro , Komono Akira , Yamada Teppei , Kojima Daibo , Mera Toshiyuki , Tanimura Syu , Yamashita Yuichi
Published: February 2017

603

Background: Neoadjuvant chemotherapy (NAC) has a potential to increase the curative resection rate and reduce the recurrence rate. The purpose of this study was to evaluate the safety and efficacy of S-1 plus oxaliplatin (SOX) regimen as neoadjuvant (4 courses) and adjuvant (4 courses) for the treatment of patients with Stage III colorectal cancer (anyT and N+). Methods: We have treated patients with Stage III colorectal cancer undergone operation after NAC (SOX 4 courses) and adjuvant chemotherapy (SOX 4 courses) at Fukuoka University Hospital. SOX regimen (S-1 80 mg/ m2 : day1~14 and oxaliplatin 130 mg/m2 : day1) was administrated every 3 weeks. The primary endpoint was response rate and safety. Results: Of the 21 patients enrolled between September 2012 and December 2014. The median age was 62 years (range, 43–87), and 57% were female. Eastern Cooperative Oncology Group performance status scores were 0, 1, and 2 in 50%, 40%, and 10% of the patients, respectively. The patients received median 4(1-4) courses of NAC and median 4(0-4) courses of adjuvant chemotherapy. The cumulative median dose of oxaliplatin was 1204 (210-1841) mg/body. In NAC, 4 patients required treatment interruption because of the toxicity [grade2 gastrointestinal bleeding (n = 1), grade 3 thrombocytopenia (n = 2), and grade4 ileus (n = 1)]. A complete response according to Response Evaluation Criteria in Solid Tumors ver.1.1 was observed in a patient (4.8%) and a partial response was observed in 15 patients (71.4%) and a stable disease was 5 patients (23.8%). The response rate and tumor control rate were 76.1% and 100%. Curative resection was performed in all patients. No perioperative complications more than grade3 as Clavien Dindo classification was observed in all patients. The observed adverse events of Grade 3 or higher were thrombocytopenia (n = 4), neutropenia (n = 3), diarrhea (n = 1), and ileus (n = 1). Conclusions: Perioperative chemotherapy with SOX is safe and effective. Further studies are warranted to confirm the safety and efficacy of this method. A single-arm phase II trial of perioperative chemotherapy (SOX) and operation for stage III colorectal cancer patients (FUTURE1104 SOS3).
Novel drug discovery by pharmacogenomic profiling of 36 colorectal cancer cell lines.
Authors: Eide Peter , Bruun Jarle , Sveen Anita , MurumÃƒÂ¤gi Astrid , Mpindi John , Arjama Mariliina , Kallioniemi Olli , Lothe Ragnhild A
Published: February 2017

604

Background: Patients with advanced colorectal cancer (CRC) are commonly administered chemotherapy by 5-Fluorouracil in various combinations with leucovorin, oxaliplatin and irinotecan. Metastatic CRCs are additionally eligible for targeted anti-VEGF treatment and anti-EGFR therapy if the tumor is KRASwt. Unfortunately, the response rates are low and novel drugs are needed. Cell lines have successfully been employed to predict drug response and several studies have demonstrated that CRC cell lines recapitulate the genetic variation among primary CRCs. Methods: We performed a high-throughput drug screen (n= 461) of 36 CRC cell lines. A multiplexed assay assessed drug effects on cell viability and cytotoxicity from a five-fold concentration range. Sensitivities were measured by calculating a drug sensitivity score for each drug using a validated algorithm that estimates the relative inhibition by normalization against the top asymptote of the drug concentration curve. By integrating drug sensitivity data with in-house datasets on DNA copy number, gene expression and deep DNA sequencing, we aimed to validate genetically indicated drug sensitivities and identify novel drug sensitivities among subsets of CRCs. Results: Pharmacological relationships for molecular subgroups of CRC were revealed by clustering analyses, outlier analysis and t-tests of the drug sensitivity scores. We found robust correlations between BRAF-mutation status and response to BRAF-inhibitors, and lack of response to Fluorouracil and its prodrug Capecitabine for cell lines with microsatelite instability. These cell lines were sensitive to Topoisomerase I-inhibitors, such as Irinotecan, Valrubicin and Idarubicin. Cell lines with TP53wt were sensitive to the TP53-MDM2 interaction inhibitor Nutlin-3. We additionally identified a more potent novel TP53-MDM2 interaction inhibitor. Pharmacologic correlations for drug classes such as MEK-, EGFR-, Aurora A/B-, PI3K/AKT-, HSP90 and IGF1R-inhibitors were also found. Conclusions: A comprehensive drug screen of 36 CRC cell lines confirms pharmacogenomic relationships and reveals novel potentially relevant therapies for CRC.
Signal transduction and activator of transcription 3 (STAT3), host inflammatory responses and survival of patients with colorectal cancer.
Authors: Park James Hugh , Mcmillan Donald C. , Clark Jennifer , Horgan Paul G. , Roxburgh Campbell S.D. , Edwards Joanne
Published: February 2017

606

Background: In patients with colorectal cancer (CRC), the local and systemic inflammatory responses (LIR and SIR) are important determinants of disease progression, and may be linked by activation of the IL-6/JAK/STAT3 pathway. The present study examines the associations between STAT3 expression and activation with LIR and SIR of patients undergoing resection of CRC. Methods: Patients with stage I-III CRC who underwent curative resection in a single institution and who were included in a previously constructed tissue microarray were studied. IHC was utilised to examine cytoplasmic total STAT3 and nuclear phosphorylated STAT3Tyr705 (pSTAT3) expression. The relationship between STAT3/pSTAT3 expression and clinicopathological characteristics, LIR (Klintrup-Makinen (KM) grade, CD3+ and CD8+T-cell density) and SIR (modified Glasgow Prognostic Score (mGPS)) and cancer-specific survival (CSS) was examined. Results: 201 patients were included. Cytoplasmic STAT3 expression was associated with nuclear pSTAT3 expression (P= 0.019). Increased cytoplasmic STAT3 expression was associated with high density of T-cells within the intraepithelial compartment (CD3+: low STAT3 – 49% vs. high STAT3 – 29%, P= 0.008; CD8+: low STAT3 – 43% vs. high STAT3 – 20%, P = 0.002) and with an elevated mGPS (mGPS > 1: low STAT3 – 31% vs. high STAT3 – 49%, P= 0.003) but not with any other clinicopathological features. Increased nuclear pSTAT3 expression was associated with younger age and lymph node involvement (P< 0.05) but was not associated with the LIR or SIR. Combined assessment of cytoplasmic STAT3 and nuclear pSTAT3 expression stratified 5-year CSS from 78% (both low) to 50% (both high) (P= 0.006). Conclusions: Activation of the IL-6/JAK/STAT3 pathway may be an important determinant of the LIR and SIR in patients with colorectal cancer. Furthermore, assessment of host inflammatory responses may identify patients likely to benefit from therapies targeting this pathway. Taken together with the results of recent clinical trials, the results of the present study suggest that recruitment of patients into future trials of such agents should be stratified by the inflammatory status of the patient.
Prognostic significance of programmed death-ligand 1 (PD-L1) expression on tumor infiltrating immune cells (IC) in patients with stage IIIb colorectal cancer.
Authors: Koganemaru Shigehiro , Inoshita Naoko , Miura Yuji , Fukui Yudai , Ozaki Yukinori , Tomizawa Kenji , Hanaoka Yutaka , Toda Shigeo , Suyama Koichi , Tanabe Yuko , Moriyama Jin , Fujii Takeshi , Matoba Shuichiro , Kuroyanagi Hiroya , Takano Toshimi
Published: February 2017

611

Background: Programmed death 1 (PD-1)/ PD-L1 pathway is a negative feedback mechanism that suppresses the activity of T cells. Some previous studies showed that positive PD-L1 expression on tumor cells (TC) was poor prognostic factor in patients with colorectal cancer; however, recent studies suggest that IC also play important roles to determine the prognosis in cancer patients. The aim of this study is to investigate the association of clinical and pathological features with PD-L1 expression on TC and IC. Methods: We retrospectively reviewed data of consecutive patients with stage IIIb colorectal cancer (Japanese classification of colorectal carcinoma The 8th Edition), who underwent surgery and received adjuvant chemotherapy in our institution between January 2009 and July 2012. PD-L1 expression was evaluated by immunohistochemistry (IHC) on TC and IC. Specimens were scored as IHC low (L) or high (H), if < 5% or ≥ 5% of cells were PD-L1 positive, respectively. Results: Seventy-four patients were included in this analysis. Median age was 61 years (range 32-84). Thirty-one (41.9%) and 43 (58.1%) patients received fluoropyrimidine and fluoropyrimidine combined with oxaliplatin as adjuvant chemotherapy, respectively. The median follow-up time was 51.3 months (range 4.6-75.9). The number of patients with PD-L1 expression on TC/IC (H/H, H/L, L/H, and L/L) were 0, 12, 11, and 51, respectively. The median disease-free survival (DFS) in patients with high and low PD-L1 expression on TC were 29.9 months and “not reached”, respectively (hazard ratio [HR] 2.02; 95% confidence interval [CI], 0.85-4.30; P = 0.11). The median DFS in patients with high and low PD-L1 expression on IC were “not reached” and 55.1 months, respectively (HR 0.29; 95%CI, 0.05-0.95; P = 0.04). Conclusions: Although high PD-L1 expression on TC is associated with poor prognosis, high PD-L1 expression on IC positively affects the survival in patients with stage IIIb colorectal cancer.
Thrombin activatable fibrinolysis inhibitor, tissue factor pathway inhibitor, and prothrombin fragment 1+2 levels in patients with advanced colorectal cancer.
Authors: Salman Tarik , Bilici Ahmet , Arslan Cagatay , Varol Umut , Yildiz Ibrahim , Akyol Murat , Yildiz Yasar , Kucukzeybek Yuksel , Alacacioglu Ahmet , Yilmaz Ugur
Published: February 2017

615

Background: Thromboembolism is common in cancer patients.Thrombin activatable fibrinolysis inhibitor (TAFI), tissue factor pathway inhibitor (TFPI) and prothrombin fragment 1+2 (F1+2) are newly identified molecules involved in coagulation and fibrinolysis. The aim of this study was to investigate the relationship between clinicopathologic characteristics and TAFI, TFPI and F1+2 levels in patients with advanced colorectal cancer. Methods: Eighty-two patients (32 metastatic, 50 locally advanced disease) diagnosed with colorectal cancer in the medical oncology clinic, without history of thromboembolism, had not undergone an intervention, and not on medication affecting coagulation were included in the study. Serum TAFI, TFPI, and prothrombin F1+2 levels were evaluated via enzyme-linked immunosorbent assay. Clinicopathologic characteristics of the patients were investigated retrospectively from the medical records of the patients. Results: The plasma TAFI, TFPI, and prothrombin F1+2 levels were high in 70, 71, and 96% of the patients, respectively. Prothrombin F1+2 levels were higher among patients with lower performance scores. TFPI levels were higher among patients with tumor grades of 2 and 3. TAFI levels were higher among rectal cancer cases. Conclusions: There is an association between tumor grade and coagulation cascade. The higher prothrombin F1+2 levels, an indicator of active coagulation cascade, among patients with low performance scores may indicate that the coagulation cascade of these patients is more active. Higher TAFI levels among rectal cancer patients may be related to the natural course of the disease
Phase II study of dovitinib in patients (Pts) progressing on anti-vascular endothelial growth factor (VEGF) therapy.
Authors: Semrad Thomas John , Kim Edward Jae-hoon , Tanaka Michael S. , Sands Jacob , Roberts Chris , Astrow Stephanie H. , Stephens Craig , Moran Miriana , Burich Rebekah , Li Yu , Gandara David R. , Lara Primo , Mack Philip C.
Published: February 2017

616

Background: Prior work identified the fibroblast growth factor (FGF) pathway as a mediator of resistance to anti-VEGF therapy. We tested dovitinib, an oral inhibitor of both FGFRs and VEGFRs in pts progressing on anti-VEGF treatment. Methods: Pts with measurable advanced colorectal cancer (CRC) or non-small cell lung cancer (NSCLC) with progression despite treatment with an anti-VEGF agent within 56 days, good performance status (PS) and adequate organ function were eligible. A pre-treatment tumor biopsy was followed by treatment with dovitinib 500 mg on a 5 day on / 2 day off schedule for 28-day cycles. The primary endpoint of response (RECIST 1.1) was evaluated every 2 cycles. Secondary endpoints included toxicity and the disease control rate at 8 weeks. Intratumor mRNA expression was analyzed using a Next Generation Sequencing based expression array and circulating angiogenic factors analyzed by a multiplex bead-based assays and ELISAs. Results: Ten pts (9 CRC, 1 NSCLC) treated previously with bevacizumab (8) or ziv-aflibercept (2) enrolled. The study closed with termination of dovitinib development. No responses were observed in 7 evaluable pts; 3 withdrew consent during cycle 1. The best response was stable disease in 1 patient. Common toxicities included gastrointestinal, metabolic, and biochemical derangements. All pts experienced at least 1 grade 3 or higher treatment-related adverse event, most commonly fatigue, elevated GGT, and lymphopenia. Expression of multiple angiogenic mediators was common in tumors progressing on anti-VEGF therapy including high levels of FGFR1 and VEGFA. Dovitinib modulated circulating VEGF pathway components; however, no hyperphosphatemia was observed and plasma FGF2 increased continuously. Conclusions: We found no evidence for the activity of dovitinib in pts with CRC progressing on anti-VEGF therapy and could not confirm potent FGFR inhibition. Toxicities were significant. In tumors progressing despite anti-VEGF therapy, a multitude of pro-angiogenic mediators are expressed, including members of the FGF pathway. Clinical trial information: NCT01676714.
C6-ceramide's effect on KRAS-defined colorectal cancer cells treated with oxaliplatin, 5-fluoruracil with and without cetuximab.
Authors: Menendez Alvaro G. , Curzake Daniel J. , Luo LuGuang , Wanebo Harold J.
Published: February 2017

619

Background: Cetuximab (Cet) is beneficial for patients with metastatic KRAS Wild type (WT) colorectal cancer (mCRC) only. C6-Ceramide (C6-Cer) can act synergistically with chemotherapy to induce cancer cell death. The aim of this study was to compare growth inhibition percentage (GIP) of cytostatics 5-fluoruracil (5-FU), oxaliplatin (Ox) and Cet with or without C6-Cer in KRAS WT and KRAS mutant (KRAS Mut) CRC cell lines (SW48 and SW480, respectively). Methods: Both cell lines were incubated with IC50 concentrations of test drugs. Drug concentrations included 0.8µM for 5-FU, 0.04µM for Ox, 25 µg/mL for Cet, and C6-Cer concentrations ranged from 5 to 10 µM. Cell survival was assessed 72h after using 0.4% Trypan Blue. Results: With above mentioned concentrations, C6-Cer’s GIP was 78.3% for SW-480 (vs. 33.33% for SW-48). It was also noted that the addition of C6-Cer to a combination of steady concentrations of Ox, Cet and 5-FU increased GIP with an especially significant effect on SW-480. Addition of 5 and 7.5µM resulted in doubling of GIP (75% and 86.25%, respectively, vs 32.5% of 5-FU + Ox + Cet). The greatest effect was seen when 10µM of C6-Cer was added to the IC50 concentrations of chemotherapeutic agents (using the 25µg/mL concentration of Cet), where GIP increased from 32.5% to 92.5% in SW-480. Same concentration of drugs increased GIP for SW-48 to a similar 93.5%. Conclusions: C6-Cer appears to have direct inhibitory properties, especially on KRAS Mut cells. Additionally when added to Ox, 5-FU and Cet, C6-Cer reversed the apparent insensitivity of KRAS Mut to Cet. Also, the study showed C6-Cer can provide additional synergism to their cytostatic properties in KRAS WT CRC cell lines. The true mechanism of these observations is still undergoing analysis, however the effect of isolated C6-Cer on KRAS Mut raises possibility of a different pathway that could bypass EFGR pathway. We believe the results of this study provide a starting point for clinical studies with C6-Ceramide in patients with relapsing or metastatic KRAS Mut CRC in combination with standard chemotherapy plus molecular target agents hoping they will translate into clinical benefit for this difficult to treat patient population.
A single institution experience of EGFR inhibitors in patients with advanced squamous cell anal carcinomas (SCAC).
Authors: Kim Dae Won , Byer Jennifer Elizabeth , Kothari Nishi , Mahipal Amit , Kim Richard D.
Published: February 2017

623

Background: Although SCAC are relatively rare, their incidence has been increasing steadily. Because of limited data, treatment of metastatic disease is a major therapeutic challenge. Recent data has demonstrated a low rate of KRAS and EGFR mutations, suggesting a potential target of EGFR inhibitors. In this study, we report the safety and efficacy of EGFR inhibitors in patients (pts) with advanced SCAC. Methods: A retrospective analysis was conducted using the Moffitt Cancer tumor registry from 1/2009 to 1/2014. Eligible pts had advanced SCAC and received an EGFR inhibitor as part of their treatment. Results: 13 pts were identified for analysis. Median age was 59 years (range: 41-68). All pts received concurrent chemoradiation (Nigro regimen) as initial treatment and subsequently had recurrence. Upon diagnosis of recurrent disease, 5 pts received 2 lines of systemic chemotherapy, 5 pts received 1 line and 3 did not receive any treatment prior to receiving EGFR inhibitors. 5 pts received single agent cetuximab (4) or panitumumab (1) and the others received cetuximab or panitumumab with irinotecan or FOLFIRI. Pts received a median EGFR inhibitor dose of 8 (range: 2-45). Objective response rates were 30.8% (1 CR, 3 PR) and disease control rates were 46.2%. 1 pt with CR was on single agent cetuximab as second line therapy and 3 pts with PR were on cetuximab plus chemotherapy as front-line. With a median follow-up of 9.6 months (mo), the median PFS and median OS were 4.4 mo (95% confidence interval (CI) 2.99-5.81) and 11.4 mo (95% CI 7.93-14.87), respectively. No KRAS mutation was detected in 8 pts and KRAS testing was not done on 5 other pts. Grade 3 toxicities included anemia (n = 2), fatigue (n = 1), depression (n = 1), dyspnea (n = 1), anorexia (n = 1), nausea (n = 1) and diarrhea (n = 1). No grade 4 toxicities were observed. Conclusions: Our analysis suggests that EFGF inhibitors have potential efficacy and are reasonably well tolerated in patients with SCAC. These findings warrant further evaluation in a large prospective trial.
BASAL immunologic response and its modifications after treatment with ANTI-EGFR in patients with advanced colorectal cancer.
Authors: Vieitez Jose M , Moro-Garcia Marco , Jiménez-Fonseca Paula , Echeverria de Carlos A , Iglesias Escudero Mar , Sánchez Lorenzo Luisa , Solis Hernandez Maria Del Pilar , Alonso Rebeca
Published: February 2017

626

Background: CRC patients treated with anti-EGFR having skin reactions tend to have a better outcome regardless of the presence of mutations in the RAS. This fact, repeated with various antibodies makes us think that the basal immunology, or its ability to react to these proteins is actually responsible for this phenomenon. We initiated an exploratory study to identify which parameters/immunological pathways might be related to skin reactions. Methods: Seric levels of immunoglobulins (IgG, IgA, and IgM) and complement factors (c3 and c4) were measured. Leukocyte and lymphocyte subsets were also quantified in peripheral blood. We evaluated cytotoxic activity of NK lymphocytes (CD107a expression in response to K562 cells) and activation of CD4+ and CD8+ T-lymphocytes in response to anti-CD3 stimulation (expression of CD38, HLA-DR, CD25 and CD69). Results: 17 consecutive patients were included from 29/08/2012 to 17/11/14. Median age was 66 (range 50-80), median number of organ affected 1 (range 1-3), liver affected in 8 patients. 9 Patients were treated with folfiri/panitumumab, 4 cpt11/panitumumab, 4 with panitumumab monochemotherapy. Two patients presented a partial response, median days to progression were 176 days (range 15-652). Levels of immunoglobulins, complement factors, and leukocyte subsets showed no differences between both groups of patients (with or without skin reactions). Increased T-lymphocyte percentages were found in patients without skin reactions, mainly explained by higher levels of CD8+ T-lymphocytes but with a more differentiated phenotype. Neither frequencies nor cytotoxic activity of NK-lymphocytes showed differences between patients. However, anti-CD3 stimulation induced higher activation status in CD4+ and CD8+ T-lymphocytes in patients having skin reactions, with increased levels of activation marker expression of CD38, HLA-DR, CD25 and mainly CD69. Conclusions: T-lymphocytes of CRC-patients having skin reaction in response to anti-EGFR treatment seem to have a less differentiated status and a higher ability to be activated by anti-CD3 stimulation in vitro.
Clinical study on medical value of adoptive immunotherapy with chemotherapy for stage IV colorectal cancer (COMVI study).
Authors: Yoshida Yoichiro , Naito Masayasu , Yamada Teppei , Aisu Naoya , Kojima Daibo , Mera Toshiyuki , Tanimura Syu , Tanaka Toshihiro , Naitoh Keiko , Yasumoto Kosei , Kamigaki Takashi , Goto Shigenori , Yamashita Yuichi
Published: February 2017

628

Background: Adoptive immunotherapy of cancer is evolving with the development of novel technologies for generating a large number of activated killer cells such as αβ T cells, γδ T cells, and natural killer (NK) cells. We conducted a pilot study to evaluate the safety and feasibility of the combination treatment of adoptive immunotherapy with chemotherapy for stage IV colorectal cancer. Methods: The COMVI study was a prospective and single-arm pilot trial. Therapy in each 21-day treatment cycle consisted of XELOX (130 mg/m2 of oxaliplatin on day 1 plus 1,000 mg/m2 of capecitabine twice daily on days 1–14), bevacizumab (7.5 mg/kg on day 1) and αβ T lymphocytes (over 5 ×109 on day 18) cultured ex vivo with an immobilized anti-CD3 antibody and interleukin-2. Results: A total of 6 patients were enrolled from June 2013 to September 2014. Baseline characteristics included a median age of 66 years (range: 55-75) for 2 men and 4women. Median PFS was 567 days. Overall response rate was 100 % (CR 33.3%, PR 66.7%, SD 0%, PD 0%). The tumor reduction rate was 53% (38.0–100%). The majority of adverse events were mild to moderate in intensity, and no grade 4 adverse events occurred in the 6 patients. Only one patient experienced grade 3 hypertension and ileus. Immunotherapy-associated toxicity was minimal in this study. Conclusions: The combination treatment of adoptive immunotherapy with chemotherapy for stage IV colorectal cancer is feasible and safe. Phase II prospective studies are warranted to confirm the safety and efficacy of this chemoimmunotherapy. Clinical trial information: UMIN000010908.
Frequency of unplanned surgical intervention in patients with stage IV colorectal cancer receiving palliative chemotherapy: An analysis of SEER-Medicare.
Authors: Lorimer Patrick D. , Walsh Kendall K , Kirks Russell C. , Han Yimei , Hwang Jimmy J. , Salo Jonathan C. , Hill Joshua S.
Published: February 2017

640

Background: Patients (pts) with synchronous stage IV colorectal cancer commonly begin palliative chemotherapy while the primary tumor remains. Single institution series report low rates of surgical intervention, but this has not been examined nationally. The present study utilizes a large national dataset to examine the natural history of unplanned surgical intervention in stage IV colorectal cancer pts on palliative chemotherapy. Methods: SEER-Medicare was queried for pts with metastatic colorectal cancer (1998-2009) who underwent resection or diversion (ICD9 procedure/CPT). The cohort was separated into 3 groups: elective (surgery on admission without urgent/emergent flag), urgent (surgery not on day of admission but within hospitalization or with urgent flag) and emergent (emergent flag). Pts who underwent any procedure for curative intent (elective colorectal surgery, liver directed therapy or surgery for pulmonary metastases) at any time were excluded. Demographics, tumor grade and comorbidities were analyzed for effect on intervention rate. Time to event for either urgent or emergent surgical intervention or censorship by death, were measured. Conditional analyses were performed to determine the risk of surgical intervention at 6 months, 1 and 2 years post diagnosis. Results: 3,992 pts met inclusion criteria. Median age=73; 53% male. White 79%, black 11% and other 10%. The overall intervention rate was 6%; 35% emergent, 65% urgent. At 42 months, 90% of the pts had died. The probability of requiring unplanned surgery between 6-12 months was 2.5%; 12-24 months=1.9%, and >24 months=0.8%. Charlson comorbidity score of 1 was a significant predictor of surgical intervention (HR 1.64 [1.24, 2.19]). Sex, age and race had no influence on the likelihood of surgical intervention. Conclusions: This study represents a large series of stage IV colorectal cancer pts and the frequency of unplanned surgery in pts receiving palliative chemotherapy. Pts treated with palliative chemotherapy are unlikely to require urgent or emergent surgery, and therefore prophylactic surgery to reduce the risk of perforation or obstruction should not be routinely performed.
Outcomes of patients (pts) with BRAF mutated (BRAF MT) Colorectal Cancer (CRC): The Royal Marsden Experience.
Authors: Kayhanian Hamzeh , Goode Emily , Ang Joo Ern , Gonzalez de Castro David , Sclafani Francesco , Petruckevitch Ann , Rao Sheela , Watkins David J. , Gerlinger Marco , Cunningham David , Chau Ian , Starling Naureen
Published: February 2017

644

Background: BRAF MT metastatic CRC (mCRC) is associated with a poor prognosis. For the first time, we report outcomes for BRAF MT mCRC at a single tertiary centre, compared to a matched control group, since introduction of routine somatic BRAF and RAS mutation testing. Methods: Pts with BRAF MT mCRC (diagnosed Oct 2010-Nov 2014) were compared to a matched group of BRAF wildtype (WT) pts treated in same time period who were randomly selected after matching for age, sex and stage. Demographic, tumour characteristic and treatment data were collected. Overall (OS) and progression-free survival (PFS) were calculated using the Kaplan-Meier method and comparisons made using χ² test or Cox regression. Results: Of 503 pts tested, 59 (11.7%) had BRAF MT tumours (16 early stage, 16 recurrent and 27 de novo metastatic). Median age (years) at diagnosis was 68 (27-85) compared with 70 (29-85) for BRAF WT pts (p = 0.995). Median OS for pts with mCRC was 18.2 months (m) for BRAF MT and 41.1m for BRAF WT pts (HR 2.73 P < 0.01). For BRAF MT and BRAF WT pts with mCRC, median PFS on first-line treatment (1L) was 8.1m (n = 37) and 9.2m (n = 81) respectively (HR = 1.10 [P = 0.69]), PFS on 2L was 5.1m (n = 21) and 9.0m (n = 49) respectively (HR = 1.84 [P = 0.03]) while PFS on 3L was 1.7m (n = 10) and 6.6m (n = 20) respectively (HR = 2.75 [P = 0.02]). Fluoropyrimidine based doublet regimens were used in 94.6%, 85.7% and 20% of BRAF MT pts in 1L, 2L and 3L respectively compared with 87.2%, 92.5% and 52.4% in BRAF WT pts. Pts with localised disease had a recurrence rate of 50% (16/32) for pts with BRAF MT compared with 52.4% (33/63) for BRAF WT pts (p = 0.83). Conclusions: In this case-control study, poor OS of pts with BRAF MT mCRC is associated with reduced clinical benefit beyond 1L. Sequential doublet chemotherapy remains a reasonable option in these pts. The role of BRAF mutation in predicting recurrence of early CRC warrants further study. [Table: see text]
Survival determinants with matched targeted therapies in BRAF mutant metastatic colorectal cancer (mCRC).
Authors: Sanz-Garcia Enrique , Martinez Ana Maria , Elez Elena , Argiles Guillem , Grasselli Julieta , Macarulla Teresa , Capdevila Jaume , Alsina Maria , Sauri Tamara , Hierro Cinta , Matos Ignacio , Verdaguer Helena , Azaro Analia , Landolfi Stefania , Hernandez-Losa Javier , Rodón Jordi , Nuciforo Paolo , Vivancos Ana , Dienstmann Rodrigo , Tabernero Josep
Published: February 2017

649

Background: BRAF mutation (mt) occurs in 5-8% of mCRC and is associated with poor prognosis. Matched targeted therapies for this population are increasingly available in clinical trials. Methods: From Nov 2010 to June 2015, a total of 32 chemorefractory BRAF mt mCRC patients (pts) were enrolled in phase I trials with anti-BRAF matched therapy at Vall d´Hebron Institute of Oncology. BRAF mt was determined by real-time PCR (50%), mass spectrometry (Sequenom, 28%) or next-generation sequencing (Amplicon MiSeq, 22%). All demographic, treatment and survival data were retrospectively analyzed. Results: Median age was 60.4 years (range 42.8-73.5), 62% had right-sided CRC primaries and 59% were stage IV at diagnosis. Median treatment lines before matched therapy was 2 (range 1-4). Co-existing RNFA43, PI3KCA and GNAS mt were found in 4, 2 and 1 pts, respectively. Median time from diagnosis to start of anti-BRAF therapy was 18.6 months (m) (CI95% 14-36) and median time from diagnosis of mCRC to death was 28.4m (CI95% 25-50). A total of 41 anti-BRAF matched therapies were delivered, 9 pts received more than 1 regimen. BRAF inhibitor (inh) monotherapy was delivered in 34% of cases; BRAF plus MEK/EGFR/WNT/PI3K/CDK inh doublets or triplets to 37% and 29% pts, respectively. Survival from start of anti-BRAF to death was 8.9m (CI95% 7-15), without significant differences if 1 or more than 1 anti-BRAF regimen was given (HR: 0.82, p=0.6). Partial responses were observed in 7 cases (17%, 4 doublets and 3 triplets) and complete response in 2 cases (5%, 1 doublet and 1 triplet). Median time on treatment (ToT) with anti-BRAF therapy was 2.83m (CI95% 2-5.5). Of note, ToT was significantly longer for triplets compared to mono/doublets: 5.5m (CI95% 2.7-not reached) vs. 1.9m (CI95% 1.6-3.7; HR: 0.46 [CI95% 0.2-1.0], p=0.05). Median BRAFmt allele fraction (adjusted for tumor purity) was 0.25 (0.13-0.68); no correlation with ToT on anti-BRAF therapy was observed (p=0.36). Conclusions: In a selected BRAF mt population enrolled in early trials with anti-BRAF matched therapy at our institution, survival in the metastatic setting was remarkably high. Triplet matched therapies seem to control disease for longer time than mono/doublets.
Comparative effectiveness of panitumumab (P) and cetuximab (C) in metastatic colorectal cancer (mCRC) with wild-type KRAS (WTKRAS).
Authors: Xu Yifan , Hay Joel W , Lenz Heinz-Josef , Sadeghi Sarmad , Barzi Afsaneh
Published: February 2017

652

Background: In 2015, 140,000 patients will be diagnosed with colorectal cancer (CRC) with 20% diagnosed with mCRC and another 20% developing mCRC during their course. In recent years the outcome of mCRC has improved with survival reaching 30 months in clinical trials. P and C have similar effectiveness as reported in ASPECCT, though their administration and toxicities are different. Availability of more than one agent for one indication makes cost a variable in selection process. We aimed to evaluate the comparative effectiveness of P and C as monotherapy in chemo-refractory mCRC with WTKRAS from a societal perspective. Methods: We developed a Markov model with three states: stable disease, progressive disease and death. Probabilities of each state and transitions were extracted from the ASPECCT trial report. Costs of drug and administration were based on the Veteran Affairs Federal Supply Schedule and Medicare reimbursement rates for a base case of a 61-year-old male. We conducted a literature review to obtain data regarding the costs and utilities of toxicities. All costs are in 2015 US dollars. The model was constructed using a 1-month cycle length and 3-year time horizon, discounted at an annual rate of 3%. The model used quality-adjusted life-year (QALY) to measure the health outcomes for each treatment option. Results: P produced 9.8 months life-years gain and 0.56 QALYs at the cost of $74,827 per patient. C produced a 9.2 months life-years gain and 0.53 QALYs, at the cost of $79,916 per patient. The incremental net monetary benefit of P is $10,168 when compared to C under a societal willingness-to-pay threshold of $150,000 per QALY. The model showed robustness to the one-way sensitivity analysis and various alternative scenarios, and was found to be most sensitive to the cost of C. P and C are equivalent when cost of C drops from $1,038 to $782 per 100mL vial. Conclusions: In the US, effectiveness and toxicities are the main variables for choice of treatment regimen. The rising cost of care is forcing providers and policy makers to consider other data points in treatment selection. Our results indicate that P has a cost advantage over C and provide a strong argument to use P in lieu of C in mCRC.
Targeted therapy for gastrointestinaI (GI) tumors based on molecular profiles: Early results from MyPathway, an open-label phase IIa basket study in patients with advanced solid tumors.
Authors: Hurwitz Herbert , Hainsworth John D. , Swanton Charles , Perez Edith A. , Sweeney Christopher , Burris Howard A. , Spigel David , Meric-Bernstam Funda , Strickland Donald K , Leon Larry , Brammer Melissa , Beattie Mary Stanley , Bose Ron
Published: February 2017

653

Background: Next-generation sequencing often reveals potentially actionable molecular alterations; however, data on approved targeted therapies in non-indicated tumors are limited. MyPathway (NCT02091141) evaluates agents targeting the HER2, EGFR, BRAF, or Hedgehog (Hh) pathways in tumors for which these therapies are not currently indicated. Here, we present early response data for patients with GI tumors. Methods: Eligible patients had metastatic tumors with potentially actionable genomic alterations, identified by a CLIA-certified lab, and progression on standard therapy. Based on the identified alteration, patients received standard doses of trastuzumab + pertuzumab (HER2), erlotinib (EGFR), vemurafenib (BRAF), or vismodegib (Hh). Response was evaluated by the investigator using RECIST v1.1. Results: As of Aug 21, 2015, 96 patients had enrolled, 36 of whom (38%) had GI tumors with the following alterations: HER2 (n=28 [22 amplifications, 5 activating mutations, 1 both]), BRAF (n=4), Hh (n=2 [2 PTCH-1 mutations]), and EGFR (n=2). Patients had a median of 4 (range, 1–8) prior lines of therapy. Tumor types and interim best response data are shown below. Among all evaluable patients with GI tumors (n=26), 5 have had a PR to targeted therapy (duration 3–10+ months). Conclusions: Targetable molecular alterations were found in a variety of GI tumors, resulting in clinical benefit from targeted treatments that would not have otherwise been realized. These early results support this molecular testing strategy. Accrual to the trial continues; based on activity observed, the HER2-positive colorectal cancer cohort will be expanded to ≥30 patients. Additional data will be presented at the meeting. Clinical trial information: NCT02091141. [Table: see text]
Prognostic value of primary tumor resection in synchronous metastatic colorectal cancer (mCRC): Individual patient data (IPD) analysis of first-line randomized trials from the ARCAD database.
Authors: Koopman Miriam , Shi Qian , Goey Kaitlyn K.H. , Green Erin , Heinemann Volker , Diaz-Rubio Eduardo , Aranda Enrique , Falcone Alfredo , De Gramont Aimery , Sargent Daniel J. , Punt Cornelis J. A.
Published: February 2017

658

Background: In patients (pts) with mCRC with an asymptomatic primary tumor, there is limited evidence regarding the indication for primary tumor resection. The primary objective was to evaluate the prognostic value of primary tumor resection in synchronous mCRC pts. Methods: In this IPD analysis, a total of 3,423 pts from 8 first-line randomized trials (RCTs) with systemic therapy in the ARCAD (Aide et Recherche en Cancérologie Digestive) database were analyzed. Five RCTs included targeted (anti-VEGF and/or anti-EGFR) agents. Synchronous mCRC was defined as distant metastases occurring ≤ 6 months of the initial CRC diagnosis. Overall survival (OS) and progression-free survival (PFS) were compared by stratified multivariate Cox models. Results: There were 710 (21%), 1,705 (50%) and 1,008 (29%) pts with non-resected and resected synchronous mCRC and metachronous mCRC, respectively. Compared to the non-resection group, pts in the synchronous resection group were associated with female gender, colon tumor, isolated liver/lung involvement, single metastatic site, and lower LDH (all p<.001). Adjusted for age, gender, performance status and prior chemotherapy, the non-resection group had a significantly worse median OS (16.4m) compared to the resection (22.2m; HR 1.60, 95% CI 1.43-1.78) and metachronous (22.4m; HR 1.81, 95% CI 1.58-2.07) groups. Similarly, PFS was significantly worse for the non-resection group (7.9m) compared to the resection (9.7m; HR 1.31, 95% CI 1.19-1.44) and metachronous group (8.9m; HR 1.47, 95% CI 1.30-1.66). Similar trends were observed in pts treated with non-targeted vs targeted agents, and anti-VEGF vs anti-EGFR therapy. In a subset analysis (n= 526), the observed associations remained after additional adjustment for primary tumor location, liver/lung involvement, number of metastatic sites, BMI and LDH. Conclusions: In this largest IPD analysis of mCRC trials to date, primary tumor resection is associated with better OS and PFS in synchronous mCRC pts. These results may be subject to bias since reasons for (non)resection were not available. Prospective RCTs on this topic are ongoing.
Chasing the proverbial unicorn of relative value units (RVU) and block time.
Authors: Rajeev Rahul , Johnston Fabian McCartney , Gamblin T. Clark , Turaga Kiran
Published: February 2017

660

Background: Competitive market forces on healthcare have led to increasing demands on work effort of academic surgical oncologists. This has to be balanced against resource constraints of limited operating room space and block time availability. We hypothesized that current work RVU (wRVU) requirements pose an unrealistic expectation of practicing surgical oncologists. Methods: University HealthSystem Consortium (UHC) median wRVUs were utilized to determine the effort expected of a surgical oncologist. Surgical oncology subspecialties were divided into breast, colorectal, melanoma, sarcoma, liver and pancreas. Representative procedures from each specialty were determined using Healthcare Common Procedure Coding System and median wRVUs were obtained per procedure including a single consultation cost without incorporating modifiers and adjustments for multiple procedures. A work year was assumed to include 48 weeks of work time to account for CME, and vacation. Night and weekend call was excluded from the analysis. Results: The median UHC wRVU for a surgical oncologist is 7800 wRVU, which corresponds to a theoretical reimbursement of $383,387-493,459 in a pure Medicare population. In order to meet the work RVU requirements, the number of annual major procedures performed varied from 124-1625 procedures (breast 365-701, colorectal 192- 324, melanoma 677-1625, sarcoma 234-334, liver 124-571, pancreas 139-264). The number of major procedures performed per day varied from 3 procedures/day for a 4 day block time to 12 procedures/day for a single day block time. Conclusions: Current wRVU expectations and block time schedules need to be better aligned to account for increasing demands on surgical oncologists. Society driven surveys as recently conducted by ASBS might be effective ways to truly understand workforce demands in the nation.
Patterns in KRAS testing and EGFRi therapy across lines of treatment for metastatic colorectal cancer in Canada: A retrospective analysis.
Authors: Kennecke Hagen F. , Maroun Jean Alfred , Kavan Petr , Aucoin Nathalie , Couture Felix , Poulin-Costello Melanie , Gillesby Brad , Berry Scott R.
Published: February 2017

665

Background: Selection and sequencing of treatment regimens for individual metastatic colorectal cancer (mCRC) patients is governed by the goals of maintaining reasonable quality of life while extending survival. The timing of KRAS testing and its effect on EGFRi therapy is poorly described. The goals of this analysis wereto describe rates and timing of KRAS testing relative to EGFRi therapy for Canadian patients diagnosed with mCRC. Methods: A retrospective chart review conducted at 6 Canadian centres included patients diagnosed with mCRC from Jan 1, 2009 onwards, who commenced 1st-line systemic treatment for mCRC between Jan 1–Dec 31, 2009. Information on the proportion of patients who received 2nd, 3rd, or subsequent lines of systemic therapy for mCRC was determined and the rates and timing of KRAS testing was ascertained. Results: 200 patients commenced 1st-line therapy and the median age was 62 yr; 78% had mCRC at the time of diagnosis. The proportions of patients who started 2nd, 3rd, and 4th lines of systemic therapy were 70%, 30%, and 15%, respectively. 103 (52%) patients had KRAS testing; 6%, 18%, 57%, 16%, 2%, and 1% of patients were tested at diagnosis or before the 2nd, 3rd, 4th, 5th and 6th lines of therapy, respectively. Median time from testing to EGFRi treatment was 105 (range, 7–1192) days, and varied by site. The frequency of KRAS testing for patients ranged from 30%–70% across study sites; across provinces, the frequency of testing ranged from 46%–60%. 38/68 (56%) of patients with wt KRAS tumors received EGFRi; 31 (46%) patients received EGFRi therapy as next therapy following KRAS testing. 19 (28%) died and 4 were lost to follow-up within 120 days of KRAS testing with no other therapy. 2 additional patients with unknown KRAS status received EGFRi (1 without KRAS testing; 1 undetermined). Conclusions: KRAS testing occurred after starting 2nd line in 76% of cases and varied by site and province. About half of patients underwent KRAS testing and 56% of those patients with wt KRAS tumors received an EGFRi. The short time interval between (K)RAS testing and EGFRi therapy may point to the need for earlier testing if EGFRi therapy is to be used in earlier lines of therapy.