checkpoint inhibitors followed by UFT/LV can be useful for patients with left-sided CRC.
Legal entity responsible for the study: Sotaro Sadahiro, MD. Funding: Has not received any funding.
Disclosure: H. Nagase: Employee: Taiho Pharmaceutical Co. Ltd. All other authors have declared no conflicts of interest.
591P Comparing metastatic (M) young onset (YO) colorectal cancer (CRC) with average onset (AO): Do they differ clinically and genetically? G. Dos Santos Fernandes1
, W. Chatila1 , R. Yaeger1 , R. Mendelsohn1 , Z. Stadler1 , N.H. Segal2 , A. Varghese3 , D. Reidy3 , L. Diaz3 , J. Shia4 , E. Vakiani4 , J. Hechtman4 , N. Schultz5 , M. Berger4 , D. Hyman3 , D. Solit3 , L. Saltz2 , J. Garcia Aguilar6 , A. Cercek3 1
GI Medical Oncology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA, 2
Gastrointestinal Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA,3
Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA,4
Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA,5
The Nikolaus Schultz Lab, Memorial Sloan-Kettering Cancer Center, New York, NY, USA,6
Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY, USA Background: The incidence of colorectal cancer in patients(pts) under the age of 50 has been steadily on rising over the last two decades. This is in sharp contrast to average onset CRC where there has been a decline. Little is known about clinical behavior and biology of metastatic CRC in the growing YO population.
Methods: We defined YO as < 45 yo and AO as > 50 yo. To better understand the dif-ferences in biology of early onset rectal tumors, we tabulated the clinical characteristics, genomics using next generation sequencing(MSK-IMPACT), treatments and outcomes in 175 metastatic pts with EO CRC, treated at Memorial Sloan Kettering Cancer Center between 2014 and 2017 and compared these cases to a cohort of AO M CRC cases (n¼ 413) with CRC related hereditary syndromes such as Lynch Syndrome and inflam-matory bowel disease were excluded.
Results: We analyzed 175 in the YO cohort. Age at diagnosis was between 17-35yo in 46 and between 36-45 in 129 pts. Among YO patients, there were 50.2% males, 27.7% smokers and the median BMI was 25.5. Comparing to AO, YO pts have significantly less right sided tumors (22.8% vs 33%; p¼ 0.01). Treatment choices did not differ among YO vs AO groups; systemic chemotherapy (46.7% vs 42.6%; p¼ 0.40) and metastasectomy (54.6 vs 49.4; p¼ 0.33). Overall survival was 59months in the YO vs 63.9 for the AO (p¼ 0.194). Among genetic characteristics mutational burden and copy number comparison showed no significant differences between the groups. Conclusions: Our series describes a comprehensive clinical and genomic profile of EO mCRC. In contrast to prior reports YO does not appear to be associated with more aggressive disease and there was no difference in treatment modalities. Detailed genomic and clinical characteristics will be presented.
Legal entity responsible for the study: Andrea Cercek. Funding: Has not received any funding.
Disclosure: All authors have declared no conflicts of interest.
592P Impact of Charlson comorbidity index on survival of octogenarian patients with colorectal cancer
E.D. Inga Saavedra1
, J.R. Rodriguez1 , E. Casaut Lora2 , A. Gonzalez-Haba1 , V. Serrano Pecos1 , M.F. Martinez Barragan1 , E. Blanco1 , J. Gomez-Ulla1 1
Medical Oncology Service, Hospital Infanta Cristina, Badajoz, Spain,2 Oncology, Hospital Perpetuo Socorro, Badajoz, Spain
Background: Octogenarians have higher rates of comorbidity that are associated with a poor prognosis. Few studies have identified prognostic factors of elderly patients (pts) with colorectal cancer (CRC), so their optimized care strategies remain controversial. Charlson comorbidity index (CCI) is the most widely used clinical scoring system to predict the survival of patients with malignancies. The aim of this study was to investi-gate the prevalence of comorbidity and the prognostic impact of the CCI score for sur-vival among octogenarian pts with CRC in our center.
Methods: We reviewed 151 pts referred to Medical Oncology between January 2012 and March 2017. Data on demographics, staging, treatment and survival were collected and analysed. CCI score was independent variable. OS rates was estimated by the Kaplan–Meier method, with differences in survival between groups compared by the log-rank test.
Results: We reviewed 151 pts with CRC referred to Medical Oncology between January 2012 and March 2017. Data on demographics, staging, treatment and survival was col-lected and analysed. CCI score was the independent variable. OS rates was estimated by the Kaplan–Meier method, with differences in survival between groups compared by the log-rank test. Results Octogenarians were a 19% of all pts, 82 (54%) men and 69 (46%) women. The median age was 84 years. There was no difference in performance status (PS) between genders with PS 0-1 in 76%, PS 2 in 26% and PS 3-4 in 10%. Pts were divided into high CCI score (CCI 3; n ¼ 52) and low CCI score (CCI < 3; n¼ 99) groups for comparative analyses of differences in their short- and long-term outcomes. The overall survival (OS) in pts with a Low CCI Score was longer than that
in high CCI score (46 versus 25 months; p < 0.01). High CCI score significantly relates to poorer survival outcome for all stages (p < 0.001).
Table: 592P
Characteristics Low CCI
group (n¼ 99) High CCI group (n¼ 52) p value Sex (male/female) 46/53 23/29 0.74
Stage at diagnosis I II III IV 10 21 39 29 6 7 16 23 0.003 Primary tumor location Right Left Rectum 38 44 17 24 17 11 0.24
Conclusions: In our study CCI score (low or high) showed be independent factor in prognosis and survival in octogenarian patients with colorectal cancer.
Funding: Has not received any funding.
Disclosure: All authors have declared no conflicts of interest.
593P The SENECA study: Prognostic role of serum biomarkers in elderly metastatic colorectal cancer patients
C. Lisanti1, D. Basile1, S.K. Garattini1, G. Pelizzari1, A. Parnofiello1, F. Cortiula1, E. Ongaro1, M. Cattaneo1, C. Corvaja1, V.J. Andreotti1, M. Bartoletti1, M. Casagrande2, D. Iacono2, M. Bonotto2, P. Ermacora2, N. Pella2, A. Buonadonna3, F. Puglisi4, G. Fasola2, G. Miolo3 1
Department of Medicine (DAME), University of Udine, Udine, Italy,2Department of Oncology, ASUIUD Santa Maria della Misericordia, Udine, Italy,3Department of Medical Oncology and Cancer Prevention, CRO National Cancer Institute, Aviano, Italy, 4
University of Udine, Department of Medical Oncology and Cancer Prevention, CRO National Cancer Institute, Aviano, Italy
Background: Aging induces meaningful changes in immune system and inflammation response with increase in monocyte-lymphocyte ratio (MLR) and serum lactate dehy-drogenase (LDH) levels. Notably, high levels of these serum biomarkers are associated with poor prognosis in many tumors. We aim to explore the prognostic role of baseline (i.e. before first line chemotherapy) MLR and LDH levels in elderly patients (pts) with metastatic colorectal cancer (MCRC).
Methods: A retrospective analysis of a consecutive cohort of 120 elderly (>70 years) pts treated for MCRC between 2004 and 2017 at the Oncology Department of Aviano National Cancer Institute and University Hospital of Udine (Italy), was conducted. The prognostic role of MLR and LDH levels on overall survival (OS) was investigated through uni- and multivariate Cox regression analyses.
Results: At a median follow-up of 50.83 months, median OS was 19.96 months. Overall, 46 pts (38%) presented a right cancer, 43 pts (36%) a left cancer and 30 pts (25%) a rectal one. In 8 (8%) and 47 (50%) pts a mutation of BRAF or KRAS was detected, respectively. Liver (36%), lymph-nodes (22%), peritoneum (22%) and lung (17%) were the most frequent sites of metastasis. Noteworthy, 22 pts (18%) had under-gone a metastasectomy. High levels of LDH (>480 U/L) and MLR (>0.45, obtained with ROC curve) were discovered in 23 (32%) and 51 (42%) patients respectively. By univariate analysis, high levels of LDH (HR 2.81, p¼ 0.001), MLR (HR 2.26, p < 0.001) or both (HR 6.42, p < 0.001) and node involvement at diagnosis (pN2 vs. pN0 HR 2.15, p¼ 0.019; pN3 vs. pN0 HR 2.69, p ¼ 0.052) were associated with worse OS.
Metastasectomy (HR 0.47, p¼ 0.009), tumor resection (HR 0.50, p ¼ 0.010) and left sidedness (HR 0.53, p¼ 0.01) were associated with better OS. By multivariate analysis, high levels of LDH (HR 2.64, p¼ 0.004), MLR (HR 2.21, p ¼ 0.009) or both (HR 4.19, p¼ 0.019) were independently associated with worse OS.
Conclusions: High baseline levels of LDH, MLR or both are unfavorable independent prognostic factors in elderly pts treated with first line chemotherapy for MCRC. These preliminary results emphasize the need of prospective studies to validate these cost-effectiveness biomarkers in this subgroup of pts.
Legal entity responsible for the study: University of Udine. Funding: Has not received any funding.
Disclosure: All authors have declared no conflicts of interest.
594P Determinants of oncologist’s choice in offering drug holidays during first line therapy for patients with metastatic colorectal cancer S.K.K. Garattini1 , M. Bonotto1 , L. Porcu2 , E. Ongaro1 , D. Basile3 , F. Cortiula1 , G. Pelizzari3 , M. Cattaneo1 , A. Parnofiello1 , V.J. Andreotti1 , C. Corvaja3 , G.G. Cardellino1 , P. Ermacora1 , M. Casagrande1 , D. Iacono1 , N. Pella1 , A. Buonadonna3 , A.M. Minisini1 , F. Puglisi3 , G. Fasola1 1
Oncology, ASUIUD Azienda Ospedaliero-Universitaria di Udine, Udine, Italy,
2
Laboratory of Methodology for Clinical Research-Oncology, IRCCS Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy,3
Oncology, CRO di Aviano, Aviano, Italy Background:Overall survival of patients (pts) with metastatic colorectal cancer (mCRC) has been increasing over the last decades. “Drug holiday” strategies were introduced by the oncologists to reduce toxicity. We aimed at studying what are the
Annals of Oncology
abstracts
Volume 29 | Supplement 8 | October 2018
doi:10.1093/annonc/mdy281 | viii197
clinico-pathological and treatment factors that drive the decision to propose a “drug holiday” in first line.
Methods:This is a retrospective series of consecutive pts affected by mCRC treated with first line chemotherapy. The pts included were treated from 1/1/2005 to 15/03/
2017 at University Hospital of Udine and IRCCS CRO of Aviano, Italy. A “drug Holiday” was defined as 56 or more consecutive days without chemotherapy during first-line. Upfront metastasectomy were excluded. Logistic regression was used to find association between predictors and “holiday offer” in univariate and multivariate analysis.
Results:A total of 648 pts were included. In detail, 215 received a drug holiday (33.2%) while 433 (66.8%) received continuous treatment. In univariate analysis, the variables associated with holiday were: non-upfront metastasectomy (OR 11.8, IC 95% 6.62-22.6, p < 0.001), thermoablation (OR 6.08, IC 95% 3.19-11.58, p < 0.001), primary tumor (OR 2.79, IC 95% 1.79-4.34, p < 0.001), G3-G4 pathological grade (OR 1.49, IC 95% 1.01-2.19, p¼ 0.046), adjuvant CT (OR 1.54,IC 95% 1.06-2.33, p ¼ 0.023). Adjuvant RT (OR 1.62, IC 95% 0.99-2.62, p¼ 0.051) showed a trend towards associa-tion. More than one metastatic site at diagnosis (OR 0.59, IC 95% 0.42-0.83, p¼ 0.003) and nodal involvement (OR 0.57, IC 95%, 0.34-0.95, p¼ 0.032) were associated to con-tinuous treatment. In multivariate analysis, only first line non-upfront metastasectomy (OR 9.89, IC95% 4.38-22.33, p < 0.001), thermoablation (OR 4.48, IC95% 1.97-10.19, p < 0.001) and primary tumor resection (OR 2.43, IC95% 1.14-5.19, p¼ 0.022) were independently associated with drug-holiday.
Conclusions:In our cohort, clinicians were more prone to propose a drug holiday in pts who had received non-upfront metastasectomy or thermo-ablation or were treated on their primary tumor. Having more than one site of metastasis at the beginning of 1st
line and nodal involvement favored continuous therapy.
Legal entity responsible for the study:ASUIUD- Azienda Ospedaliero-Universitaria di Udine, Dipertimento di Oncologia.
Funding:Has not received any funding.
Disclosure:All authors have declared no conflicts of interest.
596P Combined inhibition of MEK and PI3KCA pathway induces synergic antitumor activity in HER2 amplified human colorectal cancer models V. Belli1 , N. Matrone1 , S. Napolitano1 , E. Martinelli1 , M.D. Castellone2 , L. Trusolino3 , E.F. Giunta1 , V. De Falco1 , N. Zanaletti1 , P.P. Vitiello1 , D. Ciardiello1 , M. Terminiello1 , F. Ciardiello4 , T. Troiani1 1
Medicina di Precisione, Universita degli Studi della Campania Luigi Vanvitelli, Naples, Italy,2
Universita degli Studi dell Istitute of Experimental Endocrinology and Oncology, CNR, Naples, Italy,3
IRCCS, Istituto di Candiolo, Candiolo, Italy,4
Dipartimento di Medicina di Precisione, Universita degli Studi della Campania Luigi Vanvitelli, Naples, Italy
Background: Cetuximab and panitumumab, monoclonal antibodies direct against the epidermal growth factor receptor (EGFR) are a therapeutic option for mCRC patients wild type for KRAS and NRAS genes. However, only a subset of mCRC patients receives clinical benefit from these therapies due to the development of resistance mechanisms. HER2 gene amplification or HER2 activating mutations have been implicated as resist-ance mechanisms to anti-EGFR therapies. However, little is known about the role of HER2 in cancer resistance to anti-EGFR antibodies.
Methods: We transfected colon cancer cells sensitive to anti-EGFR antibodies (LIM1215 and SW48) with HER2 vector in order to obtain stable clones overexpressing HER2 protein. LIM1215-HER2 and SW48-HER2 cells were characterized by their mor-phological and molecular profile through cell migration and WB assays. Moreover, dif-ferent drugs sensitivity was evaluated by MTT and colony formation. Furthermore, HER2 amplified cells were engrafted into nude mice and treated with different drugs. Results: HER2 amplified cells show an overexpression and activation of the HER family receptors coupled by an intracellular downstream activation pathway of AKT, MAPK, and MEK proteins compared to parental cells. HER2 amplified cells were treated with several combinations of drugs directed against HER receptors, such as EGFR anti-bodies of first, second and third generation (cetuximab, SYM004 and MM151); trastu-zumab, pertuzumab and lapatinib directed against HER2 receptor; and duligotuzumab direct against HER3. Subsequently, both cells were treated with drugs directed against MEK and PI3KCA proteins, such as refametinib and pictilisib. Among these therapeu-tic options, the combination of refametinib and pictilisib have shown the most syner-gist anti-proliferative activity. The in vivo xenograft CRC models have confirmed the synergistic antitumor activity of this combined treatment. Moreover, PDTX HER amplified CRC models will be used to validate the previous results.
Conclusions: These results suggest that the treatment with refamentinib and pictilisib could be a strategy for patients with HER2 amplification that do not receive clinical benefit from standard anti-EGFR therapies.
Legal entity responsible for the study: Universita Degli Studi della Campania Luigi Vanvitelli.
Funding: Has not received any funding.
Disclosure: All authors have declared no conflicts of interest.
597P Predictive value of in-vitro testing anti-cancer therapy sensitivity on 3D micro-tumors (tumoroids) from patients with metastatic colorectal cancer: A feasibility study
L.H. Jensen1 , C. Dam1 , G. Hagel2 , C. Hansen1 , H. Harling3 , B.M. Havelund1 , A. Jakobsen1 , J. Lindebjerg1 , S. Rafaelsen1 , O. Thastrup4 , T.F. Hansen1 1
Danish Colorectal Cancer Center South, Center of Clinical Excellence, Vejle Hospital, Institute of Regional Health Research, University of Southern Denmark, Vejle, Denmark, 2
Laboratory, 2cureX, Copenhagen, Denmark,3
Surgery, Bispebjerg Hospital, Copenhagen, Denmark,4
2cureX, University of Copenhagen - Department of Drug Design and Pharmacology, Copenhagen, Denmark
Background: The treatment of cancer may be improved by testing the chemo sensitiv-ity of cancer cells obtained from the patient’s tumor. 3D culture represents a promising method for modeling of patient tumors in vitro. The purpose of this study was to test the feasibility of a clinical trial offering patients with metastatic colorectal cancer treat-ment based on in-vitro testing anti-cancer therapy sensitivity.
Methods: Main inclusion criteria were stage IV colorectal cancer, PS 0-1, previous exposure to 5FU, oxaliplatin, irinotecan, bevacizumab and, if RAS/RAF wild-type, an EGFR inhibitor. Fresh cancer tissues from metastases were cultivated as tumoroids. The culturing protocol which was originally developed for resected tissue was opti-mized for the smaller tissue amounts received from needle biopsies. Ten patients were to be included and at least five of them to have clinically applicable results in order for the procedure to be feasible.
Results: Ten patients were included from September to December 2017 in one institu-tion. Biopsies were from liver (6), peritoneum (2), retroperitoneum (1) and lung (1). Rebiopsies were allowed and a total of 19 biopsy sessions were performed with ultra-sound (14), CT (3) or sigmoidoscopy (2). In seven cases, the biopsy, tumorsphere for-mation and sensitivity testing was successful. Median time from biopsy to result was 34 days (range 19-50). A notable challenge was obtaining sufficient viable tumor tissue resulting in increased culture times or the need for re-biopsies.
Conclusions: This is the first clinical study of its kind. The method of selecting last-line treatment of colorectal cancer based on fresh biopsies was feasible as results were obtained in seven out of ten cases. The trial is now extended to a phase II trial with PFS as the primary endpoint.
Clinical trial identification: NCT03251612.
Legal entity responsible for the study: Lars Henrik Jensen. Funding: 2cureX.
Disclosure: L.H. Jensen: Travel grants: Roche, Amgen, Bayer. G. Hagel, H. Harling, O. Thastrup: 2cureX. All other authors have declared no conflicts of interest.
598P Macrophage migration inhibitory factor overexpression is a mechanism of acquired resistance to anti-EGFR inhibitor cetuximab in human colorectal cancer cell line
N. Matrone1, A. Chambery2, R. Russo2, P.V. Pedone2, V. Belli1, S. Napolitano1, E. Martinelli1, E.F. Giunta1, V. De Falco1, N. Zanaletti1, P. Vitale1, M. Terminiello1, C. Cardone1, F. Ciardiello1, T. Troiani1
1
Precision Medicine, Universita degli Studi della Campania Luigi Vanvitelli, Naples, Italy, 2
Dipartimento di Scienze e Tecnologie Ambientali, Biologiche e Farmaceutiche, Universita degli Studi della Campania Luigi Vanvitelli, Naples, Italy
Background: The anti-epidermal growth factor receptor (EGFR) monoclonal antibod-ies (mAbs) cetuximab and panitumumab are effective in a subset of RAS/BRAF wild-type (WT) metastatic colorectal cancers (mCRCs) patients. Despite an accurate RAS-driven selection, not all patients will respond to EGFR inhibitors and the onset of sec-ondary resistance limits their clinical benefit.
Methods: With the aim of developing effective preclinical models for testing possible strategies to overcome acquired resistance to EGFR blockade, we have generated a series of human colon cancer cell lines with in vitro and in vivo acquired resistance to anti-EGFR inhibitors. To better investigate the differentially expressed proteins involved in EGFR resistance, we applied an advanced quantitative proteomic approach based on TMT isobaric labeling and nano-liquid chromatography coupled with high resolution tandem mass spectrometry (MS/MS).
Results: To evaluate changes in protein expression we have used human CRC cell line cetuximab-sensitive GEO, as well as its derived cell line with acquired resistance to cetuximab GEO-CR. By MS/MS, we have identified and quantified 2455 proteins; 53 proteins were found to be differentially expressed in GEO-CR compared to GEO cells. Only 11 proteins were found to be high regulated in GEO-CR, among these we focused our attention on the inhibition factor of macrophage migration (MIF) for its relevance in CRC tumorigenesis. To explore its involvement in resistance to cetuximab in CRC cell line, we have performed an MTT assay with two MIF-antagonists, ISO1 a cell-per-meable inhibitor of MIF tautomerase and 4-IPP, a selective MIF inhibitor that blocks MIF and its receptor, CD74, internalization. GEO-CR cell line was treated with two MIF antagonists alone and in combination with cetuximab. Only the combined treat-ment with cetuximab and 4-IPP induced a synergistic antiproliferative and apoptotic effects.
Conclusions: These results suggest that MIF overexpression is involved in acquired resistance to cetuximab and the inhibition of EGFR and MIF could be a strategy for overcoming anti-EGFR resistance in patients with CRC.
