Giulia Pasquini

BRAF and RAS mutations as prognostic factors in metastatic colorectal cancer patients undergoing liver resection

Background:Despite major advances in the management of metastatic colorectal cancer (mCRC) with liver-only involvement, relapse rates are high and reliable prognostic markers are needed.Methods:To assess the prognostic impact of BRAF and RAS mutations in a large series of liver-resected patients, medical records of 3024 mCRC patients were reviewed. Eligible cases undergoing potentially curative liver resection were selected. BRAF and RAS mutational status was tested on primary and/or metastases by means of pyrosequencing and mass spectrometry genotyping assay. Primary endpoint was relapse-free survival (RFS).Results:In the final study population (N=309) BRAF mutant, RAS mutant and all wild-type (wt) patients were 12(4%), 160(52%) and 137(44%), respectively. Median RFS was 5.7, 11.0 and 14.4 months respectively and differed significantly (Log-rank, P=0.043). At multivariate analyses, BRAF mutant had a higher risk of relapse in comparison to all wt (multivariate hazard ratio (HR)=2.31; 95% CI, 1.09–4.87; P=0.029) and to RAS mutant (multivariate HR=2.06; 95% CI, 1.02–4.14; P=0.044). Similar results were obtained in terms of overall survival. Compared with all wt patients, RAS mutant showed a higher risk of death (HR=1.47; 95% CI, 1.05–2.07; P=0.025), but such effect was lost at multivariate analyses.Conclusions:BRAF mutation is associated with an extremely poor median RFS after liver resection and with higher probability of relapse and death. Knowledge of BRAF mutational status may optimise clinical decision making in mCRC patients potentially candidate to hepatic surgery. RAS status as useful marker in this setting might require further studies.

First‐line treatment with FOLFOXIRI for advanced pancreatic cancer in clinical practice: patients' outcome and analysis of prognostic factors

FOLFIRINOX is a standard first‐line treatment for advanced pancreatic cancer (aPC). The Gruppo Oncologico Nord Ovest (GONO) FOLFOXIRI regimen demonstrated efficacy in metastatic colorectal cancer. We aimed to evaluate activity and tolerability of FOLFOXIRI regimen in patients with aPC and to explore putative prognostic factors. One hundred thirty‐seven consecutive aPC patients were treated with FOLFOXIRI in our institution between 2008 and 2014. Clinical, laboratory and pathological data were collected and their association with activity, progression free survival (PFS) and overall survival (OS) was investigated. After a median follow up of 30 months, median PFS and OS were 8.0 months (95% CI 6.19–9.81) and 12 months (95% CI 9.75–14.25), respectively. Response rate was 38.6%, while disease‐control rate 72.2%. At multivariate analysis liver metastases (p = 0.019; Hazard Ratio, HR, 0.59, 95% Confidence Interval, CI, 0.380.96), Eastern Cooperative Oncology Group (ECOG) performance status (PS) 1 (p = 0.001; HR 2.26, 95%CI 1.42–3.59) and neutrophil‐lymphocyte ratio (NLR)> 4 (p= 0.002; HR: 2.42; 95% CI 1.38–4.25) were associated with poorer OS. We categorized 119 pts with complete available data as good‐risk (0 factors, 38 pts), intermediate‐risk (1 factor, 49 pts) and poor‐risk (≥2 factors, 32 pts). Median OS for these three groups were 17.6, 11.1 and 7.4 months, respectively (p < 0.001). FOLFOXIRI is active and feasible in aPC. Prognosis of aPC pts treated with FOLFOXIRI is influenced by easily available factors: our analysis revealed ECOG PS, liver metastases and NLR as the most important predictors of survival. These factors could be helpful for treatment decision and clinical trial design.

Second-line therapy for advanced pancreatic cancer: Evaluation of prognostic factors and review of current literature

BACKGROUND FOLFIRINOX is a standard first-line treatment for advanced pancreatic cancer (aPC) and no accepted second-line regimen exists. MATERIAL & METHODS We enrolled 71 aPC patients progressed to modified FOLFIRINOX (mFOLFIRINOX) treated with second-line chemotherapy. RESULTS Five partial responses (7.1%) and 19 (27.1%) disease stabilizations were reported. After a median follow-up of 20.1 months, median progression-free survival was 2.5 months (95% CI: 2.1-2.9 months) and median overall survival was 6.2 months (95% CI: 5.3-7.1 months). At multivariate analysis, CA19.9 level ≥ 59 upper normal limit resulted associated with worse survival (hazard ratio: 2.32; 95% CI: 1.12-4.78; p = 0.023). CONCLUSION Salvage chemotherapy could be useful for a subgroup of aPC patients. Prognostic factors might be helpful to identify patients with greater benefit.

Reply: Comment on ‘Histopathologic evaluation of liver metastases from colorectal cancer patients treated with FOLFOXIRI plus bevacizumab'

Reply: Comment on ‘Histopathologic evaluation of liver metastases from colorectal cancer patients treated with FOLFOXIRI plus bevacizumab’

EGFR and AKT1 overexpression are mutually exclusive and associated with a poor survival in resected gastric adenocarcinomas

PURPOSE The evaluation of molecular targets in gastric cancer has demonstrated the predictive role of HER2 amplification for trastuzumab treatment in metastatic gastric cancer. Besides HER2, other molecular targets are under evaluation in metastatic gastric tumors. However, very little is known about their role in resected tumors. We evaluated the expression of HER2, EGFR, MET, AKT1 and phospho-mTOR in resected stage II-III adenocarcinomas. METHODS Ninety-two patients with resected stomach (63%) or gastro-esophageal adenocarcinomas (27%) were evaluated. Antibodies anti-HER2, EGFR, MET, AKT1 and phospho-mTOR were used for immunostaining of formalin-fixed paraffin-embedded slides. Using FISH, HER2 amplification was evaluated in cases with an intermediate (+2) staining. RESULTS EGFR overexpression (11%) was a poor prognostic factor for overall survival (3-year OS: 47% vs 77%; Log-Rank p= 0.033). MET overexpression (36%) was associated with a trend for a worse survival (3-year OS: 65% vs 77%; Log-Rank p= 0.084). HER2 amplification/overexpression and mTOR hyper-phosphorylation were observed in 13% and 48% of tumors, respectively. AKT1 overexpression (8%) was not a prognostic factor by itself (p= 0.234). AKT1 and EGFR overexpression was mutually exclusive and patients with EGFR or AKT1 overexpression experienced a poor prognosis (3-year OS: 52% vs. 79%, Log-Rank p= 0.005). CONCLUSIONS EGFR is confirmed a poor prognostic factor in resected gastric cancers. We firstly describe a mutually exclusive overexpression of EGFR and AKT1 with potential prognostic implications, suggesting the relevance of this pathway for the growth of gastric cancers.

PD-L1 mRNA expression in plasma-derived exosomes is associated with response to anti-PD-1 antibodies in melanoma and NSCLC.

This corrects the article DOI: 10.1038/bjc.2017.85

Third-Line Chemotherapy with Irinotecan plus 5-Fluorouracil in Caucasian Metastatic Gastric Cancer Patients

Purpose: The aim of this study was to evaluate the activity of the combination of 5-fluorouracil/folinic acid and irinotecan (FOLFIRI) as third-line chemotherapy (CT) in metastatic gastric cancer (mGC) patients pretreated with platinum derivatives, fluoropyrimidines, and taxanes. Methods: We prospectively collected data of mGC patients treated with third-line FOLFIRI at our institution from 2009 to 2014. Eligible patients should be treated with a fluoropyrimidine-platinum first-line CT and a subsequent taxane-based second-line CT. FOLFIRI consisted of irinotecan 180 mg/m2 and leucovorin 200 mg/m2, followed by 5-fluorouracil 2,800 mg/m2 (administered as 48-hour i.v. continuous infusion from day 1 to 3), with cycles repeated every 2 weeks. Response rate (RR) was evaluated according to RECIST version 1.0, while progression-free (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Results: A total of 33 patients were included. The majority (97%) had good performance status (0-1 according to ECOG), while median PFS after first-line and second-line CT was 5.2 and 4.4 months, respectively. Two patients experienced an objective response (RR: 6%), while 14 patients achieved disease stabilization (disease control rate: 42%). Median PFS and OS from the start of third-line CT were 3.3 and 7.5 months, respectively. Hematological and nonhematological grade 3-4 toxicities were uncommon and included neutropenia (6.1%), diarrhea (9.1%), vomiting (3%), and asthenia (3%). Febrile neutropenia was not reported. Conclusions: Third-line CT with FOLFIRI may be an option in heavily pretreated mGC patients with preserved performance status and organ function. This regimen has a favorable safety profile, and signs of activity have been observed after standard first- and second-line CT.

Contents Vol. 91, 2016

A.B. Benson, Chicago, Ill. A. Chang, Singapore A.L. Cheng, Taipei J.F. Cleary, Madison, Wis. M. Dietel, Berlin P. Dufour, Strasbourg M.S. Ernstoff, Buffalo, N.Y. M.G. Fakih, Duarte, Calif. J.J. Grau, Barcelona H. Gronemeyer, Illkirch D.F. Hayes, Ann Arbor, Mich. C.S. Johnson, Buffalo, N.Y. M.J. Kelley, Durham, N.C. L. Kumar, New Delhi P.J. Loehrer, Indianapolis, Ind. J.R. Marshall, Buffalo, N.Y. S. Monfardini, Milan R. Nagler, Haifa R. Ohno, Nagoya B. Pestalozzi, Zurich H.M. Pinedo, Amsterdam E.A. Repasky, Buffalo, N.Y. A. Semczuk, Lublin E.F. Smit, Amsterdam C.N. Sternberg, Rome R. Stupp, Zurich M.S. Tallman, New York, N.Y. S. Tanaka, Hiroshima M. Tian, Houston, Tex. D.L. Trump, Buffalo, N.Y. T. Wiegel, Ulm W. Yasui, Hiroshima H. Zhang, Hangzhou City Editor-in-Chief

Acknowledgement to the Reviewers

www.karger.com/ocl Banke Agarwal, Saint Louis, Mo., USA Bharat B. Aggarwal, Houston, Tex., USA Jaffer A. Ajani, Houston, Tex., USA Salah-Eddin Al-Batram, Frankfurt a.M., Germany Roberto Angioli, Rome, Italy Jorge Aparicio, Valencia, Spain Carl Atkins, Albany, N.Y., USA Georges Azzi, Miami, Fla., USA Eishi Baba, Fukuoka, Japan Moo Jun Baek, Cheonan, Korea Lodovico Balducci, Tampa, Fla., USA Klaus H. Baumann, Marburg, Germany Wolf O. Bechstein, Frankfurt a.M., Germany Yves Bécouarn, Bordeaux, France Al B. Benson, Chicago, Ill., USA Patrick Boland, Buffalo, N.Y., USA Philip Bonomi, Chicago, Ill., USA Marius G. Bredell, Zumikon, Switzerland Fátima Carneiro, Porto, Portugal Yee Chao, Taipei, Taiwan Yao-Tseng Chen, New York, N.Y., USA Ann-Lii Cheng, Taipei, Taiwan Dennis S. Chi, New York, N.Y., USA James Cleary, Madison, Wis., USA Manola Comar, Trieste, Italy Renzo Corvò, Genoa, Italy Allan Covens, Toronto, Ont., Canada Paola Di Bonito, Rome, Italy Reinhard Dummer, Zurich, Switzerland Michael Duruisseaux, Grenoble, France Janice P. Dutcher, Bronx, N.Y., USA Monika Eichholzer, Zurich, Switzerland Bernhard J. Eigl, Vancouver, B.C., Canada Robert M. Eisele, Homburg, Germany Peter M. Ellis, Hamilton, Ont., Canada Günter Emons, Göttingen, Germany Nobuyuki Enomoto, Yamanashi, Japan Marwan G. Fakih, Duarte, Calif., USA Nicola Fazio, Milan, Italy Steven Feigenberg, Baltimore, Md., USA Clemens Feistritzer, Innsbruck, Austria Alexandra R. Fernandes, Caparica, Portugal Thiago Ferreira, Campinas, Brazil Petra Feyer, Berlin, Germany Ralph S. Freedman, Houston, Tex., USA César O. Freytes, San Antonio, Tex., USA Martin Früh, St. Gallen, Switzerland Masashi Fujii, Tokyo, Japan Val Gebski, Sydney, N.S.W., Australia Tarik Gheit, Lyon, France Alan M. Gillespie, Sheffield, UK Priscila Goncalves, Bethesda, Md., USA Juan-José Grau, Barcelona, Spain Frank Griesinger, Oldenburg, Germany Kathrin M. Gschwendtner, Freiburg, Germany Dominique Guenot, Strasbourg, France Stephan L. Haas, Stockholm, Sweden John D. Hainsworth, Nashville, Tenn., USA Shalaka Hampras, Tampa, Fla., USA Sheng-Po Hao, Taipei, Taiwan John H. Healey, New York, N.Y., USA Stephanie Hehlgans, Frankfurt a.M., Germany Masashi Hirooka, Toon, Ehime, Japan Wouter Hogendoorn, Rotterdam, The Netherlands Shigeo Horie, Tokyo, Japan Nadine Houédé, Nimes, France M.A. Huber, San Antonio, Tex., USA Jutta Hübner, Berlin, Germany Nuhad K. Ibrahim, Houston, Tex., USA Masafumi Ikeda, Chiba, Japan Misa Imai, Tokyo, Japan Takeshi Isobe, Izumo, Japan Namiki Izumi, Tokyo, Japan Long R. Jiao, London, UK Robin L. Jones, Seattle, Wash., USA Hrishi B. Joshi, Cardiff, UK Vassilos Karavassilis, Thessaloniki, Greece Shunsuke Kato, Tokyo, Japan Satoshi Kato, Morioka, Japan Nancy Kemeny, New York, N.Y., USA Hyung Jin Kim, Suwon, Korea Duck-Woo Kim, Seongnam, Korea Lee Su Kim, Ahnyang, Korea Yasushi Kojima, Shinjuku-ku, Japan Shigehiro Kokubu, Kawasaki, Japan Srinadh Komanduri, Chicago, Ill., USA Susan Krown, New York, N.Y., USA Takashi Kumada, Ogaki, Japan Takayasu Kurata, Osaka, Japan