### MYC regulation of glutamine–proline regulatory axis is key in luminal B breast cancer

• , , , , , , , , (2005) High-throughput protein expression analysis using tissue microarray technology of a large well-characterised series identifies biologically distinct classes of breast cancer confirming recent cDNA expression analyses. Int J Cancer 116(3): 340–3450.

• , (2014) Redox control of glutamine utilization in cancer. Cell death & disease 5: e1561.

• , , , , , , , (2006) c-Myc phosphorylation is required for cellular response to oxidative stress. Mol Cell 21(4): 509–519.

• , , , , , , , (2015) Glutamate enrichment as new diagnostic opportunity in breast cancer. Int J Cancer 136(7): 1619–1628.

• , , , , , , (2014) Metabolic characterization of triple negative breast cancer. BMC Cancer 14: 941.

• , , , , , , , , , , , , , , , (2013) The mTORC1 pathway stimulates glutamine metabolism and cell proliferation by repressing SIRT4. Cell 153(4): 840–854.

• , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , (2012) The genomic and transcriptomic architecture of 2,000 breast tumours reveals novel subgroups. Nature 486(7403): 346–352.

• (2012) MYC on the path to cancer. Cell 149(1): 22–35.

• , , , , , , , , , , , , (2017) Human mitochondrial pyrroline-5-carboxylate reductase 1 promotes invasiveness and impacts survival in breast cancers. Carcinogenesis 38: 519–531.

• , , , , , , , , , , (2009) c-Myc suppression of miR-23a/b enhances mitochondrial glutaminase expression and glutamine metabolism. Nature 458(7239): 762–765.

• , , , , , , , , , , , (2016) MYC functions are specific in biological subtypes of breast cancer and confers resistance to endocrine therapy in luminal tumours. Br J Cancer 114(8): 917–928.

• , , , , , , , , , , , , , , , , , , , (2014) Antitumor activity of the glutaminase inhibitor CB-839 in triple-negative breast cancer. Mol Cancer Ther 13(4): 890–901.

• , (2011) Hallmarks of cancer: the next generation. Cell 144(5): 646–674.

• , , , , , , (2008) Human Delta1-pyrroline-5-carboxylate synthase: function and regulation. Amino Acids 35(4): 665–672.

• , , , , , (2010) Glutaminase 2, a novel p53 target gene regulating energy metabolism and antioxidant function. Proc Natl Acad Sci USA 107(16): 7455–7460.

• , , (2015) Disruption of proline synthesis in melanoma inhibits protein production mediated by the GCN2 pathway. Mol Cancer Res 13(10): 1408–1420.

• , , , (2013) Expression of glutamine metabolism-related proteins according to molecular subtype of breast cancer. Endocr Relat Cancer 20(3): 339–348.

• , , (2008) Proline modulates the intracellular redox environment and protects mammalian cells against oxidative stress. Free Radic Biol Med 44(4): 671–681.

• , , , , , , , , , , , , (2016) PYCR1 and PYCR2 interact and collaborate with RRM2B to protect cells from overt oxidative stress. Sci Rep 6: 18846.

• , (2013) Molecular pathways: targeting MYC-induced metabolic reprogramming and oncogenic stress in cancer. Clin Cancer Res 19(21): 5835–5841.

• , , , , (2015) Proline biosynthesis augments tumor cell growth and aerobic glycolysis: involvement of pyridine nucleotides. Sci Rep 5: 17206.

• , , , , , , (2012) Reprogramming of proline and glutamine metabolism contributes to the proliferative and metabolic responses regulated by oncogenic transcription factor c-MYC. Proc Natl Acad Sci USA 109(23): 8983–8988.

• , (2012) Proline dehydrogenase (oxidase) in cancer. BioFactors 38(6): 398–406.

• , , , , (2016) The oncogenic transcription factor c-Jun regulates glutaminase expression and sensitizes cells to glutaminase-targeted therapy. Nat Commun 7: 11321.

• , , , , , Statistics Subcommittee of the NCIEWGoCD (2005) REporting recommendations for tumour MARKer prognostic studies (REMARK). Br J Cancer 93(4): 387–391.

• , , , , , , , (2012) Proline dehydrogenase is essential for proline protection against hydrogen peroxide induced cell death. Free Radic Biol Med 53(5): 1181–1191.

• , , (2013) Bridging epigenetics and metabolism: role of non-essential amino acids. Epigenetics 8(3): 231–236.

• , , , (2015) Proline metabolism and cancer: emerging links to glutamine and collagen. Curr Opin Clin Nutr Metab Care 18(1): 71–77.

• , , , , (1997) A model for p53-induced apoptosis. Nature 389(6648): 300–305.

• , , , (2008) Central carbon metabolism in the progression of mammary carcinoma. Breast Cancer Res Treat 110(2): 297–307.

• , , , , , , , , , , , , , (2010) A methodology to identify consensus classes from clustering algorithms applied to immunohistochemical data from breast cancer patients. Comput Biol Med 40(3): 318–330.

• , , , , , , , , , , (2010) Targeting mitochondrial glutaminase activity inhibits oncogenic transformation. Cancer cell 18(3): 207–219.

• , , , , , , , , , , (2008) Myc regulates a transcriptional program that stimulates mitochondrial glutaminolysis and leads to glutamine addiction. Proc Natl Acad Sci USA 105(48): 18782–18787.

• , (2010) Glutamine addiction: a new therapeutic target in cancer. Trends Biochem Sci 35(8): 427–433.

• , , , , , , (2017) Knockdown of PYCR1 inhibits cell proliferation and colony formation via cell cycle arrest and apoptosis in prostate cancer. Med Oncol 34(2): 27.

• ### HER2 expression patterns in paired primary and metastatic endometrial cancer lesions

• , , , , , , , (1996) Specific P53 mutations are associated with de novo resistance to doxorubicin in breast cancer patients. Nat Med 2(7): 811–814.

• , , , , , (2017) L1CAM and HER2 expression in early endometrioid uterine cancer. Int J Gynecol Pathol 36(4): 356–363.

• , , (2015) HER2-directed therapy: current treatment options for HER2-positive breast cancer. Breast Cancer 22(2): 101–116.

• , , , , , , , , , (2012) Tissue confirmation of disease recurrence in breast cancer patients: pooled analysis of multi-centre, multi-disciplinary prospective studies. Cancer Treat Rev 38(6): 708–714.

• , , , , , , , , (2006) EZH2 expression is associated with high proliferation rate and aggressive tumor subgroups in cutaneous melanoma and cancers of the endometrium, prostate, and breast. J Clin Oncol 24(2): 268–273.

• , , , , , , , , , , , , , (2007) A functional genetic approach identifies the PI3K pathway as a major determinant of trastuzumab resistance in breast cancer. Cancer Cell 12(4): 395–402.

• , , , , , , , , , , , , , , , , , , , , , , , (2016) SYD985, a novel duocarmycin-based HER2-targeting antibody-drug conjugate, shows antitumor activity in uterine serous carcinoma with HER2/Neu expression. Mol Cancer Ther 15(8): 1900–1909.

• , , , (2013) Toward standard HER2 testing of endometrial serous carcinoma: 4-year experience at a large academic center and recommendations for clinical practice. Mod Pathol 26(12): 1605–1612.

• , (2013) Marked heterogeneity of HER2/NEU gene amplification in endometrial serous carcinoma. Genes Chromosomes Cancer 52(12): 1178–1186.

• , , (2014) HER2/neu in endometrial cancer: a promising therapeutic target with diagnostic challenges. Arch Pathol Lab Med 138(3): 343–350.

• Cancer Genome Atlas Research N, , , , , , , , , , , , , , , , , , (2013) Integrated genomic characterization of endometrial carcinoma. Nature 497(7447): 67–73.

• , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , (2017) 3rd ESO-ESMO international consensus guidelines for advanced breast cancer (ABC 3). Ann Oncol 28(1): 16–33.

• , , , , , (2017) Objective, domain-specific HER2 measurement in uterine and ovarian serous carcinomas and its clinical significance. Gynecol Oncol 145(1): 154–158.

• , , , , , , , , , , , (2014) Biopsy confirmation of metastatic sites in breast cancer patients: clinical impact and future perspectives. Breast Cancer Res 16(2): 205.

• , , , (2015) The Therapeutic Challenge of Targeting HER2 in Endometrial Cancer. Oncologist 20(9): 1058–1068.

• , (2001) J-Express: exploring gene expression data using Java. Bioinformatics 17(4): 369–370.

• , , , (2008a) GATA3 expression in estrogen receptor alpha-negative endometrial carcinomas identifies aggressive tumors with high proliferation and poor patient survival. Am J Obstet Gynecol 199(5): 543 e1–543 e7.

• , , , , , , (2008b) HER-2/neu expression is associated with high tumor cell proliferation and aggressive phenotype in a population based patient series of endometrial carcinomas. Int J Oncol 32(2): 307–316.

• , , (2013) HER2 expression beyond breast cancer: therapeutic implications for gynecologic malignancies. Mol Diagn Ther 17(2): 85–99.

• (2015) Second-line therapy for endometrial cancer: the need for better options. J Clin Oncol 33(31): 3535–3540.

• , , , , , , , , , , (2010) Phase II trial of trastuzumab in women with advanced or recurrent, HER2-positive endometrial carcinoma: a Gynecologic Oncology Group study. Gynecol Oncol 116(1): 15–20.

• , , , , , , , , , , , , , , , , , , , , , , , , , , , (2016) The genomic landscape and evolution of endometrial carcinoma progression and abdominopelvic metastasis. Nat Genet 48(8): 848–855.

• , , , , , , , , , , (2015) HER2 over-expressing high grade endometrial cancer expresses high levels of p95HER2 variant. Gynecol Oncol 137(1): 160–166.

• , , , , , , , , , (2001) Validation of tissue microarrays for immunohistochemical profiling of cancer specimens using the example of human fibroblastic tumors. Am J Pathol 158(4): 1245–1251.

• , , , (2006) Use of trastuzumab in the treatment of metastatic endometrial cancer. Int J Gynecol Cancer 16(3): 1370–1373.

• , , , , , , , (2017) Distinct molecular landscapes between endometrioid and nonendometrioid uterine carcinomas. Int J Cancer 140(6): 1396–1404.

• , , , , , , (2015) Identification of potential therapeutic targets by molecular profiling of 628 cases of uterine serous carcinoma. Gynecol Oncol 138(3): 620–626.

• , , , , (2011) Trastuzumab-DM1 (T-DM1) retains all the mechanisms of action of trastuzumab and efficiently inhibits growth of lapatinib insensitive breast cancer. Breast Cancer Res Treat 128(2): 347–356.

• , , , , , (2010) Association between gain-of-function mutations in PIK3CA and resistance to HER2-targeted agents in HER2-amplified breast cancer cell lines. Ann Oncol 21(2): 255–262.

• , , , , , , , , , (1998) Tissue microarrays for high-throughput molecular profiling of tumor specimens. Nat Med 4(7): 844–847.

• , , , , , , , , , , , (2012) Loss of GPER identifies new targets for therapy among a subgroup of ERalpha-positive endometrial cancer patients with poor outcome. Br J Cancer 106(10): 1682–1688.

• , , , , , , , , , , , (2012) Lapatinib and potential prognostic value of EGFR mutations in a Gynecologic Oncology Group phase II trial of persistent or recurrent endometrial cancer. Gynecol Oncol 127(2): 345–350.

• , (2016) Endometrial cancer-targeted therapies myth or reality? Review of current targeted treatments. Eur J Cancer 59: 99–108.

• , , , , , , , , , , , , (2008) WDR19 expression is increased in prostate cancer compared with normal cells, but low-intensity expression in cancers is associated with shorter time to biochemical failures and local recurrence. Clinical Cancer Res 14(5): 1397–1406.

• , (2016) HER2-positive breast cancer. Lancet 389(10087): 2415–2429.

• , , , , , , , (2006) HER-2 is an independent prognostic factor in endometrial cancer: association with outcome in a large cohort of surgically staged patients. J Clin Oncol 24(15): 2376–2385.

• , , , , , , , , , , , , (2004) PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients. Cancer Cell 6(2): 117–127.

• , , , , , , , , , (2012) Loss of human epidermal growth factor receptor 2 (HER2) expression in metastatic sites of HER2-overexpressing primary breast tumors. J Clin Oncol 30(6): 593–599.

• , , , , , , , (2011) Targeting both Notch and ErbB-2 signalling pathways is required for prevention of ErbB-2-positive breast tumour recurrence. Br J Cancer 105(6): 796–806.

• (2009) Revised FIGO staging for carcinoma of the vulva, cervix, and endometrium. Int J Gynaecol Obstet 105(2): 103–104.

• , , , , , , , , , , National Coordinating Committee for Breast P (2015) Updated UK Recommendations for HER2 assessment in breast cancer. J Clin Pathol 68(2): 93–99.

• , , , , , , , , , , , , , , , , , , , , , , (2009) Integrated genomic profiling of endometrial carcinoma associates aggressive tumors with indicators of PI3 kinase activation. Proc Natl Acad Sci USA 106(12): 4834–4839.

• , , (2012) Markers for individualised therapy in endometrial carcinoma. Lancet Oncol 13(8): e353–e361.

• (2010) Letter to the Editor referring to the manuscript entitled: “Phase II trial of trastuzumab in women with advanced or recurrent HER-positive endometrial carcinoma: a Gynecologic Oncology Group study” recently reported by Fleming et al., (Gynecol Oncol., 116;15-20;2010). Gynecol Oncol 118(1): 95–96, author reply 96-7.

• , , , (2017) Regression of metastatic, radiation/chemotherapy-resistant uterine serous carcinoma overexpressing HER2/neu with trastuzumab emtansine (TDM-1). Gynecol Oncol Rep 19: 10–12.

• , , , , (2008) Trastuzumab treatment in patients with advanced or recurrent endometrial carcinoma overexpressing HER2/neu. Int J Gynaecol Obstet 102(2): 128–131.

• , , , , , , , , , (2005) Amplification of c-erbB2 oncogene: a major prognostic indicator in uterine serous papillary carcinoma. Cancer 104(7): 1391–1397.

• , , , , , , (2007) Escape from HER-family tyrosine kinase inhibitor therapy by the kinase-inactive HER3. Nature 445(7126): 437–441.

• , , , , , , (2017) Biopsy of breast cancer metastases: patient characteristics and survival. BMC cancer 17(1): 7.

• , , , , , , , , , (2004) Her-2/neu overexpression and amplification in uterine papillary serous carcinoma. J Clin Oncol 22(15): 3126–3132.

• , , (2004) Prognostic impact of alterations in P-cadherin expression and related cell adhesion markers in endometrial cancer. J Clin Oncol 22(7): 1242–1252.

• , , , , , , , , , (2014) Loss of progesterone receptor links to high proliferation and increases from primary to metastatic endometrial cancer lesions. Eur J Cancer 50(17): 3003–3010.

• , , , , , (2015) Global cancer statistics, 2012. CA Cancer J Clin 65(2): 87–108.

• , , , , (2012) Discrepancies between primary tumor and metastasis: a literature review on clinically established biomarkers. Crit Rev Oncol Hematol 84(3): 301–313.

• , , , , (2006) HER-2/neu overexpression in uterine papillary serous cancers and its possible therapeutic implications. Int J Gynecol Cancer 16(5): 1897–1902.

• , , , , , , , , , , , , , , , , , , , American Society of Clinical O, College of American P (2013) Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update. J Clin Oncol 31(31): 3997–4013.

• , (2001) Untangling the ErbB signalling network. Nat Rev Mol Cell Biol 2(2): 127–137.

• ### Gemcitabine plus platinum-based chemotherapy for first-line treatment of hepatocholangiocarcinoma: an AGEO French multicentre retrospective study

• , (1949) Combined liver cell and bile duct carcinoma. Am J Pathol 25(4): 647–655.

• , , , , , , , , , (2016) Mixed hepatocellular and cholangiocarcinoma: a rare tumor with a mix of parent phenotypic characteristics. HPB 18: 886–889.

• , , , , , , , , , , , , , , , , , , , , (2009) Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol 10: 25–34.

• , , , , , , (2009) An update on long term outcome of curative hepatic resection for hepatocholangiocarcinoma. World J Surg 33: 1916–1921.

• , , , (2016) Combined intrahepatic cholangiocarcinoma and hepatocellular carcinoma. Chin Clin Oncol 5: 66.

• , , , , , , , , , (2014) Cisplatin/gemcitabine or oxaliplatin/gemcitabine in the treatment of advanced biliary tract cancer: a systematic review. Cancer Med 3(6): 1502–1511.

• , , , , , , (2013) Combined hepatocellular and cholangiocarcinoma (biphenotypic) tumors: imaging features and diagnostic accuracy of contrast enhanced CT and MRI. AJR Am J Roentgenol 201: 332.

• , , , , , , (2014) Combined hepatocellular-cholangiocarcinoma: a population-level analysis of an uncommon primary liver tumor. Liver Transplant 20: 952–959.

• , , (2013) Transplantation versus resection for patients with combined hepatocellular carcinomacholangiocarcinoma. J Surg Oncol 107: 608–612.

• , , , , , , , , (2002) Combined hepatocellular and cholangiocarcinoma: demographic, clinical, and prognostic factors. Cancer 94: 2040–2046.

• , , , , , , (2004) Primary liver carcinoma of intermediate (hepatocyte–cholangiocyte) phenotype. J Hepatol 40: 298–304.

• , , , , , , , (2010) Nonresectable combined hepatocellular carcinoma and cholangiocarcinoma: analysis of the response and prognostic factors after transcatheter arterial chemoembolization. Radiology 255: 270–277.

• , , , , , , (2006) Comparison of combined hepatocellular and cholangiocarcinoma with hepatocellular carcinoma and intrahepatic cholangiocarcinoma. Surg Today 36: 892–897.

• , , , , , , , , (2016) Combined hepatocellular carcinoma and cholangiocarcinoma (biphenotypic) tumors: clinical characteristics, imaging features of contrast-enhanced ultrasound and computed tomography. BMC Cancer 16: 158.

• , , , , , , , , , , , , , , , , , , , , , , , SHARP Investigators Study Group (2008) Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 359(4): 378–390.

• , , , , , , , (2014) Current update on combined hepatocellular- cholangiocarcinoma. Eur J Radiol Open 1: 40–48.

• , , , , , , , , , (2009) Palliative treatment with self-expandable metallic stents in patients with advanced type III or IV hilar cholangiocarcinoma: a percutaneous versus endoscopic approach. Gastrointest Endosc 69(1): 55–62.

• , , , , , , (2010) The diagnostic conundrum and liver transplantation outcome for combined hepatocellular-cholangiocarcinoma. Am J Transplant 10: 1263–1267.

• , , , , , , , , , , , , , , (2013) Long-term outcome of liver transplantation for combined hepatocellular carcinoma and cholangiocarcinoma. Transplant Proc 45: 3038–3040.

• , , , , , (2009) Establishment of cancer cell lines from rat hepatocholangiocarcinoma and assessment of the role of granulocyte-colony stimulating factor and hepatocyte growth factor in their growth, motility and survival. J Hepatol 51: 77–92.

• , , , (2011) Mixed hepatocellular cholangiocarcinoma and intrahepatic cholangiocarcinoma in patients undergoing transplantation for hepatocellular carcinoma. Liver Transplant 17(8): 934–942.

• , , , , , (1996) A clinicopathological study on combined hepatocellular and cholangiocarcinoma. J Gastroenterol Hepatol 11: 758–764.

• , , , , , , , , , (2006) Clinical and pathological features of Allen’s type C classification of resected combined hepatocellular and cholangiocarcinoma: a comparative study with hepatocellular carcinoma and cholangiocellular carcinoma. J Gastrointest Surg 10: 987–998.

• , , , (2010) Combined hepatocellular-cholangiocarcinoma. In: Who classification of tumours of the digestive system FT Bosman, F Carneiro, RH Hruban, ND Theise, (eds) 4th edn. 225–227. IARC: Lyon, France.

• , , , , , , , , , , , ABC-02 Trial Investigators (2010) Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med 362(14): 1273–1281.

• , , , , , , , , , , , (2010) Prediction of drainage effectiveness during endoscopic stenting of malignant hilar strictures: the role of liver volume assessment. Gastrointest Endosc 72(4): 728–735.

• , , , , , , , , (2016) Long-term outcome of patients undergoing liver transplantation for mixed hepatocellular carcinoma and cholangiocarcinoma: an analysis of the UNOS database. HPB 18: 29–34.

• , , , , (2008) Combined hepatocellular cholangiocarcinomas; analysis of a large database. Clin Med Pathol 1: 43–47.

• , , (2010) Outcome of combined hepatocellular and cholangiocarcinoma of the liver. J Oncol 1–7.

• , , , , , , , , , , , (2013) Gemcitabine plus oxaliplatin in advanced hepatocellular carcinoma: a large multicenter AGEO study. J Hepatol 58(1): 81–88.

• , , , , , , , , , , (2006) Phase II study of gemcitabine and oxaliplatin in combination with bevacizumab in patients with advanced hepatocellular carcinoma. J Clin Oncol 24(12): 1898–1903.

• , , , , , , , , , , , , , , , , , , , (2010) Efficacy and safety of gemcitabine, oxaliplatin, and bevacizumab in advanced biliary-tract cancers and correlation of changes in 18-fluorodeoxyglucose PET with clinical outcome: a phase 2 study. Lancet Oncol 11(1): 48–54.

• ### Inflammatory cytokine IL-8/CXCL8 promotes tumour escape from hepatocyte-induced dormancy

• , , , (2003) ERK(MAPK) activity as a determinant of tumor growth and dormancy; regulation by p38(SAPK). Cancer Res 63(7): 1684–1695.

• , , , (2006) Prognostic value of serum level of interleukin-6 and interleukin-8 in metastatic breast cancer patients. Egypt J Immunol 13(2): 61–68.

• , , , , , (2016) Gradually softening hydrogels for modeling hepatic stellate cell behavior during fibrosis regression. Integr Biol (Camb) 8(6): 720–728.

• , , , (2012) Hepatocyte induced re-expression of E-cadherin in breast and prostate cancer cells increases chemoresistance. Clin Exp Metastasis 29(1): 39–50.

• , , (2010) Breast carcinoma cells re-express E-cadherin during mesenchymal to epithelial reverting transition. Mol Cancer 9(1): 179.

• , , , , , , , , , , (2017) A liver microphysiological system of tumor cell dormancy and inflammatory responsiveness is affected by scaffold properties. Lab Chip 17(1): 156–168.

• ClinicalTrials.gov [Internet] (2015a) A Double-blind Study of Paclitaxel in Combination with Reparixin or Placebo for Metastatic Triple-Negative Breast Cancer (FRIDA). National Library of Medicine (US): Bethesda, MD.

• ClinicalTrials.gov [Internet] (2015b) HuMax-IL8 (Interleukin8) in Patients with Advanced Malignant Solid Tumors. National Library of Medicine (US): Bethesda, MD.

• , , , , , (2012) Hepatocyte-stellate cell cross-talk in the liver engenders a permissive inflammatory microenvironment that drives progression in hepatocellular carcinoma. Cancer Res 72(10): 2533–2542.

• , , , , , , , (2007) Serum IL-8 and IL-12 levels in breast cancer. Med Oncol 24(2): 163–168.

• , , , , , , (2015) Fractal heterogeneity in minimal matrix models of scars modulates stiff-niche stem-cell responses via nuclear exit of a mechanorepressor. Nat Mater 14(9): 951–960.

• , , , , , (2012) CCL2/CCR2 chemokine signaling coordinates survival and motility of breast cancer cells through Smad3 protein- and p42/44 mitogen-activated protein kinase (MAPK)-dependent mechanisms. J Biol Chem 287(43): 36593–36608.

• , , , , (2011) IL-8 signaling plays a critical role in the epithelial–mesenchymal transition of human carcinoma cells. Cancer Res 71(15): 5296–5306.

• , , , , , , , (2003) IL-8 expression and its possible relationship with estrogen-receptor-negative status of breast cancer cells. Oncogene 22(2): 256–265.

• (2008) Hepatic stellate cells: protean, multifunctional, and enigmatic cells of the liver. Physiol Rev 88(1): 125–172.

• , , , , , , , (2016) Hepatic stellate cells relay inflammation signaling from sinusoids to parenchyma in mouse models of immune-mediated hepatitis. Hepatology 63(4): 1325–1339.

• , , , , , , , , , , , , (2013) The perivascular niche regulates breast tumour dormancy. Nat Cell Biol 15(7): 807–817.

• , (2013) PROGgene: gene expression based survival analysis web application for multiple cancers. J Clin Bioinform 3(1): 22.

• , , , , , , , , (1995) Chemokine gene transfection into tumour cells reduced tumorigenicity in nude mice in association with neutrophilic infiltration. Br J Cancer 72(3): 708–714.

• , (2011) Choosing the right cell line for breast cancer research. Breast Cancer Res 13(4): 215.

• , , (2006) Gene expression profile of quiescent and activated rat hepatic stellate cells implicates Wnt signaling pathway in activation. J Hepatol 45(3): 401–409.

• , , (1999) Dormancy of mammary carcinoma after mastectomy. J Natl Cancer Inst 91(1): 80–85.

• , , , , , , (2000) IL-8 reduced tumorigenicity of human ovarian cancer in vivo due to neutrophil infiltration. J Immunol 164(5): 2769–2775.

• (1985) Patterns of metastasis and natural courses of breast carcinoma. Cancer Metastasis Rev 4: 153–172.

• , , , , , , , , , , , , , , (2012) Interleukin-8 and its receptor CXCR2 in the tumour microenvironment promote colon cancer growth, progression and metastasis. Br J Cancer 106(11): 1833–1841.

• , , , , (2007) Interleukin-8 stimulates cell proliferation in non-small cell lung cancer through epidermal growth factor receptor transactivation. Lung Cancer 56(1): 25–33.

• , , , , , (2016) Liver protects metastatic prostate cancer from induced death by activating E-cadherin signaling. Hepatology 64(5): 1725–1742.

• , , , , , (2017) IL-6, IL-8 and TNF-alpha levels correlate with disease stage in breast cancer patients. Adv Clin Exp Med 26(3): 421–426.

• , , , , , , , , , (2007) Interleukin-8 signaling promotes translational regulation of cyclin D in androgen-independent prostate cancer cells. Mol Cancer Res 5(7): 737–748.

• , , , , , , , , , , , , (2014) Tissue factor expression provokes escape from tumor dormancy and leads to genomic alterations. Proc Natl Acad Sci USA 111(9): 3544–3549.

• , , , , , (2014) Partial inhibition of Cdk1 in G 2 phase overrides the SAC and decouples mitotic events. Cell Cycle 13(9): 1400–1412.

• , , , , , , , , (2011) CCL2 recruits inflammatory monocytes to facilitate breast-tumour metastasis. Nature 475(7355): 222–225.

• , , , , , (2009) CCL2 and interleukin-6 promote survival of human CD11b+ peripheral blood mononuclear cells and induce M2-type macrophage polarization. J Biol Chem 284(49): 34342–34354.

• , , , , , , , , , , , (2007) IL-6 triggers malignant features in mammospheres from human ductal breast carcinoma and normal mammary gland. J Clin Invest 117(12): 3988–4002.

• , , (2017) Cancer statistics, 2017. CA Cancer J Clin 67(1): 7–30.

• , , , , , , , , , , , , (2013) Nuclear lamin-A scales with tissue stiffness and enhances matrix-directed differentiation. Science 341(6149): 1240104.

• , (2011) Breast cancer liver metastasis. In Liver Metastasis: Biology and Clinical Management, Brodt P (ed) Vol. 16, Chapter 10, pp 273–306. Springer: NY, USA.

• , , , (2014) Hepatic nonparenchymal cells drive metastatic breast cancer outgrowth and partial epithelial to mesenchymal transition. Breast Cancer Res Treat 144(3): 551–560.

• , , , , (2013) Modeling boundary conditions for balanced proliferation in metastatic latency. Clin Cancer Res 19(5): 1063–1070.

• , , , , , , , , , (2014) Spontaneous dormancy of metastatic breast cancer cells in an all human liver microphysiologic system. Br J Cancer 111(12): 2342–2350.

• , , , , , , , , (2005) Human hepatic stellate cell lines, LX-1 and LX-2: new tools for analysis of hepatic fibrosis. Gut 54(1): 142–151.

• , , , , (2016) Macrophage phenotypic subtypes diametrically regulate epithelial–mesenchymal plasticity in breast cancer cells. BMC Cancer 16(1): 419.

• , , , , , , , (2007) Interleukin-8 modulates growth and invasiveness of estrogen receptor-negative breast cancer cells. Int J Cancer 121(9): 1949–1957.

• , , , , , , , , , , (2014) Clinical characteristics and prognostic analysis of triple-negative breast cancer patients. Mol Clin Oncol 2(2): 245–251.

• , , , , , , , , (2011) Activated hepatic stellate cells promote hepatocellular carcinoma development in immunocompetent mice. Int J Cancer 129(11): 2651–2661.

• , , , (2004) Epithelial-cadherin and beta-catenin expression changes in pancreatic intraepithelial neoplasia. Clin Cancer Res 10(4): 1235–1240.

• , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , Initiative APCG (2016) Genomic analyses identify molecular subtypes of pancreatic cancer. Nature 531(7592): 47–52.

• , , , , , , , (2014) Downregulation of P-cadherin expression in hepatocellular carcinoma induces tumourigenicity. Int J Clin Exp Pathol 7(9): 6125–6132.

• , , , , , (2016) Cellular and molecular mechanisms of MT1-MMP-dependent cancer cell invasion. Annu Rev Cell Dev Biol 32: 555–576.

• , , , (2013) Bioluminescent orthotopic model of pancreatic cancer progression. J Vis Exp (76).

• , , (2010) Cadherin switching and activation of p120 catenin signaling are mediators of gonadotropin-releasing hormone to promote tumor cell migration and invasion in ovarian cancer. Oncogene 29(16): 2427–2440.

• , , , , , , (2007) Soluble cadherins as cancer biomarkers. Clin Exp Metastasis 24(8): 685–697.

• , , , , , , , , , , , , , , , , , , , , (2015) Transcriptomic analysis predicts survival and sensitivity to anticancer drugs of patients with a pancreatic adenocarcinoma. Am J Pathol 185(4): 1022–1032.

• , , , , , , (1993) Characterization of the oligosaccharide moiety of VIP receptor from the human pancreatic cell line BxPC-3. Peptides 14(6): 1331–1338.

• , , , , , (2012) The pancreas cancer microenvironment. Clin Cancer Res 18(16): 4266–4276.

• , , , , , , , , , , , , , , , , , , , , , (2015) A subgroup of pancreatic adenocarcinoma is sensitive to the 5-aza-dC DNA methyltransferase inhibitor. Oncotarget 6(2): 746–754.

• , , , (2008) Assembly and biological role of podosomes and invadopodia. Curr Opin Cell Biol 20(2): 235–241.

• , , , (2017) Evolution and diversity of cadherins and catenins. Exp Cell Res 358(1): 3–9.

• , , , , , , (2008) Emerging molecular biology of pancreatic cancer. Gastrointest Cancer Res 2(4 Suppl): S10–S15.

• , , , , , , , , , , , , , (2008) Identification of a novel tumor-associated antigen, cadherin 3/P-cadherin, as a possible target for immunotherapy of pancreatic, gastric, and colorectal cancers. Clin Cancer Res 14(20): 6487–6495.

• , , , , , , , , (2016) Expressions of matrix metalloproteinases 2, 7, and 9 in carcinogenesis of pancreatic ductal adenocarcinoma. Dis Markers 2016: 9895721.

• , (2016) Biomarkers and Targeted Therapy in Pancreatic Cancer. Biomark Cancer 8(Suppl 1): 27–35.

• , , , , , (2009) Generation of orthotopic and heterotopic human pancreatic cancer xenografts in immunodeficient mice. Nat Protoc 4(11): 1670–1680.

• , , , , , , , , , , (2016) Pancreatic cancer. Nat Rev Dis Primers 2: 16022.

• , , , , , , , , , , , , , , , , , , , , , (2016) Genotype tunes pancreatic ductal adenocarcinoma tissue tension to induce matricellular fibrosis and tumor progression. Nat Med 22(5): 497–505.

• , , , , , , , , , , , , , , , , , , , , , , (2016) Cancer-associated fibroblast-derived annexin A6+ extracellular vesicles support pancreatic cancer aggressiveness. J Clin Invest 126(11): 4140–4156.

• , , , , , , , , , , , , , (2004) N-cadherin expression and epithelial-mesenchymal transition in pancreatic carcinoma. Clin Cancer Res 10(12 Pt 1): 4125–4133.

• (2008) Regulation of cell–cell adhesion by the cadherin-catenin complex. Biochem Soc Trans 36(Pt 2): 149–155.

• , , (2011) Tissue organization by cadherin adhesion molecules: dynamic molecular and cellular mechanisms of morphogenetic regulation. Physiol Rev 91(2): 691–731.

• , , , (2006) Extracellular matrix-mediated membrane-type 1 matrix metalloproteinase expression in pancreatic ductal cells is regulated by transforming growth factor-beta1. Cancer Res 66(14): 7032–7040.

• , , , , , , , , (2004) P-cadherin is up-regulated by the antiestrogen ICI 182,780 and promotes invasion of human breast cancer cells. Cancer Res 64(22): 8309–8317.

• , , , , , , , , , , , (2016) P-cadherin promotes collective cell migration via a Cdc42-mediated increase in mechanical forces. J Cell Biol 212(2): 199–217.

• , , , , , (2014) Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res 74(11): 2913–2921.

• , , , , , , , (2010) Extracellular cleavage and shedding of P-cadherin: a mechanism underlying the invasive behaviour of breast cancer cells. Oncogene 29(3): 392–402.

• , (2014) P-cadherin linking breast cancer stem cells and invasion: a promising marker to identify an ‘intermediate/metastable’ EMT state. Front Oncol 4: 371.

• , , , , , , , , , , , , , (2013) P-cadherin functional role is dependent on E-cadherin cellular context: a proof of concept using the breast cancer model. J Pathol 229(5): 705–718.

• , , (2012) E-cadherin’s dark side: possible role in tumor progression. Biochim Biophys Acta 1826(1): 23–31.

• , , , , , , , , , , , (2015) Significance of P-cadherin overexpression and possible mechanism of its regulation in intrahepatic cholangiocarcinoma and pancreatic cancer. Cancer Sci 106(9): 1153–1162.

• , (2007) Precursor lesions of pancreatic cancer: molecular pathology and clinical implications. Pancreatology 7(1): 9–19.

• , , , , , , , , (2015) Interplay between cadherins and α2β1 integrin differentially regulates melanoma cell invasion. Br J Cancer 113(10): 1445–1453.

• , , , , , , , (2008) MT1-MMP-dependent invasion is regulated by TI-VAMP/VAMP7. Curr Biol 18(12): 926–931.

• , , , , (2016) N-cadherin functions as a growth suppressor in a model of K-ras-induced PanIN. Oncogene 35(25): 3335–3341.

• , , , , , , , , (2005) Overexpressed P-cadherin/CDH3 promotes motility of pancreatic cancer cells by interacting with p120ctn and activating rho-family GTPases. Cancer Res 65(8): 3092–3099.

• , , , , , , , , , , , , , (2017) Saccharomyces boulardii CNCM I-745 restores intestinal barrier integrity by regulation of E-cadherin recycling. J Crohns Colitis 11(8): 999–1010.

• (2009) [Epithelial-mesenchymal transitions in cancer onset and progression]. Bull Acad Natl Med 193(9): 1978–1979, discussion 1978–9.

• , , , , (2011) P-cadherin in adhesion and invasion: opposite roles in colon and bladder carcinoma. Int J Cancer 128(5): 1031–1044.

• , , , , , , (2005) P-cadherin promotes cell–cell adhesion and counteracts invasion in human melanoma. Cancer Res 65(19): 8774–8783.

• , (2015) P-cadherin and the journey to cancer metastasis. Mol Cancer 14: 178.

• , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , Initiative APCG (2015) Whole genomes redefine the mutational landscape of pancreatic cancer. Nature 518(7540): 495–501.

• ### Rapid nodal staging of head and neck cancer surgical specimens with flow cytometric analysis

• , , , , , , , , , , , , , , , , , , , , , , International Consortium for Outcome Research (ICOR) in Head and Neck Cancer (2013) Clinical nodal stage is a significant predictor of outcome in patients with oral cavity squamous cell carcinoma and pathologically negative neck metastases: results of the international consortium for outcome research. Ann Surg Oncol 20: 3575–35781.

• , , , (2004) Molecular assay to detect metastatic head and neck squamous cell carcinoma. Arch Otolaryngol Head Neck Surg 130: 21–27.

• , , (2009) TNM Classification of Malignant Tumours 7th edn Wiley-Blackwell: NJ, USA.

• , , , , , , , , , , , , , , , , , (2010) Sentinel lymph node biopsy accurately stages the regional lymph nodes for T1-T2 oral squamous cell carcinomas: results of a prospective multi-institutional trial. J Clin Oncol 28: 1395–1400.

• , , , , , , , , , , , , , , , , , Head and Neck Disease Management Group (2015) Elective versus therapeutic neck dissection in node-negative oral cancer. N Engl J Med 373: 521–529.

• , , , , (2008) Detection of lymph node micrometastases in patients with squamous carcinoma of the head and neck. Eur Arch Otorhinolaryngol 265: 1147–1153.

• , , , , (1995) Increased numbers of cytokeratin-positive interstitial reticulum cells (CIRC) in reactive, inflammatory and neoplastic lymphadenopathies: hyperplasia or induced expression? Virchows Arch 425: 617–629.

• , , , , , (2010) EpCAM in carcinogenesis: the good, the bad or the ugly. Carcinogenesis 31: 1913–1921.

• , , , , , , , (2016) Detection of micrometastases by flow cytometry in sentinel lymph nodes from patients with renal tumours. Br J Cancer 115: 957–966.

• , , , , , (2013) Nod-like receptors in head and neck squamous cell carcinoma. Acta Otolaryngol 133: 1333–1344.

• , , , , , (2013) Incidence of occult cervical metastasis in head and neck carcinomas: development over time. J Surg Oncol 107: 384–387.

• , , , (2006) MUC1 expression and anti-MUC1 serum immune response in head and neck squamous cell carcinoma (HNSCC): a multivariate analysis. BMC Cancer 6: 253.

• , , , , (2009) Toll-like receptor agonists induce inflammation and cell death in a model of head and neck squamous cell carcinomas. Immunologyl 128(1 Suppl): e600–e611.

• , , , , , , , , , (2006) Detection of occult carcinomatous diffusion in lymph nodes from head and neck squamous cell carcinoma using real-time RT-PCR detection of cytokeratin 19 mRNA. Br J Cancer 94: 1164–1169.

• , , , , , , , , , , , (2016) Incidental findings of thyroid tissue in cervical lymph nodes: old controversy not yet resolved? Eur Arch Otorhinolaryngol 273: 2867–2875.

• , , (2015) Phenotypic plasticity and epithelial-to-mesenchymal transition in the behaviour and therapeutic response of oral squamous cell carcinoma. J Oral Pathol Med 44: 649–655.

• , , , (2011) Quantitative expression study of four cytokeratins and p63 in squamous cell carcinoma of the tongue: suitability for sentinel node navigation surgery using one-step nucleic acid amplification. J Clin Pathol 64: 875–879.

• , , , , , (2007) Clinicopathologic significance of EpCAM expression in squamous cell carcinoma of the tongue and its possibility as a potential target for tongue cancer gene therapy. Oral Oncol 43: 869–877.

• ### The combined activation of KCa3.1 and inhibition of Kv11.1/hERG1 currents contribute to overcome Cisplatin resistance in colorectal cancer cells

• , , , , , (2009) Targeting ion channels in cancer: a novel frontier in antineoplastic therapy. Curr Med Chem 16(1): 66–693.

• , , , , , (2010) Cloning and identification of tissue-specific expression of KCNN4 splice variants in rat colon. Am J Physiol Cell Physiol 299(2): C251–C263.

• , , , , , , (2016) Transcriptome analysis of copper homeostasis genes reveals coordinated upregulation of SLC31A1, SCO1, and COX11 in colorectal cancer. FEBS Open Bio 6(8): 794–806.

• , , , , (1992) Intra and extracellular surface charges near Ca2+ channels in neurons and neuroblastoma cells. Biophys J 63(4): 954–965.

• , , (2015) Chemotherapy-induced peripheral neuropathy: What do we know about mechanisms? Neurosci Lett 596: 90–107.

• , , , , , , , , , , , , , , (2013) hERG1 channels modulate integrin signaling to trigger angiogenesis and tumor progression in colorectal cancer. Sci Rep 3: 3308.

• , , (2013) Potassium channels: novel emerging biomarkers and targets for therapy in cancer. Recent Pat Anticancer Drug Discov 8(1): 53–65.

• , , , , , , , , , , , , , , , , , (2016) Ionic immune suppression within the tumour microenvironment limits T cell effector function. Nature 537(7621): 539–543.

• , , , , , , , (2014) Systems biology of Cisplatin resistance: past, present and future. Cell Death Dis 5(5): e1257.

• , , , , , , , , , , , , (2015) New pyrimido-indole compound CD-160130 preferentially inhibits the KV11.1B isoform and produces antileukemic effects without cardiotoxicity. Mol Pharmacol 87(2): 183–196.

• , , , , (2014) Copper transporter 2 regulates intracellular copper and sensitivity to Cisplatin. Metallomics 6(3): 654–661.

• , , , , (1995) Solution structure of a cisplatin-induced DNA interstrand cross-link. Science 270(5243): 1842–1845.

• , (2014) Targeting potassium channels in cancer. J Cell Biol 206(2): 151–162.

• , , , , (2015) Knockdown of Eag1 expression by RNA interference increases chemosensitivity to Cisplatin in ovarian cancer cells. Reprod Sci 22(12): 1618–1626.

• , , , (2002) Uptake of the anticancer drug cisplatin mediated by the copper transporter Ctr1 in yeast and mammals. Proc Natl Acad Sci USA 99(22): 14298–14302.

• , , , , (2016) RAC: molecular identification as LRRC8 heteromers with differential functions. Pflugers Arch 468(3): 385–393.

• , , , , (2008) Altered localisation of the copper efflux transporters ATP7A and ATP7B associated with Cisplatin resistance in human ovarian carcinoma cells. BMC Cancer 8: 175.

• , (2001) Mechanisms of resistance to Cisplatin. Mutat Res 478: 23–43.

• , , , , , , , , (2002) Acquisition of resistance to Cisplatin is accompanied by changes in the cellular pharmacology of copper. Cancer Res 62(22): 6559–6565.

• , , , , , , , , (2011) Riluzole enhances ionizing radiation-induced cytotoxicity in human melanoma cells that ectopically express metabotropic glutamate receptor 1 in vitro and in vivo. Clin Cancer Res 17(7): 1807–1814.

• , . Role of ion transport in control of apoptotic cell death (2012) Compr Physiol 2(3): 2037–2061.

• , , , , , , , , , , , , , , (2004) herg1 gene and HERG1 protein are overexpressed in colorectal cancers and regulate cell invasion of tumor cells. Cancer Res 64(2): 606–611.

• , , , , , , , , , , , , , , , , , , , , , (2015) hERG1 channels drive tumour malignancy and may serve as prognostic factor in pancreatic ductal adenocarcinoma. Br J Cancer 112(6): 1076–1087.

• , , , , , , (2014) Correlation between potassium channel expression and sensitivity to drug-induced cell death in tumor cell lines. Curr Pharm Des 20(2): 189–200.

• , , , (2008) IK1 channel activity contributes to Cisplatin sensitivity of human epidermoid cancer cells. Am J Physiol Cell Physiol 294(6): C1398–C1406.

• , , , , , , , , , , , , (2015) cis-Pt I2(NH3)2: a reappraisal. Dalton Trans 44(33): 14896–14905.

• , , , , , (2007) Effect of copper and role of the copper transporters ATP7A and CTR1 in intracellular accumulation of cisplatin. Anticancer Res 27(4B): 2209–2216.

• , , , , , , , , , (2016) hERG1 positivity and Glut-1 negativity identifies high-risk TNM stage I and II colorectal cancer patients, regardless of adjuvant chemotherapy. Onco Targets Ther 9: 6325–6332.

• , , , , , , , , , , , , , , (2007) Copper-transporting P-type ATPase, ATP7A, confers multidrug resistance and its expression is related to resistance to SN-38 in clinical colon cancer. Cancer Res 67(10): 4860–4868.

• , , (2015) The identification of a volume-regulated anion channel: an amazing Odyssey. Acta Physiol (Oxf) 213(4): 868–881.

• , , , , , , , , , (2007) VEGFR-1 (FLT-1), beta1 integrin, and hERG K+ channel for a macromolecular signaling complex in acute myeloid leukemia: role in cell migration and clinical outcome. Blood 110(4): 1238–1250.

• , , , , , , , , , , , , (2011) Chemotherapy resistance in acute lymphoblastic leukemia requires hERG1 channels and is overcome by hERG1 blockers. Blood 117(3): 902–914.

• , , , , , , , , , (2016) Macrolide antibiotics exert antileukemic effects by modulating the autophagic flux through inhibition of hERG1 potassium channels. Blood Cancer J 6: e423.

• , , , , , , , , , , , , , , , , , (2015) Subunit composition of VRAC channels determines substrate specificity and cellular resistance to Pt-based anti-cancer drugs. EMBO J 34(24): 2993–3008.

• , , , , , , (2010) Deregulation of apoptotic volume decrease and ionic movements in multidrug-resistant tumor cells: role of chloride channels. Am J Physiol Cell Physiol 298(1): C14–C25.

• , , , , , (2016) Over-expression of miR-31 or loss of KCNMA1 leads to increased cisplatin resistance in ovarian cancer cells. Tumour Biol 37(2): 2565–2573.

• , (1990) Two components of cardiac delayed rectifier K+ current: differential sensitivity to block by class III antiarrhythmic agents. J Gen Physiol 96: 195–215.

• , , , , , , , (2009) Naphtho[1,2-d]thiazol-2-ylamine (SKA-31), a new activator of KCa2 and KCa3.1 potassium channels, potentiates the endothelium-derived hyperpolarizing factor response and lowers blood pressure. Mol Pharmacol 75(2): 281–295.

• , , , (2008) Volume-sensitive Cl(-) channel as a regulator of acquired Cisplatin resistance. Anticancer Res 28(1A): 75–83.

• (2003) Cisplatin: mode of cytotoxic action and molecular basis of resistance. Oncogene 22: 7265–7279.

• , , , , , , (2016) Riluzole mediates anti-tumor properties in breast cancer cells independent of metabotropic glutamate receptor-1. Breast Cancer Res Treat 157(2): 217–228.

• , , , , (2007) Voltage-gated K+ channels support proliferation of colonic carcinoma cells. FASEB J 21(1): 35–44.

• , , (1997) Differential inhibition by riluzole, lamotrigine, and phenytoin of sodium and calcium currents in cortical neurons: implications for neuroprotective strategies. Exp Neurol 147(1): 115–122.

• , , , , , , , , , , (2016) LRRC8 proteins form volume-regulated anion channels that sense ionic strength. Cell 164: 499–511.

• , (2005) Cellular processing of platinum anticancer drugs. Nat Rev Drug Discov 4: 307–320.

• , , , (2008) Riluzole-induced block of voltage-gated Na+ current and activation of BKCa channels in cultured differentiated human skeletal muscle cells. Life Sci 82(1-2): 11–20.

• (2011) Apoptosis in cancer: from pathogenesis to treatment. J Exp Clin Cancer Res 30(1): 87–101.

• , , , , , (2000) Design of a potent and selective inhibitor of the intermediate-conductance Ca2+-activated K+ channel, IKCa1: a potential immunosuppressant. Proc Natl Acad Sci USA 97(14): 8151–8156.

• , , , , , , , , , (2009) A phase 0 trial of riluzole in patients with resectable stage III and IV melanoma. Clin Cancer Res 15(11): 3896–3902.

• , , (1994) Biochemical pharmacology of homologous alicyclic mixed amine platinum(II) complexes in sensitive and resistant tumor cell lines. Cancer Res 54: 3468–3473.

• , , , , , , , , (2012) Human ether-à-go-go-related gene expression is essential for Cisplatin to induce apoptosis in human gastric cancer. Oncol Rep 27(2): 433–440.

• ### Determination of an optimal response cut-off able to predict progression-free survival in patients with well-differentiated advanced pancreatic neuroendocrine tumours treated with sunitinib: an alternative to the current RECIST-defined response

There is a need for optimising our currently-available tools for radiological assessment of response in patients with NETs. This could be done by (1) maximising the information provided by current standard size-based criteria (such as RECIST), (2) incorporation of morphological assessment (e.g., Choi criteria (Faivre et al, 2012)) or by (3) incorporating metabolic techniques (nuclear medicine (Sundin and Rockall, 2012)) into response assessment. This study focused on the first approach.

This post hoc analysis is the first study to identify an alternative tumour shrinkage cut-off for definition of partial response in sunitinib-treated pNET patients. While the classical cut-off of 30% of tumour diameter reduction was shown to be too restrictive and not impacting PFS in the multivariable analysis, our proposed alternative of 10% reduction did impact PFS, even when adjusted to other prognostic factors.

Best-response to treatment was achieved early-on in the treatment with sunitinib: at a median of 3 months to best-response, with 83.9% of patients achieving the best-response during the first 7 months of treatment. Therefore, this alternative definition of objective partial response can be used as an early marker of benefit from treatment and could impact patients’ management.

Our results support that a reduction of 10% may be used as an accurate surrogate for PFS. Earlier studies have shown the importance of maintenance of dose intensity in sunitinib-treated patients in renal cell carcinoma (RCC) (Houk et al, 2010). We would therefore suggest that dose reduction rather than dose interruption is considered in the event of treatment-related toxicity for those patients who have achieved our suggested 10% reduction on the size of targeted lesions, in accordance with the prescribing information. Moreover, since, as mentioned above, the best-response was achieved early-on following initiation of treatment, we also argue that should patients not achieve a 10% of tumour shrinkage after 7 months of treatment, the dose of sunitinib could be increased to 50 mg daily (if well tolerated) as suggested in the sunitinib SPC (EMA, 2016) and as detailed in the phase III clinical trial protocol which stated that ‘in patients without an objective tumour response who had grade 1 or lower non-haematologic or grade 2 or lower haematologic treatment-related adverse events during the first 8 weeks, the dose could be increased to 50 mg per day’ (Raymond et al, 2011). Although dose escalation of sunitinib has been explored in RCC and gastrointestinal stromal tumour (GIST) (Patel, 2012; Ornstein et al, 2016; Shi et al, 2016), experience of doing so in pNET is limited; only 10% of patients treated with sunitinib in the phase III pivotal clinical trial had dose increased to 50 mg daily, and its impact is unclear (Raymond et al, 2011).

Alternative response cut-offs have also been explored in the past in other malignancies such as RCC, in which targeted therapies (including sunitinib) are a cornerstone of systemic management (Thiam et al, 2010, Krajewski et al, 2011, 2014). (Krajewski et al 2011, 2014) validated a different cut-off for RECIST criteria, able to identify more accurately those patients with benefit (in terms of overall survival) from anti-angiogenic agents (including sunitinib). In keeping with our findings, a cut-off of 10% of the sum of the longest tumour diameter shrinkage on the first follow-up CT scan was predictive of outcome, however, some challenges existed such as the lack of placebo-treated patients which did not allow them to explore whether the new cut-off was a predictive factor or not (Chen et al, 2014). The fact that similar findings have been shown in small series of gastrointestinal NETs treated with somatostatin analogues provide robustness to our findings (Luo, 2017). In this series, Luo et al included 33 patients with NETs treated with SSA; the authors identified that achieving a response of 10% reduction in target lesions impacted PFS.

Our study has some note-worthy strengths such as the fact that all data were prospectively collected as part of phase II and phase III clinical trials, in addition to the previous quality-assurance of these data for registration purposes. We also explored first which was the most informative time-point, in order to calculate the response cut-off at such time-point; this, was one of the acknowledged limitations of the previous studies in RCC (Chen et al, 2014). Although the use of morphological changes (such as Choi criteria (van der Veldt et al, 2010)) have been suggested in order to improve assessment of response to targeted therapies, the incorporation of such approaches to daily practice could be challenging due to the fact that it requires specialist radiological input for assessment of changes within density of target lesions (Faivre et al, 2012). We do therefore believe that the application of our 10% alternative cut-off could be relatively straight-forward for clinicians managing patients with pNETs in daily practice.

Limitations of our study include the fact that our analysis was limited to the measurement of marker lesions; appearance of new lesions could not be included in our analysis since it is not included in the calculation of change in percentages of response. Whether this radiological response is a predictive factor in addition to prognostic remains unclear, since patients treated with placebo who achieved such response did benefit in terms of PFS as well. It is worth highlighting the fact that the phase III study included in this analysis was interrupted early by the independent data monitoring committee (IDMC); and that following final results and demonstration of superiority of sunitinib, cross-over was allowed. Thus, the fact that some of the patients initially allocated to the placebo arm will have been treated with sunitinib (including patients in the absence of disease progression) could also explain why some patients in the placebo arm did have radiological response to treatment and its impact on prognosis regardless of the treatment group (as shown in the multivariable analysis). This would warrant further investigations in future placebo-controlled clinical trials. Another of the limitations from our study was that different sunitinib schedules were used across the phase II and the phase III studies. We do wonder whether this could be the explanation why we were unable to replicate the differences in median PFS found in the phase III study when comparing patients who did/did not reach the 10% alternative cut-off in the phase II patient population. The higher partial response rate identified in the phase II study patients could have also contributed to this. Finally, since the limited sample size did not allow us to divide our sample in separate design and validation cohorts, our results should be validated in future prospective series or clinical trials. Finally, it could also be argued that the 10% reduction in sum of marker lesions might be included within the expected inter-observer and inter-examination variability, especially when CT scans are performed as part of the daily practice and assessed outside the setting of a prospective clinical trial. It is worth highlighting that, although we do agreed with this being a possibility we do believe it is unlikely to happen due the fact that the CT scans employed in this study were not centrally reviewed and that the assessments and measurements were based on local radiologist (therefore reflecting standard clinical practice).

In conclusion, our results support that reduction of 10% in the measurement of marker lesions, impacts on PFS and should be considered enough to classify pNET patients as responders to sunitinib and likely to derive clinical benefit from treatment.