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(12) Patent Application Publication (10) Pub. No.: US 2014/0227372 A1 Missiaglia Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2014/0227372 A1 Missiaglia Et Al US 20140227372A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2014/0227372 A1 Missiaglia et al. (43) Pub. Date: Aug. 14, 2014 (54) BIOMARKERS FOR LUNG CANCER Related U.S. Application Data (75) Inventors: Edoardo Missiaglia, Maracon (CH); (60) Provisional application No. 61/490,021, filed on May Simona Rossi, Bussigny-pres-Lausanne 25, 2011. (CH); Pratyaksha Wirapati, Lucens Publication Classification (CH); Werner Kroll, Wayland, MA (US) (51) Int. Cl. (73) Assignee: NOVARTIS AG, Basel (CH) CI2O I/68 (2006.01) (52) U.S. Cl. (21) Appl. No.: 14/119,604 CPC .................................... CI2O I/6886 (2013.01) USPC .................................... 424/649; 506/9; 506/2 (22) PCT Filed: May 24, 2012 (57) ABSTRACT (86). PCT No.: PCT/EP2012/059784 The present invention relates, in part, to methods for deter S371 (c)(1), mining a prognosis of early stage lung cancer in an individual (2), (4) Date: Mar. 17, 2014 using one or more biomarkers. Patent Application Publication Aug. 14, 2014 Sheet 1 of 21 US 2014/0227372 A1 "...v. SEw N V • . y V Fig. 1 Patent Application Publication Aug. 14, 2014 Sheet 18 of 21 US 2014/0227372 A1 a2 in 3 stretcaias yet cyr F1 seas sld assas Kgus respe he wear as - - - - R4 is 8%, .6 as essa s 25.3%) 4. c. 36% as: hi-1 53 1 a2, ..s p = d.o. 2 Hr-214 so,3. 5 p - se - 1 a h=1.33 1.4.1 p - c.2 h = .21 a.s. 5, 1.5s p as o.2 r ro- argo wro r o e s s & time group a sat ris. ewernits al 2.4 s as sie as g3 ses 23s e a as s SS sis a asa. es s ise. .. g es is as sa * r sts s S. So Be Spa Fe is Eauce SL1 as As PPFBP HAY is H. H. A 4. sas. c C3 (57%) s C2 (52's & ------ 1 (3.7% a ws 2 HR -1.491. 19, 1.87 p - o.o. oos C1 ws 4 HR=2.37 (1.843.asp = 3s C2 ws 3 HR -1.2 c.943, 54. p = 0. jog vs Q4 HR-136 (1.04, 1.79 p - O. as rom-em-o-room-rm s 3. a. s es tire group F at risk evalents es' 35 e s S. * 3 1 * O. 3 sax 22 s a s a 3 s e es 232 ed: s tiss s is as: s a. * a SS s ess s Fig 7 Patent Application Publication Aug. 14, 2014 Sheet 19 of 21 US 2014/0227372 A1 Cs ral Cy Ke so s S. i s t ics c ce E 3 Cs etc. - O -O.S O. s O risk score Cs - es m C SS y doc w - c s r d - d d CN se Co risk score Fig. 8 Patent Application Publication Aug. 14, 2014 Sheet 20 of 21 US 2014/0227372 A1 low risk (73%) high risk (37%) high risk vs low risk HR=6,241, 8,21.6 p = 0, 004 2 3. 4. 5 S time group at risk eWents low risk 28 26 25 2O O 2. 1 3. high risk 27 25 g 12 y d 3 5 Fig. 9 Patent Application Publication Aug. 14, 2014 Sheet 21 of 21 US 2014/0227372 A1 - O -0.5 O, 5 Affymetrix FF core .37 affyFF Fig. 10 US 2014/0227372 A1 Aug. 14, 2014 BOMARKERS FOR LUNG CANCER 0006 Based on the current shortcomings, there is a medi cal rational for the need of a prognostic and/or predictive FIELD OF THE INVENTION genomic signature for patients with NSCLC. 0001. The present invention relates to a method of prog SUMMARY OF THE INVENTION nosis and personalized therapy. 0007. The present invention relates, in part, to methods for determining a prognosis of early stage lung cancer in an BACKGROUND OF THE INVENTION individual using one or more biomarkers described herein. These findings may be used to help to determine appropriate 0002 Lung cancer is the most common cancer diagnosis treatments for patients with early stage lung cancer Such as in the world with 1.5 million new cases in 2007 (Salomonet identifying those patients who would benefit from receiving al., Crit Rev. Oncol Hematol., 19:183-232, 1995, SEER-da adjuvant therapy. tabase 05.2010). The high incidence and mortality rates make 0008. In one aspect, the invention includes a method for it the leading cause of cancer-related death with more than prognosing or classifying a Subject with non-Small cell lung 975,000 deaths per year and a 5-year survival rate of 15% cancer (NSCLC) including obtaining a test sample from a (Salomon et al., Supra). Lung cancer can be classified as Small subject suffering from NSCLC following surgical resection; cell lung cancer, or non-Small cell lung cancer (NSCLC). determining the expression level of at least one or more biom NSCLC accounts for about 80% of the cases. NSCLC can be arker identified in Table 1, Table 2 and/or Table 3, or any further subdivided into several histological types, the most combination of biomarkers identified in Table 1, Table 2 common ones are adenocarcinoma (40%) and squamous cell and/or Table 3 in the test sample, and analyzing the expres carcinoma (25%). sion level to generate a risk score, wherein the risk score can 0003. The current treatment of NSCLC is mainly based on be used to provide a prognosis or classify the Subject. tumor morphology and the tumor-node-metastasis (TNM)- 0009. In another aspect, the invention includes a method based staging system that classifies tumor in graduated cat for prognosing or classifying a subject with non-Small cell egories (Stage IA, IB, IIA, IIB, IIIA, IIIB and IV) correspond lung cancer (NSCLC) comprising: obtaining a test sample ing to the extent of tumor progression. Many staging systems from a subject suffering from NSCLC following surgical exist (e.g., clinical VS. pathological staging, as well as various resection; determining the expression level of at least one editions of staging guidelines Such as those issued by Inter biomarkers from Table 1, Table 2 and Table 3 in the test national Association for the Study of Lung Cancer (IASLC) sample; and analyzing the expression level to generate a risk (Goldstraw et al., J. Thorac. Oncol. 2, 706-714, 2007). The score, wherein the risk score can be used to provide a prog frequency of the stages, for example according to clinical nosis or classify the Subject. In one embodiment, the at least staging and IASLC 6th edition of TNM staging recommen one biomarker identified in Table 1, Table 2 and Table 3 dation, are 23% stage I, 19% stage II, 37% stage III and 21% includes CBX7, STX1A, and TPX2. In another embodiment, stage IV (Goldstraw et al. Supra). The relative proportions the at least one biomarker identified in Table 1, Table 2 and may change Substantially depending on the guidelines and Table 3 includes CBX7, TMPRSS2, STX1A, KLK6, TPX2 whether clinical or pathological staging is used. and UCK. In yet another embodiment, the at least one biom arker identified in Table 1, Table 2 and Table 3 includes 0004 Surgery is the standard treatment for early stage CBX7, TMPRSS2, GPR116, STX1A, KLK6, SLC16A3, NSCLC (stage I and II), followed by adjuvant therapy such as TPX2, UCK2, PHKA1. In still yet another embodiment, the radiation therapy, chemotherapy (for stage II and later), and at least one biomarker identified in Table 1, Table 2 and Table bevacizumab and epidermal growth factor receptor (EGFR) 3 comprises CBX7, TMPRSS2, GPR116, KCNJ15, STX1A, tyrosine kinase inhibitors (TKIs) for the advanced NSCLC KLK6, SLC16A3, PYGL, TPX2, UCK2, PHKA1, or stages (Kutikova et al., Lung Cancer; 50(2): 143-154, 2005). EIF4A3. In yet another embodiment, the at least one biom Clinical guidelines in the United States and Europe for treat arker identified in Table 1, Table 2 and Table 3 includes ment of NSCLC support these treatment options (Men CBX7, TMPRSS2, GPR116, KCNJ15, PTPN13, STX1A, delssohn et al., 2000: NCCN-Guidelines NSCLC V1, 2010). KLK6, SLC16A3, PYGL, LDHA, TPX2, UCK2, PHKA1, 0005 Based on the current TNM-based staging system for EIF4A3 or TK1. In yet another embodiment, the at least one early lung cancer Stage I NSCLC patients suffer from a 35% biomarker identified in Table 1, Table 2 and Table 3 comprises chance of relapse within 5 years after surgery (SEER-Data CBX7, TMPRSS2, GPR116, KCNJ15, PTPN13, CTSH, base, 2008). Current treatment guidelines do not recommend STX1A, KLK6, SLC16A3, PYGL, LDHA, ITGA5, TPX2, an adjuvant chemotherapy for these patients. Whereas 30% UCK2, PHKA1, EIF4A3, TK1, or CCNA2. patients with a TNM-based Stage II will not experience a 0010. In one embodiment, the risk score of the invention relapse without any adjuvant chemotherapy (SEER-Data can be used for prognosis by mapping Subjects to time-spe base) meaning that these patients experience over treatment cific probability of death due to lung cancer, distance metasta based on the current treatment guidelines (i.e., ESMO sis or local relapse. (D'Addario et al., Annals of Oncology. 2009; 20 (suppl 0011. In another embodiment, the risk score can classify 4):iv68-iv70, 2009), NCCNV1-2010). This is paralleled by the subject into a high risk group that would benefit from reports stating that 60% of patients with early NSCLC will receiving adjuvant chemotherapy or in a low risk group that have no relapse after surgery (Arriagada et al., NEJM, 350: would not benefit from receiving adjuvant chemotherapy.
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