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Method for Predicting the Occurence of Lung Metastasis in Breast Cancer Patients

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Method for Predicting the Occurence of Lung Metastasis in Breast Cancer Patients (19) TZZ ¥ __T (11) EP 2 253 721 A1 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: (51) Int Cl.: 24.11.2010 Bulletin 2010/47 C12Q 1/68 (2006.01) (21) Application number: 10175619.5 (22) Date of filing: 26.02.2008 (84) Designated Contracting States: (72) Inventors: AT BE BG CH CY CZ DE DK EE ES FI FR GB GR • Lidereau, Rosette HR HU IE IS IT LI LT LU LV MC MT NL NO PL PT 92230, Gennevilliers (FR) RO SE SI SK TR • Driouch, Keltouma Designated Extension States: 93260, Les Lilas (FR) AL BA MK RS • Landemaine, Thomas 92100, Boulogne-Billancourt (FR) (30) Priority: 26.02.2007 EP 07300823 (74) Representative: Catherine, Alain et al (62) Document number(s) of the earlier application(s) in Cabinet Harlé & Phélip accordance with Art. 76 EPC: 7 rue de Madrid 08709219.3 / 2 115 170 75008 Paris (FR) (71) Applicants: Remarks: • INSERM (Institut National de la Santé et de la This application was filed on 07-09-2010 as a Recherche Medicale) divisional application to the application mentioned 75013 Paris (FR) under INID code 62. • Centre Rene Huguenin 92210 Saint-Cloud (FR) (54) Method for predicting the occurence of lung metastasis in breast cancer patients (57) The present invention relates to the prognosis tasis in one or more tissue or organ of patients affected of the progression of breast cancer in a patient, and more with a breast cancer. particularly to the prediction of the occurrence of metas- EP 2 253 721 A1 Printed by Jouve, 75001 PARIS (FR) EP 2 253 721 A1 Description FIELD OF THE INVENTION 5 [0001] The present invention relates to the prognosis of the progression of breast cancer in a patient, and more particularly to the prediction of the occurrence of metastasis in one or more tissue or organ of patients affected with a breast cancer. BACKGROUND OF THE INVENTION 10 [0002] Breast cancer is the most common malignant disease in Western women. It is not the primary tumour, but the occurrence of metastases in distant organs that is the major cause of death for cancer patients. Once solid secondary tumours are established, the chances of long-term survival fall from 90% to around 5%. Despite the progress in the development of targeted therapies, approximately 40% of the treated patients relapse and ultimately die of metastatic 15 breast cancer. A better understanding of the molecular and cellular mechanisms underlying metastasis might improve the development of effective therapies that would ameliorate breast cancer care. [0003] Malignant breast tumours can invade and damage nearby tissues and organs. Malignant tumour cells may metastasise, entering the bloodstream or lymphatic system. When breast cancer cells metastasise outside the breast, they are often found in the lymph nodes under the arm (axillary lymph nodes). If the cancer has reached these nodes, 20 it means that cancer cells may have spread to other lymph nodes or other organs, such as bones, liver, brain or lungs. Breast cancer metastasis of various organs also occurs without previous spreading to lymph nodes. Major and intensive research has been focussed on early detection, treatment and prevention of metastatic breast cancer. [0004] The rational development of preventive, diagnostic and therapeutic strategies for women at risk for breast cancer would be aided by a molecular map of the tumorigenesis process. Relatively little is known of the molecular 25 events that mediate the transition of normal breast cells to the various stages of breast cancer progression. Similarly, little is known of the molecular events that mediate the transition of cells from one stage of breast cancer to another, and finally to metastasis. [0005] Molecular means of identifying the differences between normal, non-cancerous cells and cancerous cells have been the focus of intense study. The use of cDNA libraries to analyse differences in gene expression patterns in normal 30 versus tumourigenic cells has been described. Gene expression patterns in human breast cancers have been described by Perou et al. (1999, Proc. Natl. Acad. Sci. USA, Vol. 96 : 9212-9217), who studied gene expression between cultured human "normal" mammary epithelia cells (HMEC) and breast tissue samples by using microarrays comprising about 5000 genes. They used a clustering algorithm to identify differential patterns of expression in HMEC and tissue samples. Perou et al. (2000, Nature, Vol. 406 : 747-752) described the use of clustered gene expression profiles to classify 35 subtypes of human breast tumours. Hedenfalk et al. (2001, New Engl. J. Medicine, Vol. 344(8) : 539-548) described gene expression profiles in BRCA1 mutation positive, BRCA2 mutation positive, and sporadic tumours. Using gene expression patterns to distinguish breast tumour subclasses and predict clinical implications is described by Sorlie et al. (2001, Proc. Natl. Acad. Sci USA, Vol. 98(19) : 10869-10874) and West et al. (2001, Proc. Natl. Acad. Sci USA, Vol. 98(20) : 11462-11467). 40 [0006] Based on the assumption that primary tumours may already contain genes that are predictive of metastastatic process, several groups performed genome wide microarray studies to identify expression profiles associated with the occurrence of distant relapses and poor survival. Several highly prognostic gene signatures were reported containing genes potentially involved in metastatic processes and/or markers of distant relapses. These studies mainly tackled overall relapses problems. 45 [0007] Searches aimed at identifying biological markers that would be involved in breast cancer metastasis in several tissues or organs have also been performed in the art. For this purpose, in vivo experiments using human breast cancer xenographs in nude mice were performed, as described below. [0008] Kang et al. (2003, Cancer Cell, Vol. 3 : 537-549) identified a set of genes potentially involved in breast cancer metastasis to bone, by comparing (i) the gene expression profile obtained from in vitro cultured cells of the MDBA-MB- 50 231 human breast cancer cell line with (ii) the gene expression profile obtained from a subclone of the same cell line previously experimentally selected in vivo for their ability to form bone metastasis in mice. Using microarray gene expression analysis techniques, these authors showed that several genes were underexpressed and several other genes were overexpressed in the cell sublines selected for their ability to form bone metastasis in mice, as compared to the parental MDBA-MB-231 human breast cancer cell line. These authors concluded that, in the case of the human 55 MDA-MB-231 cell line, cell functions that are relevant for metastasis to bone might be carried out by CXCR4, CTGF, IL-11 and OPN genes, with possible contributions of other genes. [0009] Minn et al. (2005, Nature, Vol. 436(28) : 518-524) used the same human parental MDA-MB-231 breast cancer cell line for selecting in vivo cell sublines having the ability to form lung metastasis in mice. Then, these authors have 2 EP 2 253 721 A1 performed a transcriptomic microarray analysis of the highly and weakly lung-metastatic cell populations, with the view of identifying patterns of gene expression that would be associated with aggressive lung metastatic behaviour. A final list of 54 candidate lung metastagenicity and virulence genes was selected, twelve of them having been further identified for their significant association with lung-metastasis-free survival, including MMP1, CXCL1 and PTGS2. 5 [0010] In the studies reported above, the authors identified and functionally validated a set of genes that specifically mediate bone or lung metastasis in the animal model. The organ-specific gene signatures that were identified allowed to distinguish between (i) primary breast carcinomas that preferentially metastasized to bone or lung from (ii) those that metastasized elsewhere. [0011] One study recently reported a molecular signature allowing for an bone-specific metastasis prognosis of human 10 breast cancer. This work was performed by comparing primary breast tumors relapsing to bone to those relapsing elsewhere. The authors thereby identified a panel of genes associated to breast cancer metastasis to bone (Smid et al., 2006, J Clin Oncol, Vol. 24(15) : 2261-2267). [0012] However, testing the organ-specific signature on mixed cohort of primary tumors did not allow robust classifi- cation of those tumors that gave rise to specific metastases versus those that did not. This is probably due to little 15 predictive value of these gene signatures. [0013] An early detection of metastasis in breast cancer patients is crucial for adapting the anti-cancer therapeutic treatment correspondingly, with the view of increasing the chances of long term disease-free survival. [0014] However, because detection of metastasis in breast cancer patients, even if the said detection is performed at an early stage of metastasis, consists of a poor prognosis of the cancer outcome, there is an increasing need in the 20 art for the availability of reliable methods for detecting the metastasis potentiality of a breast cancer tumour, for both medical treatment and medical survey purposes. There is also a need in the art for methods that would provide a prediction of the one or more tissues or organs in which the formation and development of a breast cancer metastasis would be likely to occur. 25 SUMMARY OF THE INVENTION [0015] The present invention relates to methods and kits for predicting the occurrence of metastasis in patients affected with a breast cancer. [0016] The breast cancer metastasis prediction methods of the invention comprise a step of determining, in a tumour 30 tissue sample previously collected from a breast cancer patient to be tested the level of expression of one or more biological markers that are indicative of cancer progression towards metastasis, and more precisely, one or more bio- logical markers that are indicative of cancer progression towards metastasis to specific tissues, and especially to bones, brain, lungs and liver.
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