Method for predicting the response to CDK4/6 inhibitor therapy in cancer patients

1 . A method for predicting a response or resistance to and/or a benefit from treatment with an inhibitor of cyclin-dependent kinases 4 optionally CDK4/6 inhibitor in a subject suffering from a neoplastic disease comprising:

determining in a sample obtained from said subject the expression level of at least one marker selected from the group consisting of Desmoglein 3 (DSG3), Intraflagellar Transport Protein 52 (IFT52), genes associated with multidrug resistance, and genes associated with SUMOylation,

wherein the neoplastic disease is hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer,

wherein the genes associated with multidrug resistance are selected from the group consisting of ATP-binding Cassette Sub-Family B Member 6, mitochondrial (ABCB6), Multidrug resistance-associated protein 1 (ABCC1), ATP-binding Cassette Sub-family A Member 5 (ABCA5), ATP-binding Cassette Sub-family C Member 6 (ABCC6) and ATP-binding Cassette transporter Sub-family C Member 11 (ABCC11), ATP Binding Cassette Subfamily C Member 12 (ABCC12), and/or wherein the genes associated with SUMOylation are selected from the group consisting of Protein Inhibitor of Activated STAT 2 (PIAS2), Dual specificity mitogen-activated protein kinase kinase 6 (MAP2K6), Conserved Helix-Loop-Helix Ubiquitous Kinase (CHUK), Small ubiquitin-related modifier 1 (SUMO1), G/T mismatch-specific thymine DNA glycosylase (TDG), Inhibitor of Nuclear Factor Kappa-B Kinase Subunit gamma (IKBKG) and Xeroderma pigmentosum, complementation group C (XPC),

wherein the expression level of the at least one marker is indicative for predicting the response or resistance to and/or the benefit from the treatment with the CDK4/6 inhibitor in said subject.

2 . The method of claim 1 , wherein the at least one marker is selected from the group consisting of PD-L1, PIAS2, MAP2K6, DSG3, ABCC12 and IFT52.

3 . The method of claim 1 , wherein a panel of two or more markers is determined, optionally at least two, three, four or five markers selected from the group consisting of, PIAS2, MAP2K6, DSG3, ABCC12 and IFT52 is determined in said sample.

4 . The method of claim 1 , wherein the method further comprises determining at least one marker selected from the group consisting of Programmed Death Ligand 1 (PD-L1), CALML3, CCL13, HPSE, IL1RAP, NF2, and PEX12.

5 . The method of claim 1 , wherein the method further comprises determining at least one marker selected from the group consisting of ABCA5, ABCB6, ABCC1, ABCC12, DSG3, MAP2K6, PIAS2, CALML3, CCL13, HPSE, IL1RAP, NF2, and PEX12.

6 . The method of claim 1 , wherein the is hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer is either primary diagnosed or locally advanced or metastatic breast cancer.

7 . The method of claim 1 , wherein the CDK4/6 inhibitor is selected from the group consisting of palbociclib, ribociclib, abemaciclib and trilaciclib, optionally palbociclib.

8 . The method of claim 1 , wherein the sample is a tumor tissue sample, optionally wherein the sample is a primary tumor tissue sample, optionally a core biopsy sample, optionally a core biopsy sample from a primary tumor before any treatment.

9 . The method of claim 7 , wherein the sample is a post-surgical residual tumor tissue sample or a post-surgical lymph node sample, optionally a post-surgical and post-chemotherapy tissue sample.

10 . The method of claim 1 , wherein the expression level is determined at mRNA level in a hybridization-based method, a PCR based method, a microarray-based method, a sequencing and/or next generation sequencing method, or at protein level in an immunohistochemistry (IHC) assay.

11 . A method of treating a neoplastic disease with an CDK4/6 inhibitor in a subject, wherein the subject has been determined to have a benefit from treatment with a CDK4/6 inhibitor in the method of claim 1 ,

wherein the neoplastic disease is a hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer.

12 . A method of treating a neoplastic disease with an CDK4/6 inhibitor in a subject, wherein the subject has been determined to have an increased expression level of at least one marker selected from the group consisting of PIAS2, MAP2K6, DSG3, ABCC12, IFT52, ABCB6, ABCC1, ABCA5, ABCC6, ABCC11, CHUK, SUMO1, TDG, AURKA, SMC3 and IKBKG and/or an decreased expression level of XPC, in a sample of said subject, optionally wherein the CDK4/6 inhibitor is selected from the group consisting of palbociclib, ribociclib, abemaciclib and Trilaciclib,

wherein the neoplastic disease is a hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer.

13 . The method of claim 1 , wherein the method further comprises determining at least one marker selected from the group consisting of Programmed Death Ligand 1 (PD-L1), AURKA, and SMC3,

wherein a higher expression level of PD-L1, PIAS2, MAP2K6, DSG3, IFT52, ABCB6, ABCC1, ABCA5, ABCC6, ABCC11, ABCC12, CHUK, SUMO1, TDG, AURKA, SMC3 and IKBKG, is associated with a higher likelihood of benefit from the CDK4/6 inhibitor, and a lower expression is associated with a lower benefit, no benefit or a disadvantage from the CDK4/6 inhibitor.

14 . The method of claim 1 , wherein at least two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, or thirteen markers are selected.