Biomarkers for identifying patient classes

1. A method for classifying a patient having cancer as a candidate for therapy with a Bcl-2 family inhibitor comprising:

(a) providing a tissue, blood, plasma or serum sample from a patient;

(b) determining the level of (i) plasma pro-gastrin releasing peptide (proGRP), (ii) cytokeratin 19 fragment antigen 21-1 (CYFRA 21-1), (iii) neuron-specific enolase (NSE), (iv) circulating tumor cell (CTC) number, and (v) Bcl-2 gene copy number in the tissue, blood, plasma or serum sample;

(c) classifying the patient as a candidate for therapy with the Bcl-2 family inhibitor when the tissue, blood, plasma or serum sample is determined as having an increased level, relative to a threshold level, of (i) plasma pro-gastrin releasing peptide (pro-GRP) and (v) Bcl-2 gene copy number; and a decreased level, relative to a threshold level, of (ii) cytokeratin 19 fragment antigen 21-1 (CYFRA 21-1), (iii) neuron-specific enolase (NSE), and (iv) circulating tumor cell (CTC) number; and

(d) administering the Bcl-2 family inhibitor to the patient classified in step (c) as a candidate for therapy with the Bcl-2 family inhibitor, wherein the Bcl-2 family inhibitor is N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(morpholin-4-yl)-1-((phenylsulfanyl)methyl-)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide(navitoclax),

wherein (i) the plasma pro-GRP threshold level is about 600 pg/mL, (ii) the CYFRA 21-1 threshold level is about 2.3 ng/mL, (iii) the NSE threshold level is about 15 ng/mL, (iv) the CTC number threshold level is about 12 per 7.5 mL, and (v) Bcl-2 gene copy number is greater than 2.

2. The method of claim 1 , wherein the tissue, blood, plasma or serum sample is from a patient with a cancer selected from the group consisting of small cell lung carcinoma (SCLC) and a solid tumor cancer.

3. The method of claim 1 , wherein the tissue, blood, plasma or serum sample is from a patient with a relapsed or refractory cancer selected from the group consisting of small cell lung carcinoma (SCLC) and a solid tumor cancer.

4. The method of claim 1 , wherein the tissue, blood, plasma or serum sample is from a patient with a relapsed or refractory cancer selected from the group consisting of solid tumor cancer, squamous cell cancer (e.g., epithelial squamous cell cancer), lung cancer including small-cell lung cancer, non-small cell lung cancer, adenocarcinoma of the lung and squamous carcinoma of the lung, esophageal cancer, prostate cancer, cancer of the peritoneum, hepatocellular cancer, gastric or stomach cancer including gastrointestinal cancer, neuroendocrine cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, cancer of the urinary tract, hepatoma, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney or renal cancer, prostate cancer, vulval cancer, thyroid cancer, hepatic carcinoma, anal carcinoma, melanoma, multiple myeloma and B-cell lymphoma, brain, head and neck cancer, and associated metastases.

5. The method of claim 1 , wherein the tissue, blood, plasma or serum sample comprises a peripheral blood sample, a tumor or suspected tumor tissue, a thin layer cytological sample, a fine needle aspirate sample, a bone marrow sample, a lymph node sample, a urine sample, an ascites sample, a lavage sample, an esophageal brushing sample, a bladder or lung wash sample, a spinal fluid sample, a brain fluid sample, a ductal aspirate sample, a nipple discharge sample, a pleural effusion sample, a fresh frozen tissue sample, a paraffin embedded tissue sample or an extract or processed sample produced from any of a peripheral blood sample, a serum or plasma fraction of a blood sample, a tumor or suspected tumor tissue, a thin layer cytological sample, a fine needle aspirate sample, a bone marrow sample, a lymph node sample, a urine sample, an ascites sample, a lavage sample, an esophageal brushing sample, a bladder or lung wash sample, a spinal fluid sample, a brain fluid sample, a ductal aspirate sample, a nipple discharge sample, a pleural effusion sample a fresh frozen tissue sample or a paraffin embedded tissue sample.

6. The method of claim 1 , wherein the determining step (b) is performed by immunoassay to a peripheral blood sample or plasma or serum fraction thereof.

7. A method for classifying a patient having cancer as a candidate for second-line therapy with a Bcl-2 family inhibitor comprising:

(a) providing a tissue, blood, plasma or serum sample from a patient;

(b) determining the level of (i) plasma pro-gastrin releasing peptide (proGRP), (ii) cytokeratin 19 fragment antigen 21-1 (CYFRA 21-1), (iii) neuron-specific enolase (NSE), (iv) circulating tumor cell (CTC) number, and (v) Bcl-2 gene copy number in the tissue, blood, plasma or serum sample;

(c) classifying the patient as a candidate for second-line therapy with the Bcl-2 family inhibitor when the tissue, blood, plasma or serum sample is determined as having an increased level, relative to a threshold level, of (i) plasma pro-gastrin releasing peptide (pro-GRP) and (v) Bcl-2 gene copy number; and a decreased level, relative to a threshold level, of (ii) cytokeratin 19 fragment antigen 21-1 (CYFRA 21-1), (iii) neuron-specific enolase (NSE), and (iv) circulating tumor cell (CTC) number; and

(d) administering the Bcl-2 family inhibitor to the patient classified in step (c) as a candidate for second-line therapy with the Bcl-2 family inhibitor, wherein the Bcl-2 family inhibitor is N-(4-(4-((2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohex-1-en-1-yl)methyl)piperazin-1-yl)benzoyl)-4-(((1R)-3-(morpholin-4-yl)-1-((phenylsulfanyl)methyl-)propyl)amino)-3-((trifluoromethyl)sulfonyl)benzenesulfonamide(navitoclax),

wherein (i) the plasma pro-GRP threshold level is about 600 pg/mL, (ii) the CYFRA 21-1 threshold level is about 2.3 ng/mL, (iii) the NSE threshold level is about 15 ng/mL, (iv) the CTC number threshold level is about 12 per 7.5 mL, and (v) Bcl-2 gene copy number is greater than 2.

8. The method of claim 7 , wherein the tissue, blood, plasma or serum sample is from a patient with a relapsed or refractory cancer selected from the group consisting of solid tumor cancer, squamous cell cancer (e.g., epithelial squamous cell cancer), lung cancer including small-cell lung cancer, non-small cell lung cancer, adenocarcinoma of the lung and squamous carcinoma of the lung, esophageal cancer, prostate cancer, cancer of the peritoneum, hepatocellular cancer, gastric or stomach cancer including gastrointestinal cancer, neuroendocrine cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, cancer of the urinary tract, hepatoma, breast cancer, colon cancer, rectal cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney or renal cancer, prostate cancer, vulval cancer, thyroid cancer, hepatic carcinoma, anal carcinoma, melanoma, multiple myeloma and B-cell lymphoma, brain, head and neck cancer, and associated metastases.

9. The method of claim 7 , wherein the determining step (b) is performed by immunoassay to a peripheral blood sample or plasma or serum fraction thereof.