Diagnostic methods for determining prognosis of non-small cell lung cancer

Abstract

The invention provides methods for identifying early stage non-small cell lung cancer (NSCLC) patients who will have a favorable prognosis for the recurrence of lung cancer after surgical resection. The invention is based on the discovery that assessment of chromosomal copy number abnormalities at two or more of chromosome 5p15, 7p12, 8q24 and centromere 6 can be used for prognostic classification. The invention preferably uses fluorescence in situ hybridization with fluorescently labeled nucleic acid probes to hybridize to patient samples to quantify the chromosomal copy number of the these genetic loci. Assessment of the copy number abnormality patterns using four classifiers produced statistically significant prognostic classification for NSCLC: (i) the Range3 pattern of cells showing a difference on a cell by cell basis, of at least three FISH probe signals between the FISH signals at the chromosomal locus with the largest number of FISH signals minus the FISH signals at the chromosomal locus with the lowest number of FISH signals; (ii) the MYC/EGFR % loss pattern assessing the percentage of cells showing fewer MYC FISH probe signals than EGFR FISH probe signals; (iii) a combination of the Range3 pattern and the MYC/CEP6 ratio pattern of a percentage of cells showing a relative loss of MYC FISH probe signals to the FISH probe signal for CEP6; (iv) the combination of the MYC/5p15 ratio pattern showing the relative ratio of MYC and 5p15 locus signals of ≥0.80 and the 5p15/CEP6 ratio pattern assessing percentage of cells having a relative ratio of 5p15 FISH probe signals to CEP6 FISH probe signals ≥1.1 versus MYC/5p15 ratio of <0.80 or 5p15/CEP6 <1.1; and (v) a combination of the average range of probe signal differences of equal to or greater than about 2.5 with the Range3 pattern in a percentage of the cells. The invention can be used to identify those early stage NSCLC patients at higher risk of recurrence who should be treated with neoadjuvant chemotherapy before surgery or with adjuvant chemotherapy after surgery.

1 .- 18 . (canceled) 
     
     
         19 . A method of treating early stage non-small cell lung cancer in a human patient, the method comprising:
 (a) contacting a biological sample from an early stage non-small cell lung cancer patient with a chromosome 5p15 locus specific probe and a chromosome 6 enumeration probe under conditions sufficient to enable hybridization of the probes to chromosomes in the sample, wherein each of the chromosomal probes is directly labeled with a fluorescent label that can be separately detected;   (b) performing fluorescence in situ hybridization (FISH) on the biological sample;   (c) detecting the number of cells in the biological sample showing on a cell by cell basis a ratio of the 5p15 probe hybridization to centromere 6 probe hybridization of at least 1.1, which indicates a decreased time to recurrence (TTR) of lung cancer after surgical resection;   (d) performing surgical resection of the lung cancer in the patient; and   (e) administering adjuvant chemotherapy post-surgery or administering neoadjuvant chemotherapy before surgery.   
     
     
         20 . The method of  claim 19 , wherein the biological sample is a lung tissue biopsy or resection. 
     
     
         21 . The method of  claim 19 , wherein the biological sample is a cytology sample. 
     
     
         22 . The method of  claim 19 , wherein the patient has Stage 1b non-small cell lung cancer. 
     
     
         23 . The method of  claim 19 , wherein the patient has Stage 2 non-small cell lung cancer. 
     
     
         24 . The method of  claim 19 , wherein the contacting step (a) is performed on an automated instrument. 
     
     
         25 . The method of  claim 19 , which further comprises performing FISH on the biological sample using a fluorescently labeled chromosome 8q24 locus specific probe and detecting the number of cells in the biological sample showing on a cell by cell basis a ratio of the 8q24 locus specific probe hybridization to the 5p15 probe hybridization of at least 0.80, which indicates a decreased time to recurrence (TTR) of lung cancer after surgical resection.