Method of treating a cancer patient without the need for a tissue biopsy

1. A method of treating a cancer patient without the need for a tissue biopsy, comprising:

(a) performing or having performed a sequencing assay on cell-free DNA (cfDNA) from a sample of blood from the patient to determine if the cell-free DNA comprises actionable and non-actionable sequence variations in one or more target genes,

wherein:

(i) an actionable sequence variation is a sequence variation for which there is a therapy that targets the protein encoded by the gene having the sequence variation; and

(ii) a non-actionable sequence variation is a sequence variation for which there is no therapy that targets the protein having the sequence variation;

(b) determining that the cfDNA has no actionable sequence variations;

(c) confirming that there are no actionable sequence variations in the cfDNA by identifying non-actionable sequence variations in the cfDNA; and then

(d) administering a therapy that does not target a protein encoded by a gene having an actionable or non-actionable sequence variation to the patient,

wherein the decision to administer the therapy of step (d) is made without considering data obtained from a tumor biopsy.

2. The method of claim 1 , wherein the non-actionable sequence variations identified in step (c) are statistically unlikely to occur in the same patient as the actionable sequence variations of step (c).

3. The method of claim 1 , wherein the cancer patient has non-small cell lung cancer.

4. The method of claim 1 , wherein the target genes assessed for actionable sequence variations comprise EGFR, ALK, ROS1, and BRAF.

5. The method of claim 4 , wherein:

i) the actionable variations in EGFR are activating mutations;

ii) the actionable variations in ALK include ALK gene fusions;

iii) the actionable variations in ROS1 include ROS1 gene fusions; and

iv) the actionable variations in BRAF are activating mutations.

6. The method of claim 5 , wherein:

i) the actionable variations in EGFR comprise L858R, exon 19 deletion, L861Q, G719X, p.S7681, V765A, T783A, V774A, S784P, and L861X or any combination thereof;

ii) the actionable variations in ALK comprise EML4-ALK, TFG-ALK and KIF5B-ALK fusions or any combination thereof;

iii) the actionable variations in ROS1 comprise CD74-ROS1, SLC34A2-ROS1, SDC4-ROS1 and EZR-ROS1 fusion or any combination thereof; and

iv) the actionable variations in BRAF include V600E, L601G, K601E, L597V/Q/R and G469V/S/R/E/A or any combination thereof.

7. The method of claim 1 , wherein the method further comprises:

calculating the allele frequencies of the non-actionable sequence variations identified in step (c); and

calculating the probability that there are no actionable sequence variations in the cfDNA based on the allele frequencies of the non-actionable sequence variations.

8. The method of claim 1 , further comprising:

analyzing white blood cell DNA from the patient;

determining whether any of the actionable or non-actionable sequence variations are due to hematopoiesis of indeterminate potential or a germ-line variation; and

eliminating sequence variations that are due to hematopoiesis of indeterminate potential or a germ-line variation from the analysis of steps (b) and (c).

9. The method of claim 1 , wherein the protein that is encoded by the gene that has the actionable sequence variation is a kinase and the therapy is a kinase inhibitor.

10. The method of claim 1 , wherein the therapy administered in (d) is a platinum-based chemotherapy.