Methods for personalizing cancer treatment

Abstract

Personalized medicine involves the use of a patient's molecular markers to guide treatment regimens for the patient. The scientific literature provides multiple examples of correlations between drug treatment efficacy and the presence or absence of molecular markers in a patient sample. Methods are provided herein that permit efficient dissemination of scientific findings regarding treatment efficacy and molecular markers found in patient tumors to health care providers.

1 - 75 . (canceled) 
     
     
         76 . A method of determining one or more personalized cancer treatment options for a subject, the method comprising:
 (a) obtaining a sample from a subject, wherein the sample comprises one or more molecular markers from a tumor cell;   (b) determining a status of the one or more molecular markers, wherein the determining comprises performing an assay; and   (c) stratifying one or more cancer drug treatment options in a clinical practice guideline for a cancer based on the status of the one or more molecular markers.   
     
     
         77 . The method of  claim 76 , wherein the subject is diagnosed with a specific type of cancer, and wherein the clinical practice guideline is a clinical practice guideline for the specific type of cancer. 
     
     
         78 . The method of  claim 76 , wherein the cancer is a colon cancer. 
     
     
         79 . The method of  claim 76 , wherein the clinical practice guideline is a National Comprehensive Cancer Network (NCCN) Clinical Practice Guideline in Oncology. 
     
     
         80 . The method of  claim 76 , wherein the clinical practice guideline is an NCCN Clinical Practice Guideline in Oncology guideline for colon cancer. 
     
     
         81 . The method of  claim 76 , wherein the clinical practice guideline is an American Society of Clinical Oncology (ASCO) clinical practice guideline. 
     
     
         82 . The method of  claim 76 , wherein the stratifying comprises ranking drug treatment options with a higher likelihood of efficacy higher than drug treatment options with a lower likelihood of efficacy or for which no information exists with regard to treating subjects with the determined status of the molecular markers. 
     
     
         83 . The method of  claim 76 , wherein the stratifying comprises indicating on the clinical practice guideline one or more drug treatment options for which scientific information suggests the one or more drug treatment options will be efficacious in a subject, based on the status of the one or more molecular markers. 
     
     
         84 . The method of  claim 76 , wherein the stratifying comprises indicating on the clinical practice guideline one or more drug treatment options for which some scientific information suggests the one or more drug treatment options will be efficacious in the subject, and some scientific information suggests the one or more drug treatment options will not be efficacious in the subject, based on the status of the one or more molecular markers. 
     
     
         85 . The method of  claim 76 , wherein the stratifying comprises indicating on the clinical practice guideline one or more drug treatment options for which scientific information indicates the one or more drug treatment options will not be efficacious for the subject, based on the status of the one or more molecular markers. 
     
     
         86 . The method of  claim 76 , wherein the stratifying is further based on analysis of a Kaplan-Meier survival curve. 
     
     
         87 . The method of  claim 76 , wherein the stratifying is further based on a status of one or more molecular markers in drug absorption, distribution, metabolism, or excretion genes in a sample from the subject. 
     
     
         88 . The method of  claim 76 , wherein the stratifying is further based on whether the subject is hypermetabolic. 
     
     
         89 . The method of  claim 76 , wherein the stratifying is further based on a CYP450 status of the subject. 
     
     
         90 . The method of  claim 76 , wherein the stratifying is further based on clinical information for the subject. 
     
     
         91 . The method of  claim 76 , wherein the stratifying is further based on information in scientific literature. 
     
     
         92 . The method of  claim 76 , wherein the stratifying is indicated by color coding drug treatment options listed on the clinical practice guideline. 
     
     
         93 . The method of  claim 92 , wherein a color coded drug treatment option comprising a green shade is a drug that is recommended to the subject based on the status of the more than one molecular marker. 
     
     
         94 . The method of  claim 92 , wherein a color coded drug treatment option comprising a red shade is a drug for which the status of the more than one molecular marker does not support recommending the drug treatment option to the subject. 
     
     
         95 . The method of  claim 92 , wherein a color coded drug treatment option comprising a yellow shade is a drug that at least one piece of information supports recommending the drug as a treatment option to the subject based on the status of the more than one molecular marker and at least one piece of information does not support recommending the drug as a treatment option. 
     
     
         96 . The method of  claim 76 , further comprising annotating the clinical practice guideline with information comprising information regarding one or more additional drug treatment options not listed in the clinical practice guideline for the cancer, wherein the information is included based on the status of the one or more molecular markers. 
     
     
         97 . The method of  claim 96 , wherein the one or more additional drug treatment options target a molecular marker that is in a pathway for which the status of the one or more molecular markers indicates that targeting the pathway would be efficacious for treating the subject. 
     
     
         98 . The method of  claim 96 , wherein the annotating comprises listing one or more FDA-approved drugs for off-label use, one or more drugs listed in a Centers for Medicare and Medicaid Services (CMS) anti-cancer treatment compendia, or one or more experimental drugs found in scientific literature, in the clinical practice guideline. 
     
     
         99 . The method of  claim 76 , further comprising annotating the clinical practice guideline by connecting a listed drug treatment option to a reference containing scientific information regarding the drug treatment option. 
     
     
         100 . The method of  claim 99 , wherein the scientific information is from a peer-reviewed article from a medical journal. 
     
     
         101 . The method of  claim 76 , further comprising annotating the clinical practice guideline by adding clinical trial information regarding one or more drug treatment options. 
     
     
         102 . The method of  claim 76 , wherein the sample comprises a tumor biopsy or a cell-free sample. 
     
     
         103 . The method of  claim 76 , wherein the one or more tumor cells comprise one or more cells from a colon cancer, a bone cancer, a breast cancer, a central nervous system cancer, a gastric cancer, a cervical cancer, a blood cancer, an esophageal cancer, a head and neck cancer, a kidney cancer, a skin cancer, a lung cancer, or a carcinoma. 
     
     
         104 . The method of  claim 76 , wherein the determining comprises nucleic acid amplification, de novo DNA sequencing, fluorescent in-situ hybridization (FISH), quantitative PCR (qPCR), digital PCR, or immunohistochemistry (IHC). 
     
     
         105 . The method of  claim 104 , the determining comprises de novo DNA sequencing, and wherein the de novo DNA sequencing comprises use of reversibly terminating nucleotides. 
     
     
         106 . The method of  claim 76 , wherein the determining comprises determining a presence or absence of the one or more molecular markers. 
     
     
         107 . The method of  claim 76 , wherein the determining comprises determining an absence of one or more mutations or a presence of the one or more mutations in the one or more molecular markers. 
     
     
         108 . The method of  claim 107 , wherein the one or more mutations comprise a de novo mutation, nonsense mutation, missense mutation, silent mutation, frameshift mutation, insertion, substitution, point mutation, deletion, rearrangement, amplification, chromosomal translocation, interstitial deletion, chromosomal inversion, loss of heterozygosity, loss of function mutation, gain of function mutation, dominant negative mutation, or lethal mutation. 
     
     
         109 . A method for personalizing cancer drug treatment, the method comprising:
 (a) obtaining a sample from a subject, wherein the sample is an unstained section of a formalin-fixed, paraffin-embedded (FFPE) tumor biopsy, wherein the tumor biopsy is greater than 10% tumor;   (b) extracting DNA molecules from the sample;   (c) fragmenting the extracted DNA molecules;   (d) attaching adaptors to the fragmented DNA molecules to generate a library;   (e) amplifying the DNA molecules with attached adaptors in the library using polymerase chain reaction;   (f) performing a targeted assay to determine a status of more than one molecular marker in the amplified library, wherein the targeted assay comprises:
 (i) hybridizing a probe nucleic acid to the more than one molecular marker; and 
 (ii) performing massively parallel DNA sequencing on the more than one molecular marker; and 
   (g) generating a report indicating a status of the more than one molecular marker determined by the massively parallel DNA sequencing and one or more cancer drug treatment options.   
     
     
         110 . The method of  claim 109 , wherein the tumor biopsy comprises greater than 20% tumor. 
     
     
         111 . The method of  claim 109 , wherein the tumor biopsy is from a colon cancer resection. 
     
     
         112 . The method of  claim 109 , wherein the massively parallel DNA sequencing comprises use of a flow cell. 
     
     
         113 . The method of  claim 109 , wherein the massively parallel DNA sequencing comprises bridge amplification. 
     
     
         114 . The method of  claim 109 , wherein the massively parallel DNA sequencing comprises use of reversibly terminating nucleotides. 
     
     
         115 . The method of  claim 109 , wherein the more than one molecular marker comprises c-kit, Bcr, Abl, PDGFR, SPARC, Hsp90, MGMT, EGFR, Kras, VEGF, ER, PR, vras, TOPO1, PTEN, PIK3CA, Nrf2, DPD, OPRT, TS, and ERBB2. 
     
     
         116 . The method of  claim 109 , wherein the more than one molecular marker comprises one or more mutations selected from the group consisting of nonsense mutations, missense mutations, silent mutations, frameshift mutations, insertions, substitutions, point mutations, deletions, rearrangements, amplifications, chromosomal translocations, interstitial deletions, chromosomal inversions, copy number variation, and loss of heterozygosity. 
     
     
         117 . The method of  claim 109 , wherein the report comprises providing a link to information on a clinical trial for a drug treatment option in the report. 
     
     
         118 . The method of  claim 109 , wherein the report further comprises listing one or more drug treatment options on the report based on one or more characteristics of the subject selected from the group consisting of: type of cancer, age of the subject, status of drug metabolism genes, efficacy of other drugs the patient has received, clinical information regarding the subject, and family medical history. 
     
     
         119 . The method of  claim 109 , wherein generating the report comprises adding information to the report selected from the group consisting of scientific information regarding one or more drug treatment options, one or more links to scientific information regarding one or more drug treatment options, one or more links to citations for scientific information regarding one or more drug treatment options, and clinical trial information regarding one or more drug treatment options. 
     
     
         120 . The method of  claim 109 , wherein the report indicates an analysis of molecular pathways that include drug targets. 
     
     
         121 . The method of  claim 120 , wherein the analysis of molecular pathways indicates that the patient's tumor may be sensitive or resistant to a drug. 
     
     
         122 . The method of  claim 109 , wherein the more than one molecular marker comprises EGFR. 
     
     
         123 . The method of  claim 109 , wherein the more than one molecular marker comprises PIK3 CA. 
     
     
         124 . The method of  claim 109 , wherein the more than one molecular marker comprises ErbB2. 
     
     
         125 . A method for personalizing cancer drug treatment, the method comprising:
 (a) obtaining an unstained section of a formaldehyde-fixed, paraffin-embedded (FFPE) sample comprising a tumor biopsy, wherein the sample comprises greater than 10% tumor;   (b) extracting genomic DNA molecules from the sample;   (c) fragmenting the extracted genomic DNA molecules to produce DNA fragments;   (d) attaching adaptors to the DNA fragments to generate a library;   (e) performing a targeted assay to determine a status of more than one molecular marker within the library, wherein the targeted assay comprises:
 (i) amplifying DNA in the library to provide amplified DNA; 
 (ii) hybridizing one or more probes to the amplified DNA in solution; and 
 (iii) performing massively parallel DNA sequencing of the amplified nucleic acid fragments, wherein the massively parallel DNA sequencing comprises use of a flow cell, bridge amplification, and use of reversibly terminating nucleotides; and 
   (f) generating a report indicating the status of the more than one molecular marker, wherein the more than one molecular marker comprises c-kit, Bcr, Abl, PDGFR, SPARC, Hsp90, MGMT, Her2, EGFR, Kras, VEGF, ER, PR, vras, TOPO1, PTEN, PIK3CA, Nrf2, DPD, OPRT, TS, and ErbB2,   wherein the more than one molecular marker comprises mutations selected from the group consisting of: nonsense mutations, missense mutations, silent mutations, frameshift mutations, insertions, substitutions, point mutations, deletions, rearrangements, amplifications, chromosomal translocations, interstitial deletions, chromosomal inversions, copy number variation, and loss of heterozygosity, and   wherein generating the report comprises adding information to the report selected from the group consisting of: scientific information regarding one or more drug treatment options, one or more links to scientific information regarding one or more drug treatment options, one or more links to citations for scientific information regarding one or more drug treatment options, and clinical trial information regarding one or more drug treatment options.