Detection and treatment of disease exhibiting disease cell heterogeneity and systems and methods for communicating test results

Abstract

This disclosure provides, among other things, methods for generating and applying therapeutic interventions. The methods involve, for example, (a) sequencing polynucleotides from cancer cells from a subject; (b) identifying and quantifying somatic mutations in the polynucleotides; (c) developing a profile of tumor heterogeneity in the subject indicating the presence and relative quantity of a plurality of the somatic mutations in the polynucleotides, wherein different relative quantities indicates tumor heterogeneity; and (d) determining a therapeutic intervention for a cancer exhibiting the tumor heterogeneity, wherein the therapeutic intervention is effective against a cancer having the profile of tumor heterogeneity determined.

What is claimed is: 
     
         1 . A method comprising:
 (a) sequencing polynucleotides from cancer cells from a biological sample of a subject;   (b) identifying and quantifying somatic mutations in the polynucleotides;   (c) developing a profile of tumor heterogeneity in the subject indicating a presence and a relative quantity of a plurality of the somatic mutations in the polynucleotides, wherein different relative quantities indicate tumor heterogeneity; and   (d) determining a therapeutic intervention for a cancer exhibiting the tumor heterogeneity, wherein the therapeutic intervention is effective against a cancer having the profile of tumor heterogeneity.   
     
     
         2 .- 14 . (canceled) 
     
     
         15 . A system comprising a computer readable medium comprising machine-executable code that, upon execution by a computer processor, implements a method comprising:
 (a) receiving into memory sequence reads of polynucleotides from cancer cells from a biological sample of a subject mapping to a genetic locus;   (b) determining, among said sequence reads, identity of one or more bases that than differ from a base of a reference sequence at the locus in a total number of sequence reads mapping to the locus;   (c) reporting the determined identity a relative quantity, and a location in the reference sequence of the one or more bases; and   (d) inferring tumor heterogeneity of the cancer cells from the biological sample based on the determined identity, the relative quantity, and the location in the reference sequence of the one or more bases.   
     
     
         16 .- 42 . (canceled) 
     
     
         43 . A method, comprising:
 a) providing a plurality of nucleic acid samples from a subject, the nucleic acid samples collected at serial time points;   b) sequencing polynucleotides from the plurality of nucleic acid samples to generate sequences;   c) determining a quantitative measure of each of a plurality of genetic variants among the polynucleotides from each of the plurality of nucleic acid samples;   d) graphically representing by computer relative quantities of each of the plurality of genetic variants at each of the serial time points for somatic mutations present at a non-zero quantity for at least one of the serial time points.   
     
     
         44 . The method of  claim 43  wherein the quantitative measure is a frequency of the genetic variant among all sequences mapping to the same genetic locus. 
     
     
         45 . The method of  claim 43  wherein the relative quantities are graphically represented as a stacked area graph. 
     
     
         46 . The method of claim wherein the relative quantities are stacked, at the earliest time point of the serial time points, highest to lowest from bottom to top of the graph, and wherein a genetic variant first appearing at a non-zero quantity at a later time point of the serial time points is stacked at the top of the graph. 
     
     
         47 . A method to generate a paper or electronic patient test report from data generated by a genetic analyzer, comprising:
 a) summarizing data from two or more testing time points, whereby a union of all non-zero testing results is reported at each subsequent testing time point of the two or more time points after the first testing time point of the two or more time points, to generate testing results; and   b) rendering the testing results on the paper or electronic patient test report.   
     
     
         48 . The method of  claim 47  wherein summarizing and rendering are performed on a computer by executing code with a computer processor to (i) identify all non-zero testing results, (ii) generate the electronic patient test report and (iii) display the electronic patient test report on a graphical user interface. 
     
     
         49 . A method of graphically representing evolution of genetic variants of a tumor in a subject from data generated by a genetic analyzer, the method comprising:
 a) generating by computer a stacked representation of the genetic variants detected at each of a plurality of time points in the subject, wherein a height or width of each layer in the stacked representation that corresponds to a genetic variant represents a quantitative contribution of the genetic variant to a total quantity of the genetic variants at each of the plurality of time points; and   b) displaying the stacked representation on a computer monitor or a paper report.   
     
     
         50 . The method of  claim 49  wherein displaying comprises:
 a) receiving data representing the detected tumor genetic variants into computer memory; 
 b) executing code with a computer processor to graphically represent the quantitative contribution of each genetic variant at a time point as a line or area proportional to a relative contribution of the quantitative contribution; and 
 c) displaying the graphical representation on a graphical user interface. 
 
     
     
         51 . The method of  claim 43 , wherein the graphical representation further indicates, for each time point, the quantitative measure of the predominant genetic variant among the plurality of genetic variants. 
     
     
         52 . The method of  claim 43 , wherein graphically representing comprises normalizing and scaling the quantitative measures. 
     
     
         53 . The method of  claim 43 , wherein the polynucleotides comprise cell-free DNA (cfDNA). 
     
     
         54 . The method of  claim 44 , wherein the genetic locus is located in an oncogene. 
     
     
         55 . The method of  claim 43 , wherein the plurality of genetic variants (i) maps to different genes in the genome or (ii) maps to the same gene in the genome. 
     
     
         56 . The method of  claim 47 , wherein the paper or electronic patient test report includes one or more annotations to help a physician interpret the testing results or recommend treatment options. 
     
     
         57 . The method of  claim 49 , wherein the stacked representation includes one or more annotations to help a physician interpret the stacked representation or recommend treatment options. 
     
     
         58 . The method of  claim 49 , further comprising using allele fractions of the detected genetic variants, allelic imbalances of the detected genetic variants, and gene-specific coverage of the genetic variants detected using a bodily-fluid based test to infer the disease burden. 
     
     
         59 . The method of  claim 49 , wherein an overall stack height is representative of overall disease burden or a disease burden score in the subject. 
     
     
         60 . The method of  claim 49 , wherein only a subset of the detected genetic variants is plotted, the subset chosen based on (i) a likelihood of a genetic variant being a driver alteration or (ii) an association with increased or reduced response to treatment. 
     
     
         61 . The method of  claim 49 , wherein the method comprises estimating a disease progression or remission based on rate of change and/or quantitative precision of each testing result. 
     
     
         62 . The method of  claim 49 , wherein the method comprises displaying a therapeutic intervention between intervening testing points. 
     
     
         63 . The method of  claim 43 , wherein sequencing the polynucleotides comprises generating a plurality of sequence reads for parent polynucleotides, and collapsing the plurality of sequence reads to generate consensus calls for bases in each parent polynucleotide. 
     
     
         64 . The method of  claim 43 , wherein the serial time points comprise a first time point before a treatment is administered to the subject and a second time point after the treatment is administered to the subject. 
     
     
         65 . The method of  claim 43 , wherein the serial time points comprise a first time point and a second time point, wherein the second time point is about one month after the first time point. 
     
     
         66 . The method of  claim 45 , wherein the stacked area graph comprises areas represented by different colors.