Paradigm Shift in Genomics

The presumption  had been that the  genomic defects in cancer, revealed by sequencing data, would identify targets for treatment.  By virtue of the specificity of these targets, treatment would be more effective and less toxic. In a few situations, this has happened. The EGFR , ALK  ROS genes of lung cancer, the B RAF of melanoma, HEr2 in breast and esophageal, abl in chronic myelogenous leukemia are examples of the success of this approach ( N.B. all antedate widespread next generation sequencing.)  The estrogen receptor of breast cancers  and the androgen receptor of prostate cancers are therapy targets that are not correlated with sequencing data.

I do not want to be overly cynical about the value of sequencing.  The the technique, as clinical art and science, has not matured.  Development often  produces surprises.  When the surprise  leads to  a broader model, the  original idea needs to be placed in the new perspective.

Recent discoveries have broadened the meaning of  NG sequenced data.  Rivzi, et al  have shown that response to immunomodulatory, PD-1, directed therapy correlates with overall mutational burden. A tumor in which a large number of mutations is identified by NG sequencing tends to respond more favorably to an agent ( monclonal antibody) that blocks an "off switch" for immune reaction ( PD-1).   It is the mutable tendency, not the actual mutation that determines responsiveness to this (class of) agent(s).  The observations of Le, et al, that mismatch repair, a phenotype that would be expected to increase the mutation rate, signals sensitivity of cancers to  PD-1 blockade seems to be a complementary  finding.

These findings imply that the mechanism underlying the cancer, tolerance of mutation, rather than the mutations themselves,  can be a target for treatment.  This particular mechanism also intimates that the immunologic treatment will eventually fail since mutations will continue to occur, and be tolerated.  in the malignant cell population.

The utility of PARP inhibitors in BRCA and PALB2 mutated tumors is a corollary to these ideas.  The PARP inhibitors target the mechanism of mutational generation in these selected cases.

Understanding optimizes hope