“The greatest curse is to be stuck in one’s own time; the greatest power is to see beyond its horizon.” – Rachel Kadish, The Weight of Ink.
Is it true that all cancers are in some way genetic whether by germline or sporadic mutation or by some epigenetic event? I certainly believe this to be the case. We initially saw the benefits of germline mutation testing, as well as testing tumor genomics. Both forms of testing have assisted in risk assessment, and tumor genomics has been used in treatment selection. Much of the benefit of testing for these mutations comes from a more accurate assessment of risk or a reduction in the use of chemotherapy. It is also undeniable that the identification of oncogenes such as Her2 has led to the development of new biologic treatment options. Unfortunately, biologic therapies for breast cancer have not been highly successful when given as monotherapy. They all appear to require more standard courses of multidrug chemotherapy to maximize success.
As these thoughts creep inexorably to gain a peek beyond the horizon, one might conclude that since all cancers are in one way or another genetic, then it should follow that eventually, treatment of cancer should proceed along a path that takes advantage of this genetic knowledge. It is only in recent months that we have begun to catch a glimpse of that distant light. Several labs, including Myriad, Ambry, and Color have begun using single nucleotide polymorphisms (SNPs, which researchers are beginning to call single-nucleotide sequence variants) to examine their associations with various diseases, including cancer. As noted in an article on Genome-wide Association Studies (GWAS), over 250 SNPs are known to be associated with male-pattern baldness. Cancer has got to be, it just has to be more complex than male-pattern baldness!
SNP tests are now commercially available to assess cancer risk for this group of high-risk but germline mutation-negative patients. Both companies that offer these tests use nearly 100 SNPs, plus the Tyrer-Cuzick risk model (TC), to arrive at their score. Equally exciting data was presented at the 2019 San Antonio Breast Cancer Symposium. Hughes et al, from Myriad Genetics Laboratory, presented validated data demonstrating the use of SNPs and TC to assess risk in women who test positive for five of the more common germline mutations. Intuitively, we’ve always known that different mutations in high-risk genes carried different cancer risks. This data from Myriad finally confirms this.
But peering over the horizon, one has to believe that genetics has to carry us further than risk assessment and the treatment of one known oncogene. To me, the holy grail is the treatment of existing cancers. If all cancers are indeed genetic, then it makes perfect sense to me that ultimately, the treatment should be genetic. The fact that for an overwhelming number of patients who overexpress the Her2 oncogene, multidrug chemotherapy is required in addition to targeted biologics suggests that we have a long way to go.
“They gathered for the feast.
They stab it with their steely knives,
But they just can’t kill the beast.”
– The Eagles, Hotel California