The biology of a cancer is constantly changing. New genetic mutations appear as the tumor grows and spreads, providing new challenges for treatment and also new avenues of research for the development of additional therapies. In 2016, a landmark study provided an in-depth view of the pattern of genetic changes during development of melanoma from precursor lesions (precancer).
Cancers can also develop new genetic mutations that make them resistant to cancer therapy. Two early studies suggested that matching genetic changes in the tumor with specific treatments that target those genetic changes improves outcomes for patients with advanced cancer.
Melanoma Develops Through Successive Genetic Changes
Prior large-scale studies of genetic mutations in melanoma focused mostly on advanced cancers. As a result, the order in which distinct genetic mutations arise as melanoma progresses from benign skin lesions (e.g., melanocytic nevi or moles) is not well understood. Detailed knowledge about the genetic changes that occur as melanoma develops from precancerous lesions would improve both diagnosis and prognosis for this cancer.
A new analysis of 293 cancer-related genes from 37 primary melanomas and precancerous lesions revealed that distinct genetic changes emerge in a stepwise fashion as melanoma develops, grows, and spreads (this study was funded in part by a grant from the NIH).84 For example, benign skin tumors harbored only BRAF V600E mutations, whereas intermediate precancerous lesions also had mutations in NRAS and other genes. Changes in the CDKN2A gene appeared exclusively in invasive melanomas, and mutations in PTEN and TP53 occurred only in advanced melanomas.
The study also confirmed that UV light is a major factor in both the initial development of melanoma and its progression from early to advanced stage. Researchers found so-called mutational signatures unique to UV radiation exposure across all stages, from benign tumors to invasive melanoma. The frequency of UV light–related mutations increased as the cancer became more advanced. The findings from this landmark study establish a foundation for refining the criteria involved in melanoma diagnosis and prognosis.
Therapeutic Options Expand With Precision Medicine Approaches
Sadly, almost every patient with advanced cancer eventually reaches a point when there are no effective treatments left. In the current era of precision medicine, however, molecular testing of the tumor is opening additional treatment options for some of these patients.
One recent study supports the use of comprehensive genomic testing in patients who have hard-to-treat cancers. Researchers analyzed changes in 236 genes from the tumors of more than 300 patients with different cancers.85 So-called actionable mutations, or mutations that could be targeted with an existing therapy, were found in nearly all patients (93%), and 38% received a therapy matched to the mutation. Patients with more actionable mutations and matched therapies had more frequent and longer remissions, as well as longer survival.
An ongoing trial is assigning patients with advanced cancer whose prior genetic tests revealed abnormalities in specific molecular pathways to corresponding targeted treatments.86 The treatment assignments are outside of FDA-approved indications. Tumors shrank in 29 (22%) of the first 129 patients enrolled in the study; these patients had 12 different types of cancer.
For additional notable advances in tumor biology, please see Appendix Table A1.