Although cancer precision medicine has improved diagnosis and therapy, refractory cancers such as pancreatic cancer remain to be challenging targets. Clinical sequencing has identified the significant alterations in driver genes and traced their clonal evolutions. Recent studies indicated that the tumor microenvironment elicits alterations in cancer metabolism, although its involvement in the cause and development of genomic alterations has not been established. Genomic abnormalities can contribute to the survival of selected subpopulations, recently recognized as clonal evolution, and dysfunction can lead to DNA mutations. Here, we present the most recent studies on the mechanisms of cancer metabolism involved in the maintenance of genomic stability to update current understanding of such processes. Sirtuins, which are NAD+-dependent protein deacetylases, appear to be involved in the control of genomic stability. Alterations of deleterious subpopulations would be exposed to selective pressure for cell survival. Recent studies indicated that a new type of cell death, ferroptosis, determines the survival of clones and exert cancer-restricting or -promoting effects to surrounding cells in the tumor microenvironment. Suppressing genomic instability and eliminating deleterious clones by cell death will contribute to the improvement of cancer medicine. Furthermore, the elucidation of the mechanisms involved is seen as a bridgehead to the pharmacologic suppression of such refractory cancers as pancreatic cancer.