One of the major questions in cancer metastasis is whether tumors start out with the ability to spread, or they evolve that capacity over time. So the researchers looked for mutations found in both the metastatic tissue and in the primary tumor, to try to understand what made it eventually spread. Nineteen of the metastatic mutations were completely absent from the primary tumor, suggesting that they arose after the cancer spread. And six mutations appeared to be present in only a subset of the cells in the primary tumor, suggesting that the cells carrying these mutations may have been selected for as the cancer progressed, eclipsing other cells.
That suggests that even low-grade and medium-grade tumors can be genetically heterogeneous, which could be problematic for molecularly targeted drugs. “We think this points to the need to shift the way we develop and apply cancer treatments–we need to think about multiple mutations from the outset,” says Aparicio. “We are going to end up with recurrence of cancers unless we address the fact that there are cells that do not respond to the drug.”
Some diseases, such as malaria and HIV, have already been shown to require this strategy. “You need to use a cocktail of three different drugs, which target different bits of the pathology,” says Aparicio. “If you only have one or two, eventually you end up with resistance to the drugs. This may be going on in cancer as well, so we have to adapt our strategies accordingly.”
In the primary tumor, the researchers identified some proteins thought to play a role in cancer, such as PALB2, which is known to interact with the breast cancer risk factor BRCA2, as well as new mutations such as HAUS3, which plays a role in cell division.
The study also suggests that the mutations underlying different women’s cancers appear to be highly variable. Genetically screening other breast tumor tissue samples revealed that none shared the exact mutations identified in the original patient, although some samples contained mutations in the same gene. “A number of mutations were present in less than 1 percent frequency, so we need to look quite hard to find them,” says Aparicio.
The researchers are now sequencing tumors from women with triple-negative breast cancers in hope of identifying mutations that would suggest new drug targets for these cancers. They are also sequencing tumors of women in a clinical trial for an experimental cancer drug, in order to identify genetic markers that predict who will respond best to the drug.