In recent years, scientists have come to appreciate that breast cancer is a complex disease, triggered by myriad genetic and lifestyle factors. But the latest study of the genetics behind the disease, published in the journal Nature, shows that it may actually be slightly simpler than researchers had thought.
As part of the Cancer Genome Atlas (TCGA), a government project that is aiming to sequence tumor genomes from dozens of different cancers to help scientists better understand tumor development and treatment, scientists sequenced 510 tumors from 507 patients with breast cancer. All told, they found 30,626 mutations in these cancer cells, but those aberrations fell into four main groups.
In one subtype, basal-like tumors that account for 10% of all breast cancers, the researchers found that the mutations resembled those found in ovarian cancers, thus explaining the link between the two diseases: women at higher risk of developing breast cancer are also more vulnerable to getting ovarian cancer.
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In two related subtypes, luminal A and luminal B, which include breast cancers that contain receptors for estrogen and progesterone, the scientists found that while the mutation rate in these cancers was lower, genetic aberrations occurred in a larger number of genes, suggesting that a more complex interaction of abnormal genes contribute to these types of breast cancer.
Teasing apart such connections will be critical for improving treatment for women with these mutations: those with luminal-A cancers generally have good outcomes, while those with luminal-B tumors have more mixed results. Isolating which mutations distinguish the two subtypes may help doctors treat women with luminal-B cancers in order to make them progress more like luminal-A cases, for example.
In the final subtype, which are those that contain the HER2 receptors, the scientists found two smaller subgroups of HER2 cancers, which could explain why some women respond better to HER2-specific therapies like Herceptin than others. The good responders may have tumors with mutations that make the HER2 receptors more active and therefore enriched, making those cells better targets for the drug than those without the mutations.
“We are really getting at the genetic roots of these different types of breast cancer,” says Charles Perou, professor of genetics and pathology at the University of North Carolina at Chapel Hill and a co-author of the paper. “The work shows that really these four groups of [breast cancer] require major attention as an important first step down the road to individualized medicine.”
That road is ripe with opportunity, says another co-author, Matthew Ellis, professor of medicine and oncology at Washington University in St. Louis. A better understanding of how breast cancers are triggered, at the genetic level, can lead to more efficient treatments on many levels. First, he says, it’s possible that existing chemotherapy agents currently used in other cancers can be enlisted to treat breast cancer. The connection between breast and ovarian cancers revealed by the TCGA analysis, for example, suggests that chemotherapy used in ovarian cancer, like platinum-based agents, might be effective against basal-type breast cancers, and powerful breast cancer agents likewise might prove useful against some ovarian cancers as well. “We can tweak the recipe of chemotherapy treatment by reaching across to other diseases, and borrowing from that knowledge,” he says.
Continuing on that theme, it might also be possible that some of the newly developed targeted drugs created for other cancers may work on breast cancers too. Because the drugs are made to target specific molecular pathways, it doesn’t really matter where the tumor is, just that it is dependent on that pathway to grow. If that’s the case, then repurposing such existing targeted therapies may also improve breast-cancer outcomes.
“Now we can look at the etiology of the spectrum of disorders that is breast cancer using genomic profiling,” Ellis says. “If you understand something fundamentally, you can develop better treatments. The idea is that suddenly we really understand a lot about these cancers.”
That understanding may soon translate into a sea change in the doctor’s office as well, in the way physicians diagnose and treat cancer. It won’t be long, predict many experts, before every patient diagnosed with cancer will have his or her tumor’s genome analyzed in some way. That analysis — which includes identifying not only the mutations the tumor may harbor, but also other valuable information about how actively its various genes are expressed, or activated, and what proteins those genes produce — could become the foundation for a personalized treatment regimen. That can mean the difference between surviving a cancer and becoming a victim of the disease. “This could become an integral part of cancer care,” says Perou. “We now have the blueprint for breast-cancer genetics. It’s the most complete blueprint ever achieved.” And one that could lead to the most comprehensive and personalized way of treating cancer ever achieved as well.