In this Research Worth Watching section, we talk about recent studies that give us new insight into the science of breast cancer—insight that may ultimately change the way we approach the clinical treatment. Although this new research is unlikely to have an immediate impact on care, it helps us understand what we are seeing in the clinical setting. Two new papers have been published which are causing many to reevaluate their thinking about cancers and which cells are important. Once again, our previous theories have been stood on their heads! But first, let’s back up. One of the big shifts in cancer and especially breast cancer treatments in the past ten years has been the recognition that there is more than one kind of breast cancer. The categorization of tumor types has allowed us to match the treatments to the type; i.e., Herceptin for the HER2 positives, hormones for the ER positives, and chemotherapy for the triple negatives. We had hoped that this type of precision medicine would be the answer to better outcomes. And while it has certainly improved outcomes, it has not been the home run that we thought it might be. One reason is because tumors are NOT homogeneous; e.g., they can have some cells that are HER2 positive and others that are not. When we talk about a person having a particular breast cancer subtype, we mean that’s what was predominant on the biopsy. But how does this diversity occur in the tumor? In an effort to better understand this, a group from MD Anderson used a new technique that can look at individual cells and map the mutations in the DNA. They used this technique to map the genomes of two kinds of breast cancer: triple negative and luminal A (HER2+, ER+, PR+). They first found that no two single tumor cells were genetically identical, however there were a lot of mutations that were common to all cells. We could say this is like people (or cars?). We are not identical but we all have certain features in common. They found two kinds of mutations. Large scale rearrangements of genes seemed to occur early in a burst of evolution, followed by stable growth of the cells to form a tumor. In other words, the single cells might have been slightly different but the main changes were similar and formed the bulk of the tumor. The other type of mutations, called point mutations, were in one spot in the DNA and they accumulated gradually over long periods of time, sort of like small dents in your car. These mutations generate the extensive diversity among clones of cells, in the same way that it is unlikely any one car will have the exact same dents as another. The team confirmed what other recent studies have found: that triple negative cancers had the largest numbers of mutations and thus, the greatest variety of cells, while the hormone positive cancers had the fewest. This could explain why triple negative tumors are more resistant to treatment. Because they have a variety of mutated cells, knocking down one type with treatment may allow a second group to rise up and metastasize. Another interesting study out of Harvard by Nelly Polyak and her group showed very elegantly, how these mixtures of mutated cell types play out in tumors. They had also confirmed that all tumors have more than one type of mutated cell. Some types of cells may be fast growing, while others may plod along more slowly. In general, chemotherapy blocks cell division and therefore, is best at killing the fast growing cells. We have always assumed that the fast growing cells were the “bad ones,” more likely to metastasize and kill you. Polyak’s team showed that this may not always be the case. They found that the fast growing cells often outgrow their local supply of nutrients and metabolic support and die off. The cells that are more likely to metastasize turn out to be the slower growing cells that are able to utilize their local environment to support their growth; i.e., increase the blood supply and nutrients, and disable the immune system. These findings are very interesting in light of the use of neoadjuvant chemotherapy to predict a drug’s ability to improve survival. The neoadjuvant chemotherapy probably kills off the fast growers, making the tumor lump shrink. However, it may not actually affect the slower growing, but better supported cells, which eventually spread. Both of these studies suggest to me that we cannot assume that all cancer cells in a tumor are the same. These results are supporting a movement to biopsy metastases when possible to see whether they are the same as the primary tumor in order to make sure that the treatment matches the type of cancer cells.