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Research Worth Watching: What is Normal?

Medical science was based originally on the idea that tissues and diseases were pretty much the same in everybody.  Technological advances have allowed us to subclassify breast and other cancers based on molecular markers on the tumor.  For breast cancer, these markers are the estrogen receptor (ER), progesterone receptor (PR), and HER2. Grouping tumors by these markers is what drives treatment decisions. More recently, new technologies that allow for molecular mapping within tumors have revealed that tumors are quite heterogeneous, or having different subtypes within it and with different cells carrying different mutations. This suggests that individual tumors are a lot more complicated than we had initially thought. Several recent papers have highlighted this observation and are sending everyone back to the drawing board.

The Komen Tissue Bank at the IU Simon Cancer Center, in Indianapolis, Indiana, is a fantastic resource that collects core biopsies of normal breast tissue from healthy volunteers for researchers to study.  Studies that used biopsies from the Komen Tissue Bank were the first to indicate that tissue from reduction mammoplasties might have been easily available for research studies, but the tissue was not normal!

Nowwe’ve learned even more. A paper published online in August in Scientific Reports, by researchers from the University of Indiana, used tissue collected by the Komen Tissue Bank to study antibodies and flow cytometry in cells from seven healthy donors. They found that there was considerable variation between individuals and within breasts of these women. This means there is no “normal.” We, or at least our breasts, are unique and varied. This calls into question findings from studies that used tumor tissue and “adjacent normal” tissue to identify cancer mutations. Given the variations we now know exist in normal tissue, it is possible the differences these studies identified were actually the normal variation in that woman’s breast, rather than a malignant pattern.

The study also identified differences between the normal breast tissue taken from African-American women and that taken from white women. The African-American women had more stem cells than luminal duct cells, which may explain differences in susceptibility to breast cancer. This could be the hint we have been looking for to explain the greater incidence of triple negative breast cancer in women of African-American ancestry.

Researchers also are looking at whether cancers and the cells they shed into the blood stream are all the same or also diverse. A paper by Nicholas Navin published in July in Science Translational Medicine describes findings from his research that used a new technology to genomically categorize individual cancer cells. The single-cell sequencing technology showed cancer cells taken from triple negative breast cancer patients had an average of 13 times the mutation rates of normal breast cells, but those taken from ER+ patients did not.

This research also showed that each tumor contained hundreds of ultra-rare mutations at frequencies less than one percent! In addition, some types of mutations, called copy number changes, occurred early and in bursts whereas point mutations were acquired gradually over time.  What really surprised me was that no two cancer cells within the tumor were identical! This leads to amazing genomic diversity.

Another question we still need to answer is when the first metastatic cell leaves the primary tumor. Is it early, so that the metastasis also have the opportunity to evolve? Is it late, so that the metastases are similar to the primary tumor? Or both?

study from researchers in Denmark, published in Oncotarget in January 2015, gives us some insight into this process. The researchers followed one woman with ductal carcionoma in situ (DCIS) that progressed to an invasive cancer and then metastatic disease. In this case there was evidence for what they call the “linear progression model”— the idea that malignant cells pass through several rounds of mutations before they successfully result in a metastatic lesion. This led the researchers to postulate that metastases are seeded by the most advanced and aggressive clone of the cells that dominate the primary tumor. Of course, this was only one woman, and more research will be needed on other women to determine if this indeed correct.

I guess it should not surprise us that cancers are diverse and unique. But it does suggest that precision medicine focused on eradicating just one type of cell may not be as successful on its own as we had hoped. This takes me back to my favorite theme:  The need to change the neighborhood with hormonal therapies and/or Her2-neu blockade as well as the need to unleash the immune system to really control this disease.