Quantifying heterogeneity in breast cancer

A variety of mutations may give rise to breast cancer, but scientists generally assume that it starts off with just a few. That is because later-stage breast cancers tend to have more mutations and are more heterogeneous than early-stage cancers. Now, new findings demonstrate that heterogeneity is prevalent even within legions of ductal carcinoma in situ (DCIS), the most common, earliest stage non-invasive breast cancer (stage 0). The results, which were presented at the American Association for Cancer Research Annual Meeting 2013 in Washington, DC, suggest that a multiple-target approach to diagnosis and therapy may be needed to fight breast cancer from the very start.

"The pathologists recognize this intrapatient heterogeneity exists," said study author Xiaowei Chen, PhD, assistant professor at Fox Chase Cancer Center in Philadelphia, Pennsylvania, "but it is a challenge in the clinical setting" because pathologists have to decide on a case-by-case basis how many DCIS legions to review in order to get a complete picture of each patient's disease. "In the clinical setting, they basically only evaluate one nodule, one part of the tumor," said Chen, and so may miss heterogeneity in other legions.

During the study, Chen's team randomly selected ten DCIS legions from 38 breast cancer cases in which patients were concurrently diagnosed with DCIS and invasive ductal carcinoma (IDC). They then scored the heterogeneity of each patient's DCIS legions using standard immunohistochemistry (IHC) techniques. More than 70% of cases had heterogeneous expression in at least two of the six IHC markers for breast cancer. Chen explained that these results account for why tamoxifen, for example, which targets only one mechanism of cancer's growth, may not be sufficient for some patients: "Treating a cancer with one drug can shrink the tumor," said Chen, "but after a couple of months it may come back" because another subtype of cancer cell, already present, takes over. Chen admitted that examining every legion of every patient is not practical. But quantifying how common heterogeneity is among DCIS legions raises awareness for clinicians and researchers alike.

"Within the research community, we'll need more carefully designed experiments" to avoid relying on tissue microarrays, said Chen. Tissue microarrays are a standard technique used in preparing tumor samples for analysis, but growing evidence shows the technique contributes to conflicting results about heterogeneity when compared to the type of thorough legion analysis done as part of this study.

More research will be needed to determine whether DCIS homogeneity contributes to IDC development since the patients in this study were concurrently diagnosed with both types of cancer. Still, Chen noted that those patients exhibiting more DCIS heterogeneity were more likely to have lymph nodal involvement, an indicator of cancer's spread.

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