Tumor Microenvironment Diversity Predicts Breast Cancer Outcomes

Intratumor heterogeneity, it is known, can complicate cancer treatments. Now it appears the same may be true of tumor microenvironment heterogeneity. According to a new study from the Institute of Cancer Research (ICR), London, breast cancers that develop within an “ecologically diverse” breast cancer microenvironment are particularly likely to progress and lead to death.

The study took an unusual approach: It combined ecological scoring methods with genome-wide profiling data. Besides showing clinical utility in evaluating breast cancer outcomes, this approach demonstrated that even so contextual, a discipline such as genomics can benefit from being placed within a larger context. In this case, the context is essentially Darwinian, albeit on a small scale.

Natural selection is typically studied at the ecosystem level of animals and plants. In the current study, however, it was assessed at the level of the tumor microenvironment, which consists of cancer cells, immune system lymphocytes, and stromal cells.

The ICR scientists, led by Yinyin Yuan, Ph.D., presented their work on February 16 in the journal PLoS Medicine in an article entitled “Microenvironmental Heterogeneity Parallels Breast Cancer Progression: A Histology–Genomic Integration Analysis.” The article describes how the scientists developed a tumor ecosystem diversity index (EDI), a scoring system that indicates the degree of microenvironmental heterogeneity along three spatial dimensions in solid tumors. EDI scores account for “fully automated histology image analysis coupled with statistical measures commonly used in ecology.”

“[EDI] was compared with disease-specific survival, key mutations, genome-wide copy number, and expression profiling data in a retrospective study of 510 breast cancer patients as a test set and 516 breast cancer patients as an independent validation set,” wrote the authors. “In high-grade (grade 3) breast cancers, we uncovered a striking link between high microenvironmental heterogeneity measured by EDI and a poor prognosis that cannot be explained by tumor size, genomics, or other data types.”

By using the EDI, the ICR team was able to identify several particularly aggressive subgroups of breast cancer. The EDI was a stronger predictor of survival than many established markers for the disease.

The ICR researchers also looked at the EDI in addition to genetic factors. For example, the researchers found that the predictive value of EDI was enhanced with the addition of TP53 mutation status. By integrating EDI data and genome-wide profiling data, the researchers identified losses of specific genes on 4p14 and 5q13 that were enriched in grade 3 tumors. These tumors, which showed high microenvironmental diversity, sub stratified patients into poor prognostic groups.

“Our findings show that mathematical models of ecological diversity can spot more aggressive cancers,” said Dr. Yuan. “By analyzing images of the environment around a tumor based on Darwinian natural selection principles, we can predict survival in some breast cancer types even more effective than many of the measures used now in the clinic.

“In the future, we hope that by combining cell diversity scores with other factors that influence cancer survival, such as genetics and tumor size, we will be able to tell apart patients with more or less aggressive disease so we can identify those who might need different types of treatment.”

“This ingenious study…teaches us a valuable lesson,” added Paul Workman, Ph.D., chief executive of the ICR. “[We] should always remember that cancer cells are not developing and growing in isolation, but are part of a complex ecosystem that involves normal human cells, too. By better understanding these ecosystems, we aim to create new ways to diagnose, monitor and treat cancer.”