Patients with high-grade breast cancers that have a diverse and complex microenvironment are likely to have a worse prognosis than patients with tumors that have a less heterogeneous ecosystem, UK researchers have discovered.
Borrowing techniques used by ecologists to analyze the diversity of ecologies in the natural world, the team found that for patients with breast cancer tumors that had a particularly diverse mix of cells, 10-year survival was substantially reduced.
The impact of this cellular diversity was magnified in large tumors and those with genetic mutations associated with a poor outcome, suggesting that the technique could be combined with established tests to identify women most at risk.
"We have known for a while that genetic diversity between cancer cells in tumors is associated with more aggressive disease, and our new results also show that diversity of cells within the tumor microenvironment also contributes to aggressive breast cancer," lead author Rachael Natrajan, PhD, team leader in the Breast Cancer Now Toby Robins Research Centre at the Institute of Cancer Research, London, said in a press statement.
"Integration of our new measure with genetic alterations can actually provide additional prognostic information from just genetics alone and may pave the way for a new wave of diagnostic biomarkers," she added.
The study was published online February 16 in PLOS Medicine.
It "teaches us a valuable lesson," commented Paul Workman, PhD, chief executive of the Institute of Cancer Research, London. "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," he added.
Tools Borrowed From Ecology
To investigate the complexity of breast cancer tumors, the researchers developed the tumor ecosystem diversity index (EDI), a quantitative measure of three-dimensional microenvironmental heterogeneity that couples automated histology image analysis with the sorts of statistical tools used in ecology.
The analysis focused on the diversity and spatial variability of cancer cells, immune system lymphocytes, and stromal cells in a retrospective analysis of tumors from 510 untreated, primary breast cancer patients who took part in the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) study.
To examine the utility of the EDI, the findings were compared with disease-specific survival and known genetic mutations, as well as genome-wide copy number and expression profiling data.
Information on a further 516 breast cancer patients from the METABRIC study was then used as a validation set. For both sets of patients, top, middle, and bottom sections were taken from the single frozen tumor aliquot to represent the morphologic profile of the tumor.
In the test cohort, grade 3 breast cancer tumors with the highest EDI score of 5 were associated with significantly increased risk for worse disease-specific survival than the remaining tumors, at a hazard ratio of 2.01 (P = .0026). This was confirmed in the validation cohort, among which the hazard ratio was 2.24 (P = .025).
Combining the two cohorts indicated that the group with a high EDI score accounted for 17.3% of grade 3 tumors, which were associated with a 10-year disease-specific survival of 51% vs 70% for other grade 3 cancer patients (P < .001).
EDI score was not associated with prognosis in low grade 1 and 2 tumors.
Multivariate analysis that took into account lymph node status, tumor size, and estrogen receptor status demonstrated that EDI score was an independent predictor of survival in grade 3 breast cancer patients, at hazard ratios of 1.74 in the test cohort (P = .019) and 2.27 in the validation cohort (P = .029).
Moreover, patients with a tumor measuring greater than 5 cm and that had a high EDI score were found to have a 5-year survival probability of 16%, compared with 50% for patients with large tumors that had a low EDI score.
The prognostic value of EDI was increased further by adding in TP53 mutation status. Patients with grade 3 tumors that had a high EDI score and TP53 mutation had a 10-year survival of 35%. This was significantly worse than for other patients with grade 3 tumors.
Adding in loss of specific genes on chromosomal regions 4q14 and 5q13 to EDI score also differentiated patients with grade 3 tumors into poor prognostic groups, independently of lymph node status and tumor size.
Needs Validation in Larger Cohorts
Yinyin Yuan, PhD, team leader in the Centre for Evolution and Cancer at the Institute of Cancer Research, London, commented that although the findings are exciting, they currently remain a "scientific discovery."
She told Medscape Medical News: "We still need to validate this in large-scale patient cohorts to be absolutely confident that this can go to the clinic.
"Basically, what we're thinking now is that this is giving us new knowledge about how tumors progress. So, on top of what we already know about breast cancer, it will allow us to devise a more accurate picture of the outcome of breast cancer."
Dr Yuan explained that although it is was known that heterogeneous cancer cells are "bad news," owing to their variable response to treatment, this is the first time that it has been shown that the "heterogeneity of the environment also could be of importance."
She added: "If you just think about, for example, the Galapagos Islands, the diverse environment created diverse species, so the environment can actually drive the development of an ecosystem.
"We thought this probably could be happening in cancer, but this is the first time that we were able to show it with real data, real measurements in human tumors."
Although further studies would be required, Dr Yuan hopes that the findings can eventually be used to develop novel treatments for breast cancer.
She said: "A possibility is that we can target the type of environment instead of the cancer itself, and one of the advantages is that this is not going to be cytotoxic therapy, so it would have less toxicity than the current treatments."
The study was funded by the Institute of Cancer Research, Breast Cancer Now, the Wellcome Trust, and Cancer Research UK. The authors have received support from the Royal Marsden NIHR Biomedical Research Centre.
PLoS Med. Published online February 16, 2016. Full text
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