Scientists report on the identification of two gene-expression profiles that can predict how well breast tumors respond to specific types of chemotherapy, independent of standard variables such as age, tumor grade, and estrogen receptor status. The signatures are based on expression of either the DNA topoisomerase TOP2A, or β-tubulin, which are the targets of anthracycline and taxane drugs, respectively.
Notably, the indices reported by the McMaster University and Juravinski Hospital and Cancer Center researchers were found to be drug-specific; the TOP2A index couldn’t predict response to docetaxel therapy, for example. And unlike other expression profiles the TOP2A and β-tubulin signatures don’t just represent measures of cell proliferation, and are more accurate than proliferation-based expression profiles, claim Robin M. Hallett, M.D., and colleagues. They report the findings in BioMed Central, in a paper titled “A target based approach identifies genomic predictors of breast cancer patient response to chemotherapy.”
The McMaster team’s approach was essentially to look at the co-expression of genes whose transcripts encode the protein targets of the chemotherapy drugs anthracycline and taxane. “We hypothesized that such target-based expression indices would provide a biologically comprehensive measurement of either TOP2A or β-tubulin activity in a patient’s tumor, and thus its likely dependence on either of these targets,” they write.
The researchers initially looked at the expression of just β-tubulin and TOP2A in cohorts of patients treated using a neoadjuvant chemotherapy regime containing a taxane, or an anthracycline, respectively. This confirmed that TOP2A transcript levels were increased in patients who had achieved a complete pathological response (pCR) to anthracycline therapy, while β-tubulin expression was similarly increased in patients who responded to treatment with the taxane docetaxel.
In the next stage the investigators used three independent, publicly available datasets to identify genes whose expression was most significantly either positively or negatively correlated with the expression of TOP2A transcripts. This identified 124 TOP2A associated probe sets, 86 that displayed positive association to TOP2A transcripts and 34 that were negatively associated with TOP2A transcripts. They found that this expression index was significantly associated with pCR in a cohort of 278-breast cancer patients treated using an anthracycline in a neoadjuvant setting. Interestingly, the authors note, there was minimal overlap between the TOP2A signature and genes represented in DLDA30, a validated gene expression-based predictor of response to taxanes, anthracyclines, 5-fluorouracil, and cyclophosphamide.
The researchers then carried out a similar set of analyses to identify an expression index of β-tubulin-associated transcripts that could be used to predict complete response to taxane therapy. This picked up 42 β-tubulin transcript-associated probe sets, 28 that displayed positive association with β-tubulin transcripts and 14 that were negatively associated with β-tubulin transcript levels. The resulting signature was again validated as predictive of pCR in a cohort of patients treated with neoadjuvant doectaxel. In this case, there was no overlap at all between probe sets in the β-tubulin index and those within DLDA30.
Neoadjuvant chemotherapy often involves administering multiple chemotherapeutic agents, so the team next investigated whether the TOP2A and β-tubulin target indices could be combined to predict response to treatment using either just an anthracycline, or anthracycline plus taxane. The results confirmed that the combined indices accurately identified patients who achieved a pCR both to combined therapy, but also, interestingly, to just anthracycline therapy. In fact, the combined TOP2A and β-tubulin index was nominally more accurate than the TOP2A index alone at predicting response to just anthracycline therapy.
Notably, the predictive power of the TOP2A and β-tubulin indices didn’t appear to relate to simply a measure of proliferation. The TOP2A index was of no predictive value in predicting chemotherapy response among a cohort of patients treated using just docetaxal. “These results suggest that the predictive capacity of the TOP2A index is based on measurement of target rather than proliferation,” the authors note. And when they used their original methodology to generate a proliferation index around the well-characterized proliferation gene E2F1, the resulting predictive index was not as accurate as either the TOP2A and β-tubulin predictors.
In a final analysis, the McMaster team demonstrated that the TOP2A/β-tubulin combination index score was related to patient resonse to chemotherapy even after adjusting for standard clinical-pathological variables including age, estrogen receptor status, tumor grade, and nodal status.
The authors admit that as their findings are based on analyses of retrospective data, a prospective clinical trial will be required to demonstrate the true utility of the TOP2A and β-tubuline indices. Nevertheless, they point out, “these findings suggest the practicality of developing and testing target based indices that predict response to therapeutics...For example, it might be possible to generate a target-based expression index for additional molecular targets, such as the HER2/Neu receptor tyrosine kinase, which is the molecular target of the humanized monoclonal antibody trastuzumab, as well as the small molecule Her2/Neu kinase inhibitor, lapatinib.”