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Post-Neoadjuvant Profiling Approach IDs Breast Cancer Chemo Resistance Mechanism, Suggests Potential Drug Target

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Researchers from Vanderbilt University have profiled the gene expression of tumors that linger after neoadjuvant chemotherapy, finding that the transcript DUSP4 is highly associated with post-treatment proliferation and shorter recurrence-free survival.

DUSP4, while not directly actionable, is associated with pathway activity that could potentially be targeted with MEK inhibitors, the group reported in a paper in Nature Medicine last week.

The researchers suggested that the post-adjuvant profiling approach could be used to identify additional markers of chemotherapy resistance that could be targeted by available drugs to eliminate drug-resistant subpopulations of breast cancer cells.

Carlos Arteaga, a Vanderbilt oncologist and senior author of the paper told PGx Reporter this week that the team plans to take the same approach, now using next-generation sequencing, to identify targetable oncogenes that may be associated with chemotherapy resistance.

Arteaga said that the main point of the group's paper, and what has driven them to continue in this vein, is the potential of post-treatment analysis to guide targeted treatment in chemo-resistant cancers.

"People usually look at the pretreatment," he said. "But when we look at the post treatment you are already looking just at the drug-resistant disease … The ones that were sensitive are gone – they don't make it into the analysis.

In the study, Arteaga and his colleagues used technology from NanoString to profile the gene expression in 49 formalin-fixed paraffin-embedded tissue samples from breast cancers removed after neoadjuvant chemotherapy. The group created a priority list of transcripts culled from the literature, ending up with a set of 355 unique targets.

The group used Ki-67 immunohistochemistry scores, which correlate with long-term outcome, as a surrogate endpoint. After profiling the 49 tumor samples, the researchers found that low expression of DUSP4 has the strongest correlation with Ki-67 score, as well as with the basal-like tumor subtype.

To confirm this, the group examined DUSP4 expression in a second cohort of 89 triple-negative breast cancers sampled after neoadjuvant therapy, finding the association with Ki-67 to again be strong.

Further pathway analysis and experiments with mouse xenografts confirmed for the researchers that DUSP4 is associated with ras-ERK signaling. The group also found that DUSP4 loss has a chemoprotective effect on breast cancer cells.

The group reported in the paper that overall data from these in vitro studies and a review of DUSP4 expression in other published cohorts suggest that DUSP4 deficiency has a causal relationship with poor response to anti-cancer chemotherapy.

Because of its pathway associations, the group next sought to measure whether low expression of DUSP4 might be a marker for response to MEK inhibitor therapies. In cell lines, the researchers found that DUSP4 mRNA expression correlated inversely with sensitivity to MEK inhibitors CI-1040 and U0126.

The group then tested mouse xenografts, randomizing them to treatment with AZD6244 (selumetinib) or the chemotherapy drug docetaxel or both. They found that selumetinib alone arrested growth of the xenografts cancer, while the combination treatment arm showed "marked tumor regression."

Arteaga said that DUSP4 wasn't the only transcript that showed an association in the initial profiling, but that it was the best candidate for the group to follow through on.

With the full in vitro data, he said, the researchers were able to convince reviewers "and ourselves that this was really a marker of drug resistance that should be explored in trials of chemotherapy and MEK inhibitors in tumors that have low DUSP4."

Arteaga said that the researchers are pursuing such trials. They hope to follow future combined chemotherapy and MEK inhibitor trials, picking out those patients with low DUSP4 to see if they show a better response.

In the paper, the authors wrote that they predict "DUSP4 expression … is a testable biomarker for sensitivity to MEK inhibitors in patients with [basal-like breast cancer]."

"We don't know whether those trials should be limited to patients with low DUSP4 – but we will look in tissues of patients enrolled in those trials to see whether low DUSP4 correlates with benefit of MEK inhibitors with chemotherapy," he said.

The team is also interested in extending its post-neoadjuvant profiling approach to identify more immediately actionable targets than DUSP4 loss.

Arteaga said the researchers are planning a study to look at 250 oncogenes and tumor suppressors — many of which are associated with drugs in clinical development or already-approved therapies — using next-generation sequencing in post-disease mastectomy specimens.

According to Arteaga, results from the gene expression study seem to suggest that profiling tumor tissue after adjuvant chemotherapy can pick out markers specific to the subpopulations of tumor cells that linger in either the primary tumor site, or in metastases, which would not be identified in tumor biopsy samples before therapy.

However, he said, the data so far is limited, and the group needs "better demonstration that if these patients recur, those recurrences will look more like this residual disease than like the initial biopsy."

He said the team is working to better demonstrate this in further studies. "That would imply that information from that surgical specimen could dictate clinical conduct," he said.

"Right now patients are just watched," he said. "But that's not okay if there is something that predicts a very quick recurrence and for which there is a drug available."

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