CTC Gene Signature Score Could Guide Breast Cancer Treatment Decisions

A 17-gene signature derived from circulating tumor cells (CTCs) was found to correlate with response to therapy and various outcomes in patients with both localized and metastatic breast cancer, according to a new study. The CTC-derived signature could help inform therapy decisions.

“Despite … increasingly effective therapeutic choices, there are few biomarkers to guide initial therapy selection and identify early responses,” wrote study authors led by Shyamala Maheswaran, PhD, of the Massachusetts General Hospital Cancer Center in Boston. “As a result, treatment choices are frequently empiric, and delayed clinical ascertainment of tumor response limits the ability to rapidly define an effective regimen for an individual patient.” The new study was published in Cancer Discovery.

The researchers analyzed RNAseq and microarray gene expression datasets derived from normal breast tissue, breast cancer, and whole blood. From this analysis they selected 17 markers strongly expressed in breast-derived tissues but virtually absent in blood cells; the markers included genes such as MGP and EFHD1 that are highly expressed in breast cancer, as well as others such as SERPINA3 and WFDC2 that are implicated in endocrine signaling, and others including MUC16 and TMPRSS4 involved in cancer growth and metastasis.

After testing this gene signature in healthy donors and each of the 17 markers in various stages of breast cancer, they applied the newly developed CTC-Score first to a cohort of 54 women with localized breast cancer treated with neoadjuvant therapy. They found that an elevated CTC-Score after at least 3 cycles of neoadjuvant therapy was associated with a higher probability of residual disease at the time of surgical resection (area under the curve, 0.83; P = .047).

In a separate cohort of 87 women with metastatic breast cancer, the researchers compared CTC-Score before initiation of new therapy and after several weeks of treatment. They found that the baseline CTC-Score was significantly associated with overall survival: those with a high baseline CTC-Score had worse overall survival, with a hazard ratio of 2.70 (95% CI, 1.15–16.7; P = .02), when compared with those with a low score. The median overall survival for those with a high score was 11.1 months, compared with 17.2 months in patients with a low score. Overall survival was also better in those without ESR1 mutations, and in those who received CDK4/6 therapy.

Furthermore, patients who had low CTC-Scores at baseline that further decreased by more than 90% after 3–4 weeks of therapy had significantly better overall survival compared with those whose score did not decrease as much or those who started with a high pretreatment score (P = .001). “Together, these observations suggest that both pretreatment CTC burden, as well as the early treatment-induced changes in CTCs, are important prognostic factors in predicting patient outcome,” the authors wrote.

They also examined how the score could predict response in a subset of 36 patients with hormone receptor–positive disease beginning endocrine therapy. In patients with estrogen receptor–positive breast cancer, the persistence of a “resistance signature” involving 6 genes of the 17 in the full score after 3–4 weeks of treatment was associated with both shorter overall survival (P = .06) and faster time to progression (P = .008). This was consistent, the authors wrote, with inadequate suppression of estrogen receptor signaling.

“The application of ‘liquid biopsies’ to breast cancer therapeutics is rapidly evolving,” the authors wrote. “High throughput microfluidic enrichment of CTCs followed by multiplex digital RNA quantification may provide a novel and complementary strategy to monitor and guide therapy in both localized and advanced breast cancer.”