Practice Update: Oncology

CONFERENCE COVERAGE 24

MicroRNAs Are Identified as Possible Biomarkers of Outcome With Bevacizumab inMetastatic Breast Cancer Two microRNA profile studies have identified MicroRNAs as possible biomarkers of outcome with bevacizumab in metastatic breast cancer. These results were reported at the European Society for Medical Oncology (ESMO) 2017 Congress, from September 8–12. S imon Peter Gampenrieder, MD, of Par- acelsus University, Salzburg, Austria, explained in a written release that

groups who experienced extreme progres- sion-free survival (2.48 ± 1.85 vs 35.43 ± 8.03 months) were selected for analysis of microRNA. The following three microRNAs were used as controls: • MicroRNA U6 • MicroRNA 191-5p • MicroRNA 103-a-3p For model construction, microRNAs were selected by differential expression between the two groups. MicroRNAs were selected as candidates for profile generation in the 49 additional cases, and a combination of the following five was able to discriminate two groups with regard to progression-free survival: The stepwise-based Akaike criterion was used for profile generation. Additionally, integrative microRNA and messenger RNA analyses were performed to reveal mark- ers and pathways with potential clinical impact. Expression profiles of microRNAs in both groups were highly correlated, except for 14 microRNAs in which statistical differ- ences arose. Additionally, Kyoto Encyclopedia of Genes and Genomes analyses of microRNA target genes revealed interesting pathways, such as cellular adhesion, to explore in these patients. According to Dr. Mendiola, her team was able to identify candidate markers of out- come for bevacizumab-containing therapy by combining computational biology and experimental approaches. The five microRNAs cited above and cellular adhesion-related genes should be explored as potential biomarkers of outcome with bevacizumab-containing therapy for metastatic breast cancer. • MicroRNA 362-3p • MicroRNA 150b-5p • MicroRNA 671-3p • MicroRNA 744-3p • MicroRNA 941

clinical and pathological information. MicroRNAs significantly associated with progression-free survival were further val- idated in 203 patients treated within the TANIA phase III trial. Samples were cate- gorized as chemotherapy + bevacizumab and chemotherapy alone for two consec- utive treatment lines in patients pretreated with first-line bevacizumab. Low expression of the following five microRNAs was significantly associated with longer progression-free survival in

microRNAs are involved in regulation of angiogenesis and the development of treatment resistance and could provide predictive information. Marta Mendiola, PhD, of the Hospital Uni- versitario La Paz, Madrid, Spain, noted in a written release that microRNAs have emerged as regulators of most cancer cell processes. They form tight, intercon- nected feedback loops with genes under their regulation.

the study group: • MicroRNA 9-5p • MicroRNA 20a-5p • MicroRNA 21-5p • MicroRNA 210-3p • MicroRNA 224-5p

The five microRNAs cited above and cellular adhesion-related genes should be explored as potential biomarkers of outcome with bevacizumab-containing therapy for metastatic breast cancer.

For microRNAs 20a-5p (P = .0035) and 21-5p (P = .004), the association remained significant in multivariate analysis. In the control set, no correlation between expression of the five microRNAs and pro- gression-free survival was seen. In tumor samples from the TANIA trial, low expression of microRNA 20a-5p was also significantly associated with longer sec- ond-line progression-free survival and longer overall survival in the bevacizumab arm (hazard ratio 0.60, 95% confidence interval 0.37–0.89; P = .012 and hazard ratio 0.54; 95% confidence interval 0.32–0.83, P = .007, respectively). The association was not seen in the chemotherapy-only arm (hazard ratio 0.73, 95% confidence interval 0.48–1.09; and hazard ratio 1.01, 95% confidence interval 0.63–1.62, respectively). For microRNA 21-5p, no significant asso- ciation with progression-free or overall survival was observed in either treatment arm. Dr. Gampenrieder noted that the expres- sion of microRNA 20a-5p in breast cancer tissue may provide predictive value for identifying patients who experience greater benefit from bevacizumab-con- taining therapy. Dr. Mendiola and colleagues recorded clin- ical data from 57 patients with metastatic breast cancer and selected two (4 + 4)

She added that bevacizumab-containing therapy improves progression-free survival in human epidermal growth factor receptor 2-negative metastatic breast cancer, but its use has been questioned due to the lack of benefit in overall survival. According to Dr. Gampenrieder, biomarkers predictive of response to bevacizum- ab-containing therapy in metastatic breast cancer are urgently needed. Dr. Gampenrieder profiled 754 microRNAs in tumor samples from 58 patients with metastatic breast cancer who received bevacizumab-containing first-line treatment (study group). Based on median progres- sion-free survival, patients were divided into responders and nonresponders. Differentially expressed microRNAs between responders and nonresponders were selected and validated in a cohort of 57 patients treated with first-line chemo- therapy without bevacizumab (control group) to exclude microRNAs that pro- vided prognostic information only. In the study group, multivariate analysis included

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PRACTICEUPDATE ONCOLOGY