Practice Update: Oncology

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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.
Simon Peter Gampenrieder, MD, of Par-
acelsus University, Salzburg, Austria,
explained in a written release that
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.
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
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
the study group:
• MicroRNA 9-5p
• MicroRNA 20a-5p
• MicroRNA 21-5p
• MicroRNA 210-3p
• MicroRNA 224-5p
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)
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:
• MicroRNA 362-3p
• MicroRNA 150b-5p
• MicroRNA 671-3p
• MicroRNA 744-3p
• MicroRNA 941
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.
PracticeUpdate Editorial Team
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.
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