Abstract
Mutations in
RAS
occur in 30–50% of metastatic
colorectal carcinomas (mCRCs) and correlate with resistance to anti-EGFR
therapy. Consequently, mCRC biomarker guidelines state
RAS
mutational testing should be performed when considering EGFR inhibitor
treatment. However, a small subset of mCRCs are reported to harbor
RAS
amplification. In order to elucidate the
clinicopathologic features and anti-EGFR treatment response associated with
RAS
amplification, we retrospectively reviewed a large
cohort of mCRC patients that underwent targeted next-generation sequencing and
copy number analysis for
KRAS
,
NRAS
,
HRAS
,
BRAF
and
PIK3CA
.
Molecular testing was performed on 1,286 consecutive mCRC from 1,271 patients as
part of routine clinical care, and results were correlated with
clinicopathologic findings, mismatch repair (MMR) status and follow-up.
RAS
amplification was detected in 22 (2%) mCRCs and
included:
KRAS
,
NRAS
and
HRAS
for 15, 5 and 2 cases, respectively (6 to 21 gene copies). Patients with a
KRAS
-amplified mCRC were more likely to report a history of
inflammatory bowel disease (p < 0.001). In contrast, mutations in
KRAS
were associated with older patient age, right-sided
colonic origin, low-grade differentiation, mucinous histology and MMR
proficiency (p ≤ 0.017). Four patients with a
KRAS
-amplified mCRC and no concomitant
RAS
/
BRAF
/
PIK3CA
mutations
received EGFR inhibitor-based therapy, and none demonstrated a
clinicoradiographic response. The therapeutic impact of
RAS
amplification was further evaluated using a separate, multi-institutional cohort
of 23 patients. Eight of 23 patients with
KRAS
-amplified mCRC
received anti-EGFR therapy and all 8 patients exhibited disease progression on
treatment. Although the number of
KRAS
-amplified mCRCs is
limited, our data suggests the clinicopathologic features associated with mCRC
harboring a
KRAS
amplification are distinct from those
associated with a
KRAS
mutation. However, both alterations seem
to confer EGFR inhibitor resistance and, therefore,
RAS
testing
to include copy number analyses may be of consideration in the treatment of
mCRC.
