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Page 10 of 25 Battaglin et al. J Cancer Metastasis Treat 2018;4:12 I http://dx.doi.org/10.20517/2394-4722.2018.04

xeno-patients demonstrated a significant tumor regression after combined treatment with HER2 and EGFR
blockade . These results were subsequently challenged in an Italian phase II clinical trial, the HERACLES
[131]
study. More than 1000 mCRC cases were analysed in order to identify strict criteria for the definition of
HER2 amplification in the dedicated HERACLES diagnostic. Afterwards, the activity of an HER2 double
[132]
blockade with trastuzumab and lapatinib was evaluated in chemorefractory mCRC patients with HER2-
positive tumors. Initial results of the study have been published, showing a 30% objective response rate (95%
CI, 14-50), with one patient achieving a complete response, and a 44% stable disease rate (95% CI, 25-63) .
[133]
Of note, none of the 15 patients (56%) evaluable for response to anti-EGFRs achieved an objective response
to previous treatment with either cetuximab or panitumumab, supporting the role of HER2 amplification
as a mechanism of primary resistance to anti-EGFR targeted agents. Moving from such promising results, a
second cohort of the study has enrolled patients to treatment with a combination of trastuzumab-emtansine
(TDM1) and pertuzumab, and patients experiencing disease progression after treatment with trastuzumab
and lapatinib are receiving TDM1 monotherapy within the HERACLES Rescue trial. New results from these
studies are highly anticipated.

Confirmatory results on HER2 as a possible target in mCRC came also from the phase II MyPathway trial,
and retrospective series confirmed data on HER2 as a possible predictive biomarker of resistance to anti-
EGFRs . Additionally, HER2 amplification detected on tissue or on circulating tumor DNA (ctDNA)
[134]
was identified as a possible mechanism of acquired resistance in HER2 negative, RAS/BRAF WT, patients
progressed during anti-EGFR treatment . Of note, a randomized phase II trial, the S1613 study, has
[135]
been recently opened to explore the efficacy of trastuzumab and pertuzumab compared to cetuximab and
irinotecan in pre-treated anti-EGFR naïve mCRC patients carrying a tumor with HER2/neu amplification .
[136]
Supported by a strong preclinical rationale and confirmatory clinical data HER2 testing might be soon
implemented in clinical practice for patients with mCRC candidate to receive anti-EGFR and/or anti-HER2
treatments.

Anti-EGFR agents: other biomarkers of primary and acquired resistance
Alongside HER2 amplification, several other mechanisms of primary resistance to anti-EGFR targeted
treatment have been identified so far, including phosphatidylinositol-3-kinasecatalytic subunit alpha
(PIK3CA) mutations (exon 9 and 20 hotspot mutations), MET amplification, FGFR1 and PDGFRA mutations,
loss of PTEN function and low EGFR copy number . However, the routine use of these biomarkers in
[137]
clinical practice cannot be recommended at present, and further prospective validation of their predictive
role is warranted. Nevertheless, different combined strategies and novel targeted agents aimed to overcome
primary resistance to anti-EGFRs are currently under investigation, such as the combination of anti-
EGFR agents with mammalian target of rapamycin (mTOR) inhibitors [138] . Recently, a panel of genomic
alterations (the PRESSING panel) comprising activating mutations of the MAPKs or PI3K/AKT axis, HER-
2 amplification or mutations, MET amplification and NTRK/ROS1/ALK/RET rearrangements, have been
tested in an interesting retrospective case-control study aiming to dissect primary resistance to anti-EGFR
treatment, demonstrating the negative predictive impact of these mutations in RAS/BRAF WT mCRCs
treated with anti-EGFRs [139] . The study included 47 cases (patients resistant to anti-EGFR-containing
regimens) and 47 controls (patients who responded to single agent anti-EGFRs or to a combination of
irinotecan with anti-EGFRs if previously clearly irinotecan refractory). Aforementioned genomic
alterations were reported in 20 (42.6%) cases and 1 (2.1%) control (P < 0.001), meeting the primary endpoint
of the study. Additionally, primary tumor right-sidedness was found to be associated with resistance to
anti-EGFRs, confirming recent literature evidence, and the combined evaluation of PRESSING panel
and primary tumor location demonstrated the best predictive accuracy. These results open promising
perspectives on the clinical application of a more comprehensive molecular characterization of RAS/BRAF
WT mCRCs to further improve and refine patients selection.