Abstract
Cancer treatment is increasingly focused on targeting molecular alterations identified
across different tumor histologies. While some oncogenic drivers such as microsatellite
instability (MSI) and NTRK fusions are actionable with the very same approach regardless of tumor type (“histology-agnostic”),
others require histology-specific therapeutic adjustment (“histology-tuned”) by means
of adopting specific inhibitors and ad hoc combinations.
Among histology-agnostic therapies, pembrolizumab or dostarlimab demonstrated comparable
activity in MSI metastatic colorectal cancer (mCRC) as in other tumors with MSI status
(ORR 38% vs 40% and 36% vs 39%, respectively), while entrectinib or larotrectinib
proved effective in NTRK rearranged mCRC even though less dramatically than in the overall population (ORR
20% vs 57%, and 50% vs 78%, respectively). Histology-tuned approaches in mCRC are
those targeting BRAFV600E mutations and ERBB2 amplification, highlighting the need of simultaneous anti-EGFR blockade or careful
choice of companion inhibitors in this tumor type. Anti-RET and anti-ALK therapies
emerged as a potential histology-agnostic indications, while anti-KRASG12C strategies could develop as future histology-tuned therapies. Targeting of ERBB2 mutations and NRG1 fusion provided discrepant results. In conclusion, agnostic targets such as MSI and
NTRK fusions are already exploitable in mCRC, while the plethora of emerging histology-tuned
targets represent a challenging opportunity requiring concurrent evolution of molecular
diagnostic tools.
Keywords
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Article info
Publication history
Published online: June 11, 2022
Accepted:
May 26,
2022
Received:
March 20,
2022
Identification
Copyright
© 2022 Published by Elsevier Ltd on behalf of Editrice Gastroenterologica Italiana S.r.l.
