Editors' ChoiceCancer

Why location is (still) everything

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Science Translational Medicine  29 Jul 2015:
Vol. 7, Issue 298, pp. 298ec128
DOI: 10.1126/scitranslmed.aac9739

With the increasing use of drugs and antibodies designed to counter the influence of specific genetic drivers in colorectal cancer (CRC), understanding the molecular events underlying tumor site/subsite-related biological differences will likely guide risk assessment and prognosis, as well as tailor personalized therapeutic strategies. Mortality rates have consistently been reported to be higher in proximal compared with distal colon cancers, but previous studies examining tumor site and prognosis generally lacked data on key molecular markers that may explain this difference in survival.

Sinicrope et al. determined the frequency of BRAFV600E and KRAS (exon 2) mutations, as well as DNA mismatch repair (MMR) status, in tumors of patients with stage III CRC (N=3,018) treated in a large adjuvant chemotherapy trial and examined the association of these molecular markers with primary tumor subsite and clinical outcome. Proximal cancers had higher mutation rates even after excluding MMR-deficient (dMMR) tumors, with more KRAS codon 12 and BRAFV600E mutations, whereas cancers lacking mutations in either gene were more likely to be located in the distal colon. As expected, in the overall patient cohort, survival was found to be improved in patients with distal versus proximal cancers. Mutations in KRAS and BRAFV600E were each associated with worse clinical outcomes, whereas dMMR was associated with a delay in time to disease relapse. Interestingly, distal cancers with mutated KRAS had poorer outcomes compared with proximal cancers carrying the mutation, and the same was true for dMMR tumors for which the improved outcome was limited to proximal tumors.

Identification of molecular alterations by tumor subsite can help place these data into clinical context, with implications for personalized therapy. Tumors of similar types but different anatomic locations can have patterns of mutations that are strikingly different, and it is becoming apparent that these molecular signatures may predict response to targeted therapies as well as to immune checkpoint inhibitors. For this reason, it is likely that successful interpretation of cancer genomes will require comprehensive knowledge of the biological context to make successful therapeutic predictions in the clinic.

F. A. Sinicrope et al., Analysis of molecular markers by anatomic tumor site in stage III colon carcinomas from adjuvant chemotherapy trial NCCTG N0147 (Alliance). Clin. Cancer Res. 10.1158/1078-0432.CCR-15-0527 (2015). [Abstract]

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