Drew Moss

New paper from the @TheGutOncLab , led by @NorthwellHealth resident Lingzhi Liu. We usually define EOCRC as CRC diagnosed before 50. 28? 48? Same bucket. Biologically, that always made me scratch my head. We looked at the molecular background and outcomes of ~7000 patients with Colorectal Cancer (thanks cBioPortal and Project Genie!) and, rather than simply comparing <50 vs ≥50, broke patients down by decade: 18–29 30–39 40–49 ≥50 Trends are clearer, biology a little more obvious. 🧬 APC mutations were ~50% more common in patients ≥50 than in those under 30. That signals clear biological difference in these groups. APC/WNT is basically the canonical starting point we teach for colorectal tumorigenesis. Yet in our youngest patients, half of cancers didn't have an APC mutation at all. 🔀 SMAD4 (as scary or worse than TP53 IMO) went the opposite direction. SMAD4 mutations were roughly 2x as common in our youngest patients compared with older patients. That points toward greater disruption of TGF-β signaling in very young CRC, a pathway associated with metastatic behavior, treatment resistance, and aggressive biology. And then perhaps the most clinically interesting finding: 🔥 POLE alterations were nearly 2x as common in patients under 40 as in those over 40. These can be extraordinarily immunogenic tumors, including MSS CRCs (that wouldn't be picked up by IHC alone). In a 2024 series of POLE/POLD1 proofreading-deficient mCRC, ICI produced an 89% ORR. For context: dMMR/MSI-H was 54%. 🤯 We also saw enrichment of several chromatin-remodeling genes, while KRAS and TP53 were basically unchanged with age. So where does this fit? Prior studies have told us that EOCRC looks different. This data add another piece: Maybe the arbitrary age-50 line that works for epidemiology doesn't work nearly as well for biology. And clinically, this is another reason I think broad NGS matters in young patients with CRC. 🔬 Don't assume their cancer simply got the usual CRC playbook 30 years early. It may have taken a very different road to get there. Great work by Lingzhi Liu and the whole team, including @TimothyJBrownMD @UGrewalMD. @Onco_Nexus @OncoAlert @OncoDailyGI @ESMO_Open sciencedirect.com/science/ar…

Had the chance to give the colorectal cancer update at Best of ASCO Los Angeles. Always fun to summarize a year of CRC data in ~20 minutes while pretending that is a normal thing to ask of a human being. 4 takeaways (without getting into some of the really exciting drugs that are coming to CRC soon): 🔹 MSI-H CRC in complete clinical response on PD-1 Stopping at confirmed cCR looks safe. Maintenance may add toxicity without clear benefit. 🔹 BRAF V600E MSS mCRC Encorafenib + cetuximab + chemotherapy is now a 1L standard. FOLFIRI is a great option, and FOLFOX is reasonable too. Either way, the targeted therapy backbone is here. 🔹 ctDNA / MRD Not fully in NCCN yet, but increasingly actionable. I escalate select stage II patients, use it to frame de-escalation discussions, and strongly favor trials when possible. 🔹 Exercise Prescribe it like we prescribe oxaliplatin. 30 min, 3x/week, ~80% max HR improves DFS/OS and is cost-saving. CRC is moving fast. The challenge now is not just knowing the data, but figuring out how to apply it thoughtfully in clinic. Grateful to be part of the conversation. @TheGutOncLab @Onco_Nexus @OncoAlert @TotalHealthConf