Leonard B. Saltz

Supplemental Table 3: Characteristics of patients with stage IV MMRd sporadic CRC from three academic Italian medical centers.

Supplemental Table 5: Clinical course and features of patients with stage IV MMRd sporadic CRC treated with kinase inhibitors.

Purpose:Mismatch repair–deficient (MMRd) colorectal cancers are classified based on MMR protein loss and BRAFV600E mutations. BRAF wild-type sporadic MMRd tumors exhibit a diverse landscape of alternative oncogenes, including gene fusions, with unclear biological and clinical significance. We evaluated mutually exclusive subtypes of sporadic MMRd tumors defined by oncogenic mitogen-activated protein kinase (MAPK) variants and gene fusions to determine the relationship among predominant genomic driver, MMR deficiency mechanism, and clinical outcomes.Experimental Design:We assessed 6,789 patients with colorectal cancer sequenced by MSK-IMPACT to identify 518 patients with sporadic MMRd colorectal cancer. We defined mutually exclusive oncogenic alteration subtypes and then assessed differences in allele-specific MMR-inactivating events, co-occurring oncogenic variants, and patient outcomes. We validated findings in an Italian cohort (n = 69).Results:We identify 4 sporadic MMRd colorectal cancer subtypes: (i) oncogenic fusion–positive, (ii) RAS-mutant (mut), (iii) BRAFV600E-mut, and (iv) MAPK/fusion driver–negative. These mutually exclusive subtypes were associated with conserved molecular lineages of MMR gene inactivation and WNT signaling variants. Oncogenic fusions were disproportionately prevalent in non-Caucasians, among nonsmokers, and in the transverse colon, compared with subtypes that were enriched in smokers (BRAF-mut) and male, younger patients (RAS-mut and MAPK/fusion-driverless). Oncogene-defined molecular lineages were strong predictors of patient outcomes and response to immunotherapy and tyrosine kinase inhibition for metastatic disease. Fusion-positive patients demonstrated improved survival compared with BRAF-mut cancers and benefited from immunotherapy and fusion inhibitors. MAPK/fusion driver–negative tumors were aneuploid, responded poorly to immunotherapy, and were sensitive to EGFR blockade.Conclusions:Overall, MAPK and fusion oncogenic drivers distinguish MMRd colorectal cancer molecular lineages that inform molecular and clinical phenotypes.

Supplemental Table 1: Patients with MMRd sporadic CRC defined by MAPK and fusion oncogenes.

Supplemental Figures with Legends.

Supplemental Table 4: Clinicopathologic features of patients with stage IV disease from the main MSK cohort treated with immune checkpoint blockade.

Supplemental Table 2: Patients with stage IV MMRd sporadic CRC from the main MSK cohort.

Purpose: Mismatch repair–deficient (MMRd) colorectal cancers are classified based on MMR protein loss and BRAFV600E mutations. BRAF wild-type sporadic MMRd tumors exhibit a diverse landscape of alternative oncogenes, including gene fusions, with unclear biological and clinical significance. We evaluated mutually exclusive subtypes of sporadic MMRd tumors defined by oncogenic mitogen-activated protein kinase (MAPK) variants and gene fusions to determine the relationship among predominant genomic driver, MMR deficiency mechanism, and clinical outcomes. Experimental Design: We assessed 6,789 patients with colorectal cancer sequenced by MSK-IMPACT to identify 518 patients with sporadic MMRd colorectal cancer. We defined mutually exclusive oncogenic alteration subtypes and then assessed differences in allele-specific MMR-inactivating events, co-occurring oncogenic variants, and patient outcomes. We validated findings in an Italian cohort (n = 69). Results: We identify 4 sporadic MMRd colorectal cancer subtypes: (i) oncogenic fusion–positive, (ii) RAS-mutant (mut), (iii) BRAFV600E-mut, and (iv) MAPK/fusion driver–negative. These mutually exclusive subtypes were associated with conserved molecular lineages of MMR gene inactivation and WNT signaling variants. Oncogenic fusions were disproportionately prevalent in non-Caucasians, among nonsmokers, and in the transverse colon, compared with subtypes that were enriched in smokers (BRAF-mut) and male, younger patients (RAS-mut and MAPK/fusion-driverless). Oncogene-defined molecular lineages were strong predictors of patient outcomes and response to immunotherapy and tyrosine kinase inhibition for metastatic disease. Fusion-positive patients demonstrated improved survival compared with BRAF-mut cancers and benefited from immunotherapy and fusion inhibitors. MAPK/fusion driver–negative tumors were aneuploid, responded poorly to immunotherapy, and were sensitive to EGFR blockade. Conclusions: Overall, MAPK and fusion oncogenic drivers distinguish MMRd colorectal cancer molecular lineages that inform molecular and clinical phenotypes.

PURPOSE: Second opinions in oncology may optimize treatment plans, resulting in improved outcomes such as prognosis and morbidity. Changes in treatment plans are often de-escalations in treatment intensity. However, data on the cost impact of changes in cancer treatment resulting from second opinions are limited. METHODS: We used a cohort of 120 patients who presented to a high-volume cancer center for a second opinion and also had a documented first opinion—30 patients each from four disease types: colorectal, head and neck, lung, and myeloma. For the 43 total patients who had a change in treatment from the second opinion compared with the first opinion, we estimated costs of treatment for the first and second opinions across the modalities of surgery, radiation, and drug treatment. RESULTS: Among the 43 patients with a change between the first and second opinions, seven patients had a higher cost from the second opinion, 31 had a lower cost, and five had the same cost. Averaged across all 120 cases—43 with changes in treatment and the rest without—mean cost savings were $15,015 in US dollars (USD) per patient, ranging by disease type from $2,517 USD (lung) to $43,437 USD (myeloma). Decreases in cost were due to less-intensive surgery or drug therapy regimens, or shifts from treatment to no treatment (observation). CONCLUSION: Further investigation is needed across cancer types and in other settings to confirm the finding of de-escalations and resulting cost savings from second opinions.

PURPOSE: Colorectal cancer (CRC) incidence and mortality have decreased since the 1970s, but the incidence in young adults (v 6.8 months; hazard ratio [HR], 0.66 [95% CI, 0.54 to 0.80]; P < .0001), which was similar to the findings in aoCRC population (9.4 v 7.3 months; HR, 0.73 [95% CI, 0.67 to 0.80]; P < .001; interaction P = .5415). However, epithelial growth factor receptor inhibitor (EGFRi) did not improve PFS in RAS wild-type (WT) patients with eoCRC who had left-sided primary tumors (8.3 v 8.9 months; HR, 1.20 [95% CI, 0.81 to 1.77]; P = .36), whereas EGFRi significantly improved PFS in the aoCRC population (9.9 v 8.5 months; HR, 0.74 [95% CI, 0.64 to 0.86]; P < .0001; interaction P = .083). CONCLUSION: Treatment-naïve patients with metastatic eoCRC appear to derive similar benefit from bevacizumab as patients with aoCRC. However, patients with eoCRC with left-sided RAS/RAF WT tumors did not appear to derive benefit from first-line EGFRi.