Abstract 114P
Background
RAS and BRAF mutations (mt) are predictive and prognostic in mCRC, whereas other genes have not been studied as thoroughly; the aim was to study these in a population-based mCRC cohort.
Methods
The cohort included all 765 patients in the Uppsala region in Sweden with a mCRC diagnosis 2010-2020. Molecular testing was done using a next-generation sequencing panel (OncomineTM Tumor Mutation Load Assay) including 409 cancer genes. Genes with a mutation frequency of ≥5% and NRAS were included in the analyses.
Results
Molecular testing was done in 396 patients, their median age was 71 years, primary location was right colon in 37%, left colon in 25%, and rectum in 38%. Incidence of genes included in further analyses, divided by primary tumour location, are shown in the table. The most frequently mutated genes were APC, KRAS, TP53, and BRAF. Mutations in BRAF, PIK3CA, SYNE1, and CSMD3were more common in right colon, whereas TP53 and APC were mutated more often in left colon and rectum. A worse prognosis was seen for those with BRAFmt (median overall survival [mOS] 19.8 vs 5.9 months, p<0.001) and ARID1Amt (mOS 15.1 vs 4.3 months, p=0.017), whereas no other mutations were prognostic. Both remained statistically significant in a multivariable model adjusting for age, primary tumour location, number of metastatic sites, performance status, and treatment; hazard ratio 1.90 (95% confidence interval [CI] 1.40-2.6) for BRAFmt and 1.96 (95% CI 1.17-3.30) for ARID1Amt. ARID1Amt were more common among BRAFmt (11% vs 3%, p=0.003), and deficient mismatch repair (11% vs 1%, p=0.005). ARID1Amt patients were older (median 75 vs 70 years, p=0.015), and had a trend for worse performance status (ECOG 2-4 in 56% vs 34%, p=0.080) compared with ARID1A wildtype, whereas no differences were seen for sex, tumour grade, presentation of metastases, or metastatic sites. Table: 114P
| Total ∗ | Right colon | Left colon | Rectum | p-value | |||||
| Total | 396 | 100% | 145 | 100% | 99 | 100% | 151 | 100% | |
| KRAS | 170 | 43% | 58 | 40% | 38 | 38% | 74 | 49% | 0.164 |
| NRAS | 16 | 4% | 2 | 1% | 4 | 4% | 10 | 7% | 0.073 |
| BRAF | 75 | 19% | 46 | 32% | 16 | 16% | 13 | 9% | <0.001 |
| TP53 | 222 | 56% | 68 | 47% | 61 | 62% | 93 | 62% | 0.018 |
| APC | 168 | 42% | 45 | 31% | 47 | 47% | 76 | 50% | 0.002 |
| SMAD4 | 62 | 16% | 22 | 15% | 19 | 19% | 21 | 14% | 0.520 |
| PIK3CA | 52 | 13% | 27 | 19% | 12 | 12% | 13 | 9% | 0.037 |
| FBXW7 | 32 | 8% | 13 | 9% | 5 | 5% | 14 | 9% | 0.436 |
| SYNE1 | 32 | 8% | 17 | 12% | 9 | 9% | 6 | 4% | 0.046 |
| CSMD3 | 30 | 8% | 20 | 14% | 3 | 3% | 7 | 5% | 0.002 |
| LRP1B | 26 | 7% | 13 | 9% | 7 | 7% | 6 | 4% | 0.218 |
| ATM | 25 | 6% | 13 | 9% | 4 | 4% | 8 | 5% | 0.241 |
| AMER1 | 22 | 6% | 8 | 6% | 7 | 7% | 7 | 5% | 0.713 |
| ARID1A | 18 | 5% | 7 | 5% | 2 | 2% | 9 | 6% | 0.337 |
∗1 with unknown primary tumour not presented separately
Conclusions
The mutation frequency of BRAF, PIK3CA, SYNE1, CSMD3, TP53, and APC differ per primary tumour location. Only BRAFmt and ARID1Amt confer a worse prognosis.
Clinical trial identification
The study was approved by the Ethics Committee of Uppsala University (2009-408, 2010-198, 2011-092, 2012-224, 2015-419, 2018-490).
Legal entity responsible for the study
The authors/Uppsala University.
Funding
This work was funded by grants from the Swedish Cancer Society, Lions Cancerforskningsfond Mellansverige, and an unrestricted start-up grant from Amgen.
Disclosure
E. Osterlund: Financial Interests, Personal, Invited Speaker: Amgen; Financial Interests, Personal, Training, Travel expenses: Nordic Drugs, Merck KGaA. L. Nunes: Financial Interests, Personal, Full or part-time Employment: Oncodia AB. T. Sjöblom: Financial Interests, Personal, Ownership Interest: Oncodia AB. B. Glimelius: Financial Interests, Institutional, Funding, Unrestricted grant: Amgen. All other authors have declared no conflicts of interest.