Abstract 228P
Background
BRAF V600E CRC tumors are associated with rapid growth and poor prognosis but are known to respond to dual BRAF and EGFR inhibition; however BRAF mutation in Appendiceal Adenocarcinoma (AA) has not been previously described. Here, we use a retrospective analysis to characterize BRAF mutant AA and its response to BRAF inhibition.
Methods
The University of Texas MD Anderson Cancer Center internal database was queried in a semi-automated fashion to identify all 792 patients with AA tested for BRAF mutation from 1/1/2003 to 12/31/2023 as well as a control cohort of 7327 patients with CRC.
Results
Incidence of BRAF mutation was lower in AA (3.4%, n=27) relative to CRC (5.7%, n=416, chi-squared p = 0.007). The proportion of BRAF mutations that were BRAF V600E was similar (63.0% AA vs. 77.4% CRC, p=0.09). Histologically, BRAF V600E was significantly associated with mucinous histology (82.3% vs. 45.8%, p = 0.003, Table) but there was no association with grade. In contrast to CRC, in AA BRAF V600E was not associated with poor survival (OS 91.9 mo wildtype vs. 92.2 mo BRAF V600E , HR= 1.0, p = .87). Interestingly, all 10 atypical BRAF (non-V600E) mutations were observed in high-grade tumors; median OS was 42.9 mo for this group, similar to other high-grade tumors. 9 of 17 patients with BRAF V600E AA received BRAF V600E inhibitors, given after at least one 5-fluorouracil-based (5-FU) regimen ± bevacizumab. Response, defined either radiographically or biochemically, was seen from 8 of 10 treatment regimens (80%, one patient treated w 2 regimens). Comparing BRAF inhibition to prior 5-FU-based regimens in the same 9 patients, PFS was twice as long with BRAF inhibition (ratio 2.02, 9.9 vs. 4.9 mo, p = .056). Table: 228P
AA cohort demographics
| Wt | BRAFV600E | aBRAF | |
| Median age (range) | 61 (20-91) | 67 (46-91) | 59 (39-75) |
| Median OS±95%CI | 91.9±13.2 | 92.2±42.0 | 42.9±41.1 |
| Sex | |||
| F | 433 (56.1) | 9 (52.9) | 5 (50) |
| M | 339 (43.9) | 8 (47.1) | 5 (50) |
| Race | |||
| White | 644 (83.4) | 15 (88.2) | 9 (90) |
| Non-white | 103 (9.6) | 0 | 1 (10) |
| Unknown | 25 (3.2) | 2 (11.8) | 0 |
| Grade | |||
| High | 563 (72.9) | 12 (70.1) | 9 (100) |
| Low | 209 (27.1) | 5 (29.4) | 0 |
| Stage | |||
| 1 to 3 | 132 (24.4) | 4 (25) | 3 (30) |
| 4 | 408 (75.6) | 12 (75) | 7 (70) |
| Histopathology | |||
| Colonic | 43 (9.2) | 3 (17.6) | 1 (11.1) |
| Mucinous only | 215 (45.8) | 11 (64.7) | 6 (66.7) |
| Goblet only | 21 (4.5) | 0 | 0 |
| Signet only | 120 (25.6)) | 0 | 0 |
| Mucinous, signet | 0 | 3 (17.6) | 1 (11.1) |
| Goblet, signet | 70 (14.9) | 0 | 1 (11.1) |
Conclusions
The prognostic implications of BRAF mutation in AA are distinct from CRC. Real World Evidence suggests that AA patients with BRAF V600E benefit from BRAF inhibitors. Further pre-clinical and clinical investigation is warranted.
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
J.P.Y. Shen: Financial Interests, Personal, Other, general consultation and expert testimony: ShenJPMD Inc; Financial Interests, Personal, Other, advisory board: Engine Biosciences, NaDeNo Nanosciences; Financial Interests, Institutional, Invited Speaker, research project: Celsius Therapeutics; Financial Interests, Institutional, Other, research funding for pilot project: BostonGene. All other authors have declared no conflicts of interest.