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The KRAS A146T mutation is a point substitution at codon 146 of the KRAS gene (exon 4), replacing alanine with threonine. This mutation occurs in a region of the KRAS protein that interacts with GDP/GTP and influences how KRAS switches between active and inactive states Frontiersin.org.
Biochemical studies show that KRASA146T increases the intrinsic and SOS-mediated nucleotide exchange rate (GDP dissociation), leading to more rapid loading of GTP and KRAS activation PMC.NCBI.NLM.NIH.GOV. Unlike the common codon 12 mutations (which primarily impair GTP hydrolysis by preventing GAP-mediated inactivation), A146T’s oncogenic effect derives from accelerated GDP-GTP exchange rather than pronounced GAP insensitivity PMC.NCBI.NLM.NIH.GOV.
In simpler terms, KRAS A146T keeps the KRAS protein active by speeding up the “on” switch (nucleotide exchange) without greatly blocking the “off” switch (GTP hydrolysis). This mutation was first identified as an oncogenic variant in colorectal cancer (CRC) in 2006 PMC.NCBI.NLM.NIH.GOV. Notably, KRAS A146 mutations (including A146T and A146V) appear to be tissue-selective. They are predominantly found in colorectal tumors and are rare in other cancers (for example, codon 146 alterations are seldom seen in lung adenocarcinoma, which is dominated by codon 12/13 mutations) PMC.NCBI.NLM.NIH.GOV.
This suggests that the KRASA146T allele confers a growth advantage mainly in the colonic cellular context PMC.NCBI.NLM.NIH.GOV. Like other activating KRAS mutations, A146T drives aberrant signaling through pathways such as RAF-MEK-ERK and PI3K-AKT, promoting tumor cell proliferation and survival. Importantly, any KRAS-activating mutation (including A146T) causes resistance to EGFR-targeted monoclonal antibody therapy. Indeed, codon 146 mutants, much like codon 12 mutants, do not respond to anti-EGFR treatments (e.g., cetuximab or panitumumab) PMC.NCBI.NLM.NIH.GOV.
In summary, KRAS A146T is an oncogenic KRAS variant that is biochemically distinct but functionally similar in end result (constitutive KRAS activation) to the classic codon 12/13 mutants, and it predominantly occurs in colon cancer.
KRAS is mutated in roughly 40–50% of colorectal cancers PMC.NCBI.NLM.NIH.GOV. The vast majority of these mutations occur in codons 12 and 13 (exon 2). By contrast, mutations in codon 146 (exon 4) are less frequent but still clinically relevant. KRAS A146T is a relatively rare variant, accounting for approximately 4% of all metastatic CRC cases PMC.NCBI.NLM.NIH.GOV.
When considering only KRAS-mutant tumors, codon 146 mutations represent about 8–10% of KRAS mutations in CRC PMC.NCBI.NLM.NIH.GOV. In fact, some studies have noted that A146 is the third most common KRAS mutation in metastatic CRC, after the major codon 12 and 13 variants PMC.NCBI.NLM.NIH.GOV. This underscores the need to include exon 4 in KRAS mutation testing panels, since routine diagnostics that only screen exon 2 could miss this subset PMC.NCBI.NLM.NIH.GOV.
By comparison, the most common KRAS mutations in colon cancer are in codon 12 and 13. The single most prevalent specific mutations are:
Other KRAS mutations (G12C, G12A, G12S, Q61, K117, etc.) make up the remainder. For context, codon 61 and 117 mutations each appear in only ~1–3% of CRC PMC.NCBI.NLM.NIH.GOV.
Thus, while A146T is clearly less common than G12D/V or G13D, it is one of the more frequent “non-classical” KRAS mutations in colon cancer.
| KRAS Mutation | Prevalence in CRC | Prognosis | Treatment Response |
|---|---|---|---|
| A146T (Exon 4) | ~4% of CRC (~8–10% of KRAS-mutant cases) | Mixed data; historically thought not worse than codon 12/13 but recent data suggest worse outcomes in metastatic cases | Anti-EGFR: No response. Chemo+Bevacizumab: Benefits similar to other KRAS mutants, but aggressive behavior suggests need for intensive therapy |
| G12D (Exon 2) | 20–30% | Poor prognosis compared to KRAS wild-type | Anti-EGFR: No response. Chemo+Bevacizumab: Standard benefits |
| G12V (Exon 2) | 20–25% | Worst prognosis among KRAS variants | Anti-EGFR: No response. Chemo+Bevacizumab: Significant OS benefit |
| G13D (Exon 2) | 15–20% | Intermediate prognosis | Anti-EGFR: Some reports suggest occasional benefit. Chemo+Bevacizumab: Standard benefit |
Sources: Prevalence and prognostic data from Refs
Treatment response data from Refs
KRAS-Mutant vs Wild-Type: It is well-established that, as a whole, KRAS mutations confer a worse prognosis in colorectal cancer. Patients with KRAS-mutant tumors have shorter survival compared to those with KRAS wild-type tumors PMC.NCBI.NLM.NIH.GOV. For example, a meta-analysis of metastatic CRC found that even with modern therapy, median overall survival was about 20.2 months for KRAS-mutant patients vs 24.5 months for KRAS wild-type FRONTIERSIN.ORG. Thus, any KRAS mutation is a negative prognostic factor.
Prognosis of A146T: The prognostic impact of the KRAS A146T mutation specifically has been a subject of evolving insight. Earlier retrospective analyses suggested that tumors with codon 146 mutations had outcomes comparable to, or even slightly better than, those with codon 12 mutations. For instance, an epidemiologic study noted colorectal cancers with codon 146 mutations showed no significant difference in survival compared to other KRAS-mutant cases PUBMED.NCBI.NLM.NIH.GOV. In fact, one report observed that codon 146 mutant CRCs were associated with better overall survival than codon 12 mutants PMC.NCBI.NLM.NIH.GOV. However, these observations may have been influenced by patient populations that included earlier-stage disease. More recent data focusing on advanced cancer paint a different picture.
A 2021 analysis by van ’t Erve et al. examined metastatic CRC patients with various KRAS variants. They identified KRAS A146 mutations as a distinct high-risk subgroup. Patients harboring A146 mutations had a significantly greater tumor burden and dramatically worse survival compared to those with common KRAS exon 2 mutations PMC.NCBI.NLM.NIH.GOV PMC.NCBI.NLM.NIH.GOV. Specifically, median overall survival for A146-mutant patients was only 10.7 months, versus 26.4 months for patients with KRAS G12 mutations in that cohort PMC.NCBI.NLM.NIH.GOV. This suggests that in the metastatic setting, KRAS A146T can portend a particularly poor prognosis. The A146 group’s hazard of death was about 2.5 times that of the G12 group PMC.NCBI.NLM.NIH.GOV. These patients also had much higher circulating tumor DNA levels, reflecting heavier disease burden. The authors concluded that KRAS A146–mutant mCRC represents a distinct, aggressive subtype, potentially meriting more intensive treatment approaches.
It’s important to reconcile these seemingly conflicting findings. In early-stage or general CRC populations, having an A146 mutation does not appear to drastically worsen outcomes relative to other KRAS mutations PUBMED.NCBI.NLM.NIH.GOV. In fact, some have reported slightly favorable trends for exon 4 mutants (codons 146/117) in certain contexts FRONTIERSIN.ORG. But in metastatic disease, A146T may indicate a tumor biology that is harder to control, resulting in shorter survival if not adequately treated PMC.NCBI.NLM.NIH.GOV. One possible explanation is that all A146T tumors keep KRAS active (driving growth), but only a subset manifest the very aggressive phenotype – perhaps those that progress to widespread metastases. Additionally, treatment differences and co-mutations could account for outcome variability in different studies. In summary, KRAS A146T should be viewed as an oncogenic mutation with at least the same adverse prognostic implications as classical KRAS mutations, and possibly worse in the advanced-disease setting.
Prognosis of Common KRAS Variants: KRAS mutations as a group worsen prognosis in colon cancer. Among them, A146T and G12V stand out as potentially conferring the poorest outcomes (A146T in advanced CRC, and G12V broadly).
Specific Survival Data for KRAS A146T: Published survival statistics exclusively for KRAS A146T-mutant colon cancer are limited, given the rarity of this mutation. The van ’t Erve et al. study provides one of the few glimpses: in a metastatic setting (patients with unresectable colorectal liver metastases on first-line therapy), median overall survival was ~10.7 months for KRAS A146-mutant patients PMC.NCBI.NLM.NIH.GOV. This is notably short, reflecting the aggressive disease course in that subset (by comparison, KRAS G12-mutant patients in the same study had a median OS of 26.4 months). It should be emphasized that this figure comes from a specific high-tumor-burden cohort under clinical trial conditions, so 10.7 months is not a universal number for all A146T cases, but it underscores the potential severity.
Outside of that study, there is no separate published survival curve just for A146T in a general population. Instead, A146T is often grouped with other exon 4 mutants. Data from large databases (including early-stage cancers) suggest that having a codon 146 mutation does not significantly worsen or improve survival compared to having a KRAS codon 12/13 mutation. In other words, A146T-mutant patients generally follow the same pattern as “KRAS-mutant CRC” overall, especially when the disease is localized or treated surgically. For instance, Imamura et al. reported no prognostic difference for codon 146 vs codon 12/13 mutants in a cohort of >1000 colorectal cancers, after adjusting for other factors PUBMED.NCBI.NLM.NIH.GOV.
General Survival for KRAS-Mutant CRC: If specific A146T survival rates are unavailable, we can look at overall survival benchmarks for KRAS-mutant metastatic colon cancer. In the era of combination chemotherapy and biologics, median survival for unselected metastatic CRC patients now often exceeds 2 years. However, KRAS-mutant cases tend to do slightly worse than RAS wild-type (partly because they cannot benefit from EGFR inhibitors). For example:
In summary, KRAS-mutant metastatic colon cancer has a poorer prognosis than wild-type, with median survival on the order of ~20 months in contemporary series. Specific data on KRAS A146T suggest it could be at the lower end of that spectrum in advanced disease (potentially <1 year median OS if not optimally managed). For earlier-stage disease, the presence of A146T does not dramatically change cure rates; these patients should still be cured by surgery if the tumor is localized, much like other KRAS-mutant cases.
Background: FOLFOX (5-fluorouracil, leucovorin, and oxaliplatin) combined with bevacizumab (an anti-VEGF monoclonal antibody) is a standard first-line regimen for metastatic colorectal cancer, particularly in patients with KRAS-mutant tumors. Since KRAS-mutant tumors do not respond to anti-EGFR therapy, the typical strategy is to use chemotherapy plus an anti-angiogenic agent like bevacizumab. The question is how much this regimen improves outcomes and whether its efficacy varies for specific KRAS mutations (like A146T).
Overall Efficacy of FOLFOX+Bev: Numerous trials and meta-analyses have shown that adding bevacizumab to first-line chemotherapy improves outcomes in metastatic CRC. A meta-analysis of 9 randomized trials found that chemotherapy + bevacizumab significantly prolongs progression-free survival (PFS) and overall survival (OS) compared to chemotherapy alone PMC.NCBI.NLM.NIH.GOV. Specifically, the addition of bevacizumab reduced the risk of progression by ~34% (HR ~0.66) and the risk of death by aprox. 16% (HR 0.84) PMC.NCBI.NLM.NIH.GOV. In practical terms, this often translates to a few months’ gain in median survival. For instance, median OS might improve from aprox 20 months with chemo alone to 24 months with chemo+bev in an average patient population FRONTIERSIN.ORG . Notably, bevacizumab’s benefit was observed across KRAS statuses; it is not restricted to wild-type or mutant subgroups. In fact, bevacizumab is one of the key options for KRAS-mutant patients since they lack other targeted therapies.
Evidence in KRAS-Mutant Patients: Bevacizumab appears to confer a survival benefit in KRAS-mutant colon cancer similar to that in wild-type. Petrelli et al. compared outcomes by RAS status and confirmed that while RAS-mutant patients have worse baseline prognoses, those who received bevacizumab still lived longer than those who did not, and the magnitude of benefit was comparable FRONTIERSIN.ORG. In one analysis, KRAS-mutant patients on chemo+bev had a median OS ~20.2 months versus aprox. 13–16 months historically without bevacizumab, indicating a clear improvement.
Looking at specific KRAS variants, emerging data hint that some mutations might particularly benefit from anti-VEGF therapy:
A 2022 observational study by Lavacchi et al. stratified metastatic KRAS-mutant patients by variant and treatment. They found that adding bevacizumab to first-line chemo was associated with a marked improvement in outcome for certain subgroups. In patients with KRAS G12V (often the worst prognosis group), bevacizumab plus chemo more than doubled median overall survival (32.0 vs 14.0 months in their series). This suggests G12V-driven tumors, which tend to be highly angiogenic, derive substantial benefit from VEGF inhibition. Similarly, KRAS G13D patients saw a meaningful gain in PFS with bevacizumab (median PFS ~10.4 months with bev vs shorter without) . In contrast, for G12D the bevacizumab benefit was not as clearly distinct (though G12D still benefits in line with the class effect).
The biological rationale is that mutations like G12V strongly activate the RAF-MEK-ERK pathway and can upregulate pro-angiogenic factors (e.g. G12V has been linked to higher VEGF-A production). Bevacizumab targets this angiogenesis, which may disproportionately slow down G12V tumors. All KRAS mutant tumors, however, rely on blood supply, so anti-VEGF provides at least some advantage broadly.
Focus on KRAS A146T: Unfortunately, no clinical trial to date has reported separate results for KRAS A146T-mutant patients due to the low frequency of this mutation. Most trials and subgroup analyses lump A146T in with “other KRAS” or simply “KRAS mutant.” Therefore, we have to infer its response to FOLFOX+Bev from general principles and limited observations:
Clinically, FOLFOX+Bevacizumab is considered a standard of care for metastatic KRAS-mutant CRC because it has been shown to extend survival. For instance, the pivotal trial by Hurwitz et al. (although not KRAS-selected) demonstrated that adding bevacizumab to chemo significantly improved response rates and OS in metastatic CRC. Subsequent trials (e.g. NO16966 for FOLFOX+Bev) reinforced the PFS benefit in first-line treatment. Based on all available evidence, oncologists routinely use FOLFOX (or FOLFIRI) with bevacizumab for KRAS-mutant cases, and this approach does improve median survival and disease control.
Summary of FOLFOX+Bev Impact: The regimen of 5-FU/oxaliplatin plus bevacizumab has been proven to increase progression-free survival and overall survival in metastatic colon cancer PMC.NCBI.NLM.NIH.GOV. KRAS-mutant patients derive benefit from bevacizumab, as it targets an alternative pathway (angiogenesis) that KRAS status does not influence directly. For high-risk KRAS mutations like A146T, FOLFOX+Bev is a logical first-line choice and likely offers the best chance at extending survival, since EGFR inhibitors are ineffective. While no A146T-specific trial data exist, experts suggest that these patients should absolutely receive bevacizumab-based therapy and possibly even more aggressive treatment, given their tendency toward worse outcomes . In practice, if a patient with a KRAS A146T metastatic colon cancer presents, a regimen such as FOLFOX + bevacizumab (or FOLFIRI + bevacizumab) would be recommended, and one would monitor closely for response.
It’s worth noting ongoing research into KRAS-directed therapies (for example, MEK inhibitors or allele-specific KRAS inhibitors) – however, none are yet standard for KRAS A146T. There is some preclinical evidence that MEK/ERK pathway dependence is pronounced in codon 146-mutant CRC cells FRONTIERSIN.ORG, which raises hope that MEK inhibitors could be effective for this subset in the future. For now, the combination of cytotoxic chemotherapy and bevacizumab remains the cornerstone, and clinical trial enrollment is encouraged for patients with rare KRAS variants like A146T.