Japanese Cohort: Prognostic Significance

Yuki Matsubara, MD, of the Aichi Cancer Center Hospital in Nagoya, Japan, presented a retrospective review of medical records at the meeting.4 The review included patients who received first-line chemotherapy for mCRC between January 2005 and December 2017 at 4 large oncology facilities in Japan. 

The researchers analyzed data on 696 patients — 45 (2.8%) with G12C mutations and 651 (93.5%) with other KRAS mutations.


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Patient characteristics were not significantly different between the G12C-mutant and other KRAS-mutant groups. However, there were slight differences in the proportion of patients with primary tumor resection (47% and 37%, respectively), synchronous metastasis (78% vs 64%), and peritoneal metastasis (36% vs 23%).

Patients with G12C mutations had a significantly shorter median PFS than patients with other KRAS mutations — 9.4 months and 10.8 months, respectively (hazard ratio [HR]: 1.47, 95% CI 1.08-2.01; P =.015).

Patients with the G12C mutations also had a significantly shorter median OS than patients with other KRAS mutations — 21.1 months and 27.3 months, respectively (HR: 1.50, 95% CI 1.08-2.08, P =.015).

The independent prognostic significance of G12C mutations compared with other KRAS mutations persisted in a multivariate analysis. The adjusted HR for PFS was 1.43 (95% CI, 1.04-1.96, P =.030), and the adjusted HR for OS was 1.42 (95% CI, 1.01-2.00, P =.044).

Dr Matsubara concluded that G12C mutations were significantly correlated with shorter PFS and OS with first-line systemic treatment, when compared with other KRAS mutations. He said these findings highlight the importance of stratifying mCRC patients by G12C mutation status.

What We Know and Don’t Know

Studies suggest that G12C mutations occur in 3% to 8% of total CRC cases and constitute 6% to 17% of KRAS mutations, according to ESMO discussant Pierre Laurent-Puig, MD, PhD, of the University of Paris in France.

Having a G12C mutation may be an adverse prognostic factor in mCRC, but confounding factors may be more responsible for differences in treatment outcomes than the G12C mutation itself, Dr Laurent-Puig said.

A retrospective review of 17,009 patients with gastrointestinal cancers indicated that the frequency of G12C mutations in mCRC is highest among smokers and former smokers, as it is in lung cancer.5

If verified, smoking history is a potential additional explanation for poorer prognosis for G12C-mutant mCRC after recurrence and may also explain the prevalence of co-mutation with other oncogenes that have been described more commonly with G12C mutations than with other KRAS-mutant cancers.6

The recent US approval of specific inhibitors of the G12C mutation dictates that attention should be directed to this mutation in CRC and other gastrointestinal cancers when designing studies. The potential role of therapy targeted to G12C mutations must be defined in prospective clinical trials.

The presentations at the ESMO World Congress on Gastrointestinal Cancer highlight the critical need to define the prognostic significance of the G12C mutation and the resulting treatment implications more precisely.

Disclosures: Dr Österlund declared affiliations with Amgen, Merck, Roche, Sanofi, and Servier. Dr Matsubara declared no conflicts of interest. Dr Laurent-Puig declared affiliations with Servier, Roche, Bristol Myers Squibb, Biocartis, Amgen, Sanofi, Pierre Fabre, Merck, and Lilly. Please see the original references for a full list of disclosures.

References

  1. Rosen N. Finally, effective inhibitors of mutant KRAS. N Engl J Med. 2021;384(25):2447-2449.
  2. Schirripa M, Nappo F, Cremolini C, et al. KRAS G12C metastatic colorectal cancer: Specific features of a new emerging target population. Clin Colorectal Cancer. 2020; 19(3):219-225. doi:10.1016/j.clcc.2020.04.009
  3. Österlund E, Muhonen T, Ristimaki A, et al. KRAS-G12C mutations in a Nordic cohort of 1441 metastatic colorectal cancer patients. Presented at: ESMO World Congress on Gastrointestinal Cancer; June 30-July 3, 2021. Abstract SO-13.
  4. Matsubara Y, Masuishi T, Fushiki K, et al. The prognostic impact of KRAS G12C mutation in patients with metastatic colorectal cancer: A multicenter retrospective observational study. Presented at: ESMO World Congress on Gastrointestinal Cancer; June 30-July 3, 2021. Abstract SO-14.
  5. Dogan S, Shen R, Ang DC, et al. Molecular epidemiology of EGFR and KRAS mutations in 3026 lung adenocarcinomas: Higher susceptibility of women to smoking-related KRAS-mutant cancers. Clin Cancer Res. 2012;18(22):6169-77. doi:10.1158/1078-0432.CCR-11-3265
  6. Salem M, El-Refai S , Sha W, et al. Characterization of KRAS mutation variants and prevalence of KRAS-G12C in gastrointestinal malignancies. Presented at: ESMO World Congress on Gastrointestinal Cancer; June 30-July 3, 2021. Abstract O-3.