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In Response to “De Novo KRAS G12C-Mutant SCLC: A Case Report”

Open AccessPublished:September 26, 2022DOI:https://doi.org/10.1016/j.jtocrr.2022.100418
      To the Editor:
      Balbach et al.
      • Balbach M.L.
      • Eisenberg R.
      • Iams W.T.
      De novo KRAS G12C–mutant SCLC: a case report.
      report SCLC with a KRAS G12C somatic mutation at 92.6% variant allele frequency (VAF). KRAS G12C is a substantial driver of NSCLC, for which the inhibitor sotorasib has been approved for second-line treatment. Balbach et al.
      • Balbach M.L.
      • Eisenberg R.
      • Iams W.T.
      De novo KRAS G12C–mutant SCLC: a case report.
      consider whether their patient with SCLC would benefit from this treatment as there is no approved KRAS G12C-targeted therapy in SCLC. Given the well-established oncogenicity of KRAS G12 mutations, it is natural to expect KRAS G12C to play on oncogenic role in tumors where it is found. Nevertheless, G12C is so rare in SCLC that the alternative hypothesis—that the variant confers little proliferative advantage—should be considered. Even passenger mutations can achieve high VAF by chance. By calculating site-specific neutral cancer cell mutation rates in sequenced SCLC tumors, we can quantify the relative strength of selection driving prevalence of KRAS G12C in comparison to known SCLC drivers, gaining insight into the potential therapeutic efficacy of a KRAS G12C inhibitor.
      • Cannataro V.L.
      • Gaffney S.G.
      • Townsend J.P.
      Effect sizes of somatic mutations in cancer.
      To quantify the tumorigenic effect of KRAS G12C mutation, we aggregated somatic variant calls from whole-exome sequencing of 1042 NSCLC tumors
      • Zhuo Y.
      YuyangZhuo/SCLC_cancereffectsizeR: SCLC_cancereffectsizeR.
      and from sequencing of 514 SCLC tumors (110 whole-genome sequencing, 139 whole-exome sequencing, and 265 panel sequencing of driver genes).
      • Zhuo Y.
      YuyangZhuo/SCLC_cancereffectsizeR: SCLC_cancereffectsizeR.
      The NSCLCs featured 132 G12 mutations versus eight in SCLC (13% versus 2%, two-sided Boschloo’s test, P = 6.7 × 10−16) and 54 G12C mutations versus two in SCLC (5% versus 0.4%, two-sided Boschloo’s test, P = 7.4 × 10−8). The lower prevalence in SCLC is suggestive of reduced oncogenic effect, but the difference could be explainable by differences in underlying KRAS G12 mutation rates between SCLC and NSCLC. Therefore, we calculated neutral mutation rates and quantified selection for KRAS G12C in each cancer type with cancereffectsizeR 2.6.4.
      • Cannataro V.L.
      • Gaffney S.G.
      • Townsend J.P.
      Effect sizes of somatic mutations in cancer.
      In NSCLC, the scaled selection coefficient for the KRAS G12C variant was 1.4 × 104, 23rd of 3272 recurrent variants. In SCLC, it was 1.2 × 103—12-fold lower, 1120th of 1259. Lower effect indicates a lesser role in the growth and proliferation of SCLC than of NSCLC. Treatment with sotorasib may trend less beneficial for patients with KRAS G12C SCLC than for patients with KRAS G12C NSCLC.
      Potential treatments may also be informed by the effect sizes of other variants in the patient which are quantified at higher oncogenic effect than KRAS G12C. For example, a point mutation of B2M was present at 88.4% VAF. A similar B2M loss-of-function mutation in SCLC exhibits sixfold higher effect than KRAS G12C—ranking 382nd at 6.9 × 103. Prospects for immune checkpoint therapy should be tempered by the presence of B2M mutation, which has been linked to mismatch-repair deficiency in colon cancer and to acquired resistance to immune checkpoint inhibitors in melanoma
      • Wang H.
      • Liu B.
      • Wei J.
      Beta 2-microglobulin(B2M) in cancer immunotherapies: biological function, resistance and remedy.
      ; alterations correlate with immunotherapy resistance and with tumor immune escape in lung cancer.
      • Zhao Y.
      • Cao Y.
      • Chen Y.
      • et al.
      B2M gene expression shapes the immune landscape of lung adenocarcinoma and determines the response to immunotherapy.
      In summary, considerations of the potential outcomes of off-label–targeted treatments should be informed by the tumor-type–specific cancer effect sizes of the targeted variants.

      CRediT Authorship Contribution Statement

      Margaret Moore: Conceptualization, Investigation, Writing—original draft, Writing—review and editing, Project administration.
      Yuyang Zhuo: Software, Formal analysis, Investigation, Data curation, Writing—review and editing.
      Jeffrey Mandell: Methodology, Software, Validation, Formal analysis, Data curation, Writing—review and editing.
      Stephen Gaffney: Validation, Data curation, Writing—review and editing, Supervision.
      Jeffrey Townsend: Conceptualization, Methodology, Resources, Writing—original draft, Writing—review and editing, Supervision, Project administration.

      References

        • Balbach M.L.
        • Eisenberg R.
        • Iams W.T.
        De novo KRAS G12C–mutant SCLC: a case report.
        JTO Clin Res Rep. 2022; 3100306
        • Cannataro V.L.
        • Gaffney S.G.
        • Townsend J.P.
        Effect sizes of somatic mutations in cancer.
        J Natl Cancer Inst. 2018; 110: 1171-1177
        • Zhuo Y.
        YuyangZhuo/SCLC_cancereffectsizeR: SCLC_cancereffectsizeR.
        https://zenodo.org/record/7010662#.YzLUPnZBy3A
        Date accessed: September 9, 2022
        • Wang H.
        • Liu B.
        • Wei J.
        Beta 2-microglobulin(B2M) in cancer immunotherapies: biological function, resistance and remedy.
        Cancer Lett. 2021; 517: 96-104
        • Zhao Y.
        • Cao Y.
        • Chen Y.
        • et al.
        B2M gene expression shapes the immune landscape of lung adenocarcinoma and determines the response to immunotherapy.
        Immunology. 2021; 164: 507-523

      Linked Article

      • De Novo KRAS G12C–Mutant SCLC: A Case Report
        JTO Clinical and Research ReportsVol. 3Issue 5
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          The application of KRAS G12C inhibitors in the setting of NSCLC represents a major milestone for a previously “undruggable” target. Here, we present the second reported case of de novo KRAS G12C–mutant primary SCLC. Would our patient benefit from a KRAS G12C inhibitor?
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      • Author Reply: In Response to “De Novo KRAS G12C-Mutant SCLC: A Case Report”
        JTO Clinical and Research ReportsVol. 3Issue 11
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          We thank Moore et al.1 for their thoughtful consideration of our patient case with de novo KRAS G12C-mutant SCLC. We agree that the variant allele frequency, although quite high in this patient, does not ensure the importance of this mutation in driving the patient’s SCLC. In the era of ever-increasing breadth and depth of tumor genomic profiling, a plentitude of patients with “targetable” mutations in noncanonical settings continue to present challenges and opportunities akin to this case. The ability to reliably estimate the cancer effect size of individual mutations is a tool of immense value to molecular tumor board discussions, clinical trial design, and practicing oncologists.
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