KRAS G12D mutation predicts lower TMB and drives immune suppression in lung adenocarcinoma

Gao, Ge; Liao, Wei‐Ting; Ma, Qian; Zhang, Benxia; Chen, Yue; Wang, Yongsheng

doi:10.1016/j.lungcan.2020.09.004

Cited by 49 publications

(54 citation statements)

References 14 publications

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“…Since IPM in our cohorts all exhibited at least three common mutations and generally high concordance rate and high mutational burden, possibly due to comprehensive increase in the number of mutations, it can be concluded from our data that MPLC should be given priority in diagnosis for patients with only one common driver gene mutation among separate lesions, especially when multiple non-overlapping mutations are found. Latest evidence suggest that TKI-related EGFR mutations and KRAS G12D led to lower TMB compared with those without mutations ( 16 , 17 ). In contrast, our own data suggest that lung cancer patients with TP53 mutations but without EGFR or KRAS mutations may have higher TMB than those without TP53 mutations.…”

Section: Discussionmentioning

confidence: 99%

RETRACTED: Establishment of Criteria for Molecular Differential Diagnosis of MPLC and IPM

et al. 2021

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BackgroundsDifferential diagnosis of multiple primary lung cancer (MPLC) and intrapulmonary metastasis (IPM) is one difficulty in lung cancer diagnosis, and crucial for establishment of treatment strategies and prognosis prediction. This study aims to establish the criteria for molecular differential diagnosis of synchronous MPLC and IPM by the next-generation sequencing (NGS) method.MethodsTraining cohort included 30 synchronous MPLC (67 samples) patients and 5 synchronous IPM (13 samples) patients with adenocarcinoma. Criteria of MPLC/IPM differential diagnosis were established by results from a NGS-based 605-gene panel test. Subsequently, 16 patients (36 samples) were recruited as the validation cohort to verify the criteria.ResultsIPM lesions showed a high degree of mutation overlap with an average concordance rate of 60.2% (range: 15.8%–91.7%). IPM lesions had at least three common alterations, including both high-frequency driver gene alterations and low-frequency gene alterations. In contrast, the average concordance rate of MPLC was 11.0% (range: 0.0%–100.0%), among which 66.7% (20/30) of patients had no common alterations (concordance rate: 0%). In the remaining 10 patients, 9 had only one overlapping alteration while 1 had two overlapping alterations, in which 6 patients had EGFR L858R overlapping mutation. Alterations were classified into trunk, shared, and branch subtypes. Branch alterations accounted for 94.4% of mutations in MPLC, while accounted for only 45.0% in IMP. In contrast, the ratio of trunk (38.3%) and shared (16.7%) alterations in IPM was significantly higher. The criteria for differentiating MPLC from IPM using 605-gene panel was established: 1) MPLC can be interpreted if no overlapping alterations is found; 2) MPLC is recommended if one overlapping high-frequency drive gene alteration and/or one overlapping low-frequency gene alteration are/is found; 3) IPM can be interpreted if more than three common alterations are found. Subsequently, 16 patients were recruited as the validation cohort in the single-blind manner to verify the criteria, and 14 MPLC and 2 IPM were identified, which was 100% consistent with the results from independent imaging and pathological diagnosis.ConclusionsNGS detection can distinguish synchronous MPLC from IPM and is a useful tool to assist differential diagnosis.

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Section: Discussionmentioning

confidence: 99%

RETRACTED: Establishment of Criteria for Molecular Differential Diagnosis of MPLC and IPM

et al. 2021

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“…By contrast, it was reported that the TP53/KRAS co-mutant group had higher levels of TMB and PD-L1 than other groups based on the results obtained by Dong et al 138 Improved ORR was also found in co-mutant patients. 139,141 Additionally, subtypes with the KRAS G12D mutation showed the lowest level of TMB compared to other subtypes, 140 even when co-mutated with TP53. By contrast, the PD-L1 level of KRAS G12D subtypes did not show a significant difference compared to other subtypes of KRAS mutations.…”

Section: Mutation Prediction With Respect To Icbsmentioning

confidence: 94%

“…The levels of PD‐L1 and TMB in patients with TP53 or KRAS mutations are higher than those in patients with wide‐type TP53 or KRAS (Table 3), especially for TP53 mutant patients. A study by Gao et al 140 reported no statistical difference between the levels of PD‐L1 and TMB in TP53 mutant patients compared to patients with TP53/KRAS co‐mutations. By contrast, it was reported that the TP53/KRAS co‐mutant group had higher levels of TMB and PD‐L1 than other groups based on the results obtained by Dong et al 138 Improved ORR was also found in co‐mutant patients 139,141 .…”

Section: Future Outlook: Potential Biomarkers Of Icbsmentioning

confidence: 95%

“…Previous studies [137][138][139][140][141][142][143] reported that both KRAS and TP53 mutations are positive predictors for immunotherapy. The levels of PD-L1 and TMB in patients with TP53 or KRAS mutations are higher than those in patients with wide-type TP53 or KRAS (Table 3), especially for TP53 mutant patients.…”

Section: Mutation Prediction With Respect To Icbsmentioning

confidence: 99%

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PD‐L1 versus tumor mutation burden: Which is the better immunotherapy biomarker in advanced non‐small cell lung cancer?

Dong

Zhao

et al. 2021

The Journal of Gene Medicine

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PD‐L1 and tumor mutation burden (TMB) are the most widely used immunotherapy biomarkers to identify populations who would attain clinical benefit, with the higher values predicting better therapeutic efficacy. This review addresses the predictive values and unresolved challenges of these two biomarkers. PD‐1 and PD‐L1 inhibitors have induced durable and effective responses in patients with advanced non‐small cell lung cancer, confirmed by multiple clinical trials and real‐world studies. Different clinical trials, involving both PD‐1/PD‐L1 inhibitors alone and combination regimens, adopted either PD‐L1 or TMB to stratify the patients, although the predictive capabilities of these two biomarkers are different. In the first‐line setting, PD‐L1 of 50% or more as a cut‐off value can help select candidates for pembrolizumab or atezolizumab monotherapy; however, these two biomarkers poorly predict the efficacy of immunotherapy combination regimens as first‐line treatments. In the second‐line setting, although patients can benefit from nivolumab regardless of PD‐L1 expression, both PD‐L1 and blood TMB can be used as biomarkers to find patients suitable for atezolizumab. Except for inaccurate predictiveness, there are many unresolved problems with regard to the two biomarkers, such as the lack of standard detection methods, and their susceptibilities to other dynamic changes. The predictive values of TMB and PD‐L1 were low in most circumstances; however, PD‐L1 expression greater than ≥ 50% can help select appropriate patients for pembrolizumab and atezolizumab, respectively, as first‐line monotherapies. Higher PD‐L1 or TMB was associated with greater efficacy for atezolizumab as a second‐line monotherapy.

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“…Indeed, the worst prognosis seems to be associated with the presence of this mutation, nonetheless this has been questioned in some studies [168]. A lower TMB is associated with a KRASG12D mutation than with other subtypes of mutations [169].…”

Section: Kras G12c Mutationsmentioning

confidence: 99%

What Is New in Biomarker Testing at Diagnosis of Advanced Non-Squamous Non-Small Cell Lung Carcinoma? Implications for Cytology and Liquid Biopsy

Hofman

2021

JMP

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The discovery and clinical validation of biomarkers predictive of the response of non-squamous non-small-cell lung carcinomas (NS-NSCLC) to therapeutic strategies continue to provide new data. The evaluation of novel treatments is based on molecular analyses aimed at determining their efficacy. These tests are increasing in number, but the tissue specimens are smaller and smaller and/or can have few tumor cells. Indeed, in addition to tissue samples, complementary cytological and/or blood samples can also give access to these biomarkers. To date, it is recommended and necessary to look for the status of five genomic molecular biomarkers (EGFR, ALK, ROS1, BRAFV600, NTRK) and of a protein biomarker (PD-L1). However, the short- and more or less long-term emergence of new targeted treatments of genomic alterations on RET and MET, but also on others’ genomic alteration, notably on KRAS, HER2, NRG1, SMARCA4, and NUT, have made cellular and blood samples essential for molecular testing. The aim of this review is to present the interest in using cytological and/or liquid biopsies as complementary biological material, or as an alternative to tissue specimens, for detection at diagnosis of new predictive biomarkers of NS-NSCLC.

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KRAS G12D mutation predicts lower TMB and drives immune suppression in lung adenocarcinoma

Cited by 49 publications

References 14 publications

RETRACTED: Establishment of Criteria for Molecular Differential Diagnosis of MPLC and IPM

RETRACTED: Establishment of Criteria for Molecular Differential Diagnosis of MPLC and IPM

PD‐L1 versus tumor mutation burden: Which is the better immunotherapy biomarker in advanced non‐small cell lung cancer?

What Is New in Biomarker Testing at Diagnosis of Advanced Non-Squamous Non-Small Cell Lung Carcinoma? Implications for Cytology and Liquid Biopsy

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