Common driver mutations and smoking history affect tumor mutation burden in lung adenocarcinoma

Nagahashi, Masayuki; Sato, Seijiro; Yuza, Kizuki; Shimada, Yasuhiro; Ichikawa, Hiroshi; Watanabe, Satoshi; Takada, Kazuki; Okamoto, Tatsuro; Okuda, Shujiro; Lyle, Stephen; Takabe, Kazuaki; Tsuchida, Masanori; Wakai, Toshifumi

doi:10.1016/j.jss.2018.07.007

Cited by 61 publications

(50 citation statements)

References 27 publications

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“…Consistent with these findings, our results also showed that patients in the EGFR mutation subgroup who received single agent ICI treatment exhibited the shortest PFS (Fig b). On the other hand, the histological subtype of lung adenocarcinoma, compared to squamous cell or poorly differentiated NSCLC, frequently showed a lower TMB level . This characteristic is associated with a lower frequency of tumor neoantigens, weaker immunogenicity, and thereby weaker antitumor immunity .…”

Section: Discussionmentioning

confidence: 99%

“…On the other hand, the histological subtype of lung adenocarcinoma, compared to squamous cell or poorly differentiated NSCLC, frequently showed a lower TMB level. 29,30 This characteristic is associated with a lower frequency of tumor neoantigens, weaker immunogenicity, and thereby weaker antitumor immunity. 23 The addition of chemotherapy in this context has been shown to play an important role in damaging the DNA mismatch repair mechanism and dramatically increasing tumor immunogenicity.…”

Section: Discussionmentioning

confidence: 99%

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Comparison of a combination of chemotherapy and immune checkpoint inhibitors and immune checkpoint inhibitors alone for the treatment of advanced and metastatic non‐small cell lung cancer

et al. 2019

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Background Single agent immune checkpoint inhibitors (ICIs) improve survival outcomes compared to chemotherapy for advanced non‐small cell lung cancer (NSCLC), but treatment efficacy widely varies. The combination of ICIs with chemotherapy has shown promising efficacy over chemotherapy alone; however, whether this strategy is superior to single agent ICIs for the treatment of advanced NSCLC remains unknown. Methods The records of 109 patients with advanced NSCLC who were administered at least one cycle of ICIs were retrospectively reviewed. Patients were grouped based on the presence or absence of a chemotherapy treatment combination. Efficacy and survival outcomes were analyzed. Result Sixty‐nine (58.0%) patients received single agent ICIs (ICI group) and 50 (42.0%) received ICIs and chemotherapy (ICC group). The median (3.2 vs. 3.0 months; P = 0.025) and one‐year (34.5 vs. 9.6%; P = 0.026) progression‐free survival (PFS) rates were significantly better in the ICC than in the ICI group. The superior efficacy of ICC remained in the propensity score matched pairs (median PFS 3.2 vs. 2.6 months, P = 0.032; 1‐year PFS 35.2 vs. 7.6%; P = 0.035). Eastern Cooperative Oncology Group performance status 0–1 (HR 0.37, 95% CI 0.22–0.62; P < 0.001) and the ICC group (HR 0.56, 95% CI 0.34–0.94; P = 0.028) were predictive of PFS. Subgroup‐to‐chemotherapy interaction revealed improved risk reduction for adenocarcinoma and EGFR mutation. Conclusion Combing chemotherapy with ICIs improved treatment efficacy over ICIs alone. The additional efficacy of chemotherapy may differ between histological subtypes and EGFR mutation status.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Comparison of a combination of chemotherapy and immune checkpoint inhibitors and immune checkpoint inhibitors alone for the treatment of advanced and metastatic non‐small cell lung cancer

et al. 2019

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“…Since breast cancers have overall lower mutation rates compared to other cancer types 5 , we used different mutation cutoffs to define BCs with high mutation rate to differentiate from commonly defined hypermutation in the literature. Given no standardized definition of high mutation in BCs in the literature 6,28,29 , we defined high mutation in breast cancer as the top 10% of the whole cohort, which was similar to other studies 8,28 . We rounded this number to 3 mutations/Mbps in TCGA for simplicity.…”

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confidence: 99%

Biologically Aggressive Phenotype and Anti-cancer Immunity Counterbalance in Breast Cancer with High Mutation Rate

Takahashi

Asaoka

Yan

et al. 2020

Sci Rep

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While cancer cells gain aggressiveness by mutations, abundant mutations release neoantigens, attracting anti-cancer immune cells. We hypothesized that in breast cancer (BC), where mutation is less common, tumors with high mutation rates demonstrate aggressive phenotypes and attract immune cells simultaneously. High mutation rates were defined as the top 10% of the mutation rate, utilizing TCGA and METABRIC transcriptomic data. Mutation rate did not impact survival although high mutation BCs were associated with aggressive clinical features, such as more frequent in ER-negative tumors (p < 0.01), in triple-negative subtype (p = 0.03), and increased MKI-67 mRnA expression (p < 0.01) in both cohorts. Tumors with high mutation rates were associated with APOBEC3B and homologous recombination deficiency, increasing neoantigen loads (all p < 0.01). Cell proliferation and immune activity pathways were enriched in BCs with high mutation rates. Furthermore, there were higher lymphocytes and M1 macrophage infiltration in high mutation BCs. Additionally, T-cell receptor diversity, cytolytic activity score (CYT), and T-cell exhaustion marker expression were significantly elevated in BCs with high mutation rates (all p < 0.01), indicating strong immunogenicity. In conclusion, enhanced immunity due to neoantigens can be one of possible forces to counterbalance aggressiveness of a high mutation rate, resulting in similar survival rates to low mutation BCs. Accumulation of somatic mutations, or somatic genome instability, has been the principle of carcinogenesis; cancer cells stem from a clone that has gained the somatically acquired genetic abnormalities, leading to malignant transformation and further progression 1. With advances in next-generation sequencing technologies, clinical interest in assessing mutation burden and identifying specific mutations in certain cancer types has been growing to utilize targeted therapies or to assess tumor biology, such as FoundationOne genomic panel testing 2-4. Mutation rates are variable among cancer types and outliers with significantly high mutation burdens, hypermutation, do exist in many cancer types 5. Interestingly, the definition of hypermutation has been variable in the literature 5-7 , although the common definition is usually greater than 10-100 mutations per Mega base pairs (Mbps). Campbell and colleagues recently performed comprehensive analysis of hypermutation in various tumor types, providing more insight into tumor evolution and identifying possible clinically actionable mutation signatures 6. The etiology of hypermutation varies between cancer types; ultraviolet (UV) light is the significant cause of mutations in melanoma, while smoking causes the mutations in non-small cell lung cancer (NSCLC) and head and neck squamous cell carcinoma (SCC) 7,8. Whereas UV light and smoking are examples of exogenous mutagens, there are endogenous processes for mutation, such as microsatellite instability (MSI), and Apolipoprotein

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“…These features are consistent with biomarkers associated with immune checkpoint inhibitors 29,30 . Patients with driver mutations such as EGFR mutations display a low mutation burden 31 , and the efficacy of immune checkpoint inhibitor in such patients is controversial 32 . The EGFR impact score identified patients with high PD-L1 expression and a high mutation burden.…”

Section: Discussionmentioning

confidence: 99%

A novel diagnostic system to evaluate epidermal growth factor receptor impact as a prognostic and therapeutic indicator for lung adenocarcinoma

Takakuwa

Mogushi

Han

et al. 2020

Sci Rep

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Many driver pathways for cancer cell proliferation have been reported. Driver pathway activation is often evaluated based on a single hotspot mutation such as EGFR L858R. However, because of complex intratumoral networks, the impact of a driver pathway cannot be predicted based on only a single gene mutation. Here, we developed a novel diagnostic system named the "eGfR impact score" which is based on multiplex mRNA expression profiles, which can predict the impact of the EGFR pathway in lung cancer cells and the effect of EGFR-tyrosine kinase inhibitors on malignancy. The EGFR impact score indicated robust predictive power for the prognosis of early-stage lung cancer because this score can evaluate the impact of the eGfR pathway on the tumor and genomic instability. Additionally, the molecular features of the poor prognostic group resembled those of biomarkers associated with immune checkpoint inhibitors. the eGfR impact score is a novel prognostic and therapeutic indicator for lung adenocarcinoma.

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Common driver mutations and smoking history affect tumor mutation burden in lung adenocarcinoma

Cited by 61 publications

References 27 publications

Comparison of a combination of chemotherapy and immune checkpoint inhibitors and immune checkpoint inhibitors alone for the treatment of advanced and metastatic non‐small cell lung cancer

Comparison of a combination of chemotherapy and immune checkpoint inhibitors and immune checkpoint inhibitors alone for the treatment of advanced and metastatic non‐small cell lung cancer

Biologically Aggressive Phenotype and Anti-cancer Immunity Counterbalance in Breast Cancer with High Mutation Rate

A novel diagnostic system to evaluate epidermal growth factor receptor impact as a prognostic and therapeutic indicator for lung adenocarcinoma

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