Correlations between pathogenic variants in <scp>DNA</scp> repair genes and anticancer treatment efficacy in stage <scp>IV</scp> non‐small cell lung cancer: A large real‐world cohort and review of the literature

Averbuch, Itamar; Tschernichovsky, Roi; Icht, Oded; Goldstein, Daniel A.; Mutai, Raz; Dudnik, Elizabeth; Rotem, Ofer; Peled, Nir; Allen, Aaron M.; Laufer‐Geva, Smadar; Goldberg, Yael; Zer, Alona

doi:10.1111/1759-7714.14902

Cited by 3 publications

(1 citation statement)

References 32 publications

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“…For example, DNA damage response pathway-altered biliary tract cancers exhibited favorable chemotherapy responses ( 123 ). In the stage 4 non-small cell lung cancer (NSCLC), pathogenic variants in DDR pathway genes was associated with higher efficacy of radiotherapy and ICIs ( 124 ). The efficacy of chemotherapy can be reduced by STING through suppressing DDR and genotoxicity and DNA instability ( 125 ).…”

Section: Cell Cycle Checkpoint and Dna Damage Repair Pathway Impacts ...mentioning

confidence: 99%

Immunogenic chemotherapy: great potential for improving response rates

Huang,

Ren,

Yang

et al. 2023

Front. Oncol.

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The activation of anti-tumor immunity is critical in treating cancers. Recent studies indicate that several chemotherapy agents can stimulate anti-tumor immunity by inducing immunogenic cell death and durably eradicate tumors. This suggests that immunogenic chemotherapy holds great potential for improving response rates. However, chemotherapy in practice has only had limited success in inducing long-term survival or cure of cancers when used either alone or in combination with immunotherapy. We think that this is because the importance of dose, schedule, and tumor model dependence of chemotherapy-activated anti-tumor immunity is under-appreciated. Here, we review immune modulation function of representative chemotherapy agents and propose a model of immunogenic chemotherapy-induced long-lasting responses that rely on synergetic interaction between killing tumor cells and inducing anti-tumor immunity. We comb through several chemotherapy treatment schedules, and identify the needs for chemotherapy dose and schedule optimization and combination therapy with immunotherapy when chemotherapy dosage or immune responsiveness is too low. We further review tumor cell intrinsic factors that affect the optimal chemotherapy dose and schedule. Lastly, we review the biomarkers indicating responsiveness to chemotherapy and/or immunotherapy treatments. A deep understanding of how chemotherapy activates anti-tumor immunity and how to monitor its responsiveness can lead to the development of more effective chemotherapy or chemo-immunotherapy, thereby improving the efficacy of cancer treatment.

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Section: Cell Cycle Checkpoint and Dna Damage Repair Pathway Impacts ...mentioning

confidence: 99%

Immunogenic chemotherapy: great potential for improving response rates

Huang,

Ren,

Yang

et al. 2023

Front. Oncol.

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Correlations between pathogenic variants in DNA repair genes and anticancer treatment efficacy in stage IV non‐small cell lung cancer: A large real‐world cohort and review of the literature

et al. 2023

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Background Mutations in genes involved in DNA damage repair (DDR), a hallmark of cancer, are associated with increased cancer cell sensitivity to certain therapies. This study sought to evaluate the association of DDR pathogenic variants with treatment efficacy in patients with advanced non‐small cell lung cancer (NSCLC). Methods A retrospective cohort of consecutive patients with advanced NSCLC attending a tertiary medical center who underwent next‐generation sequencing in 01/2015‐8/2020 were clustered according to DDR gene status and compared for overall response rate (ORR), progression‐free survival (PFS) (patients receiving systemic therapy), local PFS (patients receiving definitive radiotherapy), and overall survival (OS) using log‐rank and Cox regression analyses. Results Of 225 patients with a clear tumor status, 42 had a pathogenic/likely pathogenic DDR variant (pDDR), and 183 had no DDR variant (wtDDR). Overall survival was similar in the two groups (24.2 vs. 23.1 months, p = 0.63). The pDDR group had a higher median local PFS after radiotherapy (median 45 months vs. 9.9 months, respectively; p = 0.044), a higher ORR (88.9% vs. 36.2%, p = 0.04), and a longer median PFS (not reached vs. 6.0 months, p = 0.01) in patients treated with immune checkpoint blockade. There was no difference in ORR, median PFS, and median OS in patients treated with platinum‐based chemotherapy. Conclusion Our retrospective data suggest that in patients with stage 4 NSCLC, pathogenic variants in DDR pathway genes may be associated with higher efficacy of radiotherapy and immune checkpoint inhibitors (ICIs). This should be further explored prospectively.

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Long-term follow-up of combination therapy with pembrolizumab and anlotinib in thoracic SMARCA4-deficient undifferentiated tumor: a case report and molecular features

Duan,

Xu,

Zhang

et al. 2024

Front. Oncol.

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Thoracic SMARCA4-deficient undifferentiated tumors (SMARCA4-UTs), recently recognized as a rare malignancy described in the 5th edition of the World Health Organization Classification of Tumors, are characterized by an inactivating mutation in SMARCA4, most commonly found in the mediastinum of male smokers. Despite the aggressive nature and poor prognosis associated with these tumors, which have a median survival time of approximately 4-7 months, no standardized treatment guidelines are currently established. There are currently no reported cases of extended progression-free survival (PFS) in SMARCA4-UT patients treated with surgery and immunotherapy. Here, we report the clinical features and genomic information of a SMARCA4-UT case in which the patient responded significantly to a combination therapy involving surgery, immunotherapy, and amlotinib. A 56-year-old male non-smoker presented with a mass in the superior lobe of left lung and left hilar adenopathy. A left upper lobectomy and lymphadenectomy were performed, and postoperative pathology confirmed that the tumor was Thoracic SMARCA4-UT. The patient subsequently received chemotherapy with pemetrexed and carboplatin. Five months post-operation, the disease progressed with left adrenal metastasis and mediastinal adenopathy. An adrenalectomy was performed, followed by whole exon sequencing (WES). SMARCA4, SMARCA2 and SMARCA1 gene mutations were detected in this case. Given a tumor proportion score (TPS) of 60% for programmed death-ligand 1(22C3)immunoexpression and high TMB(361.32 muts/Mb), a combination of Pembrolizumab plus anlotinib was initiated as a second-line approach. After 46 cycles, the patient demonstrated no disease progression with a PR lasting 31 months and long progression-free survival(PFS) of 43 months. The lung tumor was initially detected in September 2020, and the patient remained alive at the latest follow-up in November 2024. This case offers a long-term follow-up of the effectiveness and safety of combining pembrolizumab and anlotinib in advanced SMARCA4-UT, and substantiates the role of long-term immunotherapy in preventing radiographic/clinical recurrence following surgery. This case illustrates new potential efficacy of immunotherapy in combination with surgery as a treatment approach of SMARCA4-UT.

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Correlations between pathogenic variants in DNA repair genes and anticancer treatment efficacy in stage IV non‐small cell lung cancer: A large real‐world cohort and review of the literature

Cited by 3 publications

References 32 publications

Immunogenic chemotherapy: great potential for improving response rates

Immunogenic chemotherapy: great potential for improving response rates

Correlations between pathogenic variants in DNA repair genes and anticancer treatment efficacy in stage IV non‐small cell lung cancer: A large real‐world cohort and review of the literature

Long-term follow-up of combination therapy with pembrolizumab and anlotinib in thoracic SMARCA4-deficient undifferentiated tumor: a case report and molecular features

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