Concomitant genetic alterations are associated with response to EGFR targeted therapy in patients with lung adenocarcinoma

Chen, Hualin; Liu, Meilian; Dai, Zhiwei; Li, Shujun; Luo, Yiping; Wang, Yongcun; Su, Wenmei; Cai, Weiping; Yang, Donghong; Huang, Jian; Yang, Zhitao

doi:10.21037/tlcr-20-679

Cited by 14 publications

(11 citation statements)

References 34 publications

(32 reference statements)

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“…Though seldom previous research explored the clinical implications of concomitant mutations from multiple pathways in HER2-related signaling network for breast cancer, several previous studies [ 21 – 25 ] in EGFR-mutant advanced non-small cell lung cancer investigated the relationship between concomitant genetic alterations and survival outcomes. The results based on updated data in this analysis is consistent with previous studies [ 21 – 25 ], suggesting that significant concomitant genetic mutations may play a key role in drug resistance and tumor progression, and may be a significant factor affecting clinical survival outcomes [ 24 ]. Besides that, significantly shorter PFS was observed in the patients with PIK3CA mutation and ERBB2 mutation via the biomarker analysis of ctDNA when compared to those of wide type in this study.…”

Section: Discussionsupporting

confidence: 90%

Survival benefit and biomarker analysis of pyrotinib or pyrotinib plus capecitabine for patients with HER2-positive metastatic breast cancer: a pooled analysis of two phase I studies

Guan

et al. 2023

Biomark Res

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Background Pyrotinib, a novel irreversible tyrosine kinase inhibitor (TKI), has demonstrated promising antitumor activity to improve the overall response rate and progression-free survival (PFS) in patients with HER2-positive metastatic breast cancer (MBC). However, the survival data of pyrotinib or pyrotinib plus capecitabine in HER2-positive MBC remains scarce. Thus, we summarized the updated individual patient data from the phase I trials of pyrotinib or pyrotinib plus capecitabine, to provide a cumulative assessment on long-term outcomes and associated biomarker analysis of irreversible TKIs in HER2-positive MBC patients. Methods We performed a pooled analysis of the phase I trials for pyrotinib or pyrotinib plus capecitabine based on the updated survival data from individual patients. Next-generation sequencing was performed on circulating tumor DNA for predictive biomarkers. Results A total of 66 patients were enrolled, including 38 patients from the phase Ib trial for pyrotinib and 28 patients from the phase Ic trial for pyrotinib plus capecitabine. The median follow-up duration was 84.2 months (95% CI: 74.7–93.7 months). The estimated median PFS in the entire cohort was 9.2 months (95% CI: 5.4–12.9 months) and median OS was 31.0 months (95% CI: 16.5–45.5 months). The median PFS was 8.2 months in the pyrotinib monotherapy cohort and 22.1 months in the pyrotinib plus capecitabine group, while the median OS was 27.1 months in the pyrotinib monotherapy group and 37.4 months in the pyrotinib plus capecitabine group. Biomarker analysis suggested that the patients harbored concomitant mutations from multiple pathways in HER2-related signaling network (HER2 bypass signaling pathways, PI3K/Akt/mTOR pathway and TP53) were observed with significantly poorer PFS and OS when compared to those with none or one genetic alteration (median PFS, 7.3 vs. 26.1 months, P = 0.003; median OS, 25.1 vs. 48.0 months, P = 0.013). Conclusions The updated survival results based on individual patient data from the phase I trials of pyrotinib-based regimen revealed promising PFS and OS in HER2-positive MBC. Concomitant mutations from multiple pathways in HER2-related signaling network may be a potential efficacy and prognosis biomarker for pyrotinib in HER2-positive MBC. Trial registration ClinicalTrials.gov. (NCT01937689, NCT02361112).

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Section: Discussionsupporting

confidence: 90%

Survival benefit and biomarker analysis of pyrotinib or pyrotinib plus capecitabine for patients with HER2-positive metastatic breast cancer: a pooled analysis of two phase I studies

Guan

et al. 2023

Biomark Res

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“…Their results showed that TP53 mutations were independently associated with worse outcomes in cohort 1, while in cohort 2, TP53 , RB1 , and PTEN mutations as well as MDM2 amplifications all resulted in shorter PFS ( 11 ), suggesting that concurrent genomic alterations accelerated the resistance to EGFR TKIs. Additionally, co-occurring TP53 mutations were reported to be associated with worse outcomes of EGFR TKIs in several studies ( 10 , 11 , 13 , 32 ). However, these concomitant genetic alterations in previous studies were mostly considered untargetable without available drugs.…”

Section: Discussionmentioning

confidence: 99%

Co-Occurring Potentially Actionable Oncogenic Drivers in Non-Small Cell Lung Cancer

et al. 2021

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BackgroundSeveral oncogenic drivers in non-small cell lung cancer (NSCLC) are considered actionable with available or promising targeted therapies. Although targetable drivers rarely overlap with each other, there were a minority of patients harboring co-occurring actionable oncogenic targets, whose clinical characteristics and prognosis are not yet clear.MethodsA total of 3,077 patients with NSCLC who underwent molecular analysis by NGS were included, and their demographic and clinical data were retrospectively collected.ResultsOur study found that the frequency of NSCLC patients harboring co-occurring potentially actionable alterations was approximately 1.5% (46/3077); after excluding patients with EGFR-undetermined mutations, the incidence was 1.3% (40/3077); 80% (37/46) harbored both EGFR mutations and other potentially actionable drivers such as MET amplification (21.6%; 8/37) and alterations in ERBB2 including mutations (27%; 10/37) and amplification (21.6%; 8/37); other combinations of potentially actionable drivers including alterations in ERBB2, KRAS, MET, ALK, and RET were also identified. Additionally, de novo MET/ERBB2 amplification in patients harboring EGFR-mutant NSCLC treated with first-generation EGFR tyrosine kinase inhibitors (TKIs) was associated with shorter PFS (p < 0.05). The efficacy of TKIs in NSCLC patients harboring other co-occurring potentially actionable drivers varied across different molecular subtypes.ConclusionsApproximately 1.5% of NSCLCs harbored co-occurring potentially actionable oncogenic drivers, commonly involving EGFR mutations. Co-occurring actionable targets may impact the efficacy of TKIs; therefore, future clinical trials in these patients should be anticipated to tailor the combination or sequential treatment strategies.

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“…[31] Several studies have indicated that concomitant EGFR mutations affect the prognosis of patients with cancer. Chen et al [46] found that patients with concomitant mutations had significantly lower ORR (43.8 vs. 80.0%; P = 0.02) and PFS (P < 0.01) than those without concomitant mutations, after receiving EGFR-TKI treatment. In the BENEFIT phase 2 clinical trial, among patients with EFGR mutations, patients with single EGFR mutations had a better prognosis than patients with concomitant tumor suppressor gene mutations and concomitant oncogene mutations, with a median PFS duration of 13.2 (95% CI: 11.5-15.0) months, 9.3 (95% CI: 7.6-11.0) months, and 4.7 (95% CI: 1.9-9.3) months, respectively.…”

Section: Egfr Concomitant Mutationsmentioning

confidence: 99%

Epidermal growth factor receptor compound and concomitant mutations: advances in precision treatment strategies

Bai

Guo

et al. 2023

Chinese Medical Journal

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Epidermal growth factor receptor (EGFR) mutations are common oncogenic driver mutations in patients with non-small cell lung cancer (NSCLC). The application of EGFR-tyrosine kinase inhibitors (TKIs) is beneficial for patients with advanced and early-stage NSCLC. With the development of next-generation sequencing technology, numerous patients have been found to have more than one genetic mutation in addition to a single EGFR mutation; however, the efficacy of conventional EGFR-TKIs and the optimal treatments for such patients remain largely unknown. Thus, we review the incidence, prognosis, and current treatment regimens of EGFR compound mutations and EGFR concomitant mutations to provide treatment recommendations and guidance for patients with these mutations.

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Concomitant genetic alterations are associated with response to EGFR targeted therapy in patients with lung adenocarcinoma

Cited by 14 publications

References 34 publications

Survival benefit and biomarker analysis of pyrotinib or pyrotinib plus capecitabine for patients with HER2-positive metastatic breast cancer: a pooled analysis of two phase I studies

Survival benefit and biomarker analysis of pyrotinib or pyrotinib plus capecitabine for patients with HER2-positive metastatic breast cancer: a pooled analysis of two phase I studies

Co-Occurring Potentially Actionable Oncogenic Drivers in Non-Small Cell Lung Cancer

Epidermal growth factor receptor compound and concomitant mutations: advances in precision treatment strategies

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