Clinical Outcome of ALK -Positive Non–Small Cell Lung Cancer (NSCLC) Patients with De Novo EGFR or KRAS Co-Mutations Receiving Tyrosine Kinase Inhibitors (TKIs)

Schmid, Sabine; Gautschi, Oliver; Rothschild, Sacha I.; Mark, Michael; Froesch, Patrizia; Klingbiel, Dirk; Reichegger, Hermann; Jochum, Wolfram; Diebold, Joachim; Früh, Martin

doi:10.1016/j.jtho.2016.12.003

Cited by 62 publications

(45 citation statements)

References 30 publications

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“…ALK rearrangements have generally been reported to be mutually exclusive with other driver alterations in NSCLC such as EGFR and KRAS mutations, although few studies have shown that they can coexist [30][31][32]. We found KRAS mutations in three of the examined patients, which likely represented different tumor clones, indicative of the heterogenous nature of lung cancer.…”

Section: Discussionmentioning

confidence: 55%

“…However, the KRAS mutation was found at an AF of 79% in the diagnostic biopsy taken 5 years earlier in connection with curative-intended stereotactic treatment (Table S3). Thus, KRAS mutations and ALK rearrangements can coexist, and, interestingly, the three patients with this genomic profile had response or stable disease at their first evaluation following ALK TKI start [32].…”

Section: Discussionmentioning

confidence: 96%

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Genomic Profiling of Circulating Tumor DNA Predicts Outcome and Demonstrates Tumor Evolution in ALK-Positive Non-Small Cell Lung Cancer Patients

Madsen

Winther‐Larsen

McCulloch

et al. 2020

Cancers

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With the rapid development of targeted therapies for the treatment of cancer, methods for predicting response and outcome are in high demand. Non-small cell lung cancer driven by genomic rearrangements of the anaplastic lymphoma kinase (ALK) gene can be successfully treated with ALK-targeted therapy. Unfortunately, a subset of patients does not respond, and all patients ultimately acquire resistance, highlighting the need for better clinical tools to manage these patients. Here, we performed targeted next-generation sequencing on plasma circulating tumor DNA (ctDNA) from 24 patients to assess the clinical utility of ctDNA genomic profiling. Patients with detectable ctDNA prior to treatment had worse progression-free survival (PFS) than those without (median 8.7 vs. 15.2 months, p = 0.028). In addition, the presence of ctDNA within two months after treatment initiation predicted inferior PFS (median 4.6 vs. 14.5 months, p = 0.028). Longitudinal monitoring of ctDNA with droplet digital PCR during treatment reflected the radiological response and revealed potential acquired resistance mutations. Interestingly, an increase in the ctDNA concentration was evident prior to the determination of progressive disease by conventional radiological imaging, with a median lead time of 69 days (range 30–113). Genomic profiling of ctDNA is a promising tool for predicting outcome and monitoring response to targeted therapy.

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Section: Discussionmentioning

confidence: 55%

Section: Discussionmentioning

confidence: 96%

Genomic Profiling of Circulating Tumor DNA Predicts Outcome and Demonstrates Tumor Evolution in ALK-Positive Non-Small Cell Lung Cancer Patients

Madsen

Winther‐Larsen

McCulloch

et al. 2020

Cancers

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“…30 Recently, however, some cases of NSCLC with coalteration have been reported in the literature, [38][39][40][41] and these coaltered patients may benefit from treatment with more than one targeted drug. 42 There were 33 cases (3.7%) with coalteration in our study, including EGFR/PIK3CA (2.1%, 19 cases), EGFR/HER2 (0.7%, six cases), HER2/KRAS (0.3%, three cases), EGFR/KRAS (0.1%, one case), EGFR/ ROS1 (0.1%, one case), EGFR/NRAS (0.1%, one case), KRAS/PIK3CA (0.1%, one case), and a triple KRAS/ PIK3CA/HER2 (0.1%, one case) coalteration. Previous studies revealed that KRAS, BRAF, and PIK3CA mutation have been related to efficacy of EGFR-TKI, metastasis or overall survival.…”

Section: Discussionmentioning

confidence: 99%

Status of 10 targeted genes of non‐small cell lung cancer in eastern China: A study of 884 patients based on NGS in a single institution

Ran

et al. 2020

Thoracic Cancer

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Background The status of targeted genes and the association between targeted genes and clinicopathological features in Chinese lung cancer patients remains to be elucidated. Methods The status of 10 targeted genes was evaluated by next‐generation sequencing (NGS) in 884 non‐small cell lung cancer (NSCLC) patients. The relationship between gene alterations and clinicopathological characters was analyzed. Results Overall, 684 (77.4%) patients harbored gene alterations, and EGFR (510, 57.7%) was found to be the most common type of mutation followed by KRAS (91, 10.3%), HER2 (38, 4.3%), PIK3CA (32, 3.6%), ALK (21, 2.4%), BRAF (10, 1.1%), ROS1 (5, 0.6%), RET (5, 0.6%), MET (4, 0.5%) and NRAS (1, 0.1%). Gene alterations were more frequent in females, non‐smokers and adenocarcinoma (P < 0.001). EGFR mutations were associated with women, non‐smokers, normal level of serum tumor markers, and adenocarcinoma (P < 0.001). Patients without lymph node metastasis (P = 0.012), or early stage disease (P < 0.001) exhibited a higher EGFR mutation rate. KRAS mutations tended to arise in men (P < 0.001), smokers (P < 0.001) and patients with higher levels of serum tumor markers (P = 0.048). A mucus‐producing component was associated with KRAS (P < 0.001), ROS1 (P = 0.033) and ALK (P < 0.001) alterations. ALK and ROS1 rearrangements were more frequent in micropapillary structures (P = 0.004, P = 0.012). BRAF mutation was associated with advanced disease patients and micropapillary structure (P < 0.001). PIK3CA mutation was more likely to be found in elderly patients (P = 0.014). Some patients had synchronous gene alterations, including EGFR/PIK3CA, EGFR/HER2, HER2/KRAS, EGFR/KRAS, EGFR/ROS1, EGFR/NRAS, KRAS/PIK3CA, KRAS/PIK3CA/HER2. Conclusions Most patients had at least one genetic alteration, and individual patients harbored synchronous mutation. Each gene alteration had unique clinicopathological characteristics. Key points Significant findings of the study This study revealed the frequency and distribution of 10 targeted gene abnormalities and their association with clinicopathological parameters of Chinese non‐small cell lung cancer (NSCLC) patients in eastern China. What this study adds Some rare synchronous mutations were detected in our study by next‐generation sequencing (NGS).

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“…Concomitant driver gene mutations in EGFR and ALK have been detected in 1.3%‐15.4% of the patients with non‐small cell lung cancer (NSCLC), depending on the method used . Among the patients harboring EGFR / ALK coalterations, some responded to treatment with an EGFR‐TKI (ie, gefitinib, erlotinib, icotinib, or afatinib), while others responded to treatment with an ALK‐TKI (crizotinib) or both . To the best of our knowledge, there is currently no consensus for the optimal management for these patients.…”

Section: Introductionmentioning

confidence: 99%

“…KRAS proto‐oncogene ( KRAS ) and B‐Raf proto‐oncogene ( BRAF ) have been frequently studied in NSCLC, and mutation testing for these genes is recommended in the National Comprehensive Cancer Network guidelines for NSCLC KRAS mutations have been found more frequently in non‐Asian patients and former or current smokers and have been associated with mucinous adenocarcinoma . Furthermore, evidence suggested that KRAS mutations combined with EGFR mutations or ALK rearrangements could negatively impact the effects of TKI therapy . Meanwhile, the BRAF V600E mutation has been reported to be mutually exclusive with EGFR and KRAS mutations but has been found to co‐occur with other driver gene mutations …”

Section: Introductionmentioning

confidence: 99%

Clinical features and therapeutic options in non‐small cell lung cancer patients with concomitant mutations of EGFR, ALK, ROS1, KRAS or BRAF

Zhuang

Zhao

et al. 2019

Cancer Medicine

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Background Although oncogenic driver mutations were thought to be mutually exclusive in non‐small cell lung cancer (NSCLC), certain tumors harbor co‐occurring mutations and represent a rare molecular subtype. The evaluation of the clinical features and therapeutic response associated with this NSCLC subtype will be vital for understanding the heterogeneity of treatment response and improving the management of these patients. Methods This retrospective study included 3774 samples from patients diagnosed with NSCLC. All samples were screened for EGFR, ALK, ROS1, KRAS, and BRAF mutation using the amplification‐refractory mutation system. The relationship between concomitant driver mutations and clinicopathologic characteristics, and patient clinical outcomes were evaluated. Results Sixty‐three (1.7%) samples had more than one driver gene mutation. Among these, 43 were coalterations with an EGFR mutation, 20 with an ALK rearrangement, and eight with an ROS1 rearrangement. Except for ROS1 concomitant mutations that were more frequent in male patients (87.5%, P = 0.020), the clinicopathological features of the concomitant mutation patients were not significantly different from those harboring a single EGFR, ALK, or ROS1 mutation. Furthermore, first‐line EGFR‐TKI treatment did not significantly improve the progression‐free survival (PFS) of patients harboring EGFR concomitant mutation, compared to patients harboring a single EGFR mutation. However, for EGFR concomitant mutation patients, TKI therapy was more effective than chemotherapy (median PFS of 10.8 vs 5.2 months, P = 0.023). Lastly, KRAS mutations did not influence the EGFR‐TKI therapy treatment effect. Conclusion In this study, concomitant mutations were found in 1.7% of the NSCLC. EGFR‐TKI therapy was more effective than chemotherapy for patients harboring EGFR concomitant mutation, and ROS1 concomitant mutations were more frequent in male patients. For patients harboring coalterations with an ALK or ROS1 rearrangement, we should be cautious when considering the therapeutic options.

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Clinical Outcome of ALK -Positive Non–Small Cell Lung Cancer (NSCLC) Patients with De Novo EGFR or KRAS Co-Mutations Receiving Tyrosine Kinase Inhibitors (TKIs)

Cited by 62 publications

References 30 publications

Genomic Profiling of Circulating Tumor DNA Predicts Outcome and Demonstrates Tumor Evolution in ALK-Positive Non-Small Cell Lung Cancer Patients

Genomic Profiling of Circulating Tumor DNA Predicts Outcome and Demonstrates Tumor Evolution in ALK-Positive Non-Small Cell Lung Cancer Patients

Status of 10 targeted genes of non‐small cell lung cancer in eastern China: A study of 884 patients based on NGS in a single institution

Clinical features and therapeutic options in non‐small cell lung cancer patients with concomitant mutations of EGFR, ALK, ROS1, KRAS or BRAF

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