High Prevalence of Concomitant Oncogene Mutations in Prospectively Identified Patients with ROS1-Positive Metastatic Lung Cancer

Wiesweg, Marcel; Eberhardt, Wilfried; Reis, Henning; Ting, Saskia; Savvidou, Nikoleta; Skiba, Charlotte; Herold, Thomas; Christoph, Daniel C.; Meiler, Johannes; Worm, Karl; Kasper, Stefan; Theegarten, Dirk; Hense, J.; Hager, Thomas; Darwiche, Kaid; Oezkan, Filiz; Aigner, Clemens; Welter, Stefan; Kühl, Hilmar; Stuschke, Martin; Schmid, Kurt Werner; Schüler, Martin

doi:10.1016/j.jtho.2016.08.137

Cited by 68 publications

(52 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In the recently published report by Wiesweg and colleagues, 12 36% (9 of 25) of the ROS1 -positive cases were found to harbor overlapping oncogenic mutations in EGFR, KRAS, PIK3CA , or BRAF . If this were the true frequency of overlap, then we would expect approximately 22 cases in the MGH cohort to have a concurrent driver mutation.…”

Section: Resultsmentioning

confidence: 96%

“…22 In one recent study reporting a high prevalence of concurrent driver mutations with ROS1 , 25 ROS1 IHC-positive cases were examined. 12 Of these, only roughly half (n = 13) were positive for ROS1 rearrangement by FISH. Several of the cases found to harbor concomitant mutations in EGFR, KRAS, BRAF , and PIK3CA were, in fact, ROS1 FISH-negative, 12 suggesting that the IHC result for these cases may have represented false positives.…”

Section: Discussionmentioning

confidence: 98%

“…11,12,18–21 One explanation for the discrepancy may be the difference in ROS1 testing techniques. At present, options for ROS1 detection include IHC, FISH, RT-PCR, and DNA or RNA sequencing.…”

Section: Discussionmentioning

confidence: 99%

“…2,4,6,10 However, conflicting findings have since been reported. 11,12 For example, in a recent analysis of 25 NSCLCs positive for ROS1 rearrangement by immunohistochemistry (IHC), 36% were reported to harbor concomitant oncogenic driver mutations (including in EGFR, KRAS, PIK3CA , and BRAF ). 12 Five of the six patients with tumors harboring concurrent EGFR mutations in this cohort derived significant clinical benefit from an EGFR inhibitor and did not receive a ROS1-targeted therapy, 12 raising the question of whether ROS1 rearrangements truly define a distinct molecular subset of NSCLC.…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

ROS1 Fusions Rarely Overlap with Other Oncogenic Drivers in Non–Small Cell Lung Cancer

Lin

Ritterhouse

Ali³

et al. 2017

Journal of Thoracic Oncology

View full text Add to dashboard Cite

Introduction Chromosomal rearrangements involving the ROS proto-oncogene 1 receptor tyrosine kinase gene (ROS1) define a distinct molecular subset of non-small cell lung cancer (NSCLC) with sensitivity to ROS1 inhibitors. Recent reports have suggested a significant overlap between ROS1 fusions and other oncogenic driver alterations, including mutations in epidermal growth factor receptor (EGFR) and KRAS proto-oncogene (KRAS). Methods We identified patients at our institution with ROS1-rearranged NSCLC who had undergone testing for genetic alterations in additional oncogenes, including EGFR, KRAS, and anaplastic lymphoma kinase (ALK). Clinicopathologic features and genetic testing results were reviewed. We also examined a separate database of ROS1-rearranged NSCLCs identified through a commercial FoundationOne assay. Results Among 62 patients with ROS1-rearranged NSCLC evaluated at our institution, none harbored concurrent ALK fusions (0%) or EGFR activating mutations (0%). KRAS mutations were detected in two cases (3.2%), one of which harbored a concurrent non-canonical KRAS I24N mutation of unknown biological significance. In a separate ROS1 FISH-positive case, targeted sequencing failed to confirm a ROS1 fusion, but instead identified a KRAS G13D mutation. No concurrent mutations in BRAF, ERBB2, PIK3CA, AKT1, or MAP2K1 were detected. Analysis of an independent dataset of 166 ROS1-rearranged NSCLCs identified by FoundationOne demonstrated rare cases with co-occurring driver mutations in EGFR (1/166) and KRAS (3/166), and no cases with co-occurring ROS1 and ALK rearrangements. Conclusions ROS1 rearrangements rarely overlap with alterations in EGFR, KRAS, ALK, or other targetable oncogenes in NSCLC.

show abstract

Section: Resultsmentioning

confidence: 96%

Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

ROS1 Fusions Rarely Overlap with Other Oncogenic Drivers in Non–Small Cell Lung Cancer

Lin

Ritterhouse

Ali³

et al. 2017

Journal of Thoracic Oncology

View full text Add to dashboard Cite

show abstract

“…An early analysis of 1,073 NSCLC tumor specimens demonstrated no overlap between ROS1 and ALK rearrangements (2). However, conflicting findings have subsequently been reported, with some later studies suggesting a co-occurrence of ROS1 rearrangements and mutations in EGFR (28, 44), KRAS (44), or BRAF (44). In the most recent and largest series to date, a total of 220 cases of ROS1 -rearranged NSCLCs were examined (45).…”

Section: Clinicopathologic Characteristics Of Ros1-rearranged Lung Camentioning

confidence: 99%

Recent Advances in Targeting ROS1 in Lung Cancer

Lin

Shaw

2017

Journal of Thoracic Oncology

214

208

View full text Add to dashboard Cite

ROS1 is a validated therapeutic target in non-small cell lung cancer (NSCLC). In a phase I study, the multi-targeted MET/ALK/ROS1 inhibitor crizotinib demonstrated remarkable efficacy in ROS1-rearranged NSCLCs, and consequently gained approval by the United States Food and Drug Administration as well as the European Medicines Agency in 2016. However, similar to other oncogene-driven lung cancers, ROS1-rearranged lung cancers treated with crizotinib eventually acquire resistance, leading to disease relapse. Novel ROS1 inhibitors and therapeutic strategies are therefore needed. Insights into the mechanisms of resistance to ROS1-directed tyrosine kinase inhibitors (TKIs) are now beginning to emerge and are helping to guide the development of new ROS1 inhibitors. This review discusses the biology and diagnosis of ROS1-rearranged NSCLC, and current and emerging treatment options for this disease. Future challenges in the field are highlighted.

show abstract

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

View full text Add to dashboard Cite

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.

show abstract

High Prevalence of Concomitant Oncogene Mutations in Prospectively Identified Patients with ROS1-Positive Metastatic Lung Cancer

Abstract: ROS1-positive metastatic lung adenocarcinomas frequently harbor concomitant oncogenic driver mutations. Levels of ROS1 FISH-positive events are variable over time. This heterogeneity provides additional therapeutic options if discovered by multiplex biomarker testing and repeat biopsies.

Cited by 68 publications

References 47 publications

ROS1 Fusions Rarely Overlap with Other Oncogenic Drivers in Non–Small Cell Lung Cancer

ROS1 Fusions Rarely Overlap with Other Oncogenic Drivers in Non–Small Cell Lung Cancer

Recent Advances in Targeting ROS1 in Lung Cancer

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

Contact Info

Product

Resources

About