Poor Prognosis of Pulmonary Adenosquamous Carcinoma with NRAS and HRAS Double Mutation
Authors Zhao J, Zhang X, He M, Chen X, Cui X, Qin T, Niu X, Zhao L
Received 4 December 2020
Accepted for publication 22 January 2021
Published 17 February 2021 Volume 2021:14 Pages 1113—1116
Checked for plagiarism Yes
Review by Single anonymous peer review
Peer reviewer comments 2
Editor who approved publication: Prof. Dr. Nicola Silvestris
Jidong Zhao,1 Xiangmei Zhang,2 Ming He,1 Xin Chen,1 Xing Cui,1 Tian Qin,3 Xueliang Niu,3 Liyan Zhao4
1Department of Thoracic Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, People’s Republic of China; 2Research Center, The Fourth Hospital of Hebei Medical University, Shijiazhuang, People’s Republic of China; 3Medical Department, Burning Rock Biotech, Guangzhou, People’s Republic of China; 4Department of Internal Medicine, The First Hospital of Xingtai, Xingtai, People’s Republic of China
Correspondence: Xin Chen
Department of Thoracic Surgery, The Fourth Hospital of Hebei Medical University, No. 12, Jiankang Road, Shijiazhuang, Hebei Province, 050010, People’s Republic of China
Abstract: RAS mutations constitute one of the major tumorigenic mechanisms and are detected in approximately 20% of lung cancers. The most frequent mutated and well-studied RAS isoform is KRAS, which is associated with an overall poor prognosis in non-small-cell lung cancer (NSCLC). However, the clinical significances of NRAS and HRAS in NSCLC are rarely reported. Here, we present a 58-year-old male smoker who was diagnosed with stage IV lung adenosquamous carcinoma. A rare NRAS and HRAS double mutation was detected in the primary tumor and lymph node samples using next-generation sequencing (NGS). The patient showed rapid disease progression and passed away due to respiratory failure after 15 days of osimertinib in combination with cisplatin. To the best of our knowledge, this is the first report associating NRAS and HRAS double mutation in the poor prognosis of NSCLC.
Keywords: NSCLC, NRAS, HRAS
The RAS oncogene affects numerous cellular functions, including proliferation, growth, apoptosis, migration, division, and differentiation of the cells. It has 3 known isoforms: Harvey-RAS (HRAS), Kirsten-RAS (KRAS), and neuroblastoma-RAS (NRAS).1 The incidence of KRAS mutation in lung adenocarcinoma is between 12% and 36%. Previous studies have demonstrated that KRAS mutation frequently occurs in lung adenocarcinoma patients who are former or current smokers and are associated with poor overall prognosis.2,3 In contrast, NRAS and HRAS mutations are extremely rare in lung cancer regardless of histopathological subtypes, with only a few cases reported in the literature. Here, we present a case of pulmonary adenosquamous carcinoma harboring NRAS and HRAS double mutation, who failed to respond to chemotherapy plus targeted therapy.
A 58-year-old male smoker presented to our hospital with one-month history of chest and back pain. The performance status (PS) value of the patient was 0. Systemic evaluation including brain magnetic resonance imaging (MRI) and contrast-enhanced computed tomography (CT) scan showed a cavitary nodule on the inferior lobe of the right lung and the presence of malignant pleural effusion (Figure 1). Histopathology review of the tissue biopsy sample suggested stage IV poorly differentiated carcinoma. Twelve days after admission, malignant pleural effusion was aggravated and a video-assisted thoracoscopic lobectomy and lymph node dissection was performed for symptom management. Pathological examination of tumor, visceral pleura, and lymph nodes confirmed the diagnosis of poorly differentiated adenosquamous carcinoma and the presence of tumor cells in the visceral pleura and lymph nodes. Amplification refractory mutation system (ARMS)-polymerase chain reaction (PCR) assay was performed using pleural effusion samples to profile the EGFR mutation status, which showed weak signals for L858R and T790M mutations (CT value: 43.83 and 40.67, respectively, Figure 2A). The patient was administered with third-generation EGFR-TKI osimertinib (150 mg, orally thrice daily) combined with cisplatin (40 mg every ten days). After 5 days of osimertinib treatment, pleural effusion was reduced. Unfortunately, the patient showed a rapid disease progression and died of respiratory failure after 15 days of osimertinib plus cisplatin administration. To understand the underlying mechanism of treatment failure, both surgical and lymph node tissue samples were subjected to capture-based ultra-deep sequencing that target the exons and critical introns of 520 cancer-related genes (Oncoscreen PlusTM, Burning Rock Biotech, China). HRAS Q61L and NRAS Q61K were consistently found in the primary tumor and lymph nodes (Figure 2B and C). However, EGFR mutations were not detected, indicating that the EGFR L858R and T790M detected by ARMS-PCR may be false-positive mutations.
Figure 1 Chest CT at the time of the diagnosis.
Figure 2 ARMS-PCR demonstrated EGFR mutations L858R and T790M (A) and NGS identified HRAS Q61L (B) and NRAS Q61K (C) mutations.
This case reported the poor prognosis of pulmonary adenosquamous carcinoma with NRAS and HRAS mutation. The patient had a rapid progression leading to death. To the best of our knowledge, this is the first case which describes the detection of NRAS/HRAS double mutation and its prognostic value in lung cancer.
RAS mutations constitute a major tumorigenic mechanism and are detectable in approximately 20% of lung cancers. The most common KRAS mutations account for 80–90% of all RAS mutations. KRAS mutations are generally considered to be a negative predictive factor for EGFR-tyrosine kinase inhibitor (TKI) therapy and are associated with a poor overall prognosis in NSCLC.2,3 HRAS and NRAS mutations have been reported in various cancer types including head and neck carcinoma, gastrointestinal cancer, genitourinary cancer, and malignant melanoma.4–7 The frequency of HRAS and NRAS mutations in bladder cancer is up to 84%.8 In colorectal cancer, patients with any known KRAS or NRAS mutation should not be treated with either cetuximab or panitumumab according to the NCCN guidelines. Likewise, HRAS-mutated colorectal cancer also results in the resistance to anti-EGFR therapies.9 However, HRAS and NRAS mutations are extremely rare in lung cancer; hence, studies documenting their clinical significance are scarce. Cathcart-Rake et al have reported an elderly former smoker with HRAS mutant NSCLC. The patient had a rapid progression from stage IB disease to metastatic adenocarcinoma and death, indicating that HRAS mutations are associated with poor overall prognosis in NSCLC, similar to KRAS.10 An in vitro study has showed that mutant HRAS hyperactivates the RAS and the mTOR pathway in various cancer cell lines including lung cancer, which might serve as a therapeutic target.11 NRAS mutations are more common in current/former smokers with NSCLC and NRAS-mutant cell lines were demonstrated to be sensitive to the MEK inhibitors, selumetinib and trametinib.12
While the single mutation in either NRAS or HRAS is rare in lung cancer, the double mutation in NRAS and HRAS, which we present in this case report, is even rarer and had never been reported before. The patient had rapid progression and died about 1 month after diagnosis. It is worth mentioning that EGFR L858R/T790M mutations were detected by ARMS-PCR in the pleural effusion sample, prompting the administration of osimertinib. However, no EGFR mutation was found by NGS, a more precise and comprehensive methodology for mutation analysis. Whether tumor heterogeneity or false detection that brought about these inconsistent results from the two molecular assays is unclear; however, the use of EGFR-TKIs could partly account for the patient’s poor prognosis. In conclusion, our case indicates that NRAS and HRAS mutations in NSCLC are associated with poor prognosis. Further research and description of clinical cases are needed for improved better understanding of these genetic mutations in NSCLC.
Institutional approval was not required to publish the case details.
Patient Informed Consent
Written informed consent was obtained from the patient for the publication of his case details and images.
We are grateful to the patient and her family. Also, we wish to express our gratitude to the clinical investigators, study coordinators, operation staff, and all other team members on this project.
Tian Qin and Xueliang Niu are affiliated with Burning Rock Biotech. The authors declare no other conflicts of interest.
1. Cox AD, Fesik SW, Kimmelman AC, Luo J, Der CJ. Drugging the undruggable RAS: mission possible? Nat Rev Drug Discov. 2014;13(11):828–851.
2. Karachaliou N, Mayo C, Costa C, et al. KRAS mutations in lung cancer. Clin Lung Cancer. 2013;14(3):205–214. doi:10.1016/j.cllc.2012.09.007
3. Chapman AM, Sun KY, Ruestow P, Cowan DM, Madl AK. Lung cancer mutation profile of EGFR, ALK, and KRAS: meta-analysis and comparison of never and ever smokers. Lung Cancer. 2016;102:122–134. doi:10.1016/j.lungcan.2016.10.010
4. Clinkscales W, Ong A, Nguyen S, Harruff EE, Gillespie MB. Diagnostic value of RAS mutations in indeterminate thyroid nodules. Otolaryngol Head Neck Surg. 2017;156(3):472–479. doi:10.1177/0194599816685697
5. Cicenas J, Tamosaitis L, Kvederaviciute K, et al. KRAS, NRAS and BRAF mutations in colorectal cancer and melanoma. Med Oncol. 2017;34(2):26. doi:10.1007/s12032-016-0879-9
6. Tripathi K, Goel A, Singhai A, Garg M. Mutational analysis of Ras hotspots in patients with urothelial carcinoma of the bladder. World J Clin Oncol. 2020;11(8):614–628. doi:10.5306/wjco.v11.i8.614
7. Nassar KW, Tan AC. The mutational landscape of mucosal melanoma. Semin Cancer Biol. 2020;61:139–148. doi:10.1016/j.semcancer.2019.09.013
8. Mo L, Zheng X, Huang HY, et al. Hyperactivation of Ha-ras oncogene, but not Ink4a/Arf deficiency, triggers bladder tumorigenesis. J Clin Invest. 2007;117(2):314–325. doi:10.1172/JCI30062
9. Boidot R, Chevrier S, Julie V, Ladoire S, Ghiringhelli F. HRAS G13D, a new mutation implicated in the resistance to anti-EGFR therapies in colorectal cancer, a case report. Int J Colorectal Dis. 2016;31(6):1245–1246. doi:10.1007/s00384-015-2448-7
10. Cathcart-Rake E, Corless C, Sauer D, Lopez-Chavez A. Elderly former smoker with HRAS mutant non-small-cell lung cancer. J Thorac Oncol. 2014;9(10):e75–78. doi:10.1097/JTO.0000000000000315
11. Kiessling MK, Curioni-Fontecedro A, Samaras P, et al. Mutant HRAS as novel target for MEK and mTOR inhibitors. Oncotarget. 2015;6(39):42183–42196. doi:10.18632/oncotarget.5619
12. Ohashi K, Sequist LV, Arcila ME, et al. Characteristics of lung cancers harboring NRAS mutations. Clin Cancer Res. 2013;19(9):2584–2591. doi:10.1158/1078-0432.CCR-12-3173
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