Concomitant epidermal growth factor receptor mutation/c-ros oncogene 1 rearrangement in non-small cell lung cancer: A case report

Abstract

BACKGROUND

Epidermal growth factor receptor (EGFR) mutation and c-ros oncogene 1 (ROS1) rearrangement are key genetic alterations and predictive tumor markers for non-small cell lung cancer (NSCLC) and are typically considered to be mutually exclusive. EGFR/ROS1 co-mutation is a rare event, and the standard treatment approach for such cases is still equivocal.

CASE SUMMARY

Herein, we report the case of a 64-year-old woman diagnosed with lung adenocarcinoma, with concomitant EGFR L858R mutation and ROS1 rearrangement. The patient received two cycles of chemotherapy after surgery, but the disease progressed. Following 1-month treatment with gefitinib, the disease progressed again. However, after switching to crizotinib, the lesion became stable. Currently, crizotinib has been administered for over 53 months with a remarkable treatment effect.

CONCLUSION

The efficacy of EGFR tyrosine kinase inhibitors and crizotinib was vastly different in this NSCLC patient with EGFR/ROS1 co-mutation. This report will aid future treatment of such patients.

Key Words: Non-small cell lung cancer; Epidermal growth factor receptor; C-ros oncogene 1; Co-mutation; Treatment strategies; Case report

Core Tip: Over the past two decades, molecular targeted therapies have improved clinical outcomes significantly for non-small cell lung cancer (NSCLC) patients with either epidermal growth factor receptor (EGFR) mutation or c-ros oncogene 1 (ROS1) fusion. Nevertheless, EGFR/ROS1 co-mutation is a rare event in NSCLC, and the standard treatment for such cases is still equivocal. We report an EGFR/ROS1 co-mutation in an NSCLC patient who remained clinically stable after 53 months of treatment with crizotinib. This is the longest progression-free survival reported in the literature. This case suggested that crizotinib may be a potential choice for NSCLC patients with such EGFR/ROS1 co-mutations.

INTRODUCTION

Lung cancer has the second-highest incidence of all cancers and the highest cancer-related death rate in the world[1]. Non-small cell lung cancer (NSCLC) accounts for about 85% of all lung cancers. Lung adenocarcinoma is the most common histopathological subtype of NSCLC, accounting for about 55% of cases. The mutation rate of epidermal growth factor receptor (EGFR) in Asian patients with lung adenocarcinoma is approximately 51%, and the mutation rate of c-ros oncogene 1 (ROS1) in NSCLC is 2%-3%[2-4]. EGFR/ROS1 co-mutation is relatively rare, and the incidence of concomitant EGFR mutations in patients with ROS1 fusion genes is less than 24%[5-7].

Early studies have shown that tyrosine kinase inhibitors (TKIs) targeting EGFR and ROS1 are the first-line treatment for patients with EGFR mutations or ROS1 rearrangement[8-11]. However, there is currently no consensus on the optimal management of patients with these co-mutations. This article reports the treatment of an NSCLC patient with EGFR and ROS1 co-mutation to provide a reference for the treatment and management of other NSCLC patients with these co-mutations.

CASE PRESENTATION

Chief complaints

A 64-year-old Chinese woman presented on November 1, 2018 with a complaint of cough and sputum production for 1 wk.

History of present illness

Symptoms started 1 wk before presentation, with cough and sputum production.

History of past illness

An appendectomy due to appendicitis had been performed approximately 30 years prior to the presentation. Cholecystectomy due to cholelithiasis had been performed 10 years after the appendectomy.

Personal and family history

The patient denied any family history of malignant tumors. The patient also had no history of smoking.

Physical examination

On physical examination, the vital signs were as follows: Body temperature, 36.6 °C; blood pressure, 136/75 mmHg; heart rate, 74 beats per min; and respiratory rate, 20 breaths per min.

Laboratory examinations

Levels of serum tumor markers were normal. Carcinoembryonic antigen was < 0.5 ng/mL (normal range: 0-5 ng/mL), squamous cell carcinoma antigen was 0.6 ng/mL (normal range: 0-1.5 ng/mL), and cytokeratin 19 fragment was 1.57 ng/mL (normal range: 0-2.08 ng/mL). No abnormality was found in the routine blood and urine analyses.

Imaging examinations

On November 2, 2018, chest computed tomography (CT) showed a 2.8 cm × 1.8 cm patchy shadow in the inferior lobe of the right lung. The scan also showed multiple ground-glass nodules in bilateral lungs. The patient was prescribed oral anti-tuberculosis drugs. She discontinued the medication after 1 month due to intolerance. On March 25, 2019, the patient visited our hospital again. Chest CT showed a 4.0 cm × 2.7 cm shadow in the lower lobe of the right lung. Due to the significant growth, the possibility of a neoplastic lesion was considered.

FINAL DIAGNOSIS

Combined with the patient’s medical history, the final diagnosis was determined to be NSCLC.

TREATMENT

On April 3, 2019, thoracoscopic radical resection of the lower right lung cancer and pleural adhesion cauterization was performed under general anesthesia. Postoperative pathological diagnosis was acinar adenocarcinoma grade Ⅲ, micropapillary adenocarcinoma (accounting for about 5% of tumor tissue) in the local area, and tumor thrombus in the alveolar cavity (Figure 1). ROS1 rearrangement and EGFR L858R mutation were detected by next-generation sequencing of 13 lung cancer driver genes. The frequency of the EGFR mutation found in this patient was only 1.3% (Figure 2).

Figure 1 Histological and immunohistochemical features. A: Histology of lung biopsy; B: Expression pattern of thyroid transcription factor 1.

Figure 2 Detection of epidermal growth factor receptor mutation and c-ros oncogene 1 rearrangement using high sensitivity next-generation sequencing. A: Epidermal growth factor receptor L858R mutation; B: EZR-ROS1 E10R34 fusion.

After thoracoscopic radical resection, the patient received two cycles of chemotherapy (pemetrexed 690 mg D1 + cisplatin 50 mg D1-2; on May 14, 2019 and June 5, 2019). Comparison of the CT film obtained on June 25, 2019 with the previous film (May 7, 2019) showed progression of the lesion. Multiple lymph nodes in the mediastinum and right hilum were also enlarged, suggesting metastasis (Figure 3).

Figure 3 Serial computed tomography images. A: Computed tomography (CT) after postoperative recurrence; B: CT after 1 month of gefitinib therapy. Progressive disease of the lung was detected; C: CT after 53 months of crizotinib therapy. Stable disease was detected.

Gefitinib was administered for 1 month starting on June 26, 2019. During this period, the patient developed drug-induced diarrhea, which improved after treatment with loperamide. Chest CT on July 30, 2019 revealed that multiple lymph nodes in the mediastinum, right cardiophrenic angle, and right hilum were enlarged, indicating progression of the disease (Figure 3).

On August 7, 2019, crizotinib was administered. The efficacy of crizotinib was evaluated after 1 month, which revealed stable disease. Since then, the patient has been treated with crizotinib for over 53 months and continues to have stable disease (Figure 3).

OUTCOME AND FOLLOW-UP

After 53 months of treatment with crizotinib, the patient is still alive.

DISCUSSION

Genetic mutations are typically considered to be mutually exclusive[12-15]. A recent study[16] demonstrated that patients with co-mutations have a poor progression-free survival. Patients with both ROS1 fusion and EGFR mutations are exceedingly rare in comparison to the co-occurrence of EGFR/PIK3CA, ALK/KRAS, and EGFR/MET mutations[16-18]. However, using highly sensitive methods such as the amplification-refractory mutation system analysis leads to an increase in the detection rate of co-mutations of KRAS or BRAF mutations and ALK or ROS1 rearrangements[13]. Studies[13-15] have shown that the incidence of concomitant gene mutations in lung adenocarcinoma was 3.8%, and EGFR/ROS1 and EML4-ALK were among the mutations detected. There is no consensus on the clinical characteristics, treatment options, and prognosis of NSCLC patients with co-mutations.

The mechanism of EGFR/ROS1 co-mutation remains unclear. Wu et al[19] hypothesized that two gene alterations can be detected within the same tumor cells in NSCLC, which might result in cancer development through co-action. Won et al[20] proposed that genetic instability in cancer cells leads to genetic and phenotypic heterogeneity in tumors, indicating that different genetic mutations might occur in tumor cells rather than in a single clone. Accumulating evidence shows co-existence of classical oncogenes, including EGFR, ALK, ROS1, and MET, in lung adenocarcinoma patients, especially in young females with no history of smoking[21]. In this case report, the patient was an elderly woman and the pathology suggested adenocarcinoma, which was consistent with the literature reports.

Cases of EGFR/ROS1 co-mutation have been infrequently reported in NSCLC, creating a lack of clear treatment standards. Zhang et al[22] reported a patient with an EGFR exon 21 L858R mutation. The disease progressed after gefitinib treatment for 11 months. The gene test showed EGFR exon 21 L858R mutation (abundance 36.62%), EGFR exon 20 T790M (7.95%), and ROS1 fusion (15.81%), as well as EGFR, HER2, and BRAF amplification. The second-line treatment included osimertinib, and the disease progressed after 7 months. The third-line chemotherapy included two cycles of pemetrexed and carboplatin, which did not prevent disease progression.

Another study reported the cases of three stage IA NSCLC patients with EGFR/ROS1 co-mutation who received chemotherapy (regimen not reported) for 3 months after surgery[23]. During the 12-month follow-up, one patient developed relapse and the other two were in stable condition. In another case report, a 53-year-old man was diagnosed with lung adenocarcinoma with concomitant EGFR and KRAS mutations and ROS1 rearrangement[24]. He was treated with crizotinib as the first-line treatment, but the disease progressed after 1 month. After icotinib was administered for 1 month, a partial curative effect was observed. The condition of that patient was stable after 8 months of maintenance treatment.

According to Zhuang et al[21], the progression-free survival of patients with an EGFR co-mutation treated with first-line TKIs was better than that of patients treated with first-line chemotherapy. A recent study described the case of a 48-year-old woman diagnosed with NSCLC with an EGFR 19 deletion/ROS1 rearrangement who achieved a favorable outcome[19]. Following 1 month of treatment with a combination of almonertinib and crizotinib, there was a significant reduction in the primary mass and all lymph nodes. Almonertinib was subsequently replaced by furmonertinib due to elevated levels of creatine kinase. The patient received furmonertinib and crizotinib treatment for 7 months, and stable disease was achieved throughout the follow-up period.

It appears that the clinical efficacy of EGFR TKIs and crizotinib treatment is quite different based on these clinical reports and our experience. The best choice for first-line treatment remains unclear. It has been reported, though, that the efficacy of TKIs can be predicted by the phosphorylation levels of EGFR and ALK in patients with EGFR/ALK co-mutation[25].

Nevertheless, there are still several challenges in predicting the efficacy of treatment in patients with EGFR/ROS1 co-mutations. First, current genetic testing is unable to determine the dominant oncogene aberration in a single tumor cell. Second, there is limited research on the relationship between the abundance of a ROS1 mutation and lung cancer prognosis. Finally, there have been no reports on whether EGFR phosphorylation levels and ROS1 mutation abundance can predict the effectiveness of TKIs. In our report, we found that the patient had a very low EGFR mutation frequency (1.3%), which may explain the poor response to the gefitinib treatment. Therefore, it is possible that low EGFR phosphorylation levels could be associated with a poorer prognosis when treated with TKI therapy.

Liu et al[26] observed that TKI combination therapy was more effective than single TKI treatment in patients with EGFR/ALK co-mutations. Wu et al[19] demonstrated similar outcome in one patient with an EFGR 19 deletion/ROS1 rearrangement upon treatment with a combination of third-generation EGFR TKIs and crizotinib. Combination therapy appears to exhibit a favorable efficacy. However, not all patients are able to tolerate the toxicity associated with TKI combination therapy. Therefore, further investigation is required to determine the necessity of combination therapy.

There is no overall survival difference between patients with single EGFR mutations and those with concomitant ALK/ROS1 mutations (21.0 months vs 23.0 months, respectively, P = 0.196)[27]. However, concomitant EGFR mutation and ALK/ROS1 mutation reduced the therapeutic effect of EGFR TKIs in patients. Patients with co-mutations had a significantly shorter progression-free survival than those with a single EGFR mutation (6.6 months vs 10.7 months, respectively, P = 0.004)[27]. In our report, the patient remained stable after 53 months of crizotinib treatment, which is the longest reported progression-free survival of a patient with an EGFR/ROS1 co-mutation.

CONCLUSION

EGFR/ROS1 co-mutation is rare in patients with NSCLC. Due to its rarity, the best treatment approach is unclear. TKI therapy can be used as the first-line option, but the clinical efficacy of EGFR-TKIs and crizotinib therapy appears to vary significantly between patients. The level of EGFR phosphorylation may play a crucial role in the selection of therapeutic drugs. Further investigation is required to examine the correlation between ROS1 mutation frequency and the prognosis of lung cancer.

ACKNOWLEDGEMENTS

We are grateful to Dr. Xiao-Xiao Wang for her help with the artwork.