Accumulating evidence indicates the co-existence of classic oncogenes, involving EGFR, ALK, ROS1, and MET, has identified in lung adenocarcinoma patients, especially in younger and women patients without a smoking history. However, few studies have focused on the frequency of two-driver alterations of EGFR, ROS1 or EML4-ALK in MPA and LA. Therefore, we investigated the relationship between the most common oncogenic mutations and molecular pathological characteristics in Chinese lung adenocarcinoma patients.
Consistent with previous reports[30, 31], we here discovered that MPA has positive lymph node metastasis, positive pleural invasion, and earlier disease staging compared with LA (Table 1). Increasing studies have shown that a micropapillary component was associated with lymph node metastasis, pleural invasion and an early recurrence in stage I patients, suggesting MPA had a poorer prognosis compared with those without micropapillary component or other histological subtypes[32-39]. Our results further implied that the higher prevalence of lymph node metastasis and pleural invasion may be a valuable poor prognostic marker for MPA.
An investigation of 15 MPAs revealed that the mutational status of EGFR, KRAS and BRAF harbored 73% mutually exclusive mutations in the Western population[40]. A study involving 21 micropapillary predominant lung adenocarcinoma patients showed that oncogenic mutations in EGFR, HER2 and RET were apparently frequent in 95.2% Chinese people[22]. Here, our results manifested the majority (47 out of 55, 85.5%) of MPA harbored the genetic driver alterations of EGFR (76.4%), ROS1 (10.9%), or EML4-ALK (5.5%) from a Chinese cohort. Though previous cohort detected no ROS1 fusions[22], two another independent teams found ROS1 rearrangements in MPA[23, 24]. Therefore, there are no consistent conclusions about ROS1 rearrangements in MPA patients. Here, our cohort reported that 6 MPA cases possessed ROS1 rearrangements. In the past, oncogenic mutations involving EGFR, KRAS, ALK, RET, ROS1, and MET were regarded as mutually independent events. However, two or more cancer-associated gene alterations were recently found in lung adenocarcinoma cases[41-44]. Our study indicated that 3.8% of lung adenocarcinoma cases harbored two-driver alterations of EGFR, ROS1 or EML4-ALK, including 7.3% of MPA cases and 1.3% of LA cases, and this result was in agreement with recent reports[41-45].
According to previous reports, patients with co-alterations of EGFR, ALK, ROS1, and other oncogenic drivers showed distinctive clinical responses to TKIs in lung adenocarcinoma[44, 46-48]. Yang et al demonstrated that the median progression-free survival of gefitinib was 11.2 months in patients with concomitant EGFR and ALK alteration[49]. Mao et al indicated that the median progression-free survival of EGFR-TKIs and/or ALK/ROS1 inhibitor was 6.6 months in patients with concomitant EGFR and ALK alteration[44]. However, 75% of patients with crizotinib treatment obtained disease control[44]. In the present study, all patients undertook the operation and chemotherapy initially and undertook subsequently targeted therapy. In addition, Katsuya et al showed that the micropapillary component was associated with an early recurrence in stage I patients but not in advanced-stage patients, indicating MPA retained a high risk of early recurrence after one-year surgery[39]. In the present study, among five patients with concomitant alterations of EGFR, ROS1 and EML4-ALK, four patients partially responded and one patient suffered a recurrence during one year follow-up. Our study provided evidence that lung adenocarcinoma patients with co-alterations of EGFR, ROS1 or EML4-ALK may benefit from TKIs treatment.
So far, there is little progress in digging the pathogenic mechanism of MPA or the treatment of this subtype by TKIs. Therefore, based on our findings, we will focus on elucidating the function of ROS1 rearrangement and EGFR mutations in MPA by establishing the cell and animal models both in vitro and in vivo in the future. In addition, we will verify the efficacy of one targeted TKI or combined TKIs for MPA, and provide the potential treatment strategy.
In summary, we report for the first time the relationship between the most common oncogenic mutations and pathological characteristics in Chinese lung adenocarcinoma patients. We discover the higher incidence of ROS1 rearrangements and the coexistence of genetic alterations involving EGFR, ROS1 and EML4-ALK in MPA cases, indicating that targeting of ROS1 combined with EGFR mutations may provide a novel therapeutic strategy for these patients. However, these results still should be supported by further studies with larger cases and in multi-centers.