The present study aimed to evaluate clinical outcomes in patients with surgically resected non-small cell lung cancer (NSCLC) with anaplastic lymphoma kinase (ALK)-rearranged mutations. A matched-pair analysis in completely resected ALK-rearranged NSLC patients and those with neither ALK nor epidermal growth factor receptor (EGFR) mutations diagnosed at 11 institutes was performed between April 2008 and March 2019. A total of 51 patients with surgically resected ALK-rearranged NSCLC were included. Women constituted 68.6%, and smokers 29.4%. The median age was 65 years. In matched-pair analysis, disease-free survival and overall survival did not differ between patients with ALK-rearranged mutations and those without mutations. Post-recurrence survival in patients with ALK mutations was longer than that of patients with neither ALK nor epidermal growth factor receptor mutations. ALK genetic testing should be performed, even in elderly patients with NSCLC. Favorable prognosis might be expected after appropriate treatment for patients with recurrent ALK-mutated disease.
Lung cancer is an important public health problem and the leading cause of cancer death worldwide, with more than 1.38 million deaths worldwide (
This was a retrospective study in which all medical institutions covering one prefecture in our country participated. We included patients who were diagnosed as having ALK-rearranged NSCLC between April 2008 and March 2019. Patients, who had undergone surgery before the diagnostic method of ALK fusion mutations was approved by medical insurance in our country in May 2012 and were diagnosed as having ALK-rearranged NSCLC during the study period, were included in the study. Controls were 232 patients who were diagnosed as having neither ALK rearrangement mutations nor epidermal growth factor (EGFR) mutations and had had surgical resections during the study period at the Mito Medical Center and Mito Kyodo General Hospital. The control matched-pair patients were those among the 232 control patients whose main clinical characteristics were consistent with ALK-rearranged mutated patients, including age, sex, performance status, pathological stage, and smoking habit, which are known prognostic factors for NSCLC patients. Histopathological diagnoses were defined according to the World Health Organization classification system, and the patients were staged according to the Union for International Cancer Control (UICC) tumor-node-metastasis (TNM) staging system (8th edition). The patient characteristics, efficacy, safety, DFS, OS were evaluated using patient data extracted from the database of each institution. DFS was calculated from the date of surgery to the recurrence or any cause of death and OS was the interval from the date of surgery to the date of death, or latest follow-up contact. PRS was defined as the interval between the date of recurrence and to the date of death or latest follow-up contact.
The present non-interventional and observational retrospective study conformed to the Ethical Guidelines for Clinical Studies issued by the Ministry of Health, Labor and Welfare of Japan. This study was approved by the Institutional Review Board of the Mito Kyodo General Hospital-Mito Medical Center, University of Tsukuba (no. 16-66, 18-15) or independent ethics committees associated with each study institute. Written comprehensive informed consent for reporting clinical course was obtained from each patient at the time of admission.
Analysis of ALK fusion mutations was performed by the respective assay method used by each institution, such as fluorescence
All analyses were performed using SPSS version 23 (IBM Corporation). Differences in proportions between two independent groups were compared using the χ2 test. The Mann-Whitney U test was used to compare two groups of sample data. The survival rate was analyzed by the Kaplan-Meier method and comparisons performed using the log-rank test. The effects of clinicopathological factors on survival were analyzed using the Cox proportional hazards model. P<0.05 was considered to indicate a statistically significant difference.
During the study period, 129 patients were diagnosed as having ALK-rearranged NSCLC. The analysis of ALK fusion mutation was examined using FISH in 78 patients, IHC in 30 patients, and both tests in 21 patients. Fifty-eight patients had surgical resection. Among them, 51 patients had curative complete resection. Seven patients were excluded from this study because they did not have no curative resection.
In 51 patients with ALK-rearranged mutations, the median age was 65 (range, 32-82) years. Presence of ALK fusion mutation was confirmed in FISH, IHC, and both tests in 27, 19 and 5 patients, respectively. There were 16 (31.4%) males and 35 females. Fifty (98.0%) patients had good performance status (Eastern Cooperative Oncology Group 0-1). Fifteen (29.4%) of them were non-smokers. All 51 patients had adenocarcinoma. The median maximum diameter of the primary lesion was 20 mm (range, 12-82 mm). At the time of initial diagnosis, 21 patients (41.2%) were diagnosed as having pathological stage IA-B, 14 (27.5%) patients with IIA-B, and 16 (31.4%) patients with IIIA. The average 5-year survival rate of the 51 patients who underwent complete resections was 84.0%.
It is well known that the proportion of patients with ALK-rearranged mutations is higher among young patients, female patients, and non-smokers (
Previous studies on the survival of ALK-mutated patients focused on one of three groups: All ALK-mutated patients; patients with advanced or recurrent disease; and patients who underwent resections (
In the present study, we obtained another important finding. PRS of patients with ALK-rearranged mutations was significantly longer than that of patients without the mutations. Clinical trials in ALK-TKIs included patients with advanced, as well as those with recurrent disease (
In this research, we chose the matched-pair analysis because we wanted to make the clinical and pathological variables as even as possible in comparison the survival with ALK rearranged mutations. We matched background characteristics that were previously associated with prognosis, such as age, gender, performance status, pathological stage, and smoking habit. Regarding OS, no difference could be confirmed between the two patients with or without ALK rearrangement mutations. This might relate to the short observation period and the small number of patients. Alternatively, it might suggest that ‘curative resections’ had overwhelmingly larger impact on contributing to overall survival than ‘ALK rearrangement mutations and presence of ALK-TKI treatment’ did.
The present study had several limitations. Firstly, it was a retrospective study with patients from miscellaneous backgrounds. Secondly, the methods for examining ALK-fusion gene mutations were not unified. For ALK examination, FISH and immunostaining were performed. Patients who confirmed the presence of the ALK fusion gene by both examinations were also included. The effects of the difference in detection sensitivity of these measurements on our results could not be fully investigated. Comprehensive screening with next generation sequencer was not used in this study population. Thirdly, the limited number of patients and the short period of investigation were also limitations. Fourthly, it was a matched-pair study with a one-to-one patient ratio, but it would be favorable to include more control patients with matched clinical characteristics. Fifthly, as for the survival, our study could not analyze the presence of the ALK mutations and the use of ALK-TKI separately. At present, administration of ALK-TKI is the standard treatment in recurrent patients with ALK mutations, so it is not realistic to consider these separately in clinical practice. Despite these limitations, we suppose that our data from ALK-rearranged patients collected by multiple institutions will provide clinically meaningful information.
In summary, DFS and OS of patients with ALK-rearranged mutations were not significantly different from those with neither ALK nor EGFR mutations. PRS of patients with ALK-rearranged mutations was significantly longer than that of patients without the mutations. ALK-TKI treatment after recurrence might play an important role. It is important to treat patients with resected ALK-rearranged NSCLC with consideration of driver gene mutations. Successful treatment with ALK-TKI might be required, even for patients who experience recurrence after surgery. In order to fully elucidate these relationships, it is necessary to accumulate information obtained, not only by clinical trials, but also from clinical practice.
Not applicable.
No funding was received.
The datasets used and/or analyzed during the present study are available from the corresponding author on reasonable request.
MI, NH, KF, HSa and YS designed the study. MI, HIc, SU, KI, OI, RN, YI, HS, MaK, KK, MoK, SY, MS, NK, KF collected the data. MI, KM and HSa analyzed the data and prepared the article. All authors approved the final version of the article.
The present study was approved by the Institutional Review Board of the Mito Kyodo General Hospital-Mito Medical Center, University of Tsukuba (approval no. 16-66, 18-15).
Not applicable.
The authors declare that they have no competing interests.
Comparison of disease-free survival and overall survival after surgery between the two groups of patients with or without ALK-rearranged mutation. (A) Disease-free survival and (B) overall survival after surgery of the 38 ALK-rearranged mutated patients and 38 matched-pair control patients. ALK, anaplastic lymphoma kinase.
Comparison of post-recurrence survival between the two groups of patients with or without ALK-rearranged mutation. Survival time after recurrence in the 38 ALK-rearranged mutated patients and 38 matched-pair control patients. ALK, anaplastic lymphoma kinase.
Clinicopathological characteristics of enrolled patients: 51 surgically resected patients with ALK mutation and 232 surgically resected controls who had neither ALK rearranged mutation nor EGFR mutations.
Characteristics | Resected patients with ALK mutation | Resected controls with neither ALK nor EGFR | P-value |
---|---|---|---|
Age (year), median, range | 65, 32-82 | 70, 39-89 | <0.001 |
Sex | <0.001 | ||
Male | 16 | 748 | |
Female | 35 | 84 | |
Performance status | 0.078 | ||
0 | 41 | 149 | |
1 | 9 | 78 | |
2 | 1 | 5 | |
Smoking status | 0.516 | ||
Never | 36 | 151 | |
Past or current | 15 | 81 | |
P-stage | <0.001 | ||
IA-IB | 21 | 162 | |
IIA-IIB | 14 | 37 | |
IIIA | 16 | 33 | |
5-year survival (%) | 84.0 | 69.8 | 0.059 |
ALK, anaplastic lymphoma kinase; EGFR, epidermal growth factor receptor.
Clinicopathological characteristics of patients matched according to clinical characteristics: 38 patients with ALK-rearranged mutation and 38 patients with neither ALK nor EGFR mutation.
Characteristics | Resected patients with ALK mutation | Resected controls with neither ALK nor EGFR | P-value |
---|---|---|---|
Age (year), median, range | 65, 40-82 | 67, 46-82 | 0.763 |
Sex | 0.807 | ||
Male | 13 | 12 | |
Female | 25 | 26 | |
Performance status | 0.361 | ||
0 | 30 | 33 | |
1 | 8 | 5 | |
Smoking status | 0.622 | ||
Never | 13 | 11 | |
Past or current | 25 | 27 | |
P-stage | 0.841 | ||
IA-IB | 20 | 22 | |
IIA-IIB | 9 | 9 | |
IIIA | 9 | 7 | |
Recurrence during the study period | 0.803 | ||
Present | 11 | 12 | |
Absent | 27 | 26 | |
5-year survival | 77.5 | 71.5 | 0.820 |
ALK, anaplastic lymphoma kinase; EGFR, epidermal growth factor receptor.
Clinicopathological characteristics of pair-matched recurrent patients: Patients with ALK-rearranged mutation and patients with neither ALK-rearranged mutation nor EGFR mutation.
Characteristic | Patients with ALK | Patients with neither ALK nor EGFR | P-value |
---|---|---|---|
Number of patients | 11 | 12 | |
ALK-TKI therapy after recurrence | |||
Present | 9 | 0 | |
Absent | 2 | 10 | |
Period until recurrence, median (range) | 4 (1-62) months | 17 (2-94) months | 0.104 |
Survival status | 0.059 | ||
Dead | 3 | 8 | |
Alive | 8 | 4 | |
Survival from recurrence | 14 (1-91) months | 7 (1-72) months | 0.487 |
ALK, anaplastic lymphoma kinase; EGFR, epidermal growth factor receptor.