Pathological Signature and Therapeutic Status of NSCLC Patients with Common or Rare Driver Gene Alterations in North China：A real world retrospective study

doi:10.21203/rs.3.rs-30399/v1

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Pathological Signature and Therapeutic Status of NSCLC Patients with Common or Rare Driver Gene Alterations in North China：A real world retrospective study

https://doi.org/10.21203/rs.3.rs-30399/v1

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Background: Although guidelines recommended to test EGFR/ALK/ROS-1 gene alterations in advanced non-small cell lung cancer (NSCLC) patients before treatment, there is now growing evidence that rare driver genes and mutations also can inform targeted therapy and improve outcomes for this traditionally underrepresented population. This study aimed to describe mutational patterns and linked clinical parameters in a Chinese population-based NSCLC cohort.

Methods: This study included patients with pathologically confirmed NSCLC, who were routinely screened for EGFR, KRAS, BRAF, ALK, ROS1, RET, MET, HER2, and PIK3CA mutations by the NMPA approved multi-gene detection kit. The demographic and clinicopathological data, treatment information, clinical outcomes after first-line treatment, as well as nine driver gene mutation statuses and PD-L1 expression level of these patients were retrospectively collected.

Results: Finally, 431 patients were enrolled, most patients were male (55.9%), with adenocarcinoma or adenosquamous carcinoma (80.7%) and in stage IV (50.6%). Among all the 431 patients, 61.5% patients were identified with gene mutation including 101 with rare mutation, 164 with 19del or with L858R mutation. Adenocarcinoma patients have a higher mutation rate (73.6%), and the mutations mainly occur in EGFR, KRAS, ALK and HER2. While, the gene mutation characteristics in squamous cell carcinoma patients with were relatively simple, only 2 patients with EGFR 19del and 2 patients with PIK3CA mutation. More PD-L1 expression could detected in patients with rare mutation. The median PFS1 of patients with common mutation (13 months, 95% CI: 9.9-16) was longer than the patients with rare mutation (5 months, 95 % CI: 0-10.5).

Conclusions: The clinicopathologic features and clinical treatment status among NSCLC patients with common or rare driver gene mutations were different. The survival of patients with rare mutation was worse than that of patients with common mutation. Therefore, more attention should be paid to the treatment strategy and survival status of patients with rare mutations in clinical practice.

Cancer Biology

Oncology

Non-small cell lung cancer

Common mutation

Rare mutation

Therapeutic signature

Survival status.

The morbidity and mortality of lung cancer rank first in malignancy in China. It was reported an estimated 733,300 new cases of lung cancer and 610,200 lung cancer-related deaths in China in 2015.^[1] Non-small cell lung cancer (NSCLC) is the major type of lung cancer, accounting for 80–85% of all cases.^[2] In recent years, the emergence of oncogenic driver gene identification has created a new situation for the treatment of advanced NSCLC. Epidermal growth factor receptor (EGFR) gene mutations can be detected approximately 40%-50% in nonsmoking Asian population.^[3] Treatment with EGFR tyrosine kinase inhibitors (EGFR-TKIs) has increased the objective response rate of patients with EGFR mutations (19del, L858R) to about 70%, and the median progression free survival (PFS) has been extended to about 10 months.^[4] NSCLC is a disease driven by multiple genes, except for EGFR common mutation, there are still about 20–30% cases caused by other drugable driver gene mutations. Although the frequency of those relatively rare mutations is less than 10%, and some even less than 1%, they can make a big difference in clinical practice.^[5]

Uncommon EGFR mutations mainly include G719X, exon 20 insertions, S768I, and L861Q. Their overall incidence can reach 5%-7% in NSCLC patients.^[6] The average PFS of NSCLC patients with uncommon EGFR mutations treated with gefitinib is only 7.7 months, significantly shorter than the patients with EGFR common mutations.^[7] Patients with exon 20 insertions generally have low response or complete resistance to most EGFR-TKIs, while have dramatic response to new drug TAK-788 and pozitinib (NCT02716116,NCT03066206).^[8] Human Epidermal Growth Factor Receptor 2 (HER2), a homologous gene of EGFR, has a similar exon 20 mutation type with EGFR, and the incidence rate is about 1%-3%.^[9] There were no effective targeted drugs for the treatment of HER2 mutant NSCLC patients. The primary results of clinical trial NCT03318939 showed that the patients with HER2 mutation are predicted to benefit from pozitinib. ^{[10, 11]}

Gene fusion, especially kinase gene fusion, is another uncommon mutation type in lung cancer. For example, anaplastic lymphoma kinase (ALK), ROS proto-oncogene receptor tyrosine kinase 1 (ROS1), and rearranged during transfection proto-oncogene gene (RET) are known to have fusion mutations, which account for 2–7%, 1–2%, and 1–2%of advanced NSCLC patients, respectively. The EML4-ALK, CD74-ROS1 and KIF5C-RET constitute the major subset of those fusion variations.^[12–14] ALK, ROS1 and RET rearrangement positive patients appears to be more common in young and never or light smokers diagnosed with adenocarcinoma.^[15] Patients with ALK and ROS1 rearrangements can benefit from TKIs, such as crizotinib, which are now widely used in clinical practice.^{[16, 17]} For patients with RET fusion, selective RET inhibitors LOXO-292 (selpercatinib^[18]) and BLU-667 (pralsetinib^{[19, 20]}) are also undergoing phase I/II and I clinical trials, respectively, with preliminary results demonstrating partial response and low incidence of serious adverse events.^[5] Mesenchymal-to-epithelial transition factor (MET) exon 14 skipping mutation is another kind of fusion in RNA level with incidence rate of 1%-2% in NSCLC patients, and the mutation positive patients responded to crizotinib or capmatinib.^[21] Kirsten rat sarcoma viral oncogene homolog (KRAS) is a downstream molecular of the above kinase genes. The frequency of KRAS mutations in the Chinese NSCLC patients is less than 10%, and it is usually considered to be a drug resistance gene mutation.^[22] AMG510, a KRAS G12C inhibitor, and other agents are currently being investigated, and patients with mutation in KRAS may benefit from these novel inhibitors.^[23]

In the present study, we retrospectively analyzed the mutation profiles of nigh major driver genes, EGFR, ALK, ROS1, RET, HER2, KRAS, BRAF, PIK3CA, and MET in 431 Chinese NSCLC patients, as well as their relationship with patient demographic and clinicopathological information. We also collected the treatment data of some patients, and preliminarily described the treatment status and efficacy of patients with driver gene mutations in the real world.

Patients and study design

A total of 431 patients with pathologically confirmed NSCLC from north China were enrolled during the period of 2017 to 2019 in this study. The demographic and clinicopathological data, treatment information, as well as driver gene mutation status and PD-L1 expression level of these patients were retrospectively collected. The whole patients were divided into two groups, patients with common mutation (EGFR 19del or L858R) and patients with rare mutation (all the other eight driver genes and uncommon EGFR mutations). For the survival data analysis, we calculated the progression-free survival of these two groups of patients receiving the first-line treatment (PFS1).

Driver Gene Mutation Detection

All the tumor tissue and cytology samples were fixed in 10% neutral formalin buffer and embedded in paraffin. Five-ten sections (5 µM thickness) of tumor samples were used for both DNA and RNA extraction by using AmoyDx FFPE DNA/RNA Kit (Amoy Diagnostics, Xiamen, China) according to the manufacturer's instructions. The quantity and quality of isolated DNA and RNA were determined with trace ultraviolet spectrophotometer.

The isolated DNA and RNA were tested for multiple genomic alterations by AmoyDx Multi-Gene assay (Amoy Diagnostics, Xiamen, China). Experimental procedure and data analysis were followed the manufacturer's instructions. This qPCR assays for detection of oncogenic driver alterations have been approved by China NMPA.

Pd-l1 Expression Detection

PD-L1 expressions were detected by PD-L1 IHC 22C3 assay kit according to the manufacturer's instructions. The Dako Autostainer Link 48 (ASL48) immunohistochemical staining machine was used. The data analysis was followed the manufacturer's instructions as well.

Statistical analysis

The data were analyzed using SPSS software version 19 (IBM Corp., Armonk, NY, USA). Chi-square test was used to evaluate differences in the clinicopathological characteristics between the common mutation and rare mutation groups. Logistic regression analysis was used to evaluate independent factors associated with driver gene mutation. Kaplan–Meier analysis was performed for PFS1 curves, and statistical significance was assessed using the log-rank test. p < 0.05 was considered to be statistically significant. Graphic drawing was performed using GraphPad Prism 6.0 software (GraphPad Software, Inc., La Jolla, CA, USA).

Demographic and clinicopathological features of patients

The basic demographic and clinicopathological data of the 431 NSCLC patients, including age, gender, smoking history, family history, and chronic disease history, clinical stage, and pathological type are shown in Table 1. Most of the patients enrolled in this study were younger than 65 years old, male, no family history and chronic disease history. There was approximately equal number of former smoker and patients without smoking history. Patients in this study were distributed in stage I-IV, according to the American Journal of Critical Care Cancer Staging Manual (version eight), with the most patients in stage IV (50.6%). The proportion of stage I, II, and III were 22.5%, 5.8%, and 20.0% respectively. Regarding pathological subtype, adenocarcinoma or adenosquamous carcinoma was the most common subtype (80.7%), and then was the squamous carcinoma (14.4%). 60.3% of the specimens used for molecular diagnosis were biopsy specimens, surgical and cytology specimens were 31.6% and 7.9% separately. A total of 315 specimens had the PD-L1 test records, the positive rate was 49.5%.

Table 1

Demographic and clinicopathological data of 431 NSCLC patients
	Overall (n = 431)		P value (95% CI)
Age			0.046(0.041-0.50)
< 65	237	55.0%
>=65	194	45.0%
Gender			0.018(0.015–0.021)
Male	241	55.9%
Female	190	44.1%
Smoking status			0.810(0.803–0.818)
Never	218	50.6%
Former	213	49.7%
Family history of cancer			< 0.01
Yes	71	16.5%
No	360	83.5%
History of chronic diseases			< 0.01
Yes	50	11.6%
No	381	88.4%
Clinical stage			< 0.01
I	97	22.5%
II	25	5.8%
III	86	20.0%
IV	218	50.6%
Not available	5	1.2%
Specimen type			< 0.01
Biopsy specimen	260	60.3%
Cytology specimen	34	7.9%
Surgical specimen	136	31.6%
Pathological type			< 0.01
Adenocarcinoma or adenosquamous carcinoma	348	80.7%
Squamous Carcinoma	62	14.4%
others	21	4.9%
PD-L1 (n = 315)			0.018
Positive	156	49.5%
Negative	159	50.5%

Oncogenic Driver Gene Alterations In Nsclc Patients

The multigene PCR detection data of 431 patients were obtained, shown in Fig. 1. Among all the 431 patients, 61.5% patients were identified with gene mutation. The most frequent genomic alterations (38.1%) in this Chinese NSCLC cohort was the common EGFR mutations, and other frequent genomic alterations were as follows: KRAS mutation (8.1%,), uncommon EGFR mutations (5.3%), ALK rearrangement (3.9%), HER2 mutations (1.9%), BRAF mutation (1.4%), RET rearrangement (1.2%), PIK3CA mutation (0.7%), ROS1 rearrangement (0.5%), and MET exon 14 skipping (0.5%).

There was a similar gene mutation pattern in adenocarcinoma and adenosquamous carcinoma patients. The difference in oncogenic driver mutations between adenocarcinoma and squamous cell carcinoma patients was mainly manifested in the high gene mutation rate (73.6%) in adenocarcinoma patients, and the mutations were mainly occurred in EGFR, KRAS, ALK and HER2. However, the genetic mutation characteristics of patients with squamous cell carcinoma were relatively simple, of the 62 squamous cell carcinoma patients in this study, EGFR 19del was only detected in 2 patients and 2 patients was detected with PIK3CA mutation.

Comparison of the characteristics between common and rare mutations in NSCLC patients

Among the 164 patients with common mutations and the 101 patients with rare mutations, there was no statistics difference in age, smoking history, family history of cancer, chronic disease history and clinical stage (p > 0.05). In terms of gender, female accounted for the majority (61.0%) in common mutation group, showing a statistical difference, while there was no significant difference in the proportion of male (55.4%) and female (44.6%) in rare mutation group. In this study, more than 90% samples were obtained from biopsy (60.3%) and surgery (31.6%). Although the distribution of sample types in each group is not very uniform, the proportion of each sample type is not statistically different between the two groups and the pathological types also has a similar phenomenon between the two groups. Among all the patients, PD-L1 expression data were obtained in 315 patients, and the positive rate was 49.5%. PD-L1-positive cases accounted for 29.9% (49/164) in common mutation group and 40.6% (41/101) in rare mutation group, the difference was statistically significant (Table 2).

Table 2

Comparison of characteristics between common mutation and rare mutations in NSCLC patients
Characteristics	Patients with common mutation (n = 164)	Patients with rare mutation (n = 101)	P value (95% CI)
	N(%)	N(%)
Age			0.614 (0.604, 0.624)
< 65	93(56.7%)	61(60.4%)
>=65	71(43.3%)	40(39.6%)
Gender			0.012 (0.10, 0.014)
Male	64(39.0%)	56(55.4%)
Female	100(61.0%)	45(44.6%)
Smoking status			0.070 (0.065, 0.075)
Never	110(67.1%)	56(55.4%)
Former	54(32.9%)	45(44.6%)
Family history of cancer			0.746 (0.737, 0.754)
Yes	31(18.9%)	17(16.8%)
No	133(81.1%)	84(83.2%)
Chronic diseases history			0.311(0.302, 0.320)
Yes	20(12.2%)	8(7.9%)
No	144(87.8%)	93(92.1%)
Clinical stage			0.757 (0.748, 0.765)
I	50(30.5%)	21(20.8%)
II	2(1.2%)	8(7.9%)
III	17(10.4%)	22(21.8%)
IV	94(57.3%)	50(49.5%)
Specimen type			0.665 (0.656, 0.774)
Biopsy specimen	94(57.3%)	60(59.4%)
Cytology specimen	14(8.5%)	10(9.9%)
Surgical specimen	56(34.1%)	31(30.7%)
Pathological type			0.264 (0.255, 0.272)
Adenocarcinoma or adenosquamous carcinoma	160(97.6%)	96(95.0%)
Squamous Carcinoma	2(1.2%)	2(2.0%)
others	2(1.2%)	3(3.0%)
PD-L1			0.001 (0.001, 0.002)
Positive	49(29.9%)	41(40.6%)
negative	79(48.2%)	27(26.7%)

In addition, logistic regression was used to analyze the risk factors associated with mutation status. The independent risk factors for common mutations were smoking history; pathology subtype and PD-L1 expression level, for rare mutations were pathology subtype and PD-L1 expression level (data not shown).

Treatment Data Of Nsclc Patients After Genetic Analysis

A total of 241 treatment records of NSCLC patients were obtained after genetic testing, details are shown in Table 3. For patients with common mutation, mono or combined targeted therapy was preferred, including 91% of the patients. For patients with rare mutations, 45.8% received mono or combined targeted therapy, the same number of patients received traditional treatment, and another 8.5% received mono or combined immunotherapy owing to enter clinical trials. Forty-six advanced patients achieved first-line treatment progress. The proportions of these patients carrying common mutation, rare mutation and with no detected mutations were 47.8% (22), 17.4% (8), and 34.8% (16), respectively. Their treatment options are shown in Table 3. The median PFS1 of patients with common mutation was longer than the other two groups, which was 13 months (95% CI: 9.9–16). The patients with rare mutation and no detected mutations were 5 months (95% CI: 0-10.5), and 5 months (95% CI: 1.1–8.9) respectively. However, due to the small amount of data, there was no statistical difference (p = 0.270) (Fig. 2). It is worth noting that four of the patients who were no detected mutations for the first genetic test, however, after the progress of chemotherapy the second driver gene mutation detection shown 2 of them with common mutation, and 2 of them with HER2 exon 20 insertions (Table 4).

Table 3

Details of gene mutation status and subsequent treatment options
	All patients	Patients with common mutation	Patients with rare mutation	Patients with wild type
	241 patients with treatment recorded
	N = 241	N = 100	N = 59	N = 82
mono or combined targeted therapy	124(51.4%)	91(91%)	27(45.8%)	6(7.3%)
mono or combined Immunotherapy	16(6.6%)	0	5(8.5%)	11(13.4%)
Other	101(41.9%)	9(9%)	27(45.8%)	65(79.3%)
	46 patients with first line treatment progressed
	N = 46	N = 22	N = 8	N = 16
mono or combined targeted therapy	26(56.5%)	21(95.5%)	3(37.5%)	2(12.5%)
mono or combined Immunotherapy	1(2.2%)	0	1*(12.5%)	0
Other	19(21.3%)	1(4.5%)	4(50%)	14(87.5%)

Table 4

The basic clinical and genetic information of the 4 patients with the first genetic test negative
Sample NO.	Gender	Smoking status	Pathological subtype	1st gene mutation testing	1st line therapy	2nd gene mutation testing after progression
174	female	Never	NSCLC	negative	chemotherapy	EGFR L858R
209	male	Yes	Adenocarcinoma	negative	chemotherapy	EGFR 19del
361	female	Never	Adenocarcinoma	negative	chemotherapy	HER2 20ins
444	female	Never	Adenocarcinoma	negative	chemotherapy	HER2 20ins

Non-small cell lung cancer is a genetic disease with high heterogeneity. The development process of cancer is related to driver genes, and the mutation status of driver genes also determines the choice of clinical treatment. It is reported that in Chinese NSCLC patients, the major driver genes include EGFR, ALK, ROS1, RET, HER2, MET, KARS, BRAF and PIK3CA.^[5] In the present study, we retrospectively analyzed the major driver gene mutation status in 431 NSCLC patients by the NMPA approved multi-gene detection kit. The nine-major driver gene mutation rate was 61.5% in all patients, which was higher in lung adenocarcinoma or adenosquamous carcinoma patients (73.6%), and the highest mutation rate in adenocarcinoma and adenosquamous carcinoma patients was the common EGFR mutation, 38.1% and 46.0%, respectively. For the rare mutations, KRAS (8.1% in adenocarcinoma, and 9.2% in adenosquamous carcinoma), uncommon EGFR mutation (5.3% in adenocarcinoma, and 6.6% in adenosquamous carcinoma in adenosquamous carcinoma), ALK (3.9% in adenocarcinoma, and 4.9% in adenosquamous carcinoma), HER2 (1.9% in adenocarcinoma, and 2.3% in adenosquamous carcinoma), and BRAF (1.4% in adenocarcinoma, and 1.7% in adenosquamous carcinoma) were the top five mutation types. Unfortunately, in our study the detection method was based on PCR, and most rare mutations cannot be distinguished the mutation sites, so the details of mutations cannot be shown here. The nine-major driver gene mutation frequency in squamous cell carcinoma patients in our study was 6.4%, including 3.2% of EGFR 19del and 3.2% of PIK3CA mutation, which was consistent with the previous studies.^[6] This also indicates that for patients with squamous cell carcinoma, it is necessary to improve the method to increase the positive detection rate of the major driver genes in clinical testing.

To analyze the relationship between the demographic and clinicopathological data with gene mutations can reveal the clinical characteristics of patients with mutations and provide references for clinical diagnosis and treatment. As it was reported that histology and smoking status are associated with EGFR status ^[24], which was proved in our study. For gender, previous studies indicated that the detection rate of EGFR mutations in women was higher, partly due to the higher proportion of non-smokers in the female population.^{[24, 25]} In the present study, female patients had a higher incidence of common mutations than those with rare mutations. Rare mutations occurred more frequently in male patients. Apart from gender, the expression of PD-L1 was also observed oppositely in common mutation and rare mutations groups with significantly difference. PD-L1 expression was positively correlated with rare mutation and negatively with common mutation in this study. Previous reports only consistently shown that KRAS mutations are positively correlated with PD-L1 expression, while the relationship between other gene mutation status and PD-L1 expression shown inconsistent conclusions.^[26] Therefore, in clinical practice, it is meaningful to pay more attention to rare mutations in male patients with adenocarcinoma. Also, for patients with rare mutations, further detection of PD-L1 expression level will have more hints for clinical treatment.

In China, the Chinese Society of Clinical Oncology (CSCO) guidelines, have taken the lead in compiling annual diagnosis and therapeutic approaches for cancer patients. In the CSCO guidelines, EGFR mutations, ALK and ROS1 rearrangements and their targeted drugs are recommended for routine clinical practice due to the limited availability of drugs. It is recommended to detect the expression of PD-L1 in patients with negative mutations of EGFR, ALK and ROS1 and to adopt the corresponding immunotherapy regimen..^{[5, 27]} In our study, treatment information was collected from 55.9% (241/431) of patients after genetic testing. For patients with common mutation, 91% received mono or combined targeted therapy compared with 45.8% of patients with rare mutation. The rare mutation types in these patients with treatment information were 11 uncommon EGFR mutation, 11 ALK fusion, 2 BRAF V600E mutation,2 MET exon 14 skipping, and 1 HER2 20ins. Among all the 241 patients with treatment information, only 6.6% of patients received mono or combined immunotherapy, and most patients chose this treatment because they participated in clinical trials. Due to the disparities and imbalance in resources, immunotherapy is still in its infancy in clinical practice in China.

In this study, we calculated the survival data from 46 patients who underwent first-line therapy after genetic testing based on limited data. Regardless of the specific treatment regimen adopted by these patients, only the relationship between the genetic mutation of patients and the median PFS1 was analyzed, we found some clues. Although the data were not statistically different, it could be found that the median PFS1 of patients with rare mutations was similar to mutation-negative patients, while shorter than the patients with common mutations. Previous studies have reported that the average PFS of NSCLC patients with uncommon EGFR mutations treated with EGFR-TKIs was significantly shorter than the patients with common EGFR mutations. ^{[7, 8]}This also suggests that for patients with rare mutations, better efficacy targeted drugs are needed in clinical practice. Furthermore, we identified 4 patients with negative primary genetic testing, however the driver gene mutation detection was positive after of chemotherapy progressed. In a study about the influence of chemotherapy on the status of EGFR mutation, the result showed that 24 (9.1%) of 264 NSCLC patients with EGFR wild type, but became mutant after first-line chemotherapy. ^[28] Furthermore, compared with first-line treatment, the efficiency of second-line EGFR-TKI treatment was lower.^{[29, 30]} Therefore, for NSCLC patients, if possible, the mutation status should be fully detected at the initial test. In addition, if the initial test is negative, the driver gene mutation status needs to be detected again before the second-line treatment.

There are also several limitations in this study. Firstly, the sample size is not large enough, especially the patients with rare mutations, so further investigation in larger sample size is warranted to validate the results of this work. Secondly, the collection of treatment records is incomplete, leading to inablilty to perform deeper analysis of survival data. Finally, due to the limited availability of new targeted drugs, the majority of patients with rare mutations did not have the opportunity to receive targeted therapy. Therefore, the resulting PFS may not objectively reflect the characteristics of the disease itself.

NSCLC patients with rare and common driver gene mutations differ in clinicopathological characteristics and clinical treatment status. Although the frequency of rare driver gene mutations is low, the number of patients in this group is also quite large due to the huge base of lung cancer patients. In clinical practice, these patients should be accurately diagnosed and more personalized attention should be paid in the follow-up treatment.

Ethics approval and consent to participate

Ethics Committee of Beijing Chest Hospital, Capital Medical University, Beijing, China. N.O.2019(62)

The consent to participate was waived

Consent for publication

Not applicable

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Competing interests:

The authors declare that they have no competing interests.

Funding

Not applicable

Authors’ contributions

Study design, ethical application and integrated management: Shucai Zhang and Nanying Che

Patient screening and patient clinical data collection: Hui Zhang, Xinjie Yang, Jinghui Wang, Jialin Lv, Xi Li, Xinyong Zhang, Zichen Liu, Na Qin, Zhang Quan, Yuhua Wu, Li Ma

Patient pathological data and molecular diagnostic data collection: Nanying Che, Xiaodie Qu, Kun Li

Data analysis, writing and review the manuscript: Fei Gai, Zhan Huang, Shucai Zhang, Hui Zhang, Nanying Che

The authors read and approved the final manuscript.

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Pathological Signature and Therapeutic Status of NSCLC Patients with Common or Rare Driver Gene Alterations in North China：A real world retrospective study

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Abstract

Figures

Background

Methods

Patients and study design

Driver Gene Mutation Detection

Pd-l1 Expression Detection

Statistical analysis

Results

Demographic and clinicopathological features of patients

Oncogenic Driver Gene Alterations In Nsclc Patients

Comparison of the characteristics between common and rare mutations in NSCLC patients

Treatment Data Of Nsclc Patients After Genetic Analysis

Discussion

Conclusions

Declarations

References

Status:

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