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KRAS G12C Mutant Non–Small Cell Lung Cancer Linked to Female Sex and High Risk of CNS Metastasis: Population-based Demographics and Survival Data From the National Swedish Lung Cancer Registry
Department of Immunology Genetics and Pathology, Science for life laboratory, Uppsala University, Uppsala, SwedenCenter for Research and Development, Uppsala University/Region Gävleborg, Uppsala, Sweden
Center for Research and Development, Uppsala University/Region Gävleborg, Uppsala, SwedenDepartment of Radiation Sciences, Oncology, Umeå University, Umeå, Sweden
Department of Clinical Genetics, Pathology and Molecular Diagnostics, Region Skåne, SwedenDivision of Pathology, Department of Clinical Sciences, Lund University, Lund, Sweden
Address for correspondence: Johan Botling, MD, PhD, Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, 41345 Gothenburg, Sweden
Department of Immunology Genetics and Pathology, Science for life laboratory, Uppsala University, Uppsala, SwedenDepartment of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden
Real-world data on demographics related to KRAS mutation subtypes are crucial as targeted drugs against the p.G12C variant have been approved.
Method
We identified 6183 NSCLC patients with reported NGS-based KRAS status in the Swedish national lung cancer registry between 2016 and 2019. Following exclusion of other targetable drivers, three cohorts were studied: KRAS-G12C (n = 848), KRAS-other (n = 1161), and driver negative KRAS-wild-type (wt) (n = 3349).
Results
The prevalence of KRAS mutations and the p.G12C variant respectively was 38%/16% in adenocarcinoma, 28%/13% in NSCLC-NOS and 6%/2% in squamous cell carcinoma. Women were enriched in the KRAS-G12C (65%) and KRAS-other (59%) cohorts versus KRAS-wt (48%). A high proportion of KRAS-G12C patients in stage IV (28%) presented with CNS metastasis (vs. KRAS-other [19%] and KRAS-wt [18%]). No difference in survival between the mutation cohorts was seen in stage I-IIIA. In stage IV, median overall survival (mOS) from date of diagnosis was shorter for KRAS-G12C and KRAS-other (5.8 months/5.2 months) vs. KRAS wt (6.4 months). Women had better outcome in the stage IV cohorts, except in KRAS-G12C subgroup where mOS was similar between men and women. Notably, CNS metastasis did not impact survival in stage IV KRAS-G12C, but was associated with poorer survival, as expected, in KRAS-other and KRAS-wt.
Conclusion
The KRAS p.G12C variant is a prevalent targetable driver in Sweden and significantly associated with female sex and presence of CNS metastasis. We show novel survival effects linked to KRAS p.G12C mutations in these subgroups with implications for clinical practice.
The treatment landscape in non–small cell lung cancer (NSCLC) is rapidly evolving with increasing focus on biomarkers for treatment decisions for the individual patient. At advanced stages, instead of administering chemotherapy, current best practice includes use of immunotherapy, in the form of checkpoint inhibitors, with or without concurrent chemotherapy, as well as targeted therapies based on the presence of oncogenic driver mutations.
Current diagnostic guidelines include treatment-predictive molecular testing for several genetic oncogenic driver aberrations for targeted therapy, as well as PD-L1 immunohistochemistry for immunotherapy.
The two largest histologic subgroups of NSCLC, adenocarcinoma and squamous cell carcinoma, are genetically different with regard to patterns of acquired oncogenic mutations. Notably, targetable driver mutations are far more common in adenocarcinoma.
This link is strengthened further by the high prevalence of smoking associated mutations in squamous cell carcinoma, ie, in the tumor suppressor genes TP53 and KEAP1.
The RAS superfamily of intracellular proteins mediate cellular signal transduction and in turn regulate proteins involved in cell growth, differentiation and survival. Activating mutations in RAS-proteins are common in many solid human cancers, particularly in adenocarcinoma of the lung where up to 40% of patients, depending on demographic factors, harbor KRAS driver mutations.
Furthermore, co-mutations are of particular interest in KRAS-mutated tumors as some common co-mutations are linked to prognosis, distinct immune response patterns and response to treatment.
Co-occurring genomic alterations define major subsets of KRAS-mutant lung adenocarcinoma with distinct biology, immune profiles, and therapeutic vulnerabilities.
The first KRAS p.G12C targeted therapy has been approved for patients with disease progression after first line systemic treatment. Also, combination therapy strategies with other drugs are under investigation in clinical trials.
Given the high prevalence of KRAS G12C mutations, this development has the potential to transform daily clinical practice and might improve survival prospects for a substantial part of the NSCLC patient population.
Sweden has a tax-financed health care system providing a uniform system for lung cancer diagnostics and treatment across geographic areas, socio-economic strata, and age groups.
The Swedish National Lung Cancer Registry (NLCR) contains data on demographics and diagnostic procedures, and linkage to the Swedish Cause of Death Registry allows comprehensive analysis of survival. Thus, access to a national registry with near complete inclusion rate in a setting with public uniform health care allows for analysis of truly population-based data.
KRAS-mutated NSCLC represents a large and markedly heterogenous group of tumors. Given the variability in mutation prevalence in different patient populations linked to ethnicity and smoking patterns and lack of knowledge on the specific biological properties of different KRAS-mutation variants, real-life data based on large population-based NSCLC cohorts are highly warranted. To this end, we aimed to explore the demographics and clinical outcomes in patients with KRAS-mutated tumors, with a focus on the p.G12C variant, using a large nationwide cohort of NSCLC patients.
Material and Methods
Patient Cohort and the National Lung Cancer Registry
The study was performed according to the guidelines of the declaration of Helsinki. The study was approved by The Swedish Ethical Review Authority (reference 2021-03039).
The Swedish National Lung Cancer Registry includes information on diagnostic procedures and parameters such as date of diagnosis, histopathologic diagnosis, stage, location of primary tumor, performance status (PS) as well as metastatic pattern at diagnosis. The coverage of the registry is 97% of pathologically confirmed cases.
There has been a coordinated national implementation of tumor genetic testing for diagnostics, treatment, and follow-up of lung cancer patients in routine clinical practice, as targeted treatments have become available. Genetic testing is conducted on tissue biopsy and cytology samples at molecular pathology laboratories in Sweden. Between 2015 and 2018, reflex NGS panel analysis (including KRAS status) for all NSCLC was gradually introduced across the regions in Sweden using clinically validated commercial platforms or in-house designed panels with relevant coverage of aberrations in oncogenic driver genes (see below). Mutation status retrieved from the respective laboratory information systems have been reported to the NLCR molecular pathology module since 2015 at varying coverage levels between regional centers.
Data Extraction
A total of 13,671 unique patients with a NSCLC diagnosis between 2016 and 2019 were identified from the NLCR, and 7680 patients had a corresponding record in the molecular pathology module (Figure 1). Data was extracted in August 2021. Patients without any molecular record (n = 5591) were included in the “Control Group.” Patients with a molecular test other than NGS (n = 1366, ie, mainly PCR-based analyses of hot-spot mutations) or with NGS failure (n = 127) were excluded. The resulting NGS Cohort includes 6183 patients with conclusive NGS analysis. Following exclusion of patients with reported established driver aberrations (hotspot mutations in EGFR, BRAF or NRAS, and rearrangements in ALK or ROS1; n = 825), three cohorts were selected for further study: a cohort with no known driver mutation (“KRAS-wild-type [wt]”; n = 3349), a KRAS p.G12C cohort (“KRAS-G12C” n = 848) and a cohort with all other non-G12C KRAS mutation variants (“KRAS-other” n = 1161). For subgroup analysis based on histology, the cohorts were further divided into three groups, adenocarcinoma, squamous cell carcinoma, and NSCLC NOS (all other histologies, mainly adenosquamous carcinoma, and variants of large cell carcinoma). Demographic data for all cohorts and all histologic subtypes are shown in Table 1.
Figure 1Patient source cohort in NLCR with data extraction of the NGS Cohort and sorting into mutational subgroups.
Descriptive statistics for all subjects and analysis of associations between tumor mutation status and clinicopathological parameters were performed using Pearson's X2 test or Fisher's exact test. Overall survival (OS) was defined from date of diagnosis to death of any causes, or end of study follow-up (June 30, 2021). The registry defines date of diagnosis as the date of the first histopathological or cytological test that confirms the NSCLC diagnosis. Survival analysis by Kaplan–Meier analysis was conducted for all subjects, by sex, stage at diagnosis, presence CNS metastasis, and within specific histological subgroups (adenocarcinoma, squamous cell carcinoma, and NSCLC NOS). In a subsequent step, mortality was evaluated in Cox regression models expressed as hazard ratios (HR) with 95% confidence intervals (CI) for individuals with adenocarcinoma and stage IV disease-for all subjects, and within the KRAS-G12C, KRAS-other, and KRAS-wt subgroups. All tests were two-sided, and a 5% level was considered statistically significant. Statistical analyses were performed using R version 4.1.2.
Results
NGS Cohort and Control Group
The NGS cohort, derived from the NLCR, represents 6183 NSCLC patients with reported conclusive molecular test results based on NGS (Table 1). In accordance with national guidelines, most patients in the Control Group were actually tested for driver mutations as well but lack a report of molecular status to the molecular pathology module in the registry. In addition, there are regional variations in testing practices regarding patients not eligible for systemic treatment (ie, low stage, poor PS) or in histologic subtypes where testing for driver mutations is not mandatory (ie, squamous cell carcinoma). To illustrate such bias, a comparison was made between the NGS Cohort and the Control Group.
Indeed, the prevalence of squamous cell carcinoma was higher in the Control Group compared to the NGS cohort (32.4% vs. 14.2%). Also, fewer patients in the Control Group presented with favorable PS 0 to 1 (60% vs. 68.3%) and more patients presented with PS 3 to 4 (16.6% vs. 11.4%). In the NGS Cohort, 54.3% of patients were female compared to 50.4% in the Control Group. Smoking status, age and stage at diagnosis were largely similar. In summary, we consider the NGS Cohort representative for the general population of patients eligible for systemic treatment, with some expected bias resulting from different regional practices with regard to molecular testing of squamous cell carcinoma and testing strategies in patients with poor PS.
Demographics Linked to KRAS status
Patients in the NGS cohort were subdivided by mutational status into three molecular groups, KRAS-G12C, KRAS-other and KRAS-wt, and compared to each other (Table 1).
As expected, prevalence varied by histology with KRAS mutations being most common in adenocarcinoma. The prevalence of KRAS mutations were 32% in the overall NGS Cohort, 38% in adenocarcinoma, 28% in NSCLC NOS and 6% in squamous cell carcinoma. The fraction of KRAS G12C mutations amounted to 13.7% in the total NSCLC NGS cohort. The prevalence of KRAS G12C was 15.9% in adenocarcinoma, 13.2% in NSCLC NOS and 2.1% in squamous cell carcinoma, respectively. These results indicate that a significant number of KRAS mutations, including targetable KRAS G12C, will be missed unless NSCLC NOS and squamous cell carcinoma are routinely tested.
The fraction of female patients was high in the two KRAS groups, 65.0% in KRAS-G12C and 58.7% of KRAS-other, compared to 47.5% in KRAS-wt subgroup. Patients with a self-reported history of smoking were 86.2% in the total NGS cohort (35.0% current smokers and 51.2% former smokers) with similar numbers (87.7%) in the KRAS-wt group (37.1% current smokers and 50.6% former smokers). Higher numbers were found in the KRAS-G12C where reported incidence of smoking was 97.6% (40.9% current smokers and 56.7% former smokers). Advanced stage disease at time of diagnosis was largely similar between the mutation subgroups. Presentation in PS 0–1 was somewhat more common in KRAS-G12C (70.1%) compared to KRAS-other (67.6%) or KRAS wt (66.6%).
Survival Analysis By Stage
For survival analysis, we chose to focus on adenocarcinoma patients to avoid bias in regard to testing guidelines based on histologic subtypes. Also, the treatment options, based on national guidelines, for adenocarcinoma patients have been uniform across Sweden as opposed to more divergent practices for patients with squamous cell carcinoma. Figure 2 shows results from the Kaplan-Meier analysis of adenocarcinoma patients in stage I to IV comparing the KRAS-G12C, KRAS-other and KRAS-wt cohorts. The overall survival from date of diagnosis is based on all patients in the respective stage groups, across all PS strata and age groups, and includes treated and non-treated patients. Demographic data by stage can be found in Supplementary Tables 5A-E.
Figure 2Kaplan-Meier curves for survival in adenocarcinoma by stage (I, II, IIIA, IIIB-C and IV) stratified by molecular subgroup.
OS in stage I was similar between the mutation cohorts with 12-month survival above 90% in all groups. No statistically significant differences in survival could be detected. Median OS (mOS) was not reached in either group.
In stage II disease there was a trend towards improved survival in KRAS-G12C but it was not statistically significant (P = .071). In KRAS-G12C, mOS was not reached. In KRAS-other the mOS was 50.6 months and in KRAS-wt 43.0 months.
In stage IIIA no survival differences were detected between the three groups. The mOS ranged between 27.1 and 29.2 months. A similar pattern was seen in stage IIIBC with no difference in survival and mOS between 17.8 and 21.2 months.
In stage IV there was a small but statistically significant survival benefit for the KRAS-wt group (P = .006) at mOS of 6.9 months. The mOS for KRAS-G12C was 6.2 months and 5.5 months in KRAS-other.
Thus, in contrast to other published studies, we did not detect any significant survival differences linked to KRAS status in early-stage disease, nor in locally advanced disease.
There was a small but statistically significant difference in metastatic disease with poorer outcomes in KRAS mutated patients, but this was less pronounced in the KRAS-G12C group.
Men Versus Women
As the female-male ratios were different in the mutation subgroups, with a predominance of women in KRAS-G12C group, we next compared men and women in the adenocarcinoma subgroup. Demographic data is shown in Table 2(data per stage is found in Supplementary Table 6A-E). Women with KRAS p.G12C were slightly younger than men (median 71 years vs. 72 years). Smoking history was almost identical. The fraction of patients with KRAS p.G12C in advanced stage at time of diagnosis was largely similar between the sexes, but PS was slightly more favorable in women (73.3% in ECOG PS 0–1, 69.4% in men). At stage 4 (Supplementary Table 6E), the metastatic pattern differed slightly between women and men; bone metastasis (38.0% vs. 43.1%) and adrenal gland metastasis (15.2% vs. 21.2%) were less common in women compared to men. Conversely, CNS metastasis were more common in women (28.7% vs. 25.5%).
Table 2Demographics of NGS Cohort Stratified by Sex (Adenocarcinoma)
Overall survival data from diagnosis in stage IV adenocarcinoma stratified by sex and KRAS mutation status is shown in Figure 3A. There was no statistical difference in mOS between women and men in the KRAS p.G12C cohort (6.1 months vs. 6.6 months). However, in the other two subgroups, survival differed in line with the established survival benefit linked to female sex. In the KRAS-other cohort mOS for women was 6.4 months versus 4.5 months for men, and in KRAS wt mOS for women was 8.0 months versus 6.0 months for men. Although not statistically significant, the trend in multi-variable analysis supports a discordant survival impact related to female sex (Table 4) in the KRAS-G12C group after adjustment for age, PS and presence of CNS metastasis. The hazard ratios for death in women (vs. men as reference) were HR 1.21 in the KRAS-G12C group compared to HR 0.65 and HR 0.89 in KRAS-other and KRAS-wt groups, respectively. Thus, so far, we cannot explain this sex-related survival pattern by known baseline clinical confounders.
Figure 3Kaplan-Meier curves for survival in stage IV adenocarcinoma stratified by (A) sex and (B) presence of CNS-metastasis at diagnosis in the different molecular subgroups.
The metastatic patterns in stage IV adenocarcinoma were significantly different between the KRAS-G12C, KRAS-other and KRAS wt groups (Supplementary Table 5E). CNS metastasis was more common in KRAS-G12C (27.5%) compared to both KRAS-other (18.8%) and KRAS-wt (18.5%). Bone metastasis was more common in KRAS-mutated tumors, KRAS-G12C (39.8%) and KRAS-other (40.6%), compared to KRAS wt (35.0%). Similar patterns between the groups were seen in metastasis to the liver and adrenal glands. Metastasis to other sites, recorded as free text in the registry (not available for this study), were less common in KRAS-G12C (44.1%) compared to KRAS-other (55.1%) and KRAS-wt (50.3%).
CNS Metastasis and Concurrent Metastasis in Patients With KRAS p.G12C Mutations
As patients with CNS metastasis in stage IV adenocarcinoma were enriched in the KRAS-G12C subgroup, in comparison to KRAS-other and KRAS-wt, we next sought to study the mutation cohorts further with regard to the rate of metastasis at other anatomical sites in relation to reported presence of CNS metastasis at diagnosis (Table 3).
Table 3KRAS Mutation Status and CNS Metastasis (Adenocarcinoma, Stage IV)
In the larger group of patients without CNS metastasis, bone metastasis was more common in patients with KRAS-mutations, ie, in the KRAS-G12C and KRAS-other subgroups, as described above. No significant differences between the mutation cohorts were detected for other metastatic sites. Notably, the metastatic rates at different sites were relatively similar between patients with KRAS p.G12C and other KRAS mutations.
In the group of patients with CNS metastasis, another pattern emerged. The rate of additional metastasis at other sites (bone, liver, adrenal gland, and other) was consistently lower for patients in the KRAS-G12C group in comparison to patients in the KRAS-other and KRAS-wt subgroups. This was especially striking for liver metastasis, 4.9% in KRAS-G12C versus 15.7% in KRAS-other and 14.8% in KRAS-wt. Also, the rate of concurrent metastasis in bone was lower in KRAS-G12C (19.4%) compared to KRAS-other (34.3%).
We hypothesize that the common occurrence of CNS metastasis detected at diagnosis in KRAS p.G12C patients could reflect an early metastatic event linked to a higher probability of oligometastatic CNS disease in stage IV adenocarcinoma patients. Indeed, CNS metastasis reported as the sole metastatic event was more common in the KRAS-G12C subgroup (64.1%) in comparison to KRAS-other (40.2%) and KRAS-wt (52.9%).
CNS Metastasis and Survival
CNS-metastasis is a known negative factor for survival and morbidity in all solid tumors as well as in NSCLC. Figure 3B illustrates the survival outcome in the three mutation cohorts in relation to presence or absence of CNS metastasis. A significant difference in survival was seen in the KRAS-other subgroup - mOS with CNS metastasis 4.3 months and without 6.0 months. Similarly, in KRAS-wt the mOS was 5.2 months with CNS metastasis and 7.3 months without. In contrast, survival in the KRAS-G12C group was similar in the patients with or without CNS metastasis - the mOS with CNS metastasis was 6.1 months and without CNS metastasis 6.2 months.
In multi-variable analysis (Table 4), a significant negative survival impact was noted for presence of CNS metastasis in the total adenocarcinoma stage IV subgroup at HR 1.20 (CI 1.07-1.35). Likewise, an independent significant impact of CNS metastasis remained in the KRAS-wt cohort at HR 1.28 (CI 1.09-1.52). A similar trend, but non-significant was seen in the KRAS-other subgroup at HR 1.19 (CI 0.94-1.51). In concordance with the Kaplan-Meier analysis, the trend for survival impact related to CNS metastasis was less pronounced in the KRAS-G12C subgroup, at HR 1.08 (CI 0.84-1.39).
Table 4Multivariable Analyses for Survival in Stage IV Adenocarcinoma (HR for Mortality)
Thus, we were not able to find any obvious clinical baseline confounders that could explain the survival pattern associated with CNS metastasis in KRAS p.G12C mutated patients, except for the described pattern of concurrent metastasis at other anatomic sites.
Discussion
We here describe a population-based Swedish registry cohort of 6183 NSCLC patients with annotated driver mutations status based on NGS analysis in routine health care. To illustrate the impact of KRAS mutations on demographics, clinical baseline characteristics and overall survival, patient cohorts with KRAS p.G12C mutations, other KRAS mutations and a driver negative reference cohort were analyzed and compared.
KRAS mutation are common in NSCLC in western populations. Indeed, in the Swedish patient population the prevalence of KRAS mutations was high, 38% in adenocarcinoma and 28% in the NSCLC NOS cases. Similar frequencies have been reported for the non-squamous subgroups in other European populations.
The p.G12C variant was seen at 15.9% and 13.2% in adenocarcinoma and NOS patients, respectively. Thus, KRAS p.G12C mutations represent the most common targetable driver aberration in the Swedish lung cancer population.
Given the approval of specific therapeutic inhibitors, the presence of a significant number of p.G12C mutations in squamous cell carcinoma indicate that current guidelines for molecular testing need to be revised.
Molecular testing guideline for the selection of patients with lung cancer for treatment with targeted tyrosine kinase inhibitors: American Society of Clinical Oncology Endorsement of the College of American Pathologists/International Association for the Study of Lung Cancer/Association for Molecular Pathology Clinical Practice Guideline Update.
KRAS p.G12C mutations at 2.1% in squamous cell carcinoma represents a larger targetable fraction than aberrations such as BRAF, ROS1, RET or MET exon 14 skipping in the adenocarcinoma subgroup. Adding reported “other drivers” at 1.7% (Table 1) would indicate that 3.8% of the squamous cell carcinoma patients, if tested, could be candidates for targeted therapy. The presence of driver mutations in true squamous NSCLC has been questioned given the difficulty to assess histologic subtypes in small cytology and biopsy specimens. However, the registry data shows that Swedish pathologists, that applied the guideline algorithms from 2011, annotate a significant fraction of cases with driver mutations as squamous cell carcinomas. In addition, it should be noted that suggested “rescue” procedures to focus molecular testing on young patients and never smokers with squamous cell carcinoma would not be effective for the KRAS p.G12C population, as shown here.
The survival outcome data in this study showed no significant impact of KRAS status in stage I to IIIB disease. This contrasts with a recent study by the ETOP group on surgical NSCLC cases where KRAS p.G12C cases exhibited worse survival outcome than cases with other KRAS mutations, and better survival was seen in KRAS-negative patients. However, in the ETOP study, the KRAS negative group also included other driver mutations,
In stage IV disease, KRAS-wt had a small but statistically significant better survival outcome. In comparison, other studies have failed to show significant differences in survival comparing KRAS mutant and non-mutated cases, or between patients with KRAS p.G12C and other KRAS mutations.
KRAS G12C-mutated advanced non-small cell lung cancer: A real-world cohort from the German prospective, observational, nation-wide CRISP Registry (AIO-TRK-0315).
The three mutation cohorts all had the same treatment options available for the duration of the study, primarily guided by ECOG PS. The survival analyses included all patients, including patients with poor ECOG PS which negatively affects the observed median overall survival. It is important to consider that a substantial number of patients likely received no treatment at all due to ECOG PS or by their own choice. Thus, our findings to a large extent reflect prognostic effects of the particular mutation subtypes rather than treatment-predictive impact.
Results on the sex distribution in KRAS mutated and KRAS p.G12C patients are conflicting. Other European studies show fairly equal distribution between men and women.
KRAS G12C-mutated advanced non-small cell lung cancer: A real-world cohort from the German prospective, observational, nation-wide CRISP Registry (AIO-TRK-0315).
Notably, in our study, 65.0% of KRAS-G12C, and 58.7% of KRAS-other were women. This finding is in agreement with a US study (61.1% women in KRAS p.G12C group), findings in a retrospective Norwegian cohort (KRAS mutated, not separated for KRAS p.G12C with 56.9% women) and data from the Lung Cancer Consortium (57.9% women).
A retrospective observational study of the natural history of advanced non-small-cell lung cancer in patients with KRAS p.G12C mutated or wild-type disease.
We believe that the sex distribution can be explained by differences in ethnicity as well as male and female smoking habits. In addition, a high rate of smoking related mutations (ie, KRAS p.G12C) have been described in women, at comparable or lower tobacco consumption.
Molecular epidemiology of EGFR and KRAS mutations in 3,026 lung adenocarcinomas: higher susceptibility of women to smoking-related KRAS-mutant cancers.
Our finding that men and women in the KRAS-G12C subgroup have the same survival outcome in stage IV adenocarcinoma is intriguing. We can only speculate on the causes underpinning this result. We could not find any obvious confounding registry parameter that could explain the lack of survival impact related to female sex in the KRAS-G12C group. Further studies on the distribution of prognostic co-mutations and treatment response after chemotherapy and immunotherapy in men versus women are warranted to better understand this finding.
Co-occurring genomic alterations define major subsets of KRAS-mutant lung adenocarcinoma with distinct biology, immune profiles, and therapeutic vulnerabilities.
Our study shows a high prevalence of CNS metastasis at diagnosis in the stage IV KRAS-G12C group (26.7%). This fraction is slightly larger than in the study by Spira et al.
A retrospective observational study of the natural history of advanced non-small-cell lung cancer in patients with KRAS p.G12C mutated or wild-type disease.
which describe CNS metastases in 23.4% of patients with KRAS p.G12C mutations. Notably, in our cohort, the frequencies of CNS metastases were similar in the KRAS-other and KRAS-wt groups (19.1% and 18.5%). This result indicates that the enrichment of CNS metastasis linked to KRAS mutations in NSCLC is driven mainly by the p.G12C mutation. In general terms, the results related to KRAS mutations mirror findings in other oncogenic driver subsets of NSCLC that also present with a high rate of CNS metastasis.
Summary report on the graded prognostic assessment: an accurate and facile diagnosis-specific tool to estimate survival for patients with brain metastases.
patients with confirmed metastatic disease on CT scans of thorax/abdomen are not required to undergo CT/MRT of the brain. Thus, asymptomatic brain metastases are likely under-reported in our registry study. Still, the high fraction of reported CNS metastasis raise the question whether KRAS p.G12C mutated patients should be screened for CNS metastasis during the diagnostic work-up. Targeted therapies directed at other driver mutations have been shown to be superior compared to chemotherapy, and current treatment standards recommend initial treatment with tyrosine kinase inhibitors and evaluation rather than radiotherapy in EGFR/ALK positive NSCLC with brain metastases.
First-Line Afatinib versus chemotherapy in patients with non-small cell lung cancer and common epidermal growth factor receptor gene mutations and brain metastases.
New targeted therapies against KRAS p.G12C might be an additional first-line treatment modality for this patient category.
Interestingly, we could not demonstrate any impact on mOS related to the presence of CNS metastasis in KRAS-G12C group of stage IV adenocarcinoma. Given the known link between CNS metastasis and poor outcome, worse survival was expected. Indeed, a negative survival impact of CNS metastasis was seen in the KRAS-other and KRAS-wt groups. We can only speculate on the mechanisms behind this finding. One possible explanation is that KRAS mutated patients with brain metastasis, as described, responds well to immunotherapy.
Another possible explanation is that intrinsic biological properties of KRAS p.G12C mutations are linked, not only to a high frequency of CNS metastasis, but also to early metastatic dissemination to the CNS. This hypothesis is supported by a higher proportion of patients presenting with CNS metastasis as the only metastatic site. If confirmed in other studies, patients with the combination of a CNS metastasis and KRAS p.G12C could represent a specific oligometastatic subgroup in lung adenocarcinoma with a comparatively favorable survival outcome.
The strengths of this study lie in the size and the high degree of patient coverage in a population with equal access to health care and advanced diagnostics rather than being based on cohorts from clinical studies or selected specialist centers. The main weakness, as discussed, is the lack of follow-up data after systemic treatments, in relation to the survival results in stage IV adenocarcinoma subgroups. Ongoing retrospective registration of treatment and follow-up data in the NLCR will allow future detailed studies on the predictive impact of KRAS mutation subtypes in relation to chemotherapy and checkpoint inhibitor regimens. Also, as co-mutations beyond driver mutations such as TP53, KEAP1 and STK11 were not reported to the registry, we were not able to assess the impact of these in the respective mutation sub-cohorts.
In conclusion, real-world data from the national lung cancer registry indicate that KRAS p.G12C is the most common targetable aberration in the Swedish NSCLC population, and significantly linked to baseline parameters such as smoking, female sex, and presence of brain metastasis. We believe that the distribution of KRAS p.G12C across all histologic subtypes warrants molecular testing of all NSCLC patients. Reflex radiologic brain scans at diagnosis in patients with KRAS p.G12C mutations should be discussed based on the high frequency of CNS metastasis and hypothesis generating data indicating the brain as a vulnerable compartment for early metastatic dissemination.
Clinical Practice Points
This large, population-based, study illustrates key demographic findings related to the KRAS G12C mutation subtype. It is the most common targetable oncogenic driver in NSCLC in a typical western population, has a strong correlation to smoking and is predominantly seen in women.
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A significant prevalence of KRAS G12C in NSCLC-NOS (13.2%) and squamous cell carcinoma (2.1%) highlights the need for NGS testing in all histologic NSCLC subtypes, in addition to lung adenocarcinoma.
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The link between KRAS mutations and CNS metastasis is strongly attributed to the KRAS G12C variant. In addition, as opposed to patients with other KRAS mutations, the majority of stage IV patients with KRAS G12C presented with CNS metastasis as the sole metastatic compartment. Thus, we suggest that CT/MRI brain scans should be considered in KRAS G12C patients to discover isolated asymptomatic CNS disease for potential treatment.
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Lack of overall survival differences in stage IV disease between men and women, and between patients with and without CNS metastasis, are unique findings which warrant further research into the distinct biology of KRAS G12C mutated NSCLC.
Disclosure
The study was funded by Amgen Ltd
Johan Isaksson declares research grants from Amgen Sweden AB. Lecture honoraria from Amgen Sweden, AstraZeneca, BMS, MSD and Roche. Participation in advisory boards for Amgen, AstraZeneca and Roche
Anders Berglund declares no conflicts of interest outside funding of the study.
Karly Louie was an employee of Amgen Ltd while conducting the research and holds stock options in Amgen and Biomarine.
Linda Willén declares lecture honoraria and consulting fees from BMS
Arash Hamidian is an employee of Amgen Sweden and holds company stock.
Anders Edsjö declares lecture honoraria from Amgen, AstraZeneca, Bayer and Diaceutics
Fredrik Enlund declares lecture honoraria from AstraZeneca, BMS, Boehringer-Ingelheim, Novartis, PierreFabre and Pfizer.
Maria Planck declares research grants from the Swedish Cancer society, the Sjöberg foundation and the Kamprad foundation outside the scope of this study as well as lecture honoraria from Roche.
Anders Vikström declares research support from Boehringer-Ingelheim, lecture honoraria from Amgen, AstraZeneca, Boehringer-Ingelheim, BMS, MSD, Novartis, Pfizer, Roche and Takeda. Travel support from Roche. Advisory board participation from AstraZeneca, Boehringer-Ingelheim, Lilly, MSD, Novartis, Pfizer, Roche, Sanofi and Takeda
Mikael Johansson declares no conflict of interest outside study funding
Andreas Hallqvist declares research grants from AstraZeneca and Novartis. Lecture honoraria from AstraZeneca, BMS and Roche.
Gunnar Wagenius declares no conflicts of interest outside funding of the study.
Johan Botling declares research grants from BMS, consulting fees and stock options from Strike Pharma and travel support from Amgen Sweden as well as lecture honoraria from Amgen, AstraZeneca, Boehringer-Ingelheim, BMS, GSK, Illumina, Lilly, MSD, Novartis, Pfizer and Roche.
Acknowledgments
This study was sponsored by Amgen Ltd (Uxbridge, United Kingdom). The authors gratefully acknowledge support and scientific input from the National Lung Cancer Registry (NLCR), the Swedish Lung Cancer Study Group (SLUSG), and the Solid Tumor working group in the Genomic Medicine Sweden initiative. The authors thank clinicians, pathologists and staff at the Swedish lung cancer care units and molecular pathology laboratories for reporting clinical and molecular data to the NLCR.
Co-occurring genomic alterations define major subsets of KRAS-mutant lung adenocarcinoma with distinct biology, immune profiles, and therapeutic vulnerabilities.
Molecular testing guideline for the selection of patients with lung cancer for treatment with targeted tyrosine kinase inhibitors: American Society of Clinical Oncology Endorsement of the College of American Pathologists/International Association for the Study of Lung Cancer/Association for Molecular Pathology Clinical Practice Guideline Update.
KRAS G12C-mutated advanced non-small cell lung cancer: A real-world cohort from the German prospective, observational, nation-wide CRISP Registry (AIO-TRK-0315).
A retrospective observational study of the natural history of advanced non-small-cell lung cancer in patients with KRAS p.G12C mutated or wild-type disease.
Molecular epidemiology of EGFR and KRAS mutations in 3,026 lung adenocarcinomas: higher susceptibility of women to smoking-related KRAS-mutant cancers.
Summary report on the graded prognostic assessment: an accurate and facile diagnosis-specific tool to estimate survival for patients with brain metastases.
First-Line Afatinib versus chemotherapy in patients with non-small cell lung cancer and common epidermal growth factor receptor gene mutations and brain metastases.
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