A Critical Review of the Impact of SMARCA4 Mutations on Survival Outcomes in Non-Small Cell Lung Cancer
Abstract
:1. Introduction
2. Materials and Methods
3. Results
3.1. Results and Description of Studies
3.2. SMARCA4 Mutations
3.3. SMARCA4/KRAS Co-Mutations
4. Discussion
4.1. SMARCA4 Molecular Sub-Types and Genomic Features
4.2. Clinicopathological Features
4.3. SMARCA4/KRAS Co-Mutations
4.4. SMARCA4/KRAS Co-Mutation Treatment Analysis
5. Future Direction
6. Limitations
7. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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(A) | |||||
Author | Publication Year | Treatment | NSCLC Mutation Analyzed | Number of NSCLC Patients with Mutation Analyzed | Outcomes/Relevance |
Schoenfeld | 2020 | Various SOC | SMARCA4 | N = 292 mut [class 1 mut (N = 149) and class 2 (N = 143)] | In a multivariate analysis, both SMARCA4 mut class 1 and 2 had worse OS (p < 0.001) vs. WT. Class 1 mut had worse OS compared to class 2 mut or WT (p < 0.001). |
ICI cohort | SMARCA4 | N = 87 mut | OS improvement for SMARCA4 mut with ICI treatment vs. without ICI treatment regardless of class 1 or class 2 mut status (p = 0.01). | ||
The unadjusted ICI analysis showed no difference in PFS (p = 0.74) or OS (p = 0.35) with class 1 mut vs. class 2 mut. | |||||
Alessi | 2023 | CIT | SMARCA4 | 114 mut | In multivariate analysis: worse OS for SMARCA4 mut vs. WT (8.1 versus 15.0 months, HR: 1.70; p < 0.001) and worse PFS: (2.7 versus 6.1 months, HR: 1.62; p < 0.001). |
Alessi | 2021 | Various SOC | SMARCA4 | 163 mut | SMARCA4 mut had worse OS (15.6 months) vs. SMARCA4 WT (25 months) (HR: 0.64; p < 0.001). |
ICI or ICI/CTLA4 cohort | SMARCA4 | 57 mut class 1 non-sense, frameshift, and splice site mut (N = 26) and class 2 missense mut (N = 31) | There were no significant differences in SMARCA4 WT vs. mut: PFS (3.1 vs. 2.1 months; HR = 0.93, p = 0.62) or OS (12.4 vs. 11 months; HR = 0.83, p = 0.25 months). | ||
There was no OS difference in outcomes after receiving ICI therapy when comparing class 1 nonsense, frameshift, and splice site mut (6.7 months; p = 0.11) vs. WT patients (12.4 months) vs. class 2 missense mut (11.9 months, HR = 1.03, p = 0.87). | |||||
Fernando | 2020 | Various SOC | SMARCA4 | SMARCA4 mut in four categories: (1) homozygous truncated (N = 102), (2) homozygous nontruncated (N = 101), (3) heterozygous truncated (N = 16), (4) heterozygous nontruncated (N = 49) | There was a significant OS difference when comparing SMARCA4 homozygous truncated mut vs. SMARCA4 WT (7.9 vs. 16.3 months, HR: 1.85; p < 0.0001), but no significant differences when comparing the other SMARCA4 mut categories with WT. |
ICI cohort | SMARCA4 mut four categories: (1) homozygous truncated (N = 38), (2) homozygous nontruncated (N = 41), (3) heterozygous truncated (N = 5), (4) heterozygous nontruncated (N = 23) | There was a significant OS difference when comparing SMARCA4 mut homozygous truncated vs. SMARCA4 WT (9.9 vs. 19.5 months, HR: 1.62; p = 0.01), but no significant differences when comparing the other SMARCA4 mut categories with WT. | |||
Dagogo-Jack | 2020 | Chemo or CIT | SMARCA4 | 16 mut | Extremely short PFS for chemo and CIT treatment (38 and 35 days), respectively. |
Liang | 2023 | Various SOC | SMARCA4 | Stage III mut (N = 21), Stage IV mut (N = 69) | Median OS survival for SMARCA4 mut vs. SMARCA4 WT patients was notably lower in Stage III (23.73 vs. 29.43 months, p = <0.01) and Stage IV (11.93 vs. 28.23 months, p = <0.01). |
SMARCA4 | 221 mut women (N = 88), men (N = 25) | Multivariate analysis resulted in statistically worse OS for women vs. men (HR = 4.1, p = 0.04). | |||
Talvitie | 2022 | Various SOC | SMARCA4 | 135 mut | SMARCA4 mut patients had a worse OS than SMARCA4 WT (HR: 3.522; p < 0.002). |
SMARCA4 | Stage III mut (N = 31) | Stage III multivariate analysis SMARCA4 mut patients had a worse OS vs. WT patients (HR:1.93; p = 0.04). | |||
Xu | 2023 | Various SOC | SMARCA4 | Four Arms: (1) SMARCA4 WT, TMB Low (N = 761), (2) SMARCA4 WT, TMB High (N = 722), (3) SMARCA4 mut, TMB Low (N = 26), and (4) SMARCA4 mut, TMB High (N = 69). | Statistically better OS for SMARCA4 WT/TMB High (p = 0.00019). |
Miao | 2023 | Alectinib (ALK) | SMARCA4/ALK | 3 mut | In a multivariate analysis, SMARCA4 mut patients with brain metastasis were the only co-mut with ALK with worse outcomes (HR: 8.76; p = 0.009). |
Pan | 2023 | Various SOC | SMARCA4 | 44 mut: women (N = 19), men (N = 25) | Multivariate analysis with SMARCA4 mut: men had a significantly worse OS than women (2.75 months vs. un-estimable, HR:14.2; p = 0.02). |
Wang | 2021 | Atezo (ICI) or docetaxel | SMARCA4 | 100 mut | OAK analysis: there is no statistical difference in OS when comparing atezolizumab vs. docetaxel in SMARCA4 mut, whether PDL-1 high or negative (HR = 0.67; p = 0.256). |
SMARCA4 | 39 mut | No difference in OS with PDL-1 high vs. low when treated with atezo (HR = 1.185, p = 0.513) | |||
Marinelli | 2020 | Atezo (ICI) | SMARCA4 | 18 mut | OAK uni-variate analysis: SMARCA4-mutated patients receiving atezo did not fare worse than SMARCA4 WT patients (HR: 1.70; p = 0.064). |
Velut | 2022 | Nivolumab or pembro | SMARCA4 | 7 mut | SD-NSCLC patients had a shorter OS than patients with non-SD-NSCLC, considering either from the date of diagnosis (p = 0.01, HR: 2.9) or from the date of immunotherapy (p = 0.006, HR: 3.2). OS rates at 1 year were not significantly different between SMARCA4 mut and WT patients but dropped significantly at 2 (58% vs. 74%) and 5 years (37% vs. 53%). |
Chang | 2022 | ICI (87% of patients) | SMARCA4 | 16 mut | No significant PFS difference in SMARCA4 WT vs. mut (6.3 vs. 3.9 months, HR: 0.64; p = 0.15). |
Yang | 2023 | Various SOC | SMARCA4 | 5 mut | SMARCA4 mut patients had a worse OS compared to WT patients (4.5 months vs. 13.3 months; HR: 2.86; p = 0.031). Significantly worse PFS for SMARCA4 mut vs. WT (2.3 months vs. 8.1 months, HR: 2.80; p = 0.035). |
Wang | 2021 | SOC | SMARCA4 | 4 mut | In multivariate analysis, SMARCA4 mut patients fared worse than SMARCA4 WT (HR = 3.098, p = 0.038) and had worse PFS (3 vs. 8 months, p = 0.007). |
Le Fleur | 2019 | Various SOC | SMARCA4 | 21 mut | In a multivariate all-cause mortality analysis, SMARCA4 mut were independently associated with a worse OS prognosis (HR: 2.06, p = 0.003). |
(B) | |||||
Author | Publication Year | Treatment | NSCLC Mutations Analyzed | Number of NSCLC Patients with Mutations Analyzed | Outcomes/Relevance |
Cooper | 2022 | Various SOC | SMARCA4/KRAS G12D co-mut | 8 co-mut | Significantly worse PFS for co-mut patients; PFS: SMARCA4/KRAS G12D mut vs. SMARCA4 WT/KRAS G12D mut (1.5 vs. 4.0 months; p = 0.0039). |
SMARCA4 WT/KRAS G12D mut | 49 mut | No significant difference in OS: SMARCA4/KRAS G12D co-mut vs. SMARCA4 WT/KRAS G12D mut (6.1 vs. 17.3 months; p = 0.4202). | |||
Negrao | 2023 | Sotorasib or adagrasib | SMARCA4/KRAS G12C co-mut | 20 co-mut | SMARCA4/KRAS co-mut patients had significantly worse PFS than SMARCA4 WT/KRAS mut (1.6 months vs. 5.4, HR: 3.04; p < 0.001) and had a significantly worse OS (4.9 months vs. 11.8 months, HR: 3.07; p < 0.001). |
SMARCA4 WT/KRAS G12C | 214 mut | ||||
Boiarsky | 2023 | Various SOC | SMARCA4/KRAS co-mut | 33 co-mut | OS was significantly worse for SMARCA4/KRAS co-mut patients with brain metastasis vs. SMARCA4 WT/KRAS-mutated (7.4 months vs. 15.0 months, HR: 2.1; p = 0.0003). |
SMARCA4 WT/KRAS mut | 231 mut | Liver metastasis: SMARCA4/KRAS co-mut had worse outcomes vs. SMARCA4 WT/KRAS-mutated (5.2 months vs. 13.2 months, HR: 2.1; p = 0.00015). | |||
Alessi | 2021 | CIT | SMARCA4/KRAS co-mut | 44 co-mut | Significantly worse OS (6.6 vs. 14.6 months; HR: 2.52, p < 0.001) and PFS (2.2 vs. 6.2 months; HR: 2.39, p < 0.001) in SMARCA4/KRAS co-mut vs. SMARCA4 WT/KRAS mut patients. |
SMARCA4 WT/KRAS mut | 232 mut | ||||
Alessi | 2023 | Single-agent ICI or ICI combined with CTLA-4 | SMARCA4/KRAS co-mut | 17 co-mut | SMARCA4/KRAS co-mut had significantly shorter PFS (1.4 vs. 4.1 months, HR: 0.25; p < 0.001) and OS (3 vs. 15.1 months, HR: 0.29; p < 0.001) compared with SMARCA4 WT/KRAS mut patients. |
SMARCA4 WT/KRAS mut | 159 mut | The presence of a SMARCA4/KRAS co-mut may confer a worse outcome to ICIs. | |||
Schoenfeld | 2020 | Various SOC | SMARCA4/KRAS co-mut | 110 co-mut 58 co-mut (class 1 SMARCA4) 52 co-mut (class 2 SMARCA4) | Multivariate SMARCA4/KRAS co-mut analysis resulted in worse statistical OS regardless of class 1 or 2 alterations. [Class 1: HR: 1.59, and class 2: HR: 2.75] vs. WT (p < 0.001). |
Liu | 2021 | Various SOC | SMARCA4/KRAS co-mut | Cohort A: SMARCA4/KRAS co-mut (N = 9) vs. SMARCA4 WT/KRAS mut (N = 146) | Cohort A: SMARCA4/KRAS co-mut vs. SMARCA4 WT/KRAS mut had worse OS (15.73 vs. 19.73 months) in non-immunotherapy cohort in The Cancer Genome Atlas (TCGA) (HR: 2.32, p = 0.047). |
SMARCA4 WT/KRAS mut | Cohort B: SMARCA4/KRAS co-mut (N = 34) vs. SMARCA4 WT/KRAS mut (N = 280) | Cohort B: SMARCA4/KRAS co-mut vs. SMARCA4 WT/KRAS mut had worse OS (5.2 vs. 6.5 months) in non-immunotherapy MSK-CT cohort (HR: 1.95, p = 0.015). | |||
Cohort C: SMARCA4/KRAS co-mut (N = 9) vs. SMARCA4 WT/KRAS mut (N = 68) | Cohort C: SMARCA4/KRAS co-mut vs. SMARCA4 WT/KRAS mut (1.73 vs. 4.22 months) had worse PFS in immunotherapy MSK-IO cohort (HR: 2.15; p = 0.048). | ||||
Cohort D: SMARCA4/KRAS co-mut (N = 2) vs. SMARCA4 WT/KRAS mut (N = 16) | Cohort D: SMARCA4/KRAS co-mut vs. SMARCA4 WT/KRAS mut had worse OS in immunotherapy Wake Forest cohort (HR: 11.98, p = 0.0018). |
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Manolakos, P.; Boccuto, L.; Ivankovic, D.S. A Critical Review of the Impact of SMARCA4 Mutations on Survival Outcomes in Non-Small Cell Lung Cancer. J. Pers. Med. 2024, 14, 684. https://doi.org/10.3390/jpm14070684
Manolakos P, Boccuto L, Ivankovic DS. A Critical Review of the Impact of SMARCA4 Mutations on Survival Outcomes in Non-Small Cell Lung Cancer. Journal of Personalized Medicine. 2024; 14(7):684. https://doi.org/10.3390/jpm14070684
Chicago/Turabian StyleManolakos, Peter, Luigi Boccuto, and Diana S. Ivankovic. 2024. "A Critical Review of the Impact of SMARCA4 Mutations on Survival Outcomes in Non-Small Cell Lung Cancer" Journal of Personalized Medicine 14, no. 7: 684. https://doi.org/10.3390/jpm14070684
APA StyleManolakos, P., Boccuto, L., & Ivankovic, D. S. (2024). A Critical Review of the Impact of SMARCA4 Mutations on Survival Outcomes in Non-Small Cell Lung Cancer. Journal of Personalized Medicine, 14(7), 684. https://doi.org/10.3390/jpm14070684