Abstract
Purpose
To investigate whether TP53 variants may be correlated with overall survival and local control following stereotactic radiosurgery (SRS) for brain metastases (BMs) from non-small cell lung cancer (NSCLC).
Methods
Patients undergoing an initial course of SRS for NSCLC brain metastases between 1/2015 and 12/2020 were retrospectively identified. Overall survival and freedom from local intracranial progression (FFLIP) were estimated via Kaplan-Meier method. Cox models assessed TP53 variant status (pathogenic variant, PV; variant not detected, ND).
Results
255 patients underwent molecular profiling for TP53, among whom 144 (56%) had a TP53 PV. Median follow-up was 11.6 months. OS was not significantly different across TP53 status. A trend toward superior FFLIP was observed for PV (95% CI 62.9 months-NR) versus ND patients (95% CI 29.4 months-NR; p=0.06). Superior FFLIP was observed for patients with one TP53 variant versus those with TP53 ND.
Conclusion
Among NSCLC patients with BMs, the potential association between TP53 status and post-SRS FFLIP warrants further investigation in a larger prospective cohort.
Keywords: SRS, NSCLC, TP53, brain metastases
INTRODUCTION
The TP53 gene is the most frequently mutated gene in human cancer, and is present in approximately half of all human cancers.[1,2] TP53 encodes the tumor suppressor protein p53, which regulates the expression of hundreds of genes involved in cell cycle arrest, DNA repair, and apoptosis.[3–5] As a known tumor suppressor gene that is crucial for inducing apoptosis after DNA damage,[6] it has been proposed that mutations in TP53 might lead to a sub-optimal response to ionizing radiation. Several studies have suggested that p53 mutations lead to radioresistance in various models including bladder, head and neck, ovarian, and non-small cell lung cancer (NSCLC) cell lines.[7–11]
TP53 mutations occur frequently in NSCLC, and are associated with inferior tumor response and overall survival (OS) after lung-directed conventionally fractionated radiotherapy.[12–14] NSCLC is the most common primary known to metastasize to the brain, for which stereotactic radiosurgery (SRS) represents a standard of care for many patients.[15] Like primary NSCLC, TP53 mutations are exceedingly common in NSCLC brain metastases (BMs). In a series of 244 patients with resected brain metastases (BMs) from NSCLC, TP53 mutations were present in 72% of samples.[16] Prior studies have suggested that patients harboring these mutations have worse outcomes when treated with targeted therapies.[17] Recent in vitro work in normal and cancer cell lines suggests that cells with p53 loss may be less sensitive to radiotherapy fraction size, which may reflect dependence of fraction size sensitivity on intact non-homologous end joining DNA repair machinery.[18] Together these data led us to hypothesize that p53-mutant brain metastases may be respond differently to high-dose single-fraction and hypofractionated SRS treatments compared to brain metastases with intact p53 function.
With an increased reliance on genetic sequencing of NSCLC driver mutations to guide systemic therapy, there is an increasing need to characterize the molecular signatures that may drive response to SRS and patterns of CNS failure.[19] As systemic therapies continue to significantly prolong survival,[20] durable local intracranial control becomes an increasingly relevant outcome. The current study aims to examine the correlation between molecular variants of p53 and the clinical outcomes following stereotactic radiosurgery (SRS) in NSCLC patients. In the context of established molecular mechanisms for radioresistance with TP53 as well as recent studies demonstrating worse outcomes with these mutations in response to systemic therapy, we hypothesized that TP53 may also be associated with decreased local control following an initial course of SRS for BMs in the setting of NSCLC.
MATERIALS AND METHODS
Following institutional board review approval (Duke University Health System protocol Pro00108074), we identified all NSCLC patients who completed an initial SRS course for brain metastases at our institution between January 1, 2015 and December 31, 2020. Next-generation sequencing (NGS) was conducted on the commercial FoundationOne and Guardant360 platforms in this cohort. Patients were cross-referenced with the Duke Molecular Registry of Tumors (MrT), an internally developed data warehouse solution that stores comprehensive genomic testing results.[21] Additional data obtained included demographic, clinical, and treatment parameters. SRS was delivered using institutional guidelines, typically 18-22 Gy / 1 fraction for metastases <2cm and in non-eloquent regions or 24-27 Gy / 3 fractions and 25-27.5 Gy / 5 fractions for metastases >2cm or in eloquent regions.
Survival outcomes were recorded from the time of SRS completion to the date of death or last follow-up. Intracranial treatment effect and local intracranial progression (LIP) events were determined by multidisciplinary clinical consensus, which incorporated histopathologic diagnosis, response to steroids, and findings from serial MR brain scans. Distant intracranial progression (DIP) events were determined by combined radiation oncology and neuroradiology review of serial MR imaging. The Kaplan-Meier method was used to calculate actuarial event rates. Cox regression models were used to estimate all hazard ratios for freedom from local intracranial progression (FFLIP) and freedom from distant intracranial progression (FFDIP), using factors of TP53 status, allelic fraction, variant frequency, tissue origin, and number of discrete TP53 variants. In analyses of FFLIP and FFDIP, death was analyzed as a censoring event.
Three sensitivity analyses were performed for survival analysis across patients with TP53 pathogenic variants. First, TP53 PV patients were categorized by the presence of tumor tissue versus circulating tumor cell DNA (ctDNA) only. Second, to minimize the false positive risk of non-target variants, categorization was performed by TP53 variant fraction ≤1% versus >1%.[22] Finally, categorization was performed by the number of discrete TP53 variants identified: 0 versus 1 versus >1. Analysis was performed using R software, version 4.1.2 (Vienna, Austria).
RESULTS
Cohort characteristics. In this cohort study of NSCLC BM patients undergoing SRS, we identified 255 patients who were tested for TP53 mutations (Table 1). A total of 144 patients (56%) had a pathogenic variant (PV) of TP53, and 111 (44%) did not have a detectable TP53 variant (ND). There were 126 women (49%) and 129 men (51%). At the time of SRS, the mean age was 64.7 years (SD=11.0). A total of 119 patients (47%) had a Karnofsky performance status score of 90 or greater. Fifty-nine (23%) patients were black, 177 (69%) were white, and 19 (7%) were other or unknown races. Most patients (77%) had a history of smoking. PD-L1 expression was 0% in 67 patients (26%), 1-49% in 52 patients (20%), >49% in 51 patients (20%), and unknown or not tested in 85 (33%) of patients. Prior to SRS, 49 (19%) underwent brain metastasis resection, 78 (31%) received chemotherapy (CHT), 19 (7%) received targeted therapy (TT), 38 (15%) received immunotherapy (IT), and 15 (6%) underwent whole-brain radiotherapy (WBRT). At the time of SRS, 109 patients (43%) had a single brain metastasis, 95 (37%) had 2-5 BMs, 35 (14%) had 6-10 BMs, and 16 (6%) had >10 BMs. The mean (SD) planned target volume (PTV) was 11.8 (16.6) cc for the largest single brain metastasis and 14.3 (19.1) cc for all irradiated brain metastases within a single patient. Furthermore, 163 patients (64%) had extracranial metastases at the time of SRS. Of these patients, 66 received any pre-SRS systemic therapy and 120 (74%) received post-SRS systemic therapy. In terms of categories of systemic therapy after SRS, 106 patients (42%) were treated with CHT, 61 (24%) were treated with TT, 124 (49%) were treated with IT, 10 patients (4%) underwent salvage intracranial surgery, and 15 (6%) underwent salvage WBRT. Overall, patients with a PV were more likely to have a single BM compared to patients with ND (49% vs 34%) and were more likely to receive post-SRS IT (55% vs 41%). Otherwise, demographic, clinical, and treatment parameters did not differ significantly across TP53 variant status.
Table 1.
Demographic, clinical, and treatment parameters across patients by TP53 variant status
| All pts (n=255) | ND (n=111) | PV (n=144) | |
|---|---|---|---|
| Mean age at BM dx, years (SD) | 64.7 (11.0) | 65.7 (11.1) | 63.9 (10.9) |
| Sex | |||
| Female | 126 (49) | 49 (44) | 77 (53) |
| Male | 129 (51) | 62 (56) | 67 (47) |
| Race | |||
| Black | 59 (23) | 28 (25) | 31 (22) |
| White | 177 (69) | 74 (67) | 103 (72) |
| Other/ Unknown | 19 (7) | 9 (8) | 10 (7) |
| KPS at BM dx | |||
| 100-90 | 119 (47) | 51 (46) | 68 (47) |
| 80-70 | 108 (42) | 45 (41) | 63 (44) |
| 60 or less | 17 (7) | 8 (7) | 9 (6) |
| Unknown | 11 (4) | 7 (6) | 4 (3) |
| Histo-pathologic grade | |||
| 1 | 2 (1) | 1 (1) | 1 (1) |
| 2 | 19 (7) | 11 (10) | 8 (6) |
| 3 | 148 (58) | 59 (53) | 89 (62) |
| 4 | 3 (1) | 2 (2) | 1 (1) |
| Cannot be assessed | 83 (33) | 38 (34) | 45 (31) |
| PD-L1 Expression | |||
| 0% | 67 (26) | 31 (28) | 36 (25) |
| 1%-49% | 52 (20) | 22 (20) | 30 (21) |
| >49% | 51 (20) | 26 (23) | 25 (17) |
| Unknown/not performed | 85 (33) | 32 (29) | 53 (37) |
| Smoking status | |||
| Yes | 197 (77) | 80 (72) | 117 (81) |
| Never | 58 (23) | 31 (28) | 27 (19) |
| T stage at initial dx | |||
| 1 | 72 (28) | 33 (30) | 39 (27) |
| 2 | 85 (33) | 36 (32) | 49 (34) |
| 3 | 55 (22) | 20 (18) | 35 (24) |
| 4 | 19 (7) | 9 (8) | 10 (7) |
| x | 24 (9) | 13 (12) | 11 (8) |
| N stage at initial dx | |||
| 0 | 50 (20) | 22 (20) | 28 (19) |
| 1 | 39 (15) | 17 (15) | 22 (15) |
| 2 | 94 (37) | 41 (37) | 53 (37) |
| 3 | 51 (20) | 20 (18) | 31 (22) |
| x | 21 (8) | 11 (10) | 10 (7) |
| M stage at initial dx | |||
| 0 | 67 (26) | 35 (32) | 32 (22) |
| 1 | 187 (73) | 76 (68) | 111 (77) |
| x | 1 (0) | 0 (0) | 1 (1) |
| Prior treatment for NSCLC | |||
| None | 18 (7) | 7 (6) | 11 (8) |
| Thoracic surgery | 43 (17) | 22 (20) | 21 (15) |
| Chemotherapy | 163 (64) | 66 (59) | 97 (67) |
| Targeted Therapy | 63 (25) | 25 (23) | 38 (26) |
| Immuno-therapy | 145 (57) | 57 (51) | 88 (61) |
| Thoracic RT | 82 (32) | 36 (32) | 46 (32) |
| Unknown | 4 (2) | 2 (2) | 2 (1) |
| Number of BMs at time of SRS | |||
| 1 | 109 (43) | 38 (34) | 71 (49) |
| 2 to 5 | 95 (37) | 45 (41) | 50 (35) |
| 6 to 10 | 35 (14) | 19 (17) | 16 (11) |
| >10 | 16 (6) | 9 (8) | 7 (5) |
| Extracranial mets at time of SRS | |||
| Yes | 163 (64) | 71 (64) | 92 (64) |
| Lung | 110 (43) | 47 (42) | 63 (44) |
| Liver | 27 (11) | 16 (14) | 11 (8) |
| Bone | 87 (34) | 42 (38) | 45 (31) |
| Other | 64 (25) | 25 (23) | 39 (27) |
| BM resection prior to SRS | |||
| Yes | 49 (19) | 17 (15) | 32 (22) |
| No | 206 (81) | 94 (85) | 112 (78) |
| WBRT prior to SRS | |||
| Yes | 15 (6) | 11 (10) | 4 (3) |
| No | 240 (94) | 100 (90) | 140 (97) |
| Pre-SRS CHT | |||
| Yes | 78 (31) | 34 (31) | 44 (31) |
| No | 177 (69) | 77 (69) | 100 (69) |
| Pre-SRS TT | |||
| Yes | 19 (7) | 7 (6) | 12 (8) |
| No | 236 (93) | 104 (94) | 132 (92) |
| Pre-SRS IT | |||
| Yes | 38 (15) | 16 (14) | 22 (15) |
| No | 217 (85) | 95 (86) | 122 (85) |
| Post-SRS CHT | |||
| Yes | 106 (42) | 44 (40) | 62 (43) |
| No | 149 (58) | 67 (60) | 82 (57) |
| Post-SRS TT | |||
| Yes | 61 (24) | 26 (23) | 35 (24) |
| No | 194 (76) | 85 (77) | 109 (76) |
| Post-SRS IT | |||
| Yes | 124 (49) | 45 (41) | 79 (55) |
| No | 131 (51) | 66 (59) | 65 (45) |
| Salvage SRS | |||
| Yes | 92 (36) | 54 (49) | 38 (26) |
| No | 163 (64) | 57 (51) | 106 (74) |
| Salvage WBRT | |||
| Yes | 15 (6) | 3 (3) | 12 (8) |
| No | 240 (94) | 108 (97) | 132 (92) |
| Salvage Surgery | |||
| Yes | 10 (4) | 4 (4) | 6 (4) |
| No | 245 (96) | 107 (96) | 138 (96) |
| Total PTV of all lesions, mean (SD), cc | 14.3 (19.1) | 15.7 (21.2) | 13.3 (17.2) |
| PTV of largest lesion, mean (SD), cc | 11.8 (16.6) | 12.2 (17.1) | 11.6 (16.3) |
Abbreviations: Patients, pts; TP53 variant not detected, ND; TP53 pathogenic variant, PV; brain metastases, BM; diagnosis, dx; standard deviation, SD; KPS, Karnofsky performance status; non-small cell lung carcinoma, NSCLC; stereotactic radiosurgery; SRS; whole brain radiotherapy, WBRT; chemotherapy, CHT; targeted therapy, TT; immunotherapy, IT; planning target volume, PTV.
TP53 variant characteristics. Among TP53 PV patients (Table 2), a total of 32 (22%) had molecular profiling from a brain biopsy, 21 (15%) from a lung biopsy, 66 (46%) from a blood sample, and 12 (8%) from multiple sites. Per TP53 variant (191 in total), 102 (71%) were profiled through a blood sample, 37 (26%) from brain biopsy, 27 (19%) from lung biopsy, and 16 (11%) from a lymph node biopsy. Common TP53 variant subtypes included missense substitutions (n=70, 49%), other substitutions (n=15, 10%), insertion/deletions (n=13, 9%), and splicing mutations (n=7, 5%). Patients with multiple variants accounted for 26% of this population (n=37).
Table 2.
Molecular profiling origin and findings across TP53 variants and across individual patients
| PV (n=144) | ||
|---|---|---|
| N | % | |
| Tissue origin, per TP53 variant | ||
| Blood | 102 | 71 |
| Brain | 37 | 26 |
| Lung | 27 | 19 |
| Node | 16 | 11 |
| Other | 9 | 6 |
| Tissue origin, per pt | ||
| Blood | 66 | 46 |
| Brain | 32 | 22 |
| Lung | 21 | 15 |
| Node | 11 | 8 |
| Other | 2 | 1 |
| Multiple sites | 12 | 8 |
| TP53 variant subtype, per pt | ||
| Substitution, missense | 70 | 49 |
| Substitution, other | 15 | 10 |
| Insertion/deletion | 13 | 9 |
| Splice | 7 | 5 |
| Other | 2 | 1 |
| Multiple variants | 37 | 26 |
| Maximum variant allelic fraction, per pt | ||
| ≤1% | 20 | 14 |
| >1% | 124 | 86 |
Abbreviations: patient, pt.
Outcomes by TP53 variant status. A total of 83 patients (33%) were alive at the last follow up, with a median follow-up of 11.6 months (IQR, 5.0-25.3 months). Overall survival (OS), FFLIP, FFDIP, and freedom from radionecrosis (FFRN) are presented in Figure 1. For all patients, a total of 172 deaths were observed, and the median OS was 13.8 months (95% CI, 11.0-19.2 months). 37 patients (14.5%) experienced local progression, with a median FFLIP of 70.5 months (95% CI, 92.9 months-not reached [NR]). 114 patients (44.7%) experienced distant progression, with a median FFDIP of 15.6 months (95% CI, 10.3-27.0 months). Finally, 32 patients (12.5%) experienced RN, with a median FFRN of 69.3 months (95% CI, 35.5 months-NR). OS was not significantly different for TP53 PV patients compared to those with ND (Figure 2), with a median OS of 15.7 months (95% CI, 11.6-25.1 months) and 11.9 months (95% CI, 9.1-19.2 months, p=0.30) respectively. While not statistically significant, median FFLIP was numerically greater in the TP53 ND group (70.5 months; 95% CI, 62.9 months-NR) versus the TP53 PV group (36.5 months; 95% CI, 29.4 months-NR, p=0.06).
Figure 1.
Clinical endpoints with 95% confidence intervals shown across all patients (n = 255): A, overall survival; B, freedom from local progression; C, freedom from distant intracranial progression; D, freedom from radionecrosis
Figure 2.
Overall survival (A) and freedom from local progression (B) are shown for all patients by TP53 status. Abbreviations: Not detected, ND; Pathogenic variant, PV
Outcomes by biopsy type and variant fraction. Since discrepancies may exist between variants observed in blood biopsies and variants observed in solid tumor biopsies, we sought to explore whether the type of biopsy was linked to FFLIP outcomes. To do so we performed sensitivity analyses of FFLIP by TP53 variant subtypes (Table 3, Figure 3). The first sensitivity analysis included patients with TP53 pathogenic variants by ctDNA only compared to those with variants detected by solid tumor sequencing (Figure 3A), which showed no significant difference in local control compared to TP53 ND patients (HR= 0.51 for ctDNA, 95% CI 0.22-1.21, p=0.13; HR=0.51 for solid tumor sequencing 95% CI 0.26-1.20, p=0.13).
Table 3.
Sensitivity analyses for freedom from local progression
| HR (95% CI) | p value | |
|---|---|---|
| TP53 status, all pts | ||
| ND | Reference | - |
| PV | 0.54 (0.28-1.04) | 0.06 |
| Allelic Fraction | ||
| TP53 ND | Reference | - |
| TP53 PV, ≤1% | 0.23 (0.03-1.74) | 0.16 |
| TP53 PV, >1% | 0.58 (0.30-1.15) | 0.12 |
| TP53 variant frequency | ||
| 0 | Reference | - |
| 1 | 0.42 (0.20-0.92) | 0.03 |
| >1 | 0.86 (0.36-2.06) | 0.74 |
| TP53 tissue origin | ||
| TP53 ND | Reference | - |
| TP53 PV, ctDNA | 0.51 (0.22-1.21) | 0.13 |
| TP53 PV, solid tumor | 0.55 (0.26-1.20) | 0.13 |
Abbreviations: Not detected, ND; Pathogenic variant, PV
Figure 3.
Sensitivity analyses of freedom from local intracranial progression by TP53 pathogenic variant subtype: A, TP53 pathogenic variants of ctDNA origin only, TP53 pathogenic variants of solid tissue origin, and those without detectable TP53 variants; B, TP53 pathogenic variants with an allelic fraction up to 1%, TP53 pathogenic variants with an allelic fraction >1%, and those without detectable TP53 variants; C, patients with no detectable TP53 variants, those with a single TP53 variant, those with multiple TP53 variants. Sensitivity analysis of local control by TP53 not detected subtype
Since variant fraction can reflect the etiology of the variant, we examined whether variant fraction influenced outcomes associated with TP53 variant status. To do so, we performed a second sensitivity analysis including patients by TP53 variant fraction ≤1% versus >1% (Figure 3B), which showed no significant difference in local control compared to TP53 ND patients (HR=0.23 for the TP53 PV ≤1% group, 95% CI 0.03-1.74, p=0.16; HR=0.58 for the TP53 PV >1% group, 95% CI 0.30-1.15, p=0.12). Finally, the third sensitivity analysis (Figure 3C) included patients stratified by the number of identifiable TP53 pathologic variants. Patients with one TP53 variant had significantly greater FFLIP compared to patients with TP53 ND (HR=0.42, 95% CI, 0.20-0.92, p=0.03).
Number of TP53 variants and co-altered genes. Exploratory analysis of distant intracranial control and overall survival by the number of discrete TP53 variants were summarized in Supplemental Figure 1, where there was no significant difference found in FFDIP or OS by the number of discrete TP53 variants (Supplemental Table 2). The co-mutational frequencies of TP53 with other mutations were summarized in Supplemental Table 1. Commonly mutated genes within the present cohort included TP53, KRAS, EGFR, CDKN2A, STK11, NF1, ARID1A, KEAP1, and MET, with the most frequently co-occurring genetic mutations being EGFR (53 patients, 37%) and KRAS (36 patients, 25%). 27 patients (19%) had both an ATM and TP53 mutation, and 5 patients (3%) had both an ALK rearrangement and TP53 mutation. Further analyses of FFLIP by TP53 and KRAS co-mutational status and by TP53 variant subtype (insertion, deletion, splice, missense, other, or multiple) are summarized in Supplemental Figures 2 and 3.
Supplemental Figure 1.
Exploratory analyses of freedom from distant intracranial progression (FFDIP; A) and overall survival (OS; B) across all patients by number of discrete TP53 variants.
Supplemental Table 2.
Hazard ratios and 95% confidence intervals for freedom from distant intracranial progression (FFDIP) and overall survival (OS) by number of discrete TP53 variants per patient.
| DIP | OS | |||
|---|---|---|---|---|
| HR (95% CI) | p value | HR (95% CI) | p value | |
| TP53 variant | ||||
| Not detected | Reference | – | Reference | – |
| Single | 0.706 (0.474–1.051) | 0.087 | 0.812 (0.586–1.126) | 0.212 |
| Multiple | 0.723 (0.404–1.293) | 0.274 | 0.935 (0.600–1.456) | 0.766 |
Supplemental Table 1.
Co-mutational frequencies across patients by TP53 variant status
| All pts (n=255) | ND (n=111) | PV (n=144) | |
|---|---|---|---|
| N (%) | N (%) | N (%) | |
| ATM | |||
| ND | 220 | 103 (93) | 117 (81) |
| PV/VUS | 35 | 8 (7) | 27 (19) |
| EGFR | |||
| ND | 190 | 99 (89) | 91 (63) |
| PV/VUS | 65 | 12 (11) | 53 (37) |
| KRAS | |||
| ND | 197 | 89 (80) | 108 (75) |
| PV/VUS | 58 | 22 (20) | 36 (25) |
| CDKN2A | |||
| ND | 209 | 97 (87) | 112 (78) |
| PV/VUS | 46 | 14 (13) | 32 (22) |
| STK11 | |||
| ND | 214 | 98 (88) | 116 (81) |
| PV/VUS | 41 | 13 (12) | 28 (19) |
| NF1 | |||
| ND | 218 | 105 (95) | 113 (78) |
| PV/VUS | 37 | 6 (5) | 31 (22) |
| ARID1A | |||
| ND | 219 | 105 (95) | 114 (79) |
| PV/VUS | 36 | 6 (5) | 30 (21) |
| KEAP1 | |||
| ND | 220 | 101 (91) | 119 (83) |
| PV/VUS | 35 | 10 (9) | 25 (17) |
| MET | |||
| ND | 225 | 104 (94) | 121 (84) |
| PV/VUS | 30 | 7 (6) | 33 (16) |
| ALK | |||
| ND | 244 | 105 (95) | 139 (97) |
| PV/VUS | 11 | 6 (5) | 5 (3) |
Abbreviations: Not detected, ND; Pathogenic variant, PV; Variant of unknown significance, VUS.
Supplemental Figure 2.
Freedom from local intracranial progression by TP53 and KRAS comutational status.
DISCUSSION
In this study, we report TP53 variant incidence in an NSCLC population undergoing SRS for the treatment of brain metastases. Overall, there was a trend towards improved local control after SRS in patients with TP53 pathogenic variants. Patients with TP53 variants were significantly more likely to have other gene mutations, including in EGFR and KRAS. Additionally, subgroup analyses showed significantly improved local intracranial control among patients with a single TP53 variant and decreased local intracranial control among TP53 ND patients without any other identified molecular variants.
The Lung Cancer Mutation Consortium (LCMC) previously found TP53 variants in 40% of EGFR and 50% of KRAS-mutant tumors in a cohort of 154 subjects with complete genotyping profiles.[17] Our study found similarly high rates of co-mutation between TP53 and these mutations, with TP53 PV patients overall being much more likely to exhibit other molecular variants. One possibility is that biopsy type and/or tumor heterogeneity influence the detectability of variants, thus suggesting that technical factors may contribute to observed associations between the detection of TP53 variants and variants in other genes. However, our sensitivity analyses did not detect a significant difference in outcomes based on biopsy type or TP53 variant fraction (Figure 3A, 3B), indicating that associations between TP53 mutations and other variants may reflect tumor biology. Mechanistically, TP53 mutations may cause genomic instability in NSCLC, leading to increased tumor mutational burden and increased likelihood of co-occurring molecular mutations.[23] These co-mutations can confer additional prognostic information. For instance, prior studies have suggested an adverse impact of TP53 for patients treated with targeted therapies in EGFR-mutated lung cancer.[17,24,25] Conversely, for patients receiving PD-1 inhibition, KRAS, and TP53 co-mutation may confer a clinical benefit.[26]
A meta-analysis of 19 prior studies with a total of 1,406 patients with TP53 variants suggests that TP53 mutations may be associated with poor clinical outcomes in patients with NSCLC; however, these studies have often yielded mixed results.[14] Our study found no difference in overall survival in this cohort, but patients with TP53 variants may have better LC after treatment with SRS. For patients without a TP53 variant, the rates of post-SRS targeted therapy were similar despite higher rates of targetable mutations in the TP53 PV cohort, which may have accounted for the trend towards decreased LC. Interestingly, patients with a single TP53 variant had favorable LC compared to those with multiple mutations. This may reflect increased mutational burden and activation of pathways that confer resistance to SRS and post-SRS systemic therapy.[27] In this study, our subgroup analysis by mutational subgroup (Supplemental Figure 2) was underpowered for formal analysis. Finally, distant intracranial control remains a significant driver of complications in this population, where additional courses of SRS is often used for treatment in clinical practice.
This retrospective analysis is limited by its small sample size across a single institution. As multiple lesions are treated in the majority patients, lesion-specific data and outcomes relating to specific doses and volume of each lesion was not included in this study. Finally, patients who have received prior WBRT likely have different risks of intracranial failure, however we did not have the numbers to comment meaningfully on this subpopulation of patients (n=15). We note that the primary outcome measures of local progression after SRS in relation to TP53 in this study may be less affected than measures such as distant intracranial control. However, alongside prior data demonstrating the sample sizes needed to power analyses of local intracranial control and radionecrosis for a given allelic frequency,[28] these data may inform larger prospective analyses of TP53 variants in patients with brain metastases.
The present analysis provides insight into patient-specific and genomic correlates of TP53 mutations in NSCLC, which may predict a local control benefit after SRS. This warrants further investigation in a larger prospective cohort.
Supplementary Material
Supplemental Figure 3.
Freedom from local intracranial progression by TP53 variant subtype. Abbreviations: Ins/Del, insertion or deletion; MS Subst, missense substitution
ACKNOWLEDGEMENTS
We thank Karen Allen for her assistance maintaining the prospective QA database.
Authors’ disclosure of potential conflicts of interest
The funding sources for this study (NIH grant R38CA24520401 to DJC, K08CA256045 to ZJR and NIH 5R38CA245204 to EJV and an Office of Physician Scientist Development Technician Award to EJV) had no role in the collection, analysis, or interpretation of the data, the writing of the manuscript, or the decision to submit it for publication. ZJR has intellectual property managed by Duke University that has been licensed to GeneTron Health related to brain tumor genomic profiling tests, and has received honoraria from Eisai Pharmaceuticals and Oakstone Publishing. JK reported receiving grants from Varian Medical Systems and BioMimetix SBR, receiving personal fees from Monteris Medical, and owning ClearSight LLC outside the submitted work. None of the above entities played a role in the collection, analysis, or interpretation of the data, the writing of the manuscript, or the decision to submit it for publication.
Author contributions
Conception and design: Jim X. Leng, Chang Su, David J. Carpenter, Zachary J. Reitman
Data collection: Chang Su, David J. Carpenter, Eugene Vaios, Rachel Shenker, Peter Hendrickson, Warren Floyd, Will Giles, Trey Mullikin, Scott Floyd, John Kirkpatrick, Michelle Green, Zachary J. Reitman
Data analysis and interpretation: Jim X. Leng, David J. Carpenter, Zachary J. Reitman
Manuscript writing: Jim X. Leng, David J. Carpenter, Zachary J. Reitman
Final approval of manuscript: all authors
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Associated Data
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Supplementary Materials
Supplemental Figure 3.
Freedom from local intracranial progression by TP53 variant subtype. Abbreviations: Ins/Del, insertion or deletion; MS Subst, missense substitution