Brainmetastases are the most common intracranial tumor and occur in 10%–40% of all systemic malignancies.1,2Patient prognosis is heterogeneous and varies depending on factors such as primary tumor type, genomic features, systemic disease status, and intracranial metastatic burden.3
Resection is indicated for single brain metastases, a dominant symptomatic lesion with limited CNS burden, and patients with good functional status and controlled systemic disease.4,5However, resection alone is considered inadequate to provide local metastatic control, and local recurrence is seen in up to 48% of patients receiving a gross-total resection (GTR).5因此,手术是经常与adjuvan相结合t whole-brain radiotherapy or stereotactic radiosurgery (SRS).6,7Adjuvant SRS has been shown to increase recurrence-free survival from 7.6 months to 15.6 months.5Nevertheless, control of brain metastases remains a therapeutic challenge, and 30%–40% of patients treated with surgery and radiotherapy (RT) still develop distant brain metastases.5,7,8However, factors predicting either local or distant CNS recurrence after resection have not been well defined.
A study by Garcia and colleagues demonstrated that on the day of adjuvant SRS, additional brain metastases were discovered in 48.9% of patients on the planning Gamma Knife MRI.8However, there was no association in their study between a number of clinical factors and rapid recurrence.8Tumor intrinsic genomic alteration may be associated with rapid recurrence, yet to date prior studies associating surgical outcomes with brain metastasis genomic alterations are sparse.9Our group has previously identifiedCDKN2A/Bcodeletion, which disrupts cell cycle regulation, as a risk factor for both local and distant CNS progression on long-term follow-up.9However, to our knowledge, associations between genomic alterations and rapid progression of brain metastases after surgery have not yet been evaluated and would be important to guide the timing of postoperative adjuvant RT.
In this study, we sought to investigate associations between genomic alterations in resected brain metastases across several cancer types and rapid local and distant CNS progression identified at the time of postoperative adjuvant radiosurgery.
开云体育世界杯赔率
Study Design
A retrospective cohort study was conducted using a database from a single-center academic institution (University of California, San Francisco [UCSF]) containing the clinical and genomic data of patients aged 18 years or older who underwent resection of an intracranial brain metastasis between 2014 and 2022. To be included in the study, patients needed to 1) have been treated with adjuvant postoperative SRS or whole-brain RT, 2) have pathology-confirmed malignant tissue present at the time of resection (i.e., radiation necrosis cases were excluded), 3) have available gene sequencing data for analysis, and 4) have an electronic medical record with available pre- and postoperative imaging available in addition to MRI at the time of radiosurgical planning. Patients were excluded if they 1) were treated with brachytherapy or preoperative SRS as a means of adjuvant RT, 2) did not have gene sequencing performed, or 3) had only radiation necrosis on pathology. The study was approved by the UCSF IRB. The IRB waived the requirement for written informed consent for this retrospective observational study. MRI slice thickness was typically on the order of 1–2 mm, and the standard protocol was similar between preoperative, immediately postoperative, and postoperative RT MR images.
Patient, Tumor, and Treatment Variables
病人变量我ncluded age at the time of surgery and sex. Tumor variables included primary cancer type, the total number of brain metastases at the time of surgery, and extracranial malignant disease status. Extracranial malignant disease status was based on results from either total-body PET imaging or CT imaging of the body with and without contrast performed for staging purposes within 1 month of the surgery date. Treatment variables included the extent of resection (GTR vs subtotal resection [STR] of the enhancing disease), prior RT, and the time between the craniotomy and postoperative RT.
Next-generation sequencing of all brain metastasis specimens was performed in a Clinical Laboratory Improvement Amendments (CLIA)–certified laboratory on the coding regions of 529 oncogenes and select introns of 47 genes as part of clinical care. Genomic data were extracted from the medical record for analysis.
Clinical Outcomes of Interest
The primary outcomes of the study were rapid local recurrence and rapid distant CNS progression. The MR images obtained on the day of RT were compared with the immediately postoperative MR images, which were obtained within 48 hours after surgery. Rapid local recurrence was defined as the detection of new tumor growth in the surgical cavity on MRI on the day of postsurgical RT, agreed on by a radiologist and the treating oncologist/neurosurgeon, with review by the senior author (R.A.M.). Progression of tumor remnants after STR was, for the purpose of this study, considered as rapid recurrence. Examples can be found inFig. 1．Rapid distant CNS progression was defined as the presence of new brain metastases on the MRI performed for radiosurgical planning. Examples can be found inFig. 2．已知脑转移的增长was not considered a distant progression event, given that these known lesions had not been treated between surgery and the date of adjuvant RT.
A and B:Case examples comparing preoperative, immediately postoperative, and postoperative/preradiosurgery MR images from 2 patients with rapid local CNS recurrence.Arrows上海ow recurrence at the local surgical site.
A and B:Case examples comparing preoperative, immediately postoperative, and postoperative/preradiosurgery MR images from 2 patients with rapid distant CNS recurrence.Arrows上海ow new brain metastases.
Statistical Analysis
Statistical analyses were performed in Stata (version 17, StataCorp LLC) and JMP Pro (version 16.0, SAS Institute Inc.). Demographic data and baseline characteristics were collected and analyzed in a standard fashion. JMP’s bootstrap forest algorithm was used to screen genomic alterations associated with either rapid local CNS recurrence or rapid distant CNS recurrence. The bootstrap forest algorithm builds a collection of recursive partitioning trees by repeatedly bootstrapping the data. In-bag subsets are used to build a partitioning tree, and predictions are made using out-of-bag subsets of patients. The final predictive model is based on a majority input from 100 trees. Missing categorical values within the database were imputed as a separate level of the variable, and missing continuous values within the database were assigned values via an optimal split algorithm. Top predictors with the biggest effect on the model were assessed with traditional univariate analysis for their association with recurrence. Univariate and multivariate nominal logistic regression analyses were performed to identify an association between clinical factors and top genomic alterations identified with the bootstrap forest algorithm. Odds ratios and their 95% CI were computed. Multivariate regression analyses were performed with variables with p values < 0.10 on univariate analysis. A post hoc log-rank test was performed to test associations with rapid recurrence and overall survival. The level of significance was p < 0.05 for all analyses.
Results
Clinical Cohort
The cohort comprised 92 patients with 92 brain metastases treated with resection and adjuvant postoperative RT. The median age at the time of surgery was 65 years (range 27–83 years). The cohort consisted of 41 (44.6%) males and 51 (55.4%) females. The most common primary cancer types were non–small cell lung cancer (NSCLC) (n = 29, 31.5%), malignant melanoma (n = 18, 19.6%), and breast cancer (n = 13, 14.1%). Forty-two (45.7%) patients had 1 brain metastasis at the time of surgery, 33 (35.9%) had between 2 and 4, and 17 (18.5%) had 5 or more brain metastases. Sixty-eight (73.9%) patients had systemic disease present at the time of surgery. A GTR was attained in 78 (84.8%) patients, and 8 (8.7%) patients had received prior RT for the index lesion, which was not considered a form of adjuvant radiosurgery. The median time to postoperative RT was 25 days (range 3–85 days). Patient, tumor, and treatment variables are displayed inTable 1．
Patient, tumor, and treatment characteristics
| Characteristic | Value |
|---|---|
| Total no. of metastases | 92 (100) |
| Patient | |
| Age, yrs | 65 (27–83) |
| Male sex | 41 (44.6) |
| Tumor | |
| Primary cancer | |
| NSCLC | 29 (31.5) |
| Breast cancer | 13 (14.1) |
| Malignant melanoma | 18 (19.6) |
| 胃肠道癌症 | 8 (8.7) |
| Gynecological cancer | 4 (4.4) |
| Renal cell carcinoma | 4 (4.4) |
| Other | 16 (17.4) |
| Total no. of BMs | |
| 1 | 42 (45.7) |
| 2–4 | 33 (35.9) |
| ≥5 | 17 (18.5) |
| Systemic disease status | |
| Not present | 24 (26.1) |
| Present | 68 (73.9) |
| 海藻糖酶tment | |
| Extent of resection | |
| GTR | 78 (84.8) |
| STR | 14 (15.2) |
| Prior RT | 8 (8.7) |
| Time to RT, days | 25 (3–85) |
| Progression | |
| Rapid local progression | 13 (14.1) |
| Rapid distant progression | 64 (69.6) |
BM = brain metastasis.
Values are given as number (%) or median (range).
Rapid Local Recurrence
Thirteen (14.1%) patients had a rapid local recurrence within the resection cavity as detected on postoperative RT MRI and confirmed by a radiologist in conjunction with the treating oncologist. Bootstrap forest analysis identified mutations inCTNNB1,PIK3CA, andRB1to be the most frequent alterations associated with rapid local recurrence. Genomic alterations inCTNNB1,RB1, andPIK3CAoccurred in 9.8% (n = 9), 8.7% (n = 8), and 8.7% (n = 8) of the cohort, respectively. One patient had alterations in bothRB1andPIK3CA, and another patient had alterations in bothCTNNB1andPIK3CA．No patients had alterations in bothRB1andCTNNB1．(For a list of specific genomic alterations inRB1,PIK3CA, andCTNNBin the cohort, seeSupplementary Table 1．) All three alterations occurred across multiple primary cancer types (Fig. 3).
Distributions ofRB1(A),CTNNB1(B),PIK3CA(C),NF1(D),APC(E), andERBB2(F) mutations across the various primary cancer types.
Genomic alterations inRB1andCTNNB1were associated with a significantly higher risk of rapid local recurrence (p = 0.007 and p = 0.013, respectively). A trend for a higher risk of rapid local recurrence was seen with alterations inPIK3CAas well (OR 4.44, 95% CI 0.92–21.48, p = 0.064) (Table 2). No other clinical features were associated with rapid local recurrence. In a multivariate analysis, bothRB1(OR 13.6, 95% CI 2.0–92.39, p = 0.008) andCTNNB1(OR 11.97, 95% CI 2.25–63.78, p = 0.004) were still significantly associated with rapid local recurrence (Table 2). No associations between rapid local progression and age, sex, primary cancer type, more brain metastases at the time of surgery, presence of extracranial disease, STR, or time to RT were found (Table 2). Although STR was not associated with rapid recurrence on univariate analysis, a second multivariate analysis was performed including extent of resection as a variable, andRB1andCTNNB1were still associated with rapid local recurrence.
Univariate and multivariate nominal logistic regression examining variables associated with rapid local CNS recurrence
| Variable | Univariate Analysis | Multivariate Analysis | ||||
|---|---|---|---|---|---|---|
| OR | 95% CI | p Value | OR | 95% CI | p Value | |
| Age | 1.03 | 0.98–1.08 | 0.26 | |||
| Sex | 1.54 | 0.48–5.01 | 0.47 | |||
| Primary cancer risk group | 3.1 | 0.89–11.1 | 0.08 | 2.7 | 0.68–10.9 | 0.15 |
| No. of BMs at op | 0.92 | 0.73–1.15 | 0.45 | |||
| Present extracranial disease | 1.2 | 0.3–4.81 | 0.79 | |||
| STR | 1.02 | 0.20–5.17 | 0.98 | |||
| Prior RT | * | |||||
| Time to RT treatment | 1.01 | 0.97–10.5 | 0.58 | |||
| RB1 | 8.33 | 1.77–39.22 | 0.007 | 13.6 | 2.0–92.39 | 0.008 |
| CTNNB1 | 6.57 | 1.49–29.06 | 0.013 | 11.97 | 2.25–63.78 | 0.004 |
| PIK3CA | 4.44 | 0.92–21.48 | 0.064 | 5.58 | 0.87–35.75 | 0.069 |
Multivariate analysis was performed with variables with p values < 0.10 on univariate analysis.
There were no or too few events in the subgroup, precluding analysis.
Rapid Distant CNS Progression
Sixty-four (69.6%) patients had at least 1 new brain metastasis detected on postoperative RT MRI and confirmed by a radiologist in conjunction with the treating oncologist. Bootstrap forest analysis identified mutations inAPC,ERBB2, andNF1to be most likely associated with rapid distant recurrence. Genomic mutations inNF1,APC, andERBB2occurred in 8.7% (n = 8), 6.5% (n = 6), and 9.8% (n = 9) of the cohort, respectively. One patient had alterations in bothAPCandERBB2, and another had alterations in bothAPCandNF1．No patients had alterations in bothNF1andERBB2．(For a list of specific genomic alterations inNF1,APC, andERBB2in the cohort, seeSupplementary Table 1．) All three alterations occurred across multiple cancer types (Fig. 3).
On univariate analysis, there was no significant association between these genomic alterations and rapid distant recurrence. However, the presence of extracranial disease was significantly associated with a higher risk of detection of new brain metastases on postoperative RT MRI on multivariate analysis (OR 4.06, 95% CI 1.08–15.34, p = 0.039) (Table 3). No associations between rapid distant progression and age, sex, primary cancer, a higher number of brain metastases at the time of surgery, STR, or time to RT were found (Table 3).
Univariate and multivariate nominal logistic regression examining variables associated with rapid distant CNS progression
| Variable | Univariate Analysis | Multivariate Analysis | ||||
|---|---|---|---|---|---|---|
| OR | 95% CI | p Value | OR | 95% CI | p Value | |
| Age | 0.97 | 0.94–1.00 | 0.074 | 0.97 | 0.94–1.00 | 0.086 |
| Sex | 1.1 | 0.45–2.71 | 0.83 | |||
| Primary cancer risk group | 1.0 | 0.99–1.02 | 0.73 | |||
| No. of BMs at op | 0.93 | 0.83–1.04 | 0.21 | |||
| Present extracranial disease | 4.07 | 1.10–15.03 | 0.035 | 4.06 | 1.08–15.34 | 0.039 |
| STR | 1.11 | 0.32–3.9 | 0.87 | |||
| Prior RT | 0.74 | 0.14–3.9 | 0.869 | |||
| Time to RT treatment | 1.01 | 0.58–10.8 | 0.47 | |||
| NF1 | 0.26 | 0.03–2.18 | 0.21 | |||
| APC | 2.5 | 0.58–10.8 | 0.22 | |||
| ERBB2 | * | |||||
Multivariate analysis was performed with variables with p values < 0.10 on univariate analysis.
There were no or too few events in the subgroup, precluding analysis.
Survival
No association with overall survival from the day of surgery was found with rapid local recurrence (p = 0.162), rapid distant CNS progression (p = 0.236), or overall rapid recurrence (either rapid local or rapid distant CNS progression) (p = 0.37).
Discussion
In this study, more than 500 genomic alterations across 92 brain metastases were examined to evaluate for an association with rapid local recurrence as well as rapid distant CNS progression of the disease. In the cohort, 14.1% of the patients demonstrated rapid local recurrence and 69.6% demonstrated rapid distant progression, with new lesions discovered at the time of RT despite having a similar MRI slice thickness. These findings demonstrate that rapid progression is a fairly frequent phenomenon, albeit one that can be managed with the implementation of RT in the postoperative setting. Having eitherRB1orCTNNB1alterations was associated with a considerably higher risk of rapid recurrence at the resection site. No genes, however, were found to be associated with the rapid development of new distant brain metastases. Furthermore, we did not find any association between rapid local or distant recurrence and overall survival, suggesting that implementation of appropriate adjuvant RT may help mitigate the risk of rapid recurrence.
A genomic alteration in theRB1(i.e., retinoblastoma 1) gene was found to be significantly associated with higher odds of rapid recurrence in the resection site compared with patients lacking this alteration.RB1mutations occurred in 9% of the samples and were seen among multiple primary cancer types (Fig. 3).RB1is a known tumor suppressor gene and is located on 13q14.2. Genomic alterations inRB1可能会影响各种不同的功能,包括ding cell metabolism, angiogenesis, differentiation of cell lineages, and cell cycle, all of which are known hallmarks of cancer. In fact, inactivation of theRB1gene has been found to occur widely across multiple different cancer types, including retinoblastoma, lung cancer, and breast cancer.10The RB1 protein is also part of the AKT/mTOR pathway, where it plays an important role in cell cycle regulation.11A prior study from our institution similarly found that a codeletion ofCDKN2A/B, another important inhibitor in cell cycle progression, was associated with an increased risk of both local and distant brain metastasis recurrence.9It is interesting thatRB1was associated with a more rapid local recurrence, whereasCDKN2A/Bcodeletion was associated with both local and distant recurrence on more long-term follow-up. One explanation for this finding may be thatRB1has a larger variety of tumor suppressor functions compared withCDKN2A/B, potentially accounting for its association with more rapid progression.
The results similarly showed significantly higher odds of rapid recurrence in the resection site in patients with aCTNNB1mutation. ACTNNB1mutation occurred in 10% of the metastases and, likeRB1, was found across multiple different primary cancer types (Fig. 3).CTNNB1is located on 3p22.1 and encodes for β-catenin, which is important for cell-to-cell adhesion.12A possible explanation for the association with rapid local recurrence in the surgical site could be that during tumor resection, microscopic tumor cell spillage was more likely to reattach to the resection cavity and grow if the tumor had aCTNNB1mutation. Another function of β-catenin is being a coactivator in the Wnt pathway, where several important oncogenes are activated.12A study of β-catenin in endometrial cancer, for example, found thatCTNNB1mutations activated the Wnt/β-catenin transcriptional program, causing an increase in the expression of Wnt/β-catenin target genes. Furthermore, this was found to be associated with recurrence risk.13A similar association betweenCTNNB1exon 3 mutations and a higher risk of recurrence in endometrial endometrioid carcinoma was found by Ruz-Caracuel and colleagues.14Taken together, these results suggest that genomic alterations inCTNNB1play a role in the recurrence of some gynecological cancers, and it is possible thatCTNNB1might play a role in recurrence in other cancer types and metastases as well.
No genes were found to be associated with rapid distant CNS progression, and to our knowledge, no gene has yet been reported to be associated with a rapid occurrence of new brain metastases. However, in a multivariate analysis, the presence of systemic extracranial disease was significantly related to rapid distant progression. Local recurrence after resection has been thoroughly investigated; however, examination of the development of new brain metastases after surgery is sparse. Garcia and colleagues found that having a higher number of brain metastases on the day of surgery was strongly associated with finding new brain metastases on the Gamma Knife MRI prior to SRS.8Surprisingly, no association was found between the rapid occurrence of new brain metastases and a higher number of brain metastases on the postsurgical MRI in the current study, although our group has previously identified an association between an increased number of brain metastases and distant progression with more long-term follow-up.9Patient age and sex were similar in both studies; however, Garcia and colleagues had a larger study population, albeit without genomic data available. A similar association between a greater number of brain metastases on the day of treatment and the development of new brain metastases was found by Byun and colleagues.15然而,这些研究之前,室内外ted associations between the presence of systemic extracranial disease and the development of new brain metastases. A likely explanation for our finding could be that when systemic disease is present, there is the potential for circulating tumor cells and a likelihood of formation of new brain metastases.
There are several limitations to the current study. The first is that recurrence and progression were defined by imaging evaluation and tissue sampling was not undertaken. Although the diagnosis of recurrence relied on agreement between a radiologist and the treating oncologist/neurosurgeon, with review by the senior author, it is possible that some cases of local recurrence may be related to nonspecific enhancement after surgery.16We attempted to avoid inclusion of nonspecific changes by including only cases with obvious nodular growth in the resection cavity. Another drawback is the retrospective nature of the study, making it prone to misclassification bias as well as subject to confounding. Furthermore, we could only include patients with adequate clinical data with available genomic analysis and imaging, making the study prone to selection bias. Other limitations with this study include a small number of events, which may limit the validity of the findings in the multivariate analysis, and the heterogeneity of the cohort related to inclusion of multiple cancer types.
Conclusions
In this study, which included patients with brain metastases from various cancers, having a mutation in eitherRB1orCTNNB1was associated with a significantly increased risk of rapid local recurrence. This information should be taken into consideration for timing postoperative adjuvant RT. However, no associations between rapid local or distant CNS recurrence and overall survival were found. Additional work is needed to determine if more rapid implementation of adjuvant RT or preoperative SRS improves patient outcomes.
Disclosures
The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.
Author Contributions
Conception and design: Morshed, Uggerly, Berger, Theodosopoulos, Hervey-Jumper, Aghi. Acquisition of data: Morshed, Uggerly, Cummins, Saggi, Goldschmidt, Theodosopoulos. Analysis and interpretation of data: Morshed, Uggerly, Cummins, Nguyen, Saggi, Berger, Daras, Aghi. Drafting the article: Morshed, Uggerly, Saggi, Chang, McDermott, Theodosopoulos, Daras. Critically revising the article: Morshed, Uggerly, Cummins, Nguyen, Chang, McDermott, Berger, Theodosopoulos, Daras. Reviewed submitted version of manuscript: Morshed, Uggerly, Cummins, Nguyen, Saggi, Goldschmidt, Chang, McDermott, Hervey-Jumper, Aghi. Approved the final version of the manuscript on behalf of all authors: Morshed. Statistical analysis: Morshed, Uggerly. Administrative/technical/material support: Berger, Hervey-Jumper. Study supervision: Morshed, Chang, Berger, Daras.
Supplemental Information
Online-Only Content
Supplemental material is available online.
Supplementary Table 1.//www.prize-show.com/doi/suppl/10.3171/2023.5.FOCUS23214．
References
-
2 ↑
SchoutenLJ,RuttenJ,HuveneersHA,TwijnstraA．Incidence of brain metastases in a cohort of patients with carcinoma of the breast, colon, kidney, and lung and melanoma．Cancer．2002;94(10):2698–2705．
-
3 ↑
SuJ,SongQ,QasemS,et al.Multi-omics analysis of brain metastasis outcomes following craniotomy．Front Oncol．2021;10:615472．
-
4 ↑
LeeCH,KimDG,KimJW,et al.The role of surgical resection in the management of brain metastasis: a 17-year longitudinal study．Acta Neurochir (Wien)．2013;155(3):389–397．
-
5 ↑
MahajanA,AhmedS,McAleerMF,et al.Post-operative stereotactic radiosurgery versus observation for completely resected brain metastases: a single-centre, randomised, controlled, phase 3 trial．Lancet Oncol．2017;18(8):1040–1048．
-
6 ↑
AbelRJ,JiL,YuC,et al.Stereotactic radiosurgery to the resection cavity for brain metastases: prognostic factors and outcomes．J Radiosurg SBRT．2015;3(3):179–186．
-
7 ↑
DoL,PeznerR,RadanyE,LiuA,StaudC,BadieB．Resection followed by stereotactic radiosurgery to resection cavity for intracranial metastases．Int J Radiat Oncol Biol Phys．2009;73(2):486–491．
-
8 ↑
GarciaMA,LazarA,DurisetiS,et al.Discovery of additional brain metastases on the day of stereotactic radiosurgery: risk factors and outcomes．J Neurosurg．2017;126(6):1756–1763．
-
9 ↑
MorshedRA,NguyenMP,CumminsDD,et al.CDKN2A/B co-deletion is associated with increased risk of local and distant intracranial recurrence after surgical resection of brain metastases．Neurooncol Adv．2023;5(1):vdad007．
-
11 ↑
SchwaederléM,DanielsGA,PiccioniDE,et al.Cyclin alterations in diverse cancers: outcome and co-amplification network．Oncotarget．2015;6(5):3033–3042．
-
12 ↑
FuY,ZhengS,AnN,et al.β-catenin as a potential key target for tumor suppression．Int J Cancer．2011;129(7):1541–1551．
-
13 ↑
MoroneyMR,WoodruffE,QamarL,et al.Inhibiting Wnt/beta-catenin in CTNNB1-mutated endometrial cancer．Mol Carcinog．2021;60(8):511–523．
-
14 ↑
Ruz-CaracuelI,López-JaneiroÁ,Heredia-SotoV,et al.Clinicopathological features and prognostic significance of CTNNB1 mutation in low-grade, early-stage endometrial endometrioid carcinoma．Virchows Arch．2021;479(6):1167–1176．
-
15 ↑
ByunJ,KimJH,KimM,et al.Survival outcomes and predictors for recurrence of surgically treated brain metastasis from non-small cell lung cancer．Brain Tumor Res Treat．2022;10(3):172–182．
-
16 ↑
ShahJK,PottsMB,SneedPK,AghiMK,McDermottMW．Surgical cavity constriction and local progression between resection and adjuvant radiosurgery for brain metastases．Cureus．2016;8(4):e575．
