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. 2016;4(2):97–106.

Demonstration of differential radiosensitivity based upon mutation profile in metastatic melanoma treated with stereotactic radiosurgery

Charles E Rutter 1, Kimberly L Johung 1, Xiaopan Yao 2, Alex Y Lu 3, Lucia B Jilaveanu 2, James B Yu 1, Joseph N Contessa 1, Harriet M Kluger 2, Veronica LS Chiang 4, Ranjit S Bindra 1,✉
PMCID: PMC5658871  PMID: 29296434

Abstract

Background

Metastatic melanoma often involves the brain. Radiotherapy is an important treatment of melanoma brain metastases, although melanoma radiosensitivity is considered heterogeneous. Thus, identifying subsets with differential radiosensitivity is essential.

Materials and Methods

Patients with metastatic melanoma were identified in a prospective stereotactic radiosurgery (SRS) database. Tumor were tested for alterations in B-RAF, N-RAS, and c-KIT. Standardized imaging following SRS was reviewed for recurrence. Differences in local and distant failure were determined using modified Cox proportional hazards models.

Results

102 patients and 1,028 brain metastases were included. N-RAS mutated patients were significantly less likely to develop local recurrence after SRS than wild type patients (HR 0.17, 95% CI 0.04-0.72, p=0.017). B-RAF and c-KIT mutations were not associated with altered rates of local recurrence. Lower local recurrence rates for N-RAS mutated tumors persisted on multivariate analysis (HR 0.18, 95% CI 0.04-0.84p=0.029).

Conclusions

N-RAS mutation is associated with improved local control following SRS. Local recurrence is more common in wild type patients and those with B-RAF or c-KIT mutations. Further research is needed to validate these findings and integrate into practice.

Keywords: melanoma, BRAF, NRAS, radiosensitivity, radiosurgery

Introduction

Melanoma is the most aggressive form of skin cancer, and continues to increase in annual incidence [1-3]. While clinical behavior is heterogeneous, patients with metastatic disease are at high risk of brain involvement [4-6]. Melanoma disproportionately represents the third most common cancer metastasizing to the brain, despite an overall incidence far lower than other systemic malignancies [4,7]. Indeed, approximately 50-75% of patients with metastatic melanoma will develop brain metastasis at some point [6,8]. It is therefore unsurprising that central nervous system (CNS) involvement is a common cause of diminished quality of life and ultimately death in patients with metastatic melanoma [8-11].

Radiotherapy, including whole brain radiotherapy (WBRT) and stereotactic radiosurgery (SRS), represents a standard treatment for patients with brain metastases. Historically, melanomas were considered to be relatively radioresistant, with subsequent studies suggesting that higher doses-per–fraction are required to surmount this phenomenon [12-15]. Nevertheless, there exists a broad spectrum of radiation sensitivities in melanoma, although the basis for these differences remain poorly understood [16]. Even with the high single-fraction doses that can be delivered with SRS, reported control rates for melanoma brain metastases range widely from 63% to 90% following SRS, recapitulating results of in vivo radiosensitivity assays that displayed heterogeneous sensitivity to ionizing radiation [9-11,17,18]. An evolving understanding of melanoma biology suggests that several distinct subgroups can be identified based upon mutations in B-RAF, N-RAS, and KIT, raising the possibility that these genetic differences may affect radiation response patterns [19,20]. Here, we used an imaging-based radiosensitivity model to determine if these mutations can serve as biomarkers of altered response of brain metastases to SRS [21].

Materials and Methods

Patients and Treatment

Patients with melanoma brain metastases treated with SRS at Yale Comprehensive Cancer Center were prospectively enrolled in an Institutional Review Board approved data repository. Informed consent or a waiver of consent was obtained for each patient. As part of the prospective data collection, demographic and treatment characteristics were recorded. Demographic details included age, gender, and race. Treatment details included history of craniotomy, prior SRS or WBRT, and previously or concurrently delivered systemic agents. SRS treatment parameters were noted, including the number of lesions treated per SRS session, tumor volume, and margin dose. Patients were identified within this data repository for inclusion in this retrospective analysis.

Following fixation of a stereotactic head frame, patients were treated with a Leksell Gamma Knife Model C or Leksell Gamma Knife Perfexion, using treatment plans generated with GammaPlan treatment planning software (Elekta Inc., Stockholm, Sweden). Treatment was typically designed to encompass each metastasis within the 50-60% isodose line, as defined on T1 post-gadolinium MRI using a high-resolution protocol. Single fraction radiosurgery doses were delivered in a standardized size-adjusted fashion based upon institutional modifications of doses used in successive Radiation Therapy Oncology Group (RTOG) trials 9005 and 9508 [22,23]. Doses of 22–24 Gy to the tumor margin were prescribed for metastases less than 1cm in diameter, 20Gy if 1–2cm, 18Gy if 2–3cm, and 16Gy if 3–4cm.

Mutation Profiling

Tissue samples from primary tumor or metastatic sites were tested for mutations in B-RAF, N-RAS, and KIT, as described previously [24]. The presence of B-RAF mutations was determined using polymerase chain reaction (PCR) amplification and sequence analysis of exon 15. Similarly, PCR amplification and sequencing of exons 1 and 2 of the N-RAS gene was performed to identify alterations in this gene. Typically, identification of a mutated form of B-RAF obviated the need for sequencing of N-RAS, given that alterations in these genes are believed to be essentially mutually exclusive [25,26]. Finally, mutated KIT was identified using PCR amplification and sequencing of exons 11, 13, 17, and 18. Tumors which tested negative for mutations in the three genes were regarded as wild-type (WT) for the purpose of this analysis.

Response Evaluation

Post-SRS gadolinium-enhanced MRI studies were obtained every six to eight weeks for surveillance based upon institutional practice for patients with CNS metastases. Response to SRS was defined as the absence of local recurrence; the latter was used as the main outcome variable in this analysis. MRI images from treatment planning scans and all subsequent MRI studies were independently reviewed by two investigators (K.L.J., A.Y.L.) to assess for local recurrence in treated lesions. Lesions with suspected local recurrence or radionecrosis were subsequently reviewed by a separate investigator (C.E.R.) to ensure consistent assessment of local recurrence. Local recurrence was defined as a ≥20% increase in longest diameter relative to nadir following treatment, observed on ≥2 consecutive scans, or consensus among investigators [21]. Confirmatory pathologic findings of viable-appearing malignant melanoma in patients who underwent post-SRS resection, as well as evidence from brain PET scan and magnetic resonance spectroscopy (MRS) were also used in applicable cases to support a diagnosis of local recurrence [27,28]. This study did not assess local control of lesions treated with resection followed by consolidative SRS to the surgical cavity. Thus, while several patients in the study had a pre-SRS craniotomy, local control at the resection site was not assessed, and only control of such patients’ unresected lesions was recorded. In all patients, failure elsewhere in the brain outside of SRS-treated lesions was recorded as distant brain recurrence. This was defined as the emergence of a new brain metastasis as noted on serial imaging.

Statistical Analysis

Statistical analyses were performed using SAS 9.2 (SAS Institute), as previously described [21]. Patient and treatment characteristics were compared among molecular subtypes of tumors at the patient level using Fisher’s exact test for categorical variables. Linear mixed models were built to compare continuous variables for both per-treatment and per-lesion analysis of different genotypes, with patients included as a random variable to account for within-subject correlation. The duration of local control and time to elsewhere brain recurrence were calculated from the date of SRS to last radiographic follow-up or recurrence as documented by MRI. However, for patients with greater than one course of SRS for metachronous brain metastases, the time to elsewhere brain recurrence was reset with each recurrence, and calculated from the most recent SRS treatment. Analysis was performed at the lesion level for local recurrence, meaning that individual lesions were considered separately while controlling for within-subject correlation. For distant brain recurrence analysis, time to recurrence following each SRS treatment was compared. Analysis at these levels (rather than the patient level as in standard analyses) was performed to increase statistical power. The standard Kaplan–Meier method excludes events for patients who undergo subsequent SRS treatment or have multiple sequential recurrences. Thus, for time to event analyses, a modified Cox proportional hazards model was built with a robust sandwich covariance matrix estimate to account for the dependence of recurrence events within a single patient after serial SRS sessions, and for multiple lesions treated per SRS session. Recurrence probability curves for both local and distant-brain sites were generated from the Cox proportional hazards model by mutant genotype to compare these risks between patient groups. Death was not considered as an event in these analyses, as death is a patient-level event, different from the lesion-level and SRS treatment-level of analyses used for local and distant-brain failure models. The median time to recurrence for each melanoma molecular subgroup was calculated according to the predicted survival function. Multivariate analysis was then carried out to investigate the effect of genotypes on local recurrence risk, accounting for age, number of lesions treated, lesion volume, and margin dose prescribed. Multivariate analysis was performed for distant brain recurrence as well, with age, number of lesions treated, and age as covariates. A two-sided P value of 0.05 was considered statistically significant.

Results

Patient and Treatment Characteristics

One hundred two patients treated consecutively between November 2002 and February 2014 were included in the analysis, with median clinical follow-up of 7.8 months from patients’ first SRS treatment. Median radiographic follow-up time for local or distant recurrence was 6.0 months (range 0–79.4 months). The majority of patients died during the follow-up period (n=73, 71.6%). Median survival from first SRS was 5.9 months (range 1.2-79.6 months) for B-RAF mutated patients, 33.7 months (range 3.4-49.1 months) for N-RAS mutated patients, 16.3 months (range 2.2-21.7 months) for KIT mutated patients, and 7 months (range 0.4-44.3 months) for wild type patients. B-RAF mutations were found in 45 patients (44.1%), N-RAS mutations in nine (8.8%), and KIT mutations in four (3.9%), while the remaining 44 patients were wild-type (43.2%). The 102 patients in the cohort underwent 190 SRS sessions (78 B-RAF mutant, 23 N-RAS mutant, 10 KIT mutant, 79 wild type) for treatment of 1,028 brain metastases (505 B-RAF mutant, 68 N-RAS mutant, 78 KIT mutant, 377 wild type). Table 1 shows patient and treatment characteristics. Those in the KIT group were treated to a lower median dose (18Gy vs. 20Gy in all other groups, p=0.03). The median number of SRS treatments per patient was one (range 1–6), and the distribution in number of SRS treatments did not differ by mutation status (p=0.42). The median number of lesions treated per SRS session was highest among KIT mutated patients, lowest among N-RAS mutated patients, and intermediate in B-RAF mutated and wild type patients (p=0.04, Table 1). Lesion volume was similar between groups (p=0.68). A minority of patients received WBRT, before (n=4, 3.9%) or after (n=10, 9.8%) their first SRS treatment. WBRT was delivered in five wild type patients (11.4%), five B-RAF mutated patients (11.1%), three KIT mutated patients (75%), and one N-RAS mutated patient (11.1%). Similarly, a minority underwent craniotomy before (n=9, 8.8%) or after SRS (n=9, 8.8%). Two patients had two craniotomies apiece following SRS, yielding a total of 11 post-SRS craniotomies. Pathologic findings from these procedures were viable tumor (n=6, 54.5%) and radionecrosis (n=5, 45.5%). Brain PET and MRS were used to define or confirm local recurrence in six and two recurrences, respectively.

Table 1.

Patient treatment characteristics.

Characteristic Overall
102 Patients
1028 Metastases		 Wild Type
44 Patients
377 Metastases		 B-RAF Mutant
45 Patients
505 Metastases		 N-RAS Mutant
9 Patients
68 Metastases		 KIT Mutant
4 Patients
78 Metastases		 p Value
Median F/U (Months; Range)* 5.99 (0-79.4) 5.13 (0-79.4) 5.02 (0-79.4) 12.9 (0.9-54.6) 9.7 (1.3-33.9) –
Median age (Years) 62 65 59 63 63 0.86
Sex 0.66
 Male 68 31 28 7 2
 Female 34 13 17 2 2
Race 0.56
 White 101 43 45 9 4
 Black 1 1 0 0 0
Lesions per SRS Session 0.04
 Median 3 3 4 1 7
 Range 1 – 37 1 – 37 1 – 32 1 – 14 3 – 21
Lesion Volume (cm3) 0.68
 Median 0.20 0.20 0.19 0.39 0.13
 Range 0.01 – 36.5 0.02 – 18.6 0.01 – 30.3 0.03 – 36.5 0.021 – 9.7
Dose (Gy) 0.03
 Median 20 20 20 20 18
 Range 8 – 25 8 – 24 9 – 25 18 – 22 16 – 24
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*

Median radiographic follow-up from SRS.

Overall Recurrence Patterns

The distribution of local and distant brain recurrence by mutation type is shown in Table 2, at the patient (for both local and distant brain recurrence), lesion (for local recurrence only), and SRS treatment (for distant brain recurrence) levels of analysis. Approximately 25% of patients developed at least one local failure. However, when assessing at the lesion level, only 5.4% of lesions recurred locally after SRS. The lowest local recurrence rate was observed in N-RAS mutated patients (4.4% vs. 5.0–7.7% in other mutation profiles). A majority of patients in all mutation subgroups experienced distant brain failure.

Table 2.

Local distant brain recurrence rates by mutation profile.

Overall Wild Type B-RAF Mutant N-RAS Mutant KIT Mutant
Patient-level
 Local 26 / 102 (25.5%)  13 / 44 (29.5%) 8 / 45 (17.8%) 2 / 9 (22.2%) 3 / 4 (75%)
 Distant brain 61 / 102 (59.8%) 26 / 44 (59.1%) 26 / 45 (57.8%) 6 / 9 (66.7%) 3 / 4 (75%)
Lesion-level
 Local 56 / 1028 (5.4%) 22 / 377 (5.8%) 25 / 505 (5.0%) 3 / 68 (4.4%) 6 / 78 (7.7%)
SRS Treatment-level
 Distant brain 115 / 190 (60.5%) 49 / 79 (62.0%) 45 / 78 (57.7%) 14 / 23 (60.9%) 7 / 10 (70%)
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Local Recurrence by Mutation Type

B-RAF mutated patients had time to local recurrence equivalent to wild-type patients (HR 0.89, 95% confidence interval (CI) 0.50–1.58, p=0.681). Similarly, time to local recurrence among KIT mutated patients approximated those of wild-type patients (HR 1.75, 95% CI 0.79–3.92, p=0.170). N-RAS mutated patients, though, had time to local recurrence that was significantly better than wild type patients. (HR 0.17, 95% CI 0.04–0.74, p=0.018, Figure 1). Comparing the four mutation profiles, superior local control was seen in N-RAS mutated patients. At one year after SRS, local control was 97% in patients with N-RAS mutations (95% CI 92-100%), versus 89%, 84%, and 80% for B-RAF mutated (95% CI 80-97%), wild type (95% CI 76-93%), and KIT mutated (95% CI 61-100%) melanomas, respectively (p=0.046). Local-recurrence curves for the four groups are shown in Figure 2. Table 3 shows results of multivariable regression, performed at the lesion level for local recurrence, demonstrating that younger age, smaller metastasis volume, and N-RAS mutated status remained significantly associated with improved time to local recurrence (p<0.05).

Figure 1.

Figure 1

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Comparison of local recurrence probability by N-RAS mutation status in lesion level analysis.

Figure 2.

Figure 2

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Comparison of local recurrence probability based on mutation profile.

Table 3.

Results of multivariate time-to-event analysis of local distant brain recurrence.

Local Recurrence Distant Brain Recurrence
HR 95% CI p – value HR 95% CI p – value
Mutation Profile 0.041 0.227
 Wild type – – – – – –
 B-RAF Mutated 0.55 0.28 – 1.08 0.083 0.88 0.57 – 1.34 0.541
 N-RAS Mutated 0.13 0.03 – 0.64 0.012 0.53 0.29 – 0.97 0.041
 KIT Mutated 0.92 0.34 – 2.49 0.862 1.02 0.45 – 2.33 0.958
Number of Lesions Treated 1.11 1.06 – 1.15 <0.001 1.03 1.00 – 1.06 0.075
Age (>55 years) 1.95 0.84 – 4.52 0.119 1.38 0.88 – 2.17 0.162
Metastasis volume 1.17 1.07 – 1.28 <0.001 – – –
Margin dose 1.12 0.90 – 1.39 0.299 – – –
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Note: Local recurrence assessed at lesion level. Distant brain recurrence assessed at SRS treatment level.

Distant Brain Recurrence by Mutation Type

B-RAF mutated and wild type patients had similar time to distant brain recurrence (HR 1.04, 95% CI 0.71–1.52, p=0.850), as did KIT mutated patients (HR 1.44, 95% CI 0.67–3.10, p=0.356). On univariate analysis, N-RAS mutated patients had improved time to distant recurrence relative to wild-type patients (HR 0.55, 95% CI 0.31–0.98, p=0.041). Rates of distant brain control at 1 year post-SRS were 47% (95% CI 31-72%) in N-RAS mutated patients, 28% (95% CI 18-44%) in B-RAF mutated patients, 24% (95% CI 15-41%) in wild-type patients, and 17% (95% CI 8-38%) in KIT mutated patients (p=0.177). Median time to distant recurrence was 9.6, 4.4, 3.6, and 3.1 months in patients with N-RAS mutated, B-RAF mutated, wild type, and KIT mutant tumors, respectively. Distant brain recurrence curves are shown in Figure 3. On multivariable analysis, N-RAS mutated patients appeared to have improved time to distant brain recurrence relative to wild type patients, while rates in B-RAF and KIT were not significantly different than wild type (Table 3). However, there was no difference in time to distant recurrence when comparing the four groups to one another on multivariable analysis (p=0.227).

Figure 3.

Figure 3

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Comparison of distant brain recurrence probability based on mutation profile.

Discussion

Our results suggest that mutation profile in metastatic melanoma may serve as a biomarker for radiosensitivity. We observed superior local control following radiosurgery among N-RAS mutated patients. These findings may in part explain the heterogeneity that typifies the response of melanoma to radiotherapy [11,18]. This information may allow for improved treatment selection and intensity among patients with melanoma for whom radiotherapy is considered. Because melanoma has a predilection for the development of brain metastasis, and CNS involvement is in turn a leading cause of death and disability, informing decision making with biomarkers may yield substantive improvements in duration and quality of life [4,6-11].

The mutations assessed in this study are drivers of melanoma progression and metastasis [2,25,29-31]. These mutations lead to heightened activity of the Mitogen-Activated Protein Kinase (MAPK) pathway (B-RAF, N-RAS) and phosphatidylinositol 3’ Kinase (PI3K) pathway (N-RAS), resulting in enhanced proliferation and survival [2,19]. Activating mutations of B-RAF occur in 40-60% of melanomas, while mutations in N-RAS are identified in only 10-20% [2,19,20,25,31-33]. Notably, mutations in B-RAF and N-RAS are considered mutually exclusive [20,26]. A subset of patients without mutations in these two proteins may have activating mutations in the receptor tyrosine kinase KIT [20]. The identification of these mutations has had significant ramifications on the systemic treatment and outcomes for melanoma [34-37]. However, our findings represent the first association of these mutations and altered response to radiotherapy.

The explanation for enhanced radiosensitivity in N-RAS mutated melanoma relative to other subtypes remains unclear. While both RAS and RAF function in the MAPK pathway, only activated RAS also increases PI3K pathway signaling, resulting in improved cell survival and augmented DNA damage repair [38]. Thus, differences in PI3K pathway signaling may contribute to our findings. Unmeasured-but-associated alterations in other members of the MAPK or PI3K pathways could have contributed to our observations as well. One possibility is PTEN, a tumor suppressor gene which is lost in 30-50% of melanoma cell lines, in a distribution that is mutually exclusive with N-RAS mutations but frequently concomitant with B-RAF mutations [32,33,39]. PTEN loss is common in gliomas, a group of highly radioresistant malignancies, while restoration of intact PTEN in glioma cell lines leads to redistribution of cells into radiosensitive portions of the cell cycle [38,40]. Therefore, differences in PTEN expression between N-RAS mutated patients and patients in other mutation groups may contribute to our findings. That is, intact PTEN in N-RAS mutants may engender greater radiosensitivity while frequent loss of PTEN in B-RAF mutant melanomas could lead to radioresistance. Further study to address these hypotheses is required.

Given the excellent local controlled observed in our cohort of N-RAS mutated patients following SRS, trials of radiosurgery dose de-escalation may be appropriate in this group. If successful, this would allow for widening of the therapeutic window via a reduction in the dose-dependent risk of radionecrosis [41,42]. The superior local control rates observed in our study may also be attributable to the small volume of treated metastases. We also observed improved rates of distant brain recurrence following SRS among patients with N-RAS mutated tumors relative to patients with wild type tumors, despite similar rates of WBRT utilization. This may suggest that a more indolent disease course in these patients, or greater central nervous system control with systemic therapy in part explains improved local control following SRS in N-RAS mutated patients. The rate of distant brain recurrence in this study is likely confounded by extra-cranial disease burden and variations in systemic therapy, and thus requires further evaluation. Nevertheless, these findings are of prognostic value for patients with melanoma brain metastases.

We applied a radiosensitivity model that has been previously described [21]. In previous work to determine differential radiosensitivity by tyrosine kinase mutation type in metastatic non-small cell lung cancer, results of this model mirrored established in vitro findings (Johung et al., 2013). While radiosensitivity can be inferred from response to other forms of radiation, a SRS model allows for more precise and reliable assessment because delivered dose, target delineation, and treatment planning are standardized, thereby minimizing the influence of treatment variation on observed results. Additionally, the statistical analysis we used allows for the assessment of control at the lesion level, rather than patient level, thereby increasing statistical power. Finally, this model avoids the limitations of traditional in vitro radiosensitivity analyses, including selection bias when propagating cell cultures and the loss of interactions with the tumor microenvironment [43,44].

This study has several limitations. The number of KIT mutated patients was low, limiting the power to detect differential radiosensitivity based on this alteration. Because of the definition of local recurrence primarily by imaging criteria, there is the potential for inaccurate attribution of abnormal MRI findings post-SRS to local recurrence versus radionecrosis. However, stringent and previously-described criteria were employed, with a second independent review by a separate investigator [21]. Our observed recurrence rate approximates published estimates of recurrence in melanoma brain metastases following SRS, suggesting the potential for misclassification of recurrence did not unduly influence our findings [9,10]. Prior application of this SRS-based radiosensitivity model produced similarly reliable findings in mutated non-small cell lung cancer patients, again supporting the validity of our findings [21]. We did not assess systemic disease status due to the subjectivity of defining this factor. Additionally, systemic therapy receipt was not included in our analyses, as heterogeneous treatment regimens were used, data availability and completeness was at times inconsistent, and because of uncertainty regarding activity of various agents beyond the blood brain barrier. Finally, the potential for tumor heterogeneity between biopsied and treated lesions exists, potentially confounding our lesion-level analysis of local control. This is unlikely, though, given that oncogenic mutations in B-RAF, N-RAS, and KIT appear to be early events in melanoma development and local progression, and such mutations are conserved between primary sites and metastatic foci in the majority of cases [20,26,30,45,46]. Because of the retrospective design of our study, along with the above-noted limitations, prospective validation of our findings in an expanded sample of patients is needed prior to the clinical application of our results, with close attention to the impact of systemic therapy on brain metastasis control.

In conclusion, we observed superior local control following radiosurgery among patients with N-RAS mutated metastatic melanoma. The difference in local control based on mutation profile may explain in part the range of radiosensitivity seen in melanoma. While further study is required to confirm these results, our findings suggest that a melanoma patient’s mutation profile can be used to predict their risk of local recurrence following radiosurgery. Ultimately, such knowledge may allow for individualized treatment decisions and potentially improved outcomes.

Footnotes

Authors’ disclosure of potential conflicts of interest

Dr. Rutter reports personal fees from Elekta AB, outside the submitted work.

Dr. Yu reports grants from the PhRMA Foundation, grants from 21st Century Oncology, outside the submitted work.

Dr. Bindra. Dr. Chiang, Dr. Contessa, Dr. Jilaveanu, Dr. Johung, Dr. Kluger, Mr. Lu, and Dr. Yao have nothing to disclose.

Author contributions

Conception and design: Charles Rutter, Ranjit Bindra, Kimberly Johung, Joseph Contessa

Data collection: Charles Rutter, Kimberly Johung, Alex Lu, Lucia Jilaveanu

Data analysis and interpretation: Xiaopan Yao, Charles Rutter, Ranjit Bindra

Manuscript writing: Charles Rutter, Ranjit Bindra, Xiaopan Yao

Final approval of manuscript: All authors

Charles Rutter, Kimberly Johung, and Xiaopan Yao made equal contibutions.

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