Unique genomic alterations in the circulating tumor DNA of patients with solid tumors brain metastases.

Background: Although serum circulating tumor DNA (ctDNA) is routine, data from patients with brain metastases (BrMs) is limited. We assessed genomic alterations in ctDNA from patients with solid tumor BrMs in 3 groups: Isolated BrMs with stable extracranial disease (iCNS), concurrent brain and extracranial progression (cCNS), and extracranial progression with no active BrMs (eCNS). We also compared ctDNA alterations between patients with and without BrMs. Methods: Patients with a Guardant360 ctDNA profile with (n = 253) and without BrMs (n = 449) from the Duke Molecular Registry between January 2014 and December 2020 were identified. Actionable alterations were defined as FDA-recognized or standard-of-care biomarkers. Disease status was determined via investigator assessment within 30 days of ctDNA collection. Results: Among the 253 patients with BrMs: 29 (12%) had iCNS, 160 (63%) cCNS, and 64 (25%) eCNS. Breast (BC; 12.0%) and non-small cell lung cancer (NSCLC; 76.4%) were the most common tumor types. ESR1 (60% vs 25%, P < .001) and BRCA2 (17% vs 5%, P = .022) were more frequent in BC BrMs. In NSCLC BrMs, EGFR alterations were most frequent in the iCNS group (iCNS: 67%, cCNS: 40%, eCNS:37%, P = .08) and in patients with BrMs (36% vs 17%, P < .001). Sequencing from both brain tissue and ctDNA were available for 8 patients; 7 (87.5%) had identical alterations. Conclusions: This study illustrates the feasibility of detecting alterations from ctDNA among patients with BrMs. A higher frequency of actionable mutations was observed in ctDNA in patients with BrMs. Additional studies comparing ctDNA and alterations in BrMs tissue are needed to determine if ctDNA can be considered a surrogate to support treatment decisions.

Atopy improves survival and decreases risk of brain metastasis in cutaneous melanoma.

Importance: Development of new therapies in melanoma has increased survival, and as a result more patients are living to develop brain metastasis (BrM). Identifying patients at increased risk of BrM is therefore of significant public health importance. Objective: To determine whether history of atopy is associated with improved survival or reduced incidence of BrM in cutaneous melanoma. Design: A retrospective cohort study conducted from June 2022 to March 2024. Setting: Population-based in states with Surveillance, Epidemiology and End Results (SEER) supported cancer registries. Participants: Individuals (≥65 years) diagnosed with cutaneous melanoma between January 1, 2008 and December 31, 2017 that are participants in traditional Medicare. Exposures: Individuals were compared that had history of atopy (allergic rhinitis, atopic dermatitis, asthma, and/or allergic/atopic conjunctivitis) diagnosed prior to melanoma diagnosis, ascertained using ICD-9 or ICD-10 codes in Medicare claims. Main Outcomes and Measures: Primary endpoints were diagnosis with a BrM or death during the follow-up period. Associations between atopy and endpoints were assessed using cox proportional hazards models to estimate hazard ratios (HR) and p-values. Results: A total of 29,956 cutaneous melanoma cases were identified (median age 76, 60% male and 97% non-Hispanic White). Overall, 7.1% developed BrM during follow up. Among the 35% that had history of atopy, the most common condition was atopic dermatitis (19%). After adjustment for demographic and prognostic factors, atopy was associated with a 16% decrease in death (HR=0.84 [95%CI:0.80-0.87], pFDR<0.001). Among those with non-metastatic disease at time of diagnosis, atopy conferred a 15% decrease in cumulative incidence BrM (HR=0.85 [95%CI: 0.76-0.94], pFDR=0.006), with a 25% decrease associated with atopic dermatitis (HR=0.75 [95%CI:0.65-0.86], pFDR<0.001). Among those with metastatic disease at diagnosis (any metastatic site), only those who received immune checkpoint inhibitors had a survival benefit associated with atopy (HR=0.31, [95%CI:0.15-0.64], p=0.001 vs HR=1.41, [95%CI:0.87-2.27], p=0.165). Conclusions and Relevance: Atopy, particularly atopic dermatitis, was significantly associated with improved survival and decreased incidence of BrM. The improved survival associated with these conditions in the context of immunotherapy suggests that these conditions in the elderly may identify those with more robust immune function that may be more responsive to treatment.

Impact of systemic disease on CNS disease control after stereotactic radiosurgery to breast cancer brain metastases (The SYBRA Study).

The objective of the study is to assess impact of systemic disease (SD) status on overall survival and brain metastasis (BM) control, adopting a novel landmark approach to categorize SD among breast cancer (BC) patients. This single institution retrospective study included BCBM patients who have received stereotactic radiosurgery (SRS) to brain. Separate endpoints [CNS failure-free survival (cFFS), overall survival (OS)] were analyzed from each Landmark (LM): LM1 (3-months), LM2 (6-months). Patients were categorized into early and non-early progression (EP, NEP) groups depending on SD status before LMs. Median survivals from LM were assessed with Kaplan Meier plots, compared with Log-Rank test. EP was associated with worse median cFFS and OS vs NEP in both LM analyses (cFFS- LM1: 3.6 vs. 9.7 months, p = 0.0016; LM2: 2.3 vs. 12.5 months, p < 0.0001; OS- LM1: 3.6 vs. 24.3 months, p < 0.0001; LM2: 5.3 vs. 30.2 months, p < 0.0001). In multivariate analyses, EP was associated with shorter cFFS [LM1: Hazard Ratio (HR) with 95% confidence interval (CI) 3.16, 1.46-6.83, p = 0.0034; LM2: 5.32, 2.33-12.15, p = <0.0001] and shorter OS (LM1: HR with 95% CI 4.28, 1.98-9.12, p = 0.0002; LM2: 7.40, 3.10-17.63, p = <0.0001) vs NEP. Early systemic disease progressions after 1st SRS to brain is associated with worse cFFS and OS in patients with BCBM.