Diagnosis Of Brain Metastases Research Articles

Successful treatment of an 82-year-old COVID-19 delta variant-infected patient with haemorrhagic stroke and active prostate cancer brain metastasis.

Successful treatment of an 82-year-old COVID-19 delta variant-infected patient with haemorrhagic stroke and active prostate cancer brain metastasis.

Brain metastases originating in breast cancer: clinical-pathological analysis and immunohistochemical profile.

The incidence of brain metastases (BMs) originating in breast cancer (BC) is increasing due to advances in imaging techniques, which can detect such events early, and due to new therapies that can ensure longer survival. We performed a retrospective study on patients with BMs originating in BC and receiving surgical treatment in Neurosurgery Clinics of Prof. Dr. Nicolae Oblu Emergency Clinical Hospital, Iaşi, Romania, from January 2018 to December 2019. We identified 10 consecutive patients who underwent a craniotomy for a BMs originating in a BC (either for diagnostic purpose or with therapeutic intent). Clinicopathological data were collected from the electronic medical record and included the patient demographics (age at diagnosis of their BM), morphological characteristics of BM [location, cytopathological features, histopathological (HP) subtype, and immunohistochemical features, i.e., cytokeratin 5/6 (CK5/6), mammaglobin, estrogen receptor (ER), progesterone receptor (PR), and Ki67 labeling index (LI)], and time from BC diagnosis to BM diagnosis. Ninety percent of patients were in their sixth and seventh decades of life, with a median age of 57.9 years (47–65 years). Median time from BC diagnosis to BM was 34.42 months. Fifty percent of BMs were located in the parietal lobes, and 70% of all cases have multiple (≥2) BMs. All cases (100%) had a cytopathological examination, showing a hypercellular pattern, with poorly cohesive clusters of mild or pleomorphic cells, with nuclei with homogeneously distributed fine granular chromatin membrane, and with small or enlarged and irregular nucleoli. The dominant histopathology was invasive breast carcinoma of no special type (IBC-NST) (70%), but we also identified specific subtypes, i.e., tubular carcinoma (TC) (20%) and invasive micropapillary carcinoma (IMPC) (10%). Correlating location with HP subtypes of BMs from BC, IBC-NST and IMPC were located mostly in parietal lobes, and TC developed only in the occipital lobe. We found three patterns of immunostaining: (i) CK5/6 +/-, mammaglobin+, ER+, PR-, which was much more characteristic for IBC-NST; (ii) CK5/6-, mammaglobin+, ER-, PR-, being identified in tubular breast carcinoma; (iii) CK5/6 +/-, mammaglobin-, ER-, PR-, which were revealed by invasive micropapillary breast carcinoma. Our study revealed the fact that BMs originating in BC show heterogeneity of hormone receptor status, although morphologically there is not so much diversity. We also found a very variable Ki67 LI, which correlated especially with the morphological subtype.

Upfront Treatment With Osimertinib vs. Osimertinib and Radiotherapy for Patients With EGFR-Positive Non-Small Cell Lung Cancer Brain Metastases

<h3>Purpose/Objective(s)</h3> Given the improved central nervous system penetration of 3^rd generation tyrosine kinase inhibitors, such as osimertinib, the role of upfront radiation therapy (RT) in the setting of brain metastases (BM) has been brought into question. We sought to retrospectively evaluate outcomes at our institution for patients with EGFR-positive NSCLC treated with osimertinib as the upfront treatment for new or progressing BM versus osimertinib in combination with intracranial RT. <h3>Materials/Methods</h3> This single-institution retrospective analysis of EGFR-positive NSCLC with new or progressing BM included a total of 92 patients with 405 BM treated between 2013 to 2021 and followed until July 2021. Two BM treatment groups were evaluated: (1) patients treated with upfront osimertinib alone (n=58), and (2) patients treated with osimertinib combined with RT [either whole brain radiation therapy (WBRT) or stereotactic radiosurgery (SRS) prior or concurrently with osimertinib (n=34)]; both groups began treatment within 2 months of BM diagnosis. Time-to-event analysis was conducted with the Kaplan-Meier (KM) method, and outcomes included distant intracranial control (DIC), local control (LC), and overall survival (OS). Cox proportional hazards model was utilized for multivariate analysis (MVA) to identify correlations of clinical outcomes. <h3>Results</h3> Median follow-up from BM diagnosis was 13.2 months (0.8-48.9 months). Of the patients treated with osimertinib and RT, 17 were treated with SRS and 17 with WBRT. No significant differences in age (p=0.96), gender (p=0.42), DS-GPA (p=0.73), KPS (p=0.54, number (p=0.52) or volume (p=0.29) of BM, SRS dose (p=0.44), or number of systemic metastases (p=0.88) were noted between groups. No difference between osimertinib vs osimertinib and RT groups was noted for 12 month KM rates of DIC 84.9% and 68.7% (p=0.80); LC 99.6% and 93.1% (p=0.31); and OS 66% and 73.5% (p=0.). Of the 58 patients treated with upfront osimertinib, 19 patients with 77 lesions eventually required radiation for intracranial progression with 62 of those lesions being treated with SRS. Upon MVA, higher KPS (p=.001) and DS-GPA (p=0.002) were associated with increased OS and systemic metastasis at time of treatment with worse OS (p=0.001). <h3>Conclusion</h3> The results of this study support other preliminary data suggesting that upfront osimertinib alone may provide sufficient intracranial control to allow RT to be deferred until further intracranial progression. Prospective trials are needed to further guide treatment.

Survival analysis of patients with breast cancer and secondary brain metastasis: a retrospective cohort

Introduction: The presence of brain metastases secondary to primary breast cancer implies a worse prognosis for those affected. Therefore, the aim of this study was to determine the median survival after the diagnosis of brain metastasis in patients with breast carcinoma in a center in northeastern Brazil. Methods: The medical records of 345 patients diagnosed with breast cancer, treated between 1998 and July 2018, were analyzed. Those with brain metastasis along with their treatment performed and survival were identified. Results: Nine (2.6%) patients had brain metastasis; the mean age was 56.8 years. The mean survival time determined by the Kaplan-Meier method was 23.8 months (95%CI 6.9–40.8). Seven patients (78%) died from the disease and two were lost to follow-up (22%); invasive carcinoma of no special type was the most frequent (78%). Molecular classification by immunohistochemistry was possible in seven patients: five luminal B subtype cases, one luminal A case and one triple-negative case; luminal B subtype was associated with longer survival: 23.3 months (95%CI 3.0–43.6). As for the initial clinical staging, according to the TNM Classification of Malignant Tumors, there was one IA case, one IIA case, three IIB cases and two IIIB cases. Three patients underwent modified radical mastectomy, and six underwent conservative treatment (quadrantectomy); there was no statistical difference in survival between the different forms of treatment (p=0.771). Conclusion: The median survival after diagnosis of brain metastasis from breast cancer was 23.80 months.

Targeted Therapies and Utility of the Lung-molGPA in Non-Small-Cell Lung Cancer Patients with Brain Metastases.

Therapeutic advances have increased the survival of non-small-cell lung cancer (NSCLC) patients as well as the lifetime risk of being diagnosed with brain metastases (BM). Although BM have historically been associated with poor prognosis, it is unclear whether they remain a strong predictor of reduced survival. This study aimed to evaluate the prognostic value of BM and the utility of the Lung-molGPA. This single-center retrospective database analysis included 1,393 NSCLC patients with newly diagnosed BM who registered at the Instituto Nacional de Cancerología of Mexico (INCan) from 2010 to 2020. The Kaplan-Meier method and log-rank test were used for the survival analysis. Survival times were calculated from the date of NSCLC diagnosis (OS), or BM diagnosis, to the date of death or last follow-up. Cox proportional-hazards models were used to calculate the hazard ratio (HR) for death and the significance of the parameters evaluated. Out of 1,058 patients who underwent genetic testing for epidermal growth factor receptor (EGFR) mutations and/or anaplastic lymphoma kinase (ALK) rearrangements, 650 had a positive tumor mutational/rearrangement status (543 had EGFR mutations, 104 had ALK rearrangements, and 3 had both EGFR and ALK alterations). Median OS did not differ between patients with BM and without BM (17.7 months [95% CI, 15.4-19.0] vs. 16.6 months [95% CI, 14.3-19.0]; p = 0.362). In contrast, the presence of BM was associated with worse OS in patients with a negative tumor mutational status (HR: 1.225 [95% CI, 1.041-1.443]; p = 0.015), who did not receive TKI therapy (HR: 1.269 [95% CI, 1.082-1.488]; p = 0.003), or with non-adenocarcinoma histology (HR: 1.582 [95% CI, 1.118-2.238]; p = 0.01). The median survival after BM diagnosis was 4.27, 6.96, 14.68, and 18.89 months for adenocarcinoma patients with Lung-molGPA scores 0-1, 1.5-2, 2.5-3, and 3.5-4, respectively (p < 0.0001). For non-adenocarcinoma patients with Lung-molGPA scores 0-1, 1.5-2, and 2.5-3, the corresponding estimates were 0.95, 2.89, and 9.39 months, respectively (p < 0.0001). These results show that the prognosis of NSCLC patients with BM is no longer uniformly poor and should be individually assessed. Furthermore, the validity of the Lung-molGPA was confirmed in an independent population from a different geographical region.

Management of brain metastases in 2022

Brain metastases (BM) are a common occurrence of systemic cancers. Technical improvements in neuroimaging offer additional tools for an early detection of BM, to target them precisely and differentiate these lesions from other cerebral pathologies. The therapeutic tools have also evolved from neurosurgery and whole brain therapy to include stereotactic radiosurgery, targeted and immune therapies. Given the numerous treatment options available, a multidisciplinary approach is essential to offer the patient a personalized approach to optimize the sequence and combination of treatments to offer the best outcome possible. This article aims to review key elements of diagnosis, risk stratification and modern treatment paradigms in the diagnosis and management of BM.

PD-L1 expression in breast cancer brain metastases.

BackgroundTo evaluate the potential intracranial efficacy of immunotherapy among patients with breast cancer brain metastases (BrM), we analyzed the immunohistochemical expression of programmed death-ligand 1 (PD-L1), a predictive biomarker of response to immunotherapy.MethodsIn this single-center retrospective cohort study, consecutive patients with breast cancer BrM (immunotherapy naïve) who underwent surgery for BrM at Sunnybrook Health Sciences Center between July 1999 and June 2013 were identified. PD-L1 expression by immunohistochemistry (IHC) was assessed on BrM samples in triplicate; PD-L1 positive status was defined as PD-L1 expression ≥1% on tumor-infiltrating cells as a percentage of tumor area using the Ventana SP142 antibody. Estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor (HER2) status was determined using 2018 ASCO/CAP guidelines.ResultsThe median patient age at the time of BrM diagnosis was 52 (range 32–85). PD-L1 expression using the SP42 antibody was identified in 9 out of 59 (15.3%) breast cancer BrM. The frequency of PD-L1 positive BrM by subtype is as follows: TNBC (n = 3/12, 25.0%), HER2+/HR- (n = 3/14, 21.4%), HR+/HER2- (n = 2/18, 11.1%), and HER2+/HR+ (n = 1/14, 7.1%). 24-month brain-specific progression-free survival was 66.7% (95% CI 37.9%–100%) among patients with PD-L1 positive BrM versus 42% (95% CI 26.6%–67.3%) among those with PD-L1 negative BrM (log-rank P-value .142).ConclusionsOne in 7 patients in our cohort had PD-L1 positive BrM; this proportion was highest (25%) among those with TNBC. Intracranial efficacy of immunotherapy warrants further study, particularly among patients with treatment-naïve metastatic TNBC, for whom extracranial efficacy has already been established.

Differential diagnosis of glioblastoma and solitary brain metastasis – the success of artificial intelligence models created with radiomics data obtained by automatic segmentation from conventional MRI sequences

Differential diagnosis of glioblastoma and solitary brain metastasis – the success of artificial intelligence models created with radiomics data obtained by automatic segmentation from conventional MRI sequences

The Pattern of Care for Brain Metastasis from Breast Cancer over the Past 10 Years in Korea: A Multicenter Retrospective Study (KROG 16-12).

PurposeWe aimed to investigate manifestations and patterns of care for patients with brain metastasis (BM) from breast cancer (BC) and compared their overall survival (OS) from 2005 through 2014 in Korea.Materials and MethodsWe retrospectively reviewed 600 BC patients with BM diagnosed between 2005 and 2014. The median follow-up duration was 12.5 months. We categorized the patients into three groups according to the year when BM was initially diagnosed (group I [2005–2008], 98 patients; group II [2009–2011], 200 patients; and group III [2012–2014], 302 patients).ResultsOver time, the median age at BM diagnosis increased by 2.2 years (group I, 49.0 years; group II, 48.3 years; and group III, 51.2 years; p=0.008). The percentage of patients with extracranial metastasis was 73.5%, 83.5%, and 86.4% for group I, II, and III, respectively (p=0.011). The time interval between BC and BM was prolonged in patients with stage III primary BC (median, 2.4 to 3 years; p=0.029). As an initial brain-directed treatment, whole-brain radiotherapy alone decreased from 80.0% in 2005 to 41.1% in 2014. Meanwhile, stereotactic radiosurgery or fractionated stereotactic radiotherapy alone increased from 13.3% to 34.7% during the same period (p=0.005). The median OS for group I, II, and III was 15.6, 17.9, and 15.0 months, respectively, with no statistical significance.ConclusionThe manifestations of BM from BC and the pattern of care have changed from 2005 to 2014 in Korea. However, the OS has remained relatively unchanged over the 10 years.

Brain Metastases from Adult Sarcomas: A Retrospective Cohort Study from the Hellenic Group of Sarcomas and Rare Cancers (HGSRC).

Brain metastases are rare events in patients with sarcoma and the available information is relatively limited. We retrospectively reviewed medical records of patients with sarcoma who developed brain metastases between April 2010 and April 2020 in six centers. Thirty-four adult patients were included with a median age at brain metastases diagnosis of 55.5 years (range, 18–75). The primary sarcomas originated either from soft tissue (n = 27) or bone (n = 7) and the most common subtypes were leiomyosarcoma (n = 8), Ewing sarcoma/peripheral neuroectodermal tumor (PNET) (n = 7) and osteosarcoma (n = 3). Most primary tumors were of high grade and located mainly in the extremities (n = 18). The vast majority of patients at the time of brain metastasis diagnosis already had extracranial metastatic disease (n = 26). The median time from sarcoma diagnosis to cerebral metastasis diagnosis was 16 months (range, 1–136). Treatment modalities for brain metastatic disease included whole-brain radiation therapy (WBRT) (n = 22), chemotherapy (n = 17), exclusive palliative care (n = 5), surgery (n = 9), targeted therapy (n = 6) or stereotactic radiosurgery (n = 2). Most patients experienced a progression of brain metastases (n = 11). The median overall survival from brain metastasis diagnosis was 3 months (range, 0–80). OS was significantly influenced by time-to-brain metastases (p = 0.041), WBRT (p = 0.018), surgery (p = 0.002) and chemotherapy (p = 0.006). In a multivariate analysis, only the localization of the primary (p = 0.047) and WBRT (p = 0.038) were associated with survival with statistical significance. Patients with sarcoma brain metastases have a particularly poor prognosis and an appropriate therapeutic approach is yet to be defined.

Survival benefit with resection of brain metastases from renal cell carcinoma in the setting of molecular targeted therapy and/or immune therapy

Patient survival with renal cell carcinoma (RCC) has improved with the use of molecular targeted agents and immunotherapy. Given the potential activity of these agents in treating brain metastases, the role of aggressive local management with surgery and/or radiation may diminish. The aim of this study was to evaluate the role of aggressive local therapy for RCC brain metastasis in the setting of molecular targeted agents and/or checkpoint inhibitor therapy. A retrospective single-center review between 2011-2018 identified patients that developed brain metastasis from RCC. Data analyzed included demographic information, systemic treatments, intracranial interventions, progression free survival and overall survival (OS). Of 1194 patients, 108(9.0%) were diagnosed with brain metastasis from RCC. OS from diagnosis of brain metastasis (OSBM) was 12.3 months. OSBM was analyzed based on three treatment groups: systemic therapy (ST) only (2.0 months, n = 23), systemic and radiotherapy (RT + ST) (12.3 months, n = 52), and systemic and radiotherapy plus resection (Surg + RT + ST) (21.7 months, n = 33). Survival benefit was seen with Surg + RT + ST compared to ST (P = 0.001), but not RT + ST (P = 0.081). Progression free survival was significantly prolonged with Surg + RT + ST compared to RT + ST (10.9 vs 5.9 months, respectively, P = 0.04). Variables such as performance status and number of brain metastases at the time of brain metastasis diagnosis did not differ significantly. In the setting of molecular targeted agents and immunotherapy, resection may benefit the appropriate surgical candidate. Prospective clinical trials are necessary to better understand the role of aggressive RCC brain metastasis treatment.Micro Abstract• Renal cell brain metastasis is often excluded from studies and brain metastases effect a large portion of RCC patients.• Retrospective study of 1194 RCC patients, 108 patients had brain metastasis, determination of the role of surgical resection in the setting of recent advances in checkpoint inhibitors.• A benefit was seen in overall survival in patients that had surgical while undergoing radiation therapy and systemic therapies.• In the setting of molecular targeted agents and immunotherapy, resection may benefit the appropriate surgical candidate(s).

RADT-03. OUTCOMES OF PATIENTS WITH HER2-POSITIVE BREAST CANCER METASTATIC TO BRAIN TREATED WITH HER2-TARGETED SYSTEMIC THERAPY AND STEREOTACTIC RADIOSURGERY

Abstract OBJECTIVE For patients with HER2-positive breast cancer metastatic to brain, HER2-directed systemic therapies are increasingly used with stereotactic radiosurgery (SRS). These include monoclonal antibodies such as trastuzumab (H) and pertuzumab (P), antibody-drug conjugates such as ado-trastuzumab emtansine (T-DM1), and tyrosine kinase inhibitors such as lapatinib. Limited data exist regarding appropriate timing with SRS and outcomes of this treatment regimen. METHODS A single-institution retrospective review collected clinical data on patients with breast cancer metastatic to brain who were treated with SRS from 2009-2020. Statistical analyses were performed using the Kaplan-Meier method and chi-square statistic. RESULTS Of 82 patients with breast cancer metastatic to brain treated with SRS, 33 (40%) were HER2-positive, 18 of whom were hormone receptor-positive. At brain metastasis diagnosis, 15 patients (45%) had &amp;gt;1 intracranial metastasis (range 2-7), and the median brain metastasis maximal dimension was 2.0 cm. Fifteen patients had uncontrolled extracranial disease. After brain metastasis diagnosis, 9 patients (27%) were treated with systemic therapy first (T-DM1+/-HP, lapatinib+HP, chemotherapy+/-HP) followed by SRS at a median of 18.6 months after starting systemic therapy. Seven patients (21%) were treated with SRS first, followed by systemic therapy in 6 of these patients (multi-agent regimens, 4 including T-DM1 or lapatinib). Seventeen (52%) received concurrent systemic therapy and SRS (T-DM1+/-chemotherapy, lapatinib, HP, hormone therapy, chemotherapy). Median follow-up time was 21.1 months. Median overall survival was 24.8 months and not statistically different between treatment groups. Four patients (12%) developed symptomatic radionecrosis; 3 were on T-DM1 concurrent with SRS. CONCLUSION In this small patient sample, we noted favorable survival outcomes for patients with HER2-positive breast cancer metastatic to brain when treated with HER2-targeted therapies together with SRS. The sequence of systemic therapy and SRS does not appear to impact survival outcomes. Concurrent treatment with T-DM1 and SRS may be associated with higher rates of radionecrosis.

Survival Outcomes of Local Compared With Systemic First Treatment of Non-Small Cell Lung Cancer Brain Metastases.

ObjectiveThis retrospective study evaluated the survival advantage of local treatment targeted to brain metastases, relative to systemic therapy, as the first option for brain metastases of non-small cell lung cancer (NSCLC).MethodsFirst reviewed were 291 cases of NSCLC brain metastases from two centers. All patients were at least 18 years old, with histologically confirmed NSCLC, and required and underwent both local (radiotherapy or brain surgery) and systemic treatment (chemotherapy and tyrosine kinase inhibitor [TKI] medication). Demographics, clinical characteristics, and treatment-related variables were collected.ResultsThe final population comprised 160 patients. Overall, the multivariate analysis suggested that the following were associated with better survival: >3 cycles of chemotherapy; stereotactic radiosurgery; and TKI medication (all, P = 0.000). Local treatment that began within 1 week of the diagnosis of brain metastases was associated with poorer survival (P = 0.006). Among the 111 patients with symptomatic brain metastases, the multivariate analysis indicated that better survival was associated with >3 cycles of chemotherapy (P = 0.000), radiation dose >40 Gy (P = 0.001), stereotactic radiosurgery (P = 0.000), and TKI medication (P = 0.000), while local treatment that began within 1 week after the diagnosis of brain metastases was associated with poorer survival (P = 0.015).ConclusionsFor patients with NSCLC brain metastases, regardless of the presence of clinical symptoms associated with brain metastases, systemic treatment before local may be better for survival. Even when used to relieve clinical symptoms, local treatment should be within a setting of sufficient systemic treatment.

Value of screening and follow-up brain MRI scans in patients with metastatic melanoma.

BackgroundNovel treatments make long‐term survival possible for subsets of patients with melanoma brain metastases. Brain magnetic resonance imaging (MRI) may aid in early detection of brain metastases and inform treatment decisions. This study aimed to determine the impact of screening MRI scans in patients with metastatic melanoma and follow‐up MRI scans in patients with melanoma brain metastases.MethodsThis retrospective cohort study included patients diagnosed with metastatic melanoma or melanoma brain metastases between June 2015 and January 2018. The impact of screening MRI scans was evaluated in the first 2 years after metastatic melanoma diagnosis. The impact of follow‐up MRI scans was examined in the first year after brain metastases diagnosis. The number of MRI scans, scan indications, scan outcomes, and changes in treatment strategy were analyzed.ResultsIn total, 116 patients had no brain metastases at the time of the metastatic melanoma diagnosis. Twenty‐eight of these patients (24%) were subsequently diagnosed with brain metastases. Screening MRI scans detected the brain metastases in 11/28 patients (39%), of which 8 were asymptomatic at diagnosis. In the 96 patients with melanoma brain metastases, treatment strategy changed after 75/168 follow‐up MRI scans (45%). In patients treated with immune checkpoint inhibitors, the number of treatment changes after follow‐up MRI scans was lower when patients had been treated longer.Conclusion(s)Screening MRI scans aid in early detection of melanoma brain metastases, and follow‐up MRI scans inform treatment strategy. In patients with brain metastases responding to immune checkpoint inhibitors, treatment changes were less frequently observed after follow‐up MRI scans. These results can inform the development of brain imaging protocols for patients with immune checkpoint inhibitor sensitive tumors.

Modern Radiation Therapy for the Management of Brain Metastases From Non-Small Cell Lung Cancer: Current Approaches and Future Directions.

Brain metastases (BMs) represent the most frequent event during the course of Non-Small Cell Lung Cancer (NSCLC) disease. Recent advancements in the diagnostic and therapeutic procedures result in increased incidence and earlier diagnosis of BMs, with an emerging need to optimize the prognosis of these patients through the adoption of tailored treatment solutions. Nowadays a personalized and multidisciplinary approach should rely on several clinical and molecular factors like patient’s performance status, extent and location of brain involvement, extracranial disease control and the presence of any “druggable” molecular target. Radiation therapy (RT), in all its focal (radiosurgery and fractionated stereotactic radiotherapy) or extended (whole brain radiotherapy) declinations, is a cornerstone of BMs management, either alone or combined with surgery and systemic therapies. Our review aims to provide an overview of the many modern RT solutions available for the treatment of BMs from NSCLC in the different clinical scenarios (single lesion, oligo and poly-metastasis, leptomeningeal carcinomatosis). This includes a detailed review of the current standard of care in each setting, with a presentation of the literature data and of the possible technical solutions to offer a “state-of-art” treatment to these patients. In addition to the validated treatment options, we will also discuss the future perspectives on emerging RT technical strategies (e.g., hippocampal avoidance whole brain RT, simultaneous integrated boost, radiosurgery for multiple lesions), and present the innovative and promising findings regarding the combination of novel targeted agents such as tyrosine kinase inhibitors and immune checkpoint inhibitors with brain irradiation.

Characterization of Treatments and Disease Course for Women with Breast Cancer Brain Metastases: 5-Year Retrospective Single Institution Experience.

PurposeAround 30% of patients with breast cancer will develop brain metastases (BM). We sought to characterize the disease course, treatments and outcome for our patient cohort.Materials and MethodsWe extracted clinicopathological data from electronic records from January 2015 to December 2020. Results were generated using SPSS statistics v27.ResultsWe identified 98 patients. Median overall survival (OS) from BM diagnosis was 3 months [hormone receptor (HR)+/human epidermal growth factor receptor 2 (HER2)–], 8 months [HR+/HER2+], 7 months [HR–/HER2+] and 2 months [triple negative breast cancer (TNBC)]. Whole brain radiotherapy (WBRT) (n=48, 70%) was most frequently used followed by surgery (n=15, 22%) and stereotactic radiosurgery (n=6, 8%). In patients who received WBRT alone (n=40) the median OS post WBRT was 2.6 months.ConclusionAfter BM development, half of the patients had systemic therapy and 70% had local therapy, but only the HER2 subgroup had a prolonged OS likely reflecting central nervous system (CNS) activity of anti-HER2 drugs. TNBC patients had the worst prognosis. Although our cohort is small, OS was >1 year for 60% of HER2+ patients who received trastuzumab emtansine after BM development, which is encouraging for antibody drug conjugates and CNS activity. Patients who received WBRT had a higher burden of CNS disease and had an OS of less than 3 months.

The Role of the Immune Response in Brain Metastases: Novel Imaging Biomarkers for Immunotherapy.

Brain metastases are a major clinical problem, and immunotherapy offers a novel treatment paradigm with the potential to synergize with existing focal therapies like surgery and radiosurgery or even replace them in future. The brain is a unique microenvironment structurally and immunologically. The immune response is likely to be crucial to the adaptation of systemic immune modulating agents against this disease. Imaging is frequently employed in the clinical diagnosis and management of brain metastasis, so it is logical that brain imaging techniques are investigated as a source of biomarkers of the immune response in these tumors. Current imaging techniques in clinical use include structural MRI (post-contrast T1W sequences, T2, and FLAIR), physiological sequences (perfusion- and diffusion-weighted imaging), and molecular imaging (MR spectroscopy and PET). These are reviewed for their application to predicting and measuring the response to immunotherapy in brain metastases.

Outcomes of Patients With HER2-Positive Breast Cancer Metastatic to Brain Treated With HER2-Targeted Systemic Therapy and Stereotactic Radiosurgery

For patients with HER2-positive breast cancer metastatic to brain, HER2-directed systemic therapies are increasingly used with stereotactic radiosurgery (SRS), with a goal to avoid or delay whole brain radiotherapy. These include monoclonal antibodies such as trastuzumab (Herceptin, H) and pertuzumab (Perjeta, P), antibody-drug conjugates such as ado-trastuzumab emtansine (T-DM1), and tyrosine kinase inhibitors such as lapatinib. Limited data exist regarding appropriate timing with SRS and outcomes of this treatment regimen for HER2-positive breast cancer metastatic to the brain.A single-institution retrospective review was performed to identify and collect clinical data on patients with biopsy-proven breast cancer metastatic to the brain who were treated with SRS. Outcomes analyses were performed using the Kaplan-Meier method, and the chi-square statistic was used to compare different treatment groups.Of 82 patients with breast cancer metastatic to the brain treated with SRS from 2009-2020, 33 (40%) had positive HER2 status, 18 of whom had hormone receptor positivity. At brain metastasis diagnosis, 15 patients (45%) had > 1 intracranial metastasis (range 2-7), and the median maximal brain metastasis dimension was 2.0 cm. Fifteen patients had uncontrolled extracranial disease. After brain metastasis diagnosis, 9 patients (27%) were treated with systemic therapy first (3 with T-DM1, 1 with T-DM1+HP, 1 with lapatinib+HP, 3 with chemotherapy+HP, 1 with chemotherapy) with a median of 18.6 months between the start of systemic therapy and SRS. Seven patients (21%) were treated with SRS first, followed by systemic therapy in 6 of these patients (these were multi-agent regimens with 4 including T-DM1 or lapatinib). Seventeen (52%) received concurrent systemic therapy and SRS upfront (3 with T-DM1, 2 with T-DM1+chemotherapy, 2 with lapatinib, 4 with HP, 5 with hormone therapy, 1 with chemotherapy). Median follow-up time was 21.1 months. Median overall survival was 24.8 months and not statistically different between treatment groups (table). Four patients (12%) developed symptomatic radionecrosis; 3 were on T-DM1 concurrent with SRS (of a total of 10 patients treated with this combination whether upfront or following initial systemic therapy).In this small patient sample, we noted favorable survival outcomes for patients with HER2-positive breast cancer metastatic to the brain when treated with HER2-targeted therapies together with SRS. The sequence of systemic therapy and SRS does not appear to impact survival outcomes. Concurrent treatment with T-DM1 and SRS may be associated with higher rates of radionecrosis.

Predictors of Long-Term Survival Among Patients With Brain Metastases

The prognosis for patients with brain metastases (BrM) remains guarded, with population-based data indicating a median survival of 3-12 months. However, a subset of patients with BrM display prolonged survival. We sought to characterize the likelihood and predictors associated with survival ≥ 5 years after BrM diagnosis.We identified 1,370 patients diagnosed with BrM at a tertiary cancer center between 2008 and 2015 who either died or survived ≥ 5 years. Patients censored before 5 years were excluded from the analysis (N = 66). Multivariable logistic regression was used to characterize predictors of long-term (i.e., ≥ 5 years) survival after BrM diagnosis (odds ratios > 1 indicated a greater odds of long-term survival). Median survival for subgroups was calculated with the Kaplan-Meier method; comparisons were made with the log-rank test.Among all 1,304 patients, median survival after BrM diagnosis was 10.8 months. In total, 123 patients (9.4%) survived ≥ 5 years. On multivariable logistic regression, significant predictors of survival ≥ 5 years included: breast as the primary tumor site vs. the reference of non-small cell lung cancer (NSCLC) (OR: 2.44 [95% CI, 1.23-4.83], P = 0.01), high Karnofsky performance score (KPS) (90-100) vs. low KPS (< 90) (OR: 2.32 [95% CI, 1.48-3.62], P < 0.001), and lack of progressive extracranial disease at time of BrM diagnosis (OR: 2.33 [95% CI, 1.47-3.70], P < 0.001). Factors significantly associated with not surviving ≥ 5 years included: receipt of whole brain radiation therapy vs. the reference of SRT as initial management (OR: 0.30 [95% CI, 0.13-0.70], P = 0.005), presence of 2-4 BrM vs. 1 BrM (OR: 0.63 [95% CI, 0.40-1.00], P = 0.05), an increasing number of extracranial sites of disease (OR: 0.73 per additional site [95% CI, 0.59-0.90], P = 0.003), and an increasing number of systemic therapy regimens for metastatic disease prior to diagnosis of BrM (OR: 0.64 per additional regimen [95% CI, 0.50-0.84], P = 0.001). When limiting to patients with NSCLC for whom EGFR and ALK status were known, there were significant differences in survival among patients with an ALK rearrangement, EGFR mutation, or neither (median survival of 30.9, 15.0, and 12.7 months, respectively, P = 0.04). Subsetting patients with breast cancer based on receptor subtype, there were significant differences in survival among patients with HER2-positive, hormone receptor-positive/HER2-negative, or triple-negative breast cancer (median survival of 26.0, 11.2, and 6.5 months, respectively, P < 0.001).Although patients with BrM generally have a poor prognosis, select patients live for ≥ 5 years. Multidisciplinary teams caring for favorable sub-populations should consider the long-term impact of oncologic therapy when formulating treatment recommendations.N. Lamba: None. D.N. Cagney: Research Grant; NhTheraguix, Viewray. P.J. Catalano: None. P. Wen: None. D. Haas-Kogan: Research Grant; Novartis; Cellworks. A.A. Aizer: Research Grant; Varian. Consultant; Novartis. Advisory Board; Seattle Genetics.

Circadian Factors Impact Survival From Brain Metastases for Patients Treated With Whole Brain Radiation

There are established links between circadian clock dysregulation, and cancer risk. Numerous reports of increased risk for breast cancer in night shift workers led the World Health Organization to classify circadian disruption as a probable carcinogen. Additionally, the circadian clock has been known to influence the body's response to medications and most recently, a handful of studies demonstrate a link between radiation toxicity and time of day the patient received radiation. Prior studies investigating the temporal association of radiotherapy outcomes have yielded overall conflicting data and contemporary evaluations of this effect are sparse. To determine if chronotherapy should be considered to modulate radiation outcomes, we sought to evaluate if the time of day when radiation treatment was delivered affected outcomes for patients with brain metastases.Retrospective data was collected for all consecutive patients between 2010 and 2020 with a diagnosis of brain metastases who were treated with whole brain radiotherapy. Patients were eligible to be included if ≥80% of their total dose was delivered either before or after 12:00 noon as documented by treatment times in the electronic medical record and if outcome data was available. Data on sex, age, performance status, control of primary disease, extracranial metastases, radiation dose, race, BMI, and zip code were collected. Radiation was delivered as whole-brain radiation to a median dose of 3000 cGY. Analysis of survival was performed using Mantel-Haenszel hazard ratio and log-rank test to compare Kaplan-Meier curves between groups.Complete data were available for 84 patients. The majority of patients had a primary diagnosis of breast or lung cancer (93%) and a small minority had a melanoma, thyroid, or unknown primary. 43 (51%) patients were excluded who did not receive ≥80% of their cumulative radiation either before or after noon, leaving n = 41 patients included for analysis. Demographic data were comparable between groups and overall: 56% female, 44% male; 56% ≥65 years, 44% younger. Distributions for BMI, extracranial metastasis, control of primary disease, and performance status were also similar between groups. Results showed a strong trend toward improved survival in the group that received ≥80% treatment in the afternoon (P = 0.057, HR 0.28-1.02).Treatment time of day impacted survival from brain metastases in our patient population treated with whole brain radiation. Potential explanations for these results include the influence of multiple circadian pathways on tissue and tumor sensitivity through melatonin signaling and other mechanisms, warranting further exploration. Future investigations into entraining circadian rhythms via time of day treatments, light therapy or pharmaceutical interventions to alter radiation outcomes and toxicity should be considered.