Comprising the majority of central nervous system (CNS) malignancies, CNS metastases from systemic cancers are a common and devastating complication in adult cancer patients. Up to 19% of cancer patients develop complications from brain metastases (BM), and at autopsy over 25% are found to have metastases to the CNS (1,2). Most metastatic disease affects the brain parenchyma with 80% of BM found supratentorially and 20% infratentorially (15% in the cerebellum and 5% in the brainstem), with the spinal cord most infrequently involved (3,4). In about 4-15% of patients with CNS disease, cerebrospinal fluid and leptomeninges are involved with devastating sequelae (3,4).
Common cancers to metastasize to the CNS include, lung (40-50%) and breast cancer (15-30%), followed by melanoma (5-20%), renal cell cancer (2-4%), colorectal cancer (3-8%), and less frequently, ovarian cancer (1%) (5,6). Cancers that metastasize the brain need to undergo multiple steps, including invasion, intravasation into the blood stream, extravasion, survival and proliferation (5). Although an area of active investigation, it is hypothesized that invasion and proliferation into the CNS may be associated with specific molecular programs that may be common in BM (7,8) and likely dependent upon tumor microenvironment (9).
A diagnosis of brain metastasis carries with it a dismal prognosis, especially in cases of poor performance status (Karnofsky performance score, KPS <70) where median overall survival (OS) is 2.3 months (10,11). For younger patients (age <65) with good performance status (KPS >70) OS is about 7.1 months. To date, treatment regimens have included neurosurgical resection of a single lesion when possible or when tissue diagnosis is required, stereotactic radiosurgery (SRS) in oligometastatic disease, as well as whole brain radiotherapy (WBRT) for oligometastatic or widespread disease (12,13). While WBRT has been the standard treatment of metastatic disease to the CNS for several decades, neurotoxicity occurs in up to 45% of patients and negatively impacts quality of life (14), highlighting the need for alternative therapies. A substantial obstacle in chemotherapeutic approaches is the difficulty in achieving therapeutic doses in the CNS due to limited BBB penetration (15). With the genomic revolution leading to targeted systemic therapies, targeted agents are assuming an increasingly central role in treatment of brain metastasis with early success in oncogene-addicted cancers such as EGFR or ALK positive non-small cell lung cancer (NSCLC), BRAFV600E expressing melanoma, and HER2/Neu expressing breast cancer (3,4). Because craniotomies are indicated in only a subset of patients, exploring the genomic differences between BM and matched primary tumors has been challenging. This review focuses on advances made in the understanding of the genetics of BM and their primary tumors and how these advances may change the role for systemic therapies in this common complication of cancer.
Brain metastases (BM) from melanoma
While the cumulative incidence of brain metastasis in melanoma patients is less than 10% (16,17), patients with advanced melanoma have a particularly high incidence of BM with brain involvement in 45-50% of patients, rising to 75% at autopsy (18-20). Upon detection of BM, median survival has historically been approximately 4 months (21). Conventional treatment strategies, including surgical removal when possible and radiotherapy (either SRS or WBRT), have been disappointing in disease control since melanoma is not radiosensitive (20,22). Approximately 1-5% of melanoma patients present with leptomeningeal disease, which is associated with an especially dismal prognosis (23). Conventional chemotherapy (including temozolomide, thalidomide, and sorafenib) has also proved disappointing with an objective response rate of 3-5% for temozolomide monotherapy (24,25), increased to 9-44% when combined with WBRT (26,27). Targeted therapies and immunotherapies have revolutionized the management of advanced melanoma, including BM.
Approximately 50% of metastatic melanomas have BRAF mutations, the majority of which are the V600E mutation resulting in constitutive activation. The mutation prevalence of BRAF is similar between CNS metastases and extracranial sites (3,28). Vemurafenib, a small-molecule inhibitor of the serine-threonine kinase activity of BRAF and its downstream MAP-kinase pathway activation, was FDA-approved for the treatment of BRAFV600E positive metastatic melanoma in 2011 (21). The seminal trial (29) that leaded to FDA approval of vemurafenib unfortunately excluded patients with active BM. In a pilot study of 24 patients with melanoma metastatic to the CNS treated with vemurafenib, median PFS was 3.9 months, and median OS was 5.3 with an overall PR at both intracranial and extracranial sites achieved in 42% of patients and SD in 38% patients (30). Resistance to therapy with BRAF kinase inhibitors is associated with reactivation of the mitogen-activated protein kinase (MAPK) pathway. Combining BRAF and MEK inhibitor has resulted in increased efficacy compared to BRAF monotherapy (31). The BRAF inhibitor, dabrafenib, in combination with the MEK inhibitor, trametinib, was FDA approved in 2014 for advanced melanoma. Dabrafenib has promising activity in the brain as demonstrated by a Phase 2 trial in patients with BRAFV600E/V600K BM (32).
Immunotherapy in melanoma
Ipilimumab was FDA approved for treatment of metastatic melanoma in 2011 (21). Ipilimumab is a humanized monoclonal antibody blocking the function of the cytotoxic T-lymphocyte antigen 4 (CTLA-4) receptor on T cells, allowing for increased and sustained T cell activation, thus counteracting immune evasion by the tumor (33). In a phase III trial which included patients with treated and radiographically stable melanoma BM, patients treated with ipilimumab had a median survival of 11.2 months compared to 9.8 months for the control arm and 20.8% of patients were alive at three years compared to 12.2% in the control arm, showing capacity for a durable effect (34,35). Promising results were demonstrated in a phase II trial in patients with BM receiving ipilimumab; intracranial disease control was achieved in 18% of patients with asymptomatic BM (36). Whole exome sequencing of tumor tissue from patients with melanoma and treated with anti-CTLA-4 blockade demonstrated a specific neo-antigen landscape in tumors that responded to therapy (37). Whether this same signature correlates with response in BM will need to be evaluated.
Another immunotherapy-based strategy is to target programmed cell death-1 (PD-1), an inhibitory signal to activated T cells that is engaged by the programmed cell death ligand-1 (PDL-1) expressed on tumor cells (38). The PD-1 inhibitors nivolumab and pembrolizumab have demonstrated remarkable efficacy in advanced melanoma (38-40). Notably, melanoma BM frequently express PD-1 and PDL-1 (41) and clinical trials evaluating the efficacy of pembrolizumab in CNS metastases are underway (NCT02085070).
Likely secondary to ultraviolet light mutagenesis, melanoma has a significantly higher mutation rate compared to other cancers (42). Mutations in CDKN2A/p16INK4a appear to be initiators in oncogenesis (43), mutated in 10-25% of sporadic melanomas (43). Accumulation of other somatic mutations in melanoma oncogenesis may provide future targets for therapies and include amplifications in MYC, loss of PTEN, and mutations in STK19, ARID2, APAF-1, PKB/AKT, N-RAS, GRM-3, CHRM3, and GPR98 (42). The role of these alterations in melanoma progression needs to be explored. BM from melanoma are genomically complex and large scale sequencing studies exploring these differences are being performed (44). Molecular profiling of 16 matched CNS and extracranial metastases showed that CNS metastases distinguished themselves through specific molecular differences in the activation of the PI3K/mTOR/Akt pathway through mechanisms that are under further investigation (45). Preclinical mouse studies demonstrated that treatment of mice harboring intracranial human melanoma with the PI3K inhibitor BKM120 improved OS (45). These findings have been repeated in several melanoma xenografts as well as genetically engineered mouse models (46). These studies highlight the potential of adding PI3K inhibitors as adjunct targeted therapy in the treatment of CNS melanoma metastases.
NSCLC is the most common lung cancer (>85% of all lung cancers) and has a propensity for CNS spread (47). BM will develop in up to 40% of patients and indicate a poor prognosis. Survival ranges from 2 months if treated symptomatically with glucocorticoids to 14 months if treated with SRS, WBRT, and/or neurosurgical resection (48,49). Systemic therapy has fallen short to date, with platinum-based therapy showing response rates of 28-45% in the up-front treatment of NSCLC metastatic to the CNS (50-54). Temozolomide, an alkylating agent with BBB penetration, which has activity in primary brain tumors (55), demonstrates only modest effects in NSCLC BM (56,57). The antifolate, pemetrexed, has promising activity as combination therapy with cisplatin (58) and as monotherapy (59).
With the discovery of targetable genetic alterations in the treatment of NSCLC, patients are now stratified based on genetic alterations in the primary tumor including the epidermal growth factor receptor (EGFR), Kirsten rat sarcoma viral oncogene homolog (KRAS), and translocations involving the echinoderm microtubule-associated protein like 4 (EML4)-anaplastic lymphoma kinase (ALK) genes (60). In a retrospective study of 89 patients with NSCLC treated with SRS for BM, addition of targeted therapies was associated with significantly better outcomes. Patients treated with targeted therapy (against EGFR or ALK) had a median survival of 21 months compared with 11 months for patients who did not receive targeted therapy (60).
Approximately 10% of patients with NSCLC harbor activating mutations in EGFR with higher rates found in East Asians, non—or light former smokers, women, and in adenocarcinomas (61,62). Mutations in EGFR predict sensitivity to the small molecule tyrosine kinase inhibitors (TKI) gefitinib and erlotinib (3,4). When EGFR mutation rates were compared in matched tumor and metastases, discordance rates were reported in up to a third of cases (63-65); specifically, the rate of discordance was 27% in BM compared to their primary tumors (63).
Erlotinib shows promise for treatment of BM in patients with NSCLC. In a study of 69 NSCLC patients with BM, 17 harbored the EGFR mutation and were predictive of benefit from EGFR-targeted therapy in systemic metastatic disease. Of this subgroup, 82.4% had a response to therapy and time to progression in the brain was 11.7 months compared to 5.8 months in patients without an activating mutation (66). In a study of erlotinib with WBRT in a cohort of newly diagnosed NSCLC patients, 50% of whom harbored an EGFR mutation, response rates were 86% (67). In a randomized study comparing WBRT vs. WBRT with erlotinib in unselected patients with newly diagnosed brain metastasis, only 3% of which harbored EGFR mutations, there was no improvement in survival in the erlotinib arm (68).
In addition to the success seen with erlotinib treatment, gefitinib has demonstrated promise in the management of BM from NSCLC. In heavily-pretreated unselected patients with recurrent BM, gefitinib showed a response rate of 10% (69), and in a selected population of non-smokers of Asian origin, a response rate of 32% (70). When combined with WBRT, gefitinib showed an 81% response rate in a prospective study of Asian patients with newly diagnosed metastatic NSCLC (71). Given the limited response in studies of unselected patient groups, treatment with EGFR-targeted therapy should be reserved for patients harboring actionable mutations in EGFR (72).
The EML4-ALK translocation results in a cytoplasmic protein with constitutively active kinase activity (73) and is found in 2-7% of all NSCLC with a higher prevalence in light or never smokers, younger patients, and adenocarcinomas (74). EML4-ALK translocation predicts sensitivity to the small molecule TKI, crizotinib, and responses have been seen in patients with EML4-ALK translocation with lung cancer BM (75,76). ALK translocations were reported to be 100% concordant between primary tumor and BM. ALK amplifications, however, are more frequently found in BM compared to primary tumors with a discordance rate of 12.5% in matched primary tumor and brain metastasis studies (77). Progression of BM in patients with ALK translocations receiving crizotinib have been reported (78), and a highly selective and potent ALK inhibitor with strong CNS efficacy, alectinib, is showing promising results in crizotinib-resistant NSCLC metastases (79,80). In a study of 47 patients who progressed on or were intolerant to crizotinib, alectinib was well tolerated: objective responses rates were 55% with 2% complete response (CR), 52% partial response (PR), and 36% stable disease (SD) (80). Of the 21 patients with baseline BM, intracranial responses were found in 52%, with 29% showing CR, making alectinib an attractive salvage therapy in the setting of crizotinib failure (80). NCT02075840 is a phase III trial comparing crizotinib and alectinib in treatment-naïve patients (72).
Other candidate targets in systemic treatment of NSCLC BM
With immunomodulatory agents showing durable responses in advanced NSCLC (81), trials are underway to explore the role of these therapies in NSCLC BM (NCT02085070). Comprehensive genetic assays have also uncovered many additional candidate genes that are now crystallizing as potential future predictive biomarkers or therapeutic targets in NSCLC (65,82,83). Sequencing of squamous cell carcinomas demonstrated that PI3K pathway alterations are associated with more aggressive disease and with the development of BM (84). The v-Ros avian UR2 sarcoma virus oncogene homolog 1 (ROS1) harbors mutations in 1.3% in NSCLC BM and predicts response to crizotinib (85), providing a further target for systemic therapy. Mutations in BRAF have been reported in ~3% of NSCLC and 0.3% of NSCLC BM (28,86). Additionally, LKB1 copy number alterations combined with KRAS mutations indeed are predictive of brain metastasis in NSCLC (87). Gene expression analysis suggests the importance of the WNT/TCF pathway in the formation of brain and bone metastases; knockdown of the two WNT genes, HOXB9 and LEF1, decreased brain metastasis formation in mice (88). Overexpression of Oct4, a stemness gene encoding a transcription factor, may correlate with poor disease-free survival and metastasis (89). Approximately 45% of NSCLC BM show overexpression of C-MET that encodes the hepatocyte growth factor receptor (HGFR) with gene amplification found in 21.6% of NSCLC (83). With multiple c-Met inhibitors under development, this is a further attractive target for therapy. Finally, the relatively high rate of FGFR1 amplifications, reported in 19% of BM from squamous cell lung carcinoma and 15% of BM from adenocarcinomas, makes FGFR1 inhibitors a promising target for drug development (82). While many of these multiple potential targets may not always be expressed in a high proportion of lung cancer BM, the potentially potent response in individual patients harboring actionable mutations in either the primary tumors or the BM highlights the need for sequencing of lung cancer BM and adoption of personalized treatment for patients.
Ten to thirty percent of breast cancer patients develop BM, with younger age and the presence of lung metastases as risk factors for CNS spread (90,91). Breast cancer is a histologically and genetically heterogeneous disease, classified by expression of the estrogen (ER) and progesterone receptor (PR) and the human epidermal growth factor receptor 2 (HER2/neu).
HER2-amplifed tumors have a high rate of spread to the CNS (92). Similarly, triple negative breast cancer has a propensity for CNS spread and up to 46% of patients with advanced triple negative disease develop BM (4). Cytotoxic therapies in breast cancer BM have been employed with some success. Phase II trials of methotrexate or cyclophosphamide containing regimens show response rates of 17-59% (93,94), cisplatin combined with etoposide show responses of 38-55% (52,95), and topotecan (96) and capecitabine (97,98) have activity in small studies and case reports.
Steroid hormone receptors
About 60% of breast cancers are ER and/or PR positive and respond to endocrine treatment (99). Modulation of steroid hormone receptors is one of the earliest targeted therapies used in CNS metastases (100). Tamoxifen, a selective estrogen receptor modulator, harbors activity in the CNS (100). Case reports have also described activity of letrozole in the CNS (101,102). Loss of hormone receptor expression occurs in up to 50% of BM in a retrospective series of matched primary and BM pairs (103). Heterogeneous expression of ER/PR in patients with multiple BM may lead to mixed responses to hormone treatment (3).
HER2-positive breast cancer has a higher risk of CNS spread and up to 30% of patients with HER2-positive breast cancer will develop BM (4,92,104,105) with up to 50% of these patients succumbing to CNS disease (106). Protein overexpression or gene amplification of HER2 is found in ~15% of breast cancer and strong HER2 overexpression (3+ by IHC) predicts response to HER2-targeted agents such as trastuzumab, lapatinib and T-DM1 (3,107,108). HER2 discordance between primary tumors and metastases is associated with decreased OS and occurs in up to 24% of cases (109,110), with up to 14% of BM patients showing a change in HER2 status (111). Lapatinib, a small molecule TKI of HER2 and HER1 is FDA approved in combination with capecitabine for the treatment of trastuzumab-resistant metastatic HER2 positive breast cancer (4). While lapatinib monotherapy showed a CNS response rate of only 6% (112), combination with capecitabine increased response rate to 65% in newly diagnosed HER2 positive BM (113) and 20% in patients pre-treated with WBRT or SRS (112). T-DM1 is an antibody-cytotoxic drug conjugate of trastuzumab and emtansine (4). Case reports showing shrinkage of HER2-positive BM (114,115) have led to a phase 1 clinical trial of T-DM1 in combination with WBRT (NCT02135159) for treatment of HER2-positive BM. Leptomeningeal carcinomatosis occurs in 2-5% of HER2-positive breast cancer patients with a high concordance rate of HER2 expression in CSF tumor cells and primary tumors (3,116). Trials are underway to investigate the use of intrathecal trastuzumab in this setting (NCT01325207).
Triple-negative breast cancer poses a special treatment challenge, lacking actionable targets to date. Because patients with triple negative disease have a high extracranial metastatic burden, they typically succumb from systemic disease (117). Since BM are common in these patients and median OS is a dismal 5 months (117,118), targetable genetic alterations in triple-negative breast cancer is an active area of investigation (44). Recent genomic profiling studies have focused on identifying metastases specific pathway alterations (119,120) with advances made in stratifying triple-negative breast cancer into four molecular subtypes, offering future therapeutic targets (121). Whole genome sequencing of metastatic triple-negative breast cancer found recurrent mutations in TP53, LRP1B, HERC1, CDH5, RB1, and NF1; while RNA sequencing resulted in the finding of consistent overexpression of the FOXM1 gene (122). Moreover, 20% of triple-negative breast cancers show expression of PDL-1 (123), resulting in checkpoint-blockade immunotherapy as an attractive option for patients with triple-negative BM (3). Methylome sequencing in triple-negative breast cancer showed distinct methylation profiles which correlate with prognosis (124). Characterization of methylation patterns may help identify additional predictive biomarkers in the future.
Angiogenesis plays a key role in brain metastasis formation and in mouse models of breast cancer BM, increased VEGF expression contributed to BM formation (125). Bevacizumab is an antiangiogenic humanized monoclonal antibody targeting the vascular endothelial growth factor A that is being investigated for the treatment of breast cancer BM (126,127). Newer targets are also emerging as genomics are broadly applied to primary and metastatic breast cancers. Large-scale genomic characterization of primary breast tumors demonstrated that the only genes to occur at more than 10% incidence across all subtypes were TP53, PIK3CA, and GATA3 (128). Other genes recurrently mutated in breast cancers include AKT1, CDH1, MAP3K1, PTEN, CDH1, RB1 and CDKN1B. Notably, the PI3K-mamalian target of rapamycin (mTOR) pathway shows consistent activation in breast cancer BM (129,130) and clinical trials of small molecule inhibitors of the PI3K/mTOR pathway for treatment of breast cancer CNS metastases are underway (NCT01783756). Analysis of BRCA-1 and 2 mutations is an important avenue, as these tumors are particularly sensitive to PARP inhibitors such as olaparib (131), which penetrates the BBB (132), making this drug an attractive targeted therapy in the treatment of BRCA-1 and 2 mutated BM. Furthermore, gene expression and functional analyses in in vitro and in vivo models identified ST6GALNAC5, COX2 and HBEGF as potential mediators of CNS metastasis (133). The role of these genes as potential therapeutic targets needs to be explored.
Gastrointestinal (GI) malignancies
Morbidity and mortality resulting from advanced GI cancers are most commonly associated with systemic metastases, but clinically significant metastatic involvement of the CNS is seen in all types of GI cancers, with an estimated overall incidence of 3-8% (134). The reported frequency of diagnosed CNS metastases in GI cancers varies by primary site. In a large, retrospective analysis of CNS metastases in cancer patients, BM were detected in 1.8-3% of patients with colorectal carcinoma (CRC) (16,135). CNS disease is also found in association with esophageal cancer (82% of CNS metastases with adenocarcinoma histology), and the incidence of BM was greater in patients who had received systemic therapy (neoadjuvant 8.4%, adjuvant 7.0%, or both 18.4%) than in those treated with surgery only (2.5%) (136). BM appears to be a rare complication of gastric cancer in 0.16-0.69% of patients (137,138).
Presentation of CNS involvement in GI primary tumors tends to occur late, usually in the setting of extracranial systemic disease, and is associated with poor prognosis. Median survival for patients with CRC BM is approximately 6 months (139,140). In patients with esophageal cancer and CNS involvement, median survival is 3.8 months (141) with survival rates at 12 and 24 months of 14% and 3%, respectively (142). In a case series of gastric cancer patients with BM, it was estimated that in unresectable patients, median survival was less than two months, while patients who underwent resection survived an average of 5.4 months (143).
As with all BM, current treatment options include resection, SRS with or without subsequent WBRT, and WBRT alone. For patients with CRC BM, SRS provided local tumor control in 94% with a median OS of 9 months from CNS diagnosis and 5 months from the date of SRS in one case series (144). A number of chemotherapeutic agents have been used in CNS metastatic disease of GI origin, including capecitabine, topotecan, dacarbazine, and temozolomide, which were chosen for some degree of CNS penetration, relative tolerability, and activity in a variety of tumor types that commonly metastasize to the brain as well as primary CNS neoplasms. The most studied agent has been temozolomide, but temozolomide monotherapy showed no benefit in patients with CRC (56,145,146). Targeted therapy for GI BM has been disappointing to date, partly because commonly found mutations lack effective small molecule inhibitors.
Colorectal carcinoma (CRC)
Up to 50% of metastatic CRC show mutations in RAS which are associated with a shorter OS and a higher incidence of BM (147). Development of RAS inhibitors has been unsuccessful to date, and drugs targeting RAS processing (R115777/Zanestra, SCH66336/Sarasar, L778,123, BMS-214662) as well as RAS antisense nucleotides (ISIS 2503 and 5732) have been disappointing in clinical trials (148). Targeting MEK (Cl-1040/PD184352) and RAF (BAY43-9006), the immediate upstream effectors of RAF, has shown more promise, but trials in CNS metastatic disease are lacking (148). Notwithstanding, intense efforts at developing RAS inhibitors are underway and are targeting different enzymes required for post-translational RAS processing, inhibition of RAS localization to plasma membrane, and disruption of protein-protein interactions required for RAS signaling (148). BRAFV600E mutations, found in up to 10% of CRC and 5.5% of CRC BM, are associated with unfavorable prognosis and may influence the efficacy of EGFR inhibitors (3,28,149). In a phase I trial of dabrafenib for treatment of melanoma, untreated BM, and other solid tumors, apparent antitumor activity was noted in one case of CRC, making BRAF targeting a potentially useful tool in treatment of BRAF mutated CRC BM (149).
Mutations in the PI3K pathway were reported in 10-15% of patients with metastatic CRC (147,150). Approximately 10% of patients have alterations in both the RAS/RAF and PI3K pathway. Whether PI3K pathway alterations are independently correlative with prognosis and pattern of metastatic spread (specifically to the CNS) is still an active area of investigation (147,150). While genomic characterization between matched primary and liver metastasis identified shared mutations in APC, KRAS, ARID1A, as well as PIK3CA (151), the relationship between primary CRC and BM is currently unknown.
Up to 15% of gastroesophageal adenocarcinomas harbor HER2 overexpression or amplification (3,152). HER2 overexpression is also found in ~14% of gastroesophageal CNS metastases (153). Discordant HER2 overexpression between primary tumors and matched metastases may be an independent predictor of poor OS (154). HER2 overexpression and amplification predicts response to anti-HER2 therapy in gastroesophageal cancer. In a randomized, multicenter phase III trial of 594 patients with advanced HER2 positive gastric or gastroesophageal cancer were randomized to receive trastuzumab with chemotherapy or chemotherapy alone; the addition of trastuzumab increased median OS to 13.8 versus 11.1 months with chemotherapy alone (152). However, this trial excluded patients with BM. Given the poor prognosis of gastroesophageal cancer in the CNS, anti-HER2 therapy, particularly agents that have blood brain barrier penetration, should be considered for selected patients.
Exome and genome sequencing of primary esophageal adenocarcinoma identified recurrent mutations in TP53, CDKN2A, SMAD4, ARID1A, PIK3CA, ELMO1, TLR4, and DOCK2, many of which are potential therapeutic targets (155). Further work is needed to characterize driver mutations between primary site and BM in gastroesophageal cancers.
Renal cell carcinoma (RCC)
Two to four percent of BM derive from RCC and pose an interesting scientific challenge, since they respond to a variety of targeted therapies, but reliable biomarkers for response have not been identified to date, possibly due to the heterogeneity of RCC, which consists of several subtypes (3,156). Comprehensive sequencing studies in primary RCC have demonstrated the importance of the PI3K/AKT/mTOR pathway in the development of renal cell cancer (157,158). A study exploring genetic differences in four patients with renal cell primaries and matched extracranial metastases using whole exome sequencing, chromosome aberration analysis and ploidy profiling demonstrated significant intratumoral heterogeneity, particularly within the primary tumor (159). This heterogeneity likely accounts for differential therapeutic responses observed in the clinic. Current clinical practice employs a gamut of targeted agents and immunotherapies ranging from TKIs (sunitinib, sorafenib), immune modulators (IL-2, IFN-alpha) (160), bevacizumab, as well as immune checkpoint inhibitors including PD-1 inhibitors (3,161). Indeed, targeted therapies in RCC brain metastasis management have not been associated with an increase in neurologic adverse events (162). Notwithstanding relative efficacy of various therapies, resistance occurs especially to TKIs and active efforts to identify predictive molecular markers for targeted therapy are essential (156).
Ovarian carcinoma is the most common gynecologic malignancy with a rare predilection to develop BM (1.19%) (6). While there is a documented association between BM incidence from primary ovarian carcinoma and loss of BRCA1 function, little is known of the genomic makeup of these CNS metastases (163). Subtype stratification of ovarian carcinoma BM is currently limited to histology, namely between high-grade serous carcinoma, clear cell carcinoma, carcinosarcoma, and high-grade adenocarcinoma (164). Comprehensive genomic analyses of primary ovarian carcinomas revealed TP53 mutations in 96% of the high-grade serous subtype (165). Additional recurrent somatic mutations across all subtypes included NF1, BRCA1, BRCA2, RB1, and CDK12. Furthermore, changes in NOTCH and FOXM1 signaling are indeed important in serous ovarian cancers. Beyond these now characterized genomic aberrations in the primary tumor, too little is currently known about the genomics of systemic and CNS metastases from ovarian carcinoma to offer a potential pathway for targeted therapeutics in this disease.
Given the increasingly prominent role that molecular genetics and targeted therapy are playing in metastatic CNS disease treatment, there is a rising need for reliable and affordable genetic testing as well as for biomarkers of treatment effect in an era when our understanding of the molecular heterogeneity of cancer and its interaction with the local microenvironment is changing dramatically. With the increase of effective small molecule inhibitors, paralleled by the increase in known actionable genetic alterations, high-throughput whole genome sequencing, copy number assessment, and genome-wide methylation screens are increasingly incorporated into clinical practice and are vastly expanding the clinical trial landscape for CNS metastatic disease. The genetic signature of CNS and systemic metastases can differ, however, from the primary tumor and may be shaped by the microenvironment and changes in clone-specific gene expression. For both breast and melanoma CNS metastatic disease, the PI3K/AKT/mTOR pathway is activated compared to primary tumors, revealing targetable mutations that may be induced by the CNS microenvironment (112,114,115,118,130). Further studies are now honing in on common mutations. An expanded repertoire of targeted therapies for CNS BM combined with rapidly improving high throughput genomic analysis point to a future of personalized medicine in CNS metastases.
Disclosure: The authors declare no conflict of interest.
- Fox BD, Cheung VJ, Patel AJ, et al. Epidemiology of metastatic brain tumors. Neurosurg Clin N Am 2011;22:1-6. [PubMed]
- Nayak L, Lee EQ, Wen PY. Epidemiology of brain metastases. Curr Oncol Rep 2012;14:48-54. [PubMed]
- Berghoff AS, Bartsch R, Wohrer A, et al. Predictive molecular markers in metastases to the central nervous system: recent advances and future avenues. Acta Neuropathol 2014;128:879-91. [PubMed]
- Brastianos HC, Cahill DP, Brastianos PK. Systemic therapy of brain metastases. Curr Neurol Neurosci Rep 2015;15:518. [PubMed]
- Eichler AF, Chung E, Kodack DP, et al. The biology of brain metastases-translation to new therapies. Nat Rev Clin Oncol 2011;8:344-56. [PubMed]
- Piura E, Piura B. Brain metastases from ovarian carcinoma. ISRN Oncol 2011;2011:527453.
- Ba JL, Jandial R, Nesbit A, et al. Current and emerging treatments for brain metastases. Oncology (Williston Park) 2015;29:250-7. [PubMed]
- Gandaglia G, Abdollah F, Schiffmann J, et al. Distribution of metastatic sites in patients with prostate cancer: A population-based analysis. Prostate 2014;74:210-6. [PubMed]
- Sevenich L, Bowman RL, Mason SD, et al. Analysis of tumour- and stroma-supplied proteolytic networks reveals a brain-metastasis-promoting role for cathepsin S. Nat Cell Biol 2014;16:876-88. [PubMed]
- Gaspar L, Scott C, Rotman M, et al. Recursive partitioning analysis (RPA) of prognostic factors in three Radiation Therapy Oncology Group (RTOG) brain metastases trials. Int J Radiat Oncol Biol Phys 1997;37:745-51. [PubMed]
- Sperduto PW, Berkey B, Gaspar LE, et al. A new prognostic index and comparison to three other indices for patients with brain metastases: an analysis of 1,960 patients in the RTOG database. Int J Radiat Oncol Biol Phys 2008;70:510-4. [PubMed]
- Kalkanis SN, Linskey ME. Evidence-based clinical practice parameter guidelines for the treatment of patients with metastatic brain tumors: introduction. J Neurooncol 2010;96:7-10. [PubMed]
- Ramakrishna N, Temin S, Chandarlapaty S, et al. Recommendations on disease management for patients with advanced human epidermal growth factor receptor 2-positive breast cancer and brain metastases: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol 2014;32:2100-8. [PubMed]
- Chang EL, Wefel JS, Hess KR, et al. Neurocognition in patients with brain metastases treated with radiosurgery or radiosurgery plus whole-brain irradiation: a randomised controlled trial. Lancet Oncol 2009;10:1037-44. [PubMed]
- Lockman PR, Mittapalli RK, Taskar KS, et al. Heterogeneous blood-tumor barrier permeability determines drug efficacy in experimental brain metastases of breast cancer. Clin Cancer Res 2010;16:5664-78. [PubMed]
- Barnholtz-Sloan JS, Sloan AE, Davis FG, et al. Incidence proportions of brain metastases in patients diagnosed (1973 to 2001) in the Metropolitan Detroit Cancer Surveillance System. J Clin Oncol 2004;22:2865-72. [PubMed]
- Schouten LJ, Rutten J, Huveneers HA, et al. Incidence of brain metastases in a cohort of patients with carcinoma of the breast, colon, kidney, and lung and melanoma. Cancer 2002;94:2698-705. [PubMed]
- Amer MH, Al-Sarraf M, Baker LH, et al. Malignant melanoma and central nervous system metastases: incidence, diagnosis, treatment and survival. Cancer 1978;42:660-8. [PubMed]
- Patel JK, Didolkar MS, Pickren JW, et al. Metastatic pattern of malignant melanoma. A study of 216 autopsy cases. Am J Surg 1978;135:807-10. [PubMed]
- Sampson JH, Carter JH Jr, Friedman AH, et al. Demographics, prognosis, and therapy in 702 patients with brain metastases from malignant melanoma. J Neurosurg 1998;88:11-20. [PubMed]
- Fonkem E, Uhlmann EJ, Floyd SR, et al. Melanoma brain metastasis: overview of current management and emerging targeted therapies. Expert Rev Neurother 2012;12:1207-15. [PubMed]
- Madajewicz S, Karakousis C, West CR, et al. Malignant melanoma brain metastases. Review of Roswell Park Memorial Institute experience. Cancer 1984;53:2550-2. [PubMed]
- Gleissner B, Chamberlain MC. Neoplastic meningitis. Lancet Neurol 2006;5:443-52. [PubMed]
- Agarwala SS, Kirkwood JM, Gore M, et al. Temozolomide for the treatment of brain metastases associated with metastatic melanoma: a phase II study. J Clin Oncol 2004;22:2101-7. [PubMed]
- Boogerd W, de Gast GC, Dalesio O. Temozolomide in advanced malignant melanoma with small brain metastases: can we withhold cranial irradiation? Cancer 2007;109:306-12. [PubMed]
- Antonadou D, Paraskevaidis M, Sarris G, et al. Phase II randomized trial of temozolomide and concurrent radiotherapy in patients with brain metastases. J Clin Oncol 2002;20:3644-50. [PubMed]
- Hofmann M, Kiecker F, Wurm R, et al. Temozolomide with or without radiotherapy in melanoma with unresectable brain metastases. J Neurooncol 2006;76:59-64. [PubMed]
- Capper D, Berghoff AS, Magerle M, et al. Immunohistochemical testing of BRAF V600E status in 1,120 tumor tissue samples of patients with brain metastases. Acta Neuropathol 2012;123:223-33. [PubMed]
- Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 2011;364:2507-16. [PubMed]
- Dummer R, Goldinger SM, Turtschi CP, et al. Vemurafenib in patients with BRAF(V600) mutation-positive melanoma with symptomatic brain metastases: final results of an open-label pilot study. Eur J Cancer 2014;50:611-21. [PubMed]
- Long GV, Stroyakovskiy D, Gogas H, et al. Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma. N Engl J Med 2014;371:1877-88. [PubMed]
- Long GV, Trefzer U, Davies MA, et al. Dabrafenib in patients with Val600Glu or Val600Lys BRAF-mutant melanoma metastatic to the brain (BREAK-MB): a multicentre, open-label, phase 2 trial. Lancet Oncol 2012;13:1087-95. [PubMed]
- Hodi FS, O'Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010;363:711-23. [PubMed]
- Maio M, Grob JJ, Aamdal S, et al. Five-Year Survival Rates for Treatment-Naive Patients With Advanced Melanoma Who Received Ipilimumab Plus Dacarbazine in a Phase III Trial. J Clin Oncol 2015;33:1191-6. [PubMed]
- Robert C, Thomas L, Bondarenko I, et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N Engl J Med 2011;364:2517-26. [PubMed]
- Margolin K, Ernstoff MS, Hamid O, et al. Ipilimumab in patients with melanoma and brain metastases: an open-label, phase 2 trial. Lancet Oncol 2012;13:459-65. [PubMed]
- Snyder A, Makarov V, Merghoub T, et al. Genetic basis for clinical response to CTLA-4 blockade in melanoma. N Engl J Med 2014;371:2189-99. [PubMed]
- Wolchok JD, Kluger H, Callahan MK, et al. Nivolumab plus ipilimumab in advanced melanoma. N Engl J Med 2013;369:122-33. [PubMed]
- Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma. N Engl J Med 2015. [Epub ahead of print]. [PubMed]
- Robert C, Schachter J, Long GV, et al. Pembrolizumab versus Ipilimumab in Advanced Melanoma. N Engl J Med 2015. [Epub ahead of print]. [PubMed]
- Berghoff AS, Ricken G, Widhalm G, et al. Tumour-infiltrating lymphocytes and expression of programmed death ligand 1 (PD-L1) in melanoma brain metastases. Histopathology 2015;66:289-99. [PubMed]
- Hodis E, Watson IR, Kryukov GV, et al. A landscape of driver mutations in melanoma. Cell 2012;150:251-63. [PubMed]
- Monzon J, Liu L, Brill H, et al. CDKN2A mutations in multiple primary melanomas. N Engl J Med 1998;338:879-87. [PubMed]
- Brastianos PK, Carter SL, Santagata S, et al. Abstract: Genomic characterization of 101 brain metastases and paired primary tumors reveals patterns of clonal evolution and selection of driver mutations. AACR. San Diego, 2014.
- Chen G, Chakravarti N, Aardalen K, et al. Molecular profiling of patient-matched brain and extracranial melanoma metastases implicates the PI3K pathway as a therapeutic target. Clin Cancer Res 2014;20:5537-46. [PubMed]
- Fedorenko IV, Gibney GT, Sondak VK, et al. Beyond BRAF: where next for melanoma therapy? Br J Cancer 2015;112:217-26. [PubMed]
- Herbst RS, Heymach JV, Lippman SM. Lung cancer. N Engl J Med 2008;359:1367-80. [PubMed]
- Bhangoo SS, Linskey ME, Kalkanis SN. American Association of Neurologic S, Congress of Neurologic S. Evidence-based guidelines for the management of brain metastases. Neurosurg Clin N Am 2011;22:97-104. [PubMed]
- Sperduto PW, Chao ST, Sneed PK, et al. Diagnosis-specific prognostic factors, indexes, and treatment outcomes for patients with newly diagnosed brain metastases: a multi-institutional analysis of 4,259 patients. Int J Radiat Oncol Biol Phys 2010;77:655-61. [PubMed]
- Bernardo G, Cuzzoni Q, Strada MR, et al. First-line chemotherapy with vinorelbine, gemcitabine, and carboplatin in the treatment of brain metastases from non-small-cell lung cancer: a phase II study. Cancer Invest 2002;20:293-302. [PubMed]
- Cotto C, Berille J, Souquet PJ, et al. A phase II trial of fotemustine and cisplatin in central nervous system metastases from non-small cell lung cancer. Eur J Cancer 1996;32A:69-71. [PubMed]
- Franciosi V, Cocconi G, Michiara M, et al. Front-line chemotherapy with cisplatin and etoposide for patients with brain metastases from breast carcinoma, nonsmall cell lung carcinoma, or malignant melanoma: a prospective study. Cancer 1999;85:1599-605. [PubMed]
- Kleisbauer JP, Guerin JC, Arnaud A, et al. Chemotherapy with high-dose cisplatin in brain metastasis of lung cancers. Bull Cancer 1990;77:661-5. [PubMed]
- Minotti V, Crino L, Meacci ML, et al. Chemotherapy with cisplatin and teniposide for cerebral metastases in non-small cell lung cancer. Lung Cancer 1998;20:93-8. [PubMed]
- Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 2005;352:987-96. [PubMed]
- Abrey LE, Olson JD, Raizer JJ, et al. A phase II trial of temozolomide for patients with recurrent or progressive brain metastases. J Neurooncol 2001;53:259-65. [PubMed]
- Giorgio CG, Giuffrida D, Pappalardo A, et al. Oral temozolomide in heavily pre-treated brain metastases from non-small cell lung cancer: phase II study. Lung Cancer 2005;50:247-54. [PubMed]
- Barlesi F, Gervais R, Lena H, et al. Pemetrexed and cisplatin as first-line chemotherapy for advanced non-small-cell lung cancer (NSCLC) with asymptomatic inoperable brain metastases: a multicenter phase II trial (GFPC 07-01). Ann Oncol 2011;22:2466-70. [PubMed]
- Bearz A, Garassino I, Tiseo M, et al. Activity of Pemetrexed on brain metastases from Non-Small Cell Lung Cancer. Lung Cancer 2010;68:264-8. [PubMed]
- Wang TJ, Saad S, Qureshi YH, et al. Does lung cancer mutation status and targeted therapy predict for outcomes and local control in the setting of brain metastases treated with radiation? Neuro Oncol 2015. [Epub ahead of print]. [PubMed]
- Bauml J, Mick R, Zhang Y, et al. Frequency of EGFR and KRAS mutations in patients with non small cell lung cancer by racial background: do disparities exist? Lung Cancer 2013;81:347-53. [PubMed]
- Shi Y, Au JS, Thongprasert S, et al. A prospective, molecular epidemiology study of EGFR mutations in Asian patients with advanced non-small-cell lung cancer of adenocarcinoma histology (PIONEER). J Thorac Oncol 2014;9:154-62. [PubMed]
- Gow CH, Chang YL, Hsu YC, et al. Comparison of epidermal growth factor receptor mutations between primary and corresponding metastatic tumors in tyrosine kinase inhibitor-naive non-small-cell lung cancer. Ann Oncol 2009;20:696-702. [PubMed]
- Sun M, Behrens C, Feng L, et al. HER family receptor abnormalities in lung cancer brain metastases and corresponding primary tumors. Clin Cancer Res 2009;15:4829-37. [PubMed]
- Ulivi P, Zoli W, Capelli L, et al. Target therapy in NSCLC patients: Relevant clinical agents and tumour molecular characterisation. Mol Clin Oncol 2013;1:575-81. [PubMed]
- Porta R, Sanchez-Torres JM, Paz-Ares L, et al. Brain metastases from lung cancer responding to erlotinib: the importance of EGFR mutation. Eur Respir J 2011;37:624-31. [PubMed]
- Welsh JW, Komaki R, Amini A, et al. Phase II Trial of Erlotinib Plus Concurrent Whole-Brain Radiation Therapy for Patients With Brain Metastases From Non-Small-Cell Lung Cancer. J Clin Oncol 2013;31:895-902. [PubMed]
- Lee SM, Lewanski CR, Counsell N, et al. Randomized trial of erlotinib plus whole-brain radiotherapy for NSCLC patients with multiple brain metastases. J Natl Cancer Inst 2014;106:dju151. [PubMed]
- Ceresoli GL, Cappuzzo F, Gregorc V, et al. Gefitinib in patients with brain metastases from non-small-cell lung cancer: a prospective trial. Ann Oncol 2004;15:1042-7. [PubMed]
- Wu C, Li YL, Wang ZM, et al. Gefitinib as palliative therapy for lung adenocarcinoma metastatic to the brain. Lung Cancer 2007;57:359-64. [PubMed]
- Ma S, Xu Y, Deng Q, et al. Treatment of brain metastasis from non-small cell lung cancer with whole brain radiotherapy and Gefitinib in a Chinese population. Lung Cancer 2009;65:198-203. [PubMed]
- Brastianos PK, Cahill DP. Management of brain metastases in the era of targeted and immunomodulatory therapies. Oncology (Williston Park) 2015;29:261-3. [PubMed]
- Kwak EL, Bang YJ, Camidge DR, et al. Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer. N Engl J Med 2010;363:1693-703. [PubMed]
- Shaw AT, Kim DW, Nakagawa K, et al. Crizotinib versus chemotherapy in advanced ALK-positive lung cancer. N Engl J Med 2013;368:2385-94. [PubMed]
- Kaneda H, Okamoto I, Nakagawa K. Rapid response of brain metastasis to crizotinib in a patient with ALK rearrangement-positive non-small-cell lung cancer. J Thorac Oncol 2013;8:e32-3. [PubMed]
- Peled N, Zach L, Liran O, et al. Effective crizotinib schedule for brain metastases in ALK rearrangement metastatic non-small-cell lung cancer. J Thorac Oncol 2013;8:e112-3. [PubMed]
- Preusser M, Berghoff AS, Ilhan-Mutlu A, et al. ALK gene translocations and amplifications in brain metastases of non-small cell lung cancer. Lung Cancer 2013;80:278-83. [PubMed]
- Weickhardt AJ, Scheier B, Burke JM, et al. Local ablative therapy of oligoprogressive disease prolongs disease control by tyrosine kinase inhibitors in oncogene-addicted non-small-cell lung cancer. J Thorac Oncol 2012;7:1807-14. [PubMed]
- Ajimizu H, Kim YH, Mishima M. Rapid response of brain metastases to alectinib in a patient with non-small-cell lung cancer resistant to crizotinib. Med Oncol 2015;32:477. [PubMed]
- Gadgeel SM, Gandhi L, Riely GJ, et al. Safety and activity of alectinib against systemic disease and brain metastases in patients with crizotinib-resistant ALK-rearranged non-small-cell lung cancer (AF-002JG): results from the dose-finding portion of a phase 1/2 study. Lancet Oncol 2014;15:1119-28. [PubMed]
- Gettinger SN, Horn L, Gandhi L, et al. Overall Survival and Long-Term Safety of Nivolumab (Anti-Programmed Death 1 Antibody, BMS-936558, ONO-4538) in Patients With Previously Treated Advanced Non-Small-Cell Lung Cancer. J Clin Oncol 2015. [Epub ahead of print]. [PubMed]
- Preusser M, Berghoff AS, Berger W, et al. High rate of FGFR1 amplifications in brain metastases of squamous and non-squamous lung cancer. Lung Cancer 2014;83:83-9. [PubMed]
- Preusser M, Streubel B, Berghoff AS, et al. Amplification and overexpression of CMET is a common event in brain metastases of non-small cell lung cancer. Histopathology 2014;65:684-92. [PubMed]
- Paik PK, Shen R, Won H, et al. Next-Generation Sequencing of Stage IV Squamous Cell Lung Cancers Reveals an Association of PI3K Aberrations and Evidence of Clonal Heterogeneity in Patients with Brain Metastases. Cancer Discov 2015;5:610-21. [PubMed]
- Preusser M, Streubel B, Birner P. ROS1 translocations and amplifications in lung cancer brain metastases. J Neurooncol 2014;118:425-6. [PubMed]
- Chen D, Zhang LQ, Huang JF, et al. BRAF mutations in patients with non-small cell lung cancer: a systematic review and meta-analysis. PLoS One 2014;9:e101354. [PubMed]
- Zhao N, Wilkerson MD, Shah U, et al. Alterations of LKB1 and KRAS and risk of brain metastasis: comprehensive characterization by mutation analysis, copy number, and gene expression in non-small-cell lung carcinoma. Lung Cancer 2014;86:255-61. [PubMed]
- Nguyen DX, Bos PD, Massague J. Metastasis: from dissemination to organ-specific colonization. Nat Rev Cancer 2009;9:274-84. [PubMed]
- Tang YA, Chen CH, Sun HS, et al. Global Oct4 target gene analysis reveals novel downstream PTEN and TNC genes required for drug-resistance and metastasis in lung cancer. Nucleic Acids Res 2015;43:1593-608. [PubMed]
- Lin NU, Bellon JR, Winer EP. CNS metastases in breast cancer. J Clin Oncol 2004;22:3608-17. [PubMed]
- Slimane K, Andre F, Delaloge S, et al. Risk factors for brain relapse in patients with metastatic breast cancer. Ann Oncol 2004;15:1640-4. [PubMed]
- Kennecke H, Yerushalmi R, Woods R, et al. Metastatic behavior of breast cancer subtypes. J Clin Oncol 2010;28:3271-7. [PubMed]
- Boogerd W, Dalesio O, Bais EM, et al. Response of brain metastases from breast cancer to systemic chemotherapy. Cancer 1992;69:972-80. [PubMed]
- Rosner D, Nemoto T, Lane WW. Chemotherapy induces regression of brain metastases in breast carcinoma. Cancer 1986;58:832-9. [PubMed]
- Cocconi G, Lottici R, Bisagni G, et al. Combination therapy with platinum and etoposide of brain metastases from breast carcinoma. Cancer Invest 1990;8:327-34. [PubMed]
- Oberhoff C, Kieback DG, Wurstlein R, et al. Topotecan chemotherapy in patients with breast cancer and brain metastases: results of a pilot study. Onkologie 2001;24:256-60. [PubMed]
- Hikino H, Yamada T, Johbara K, et al. Potential role of chemo-radiation with oral capecitabine in a breast cancer patient with central nervous system relapse. Breast 2006;15:97-9. [PubMed]
- Wang ML, Yung WK, Royce ME, et al. Capecitabine for 5-fluorouracil-resistant brain metastases from breast cancer. Am J Clin Oncol 2001;24:421-4. [PubMed]
- Ali S, Coombes RC. Endocrine-responsive breast cancer and strategies for combating resistance. Nat Rev Cancer 2002;2:101-12. [PubMed]
- Lien EA, Wester K, Lonning PE, et al. Distribution of tamoxifen and metabolites into brain tissue and brain metastases in breast cancer patients. Br J Cancer 1991;63:641-5. [PubMed]
- Goyal S, Puri T, Julka PK, et al. Excellent response to letrozole in brain metastases from breast cancer. Acta Neurochir (Wien) 2008;150:613-4; discussion 4-5. [PubMed]
- Madhup R, Kirti S, Bhatt ML, et al. Letrozole for brain and scalp metastases from breast cancer--a case report. Breast 2006;15:440-2. [PubMed]
- Bachmann C, Grischke EM, Staebler A, et al. Receptor change-clinicopathologic analysis of matched pairs of primary and cerebral metastatic breast cancer. J Cancer Res Clin Oncol 2013;139:1909-16. [PubMed]
- Bendell JC, Domchek SM, Burstein HJ, et al. Central nervous system metastases in women who receive trastuzumab-based therapy for metastatic breast carcinoma. Cancer 2003;97:2972-7. [PubMed]
- Brufsky AM, Mayer M, Rugo HS, et al. Central nervous system metastases in patients with HER2-positive metastatic breast cancer: incidence, treatment, and survival in patients from registHER. Clin Cancer Res 2011;17:4834-43. [PubMed]
- Kirsch DG, Ledezma CJ, Mathews CS, et al. Survival after brain metastases from breast cancer in the trastuzumab era. J Clin Oncol 2005;23:2114-6; author reply 6-7. [PubMed]
- Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 2005;353:1659-72. [PubMed]
- Romond EH, Perez EA, Bryant J, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 2005;353:1673-84. [PubMed]
- Amir E, Miller N, Geddie W, et al. Prospective study evaluating the impact of tissue confirmation of metastatic disease in patients with breast cancer. J Clin Oncol 2012;30:587-92. [PubMed]
- Niikura N, Liu J, Hayashi N, et al. Loss of human epidermal growth factor receptor 2 (HER2) expression in metastatic sites of HER2-overexpressing primary breast tumors. J Clin Oncol 2012;30:593-9. [PubMed]
- Duchnowska R, Dziadziuszko R, Trojanowski T, et al. Conversion of epidermal growth factor receptor 2 and hormone receptor expression in breast cancer metastases to the brain. Breast Cancer Res 2012;14:R119. [PubMed]
- Lin NU, Dieras V, Paul D, et al. Multicenter phase II study of lapatinib in patients with brain metastases from HER2-positive breast cancer. Clin Cancer Res 2009;15:1452-9. [PubMed]
- Bachelot T, Romieu G, Campone M, et al. Lapatinib plus capecitabine in patients with previously untreated brain metastases from HER2-positive metastatic breast cancer (LANDSCAPE): a single-group phase 2 study. Lancet Oncol 2013;14:64-71. [PubMed]
- Bartsch R, Berghoff AS, Preusser M. Breast cancer brain metastases responding to primary systemic therapy with T-DM1. J Neurooncol 2014;116:205-6. [PubMed]
- Torres S, Maralani P, Verma S. Activity of T-DM1 in HER-2 positive central nervous system breast cancer metastases. BMJ Case Rep 2014;2014.
- Park IH, Kwon Y, Ro JY, et al. Concordant HER2 status between metastatic breast cancer cells in CSF and primary breast cancer tissue. Breast Cancer Res Treat 2010;123:125-8. [PubMed]
- Lin NU, Claus E, Sohl J, et al. Sites of distant recurrence and clinical outcomes in patients with metastatic triple-negative breast cancer: high incidence of central nervous system metastases. Cancer 2008;113:2638-45. [PubMed]
- Niikura N, Hayashi N, Masuda N, et al. Treatment outcomes and prognostic factors for patients with brain metastases from breast cancer of each subtype: a multicenter retrospective analysis. Breast Cancer Res Treat 2014;147:103-12. [PubMed]
- Burnett RM, Craven KE, Krishnamurthy P, et al. Organ-specific adaptive signaling pathway activation in metastatic breast cancer cells. Oncotarget 2015;6:12682-96. [PubMed]
- Salhia B, Kiefer J, Ross JT, et al. Integrated genomic and epigenomic analysis of breast cancer brain metastasis. PLoS One 2014;9:e85448. [PubMed]
- Burstein MD, Tsimelzon A, Poage GM, et al. Comprehensive genomic analysis identifies novel subtypes and targets of triple-negative breast cancer. Clin Cancer Res 2015;21:1688-98. [PubMed]
- Craig DW, O'Shaughnessy JA, Kiefer JA, et al. Genome and transcriptome sequencing in prospective metastatic triple-negative breast cancer uncovers therapeutic vulnerabilities. Mol Cancer Ther 2013;12:104-16. [PubMed]
- Mittendorf EA, Philips AV, Meric-Bernstam F, et al. PD-L1 expression in triple-negative breast cancer. Cancer Immunol Res 2014;2:361-70. [PubMed]
- Stirzaker C, Zotenko E, Song JZ, et al. Methylome sequencing in triple-negative breast cancer reveals distinct methylation clusters with prognostic value. Nat Commun 2015;6:5899. [PubMed]
- Kim LS, Huang S, Lu W, et al. Vascular endothelial growth factor expression promotes the growth of breast cancer brain metastases in nude mice. Clin Exp Metastasis 2004;21:107-18. [PubMed]
- Lu YS, Chen TW, Lin CH, et al. Bevacizumab preconditioning followed by Etoposide and Cisplatin is highly effective in treating brain metastases of breast cancer progressing from whole-brain radiotherapy. Clin Cancer Res 2015;21:1851-8. [PubMed]
- Lu YS, Chen WW, Ling CH, et al. Bevacizumab, etoposide, and cisplatin (BEEP) in brain metastases of breast cancer progressing from radiotherapy: results of the first stage of a multicenter phase II study. J Clin Oncol 2012;30:abstr 1079.
- Cancer Genome Atlas Network. Comprehensive molecular portraits of human breast tumours. Nature 2012;490:61-70. [PubMed]
- Adamo B, Deal AM, Burrows E, et al. Phosphatidylinositol 3-kinase pathway activation in breast cancer brain metastases. Breast Cancer Res 2011;13:R125. [PubMed]
- Wikman H, Lamszus K, Detels N, et al. Relevance of PTEN loss in brain metastasis formation in breast cancer patients. Breast Cancer Res 2012;14:R49. [PubMed]
- Tutt A, Robson M, Garber JE, et al. Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-of-concept trial. Lancet 2010;376:235-44. [PubMed]
- Chalmers AJ. Overcoming resistance of glioblastoma to conventional cytotoxic therapies by the addition of PARP inhibitors. Anticancer Agents Med Chem 2010;10:520-33. [PubMed]
- Bos PD, Zhang XH, Nadal C, et al. Genes that mediate breast cancer metastasis to the brain. Nature 2009;459:1005-9. [PubMed]
- Kruser TJ, Chao ST, Elson P, et al. Multidisciplinary management of colorectal brain metastases: a retrospective study. Cancer 2008;113:158-65. [PubMed]
- Sundermeyer ML, Meropol NJ, Rogatko A, et al. Changing patterns of bone and brain metastases in patients with colorectal cancer. Clin Colorectal Cancer 2005;5:108-13. [PubMed]
- Rice TW, Khuntia D, Rybicki LA, et al. Brain metastases from esophageal cancer: a phenomenon of adjuvant therapy? Ann Thorac Surg 2006;82:2042-9, 2049.e1-2.
- York JE, Stringer J, Ajani JA, et al. Gastric cancer and metastasis to the brain. Ann Surg Oncol 1999;6:771-6. [PubMed]
- Han JH, Kim DG, Chung HT, et al. Radiosurgery for brain metastasis from advanced gastric cancer. Acta Neurochir (Wien) 2010;152:605-10. [PubMed]
- Schoeggl A, Kitz K, Ertl A, et al. Prognostic factor analysis for multiple brain metastases after gamma knife radiosurgery: results in 97 patients. J Neurooncol 1999;42:169-75. [PubMed]
- Jung M, Ahn JB, Chang JH, et al. Brain metastases from colorectal carcinoma: prognostic factors and outcome. J Neurooncol 2011;101:49-55. [PubMed]
- Weinberg JS, Suki D, Hanbali F, et al. Metastasis of esophageal carcinoma to the brain. Cancer 2003;98:1925-33. [PubMed]
- Ogawa K, Toita T, Sueyama H, et al. Brain metastases from esophageal carcinoma: natural history, prognostic factors, and outcome. Cancer 2002;94:759-64. [PubMed]
- Kasakura Y, Fujii M, Mochizuki F, et al. Clinicopathological study of brain metastasis in gastric cancer patients. Surg Today 2000;30:485-90. [PubMed]
- Ewend MG, Brem S, Gilbert M, et al. Treatment of single brain metastasis with resection, intracavity carmustine polymer wafers, and radiation therapy is safe and provides excellent local control. Clin Cancer Res 2007;13:3637-41. [PubMed]
- Christodoulou C, Bafaloukos D, Kosmidis P, et al. Phase II study of temozolomide in heavily pretreated cancer patients with brain metastases. Ann Oncol 2001;12:249-54. [PubMed]
- Iwamoto FM, Omuro AM, Raizer JJ, et al. A phase II trial of vinorelbine and intensive temozolomide for patients with recurrent or progressive brain metastases. J Neurooncol 2008;87:85-90. [PubMed]
- Yaeger R, Cowell E, Chou JF, et al. RAS mutations affect pattern of metastatic spread and increase propensity for brain metastasis in colorectal cancer. Cancer 2015;121:1195-203. [PubMed]
- Downward J. Targeting RAS signalling pathways in cancer therapy. Nat Rev Cancer 2003;3:11-22. [PubMed]
- Falchook GS, Long GV, Kurzrock R, et al. Dabrafenib in patients with melanoma, untreated brain metastases, and other solid tumours: a phase 1 dose-escalation trial. Lancet 2012;379:1893-901. [PubMed]
- Lan YT, Jen-Kou L, Lin CH, et al. Mutations in the RAS and PI3K pathways are associated with metastatic location in colorectal cancers. J Surg Oncol 2015;111:905-10. [PubMed]
- Lee SY, Haq F, Kim D, et al. Comparative genomic analysis of primary and synchronous metastatic colorectal cancers. PLoS One 2014;9:e90459. [PubMed]
- Bang YJ, Van Cutsem E, Feyereislova A, et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet 2010;376:687-97. [PubMed]
- Preusser M, Berghoff AS, Ilhan-Mutlu A, et al. Brain metastases of gastro-oesophageal cancer: evaluation of molecules with relevance for targeted therapies. Anticancer Res 2013;33:1065-71. [PubMed]
- Hedner C, Tran L, Borg D, et al. Discordant HER2 overexpression in primary and metastatic upper gastrointestinal adenocarcinoma signifies poor prognosis. Histopathology 2015. [Epub ahead of print]. [PubMed]
- Dulak AM, Stojanov P, Peng S, et al. Exome and whole-genome sequencing of esophageal adenocarcinoma identifies recurrent driver events and mutational complexity. Nat Genet 2013;45:478-86. [PubMed]
- Stassar MJ, Devitt G, Brosius M, et al. Identification of human renal cell carcinoma associated genes by suppression subtractive hybridization. Br J Cancer 2001;85:1372-82. [PubMed]
- Comprehensive molecular characterization of clear cell renal cell carcinoma. Nature 2013;499:43-9. [PubMed]
- Sato Y, Yoshizato T, Shiraishi Y, et al. Integrated molecular analysis of clear-cell renal cell carcinoma. Nat Genet 2013;45:860-7. [PubMed]
- Gerlinger M, Rowan AJ, Horswell S, Larkin J, Endesfelder D, Gronroos E, et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med 2012;366:883-92. [PubMed]
- Negrier S, Escudier B, Lasset C, et al. Recombinant human interleukin-2, recombinant human interferon alfa-2a, or both in metastatic renal-cell carcinoma. Groupe Francais d'Immunotherapie. N Engl J Med 1998;338:1272-8. [PubMed]
- Pal SK, Hu A, Chang M, et al. Programmed death-1 inhibition in renal cell carcinoma: clinical insights and future directions. Clin Adv Hematol Oncol 2014;12:90-9. [PubMed]
- Bastos DA, Molina AM, Hatzoglou V, et al. Safety and efficacy of targeted therapy for renal cell carcinoma with brain metastasis. Clin Genitourin Cancer 2015;13:59-66. [PubMed]
- Sekine M, Yoshihara K, Komata D, et al. Increased incidence of brain metastases in BRCA1-related ovarian cancers. J Obstet Gynaecol Res 2013;39:292-6. [PubMed]
- Nafisi H, Cesari M, Karamchandani J, et al. Metastatic ovarian carcinoma to the brain: an approach to identification and classification for neuropathologists. Neuropathology 2015;35:122-9. [PubMed]
- Cancer Genome Atlas Research Network. Integrated genomic analyses of ovarian carcinoma. Nature 2011;474:609-15. [PubMed]