High Rate Of Brain Metastases Research Articles

EXTH-42. PRECLINICAL INVESTIGATION OF A NOVEL BRAIN PENETRANT MEK INHIBITOR TO TARGET BRAIN METASTASIS

Abstract Melanoma is one of the most common cancers with a high rate of brain metastases, with up to 75% of cases showing brain metastases upon autopsy. BRAF mutations are common in melanoma and found in up to 50-55% of melanoma brain metastases. Despite the clinical success of BRAF/MEK inhibitors for the treatment of advanced melanoma, dabrafenib and vemurafenib have limited intracranial overall response rates of 42-50% and median progression-free survival of 3.6-5.5 months. This limited efficacy is in part attributed to minimal blood-brain barrier penetration of the current available inhibitors. The goal of this study was to characterize a novel MEK inhibitor KIN-7136 as a potential therapeutic agent for brain metastasis driven by aberrant BRAF-MEK signaling, such as BRAF-mutant melanoma, using in vitro assays and an in vivo model of metastasis. KIN-7136 showed improved rodent brain exposure compared to conventional agents; the brain-to-plasma concentration ratio (Kp) of KIN-7136 was >1.0, much higher than comparators binimetinib and mirdametinib. In vitro cell viability assays showed potent cytotoxic effects of KIN-7136, with IC50s ranging from 15.4 to 204.9 nM in models of MAPK dysregulation including A375 (melanoma, BRAFV600E), NCI-H2405 (lung adenocarcinoma, BRAFΔNVTAP), HMVII (melanoma, BRAFG469V), and LN001 (patient derived lung adenocarcinoma, KRASG12V). Western blotting for phospho-ERK confirmed KIN-7136-mediated on-target downstream suppression in the A375 cell line. In vivo, daily oral treatment with KIN-7136 was well tolerated and produced a significant extension of overall survival compared to the vehicle control (p=0.0289, log-rank test) in the A375 intracranial tumor model in athymic mice. These preclinical data confirm activity of KIN-7136 in BRAF-mutant melanoma brain metastases models and support further research to advance its clinical progression.

DO GENOMIC ALTERATIONS INflUENCE THE DEVELOPMENT OF BRAIN METASTASES IN ADVANCED AND METASTATIC NON-SMALL CELL LUNG CANCER? A SYSTEMATIC REVIEW AND META-ANALYSIS

Abstract AIMS Establish prevalence at diagnosis, and incidence of BM in patients with advanced and metastatic non-small cell lung cancer (NSCLC), stratified by genomic alterations. METHOD A systematic review and meta-analysis was conducted in accordance with PRISMA guidelines (PROSPERO ID CRD42022315915). Three databases were searched (Search date 30th April 2022). Prevalence at diagnosis, and per-patient year incidence of brain metastases were obtained, including patients with EGFR, ALK, KRAS, ROS1, RET, and other genomic alterations. Pooled incidence rates were calculated using random effects models. RESULTS Of 960 articles identified, 65 were included (24,784 patients). The combined BM prevalence at diagnosis was 28.6% (45 studies, 95% Confidence Interval [CI] 26.1-31.0). Median follow-up was 24 months (Interquartile range [IQR] 16-36 months). The combined incidence of BM development was 10.8% per year (40 studies, 95% CI 9.2- 12.6). The per-year incidence of new BM was 15.6%/year in the EGFR +ve group (16 studies, 95% CI 11.4-21.2), 17.0% in the ALK+ve group (7 studies, 95% CI 11.3-25.8), 9.8% in the KRAS +ve group (4 studies, 95% CI 5.5-17.5), 12.5% in the ROS1 +ve group (3 studies, 95% CI 5.7-27.6), and 11.8% in the RET +ve group (2 studies, 95% CI 8.0-17.5). Combined overall prevalence was 55.0% (21 studies, IQR 44.2-67.8). CONCLUSIONS This systematic review indicates a high rate of brain metastases in NSCLC and is the first and only study to describe incidence, stratified by genomic alterations. This will have a major clinical impact by stratifying brain imaging at staging and follow-up by patient subgroup, particularly in ALK and EGFR mutations.

PD-L1, brain metastases, and survival among patients with metastatic non-small cell lung cancer treated with immune checkpoint inhibitors.

e21655 Background: PD-L1 expression is predictive of response to treatment with PD-1/PD-L1 immune checkpoint inhibitors (ICI) among patients with metastatic non-small cell lung cancer (mNSCLC). Brain metastases (BM) are common in patients with mNSCLC and carry significant morbidity. While the use of ICI has significantly improved survival for mNSCLC, it is unclear if patients with brain metastases have the same survival benefit. Methods: In this retrospective study, we reviewed data from all patients treated at our center with mNSCLC who had PD-L1 testing from 2015-2019. Patients with another active malignancy were excluded. Descriptive statistics were calculated using proportions and means using SAS v9.4. We examined the relationship between PD-L1 level ( < 50% vs ≥50%) and BM at diagnosis among patients with mNSCLC using chi-square analysis. We then compared overall survival (OS) and progression free survival (PFS) among mNSCLC patients with and without BM at diagnosis treated with ICI using Kaplan-Meier plots followed by log rank tests. Results: 141 mNSCLC patients with PD-L1 results were identified. 71 (50.4%) were female. Mean age was 63. 71 (50.4%) were current smokers, 53 (37.6%) were former smokers. Histology included 111 (78.7%) adenocarcinoma, 19 (13.5%) squamous cell carcinoma, and 11 (7.8%) other or mixed types. 19 (13.5%) had KRAS mutation, 13 (9.2%) had EGFR mutation, 1 had ALK rearrangement, 3 had ROS1 rearrangement, and 2 had BRAF mutations. 86 (61.0%) were PD-L1 high (≥50%). 57 (40.4%) had BM at diagnosis. Patients with high PD-L1 had a higher rate of BM at diagnosis (47.3% vs 36.0%), but this trend was not statistically significant (p = 0.18). There were significantly more current smokers among those with BM at diagnosis than those without BM (p = 0.01). Among patients treated with first line ICI (n = 78), median OS was 26.5 months for those without BM and 12.2 months for those with BM at diagnosis, although this difference was not significant (p = 0.11). Median PFS was 8.9 months for patients without BM and 8.6 for those with BM (p = 0.58). Conclusions: While a higher proportion of patients with high PD-L1 had BM at the time of metastatic diagnosis, this trend was not significant. Among patients treated with ICI, survival for those with or without BM at the time of diagnosis was not significantly different. Our observations may be limited by the number of patients.

Abstract 1319: Repotrectinib, a new generation ROS1 inhibitor, is highly potent against fusion ROS1s and emerging resistance mutations

Abstract Chromosome rearrangements of ROS1 have been identified as oncogenic drivers in many malignancies, especially non-small cell lung cancer (NSCLC). Crizotinib is the only approved treatment for ROS1+ NSCLC. The efficacy of crizotinib varies among different types of ROS1 fusion partners in patients with ROS1-rearranged NSCLC, and the most dominant fusion CD74-ROS1 was associated with a higher rate of brain metastases and shorter overall survival. Unfortunately, the emergence of drug resistance to crizotinib and other ROS1-targeted therapies represents a major obstacle. The most common resistance mutations to crizotinib in ROS1+ NSCLC are the solvent front mutation (SFM) ROS1 G2032R and gatekeeper mutation ROS1 L2026M. Repotrectinib was rationally designed to overcome resistance mutations. The activity of repotrectinib against multiple fusion ROS1s and corresponding resistance mutations is outlined in the Table. Repotrectinib potently inhibited both wildtype and mutated fusion ROS1s including SFMs and gatekeeper mutations. In cell growth assays using engineered Ba/F3 cells expressing ROS1 fusions with several different partners, such as SDC4, CD74, TPM3 and EZR, repotrectinib demonstrated superior potency in comparison to other ROS1 inhibitors against multiple ROS1 mutations, especially the solvent front and gatekeeper mutations. In xenograft tumor model studies, repotrectinib resulted in tumor regression in the tumors carrying WT or SFM ROS1 fusion genes. Overall, repotrectinib demonstrated a strong inhibition profile against WT and various mutated ROS1s across different fusion partners when compared to many other ROS1 TKIs. A Phase 1/2 clinical trial of repotrectinib is currently enrolling ROS1+ NSCLC patients (NCT03093116). Ba/F3 Cell Proliferation IC50 (nM)No Kinase Domain MutationROS1 G2032RROS1 L2026MInhibitorCD74-ROS1SDC4-ROS1EZR-ROS1TPM3-ROS1CD74-ROS1SDC4-ROS1EZR-ROS1TPM3-ROS1EZR-ROS1TPM3-ROS1Repotrectinib<0.20.2<0.1<0.13.33516.3<0.2<0.1Crizotinib14.619.619.431.1266.24661660500.695.6236.2Lorlatinib0.20.30.20.3160.7352.9190.5434.91.61.9Entrectinib10.5ND1.59.41813ND2947109313.340.7Ceritinib42.859.833.110513911883885.8543.712.666.5Brigatinib2138.725.86111721473360.6300024.441.3Cabozantinib0.530.44.511.3169.439.560.73.412.6Ensartinib39.5ND118.6433.1371.8ND17574814543.31463 Citation Format: Wei Deng, Dayong Zhai, Xin Zhang, Dong Lee, Evan Rogers, Jeffrey Whitten, J. Jean Cui. Repotrectinib, a new generation ROS1 inhibitor, is highly potent against fusion ROS1s and emerging resistance mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1319.

Efficacy of Crizotinib among Different Types ofROS1 Fusion Partners in Patients with ROS1-Rearranged Non-Small Cell Lung Cancer.

ROS1 rearrangement-positive NSCLC can be treated effectively with an anaplastic lymphoma kinase/ROS1/mesenchymal-epithelial transition factor inhibitor such as crizotinib; however, the rate of response remains variable. Although several ROS1 fusion partners have been identified, the efficacy of crizotinib in patients with different types of ROS1 fusion partners is poorly understood. We reviewed clinicopathological data of patients with ROS1 rearrangement who received crizotinib therapy at our institution between April 2014 and December 2016. ROS1 fusion partners were evaluated by using Sanger sequencing for available tumor tissue. During the study, 49 patients were found to have ROS1 rearrangement and were subsequently treated with crizotinib. Tumor specimens were available for 36 patients, of whom 19 were found to have CD 74 molecule gene (CD74)-ROS1 fusion partners. Before therapy, those in the CD74-ROS1 group were found to have a higher rate of brain metastases (six versus 0 [p= 0.020]). The objective response rate for crizotinib was 83.3% in all patients, whereas it was 94.11% and 73.68% in the non-CD74-ROS1 and CD74-ROS1 groups, respectively. As compared with the CD74-ROS1 group, the non-CD74-ROS1 group had both a significantly longer progression-free survival (17.63 months versus 12.63 months [p= 0.048]) and a significantly longer overall survival (44.50 months versus 24.33 months [p= 0.036]). On multivariable analysis, the only factor associated with overall survival was presence of brain metastases before therapy (p= 0.010). There were no significant factors associated with progression-free survival in the multivariable analysis. These findings suggests that patients with CD74-ROS1 fusion partners are more likely to present with brain metastases. Although not independently significant, a trend toward improved survival was observed in patients in the non-CD74-ROS1 group when they were treated with crizotinib.

Abstract A55: A novel mediator of brain metastasis from breast cancer

Abstract Purpose: Brain metastasis poses a major treatment challenge and remains an unmet clinical need. Finding novel therapies to prevent and treat brain metastases requires an understanding of the biology and molecular basis of the process, which currently is constrained by a dearth of experimental models and specific therapeutic targets. The purpose of this study was to identify molecular mediators of brain metastasis from breast cancer using novel preclinical brain metastasis models we developed recently. Methods: GFP-labeled cells were injected via tail vein into SCID/beige mice and metastatic colonization to the brain and lung was evaluated by fluorescent stereomicroscope and histology 8-weeks after injection. miRNA microarray was performed with miRNA 3.0 Array. Stable knockdown and overexpression of miR-141 was achieved with lentiviral vectors. miR-141 serum levels in patients with metastatic breast cancer was measured using quantitative PCR and was associated with outcome data. Results: We developed novel brain metastasis models in which tail-vein injection of parental triple-negative and a HER2-overexpressing inflammatory breast cancer lines led to a high rate of brain metastases (67%) in SCID/Beige mice (SUM149, 6 of 9 mice; MDA-MB-IBC3, 10 of 15 mice). Sub-lines derived from brain metastases (BrMS) or lung metastases (LuMS) tissues were morphologically and molecularly distinct. The BrMS showed epithelial morphology and overexpressed epithelial markers and miR-141 while the LuMS showed mesenchymal morphology and overexpressed mesenchymal markers. Knockdown of miR-141 significantly inhibited metastatic colonization to the brain compared to parental controls in both cell lines (miR-141 knockdown vs. control: SUM149, 0 of 8 mice vs. 6 of 9 mice, p=0.009; MDA-MB-IBC3, 2 of 14 mice vs. 10 of 15 mice, p=0.007). Further, ectopic expression of miR-141 in non-expressing MDA-MB-231 significantly enhanced brain metastatic colonization via tail-vein injection (5 of 9 mice vs. 0 of 10 mice, P=0.02). On multivariate analyses high serum level of miR-141 was an independent predictor of progression free survival [HR 4.8 (95%CI, 2.6-8.7), P<0.001] and overall survival [HR 7.0 (95%CI 3.5-15.1), P<0.001] in patients with metastatic breast cancer. Importantly, it is associated with shorter brain metastasis free survival (P=0.03). Conclusion: We have generated novel brain metastasis models that can be utilized to develop therapies. Further, we demonstrated miR-141 as a key regulator of brain metastasis and provided clinical evidence supporting the prognostic relevance of miR-141 in patients with brain metastasis. Our work could lead to novel targets for the prevention and treatment of brain metastasis that could improve patient survival in addition to fundamentally advancing the field of brain metastasis research. We propose that miR-141 should be examined as a biomarker and potential target to prevent or treat brain metastases. Citation Format: Bisrat G. Debeb, Lara Lacerda, Simone Anfossi, Parmeswaran Diagaradjane, Richard Larson, Khoi Chu, Lei Huo, Daniel Smith, Li Li, Cristina Ivan, Pamela Allen, Xiang Zhang, George Calin, Savitri Krishanmurthy, Thomas Buchholz, Naoto Ueno, James Reuben, Wendy A. Woodward. A novel mediator of brain metastasis from breast cancer. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr A55.

Abstract 3087: MicroRNA 141: A novel regulator of brain metastasis from breast cancer

Abstract Purpose: Brain metastasis poses a major treatment challenge and remains an unmet clinical need. Finding novel therapies to prevent and treat brain metastases requires an understanding of the biology and molecular basis of the process, which currently is constrained by a dearth of experimental models and specific therapeutic targets. The purpose of this study was to identify molecular mediators of brain metastasis from breast cancer using novel preclinical brain metastasis models we developed recently. Methods: GFP-labeled cells were injected via tail vein into SCID/beige mice and metastatic colonization to the brain and lung was evaluated by fluorescent stereomicroscope and histology 8-weeks after injection. miRNA microarray was performed with miRNA 3.0 Array. Stable knockdown and overexpression of miR-141 was achieved with lentiviral vectors. miR-141 serum levels in patients with metastatic breast cancer was measured using quantitative PCR and was associated with outcome data. Results: We developed novel brain metastasis models in which tail-vein injection of parental triple-negative and a HER2-overexpressing inflammatory breast cancer lines led to a high rate of brain metastases (67%) in SCID/Beige mice (SUM149, 6 of 9 mice; MDA-MB-IBC3, 10 of 15 mice). Sub-lines derived from brain metastasis (BrMS) or lung metastasis (LuMS) tissues were morphologically and molecularly distinct. The BrMS showed epithelial morphology and overexpressed epithelial markers and miR-141 while the LuMS showed mesenchymal morphology and overexpressed mesenchymal markers. Knockdown of miR-141 significantly inhibited metastatic colonization to the brain in both cell lines (miR-141 knockdown vs. control: SUM149, 0 of 8 mice vs. 6 of 9 mice, p = 0.009; MDA-MB-IBC3, 2 of 14 mice vs. 10 of 15 mice, p = 0.007). Ectopic expression of miR-141 in non-expressing MDA-MB-231 significantly enhanced brain metastatic colonization via tail-vein injection (5 of 9 mice vs. 0 of 10 mice, P = 0.02). On multivariate analyses high serum level of miR-141 was an independent predictor of progression free survival [HR 4.8 (95%CI, 2.6-8.7), P<0.001] and overall survival [HR 7.0 (95%CI 3.5-15.1), P<0.001], and was associated with shorter brain metastasis free survival (P = 0.03). Conclusion: We have generated novel brain metastasis models, demonstrated miR-141 as a key regulator of brain metastasis and provided clinical evidence supporting the prognostic relevance of miR-141 in patients with brain metastasis. We propose that miR-141 should be examined as a biomarker and potential target for the prevention and treatment of brain metastases from breast cancer. Citation Format: Bisrat G. Debeb, Lara Lacerda, Simone Anfossi, Parmesh Diagaradjane, Khoi Chu, Lei Huo, Caimiao Wei, Richard Larson, Adam Wolfe, Wei Xu, Li Li, Daniel Smith, Cristina Ivan, Pamela Allen, Savitri Krishnamurthy, George Calin, Xiang Zhang, Thomas Buchholz, Naoto Ueno, James Reuben, Wendy Woodward. MicroRNA 141: A novel regulator of brain metastasis from breast cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3087. doi:10.1158/1538-7445.AM2015-3087

Abstract P6-16-01: The microRNA miR-141 is a key regulator of brain metastasis from breast cancer

Abstract Purpose: Brain metastasis poses a major treatment challenge and remains an unmet clinical need. Finding novel therapies to prevent and treat brain metastases requires an understanding of the biology and molecular basis of the process, which currently is constrained by a dearth of experimental models and specific therapeutic targets. The purpose of this study was to develop preclinical models and identify molecular mediators of brain metastasis from breast cancer. Methods: We used MDA-MB-IBC3 (ER-/HER2+), SUM149 (ER-/HER2-), MCF7 (ER+/HER2-), SUM159 (ER-/HER2-) and MDA-MB-231 (ER-/HER2-) cell lines for this study. GFP-labeled cells were injected via tail vein into SCID/beige mice and metastatic colonization to the brain and lung evaluated by fluorescent stereomicroscope and histology 8-weeks after injection. miRNA microarray was performed with miRNA 3.0 Array. Stable knockdown of miR-141 was achieved with the lentiviral miRZip system. MiR-141 serum levels in 105 breast cancer patients were measured using quantitative PCR. Results: We developed novel brain metastasis models in which tail-vein injection of both triple-negative and a HER2-overexpressing inflammatory breast cancer lines led to a high rate of brain metastases (67%) in SCID/Beige mice (SUM149, 6 of 9 mice; MDA-MB-IBC3, 10 of 15 mice). Sub-lines derived from lung or brain metastases in these models were morphologically and molecularly distinct. The brain metastasis-derived sublines showed epithelial morphology and overexpressed epithelial markers and miR-141 while sublines from lung metastases showed mesenchymal morphology and overexpressed mesenchymal markers. Knockdown of miR-141 significantly inhibited metastatic colonization to the brain compared to controls (miR-141 knockdown vs. control: SUM149, 0 of 8 mice vs. 6 of 9 mice, p=0.009; MDA-MB-IBC3, 2 of 14 mice vs. 10 of 15 mice, p=0.007) but it did not affect colonization to the lung. Importantly, ectopic expression of miR-141 in non-expressing MDA-MB-231 significantly enhanced brain metastatic colonization (5 of 9 mice vs. 0 of 10 mice, P=0.02). On multivariate analyses high serum level of miR-141 was an independent predictor of progression free survival [HR 4.8 (95%CI, 2.6-8.7), P<0.001] and overall survival [HR 7.0 (95%CI 3.5-15.1), P<0.001] in patients with metastatic breast cancer. Conclusion: We demonstrated high rates of brain metastases from a heterogeneous group of cell lines that have not previously been associated with brain metastases, demonstrated miR-141 as a key regulator of brain metastasis and provided clinical evidence supporting the prognostic relevance of miR-141. We propose that miR-141 should be examined as a biomarker and potential target in the prevention and treatment of brain metastases from breast cancer. Citation Format: Bisrat G Debeb, Lara Lacerda, Simone Anfossi, Parmeswaran Diagaradjane, Khoi Chu, Lei Huo, Caimiao Wei, Richard A Larson, Adam R Wolfe, Wei Xu, Daniel L Smith, Li Li, Cristina Ivan, Pamela K Allen, Xiang H Zhang, George A Calin, Savitri Krishnamurthy, Naoto T Ueno, Thomas A Buchholz, James M Reuben, Wendy A Woodward. The microRNA miR-141 is a key regulator of brain metastasis from breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P6-16-01.

Traitement systémique des métastases cérébrales de mélanome

Melanomas have a high rate of brain metastases. Both the functional prognosis and the overall survival are poor in these patients. Until now, surgery and radiotherapy represented the two main modalities of treatment. Nevertheless, due to the improvement in the management of the extracerebral melanoma, the systemic treatment may be an option in patients with brain metastases. Immunotherapy with anti-CTLA4 (cytotoxic T-lymphocyte-associated protein 4) – ipilimumab – or BRAF (serine/threonine-protein kinase B-raf) inhibitors – vemurafenib, dabrafenib – has shown efficacy in the management of brain metastases in a- or pauci-symptomatic patients. Studies are ongoing with anti-PD1 (programmed cell death 1) and combinations of targeted therapies associating anti-RAF (raf proto-oncogene, serine/threonine kinase) and anti-MEK (mitogen-activated protein kinase kinase).

Brain metastases in patients who receive trastuzumab-containing chemotherapy for HER2-overexpressing metastatic breast cancer

Recently, a high rate of brain metastases has been reported among patients with human epidermal growth factor receptor (HER2)-overexpressing metastatic breast cancer who were treated with trastuzumab. The present study examined risk factors for the development of brain metastasis in patients with HER2-overexpressing breast cancer who were treated with trastuzumab. We retrospectively reviewed 204 patients with HER-2-overexpressing breast cancer who were treated with a trastuzumab-containing regimen between 1999 and 2006. Patients with clinical symptoms were diagnosed as having brain metastases when brain magnetic resonance imaging (MRI) or a computed tomography (CT) scan revealed positive findings for brain metastases. The median follow-up time of this cohort was 53.6 months. Among the patients who received a trastuzumab-containing regimen, 74 patients (36.3%) developed brain metastases. The median survival from the diagnosis of brain metastases was 13.5 months (95% confidence interval [CI], 12.2-14.7 months). The median time interval between the beginning of trastuzumab treatment and the diagnosis of brain metastases was 13.6 months (range, 0.0-45.8 months). Among patients with brain metastases, the median overall survival period was 39 months. A multivariate logistic regression analysis showed that age (<or=50 years), recurrent breast cancer, and liver metastases were significant risk factors for the development of brain metastases. Patients with HER2-overexpressing breast cancer treated with trastuzumab had a high incidence of brain metastases (36.3%). Routine screening for brain metastases 1 year after the start of trastuzumab treatment, may be warranted in younger patients (</=50 years) who had recurrent breast cancer with liver metastases.

Management of nonsinonasal neuroendocrine carcinomas of the head and neck.

Nonsinonasal neuroendocrine carcinomas (NSNEC) of the head and neck are rare and pose a diagnostic and management challenge. The authors undertook a retrospective study to gain insights into the spectrum of clinicopathologic characteristics, patterns of failure, and optimal management of patients with this disease. The authors treated 23 adults with pathologically proven, nonmetastatic, primary NSNEC from 1984 to 2001. The majority (13 patients) had laryngeal origin with the following American Joint Committee on Cancer stage distribution: Stage I disease in 1 patient, Stage II disease in 2 patients, Stage III disease in 6 patients, and Stage IV disease in 14 patients. Nine patients underwent definitive surgery with or without postoperative radiation, and 14 patients received definitive radiotherapy. The median definitive radiation dose was 66 grays (Gy) (range, 44-72 Gy) using conventional fractionation. Fourteen patients received chemotherapy, with two to four cycles of induction platinum plus etoposide used most commonly. The median follow-up time for surviving patients was 40 months (range, 15-89 months). The actuarial 2-year and 5-year overall survival (OS) rates were 53% and 33%, respectively; and the disease-free survival (DFS) rates were 41% and 25%, respectively. Both the 2-year OS rate (68% vs. 30%; P = 0.002) and the 2-year DFS rate (55% vs. 17%; P = 0.004) were improved with chemotherapy compared with local therapy alone. Seventy-five percent of patients with measurable disease had complete clinical responses to induction chemotherapy. There was 100% complete clinical response of tumor after radiotherapy. The actuarial 2-year local failure rate was 23%. Chemotherapy did not reduce local failure (P = 0.91). There was no regional failure. The 2-year and 5-year distant metastasis rates were 54% and 71%, respectively. The 2-year rates of metastases without and with chemotherapy were 79% and 39%, respectively (P = 0.006). The 2-year and 5-year rates of intracranial metastases were 25% and 44%, respectively, and the 2-year and 5-year rates of isolated brain metastases were 21% and 41%, respectively. Based on these results, the authors' treatment strategy for patients with NSNEC is sequential chemotherapy and radiation. They recommend full-dose radiotherapy alone for patients with NSNEC who achieve a complete clinical response to induction chemotherapy. Newer chemotherapeutic regimens or additional adjuvant chemotherapy should be investigated for patients with NSNEC given the high rate of distant failure. Due to the very high rate of brain metastases among patients in the current study, the authors now consider incorporating prophylactic cranial irradiation into primary radiotherapy for individual patients who have complete clinical responses to induction chemotherapy.

Association of Ki-67, p53, and bcl-2 expression of the primary non-small-cell lung cancer lesion with brain metastatic lesion

Purpose : The study was conducted to determine whether immunohistochemical analysis of Ki-67, p53, and bcl-2 in patients with non-small-cell lung cancer is associated with a higher rate of brain metastases and whether the intrapatient expression of these biomarkers (in the primary tumors vs. brain lesions) is similar. Methods and Materials : At the M. D. Anderson Cancer Center, tumors from 29 case patients with primary lung tumor and brain metastasis and 29 control patients with primary lung tumor but no brain metastasis were resected and examined for immunohistochemical expression. Ki-67, p53, and bcl-2 were analyzed in resected primary lung, lymph node, and metastatic brain tumors. Each control patient was matched by age, gender, and histology to a patient with brain metastasis. Results : No significant differences in patient survival characteristics were detected between the case group and control group. Also, difference in patient outcome between the two groups was not generally predicted by biomarker analysis. However, when the groups were combined, the biomarker analysis was predictive for certain patient outcome end points. Using median values as cutoff points between low and high expression of biomarkers, it was observed that high expression of Ki-67 (>40%) in lung primaries was associated with poorer disease-free survival ( p = 0.04), whereas low expression of p53 in lung primaries was associated with poorer overall survival ( p = 0.04), and these patients had a higher rate of nonbrain distant metastases ( p = 0.02). The patients with brain metastases were particularly prone to developing nonbrain distant metastases if the percentage of p53-positive cells in brain metastases was low ( p = 0.01). There was a positive correlation in the expression of Ki-67 ( p = 0.02)( r 2 = 0.1608), as well as p53 ( p < 0.001) ( r 2 = 0.7380), between lung primaries and brain metastases. Compared to Ki-67 and p53, bcl-2 was the least predictive. Conclusion : Differences in biomarker expression between the case and control groups did not serve as significant predictors of brain metastasis or patient survival. There was a strong correlation between lung primary biomarker expression and brain metastasis expression for Ki-67 and p53. Univariate analysis showed that low p53 and high Ki-67 expression predicted poor prognosis. This study shows that there may be a strong correlation between biomarker expression in non-small-cell lung cancer primary tumors and their brain metastases.