Systematic Review and Meta-analysis of Breast Cancer Brain Metastasis and Primary Tumor Receptor Expression Discordance

Abstract Background Change in hormone receptor (estrogen [ER] and progesterone [PR]) and/or HER2 status during the evolutionary course of metastatic breast cancer and the effect of tumor classification subtype switching remain understudied and underappreciated in brain metastasis patients. Methods Using PRISMA guidelines, a systematic review of series published prior to April 2020 obtained from the Medline database of biopsied or resected breast cancer brain metastasis (BCBM) was performed. Weighted random effects models were used to calculate pooled estimates. Results 15 full-text articles were included with receptor expression analyses on 1373 patients who underwent biopsy or resection of at least one intracranial lesion to compare to the primary tumor. Primary tumor receptor expression immunophenotypes were 45.0% ER+, 41.0% ER-, 31.0% PR+, 51.0% PR-, 35% HER2+, and 47.0% HER2-. Corresponding BCBM immunophenotypes were 19.0% ER+, 31.0% ER-, 13.0% PR+, 40.0% PR-, 21.0% HER2+, and 26.0% HER2-. On primary/BCBM comparison, 540 patients (42.6%) exhibited discordance in any receptor with 17.0% (95% CI: 13.0%-23.0%) discordant on ER, 23.0% (95% CI: 18.0%-30.0%) discordant on PR, and 12.0% (95% CI: 8.0%-16.0%) discordant on HER2 status. The most common receptor conversions found in BCBM were ER loss 11.0% (95% CI: 8.0%-16.0%), PR loss 15.0% (95% CI: 11.0%-21.0%), and HER2 gain 9.0% (95% CI: 7.0%-11.0%). Conclusions BCBM exhibit significant receptor expression discordance in comparison to primary tumors in approximately 40% of patients. Classification patterns need to be analyzed to determine factors predictive of BCBM/primary tumor discordance. Overall, tumor subtype switching and its effect on clinical management remains underappreciated.

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33. SYSTEMATIC REVIEW AND META-ANALYSIS OF BREAST CANCER BRAIN METASTASIS AND PRIMARY TUMOR RECEPTOR EXPRESSION DISCORDANCE

Neuro-Oncology Advances ◽

10.1093/noajnl/vdaa073.021 ◽

2020 ◽

Vol 2 (Supplement_2) ◽

pp. ii6-ii6

Author(s):

Rupesh Kotecha ◽

Raees Tonse ◽

Muni Rubens ◽

Michael McDermott ◽

Yazmin Odia ◽

...

Keyword(s):

Breast Cancer ◽

Systematic Review ◽

Brain Metastasis ◽

Primary Tumor ◽

Expression Profiles ◽

Receptor Expression ◽

Her2 Status ◽

Tumor Subtype ◽

Primary Tumors ◽

Breast Cancer Brain Metastasis

Abstract BACKGROUND Discordance in hormone receptor (estrogen [ER] and progesterone [PR]) and human epidermal growth factor receptor2 (HER2) status between the primary tumor and brain metastases and its effect on tumor classification subtype switching has been described but remains understudied. METHODS Using the PRISMA guidelines, a systematic review was performed of series published prior to April 2020 of biopsied or resected breast cancer brain metastasis (BCBM) from the Medline database using the keywords “breast cancer” and “brain metastasis” combined with “estrogen receptor/ER,” “progesterone receptor/PR,” “HER2/neu,” and “receptor conversion/dis- or concordance.” Weighted random effects models were used to calculate pooled estimates. RESULTS Fifteen full-text articles met inclusion criteria and cumulatively reported on 1373 patients who underwent biopsy or resection of at least one BCBM to compare to their primary tumor. At initial diagnosis, receptor expression profiles were 45.0% ER+, 41.0% ER-, 31.0% PR+, 51.0% PR-, 35% HER2+, and 47.0% HER2-. Corresponding receptor expression profiles from the BCBM were 19.0% ER+, 31.0% ER-, 13.0% PR+, 40.0% PR-, 21.0% HER2+, and 26.0% HER2-. Intra-patient receptor discordance comparisons revealed that 540 patients (42.6%) exhibited discordance in any receptor with 17.0% (95% CI: 13.0%-23.0%) discordance for ER status, 23.0% (95% CI: 18.0%-30.0%) for PR status, and 12.0% (95% CI: 8.0%-16.0%) for HER2 status. The most common receptor discordance events found in BCBM compared to primary tumors were ER loss 11.0% (95% CI: 8.0%-16.0%), PR loss 15.0% (95% CI: 11.0%-21.0%), and HER2 gain 9.0% (95% CI: 7.0%-11.0%). CONCLUSIONS BCBM commonly exhibit receptor expression changes on comparison to primary tumors including a 10% HER2 gain rate, a potential actionable target. Classification patterns need to be updated to reflect changes in overall tumor subtype grouping and which factors predict for BCBM/primary tumor discordance. Overall, tumor subtype switching and its effect on clinical management remains underappreciated.

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The Incidence of Brain Metastases Among Patients with Metastatic Breast Cancer: A Systematic Review and Meta-Analysis

Neuro-Oncology ◽

10.1093/neuonc/noaa285 ◽

2020 ◽

Author(s):

Markus Kuksis ◽

Yizhuo Gao ◽

William Tran ◽

Christianne Hoey ◽

Alex Kiss ◽

...

Keyword(s):

Breast Cancer ◽

Systematic Review ◽

Metastatic Breast Cancer ◽

Brain Metastases ◽

Triple Negative ◽

Screening Program ◽

Meta Analysis ◽

Metastatic Breast ◽

Breast Cancer Brain Metastasis

Abstract Background Patients with metastatic breast cancer (MBC) are living longer, but development of brain metastases often limits their survival. We conducted a systematic review and meta-analysis to determine the incidence of brain metastases in this patient population. Methods Articles published from January 2000 to January 2020 were compiled from four databases using search terms related to: breast cancer, brain metastasis, and incidence. The overall and per patient-year incidence of brain metastases were extracted from studies including patients with HER2+, triple negative, and hormone receptor (HR)+/HER2- MBC; pooled overall estimates for incidence were calculated using random effects models. Results 937 articles were compiled, and 25 were included in the meta-analysis. Incidence of brain metastases in patients with HER2+ MBC, triple negative MBC, and HR+/HER2- MBC was reported in 17, 6, and 4 studies, respectively. The pooled cumulative incidence of brain metastases was 31% for the HER2+ subgroup (median follow-up: 30.7 months, IQR: 24.0 – 34.0), 32% for the triple negative subgroup (median follow-up: 32.8 months, IQR: 18.5 – 40.6), and 15% among patients with HR+/HER2- MBC (median follow-up: 33.0 months, IQR: 31.9 – 36.2). The corresponding incidences per patient-year were 0.13 (95% CI: 0.10 – 0.16) for the HER2+ subgroup, 0.13 (95%CI: 0.09 – 0.20) for the triple negative subgroup, and only 0.05 (95%CI: 0.03 – 0.08) for patients with HR+/HER2- MBC. Conclusion There is high incidence of brain metastases among patients with HER2+ and triple negative MBC. The utility of a brain metastases screening program warrants investigation in these populations.

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Systematic Review and Meta-analysis of PD-L1 Expression Discordance between Primary Tumor and Lung Cancer Brain Metastasis

Neuro-Oncology Advances ◽

10.1093/noajnl/vdab166 ◽

2021 ◽

Author(s):

Raees Tonse ◽

Muni Rubens ◽

Haley Appel ◽

Martin C Tom ◽

Matthew D Hall ◽

...

Keyword(s):

Lung Cancer ◽

Systematic Review ◽

Brain Metastasis ◽

Meta Analysis ◽

Tumor Infiltrating Lymphocytes ◽

Receptor Expression ◽

Primary Tumors ◽

Random Effects Models ◽

Expression Category ◽

Metastatic Sites

Abstract Background Novel immunotherapeutic strategies targeting the PD-1/PD-L1 axis are often administered when metastatic tumors show PD-L1 positivity, even in the setting of lung cancer brain metastasis (LCBM). However, biological differences exist between primary tumors and metastatic sites. The objective of this study was to analyze rates of PD-L1 receptor discordance between primary tumors and LCBM. Methods A systematic review of studies of biopsied or resected LCBM evaluating PD-L1 discordance published in the Medline database was performed using PRISMA guidelines. Weighted random effects models were used to calculate pooled estimates. Results Six full-text articles (n=230 patients) with a median of 32 patients in each study (range: 24-73) reported PD-L1 receptor expression analyses of both primary lung tumors and brain metastases and met inclusion criteria. The pooled estimate for tumor cell (TC) PD-L1 receptor discordance between primary tumors and LCBM was 19% (95% CI: 10%-27%). For PD-L1 receptor expression in tumor infiltrating lymphocytes (TIL), the weighted pooled estimate for discordance was 21% (95% CI: 8%-44%). For primary versus LCBM, the positive rates by expression levels of <1%, 1-50%, and >50% were 52% (95% CI: 30-73%) vs. 56% (95% CI: 34-76%), 30% (95% CI: 22-40%) vs. 20% (95% CI: 10-35%), and 15% (95% CI: 6-36%) vs. 22% (95% CI: 15-31%) (p=0.425), respectively. Conclusions PD-L1 discordance occurs in ~20% of LCBM, with the greatest discordance in the 1-50% expression category. Although controversial, confirming discordance might be important for selection of immune checkpoint inhibitor therapy and in the analysis of patterns of failure after treatment.

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Number of tumor-infiltrating lymphocytes in breast cancer brain metastases compared to matched breast primaries.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.2049 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. 2049-2049 ◽

Cited By ~ 1

Author(s):

Jessie Narloch ◽

Catherine Luedke ◽

Gloria Broadwater ◽

Nolan Priedigkeit ◽

Allison Hall ◽

...

Keyword(s):

Breast Cancer ◽

Brain Metastasis ◽

Brain Metastases ◽

Tumor Infiltrating Lymphocytes ◽

Cox Proportional Hazards Model ◽

Her2 Status ◽

Primary Tumors ◽

Metastatic Setting ◽

Breast Cancer Brain Metastasis ◽

Infiltrating Lymphocytes

2049 Background: Breast cancer brain metastasis (BCBM) is frequent in advanced disease, has limited therapies, and is associated with poor prognosis. Increased stromal tumor infiltrating lymphocytes (sTILs) are prognostic in triple-negative breast cancer (TNBC) and predictive of therapeutic response in early breast cancer (BC). However, little is known about sTILs in the metastatic setting. We compared %sTILs between the largest known cohort of matched primary tumors and BCBM and correlated the results with clinical endpoints. Methods: We retrospectively investigated 37 matched primary tumors and BCBM tissue from three institutions. In addition, we identified 29 primary tumors from patients later diagnosed with BCBM. H&E-stained sections were manually measured for %sTILs using standard criteria. Wilcoxon signed rank tests assessed for changes in %sTILs between primary and metastatic lesions. A Cox proportional hazards model was used to determine if %sTILs in the breast tissue predicts time from primary tumor biopsy to diagnosis of brain metastasis (TTDBM) while adjusting for clinicopathologic features. Results: Average age at time of BCBM diagnosis was 53.6 (SD 12.3). 52% (34/66) of primary tumors were hormone receptor (HR) positive. Of 60 patients with known HER2 status, 28% (17) were HER2 positive and 40% (24) TNBC. Median %sTILS was significantly different between all primary tumors (15, IQR 5-20) and brain metastases (10, IQR 5-10), p = 0.001. The TNBC subtype (n = 11) showed the largest decrease in %sTILs between primary tumors (20, IQR 10-20) and brain metastases (5, IQR 5-10), p = 0.022. Comparing primary tumors and brain metastases, there was a 5% decrease in %sTILs in HR-/HER2+ (n = 5, p = 0.13) and HR+/HER2- (n = 7, p = 0.13), and a 5% increase in %sTILs in the HR+/Her2+ subtype (n = 9, p = 0.69). Percent sTILs in the primary tumors was not a significant predictor of TTDBM, when adjusting for race, age, HR status, and HER2 status, p = 0.87. Conclusions: BCBM have a significantly decreased %sTILs compared to their primary tumors, most prominent in TNBC. These results suggest altered tumor immunogenicity in the metastatic setting which has broad implications for the development of immunotherapy.

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Comparative effectiveness and safety of eribulin in advanced or metastatic breast cancer: A systematic review and meta-analysis

Critical Reviews in Oncology/Hematology ◽

10.1016/j.critrevonc.2021.103375 ◽

2021 ◽

pp. 103375

Author(s):

Kaniz Afroz Tanni ◽

Cong Bang Truong ◽

Brandon S. Johnson ◽

Jingjing Qian

Keyword(s):

Breast Cancer ◽

Systematic Review ◽

Metastatic Breast Cancer ◽

Comparative Effectiveness ◽

Meta Analysis ◽

Metastatic Breast

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Prospective Study Evaluating the Impact of Tissue Confirmation of Metastatic Disease in Patients With Breast Cancer

Journal of Clinical Oncology ◽

10.1200/jco.2010.33.5232 ◽

2012 ◽

Vol 30 (6) ◽

pp. 587-592 ◽

Cited By ~ 256

Author(s):

Eitan Amir ◽

Naomi Miller ◽

William Geddie ◽

Orit Freedman ◽

Farrah Kassam ◽

...

Keyword(s):

Breast Cancer ◽

Prospective Study ◽

Treatment Plan ◽

Growth Factor Receptor ◽

Metastatic Breast ◽

Her2 Status ◽

Primary Tumors ◽

Receptor Status ◽

Metastatic Recurrence ◽

The Impact

Purpose Decisions about treatment for women with metastatic breast cancer are usually based on the estrogen (ER), progesterone (PgR), and human epidermal growth factor receptor 2 (HER2) status of the primary tumor. Retrospective data suggest that discordance between primary and metastatic lesions leads to detrimental outcome. This prospective study investigated receptor status of primary tumors and metastases in the same patient and assessed the impact of discordance on patient management and survival. Patients and Methods Biopsies of suspected metastases were analyzed for ER, PgR, and HER2. Primary tumors and metastases were analyzed using similar methodology. The treating oncologist indicated a treatment plan before and after biopsy to determine whether the result influenced management. Patients were followed up for progression or death. Results Of 121 women undergoing biopsy, 80% could be analyzed for receptor status. Discordance in ER, PgR, and HER2 between the primary and the metastasis was 16%, 40%, and 10%, respectively. Biopsy led to a reported change of management in 14% of women (95% CI, 8.4% to 21.5%). Fine-needle aspiration and biopsy of bone led to reduced ability to analyze receptors. After a median follow-up of 12 months, there were no trends for an association between receptor discordance and either time to treatment failure or overall survival. Conclusion Biopsy of metastases is technically feasible. Clinicians alter immediate management in one of seven patients on the basis of results of the biopsy, and discordance is not then associated with detrimental effects on outcome. Tissue confirmation should be considered in women with breast cancer and suspected metastatic recurrence.

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OTHR-07. Systematic Review and Meta-analysis of Lung Cancer Brain Metastasis and Primary Tumor PD-L1 Expression Discordance

Neuro-Oncology Advances ◽

10.1093/noajnl/vdab071.062 ◽

2021 ◽

Vol 3 (Supplement_3) ◽

pp. iii15-iii16

Author(s):

Raees Tonse ◽

Muni Rubens ◽

Haley Appel ◽

Martin C Tom ◽

Matthew D Hall ◽

...

Keyword(s):

Lung Cancer ◽

Systematic Review ◽

Brain Metastasis ◽

Tumor Cell ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Primary Tumor ◽

Small Cell ◽

Receptor Expression ◽

Small Cell Lung

Abstract Background Novel immunotherapeutic strategies, such as those targeting the PD-1/PD-L1 axis, are promising in patients with metastatic lung cancer and are often administered when tumors show PD-L1 positivity. The objective of this study was to analyze PD-L1 receptor discordance in tumor cell between the primary tumor and lung cancer brain metastasis (LCBM). Methods A systematic review of series published prior to April 2021 obtained from the Medline database of biopsied or resected LCBM evaluating PD-L1 discordance was performed using PRISMA guidelines. Weighted random effects models were used to calculate pooled estimates. Results Six full-text articles (n=247 patients) with a median of 32 patients in each study (range: 24–73 patients) reported PD-L1 receptor expression analyses of both primary lung tumors and brain metastases. The majority of patients (81%) were smokers, with 67% non-small cell lung cancer and 33% small cell lung cancer. The pooled estimate for overall PD-LI receptor concordance between primary and LCBM was 76% (95% CI: 52%-90). The positivity rate varied when analyzed by various cutoff levels of PD-L1 expression; for <1% expression, it was 41% (95% CI: 22%-62%) for primary vs. 58% (95% CI: 35%-78%) for LCBM; for PD-L1 expression of 1–50%, it was 24% (95% CI: 13%-40%) vs. 19% (95% CI: 10%-33%); and for PD-L1 >50% it was 12% (95% CI: 4%-33%) vs. 21% (95% CI: 14%-29%) (p=0.425). The pooled estimate for overall PD-LI receptor discordance between primary and LCBM was 17% (95% CI: 10%-27%). Meta-regression analysis showed that age, sex, smoking status, and histology were not associated with PD-LI receptor discordance. Conclusions PD-L1 status discordance in tumor cell occurs in approximately 20% of LCBM, with the greatest discordance in the <1% expression category. Awareness of this discordance is important for the selection of immune checkpoint inhibitor therapy as well as in the analysis of patterns of failures.

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The gastrin releasing peptide, GRP, is differentially expressed in brain metastatic breast cancer.

10.31219/osf.io/5d2n9 ◽

2020 ◽

Author(s):

Shahan Mamoor

Keyword(s):

Breast Cancer ◽

Metastatic Breast Cancer ◽

Brain Metastasis ◽

Microarray Data ◽

Metastatic Breast ◽

Metastatic Tumor ◽

Clinical Problem ◽

Primary Tumors ◽

Gastrin Releasing Peptide ◽

The Brain

Metastasis to the brain is a clinical problem in patients with breast cancer (1-3). We mined published microarray data (4, 5) to compare primary and metastatic tumor transcriptomes to discover genes associated with brain metastasis in patients with metastatic breast cancer. We found that the gastrin releasing peptide, encoded by GRP, was among the genes whose expression was most different in the brain metastases of patients with metastatic breast cancer as compared to primary tumors of the breast. Molecular functions of gastrin releasing peptide may be relevant to the processes by which tumor cells of the breast metastasize to the breast. Down-regulation of GRP may be an important event for metastasis of primary tumor-derived cancer cells to the brain in humans with metastatic breast cancer.

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