Brain Metastases in Newly Diagnosed Breast Cancer

Martin, Allison; Cagney, Daniel; Catalano, Paul J.; Warren, Laura; Bellon, Jennifer R.; Punglia, Rinaa S.; Claus, Elizabeth B.; Lee, Eudocia Q.; Wen, Patrick Y.; Haas‐Kogan, Daphne A.; Alexander, Brian M.; Lin, Nancy U.; Aizer, Ayal A.

doi:10.1001/jamaoncol.2017.0001

Cited by 261 publications

(242 citation statements)

References 51 publications

(78 reference statements)

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“…Twelve studies compared clinicopathological characteristics of BCBM patients that developed BM as a first site of relapse, with those who first developed metastases elsewhere [10,12,21,28,30,31,39,46,54,63,66,73]. In the majority of the studies potential risk factors for BCBM were assessed via univariate followed by multivariable analysis; variables were assessed via only univariate analysis in twenty-nine studies [10, 12, 15, 16, 19, 20, 22, 27, 30-32, 35-37, 41, 43, 45-48, 54, 56, 60, 65, 67, 68, 73, 77, 81] and via only multivariable analysis in five [25,36,50,55,74]. Tables 2 and 3 provide shortlists of the factors that were reported at least once to significantly and independently associate with the risk for BCBM, in studies with unselected BC patients and HER2-positive patients, respectively.…”

Section: Group a -Prognostic Factors Associated With The Risk For Bcbmmentioning

confidence: 99%

“…However, the trend did not reach statistical significance in two case-control studies comparing the mean/median age of patients between the two groups [10,21]. Interestingly, in a large retrospective study examining prognostic factors in patients with synchronous BM and BC, older age (>40) was found to be a significant predictor of BCBM, in multivariable analysis (OR: 1.41, p = 0.02 for 41-60 years and OR: 1.40, p = 0.03 for 61-80 years) [74].…”

Section: Agementioning

confidence: 99%

“…The prognostic value of immunohistochemistry (IHC) defined BC subtypes in predicting BCBM progression was examined in 28 studies [12, 24, 29-31, 33, 36, 38, 41-43, 46, 49-52, 54, 55, 57, 59, 63, 67, 70, 72-74, 78, 79]. Irrespective of the heterogeneity in the definition of BC subtypes and IHC cut-offs used for calling ER/PR positivity across studies (Allred scoring system or >1%, >5% and 10% staining as cut-offs for ER/ PR positivity), the TNBC (effect estimate range: 1.4 -5.5) [24,29,31,36,41,42,46,50,52,54,55,57,59,67,70,72,74,79] and/or HER2-positive subtypes (HR-/HER2+ or HR±/HER2-) were constantly found to associate with a significantly higher cumulative incidence of BM (effect estimate range: 1.916 -6.799) [12, 24, 29, 43, 49, 50, 55, 67, 70, 72-74, 78, 79]. Of note, comparison of the two HR-positive groups revealed HR/HER2 co-positivity to associate with significant higher incidences of BCBM progression over HR+/HER2-tumors [24,43,55,72,74,79] with three studies reporting statistically significant multivariate association (HR: 2.514, p < 0.001; SHR: 1.70, p < 0.037; OR: 1.41, p = 0.001, respectively) [55,72,74].…”

Section: Er Pr and Her2 Statuses And Ihc Bc Subtypesmentioning

confidence: 99%

“…Additional primary tumor markers found to associate with BCBM progression by more than one study included Ki67, EGFR, FOXC1 and CK5/6. Although different IHC staining cut-offs were used across studies, Metastatic status 4 [33,38,53,70] 3 [33,38,53] 2 Primary metastatic status M0, SHR:2.64 p = 0.007 [33]; Extracranial distant metastases, AHR=28.46, p < 0.001 [38] Number of nonbrain metastatic sites 6 [29,33,55,70,74,79] 3 [29,33,70] 5 >1 OR: 1.76, p < 0.001 [29]; ≥3, HR = 2.712, p < 0.0001 [55]; <1, sHR: 1.77 p = 0.04 [70] 1 Abnormal serum levels, HR: 3.51 p = 0.005 [64] p16 expression on metastatic lymph nodes 1 [69] 1 [69] 1 High score p = 0.01 [69] CRYAB expression 1 [63] 1 HR:1.2 p = 0.021 [63] 3q gene signature 1 [76] 1 HR: 1.61 p = 0.001 [76] GRP94 Status 2 [35,62] 1 Strong positive vs. negative [35] FN14 Status 2 [35,62] 1 Strong positive vs. negative [35] CTC status 1 [34] 1 Undetectable CTC status OR: 6.17 p = 0.001 [34] SNPs 1 [72] 1 AKT1 -RS3803304, SHR: 2.72 p = 0.008, AKT2 -RS3730050, SHR: 2.06 p = 0.041, PDK1 -RS11686903 SHR: 2.38 p = 0.001, PI3KR1 -RS706716, SHR: 2.42 p = 0.025 [72] HR -Hazard Ratio; OR -Odds Ratio; NS -Non Significant; NR -Not Reported; SHR -Subhazard ratio; IDC -Infiltrating ductal carcinoma; CTC -C...…”

Section: Other Markersmentioning

confidence: 99%

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Risk factors for breast cancer brain metastases: a systematic review

et al. 2020

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Background: Brain metastasis (BM) is an increasingly common and devastating complication of breast cancer (BC).Methods: A systematic literature search of EMBASE and MEDLINE was conducted to elucidate the current state of knowledge on known and novel prognostic factors associated with 1) the risk for BCBM and 2) the time to brain metastases (TTBM).Results: A total of 96 studies involving institutional records from 28 countries were identified. Of these, 69 studies reported risk factors of BCBM, 46 factors associated with the TTBM and twenty studies examined variables for both outcomes. Young age, estrogen receptor negativity (ER-), overexpression of human epidermal factor (HER2+), and higher presenting stage, histological grade, tumor size, Ki67 labeling index and nodal involvement were consistently found to be independent risk factors of BCBM. Of these, triple-negative BC (TNBC) subtype, ER-, higher presenting histological grade, tumor size, and nodal involvement were also reported to associate with shorter TTBM. In contrast, young age, hormone receptor negative (HR-) status, higher presenting stage, nodal involvement and development of liver metastasis were the most important risk factors for BM in HER2-positive patients.Conclusions: The study provides a comprehensive and individual evaluation of the risk factors that could support the design of screening tools and interventional trials for early detection of BCBM. Lymph node status (N-Stage)

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Section: Group a -Prognostic Factors Associated With The Risk For Bcbmmentioning

confidence: 99%

Section: Agementioning

confidence: 99%

Section: Er Pr and Her2 Statuses And Ihc Bc Subtypesmentioning

confidence: 99%

Section: Other Markersmentioning

confidence: 99%

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Risk factors for breast cancer brain metastases: a systematic review

et al. 2020

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“…In this regard, the usefulness of surveillance with MRI in subgroups of patients with high risk of relapse in the brain, such as HER 2+ breast cancer patients, is now recognized [20].…”

mentioning

confidence: 99%

Imaging and Clinical End Points in Brain Metastases Trials

Soffietti¹,

Chiavazza²,

Rudà³

2017

CNS Oncol.

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When designing a clinical trial on brain metastases the choice of end points is critical. The Response Assessment in Neuro-Oncology (RANO) International Group has recently critically reviewed the different end points used in the clinical trials on brain metastases [1,2].Some factors heavily influence the choice of end points. First, patients with solid tumors may differ in prognosis and competing risk of extracranial progression. Second, the trial setting (Phase II vs Phase III trials) and type of intervention (CNS-directed vs systemic therapies) also require different end points.The knowledge of prognostic factors, in other words, of those factors influencing the outcome regardless of treatments, is critical in order to identify subgroups of patients with different outcomes (e.g., Recursive Partitioning Analysis [RPA] and Graded Prognostic Assessment [GPA] classes) [3][4][5]. In clinical trials, these subgroups are essential either as a stratification factor or inclusion criteria or even for post hoc analyses.There are key issues in imaging brain metastases in clinical trials: modalities and frequency of assessment, type and magnitude of change used to define response or progression of disease, and incorporation of steroid use and neurological symptoms/signs with current imaging definitions of response and progression. Last but not least, the ability to differentiate tumor-related and treatment-related changes is another critical point.The objective response is used to screen the activity of novel compounds and represents a primary end point in Phase II trials. It may be a surrogate for other markers of clinical benefit, such as neurological symptoms, neurocognitive function or survival. The interlesional variability of response to treatment can render problematic the evaluation of response in multiple metastases. A methodological open issue is whether it is preferable a randomized Phase II trial or a single arm Phase II trial with historical control in large datasets (e.g., Radiaition Therapy Oncology Group [RTOG] datasets) when larger Phase III trials are not feasible.The criteria of response used in brain metastasis trials in the past were quite heterogeneous. The use of MRI for response assessment was not always a standard procedure. There were major areas of difference across trials on brain metastases regarding the evaluation of response to treatment: definition of a target lesion (not defined, ≥1 cm); number of lesions (variable); type of measurement (unidimensional, bidimensional, volumetric); degree of tumor shrinkage required for response (≥30%, ≥50%); requirement for confirmatory scans (more commonly not required); inclusion of steroids and neurological symptoms (more commonly not done); evaluation of extracranial disease (more commonly not included). Overall, none of the Standard Response Criteria (Response Evaluation Criteria In Solid Tumors [RECIST], WHO, MacDonald and RANO for high-grade gliomas) were designed specifically to evaluate brain metastases, thus investigators have not consistently ch...

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