Table 2.
Prognostic Factors Associated with Developing Brain Metastasis Among Patients with HER2+ Breast Cancer
| Citation | Prognostic Factors for Shorter Time to BM | |||||||
|---|---|---|---|---|---|---|---|---|
| HER2+ Group | Sample Size, n | Median Time to BMa, mo | Age | HR Status | Anti-HER2 Therapy | Tumor Grade | Other | |
| Ahn et al., 2013 [17] | Without trastuzumab | 39 | 32.1 | NR | NR | No association | NR | ▪ NR |
| With trastuzumab | 47 | 35.4 | ||||||
| Anders et al., 2011 [15] | HR+ | 21 | 49.8 (95% CI, 10.2–54.5) | NR | HR- vs. HR+ (suggestive association) | NR | NR | ▪ NR |
| HR- | 18 | 19.8 (95% CI, 13.6–36.2) | ||||||
| Berghoff et al., 2012 [30] | All | 102 | 18 (95% CI, 14.5–21.5)b | NR | ER- vs. ER+ | No association | NR | ▪ NR |
| ER+ | NR | NR | NR | NA | NR | NR | ▪ Did not receive palliative endocrine therapy | |
| Braccini et al., 2013 [36] | All | 109 | 36 (range, 0–287) | NR | NR | NR | NR | ▪ NR |
| Brufsky et al., 2011 [31] | All | 377 | 10.8 | < 50 y vs. ≥50 y | HR- vs. HR+ | No trastuzumab vs. trastuzumab | NR | ▪ ≥2 vs. < 2 metastatic sites |
| Duchnowska et al., 2012 [21] | All | 142 | 13 (95% CI, 9–18) | No association | No association | NR | Tumor grade 3 vs. grade 1–2 |
▪ Higher H2T levels (≥50 RF/mm2)c ▪ Time to nonbrain progressiond ▪ HER-2 gene amplifications as defined by the HER-2/CEP17 ratio (no association) ▪ Menopausal status (no association) |
| Duchnowska et al., 2009 e [22] | All | 264 | 15 (range, 0–81)b | No association | No association | No association | NR | ▪ Time to distant relapse ≤2 y vs. > 2 y |
| Duchnowska et al., 2015 [23] | Cohort A (discovery) | 83f | 36 (range, 2–141) | NR | ER- vs. ER + e | No trastuzumab vs. trastuzumab | No association |
▪ Visceral site of first distant relapse ▪ 3-gene classifierg |
| Cohort B (validation) | 75 | 40 (range, 0.33–125) | NR | ER- vs. ER+ | No trastuzumab vs. trastuzumab | Grade high vs. low e | ▪ Visceral site of first distant relapse | |
| Gori et al., 2019 [24] | All | 154 | 39.1 (IQR, 20.3–62.4) | NR | NR | NR | NR | ▪ NR |
| Hayashi et al., 2015 [25] | All | 432 | 33.5 | NR | NR | NR | NR | ▪ NR |
| Heitz et al., 2009 e [29] | All | 245 | 30 | No association | No association | No association | No association |
▪ Pathological tumor size category 3/4 vs. category 1/2 ▪ TNM classification of metastatic (M) status at diagnosis is 1 vs. 0 |
| Jang et al., 2011 [34] | All | 137 | 31.6 (95% CI, 27.3–35.9) | NR | NR | NR | NR | ▪ NR |
| Kuba et al., 2014 [35] | All | 26 | 15.6 (range, 0–52.8) | NR | NR | NR | NR | ▪ NR |
| Maurer et al., 2018 [26] | All | 483 | 76.2 | ≤40 y vs. > 40 y | No association | No association | No association |
▪ No surgery vs. surgery for primary BC ▪ Larger tumor size ▪ Nodal involvement ▪ Received adjuvant endocrine treatment ▪ Received no anthracyclines + taxanes as (neo) adjuvant chemotherapy |
| Morikawa et al., 2018 [27] | All | 100 | 34.6 (range, 0–176) | NR | NR | NR | NR | ▪ NR |
| Mounsey et al., 2018 [20] | All | 123 | 34.6 (95% CI, 26.6–41.0) | NR | NR | NR | NR | ▪ NR |
| Sperduto et al., 2013 [37] | HR+ | 98 | 47.4 (IQR, 26.3–70.5) | NR | NR | NR | NR | ▪ NR |
| HR- | 119 | 35.8 (IQR, 13.4–69.2) | NR | NR | NR | NR | ▪ NR | |
| Witzel et al., 2018 [16] | All | 732 | 32.4 (95% CI, 29.6–36.1) | NR | NR | NR | NR | ▪ NR |
| Yap et al., 2012 [18] | All | 280 | 30.1 (95% CI, 25.0–32.7) | NR | NR | No anti-HER2 treatment vs. anti-HER2 treatment | NR | ▪ NR |
| Zhang et al., 2016 [28] | All | 60 | 12 (range, 1–94) | NR | NR | NR | NR | ▪ NR |
BC breast cancer; BM brain metastasis; CI confidence interval; ER estrogen receptor; H2T the quantitative HER2 level as measured by the HERmark® Breast Cancer Assay; HER-2/CEP17 HER-2/centromeric probe for chromosome 17 ratio > 2.0; HR hormone receptor; IQR interquartile range; NA not applicable; NR not reported; RF relative fluorescence; TNM TNM staging system (T tumor size and spread, N nodal involvement, M = metastatic status) developed by the American Joint Committee on Cancer
a From the time of breast cancer diagnosis
b From the time of diagnosis of metastatic disease
c H2T is the quantitative HER-2 level as measured by the HERmark® Breast Cancer Assay (i.e., The VeraTag™ proximity-based assay; Monogram Biosciences, Inc., South San Francisco, California). The assay enables precise quantitative measurements of total HER-2 expression in formalin-fixed, paraffin-embedded tissue specimens. Higher H2T levels modeled as a continuous variable or as a categorical variable were associated with a shorter time to BM
d Time from initiation of trastuzumab therapy to nonbrain progression. The direction of the effect was not specified in the article
e Based on univariable analyses only
f 83 of the 84 patient samples were analyzable
g 3-gene classifier (including hepatoma-derived growth factor [HDGF], RAD51 homolog [RAD51], and translocated promoter region [TPR]) as a predictive model representing a 13-gene profile, which was associated with early (≤ 36 months) vs. late (> 36 months) BM and included the 3 genes in the 3-gene classifier and the following 11 genes: cyclin-dependent kinase 4 (CDK4), cyclin C (CCNC), focal adhesion kinase (protein tyrosine kinase 2, PTK2), v-myc avian myelocytomatosis viral oncogene homolog (MYC), breast cancer 1 [BRCA1] associated RING domain 1 (BARD1), Fanconi anemia group G (FANCG), proliferating cell nuclear antigen (PCNA), papillary renal cell carcinoma-translocation associated (PRCC), cortactin (CTTN), and desmoplakin (DSP)