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Table 2 Prognostic Factors Associated with Developing Brain Metastasis Among Patients with HER2+ Breast Cancer

From: Prognostic factors of brain metastasis and survival among HER2-positive metastatic breast cancer patients: a systematic literature review

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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

  1. 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
  2. a From the time of breast cancer diagnosis
  3. b From the time of diagnosis of metastatic disease
  4. 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
  5. d Time from initiation of trastuzumab therapy to nonbrain progression. The direction of the effect was not specified in the article
  6. e Based on univariable analyses only
  7. f 83 of the 84 patient samples were analyzable
  8. 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)