Table 3.

Predictors of Survival Among Patients with HER2+ Breast Cancer and Brain Metastasis

Citation				Predictors for Shorter Time to Death (i.e., Survival) After BM Diagnosis
	HER2+ Group	Sample Size, n	Median Time to Death After BM Diagnosis, mo	Age	HR Status	No. of Brain Lesions	Anti-HER2 Therapy	Any Systemic Treatment	Other
Ahn et al., 2013 [17]	Without trastuzumab	39	19.1a	NR	NR	NR	No trastuzumab vs. trastuzumab	NR	NR
	With trastuzumab	47	26.9a
Anders et al., 2011 [15]	HR-	18	14.3 (95% CI, 3.2–36.2)	No association	No association	NR	NR	NR	Race (no association)
	HR+	21	15.2 (95% CI, 7.8–40.4)
Anwar et al., 2021 [32]	All	39	13.93 (95% CI 10.53–20.67)b	NR	No association	NR	NR	NR	▪ Number of prior lines of therapy (no association) ▪ Liver metastasis (no association) ▪ Lung metastasis (no association) ▪ Bone metastasis (no association)
Bergen et al., 2021 [19]	All	252	Before 2000: 12 2000–2010: 11 After 2010: 22	Included in DS-GPA but not reported independently	Included in DS-GPA but not reported independently	NR	▪ No HER2-targeted therapy vs. therapy with trastuzumab + pertuzumab, or trastuzumab alone, or lapatinib alone, or T-DM1 alone ▪ Other HER2-targeted therapy vs. trastuzumab + pertuzumab ▪ No HER2-targeted therapy vs. trastuzumab + lapatinib (no association)	NR	▪ DS-GPA ▪ Time period (year) of initial BC diagnosis (<  2000, 2000–2010, >  2010) (no association)
Berghoff et al., 2012 [30]	All	102	7 (95% CI, 4.3–969)	NR	NR	NR	▪ Local therapyc alone vs. trastuzumab-based therapy after local therapy	NR	NR
Braccini et al., 2013 [36]	All	109	11.9 (95% CI, 8.7–15.5)	NR	No association	NR	▪ No anti-HER2 therapy vs. anti-HER2 therapy ▪ Trastuzumab alone or lapatinib alone vs. trastuzumab + lapatinib (sequentially)	NR	NR
Brufsky et al., 2011 [31]	All	377	13.0 (range, 0.1–55.5)d	No association	No association	NR	▪ No trastuzumab vs. trastuzumab	▪ No chemotherapy vs. chemotherapy	▪ No surgery vs. surgery ▪ Radiotherapy – no association ▪ ECOG PS ≥ 2 vs. 0 or 1 ▪ CNS disease at mBC diagnosis vs. no CNS disease at mBC diagnosis
Duchnowska et al., 2012 [21]	All	142	28 (95% CI, 16–32)	NR	NR	NR	▪ NR	NR	NR
Gori et al., 2019 [24]	All	154	24.5	≥ 60 y vs. <  60 y at BM diagnosise	No association	>  3 vs. 1–3 BMse	▪ Systemic therapy without HER2-targeted agents or no systemic therapy vs. HER2-targeted agents	NR	▪ WBRT or no local treatment vs. surgery and/or SRS ▪ KPS ≤ 7 0 vs. >  70 ▪ Presence of neurologic symptoms
Hayashi et al., 2015 [25]	ER+	162	16.5 (95% CI, 11.9–21.1)	NR	No association	>  3 vs. ≤ 3 BMs	▪ Neither trastuzumab nor lapatinib vs. at least one of these after BM diagnosis ▪ Either trastuzumab alone, lapatinib alone, or no HER2-targeting agent vs. trastuzumab and lapatinib after BM diagnosis	NR	NR
	ER-	270	11.5 (95% CI, 9.1–13.8)
Heitz et al., 2009 f [29]	All	245	11	NR	NR	NR	▪ NR	NR	▪ NR
Jang et al., 2011 [34]	All	137	5.2 (95% CI, 3.6–6.8)	NR	NR	NR	▪ NR	NR	▪ NR
Kaplan et al., 2012 [33]	ER−/PR-	102	11.04 (95% CI, 6.18–15.90)	≥ 46 y vs. <  46 y at BM diagnosise (suggestive association in multivariable analyses)	No association	>  3 vs. ≤ 3 BMse (suggestive association in multivariable analyses)	▪ Trastuzumab- or lapatinib-based therapy alone vs. trastuzumab- and lapatinib-based therapy (sequential) ▪ Trastuzumab-based therapy alone vs. lapatinib-based therapy alone	NR	▪ KPS ≤ 70 vs. >  70 ▪ Tumor grade 3 vs. grade 1–2 ▪ ≥ 2 vs. <  2 metastatic sites outside the brain ▪ No neurosurgery vs. neurosurgery ▪ No radiosurgery vs. radiosurgery
	Luminal Bf	113	9.99 (95% CI, 4.99–14.98)
Kuba et al., 2014 [35]	All	26	23 (95% CI, 14–31)	No association	NR	No association	▪ NR	NR	▪ PS ≥ 2 vs. 0/1 ▪ Undergoing surgery or SRS (no association)
Martin et al., 2017 [38]	HR+	136	21 (IQR: 6-not reached)g	NR	NR	NR	▪ NR	NR	▪ NR
	HR-	106	10 (IQR: 4–27)g
Maurer et al., 2018 [26]	All	483	20.8 (IQR: 5.36-not reached)	NR	NR	NR	▪ No association	NR	▪ CNS symptomsh vs. no CNS symptoms at BM diagnosis
Morikawa et al., 2018 [27]	All	100	19.4 (95% CI, 15.5–26.6)	No association	No association	Multiple lesions vs. single lesion	▪ No anti-HER2 use vs. anti-HER2 use after BM diagnosis ▪ No anti-HER2 use vs. lapatinib use after BM diagnosis	NR	▪ KPS < 70 vs. ≥ 70 ▪ Neurologic symptoms vs. no neurologic symptoms ▪ Uncontrolled extracranial disease vs. controlled
Mounsey et al., 2018 [20]	All	123	18.1 (95% CI, 14.9–24.6)	NR	NR	NR	▪ No HER2-targeted therapy vs. HER2-targeted therapy after BM diagnosis	NR	▪ NR
Niwinska et al., 2010 [39]	All	109	9 (range, 0.6–3.4)	NR	NR	NR	▪ No systemic therapy or chemotherapy without trastuzumab vs. chemotherapy with trastuzumab	WBRT alone vs. systemic therapyi after WBRT	▪ KPS < 70 vs. ≥ 70 ▪ RPA RTOG Prognostic class III vs. class I/II ▪ Visceral metastasis vs. no visceral metastasis
Sperduto et al., 2013 [37]	HR+	98	22.9 (95% CI, 16.1–29.5)	NR	NR	NR	▪ NR	NR	▪ NR
	HR-	119	17.9 (95% CI, 13.4–22.9)
Witzel et al., 2018 [16]	All	732	11.6 (95% CI, 10.0–13.4)	NR	NR	NR	▪ NR	NR	▪ NR
Yap et al., 2012 [18]	All	280	10.9 (95% CI, 9.0–11.9)	Older age vs. younger age at BM	NR	Multiple lesions vs. single lesion	▪ No anti-HER2 treatment vs. anti-HER2 treatment after BM diagnosis ▪ No anti-HER2 treatment or trastuzumab alone vs. lapatinib alone after BM diagnosis ▪ No anti-HER2 treatment vs. trastuzumab alone after BM diagnosis ▪ Anti-HER2 therapy before BM (no association with survival after BM)	▪ No chemotherapy vs. receipt of chemotherapy after BM diagnosis ▪ No hormonal therapy vs. receipt of hormonal therapy after BM	▪ NR
Zhang et al., 2016 [28]	All	60	12 (range, 1–94)	<  50 y vs. ≥ 50 y at BM diagnosise	No association	Multiple lesions vs. single lesione	▪ No anti-HER2 therapy after WBRT vs. anti-HER2 therapy after WBRT ▪ No systemic therapy, anti-HER2 therapy alone, or chemotherapy alone after WBRT vs. both anti-HER2 therapy and chemotherapy after WBRT	[See “Anti-HER2 therapy” column]	▪ Uncontrolled extracranial metastasis vs. controlled ▪ KPS < 70 vs. ≥ 70e ▪ Total dose radiotherapy (no association)e ▪ Time from BC diagnosis to BM diagnosis (no association)e

BC breast cancer; BM brain metastasis; CI confidence interval; CNS central nervous system; DS-GPA diagnosis specific graded prognostic assessment

Score (includes BC subtype, age < 60 or > 60 years, Karnofsky performance status), ECOG Eastern Cooperative Oncology Group; ER estrogen receptor; HER2 human epidermal growth factor receptor 2; HR hormone receptor; IQR interquartile range; KPS Karnofsky performance score; mBC metastatic breast cancer; NR not reported; PR progesterone receptor; PS performance status; RPA RTOG recursive partitioning analysis of Radiation Therapy Oncology Group prognostic class; SRS stereotactic radiosurgery; T-DM1 trastuzumab emtansine; WBRT whole-brain radiotherapy

^a Time from diagnosis of distant metastasis

^b Represents median time to death after start of pyrotinib therapy

^c Local therapy for BM including surgery and/or radiotherapy

^d Overall survival after BM for all patients diagnosed with BM, including patients who presented with BM at the time of their mBC diagnosis (n = 75 [19.9%]; overall survival after diagnosis was 20.3 months [range, 1.0–55.5]) and patients who were diagnosed with BM after their mBC diagnosis (n = 302 [80.1%]; overall survival after BM diagnosis was 9.6 months [range, 0.1–54.5])

^e Based on univariable analyses only

^f Luminal B subtype is defined as HER2+ status with ER+ and/or PR+

^g Survival defined as the time between BC diagnosis and death

^h The most common symptoms were headaches (50.0%), nausea and vomiting (25.0%), confusion and memory impairment (18.2%), paresis (18.2%), aphasia and dysarthria (6.8%), and seizures (6.8%)

ⁱ Includes chemotherapy, endocrine therapy, and HER2-targeted therapy