Table 3. Stereotactic radiotherapy combined with targeted therapy or immunotherapy for the treatment of brain metastases of breast cancer.

Reference	Study type	Study population	Treatment	Toxicity	Intracranial response	Median overall survival
Bartsch 2012 (31)	retrospective	n = 80	RT (WBRT/RS) + trastuzumab +/− lapatinib	not reported	not reported	RT + trastuzumab: 13 m RT + trastuzumab + lapatinib: not reachet at 24 m FU, (HR: 0.279; 95% CI: [0.1; 0.76])
Yap 2012 (20)	retrospective	n = 280	RT (WBRT/RS) +/− trastuzumab +/− lapatinib	not reported	not reported	RT + trastuzumab + lapatinib: 25.9 m, RT + lapatinib: 21.4 m, RT + trastuzumab: 10.5 m RT without sys. treatment: 5.7 m
Yomo 2013 (21)	retrospective	n = 40	RT (RS) +/− lapatinib	not reported	local 1-year tumor control: RS – lapatinib: 69% RS + lapatinib: 86% (p < 0.001)	RS – lapatinib: 15 m RS + lapatinib: 19.5 m (p = 0.530)
Miller 2017 (22)	retrospective	n = 233	RT (WBRT/RS) +/− HER2 new +/− lapatinib	incidence of radio- necrosis at‧ 12 m: RT: 6.3%, RT + lapatinib: 1.3% (p = 0,001)	incidence of local recurrence at 12 m: RT: 15.1% RT+ lapatinib: 5.7% (p < 0.001)	RT: 15.4 m RT + lapatinib: 21.1 m (p = 0.03)
Kim 2019 (23)	retrospective	n = 84	RT (RS) +/− lapatinib	incidence of radio- necrosis at 12 m: RT – lapatinib: 3.5%, RT + lapatinib: 1.0% (p = 0.27)	PD local RT − lapatinib: 43%, RT + lapatinib: 25% p = 0121 PD at 12 m: RT – lapatinib: 49%, RT + lapatinib: 48% (p = 0.91)	RT – lapatinib: 2.,1 m, RT + lapatinib: 40.4 m (p = 0.155)
Parsai 2019 (24)	retrospective	n = 126	RT (RS) +/− lapatinib	incidence of radio- necrosis at 12 m: RT: 6.3%, RT + lapatinib: 1.3% (p < 0.01)	incidence of local recurrence at 12 m: RT: 15.1%, RT + lapatinib: 5.7% (p < 0.01)	RT: 19.5 m, RT + lapatinib: 27.3 m (p = 0.03)
Kotecha 2019 (32)	retrospective	n = 150	RT (RS) +/− ICI	not reported	intracranial response rate:immediate ICI: 71% non-immediate ICI: 53% (p < 0.008)	30 m

FU, follow-up; HR, hazard ratio; Her2, human epidermal growth receptor 2; ICI, immune checkpoint inhibitor; m, months; PD, progressive disease;

RS, radiosurgery; RT, radiotherapy; WBRT, whole-brain radiation therapy; 95% CI, 95% confidence interval