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Abstract
Purpose: To identify the risk factors leading to new brain metastases (BM) following brain-directed treatment for initial BM resulting from breast cancer (BC).

Methods: In this multi-institutional study, 538 BC patients with available follow-up imaging after brain-directed treatment for initial BM were analyzed. Tumor molecular subtypes were classified as follows: hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-, n = 136), HER2-positive (HER2+, n = 253), or triple-negative BC (TNBC, n = 149).

Results: In 37.4% of patients, new BM emerged at a median of 10.5 months after brain-directed treatment for initial BM. The 1-year actuarial rate of new BM for HR+/HER2-, HER2+, and TNBC were 51.9%, 44.0%, and 69.6%, respectively (p = 0.008). Initial whole-brain radiotherapy (WBRT) reduced new BM rates (22.5% reduction at 1 year, p < 0.001) according to molecular subtype (HR+/HER2-, 42% reduction at 1 year, p < 0.001; HER2+, 18.5%, p = 0.004; TNBC, 16.9%, p = 0.071). Multivariate analysis revealed an increased risk of new BM for the following factors: shorter intervals between primary BC diagnoses and BM (p = 0.031); TNBC (relative to HR+/HER2-) (p = 0.016); presence of extracranial metastases (p = 0.019); number of BM (>4) (p < 0.001); and BM in both tentorial regions (p = 0.045). Anti-HER2 therapy in HER2+ patients (p = 0.013) and initial use of WBRT (p < 0.001) significantly lowered new BM development.

Conclusions: Tumor molecular subtypes were associated with both rates of new BM development and the effectiveness of initial WBRT. Anti-HER2 therapy in HER2+ patients significantly lowered new BM occurrence.

Fig 1. Tumor subtype에 따라 새로운 뇌전이 병변 (distant intracranial failure) 발생률의 차이를 보였습니다.

Fig 2. 전뇌방사선치료 (whole-brain radiotherapy)를 통해 새로운 뇌전이 병변 발생을 감소시켰으며, tumor subtype에 따라 감소율에 차이를 보였습니다. 

Affiliations

Jae Sik Kim #  1 , Kyubo Kim #  2 , Wonguen Jung  2 , Kyung Hwan Shin  1 , Seock-Ah Im  3 , Hee-Jun Kim  4 , Yong Bae Kim  5 , Jee Suk Chang  5 , Jee Hyun Kim  3 , Doo Ho Choi  6 , Yeon Hee Park  7 , Dae Yong Kim  8 , Tae Hyun Kim  8 , Byung Ock Choi  9 , Sea-Won Lee  9   10 , Suzy Kim  11 , Jeanny Kwon  12 , Ki Mun Kang  13 , Woong-Ki Chung  14 , Kyung Su Kim  2   15 , Won Sup Yoon  16 , Jin Hee Kim  17 , Jihye Cha  18 , Yoon Kyeong Oh  19 , In Ah Kim  20   21
1 Department of Radiation Oncology, Seoul National University College of Medicine, Seoul, Republic of Korea.
2 Department of Radiation Oncology, Ewha Womans University College of Medicine, Seoul, Republic of Korea.
3 Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea.
4 Department of Internal Medicine, Chung-Ang University College of Medicine, Seoul, Republic of Korea.
5 Department of Radiation Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Republic of Korea.
6 Department of Radiation Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
7 Department of Internal Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
8 Proton Therapy Center, National Cancer Center, Goyang, Republic of Korea.
9 Department of Radiation Oncology, Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul, Republic of Korea.
10 Department of Radiation Oncology, Eunpyeong St. Mary's Hospital, The Catholic University of Korea, Seoul, Republic of Korea.
11 Department of Radiation Oncology, Seoul Metropolitan Government Seoul National University Boramae Medical Center, Seoul, Republic of Korea.
12 Department of Radiation Oncology, Chungnam National University College of Medicine, Daejeon, Republic of Korea.
13 Department of Radiation Oncology, Gyeongsang National University School of Medicine and Gyeongsang National University Changwon Hospital, Changwon, Republic of Korea.
14 Department of Radiation Oncology, Chonnam National University Hwasun Hospital, Chonnam National University Medical School, Hwasun, Republic of Korea.
15 Department of Radiation Oncology, Dongnam Institute of Radiological and Medical Sciences, Busan, Republic of Korea.
16 Department of Radiation Oncology, Ansan Hospital, Korea University Medical College, Ansan, Republic of Korea.
17 Department of Radiation Oncology, Keimyung University Dongsan Medical Center, Keimyung University School of Medicine, Daegu, Republic of Korea.
18 Department of Radiation Oncology, Wonju Severance Christian Hospital, Yonsei University Wonju College of Medicine, Wonju, Republic of Korea.
19 Department of Radiation Oncology, Chosun University Medical School, Gwangju, Republic of Korea.
20 Department of Radiation Oncology, Seoul National University College of Medicine, Seoul, Republic of Korea. inah228@snu.ac.kr.
21 Department of Radiation Oncology, Seoul National University Bundang Hospital, Seongnam, Republic of Korea. inah228@snu.ac.kr.
# Contributed equally.