Trastuzumab treatment improves brain metastasis outcomes through control and durable prolongation of systemic extracranial disease in HER2-overexpressing breast cancer patients

Yh, Park; Mj, Park; Sh, Ji; Sy, Yi; Dh, Lim; Nam, Dahyun; Lee, Ji; Park, Kyeongmee; Choi, Dong‐Hee; Huh, SJ; Js, Ahn; Wk, Kang; Park, K; Im, Y-H.

doi:10.1038/sj.bjc.6604941

Cited by 162 publications

(115 citation statements)

References 34 publications

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“…Trastuzumab, a standard treatment agent for HER2-positive patients, is known to have little activity for reducing intracranial lesions due to poor BBB permeability. Previous studies have indicated that treatment with trastuzumab was not associated with incidence of BM [23,24], and survival after BM development was significantly longer in patients with trastuzumab than those without trastuzumab [11,25,26]. Trastuzumab combined with chemotherapy may favorably affect systemic metastatic lesions, probably leading to better systemic control and improved outcome of HER2-positive patients after BM development.…”

Section: Discussionmentioning

confidence: 99%

Clinicopathological Factors Related to the Prognosis of Metastatic Breast Cancer Patients after Development of Brain Metastasis

et al. 2015

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Background: The prognosis of breast cancer patients with brain metastasis (BM) is extremely poor, and the survival after development of BM is very short. We aimed to investigate clinicopathological factors related to significant effects on the prognosis after BM development. Patients and Methods: This is a retrospective study of 75 early breast cancer patients who received the standard of care and subsequently developed BM. Results: Breast cancer subtype was one of the significant predictors for prognosis after BM diagnosis. Luminal HER2 patients had the most favorable prognosis after BM diagnosis (p = 0.011). Favorable performance status (PS) at BM diagnosis (p < 0.001) and a single metastatic brain tumor (p = 0.032) were significantly associated with good prognosis after BM diagnosis. Metastatic time courses of the patients was found not to be significantly associated with survival after BM diagnosis. Univariate and multivariate analysis indicated that luminal HER2 cancer, favorable PS at BM diagnosis, and a single metastatic brain tumor were the independent prognostic factors for survival after BM development, making a decisive influence on local or systemic control. Conclusion: Appropriate treatments for tumor subtypes and to improve the general condition of patients would result in improved outcomes for the patients with BM.

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Section: Discussionmentioning

confidence: 99%

Clinicopathological Factors Related to the Prognosis of Metastatic Breast Cancer Patients after Development of Brain Metastasis

et al. 2015

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“…Кроме того, несколько клини-ческих исследований показали, что сочетание химио-терапии с трастузумабом повышает выживаемость даже после развития метастазов в ГМ [28,29]. Это пре-имущество, как предполагают, в основном обусловле-но улучшением контроля системного заболевания [30].…”

Section: опухоли женской репродуктивной системы Tumors Of Female Reprunclassified

Role of targeted therapy in the treatment of HER-2-positive breast cancer brain metastases

Дашян¹,

Семиглазов²,

Krivorotko³

et al. 2016

Tumors of female reproductive system

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46М а м м о л о г и я / M a m m o l o g y 1 ' 2 0 1 6 Том 12 / Vol. 12 ОПУХОЛИ ЖЕНСКОЙ РЕПРОДУКТИВНОЙ СИСТЕМЫ TUMORS OF FEMALE REPRODUCTIVE SYSTEM Лечение После рака легких 2-й наиболее частой причиной метастазов в головной мозг (ГМ) является рак мо-лочной железы (РМЖ), метастазирование при кото-ром наблюдается в 10-16 % случаев [1]. Еще у 10 % больных происходит бессимптомное метастазирова-ние, что подтверждается данными аутопсии [2]. В по-следние годы отмечается более частое выявление метастазов в ГМ, что, вероятно, связано с более дли-тельной выживаемостью больных, получающих со-временные эффективные методы лечения, а также с применением более чувствительных методов визу-ализации.Развитие метастазов в ГМ представляет собой сложный процесс, предполагающий инвазию клеток РМЖ в окружающие ткани и сосуды, циркуляцию

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“…Trastuzumab has no effect, or a limited effect, in controlling Her2 positive brain metastasis; it has been observed that the cause of death in Her2 positive BC patients due to developed brain metastases was 45.7% in a pretrastuzumab treatment group and 59.5% in a post-trastuzumab treatment group (Park et al, 2009). This is consistent with the fact that trastuzumab hardly penetrates into CNS (CSF-to-serum ratio at 0.003) (Pestalozzi and Brignoli, 2000) because of its large molecular size.…”

Section: Cns Penetration Of 5-fu To Treat Breast Cancer Brain Metastamentioning

confidence: 99%

Are Capecitabine and the Active Metabolite 5-FU CNS Penetrable to Treat Breast Cancer Brain Metastasis?

Zhang¹,

Zhang²,

Yan³

et al. 2014

Drug Metab Dispos

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Brain metastasis (BM) is increasingly diagnosed in Her2 positive breast cancer (BC) patients. Lack of effective treatment to breast cancer brain metastases (BCBMs) is probably due to inability of the current therapeutic agents to cross the blood-brain barrier. The central nervous system (CNS) response rate in BCBM patients was reported to improve from 2.6%-6% (lapatinib) to 20%-65% (lapatinib in combination with capecitabine). Lapatinib is a poor brain penetrant. In this study, we evaluated the CNS penetration of capecitabine and hoped to interpret the mechanism of the improved CNS response from the pharmacokinetic (PK) perspective. Capecitabine does not have antiproliferative activity and 5-fluorouracil (5-FU) is the active metabolite. Capecitabine was orally administered to mouse returning an unbound brain-to-blood ratio (K p,uu,brain ) at 0.13 and cerebrospinal fluid (CSF)-to-unbound blood ratio (K p,uu,CSF ) at 0.29 for 5-FU. Neither free brain nor CSF concentration of 5-FU can achieve antiproliferative concentration for 50% of maximal inhibition of cell proliferation of 4.57 mM. BCBM mice were treated with capecitabine monotherapy or in combination with lapatinib. The K p,uu,brain value of 5-FU increased to 0.17 in the brain tumor in the presence of lapatinib, which is still far below unity. The calculated free concentration of 5-FU and lapatinib in the brain tumor did not reach the antiproliferative potency and neither treatment showed antitumor activity in the BCBM mice. The CNS penetration of 5-FU in human was predicted based on the penetration in preclinical brain tumor, CSF, and human PK and the predicted free CNS concentration was below the antiproliferative potency. These results suggest that CNS penetration of 5-FU and lapatinib are not desirable and development of a true CNS penetrable therapeutic agent will further improve the response rate for BCBM.

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Trastuzumab treatment improves brain metastasis outcomes through control and durable prolongation of systemic extracranial disease in HER2-overexpressing breast cancer patients

Cited by 162 publications

References 34 publications

Clinicopathological Factors Related to the Prognosis of Metastatic Breast Cancer Patients after Development of Brain Metastasis

Clinicopathological Factors Related to the Prognosis of Metastatic Breast Cancer Patients after Development of Brain Metastasis

Role of targeted therapy in the treatment of HER-2-positive breast cancer brain metastases

Are Capecitabine and the Active Metabolite 5-FU CNS Penetrable to Treat Breast Cancer Brain Metastasis?

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