Breast cancer leptomeningeal metastasis: propensity of breast cancer subtypes for leptomeninges and the analysis of factors influencing survival

Niwińska, Anna; Rudnicka, H; Murawska, Magdalena

doi:10.1007/s12032-012-0408-4

Cited by 97 publications

(97 citation statements)

References 31 publications

(49 reference statements)

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“…Although the study did not report whether patients were in remission prior to presenting with LM, the incidence rate was similar to that reported by Niwińska et al (7). Niwińska et al (7) also reported the concurrent occurrence of distant metastases in breast cancer patients: 48% of patients exhibited bone metastases, 38% exhibited metastases of the brain parenchyma, 36% exhibited lung metastases and 25% exhibited liver metastases (7).…”

Section: Frequency Of Lm As the First Presentation Of Distant Metastasissupporting

confidence: 71%

“…Such patients were followed up prospectively following diagnosis with the aim to identify prognostic markers of survival (7,11). No prospective studies that determined the absolute rate of LM as the only presentation of distant metastasis in breast cancer were identified.…”

Section: Frequency Of Lm As the First Presentation Of Distant Metastasismentioning

confidence: 99%

“…Previous studies have analysed the incidence and prognostic implications of LM in the following four molecular subtypes: Luminal A [estrogen receptor (ER)/progesterone receptor (PR) positive, human epidermal growth factor receptor 2 (HER2) negative]; luminal B (ER/PR positive, HER2 positive); HER2 positive (ER/PR negative, HER2 positive); and TN (ER/PR negative, HER2 negative) (7,10,13). In a cohort of 99 patients with LM, 40.5% patients were classified as TN, 37.5% as luminal A, 14% as HER2 positive and 8% luminal B, which indicates that metastasis to the meninges is most common in patients exhibiting TN breast cancer (7). When comparing the frequency of molecular subtypes in LM with that in the whole breast cancer population, the results indicate that TN patients exhibit a higher predisposition for LM than the luminal A subtype.…”

Section: Predilection Of Histological and Biological Breast Cancer Sumentioning

confidence: 99%

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Leptomeningeal carcinomatosis as the primary presentation of relapse in breast cancer

et al. 2016

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Abstract. Leptomeningeal metastasis (LM) is an uncommon presentation of relapse in breast cancer, which is associated with poor clinical outcomes and poor prognosis. Notably, LM most commonly occurs in breast cancer. The aim of the present review was to investigate the occurrence of LM as the primary presentation of relapse following remission in breast cancer patients and to determine whether specific histological subtypes are predisposed to meningeal metastases. In addition, the present review evaluated whether patients presenting with LM as the primary site of relapse exhibit differences in survival when compared with patients exhibiting metastasis to other sites. Cross-sectional studies have demonstrated that LM is commonly associated with other sites of distant metastasis including lung, liver and bone metastases. The histological breast cancer subtype most commonly associated with LM was invasive lobular carcinoma, while triple-negative breast cancer patients appear to be predisposed to the development of LM when considering the overall prevalence of histological breast cancer subtypes. At present, data regarding LM as the primary site of relapse are limited due to its rarity as the first site of metastasis in breast cancer. Case-controlled studies are required to investigate the incidence of LM as the primary site of recurrence in breast cancer patients as this would enable treatment standardization and identification of prognostic factors for improved survival.

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Section: Frequency Of Lm As the First Presentation Of Distant Metastasissupporting

confidence: 71%

Section: Frequency Of Lm As the First Presentation Of Distant Metastasismentioning

confidence: 99%

Section: Predilection Of Histological and Biological Breast Cancer Sumentioning

confidence: 99%

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Leptomeningeal carcinomatosis as the primary presentation of relapse in breast cancer

et al. 2016

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“…Leptomeningeal carcinomatosis, in which tumor cells metastasize to the leptomeninges and cerebrospinal fluid (CSF), is a particularly virulent syndrome with extremely high morbidity and mortality (1)(2)(3)(4)(5). Furthermore, central nervous system (CNS) involvement in breast cancer, including leptomeningeal carcinomatosis, seems to be increasing due to longer survival times and more efficacious treatment against other sites of systemic disease (6).…”

Section: Introductionmentioning

confidence: 99%

Molecular Profiling of Tumor Cells in Cerebrospinal Fluid and Matched Primary Tumors from Metastatic Breast Cancer Patients with Leptomeningeal Carcinomatosis

et al. 2013

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Although leptomeningeal carcinomatosis is a well-established clinical syndrome, virtually nothing is known about the tumor cells responsible for this particularly aggressive metastatic process. To isolate cerebrospinal fluid-derived tumor cells (CSFTC) from 15 patients with metastatic breast cancer diagnosed with leptomeningeal carcinomatosis, CSF samples were subjected to a two-step method involving immunomagnetic enrichment and fluorescence-activated cell sorting (IE/FACS), a technique previously used for isolating circulating tumor cells (CTC) from blood. CSFTCs were subjected to genome-wide copy number analysis by array comparative genomic hybridization. Genomic profiling was successfully performed for 13 of 15 patients (87%). Copy number analysis in CSFTCs revealed genomic alterations commonly observed in primary breast cancer and CTCs, indicating their malignant origin. Interestingly, 12 (92%) harbored high-level gains on the 8q24 locus, which includes the MYC oncogene. Comparison of CSFTCs against corresponding archival primary tumors in six patients revealed clonal relationships with some divergence. Good concordance among serial samples attested to the reproducibility of the assay. Our approach for isolation and molecular analysis of CSFTCs yielded new insights into the molecular nature of these cells. Further genomic and functional analyses may help elucidate mechanisms by which tumor cells metastasize to the central nervous system. Cancer Res; 73(23); 7134-43. Ó2013 AACR.

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“…However, the projected human CSF concentration of 5-FU at the approved clinical dose of capecitabine was still lower than the in vitro antiproliferative activity, suggesting that systemic dose of capecitabine should have little benefit in treating leptomeningeal metastasis (LM) from BC. This may explain the current clinical practice for the treatment of BC LM; 79% of the LM patients were treated by intrathecal chemotherapy, whereas only 13% of the LM patients were selected for systemic administration of capecitabine (Niwi nska et al, 2013). The BBB became structurally and functionally compromised in macroscopic brain metastasis with brain tumor beyond 1-2 mm in diameter (Eichler et al, 2011).…”

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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Breast cancer leptomeningeal metastasis: propensity of breast cancer subtypes for leptomeninges and the analysis of factors influencing survival

Cited by 97 publications

References 31 publications

Leptomeningeal carcinomatosis as the primary presentation of relapse in breast cancer

Leptomeningeal carcinomatosis as the primary presentation of relapse in breast cancer

Molecular Profiling of Tumor Cells in Cerebrospinal Fluid and Matched Primary Tumors from Metastatic Breast Cancer Patients with Leptomeningeal Carcinomatosis

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

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