The value of adjuvant radiotherapy on survival and recurrence in triple-negative breast cancer: A systematic review and meta-analysis of 5507 patients

O’Rorke, Michael; Murray, Liam; Brand, Judith S.; Bhoo‐Pathy, Nirmala

doi:10.1016/j.ctrv.2016.05.001

Cited by 39 publications

(27 citation statements)

References 46 publications

(77 reference statements)

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“…Nonetheless, some patients fail targeted therapy and/or experience recurrence, prompting the continuing search for new prognostic markers (2). Confirming previous data (3), our group recently documented that the testicular antigen fibrous sheath interacting protein 1 (FSIP1) was expressed abundantly in breast cancer tissues (4), and that its abundance is correlated positively with HER2 expression and tumor invasiveness and negatively with disease-specific survival (5).…”

supporting

confidence: 71%

FSIP1 binds HER2 directly to regulate breast cancer growth and invasiveness

Liu

Zhang

Sun

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Fibrous sheath interacting protein 1 (FSIP1), a spermatogenesisrelated testicular antigen, is expressed in abundance in breast cancers, particularly in those overexpressing human epidermal growth factor receptor 2 (HER2); however, little is known about its role in regulating the growth and metastasis of breast cancer cells. We and others have shown previously that FSIP1 expression in breast cancer correlates positively with HER2-positivity, recurrence, and metastases and negatively with survival. Here, using coimmunoprecipitation and microscale thermophoresis, we find that FSIP1 binds to the intracellular domain of HER2 directly. We further show that shRNA-induced FSIP1 knockdown in SKBR3 and MCF-7 breast cancer cells inhibits proliferation, stimulates apoptosis, attenuates epithelial-mesenchymal transition, and impairs migration and invasiveness. Consistent with reduced proliferation and enhanced apoptosis, xenotransplantation of SKBR3 cells stably transfected with sh-FSIP1 into nu/nu mice results in reduced tumor volumes compared with sh-NC transplants. Furthermore, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) mapping using sh-FSIP1 gene signature yielded associations with extracellular matrix protein pathways, and a reduction in SNAI2 protein expression was confirmed on Western blot analysis. Complementarily, interrogation of the Connectivity Map using the same gene signature yielded, as top hits, chemicals known to inhibit epithelial-mesenchymal transition, including rapamycin, 17-N-allylamino-17-demethoxygeldanamycin, and LY294002. These compounds phenocopy the effects of sh-FSIP1 on SKBR3 cell viability. Thus, FSIP1 suppression limits oncogenesis and invasiveness in breast cancer cells and, considering its absence in most other tissues, including normal breast, may become a potential target for breast cancer therapy.GO analysis | KEGG pathway analysis | gene expression signature | breast cancer therapeutics

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supporting

confidence: 71%

FSIP1 binds HER2 directly to regulate breast cancer growth and invasiveness

Liu

Zhang

Sun

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…Cox regression analyses stratified by age at diagnosis (less than 40 years, 40–49 years) and country (Malaysia, Singapore, Hong Kong) were also performed. Subgroup analyses within patients with node‐negative disease (T1–2 N0 M0 tumours) and triple‐negative breast cancers (TNBC) were also undertaken.…”

Section: Methodsmentioning

confidence: 99%

Breast-conserving surgeryversusmastectomy in young women with breast cancer in Asian settings

et al. 2018

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BackgroundMastectomy rates among women with early breast cancer in Asia have traditionally been high. This study assessed trends in the surgical management of young women with early‐stage breast cancer in Asian settings. Survival in women treated with breast‐conserving surgery (BCS; lumpectomy with adjuvant radiotherapy) and those undergoing mastectomy was compared.MethodsYoung women (aged less than 50 years) newly diagnosed with stage I or II (T1–2 N0–1 M0) breast cancer in four hospitals in Malaysia, Singapore and Hong Kong in 1990–2012 were included. Overall survival (OS) was compared for patients treated by BCS and those who had a mastectomy. Propensity score analysis was used to account for differences in demographic, tumour and treatment characteristics between the groups.ResultsSome 63·5 per cent of 3536 women underwent mastectomy. Over a 15‐year period, only a modest increase in rates of BCS was observed. Although BCS was significantly associated with favourable prognostic features, OS was not significantly different for BCS and mastectomy; the 5‐year OS rate was 94·9 (95 per cent c.i. 93·5 to 96·3) and 92·9 (91·7 to 94·1) per cent respectively. Inferences remained unchanged following propensity score analysis (hazard ratio for BCS versus mastectomy: 0·81, 95 per cent c.i. 0·64 to 1·03).ConclusionThe prevalence of young women with breast cancer treated by mastectomy remains high in Asian countries. Patients treated with BCS appear to survive as well as those undergoing mastectomy.

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“…Since TNBC is not susceptible to ER- or HER2-targeted therapies, these cancers are generally treated with adjuvant, and sometimes neoadjuvant, chemotherapy, often with substantial survival benefit [ 4 ]. Adjuvant radiotherapy may also improve survival in some patient groups [ 6 ]. However, the risk of relapse within the first 3–4 years is relatively high [ 2 ].…”

Section: Introductionmentioning

confidence: 99%

Inhibition of basal-like breast cancer growth by FTY720 in combination with epidermal growth factor receptor kinase blockade

et al. 2017

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BackgroundNew molecular targets are needed for women with triple-negative breast cancer (TNBC). This pre-clinical study investigated the combination of the EGFR inhibitor gefitinib with the sphingosine kinase (SphK) inhibitor FTY720 (Fingolimod), aiming to block tumorigenic signaling downstream of IGFBP-3, which is abundantly expressed in basal-like TNBC.MethodsIn studies of breast cancer cell growth in culture, proliferation was monitored by IncuCyte live-cell imaging, and protein abundance was determined by western blotting. In vivo studies of mammary tumor growth used two models: orthotopic xenograft tumors derived from three basal-like TNBC cell lines, grown in immune-deficient mice, and syngeneic murine 4T1 tumors grown in immune-competent mice. Protein abundance in tumor tissue was assessed by immunohistochemistry.ResultsQuantitated by live-cell imaging, the inhibitor combination showed synergistic cytostatic activity in basal-like cell lines across several TNBC molecular subtypes, the synergy being decreased by IGFBP-3 downregulation. Suppression of the tumorigenic mediator CD44 by gefitinib was potentiated by FTY720, consistent with CD44 involvement in the targeted pathway. In MDA-MB-468 and HCC1806 orthotopic TNBC xenograft tumors in nude mice, the drug combination inhibited tumor growth and prolonged mouse survival, although this effect was not significant for the gefitinib-resistant cell line HCC70. Combination treatment of murine 4T1 TNBC tumors in syngeneic BALB/c mice was more effective in immune-competent than immune-deficient (nude) mice, and a relative loss of tumor CD3 (T-cell) immunoreactivity caused by FTY720 treatment alone was alleviated by the drug combination, suggesting that, even at an FTY720 dose causing relative lymphopenia, the combination is still effective in an immune-competent setting. Immunohistochemistry of xenograft tumors showed significant enhancement of caspase-3 cleavage and suppression of Ki67 and phospho-EGFR by the drug combination, but SphK1 downregulation occurred only in MDA-MB-468 tumors, so is unlikely to be integral to treatment efficacy.ConclusionsOur data indicate that targeting IGFBP-3-dependent signaling pathways through gefitinib-FTY720 co-therapy may be effective in many basal-like breast cancers, and suggest tissue IGFBP-3 and CD44 measurement as potential biomarkers of treatment efficacy.Electronic supplementary materialThe online version of this article (doi:10.1186/s13058-017-0882-x) contains supplementary material, which is available to authorized users.

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The value of adjuvant radiotherapy on survival and recurrence in triple-negative breast cancer: A systematic review and meta-analysis of 5507 patients

Abstract: N. (2016). The value of adjuvant radiotherapy on survival and recurrence in triple-negative breast cancer: a systematic review and meta-analysis of 5,507 patients. Cancer treatment reviews, 47, 12-21.

Cited by 39 publications

References 46 publications

FSIP1 binds HER2 directly to regulate breast cancer growth and invasiveness

FSIP1 binds HER2 directly to regulate breast cancer growth and invasiveness

Breast-conserving surgeryversusmastectomy in young women with breast cancer in Asian settings

Inhibition of basal-like breast cancer growth by FTY720 in combination with epidermal growth factor receptor kinase blockade

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