Serum TIMP-1 and Response to the Aromatase Inhibitor Letrozole Versus Tamoxifen in Metastatic Breast Cancer

Lipton, Allan; Leitzel, Kim; Chaudri-Ross, Hilary A.; Evans, Dean B.; Ali, Suhail M.; Demers, Laurence M.; Hamer, Peter; Brown-Shimer, Sheryl; Pierce, Karen; Gaur, Victor; Carney, Walter P.

doi:10.1200/jco.2007.15.4336

Cited by 37 publications

(33 citation statements)

References 26 publications

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“…Interestingly, this association has also been demonstrated in metastatic colorectal cancer [23]. Furthermore, Lipton et al [13] showed that high serum TIMP-1 levels were predictive of low objective response rate of endocrine therapy in metastatic breast cancer. Recently, we have also shown that TIMP-1 immunoreactivity in breast cancer is associated with benefit from adjuvant anthracycline treatment but not from adjuvant treatment with CMF [15].…”

Section: Discussionmentioning

confidence: 84%

“…Tissue inhibitor of metalloproteinases-1 (TIMP-1) has proven to be a promising marker in breast cancer carrying both prognostic [7][8][9][10][11] and, as shown more recently, predictive information [12][13][14][15]. For example, our laboratory has previously demonstrated that high primary tumor tissue levels of TIMP-1 were significantly associated with a poor response to the most frequently used chemotherapeutic drugs in metastatic breast cancer [14].…”

Section: Introductionmentioning

confidence: 99%

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Association between tumor tissue TIMP-1 levels and objective response to first-line chemotherapy in metastatic breast cancer

Klintman¹,

Würtz²,

Christensen³

et al. 2009

Breast Cancer Res Treat

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In a previous study from our laboratory, high tumor levels of tissue inhibitor of metalloproteinases-1 (TIMP-1) have been associated with an adverse response to chemotherapy in metastatic breast cancer suggesting that TIMP-1, which is known to inhibit apoptosis, may be a new predictive marker in this disease. The purpose of this study was to investigate the association between TIMP-1 and objective response to chemotherapy in an independent patient population consisting of patients with metastatic breast cancer from Sweden and Denmark. TIMP-1 was measured using ELISA in 162 primary tumor extracts from patients who later developed metastatic breast cancer and these levels were related to the objective response to firstline chemotherapy. Increasing levels of TIMP-1 were associated with a decreasing probability of response to treatment, reaching borderline significance (OR = 1.59, 95% CI: 0.97-2.62, P = 0.07). This OR is very similar to the result from our previous study. Increasing levels of TIMP-1 were also associated with a shorter disease-free survival and overall survival, however, not statistically significant. The results from the present study support previous data that TIMP-1 is associated with objective response to chemotherapy for metastatic breast cancer.

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Section: Discussionmentioning

confidence: 84%

Section: Introductionmentioning

confidence: 99%

Association between tumor tissue TIMP-1 levels and objective response to first-line chemotherapy in metastatic breast cancer

Klintman¹,

Würtz²,

Christensen³

et al. 2009

Breast Cancer Res Treat

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“…The full network included 4 unique studies comparing tamoxifen (20 mg/day) to letrozole [31][32][33][34][35][36][37][38][39][40], anastrozole (TARGET [30,[41][42][43] and North American [29,44] studies), and exemestane [45][46][47][48][49][50][51][52]. One study comparing anastrozole to tamoxifen (40 mg/day) [53] was excluded because the dosage was incomparable to dosages of tamoxifen used in the other studies.…”

Section: Resultsmentioning

confidence: 99%

Systematic review of aromatase inhibitors in the first-line treatment for hormone sensitive advanced or metastatic breast cancer

Riemsma

Forbes

Kessels

et al. 2010

Breast Cancer Res Treat

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To undertake a systematic review of three firstline treatments (letrozole, anastrozole and exemestane) for hormone sensitive advanced or metastatic breast cancer (MBC) in post-menopausal women. We searched six databases from inception up to January 2009 for relevant trials regardless of language or publication status. Randomised controlled clinical trials assessing the safety and efficacy of first-line AIs for post-menopausal women with hormone receptor-positive (HR?, i.e. ER? and/or PgR?) with or without ErbB2 (HER2)-positive MBC, who have not received prior therapy for advanced or metastatic disease were included. Where meta-analysis using direct or indirect comparisons was considered unsuitable for some or all of the data, we employed a narrative synthesis method. Four studies (25 papers) met the inclusion criteria. From the available evidence, it was possible to directly compare the three AIs with tamoxifen. In addition, by using a network meta-analysis it was possible to compare the three AIs with each other. Based on direct evidence, letrozole seemed to be significantly better than tamoxifen in terms of time-toprogression (TTP) (HR = 0.70 (95% CI: 0.60, 0.82)), objective response rate (RR = 0.65 (95% CI: 0.52, 0.82)) and quality-adjusted time without symptoms or toxicity (QTwist difference = 1.5; P \ 0.001). Exemestane seemed significantly superior to tamoxifen in terms of objective response rate (RR = 0.68 (95% CI: 0.53, 0.89)). Anastrozole seemed significantly superior to tamoxifen in terms of TTP in one trial (HR = 1.42 (95% CI: 1.15, NR)), but not in the other (HR = 1.01 (95% CI: 0.87, NR)). In terms of adverse events, no significant differences were found between letrozole and tamoxifen. Tamoxifen was associated with significantly more serious adverse events in comparison with exemestane (OR = 0.61 (95% CI: 0.38, 0.97)); while exemestane was associated with significantly more arthralgia in comparison with tamoxifen (OR = 2.33 (95% CI: 1.07, 5.11)). Anastrozole was associated with significantly more total adverse events (OR = 1.04 (95% CI: 1.00, 1.09)) and hot flushes (OR = 1.39 (95% CI: 1.03, 1.89)) in comparison with tamoxifen in one trial; however, the other trial showed no significant differences in adverse events between anastrozole and tamoxifen. The indirect comparison of AIs with each other in women with postmenopausal, hormone sensitive advanced or MBC showed that letrozole and exemestane were better in terms of objective response rate than anastrozole; while the more clinically relevant outcomes overall survival (OS) and progression-free survival (PFS) showed no significant differences between AIs. OS and PFS showed no significant differences between AIs and hence based on these results a class effect for all AIs is possible. However, these results are based on indirect comparisons and a network analysis for which the basic assumptions of homogeneity, similarity and consistency were not fulfilled. Therefore, despite the 123Breast Cancer Res Treat (2010) 123:9-24 DOI 10.1007 fact th...

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“…From a clinical point of view, it is therefore of particluar interest that low expression of TIMP1 in resected lung tumour tissue could be also an effective prognosis marker. However, other reports indicate that high TIMP1 levels in blood are associated with poor prognosis in some cancers 37,38 . A murine model of experimental liver metastasis suggests that the metastasis-mediated by TIMP1 may depend on the specific microenvironmental context 39 .…”

Section: Wt-timp1kd +Timp1mentioning

confidence: 98%

Small GTPase Rab37 targets tissue inhibitor of metalloproteinase 1 for exocytosis and thus suppresses tumour metastasis

et al. 2014

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Rab small GTPases are master regulators of membrane trafficking and guide vesicle targeting. Recent publications show that Rab-controlled trafficking pathways are altered during tumorigenesis. However, whether any of the Rabs plays a metastasis suppressor role is least explored. Here we address the metastasis suppressive function of human Rab37 (hRAB37) using secretomics, cell, animal and clinical analyses. We show that tissue inhibitor of metalloproteinase 1 (TIMP1), a secreted glycoprotein that inhibits extracellular matrix turnover, is a novel cargo of hRAB37. hRAB37 regulates the exocytosis of TIMP1 in a nucleotide-dependent manner to inactivate matrix metalloproteinase 9 (MMP9) migration axis in vitro and in vivo. Dysfunction of hRAB37 or TIMP1 abrogates metastasis suppression. Lung cancer patients with metastasis and poor survival show low hRAB37 protein expression coinciding with low TIMP1 in tumours. Our findings identify hRAB37 as a novel metastasis suppressor Rab that functions through the TIMP1-MMP9 pathway and has significant prognostic power.

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Serum TIMP-1 and Response to the Aromatase Inhibitor Letrozole Versus Tamoxifen in Metastatic Breast Cancer

Abstract: Patients with elevated pretreatment serum TIMP-1 had a significantly reduced response and survival. Serum TIMP-1 was an independent predictive and prognostic factor. Blockade of TIMP-1 and HER-2/neu activity may be beneficial in a subset of patients with breast cancer.

Cited by 37 publications

References 26 publications

Association between tumor tissue TIMP-1 levels and objective response to first-line chemotherapy in metastatic breast cancer

Association between tumor tissue TIMP-1 levels and objective response to first-line chemotherapy in metastatic breast cancer

Systematic review of aromatase inhibitors in the first-line treatment for hormone sensitive advanced or metastatic breast cancer

Small GTPase Rab37 targets tissue inhibitor of metalloproteinase 1 for exocytosis and thus suppresses tumour metastasis

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