Tamoxifen In Metastatic Breast Cancer Research Articles

FES Imaging to Optimize Tamoxifen for Metastatic Breast Cancer

FES Imaging to Optimize Tamoxifen for Metastatic Breast Cancer

Abstract P3-06-14: Serum activin A and response to the aromatase inhibibitor (AI) letrozole versus tamoxifen in metastatic breast cancer

Abstract Introduction: The prognostic and predictive utility of pretreatment serum activin A (TGF-B superfamily ligand) was correlated with the response of first-line metastatic breast cancer patients (MBC) in the phase 3 randomized trial of letrozole vs. tamoxifen. Methods: 555 ER+ first-line MBC patients had pretreatment serum available for activin A ELISA (R&D Systems). Clinical outcomes were analyzed using Cox proportional hazards modeling. Actin A levels were analyzed using continuous and categorical (median cutpoint) pretreatment serum activin A levels. A pretreatment serum activin A analysis was performed within the normal (not elevated, <15 ng/ml) pretreatment serum HER2 patient subgroup since tumor HER2 status was not available in this older clinical trial. Results: Serum activin A had a median of 971 pg/ml and an interquartile range of 623 and 1751 pg/ml. In the total population with available serum (n=555), patients with higher serum activin A (> median) had significantly reduced objective response rate (ORR)(17.33% vs 34.6%, Odds Ratio (OR)=0.4; p<0.0001) and reduced clinical benefit rate (CBR)(33% vs 53%, OR= 0.45; p<0.0001), as well as significantly shorter time to progression (TTP) [median 5.88 vs 10.98 mo, HR=1.69; p<0.0001], and reduced overall survival (OS) (median 22.78 vs 48.59 mo, HR=2.43; p<0.0001) compared to those with lower serum activin A (<median) (table). The results were similar in subgroup analyses within treatment arms (letrozole or tamoxifen), as well as within the subgroup of patients with normal (not elevated, <15 ng/ml) pretreatment serum HER2 levels (table). In the total population with available serum (n=555), multivariate analysis for TTP revealed that high serum activin A was a significant adverse prognostic factor (HR=1.46, p<0.001). Multivariate analysis for OS also revealed that high serum activin A was an independent adverse prognostic factor (HR 1.78, p<0.0001). Outcome (Serum activin A by median cutpoint, high vs. low)TTPOSCohortPatientsHRpHRpTotal Population5551.69<0.00012.43<0.0001Letrozole Arm2741.580.0012.24<0.0001Tamoxifen Arm2611.92<0.00012.6<0.0001Serum HER2 (not elevated)3951.55<0.00012.45<0.0001 Conclusions: Patients with high pretreatment serum activin A levels had a significantly reduced ORR, CBR, TTP and OS compared to patients with low serum activin A. The results were similar within the letrozole or tamoxifen treatment arms, and within the serum HER2 not-elevated subgroups. High pretreatment serum activin A level is associated with relative resistance to hormone therapy in first-line metastatic breast cancer. Citation Format: Meghan Jensen, Ashley Kang, Suhail M Ali, Kim Leitzel, Ashwani Garg, Jaqueline Rogerio, David Chen, Raymond Hall, Scott Hofsess, Hilary A Chaudri-Ross, Nicholas Bade, Walter P Carney, Allan Lipton. Serum activin A and response to the aromatase inhibibitor (AI) letrozole versus tamoxifen in metastatic breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-06-14.

Abstract P4-02-02: Targeted molecular characterization of serum derived cell free DNA from metastatic breast cancer patients treated with first-line tamoxifen

Abstract Background: Evaluation of cell-free DNA (cfDNA) is a very attractive tool to serve as "liquid biopsy" to define and establish mutational changes in circulating tumor DNA (ctDNA) non-invasively during therapy. Aim: To identify tumor specific mutations in serum cfDNA associated with resistance against tamoxifen in metastatic breast cancer. Materials & Methods: Ten metastatic ER-positive breast cancer patients treated with first-line tamoxifen of whom blood sera was available at start therapy, during treatment and at disease progression were selected. DNA was isolated from normal (nDNA) and primary tumor (ptDNA) tissue and from sera (cfDNA). DNA was analyzed with next generation sequencing by the ion-PGM system (Life Technologies) for a panel of 45 cancer genes. This panel included the most frequently mutated genes for breast, colon, prostate and ovarian cancer reported in the Catalogue Of Somatic Mutations In Cancer (Cosmic database, Release 67; cancer.sanger.ac.uk/). In total 1242 exons (∼255kb) were sequenced with 200 to 5000x reads depth coverage. The panel analyzed all exons for 39 genes and only hotspot exons for 6 oncogenes. Variant Caller software (Life Technologies; version 4.16) was applied to detect non-synonymous and stop-gain single nucleotide variants (SNVs) within the sequenced DNA. Hotspot mutations detected in PIK3CA exons 9 and 20 were validated with snapshot multiplex assays. Results: Variant Caller analyses revealed in total 252 SNVs within the 40 DNAs from tumor tissue and/or serum analyzed which were not detected in normal tissue. Of these, 229 SNVs were novel and not yet reported in the Cosmic database. Mutations were detected for 10 genes in both ptDNA and cfDNA, which enabled us to characterize ctDNA in serum of nine out of ten patients. The discovered mutations were already reported in Cosmic for PIK3CA, TP53, and NF1, but not for CDH1, APC, SMAD4, MLL, AKAP, CREBBP and MLL2. The PIK3CA, TP53 and APC mutations were observed in tumor and sera for 2, 3 and 2 patients, respectively. Mutations in the other genes, except MLL, were unique for individual patients. The mutation for MLL was seen in almost all patients at low frequencies (1-5%). The hotspot mutations in PIK3CA were confirmed with snapshot assays in the sequenced samples and in additional sera. In four patients, Cosmic reported mutations in BRCA1, KAT6B, MAP3K1, MLL2, PTCH1 and PTEN occurred in ctDNA at disease progression while they were not found in the primary tumor nor in preceding sera. The mutation frequencies ranged from 3% for BRCA1 and MAP3K1 to 6% for MLL2. Moreover, mutations for MED12 (3%) and MLL3 (4%), not yet reported in Cosmic, were each observed in two sera at disease progression for two additional patients. The remaining SNVs are currently verified for their authenticity and occurrence in ptDNA and/or ctDNA. Conclusion: Molecular characterization of tumor and serum derived DNA with targeted next generation sequencing enabled us to identify ctDNA in serum and to detect mutations at disease progression that might play a role in resistance to first-line tamoxifen. Citation Format: Maurice Jansen, Corine Beaufort, Jean Helmijr, Ronald van Marion, Niels Krol, Kim Monkhorst, Marian van Fessem, Ron van Schaik, Marcel Smid, Marion Meijer van Gelder, Maxime Look, Anita Trapman, Diana Ramirez-Ardila, Irene Lurkin, Ellen Zwarthoff, John Martens, John Foekens, Winand Dinjens, Stefan Sleijfer, Els Berns. Targeted molecular characterization of serum derived cell free DNA from metastatic breast cancer patients treated with first-line tamoxifen [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-02-02.

High protein expression of EZH2 is related to unfavorable outcome to tamoxifen in metastatic breast cancer

Metastatic breast cancer (MBC) is a highly heterogeneous disease with great differences in outcome to both chemo- and endocrine therapy. Better insight into the mechanisms underlying resistance is essential to better predict outcome to therapy and to obtain a more tailored treatment approach. We have previously described that increased mRNA expression levels of Enhancer of Zeste homolog (EZH2) are associated with worse outcome to tamoxifen therapy in MBC. Here, we explored whether this is also the case for EZH2 protein expression. A tissue microarray (TMA) was created using formalin-fixed, paraffin-embedded estrogen receptor (ER)-positive primary breast tumor tissues of 250 MBC patients treated with first-line tamoxifen. Quantity and intensity of EZH2 expression were determined by immunohistochemistry (IHC) and both were used to generate and group scores according to a previously described method for scoring EZH2. In total, 116 tumors (46%) were considered to be EZH2 positive. The presence of EZH2 protein expression was significantly associated with progression-free survival (PFS) in both univariate [hazard ratio (HR) 1.51, 95% confidence interval (CI) 1.17-1.97, P = 0.002] and multivariate analysis including traditional factors associated with tamoxifen outcome (HR 1.41, 95% CI 1.06-1.88, P = 0.017). Considering quantity irrespective of intensity, tumors with >50% EZH2-positive cells had the worst PFS (HR 2.15, 95% CI 1.42-3.27, P < 0.001), whereas intensity alone did not show a significant association with PFS. Application of other methods of scoring EZH2 positivity resulted in a similar significant association between the amount of EZH2 positive cells and PFS. In addition to EZH2 mRNA levels, these results suggest that protein expression of EZH2 can be used as a marker to predict outcome to tamoxifen therapy. This provides new rationale to explore EZH2 inhibition in the clinical setting and increases the possibilities for a more personalized treatment approach in MBC patients.

A phase I pharmacokinetics study of lapatinib and tamoxifen in metastatic breast cancer (EORTC 10053 Lapatam study)

ObjectiveThis phase I study assessed the pharmacokinetic (PK), tolerability, safety and preliminary clinical activity of tamoxifen (T) and lapatinib (L) in patients with metastatic breast cancer (MBC). MethodsPatients (pts) with hormone receptor positive MBC, irrespective of HER-2 status, were randomly assigned to T → T + L group, tamoxifen in cycle 1 for 28 days then adding lapatinib on day 1 of cycle 2; or L → T + L group, lapatinib in cycle 1 for 14 days, then adding tamoxifen on day 1 of cycle 2 to evaluate the potential drug–drug PK interaction at steady-state. The dose of tamoxifen was 20 mg/day and lapatinib 1500 mg/day. ResultsTwenty-five pts were enrolled of which 23 started treatment, five (22%) of them were HER-2 positive. Median age was 59 years and 96% had PS ≤1. Eleven (91.7%) pts in the T → T + L group and 10 (76.9%) in L → T + L group received at least 2 cycles of treatment. The most frequently reported drug-related adverse events (>25% of patients) were diarrhoea (62%), anaemia (56%), rash (52%), fatigue (52%), dermatology other (34%) and leukopenia (28%). Grade 3–4 drug-related toxicities were infrequent (<10%). No cardiotoxicity was observed. T plasma concentrations did not appeared to be affected by the presence of lapatinib. L steady-state plasma concentrations were 20% lower after 28 days of co-administration with T. Eight (36.4%) patients experienced stable disease and median progression free survival was 2.7 months. ConclusionsThe combination of L and T was safe and clinically active. T affected L plasma concentrations, which remained within the therapeutic index.

Abstract P6-04-08: FOXA1 expression: regulated by EZH2 and associated with favorable outcome to tamoxifen in advanced breast cancer

Abstract Background: Enhancer of Zeste Homolog 2 (EZH2) is a member of the polycomb complex 2 and serves as a histone methyltransferase. Through trimethylation of histone 3 of lysine 27, EZH2 regulates ‘genome wide’ gene transcription silencing. Downregulation of EZH2 is associated with increased expression of the estrogen receptor (ER) and favorable outcome to tamoxifen in metastatic breast cancer. The binding of ER to its target genes is enhanced by Forkhead Box A1 (FOXA1), a pioneer factor that binds to and opens chromatized DNA. The aim of this study is to investigate the potential association between EZH2 and FOXA1 and their relation with treatment outcome in patients with advanced breast cancer. Experimental design: EZH2 and FOXA1 mRNA levels were analysed using available gene expression profile-data of 344 primary breast cancer specimens of lymph-node-negative (LNN) patients and in 109 ER-positive (ER+) tumors of patients with metastatic disease treated with first-line tamoxifen. To functionally analyze EZH2, cell lines were generated with different knockdown-constructs for EZH2, followed by evaluation of mRNA and protein expression levels and chromatin immunoprecipitation (ChIP) experiments combined with qPCR and/or next generation sequencing (NGS; ChIPseq). Results: In the 344 LNN breast tumors, EZH2 was highly expressed in breast tumors of the basal subtype. In contrast, FOXA1 was hardly expressed in this subtype, but highly in the luminal A and B subtypes. FOXA1 was related to a prolonged time to progression (TTP) after tamoxifen (HR = 0.51 [0.35–0.74], P &amp;lt; 0.001) in 59 LNN patients with ER+ primary tumors and advanced disease. This positive association between FOXA1 and TTP could be confirmed in an independent set of 109 ER+ primary tumors of patients with metastatic disease treated with tamoxifen (HR = 0.56 [0.37–0.85] p = 0.006). We obtained 50–70% EZH2 knockdown in the breast cancer cell lines MCF7 (ER+/PR+/FOXA1+), SUM52PE (ER+/PR−/FOXA1+), and MM231 (ER−/PR−/FOXA1−). ChIP followed by qPCR demonstrated higher levels of H3K27 trimethylation at the ER-locus in the parental cell lines compared to the EZH2-knockdowns for MM231 and at the PR-locus for SUM52PE and MM231. ChIPseq evaluation in the EZH2 knockdown of MM231 identified 200 loci with a significant decrease in read numbers for H3K27me3 compared to the parental. Interestingly, amongst these 200 loci the FOXA1-locus was identified. These results suggest FOXA1 as an EZH2-target since its expression was not seen in the parental MM231. Conclusion: High EZH2 and low FOXA1 mRNA levels are associated with poor clinical outcome for tamoxifen therapy of advanced breast cancer. Functional studies indicate that EZH2 might regulate the expression of FOXA1. These results suggest that EZH2 and/or FOXA1 could be used as a predictive marker to identify patients at risk for tamoxifen therapy failure and possibly as a target for therapy. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-04-08.

P4-01-17: TIMP-1 Over-Expression Confers Resistance of MCF-7 Breast Cancer Cells to Fulvestrant.

Abstract Background Endocrine resistance represents a major challenge in the management of estrogen receptor (ER) positive breast cancer. Currently no predictive biomarkers for endocrine resistance in ERpositive breast cancer patients are in clinical use. In a clinical study, patients with metastatic breast cancer and high levels of serum Tissue Inhibitor of Metalloproteinases-1 (TIMP-1) had less benefit from endocrine therapy than patients with a lower level of serum TIMP-1 [1]. Therefore, we evaluated the association between TIMP-1 and response to endocrine therapy using an in vitro approach. We have previously presented initial results on TIMP-1 and response to endocrine therapy [2]. Materials and Methods: MCF-7 cells were stably transfected with pcDNA3.1(Hyg)-TIMP-1 plasmid, and a panel of 11 subclones with different expression levels of TIMP-1 was generated. TIMP-1 expression levels were confirmed using enzyme-linked immunosorbent assay (ELISA). Four subclones with high or low TIMP-1 expression were analyzed for the growth response to estrogen, 4-hydroxytamoxifen and fulvestrant. These four subclones were analyzed for protein expression by western blotting. All subclones were analyzed by whole human genome oligo microarrays 4×44K for determination of gene expression levels. Data were analyzed using the limma R/Bioconductor package. Paired-end Solexa sequencing was applied to selected subclones with high and low TIMP-1 levels to identify transcriptomic changes. Results: High expression of TIMP-1 was associated with resistance to fulvestrant, whereas growth response to either estrogen or 4-hydroxytamoxifen was independent of TIMP-1 expression levels. High expression of TIMP-1 protein and mRNA was associated with undetectable levels of progesterone receptor (PgR) protein and mRNA whereas ER protein and mRNA levels were unaffected by TIMP-1. To characterize the potential role of TIMP-1 in estrogen signaling we analyzed the expression of reported estrogen-responsive genes and no general change was observed. We identified genes that correlated positively or negatively to TIMP-1 expression. Among the identified genes was PgR, which is a direct target for ER. Conclusion: Our data suggest that a high expression of TIMP-1 in vitro is associated with resistance to fulvestrant but not to 4-hydroxytamoxifen. Estrogen-regulated genes are not generally affected by changes in TIMP-1 expression levels and therefore TIMP-1 appears to affect endocrine resistance through other mechanisms than globally regulating ER signaling. However, high expression of TIMP-1 is associated with loss of PgR and this may be related to the resistance towards fulvestrant.

High miR-26a and low CDC2 levels associate with decreased EZH2 expression and with favorable outcome on tamoxifen in metastatic breast cancer

For patients with metastatic breast cancer, we previously described that increased EZH2 expression levels were associated with an adverse outcome to tamoxifen therapy. Main objective of the present study is to investigate miR-26a and miR-101 levels, which both target EZH2, for their association with molecular pathways and with efficacy of tamoxifen as first-line monotherapy for metastatic breast cancer. Expression levels were measured using quantitative Real-Time Polymerase Chain Reaction (qRT-PCR) in primary breast cancer specimens of 235 estrogen receptor-α (ER)-positive patients. Pathway analysis was performed on microarray data available for 65 of these tumors. Logistic regression and Cox uni- and multivariate analysis were performed to relate expression levels with clinical benefit and time to progression (TTP). Increasing levels of miR-26a were significantly (P < 0.005) associated with both clinical benefit and prolonged TTP, whereas miR-101 was not. Cell cycle regulation and CCNE1 and CDC2 were the only significant overlapping pathway and genes differentially expressed between tumors with high and low levels of miR-26a and EZH2, respectively. In addition, increasing mRNA levels of CCNE1 (P < 0.05) and CDC2 (P < 0.001) were related to poor outcome. Multivariate analysis revealed miR-26a and CDC2 as an optimal set of markers associated with outcome on tamoxifen therapy, independently of traditional predictive factors. To summarize, only miR-26a levels are related with treatment outcome. Cell cycle regulation is the only overlapping pathway linked to miR-26a and EZH2 levels. Low mRNA levels of EZH2, CCNE1, and CDC2, and high levels of miR-26a are associated with favorable outcome on tamoxifen.Electronic supplementary materialThe online version of this article (doi:10.1007/s10549-011-1877-4) contains supplementary material, which is available to authorized users.

The impact of CYP2D6-predicted phenotype on tamoxifen treatment outcome in patients with metastatic breast cancer

Background:Cytochrome P450 2D6 (CYP2D6) has a crucial role in the metabolic conversion of tamoxifen into the active metabolite endoxifen. In this cohort study, the effect of CYP2D6-predicted phenotype, defined as the combined effect of CYP2D6 genetic variation and concomitant use of CYP2D6-inhibiting medication, on time to breast cancer progression (TTP) and overall survival (OS) in women who use tamoxifen for metastatic breast cancer (MBC) was examined.Methods:We selected patients treated with tamoxifen (40 mg per day) for hormone receptor-positive MBC from whom a blood sample for pharmacogenetic analysis (CYP2D6*3, *4, *5, *6, *10 and *41) was available. Patient charts (n=102) were reviewed to assess TTP and OS, and to determine whether CYP2D6 inhibitors were prescribed during tamoxifen treatment.Results:OS was significantly shorter in patients with a poor CYP2D6 metaboliser phenotype, compared with extensive metabolisers (HR=2.09; P=0.034; 95% CI: 1.06–4.12). Co-administration of CYP2D6 inhibitors alone was also associated with a worse OS (HR=3.55; P=0.002; 95% CI: 1.59–7.96) and TTP (HR=2.97; P=0.008; 95% CI: 1.33–6.67) compared with patients without CYP2D6 inhibitors.Conclusion:CYP2D6 phenotype is an important predictor of treatment outcome in women who are receiving tamoxifen for MBC. Co-administration of CYP2D6 inhibitors worsens treatment outcome of tamoxifen and should therefore be handled with care.

Abstract C118: Influence of CYP2D6 phenotype on tamoxifen-treatment outcome in women with metastatic breast cancer

Abstract Introduction: Cytochrome P450 2D6 (CYP2D6) plays a crucial role in the metabolism of tamoxifen into the active metabolite endoxifen. Genetic variation in the CYP2D6 gene and co-administration of CYP2D6 inhibiting medication markedly reduce endoxifen plasma concentrations in patients. The impact hereof on the outcome of tamoxifen therapy in metastatic breast cancer is insufficiently known. In this cohort study, we examined the effect of CYP2D6 predicted phenotype (the combined effect of genetic variants and concomitant use of CYP2D6 inhibiting medication) on time to progression (TTP) and overall survival (OS) in women using tamoxifen for metastatic breast cancer was examined. Methods: We selected patients treated with tamoxifen (40mg/day) for hormone receptor positive metastatic breast cancer of whom blood samples for pharmacogenetic analysis (CYP2D6*3,*4,*5,*6) were available. Patient charts were reviewed to assess patient and tumor characteristics, TTP, OS, and use of CYP2D6 inhibitors. Results: Patients with poor CYP2D6 metabolizer phenotype (PMs) had a worse OS compared to extensive metabolizers (EMs) (HR = 2.11; P=0.031; 95% CI: 1.07–4.15, see Table). Patients with an intermediate (IM) and extensive metabolizer (EM) phenotype had comparable TTP and OS, and were further considered as one group in the Kaplan-Meier estimates. For PMs, the Kaplan-Meier estimate demonstrated a shorter TTP compared to the combined group of IMs and EMs: 1.7 years (95% CI: 0.9–2.5) versus 2.9 years (95% CI: 2.3 – 3.6) respectively (P = 0.089). Overall survival of the group of IM/EM patients was significantly longer than for PM patients, being 9.9 years (95% CI: 8.2–11.6) versus 5.4 years (95% CI: 3.7–7.1), respectively (P=0.012). Co-administration of CYP2D6 inhibitors alone was also associated with a worse OS (HR=3.55; P=0.002; 95% CI: 1.59–7.96) and a worse TTP (HR=2.97; P=0.008; 95% CI: 1.33–6.67) compared to patients without CYP2D6 inhibitors. Conclusions: CYP2D6 phenotype is an important predictor of treatment outcome in women treated with tamoxifen for hormone receptor positive metastatic breast cancer. Co-administration of CYP2D6 inhibitors worsens outcome of tamoxifen therapy, and should therefore be discouraged. Effect of CYP2D6 phenotype on TTP and OS CYP2D6 phenotype Time to progression (TTP) Overall Survival(OS) Cases (n=99) Cases (n=99) HR (95% CI) HR (95% CI) P-value P-value EM n=50 n=33 HR=1.00 (ref) HR=1.00 (ref) IM n=36 n=22 HR=1.05 (0.67–1.65) HR=0.88 (0.51–1.53) P=0.82 P=0.66 PM n=13 n=12 HR=1.74 (0.92–3.28) HR=2.11 (1.07–4.15) P=0.09 P=0.03 Citation Information: Mol Cancer Ther 2009;8(12 Suppl):C118.

Prevalent breast cancer patients with a homozygous mutant status for CYP2D6*4: response and biomarkers in tamoxifen users

Retrospective studies suggest that single nucleotide polymorphisms in the cytochrome P450 2D6 (CYP2D6) gene predict reduced tamoxifen metabolism, better tolerance and worse treatment outcome. We hypothesized that women with this genotype lack tamoxifen-induced endometrial and biochemical changes in follicle-stimulating hormone (FSH) and sex hormone-binding globulin (SHBG). We identified 56 breast cancer patients attending the follow-up clinic with a homozygous mutant (HM) status for the CYP2D6*4 null variant. Here, we report a detailed assessment of tamoxifen activity in 19 CYP2D6 HM women, while they were using tamoxifen either for metastatic (n = 5) or for early disease (n = 14). We assessed response to tamoxifen in metastatic disease. Endometrial appearances and serum levels of FSH and SHBG were assessed from retrospective and prospective testing. Our findings do suggest that the presence of two CYP2D6*4 alleles does not exclude a durable response of tamoxifen in metastatic breast cancer. The transvaginal ultrasonographic appearance of the endometrium in CYP2D6*4/*4 patients on tamoxifen is similar as seen in the normal population of tamoxifen users. The endometrium is increased in thickness with subepithelial cysts and endometrial polyps. Serum levels of FSH and SHBG in CYP2D6*4 HM tamoxifen users were in the range of what would be expected during tamoxifen treatment in the general population. Our findings do show CYP2D6*4/*4 carriers to have activity of tamoxifen on breast cancer, endometrium and serum levels of FSH and SHBG. They support clinical trials prospectively testing the effect of CYP2D6 genetic variability in response to tamoxifen before denying this drug to breast cancer patients only based on their CYP2D6*4 status.

Beta-interferon, retinoids and tamoxifen in metastatic breast cancer: Long-term follow-up of a phase II study

Based on a series of in vitro data, including the additive and/or synergistic antiproliferative effect of interferon and tamoxifen on breast cancer cell lines, and on clinical reports, we designed a pilot phase II study to test the activity and toxicity of simultaneous administration of beta-interferon (beta-IFN), retinoids (R) and tamoxifen (TAM) as a salvage therapy in a group of patients with metastatic breast cancer (MBC). Herein we describe the outcome of this cohort of patients after a median follow-up of 150 months. Sixty-five stage IV breast cancer patients, 13 pre-treated with hormones, 38 with chemotherapy and 15 with both, received, as a salvage therapy, TAM, beta-IFN and R. Among 65 evaluable patients, 36 achieved a clinical response (55.5%) (95% c.i. 42-67.7%). Toxicity was moderate and mainly hepatic. Median progression-free and overall survival, which did not show any statistically significant difference in patients with different estrogen and progesterone receptor content, were 43 months and 47.9 months, respectively. In conclusion, the study shows that long-term treatment with TAM, beta-IFN and R in MBC is feasible, has moderate toxicity and seems to give a long-term benefit, irrespective of the receptorial status.

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

To determine the effect of elevated serum TIMP-1 on the response of patients with metastatic breast cancer to an aromatase inhibitor versus tamoxifen. Five hundred twenty-two patients estrogen receptor-positive metastatic breast cancer were randomly assigned to receive first-line hormone therapy with letrozole or tamoxifen. Serum tissue inhibitor of metalloproteinases-1 (TIMP-1) levels were measured using an enzyme-linked immunosorbent assay. Pretreatment serum TIMP-1 was elevated in 120 (23%) of 522 patients. Patients with elevated serum TIMP-1 had a significantly reduced objective response rate (19.2% v 30.6%; odds ratio, 0.54; P = .01), duration of response (median, 15.5 v 26.2 months; P = .001), time to treatment progression (TTP; median, 4.5 v 9.2 months; HR, 1.78; P = .0001), time to treatment failure (median, 3.5 v 9.0 months; HR, 1.77; P = .0001), and overall survival (median, 20.3 v 35.8 months; HR, 1.77; P = .0001) compared with patients with normal pretreatment TIMP-1 levels. Letrozole was superior to tamoxifen in both the normal serum TIMP-1 group (median TTP, 11.8 v 8.6 months; P = .003) and in the elevated serum TIMP-1 group (median, 6.1 v 3.2 months; P = .03) In multivariate analysis, elevated serum TIMP-1 remained an independent predictor of both shorter TTP (HR, 1.46; P = .002) and survival (HR, 1.44; P = .002), as did serum HER-2. Combined analysis of both serum TIMP-1 and HER-2/neu conferred additional ability to predict significantly different clinical outcomes compared to using either biomarker alone. 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.

A Phase I Trial and Pharmacokinetic Study of Tipifarnib, a Farnesyltransferase Inhibitor, and Tamoxifen in Metastatic Breast Cancer

Farnesyltransferase (FTase) inhibitors, which were designed to inhibit oncogenic Ras, act synergistically with tamoxifen in preclinical breast cancer models. We studied the safety and toxicity of tipifarnib in combination with tamoxifen in metastatic breast cancer. The pharmacokinetics and pharmacodynamics of tipifarnib were also assessed. Patients with metastatic, hormone receptor-positive breast cancer were enrolled. Two cohorts of patients were treated with tipifarnib at either 200 or 300 mg p.o. twice daily for 21 of 28 days. Tamoxifen (20 mg once daily) was started after 1 week of tipifarnib monotherapy to perform pharmacokinetics and FTase inhibition levels in peripheral blood mononuclear cells with tipifarnib alone and with tipifarnib and tamoxifen. A total of 12 heavily pretreated patients with prior progression on hormonal therapy were enrolled. Minimal toxicity was observed at the 200-mg dose level of tipifarnib. At the 300-mg dose, all six patients required dose reduction of tipifarnib due to toxicities that included grade 2 nausea, rash, and fatigue and grade 3 diarrhea and neutropenia. Tipifarnib pharmacokinetic and pharmacodynamic variables were similar in the presence and absence of tamoxifen. Average FTase inhibition was 42% at 200 mg and 54% at 300 mg in peripheral blood mononuclear cells. Of the 12 patients treated, there were two partial responses and one stable disease for >6 months. Tipifarnib (200 mg twice daily for 21 of 28 days) and tamoxifen (20 mg once daily) can be given safely with minimal toxicity. Tamoxifen does not have a significant effect on tipifarnib pharmacokinetics.

Exemestaneʼs advantages over tamoxifen in metastatic breast cancer

Exemestaneʼs advantages over tamoxifen in metastatic breast cancer

Tamoxifen versus toremifene in the adjuvant treatment of breast cancer

Toremifene, developed in the 1980s, is a triphenylethylene drug which binds to the Oestrogen Receptors (ERs). It may exert oestrogenic or anti-oestrogenic effects or both depending on the dose and duration of treatment, the target organ chosen, or the endpoint used [1]. Toremifene has been found to have comparable anticancer efficacy to that of tamoxifen in metastatic breast cancer, and it has, in general, a similar side-effect profile [2].

A randomised trial of buserelin and tamoxifen in metastatic breast cancer

A randomised trial of buserelin and tamoxifen in metastatic breast cancer

Estrogen receptor (ER) and progesterone receptor (PgR), by ligand-binding assay compared with ER, PgR and pS2, by immuno-histochemistry in predicting response to tamoxifen in metastatic breast cancer: A Southwest Oncology Group study

Estrogen receptor (ER) and progesterone receptor (PgR), by ligand-binding assay compared with ER, PgR and pS2, by immuno-histochemistry in predicting response to tamoxifen in metastatic breast cancer: A Southwest Oncology Group study

Estrogen receptor (ER) and progesterone receptor (PgR), by ligand-binding assay compared with ER, PgR and pS2, by immuno-histochemistry in predicting response to tamoxifen in metastatic breast cancer: A Southwest Oncology Group study

Results of estrogen receptor (ER) and progesterone receptor (PgR) ligand-binding assays (LBAs) are strongly correlated with ER and PgR by immuno-histochemistry (IHC). To investigate whether ER and PgR by IHC are also strongly correlated with tamoxifen response, time to treatment failure (TTF) and overall survival (OS), the results of the 2 methods were directly compared in 205 patients with ER(+) metastatic breast cancer treated with daily tamoxifen (Southwest Oncology Group protocol 8228) with 9 years median follow-up. pS2, another estrogen-regulated molecule, was also analyzed. Tumors were scored for IHC from 0 to 5, according to the proportion of positively stained cells. These IHC scores for both ER and PgR were significantly associated with LBA levels (p < 0.001). There was a significant direct relationship between higher IHC ER, PgR and pS2 and increasing response to tamoxifen. TTF and OS were also significantly longer for patients with higher ER or PgR, but not pS2, IHC scores. Low, intermediate and high ER or PgR categories showed similar differences in response rates whether defined by LBA or IHC. In logistic regression models which included ER, PgR and pS2 by IHC; ER and PgR by LBA; and menopausal status, only ER (IHC) and pS2 (IHC) retained significance for predicting tamoxifen response (p = 0. 02 and p = 0.005, respectively), along with menopausal status (for PgR by IHC, p = 0.09). Increasing ER and PgR by IHC, as by LBA, are thus significantly associated with a progressively better response and longer survival in ER(+) metastatic breast cancer. pS2 is also predictive in this setting.

A randomized trial of aminoglutethimide versus tamoxifen in metastatic breast cancer

We compared antiestrogen therapy (tamoxifen) with an estrogen suppression regimen (aminoglutethimide-hydrocortisone) in postmenopausal women with metastatic breast carcinoma. Fifteen of 39 patients (38%) who received tamoxifen experienced an objective tumor regression (3 complete, 12 partial remissions), whereas 13 of 36 women (36%) receiving aminoglutethimide responded (one complete remission, 12 partial remissions). The median duration of response was similar. The site of tumor involvement appears to be important in choosing between these hormonal treatments. Aminoglutethimide appears to offer a greater chance of response in patients with bone involvement.