"Resurrection of clinical efficacy" after resistance to endocrine therapy in metastatic breast cancer

BACKGROUND: In a significant proportion of metastatic breast cancer (MBC) patients whose tumour has progressed within 6 months of endocrine therapy (de novo resistance), it is generally believed that the chance of achieving clinical benefit (CB) with further endocrine therapy is minimal. METHODS: Data was retrieved from a prospectively updated database of metastatic breast cancer. Relevant data was exported to SPSS™ software for statistical analysis. RESULTS: In oestrogen receptor (ER) positive MBC patients with assessable disease, CB was achieved in 159 (71.3%) (1(st )line) patients. When these patients were put on further endocrine therapy, the CB rates were 63.2% (on 2(nd )line), 46.1% (on 3(rd )line) and 20% (on 4(th )line) with a median duration of response (DOR) in those with CB of 22, 12, 11 and 15 months respectively. The remaining 64(28.7%) patients had de novo resistance on 1(st )line endocrine therapy. Seventeen of these patients were treated with further endocrine therapy. The CB rates were 29.4% (on 2(nd )line) and 22.2% (on 3(rd )line) with a median DOR in those with CB of 22.7 months and 14 months respectively. CONCLUSION: The chance of further endocrine response continues to decrease with each line of therapy, yet CB is still seen with reasonable duration even with a 4(th )line agent. In addition, further endocrine response, with long duration, can be seen in a significant proportion of patients who have developed de novo resistance to 1(st )line endocrine therapy. The use of further endocrine therapy should not be excluded under these circumstances

Fulvestrant is an effective and well-tolerated endocrine therapy for postmenopausal women with advanced breast cancer: results from clinical trials

Fulvestrant (‘Faslodex’) is a new type of endocrine treatment – an oestrogen receptor (ER) antagonist that downregulates the ER and has no agonist effects. Early efficacy data from phase I/II trials have demonstrated fulvestrant to be effective and well tolerated. Two randomised phase III trials have compared the efficacy of fulvestrant and the aromatase inhibitor, anastrozole, in postmenopausal women with advanced breast cancer progressing on prior endocrine therapy. Fulvestrant (intramuscular injection 250 mg month−1) was found to be at least as effective as anastrozole (orally 1 mg day−1) for time to progression (5.5 vs 4.1 months, respectively (hazard ratio (HR): 0.95; 95.14% confidence interval (CI), 0.82–1.10; P=0.48)) and objective response 19.2 vs 16.5%, respectively; treatment difference 2.75%; 95.14% CI, −2.27 to 9.05%; P=0.31). More recently, fulvestrant has also been shown to be noninferior to anastrozole in terms of overall survival, with median time to death being 26.4 months in fulvestrant-treated patients and 24.2 months in those treated with anastrozole (HR: 0.97; 95% CI, 0.78–1.21; P=0.82). In a further randomised phase III trial, fulvestrant was compared with tamoxifen as first-line therapy for advanced disease in postmenopausal women. In the overall population, efficacy differences favoured tamoxifen and noninferiority of fulvestrant could not be ruled out. In the prospectively defined subset of patients with ER-positive and/or progesterone receptor-positive disease, there was no statistically significant difference between fulvestrant and tamoxifen. This paper reviews the efficacy and tolerability results from these trials

Gene expression profiling and histopathological characterization of triple-negative/basal-like breast carcinomas

INTRODUCTION: Breast cancer is a heterogeneous group of tumors, and can be subdivided on the basis of histopathological features, genetic alterations and gene-expression profiles. One well-defined subtype of breast cancer is characterized by a lack of HER2 gene amplification and estrogen and progesterone receptor expression ('triple-negative tumors'). We examined the histopathological and gene-expression profile of triple-negative tumors to define subgroups with specific characteristics, including risk of developing distant metastases. METHODS: 97 triple-negative tumors were selected from the fresh-frozen tissue bank of the Netherlands Cancer Institute, and gene-expression profiles were generated using 35K oligonucleotide microarrays. In addition, histopathological and immunohistochemical characterization was performed, and the findings were associated to clinical features. RESULTS : All triple-negative tumors were classified as basal-like tumors on the basis of their overall gene-expression profile. Hierarchical cluster analysis revealed five distinct subgroups of triple-negative breast cancers. Multivariable analysis showed that a large amount of lymphocytic infiltrate (HR = 0.30, 95% CI 0.09-0.96) and absence of central fibrosis in the tumors (HR = 0.14, 95% CI 0.03-0.62) were associated with distant metastasis-free survival. CONCLUSION: Triple-negative tumors are synonymous with basal-like tumors, and can be identified by immunohistochemistry. Based on gene-expression profiling, basal-like tumors are still heterogeneous and can be subdivided into at least five distinct subgroups. The development of distant metastasis in basal-like tumors is associated with the presence of central fibrosis and a small amount of lymphocytic infiltrat

In situ aromatase expression in primary tumor is associated with estrogen receptor expression but is not predictive of response to endocrine therapy in advanced breast cancer

<p>Abstract</p> <p>Background</p> <p>New, third-generation aromatase inhibitors (AIs) have proven comparable or superior to the anti-estrogen tamoxifen for treatment of estrogen receptor (ER) and/or progesterone receptor (PR) positive breast cancer. AIs suppress total body and intratumoral estrogen levels. It is unclear whether <it>in situ </it>carcinoma cell aromatization is the primary source of estrogen production for tumor growth and whether the aromatase expression is predictive of response to endocrine therapy. Due to methodological difficulties in the determination of the aromatase protein, COX-2, an enzyme involved in the synthesis of aromatase, has been suggested as a surrogate marker for aromatase expression.</p> <p>Methods</p> <p>Primary tumor material was retrospectively collected from 88 patients who participated in a randomized clinical trial comparing the AI letrozole to the anti-estrogen tamoxifen for first-line treatment of advanced breast cancer. Semi-quantitative immunohistochemical (IHC) analysis was performed for ER, PR, COX-2 and aromatase using Tissue Microarrays (TMAs). Aromatase was also analyzed using whole sections (WS). Kappa analysis was applied to compare association of protein expression levels. Univariate Wilcoxon analysis and the Cox-analysis were performed to evaluate time to progression (TTP) in relation to marker expression.</p> <p>Results</p> <p>Aromatase expression was associated with ER, but not with PR or COX-2 expression in carcinoma cells. Measurements of aromatase in WS were not comparable to results from TMAs. Expression of COX-2 and aromatase did not predict response to endocrine therapy. Aromatase in combination with high PR expression may select letrozole treated patients with a longer TTP.</p> <p>Conclusion</p> <p>TMAs are not suitable for IHC analysis of <it>in situ </it>aromatase expression and we did not find COX-2 expression in carcinoma cells to be a surrogate marker for aromatase. <it>In situ </it>aromatase expression in tumor cells is associated with ER expression and may thus point towards good prognosis. Aromatase expression in cancer cells is not predictive of response to endocrine therapy, indicating that <it>in situ </it>estrogen synthesis may not be the major source of intratumoral estrogen. However, aromatase expression in combination with high PR expression may select letrozole treated patients with longer TTP.</p> <p>Trial registration</p> <p>Sub-study of trial P025 for advanced breast cancer.</p

Decreased expression of Yes-associated protein is associated with outcome in the luminal A breast cancer subgroup and with an impaired tamoxifen response

Background: Yes-associated protein (YAP1) is frequently reported to function as an oncogene in many types of cancer, but in breast cancer results remain controversial. We set out to clarify the role of YAP1 in breast cancer by examining gene and protein expression in subgroups of patient material and by downregulating YAP1 in vitro and studying its role in response to the widely used anti-estrogen tamoxifen. Methods: YAP1 protein intensity was scored as absent, weak, intermediate or strong in two primary breast cancer cohorts (n = 144 and n = 564) and mRNA expression of YAP1 was evaluated in a gene expression dataset (n = 1107). Recurrence-free survival was analysed using the log-rank test and Cox multivariate analysis was used to test for independence. WST-1 assay was employed to measure cell viability and a luciferase ERE (estrogen responsive element) construct was used to study the effect of tamoxifen, following downregulation of YAP1 using siRNAs. Results: In the ER+ (Estrogen Receptor a positive) subgroup of the randomised cohort, YAP1 expression was inversely correlated to histological grade and proliferation (p = 0.001 and p = 0.016, respectively) whereas in the ER-(Estrogen Receptor a negative) subgroup YAP1 expression correlated positively to proliferation (p = 0.005). Notably, low YAP1 mRNA was independently associated with decreased recurrence-free survival in the gene expression dataset, specifically for the luminal A subgroup (p less than 0.001) which includes low proliferating tumours of lower grade, usually associated with a good prognosis. This subgroup specificity led us to hypothesize that YAP1 may be important for response to endocrine therapies, such as tamoxifen, extensively used for luminal A breast cancers. In a tamoxifen randomised patient material, absent YAP1 protein expression was associated with impaired tamoxifen response which was significant upon interaction analysis (p = 0.042). YAP1 downregulation resulted in increased progesterone receptor (PgR) expression and a delayed and weaker tamoxifen in support of the clinical data. Conclusions: Decreased YAP1 expression is an independent prognostic factor for recurrence in the less aggressive luminal A breast cancer subgroup, likely due to the decreased tamoxifen sensitivity conferred by YAP1 downregulation