Tamoxifen Resistance In Patients Research Articles

Estrogen induces death of tamoxifen-resistant MCF-7 cells: Contrasting effect of the estrogen receptor downregulator fulvestrant

A common problem in breast cancer therapy is resistance to the antiestrogen tamoxifen. However, tamoxifen-resistant breast tumors can still respond to other hormonal therapies. In animal models of tamoxifen-resistant breast cancer cells, physiological levels of estrogen can induce tumor regression. Recently, the estrogen receptor downregulator fulvestrant was shown to promote tumor growth of tamoxifen-resistant cells when added in combination with physiological levels of estrogen. Here, we show, using a cell culture model, that continuous exposure of tamoxifen-resistant cells to physiological levels of estrogen leads to cell death. Addition of the estrogen receptor downregulator fulvestrant prevents estrogen-induced death in a dose-dependent manner. Our data indicate that endogenous levels of estrogen affect the response of tamoxifen-resistant cells to fulvestrant. These results suggest that failure of fulvestrant to inhibit tumor growth in some tamoxifen-resistant patients may be due to endogenous estrogen levels. Moreover, these studies support short-term treatment with estrogen as a second-line hormonal therapy for tamoxifen-resistant breast cancer.

Overview of tyrosine kinase inhibitors in clinical breast cancer

Studies of cell models and profiling of clinical breast cancer material to reveal the mechanisms of resistance to anti-oestrogen therapy, and to tamoxifen in particular, have reported that this phenomenon can be associated with increased expression and signalling through erbB Type 1 growth factor receptors, notably the epidermal growth factor receptor (EGFR) and HER2. Further molecular studies have revealed an intricate interlinking between such growth factor receptor pathways and oestrogen receptor (ER) signalling. Inhibition of receptor tyrosine kinase activity involved in the EGFR signalling cascade forms the basis for the use of EGFR specific tyrosine kinase inhibitors exemplified by gefitinib (ZD1839, Iressa) and erlotinib (OSI-774, Tarceva). Such agents have proved promising in pre-clinical studies and are currently in clinical trials in breast cancer, where gefitinib has been studied more extensively to date. Here, we present an overview of the current development of gefitinib in clinical breast cancer. This includes results from our clinical breast cancer trial 1839IL/0057 that demonstrate the efficacy of gefitinib within ER-positive, tamoxifen-resistant patients with locally advanced/metastatic disease, where parallel decreases in EGFR signal transduction and the Ki67 (MIB1) proliferation marker can be detected as predicted from model system studies. We also consider trials examining combination treatment with gefitinib and anti-hormonal strategies that will begin to address the clinically important question of whether gefitinib can delay/prevent onset of anti-hormone resistance.

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in breast cancer: current status and future development

Evidence suggests that the epidermal growth factor receptor (EGFR) and its ligands are involved in the pathogenesis of different human carcinomas, including breast cancer. Results of phase II clinical trials of EGFR tyrosine kinase inhibitors (TKIs) have shown that these compounds have little activity in breast cancer patients when used as single agents. The potential pitfalls of these clinical trials, and the molecular mechanisms that might be involved in regulating the sensitivity/resistance of breast cancer cells to EGFR TKIs are discussed in this brief article. In particular, preclinical findings clearly demonstrate that breast cancer cells are able to activate different mechanisms to escape the anti-tumor effects of drugs directed against growth factor-driven pathways. Therefore, it is conceivable that significant blockade of tumor growth might be obtained only through contemporary blockade of different growth promoting pathways, at least in advanced disease. In addition, preclinical and clinical findings support the use of EGFR TKIs in specific subgroups of breast cancer patients, such as estrogen receptor positive (ER+), tamoxifen resistant patients. In this regard, we describe potential future applications of these compounds in combination with other agents in the treatment of breast carcinoma.

Low ER level is one factor in the resistance of ER-positive and HER-2-positive tumors to hormone therapy

809 Introduction: Some clinical data have suggested that HER-2 overexpression might be associated with tamoxifen resistance in patients with hormone receptor-positive breast cancer. The purpose of this study was to evaluate the inter-site variation of ER and HER-2 expression and ER and HER-2 levels as identified using immunohistochemistry. Methods: A total of 227 women with invasive breast cancer undergoing surgical treatment between 1991 and 2001 were included in this study. Paraffin-embedded tumor tissues were used in immunohistochemical study. Double staining was performed using both ER and HER-2 antibody. ER expression was assessed using the Allred score. HER-2 score was determined using the HercepTest score. Both the ER- and HER-2-positive tumors were classified into two types; co-expressed type and separately expressed type. Results: HER-2 expression was inversely correlated with ER expression. When evaluated in ER-positive patients, HER-2 overexpression was associated with lower ER levels. ER and HER-2-positive tumors were observed in 22 (9.7%) of 227 tumors. The co-expressed type was found in 10 patients, and the separately expressed type was found in 12 patients. ER and HER-2 scores were significant prognostic factors, however, there was no difference in disease-free survival between patients with the co-expressed type tumors and the separately expressed type tumors. Conclusions: Low ER levels might be one factor in the relative resistance of ER-positive and HER-2-positive tumors to hormonal therapy. No significant financial relationships to disclose.

Low ER level is one factor in the resistance of ER-positive and HER-2-positive tumors to hormone therapy

809 Introduction: Some clinical data have suggested that HER-2 overexpression might be associated with tamoxifen resistance in patients with hormone receptor-positive breast cancer. The purpose of this study was to evaluate the inter-site variation of ER and HER-2 expression and ER and HER-2 levels as identified using immunohistochemistry. Methods: A total of 227 women with invasive breast cancer undergoing surgical treatment between 1991 and 2001 were included in this study. Paraffin-embedded tumor tissues were used in immunohistochemical study. Double staining was performed using both ER and HER-2 antibody. ER expression was assessed using the Allred score. HER-2 score was determined using the HercepTest score. Both the ER- and HER-2-positive tumors were classified into two types; co-expressed type and separately expressed type. Results: HER-2 expression was inversely correlated with ER expression. When evaluated in ER-positive patients, HER-2 overexpression was associated with lower ER levels. ER and HER-2-positive tumors were observed in 22 (9.7%) of 227 tumors. The co-expressed type was found in 10 patients, and the separately expressed type was found in 12 patients. ER and HER-2 scores were significant prognostic factors, however, there was no difference in disease-free survival between patients with the co-expressed type tumors and the separately expressed type tumors. Conclusions: Low ER levels might be one factor in the relative resistance of ER-positive and HER-2-positive tumors to hormonal therapy. No significant financial relationships to disclose.

Sequencing of endocrine therapy in postmenopausal women with advanced breast cancer.

The introduction of the nonsteroidal aromatase inhibitor (NS-AI) anastrozole as an alternative to tamoxifen for adjuvant therapy of women with resected hormone receptor-positive breast cancer has added a management category into which patients presenting with metastatic disease can be placed. There are now essentially three such categories: (a) tamoxifen sensitive (no prior AI); (b) tamoxifen resistant (no prior AI); and (c) NS-AI resistant (no prior tamoxifen). Well-conducted Phase III trials provide evidence for choosing first-line therapy for advanced disease in categories a and b. In tamoxifen-sensitive patients, one can choose either NS-AI, anastrozole, or letrozole. In tamoxifen-resistant patients, one can choose either of the NS-AIs, the steroidal AI exemestane, or the estrogen receptor down-regulator fulvestrant. The situation is quite different for patients in category c. There are no Phase III trials of agents in patients who have experienced disease progression on a NS-AI. Phase II data are available for exemestane and high-dose estrogens, and retrospective data are available for tamoxifen and fulvestrant. Additional clinical trials are needed to determine an optimal sequencing strategy.

Combined hormonal therapy for advanced breast cancer in postmenopausal patients

The primary therapeutic goal for patients with locally recurrent, locally advanced, or metastatic breast cancer is retarding the progression of cancer for as long as possible, while minimizing side effects and maintaining good quality of life. The majority of breast cancers have nuclear receptors for estrogen (ER) and/or progesterone (PR) and utilize estrogen as a major growth factor. Antagonizing estrogen to control tumor growth has been achieved in two ways: by competing for the binding site of the estrogen receptor with anti-estrogens (SERMS) or by removing estrogen by inhibiting its synthesis with aromatase (estrogen synthetase) inhibitors (AIs). Cancer cells develop resistance to SERMS such as tamoxifen (Nolvadex®) or toremifene (Fareston®) by increasing uptake of estrogens from plasma, by developing hypersensitivity to the residual level of ER stimulation and by increasing levels of estrogen synthesizing enzymes, such as aromatase, within the tumor cells as much as 3–10 fold. High in-situ, intra- and peri-tumoral estrogen levels may displace the SERM and cause clinical progression of the disease. In contrast resistance to AI therapy may also develop by causing hypersensitivity to residual and exogenous estrogens. Hence it has been hypothesized that a combination of a SERM and an AI (total estrogen blockade) might be the optimal way to treat hormone dependent breast cancer and prevent the emergence of resistance. Combining tamoxifen (SERM) with an AI (anastrozole) was one of three arms of the Phase 3 adjuvant ATAC study comparing tamoxifen to anastrozole and the combination. Interestingly the combination arm performed worst of all, the hypothesis being that in the low estrogenic environment created by the AI, tamoxifen exaggerates its known partial estrogenic signal. It has been hypothesized that if a SERM with less inherent estrogenicity than tamoxifen were combined with an AI the therapy would be more successful. Similar to letrozole and tamoxifen combined in another trial, a 27% reduction in plasma levels of anastrozole was also detected. BioMedicines is currently testing that hypothesis in a clinical Phase 3 trial combining the experimental and currently unapproved AI atamestane and the approved SERM toremifene and comparing that combination to the approved AI letrozole. Toremifene is clinically equi-effective against tamoxifen in treatment naive patients, but is 40-fold less estrogenic in a low estrogen environment in preclinical models. Atamestane is a steroidal AI, which has shown a median time to progression of 8 months, with 10% of the patients progression-free at 36 months, in tamoxifen-resistant patients. It is well tolerated and may have advantages over the non-steroidal AI's in terms of efficacy and toxicity. Atamestane also does not interact pharmacologically with the toremifene. The control arm is letrozole, currently the most effective single agent endocrine therapy for postmenopausal women. Patients eligible for our study are required to have positive receptor status, have measurable tumor lesions and to have received the last dose of adjuvant hormonal therapy at least 12 months prior to enrollment. Our trial strategy is thus similar to the total androgen blockade approach to prostate cancer where this approach has been successful.

Sequencing of hormonal therapy in postmenopausal women with metastatic breast cancer

Background: Hormonal therapy (HT) is an important consideration in the management of postmenopausal women with metastatic breast cancer. Despite the fact that the advanced-stage disease is virtually incurable, HTs can offer patients disease control equivalent to that of chemotherapy, but with improved quality of life (QOL). Knowledge of the estrogen and progesterone receptor status, as well as other clinical factors, allows for selection of patients who are most likely to benefit from HT. Disease that becomes refractory to an initial HT may respond to another agent or class of HTs. Thus, HTs are generally administered sequentially, delaying the need for cytotoxic chemotherapy, which often reduces QOL. Optimal sequencing is thus one of the more important facets of HT. Prior to the release of a number of newer agents, tamoxifen had been considered as initial HT. At present, more agents exist, including the aromatase inhibitors, progestins, and the estrogen receptor antagonist fulvestrant. Objective: This article reviews key trials evaluating the use of sequential HTs. Methods: Articles were identified for inclusion in this manuscript through the following searches, limited to English-language publications: MEDLINE (mid 1960s to January 2002), American Society of Oncology abstracts (1997–2001), and San Antonio Breast Cancer Symposium abstracts (2001 and 2002). The following search terms were used: breast cancer, hormonal therapies, tamoxifen, toremifene, letrozole, anastrozole, exemestane, megestrol acetate, fulvestrant, and ICI 182,780. Results: Results of Phase III studies have shown many of these agents to be equivalent or superior to tamoxifen and can be used initially to treat patients who either have failed tamoxifen therapy or may be unable to tolerate some of the toxicities associated with tamoxifen. For example, the aromatase inhibitors have been shown to be highly active and tolerable in postmenopausal women with breast cancer who have failed tamoxifen therapy or who are naive to HT. Other clinical trials have demonstrated the efficacy of fulvestrant in patients with metastatic breast cancer who are tamoxifen-resistant, and have shown fulvestrant to be at least as effective as anastrozole in tamoxifen-resistant patients. Conclusions: Although the optimum sequence of HTs remains controversial, using the newer agents as initial or subsequent therapy should improve QOL and may improve overall survival.

Measurement of steroid hormone receptors in breast cancer patients on tamoxifen.

Estrogen (ER) and progesterone receptor (PgR) positive breast tumors often respond to tamoxifen, but ultimately progress as they become tamoxifen resistant. An accurate assessment of receptor status in specimens from tamoxifen-resistant patients could help to understand potential mechanisms of resistance and to predict response to second line hormonal therapies. However, since tamoxifen itself can affect ER and PgR determinations, assay results can be misleading. We measured ER and PgR by both ligand binding (LBA) and immunohistochemical (IHC) assays in 34 tumors from patients on tamoxifen, 30 of whom were displaying resistance to the drug. These tumors were classified into several receptor phenotypes. Eleven patients, 8 of whom were clearly progressing, expressed both receptors while on tamoxifen. ER was significantly less often negative when measured by IHC, suggesting that ER status by LBA was falsely negative in this group due to receptor occupancy by tamoxifen. Six patients had no detectable ER by LBA or IHC but still expressed PgR. The presence of PgR suggests that ER could still be functional, though undetectable, in these tumors, or that PgR is constitutively expressed by them. Finally, 12 patients were ER and PgR-negative by both assays, suggesting hormonal independence as the mechanism for resistance in this group. In a subset of patients with receptor assays both prior to tamoxifen and at the time of progression while taking the drug, we found that most ER-positive tumors converted to an apparent ER-negative status when assayed by LBA, while PgR status frequently remained unchanged. The continued expression of ER and/or PgR in many patients with tumor progression on tamoxifen indicates that mechanisms for resistance other than receptor loss are common in breast cancer.