Expression of prostate-specific antigen (PSA) correlates with poor response to tamoxifen therapy in recurrent breast cancer

Prostate-specific antigen (PSA) is a serine protease which may play a role in a variety of cancer types, including breast cancer. In the present study, we evaluated whether the level of PSA in breast tumour cytosol could be associated with prognosis in primary breast cancer, or with response to tamoxifen therapy in recurrent disease. PSA levels were determined by enzyme-linked immunosorbent assay (ELISA) in breast tumour cytosols, and were correlated with prognosis in 1516 patients with primary breast cancer and with response to first-line tamoxifen therapy in 434 patients with recurrent disease. Relating the levels of PSA with classical prognostic factors, low levels were more often found in larger tumours, tumours of older and post-menopausal patients, and in steroid hormone receptor-negative tumours. There was no significant association between the levels of PSA with grade of differentiation or the number of involved lymph nodes. In patients with primary breast cancer, PSA was not significantly related to the rate of relapse, and a positive association of PSA with an improved survival could be attributed to its relationship to age. In patients with recurrent breast cancer, a high level of PSA was significantly related to a poor response to tamoxifen therapy, and a short progression-free and overall survival after start of treatment for recurrent disease. In Cox multivariate analyses for response to therapy and for (progression-free) survival, corrected for age/menopausal status, disease-free interval, site of relapse and steroid hormone receptor status, PSA was an independent variable of poor prognosis. It is concluded that the level of PSA in cytosols of primary breast tumours might be a marker to select breast cancer patients who may benefit from systemic tamoxifen therapy.     

雌激素诱导蛋白pS2表达与ER阳性原发乳腺癌患者辅助内分泌治疗疗效的关系

目的:探讨雌激素诱导蛋白pS2的表达与乳腺癌临床参数和辅助三苯氧胺TAM治疗疗效的关系,明确pS2对辅助内分泌治疗的指导地位。方法:采用免疫组化S蛳P法检测81例ER阳性原发乳腺癌的石蜡切片pS2的表达, 统计学分析其与预后的关系。结果:原发乳腺癌pS2的阳性表达率为66.7 %,其表达与手术年龄(P=0.037)、月经状态(P=0.016)、肿瘤大小(P=0.029)、PR表达情况(P<0.001)密切相关,年龄小于50岁、绝经前、小肿瘤、PR阳性的患者pS2阳性率高。单因素分析和多因素分析均表明pS2是预测OS的独立预后因子。同时pS2对DFS也具有独立预后价值(P=0.023)。结论:pS2是预测ER阳性乳腺癌患者辅助内分泌治疗疗效的独立指标。     

Readministration of tamoxifen after adjuvant therapy for recurrent breast cancer

BACKGROUND: Previous series concerning tamoxifen (TAM) rechallenge did not obtain satisfactory results. Using stricter criteria, we now assess the usefulness of readministration of TAM as an initial therapy for patients with recurrent breast cancer. METHOD: The eligibility criteria were postmenopausal, estrogen receptor (ER) positive or unknown, at least 12 months of adjuvant TAM, a 6-month or longer drug-free period and no previous therapy after recurrence. A total of 10 patients were enrolled. TAM was administered in daily doses of 20 or 30 mg. RESULTS: The mean age of the patients at the time of recurrence was 64.8 years. The receptor status was positive in 8 patients and unknown in 2. The median disease-free interval (DFI) after mastectomy was 71.7 months. A complete response was observed in one patient, a partial response in 6, stable disease in 2, and progression in one. The response rate was thus 70%, with an additional two patients showing no progression over 6 months. Although only one patient with a DFI of less than 48 months showed a positive response, all patients with a DFI longer than 48 months showed a clinical response. The duration of response was less than 12 months in 3 patients and longer in 4. CONCLUSION: The post-adjuvant readministration of tamoxifen is a useful first choice therapy for postmenopausal recurrent breast cancer patients with positive ER and longer DFI.     

The expression of Ki-S1 and BCL-2 and the response to primary tamoxifen therapy in elderly patients with breast cancer

Ki-S1, a marker of proliferation, and bcl-2, thegene product of which is an antagonist ofapoptosis, have been measured in 51 ER-positive primarybreast cancers before and during tamoxifen treatment andthen related to clinical response. Both markers weredetected in the majority of tumours before treatmentand, quantitatively, initial expression of Bcl-2 protein, butnot Ki-S1, was significantly related to the percentagereduction in tumour volume as assessed by ultrasound.Staining for both markers was lower in posttreatment samples than in those taken prior totreatments, but concordant decreases in staining indices wereseen in only 11 of the 51 tumours.The results demonstrate, using clinical material, that theresponse to tamoxifen may involve changes in proliferationand/or susceptibility to cell-death.     

Overprolonged adjuvant tamoxifen therapy in breast cancer.

While adjuvant tamoxifen therapy given continuously for 2-3 years can lead to a modest improvement in survival rates in early breast cancer, there is no evidence that prolonging tamoxifen administration beyond that time is likely to improve survival rates any further in unselected cases. In the case of advanced disease, an alternating tamoxifen/progestagen regimen has been shown to increase the response rate and also its duration, beyond that to be expected from either agent alone. The next generation of adjuvant trials in breast cancer needs to explore the potential of an alternating tamoxifen/megestrol regimen.     

Association of DNA methylation of phosphoserine aminotransferase with response to endocrine therapy in patients with recurrent breast cancer

To understand the biological basis of resistance to endocrine therapy is of utmost importance in patients with steroid hormone receptor-positive breast cancer. Not only will this allow us prediction of therapy success, it may also lead to novel therapies for patients resistant to current endocrine therapy. DNA methylation in the promoter regions of genes is a prominent epigenetic gene silencing mechanism that contributes to breast cancer biology. In the current study, we investigated whether promoter DNA methylation could be associated with resistance to endocrine therapy in patients with recurrent breast cancer. Using a microarray-based technology, the promoter DNA methylation status of 117 candidate genes was studied in a cohort of 200 steroid hormone receptor-positive tumors of patients who received the antiestrogen tamoxifen as first-line treatment for recurrent breast cancer. Of the genes analyzed, the promoter DNA methylation status of 10 genes was significantly associated with clinical outcome of tamoxifen therapy. The association of the promoter hypermethylation of the strongest marker, phosphoserine aminotransferase (PSAT1) with favorable clinical outcome was confirmed by an independent quantitative DNA methylation detection method. Furthermore, the extent of DNA methylation of PSAT1 was inversely associated with its expression at the mRNA level. Finally, also at the mRNA level, PSAT1 was a predictor of tamoxifen therapy response. Concluding, our work indicates that promoter hypermethylation and mRNA expression of PSAT1 are indicators of response to tamoxifen-based endocrine therapy in steroid hormone receptor-positive patients with recurrent breast cancer.     

Predictive value of SRC-1 for tamoxifen response of recurrent breast cancer

Tamoxifen causes an objective response in about one-third of metastatic breast cancer and in only half of the breast cancer patients with estrogen receptor (ER) positive tumors. Steroid-receptor coactivator-1 (SRC-1) appears to be a general coactivator for steroid receptors and rate limiting factor necessary for efficient ER transactivation. We aimed to evaluate whether SRC-1 expression is an additional factor for prediction of response to first-line tamoxifen therapy in patients who developed recurrent disease. Here for the first time, we report on SRC-1 expression using a semi-quantitative RT-PCR in 21 primary breast tumors, seven mammary tumor cell-lines, 12 fibroblast cultures, and six normal breast tissues. The highest levels of SRC-1 were observed in normal tissues, intermediate levels in tumor tissues, and the lowest levels in breast tumor cell-lines. There was no relationship between the levels of SRC-1 in these primary tumors and the proportion of tumor cells within the surgical samples, nor with ER status. The median SRC-1 level was, however, lower in tumors from patients that did not respond to tamoxifen. Our findings suggest that high levels of SRC-1 indicate a favorable response to tamoxifen of patients with recurrent breast cancer. Abbreviations: PgR, progesterone receptor; ER, estrogen receptor; GR, glucocorticoid receptor; TR, thyroid hormone receptor; RXR, retinoid X receptor; SRC-1, steroid-receptor coactivator-1; EGF, epidermal growth factor; TGF, transforming growth factor; IGF, insulin like growth factor; UPA, urokinase-type plasminogen activator     

Urokinase-type plasminogen activator system in breast cancer: association with tamoxifen therapy in recurrent disease

The prognostic value of components of the urokinase-type plasminogen activator (uPA) system, its receptor uPAR (CD87), and plasminogen activator inhibitors PAI-1 and PAI-2 is well established. We studied the predictive value of these proteolytic factors by evaluating the association of their tumor expression level and the efficacy of tamoxifen therapy in patients with recurrent breast cancer. The antigen levels of the four factors were determined by ELISA in cytosols prepared from estrogen receptor-positive primary breast tumors of 691 hormone-naive breast cancer patients with recurrent disease and treated with tamoxifen as first-line systemic therapy. High tumor levels of uPA (P < 0.001), uPAR (P < 0.01), and PAI-1 (P = 0.01) were associated with a lower efficacy of tamoxifen therapy. In the multivariable analysis, uPA (P < 0.001) provided additional information independent of the traditional predictive factors to predict benefit from tamoxifen therapy. High levels of uPA, uPAR, and PAI-1 predicted a shorter progression-free survival (PFS) on tamoxifen in an analysis of the first 9 months of therapy. However in the analysis during the total follow-up period, high PAI-2 levels (P = 0.01) showed a longer response to tamoxifen. In conclusion, uPA, uPAR, and PAI-1, components of the urokinase system, are predictive for the efficacy of tamoxifen therapy in patients treated for recurrent breast cancer. Knowledge of their tumor expression levels might be helpful for future individualized therapy protocols, including possible new-targeted therapies based on the interference in the urokinase system.     

Nuclear IRS-1 predicts tamoxifen response in patients with early breast cancer

Insulin receptor substrate-1 (IRS-1) is a cytoplasmic scaffolding protein that is phosphorylated by insulin-like growth factor-I receptor and recruits downstream effectors. Recent evidence suggests that IRS-1 has a nuclear localization and function. Here we investigated whether nuclear and cytoplasmic IRS-1 levels are associated with clinico-pathological characteristics and clinical outcome in breast cancer patients. Tissue microarrays from 1,097 patients with stage I–II breast cancer were stained by immunohistochemistry for IRS-1. Nuclear and cytoplasmic IRS-1 were scored separately according to the Allred score. Nuclear IRS-1 showed a positive association with estrogen receptor (ER) (r = 0.09, P = 0.003) and progesterone receptor (PR) (r = 0.08, P = 0.008) status and a negative correlation with lymph node involvement (r = −0.10, P = 0.001). Cytoplasmic IRS-1 did not correlate with ER or PR but showed a positive correlation with tumor size (r = 0.10, P = 0.001) and S-phase fraction (r = 0.16, P < 0.001). In univariate analysis, tamoxifen-treated patients with tumors showing positive nuclear IRS-1 had a better recurrence-free survival (RFS) (P = 0.009) and overall survival (OS) (P = 0.0007), while no association was shown between cytoplasmic IRS-1 and RFS or OS in the same group of patients. In multivariate analysis of patients receiving tamoxifen, negative nuclear IRS-1 showed a significantly reduced RFS (P = 0.046) and OS (P = 0.018). Combining both PR and nuclear IRS-1, tamoxifen-treated patients with PR+/IRS-1+ tumors had a better RFS (P = 0.0003) and OS (P < 0.0001) when compared with patients with PR−/IRS-1− tumors. In conclusion, nuclear IRS-1 may be a useful marker to predict tamoxifen response in patients with early breast cancer, particularly when assessed in combination with PR.     

pS2 expression and response to hormonal therapy in patients with advanced breast cancer

Seventy-two patients with advanced breast carcinoma (42% bone, 25% visceral, 5.5% soft tissue, and 27.5% multiple site metastases) were evaluated to determine the relationship between tumor expression of the estrogen-regulated protein pS2, estrogen receptor (ER) or progesterone receptor (PgR) content, and response to hormonal therapy. Twenty-nine % of tumors were pS2 positive, 64% were ER positive, and 29% were PgR positive. Of the ER-positive patients (n = 43), 15 (35%) had greater than 10% of the invasive carcinoma which immunostained for pS2 (these were considered pS2 positive). Only 3 of 24 ER-negative tumors were pS2 positive. A weak association between pS2 expression and ER content (P = 0.08) but not PgR content was observed. Of pS2-positive patients, 52% had a partial or complete response to hormonal therapy. In 24% of pS2-positive patients the disease stabilized with treatment. In contrast, 27% of pS2-negative patients had a partial or complete response. In 10% of these patients the disease stabilized. Similar associations between therapeutic response and ER or PgR were not observed. The odds of having a clinical response to hormonal therapy was greater for pS2-positive than for ER- or PgR-positive tumors. pS2 expression may define a subset of ER-positive tumors that are more likely to respond to hormonal treatment.     

pS2 protein: a marker improving prediction of response to neoadjuvant tamoxifen in post-menopausal breast cancer patients.

Tamoxifen as sole initial therapy is gaining importance in the management of post-menopausal breast cancer patients. Age oestrogen (ER) and progesterone (PR) receptor status are accurately considered to select patients for hormonal treatment. However, additional markers are needed. By immunohistochemistry (IHC), we studied tumour expression of ER, PR, pS2, c-erbB-2 and glutathione S-transferase pi (GST pi) on initial core biopsies of 208 post-menopausal patients with a non-metastatic invasive ductal carcinoma, treated by neoadjuvant tamoxifen therapy. A good response to tamoxifen was defined as tumoral regression > or = 50% (110 patients). Relationship between response and age, tumour size, T, N, histological grade, ER and PR contents evaluated by radioimmunoassay, ER, PR, pS2, c-erbB-2 and GST pi expression evaluated by IHC were studied. Univariate and multivariate analysis showed that tumoral regression was linked only to pS2 (P = 0.004) and ER (P = 0.018) IHC expression. According to the immunohistochemical profile, three groups could be defined: pS2- and ER-positive tumours, pS2- or ER-positive tumours and pS2- and ER-negative tumours with response rates of 60%, 45% and 8% respectively. Although prospective studies are needed to confirm these results, we conclude that pS2 and ER immunohistochemical status are useful tools for predicting tumour regression with neoadjuvant tamoxifen in post-menopausal breast carcinoma patients.     

Adjuvant therapy with tamoxifen compared to aromatase inhibitors for 257 male breast cancer patients

To determine the impact of adjuvant treatment with tamoxifen and aromatase inhibitors (AI) on the survival of men with breast cancer. We analyzed 257 male patients with hormone-receptor-positive breast cancer from numerous German population-based cancer registries treated with tamoxifen (N = 207) or aromatase inhibitors (N = 50). The median follow-up was 42.2 (range 2–115) months. Median age at diagnosis was 68 (range 36–91) years. Thirty-seven (17.9 %) patients treated with tamoxifen and 16 (32.0 %) patients treated with AI died (log rank p = 0.007). After the adjustment for the patient’s age, tumor size, node status, and tumor grading, the AI treatment was linked to a 1.5-fold increase in risk of mortality compared to tamoxifen (HR 1.55; 95 % CI: 1.13–2.13; p = 0.007). The overall survival in male breast cancer was significantly better after adjuvant treatment with tamoxifen compared to an aromatase inhibitor. Tamoxifen should be considered as the treatment of choice for hormone-receptor-positive male breast cancer.     

Drug resistance to tamoxifen during breast cancer therapy

Summary Breast cancer is the most common malignancy occurring in Western women, and is one of the leading causes of cancer mortality. The nonsteroidal antiestrogen tamoxifen has been shown to be an effective treatment for pre and postmenopausal women with all stages of the disease. Tamoxifen provides effective palliation when used to treat patients with advanced disease, and adjuvant tamoxifen therapy produces significant increases in both disease-free and overall survival (Early Breast Cancer Trialists Collaborative Group. Lancet 339:1-15, 71-85, 1992). Data from the laboratory have shown that the primary action of tamoxifen is tumoristatic rather than tumoricidal, and long-term therapy is therefore recommended. Unfortunately, many patients experience disease progression while taking tamoxifen. Some tamoxifen resistant tumors may remain sensitive to alternative endocrine therapies, while others may become refractory to any hormonal manipulation. Many models have been developedin vitro andin vivo to study the progression of breast cancer growth from tamoxifen sensitive to tamoxifen resistant. We and others have used long-term estrogen deprivation and long-term tamoxifen exposure to develop cell lines and tumors capable of growth in the presence of clinically relevant tamoxifen concentrations. Recently our laboratory has also shown that mutations in the estrogen receptor can cause an antiestrogen-occupied receptor to behave as though it were occupied by an estrogen. Breast cancer is a highly heterogeneous disease and it is likely that the mechanisms which cause tamoxifen resistant growth are equally heterogeneous. Several of the models from our laboratory and others which may contribute to an understanding of this complex phenomenon are discussed here.     

Her-2/neu overexpression and response to oophorectomy plus tamoxifen adjuvant therapy in estrogen receptor-positive premenopausal women with operable breast cancer.

PURPOSE: Studies evaluating the relationship of HER-2/neu breast tumor status and response to adjuvant endocrine therapy have reached conflicting conclusions about resistance of HER-2/neu-positive tumors to this treatment. We studied 282 patients participating in a randomized controlled trial of adjuvant oophorectomy and tamoxifen or observation who had estrogen receptor-positive tumors and whose tumors were evaluated for HER-2/neu overexpression by immunohistochemistry. PATIENTS AND METHODS: Univariate and multivariate Cox proportional hazards regression models and Kaplan-Meier disease-free and overall survival estimate methods were used. RESULTS: HER-2/neu overexpression was a negative prognostic factor for overall survival. In univariate analyses, in HER-2/neu-positive patients, the hazard ratio (HR) for disease-free survival (DFS) with adjuvant endocrine therapy was 0.37 (95% confidence interval [CI], 0.26 to 0.89); for HER-2/neu-negative patients, the corresponding HR for DFS was 0.48 (95% CI, 0.31 to 0.71). The overall survival (OS) data were HR=0.26 (95% CI, 0.07 to 0.92) and HR=0.68 (95% CI, 0.32 to 1.42) for HER-2/neu-positive and HER-2/neu-negative patients, respectively. In multivariate models, the P values for tests of interaction of HER-2/neu status and response to adjuvant endocrine therapy were 0.18 and 0.07 for DFS and OS, respectively. Kaplan-Meier DFS and OS curves and 3-year DFS estimates were consistent in showing greater benefit to the HER-2/neu-positive subgroup given adjuvant treatment. CONCLUSION: HER-2/neu overexpression does not adversely and may favorably influence response to adjuvant oophorectomy and tamoxifen treatment in patients with estrogen receptor-positive tumors.     

Relationship between c-erbB-2 protein product expression and response to endocrine therapy in advanced breast cancer.

Of 221 patients with breast cancer of known epidermal growth factor receptor (EGFR) and oestrogen receptor (ER) status, 99 had developed recurrences during the period of follow-up (range 3-60 months, median 24 months). Of these, 72 received endocrine therapy as first-line treatment for relapse. Immunohistochemical assessment of c-erbB-2 protein product expression was made using paraffin-embedded tumour tissue from 65 of these 72 patients. Including patients whose disease remained stable for more than 6 months with those showing an objective response (CR or PR for more than 3 months), only one (7%) of 14 c-erbB-2 positive tumours responded to endocrine manipulation compared with 19 (37%) of 51 c-erbB-2 negative tumours (P less than 0.05). Coexpression of c-erbB-2 reduced the response rate of ER positive patients from 48% to 20% and of ER negative cases from 27% to 0% (P less than 0.01). EGFR and c-erbB-2 protein appeared to have additive effects in reducing the likelihood of response, and none of eight patients with EGFR positive, c-erbB-2 positive tumours derived benefit from endocrine therapy. The results of this study suggest that c-erbB-2 protein overexpression, a marker of poor prognosis in breast cancer, is associated with a lack of response to endocrine therapy on relapse, and particularly in combination with EGFR may be useful in directing therapeutic choices.     

Impact of concurrent versus sequential tamoxifen with radiation therapy in early-stage breast cancer patients undergoing breast conservation treatment.

PURPOSE: To assess the impact of sequencing of tamoxifen and radiation therapy (RT) on outcomes in early-stage breast cancer. PATIENTS AND METHODS: This retrospective study evaluates the effect of the sequence of tamoxifen with RT on outcomes in stage I to II breast cancer patients who underwent breast-conservation treatment (BCT) and received adjuvant tamoxifen, with or without adjuvant chemotherapy. Patients were grouped as concurrent (tamoxifen given during RT followed by continued tamoxifen; 174 patients) and sequential (RT followed by tamoxifen; 104 patients). RESULTS: Median follow-up after RT was 8.6 years for both groups. The pathologic T and N stage, race, estrogen and progesterone status, number of positive nodes, and RT were comparable between the two groups (all P >/= .08). More women age 49 years or younger and women who received chemotherapy were in the sequential group than the concurrent group (6% and 25%, respectively; P < .0001). The sequence of tamoxifen therapy did not influence 10-year local recurrence rates (sequential, 7%; concurrent, 3%; P = .52), overall survival (sequential, 86%; concurrent, 81%; P = .64), or relapse-free survival (sequential, 76%; concurrent, 85%; P = .35). When adjusting age and chemotherapy use in the multivariable Cox model, hazard ratios comparing sequential versus concurrent tamoxifen therapy were 1.56 (95% CI, 0.87 to 2.79), 1.23 (95% CI, 0.63 to 2.41), and 1.22 (95% CI, 0.33 to 4.49) for the overall survival, relapse-free survival, and local recurrence, respectively. CONCLUSION: The therapeutic regimens of tamoxifen given concurrently or sequentially with RT both appear to be reasonable options for patients treated with BCT.     

Alternating sequential endocrine therapy: tamoxifen and medroxyprogesterone acetate versus tamoxifen in postmenopausal advanced breast cancer patients.

The effects of tamoxifen (TAM) versus the alternating sequential combination of TAM plus medroxy-progesterone acetate (MPA) has been evaluated in 20 postmenopausal patients with advanced breast cancer in a randomized controlled trial. In the TAM arm, patients received 20 mg b.i.d. of TAM. In the TAM-MPA arm, patients received only 20 mg b.i.d. of TAM for 7 days and, on the following 7 days. TAM plus an oral daily dose of 500 mg of MPA, in alternating sequence. Objective tumor reduction was achieved in 22 (41%) of the 54 patients in the TAM arm and in 25 (43%) of the 58 patients in the TAM-MPA arm. With regard to the stabilization of disease, a significant difference was observed between patients treated with the TAM-MPA combination and those treated with TAM alone (47% vs 22%). The percentage of nonresponders was also significantly higher in the TAM group (37%) than in the TAM-MPA group (10%). The time to progression was significantly shorter for the TAM arm than for the TAM-MPA arm (median, 7 vs 15 months), but the duration of remission was not significantly different for either treatment.     

Prognostic factors in the initial response to therapy by patients with advanced breast cancer.

Identification of important prognostic factors with respect to the patient's initial response to therapy was made from a set of 25 covariates available on 281 patients with advanced breast cancer. Since the patients studied were all participants in a randomized clinical trial that involved three different treatment regimens (repeated weekly treatment of a combination of cyclophosphamide, methotrexate, 5-fluorouracil, vincristine, and prednisone; intermittent treatment of the same preceding five drugs given in 5-day courses every 4 weeks; or treatment every 3 weeks with adriamycin as a single agent), the effect of these treatments on the selection of important covariates was assessed. Although some evidence indicated that the set of important covariates differed by treatment, the differences were not strong enough to be of practical importance. Non-Caucasian patients did poorly on all regimens with a response rate of only 31% compared to 62% for Caucasian patients. The covariates of major prognostic importance for Caucasians were: disease-free interval, liver involvement, and performance status. Ambulatory patients with long disease-free intervals and no liver involvement had the best prognosis. After adjustments were made for these three covariates, the remaining covariates (such as menopausal status, bone involvement, number of metastatic sites, and duration of metastatic disease) were not significantly related to response. As reported earlier, the treatment effect was significant, even after adjustments were made for the important covariates.