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PubMed2004

[Endocrine therapy for localized or locally advanced prostate cancer].

The place of endocrine therapy, either alone or in combination with radiotherapy and surgery, remains highly controversial in the treatment of non-metastatic prostate cancer. The authors review the results of isolated endocrine therapy or associated with local therapy. At the present time, there are few arguments in favour of the use of endocrine therapy in the following situations: isolated treatment of localized or locally advanced cancer prior to radical prostatectomy, after radical prostatectomy. Current data suggest a benefit of endocrine therapy in combination with radiotherapy in patients with high-grade localized or locally advanced cancer.

Androgen Antagonists↗
PubMed2002

[PSA-related parameters in prostate cancer relapsed after endocrine therapy].

PURPOSE: Prostate cancer is generally controlled by endocrine therapy even in an advanced state, but relapse may occur in many cases. Generally, the prognosis of a relapsed case is poor, but the prognosis differs case by case. We experienced 74 cases of prostate cancer relapsed after effective endocrine therapy, and investigated the relationship between the PSA-related parameters, clinical stage and prognosis. PATIENTS AND METHODS: We investigated 74 prostate cancer patients whose PSA declined 10 ng/ml or lower by the treatment consisting of endocrine therapy, but relapsed later. Pre-treatment PSA, the value of PSA nadir, the period from the start of treatment to PSA nadir, the period from the start of treatment to relapse, PSA doubling time (PSA-DT) at relapse and PSA response to the second line therapy at relapse were calculated, and compared with the clinical stage and prognosis. The relationship between each PSA parameter and clinical stage was tested using the Kruskal-Wallis test and chi 2 test. Cancer-specific survival after relapse in stage D patients was calculated by the Kaplan-Meier method and differences in prognosis were tested using the Logrank test. RESULTS: Pre-treatment PSA was significantly (p < 0.01) high, while the period from the start of treatment to relapse (p < 0.05) and PSA-DT at relapse (p < 0.01) was significantly short as the stage progressed. According to PSA response to the second line therapy at relapse, the rate of CR + PR was significantly (p < 0.05) high in clinical stage B + C group compared to clinical stage D group. The prognosis after relapse was significantly poorer in patients with relapse within 10 months after start of treatment than in those with relapse later, and in patients whose PSA-DT at relapse was shorter than 2 months than in those with a longer PSA-DT. CONCLUSIONS: The period from the start of treatment to relapse, and PSA-DT at relapse were useful PSA-related parameters for predicting prognosis after relapse, and for determining the strategy of cancer therapy after relapse. Using these data, the physician can inform the family and the patient of the prognosis more accurately, so that they can adjust future plans.

Aged↗
PubMed2006

A randomized comparative study of endocrine monotherapy and a combination of estramustine phosphate with the endocrine therapy in patients with untreated stage D prostate cancer.

BACKGROUND: We investigated the clinical efficacy and the prolongation of survival with combination therapy of estramustine phosphate (EMP) and endocrine therapy in untreated patients with progressive prostate cancer. METHODS: We randomly divided 57 patients with untreated stage D prostate cancer into two groups, an endocrine monotherapy group and a group receiving combination treatment, consisting of endocrine therapy plus EMP. Treatment was continued until deterioration. RESULTS: There were no significant differences in the improvement rating for subjective/objective symptoms or in progression-free survival between the two groups. However, overall survival was significantly prolonged in the combination therapy group (log-rank test, P = 0.0394; generalized Wilcoxon's test, P = 0.0145). In particular, overall survival was significantly prolonged, compared to that in the endocrine monotherapy group, in patients in the combination therapy group who were less than 74 years old, those with a performance status (PS) of 1 to 3, a pretreatment prostate-specific antigen (PSA) level of more than 20 ng/ml, moderately or poorly differentiated carcinoma, or a partial response (PR) based on the PSA level 12 weeks after the start of treatment. There was no significant difference in the incidence of side effects between the combination therapy and the endocrine monotherapy groups. CONCLUSION: A combination of EMP with endocrine therapy may be useful for initial treatment in younger patients (aged 73 or younger) and in patients at high risk of progressive prostate cancer.

Aged↗
PubMed2000

Preoperative endocrine therapy for breast cancer.

The preoperative use of systemic therapy for primary breast cancer has the potential to downstage tumours. This would render suitable for breast conservation some tumours that were unsuitable at initial presentation, or would convert some inoperable locally advanced breast cancers into tumours that are operable. No survival benefit has been demonstrated for neoadjuvant chemotherapy compared with the same therapy given in an adjuvant setting. Preoperative endocrine therapy, in contrast to neoadjuvant chemotherapy, has fewer side effects and has the potential additional advantage that it can be continued throughout the perioperative period. Current data have shown that, in patients with an oestrogen receptor (ER)-positive tumour, a response approaching 70% could be reached in approximately 3 months using traditional endocrine manipulation such as tamoxifen. Randomised clinical trials are warranted to demonstrate the superiority of preoperative endocrine therapy over conventional adjuvant endocrine therapy, to define the optimum duration of therapy, and to identify the best endocrine agents. Both clinical and laboratory studies are also required to identify factors (in addition to ER) that would precisely predict the response and hence to select appropriate patients and to improve existing methods of monitoring response.

Antineoplastic Agents, Hormonal↗
PubMed2006

"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%) (1st line) patients. When these patients were put on further endocrine therapy, the CB rates were 63.2% (on 2nd line), 46.1% (on 3rd line) and 20% (on 4th 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 1st line endocrine therapy. Seventeen of these patients were treated with further endocrine therapy. The CB rates were 29.4% (on 2nd line) and 22.2% (on 3rd 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 4th 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 1st line endocrine therapy. The use of further endocrine therapy should not be excluded under these circumstances.

Journal Article↗
PubMed1996

[An overview of clinical trials in endocrine therapy for cancer].

To obtain information for published clinical trials in endocrine therapy for cancer in Japan, a computerized literature search of MEDLINE, EMBASE and IGAKU-CHUO-ZASSHI (CD-ROM) was done. We found four articles on randomized trials for prostate cancer and two for breast cancer. In order to obtain information for ongoing randomized phase III trials in endocrine therapy for cancer in the United States and Europe, a search of PDQ (Physician's Data Query) was done. In PDQ, 13 active trials started after January 1990 in endocrine therapy for breast cancer and six active trials started after January 1990 in endocrine therapy for prostate cancer were registered. Out of 13 trials for breast cancer, projected sample sizes were over 1,000 in eight trials, and QOL was selected as an end point in six trials. Out of six trials for prostate cancer, projected sample sizes were over 500 in three trials, and QOL or sexual function was selected as an end point in three trials.

Antineoplastic Agents, Hormonal↗
PubMed1998

Endocrine therapy of prostate cancer.

Endocrine therapy is effective treatment for patients with metastatic prostate cancer. Most patients will benefit from androgen withdrawal in terms of symptomatic relief and delay in progression of diseases. It does not, however, cure patients with metastatic prostate cancer. This finding emphasizes the need for the development of effective nonendocrine therapies.

5-alpha Reductase Inhibitors↗
PubMed2005

Biology of progesterone receptor loss in breast cancer and its implications for endocrine therapy.

The response to endocrine therapy in breast cancer correlates with estrogen receptor (ER) and progesterone receptor (PR) status. ER-positive/PR-negative breast cancers respond less well to selective ER modulator (SERM) therapy than ER-positive/PR-positive tumors. The predictive value of PR has long been attributed to the dependence of PR expression on ER activity, with the absence of PR reflecting a nonfunctional ER and resistance to hormonal therapy. However, recent clinical and laboratory evidence suggests that ER-positive/PR-negative breast cancers may be specifically resistant to SERMs, whereas they may be less resistant to estrogen withdrawal therapy with aromatase inhibitors, which is a result inconsistent with the nonfunctional ER theory. Novel alternative molecular mechanisms potentially explaining SERM resistance in ER-positive/PR-negative tumors have been suggested by recent experimental indications that growth factors may downregulate PR levels. Thus, the absence of PR may not simply indicate a lack of ER activity, but rather may reflect hyperactive cross talk between ER and growth factor signaling pathways that downregulate PR even as they activate other ER functions. Therefore, ER-positive/PR-negative breast tumors might best be treated by completely blocking ER action via estrogen withdrawal with aromatase inhibitors, by targeted ER degradation, or by combined therapy targeting both ER and growth factor signaling pathways. In this review, we will discuss the biology and etiology of ER-positive/PR-negative breast cancer, highlighting recent data on molecular cross talk between ER and growth factor signaling pathways and demonstrating how PR might be a useful marker of these activities. Finally, we will consider the clinical implications of these observations.

Antineoplastic Agents, Hormonal↗
PubMed1996

Management of hot flushes due to endocrine therapy for prostate carcinoma.

Endocrine manipulation plays a crucial role in the treatment of advanced prostate carcinoma. Recent enthusiasm for earlier use of endocrine therapy has increased the significance of diminishing treatment-related side effects, particularly vasomotor hot flushes, to ensure long-term patient compliance. Treatments that lower serum testosterone, such as orchiectomy or luteinizing hormone-releasing hormone (LHRH) analogs, cause hot flushes in over half of men. Lack of regulatory feedback in the hypothalamus from circulating serum testosterone is the presumed mechanism of hot flushes in these men. Most often, hot flushes are only mildly bothersome and can be tolerated without the need for treatment. However, if flushes are particularly annoying or problematic, treatment should be offered. Small doses of diethylstilbestrol (DES) are effective in relieving hot flushes but cause gynecomastia. Megestrol acetate, at a dose of 20 mg bid, completely eliminates hot flushes in most men, and the dose can be progressively lowered in some.

Antineoplastic Agents, Hormonal↗
PubMed1986

Metastatic pattern and response to endocrine therapy in human breast cancer.

The effect of endocrine therapy in 465 postmenopausal patients with advanced breast cancer who entered four consecutive, randomized trials has been related to the site of the metastases. Patients received either tamoxifen (T) alone or T in combination with medroxyprogesterone acetate, diethylstilbestrol, halotestin, or aminoglutethimide. The overall response rate was 40%. Responses were most frequently seen in patients with metastases in soft tissue, and the duration of response to endocrine therapy in these patients was longer than for those with metastases in bone or viscera (p less than 0.00001). In addition, the response rate was inversely correlated with the number of main metastatic sites in patients with soft tissue metastases, whereas the response rate was not associated with the number of metastatic sites in patients with metastases in bone and viscera. Survival after first recurrence was significantly longer in responding patients with soft tissue lesions compared to those with recurrence in bone or viscera. In contrast, survival after first recurrence was identical in patients with nonresponding disease, irrespective of dominant site of metastases. The outcome of endocrine therapy depends partially upon the dominant site of metastases. This may reflect a difference in biological characteristics of human breast cancer tumor cells that metastasize to different sites.

Aminoglutethimide↗
PubMed2004

[Comparison of endocrine therapy and chemotherapy for bone metastasis of breast cancer].

OBJECTIVE: To compare the efficacy of endocrine therapy with chemotherapy for bone metastasis of breast cancer. METHODS: A total of 138 breast cancer patients with bone metastasis, but without visceral metastasis as retrospectively reviewed. RESULTS: The response rates of endocrine therapy and chemotherapy as the first-line therapy were 35.4% and 31.7% (P = 0.687), and the total response rates were 27.1% and 25.0% (P = 0.690). The clinical benefit rates of endocrine therapy and chemotherapy as first-line were 43.9% and 36.6% (P = 0.437), as second-line were 47.8% and 24.2% (P = 0.033), in total treatments were 47.5% and 27.7% (P = 0.001). The median interval to treatment failure (TTF) was 5 months and 2 months (P < 0.001), and that to progression (TTP) was 5 and 2.5 months (P < 0.001) in endocrine therapy and chemotherapy group, respectively. CONCLUSION: Endocrine therapy is superior to chemotherapy for bone metastasis of breast cancer.

Antineoplastic Agents↗
PubMed1994

[A randomized clinical trial of adjuvant endocrine therapy after breast conserving surgery for early breast cancer. Cooperative Study Group for Breast Conserving Therapy].

To evaluate the clinical efficacy of adjuvant endocrine therapy after breast conserving surgery for early breast cancer, we have conducted a randomized controlled study since 1989. One hundred twelve-patients having a small breast tumor, less than 2 cm in diameter, and no palpable axillary lymph node, were the subjects of this study. All these patients underwent partial mastectomy with axillary lymph node dissection and were randomly divided into two groups according to the type of postoperative adjuvant endocrine therapy: Group I, tamoxifen (20 mg/day) for 2 years; Group II, no tamoxifen administration. The median follow-up period was 32.2 months. The incidence of local recurrence in the ipsilateral breast was 1.9% in Group I, which was lower than in Group II (6.8%). Three-year disease-free survival rates were also more favorable in Group I (94.2%) than in Group II (88.9%). This difference in prognosis was evident in patients with ER-positive tumors but not related to the menopausal status. These results suggest that adjuvant endocrine therapy with tamoxifen may be recommended for patients who underwent breast conserving surgery for early breast cancer, especially in those with ER-positive tumors.

Adult↗
PubMed2005

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.

Adult↗
PubMed1988

Combination therapy with flutamide and castration (orchiectomy or LHRH agonist): the minimal endocrine therapy in both untreated and previously treated patients with advanced prostate cancer.

One hundred fifty-four patients with clinical stage D2 prostate cancer with no previous endocrine therapy or chemotherapy received the combination therapy with the pure antiandrogen Flutamide and the LHRH agonist [D-Trp]LHRH ethylamide for an average of 22 months (3 to 49). The objective response to the treatment was assessed according to the criteria of the US NPCP. There was a 6.3-fold increase (29.2 versus 4.6%) in the percentage of patients who achieved a complete response as compared to the results achieved in 5 recent studies limited to removal (orchiectomy) or blockade (DES or Leuprolide) of testicular androgens. Only 4.5% of patients did not respond to the combination therapy as compared to an average of 18% by standard therapy. The duration of response is also significantly increased in the patients who received the combination therapy while the death rate was decreased by approximately 2-fold between 2 and 3 years of treatment. The marked (6.3-fold) improvement in the rate of complete objective responses coupled with the 4-fold decrease in the number of non responders, the increased duration of the positive responses and the 2-fold decrease in the death rate at 2 to 3 years of treatment are obtained with the combination therapy using Flutamide and castration with no or minimal secondary effects. In addition, two hundred nine patients with biopsy-proven stage D2 prostatic adenocarcinoma showing disease progression after orchiectomy, DES or an LHRH agonist used alone received the combination therapy with the pure antiandrogen Flutamide. In patients treated with DES, the estrogen was replaced by the LHRH agonist [D-Trp6]LHRH ethylamide. Objective response to therapy was also assessed according to the criteria of the US NPCP. Thirteen patients (6.2%) had a complete response to treatment while partial and stable responses were achieved in 20 (9.6%) and 39 (18.7%) patients, respectively, for a total objective response rate of 34.5%. The mean duration of response was 24 months. While, in the non responders, the median survival was 8.13 months with a 17% probability of survival at 2 years, the probability of survival of patients who showed partial and stable responses at 2 years was 87 and 67%, respectively. All patients who achieved a complete response are still alive. Considering the excellent tolerance coupled with an objective response observed in 34.5% of the patients, the combination therapy with Flutamide and castration (surgical or LHRH agonist) appears to be the treatment of choice for prostate cancer patients in relapse after standard endocrine therapy.

Adenocarcinoma↗
PubMed2001

Role of adjuvant endocrine therapy in early-stage breast cancer.

The value of adjuvant endocrine therapy in saving lives of women with estrogen receptor-positive (ER(+)) early-stage breast cancer cannot be disputed. Tamoxifen has proven to be effective in improving relapse-free and overall survival in both pre- and postmenopausal women with ER(+) early-stage breast cancer. In the meta-analysis of the Early Breast Cancer Trialists' Collaborative Group, the proportional reduction in recurrence and mortality for 5 years of tamoxifen therapy was 50% and 28% respectively for patients with ER(+) tumors. These reductions in recurrence and mortality were similar in both lymph node-negative (N(-)) and lymph node-positive (N(+)) patients and translate to an absolute improvement in 10-year survival of approximately 11% in N(+) patients and 6% in N(-) patients. Current data suggest that about 5 years of tamoxifen therapy is the optimal duration of treatment. For women with ER(-)/progesterone receptor-negative (PR(-)) tumors, tamoxifen does not lower the risk of distant metastases or improve survival. In ER(+) patients, the addition of tamoxifen to chemotherapy further lowers the risk of recurrence by about 30% to 40% when compared to chemotherapy alone. In premenopausal women with ER(+) breast cancer, ovarian ablation has proven to be as effective as chemotherapy in improving both relapse-free and overall survival and the potential additive role of ovarian ablation to chemotherapy and/or tamoxifen is presently being explored in clinical trials. The combination of tamoxifen and ovarian ablation is currently being tested and may be superior to tamoxifen alone. In addition, newer, more effective, and less toxic aromatase inhibitors are also being evaluated in clinical trials in the adjuvant setting and have great promise. "Pure" antiestrogens or selective estrogen receptor down-regulators (SERDs) will be studied in adjuvant clinical trials in the near future. Recent data also suggest that molecular markers such as HER-2/neu may predict the response to endocrine therapy, and other predictive factors are currently being evaluated. Lastly, there is renewed interest in neoadjuvant endocrine therapy, a treatment option that may select those patients with early-stage breast cancer most likely to benefit from endocrine therapy.

Antineoplastic Agents, Hormonal↗
PubMed1983

Results of endocrine therapy do not predict response to chemotherapy in advanced breast cancer.

One hundred and four patients with advanced breast cancer treated with adriamycin +/- vincristine had had prior endocrine therapy. Of 28 responders to prior endocrine therapy a response to subsequent chemotherapy occurred in 15 (54%); the response frequency in the 76 non-responders to endocrine therapy was 51% (39 patients). The median time to treatment failure was not significantly different between responders to prior endocrine treatment and non-responders (7 months vs 5 months; P = 0.136). Although the median survival from starting chemotherapy tended to be longer in the endocrine responders (18 months) than in the non-responders (12 months), there was no significant difference between the two groups (chi = 2.749; P = 0.097). In a subgroup of 31 non-responders to endocrine therapy who had had stable disease (greater than or equal to 6 months) the median time to treatment failure was 6 months and median survival 13 months. This lack of differences existed for each subgroup of endocrine therapy. Response to prior endocrine treatment was not shown to be a determinant of response to subsequent chemotherapy.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2001

Resistance to endocrine therapy of breast cancer: recent advances and tomorrow's challenges.

The role of endocrine therapy in early as well as advanced breast cancer cannot be overrated. Long-term tamoxifen exposure (5 years) in the adjuvant setting has been shown to be effective not only in improving relapse-free and overall survival but also in reducing the incidence of contralateral cancers. Promising results have been achieved in breast cancer prevention with use of antiestrogens. Novel aromatase inhibitors and inactivators have been found superior to conventional treatment in metastatic disease and are currently being evaluated in the adjuvant setting to improve relapse-free and overall survival. If potential health hazards from estrogen deprivation with regard to cardiovascular disease as well as bone metabolism can be addressed, adjuvant endocrine therapy may include such drugs in the future. However, while endocrine therapy of breast cancer has become more and more important in the clinic, the major problems in hormonal therapy are primary and acquired resistance to endocrine manipulations. The causes for endocrine resistance and possible ways to delay or avoid this phenomenon are only allusively understood. Elucidation of the mechanisms underlying endocrine resistance in vivo represents the key to improve our treatment strategies. Due to intense use of in vitro models and animal systems, many potential mechanisms of endocrine resistance have been described; however, our understanding of the problem of drug resistance in vivo remains limited. Hopefully, ongoing programs on translational research in the neoadjuvant, adjuvant, and palliative settings will provide information that will improve our understanding of the biology of endocrine resistance in vivo and, thus, provide us with a better rationale to improve early as well as late endocrine therapy in breast cancer patients. The present publication summarizes the state of the art with respect to endocrine resistance.

Antineoplastic Agents, Hormonal↗
PubMed2001

Selection of primary breast cancer patients for adjuvant endocrine therapy--is oestrogen receptor alone adequate?

Among 834 patients who had primary breast cancer treated by surgery without adjuvant systemic therapy, 363 had relapse treated by endocrine therapy alone. Patients with oestrogen receptor positive tumours (median: 70 vs. 45 months, p < 0.0001) or with non-progression at 6 months of therapy (median: 111 vs. 37 months, p < 0.0001) survived longer than those with oestrogen receptor negative tumours or with disease progression respectively, presumably due to the effect of therapy. On the other hand, the median disease-free interval, uninfluenced by therapy, showed a similar difference: oestrogen receptor positive versus negative = 29 versus 21 months, p < 0.005; non-progression versus progression = 40 versus 19 months, p < 0.0001. Patients with oestrogen receptor-positive tumours and non-progression at 6 months had the longest disease-free interval. The present study has established that there are factors, other than the oestrogen receptor, inherent in the primary tumour as reflected by the disease-free interval, which affect hormone sensitivity. Selection of adjuvant endocrine therapy based on the oestrogen receptor alone would deem inadequate. Further studies to elucidate other possible factors are warranted to refine the use of endocrine therapy, especially in the adjuvant setting when no indication of response is available.

Breast Neoplasms↗