Side Effects of Adjuvant Endocrine Treatment in Premenopausal Breast Cancer Patients: A Prospective Randomized Study

Purpose: To compare the effect of adjuvant endocrine therapies with and without chemotherapy on physical symptoms, anxiety, and depressive symptoms in premenopausal women with breast cancer in a randomized clinical trial (the Zoladex in Premenopausal Patients trial). Patients and Methods: The patients were randomly assigned to goserelin, goserelin plus tamoxifen, tamoxifen alone, or no endocrine therapy. The duration of the endocrine treatment was 2 years. The groups were observed for 3 years after primary treatment (ie, during 2 years of active treatment as well as 1 year after cessation of the adjuvant endocrine therapy). All patients with node-positive disease received adjuvant chemotherapy with cyclophosphamide, methotrexate, and fluorouracil (CMF), which was given concurrently with the endocrine treatment. Results: Patients treated with CMF typically reported higher levels of physical symptoms than did patients who did not receive CMF. It was only among patients who did not receive chemotherapy that the endocrine treatment had differential effects. Goserelin was most burdensome and resulted in similar symptom levels as those of CMF, whereas the side effects of tamoxifen alone were milder. After cessation of the endocrine treatment, the side effects diminished in patients who had not received CMF, whereas patients treated with CMF reported ongoing problems at the 3-year follow-up. In contrast, anxiety and depressive symptoms were not significantly affected by endocrine treatment or chemotherapy during the 3 years of assessment. Conclusion: Goserelin and tamoxifen resulted in menopausal symptoms, but these symptoms were reversible. However, women treated with CMF experienced physical symptoms throughout the whole study period.

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A phase III, open label, prospective, randomized, multicenter, neoadjuvant study of chemotherapy versus endocrine therapy in premenopausal patient with hormone responsive, HER2 negative, breast cancer (KBCSG 012).

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.517 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. 517-517

Author(s):

hee Jeong Kim ◽

Woo Chul Noh ◽

Eun Sook Lee ◽

Leesu Kim ◽

Yongsik Jung ◽

...

Keyword(s):

Breast Cancer ◽

Lymph Node ◽

Cancer Patients ◽

Endocrine Therapy ◽

Endocrine Treatment ◽

Breast Cancer Patients ◽

Neoadjuvant Endocrine Therapy ◽

Premenopausal Breast Cancer ◽

Ki 67 ◽

Initial Biopsy

517 Background: Neoadjuvant endocrine therapy has shown efficacy in hormone-responsive postmenopausal breast cancer patients. We aimed to assess the efficacy and safety of cytotoxic chemotherapy versus endocrine therapy for hormone-responsive lymph node-positive premenopausal breast cancer patients in a neoadjuvant setting. (NCT01622361). Methods: In this phase 3, randomized, double blind, parallel group, multicenter study, we enrolled premenopausal women with estrogen receptor (ER)-positive, HER2-negative, and lymph node-positive premenopausal breast cancer patients. Patients were randomized to either 24 weeks of neoadjuvant chemotherapy with adriamycin plus cyclophosphamide (AC) followed by taxane (T) or neoadjuvant endocrine therapy with zoladex and tamoxifen. Results: 187 patients were randomly assigned to chemotherapy (n=95) or endocrine therapy (n=92), and 174 patients completed the 24 week neoadjuvant treatment period (n=87, both). More patients in the chemotherapy group had a complete or partial response than did those in endocrine therapy arm on both caliper (chemotherapy 83.9% vs endocrine therapy 71.3%, OR 0.476 95% CI 0.228 to 0.994) and MRI (chemotherapy 83.7% vs endocrine therapy 52.9%, OR 0.219, 95% CI 0.107 to 0.447). Three patient on chemotherapy group (3.4%) and 1 patients (1.15%) on endocrine treatment group showed complete pathologic response. In the patients who had breast cancer with low Ki 67 expression (<20%) on initial biopsy, clinical response on caliper were shown similar on both treatment group (HR 0.958, 95%CI 0.296 to 3.101). Five patients who had no tumor on the breast or lymph node after 24 week neoadjuvant endocrine therapy had higher ER score (all allred score >6), all low grade (1or 2) low Ki 67(≤20%) expression (4/5 patients) on initial biopsy specimen. Conclusions: In premenopausal breast cancer patients, 24 weeks neoadjuvant chemotherapy showed better clinical response than endocrine therapy. Low Ki 67 expression could be a parameter of the endocrine treatment. Clinical trial information: NCT01622361.

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IHC-based Ki67 as response biomarker to tamoxifen in breast cancer window trials enrolling premenopausal women

npj Breast Cancer ◽

10.1038/s41523-021-00344-3 ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Stacey E. P. Joosten ◽

Marius Wellenstein ◽

Rutger Koornstra ◽

Annelot van Rossum ◽

Joyce Sanders ◽

...

Keyword(s):

Breast Cancer ◽

Postmenopausal Women ◽

Cancer Patients ◽

Endocrine Therapy ◽

Postmenopausal Breast Cancer ◽

Premenopausal Women ◽

Blood Levels ◽

Breast Cancer Patients ◽

Premenopausal Breast Cancer ◽

Estradiol Levels

AbstractWindow studies are gaining traction to assess (molecular) changes in short timeframes. Decreased tumor cell positivity for the proliferation marker Ki67 is often used as a proxy for treatment response. Immunohistochemistry (IHC)-based Ki67 on tissue from neo-adjuvant trials was previously reported to be predictive for long-term response to endocrine therapy for breast cancer in postmenopausal women, but none of these trials enrolled premenopausal women. Nonetheless, the marker is being used on this subpopulation. We compared pathologist assessed IHC-based Ki67 in samples from pre- and postmenopausal women in a neo-adjuvant, endocrine therapy focused trial (NCT00738777), randomized between tamoxifen, anastrozole, or fulvestrant. These results were compared with (1) IHC-based Ki67 scoring by AI, (2) mitotic figures, (3) mRNA-based Ki67, (4) five independent gene expression signatures capturing proliferation, and (5) blood levels for tamoxifen and its metabolites as well as estradiol. Upon tamoxifen, IHC-based Ki67 levels were decreased in both pre- and postmenopausal breast cancer patients, which was confirmed using mRNA-based cell proliferation markers. The magnitude of decrease of Ki67 IHC was smaller in pre- versus postmenopausal women. We found a direct relationship between post-treatment estradiol levels and the magnitude of the Ki67 decrease in tumors. These data suggest IHC-based Ki67 may be an appropriate biomarker for tamoxifen response in premenopausal breast cancer patients, but anti-proliferative effect size depends on estradiol levels.

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Effect of Endocrine Treatment on Sexuality in Premenopausal Breast Cancer Patients: A Prospective Randomized Study

Journal of Clinical Oncology ◽

10.1200/jco.2001.19.11.2788 ◽

2001 ◽

Vol 19 (11) ◽

pp. 2788-2796 ◽

Cited By ~ 119

Author(s):

Gunilla Berglund ◽

Marianne Nystedt ◽

Christina Bolund ◽

Per-Olow Sjödén ◽

Lars-Erik Rutquist

Keyword(s):

Breast Cancer ◽

Sexual Dysfunction ◽

Cancer Patients ◽

Randomized Study ◽

Multicenter Trial ◽

Endocrine Treatment ◽

Controlled Clinical Trial ◽

Breast Cancer Patients ◽

Premenopausal Breast Cancer ◽

Negative Effect

PURPOSE: To study the sexual effects of the 2-year adjuvant goserelin (Zoladex [Zeneca AB, Södertälje, Sweden]) alone, tamoxifen alone, and Zoladex and tamoxifen in combination (ZT) versus no adjuvant endocrine therapy among premenopausal breast cancer patients with or without chemotherapy in a controlled clinical trial (a European multicenter trial: Zoladex in Premenopausal Breast Cancer Patients). PATIENTS AND METHODS: This prospective study examined several aspects of sexuality through the use of self-administered questionnaires, which were completed by patients at seven points of assessment for 3 years after randomization. RESULTS: Patients treated with chemotherapy had a higher level of sexual dysfunction than did patients who received no systemic treatment. The addition of endocrine treatment did not alter this result. In contrast, among patients who did not receive chemotherapy, Zoladex and ZT produced a significantly higher level of dysfunction from 1 to 2 years after inclusion, as compared with those who received no endocrine treatment. Tamoxifen alone did not produce side effects. After termination of endocrine treatment, sexual dysfunction began to diminish. Those with chemotherapy had high and frequently increasing levels of dysfunction even after 2 to 3 years of independent of endocrine treatment. Zoladex had a negative effect on sexual fear, which was reduced by the addition of tamoxifen. CONCLUSION: Zoladex increased sexual dysfunction during treatment among patients without chemotherapy, but the disturbances of sexual functioning were reversible. The use of adjuvant chemotherapy was associated with continued sexual problems, even at 3 years after randomization.

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Endocrine Treatment of Breast Cancer: Current Perspectives, Future Directions

International Journal of Pharmaceutical Quality Assurance ◽

10.25258/ijpqa.v8i03.9570 ◽

2017 ◽

Vol 8 (03) ◽

Author(s):

Tazia Irfan ◽

Mainul Haque ◽

Sayeeda Rahman ◽

Russell Kabir ◽

Nuzhat Rahman ◽

...

Keyword(s):

Breast Cancer ◽

Estrogen Receptor ◽

Endocrine Therapy ◽

Ovarian Function ◽

Premenopausal Women ◽

New Drugs ◽

Effective Control ◽

Endocrine Treatment ◽

Estrogen Production ◽

Hormone Sensitive

Breast cancer remains one of the major causes of death in women, and endocrine treatment is currently one of the mainstay of treatment in patients with estrogen receptor positive breast cancer. Endocrine therapy either slows down or stops the growth of hormone-sensitive tumors by blocking the body’s capability to yield hormones or by interfering with hormone action. In this paper, we intended to review various approaches of endocrine treatments for breast cancer highlighting successes and limitations. There are three settings where endocrine treatment of breast cancer can be used: neoadjuvant, adjuvant, or metastatic. Several strategies have also been developed to treat hormone-sensitive breast cancer which include ovarian ablation, blocking estrogen production, and stopping estrogen effects. Selective estrogen-receptor modulators (SERMs) (e.g. tamoxifen and raloxifene), aromatase inhibitors (AIs) (e.g. anastrozole, letrozole and exemestane), gonadotropin-releasing hormone agonists (GnRH) (e.g. goserelin), and selective estrogen receptor downregulators (SERDs) (e.g. fulvestrant) are currently used drugs to treat breast cancer. Tamoxifen is probably the first targeted therapy widely used in breast cancer treatment which is considered to be very effective as first line endocrine treatment in previously untreated patients and also can be used after other endocrine therapy and chemotherapy. AIs inhibit the action of enzyme aromatase which ultimately decrease the production of estrogen to stimulate the growth of ER+ breast cancer cells. GnRH agonists suppress ovarian function, inducing artificial menopause in premenopausal women. Endocrine treatments are cheap, well-tolerated and have a fixed single daily dose for all ages, heights and weights of patients. Endocrine treatments are not nearly as toxic as chemotherapy and frequent hospitalization can be avoided. New drugs in preliminary trials demonstrated the potential for improvement of the efficacy of endocrine therapy including overcoming resistance. However, the overall goals for breast cancer including endocrine therapy should focus on effective control of cancer, design personalized medical therapeutic approach, increase survival time and quality of life, and improve supportive and palliative care for end-stage disease.

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MCM3 upregulation confers endocrine resistance in breast cancer and is a predictive marker of diminished tamoxifen benefit

npj Breast Cancer ◽

10.1038/s41523-020-00210-8 ◽

2021 ◽

Vol 7 (1) ◽

Author(s):

Sanne Løkkegaard ◽

Daniel Elias ◽

Carla L. Alves ◽

Martin V. Bennetzen ◽

Anne-Vibeke Lænkholm ◽

...

Keyword(s):

Breast Cancer ◽

Cell Cycle ◽

Cancer Patients ◽

Endocrine Therapy ◽

Endocrine Resistance ◽

Predictive Marker ◽

Endocrine Treatment ◽

Breast Cancer Patients ◽

Minichromosome Maintenance ◽

Primary Tumors

AbstractResistance to endocrine therapy in estrogen receptor-positive (ER+) breast cancer is a major clinical problem with poorly understood mechanisms. There is an unmet need for prognostic and predictive biomarkers to allow appropriate therapeutic targeting. We evaluated the mechanism by which minichromosome maintenance protein 3 (MCM3) influences endocrine resistance and its predictive/prognostic potential in ER+ breast cancer. We discovered that ER+ breast cancer cells survive tamoxifen and letrozole treatments through upregulation of minichromosome maintenance proteins (MCMs), including MCM3, which are key molecules in the cell cycle and DNA replication. Lowering MCM3 expression in endocrine-resistant cells restored drug sensitivity and altered phosphorylation of cell cycle regulators, including p53(Ser315,33), CHK1(Ser317), and cdc25b(Ser323), suggesting that the interaction of MCM3 with cell cycle proteins is an important mechanism of overcoming replicative stress and anti-proliferative effects of endocrine treatments. Interestingly, the MCM3 levels did not affect the efficacy of growth inhibitory by CDK4/6 inhibitors. Evaluation of MCM3 levels in primary tumors from four independent cohorts of breast cancer patients receiving adjuvant tamoxifen mono-therapy or no adjuvant treatment, including the Stockholm tamoxifen (STO-3) trial, showed MCM3 to be an independent prognostic marker adding information beyond Ki67. In addition, MCM3 was shown to be a predictive marker of response to endocrine treatment. Our study reveals a coordinated signaling network centered around MCM3 that limits response to endocrine therapy in ER+ breast cancer and identifies MCM3 as a clinically useful prognostic and predictive biomarker that allows personalized treatment of ER+ breast cancer patients.

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A validated model to predict low recurrence risk distinguished by 21-gene recurrence score in hormone receptor-positive invasive breast cancer patients.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.532 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 532-532

Author(s):

Yasue Tsuchida ◽

Sachiko Ohde ◽

Ryota Nakamura ◽

Yoko Kanada ◽

Sakiko Miura ◽

...

Keyword(s):

Breast Cancer ◽

Multivariate Analysis ◽

Prediction Model ◽

Cancer Patients ◽

Endocrine Therapy ◽

Hormone Receptor ◽

Recurrence Score ◽

Premenopausal Women ◽

Breast Cancer Patients ◽

Derivation Cohort

532 Background: In the prospective TAILORx and RxPONDER trials, the 21-gene Recurrence Score (RS) showed endocrine therapy alone was non-inferior to chemo-endocrine therapy in the analysis of invasive disease-free survival in postmenopausal hormone-receptor (HR)-positive breast cancer patients with RS < = 25. They also indicated chemotherapy was associated with benefit for women 50 years or younger with RS 11 to 25. However, in Japan, the test is not conventionally available because of non-coverage by national insurance. We aimed to develop and validate a model to predict RS using clinicopathological factors that identify patients who would have low risk shown by testing the 21-gene RS and can avoid chemotherapy. Methods: Four hundred patients, including 187 N0/1 postmenopausal, and 213 N0 premenopausal women who underwent surgery and had the RS from St. Luke’s International Hospital, Tokyo, Japan, were included in derivation cohort. Derivation cohort was divided into 2 groups by RS 25; patients with RS of 0 to 25 (n = 321) and with RS over 26 (n = 79). Multivariate logistic regression analysis was performed using candidate factors for all patients and pre- or postmenopausal patients. The prediction model was validated using an external cohort of 70 patients from Showa University School of Medicine, Tokyo, Japan. Results: Nuclear grade (NG) (adjusted OR, 5.28, 95% CI, 2.47–11.30), high Progesterone receptor (PgR) expression (Allred score 7-8) (adjusted OR, 10.62, 95% CI, 5.34–21.13) and low Ki67 level ( < = 20%) (adjusted OR, 5.29, 95% CI, 2.33-12.01) were significant independent predictors of RS of 0 to 25. With these factors could predict RS of 0 to 25 (AUC of 0.848, 95% CI, 0.803-0.893) with the highest probability of low-RS for 100%. The prediction model of the validation cohort had same discriminatory ability having an AUC of 0.812 (95% CI, 0.701-0.923). In postmenopausal patients, NG (adjusted OR, 4.81, 95% CI, 1.72–13.42), high PgR expression (adjusted OR, 10.62, 95% CI, 4.52–37.72), and low Ki67 level (adjusted OR, 4.94, 95%CI, 1.87-13.04) were significantly associated with RS of 0 to 25 in multivariate analysis. A regression model with these 4 factors could predict RS of 0 to 25 (AUC of 0.842, 95%CI, 0.782-0.902). In premenopausal patients, NG (adjusted OR, 8.76, 95% CI, 1.14–67.40), high PgR expression (adjusted OR, 3.22, 95% CI, 1.61–6.43), and low Ki67 level (adjusted OR, 2.87, 95% CI, 1.20–6.87) were significantly associated with RS of 0 to 10 in multivariate analysis. These factors could predict RS of 0 to 10 (AUC of 0.811, 95% CI, 0.731-0.891). However, the highest probability of low-RS provided this model for premenopausal women was 46.8%. Conclusions: Our validated model could provide useful information to distinguish low-RS especially for postmenopausal patients with high reproducibility. However, for premenopausal women, the 21-gene RS is warranted.

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Zoledronic Acid Prevents Cancer Treatment–Induced Bone Loss in Premenopausal Women Receiving Adjuvant Endocrine Therapy for Hormone-Responsive Breast Cancer: A Report From the Austrian Breast and Colorectal Cancer Study Group

Journal of Clinical Oncology ◽

10.1200/jco.2005.02.7102 ◽

2007 ◽

Vol 25 (7) ◽

pp. 820-828 ◽

Cited By ~ 223

Author(s):

Michael F.X. Gnant ◽

Brigitte Mlineritsch ◽

Gero Luschin-Ebengreuth ◽

Stephan Grampp ◽

Helmut Kaessmann ◽

...

Keyword(s):

Breast Cancer ◽

Zoledronic Acid ◽

Bone Loss ◽

Endocrine Therapy ◽

Premenopausal Women ◽

Adjuvant Endocrine Therapy ◽

Phase Iii ◽

Endocrine Treatment ◽

Mineral Density ◽

T Score

Purpose Adjuvant therapy for breast cancer can be associated with decreased bone mineral density (BMD) that may lead to skeletal morbidity. This study examined whether zoledronic acid can prevent bone loss associated with adjuvant endocrine therapy in premenopausal patients. Patients and Methods This study is a randomized, open-label, phase III, four-arm trial comparing tamoxifen (20 mg/d orally) and goserelin (3.6 mg every 28 days subcutaneously) ± zoledronic acid (4 mg intravenously every 6 months) versus anastrozole (1 mg/d orally) and goserelin ± zoledronic acid for 3 years in premenopausal women with hormone-responsive breast cancer. In a BMD subprotocol at three trial centers, patients underwent serial BMD measurements at 0, 6, 12, 24, and 36 months. Results Four hundred one patients were included in the BMD subprotocol. Endocrine treatment without zoledronic acid led to significant (P < .001) overall bone loss after 3 years of treatment (BMD, −14.4% after 36 months; mean T score reduction, −1.4). Overall bone loss was significantly more severe in patients receiving anastrozole/goserelin (BMD, −17.3%; mean T score reduction, −2.6) compared with patients receiving tamoxifen/goserelin (BMD, −11.6%; mean T score reduction, −1.1). In contrast, BMD remained stable in zoledronic acid–treated patients (P < .0001 compared with endocrine therapy alone). No interactions with age or other risk factors were noted. Conclusion Endocrine therapy caused significant bone loss that increased with treatment duration in premenopausal women with breast cancer. Zoledronic acid 4 mg every 6 months effectively inhibited bone loss. Regular BMD measurements and initiation of concomitant bisphosphonate therapy on evidence of bone loss should be considered for patients undergoing endocrine therapy.

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