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Fjermeros K, Ghannoum S, Geisler SB, Bhargava S, Tahiri A, Klajic J, Lüders T, Fongård M, Nawaz MS, Bosnjak-Olsen T, Buvarp UCE, Rosenskiold AKJ, Nguyen NT, Sletbak TT, Seyedzadeh M, Selsås K, Porojnicu AC, Skjerven HK, Hovda T, Sahlberg KK, Torland LA, Lyngra M, Hammarström CL, Hönigsperger EB, Noone JC, Mathiassen S, Hurtado A, Goel S, Koff A, Tekpli X, Kristensen VN, Geisler J. The NEOLETRIB trial: neoadjuvant treatment with Letrozole and Ribociclib in ER-positive, HER2-negative breast cancer. Future Oncol 2024; 20:2457-2466. [PMID: 39073142 PMCID: PMC11520546 DOI: 10.1080/14796694.2024.2377531] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2024] [Accepted: 07/04/2024] [Indexed: 07/30/2024] Open
Abstract
Chemotherapy is used as neoadjuvant therapy for all subgroups of breast cancer, including ER-positive, and HER2-negative cases. However, studies have suggested that using aromatase inhibitors combined with CDK4/6-inhibitors might be an appropriate alternative in selected patients. Thus, the NEOLETRIB trial evaluates the response of ER-positive, HER2-negative luminal A/B breast cancer to the combination of letrozole and ribociclib in the neoadjuvant setting. Comprehensive molecular biology procedures, including sequential single-cell RNA-sequencing of tumor biopsies, are performed during 6 months of treatment with extensive biobanking of blood samples, tumor biopsies and gut microbiome specimens. Our findings will hopefully contribute to an improved selection of patients who may benefit from this drug combination and give new insights into the intra-tumoral changes during this treatment.Trial registration number: NCT05163106 (ClinicalTrials.gov).
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Affiliation(s)
- Kamilla Fjermeros
- Department of Oncology, Akershus University Hospital, Lørenskog, Norway
| | - Salim Ghannoum
- Department of Medical Genetics, Oslo University Hospital, Oslo, Norway
| | | | - Sameer Bhargava
- Department of Oncology, Akershus University Hospital, Lørenskog, Norway
- Cancer Registry of Norway, Norwegian Institute of Public Health, Oslo, Norway
| | - Andliena Tahiri
- Department of Clinical Molecular Biology (EpiGen), Akershus University Hospital, Lørenskog, Norway
| | - Jovana Klajic
- Department of Clinical Molecular Biology (EpiGen), Akershus University Hospital, Lørenskog, Norway
| | - Torben Lüders
- Department of Clinical Molecular Biology (EpiGen), Akershus University Hospital, Lørenskog, Norway
- Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Norway
| | - Marie Fongård
- Department of Medical Genetics, Oslo University Hospital, Oslo, Norway
| | - Meh Sameen Nawaz
- Department of Clinical Molecular Biology (EpiGen), Akershus University Hospital, Lørenskog, Norway
- Department of Health and Exercise, School of Health Sciences, Kristiania University College, Oslo, Norway
| | | | | | | | - Nam Thi Nguyen
- Department of Oncology, Akershus University Hospital, Lørenskog, Norway
| | | | | | - Knut Selsås
- Department of Endocrine & Breast Surgery, Akershus University Hospital, Lørenskog, Norway
| | | | - Helle Kristine Skjerven
- Department of Breast & Endocrine Surgery, Drammen Hospital, Vestre Viken Hospital Trust, Drammen, Norway
| | - Tone Hovda
- Department of Radiology, Drammen Hospital, Vestre Viken Hospital Trust, Norway
| | - Kristine Kleivi Sahlberg
- Department of Research & Innovation, Vestre Viken Hospital Trust, Drammen, Norway
- Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Norway
| | - Lilly Anne Torland
- Department of Research & Innovation, Vestre Viken Hospital Trust, Drammen, Norway
- Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Norway
| | - Marianne Lyngra
- Department of Pathology, Akershus University Hospital, Lørenskog, Norway
| | | | | | | | - Silje Mathiassen
- Department of Pathology, Akershus University Hospital, Lørenskog, Norway
| | - Antoni Hurtado
- Functional Genomics group & Molecular Pathology Unit, Centro de Investigación del Cáncer (CSIC-Universidad de Salamanca), Campus Universitario Miguel de Unamuno s/n. 37007, Salamanca, Spain
| | - Shom Goel
- Peter MacCallum Cancer Centre, Australia & The Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Australia
| | - Andrew Koff
- Program in Molecular Biology, Memorial Sloan Kettering Cancer Center & Weill Cornell Medical College, New York, NY USA
| | - Xavier Tekpli
- Department of Medical Genetics, Oslo University Hospital, Oslo, Norway
| | - Vessela N. Kristensen
- Department of Medical Genetics, Oslo University Hospital, Oslo, Norway
- Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Norway
| | - Jürgen Geisler
- Department of Oncology, Akershus University Hospital, Lørenskog, Norway
- Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Norway
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Poschner S, Wackerlig J, Dobusch D, Pachmann B, Banh SJ, Thalhammer T, Jäger W. Actaea racemosa L. extract inhibits steroid sulfation in human breast cancer cells: Effects on androgen formation. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2020; 79:153357. [PMID: 33011631 DOI: 10.1016/j.phymed.2020.153357] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/29/2020] [Revised: 08/26/2020] [Accepted: 09/24/2020] [Indexed: 06/11/2023]
Abstract
BACKGROUND Actaea racemosa L., also known as black cohosh, is a popular herb commonly used for the treatment of menopausal symptoms. Because of its purported estrogenic activity, black cohosh root extract (BCE) may trigger breast cancer growth. STUDY DESIGN/METHODS The potential effects of standardized BCE and its main constituent actein on cellular growth rates and steroid hormone metabolism were investigated in estrogen receptor alpha positive (ERα+) MCF-7 and -negative (ERα-) MDA-MB-231 human breast cancer cells. Cell numbers were determined following incubation of both cell lines with the steroid hormone precursors dehydroepiandrosterone (DHEA) and estrone (E1) for 48 h, in the presence and absence of BCE or actein. Using a validated liquid chromatography-high resolution mass spectrometry assay, cell culture supernatants were simultaneously analyzed for the ten main steroids of the estrogen pathway. RESULTS Inhibition of MCF-7 and MDA-MB-231 cell growth (up to 36.9%) was observed following treatment with BCE (1-25 µg/ml) or actein (1-50 µM). Incubation of MCF-7, but not of MDA-MB-231 cells, with DHEA and BCE caused a 20.9% reduction in DHEA-3-O-sulfate (DHEA-S) formation, leading to a concomitant increase in the androgens 4-androstene-3,17-dione (AD) and testosterone (T). Actein was shown to exert an even stronger inhibitory effect on DHEA-S formation in MCF-7 cells (up to 89.6%) and consequently resulted in 12- to 15-fold higher androgen levels compared with BCE. The formation of 17β-estradiol (E2) and its glucuronidated and sulfated metabolites was not affected by BCE or actein after incubation with the estrogen precursor estrone (E1) in either cell line. CONCLUSIONS The results of the present study demonstrated that actein and BCE do not promote breast cancer cell growth or influence estrogen levels. However, androgen formation was strongly stimulated by BCE and actein, which may contribute to their ameliorating effects on menopausal symptoms in women. Future studies monitoring the levels of AD and T upon BCE supplementation of patients are warranted to verify an association between BCE and endogenous androgen metabolism.
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Affiliation(s)
- Stefan Poschner
- Department of Pharmaceutical Chemistry, University of Vienna, 1090 Vienna, Austria
| | - Judith Wackerlig
- Department of Pharmaceutical Chemistry, University of Vienna, 1090 Vienna, Austria
| | - Daniel Dobusch
- Department of Pharmaceutical Chemistry, University of Vienna, 1090 Vienna, Austria
| | - Bettina Pachmann
- Department of Pharmaceutical Chemistry, University of Vienna, 1090 Vienna, Austria
| | - Santosa J Banh
- Department of Pharmaceutical Chemistry, University of Vienna, 1090 Vienna, Austria
| | - Theresia Thalhammer
- Department of Pathophysiology and Allergy Research, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, 1090 Vienna, Austria
| | - Walter Jäger
- Department of Pharmaceutical Chemistry, University of Vienna, 1090 Vienna, Austria; Vienna Metabolomics Center (VIME), University of Vienna, 1090 Vienna, Austria.
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Hayashi Y, Takei H, Saito T, Kai T, Inoue K, Kurosumi M, Ninomiya J. Optimal Treatment Duration of Neoadjuvant Endocrine Therapy for Women Aged 60 Years or Older with Estrogen Receptor-Positive, HER2-Negative Invasive Breast Cancer. J NIPPON MED SCH 2020; 88:354-360. [PMID: 33250473 DOI: 10.1272/jnms.jnms.2021_88-509] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
BACKGROUND Neoadjuvant endocrine therapy is not the standard of care for breast cancer, primarily because the optimal treatment duration remains unclear. This phase 2 prospective multicenter study analyzed time to progression, time to maximal response, and time to treatment failure for neoadjuvant exemestane. METHODS Inclusion criteria were women aged ≥60 years with Stage II or III breast cancer classified as estrogen receptor-positive/human epidermal growth factor receptor 2-negative. Response was defined as a ≥10% and minimum of 3 mm decrease in tumor size, as compared with the most recent or smallest value, and no new lesion. Progression was defined as a >10% and minimum of over 3 mm increase in tumor size, as compared with the most recent or smallest value, or a new lesion. Maximal response was defined as the final recorded response. RESULTS This study included 24 women, most of whom had T2 N0 tumors with high estrogen receptor expression. We initially observed a response in 23 patients (96%); however, 6 patients (25%) later experienced progression. Time to progression, time to maximal response, and time to treatment failure ranged from 7 to 22 months (estimated median, 35), 1 to 22 months (estimated median, 10), and 2 to 22 months (estimated median, 22), respectively. Treatment duration varied widely, but the estimated optimal duration of neoadjuvant exemestane therapy was 22 to 35 months in patients seeking to avoid surgery and 10 months in patients wishing to receive breast-conserving surgery. CONCLUSIONS Neoadjuvant exemestane therapy is long effective for older women with hormone-sensitive breast cancer.
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Affiliation(s)
- Yuji Hayashi
- Department of Breast Surgery, Japanese Red Cross Saitama Hospital.,Division of Breast Surgery, Saitama Cancer Center
| | - Hiroyuki Takei
- Division of Breast Surgery, Saitama Cancer Center.,Department of Breast Surgery and Oncology, Nippon Medical School
| | - Tsuyoshi Saito
- Department of Breast Surgery, Japanese Red Cross Saitama Hospital
| | | | | | - Masafumi Kurosumi
- Department of Pathology, Kameda Kyobashi Clinic.,Department of Pathology, Saitama Cancer Center
| | - Jun Ninomiya
- Division of Breast Surgery, Saitama Cancer Center.,Ninomiya Hospital
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Madigan LI, Dinh P, Graham JD. Neoadjuvant endocrine therapy in locally advanced estrogen or progesterone receptor-positive breast cancer: determining the optimal endocrine agent and treatment duration in postmenopausal women-a literature review and proposed guidelines. Breast Cancer Res 2020; 22:77. [PMID: 32690069 PMCID: PMC7370425 DOI: 10.1186/s13058-020-01314-6] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2020] [Accepted: 07/06/2020] [Indexed: 12/20/2022] Open
Abstract
Introduction For patients with locally advanced estrogen receptor or progesterone receptor-positive breast cancer, neoadjuvant endocrine therapy (NET) facilitates down-staging of the tumor and increased rates of breast-conserving surgery. However, NET remains under-utilized, and there are very limited clinical guidelines governing which therapeutic agent to use, or the optimal duration of treatment in postmenopausal women. This literature review aims to discuss the evidence surrounding (1) biomarkers for patient selection for NET, (2) the optimal neoadjuvant endocrine agent for postmenopausal women with locally advanced breast cancer, and (3) the optimal duration of NET. In addition, we make initial recommendations towards developing a clinical guideline for the prescribing of NET. Method A wide-ranging search of online electronic databases was conducted using a truncated PIC search strategy to identify articles that were relevant to these aims and revealed a number of key findings. Results Randomized trials have consistently demonstrated that aromatase inhibitors are more effective than tamoxifen, in terms of objective response rate and rate of BCS, and should be used as first-line NET. The three available aromatase inhibitors have so far been demonstrated to be biologically equivalent, with the choice of aromatase inhibitor not having been shown to affect clinical outcomes. There is increasing evidence for extending the duration of NET beyond 3 to 4 months, to at least 6 months or until maximal clinical response is achieved. While on-treatment levels of the proliferation marker Ki67 are predictive of long-term outcome, the choice of adjuvant therapy in patients who have received NET and then surgery is best guided by the preoperative endocrine prognostic index, or PEPI, which incorporates Ki67 with other clinical parameters. Conclusion This study reveals that in appropriately selected patients, NET can provide equivalent clinical benefit to neoadjuvant chemotherapy in the same cohort, if suitable treatments and durations are chosen. Our findings highlight the need for better defined biomarkers both for guiding patient selection and for measuring outcomes. Development of standard guidelines for the prescribing of NET has the potential to improve both clinical outcomes and quality of life in this patient cohort.
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Affiliation(s)
- Lauren I Madigan
- Sydney Medical School - Westmead, The University of Sydney, Sydney, Australia.,Present Address: South Eastern Sydney Local Health District, and St. George and Sutherland Clinical Schools, UNSW Medicine, Sydney, Australia
| | - Phuong Dinh
- Sydney Medical School - Westmead, The University of Sydney, Sydney, Australia.,Westmead Breast Cancer Institute, Westmead Hospital, Westmead, Australia
| | - J Dinny Graham
- Sydney Medical School - Westmead, The University of Sydney, Sydney, Australia. .,Westmead Breast Cancer Institute, Westmead Hospital, Westmead, Australia. .,The Westmead Institute for Medical Research, The University of Sydney, Westmead, Australia.
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Yao LT, Wang MZ, Wang MS, Yu XT, Guo JY, Sun T, Li XY, Xu YY. Neoadjuvant endocrine therapy: A potential strategy for ER-positive breast cancer. World J Clin Cases 2019; 7:1937-1953. [PMID: 31423426 PMCID: PMC6695538 DOI: 10.12998/wjcc.v7.i15.1937] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2019] [Revised: 06/21/2019] [Accepted: 07/03/2019] [Indexed: 02/05/2023] Open
Abstract
A potential strategy for patients with estrogen receptor (ER)-positive breast cancer is necessary to replace neoadjuvant chemotherapy which has limited benefit. Neoadjuvant endocrine therapy (NAE) has been indicated to be a favorable alternate approach to downstage large or locally advanced breast cancer in ER-positive, human epidermal growth factor receptor 2 (HER2)-negative (ER+/HER2-) patients, especially postmenopausal women. Previous studies have demonstrated the efficacy of various endocrine agents in NAE. Aromatase inhibitors (AIs) have proven superiority over tamoxifen as a suitable choice to optimize treatment efficacy. Fulvestrant was recently reported as an effective agent, similar to AIs. Furthermore, the addition of targeted agents exerts synergistic antiproliferative effects with endocrine agents and rapidly improves response rates in both endocrine sensitive and resistant tumors. The neoadjuvant platform provides a unique opportunity to define the appropriate strategy and address the mechanisms of endocrine resistance. In addition, the predictive value of biomarkers and genomic assays in NAE is under investigation to evaluate individual effects and validate biomarker-based strategies. In this review, we discuss the most relevant evidence on the potential of NAE for ER+ breast cancer. The current understanding also offers new insights into the identification of the optimal settings and valuable predictive tools of NAE to guide clinical treatment decisions and achieve beneficial therapeutic effects.
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Affiliation(s)
- Li-Tong Yao
- Department of Breast Surgery, the First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
| | - Mo-Zhi Wang
- Department of Breast Surgery, the First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
| | - Meng-Shen Wang
- Department of Breast Surgery, the First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
| | - Xue-Ting Yu
- Department of Breast Surgery, the First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
| | - Jing-Yi Guo
- Department of Breast Surgery, the First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
| | - Tie Sun
- Department of Breast Surgery, the First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
| | - Xin-Yan Li
- Department of Breast Surgery, the First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
| | - Ying-Ying Xu
- Department of Breast Surgery, the First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning Province, China
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Sato N, Masuda N, Morimoto T, Ueno T, Kanbayashi C, Kaneko K, Yasojima H, Saji S, Sasano H, Morita S, Ohno S, Toi M. Neoadjuvant endocrine therapy with exemestane followed by response-guided combination therapy with low-dose cyclophosphamide in postmenopausal patients with estrogen receptor-positive breast cancer: A multicenter, open-label, phase II study. Cancer Med 2018; 7:3044-3056. [PMID: 29905023 PMCID: PMC6051169 DOI: 10.1002/cam4.1600] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2018] [Revised: 05/08/2018] [Accepted: 05/12/2018] [Indexed: 01/28/2023] Open
Abstract
Patients with estrogen receptor (ER)‐positive breast cancer are less likely to achieve a pathological complete response (pCR) with neoadjuvant chemotherapy. Neoadjuvant endocrine therapy may be more appropriate than neoadjuvant chemotherapy in these hormone‐sensitive patients. Most patients with ER‐positive breast cancer are postmenopausal, and therefore, generally older and less able to tolerate chemotherapy. We aimed to investigate the efficacy and safety of tailored neoadjuvant endocrine and chemoendocrine therapy for postmenopausal breast cancer patients. Untreated patients with primary invasive ER‐positive, HER2‐negative, stage I‐IIIA breast cancer, and Ki67 index ≤30% were enrolled. Patients received exemestane 25 mg/d for 12 weeks. Based on clinical response and change in Ki67 index, assessed at 8‐12 weeks, patients with complete response (CR), partial response (PR) with Ki67 index ≤5% after treatment, or stable disease (SD) with Ki67 index ≤5% before and after treatment were defined as responders. For the subsequent 24 weeks, responders continued exemestane monotherapy (group A), and nonresponders received exemestane 25 mg/d plus cyclophosphamide 50 mg/d (group B). The primary endpoint was clinical response at weeks 24 and 36. A total of 59 patients (median age, 69 years) started initial exemestane monotherapy. After exclusion of three patients who discontinued during this period, 56 remained enrolled to receive subsequent treatment. Clinical response rates (CR and PR) and 95% CI at weeks 24 and 36 were 85% (12/14; 57.2%‐98.2%) and 71% (10/14; 41.9%‐91.6%), respectively, in group A; and 54% (23/42; 38.7%‐70.2%) and 71% (30/42; 55.4%‐84.3%), respectively, in group B. At week 36, no significant difference was found in median Ki67 index between the groups (3.5% and 4.0%). There were no treatment‐related deaths. We found that clinical response comparable to that of responders was achieved in nonresponders after addition of cyclophosphamide to the initial endocrine therapy.
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Affiliation(s)
- Nobuaki Sato
- Department of Breast Oncology, Niigata Cancer Center Hospital, Niigata, Japan
| | - Norikazu Masuda
- Department of Surgery, Breast Oncology, National Hospital Organization Osaka National Hospital, Osaka, Japan
| | - Takashi Morimoto
- Department of Breast Surgery, Yao Municipal Hospital, Osaka, Japan
| | - Takayuki Ueno
- Breast Surgical Oncology, Breast Oncology Center, Cancer Institute Hospital, Tokyo, Japan
| | - Chizuko Kanbayashi
- Department of Breast Oncology, Niigata Cancer Center Hospital, Niigata, Japan
| | - Koji Kaneko
- Department of Breast Oncology, Niigata Cancer Center Hospital, Niigata, Japan
| | - Hiroyuki Yasojima
- Department of Surgery, Breast Oncology, National Hospital Organization Osaka National Hospital, Osaka, Japan
| | - Shigehira Saji
- Department of Medical Oncology, Fukushima Medical University, Fukushima, Japan
| | | | - Satoshi Morita
- Department of Biomedical Statistics and Bioinformatics, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Shinji Ohno
- Breast Oncology Center, Cancer Institute Hospital, Tokyo, Japan
| | - Masakazu Toi
- Department of Surgery (Breast Surgery), Graduate School of Medicine, Kyoto University, Kyoto, Japan
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Deyati A, Younesi E, Hofmann-Apitius M, Novac N. Challenges and opportunities for oncology biomarker discovery. Drug Discov Today 2013; 18:614-24. [PMID: 23280501 DOI: 10.1016/j.drudis.2012.12.011] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2012] [Revised: 11/28/2012] [Accepted: 12/24/2012] [Indexed: 12/21/2022]
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Geisler J, Smith I, Miller W. Presurgical (neoadjuvant) endocrine therapy is a useful model to predict response and outcome to endocrine treatment in breast cancer patients. J Steroid Biochem Mol Biol 2012; 131:93-100. [PMID: 22207086 DOI: 10.1016/j.jsbmb.2011.12.006] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2011] [Revised: 12/09/2011] [Accepted: 12/11/2011] [Indexed: 10/14/2022]
Abstract
Endocrine therapy of breast cancer has been improved continuously during the last decades. Currently, aromatase inhibitors are dominating treatment algorithms for postmenopausal women with hormone-receptor positive breast cancer while tamoxifen still is the most widely used drug for premenopausal women. Several research tools and study designs have been used to challenge established drugs and develop the field of antihormonal therapy. One pivotal study option has been the observation of clinical responses during presurgical/neoadjuvant endocrine therapy (PSET/NET). This strategy has several major advantages. First, the breast tumor, still present in the patient's breast during therapy, can be followed by clinical observations and radiological measurements and any treatment effect will be immediately registered. Second, tumor biopsies may be obtained before initiation and following therapy allowing intra-patient comparisons. These tumor-biopsies may be used for the evaluation of intra-tumor changes associated with drug treatment. As examples, presurgical breast cancer trials have been used to evaluate intra-tumor estrogen levels during therapy with aromatase inhibitors and also to study mechanisms involved in the adaptation processes to estrogen suppression. Biomarker studies have provided information that may be used for patient selection in the future. Finally, recently published results from presurgical trials testing combinations of classical endocrine drugs and novel targeted therapies have produced promising results.
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Affiliation(s)
- Jürgen Geisler
- Institute of Clinical Medicine, Division of Medicine and Laboratory Sciences, University of Oslo, Oslo, Norway.
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Preoperative Endocrine Therapy: Preferred Therapy for Whom? CURRENT BREAST CANCER REPORTS 2011. [DOI: 10.1007/s12609-011-0060-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/14/2022]
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Neoadjuvant endocrine treatment of women with breast cancer. Oncol Rev 2011. [DOI: 10.1007/s12156-011-0083-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
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12
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Toi M, Saji S, Masuda N, Kuroi K, Sato N, Takei H, Yamamoto Y, Ohno S, Yamashita H, Hisamatsu K, Aogi K, Iwata H, Takada M, Ueno T, Saji S, Chanplakorn N, Suzuki T, Sasano H. Ki67 index changes, pathological response and clinical benefits in primary breast cancer patients treated with 24 weeks of aromatase inhibition. Cancer Sci 2011; 102:858-65. [PMID: 21231986 DOI: 10.1111/j.1349-7006.2011.01867.x] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/15/2023] Open
Abstract
Aromatase inhibitor shows efficacy for hormone receptor positive postmenopausal breast cancer. We evaluated the activity of 24 weeks of aromatase inhibition with exemestane for primary breast cancer in a neoadjuvant setting. Patients with stage II/IIIA invasive breast cancer with estrogen receptor (ER) and/or progesterone receptor (PgR)-positive status were eligible. Primary endpoints were objective response rate (ORR) and safety. A steroidal aromatase inhibitor exemestane of 25 mg/day was administered for 16 weeks with an 8-week extension. Secondary endpoints were rates of breast-conserving surgery (BCS), and change of Ki67 index and ER/PgR expression in central laboratory analyses. Between March 2006 and December 2007, 116 patients were enrolled. Among those, 102 patients completed 24 weeks of administration. The ORR was 47% (55/116) at Week 16 and 51% (59/116) at Week 24, respectively. No serious toxicity was seen. ORR was associated with ER Allred scores but not with PgR scores. The significant reduction in Ki67 index was confirmed. No progression was experienced in tumors with less than 15% Ki67 index. Pathological response was observed in 28 (30%) of 94 evaluated cases. No statistical correlation between pre-treatment Ki67 index and pathological response was detected; however, a trend of correlation was found between the post-treatment preoperative endocrine prognostic index (PEPI), a prognostic score and the pathological response. At diagnosis, 59 patients (51%) would have required mastectomy but 40 patients were converted to BCS, showing an increase in the rate of BCS (77%). The 24-week aromatase inhibition provided preferable clinical benefits with significant reduction in Ki67 index. More precise mechanisms of the response need to be investigated.
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Affiliation(s)
- Masakazu Toi
- Department of Surgery (Breast Surgery), Kyoto University, Kyoto, Japan.
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Iwata H. Neoadjuvant endocrine therapy for postmenopausal patients with hormone receptor-positive early breast cancer: a new concept. Breast Cancer 2010; 18:92-7. [PMID: 21140250 DOI: 10.1007/s12282-010-0233-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2010] [Accepted: 09/16/2010] [Indexed: 11/29/2022]
Abstract
Patients with resectable, nonmetastatic (stage I-IIIA) breast cancer usually receive adjuvant (postoperative) systemic therapy to control micrometastasis and prevent recurrence. Neoadjuvant (preoperative) chemotherapy is a standard treatment for resectable breast cancer, potentially enabling patients to undergo partial dissection. However, it has been reported that neoadjuvant chemotherapy has a limited effect in patients with hormone receptor-positive disease in terms of pathologic complete response rate, and in elderly patients there may be safety concerns. Furthermore, the appropriateness of chemotherapy for luminal early breast cancer [defined as hormone receptor-positive and human epidermal growth factor receptor-2 (HER2)-negative tumors] is an important clinical issue. We determine the need for chemotherapy in postmenopausal patients with hormone receptor-positive, HER2-negative, lymph node-negative early breast cancer according to clinicopathologic factors, including multigene signature. The National Surgical Adjuvant Study of Breast Cancer (N-SAS-BC06) New primary Endocrine-therapy Origination Study (NEOS) is a randomized phase III trial conducted in Japanese centers. It is evaluating adjuvant endocrine therapy, with or without chemotherapy, in patients with postmenopausal breast cancer that has responded to neoadjuvant letrozole. The aims of this trial are to: define patients who might not require chemotherapy by using their response to neoadjuvant endocrine therapy; analyze the relationship between neoadjuvant endocrine therapy and long-term prognosis; and analyze the correlation between clinical and pathologic response to neoadjuvant hormonal therapy with additional postoperative chemotherapy. We hope that the results of this trial will lead to the development of a new clinical strategy of pre- and postsurgical treatment for luminal breast cancer.
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Affiliation(s)
- Hiroji Iwata
- Department of Breast Oncology, Aichi Cancer Center Hospital, 1-1 Kanokoden, Chikusa-ku, Nagoya, Aichi, Japan.
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14
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Neoadjuvant endocrine therapy of breast cancer: which patients would benefit and what are the advantages? Breast Cancer 2010; 18:85-91. [DOI: 10.1007/s12282-010-0239-0] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2010] [Accepted: 10/20/2010] [Indexed: 10/18/2022]
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Use of molecular markers for predicting therapy response in cancer patients. Cancer Treat Rev 2010; 37:151-9. [PMID: 20685042 DOI: 10.1016/j.ctrv.2010.07.004] [Citation(s) in RCA: 76] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2010] [Revised: 07/07/2010] [Accepted: 07/09/2010] [Indexed: 12/27/2022]
Abstract
Predictive markers are factors that are associated with upfront response or resistance to a particular therapy. Predictive markers are important in oncology as tumors of the same tissue of origin vary widely in their response to most available systemic therapies. Currently recommended oncological predictive markers include both estrogen and progesterone receptors for identifying patients with breast cancers likely to benefit from hormone therapy, HER-2 for the identification of breast cancer patients likely to benefit from trastuzumab, specific K-RAS mutations for the identification of patients with advanced colorectal cancer unlikely to benefit from either cetuximab or panitumumab and specific EGFR mutations for selecting patients with advanced non-small-cell lung cancer for treatment with tyrosine kinase inhibitors such as gefitinib and erlotinib. The availability of predictive markers should increase drug efficacy and decrease toxicity, thus leading to a more personalized approach to cancer treatment.
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Early metabolic response to neoadjuvant letrozole, measured by FDG PET/CT, is correlated with a decrease in the Ki67 labeling index in patients with hormone receptor-positive primary breast cancer: a pilot study. Breast Cancer 2010; 18:299-308. [PMID: 20617404 DOI: 10.1007/s12282-010-0212-y] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2010] [Accepted: 05/19/2010] [Indexed: 10/19/2022]
Abstract
PURPOSE To assess whether the early metabolic response evaluated by (18)F-fluorodeoxy-glucose positron emission combined with computed tomography (FDG PET/CT) predicts the morphological, pathological, and cell-cycle responses to neoadjuvant endocrine therapy of hormone receptor-positive primary breast cancer. STUDY DESIGN Eleven patients (12 tumors) with estrogen receptor-positive (Allred score 7 or 8) primary breast cancer were enrolled. All patients received a daily dose (2.5 mg) of letrozole for 12 weeks followed by surgery. Sequential FDG PET/CT scans were performed before treatment (baseline), at 4 weeks after the initiation of endocrine therapy (PET2), and prior to surgery (PET3). Tumors showing a 40% or more reduction and those showing a less than 40% reduction in the standardized uptake value maximum (SUV(max)) at PET2 compared with the baseline PET were defined as metabolic responders and metabolic nonresponders, respectively. Change in tumor size as measured by ultrasound (morphological response), pathological response, and change in the Ki67 labeling index in tumor tissue (cell-cycle response) during the neoadjuvant letrozole therapy were compared between the metabolic responders and nonresponders. RESULTS The average decreases in SUV(max) at PET2 compared with the baseline PET in the metabolic responders (n = 6) and the metabolic nonresponders (n = 6) were 60.9% (±21.3 SD) and 14.2% (±12.0 SD), respectively. At PET3 compared with the baseline PET, the metabolic responders showed a significantly higher decrease of 64.5% (±18.7 SD) (p = 0.0004), whereas the nonresponders showed a nonsignificant decrease of 16.7% (±14.1 SD) (p = 0.06). The morphological and pathological responses after letrozole therapy did not differ between the metabolic responders and nonresponders. The metabolic responders showed a marked decrease in the Ki67 labeling index at 2 weeks after the initiation of treatment (62.9%, ±35.9 SD, p = 0.04) and at surgery (91.7%, ±10.7 SD, p = 0.03) compared with the baseline values. In contrast, metabolic nonresponders showed no significant change in the Ki67 index either after 2 weeks of therapy or at surgery. CONCLUSION Cell-cycle response monitored by the Ki67 labeling index correlates with metabolic response monitored by tumor SUV(max). Monitoring of tumor SUV(max) using FDG PET/CT may be feasible to predict cell-cycle response to neoadjuvant endocrine therapy of primary breast cancer.
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Bertelli G, Gangadhara S. Exemestane in postmenopausal women with early or advanced breast cancer: a review. Expert Opin Pharmacother 2010; 11:1933-42. [DOI: 10.1517/14656566.2010.495945] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
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Chanplakorn N, Chanplakorn P, Suzuki T, Ono K, Chan MSM, Miki Y, Saji S, Ueno T, Toi M, Sasano H. Increased estrogen sulfatase (STS) and 17β-hydroxysteroid dehydrogenase type 1(17β-HSD1) following neoadjuvant aromatase inhibitor therapy in breast cancer patients. Breast Cancer Res Treat 2010; 120:639-48. [DOI: 10.1007/s10549-010-0785-3] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2010] [Accepted: 02/03/2010] [Indexed: 11/28/2022]
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Yamashita H, Takahashi S, Ito Y, Yamashita T, Ando Y, Toyama T, Sugiura H, Yoshimoto N, Kobayashi S, Fujii Y, Iwase H. Predictors of response to exemestane as primary endocrine therapy in estrogen receptor-positive breast cancer. Cancer Sci 2009; 100:2028-33. [PMID: 19659610 PMCID: PMC11158316 DOI: 10.1111/j.1349-7006.2009.01274.x] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2009] [Revised: 06/27/2009] [Accepted: 06/30/2009] [Indexed: 01/06/2023] Open
Abstract
Endocrine therapy is the most important treatment of choice for estrogen receptor (ER)-positive breast cancer. Potential mechanisms for resistance to endocrine therapy involve ER-coregulatory proteins and cross-talk between ER and other growth factor-signaling networks. However, the factors and pathways responsible for endocrine therapy resistance, particularly resistance to aromatase inhibitors, have not been clearly established. Sixteen postmenopausal patients with ERalpha-positive primary breast cancer were treated daily with 25 mg of exemestane (an aromatase inhibitor) for 6 months. Expressions of ERalpha, ERbeta, progesterone receptor (PgR), androgen receptor (AR), amplified in breast cancer 1 (AIB1), aromatase, epidermal growth factor receptor, human epidermal growth factor receptor type 2, Ki67, cyclin D1, p53, Bcl2, signal transducer and activator of transcription 5 (Stat5), and insulin-like growth factor binding protein 5 (IGFBP5), and phosphorylations of ERalpha serine (Ser) 118, ERalpha Ser167, Akt Ser473, and p44/42 MAPK threonine (Thr) 202/tyrosine (Tyr) 204, were examined by immunohistochemistry on pretreatment tumor biopsies and post-treatment surgical specimens. Analyses were made to test for correlations with response to exemestane. Of the 16 patients, seven responded and nine retained stable disease. High-level expression of AIB1 and phosphorylation of Akt Ser473 were significantly associated with a better response to exemestane, suggesting that these factors could be considered as predictors of exemestane response. Expressions of ERalpha, ERbeta, PgR, aromatase, Ki67, cyclin D1, and p53, and phosphorylations of ERalpha Ser118, ERalpha Ser167, and p44/42 MAPK Thr202/Tyr204, were decreased, whereas expressions of Stat5 and IGFBP5 were increased in post-treatment specimens compared to the values in pretreatment biopsies. Thus, the analysis of factors involved in the estrogen-dependent growth-signaling pathways may be useful in identifying patients responsive to exemestane.
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Affiliation(s)
- Hiroko Yamashita
- Oncology, Immunology, and Surgery, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
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Mustacchi G, Mansutti M, Sacco C, Barni S, Farris A, Cazzaniga M, Cozzi M, Dellach C. Neo-adjuvant exemestane in elderly patients with breast cancer: a phase II, multicentre, open-label, Italian study. Ann Oncol 2009; 20:655-9. [DOI: 10.1093/annonc/mdn687] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
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Fearmonti RM, Keyomarsi K, Hunt KK. Biomarkers in neoadjuvant trials. Cancer Treat Res 2009; 147:1-36. [PMID: 21461824 DOI: 10.1007/978-0-387-09463-2_8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
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Abstract
Women who suffer from large or locally advanced malignant breast tumors are now commonly treated with preoperative ('neoadjuvant') systemic therapy to improve surgical outcomes and to raise the chances for breast-conserving therapy (BCT). Until recently, chemotherapy was the treatment of choice, and primary systemic endocrine treatment was restricted to medically frail or older women with receptor-positive breast cancer. The development of modern aromatase inhibitors (Als) and their subsequent clinical evaluation in neoadjuvant trials now provides us with an alternative to chemotherapy that is thought to be equally effective, yet considerably better tolerated. Several large prospective trials have compared tamoxifen with the non-steroidal AIs letrozole and anastrozole and the steroidal Al exemestane, with improved outcomes for all AIs in terms of tumor remission and rate of BCT. A number of predictive biomarkers now also allow us to identify those tumors that most likely respond to a certain endocrine regimen.
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Affiliation(s)
- Christian F Singer
- Division of Special Gynecology, Department of OB/GYN, Medical University of Vienna, Austria
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Perez EA. Safety of aromatase inhibitors in the adjuvant setting. Breast Cancer Res Treat 2007; 105 Suppl 1:75-89. [PMID: 17912638 PMCID: PMC2001222 DOI: 10.1007/s10549-007-9704-7] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2007] [Accepted: 07/17/2007] [Indexed: 11/24/2022]
Abstract
The third-generation aromatase inhibitors (AIs) letrozole, anastrozole, and exemestane are replacing tamoxifen as adjuvant therapy in most postmenopausal women with early breast cancer. Although AIs have demonstrated superior efficacy and better overall safety compared with tamoxifen in randomized controlled trials, they may not provide the cardioprotective effects of tamoxifen, and bone loss may be a concern with their long-term adjuvant use. Patients require regular bone mineral density monitoring, and prophylactic bisphosphonates are being evaluated to determine whether they may protect long-term bone health. AIs decrease the risks of thromboembolic and cerebrovascular events compared with tamoxifen, and the overall rate of cardiovascular events in patients treated with AIs is within the range seen in age-matched, non-breast-cancer populations. AIs are also associated with a lower incidence of endometrial cancer and fewer vaginal bleeding/discharge events than tamoxifen. Compared with tamoxifen, the incidence of hot flashes is lower with anastrozole and letrozole but may be higher with exemestane. Generally, adverse events with AIs are predictable and manageable, whereas tamoxifen may be associated with life-threatening events in a minority of patients. Overall, the benefits of AIs over tamoxifen are achieved without compromising overall quality of life.
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Affiliation(s)
- Edith A Perez
- Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA.
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