scholarly journals Integration of Clinical Variables for the Prediction of Late Distant Recurrence in Patients With Estrogen Receptor–Positive Breast Cancer Treated With 5 Years of Endocrine Therapy: CTS5

2018 ◽  
Vol 36 (19) ◽  
pp. 1941-1948 ◽  
Author(s):  
Mitch Dowsett ◽  
Ivana Sestak ◽  
Meredith M. Regan ◽  
Andrew Dodson ◽  
Giuseppe Viale ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Endocrine Therapy ◽  
Validation Cohort ◽  
Prognostic Score ◽  
Distant Recurrence ◽  
Hazard Ratio ◽  
Low Risk ◽  
Endocrine Treatment ◽  
Data Set ◽  
Positive Breast Cancer

Purpose Estimating risk of late distant recurrence (DR) is an important goal for managing women with hormone receptor–positive breast cancer after 5 years of endocrine treatment without recurrence. We developed and validated a simple clinicopathologic tool (Clinical Treatment Score post–5 years [CTS5]) to estimate residual risk of DR after 5 years of endocrine treatment. Patients and Methods The ATAC (Arimidex, Tamoxifen, Alone or in Combination) data set (N = 4,735) was used to create a prognostic score for post–5-year risk of DR. Validity of CTS5 (ATAC) was tested in the BIG 1-98 data set (N = 6,711). Time to late DR, 5 years after finishing scheduled endocrine therapy, was the primary end point. Cox regression models estimated the prognostic performance of CTS5 (ATAC). Results CTS5 (ATAC) was significantly prognostic for late DR in the ATAC cohort (hazard ratio, 2.47; 95% CI, 2.24 to 2.73; P < .001) and BIG 1-98 validation cohort (hazard ratio, 2.07; 95% CI, 1.88 to 2.28; P < .001). CTS5 (ATAC) risk stratification defined in the training cohort as low (< 5% DR risk, years 5 to 10), intermediate (5% to 10%), or high (> 10%) identified 43% of the validation cohort as low risk, with an observed DR rate of 3.6% (95% CI, 2.7% to 4.9%) during years 5 to 10. From years 5 to 10, 63% of node-negative patients were low risk, with a DR rate of 3.9% (95% CI, 2.9% to 5.3%), and 24% with one to three positive nodes were low risk, with a DR rate of 1.5% (95% CI, 0.5% to 3.8%). A final CTS5 for future use was derived from pooled data from ATAC and BIG 1-98. Conclusion CTS5 is a simple tool based on information that is readily available to all clinicians. CTS5 was validated as highly prognostic for late DR in the independent BIG 1-98 study. The final CTS5 algorithm identified 42% of women with < 1% per-year risk of DR who could be advised of the limited potential value of extended endocrine therapy.

Adjuvant Endocrine Therapy for Women With Hormone Receptor–Positive Breast Cancer: ASCO Clinical Practice Guideline Focused Update

2019 ◽  
Vol 37 (5) ◽  
pp. 423-438 ◽  
Author(s):  
Harold J. Burstein ◽  
Christina Lacchetti ◽  
Holly Anderson ◽  
Thomas A. Buchholz ◽  
Nancy E. Davidson ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Clinical Practice ◽  
Endocrine Therapy ◽  
Clinical Practice Guideline ◽  
Practice Guideline ◽  
Cancer Recurrence ◽  
Endocrine Treatment ◽  
Breast Cancers ◽  
Node Negative ◽  
Positive Breast Cancer

Purpose To update the ASCO clinical practice guideline on adjuvant endocrine therapy based on emerging data about the optimal duration of aromatase inhibitor (AI) treatment. Methods ASCO conducted a systematic review of randomized clinical trials from 2012 to 2018. Guideline recommendations were based on the Panel’s review of the evidence from six trials. Results The six included studies of AI treatment beyond 5 years of therapy demonstrated that extension of AI treatment was not associated with an overall survival advantage but was significantly associated with lower risks of breast cancer recurrence and contralateral breast cancer compared with placebo. Bone-related toxic effects were more common with extended AI treatment. Recommendations The Panel recommends that women with node-positive breast cancer receive extended therapy, including an AI, for up to a total of 10 years of adjuvant endocrine treatment. Many women with node-negative breast cancer should consider extended therapy for up to a total of 10 years of adjuvant endocrine treatment based on considerations of recurrence risk using established prognostic factors. The Panel noted that the benefits in absolute risk of reduction were modest and that, for lower-risk node-negative or limited node-positive cancers, an individualized approach to treatment duration that is based on considerations of risk reduction and tolerability was appropriate. A substantial portion of the benefit for extended adjuvant AI therapy was derived from prevention of second breast cancers. Shared decision making between clinicians and patients is appropriate for decisions about extended adjuvant endocrine treatment, including discussions about the absolute benefits in the reduction of breast cancer recurrence, the prevention of second breast cancers, and the impact of adverse effects of treatment. Additional information can be found at www.asco.org/breast-cancer-guidelines .

Clinical validation of EndoPredict in premenopausal women with estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-) primary breast cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 537-537
Author(s):  
Anastasia Constantinidou ◽  
Yiola Marcou ◽  
Timothy Simmons ◽  
Ryan Bernhisel ◽  
Elisha Hughes ◽  
...  
Keyword(s):  
Breast Cancer ◽  
High Risk ◽  
Endocrine Therapy ◽  
Primary Breast Cancer ◽  
Distant Recurrence ◽  
Low Risk ◽  
Her2 Breast Cancer ◽  
Response To Chemotherapy ◽  
Menopausal Women ◽  
Low Risk Women

537 Background: The EndoPredict 12-gene prognostic assay is validated to predict distant recurrence-free survival (DRFS) and response to chemotherapy in post-menopausal women with ER+, HER2- breast cancer. This study evaluated the performance of EndoPredict in pre-menopausal women. Methods: Stored tumor samples from women with ER+, HER2- primary breast cancer who were pre-menopausal at the time of diagnosis and were systemically treated with endocrine therapy alone were obtained from two sites (University of Nottingham and University of Cyprus). These samples were tested with EndoPredict to produce a 12-gene molecular score (EP). Pathologic tumor size and nodal status were algorithmically combined with the EP score to produce the clinicomolecular EPclin score. Cases with tumors > pT3, which were treated with chemotherapy, or for whom the EPclin score was missing or invalid were excluded. Associations of EP and EPclin with 10-year DRFS were evaluated in terms of hazard ratios (HRs) from Cox proportional hazards models stratified by cohort. 10-year DRFS was estimated for EPclin high-risk and low-risk women by Kaplan-Meier analysis. Results: Out of 411 eligible cases, 385 had a valid EPclin score and were included in the analysis. Mean age at breast cancer diagnosis was 46.5 years (standard deviation 4.7). Most women (N = 239, 62.6%) had grade II tumors and 16.1% (N = 62) had node-positive disease. Over the observation period (median 9.7 years, interquartile range 6.6-13.9 years), 35 women had a distant recurrence within 10 years. Both the molecular EP score and the molecular-clinicopathologic EPclin score were associated with increased risk of distant recurrence [HR 1.3, 95% confidence interval (CI) 1.2-1.5; p < 0.001 and HR 3.6, 95% CI 2.3-5.7; p < 0.001, respectively]. Of these patients, 249 (64.7%) were categorized as low risk by EPclin score while the remaining 136 (35.3%) were categorized as high risk. Compared to EPclin low-risk women, EPclin high-risk patients were more likely to experience distant recurrence (HR 4.6, 95% CI 1.4-15.2; p = 0.004). At 10 years post-diagnosis, EPclin low-risk women who received endocrine therapy alone had a DRFS of 97% (95% CI 93-99%). Conversely, EPclin high-risk women had a DRFS of only 76% (95% CI 67-82%). Conclusions: The EPclin score is highly associated with DRFS in pre-menopausal women who received adjuvant endocrine therapy alone. Based on these data, pre-menopausal women with EPclin low-risk breast cancer may safely forgo adjuvant chemotherapy in addition to endocrine therapy.

scholarly journals Aberrant Regulation of RAD51 Promotes Resistance of Neoadjuvant Endocrine Therapy in ER-positive Breast Cancer

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Yan Jia ◽  
Yueshuai Song ◽  
Guolei Dong ◽  
Chunfang Hao ◽  
Weipeng Zhao ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Aromatase Inhibitor ◽  
Endocrine Therapy ◽  
Functional Enrichment ◽  
Endocrine Treatment ◽  
Main Function ◽  
Neoadjuvant Endocrine Therapy ◽  
Severe Problem ◽  
Er Positive ◽  
Positive Breast Cancer

Abstract Breast cancer is one of the most common malignant cancers affecting females. Estrogen receptor (ER)-positive breast cancer is responsive to endocrine therapy. Although current therapies offer favorable prospects for improving survival, the development of resistance remains a severe problem. In this study, we explored the resistance mechanisms of ER-positive breast cancer to neoadjuvant endocrine therapy. Microarray data of GSE87411 contained 109 pairs of samples from Z1031 trial, including untreated samples and post-treated samples with neoadjuvant aromatase inhibitor (AI) therapy. The differentially expressed genes (DEGs) were obtained from two different comparisons: untreated samples versus post-treated samples with AIs, and post-treated samples sensitive versus resistant to AIs. Multiple bioinformatic methods were applied to evaluate biological function, protein-protein network and potential binding between target protein and aromatase inhibitor. Then, regulation of gene expression, DNA methylation and clinicopathological factors of breast cancer were further analyzed with TCGA data. From GSE87411 dataset, 30 overlapped DEGs were identified. Cell division was found to be the main function of overlapped DEGs by functional enrichment and gene ontology (GO) analysis. RAD51 recombinase (RAD51), a key protein of homologous recombination, was detected to interact with BReast CAncer genes 2 (BRCA2). Moreover, according to the docking simulation, RAD51 might potentially bind to AIs. Overexpressed RAD51 was associated with hypermethylation of BRCA2, resistance to AIs and poor overall survival of patients with ER-positive breast cancer. Furthermore, RAD51 was found to be a better indicator than MKI67 for predicting resistance in neoadjuvant setting. The results indicated that methylation of BRCA2 led to incomplete suppression on RAD51, which caused an increased expression of RAD51, subsequently AI-resistance and poor prognosis in ER-positive breast cancer. RAD51 could be a new candidate used as a predicative marker and therapeutic target in neoadjuvant endocrine treatment.

scholarly journals Validation of the Clinical Treatment Score Post–Five Years in Breast Cancer Patients for Predicting Late Distant Recurrence: A Single-Center Investigation in Korea

2021 ◽  
Vol 11 ◽  
Author(s):  
Jun-Hee Lee ◽  
Se Kyung Lee ◽  
Byung Joo Chae ◽  
Jonghan Yu ◽  
Jeong Eon Lee ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Postmenopausal Women ◽  
Cancer Patients ◽  
Endocrine Therapy ◽  
Distant Metastasis ◽  
Premenopausal Women ◽  
Distant Recurrence ◽  
Breast Cancer Patients ◽  
Risk Of Recurrence ◽  
Positive Breast Cancer

BackgroundEndocrine therapy is administered to hormone-positive breast cancer patients to prevent distant metastasis. It is important to evaluate the risk of recurrence and to determine which patients are viable candidates for such treatment because hormone therapy has side effects that can include postmenopausal symptoms. The Clinical Treatment Score post–five years (CTS5), a simple tool for identifying candidates for endocrine therapy, was recently introduced; however, CTS5 only has been applied in validation studies with postmenopausal women. We aimed to validate CTS5 among premenopausal breast cancer patients.MethodsWe identified patients treated between 1994 and 2014 at Samsung Medical Center in Seoul, Korea, and followed their treatment outcomes for more than 60 months after surgery using clinicopathologic parameters. According to menopausal status, we divided the study population into two groups: pre- and postmenopausal women. After calculating CTS5 values based on some parameters, we stratified the rate of late distant recurrence (DR) and analyzed the correlation between CTS5 value and late DR by risk.ResultsAmong 16,904 patients treated surgically for breast cancer, 2,605 with hormone receptor–positive breast cancer who received endocrine therapy were included. Of these, 1,749 (67.14%) patients were premenopausal women, and the median age was 44.00 years. When categorizing study participants according to CTS5-related risk for late DR, 86.79% were categorized as low risk, 5.95% were categorized as intermediate risk, and 7.26% were categorized as high risk. The annual rate of DR was 1.41% for those in the present study and was similar between pre- and postmenopausal participants (1.40 vs. 1.42). Distant metastasis-free survival was not different between the two groups (hazard ratio: 0.817, 95% confidence interval [CI]: 0.547–1.221). The area under the receiver operating characteristic curve at 10 years for premenopausal and postmenopausal patients was 61.75 (95% CI: 52.97–70.53) and 72.71 (95% CIs: 63.30–82.12), respectively.ConclusionsAlthough CTS5 was able to predict late DR, it should be applied with caution in premenopausal women. A CTS5 calculator for premenopausal women might be needed to not underestimate the risk of recurrence in Korea.

scholarly journals Targeting STAT3 signalling using stabilised sulforaphane (SFX-01) inhibits endocrine resistant stem-like cells in ER-positive breast cancer

2020 ◽  
Author(s):  
Bruno M. Simões ◽  
Angélica Santiago-Gómez ◽  
Chiara Chiodo ◽  
Tiago Moreira ◽  
Daniel Conole ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Endocrine Therapy ◽  
Target Genes ◽  
Therapy Resistance ◽  
Tumor Formation ◽  
Endocrine Treatment ◽  
Aldh Activity ◽  
Stat3 Phosphorylation ◽  
Er Positive ◽  
Positive Breast Cancer

ABSTRACTPURPOSEEstrogen receptor (ER) positive breast cancer is frequently sensitive to endocrine therapy. Multiple mechanisms of endocrine therapy resistance have been identified, including cancer stem-like cell (CSC) activity. Sulforaphane (SFN) has previously been shown to target CSCs but its mechanism of action is unclear. Here we investigate SFX-01, a stabilised formulation of SFN, for its effects on breast CSC activity in ER+ preclinical models and to study its mechanism.EXPERIMENTAL DESIGNCSC activity was measured by mammosphere formation efficiency (MFE), aldehyde dehydrogenase (ALDH) activity, and tumor formation using patient samples and patient-derived xenograft (PDX) tumors treated with SFX-01 alone or in combination with tamoxifen or fulvestrant. Gene expression and SFN target proteins in treated samples were assessed.RESULTSSFX-01 reduced MFE of both ER+ primary and metastatic patient samples. Both tamoxifen and fulvestrant increased MFE and ALDH activity of PDX tumors, which was reversed by combination with SFX-01. SFX-01 significantly reduced tumor initiating cell frequency in secondary transplants at limiting dilution and reduced the formation of spontaneous lung micrometastases by PDX tumors in mice. Mechanistically, we establish that both tamoxifen and fulvestrant induce STAT3 phosphorylation. SFX-01 suppressed phospho-STAT3 and SFN directly bound STAT3 in patient and PDX samples. Analysis of ALDH+ cells from endocrine-resistant patient samples revealed activation of STAT3 target genes MUC1 and OSMR, which were inhibited by SFX-01 in patient samples. Increased expression of these genes after 3 months’ endocrine treatment of ER+ patients (n=68) predicted poor prognosis.CONCLUSIONSOur data establish the importance of STAT3 signaling in CSC-mediated resistance to endocrine therapy and the potential of SFX-01 for improving clinical outcomes in ER+ breast cancer.

Clinical validity of CTS5 for estimating risk of late recurrence in unselected, non-trial patients with early ER+ breast cancer.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 514-514 ◽  
Author(s):  
Juliet Richman ◽  
Alistair E. Ring ◽  
Mitchell Dowsett ◽  
Ivana Sestak
Keyword(s):  
Breast Cancer ◽  
Postmenopausal Women ◽  
Endocrine Therapy ◽  
Cox Regression ◽  
Premenopausal Women ◽  
Risk Groups ◽  
Late Recurrence ◽  
Distant Recurrence ◽  
Low Risk ◽  
Clinical Validity

514 Background: The Clinical Treatment Score at 5 years (CTS5) is a prognostic tool using clinicopathological data to estimate distant recurrence (DR) risk after 5 years of endocrine therapy for postmenopausal women with estrogen receptor positive (ER+) breast cancer. It was developed and validated in the ATAC and BIG 1-98 trials. Methods: The validity of CTS5 was tested in a retrospective cohort of unselected, non-trial patients diagnosed with early ER+ breast cancer at the Royal Marsden Hospital from 2000-2007 who were alive and distant recurrence-free at 5 years. The primary endpoint was time to late DR (5-10 years). Cox regression models were used to determine the prognostic value of CTS5 and to produce Kaplan-Meier curves with associated 10-year DR risks (%). Results: A total of 2428 women were included with a median follow-up of 9.34 years from diagnosis. The CTS5 was significantly prognostic for late DR in post- and premenopausal women (Table). Risk stratification by CTS5 of the postmenopausal cohort was comparable with the development cohort. 42.1% of postmenopausal women were categorised into the low risk group with a late DR risk of 4.9% and these women had significantly lower risk of late DR compared to those in the intermediate or high-risk groups (Table). Amongst the premenopausal cohort, 41% were categorised as low risk with a late DR risk of 4.9%. The prognostic effect of CTS5 was seen for chemotherapy treated (HR=2.26, 95% CI (1.68-3.03)) and untreated patients (HR=1.93, 95% (1.32-2.82)). Conclusions: CTS5 demonstrated clinical validity for predicting late DR within a large cohort of unselected, non-trial patients that included premenopausal women. The low risk cohort identified by the CTS5 represents a group of women whose risk of late DR is so low as to not warrant extended endocrine therapy to ten years. [Table: see text]

Endocrine Treatment of Breast Cancer: Current Perspectives, Future Directions

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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