Mammostrat as an immunohistochemical multigene assay for prediction of early relapse risk in the TEAM pathology study.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 516-516
Author(s):  
John M. S. Bartlett ◽  
Kenneth J. Bloom ◽  
Tammy Robson ◽  
Thomas J. Lawton ◽  
Cornelis J. H. Van De Velde ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Adjuvant Chemotherapy ◽  
Endocrine Therapy ◽  
Disease Free Survival ◽  
Postmenopausal Breast Cancer ◽  
Nodal Status ◽  
Endocrine Treatment ◽  
Breast Cancer Patients ◽  
Additional Information ◽  
Er Positive

516 Background: Some postmenopausal patients with hormone sensitive early breast cancer remain at high risk of relapse despite endocrine therapy, and might benefit additionally from adjuvant chemotherapy. The challenge is to prospectively identify such patients. The Mammostrat test uses five immunohistochemical markers to stratify patients regarding recurrence risk, and may inform treatment decisions. We tested the efficacy of this panel in the TEAM trial. Methods: Pathology blocks from 4598 TEAM patients were collected and TMAs constructed. The cohort was 47% node positive and 36% were also treated with adjuvant chemotherapy. Triplicate 0.6mm2 TMA cores were stained and positivity for p53, HTF9C, CEACAM5, NDRG1, SLC7A5 assessed. Cases were assigned a Mammostrat risk score, and distant relapse free (DRFS) and disease free survival (DFS) analysed. Results: In multivariate regression analyses, corrected for conventional clinicopathological markers, Mammostrat provided significant additional information on DRFS after endocrine therapy in ER positive node negative patients (N=1226) not receiving chemotherapy (p=0.004). Further analyses in all patients not exposed to chemotherapy, irrespective of nodal status (N=2559) and in the entire cohort (N=3837) showed Mammostrat scores provide additional information on DRFS in these groups (p=0.001 and p<0.0001 respectively; multivariate analyses). No differences were seen between the two endocrine treatment regimens. Conclusions: The Mammostrat score predicts DRFS for both exemestane and tamoxifen-exemestane treated patients irrespective of nodal status and chemotherapy. The ability of this test to provide additional outcome data following treatment provides further evidence for its’ utility in risk stratification of ER positive postmenopausal breast cancer patients.

Mammostrat As an Immunohistochemical Multigene Assay for Prediction of Early Relapse Risk in the Tamoxifen Versus Exemestane Adjuvant Multicenter Trial Pathology Study

2012 ◽  
Vol 30 (36) ◽  
pp. 4477-4484 ◽  
Author(s):  
John M.S. Bartlett ◽  
Kenneth J. Bloom ◽  
Tammy Piper ◽  
Thomas J. Lawton ◽  
Cornelis J.H. van de Velde ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Adjuvant Chemotherapy ◽  
Endocrine Therapy ◽  
Disease Free Survival ◽  
Outcome Data ◽  
Nodal Status ◽  
Endocrine Treatment ◽  
Free Survival ◽  
Additional Information ◽  
Er Positive

PurposeSome postmenopausal patients with hormone-sensitive early breast cancer remain at high risk of relapse despite endocrine therapy and, in addition, might benefit from adjuvant chemotherapy. The challenge is to prospectively identify such patients. The Mammostrat test uses five immunohistochemical markers to stratify patients regarding recurrence risk and may inform treatment decisions. We tested the efficacy of this panel in the Tamoxifen versus Exemestane Adjuvant Multicenter (TEAM) trial.Patients and MethodsPathology blocks from 4,598 TEAM patients were collected, and tissue microarrays (TMAs) were constructed. The cohort was 47% node-positive, and 36% of patients in the cohort were treated with adjuvant chemotherapy. Triplicate 0.6-mm2TMA cores were stained, and positivity for p53, HTF9C, CEACAM5, NDRG1, and SLC7A5 was assessed. Cases were assigned a Mammostrat risk score, and distant relapse-free survival (DRFS) and disease-free survival (DFS) were analyzed.ResultsIn multivariate regression analyses, which were corrected for conventional clinicopathologic markers, Mammostrat provided significant additional information on DRFS after endocrine therapy in estrogen receptor (ER) –positive node-negative patients (n = 1,226) who did not receive chemotherapy (P = .004). Additional analyses in all patients not exposed to chemotherapy, irrespective of nodal status (n = 2,559) and in the entire cohort (n = 3,837) showed Mammostrat scores provided additional information on DRFS in these groups (P = .001 and P < .001, respectively; multivariate analyses). No differences were seen between the two endocrine treatment regimens.ConclusionThe Mammostrat score predicts DRFS for patients treated with exemestane and patients treated with tamoxifen followed by exemestane irrespective of nodal status and chemotherapy. The ability of this test to provide additional outcome data after treatment provides additional evidence of its use in risk stratification of ER-positive postmenopausal patients with breast cancer.

N-SAS BC06: A phase III study of adjuvant endocrine therapy with or without chemotherapy for postmenopausal breast cancer patients who responded to neoadjuvant letrozole (LET): The New Primary Endocrine-Therapy Origination Study (NEOS).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. TPS654-TPS654
Author(s):  
Hiroji Iwata ◽  
Shoichiro Ohtani ◽  
Tomomi Fujisawa ◽  
Naruto Taira ◽  
Norikazu Masuda ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Adjuvant Chemotherapy ◽  
Cancer Patients ◽  
Endocrine Therapy ◽  
Response Rate ◽  
Postmenopausal Breast Cancer ◽  
Phase Iii ◽  
Breast Cancer Patients ◽  
Er Positive ◽  
Phase Iii Study

TPS654 Background: It is uncertain whether adjuvant chemotherapy is required in the treatment of postmenopausal women with hormone-responsive and intermediate risk breast cancer. The TAILORx and MINDACT trials are ongoing and utilize gene expression profiling in order to answer this question. We have initiated a new study to address this matter by using response to initial neoadjuvant endocrine therapy. The primary aim of this phase III study is to evaluate the necessity of using adjuvant chemotherapy for the treatment of postmenopausal breast cancer patients with node-negative, ER-positive and HER2-negative tumors who responded to neoadjuvant LET. Methods: Inclusion criteria are T1c-T2N0M0, ER-positive by IHC (<10%), HER2-negative, postmenopausal women under 75 years old and written informed consent. Lymph node positive patients as assessed by SLNB are excluded. Neoadjuvant LET is administered for 24-28 weeks before surgery. CR, PR or SD patients are then randomized into two arms receiving either chemotherapy plus LET for 4.5-5 years or LET alone for 4.5-5 years after surgery. If the primary tumor response is defined as PD before surgery, the treatment will be changed at the investigator's discretion (surgery, chemotherapy or other endocrine therapy, but these patients will be followed up). The primary endpoint is disease-free survival (DFS), and secondary endpoints are overall survival (OS), response rate of LET, pathological response, breast conserving surgery rate, DFS/OS by response rate of LET, safety, QOL and cost-effectiveness. This study utilizes a randomized selection design. The objective of this design is to select the arm with the better outcome. We also conduct an additional translational research and central pathological review of ER, PgR, HER2, and Ki67.Patient recruitment commenced in May 2008 and 803 patients were enrolled at the end of 2012. A total of 850 patients will be enrolled at the end of May 2013. This study is supported by Public Health Research Foundation. Clinical trial information: UMIN000001090.

Effectiveness of adjuvant chemotherapy in combination with tamoxifen for node-positive postmenopausal breast cancer patients.

1997 ◽  
Vol 15 (4) ◽  
pp. 1385-1394 ◽  
Author(s):  
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Disease Free Survival ◽  
Postmenopausal Breast Cancer ◽  
Breast Cancer Patients ◽  
Node Positive ◽  
Increased Risk ◽  
Node Positive Disease ◽  
Er Positive ◽  
Risk Of Relapse

PURPOSE Adjuvant tamoxifen has been shown to reduce relapse and mortality among node-positive post-menopausal breast cancer patients. The value of adding chemotherapy to tamoxifen is controversial. PATIENTS AND METHODS Between July 1986 and April 1993, 1,266 postmenopausal breast cancer patients with node-positive disease were randomly assigned to receive one of four adjuvant therapy regimens: (A) tamoxifen alone for 5 years; (B) tamoxifen plus three courses of early cyclophosphamide, methotrexate, and fluorouracil (CMF) on months 1, 2, and 3; (C) tamoxifen plus delayed single courses of CMF on months 9, 12, and 15; (D) tamoxifen plus early and delayed CMF on months 1, 2, 3, 9, 12, and 15. The two-by-two factorial design allowed two direct comparisons: early CMF (B and D) versus no early CMF (A and C), and delayed CMF (C and D) versus no delayed CMF (A and B). Estrogen receptor (ER) status was known for all patients and was used to stratify the randomization. A total of 1, 212 patients (96%) were eligible and assessable. The median follow-up duration was 60 months. RESULTS The results of the two-by-two factorial comparisons were as follows: (1) early CMF added to tamoxifen significantly improved 5-year disease-free survival (DFS; 64% v 57%; hazards ratio [HR], 0.79; 95% confidence interval [CI], 0.66 to 0.95; P = .01); and (2) delayed CMF added to tamoxifen did not improve DFS (5-year DFS, 61% v 60%; HR, 0.97; 95% CI, 0.81 to 1.17; P = .77). For patients with ER-positive tumors, the addition of CMF, either early or delayed or both, reduced the relative risk of relapse by 22% to 36%. In contrast, for patients with ER-negative tumors, tamoxifen with delayed CMF was associated with a nonsignificant increased risk of relapse (HR, 1.27; 95% CI, 0.92 to 1.76; P = .15). CONCLUSION Postmenopausal patients with node-positive breast cancer should be offered combination chemotherapy in addition to tamoxifen. Tamoxifen should not be initiated before CMF, as this might be detrimental, especially for patients with ER-negative tumors.

Sequential versus concurrent use of chemotherapy and endocrine therapy in the adjuvant treatment of ER-positive breast cancer: A systematic review and Bayesian network meta-analysis.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e12040-e12040
Author(s):  
Tianfu Li ◽  
Zhen Shan ◽  
Liang Yu ◽  
Xiaying Kuang ◽  
Deyuan Zhang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Endocrine Therapy ◽  
Adjuvant Treatment ◽  
Randomized Clinical Trials ◽  
Statistical Significance ◽  
Disease Free Survival ◽  
Breast Cancer Patients ◽  
Concurrent Use ◽  
Er Positive ◽  
Positive Breast Cancer

e12040 Background: Chemotherapy followed by endocrine therapy is the standard adjuvant treatment strategy for estrogen receptor-positive breast cancer patients. However, no direct evidence so far demonstrated better efficacy of sequential use of chemotherapy and endocrine therapy over concurrent. Objective: To evaluate the efficacy between sequential and concurrent use of chemotherapy and endocrine therapy in the adjuvant treatment of ER positive breast cancer. Methods: Randomized clinical trials comparing chemotherapy and/or endocrine therapy in the adjuvant treatment of ER positive breast cancer were included. Hazard ratios (HRs) of disease-free survival (DFS) and overall survival (OS) were extracted and analyzed in Bayesian analysis. Patients were stratified by menopause status for subgroup analysis. Results: 37 trials were identified with 37225 patients enrolled in total, 37 trials with DFS results and 24 with OS. 3 comparisons were done between sequential and concurrent arms. In DFS analysis, no statistical significance was found in all 3 comparisons [CHE seq/con TAM (HR 1.01, 95%CI 0.8497 - 1.199); CHE seq/con OFS+TAM (HR 0.9119, 95%CI 0.5666 - 1.49); CHE seq/con OFS+AI (HR 1.032, 95%CI 0.6291 - 1.776)]. The same were seen in OS analysis [CHE seq/con TAM (HR 0.9512, 95%CI 0.8053 - 1.125); CHE seq/con OFS+TAM (HR 1.065, 95%CI 0.6344 - 1.789); CHE seq/con OFS+AI (HR 1.069, 95%CI 0.665 - 1.717)]. Rankings were done for preferable treatment recommendations. In DFS analyses, sequential arms ranked higher than concurrent arms [CHE seq/con OFS+AI (1 vs. 3); CHE seq/con OFS+TAM (6 vs. 7); CHE seq/con TAM (8 vs. 8)]. The same tendency was seen in OS analyses [CHE seq/con OFS+AI (1 vs. 2); CHE seq/con TAM (4 vs. 5)] except for CHE seq/con OFS+TAM (11 vs. 6-9). In subgroup ranking results, CHE seq/con OFS+AI and CHE seq/con OFS+TAM showed consistency among comparisons with concurrent arms ranked higher than sequential arms. However, CHE seq TAM ranked higher than CHE con TAM in all comparisons. Conclusions: The combination of chemotherapy and endocrine therapy in the adjuvant treatment of ER positive breast cancer demonstrated equal efficacy either used sequentially or concurrently. However, concurrent arms were recommended over sequential arms in premenopausal patients for better DFS and OS, except for the combination of chemotherapy and tamoxifen which was recommended to be used sequentially. Others: This study has been registered in PROSPERO (CRD42018104889).

Effect of Molecular Disease Subsets on Disease-Free Survival in Randomized Adjuvant Chemotherapy Trials for Estrogen Receptor–Positive Breast Cancer

2008 ◽  
Vol 26 (28) ◽  
pp. 4679-4683 ◽  
Author(s):  
Lajos Pusztai ◽  
Kristine Broglio ◽  
Fabrice Andre ◽  
W. Fraser Symmans ◽  
Kenneth R. Hess ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Adjuvant Chemotherapy ◽  
Endocrine Therapy ◽  
Disease Free Survival ◽  
Molecular Diagnostic ◽  
Free Survival ◽  
Er Positive ◽  
Disease Free ◽  
Positive Breast Cancer

Purpose The majority of estrogen receptor (ER)–positive cancers are sensitive to endocrine therapy and may not derive much further benefit from chemotherapy, but a subset are potentially chemotherapy sensitive. Molecular diagnostic tests allow the identification of these various subsets with some accuracy. The goal of the current analysis was to examine how the proportion of cases in the various risk (recurrence score [RS]) categories of a commercially available multigene assay influences the power of randomized trials to show benefit from adjuvant chemotherapy. Methods We modeled 10-year disease-free survival (DFS) for hypothetical, two-arm clinical trials that randomly assigned patients with ER-positive breast cancer to endocrine therapy alone or endocrine therapy plus chemotherapy. We varied the proportion of patients in low, intermediate, and high RS categories and used DFS estimates for each risk group based on results from the Southwest Oncology Group 8814 study. Results The probability of observing significant improvement in DFS as a result of chemotherapy decreases as the proportion of patients in the low RS category increases. For example, if a trial is designed with 80% power and the actual proportion of low RS patients accrued to the study increases from 40% to 60%, the power drops to 63%. Conclusion Variable accrual of low RS patients into different randomized adjuvant chemotherapy trials may partly explain contradictory results in the literature. Studies can be underpowered to detect improvement with chemotherapy as a result of inclusion of too many patients with low RS. Future adjuvant studies for ER-positive breast cancer will need to consider stratifying patients by molecular subtype.

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

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.

scholarly journals Clinical CYP2D6 Genotyping to Personalize Adjuvant Tamoxifen Treatment in ER-Positive Breast Cancer Patients: Current Status of a Controversy

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 771
Author(s):  
Tessa A. M. Mulder ◽  
Mirjam de With ◽  
Marzia del Re ◽  
Romano Danesi ◽  
Ron H. J. Mathijssen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Clinical Outcome ◽  
Cancer Patients ◽  
Plasma Concentrations ◽  
Tamoxifen Treatment ◽  
Current Status ◽  
Endocrine Treatment ◽  
Breast Cancer Patients ◽  
Er Positive ◽  
Positive Breast Cancer

Tamoxifen is a major option for adjuvant endocrine treatment in estrogen receptor (ER) positive breast cancer patients. The conversion of the prodrug tamoxifen into the most active metabolite endoxifen is mainly catalyzed by the enzyme cytochrome P450 2D6 (CYP2D6). Genetic variation in the CYP2D6 gene leads to altered enzyme activity, which influences endoxifen formation and thereby potentially therapy outcome. The association between genetically compromised CYP2D6 activity and low endoxifen plasma concentrations is generally accepted, and it was shown that tamoxifen dose increments in compromised patients resulted in higher endoxifen concentrations. However, the correlation between CYP2D6 genotype and clinical outcome is still under debate. This has led to genotype-based tamoxifen dosing recommendations by the Clinical Pharmacogenetic Implementation Consortium (CPIC) in 2018, whereas in 2019, the European Society of Medical Oncology (ESMO) discouraged the use of CYP2D6 genotyping in clinical practice for tamoxifen therapy. This paper describes the latest developments on CYP2D6 genotyping in relation to endoxifen plasma concentrations and tamoxifen-related clinical outcome. Therefore, we focused on Pharmacogenetic publications from 2018 (CPIC publication) to 2021 in order to shed a light on the current status of this debate.

Advances in Adjuvant Endocrine Therapy for Postmenopausal Women

2008 ◽  
Vol 26 (5) ◽  
pp. 798-805 ◽  
Author(s):  
Nancy U. Lin ◽  
Eric P. Winer
Keyword(s):  
Breast Cancer ◽  
Postmenopausal Women ◽  
Endocrine Therapy ◽  
Hormone Receptor ◽  
Disease Free Survival ◽  
Breast Cancer Diagnosis ◽  
Endocrine Treatment ◽  
Future Research ◽  
Sequential Approach ◽  
Hormone Receptor Positive

Hormone receptor-positive cancers are the most common tumor subtype among postmenopausal women with breast cancer. Despite substantial improvements in disease-free survival and overall survival with tamoxifen and chemotherapy, recurrences still occur, and may ultimately lead to death from breast cancer. Importantly, disease recurrence includes both early and late events, with over half of all recurrences detected more than 5 years from initial breast cancer diagnosis. In recent years, a number of large, randomized trials have evaluated the role of the aromatase inhibitors (AIs) in postmenopausal women with hormone receptor-positive breast cancer. These studies have tested one of three approaches: (1) an upfront AI, (2) a sequential approach after 2-3 years of tamoxifen, and (3) extended endocrine therapy beyond 5 years. Results of these studies have challenged the previous standard of a 5-year course of tamoxifen alone. While the AIs have become a standard component of treatment for most postmenopausal women, many questions remain as to how best tailor endocrine treatment to individual patients. In addition, despite the gains achieved with the AIs, many recurrences are not prevented, and novel strategies are urgently needed, particularly for those women at high risk of recurrence. In this article, we review the efficacy and toxicity data from the available trials of endocrine therapy in the postmenopausal setting. We outline controversies in choosing the optimal endocrine approach, and we discuss selected ongoing studies. Finally, we highlight future research directions, such as the need to understand host and tumor heterogeneity.

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