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2. Twenty-Year Benefit From Adjuvant Goserelin and Tamoxifen in Premenopausal Patients With Breast Cancer in a Controlled Randomized Clinical Trial.

Author

Tobin, Nicholas, Perez-Tenorio, Gizeh, Nordenskjöld, Anna, Johansson, Ulla, Hartman, Johan, Skoog, Lambert, Yau, Christina, Benz, Christopher, Stål, Olle, Nordenskjöld, Bo, Fornander, Tommy, Lindström, Linda, Johansson, Annelie, Dar, Huma, Esserman, Laura, and van t Veer, Laura

Subjects
Female, Humans, Middle Aged, Breast Neoplasms, Genomics, Goserelin, Receptors, Estrogen, Tamoxifen, Premenopause
Abstract

PURPOSE: To assess the long-term (20-year) endocrine therapy benefit in premenopausal patients with breast cancer. METHODS: Secondary analysis of the Stockholm trial (STO-5, 1990-1997) randomly assigning 924 premenopausal patients to 2 years of goserelin (3.6 mg subcutaneously once every 28 days), tamoxifen (40 mg orally once daily), combined goserelin and tamoxifen, or no adjuvant endocrine therapy (control) is performed. Random assignment was stratified by lymph node status; lymph node-positive patients (n = 459) were allocated to standard chemotherapy (cyclophosphamide, methotrexate, and fluorouracil). Primary tumor immunohistochemistry (n = 731) and gene expression profiling (n = 586) were conducted in 2020. The 70-gene signature identified genomic low-risk and high-risk patients. Kaplan-Meier analysis, multivariable Cox proportional hazard regression, and multivariable time-varying flexible parametric modeling assessed the long-term distant recurrence-free interval (DRFI). Swedish high-quality registries allowed a complete follow-up of 20 years. RESULTS: In estrogen receptor-positive patients (n = 584, median age 47 years), goserelin, tamoxifen, and the combination significantly improved long-term distant recurrence-free interval compared with control (multivariable hazard ratio [HR], 0.49; 95% CI, 0.32 to 0.75, HR, 0.57; 95% CI, 0.38 to 0.87, and HR, 0.63; 95% CI, 0.42 to 0.94, respectively). Significant goserelin-tamoxifen interaction was observed (P = .016). Genomic low-risk patients (n = 305) significantly benefitted from tamoxifen (HR, 0.24; 95% CI, 0.10 to 0.60), and genomic high-risk patients (n = 158) from goserelin (HR, 0.24; 95% CI, 0.10 to 0.54). Increased risk from the addition of tamoxifen to goserelin was seen in genomic high-risk patients (HR, 3.36; 95% CI, 1.39 to 8.07). Moreover, long-lasting 20-year tamoxifen benefit was seen in genomic low-risk patients, whereas genomic high-risk patients had early goserelin benefit. CONCLUSION: This study shows 20-year benefit from 2 years of adjuvant endocrine therapy in estrogen receptor-positive premenopausal patients and suggests differential treatment benefit on the basis of tumor genomic characteristics. Combined goserelin and tamoxifen therapy showed no benefit over single treatment. Long-term follow-up to assess treatment benefit is critical.

Published
2022

3. Clinical and molecular characteristics of estrogen receptor‐positive ultralow risk breast cancer tumors identified by the 70‐gene signature

Author

Johansson, Annelie, Yu, Nancy Y, Iftimi, Adina, Tobin, Nicholas P, Veer, Laura 't, Nordenskjöld, Bo, Benz, Christopher C, Fornander, Tommy, Perez‐Tenorio, Gizeh, Stål, Olle, Esserman, Laura J, Yau, Christina, and Lindström, Linda S

Subjects
Genetics, Breast Cancer, Clinical Research, Cancer, 4.2 Evaluation of markers and technologies, Detection, screening and diagnosis, Biomarkers, Tumor, Breast Neoplasms, Female, Humans, Phosphatidylinositol 3-Kinases, Proto-Oncogene Proteins c-akt, Receptor, ErbB-2, Receptors, Estrogen, Receptors, Progesterone, TOR Serine-Threonine Kinases, 70-gene signature, breast cancer, gene expression, long-term survival, prognosis, ultralow risk, Receptor, erbB-2, Oncology and Carcinogenesis, Oncology & Carcinogenesis
Abstract

The metastatic potential of estrogen receptor (ER)-positive breast cancers is heterogeneous and distant recurrences occur months to decades after primary diagnosis. We have previously shown that patients with tumors classified as ultralow risk by the 70-gene signature have a minimal long-term risk of fatal breast cancer. Here, we evaluate the previously unexplored underlying clinical and molecular characteristics of ultralow risk tumors in 538 ER-positive patients from the Stockholm tamoxifen randomized trial (STO-3). Out of the 98 ultralow risk tumors, 89% were luminal A molecular subtype, whereas 26% of luminal A tumors were of ultralow risk. Compared to other ER-positive tumors, ultralow risk tumors were significantly (Fisher's test, P

Published
2022

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

Author

Løkkegaard, Sanne, Elias, Daniel, Alves, Carla L, Bennetzen, Martin V, Lænkholm, Anne-Vibeke, Bak, Martin, Gjerstorff, Morten F, Johansen, Lene E, Vever, Henriette, Bjerre, Christina, Kirkegaard, Tove, Nordenskjöld, Bo, Fornander, Tommy, Stål, Olle, Lindström, Linda S, Esserman, Laura J, Lykkesfeldt, Anne E, Andersen, Jens S, Leth-Larsen, Rikke, and Ditzel, Henrik J

Abstract

Resistance 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.

Published
2021

7. Intratumor Heterogeneity of the Estrogen Receptor and the Long-term Risk of Fatal Breast Cancer.

Author

Lindström, Linda S, Yau, Christina, Czene, Kamila, Thompson, Carlie K, Hoadley, Katherine A, Van't Veer, Laura J, Balassanian, Ron, Bishop, John W, Carpenter, Philip M, Chen, Yunn-Yi, Datnow, Brian, Hasteh, Farnaz, Krings, Gregor, Lin, Fritz, Zhang, Yanhong, Nordenskjöld, Bo, Stål, Olle, Benz, Christopher C, Fornander, Tommy, Borowsky, Alexander D, Esserman, Laura J, and STO Trialists Group

Subjects
STO Trialists Group, Humans, Breast Neoplasms, Tamoxifen, Receptors, Estrogen, Antineoplastic Agents, Hormonal, Chemotherapy, Adjuvant, Registries, Risk Factors, Survival Analysis, Retrospective Studies, Time Factors, Aged, Middle Aged, Sweden, Female, Randomized Controlled Trials as Topic, Neoplasm Grading, Breast Cancer, Estrogen, Cancer, Detection, screening and diagnosis, 4.2 Evaluation of markers and technologies, Oncology and Carcinogenesis, Oncology & Carcinogenesis
Abstract

BackgroundBreast cancer patients with estrogen receptor (ER)-positive disease have a continuous long-term risk for fatal breast cancer, but the biological factors influencing this risk are unknown. We aimed to determine whether high intratumor heterogeneity of ER predicts an increased long-term risk (25 years) of fatal breast cancer.MethodsThe STO-3 trial enrolled 1780 postmenopausal lymph node-negative breast cancer patients randomly assigned to receive adjuvant tamoxifen vs not. The fraction of cancer cells for each ER intensity level was scored by breast cancer pathologists, and intratumor heterogeneity of ER was calculated using Rao's quadratic entropy and categorized into high and low heterogeneity using a predefined cutoff at the second tertile (67%). Long-term breast cancer-specific survival analyses by intra-tumor heterogeneity of ER were performed using Kaplan-Meier and multivariable Cox proportional hazard modeling adjusting for patient and tumor characteristics.ResultsA statistically significant difference in long-term survival by high vs low intratumor heterogeneity of ER was seen for all ER-positive patients (P < .001) and for patients with luminal A subtype tumors (P = .01). In multivariable analyses, patients with high intratumor heterogeneity of ER had a twofold increased long-term risk as compared with patients with low intratumor heterogeneity (ER-positive: hazard ratio [HR] = 1.98, 95% confidence interval [CI] = 1.31 to 3.00; luminal A subtype tumors: HR = 2.43, 95% CI = 1.18 to 4.99).ConclusionsPatients with high intratumor heterogeneity of ER had an increased long-term risk of fatal breast cancer. Interestingly, a similar long-term risk increase was seen in patients with luminal A subtype tumors. Our findings suggest that intratumor heterogeneity of ER is an independent long-term prognosticator with potential to change clinical management, especially for patients with luminal A tumors.

Published
2018

8. Tamoxifen therapy benefit for patients with 70-gene signature high and low risk

Author

van ‘t Veer, Laura J, Yau, Christina, Yu, Nancy Y, Benz, Christopher C, Nordenskjöld, Bo, Fornander, Tommy, Stål, Olle, Esserman, Laura J, and Lindström, Linda Sofie

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Oncology and Carcinogenesis, Genetics, Clinical Trials and Supportive Activities, Cancer, Clinical Research, Breast Cancer, Aging, Patient Safety, 6.1 Pharmaceuticals, 4.2 Evaluation of markers and technologies, Evaluation of treatments and therapeutic interventions, Detection, screening and diagnosis, Antineoplastic Agents, Hormonal, Breast Neoplasms, Chemotherapy, Adjuvant, Female, Gene Regulatory Networks, Humans, Randomized Controlled Trials as Topic, Receptors, Estrogen, Retrospective Studies, Survival Analysis, Tamoxifen, Treatment Outcome, 70-gene signature, Tamoxifen benefit, Endocrine therapy, Breast cancer, Long-term survival, Oncology & Carcinogenesis, Clinical sciences, Oncology and carcinogenesis
Abstract

BackgroundBreast cancer molecular prognostic tools that predict recurrence risk have mainly been established on endocrine-treated patients and thus are not optimal for the evaluation of benefit from endocrine therapy. The Stockholm tamoxifen (STO-3) trial which randomized postmenopausal node-negative patients to 2-year tamoxifen (followed by an optional randomization for an additional 3-year tamoxifen vs nil), versus no adjuvant treatment, provides a unique opportunity to evaluate long-term 20-year benefit of endocrine therapy within prognostic risk classes of the 70-gene prognosis signature that was developed on adjuvantly untreated patients.MethodsWe assessed by Kaplan-Meier analysis 20-year breast cancer-specific survival (BCSS) and 10-year distant metastasis-free survival (DMFS) for 538 estrogen receptor (ER)-positive, STO-3 trial patients with retrospectively ascertained 70-gene prognosis classification. Multivariable analysis of long-term (20 years) BCSS by STO-3 trial arm in the 70-gene high-risk and low-risk subgroups was performed using Cox proportional hazard modeling adjusting for classical patient and tumor characteristics.ResultsTamoxifen-treated, 70-gene low- and high-risk patients had 20-year BCSS of 90 and 83%, as compared to 80 and 65% for untreated patients, respectively (log-rank p

Published
2017

9. Hormone receptor mRNA and protein levels as predictors of premenopausal tamoxifen benefit

Author

Engstrom, Terese, Ekholm, Maria, Ferno, Marten, Lundgren, Christine, Nordenskjöld, Bo, Stål, Olle, Bendahla, Paer-Ola, Tutzauer, Julia, Ryden, Lisa, Engstrom, Terese, Ekholm, Maria, Ferno, Marten, Lundgren, Christine, Nordenskjöld, Bo, Stål, Olle, Bendahla, Paer-Ola, Tutzauer, Julia, and Ryden, Lisa

Abstract

Background and purpose: Tamoxifen remains an important adjuvant treatment in premenopausal patients with hormone receptor-positive breast cancer. Thus, determination of hormone receptors is important. Here, we compare cytosol-based methods, immunohistochemistry (IHC), and gene expression (GEX) analysis for determining hormone receptor status in premenopausal breast cancer patients from a randomised tamoxifen trial, to evaluate their performance in identifying patients that benefit from tamoxifen. Patients and Methods: Premenopausal patients (n=564) were randomised to 2 years of tamoxifen or no measured by cytosol-based methods and IHC, and mRNA by GEX analysis were compared in 313 patients with available data from all methods. Kaplan Meier estimates and Cox regression were used to evaluate the treatment-predictive value for recurrence-free interval (RFi) and overall survival (OS). Median follow-up for event-free patients was 26 (RFi) and 33 (OS) years. Results: The mRNA data of ESR1 and PGR distributed bimodally, patterns confirmed in an independent cohort. Kappa-values between all methods were 0.76 and 0.79 for ER and PR, respectively. Tamoxifen improved RFi in patients with ER-positive (ER+) or PR-positive (PR+) tumours (Hazard Ratio [HR] and 95% confidence interval [CI]), cytosol-ER+ 0.53 [0.36-0.79]; IHC-ER+ 0.55 [0.38-0.79]; GEX-ER+ 0.54 [0.37-0.77]; cytosol-PR+ 0.49 [0.34-0.72]; IHC-PR+ 0.58 [0.40-0.85]; GEX-PR+ 0.55 [0.38-0.80]). Results were similar for OS. Interpretation: These methods can all identify patients that benefit from 2 years of tamoxifen with equal performance, indicating that GEX data might be used to guide adjuvant tamoxifen therapy., Funding Agencies|Swedish Cancer Society [19 0388 Pj, 22 2137]; Anna and Edwin Berger Foundation [2019-2022]; Governmental Funding of Clinical Research within the Swedish National Health Service [2022-40304]; Berta Kamprad Foundation [FBKS-2021-11]

Published
2024
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11. Breast cancer survival and incidence of second primary cancers after 30 years in a randomized study of two versus five years of adjuvant tamoxifen therapy

Author

Nordenskjöld, Anna, primary, Fohlin, Helena, additional, Rosell, Johan, additional, Bengtsson, Nils-Olof, additional, Fornander, Tommy, additional, Hatschek, Thomas, additional, Lindman, Henrik, additional, Malmström, Per, additional, Rydén, Lisa, additional, Wallgren, Arne, additional, Stål, Olle, additional, and Nordenskjöld, Bo, additional

Published
2023
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20. Abstract P2-03-04: Long-Term Benefit from Adjuvant Tamoxifen in Luminal A and Luminal B Breast Cancer Patients

Author

Dar, Huma, primary, Johansson, Annelie, additional, Nordenskjöld, Anna, additional, Perez-Tenorio, Gizeh, additional, Yau, Christina, additional, Benz, Christopher C., additional, Esserman, Laura J., additional, Nordenskjöld, Bo, additional, Stål, Olle, additional, Fornander, Tommy, additional, and Lindström, Linda S., additional

Published
2023
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21. Abstract P3-05-03: Long-term survival and intra-tumor heterogeneity of progesterone receptor expression in estrogen receptor-positive/progesterone receptor-positive premenopausal women with breast cancer

Author

Danielsson, Oscar, primary, Dar, Huma, additional, Perez-Tenorio, Gizeh, additional, Nordenskjöld, Anna, additional, Yau, Christina, additional, Benz, Christopher C., additional, Esserman, Laura J., additional, Nordenskjöld, Bo, additional, Stål, Olle, additional, Fornander, Tommy, additional, Johansson, Annelie, additional, and Lindström, Linda S., additional

Published
2023
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22. Abstract P2-03-11: Differential Long-Term Benefit from Adjuvant Tamoxifen Therapy in Estrogen Receptor (ER)-Positive/Human Epidermal Growth Factor Receptor 2 (HER2)-Negative Premenopausal and Postmenopausal Breast Cancer Patients

Author

Johansson, Annelie, primary, Dar, Huma, additional, Nordenskjöld, Anna, additional, Perez-Tenorio, Gizeh, additional, Yau, Christina, additional, Benz, Christopher C., additional, Esserman, Laura J., additional, Veer, Laura Van’t, additional, Nordenskjöld, Bo, additional, Stål, Olle, additional, Fornander, Tommy, additional, and Lindström, Linda S., additional

Published
2023
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23. Breast cancer survival and incidence of second primary cancers after 30 years in a randomized study of two versus five years of adjuvant tamoxifen therapy

Author

Nordenskjold, Anna, Fohlin, Helena, Rosell, Johan, Bengtsson, Nils-Olof, Fornander, Tommy, Hatschek, Thomas, Lindman, Henrik, Malmstrom, Per, Ryden, Lisa, Wallgren, Arne, Stål, Olle, Nordenskjöld, Bo, Nordenskjold, Anna, Fohlin, Helena, Rosell, Johan, Bengtsson, Nils-Olof, Fornander, Tommy, Hatschek, Thomas, Lindman, Henrik, Malmstrom, Per, Ryden, Lisa, Wallgren, Arne, Stål, Olle, and Nordenskjöld, Bo

Abstract

Background: Tamoxifen is an established treatment for breast cancer, but its long-term effects on survival and on secondary cancers are not fully evaluated. Material and methods: We studied 30 years outcome of 4124 postmenopausal patients who were randomized to receive (totally) two or five years of adjuvant tamoxifen.Results: After 5 years of follow-up, when tamoxifen treatment was finished in both groups, until 15 years of follow-up, overall mortality (HR 0.80, 95% CI 0.72-0.90, p < 0.001), breast cancer mortality for all patients (HR 0.80, 95% CI 0.68-0.94, p = 0.006) and breast cancer mortality for patients with estrogen receptor positive disease (HR 0.67, 95% CI 0.55-0.83, p < 0.001) were significantly reduced in the five-year group as compared to the two-year group. After 15 years, the difference remained but did not further increase. In the five-year group, the incidence of contralateral breast cancer was gradually reduced during the entire period of observation. The incidence of lung cancer was also reduced in the five-year group. In contrast there was an increased endometrial cancer incidence in the five-year group and for those receiving 40 mg of tamoxifen this incidence was further increased.Conclusion: Three more years of tamoxifen therapy reduced the risk of breast cancer mortality. The difference was established during the first 15 years after randomization. Moreover, the incidence of contralateral breast cancer gradually decreased for 30 years. The incidence of lung cancer was reduced in the five-year group. In contrast the incidence of endometrial cancer was increased., Funding Agencies|King Gustaf the Vth Jubilee Clinic Cancer Foundations in Gothenburg; Swedish governmental grants to scientists working in health care (ALF); Swedish Cancer Society; Alice Swenzon Foundation; Walter Anderssons Foundation; Onkologiska Klinikerna i Linkoping Forskningsfond Ulla and Tibor Veres award; Swedish Breast Cancer Association

Published
2023
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24. Twenty-Year Benefit From Adjuvant Goserelin and Tamoxifen in Premenopausal Patients With Breast Cancer in a Controlled Randomized Clinical Trial

Author

Johansson, Annelie, primary, Dar, Huma, additional, van ’t Veer, Laura J., additional, Tobin, Nicholas P., additional, Perez-Tenorio, Gizeh, additional, Nordenskjöld, Anna, additional, Johansson, Ulla, additional, Hartman, Johan, additional, Skoog, Lambert, additional, Yau, Christina, additional, Benz, Christopher C., additional, Esserman, Laura J., additional, Stål, Olle, additional, Nordenskjöld, Bo, additional, Fornander, Tommy, additional, and Lindström, Linda S., additional

Published
2022
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26. Twenty-Year Benefit From Adjuvant Goserelin and Tamoxifen in Premenopausal Patients With Breast Cancer in a Controlled Randomized Clinical Trial

Author

Johansson, Annelie, Dar, Huma, Veer, Laura J. van t, Tobin, Nicholas P., Perez-Tenorio, Gizeh, Nordenskjöld, Anna, Johansson, Ulla, Hartman, Johan, Skoog, Lambert, Yau, Christina, Benz, Christopher C., Esserman, Laura J., Stål, Olle, Nordenskjöld, Bo, Fornander, Tommy, Lindstrom, Linda S., Johansson, Annelie, Dar, Huma, Veer, Laura J. van t, Tobin, Nicholas P., Perez-Tenorio, Gizeh, Nordenskjöld, Anna, Johansson, Ulla, Hartman, Johan, Skoog, Lambert, Yau, Christina, Benz, Christopher C., Esserman, Laura J., Stål, Olle, Nordenskjöld, Bo, Fornander, Tommy, and Lindstrom, Linda S.

Abstract

PURPOSETo assess the long-term (20-year) endocrine therapy benefit in premenopausal patients with breast cancer.METHODSSecondary analysis of the Stockholm trial (STO-5, 1990-1997) randomly assigning 924 premenopausal patients to 2 years of goserelin (3.6 mg subcutaneously once every 28 days), tamoxifen (40 mg orally once daily), combined goserelin and tamoxifen, or no adjuvant endocrine therapy (control) is performed. Random assignment was stratified by lymph node status; lymph node-positive patients (n = 459) were allocated to standard chemotherapy (cyclophosphamide, methotrexate, and fluorouracil). Primary tumor immunohistochemistry (n = 731) and gene expression profiling (n = 586) were conducted in 2020. The 70-gene signature identified genomic low-risk and high-risk patients. Kaplan-Meier analysis, multivariable Cox proportional hazard regression, and multivariable time-varying flexible parametric modeling assessed the long-term distant recurrence-free interval (DRFI). Swedish high-quality registries allowed a complete follow-up of 20 years.RESULTSIn estrogen receptor-positive patients (n = 584, median age 47 years), goserelin, tamoxifen, and the combination significantly improved long-term distant recurrence-free interval compared with control (multivariable hazard ratio [HR], 0.49; 95% CI, 0.32 to 0.75, HR, 0.57; 95% CI, 0.38 to 0.87, and HR, 0.63; 95% CI, 0.42 to 0.94, respectively). Significant goserelin-tamoxifen interaction was observed (P = .016). Genomic low-risk patients (n = 305) significantly benefitted from tamoxifen (HR, 0.24; 95% CI, 0.10 to 0.60), and genomic high-risk patients (n = 158) from goserelin (HR, 0.24; 95% CI, 0.10 to 0.54). Increased risk from the addition of tamoxifen to goserelin was seen in genomic high-risk patients (HR, 3.36; 95% CI, 1.39 to 8.07). Moreover, long-lasting 20-year tamoxifen benefit was seen in genomic low-risk patients, whereas genomic high-risk patients had early goserelin benefit.CONCLUSIONThis study shows 20-year, Funding Agencies|Swedish Research Council (Vetenskapsradet); Swedish Research Council for Health, Working life and Welfare (FORTE) [2020-02466]; ALF medicine [2019-00477]; GostaMilton Donation Fund (Stiftelsen Gosta Miltons donationsfond ) [LS2018-1157]; Swedish Cancer Society (Cancerfonden); Stockholm Cancer Society (Cancerforeningen i Stockholm) [190268, 200802, 190140]; California Breast Cancer Research Program (CBCRP) [181093, 204152, 201212]; National Institutes of Health (NIH) [180B-0065]; Horizon 2020 [U01-CA196406]; [672570]

Published
2022
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29. Low RAB6C expression is a predictor of tamoxifen benefit in estrogen receptor-positive/progesterone receptor-negative breast cancer

Author

Fohlin, Helena, Bekkhus, Tove, Sandström, Josefine, Fornander, Tommy, Nordenskjöld, Bo, Carstensen, John, and Stål, Olle

Subjects
Cancer och onkologi, breast neoplasm, endocrine therapy, Cancer and Oncology, RAB6A', hormone receptors, WTH3, RAB6A, Articles
Abstract

Over the last few decades, improved and more individualized treatment has contributed to the increased survival rate of patients with breast cancer. However, certain patients may receive excessive treatment resulting in undesired side effects. In a previous study, it was demonstrated that systemically untreated patients with estrogen receptor (ER)-positive/progesterone receptor (PR)-negative tumors with high Ras-related protein Rab-6C (RAB6C) expression levels (RAB6C(+)) had prolonged distant recurrence-free survival compared with that of patients exhibiting low RAB6C (RAB6C(-))-expressing tumors. The aim of the present study was to investigate whether RAB6C predicts the effectiveness of tamoxifen treatment. The present study used a dataset comprising 486 female patients with ER+ tumors from a randomized study conducted by the Stockholm Breast Cancer Study Group between November 1976 and August 1990. The patients were considered as low-risk if their tumor size was Funding Agencies|Swedish Cancer SocietySwedish Cancer Society [17-0479]; Cancer Research Foundation of Radiumhemmet [181093]; King Gustav V Jubilee Clinical Research Foundation [181093]; Onkologiska klinikerna i Linkopings forskningsfond [2016-06-21]; ALF grants Region Ostergotland [LIO-795201]; County Council of Ostergotland [LIO-625491]; Cancer Society in Stockholm [181093]

Published
2020

34. Assessment of 25-Year Survival of Women With Estrogen Receptor–Positive/ERBB2-Negative Breast Cancer Treated With and Without Tamoxifen Therapy

Author

Dar, Huma, primary, Johansson, Annelie, additional, Nordenskjöld, Anna, additional, Iftimi, Adina, additional, Yau, Christina, additional, Perez-Tenorio, Gizeh, additional, Benz, Christopher, additional, Nordenskjöld, Bo, additional, Stål, Olle, additional, Esserman, Laura J., additional, Fornander, Tommy, additional, and Lindström, Linda S., additional

Published
2021
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35. Assessment of 25-Year Survival of Women With Estrogen Receptor-Positive/ERBB2-Negative Breast Cancer Treated With and Without Tamoxifen Therapy A Secondary Analysis of Data From the Stockholm Tamoxifen Randomized Clinical Trial

Author

Dar, Huma, Johansson, Annelie, Nordenskjöld, Anna, Iftimi, Adina, Yau, Christina, Perez-Tenorio, Gizeh, Benz, Christopher, Nordenskjöld, Bo, Stål, Olle, Esserman, Laura J., Fornander, Tommy, and Lindström, Linda S.

Subjects
Cancer och onkologi, Cancer and Oncology
Abstract

IMPORTANCE Clinically used breast cancer markers, such as tumor size, tumor grade, progesterone receptor (PR) status, and Ki-67 status, are known to be associated with short-term survival, but the association of these markers with long-term (25-year) survival is unclear. OBJECTIVE To assess the association of clinically used breast cancer markers with long-term survival and treatment benefit among postmenopausal women with lymph node-negative, estrogen receptor [ER]-positive and ERBB2-negative breast cancer who received tamoxifen therapy. DESIGN, SETTING, AND PARTICIPANTS This study was a secondary analysis of data from a subset of 565 women with ER-positive/ERBB2-negative breast cancer who participated in the Stockholm tamoxifen (STO-3) randomized clinical trial. The STO-3 clinical trial was conducted from 1976 to 1990 and comprised 1780 postmenopausal women with lymph node-negative breast cancer who were randomized to receive adjuvant tamoxifen therapy or no endocrine therapy. Complete 25-year follow-up data through December 31, 2016, were obtained from Swedish national registers. Immunohistochemical markers were reannotated in 2014. Data were analyzed from April to December 2020. INTERVENTIONS Patients in the original STO-3 clinical trial were randomized to receive 2 years of tamoxifen therapy vs no endocrine therapy. In 1983, patients who received tamoxifen therapy without cancer recurrence during the 2-year treatment and who consented to continued participation in the STO-3 study were further randomized to receive 3 additional years of tamoxifen therapy or no endocrine therapy. MAIN OUTCOMES AND MEASURES Distant recurrence-free interval (DRFI) by clinically used breast cancer markers was assessed using Kaplan-Meier and multivariable Cox proportional hazards analyses adjusted for age, period of primary diagnosis, tumor size (T1a and T1b [T1a/b], T1c, and T2), tumor grade (1-3), PR status (positive vs negative), Ki-67 status (low vs medium to high), and STO-3 clinical trial arm (tamoxifen treatment vs no adjuvant treatment). A recursive partitioning analysis was performed to evaluate which markers were able to best estimate long-term DRFI. RESULTS The study population comprised 565 postmenopausal women (mean [SD] age, 62.0 [5.3] years) with lymph node-negative, ER-positive/ERBB2-negative breast cancer. A statistically significant difference in long-term DRFI was observed by tumor size (88% for T1a/b vs 76% for T1c vs 63% for T2 tumors; log-rank P Funding Agencies|Swedish Research Council (Vetenskapsradet)Swedish Research Council [2020-02466]; Swedish Research Council for Health, Working life and Welfare (FORTE) [2019-00477]; Swedish Cancer Society (Cancerfonden)Swedish Cancer Society [180385, 190140Pj01H]; Gosta Milton Donation Fund

Published
2021

36. IP6K2 predicts favorable clinical outcome of primary breast cancer

Author

Sandström, Josefine, Balian, Alien, Lockowandt, Rebecca, Fornander, Tommy, Nordenskjöld, Bo, Lindström, Linda, Pérez-Tenorio, Gizeh, and Stål, Olle

Subjects
3p21.31, Cancer och onkologi, Akt, Cancer and Oncology, Articles, TP53, prognosis, inositol hexakisphosphate kinase 1, PI3K/Akt/mTOR pathway
Abstract

The inositol hexakisphosphate kinase (IP6K) 1 and 2 genes are localized at 3p21.31, a highly altered gene-dense chromosomal region in cancer. The IP6Ks convert IP6 to IP7, which inhibits activation of the tumor-promoting PI3K/Akt/mTOR signaling pathway. IP6K2 has been suggested to be involved in p53-induced apoptosis, while IP6K1 may stimulate tumor growth and migration. The present study aimed to elucidate the role of the two IP6Ks in predicting outcome in patients with breast cancer. To the best of our knowledge, the role of IP6K was analyzed for the first time in tumors from three cohorts of patients with breast cancer; one Swedish low-risk cohort, one Dutch cohort and the TCGA dataset. Analyses of gene -and protein expression and subcellular localization were included. IP6K2 gene expression was associated with ER positivity and nuclear p-Akt. Improved prognosis was detected with high IP6K2 gene expression compared with low IP6K2 gene expression in systemically untreated patients in the Swedish low-risk and Dutch cohorts. In the TCGA dataset, IP6K2 prognostic value was significant when selecting for tumors with wild-type TP53. A multivariable analysis testing IP6K2 against other cancer-related genes at 3p.21.31, including IP6K1 and clinical biomarkers, revealed that IP6K2 was associated with decreased risk of distant recurrence. IP6K1 was associated with increased risk of distant recurrence in the multivariable test and protein analysis revealed trends of worse prognosis with high IP6K1 in the cytoplasm. The expression levels of IP6K1 and IP6K2 were associated to a high extent; however, a diverging prognostic value of the two genes was observed in breast cancer. The present data suggest that IP6K2 can be a favorable prognostic factor, while IP6K1 may not be. Funding Agencies|Swedish Cancer SocietySwedish Cancer Society [17-0479]; Region of Ostergotland [LIO-795201]; Percy Falk Foundation [2017-02-10]; Oncology Clinic in Linkoping Research Fund [2019-10-29]

Published
2021

37. Survival patterns of invasive lobular and invasive ductal breast cancer in a large population-based cohort with two decades of follow up

Author

Chamalidou, C., Fohlin, Helena, Albertsson, P., Arnesson, Lars-Gunnar, Einbeigi, Z., Holmberg, E., Nordenskjöld, A., Nordenskjöld, Bo, Karlsson, P., Linderholm, B., Chamalidou, C., Fohlin, Helena, Albertsson, P., Arnesson, Lars-Gunnar, Einbeigi, Z., Holmberg, E., Nordenskjöld, A., Nordenskjöld, Bo, Karlsson, P., and Linderholm, B.

Abstract

Background: Invasive lobular carcinoma (ILC) comprises 8-15 % of all invasive breast cancers and large population-based studies with >10 years of follow-up are rare. Whether ILC has a long-time prognosis different from that of invasive ductal carcinoma, (IDC) remains controversial. Purpose: To investigate the excess mortality rate ratio (EMRR) of patients with ILC and IDC and to correlate survival with clinical parameters in a large population-based cohort. Material and methods: From 1989 through 2006, we identified 17,481 patients diagnosed with IDC (n = 14,583) or ILC (n = 2898), younger than 76 years from two Swedish Regional Cancer Registries. Relative survival (RS) during 20 years of follow up was analysed. Results: ILC was significantly associated with older age, larger tumours, ER positivity and well differentiated tumours. We noticed an improved survival for patients with ILC during the first five years, excess mortality rate ratio (EMRR) 0.64 (CI 95 % 0.53-0.77). This was shifted to a significant decreased survival 10-15 years after diagnosis (EMRR 1.49, CI 95 % 1.16-1.93). After 20 years the relative survival rates were similar, 0.72 for ILC and 0.73 for IDC. Conclusions: During the first five years after surgery, the EMRR was lower for patients with ILC as compared to patients with IDC, but during the years 10-15 after surgery, we observed an increased EMRR for patients with ILC as compared to IDC. These EMRR between ILC and IDC were statistically significant but the absolute difference in excess mortality between the two groups was small. (c) 2021 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)., Funding Agencies|king Gustav the Vth Jubilee Clinic Cancer Foundation in Gothenburg; Swedish Cancer SocietySwedish Cancer Society; Swedish Breast Cancer Association (Br_ostcancerf_orbundet); Swedish State under the LUA-agreement (Sahlgrenska University Hospital), Gothenburg; Swedish governmental grants

Published
2021
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40. The effect of body mass index on overall and disease-free survival in node-positive breast cancer patients treated with docetaxel and doxorubicin-containing adjuvant chemotherapy: the experience of the BIG 02-98 trial

Author

de Azambuja, Evandro, McCaskill-Stevens, Worta, Francis, Prudence, Quinaux, Emmanuel, Crown, John P. A., Vicente, Malou, Giuliani, Rosa, Nordenskjöld, Bo, Gutiérez, Jorge, Andersson, Michael, Vila, Mireia Margeli, Jakesz, Raimund, Demol, Jan, Dewar, Joanna, Santoro, Armando, Lluch, Ana, Olsen, Steven, Gelber, Richard D., Di Leo, Angelo, and Piccart-Gebhart, Martine

Published
2010
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45. Abstract PS5-09: Tumour infiltrating lymphocytes of prognostic value in different molecular breast cancer subgroups and as a suggestive predictive factor for adjuvant tamoxifen benefit in premenopausal patients after 30 years follow-up

Author

Lundgren, Christine, primary, Bendahl, Pär-Ola, additional, Ekholm, Maria, additional, Fernö, Mårten, additional, Forsare, Carina, additional, Krüger, Ute, additional, Nordenskjöld, Bo, additional, Stål, Olle, additional, and Rydén, Lisa, additional

Published
2021
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47. RAB6C is an independent prognostic factor of estrogen receptor-positive/progesterone receptor-negative breast cancer

Author

Fohlin, Helena, Bekkhus, Tove, Sandström, Josefine, Fornander, Tommy, Nordenskjöld, Bo, Carstensen, John, and Stål, Olle

Subjects
gene copy number, Cancer och onkologi, breast neoplasm, Ras-related protein Rab-6C, Cancer and Oncology, Articles, prognostic, estrogen receptor, progesterone receptor
Abstract

The majority of breast cancer tumors are estrogen receptor-positive (ER+) and can be treated with endocrine therapy. However, certain patients may exhibit a good prognosis without systemic treatment. The aim of the present study was to identify novel prognostic factors for patients with ER breast cancer tumors using gene copy data, and to investigate if these factors have prognostic value in subgroups categorized by progesterone receptor status (PR). Public data, including the whole genome gene copy data of 199 systemically untreated patients with ER+ tumors, were utilized in the present study. To assess prognostic value, patients were divided into two groups using the median gene copy number as a cut-off for the SNPs that were the most variable. One SNP was identified, which indicated that the Ras-related protein Rab-6C (RAB6C) gene may exhibit prognostic significance. Therefore, RAB6C protein expression was subsequently investigated in a second independent cohort, consisting of 469 systematically untreated patients (of which 310 were ER+) who received long term follow-up. In the public data set, a distant recurrence risk reduction of 55% was determined for copy numbers above the median value of RAB6C compared with numbers below [multivariable adjusted hazard ratio (HR), 0.45; 95% CI 0.28-0.72; P=0.001)]. It was also more pronounced in the ER+/PR- subgroup (HR, 0.15; 95% CI, 0.05-0.46; P=0.001). In the second cohort, patients of the ER+/PR- subgroup who exhibited high RAB6C expression had a reduced distant recurrence risk (HR, 0.17; 95% CI, 0.05-0.60; P=0.006). However, this was not identified among ER+/PR- tumors (HR, 1.31; 95% CI, 0.69-2.48; P=0.41). The results of the present study indicated that RAB6C serves as an independent prognostic factor of distant recurrence risk in systemically untreated patients with an ER+/PR- tumor. Funding Agencies|Swedish Cancer SocietySwedish Cancer Society [17-0479]; Cancer Research Foundations of Radiumhemmet; Cancer Society in Stockholm; King Gustav V Jubilee Clinical Research Foundation [181093]; Onkologiska klinikerna i Linkopings forskningsfond [2016-06-21]; ALF grants Region Ostergotland [LIO-795201]; County Council of Ostergotland [LIO-625491]

Published
2020

48. Additional file 1 of Tumour-infiltrating lymphocytes as a prognostic and tamoxifen predictive marker in premenopausal breast cancer: data from a randomised trial with long-term follow-up

Author

Lundgren, Christine, Bendahl, Pär-Ola, Ekholm, Maria, Fernö, Mårten, Forsare, Carina, Krüger, Ute, Nordenskjöld, Bo, Stål, Olle, and Rydén, Lisa

Subjects
hemic and immune systems, chemical and pharmacologic phenomena
Abstract

Additional file 1. Patient and tumour characteristics of study cohort (n = 477) and for the excluded patients with no scored TILs (n = 60).

Published
2020
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50. Clinical and Molecular Characteristics of ER-Positive Breast Cancer Tumors Identified as Ultralow Risk by the 70-Gene Signature in a Randomized Clinical Trial

Author

Johansson, Annelie, primary, Yu, Nancy Yiu-Lin, additional, Iftimi, Adina, additional, Tobin, Nicholas P., additional, Veer, Laura van't, additional, Nordenskjöld, Bo, additional, Benz, Christopher C., additional, Fornander, Tommy, additional, Perez-Tenorio, Gizeh, additional, Stål, Olle, additional, Esserman, Laura, additional, Yau, Christina, additional, and Lindström, Linda S., additional

Published
2020
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