Toronto Workshop on Late Recurrence in Estrogen Receptor–Positive Breast Cancer: Part 1: Late Recurrence: Current Understanding, Clinical Considerations

Abstract Disease recurrence (locoregional, distant) exerts a significant clinical impact on the survival of estrogen receptor–positive breast cancer patients. Many of these recurrences occur late, more than 5 years after original diagnosis, and represent a major obstacle to the effective treatment of this disease. Indeed, methods to identify patients at risk of late recurrence and therapeutic strategies designed to avert or treat these recurrences are lacking. Therefore, an international workshop was convened in Toronto, Canada, in February 2018 to review the current understanding of late recurrence and to identify critical issues that require future study. In this article, the major issues surrounding late recurrence are defined and current approaches that may be applicable to this challenge are discussed. Specifically, diagnostic tests with potential utility in late-recurrence prediction are described as well as a variety of patient-related factors that may influence recurrence risk. Clinical and therapeutic approaches are also reviewed, with a focus on patient surveillance and the implementation of extended endocrine therapy in the context of late-recurrence prevention. Understanding and treating late recurrence in estrogen receptor–positive breast cancer is a major unmet clinical need. A concerted effort of basic and clinical research is required to confront late recurrence and improve disease management and patient survival.

[1]  R. Gray,et al.  Toronto Workshop on Late Recurrence in Estrogen Receptor-Positive Breast Cancer: Part 2: Approaches to Predict and Identify Late Recurrence, Research Directions , 2019, JNCI cancer spectrum.

[2]  Fabrice Andre,et al.  Use of Biomarkers to Guide Decisions on Adjuvant Systemic Therapy for Women With Early-Stage Invasive Breast Cancer: ASCO Clinical Practice Guideline Update-Integration of Results From TAILORx. , 2019, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[3]  R. Gray Abstract GS3-03: Effects of prolonging adjuvant aromatase inhibitor therapy beyond five years on recurrence and cause-specific mortality: An EBCTCG meta-analysis of individual patient data from 12 randomised trials including 24,912 women , 2019, General Session Abstracts.

[4]  E. Winer,et al.  CDK4/6 inhibition in breast cancer: current practice and future directions , 2018, Therapeutic advances in medical oncology.

[5]  Jack Cuzick,et al.  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, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[6]  G. Pond,et al.  Association of Metformin with Breast Cancer Incidence and Mortality in Patients with Type II Diabetes: A GRADE-Assessed Systematic Review and Meta-analysis , 2018, Cancer Epidemiology, Biomarkers & Prevention.

[7]  J. Cuzick,et al.  Comparison of the Performance of 6 Prognostic Signatures for Estrogen Receptor–Positive Breast Cancer , 2018, JAMA oncology.

[8]  M. Rezai,et al.  Abstract GS3-03: A phase III multicentre double blind randomised trial of celecoxib versus placebo in primary breast cancer patients (REACT – Randomised EuropeAn celecoxib trial) , 2018 .

[9]  J. Cuzick,et al.  Abstract GS6-01: Integration of clinical variables for the prediction of late distant recurrence in patients with oestrogen receptor positive breast cancer treated with 5 years of endocrine therapy , 2018 .

[10]  Sean Ferree,et al.  PAM50 Risk of Recurrence Score Predicts 10-Year Distant Recurrence in a Comprehensive Danish Cohort of Postmenopausal Women Allocated to 5 Years of Endocrine Therapy for Hormone Receptor-Positive Early Breast Cancer. , 2018, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[11]  Daniel F. Hayes,et al.  20‐Year Risks of Breast‐Cancer Recurrence after Stopping Endocrine Therapy at 5 Years , 2017, The New England journal of medicine.

[12]  H. Goldvaser,et al.  Efficacy of extended adjuvant therapy with aromatase inhibitors in early breast cancer among common clinicopathologically-defined subgroups: A systematic review and meta-analysis. , 2017, Cancer treatment reviews.

[13]  C. Seynaeve,et al.  Extended adjuvant aromatase inhibition after sequential endocrine therapy (DATA): a randomised, phase 3 trial. , 2017, The Lancet. Oncology.

[14]  M. Gnant,et al.  Optimal duration of adjuvant endocrine therapy: how to apply the newest data , 2017, Therapeutic advances in medical oncology.

[15]  S. Schleicher,et al.  Extended Adjuvant Aromatase Inhibitor Therapy in Post-Menopausal Women , 2017, Current Breast Cancer Reports.

[16]  T. Wadden,et al.  Randomized phase III trial evaluating the role of weight loss in adjuvant treatment of overweight and obese women with early breast cancer (Alliance A011401): study design , 2017, npj Breast Cancer.

[17]  Ian Krop,et al.  Use of Biomarkers to Guide Decisions on Adjuvant Systemic Therapy for Women With Early-Stage Invasive Breast Cancer: American Society of Clinical Oncology Clinical Practice Guideline Focused Update. , 2017, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[18]  A. Tsung,et al.  Surgery for Cancer: A Trigger for Metastases. , 2017, Cancer research.

[19]  M. Clemons,et al.  Use of Adjuvant Bisphosphonates and Other Bone-Modifying Agents in Breast Cancer: A Cancer Care Ontario and American Society of Clinical Oncology Clinical Practice Guideline. , 2017, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[20]  A. Giobbie-Hurder,et al.  Cholesterol, Cholesterol-Lowering Medication Use, and Breast Cancer Outcome in the BIG 1-98 Study. , 2017, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[21]  S. Suissa,et al.  Cardiotoxicity of aromatase inhibitors and tamoxifen in postmenopausal women with breast cancer: a systematic review and meta-analysis of randomized controlled trials , 2016, Annals of oncology : official journal of the European Society for Medical Oncology.

[22]  S. Paik,et al.  Prognostic Impact of the Combination of Recurrence Score and Quantitative Estrogen Receptor Expression (ESR1) on Predicting Late Distant Recurrence Risk in Estrogen Receptor-Positive Breast Cancer After 5 Years of Tamoxifen: Results From NRG Oncology/National Surgical Adjuvant Breast and Bowel Proje , 2016, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[23]  R. Bast,et al.  Use of Biomarkers to Guide Decisions on Adjuvant Systemic Therapy for Women With Early-Stage Invasive Breast Cancer: American Society of Clinical Oncology Clinical Practice Guideline. , 2016, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[24]  L. V. van't Veer,et al.  70-Gene Signature as an Aid to Treatment Decisions in Early-Stage Breast Cancer. , 2016, The New England journal of medicine.

[25]  J. Cuzick,et al.  Comparison of EndoPredict and EPclin With Oncotype DX Recurrence Score for Prediction of Risk of Distant Recurrence After Endocrine Therapy , 2016, Journal of the National Cancer Institute.

[26]  T. Whelan,et al.  Extending Aromatase-Inhibitor Adjuvant Therapy to 10 Years. , 2016, The New England journal of medicine.

[27]  C. Hollenbeak,et al.  β-Blockers Reduce Breast Cancer Recurrence and Breast Cancer Death: A Meta-Analysis. , 2015, Clinical breast cancer.

[28]  M. Gnant Targeting bone microenvironment: Clinical implications. , 2015, Breast.

[29]  E. Rutgers,et al.  Adjuvant bisphosphonate treatment in early breast cancer: meta-analyses of individual patient data from randomised trials , 2015, The Lancet.

[30]  J. Forbes,et al.  Aromatase inhibitors versus tamoxifen in early breast cancer: patient-level meta-analysis of the randomised trials , 2015, The Lancet.

[31]  K. Horwitz,et al.  Luminal breast cancer metastases and tumor arousal from dormancy are promoted by direct actions of estradiol and progesterone on the malignant cells , 2014, Breast Cancer Research.

[32]  C. McCowan,et al.  Aspirin use and survival after the diagnosis of breast cancer: a population-based cohort study , 2014, British Journal of Cancer.

[33]  G. Hortobagyi,et al.  Promoting quality and evidence-based care in early-stage breast cancer follow-up. , 2014, Journal of the National Cancer Institute.

[34]  D. Cescon,et al.  Extended Adjuvant Tamoxifen for Early Breast Cancer: A Meta-Analysis , 2014, PloS one.

[35]  R. Greil,et al.  The PAM50 Risk-of-Recurrence Score Predicts Risk for Late Distant Recurrence after Endocrine Therapy in Postmenopausal Women with Endocrine-Responsive Early Breast Cancer , 2014, Clinical Cancer Research.

[36]  R. Greil,et al.  Predicting distant recurrence in receptor-positive breast cancer patients with limited clinicopathological risk: using the PAM50 Risk of Recurrence score in 1478 postmenopausal patients of the ABCSG-8 trial treated with adjuvant endocrine therapy alone. , 2014, Annals of oncology : official journal of the European Society for Medical Oncology.

[37]  R. Greil,et al.  The EndoPredict score provides prognostic information on late distant metastases in ER+/HER2− breast cancer patients , 2013, British Journal of Cancer.

[38]  G. Hortobagyi,et al.  Obesity, diabetes, and survival outcomes in a large cohort of early-stage breast cancer patients. , 2013, Annals of oncology : official journal of the European Society for Medical Oncology.

[39]  Yi Zhang,et al.  Prediction of Late Disease Recurrence and Extended Adjuvant Letrozole Benefit by the HOXB13/IL17BR Biomarker , 2013, Journal of the National Cancer Institute.

[40]  K. Winzer,et al.  The EndoPredict Gene-Expression Assay in Clinical Practice - Performance and Impact on Clinical Decisions , 2013, PloS one.

[41]  H. Earl,et al.  aTTom: Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years in 6,953 women with early breast cancer. , 2013, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[42]  Ming-Feng Hou,et al.  Long-term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor-positive breast cancer: ATLAS, a randomised trial , 2013, The Lancet.

[43]  Thomas J. Smith,et al.  Breast cancer follow-up and management after primary treatment: American Society of Clinical Oncology clinical practice guideline update. , 2013, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[44]  C. Wilson,et al.  Seed, soil and secreted hormones: potential interactions of breast cancer cells with their endocrine/paracrine microenvironment and implications for treatment with bisphosphonates. , 2012, Cancer treatment reviews.

[45]  S. Gapstur,et al.  Diabetes and Cause-Specific Mortality in a Prospective Cohort of One Million U.S. Adults , 2012, Diabetes Care.

[46]  J. Cuzick,et al.  Does trauma or an intercurrent surgical intervention lead to a short-term increase in breast cancer recurrence rates? , 2012, Annals of oncology : official journal of the European Society for Medical Oncology.

[47]  P. Goodwin,et al.  Insulin- and obesity-related variables in early-stage breast cancer: correlations and time course of prognostic associations. , 2012, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[48]  J. Cuzick,et al.  Prognostic value of a combined estrogen receptor, progesterone receptor, Ki-67, and human epidermal growth factor receptor 2 immunohistochemical score and comparison with the Genomic Health recurrence score in early breast cancer. , 2011, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[49]  T. Whelan,et al.  Randomized trial of tamoxifen versus combined tamoxifen and octreotide LAR Therapy in the adjuvant treatment of early-stage breast cancer in postmenopausal women: NCIC CTG MA.14. , 2011, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[50]  N. Loman,et al.  Risk of recurrence following delayed large flap reconstruction after mastectomy for breast cancer , 2011, The British journal of surgery.

[51]  Bingshu E. Chen,et al.  Evaluation of metformin in early breast cancer: a modification of the traditional paradigm for clinical testing of anti-cancer agents , 2011, Breast Cancer Research and Treatment.

[52]  Theodoros N. Arvanitis,et al.  A systematic review of positron emission tomography (PET) and positron emission tomography/computed tomography (PET/CT) for the diagnosis of breast cancer recurrence. , 2010, Health technology assessment.

[53]  Soonmyung Paik,et al.  Use of archived specimens in evaluation of prognostic and predictive biomarkers. , 2009, Journal of the National Cancer Institute.

[54]  L. Mariani,et al.  Serial determination of CEA and CA 15.3 in breast cancer follow-up: An assessment of their diagnostic accuracy for the detection of tumour recurrences , 2009, Biomarkers : biochemical indicators of exposure, response, and susceptibility to chemicals.

[55]  M. Beckmann,et al.  Safety and efficacy of tibolone in breast-cancer patients with vasomotor symptoms: a double-blind, randomised, non-inferiority trial. , 2009, The Lancet. Oncology.

[56]  J. Olsen,et al.  Delayed Breast Reconstruction With Implants After Invasive Breast Cancer Does Not Impair Prognosis , 2008, Annals of plastic surgery.

[57]  W. Willett,et al.  Physical Activity and Survival after Diagnosis of Invasive Breast Cancer , 2008, Cancer Epidemiology Biomarkers & Prevention.

[58]  D. Forman,et al.  Postoperative wound complications and systemic recurrence in breast cancer , 2007, British Journal of Cancer.

[59]  R. Gelber,et al.  CA15-3 and alkaline phosphatase as predictors for breast cancer recurrence: a combined analysis of seven International Breast Cancer Study Group trials. , 2006, Annals of oncology : official journal of the European Society for Medical Oncology.

[60]  S. Hilsenbeck,et al.  The HOXB13:IL17BR expression index is a prognostic factor in early-stage breast cancer. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[61]  M. Duffy,et al.  Tumor Markers in Breast Cancer – European Group on Tumor Markers Recommendations , 2005, Tumor Biology.

[62]  Y Wang,et al.  Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials , 2005, The Lancet.

[63]  L. Coussens,et al.  Inflammation and cancer , 2002, Nature.

[64]  J. Bryant,et al.  Five versus more than five years of tamoxifen for lymph node-negative breast cancer: updated findings from the National Surgical Adjuvant Breast and Bowel Project B-14 randomized trial. , 2001, Journal of the National Cancer Institute.

[65]  L. Peloso,et al.  Tumor markers in breast cancer monitoring should be scheduled according to initial stage and follow-up time: a prospective study on 859 patients. , 2001, Cancer journal.

[66]  R. Prescott,et al.  Scottish adjuvant tamoxifen trial: a randomized study updated to 15 years. , 2001, Journal of the National Cancer Institute.

[67]  Alberto Mantovani,et al.  Inflammation and cancer: back to Virchow? , 2001, The Lancet.

[68]  R. Gray,et al.  Postchemotherapy adjuvant tamoxifen therapy beyond five years in patients with lymph node-positive breast cancer. Eastern Cooperative Oncology Group. , 1996, Journal of the National Cancer Institute.

[69]  R. Molina,et al.  Utility of C-erbB-2 in tissue and in serum in the early diagnosis of recurrence in breast cancer patients: comparison with carcinoembryonic antigen and CA 15.3. , 1996, British Journal of Cancer.

[70]  I. Tomlinson,et al.  Tumour marker CA15-3: possible uses in the routine management of breast cancer. , 1995, European journal of cancer.

[71]  H. Putter,et al.  Optimal Duration of Extended Adjuvant Endocrine Therapy for Early Breast Cancer; Results of the IDEAL Trial (BOOG 2006-05) , 2018, Journal of the National Cancer Institute.

[72]  R. Baumgartner,et al.  Associations of insulin resistance and adiponectin with mortality in women with breast cancer. , 2011, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[73]  A. Liberati,et al.  Follow-up strategies for women treated for early breast cancer. , 2005, The Cochrane database of systematic reviews.

[74]  Martín Velasco,et al.  Use of serial carcinoembryonic antigen and CA 15.3 assays in detecting relapses in breast cancer patients , 2004, Breast Cancer Research and Treatment.