Nationwide evaluation of breast cancer biomarker assessment in daily - PowerPoint PPT Presentation

Nationwide evaluation of breast cancer biomarker assessment in daily practice Carmen van Dooijeweert European Congress of Pathology MD, PhD-student September 9, 2019 Nice c.vandooijeweert-3@umcutrecht.nl

I hereby declare that I have no conflict of interest

Content Hormone- and HER2-receptor assessment in 33,046 breast cancer • patients: a nationwide comparison of positivity rates between pathology laboratories in the Netherlands Significant inter- and intra-laboratory variation in grading of invasive • breast cancer: a nationwide study of 33,043 patients in the Netherlands

Breast cancer: background Most common type of cancer in European women 1 • Breast cancer management: it all starts with pathology • Subtype: PATHOLOGY – Prognosis: PATHOLOGY – Treatment: PATHOLOGY – 1. International Agency for Research on Cancer (WHO), source: GLOBOCON 2018

Breast cancer biomarkers Histologic grade Receptor-assessment • • ER, PR, HER2 B&R (modified) – – Clinical decisions Clinical decisions – – Chemotherapy Anti-endocrine therapy • • Radiotherapy Anti-HER2 therapy • • Gene-expression profiling •

Reproducibility of breast cancer biomarkers • Receptor assessment: significant differences 1-16 • Histologic grading: no more than moderate 16-19 But how are we doing in daily clinical practice? 1. McCullough et al. Breast Cancer Res Treat 2014; 143(3):48-492 8. Rosa et al. Breast J 2017:24(2);139-147 15. Rhodes et al. Am J Clin Pathol 2001: 115(1):44-58. 2. Cuadros et al. Clin Transl Oncol 2011; 13 (5):335-340 9. Viale et al. J Clin Oncol 2007:25(25):3846-3852 16. Boiesen et al. Acta Oncol 2000: 39(1):41-45 3. Denkert et al. Breast Cancer Res 2013;; 15(1): R11 10. Bianchi et al. Pathol Oncol Res 2015:21(2):477-485 17. Frierson et al. Am J Clin Pathol 1995:103(2):195-198 4. Orlando et al. Breast. 2016: 30;151-155. 11. Dowsett et al. Mod Pathol 2007:20:584 18. Italian Network for Quality Assurance of Tumour Biomarkers 5. Paik et al. J Natl Cancer Inst 2002:94(11);852-854 12. Layfield et al. Breast J 2003: 9(3):257-259 (INQAT group). Pathologica 2005:97(1):1-6 6. Perez et al. J Clin Oncol 2006:24(19):3032-3038 13. Parker et al. Am J Clin Pathol 2002:117(5):723-728 19. Meyer et al. Mod Pathol 2005:18(8):1067-1078 7. Roche et al. J Natl Cancer Inst 2002:94(11): 855-857 14. Regitnig et al. Virchows Arch 2002: 441(4):328-334

Real-life data on a Dutch nationwide level the nationwide network and registry of histo- and cytopathology in the Netherlands Synoptic reporting • Breast cancer resection specimens: 80% via synoptic protocol 1 ▪ Increased overall completeness of reports 2 ▪ Easy data extraction ▪ 1. PALGA Foundation, Annual Report 2018 2. Sluijter et al. Virchows Archiv 2016:468(4):639-649.

Breast cancer biomarkers Histologic grade Receptor-assessment • • ER, PR, HER2 B&R (modified) – – Clinical decisions Clinical decisions – – Chemotherapy Anti-endocrine therapy • • Radiotherapy Anti-HER2 therapy • • Gene-expression profiling •

Breast cancer biomarkers Histologic grade Receptor-assessment • • ER, PR, HER2 B&R (modified) – – Clinical decisions Clinical decisions – – Chemotherapy Anti-endocrine therapy • • Radiotherapy Anti-HER2 therapy • • Gene-expression profiling •

Receptor assessment: clinical decisions ER/PR • IHC – 10% cut-off – Start Anti-endocrine therapy – 5 HER2 • years IHC – 10% cut-off – Amplification testing (IHC 2+) – Start Anti-HER2 therapy – 1 year

Receptor assessment: quality control External audits mandatory • Temporary and incomplete assessment of testing performance?* • Tissue fixation – Tissue processing – Surveillance of positivity rates as new tool to identify outlying laboratories? • Choritz et al. Virchows Arch 2011:459(3):283-289 Rüsschoff et al. Mod Pathol 2016: 30:217.

ER-assessment in the Netherlands; 2013-2016 (n=33,794) Laboratory-level (n=39) 100% Proportion (%) ER positive 90% 80% Mean: 87.2% 70% Range: 80.4-94.3% 60% 50% 40% 0 500 1000 1500 2000 2500 Number of reports per laboratory Data adjusted for age, tumour size, type of surgery, histologic subtype, histologic grade, HER2-receptor status

PR-assessment in the Netherlands; 2013-2016 (n=33,794) Laboratory-level (n=39) Mean: 71.3% 100% Range: 62.5-77.5% Proportion (%) PR positive 90% 80% 70% 60% 50% 40% 0 500 1000 1500 2000 2500 Number of reports per laboratory Data adjusted for age, tumour size, type of surgery, histologic subtype, histologic grade, HER2-receptor status

HER2-assessment in the Netherlands; 2013-2016 (n=33,794) Laboratory-level (n=39) Mean: 9.9% 60% Proportion (%) HER2 positive Range: 5.5-12.7% 50% 40% 30% 20% 10% 0% 0 500 1000 1500 2000 2500 Number of reports per laboratory Data adjusted for age, tumour size, type of surgery, histologic subtype, histologic grade, ER/PR-receptor status

Conclusion: ER, PR, HER2 assessment Synoptic pathology reports of >33.000 patients • Absolute variation for ER, PR and HER2 is limited • Considerable number of outliers (PR) • Feedback reports : creating awareness –

Breast cancer biomarkers Histologic grade Receptor-assessment • • ER, PR, HER2 B&R (modified) – – Clinical decisions Clinical decisions – – Chemotherapy Anti-endocrine therapy • • Radiotherapy Anti-HER2 therapy • • Gene-expression profiling •

Breast cancer biomarkers Histologic grade Receptor-assessment • • ER, PR, HER2 B&R (modified) – – Clinical decisions Clinical decisions – – Chemotherapy Anti-endocrine therapy • • Radiotherapy Anti-HER2 therapy • • Gene-expression profiling •

Grading in the Netherlands; 2013-2016 (n=33,792) Laboratory-level (n=39) Mean: 28.1% Grade I Range: 16.3-43.3% 60% 50% Proportion (%) grade I 40% 30% 20% 10% 0% 0 500 1000 1500 2000 2500 Number of IBC reports per laboratory Case-mix: age, tumour size, type of surgery, histologic subtype, ER/PR- and, HER2-receptor status

Grading in the Netherlands; 2013-2016 (n=33,792) Laboratory-level (n=39) Mean: 47.6% Grade II Range: 38.4-57.8% 60% Proportion (%) grade II 50% 40% 30% 20% 10% 0% 0 500 1000 1500 2000 2500 Number of IBC reports per laboratory Mean: 24.3% Grade III Range: 15.5-34.3% 60% Proportion (%) grade III 50% 40% 30% 20% 10% 0% 0 500 1000 1500 2000 2500 Number of IBC reports per laboratory

Grading in the Netherlands; 2013-2016 Pathologist-level (n=68, 8 laboratories) Grade I 60% 50% Proportion (%) grade I 40% 30% 20% 10% 0% 0 50 100 150 200 250 300 Number of IBC reports per pathologist

Grading in the Netherlands; 2013-2016 Pathologist-level (n=68, 8 laboratories) 80% Grade II Proportion (%) grade II 70% 60% 50% 40% 30% 20% 0 50 100 150 200 250 300 Number of IBC reports per pathologist 60% Grade III Proportion (%) grade III 50% 40% 30% 20% 10% 0% 0 50 100 150 200 250 300 Number of IBC reports per pathologist

Grading variation; does it really matter? Chemotherapy (n=19,461) n = 5,821 According to the Dutch breast cancer guideline, adjuvant chemotherapy (aCT) Invasive breast cancer reports with complete is advised for patients with a positive lymph node status (N+) and for patients information on all relevant variables (i.e. lymph with a negative lymph node status (N0) with the following characteristics: node status (N), age, tumor size, histologic grade) n = 19,461 · Age <35 years, except for a grade I tumor <1cm · Age ≥ 35 years with a tumor of 1.1-2 cm and ≥grade II , or a tumor >2cm All patients: 29.9% • · HER2 overexpression in a tumor ≥ 0.5cm N0 N+ N0-patients: 44.5% • n = 13,077 n = 6,384 aCT HER2 - HER2 + n = 11,958 n = 1,119 ≤ 2.0 cm ≥ 0.5 cm > 2.0 cm <0.5 cm n = 9,353 n = 2,605 n = 43 n = 1,076 aCT aCT ≥ 35 years <35 years ≥ 35 years <35 years n = 72 n = 9,281 n = 3 n = 40 Grade I: no aCT no aCT ≤ 1 cm ≤ 1 cm > 1 cm 1.1-2 cm Grade II-III: aCT n = 27 n = 45 n = 3,490 n = 5,791 Grade I: no aCT Grade I: no aCT aCT no aCT Grade II-III: aCT Grade II-III: aCT Curigliano et al. Ann Oncol 2017: 28(8):1700-1712

Conclusion: histologic grading Synoptic pathology reports of >33,000 patients • Substantial inter- and intra-laboratory variation in grading of invasive breast • cancer in daily clinical practice Not explained by differences in case-mix – Biomarker of major clinical importance • Decrease in variation warranted – Interventions • Feedback reports – E-learning –

Breast cancer biomarkers in daily practice Receptor-assessment Histologic grading ER, PR, HER2 B&R (modified) – – Limited absolute variation Substantial variation between and within – – laboratories Considerable number of outlying – laboratories (PR) Interventions – Feedback reports? – Feedback reports: effect? • E-learning : effect? •

Acknowledgements Paul van Diest Carolien van Deurzen Elsken van der Wall Henk-Jan van Slooten Stefan Willems Jelle Wesseling Chantal Kuijpers Pieter Westenend Inge Baas Ivette Deckers Lucy Overbeek