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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

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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

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I hereby declare that I have no conflict of interest

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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

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Breast cancer: background

  • Most common type of cancer in European women1
  • 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
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  • Histologic grade

– B&R (modified) – Clinical decisions

  • Chemotherapy
  • Radiotherapy
  • Gene-expression profiling
  • Receptor-assessment

– ER, PR, HER2 – Clinical decisions

  • Anti-endocrine therapy
  • Anti-HER2 therapy

Breast cancer biomarkers

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Reproducibility of breast cancer biomarkers

  • Receptor assessment:

significant differences1-16

  • Histologic grading:

no more than moderate16-19

But how are we doing in daily clinical practice?

1. McCullough et al. Breast Cancer Res Treat 2014; 143(3):48-492 2. Cuadros et al. Clin Transl Oncol 2011; 13 (5):335-340 3. Denkert et al. Breast Cancer Res 2013;; 15(1): R11 4. Orlando et al. Breast. 2016: 30;151-155. 5. Paik et al. J Natl Cancer Inst 2002:94(11);852-854 6. Perez et al. J Clin Oncol 2006:24(19):3032-3038 7. Roche et al. J Natl Cancer Inst 2002:94(11): 855-857 8. Rosa et al. Breast J 2017:24(2);139-147 9. Viale et al. J Clin Oncol 2007:25(25):3846-3852 10. Bianchi et al. Pathol Oncol Res 2015:21(2):477-485 11. Dowsett et al. Mod Pathol 2007:20:584 12. Layfield et al. Breast J 2003: 9(3):257-259 13. Parker et al. Am J Clin Pathol 2002:117(5):723-728 14. Regitnig et al. Virchows Arch 2002: 441(4):328-334 15. Rhodes et al. Am J Clin Pathol 2001: 115(1):44-58. 16. Boiesen et al. Acta Oncol 2000: 39(1):41-45 17. Frierson et al. Am J Clin Pathol 1995:103(2):195-198 18. Italian Network for Quality Assurance of Tumour Biomarkers (INQAT group). Pathologica 2005:97(1):1-6 19. Meyer et al. Mod Pathol 2005:18(8):1067-1078

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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 protocol1 ▪ Increased overall completeness of reports2 ▪ Easy data extraction

1. PALGA Foundation, Annual Report 2018 2. Sluijter et al. Virchows Archiv 2016:468(4):639-649.

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  • Histologic grade

– B&R (modified) – Clinical decisions

  • Chemotherapy
  • Radiotherapy
  • Gene-expression profiling
  • Receptor-assessment

– ER, PR, HER2 – Clinical decisions

  • Anti-endocrine therapy
  • Anti-HER2 therapy

Breast cancer biomarkers

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  • Histologic grade

– B&R (modified) – Clinical decisions

  • Chemotherapy
  • Radiotherapy
  • Gene-expression profiling
  • Receptor-assessment

– ER, PR, HER2 – Clinical decisions

  • Anti-endocrine therapy
  • Anti-HER2 therapy

Breast cancer biomarkers

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Receptor assessment: clinical decisions

  • ER/PR

– IHC – 10% cut-off – Anti-endocrine therapy

  • HER2

– IHC – 10% cut-off – Amplification testing (IHC 2+) – Anti-HER2 therapy

Start 5 years Start 1 year

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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.

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ER-assessment in the Netherlands; 2013-2016 (n=33,794)

Laboratory-level (n=39)

40% 50% 60% 70% 80% 90% 100% 500 1000 1500 2000 2500

Proportion (%) ER positive Number of reports per laboratory

Mean: 87.2% Range: 80.4-94.3%

Data adjusted for age, tumour size, type of surgery, histologic subtype, histologic grade, HER2-receptor status

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PR-assessment in the Netherlands; 2013-2016 (n=33,794)

Laboratory-level (n=39)

40% 50% 60% 70% 80% 90% 100% 500 1000 1500 2000 2500

Proportion (%) PR positive Number of reports per laboratory

Mean: 71.3% Range: 62.5-77.5%

Data adjusted for age, tumour size, type of surgery, histologic subtype, histologic grade, HER2-receptor status

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HER2-assessment in the Netherlands; 2013-2016 (n=33,794)

Laboratory-level (n=39)

0% 10% 20% 30% 40% 50% 60% 500 1000 1500 2000 2500

Proportion (%) HER2 positive Number of reports per laboratory

Mean: 9.9% Range: 5.5-12.7%

Data adjusted for age, tumour size, type of surgery, histologic subtype, histologic grade, ER/PR-receptor status

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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

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  • Histologic grade

– B&R (modified) – Clinical decisions

  • Chemotherapy
  • Radiotherapy
  • Gene-expression profiling
  • Receptor-assessment

– ER, PR, HER2 – Clinical decisions

  • Anti-endocrine therapy
  • Anti-HER2 therapy

Breast cancer biomarkers

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  • Histologic grade

– B&R (modified) – Clinical decisions

  • Chemotherapy
  • Radiotherapy
  • Gene-expression profiling
  • Receptor-assessment

– ER, PR, HER2 – Clinical decisions

  • Anti-endocrine therapy
  • Anti-HER2 therapy

Breast cancer biomarkers

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Grading in the Netherlands; 2013-2016 (n=33,792)

Laboratory-level (n=39)

0% 10% 20% 30% 40% 50% 60% 500 1000 1500 2000 2500

Proportion (%) grade I Number of IBC reports per laboratory

Grade I

Mean: 28.1% Range: 16.3-43.3%

Case-mix: age, tumour size, type of surgery, histologic subtype, ER/PR- and, HER2-receptor status

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Grading in the Netherlands; 2013-2016 (n=33,792)

Laboratory-level (n=39)

0% 10% 20% 30% 40% 50% 60% 500 1000 1500 2000 2500

Proportion (%) grade II Number of IBC reports per laboratory

Grade II

0% 10% 20% 30% 40% 50% 60% 500 1000 1500 2000 2500

Proportion (%) grade III Number of IBC reports per laboratory

Grade III

Mean: 47.6% Range: 38.4-57.8% Mean: 24.3% Range: 15.5-34.3%

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Grading in the Netherlands; 2013-2016

Pathologist-level (n=68, 8 laboratories)

0% 10% 20% 30% 40% 50% 60% 50 100 150 200 250 300

Proportion (%) grade I Number of IBC reports per pathologist

Grade I

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0% 10% 20% 30% 40% 50% 60% 50 100 150 200 250 300

Proportion (%) grade III Number of IBC reports per pathologist

Grade III

20% 30% 40% 50% 60% 70% 80% 50 100 150 200 250 300

Proportion (%) grade II Number of IBC reports per pathologist

Grade II

Grading in the Netherlands; 2013-2016

Pathologist-level (n=68, 8 laboratories)

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Grading variation; does it really matter?

Chemotherapy (n=19,461)

Invasive breast cancer reports with complete information on all relevant variables (i.e. lymph node status (N), age, tumor size, histologic grade) n = 19,461 According to the Dutch breast cancer guideline, adjuvant chemotherapy (aCT) is advised for patients with a positive lymph node status (N+) and for patients with a negative lymph node status (N0) with the following characteristics: · Age <35 years, except for a grade I tumor <1cm · Age ≥35 years with a tumor of 1.1-2cm and ≥grade II, or a tumor >2cm · HER2 overexpression in a tumor ≥0.5cm N0 n = 13,077 N+ n = 6,384 HER2 + n = 1,119 HER2 - n = 11,958 <0.5 cm n = 43 ≥ 0.5 cm n = 1,076 <35 years n = 3 ≥ 35 years n = 40 Grade I: no aCT Grade II-III: aCT > 2.0 cm n = 2,605 ≤ 2.0 cm n = 9,353 <35 years n = 72 ≥ 35 years n = 9,281 ≤ 1 cm n = 27 > 1 cm n = 45 Grade I: no aCT Grade II-III: aCT aCT aCT aCT aCT no aCT ≤ 1 cm n = 3,490 no aCT 1.1-2 cm n = 5,791 Grade I: no aCT Grade II-III: aCT

n = 5,821

  • All patients:

29.9%

  • N0-patients:

44.5%

Curigliano et al. Ann Oncol 2017: 28(8):1700-1712

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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

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Histologic grading

– B&R (modified) – Substantial variation between and within laboratories – Interventions

  • Feedback reports: effect?
  • E-learning: effect?

Receptor-assessment

– ER, PR, HER2 – Limited absolute variation – Considerable number of outlying laboratories (PR)

– Feedback reports?

Breast cancer biomarkers in daily practice

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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