Vivianne Tjan-Heijnen, MJ Pepels, M de Boer, GF Borm, JA van Dijck, CH van Deurzen, EM Adang, MB Menke- Pluymers, PJ van Diest and P Bult On behalf of the Dutch Breast Cancer Trialists’ Group (BOOG)‏ Funded by The Netherlands organization for health research and development (ZonMw) Impact of omission of completion ALND or axRT in breast cancer patients with pN1mi or pN0(i+) in SN: results from the Dutch MIRROR study

Micrometastases and Isolated tumor cells: Relevant and Robust Or Rubbish? A cohort study from the Netherlands in 2680 early stage breast cancer patients who had undergone a SN procedure in 1997 – 2005 The MIRROR study

Background MIRROR study SN procedure has led to an increased detection of isolated tumor cells, pN0(i+), and micrometastases, pN1mi Previous studies - before the SN era - showed conflicting results on the prognostic impact of small nodal metastases

MIRROR conclusions, SABCS ‘08 In patients not receiving AST, pN0(i+) and pN1mi were prognostic factors for DFS –pN0(i+): HR 1.50 (95%CI ) –pN1mi: HR 1.52 (95%CI ) Our data show that both patients with pN0(i+) and pN1mi benefit from AST –pN0(i+): HR 0.67 (95%CI ) –pN1mi: HR 0.50 (95%CI ) De Boer et al. SABCS dec 2008; oral #23

Nearly 50% of 795 patients with pN0(i+)(sn) and approximately 15% of 1028 patients with pN1mi(sn) had not received further axillary treatment In 8% of patients with pN0(i+)(sn) or pN1mi(sn) axillary treatment consisted of axRT only Data on safety and efficacy of such strategies regarding axillary recurrence (AR) are, however, lacking Background 2 nd MIRROR analyses

Patients selected from the Netherlands Cancer Registry –invasive breast cancer diagnosed –SN procedure –final N-status: pN0, pN0(i+) or pN1mi –favorable characteristics (Dutch guidelines 2002)‏ tumor size ≤ 1 cm irrespective of grade OR tumor size 1-3 cm and grades I-II Patients and methods

no pathology review macrometastases unfavorable tumor characteristics other reasons n = 3205 selected from Netherlands Cancer Registry n = 2680 inclusion after central pathology review Accrual SN only N= 1218 cALND N= 1314 axRT N= 148

no pathology review macrometastases unfavorable tumor characteristics other reasons n = 3205 selected from Netherlands Cancer Registry n = 2680 inclusion after central pathology review Accrual SN only N= 1218 cALND N= 1314 axRT N= 148

no pathology review macrometastases unfavorable tumor characteristics other reasons n = 3205 selected from Netherlands Cancer Registry n = 2680 inclusion after central pathology review Accrual SN only N= 1218 cALND N= 1314 axRT N= 148 Present analysis: categorized by SN-status

SN only n= 1218 cALND n= 1314 axRT n= 148 P-value SN only vs cALND / RT SN status pN060%9%3% pN0(i+)28%30%36%< pN1mi12%61% Baseline characteristics

SN only n= 1218 cALND n= 1314 axRT n= 148 P-value SN only vs cALND / RT Tumor size ≤ 1 cm36%25%24% < cm54%58%64% cm10%18%13% Baseline characteristics

SN only n= 1218 cALND n= 1314 axRT n= 148 P-value SN only vs cALND / RT Adjuvant systemic therapy No87%45%39% < Yes13%55%61% Baseline characteristics

SN only n= 1218 cALND n= 1314 axRT n= 148 P-value SN only vs cALND / RT RT breast No29%35%5% 0.09 Yes71%65%95% Baseline characteristics

Axillary recurrence rate in all included patients 5-yrs AR 1.7%

Objectives 1.To determine the impact of omission of axillary therapy on 5-yrs AR rate by SN status 2.To determine the efficacy of axRT vs cALND 3.To determine other factors predictive for AR

Objectives 1.To determine the impact of omission of axillary therapy on 5-yrs AR rate by SN status

VariableN 5-yrs AR HR95 % CI pN0(sn) * cALND1251.6%1.00 pN0(sn) * SN only7322.3% HR, corrected for age, tumor size, differentiation grade, hormone receptor status, adjuvant systemic therapy, radiotherapy to the breast MV analysis: axillary recurrence (AR)

VariableN 5-yrs AR HR95 % CI pN0(i+)(sn) * cALND/axRT4500.9%1.00 pN0(i+)(sn) * SN only3452.0% HR, corrected for age, tumor size, differentiation grade, hormone receptor status, adjuvant systemic therapy, radiotherapy to the breast MV analysis: axillary recurrence (AR)

VariableN 5-yrs AR HR95 % CI pN1mi(sn) * cALND / axRT8871.0%1.00 pN1mi(sn) * SN only1415.0% HR, corrected for age, tumor size, differentiation grade, hormone receptor status, adjuvant systemic therapy, radiotherapy to the breast MV analysis: axillary recurrence (AR)

Conclusions For low-risk patients with pN0(sn), we confirm the safety of no further axillary treatment For low-risk patients with pN0(i+)(sn), omission of axillary treatment resulted in an increased hazard ratio (HR 2.39) for AR, though statistically not significant For patients with pN1mi(sn), omission of axillary treatment resulted in a significantly increased AR rate (5% at 5 yr, HR 4.39)

Objectives 1.To determine the impact of omission of axillary therapy on 5-yrs AR rate by SN status 2.To determine the efficacy of axRT vs cALND

VariableN 5-years AR pN0(i+)(sn) * cALND3961.0% pN0(i+)(sn) * axRT540% pN0(i+)(sn) * SN3452.0% pN1mi(sn) * cALND7931.1% pN1mi(sn) * axRT940% pN1mi(sn) * SN1415.0% Efficacy of axRT

Conclusion An AR rate of 0% at 5-years in patients treated with axRT is provocative, challenging the current recommendation of cALND However, more data on axRT are needed for a meaningful statistical analysis and before firm conclusions can be drawn (e.g. AMAROS study)

Axillary recurrence rate in pN1mi(sn) SN only: HR 4.39 (95% CI 1.46 –13.24)

Objectives 1.To determine the impact of omission of axillary therapy on 5-yrs AR rate by SN status 2.To determine the efficacy of axRT vs cALND 3.To determine other factors predictive for AR

VariableHR95 % CIP-value Tumor size – MV analysis: 5-yrs AR rate pN1mi(sn)

VariableHR95 % CIP-value Tumor size – Histological grade III – MV analysis: 5-yrs AR rate pN1mi(sn)

VariableHR95 % CIP-value Tumor size – Histological grade III – Negative ER / PgR status – MV analysis: 5-yrs AR rate pN1mi(sn)

VariableHR95 % CIP-value Tumor size – Histological grade III – Negative ER / PgR status – No systemic therapy – MV analysis: 5-yrs AR rate pN1mi(sn)

VariableHR95 % CIP-value Tumor size – Histological grade III – Negative ER / PgR status – No systemic therapy – No breast radiotherapy – MV analysis: 5-yrs AR rate pN1mi(sn)

Conclusion Tumor size, grade, and hormone receptor status were predictive for AR in patients with pN1mi(sn) Omission of adjuvant systemic therapy resulted in an increased hazard ratio for AR, though statistically not significant Radiotherapy on the breast had no impact on AR rate

Take Home Message For patients with pN0(sn), omission of axillary therapy is safe and standard policy For patients with pN0(i+)(sn), omission of axillary therapy may only be safe in the presence of otherwise favorable tumor characteristics We recommend completion axillary treatment in patients with pN1mi(sn) to reduce the AR rate

Take Home Message More data are needed on the efficacy of axRT, though results are provocative Unfavorable tumor size, grade, and hormone receptor status should be taken into account when considering ‘SN only’ in patients with pN0(i+)(sn) or pN1mi(sn)

Project Leader: Vivianne Tjan-Heijnen, Maastricht University Medical Centre Study Coordinators: Maaike de Boer, Maastricht University Medical Centre Manon Pepels, Maastricht University Medical Centre Steering Committee: Peter Bult, Radboud University Nijmegen Medical Centre Paul van Diest, University Medical Centre Utrecht Jos van Dijck, Comprehensive Cancer Centre East, Nijmegen Eddy Adang, Radboud University Nijmegen Medical Centre Hans Nortier, Leiden University Medical Centre Emiel Rutgers, National Cancer Institute / A. van Leeuwenhoek Hospital, Amsterdam Caroline Seynaeve, University Medical Centre Rotterdam Marian Menke-Pluymers, University Medical Centre Rotterdam Central Pathology Review: Peter Bult, Radboud University Nijmegen Medical Centre Carolien van Deurzen, University Medical Centre Utrecht Paul van Diest, University Medical Centre Utrecht Statistical Analysis: George Borm, Radboud University Nijmegen Medical Centre Wim Lemmens, Radboud University Nijmegen Medical Centre Participating Centres: All Dutch Pathology Laboratories (n = 60)‏ All Dutch Hospitals (n = 113)‏ All Dutch Comprehensive Cancer Centres (n = 8)‏ Data Management: Comprehensive Cancer Centre East Jolanda van Beek - Schoester Supported by: Dutch Breast Cancer Trialists’ Group (BOOG)‏ Funded by: The Netherlands organization for health research and development (ZonMw)‏ Steering group - acknowledgements