M icrometastases and I solated tumor cells: R elevant and R obust O r R ubbish?

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

procedurein 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 1.15-1.95)

– pN1mi: HR 1.52 (95%CI 1.11-2.09)

• Our data show that both patients with pN0(i+) and pN1mi benefit from AST– pN0(i+): HR 0.67 (95%CI 0.46-0.96)

– pN1mi: HR 0.50 (95%CI 0.35-0.72)

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 2nd MIRROR analyses

• Patients selected from the Netherlands Cancer Registry

– invasive breast cancer diagnosed 1997 - 2005

– 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 = 3205selected from Netherlands

Cancer Registry

n = 2680inclusion after central

pathology review

Accrual

SN onlyN= 1218

cALNDN= 1314

axRTN= 148




Cancer Registry


pathology review

Accrual

SN onlyN= 1218

cALNDN= 1314

axRTN= 148




Cancer Registry


pathology review

Accrual

SN onlyN= 1218

cALNDN= 1314

axRTN= 148

Present analysis: categorized by SN-status

SN onlyn= 1218

cALND n= 1314

axRTn= 148

P-valueSN only

vs cALND / RT

SN status

pN0 60% 9% 3%

pN0(i+) 28% 30% 36% <0.0001

pN1mi 12% 61% 61%

Baseline characteristics

SN onlyn= 1218

cALND n= 1314

axRTn= 148

P-valueSN only

vs cALND / RT

Tumor size

≤ 1 cm 36% 25% 24%

<0.00011.1-2.0

cm54% 58% 64%

2.1-3.0 cm

10% 18% 13%


SN onlyn= 1218

cALND n= 1314

axRTn= 148

P-valueSN only

vs cALND / RT

Adjuvant systemic therapy

No 87% 45% 39%<0.0001

Yes 13% 55% 61%


SN onlyn= 1218

cALND n= 1314

axRTn= 148

P-valueSN only

vs cALND / RT

RT breastNo 29% 35% 5%

0.09Yes 71% 65% 95%


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


Variable N5-yrsAR

HR 95 % CI

pN0(sn) * cALND 125 1.6% 1.00

pN0(sn) * SN only 732 2.3% 1.08 0.23-4.98

HR, corrected for age, tumor size, differentiation grade, hormone receptor status, adjuvant systemic therapy, radiotherapy to the breast

MV analysis: axillary recurrence (AR)

Variable N5-yrsAR

HR 95 % CI

pN0(i+)(sn) * cALND/axRT

450 0.9% 1.00

pN0(i+)(sn) * SN only 345 2.0% 2.39 0.67-8.48



Variable N5-yrsAR

HR 95 % CI

pN1mi(sn) * cALND / axRT

887 1.0% 1.00

pN1mi(sn) * SN only 141 5.0% 4.391.46-13.24



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



Variable N5-years

AR

pN0(i+)(sn) * cALND 396 1.0%

pN0(i+)(sn) * axRT 54 0%

pN0(i+)(sn) * SN 345 2.0%

pN1mi(sn) * cALND 793 1.1%

pN1mi(sn) * axRT 94 0%

pN1mi(sn) * SN 141 5.0%

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



3. To determine other factors predictive for AR

Variable HR 95 % CI P-value

Tumor size 8.62 1.38 – 53.84 0.021

MV analysis: 5-yrs AR rate pN1mi(sn)


Tumor size 8.62 1.38 – 53.84 0.021

Histological grade III 25.05 1.26 – 497.18 0.035



Tumor size 8.62 1.38 – 53.84 0.021


Negative ER / PgR status

4.96 1.48 – 16.62 0.010



Tumor size 8.62 1.38 – 53.84 0.021



4.96 1.48 – 16.62 0.010

No systemic therapy 1.36 0.47 – 3.99 0.572



Tumor size 8.62 1.38 – 53.84 0.021



4.96 1.48 – 16.62 0.010

No systemic therapy 1.36 0.47 – 3.99 0.572

No breast radiotherapy

1.01 0.36 – 2.88 0.979


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 CentreManon Pepels, Maastricht University Medical Centre

Steering Committee:Peter Bult, Radboud University Nijmegen Medical

CentrePaul van Diest, University Medical Centre UtrechtJos van Dijck, Comprehensive Cancer Centre East,

NijmegenEddy Adang, Radboud University Nijmegen Medical

CentreHans Nortier, Leiden University Medical CentreEmiel Rutgers, National Cancer Institute / A. van

Leeuwenhoek Hospital, AmsterdamCaroline Seynaeve, University Medical Centre

RotterdamMarian Menke-Pluymers, University Medical Centre

Rotterdam

Central Pathology Review:Peter Bult, Radboud University Nijmegen Medical

CentreCarolien van Deurzen, University Medical Centre

UtrechtPaul van Diest, University Medical Centre Utrecht

Statistical Analysis:George Borm, Radboud University

Nijmegen Medical CentreWim 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 EastJolanda 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

Documents

M icrometastases and I solated tumor cells: R elevant and R obust O r R ubbish?