“Examining Advances in

Management of Breast Cancer

During the Last 30 Years” LOCAL REGIONAL TREATMENT

7th Annual Breast Health Summit Houston, TX

10/21/2011

A. Marilyn Leitch, MD

Professor of Surgery

UT Southwestern

OUTLINE

Trends in breast cancer surgery

Tension between BCS and total mastectomy

Evolution to breast conserving surgery

Increasing rate of bilateral mastectomies

Adoption of Sentinel node biopsy of nodal

staging

Abandonment of ALND for positive sentinel

node

Death rates decreased 31% between 1989 and 2007

5 YEAR RELATIVE SURVIVAL RATES

BREAST CANCER: 1996 to 2005 SEER Data (CA Cancer J Clin 2010)

0

20

40

60

80

100

LOCAL REGIONAL DISTANT

99

85

25

93

72

17

98

84

23

Per

cen

tag

e %

WHITE AFRICAN AMERICAN ALL RACES

Trends in Breast

Cancer Surgery

Trends in Breast Cancer Surgery

BREAST CONSERVATION THERAPY:

LONG-TERM VALIDATION OF SAFETY

SURVIVAL IN RANDOMIZED TRIALS OF

BREAST CONSERVATION VS. MASTECTOMY

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

Gustave-

Roussy

Milan NSABP NCI EORTC Danish

MAST

BCT

20 YEAR FOLLOW-UP OF BREAST

CONSERVATION RANDOMIZED TRIALS:

OVERALL SURVIVAL

NEJM 2002; 347: 1227-32 & 1233-41 CANCER 2003;98 697-702

20 YEAR FOLLOW-UP OF RANDOMIZED

BREAST CONSERVATION TRIALS:

LOCAL RECURRENCE

NEJM 2002; 347: 1227-32 & 1233-41 CANCER 2003;98 697-702

PATTERN OF LOCAL

RECURRENCE OVER TIME: B-06

TOTAL

LR < 5 YRS 5-10 YRS >10 YRS

78

EVENTS

(14.3%) 40% 29% 31%

LOCAL RECURRENCE IN

RECENT BCT TRIALS

NSABP trials since B-06 show lower

rates of LR

6% LR at 10 years in node negative

patients

Attributed to use of adjuvant

systemic therapy

NEJM 2002;347:1233-41

NIH CONSENSUS CONFERENCE

ON EARLY STAGE BREAST

CANCER: 1990

Outcomes of breast conserving surgery similar to mastectomy in randomized trials

Breast conservation therapy is the preferred treatment for most stage I and II breast cancers

INCREASING UTILIZATION OF

BREAST CONSERVATION OVER TIME

0%

10%

20%

30%

40%

50%

60%

70%

1985-89 1995 2000 2007

35%

58%

68% 69%

19%

36%

46% 49%

Stage I

Stage II

Cancer 1999; 86: 628-37 / Cancer 1998;83:1262-73 / Commission on Cancer

Benchmark Reports 9/2003, 9/2010

WHY WOMEN DECLINE

BREAST CONSERVATION

Fear of radiation

Disbelief in radiation efficacy

Inconvenience of prolonged and daily radiation treatments

Lack of radiation treatment facility nearby

Disbelief in equivalency to mastectomy for survival

Strong family history breast cancer

TREND TOWARD MORE AGGRESSIVE

SURGICAL TREATMENT

SEER 1998-2003

• 152,755 patients with stage I-III

breast cancer

3.3% (4969) had contralateral

Prophylactic Mastectomy (PM)

contralateral PM increased from

1.8% to 4.5%

Contralateral Prophylactic Mastectomy (CPM):

Increased Use in U.S.

CPM increased from 4% to 11 % of all

patients having mastectomy

150% increase in opposite breast

mastectomy over 1998-2003 when

treated for Invasive breast cancer in

one breast

More likely to have contralateral

mastectomy if:

Young

White race

More favorable tumors

Women with previous history

of other cancer

Infiltrating lobular cancer

Bilateral Mastectomy Rate INCREASED

FROM 0% TO 10% from 1997-2007

0%

2%

4%

6%

8%

10%

12%

1996 1998 2000 2002 2004 2006 2008

PE

RC

EN

TA

GE

YEAR

UT SOUTHWESTERN EXPERIENCE

ASSISTING WOMEN IN DECISION MAKING

FOR MASTECTOMY OR NOT?

Inform in unbiased way about options- data driven

Discuss alternatives that make lumpectomy without opposite mastectomy less worrisome Adjuvant therapy taken after surgery

Enhanced surveillance with MRI

Lifestyle risk reduction strategies

ONCOPLASTIC ALTERNATIVES for making saved breast more attractive and matching opposite breast Insurance covers these procedures

AXILLARY STAGING:

SENTINEL NODE BIOPSY

MINIMIZING NODAL SURGERY

Has replaced ALND as standard for nodal staging

HISTORY OF AXILLARY STAGING

FOR BREAST CANCER

Formal axillary node dissection levels

2-3 standard of care for decades

NSABP B04 trial showed ALND not

associated with improved survival

With smaller tumors detected in

mammography screening, less node

positive

Thus nodes removed unnecessarily

RATIONALE FOR LYMPHATIC MAPPING

AND SENTINEL NODE BIOPSY

Axillary dissection carries morbidity of lymphedema, decreased ROM and decreased sensation of upper inner arm

The status of the axillary nodes is the most important prognostic feature for breast cancer

If axilla accurately staged with a sentinel node biopsy which removes few nodes, then less morbidity of staging procedure

SUMMARY OF SENTINEL NODE

BIOPSY SERIES DATA

False negative rate 0-12%

Success in identification of sentinel

node 70-100%, with most series better

than 90% success

Higher success in SLN identification

and lower false negative rates (<5%) in

series with more experience

WHAT WE HAVE LEARNED

FROM CLINICAL TRIALS

ACOSOG Z0010- ? significance of IHC

occult mets

NSABP B32- ? Safety of SLND

compared to ALND

ACOSOG Z0011- role of ALND for

positive sentinel node

ACOSOG Z10 TRIAL Giuliano, A. E. et al. JAMA 2011;306:385-393

To identify:

Prevalence and prognostic significance of sentinel lymph node (SLN) micrometastases and bone marrow (BM) micrometastases detected by immunohistochemistry (IHC)

• Assess risk of regional recurrence for SLN negative

by H&E

• Assess operative morbidity

Women with clinical T1-T2N0M0 breast cancer

ACOSOG Z10 METHODS

5,539 patients (4/1999 - 5/2003)

Breast conserving surgery, Bone marrow aspiration and

sentinel node biopsy

Bone marrow specimens examined with IHC (investigators

blinded to results)

SLNs processed by standard pathology with H&E staining

SLNs negative by H&E examined with IHC for cytokeratin

(investigators blinded to results)

H&E node positive patients-

Axillary node dissection (ALND) or

Randomized on ACOSOG Z0011 study to no further

surgery or ALND

Using a standard skill requirement surgeons

achieved a low SLN failure rate

98.7% SLN identification rate

Posther KE et al: Annals of Surgery 2005

Low complication rate for SLN dissection with

defined incidence of lymphedema

1-7% rate of various axillary complications

7% rate of lymphedema Wilke LG et al: Annals of Surg Oncology 2006

SURGICAL TECHNICAL OUTCOMES: Z0010

ACOSOG Z10: FINDINGS

Sentinel Lymph node data

H&E: 24% positive for metastases

IHC: 10% of cases with micrometastases

Increasing breast tumor size is associated

with positive SLN

Bone marrow data – n= 3,413

ICC: 3% micrometastases

NO relationship to breast tumor size

Bone Marrow Specimen Results and Cumulative Incidence of Death

Median follow-up 6.3 yrs

Giuliano, A. E. et al. JAMA 2011;306:385-393

Copyright restrictions may apply.

Sentinel Lymph Node Results and Cumulative Incidence of Death

NO DIFFERENCE

Giuliano, A. E. et al. JAMA 2011;306:385-393

Copyright restrictions may apply.

Conclusions from ACOSOG Z10

Outcome in this population was EXCELLENT- 5 year

overall survival of 93% in patients with H&E+ SLN

Occult SLN metastases detected by IHC not associated with

overall survival differences (95.7% IHC negative and 95.1%

for IHC positive)

Occult bone marrow metastases were significantly

associated with increased mortality

Routine IHC examination of H&E–negative SLNs and bone

marrow is not clinically warranted for early-stage (clinical

T1-T2N0) breast cancer.

Incidence BMA+ was too low to recommend incorporating

bone marrow aspiration biopsy into routine practice for

patients with clinical T1,2 N0M0 breast cancer

NSABP B-32:

Largest prospective randomized phase III

trial of SLND alone vs SLND +ALND for

sentinel node negative

5,611 women with operable, clinically N0

Median follow-up 95 mos

Kaplan-Meier Survival Estimates According to the Presence or Absence of Occult Metastases Detected in Initially Negative Sentinel Lymph Nodes.

Weaver DL et al. N Engl J Med 2011;364:412-421

NSABP B32 Conclusions

• Significant difference overall survival between patients with IHC occult metastases and those in whom no occult metastases were detected (94.6% and 95.8%)

• Occult metastases were an independent prognostic variable in patients with sentinel nodes that were negative on initial examination; however, the magnitude of the difference in outcome at 5 years was small (1.2 percentage points)

• Data do not indicate a clinical benefit of additional evaluation with IHC for initially negative sentinel nodes in patients with breast cancer.

COMPARISON ACOSOG Z10

AND NSABP B32

ACOSOG Z10 NSABP B32

Tumor size 1.4cm

T1 83% 80%

H&E pos SLNS 24% 26%

IHC pos SLNS 10.5% 15.9%

BMA positive 3% NA

Systemic Adjuvant 86% 78%

MANAGEMENT OF THE POSITIVE

SENTINEL NODE

Standard of care :

Axillary Lymph Node Dissection

Is ALND necessary?

RATIONALE TO AVOID ALND IN

SLN POSITIVE PATIENTS

SLN often the only positive node

Adjuvant therapy may treat

subclinical nodal metastases

Most data indicate that ALND

does not improve survival

ALND is for staging

38

ACOSOG Z0011

A randomized trial of axillary node dissection

VS no axillary dissection in women with

clinical T1-2 N0 M0 breast cancer who have

a positive SN

Target accrual 1900 patients (non-inferiority)

• 4/1999 - 12/2004

• Closed early with 891 pts

ACOSOG Z11 RESULTS:

REPORTED ASCO 6/2010

106 (27.4%) patients undergoing ALND had additional positive nodes removed beyond SN

Median follow-up = 6.3 years

Regional NODAL recurrence seen in only

0.7% of the entire population

40

Locoregional Recurrence-Free Survival

41

Summary

Locoregional recurrence in only 2.8% of

SLND and 4.1% of ALND patients

Only age (< 50) and higher Bloom-

Richardson score were associated with

locoregional recurrence by multivariable

analysis

Locoregional recurrence not related to

number of positive SNs, size of SN

metastasis, or number of lymph nodes

removed

Locoregional Recurrence-Free Survival

42

0

10

20

30

40

50

60

70

80

90

100

0 1 2 3 4 5 6 7 8

Time (Years)

% A

liv

e

ALND

No ALND

P-value = 0.25

Overall Survival

43

Summary

No significant difference in DFS between

patients treated with SLND (83.9%) or ALND

(82.2%)

No significant difference in OS between

patients treated with SLND (92.5%) or ALND

(91.8%)

Only older age, ER-, and lack of adjuvant

systemic therapy - NOT OPERATION -

were associated with worse OS by

multivariable analysis.

Disease-Free and Overall Survival

Z11 Conclusion

In this prospective randomized study - SLND

alone provided excellent

locoregional control and

survival comparable to

completion ALND for SLN node positive patients

REMEMBER: APPLIES TO

SELECTED PATIENTS

• Initially clinically node negative

• Patients having breast conserving

surgery + radiation

• MASTECTOMY PATIENTS

EXCLUDED

• < 2 positive SLNs and no gross

extranodal extension

ACOSOG Z10 AND Z11/ NSABP B32

PRACTICE CHANGING

• Abandon use of IHC to evaluate

sentinel nodes

• Abandon ALND for positive

sentinel node

THANK YOU

EVOLVING ROLE OF RADIATION IN

BREAST CANCER MANAGEMENT

After breast conserving surgery

Whole breast radiation

Accelerated partial breast radiation

After mastectomy

Positive margin

>3 positive nodes

Tumor > 5 cm with positive nodes

Stage III

Controversial: 1-3+ nodes

Value of Local Control for Survival Lancet 366:2087, 2005

Oxford overview 2005

Node positive breast cancer

treated with mastectomy,

radiation reduced local recurrence

from 29% to 8% at 15 years

5% increase in overall survival for

node positive with radiation

OVERCOMING RADIATION

CONCERNS: ACCELERATED

PARTIAL BREAST RADIATION Vicini, J Clin Oncol 2001;19:1993-2001,

Brachytherapy 1 (2002) 184–190

Administer radiation to lumpectomy site ONLY instead of whole breast

Treatment complete in 4-5 days instead of 5-7 weeks

Alternative methods of local radiation:

Internal devices

External beam

Limited to specific circumstances

Clinical trial at UT Southwestern for Cyberknife application of PBI

INITIAL CRITERIA FOR SELECTING

PATIENTS FOR PARTIAL BREAST

RADIATION (PBI)

ABS ASBS

AGE >45 >50

HISTOLOGY

Node negative

Solitary tumor,

invasive ductal

Invasive or

in situ ductal

Tumor size < 3 cm < 2 cm

Margins Negative > 2 mm

ACCELERATED PARTIAL BREAST IRRADIATION

CONSENSUS STATEMENT FROM

THE AMERICAN SOCIETY FOR RADIATION

ONCOLOGY (ASTRO) 2009

- Defined

Suitable candidates – age > 60

At variance with prior guidelines

Cautionary – age 50-59yrs

Unsuitable - < 50 yrs

COMPARATIVE CRITERIA FOR

SELECTING PATIENTS FOR PARTIAL

BREAST RADIATION (PBI)

ABS ASBS ASTRO

AGE >45 >50 > 60

HISTOLOGY

Node negative

Solitary tumor,

invasive ductal

Invasive ductal

DCIS

Invasive ductal

no DCIS

Tumor size < 3 cm < 2 cm < 2cm

Margins Negative > 2 mm > 2 mm

Breast Cancer Statistics, 2011 : Trends in Female Breast

Cancer Death Rates by Race and Ethnicity, 1975 to 2007

CA: A Cancer Journal for Clinicians

pages n/a-n/a, 3 OCT 2011 DOI: 10.3322/caac.20134

http://onlinelibrary.wiley.com/doi/10.3322/caac.20134/full#fig3

Overall Survival by Bone Marrow IHC

0

10

20

30

40

50

60

70

80

90

100

0 1 2 3 4 5 6 7 8 9 10

Time in Years

% A

live

Negative

Positive

P-value = 0.01

58

Associations of Prognostic Variables

with Overall Survival

PR status

Tumor Size

Histologic Type

NS

0.042

0.020

Univariable Analysis

P value

Multivariable Analysis

P value

Adjuvant Systemic Therapy

NS Treatment Arm NS

0.044 # Positive Total LN NS

ER status 0.012 0.013

NS

Age (< 50, > 50) 0.002 0.006

0.025

NS

NS NS

LVI present vs. absent NS NS

Grade NS NS

NS SN Metastasis Size NS