Memorial Sloan-Kettering Cancer Center 1275 York Avenue, New York, NY 10065 18 August 2012 18 th Annual Perspectives in Breast Cancer New York, NY Treatment Decision Making for DCIS Monica Morrow MD Chief, Breast Surgery Service Anne Burnett Windfohr Chair of Clinical Oncology Memorial Sloan-Kettering Cancer Center

Controversies in DCIS Management

• Is nipple sparing mastectomy appropriate?

• Is RT necessary for all DCIS?

• When is SN biopsy indicated?

• What about endocrine rx?

Mastectomy in DCIS

• Indicated when DCIS is too extensive to be encompassed with a cosmetic resection.

• Outcome Metaanalysis 21 studies, 1574 patients Local recurrence 1.4% (0.7-2.1%) Skin sparing mastectomy n = 223 Local recurrence 3.1%

Boyages J, Cancer 1999;85:616 Carlson G, JACS 2007;204:1074

What About Nipple Sparing Mastectomy?

Concerns

• NSM leaves behind ductal tissue + breast tissue in order to preserve blood supply.

• Occult nipple involvement present in 6-31% of cancers.

• Most studies of NSM are in invasive cancer.

10/26/2011

Clinical Outcomes NSM European Institute of Oncology 3/02-12/07

# Cases 5yr LR Breast NAC Median f/u: 50 months All patients received 16 Gy to NAC

Invasive Cancer

772

DCIS

162 3.6% 0.8% 4.9% 2.9%

CAUTION: At 20 mo f/u, no NAC recurrences, 1.4% LR Petit JY, Ann Oncol 2012;23:2053-8 Petit JY, Br Ca Res Treat 2009;117:333

NSM in DCIS

• Increased risk of LR due to retained breast tissue and poor exposure.

• Contraindicated in patients with extensive DCIS necessitating mastectomy, localized DCIS in subareolar space.

What do I really think about NSM?

It’s a great operation for a woman who doesn’t actually need a mastectomy.

Is RT Necessary for All DCIS?

Randomized Trials of Excision ± RT in DCIS Trial

NSABP B17 EORTC 10853 UK/ANZ Swedish

# Patients

813 1002

% Mammo Detected

80 71 1030 1046 100 78

Boost Tamoxifen

No No No No No No Yes No

Metaanalysis Trials of Excision ± RT in DCIS

Total Invasive DCIS

n = 3729 10 yr IBTR No RT

28.1% 15.4% 14.9%

RT

12.9% 6.8% 6.5%

p-value

< .001

< .001

< .001

EBCTCG JNCI Monograph 2010;41:162

Metaanalysis Trials of Excision ± RT in DCIS 10 yr Survival Outcomes

All deaths Death w/o recurrence Cardiac death

No RT

8.2

5.7

1.3

RT

8.4

5.4

1.5

p-value

> .1

> .1

> .1

EBCTCG JNCI Monograph 2010;41:162

Conclusions of Randomized Trials

• RT reduces the risk of LR by 50%.

• Patient subsets

NOT

benefitting from RT have not been identified.

Academic U.S. Physicians Recommending RT For DCIS Ceilley E, Cancer 2004;101:1958

Concerns Regarding Randomized Trials

• Detailed tissue processing/method of pathology evaluation not specified.

• Post-excision mammography not mandated.

• Impact of margin width on RT benefit not assessed.

Does wide excision + detailed pathology exam result in local control equivalent to excision + RT?

Local Recurrence: Margins ≥ 10 mm Silverstein M, NEJM 1999;340:1455

E5194: Excision Alone ± Tamoxifen for DCIS Eligibility

• DCIS ≥ 3mm in size • Minimum margin width ≥ 3mm • Specimen completely embedded, sequentially sectioned • Post-excision mammogram free of calcification

Hughes L, J Clin Oncol 2009;27:5319

Patient Characteristics: E5194

Number Median Size Margin ≥ 1cm Margin ≥ 5mm TAM planned

Low/Int Grade High Grade

579 6mm 46% 67% 31% 101 7mm 48% 75% 31%

Hughes L, J Clin Oncol 2009;27:5319

Intergroup Trial of Excision Alone IBTR

5yr 7yr

Contralateral

5yr 7yr

Mean f/u 6.3 years High Grade

3.9% 7.4% (1.4-13.5)

Low Grade

15.3% 18.0% (10.2-25.9) 6.1% 10.5% (7.5-13.6) 3.7% 4.8% (2.7-6.9)

Hughes L, J Clin Oncol 2009;27:5319

Local Failure According to Pathology After Lumpectomy and Radiation Solin L, J Clin Oncol 1996;14:754

Effect of Margin Width – No RT

Margin < 1cm ≥ 1cm

Intergroup Trial % Local Recurrence

Low Grade 5.6

6.7

High Grade 14.8

15.9

Hughes L, J Clin Oncol 2009;27:5319

RTOG 9084: RT vs Observation for “Good Risk” DCIS Eligibility

• Mammographic or incidental DCIS • Low or intermediate grade • Size (mammographic) ≤ 2.5 cm • Margins ≥ 3 mm

McCormick B, ASCO 2012

RTOG 9084 Schema Stratify

Age < 50 ≥ 50 Margins Negative re-excision 3-9 mm ≥ 10 mm Size ≤ 1 cm > 1 cm-2.5 cm Grade Low Intermediate Tamoxifen No Yes

R A N D O M I Z E Observation RT No Boost

Patient Characteristics: RTOG 9084

Number Median Age Mammographic size < 1 cm Grade 1 Margin 3-9 mm ≥ 10 mm Neg. re-excision Intent to use Tam Yes

Observation

298 58 72.8% 44% 35.6% 16.1% 48.3% 69.5%

RT

287 58 72.1% 42.2% 36.2% 15.7% 48.1% 68.6%

McCormick B, ASCO 2012

Local Failure Ipsilateral Breast

30 Observation RT Failed 15 2 Total 298 287 25 20 15 10 5 0 0 Patients at Risk Observation RT 298 287 Gray's test p-value=0.0022

HR = 0.14 (0.03,0.61) 5-Years Rates: 3.2% 0.4% 2 4 Years after Randomization 272 264 232 228 6 147 141

Local Recurrence After Excision +/- RT in Good Prognosis DCIS 5 yr LR

Excision Alone E5194 6.1% RTOG 9084 3.2% Excision + RT RTOG 9084 0.4%

Hughes L, J Clin Oncol 2009;27:5319 McCormick B, ASCO 2012

Conclusions E5194 + RTOG 9084

• Rates of LR after excision alone differed significantly among 2 populations with “favorable” DCIS selected with standard histopathologic criteria.

• Benefit for RT is present even in this good-risk subset.

A QUANTITATIVE MULTIGENE RT-PCR ASSAY FOR PREDICTING RECURRENCE RISK AFTER SURGICAL EXCISION ALONE WITHOUT IRRADIATION FOR DUCTAL CARCINOMA IN SITU (DCIS): A PROSPECTIVE VALIDATION STUDY OF THE DCIS SCORE FROM ECOG E5194 Solin LJ, Gray R, Baehner FL, Butler S, Badve S, Yoshizawa C, Shak S, Hughes L, Sledge G, Davidson N, Perez EA, Ingle J, Sparano J, Wood W Eastern Cooperative Oncology Group (ECOG) North Central Cancer Treatment Group (NCCTG) Genomic Health, Inc (GHI) 2011 San Antonio Breast Cancer Symposium

DCIS Recurrence Score: Unanswered Questions

• Do patients in the low-risk group benefit from RT? Is it

predictive

as well as prognostic?

• Does it apply to the wider population of women with DCIS?

• Validation needed

Sentinel Node Biopsy in DCIS

• DCIS lacks the ability to metastasize.

• Rationale for axillary surgery is risk of unsampled invasive cancer.

• ~15% risk of invasion after core bx diagnosis of DCIS.

Risk of Axillary Recurrence in DCIS

NSABP B17: 7 of 623 pts with axillary recurrence 1 s/p axillary dissection 3 with invasive IBTR 3 of 620 with DCIS at 15 yrs NSABP B24: 6 of 1799 pts at 11.6 yrs 1 with undiagnosed microinvasion

Julian, Ann Surg Oncol 2006

Risk of Axillary Recurrence in DCIS Treatment years

Lumpectomy Only L+XRT B17 L+XRT B24 L+XRT+TAM

Julian, Ann Surg Oncol 2006 Rate/1000 pt

0.76

0.86

0.49

0.46

When Should Axillary Nodes Be Examined in DCIS?

• Microinvasive carcinoma Metastases in 3% - 20% of cases.

• DCIS treated by mastectomy.

Opportunity lost if invasion found.

• Done as a second procedure if invasion found after lumpectomy.

Prior biopsy does not interfere with mapping.

Benefit of Tamoxifen in ER + DCIS NSABP B24 n = 732

Any Breast Cancer Event Any Invasive Cancer Contralateral Cancer

HR

0.58

0.53

0.50

p-value

.0015

.005

.02

Allred DC, J Clin Oncol 2012;30:1268-73

Other Therapies in DCIS

• Exemestane MAP 3 — 112 of 4560 had DCIS HR 0.47 (95% CI, 0.27-0.79) No subset analysis • Data on other AIs coming from NSABP B35, IBIS II • Raloxifene Equivalent to tamoxifen in STAR overall, better side effect profile DCIS analysis RR 1.46 (95% CI, 0.90-2.41)

Goss PE, NEJM 2011;364:2381-91 Vogel VJ, JNCI Monogr 2010:181-6

Conclusions: Endocrine Rx

• Endocrine therapy is an option for women desiring to minimize future breast cancer events.

• Most favorable risk-benefit ratio is in premenopausal women with 2 breasts.