18th Annual Perspectives in Breast Cancer Memorial Sloan-Kettering Cancer Center 1275 York Avenue, New York, NY 10065 18th Annual Perspectives in Breast Cancer New York, NY 18 August 2012 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.

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Clinical Outcomes NSM European Institute of Oncology 3/02-12/07 Median f/u: 50 months All patients received 16 Gy to NAC Invasive Cancer DCIS # Cases 772 162 5yr LR Breast 3.6% 4.9% NAC 0.8% 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 # Patients % Mammo Detected Boost Tamoxifen NSABP B17 813 80 No EORTC 10853 1002 71 UK/ANZ 1030 100 Yes Swedish 1046 78

Metaanalysis Trials of Excision ± RT in DCIS n = 3729 10 yr IBTR No RT RT p-value Total 28.1% 12.9% < .001 Invasive 15.4% 6.8% DCIS 14.9% 6.5% EBCTCG JNCI Monograph 2010;41:162

Metaanalysis Trials of Excision ± RT in DCIS 10 yr Survival Outcomes No RT RT p-value All deaths 8.2 8.4 > .1 Death w/o recurrence 5.7 5.4 Cardiac death 1.3 1.5 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 Low/Int Grade High Grade Number 579 101 Median Size 6mm 7mm Margin ≥ 1cm 46% 48% Margin ≥ 5mm 67% 75% TAM planned 31% Hughes L, J Clin Oncol 2009;27:5319

Intergroup Trial of Excision Alone Mean f/u 6.3 years High Grade Low Grade IBTR 5yr 15.3% 6.1% 7yr 18.0% (10.2-25.9) 10.5% (7.5-13.6) Contralateral 3.9% 3.7% 7.4% (1.4-13.5) 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 Intergroup Trial % Local Recurrence Margin Low Grade High Grade < 1cm 5.6 14.8 ≥ 1cm 6.7 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 RANDOMIZE Observation RT No Boost 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 RANDOMIZE Observation RT No Boost

Patient Characteristics: RTOG 9084 Observation RT Number 298 287 Median Age 58 Mammographic size < 1 cm 72.8% 72.1% Grade 1 44% 42.2% Margin 3-9 mm ≥ 10 mm Neg. re-excision 35.6% 16.1% 48.3% 36.2% 15.7% 48.1% Intent to use Tam Yes 69.5% 68.6% McCormick B, ASCO 2012

Local Failure Ipsilateral Breast 5-Years Rates: 3.2% 0.4%

Local Recurrence After Excision +/- RT in Good Prognosis DCIS 5 yr LR Excision Alone Excision + RT E5194 RTOG 9084 6.1% 3.2% 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 Rate/1000 pt Lumpectomy Only 0.76 L+XRT B17 0.86 L+XRT B24 0.49 L+XRT+TAM 0.46 Julian, Ann Surg Oncol 2006

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 HR p-value Any Breast Cancer Event 0.58 .0015 Any Invasive Cancer 0.53 .005 Contralateral Cancer 0.50 .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.