The Henry Moon Lecture Disclosures The Continuing Dilemma of • None Ductal Carcinoma in Situ Stuart J. Schnitt, M.D. Brigham and Women’s Hospital, Dana-Farber Cancer Institute, and Harvard Medical School Boston, MA DCIS Epidemiology • Heterogeneous group of lesions • Most cases today detected because of • Natural history poorly defined microcalcifications on screening (especially for small, mammogram mammographically-detected lesions) • Accounts for ~20% of breast “cancers” • Optimal treatment controversial • >50,000 new cases each year Page 1 1
Increased Detection of DCIS Due To Mammographic Screening How much of this Age-adjusted incidence of DCIS (red) and invasive breast cancer (blue) relative to number of diagnoses in 1977 (SEER) represents “over-diagnosis”? Punglia, 2013 Reservoir of DCIS in Reservoir of DCIS in General Population General Population • Autopsy studies • These studies undoubtedly underestimate – DCIS found in up to 14.7% of prevalence due to limited sampling women dying of other causes • True prevalence unknown (median 8.9%) • Reduction mammoplasty studies – DCIS found in up to 3% of patients Page 2 2
Natural History of DCIS Natural History of DCIS # Benign # with DCIS Age Histology Follow- Subsequent Bxs (# with (yrs) up Invasive ca Examined follow-up) • Not all DCIS will progress to Eusebi, 9,520 55 (55) 27-44 Comedo and 1-14 yrs 11 (20%) 1994 non-comedo invasive cancer Sanders, 11,760 45 (45) 33-74 Low grade 3-42 yrs 16 (36%) 2015 • Non-obligate precursor Rosen, >8,000 30 (15) Not Non-comedo 1-24 yrs 8 (53%) 1980 stated Collins, 1,877 13 (13) 41-63 Low, int. and 4-18 yrs OR 13.5 2005 high grades Classification of DCIS Classification of DCIS • In current practice, most often classified as • Low grade and high grade DCIS are low, intermediate or high grade (based on genetically distinct disorders nuclear grade) • Low: • 16q loss Low Intermediate High • High: • 11q, 14q, 8p, 13q losses • 17q, 8q, 5p gains • Low grade DCIS more closely related genetically to LCIS than to high grade DCIS Page 3 3
Classification of DCIS Molecular Subtypes in DCIS Using Surrogate IHC Markers* • Molecular subtypes identified in invasive NHS UNC CRN Manchester cancers also observed in DCIS (N=263) (N=229) (N=371) (N=314) Luminal A 64.4% 65.1% 74.7% 42.6% Luminal B 13.6% 10.0% 10.8% 28.0% HER2-E 14.0% 16.6% 10.0% 16.2% Basal-like/TN 8.0% 8.3% 4.6% 13.1% *Not all studies used same markers Treatment of DCIS Treatment Options Goals • Local eradication to prevent the • Mastectomy development of invasive breast cancer • Breast conserving surgery + (prophylactic) radiation therapy • Ensure sufficient treatment in women • Breast conserving surgery alone at high risk for recurrence/progression • Endocrine therapy • Avoid over-treatment in women at very low risk for recurrence/progression None offers a survival advantage over the others Page 4 4
Breast Conserving Treatment Mastectomy Role of Radiation Therapy • No randomized trials comparing • Addition of RT to breast conserving mastectomy to breast conserving surgery reduces risk of local recurrence by ~50% treatment • Cure rates approach 100% • Appropriate for patients with extensive disease or those who want to reduce their risk of recurrence to as close to zero as possible Oxford Overview Oxford Overview 2010 2010 Absolute reduction 15.2% Page 5 5
Breast Conserving Treatment Role of RT • Addition of RT to breast conserving What is an Adequate Margin surgery reduces risk of local recurrence by ~50% For Patients With DCIS Treated With Breast • 50% of recurrences are invasive Conserving Surgery and Radiation Therapy? Breast Conserving Treatment Role of Endocrine Therapy • Addition of tamoxifen to breast conserving surgery and RT reduces risk of local Ann Surg Oncol, 2016 recurrence by ~30% (NSABP B-24) – Tam benefit limited to women with ER+ DCIS (Allred, 2012) 2 mm • Anastrazole – Superior to tamoxifen, primarily in women <60 years of age (NSABP B-35) – No difference from tamoxifen (IBIS-II DCIS) Page 6 6
Breast Conserving Treatment The Continuing Dilemma • Only some patients with DCIS will • But, the addition of RT and even endocrine progress to invasive breast cancer therapy is likely over-treatment for some patients • After decades of research, we still not cannot reproducibly identify which patients are unlikely to progress and, in turn, which patients can be safely managed with excision alone or perhaps even no treatment beyond the diagnostic biopsy Combining Prognostic Risk Factors for Local Recurrence Factors to Assess Risk Treatment factors Clinical factors • Informally Extent of excision Young age Use of RT • USC/Van Nuys Prognostic Index Use of endocrine therapy Tumor factors • MSKCC Nomogram Larger size/extent • Clinical Risk Score High nuclear grade Comedo necrosis Volume of DCIS near margin Molecular subtype Positive/close margins Page 7 7
The USC/Van Nuys Prognostic Index The USC/Van Nuys Prognostic Index Silverstein, 2003 Silverstein, 2003 LR rates: 1% at 5yrs 3% at 10yrs SCORE 1 2 3 Size (mm) <15 16-40 >41 Margin (mm) >10 1-9 <1 Grade Non-high, Non-high, High no necrosis necrosis Age >60 40-60 <40 The USC/Van Nuys Prognostic Index Limitations JCO, 2010 • Retrospective study; arbitrary cut points • Total sequential embedding required to adequately assess size and margins • Interactions and relative importance of factors unknown • In practice, can only be applied in minority of cases (largely because of limitations in assessing size) Page 8 8
Observed vs. Nomogram Predicted 10-Year Probability of Local Recurrence in Community-Based Population 80 Breast Cancer Res Treat, 2018 70 • Data from 2762 women with DCIS in NCCN Observed 10-Year Probability of IBTR (%) database treated with breast conserving surgery 60 with negative margins used to develop risk score 50 – ER status 40 – Comedo necrosis 30 • DCIS pts treated with – Patient age BCT 1990-2001 20 • C-statistic 0.74 10 • 190 cases, 305 controls 0 0 10 20 30 40 50 60 70 80 Nomogram Predicted 10-Year Probability of IBTR (%) Collins, et al, Ann Surg Oncol 2015 Can patients with “low risk” Breast Cancer Res Treat, 2018 DCIS be safely treated with 91% surgical excision alone? 77% 49% Prospective Studies Page 9 9
JCO 2009 Breast Cancer Res Treat 2013 • Observational study with two arms: • 158 pts (1995-2002); median F/U 11 yrs – Low or intermediate grade, ≤2.5 cm (n=565) • DCIS <2.5 cm, predominant nuclear grade – High grade (NG3 + necrosis), <1cm (n=105) low or intermediate (median size: 8mm) • Minimum margin width 3mm • Margin width >1cm or re-excision without • Specimen totally, sequentially embedded residual DCIS (negative re-excisions in 78%) • Post-excision magnification mammogram negative • Accrual closed early due to high LR rate for microcalcifications • 10-year estimated cumulative LR rate 15.6% • Tamoxifen allowed (~30% in each group) ECOG E5194 ECOG E5194 Local Recurrence at 5, 10 and 12 years Local Recurrence at 5, 10 and 12 years 5 yrs 10 yrs 12 yrs 5 yrs 10 yrs 12 yrs Low/Intermediate grade 6% 12.5% 14.4% Low/Intermediate grade 6% 12.5% 14.4% High grade 15% 24.6% 24.6% High grade 15% 24.6% 24.6% Median size: 6mm (up to 2.5 cm allowed) Negative margin width >5mm: 70% (only 3mm required) Page 10 10
JCO, 2015 JCO, 2015 • Same entry criteria as low/intermediate grade arm of ECOG trial • Randomized to conservative surgery alone or with radiation • Whole breast irradiation without boost • Tamoxifen in 62% ASTRO 2018 ASTRO 2018 n LR at 7yrs LR at 12yrs n LR at 7yrs LR at 12yrs Inv. LR at 12yrs No RT 298 6.7% 11.4% No RT 298 6.7% 11.4% 5.8% RT 287 0.9% 2.8% RT 287 0.9% 2.8% 1.5% p-value <0.001 0.001 p-value <0.001 0.001 0.016 Page 11 11
Local Recurrence Rates in RTOG 9804 Prospective Studies of “Low Risk” Two Possible Conclusions DCIS Treated by Excision Alone • Even among patients with “low risk” Local Recurrence Rate DCIS, breast irradiation significantly reduces the risk of local recurrence 15.6% (10 yrs) Harvard • Among patients with “low risk” DCIS, the 12-yr rate of local recurrence is low, 14.4% (12 yrs) ECOG 5194 even without radiation (~1%/year) 11.4% (12yrs) RTOG 9804 Can patients with “low risk” DCIS be safely Can patients with “low risk” DCIS be safely treated with surgical excision alone? treated with surgical excision alone? The Bottom Line The Bottom Line • Views of what is an acceptably low local • Prospective studies have been unable to recurrence rate vary identify a subset of patients with “low risk DCIS” treated with surgical excision – RTOG 9804: Local recurrence rate in patients treated with excision alone (~1%/year) similar to risk of subsequent alone who have local recurrence rates of breast cancer for patients with LCIS <10% after long-term follow-up based on conventional clinical-pathologic criteria Page 12 12
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