Ductal Carcinoma In Situ

Transcription

1 23 rd Annual Seminar in Pathology Ductal Carcinoma In Situ A.A. Sahin, M.D. Professor of Pathology and Translation Molecular Pathology Section Chief of Breast Pathology Outline Incidence and natural history of Morphologic features and differential diagnosis Treatment of based on biologic factors Ongoing clinical trials Outline Morphologic features of spindle cells lesions Differential diagnosis Case presentations 1

2 Ductal Carcinoma In Situ Incidence: 62,000 new cases US % screen detected carcinomas 20% of our practice Diagnosis and Management of Ductal Carcinoma in Situ Virnig BA, Shamliyan T, Tuttle TM, et al. 2009, Diagnosis and Management of Ductal Carcinoma in Situ Virnig BA, Shamliyan T, Tuttle TM, et al. 2009,

3 Diagnosis and Management of Ductal Carcinoma in Situ Virnig BA, Shamliyan T, Tuttle TM, et al. 2009, is Heterogeneous Diverse: Presentation Clinical Features Biology (Behavior) Risk of invasive cancer after biopsy alone N Ca % Farrow 1970 (25) 5 20 Haagensen 1971 (11) 8 73 Millis 1975 (8) 2 25 Rosen 1980 (15) 8 53 Eusebi 1994 (80) Page 1995 (28) 9 32 Mean = 28% 3

4 Natural history of low grade 28 patients with low grade identified from yrs follow up 11 (39%) invasive cancer 5 (18%) breast cancer deaths 4 of the 5 breast cancer deaths occurred within 15 years M Sanders D Page et al Cancer 2005 Nurses' Health Study Review of 1877 breast bx specimens 13 bx specimens with Received no treatment beyond the diagnostic bx Collins et al Cancer 2005;103: Nurses' Health Study Result: compared with nonproliferative lesions 13.5 OR for for development of invasive breast carcinoma (n=6) 20.1 OR for the development of any subsequent invasive or in situ breast ca event (n = 10) Collins et al Cancer 2005;103:

5 Nurses' Health Study 4 - low nuclear grade 6 - intermediate nuclear grade 3 - high nuclear grade 0 - comedo-type necrosis Invasive carcinomas developed among women with of all nuclear grades All 10 breast carcinoma events (100%) were in the ipsilateral breast Collins et al Cancer 2005;103: Nurses' Health Study Conclusion: These results provided further evidence that patients with who received no treatment beyond a diagnostic biopsy were at substantially increased risk for developing ipsilateral invasive breast carcinoma, and that the increased risk in this setting was seen in of low, intermediate, and high nuclear grades Collins et al Cancer 2005;103: Sequential and Parallel Models of Breast Carcinogenesis N P Inv Inv Alternative model N Inv P 5

6 Differential Diagnosis Atypical ductal hyperplasia Lobular carcinoma in situ Intravascular tumor Invasive ductal carcinoma ATYPICAL DUCTAL HYPERPLASIA Definition Intraductal epithelial proliferation with some, but not all features of low grade intraductal carcinoma ATYPICAL DUCTAL HYPERPLASIA Revised Definition Intraductal epithelial proliferation with cytologic features identical to low grade intraductal carcinoma but lacks architectural features or quantitatively too small 6

7 FEATURES OF Uniform population of cells Smooth geographic spaces with even cellular placement Hyperchromatic nuclei ATYPICAL DUCTAL HYPERPLASIA Cytologic Features Monotonous, uniform rounded population cell Organized nuclear distribution Subtle increase in N/C ratio ATYPICAL DUCTAL HYPERPLASIA 7

8 ATYPICAL DUCTAL HYPERPLASIA ATYPICAL DUCTAL HYPERPLASIA Epithelial Proliferation Incompletely involved the duct space Completely involved duct space is too small ATYPICAL DUCTAL HYPERPLASIA What is too small? 8

9 ATYPICAL DUCTAL HYPERPLASIA Quantitative Criteria Two membrane bound spaces 2 mm in aggregate cross-sectional diameter A D H 1mm 1mm D C I S 1mm 1mm 9

10 A D H vs D C I S 0.3 mm 0.3 mm 2mm 0.3 mm ATYPICAL DUCTAL HYPERPLASIA Definition Controversies Application of histologic criteria Clinical significance ATYPICAL DUCTAL HYPERPLASIA Clinically silent lesion Either mammographic finding or incidental finding in biopsies done for clinically evident lesions Median age: 50 yrs (range: 15-78) 10

11 ATYPICAL DUCTAL HYPERPLASIA Usually less than 3-4 mm Confined to an individual TDLU Commonly associated with microcalcifications ATYPICAL DUCTAL HYPERPLASIA Is ADH merely a small example of non-comedo? Is ADH a biologically distinct lesions? ATYPICAL DUCT HYPERPLASIA The definition includes: Cytologic features Histologic pattern Some indication of size (extent) 11

12 Atypical Ductal Hyperplasia vs Intraductal Carcinoma Benign vs Malignant Intraductal Epithelial Proliferations of Breast ADH vs low grade Are they distinct entities? 12

13 Yes Magnitude of risk varies Laterality of risk different Type of subsequent ca. histology different No Histologic criteria poorly defined difficult to have standard criteria Molecular/geneticfea tures are similar ADH vs ADH appears to be a neoplastic, clonal proliferation of cells identical to those of low grade Less completely developed Changing Views of AH AH are markers of generalized increase in risk and not precursor lesions Family history more than doubles breast cancer risk among women with AH Among women with AH, risk highest in first 10 years after bx. 13

14 A D H / D C I S A D H / D C I S 14

15 15

16 Classification of In situ Epithelial Proliferations the Breast Challenges: - Understanding molecular genetic pathogenesis - Identification of clinical relevance - Effective strategies for management - Development of reproducible criteria for classification Classification of In situ Epithelial Proliferations the Breast Hyperplastic Neoplastic Usual hyperplasia Malignant Benign carcinoma in situ adenoma / neoplasia /low grade Well-informed? Some forms of LCIS ADH / low grade? Lob Neoplasia? Columnar alteration Classification of In situ Epithelial Proliferations the Breast Allelic imbalance analysis suggests that low grade & high grade carcinomas follow different genetic pathways Roylance et al. J Pathol 2002; 196:

17 Genetic alterations LOH Studies UDH ADH Approx 10% (0-30%) usually one locus only Approx 50% Similar loci to low grade and similar Alterations found in subsequent inv ca of same breast 50 80% numerous sites (similar to inv ca) Hyperplasia Neoplasia CK 5, 6, ER Heterogeneous Homogeneous Bocker et al Virchow Arch A Pathol Anat & 323, 1992 Shoker et al J Pathol 188; 237, 1999 put on an excel spreadsheet 17

18 Breast Carcinogenesis Model Moulis & Sgroi, 2008 Low Grade Pathway?Common Precursor E Cadherin 16q LOH 16q Lobular Carcinoma Low Grade Carcinoma High Grade Pathway Her-2 and p53 17q High Grade Carcinoma 18

19 ER neg ER pos Sorlie, et al. PNAS 2001 The molecular diversity of invasive breast cancers is also seen in Vincent-Salomon et al. Clin Cancer Res 2008 Molecular Features of Gene expression patterns in & invasive & metastatic tumors with serial analysis of gene expression (SAGE) (8 cases grouped) 16,430 transcripts analyzed mrna ISH to examine gene expression (18 tumors) & IHC on TMAs (769 cases) No universal "in situ" or "invasive" signature Porter D. Mol Cancer Res 2003;1:362 19

20 Heterogeneity Morphologic and biologic diversity has important implications with regard to mammographic evaluation, distribution in the breast and patient management Clinical Behavior Clinical Factors Young age Genetic background Tumor Factors Size/extent of lesion Nuclear grade/necrosis Volume of at margin Treatment Factors Extent of excision Use of XRT Use of hormonal therapy D C I S Determination of Size Frequently underestimated Accurate assessment requires careful evaluation of specimens by multidisciplinary approach 20

21 D C I S 50 yr old presented with suspicious microcalcifications on a screening mammogram She underwent a core biopsy showing and had segmental mastectomy D C I S Pathology Report Gross: 5 X 4 X 3 cm specimen is cross sectioned and representative sections are submitted in 20 cassettes Final: measuring 0.8 cm Margins free, closest margin 1.0 cm Previous biopsy changes D C I S 21

22 XX XX measures 0.8 cm and is 1.0 cm from the nearest margin

23 measures 5 cm and extends to multiple surgical margins R Breast Biopsy superior lateral 23

24 Segmental Resection R Breast Biopsy 24

25 Segmental Resection

26 B23 B22 B18 B19 B20 B X 10 4 X 11 5 X 12 6 X X X X 26

27 S L X M D X X X X Sup / inf = 3 x 5 = 15 mm Med / lat = = 12 mm X Sup / deep = 5 mm X I B23 B18 B22 B19 B20 B21 B18 B19 B20 B21 B22 B23 When is it appropriate to obtain specimen x-ray? 27

28 Whenever preoperative mammographic findings suggest that extent of the disease may not be appreciated by gross evaluation 28

29 Clinically relevant Reproducibly applicable by different observers 2012 Consensus Conference of the Classification of Histologic grading should include: nuclear grade architectural pattern presence of necrosis 29

30 Heterogeneity LG IG HG ER/PR Her2/neu p53 Proliferation Number of changes Ploidy Recurrent changes Amplifications Molecular subtype Low low near diploid 1q+, 16q- No; 8p11.2-p12 (rare) Luminal A > B +/- -/+ -/+ Variable intermediate aneuploid (50%) 1q+, 8p-, 11q-, 16q-, 8p11.2-p12, 11q13 Luminal A, B -/+ +/- +/- High High frequently aneuploid 1q+, 3q+, 17q+, 8q+, 5q-, 11q-, 14q-, 8p-, 13q- 17q12, 6q22, 8q22,11q13, 20q13 Luminal B, Her2, Basal Margin Status Most important factor in successful treatment Negative Positive? 30

31 Margin Status Positive Margin extends inked surface of tissue section Margin Status Negative Margin does not extend to inked surface 31

32 32

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34 Margin Evaluation Residual disease with < 1 mm clearance For 50 % For inv. ca 5-20 % Time trends of treatment and survival among Ductal Carcinoma in Situ Mathias Worni et al. JNCI J Natl Cancer Inst 2015;107:djv263 Total Mastectomy for N Recurrenc e Follow-up (yrs) Farrow et al Sunshine et al >10 Schuh et al Fisher et al Arneson et al Silverstein et al

35 Grade of Invasive Ca Developing within Histological grade of invasive ca grade I II III Total Low 13 81% Intermediate 22 24% High 3 1% % % 6% 90 42% % 318 Cadman et al. The Breast (1997) 6, ; Olubunmi et al (1994) Seminar in Diag Path 11, % Local Recurrence after WLE alone N All Invasive NSABP EORTC Milan Florence Manchester Edinburgh Nottingham Philadelphia Mean = Van Nuys Prognostic Index Score Size <16mm 16-40mm >40mm Margin width >9mm 1-9mm <1mm Pathology Not high Not high High No necrosis +/- Necrosis Necrosis Age >60yr 40-60yr <40yr Van Nuys Score yr LR free 96% 73% 37% 35

36 NSABP B - 24 Lumpectomy/XRT +/- Tamoxifen 1804 women randomized Tamoxifen vs. Placebo Ipsilateral cancer events were evaluated NSABP B 24 Tamoxifen reduced the risk of developing subsequent events (invasive carcinoma or ) 37% reduction in the event incidence ER status was determined retrospectively in 628 patients 77% (428 tumors) were ER positive 36

37 IBCR ER+ ER- 7% 17% P = <001 37

38 Breast Cancer Develops Over Time Breast cancer cells progress through changes over a period of years Normal Duct Ductal Hyperplasia Ductal Hyperplasia with Atypia Ductal Carcinoma In situ Invasive Ductal Carcinoma Reversible with Tamoxifen Reversible? Endocrine Therapy for NSABP B-24 All patients: Lumpectomy + XRT 1804 women randomized: Tamoxifen vs. Placebo Breast cancer events (Ipsilateral, Contralateral,, invasive) 38

39 NSABP B-24 (UPDATED 12 year follow up) Ipsilateral Breast Events Placebo Tamoxifen p 7.6% 6.7% NS Invasive Cancer 9% 6.6% <0.05 Contralateral Breast Events Placebo Tamoxifen p 8.1% 4.9% < % 3.2% JNCI Monograph, 2010 NSABP B-24 Stratification Based on ER Status ER determined in 732 cases Median f/u 14.5 years No benefit in ER negative HR 0.49 for all breast cancer events among ER+ 10-year IBTR ER negative = 20% ER+ placebo= 16% ER+ tam= 10% Allred et al, JCO, 2012 UCSF Preoperative Endocrine Treatment for ER-positive N= 62 3-month Letrozole 2.5 mg PO QD Tamoxifen 20 mg PO QD Exclusion criteria: palpable disease microinvasion not visible on MRI MMG MRI core bx MMG MRI Surgery Chen et al, BMC Cancer,

40 Baseline Baseline Treated Treated Baseline Baseline Treated Treated 04/04/2016 Alteration of biomarker expression is associated with endocrine treatment for baseline Ki67 CD68 treated Chen et al, BMC Cancer, 2009 Biomarker changes associated with endocrine treatment Ki67, premenopausal Ki67, postmenopausal p=0.04 p= CD68, premenopausal CD68, postmenopausal p=0.002 p=0.001 Chen et al, BMC Cancer, 2009 Three-Month Pre-op Endocrine Therapy in Preoperative endocrine therapy of ERpositive Safe Histologic and radiologic changes are evident No long term data on efficacy and the question remains in what proportion of women might this therapy actually prevent the occurrence of invasive breast cancer 40

41 HER-2/Neu Gene Amplification in High grade- 56% Low grade- 19% This also parallels IDC with Hoque et al, Cancer Epi & Prev 2002 Trastuzumab for Treatment of? HER2 3+ Kuerer et al. CANCER, 2011 Can we selectively eradicate or prevent HER-2 + invasive breast cancer? ER Neg HER2 + Trastuzumab ER Neg HER2 + Invasive 41

42 MDACC Preoperative Trastuzumab Schema for C O N S E N T by Core Biopsy Her 2 + Blood Ki67 ccaspase-3 Trastuzumab 8 mg/kg X One-dose SURGERY at 3 weeks Segmental or Mastectomy Ki67 ccaspase-3 Pathologic & Immune Response Trastuzumab for Trial Clinical Pathologic Factors Median age: 53 yrs Mean Mammographic Size: 5.1 cm Overall ER+: 80% Overall HER2+: 35% Total eligible: 24 patients HER2 Pos 12 patient samples not receiving drug used as control experiments Trastuzumab for Trial HER2 Correlated With Grade Grade Total Percent Percent HER2+ I 6% 0% II 38% 27% III 56% 44% 42

43 % CD107a+ among CD56+ NK cells 04/04/2016 Trastuzumab for Trial Relationship ER and HER2 ER Status Number (Percent) Percent HER2+ Positive 54 (81%) 28% Negative 13 (19%) 62% Immune Response Studies Patient s PBMC and Serum obtained Before and after Trastuzumab therapy Evaluated for ADCC Development of HER2 Specific CD4 response Proliferation and Apoptotic Markers Ki67 and Cleaved Caspace-3 Patient s NK Cells Actively Kill HER2 Target Cells CD107a Assay with autologous serum P = Pre-Herceptin Post-Herceptin HD001 HD002 HD003 HD004 HD005 HD006 HD007 HD008 HD010 HD011 HD012 Patient s CD56+ NK cells are functional in presence of HER2+ target cells and trastuzumab CD107a+= degranulating NK cells 43

44 Trastuzumab for Trastuzumab can induce specific immunity in pts w HER2+ after 3 weeks of treatment Future studies- PRE-surgical What kind of histologic response should we be looking for? Which biomarkers to measure? Pre-Cancer But Treated Like Cancer is a marker for development of invasive breast cancer Diagnosis and treatment critical Rule out concurrent presence of invasive carcinoma (11-25%) Prevent development of invasive ca Much like LCIS or ADH NIH Recommendations Develop risk-stratification models to identify subsets of women who have who are candidates for: active surveillance only local excision only local excision with radiotherapy Mastectomy 44

45 Treatment of = Prevention of Invasive Cancer Which patients will go on to develop invasive disease? Addressing overtreatment of Screen detected ; the LORIS Trial Francis, A. et al European Journal of Cancer 51 (2015) LORIS Trial in UK 2014 Watch and Wait: Active Surveillance Screen detected low/intermediate grade, > 46 years Randomize surgery versus no surgery Non-inferiority trial 932 patients Primary endpoint: invasive disease at 5 year Secondary: Mastectomy rate, quality of life, biomarkers 45

46 registration 04/04/2016 NEW Trial Alliance-CALGB 40903: Phase II Single-Arm Study of Neoadjuvant letrozole for ER(+) postmenopausal 3 months Letrozole stable or responding 3 months Letrozole progression MMG MRI core bx MRI Clinical exam 8/1/14: 54 MMG MRI Surgery Measure change Ki67, Imagingpath correlation PI: Shelley Hwang N=96 LAPIS Trial (LAPatinib for In Situ Breast Cancer) PI: Powel Brown Endpoints Women with on BX Pre- or post Menopausal R A N D O M I Z E EGFR+ or Her2+ Tissue used for marker analysis ( Pre-treatment ) Lapatinib (1000mg) (N=30) Placebo (N=30) 2-6 weeks S U R G E R Y Tissue used for marker analysis ( Post-treatment ) Primary: 1. Proliferation (Ki67 IHC) in 2. Toxicity Secondary: 1. Incidence on excision 2. Modulation of tissue markers Being conducted at BCM, DFCI, WRAMC, Georgetown University, M.D. Anderson, Mayo Clinic Supported by the SPORE Grant and a grant from the Breast Cancer Research Foundation Rationale for using Trastuzumab in combination w/ RT in Trastuzumab is a radiosensitizer in HER2 overexpressing cancer cells Trastuzumab does not radiosensitize cells which do not overexpress HER2 46

47 Summary & Conclusions Preoperative therapy paradigm has moved into May allow for more rapid identification of useful alternative pharmacologic interventions Sets stage for potential for observation in select patients without further local therapy The Oncotype DX Breast Cancer Assay for Report: A Tool for Shared Treatment Decisions Score Result: Gene Selection Proliferation Ki-67 STK15 Survivin Cyclin B1 MYBL2 Hormone Receptor Group PR GSTM1 Reference Beta-actin GAPDH RPLPO GUS TFRC The Score result: Is a continuous variable Is a quantitative risk assessment (number between 0 100) Reflects each individual patient s tumor biology Solin et al. J Natl. Cancer Inst

48 Score Result: 10-Year Local Recurrence by Risk Group in E5194 Any Local Recurrence Invasive Local Recurrence The ECOG 5194 study validated the Score result as a predictor of any LR or an invasive LR The Score result provides greater visibility into the risk of LR based on the underlying tumor biology and separates patients with a lower risk from patients with a higher risk of LR Solin et al. J Natl Cancer Inst Score Result: 10-Year Local Recurrence in E5194 Any Local Recurrence Invasive Local Recurrence The ECOG E5194 study validated the Score result as a predictor of LR (increasing Score corresponds to increasing risk) Any or invasive LR An invasive LR Solin et al. J Natl Cancer Inst Score Result: 10-Year Invasive or Local Recurrence by Risk Group in the Ontario Provincial Cohort Local Recurrence Invasive Local Recurrence As in the E5194 study, this study showed that the Score result stratifies patients for risk of an invasive LR Further, the Score result was able to stratify patients for risk of a LR Rakovitch et al. SABCS

49 Summary: Novel clinical trial designs New emerging targets for Multigene RTPCR Biologic Assays may be ideal opportunity to study promising agents for prevention VISION: Selective approach for surgery and radiation 49