Disclosures. Premalignant Lesions of the Breast: What Clinicians Want and Why. NY Times: Prone to Error: Earliest Steps to Find Cancer.

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1 Disclosures Premalignant Lesions of the Breast: What Clinicians Want and Why I have nothing to disclose Rick Baehner, MD Assistant Professor, UCSF Pathology NY Times: Prone to Error: Earliest Steps to Find Cancer 3 Agenda Discussion of clinical significance of premalignant lesions of the breast focusing on: atypical ductal hyperplasia and ductal carcinoma in situ The important prognostic factors in ductal carcinoma in situ Discussion of Oxford overview of DCIS trials: what does this data tell us about the standard clinical and pathologic covariates? The importance of predictive factors, i.e., estrogen receptor testing in DCIS 4 Now she was being told the pathologist had made a mistake. Her new doctor was certain she never had the disease, called ductal carcinoma in situ, or D.C.I.S. It had all been unnecessary the surgery, the radiation, the drugs and, worst of all, the fear 1

2 5 6 Introduction: DCIS Has Increased Markedly Since the Advent of Mammographic Screening What Clinicians Need to Know Incidence rate (per,) Figure 2. SEER9 Age-adjusted incidence rate of breast cancer by stage (1973-5) Localized Regional In Situ Metastatic Year of diagnosis In situ Rate Localized Rate Regional Rate Distant Rate Following Biopsy: Is it cancer or not (UDH, ALH, LCIS, ADH, DCIS, IBC)? Do they need to excise the area? What is the appropriate surgery (size; margin control)? Lumpectomy Mastectomy Following Excision: Is additional surgery required? What is the likelihood of local regional recurrence? Do they need to do radiation therapy? Do they need to offer tamoxifen? Courtesy of Dr. Laura Esserman 7 8 NCCN Guidelines Case Presentation #1 A 58 y/o post-menopausal woman has an abnormal screening mammogram with prior normal annual screening mammograms in the past Diagnostic mammogram shows fine calcifications in a segmental distribution, BIRADS 4 She had no palpable masses or lymph adenopathy on exam No family history of breast cancer 2

3 9 BIRADS Categories Breast Imaging Reporting and Data System: A tool to standardize mammography reporting and facilitate outcome monitoring : Needs additional imaging (diagnostic mammogram or prior mammograms) 1: Negative 2: Benign 3: Probably benign (2% malignant); short interval follow up recommended 4: Suspicious abnormality; should consider biopsy 5: Highly suggestive of malignancy (95% malignant); appropriate action should be taken 6: Known malignancy Stereotactic core biopsy showed: Adv Anat Pathol. 3 May;(3): Adv Anat Pathol. 3 May;(3):

4 13 14 Adv Anat Pathol. 3 May;(3): Differential Diagnosis & Recommendation Is the H&E sufficient for diagnosis? UDH, CCH, FEA ADH, CCH, FEA DCIS, CCH, FEA Are there other studies that might be useful? Level H&E sections IHC: basal/luminal cytokeratins Clinical recommendation? 4

5 Guidelines for Evaluation of Proliferative Ductal Pattern Lesions Usual Ductal Hyperplasia Florid hyperplasia without atypia has swirling streaming patterns of cells. There is irregularity of nuclear shape, chromasia, and position, and there are irregular, often ragged, serpigninous slit-like secondary spaces, most marked centrally. Intercellular borders are usually ill defined. 17 Usual Ductal Hyperplasia 18 Human Pathol 1992;23():95-97 Guidelines for Evaluation of Proliferative Ductal Pattern Lesions Ductal Carcinoma In Situ Population of evenly spaced, uniform cells with uniformly oval to rounded nuclear features, comprising without doubt the entire population throughout two membranebound spaces. Cytoplasm is pale and intracellular borders are usually distinct. 2 nd spaces have smooth, rounded punched-out borders (cribriform architecture and rigid, nontapering bars can be found. An overall size criterion is a useful adjunct. 19 Human Pathol 1992;23():

6 Guidelines for Evaluation of Proliferative Ductal Pattern Lesions Atypical Ductal Hyperplasia Exhibits partial involvement of the basement membrane-bound space by a cell population of the type defined for DCIS, noncomedo type. The nonatypical cell population consists of columnar, polarized cells of the type usually seen in the ductal lamina positions immediately above the basement membrane. The bothersome cells need to constitute an entire bar crossing a space or at least a cell population of six or seven cells across When in doubt between ADH and DCIS use the more benign designation Human Pathol 1992;23(): Sent out ductal and 7 lobular borderline lesions There was not a single case in which all pathologists agreed 6 cases that ranged the gamut of hyperplasia to CIS Significant bias of pathologists: benign or malignant Rosai J. Am J Surg Pathol Mar;15(3):9-21. Teaching set 15 slides, written set of definitions, illustrations Complete agreement among all 6 observers 14/24; >5 observers same dx in 17/24; >4 observers same dx in 22/24 (92%) Agreement between diagnoses of 5 pathologists with Dr. Page: 92%, 88%, 79%, 71%, 88% Schnitt SJ, Connolly JL, Tavassoli FA, Fechner RE, Kempson RL, GelmanR, Page DL. Am J Surg Pathol Dec;16(12):

7 Characterization of Breast Cells Distinction of ADH 25. N Engl J Med 1985;312: Numerous studies have shown the proliferating epithelium of UDH in fibrocystic change will react with both basal (CK 5, 5/6, 14, 17) and luminal type (CK 18, 19) cytokeratins Low grade DCIS are usually negative for basal cytokeratins and positive for luminal type cytokeratins (CK 18, 19) CK 5/6 CK 18 CK 19 Jarasch ED. Hum Pathol Mar;19(3): Otterbach F. Histopathology. Sep;37(3):232- Moinfar F. Am J Surg Pathol Sep;23(9): , 9 individuals 2,942 women with atypical breast lesions Mean Age Dx: 53 years (range: 19-93) Mean FU all: 66 months 7

8 29 Case Presentation #1 Conclusions Patients with ADH are at greater risk of local regional recurrence when compared to UDH patients Distinction of ADH from UDH and DCIS is a clinically significant distinction Use of clinically validated criteria for distinction of UDH, ADH and DCIS are warranted When in doubt between ADH and DCIS use the more benign designation Case Presentation #2 A y/o peri-menopausal woman has an abnormal screening mammogram Diagnostic mammogram shows coarse pleomorphic calcifications in a segmental distribution, BIRADS 5 She had slight palpable mass but no adenopathy on exam She has no family history of breast cancer 8

9 Differential Diagnosis & Recommendation Diagnostic markers DCIS Invasive ductal carcinoma Prognostic markers Tumor size, margins, nuclear grade, comedo necrosis, histologic subtype Predictive markers ER/PR Recommendations 9

10 17:41:28 9 Sep 9 Provisional results: subject to revision (Name: gr_cis_sc_rt_rlili_all_) 17:42:3 9 Sep 9 Provisional results: subject to revision (Name: gr_cis_sc_rt_rlilii_all_) 17:42:38 9 Sep 9 Provisional results: subject to revision (Name: gr_cis_sc_rt_rllic_all_) (Name: gr_cis_sc_rt_bcdth_all_) (Name: gr_cis_sc_rt_dead_all_) (Name: gr_cis_sc_rt_heart_all_) Oxford Overview of Randomized Trials of BCS±RT for DCIS Oxford Overview of Randomized Trials of BCS±RT for DCIS Ips. BREAST RECURRENCE (CIS & Inv) (%) DCIS: BCS + RT vs. BCS Ips. BREAST RECURRENCE (CIS & Inv) 3723 women 5-year gain.5 % (SE 1.2) -year gain 15.2 % (SE 1.6) logrank 2p < BCS 28.1% BCS+RT 12.9% 5 15 Years since randomisation Ips. BREAST RECURRENCE (Inv only) (%) DCIS: BCS + RT vs. BCS Ips. BREAST RECURRENCE (Inv only) 3723 women 5-year gain 5.4 % (SE.8) -year gain 8.5 % (SE 1.3) logrank 2p < BCS 15.4% BCS+RT 6.8% 5 15 Years since randomisation Ips. BREAST RECURRENCE (CIS only) (%) DCIS: BCS + RT vs. BCS Ips. BREAST RECURRENCE (CIS only) 3723 women 5-year gain 5.8 % (SE.9) -year gain 8.4 % (SE 1.2) logrank 2p < BCS 14.9% BCS+RT 6.5% 5 15 Years since randomisation BREAST CANCER MORTALITY (%) DCIS: BCS + RT vs. BCS BREAST CANCER MORTALITY 3726 women 5-year loss.4 % (SE.4) -year loss.5 % (SE.8) logrank 2p >.1; NS :46:8 9 Sep 9 Provisional results: subject to revision BCS+RT 4.1% BCS 3.7% 5 15 Years since randomisation ANY DEATH (%) 3726 women DCIS: BCS + RT vs. BCS ANY DEATH 5-year loss.1 % (SE.6) -year loss.2 % (SE 1.1) logrank 2p >.1; NS BCS+RT 8.4% 2.8 BCS 8.2% Years since randomisation 17:46:47 9 Sep 9 Provisional results: subject to revision HEART DISEASE MORTALITY (%) DCIS: BCS + RT vs. BCS HEART DISEASE MORTALITY 3723 women 5-year gain.1 % (SE.3) -year loss.1 % (SE.5) logrank 2p >.1; NS.6 BCS+RT 1.5% BCS % 15 Years since randomisation 17:49:38 9 Sep 9 Provisional results: subject to revision 4 Landmark DCIS Trials: B17, EORTC 853, SweDCIS, DCIS UK J Natl Cancer Inst Monogr. ;(41): Review. 4 Landmark DCIS Trials: B17, EORTC 853, SweDCIS, DCIS UK J Natl Cancer Inst Monogr. ;(41): Review. 39 Prognosis: DCIS & Tumor Size Histologic Grade: EORTC 853 Of the 4 landmark DCIS trials of local excision (LE) versus LE + radiotherapy two reported histologic grade to be associated with the risk of local regional recurrence Br J Cancer. Jun 29;3(1):94-. Epub Jun 1. J Clin Oncol. 1 Apr 15;19(8): J Clin Oncol. 6 Jul ;24(21): Epub 6 Jun 26.

11 Oxford Overview of Randomized Trials of BCS±RT for DCIS Patient Subset Identified A Priori As Potentially At Low Risk: Low Nuclear Grade, Negative Margins, Path Tumor Size < mm ECOG 5194: Histologic Grade local excision (LE) alone 42 Low & Intermediate Grade < 2.5 cm in greatest dimension High Grade < 1. cm in greatest dimension Presented NIH DCIS Conference, 9 Darby, JNCI Monograph, J Clin Oncol. 9 Nov ;27(32): Epub 9 Oct 13. College of American Pathologists DCIS Nuclear Grading System 43 Comedo Necrosis NSABP B17: local excision (LE) versus LE + radiotherapy 44 Grade 1 Grade 3 Grade 2 NSABP definition: Absent % Slight <% Moderate /Marked % Patients with Moderate /Marked % had 2-fold higher risk or LRR 1-Arch Pathol Lab Med Vol 133, January 9 Cancer Aug 1;86(3):

12 45 46 J Natl Cancer Inst Monogr. ;(41): Review. Margin Status Women for whom the surgical margins were close (<2 mm) were classified as having negative surgical margins. Tamoxifen NSABP B-24 Established benefit of tamoxifen in DCIS treated with lumpectomy and radiation Demonstrated a small but significant reduction of local invasive recurrence as well as contralateral breast cancer when used for 5 years. 8.2% in tamoxifen group versus 13.4% in placebo Tamoxifen resulted in absolute 5 year lowering of ipsilateral events by 3.3% and contralateral events by 1.4% Study initiated before clear relationship established between ER/PR+ disease and effectiveness of hormone therapy Fisher B, et al. Lancet 1999; 353: NSAPB B-17 AND B-24 All IBTR Invasive IBTR 47 Proportion Disease-Free TIME TO FIRST BREAST CANCER EVENT IN NSABP B ER-pos tamoxifen (n=264) ER-pos placebo (n=257) ER-neg tamoxifen (n=87) ER-neg placebo (n=66) Wapnir, ASCO, 7 Years Since Surgery Recommend use of ASCO/CAP cutoffs for DCIS ER assessment Courtesy of L Solin Allred, San Antonio, 2 J Clin Oncol. 12 Apr ;(12): Epub 12 Mar 5. 12

13 Case Presentation #2 Conclusions 49 Summary DCIS Most consistent prognostic variable is DCIS tumor size however nuclear grade and percentage of comedo necrosis should be carefully documented using CAP guidelines Margins 2. mm have significantly lower risk of local regional recurrence ER status is important for identification of patients who will benefit from hormonal therapy with reduced local regional recurrence risk Careful distinction between UDH, ADH and low grade DCIS is critical in patient management as ADH differs in clinical outcome and is often is managed surgically whereas DCIS is often is managed with radiotherapy Prognostic factors including: patient age, tumor size, comedo necrosis, nuclear grade and margin status are the most important prognostic covariates and need to be carefully assessed using current guidelines Assessment of ER has been shown in DCIS to be associated with both ipsilateral and contralateral recurrence risk reduction 51 Thank you 13