Updates on Breast Diseases: What clinicians need to know from pathologists

Updates on Breast Diseases:What clinicians need to know from pathologists Preah Bat Norodom Sihanouk Hopsital, 22 April 2009 Monirath Hav, MD, Ph.D. fellow (VLIR project) Pathology Department, Ghent University Hospital Ghent University, Belgium

Benign breast lesions Richard J et al. The New England Journal of Medicine. Volume 353:275-285 (July 2005)

Benign breast lesions: standard pathology report 1. Histologic type + type of proliferation 2. Maximum diameter 3. Nuclear grade (for DCIS only) 4. Resection margin (for DCIS & pleomorphic LCIS only) 5. Presence/absence of micro-invasion (for DCIS only) 6. Areas of involvement (unifocal, multifocal, multicentric)

VAN NUYS Prognostic Index for the management of DCIS • Size (measured on histology exam) • Score 1: size < or = 1.5 cm • Score 2: size 1.6 – 4 cm • Score 3: size > or = 4.1 cm • Age of patient • Score 1: > 60 y.o • Score 2: 40 – 60 y.o • Score 3: < 40 y.o • Nuclear grade • Score 1: DCIS nuclear grade 1 • Score 2: DCIS nuclear grade 2 • Score 3: DCIS nuclear grade 3 • Management • Score 4 – 6 : lumpectomy • Score 7 – 9 : lumpectomy + radiation Th. • Score 10 – 12 : mastectomy • Surgical margin • Score 1: tumor-free margin < or = 1 cm • Score 2: tumor-free margin 0.1 – 0.9 cm • Score 3: tumor-free margin < 0.1 cm Silverstein MJ, Lagios MD, Craig PH, et al. Cancer 77(11): 2267-2274, 1996

Malignant lesions

Malignant lesions • Secretory/Juvenile carcinoma (<0.15%) • Tubular carcinoma (<2%)- so low recurrence that some centers consider adjuvant th. unnecessary. • Invasive cribriform carcinoma (0.8-3.5%) • Metaplastic carcinoma (<1%) • Invasive papillary carcinoma (1-2%) • Mucinous carcinoma (~2%) • Neuroendocrine carcinoma (2-5%) • Medullary carcinoma (1-7%) • Invasive lobular carcinoma (5-15%) • Invasive ductal carcinoma (75%)

Invasive carcinoma – standard pathology report

1. Histologic type 2. Histologic grade (Bloom-Richardson) 3. TNM (size, node, distant metastasis) 4. Ki-67 index 5. Lympho-vascular invasion 6. Necrosis 7. Tumour border 8. Status of resection margins 9. ER, PR, HER2/neu status 10. In situ components, if present

Histologic type: different prognosis Darius Dian et al . Arch Gynecol Obstet (2009) 279:23–28

Histologic type Gives pathologists and clinicians the ideas of: 1. Tumour’s aggressiveness 2. Patients’ overall prognosis 3. Tumour’s origin (i.e. basal-like + family history of breast CA  highly suggestive for hereditary origin of BRCA1 mutation*) 4. Response to chemotherapy (i.e. basal-like 45% pCR after neoadjuvant therapy using anthracycline and taxane**) *Turner NC & Reis-Filho JS (2006). Oncogene 25:5846–5853 * *Rouzier R et al. (2005). Clin Cancer Res 11:5678–585

Basal-like?

Features of basal-like breast CA Histology: • Solid growth pattern • High nuclear grade • < 5% DCIS • Lympho-vascular invasion • Central scar • Pushing border • Marked lymphocytic infiltrates Immunohistochemical profile: CK5 + or CK14 + or CK17 + or EGFR + Mamatha Chivukula Appl Immunohistochem Mol Morphol Volume 16, Number 5, October 2008

Modifed Bloom-Richardson grade

Ki-67 index • Ki-67  recurrence rate ; overall survival (1) • Ki-67 < 10%  no benefit from chemotherapy (2) • Ki-67 > 25%  sensitive to chemotherapy (2) • Ki-67 between 10 to 25%?  other factors (Bloom-richardson grade, TNM stage, resection margin etc) (2) (1)E de Azambuja et al. British Journal of Cancer (2007) 96, 1504-1513 (2)Frédérique Spyratos et al. Cancer 2002 Apr 15;94(8):2151-9

Sebastian F et al. Ann Surg. 2004 August; 240(2): 306–312.

How about peri-neural invasion? Present in ~10% of high-grade tumours No study has yet proven its independent prognostic significance

Prognostic value of Tumor necrosis & Tumor border Carter D et al. Am J Surg Pathol 1978;2:39–46

Survival analysis: DCIS in invasive breast CA Rosemary R. Millis et al. Breast Cancer Research and Treatment 84: 197–198, 2004.

Estogen receptor HER2/neu 1. Histologic type 2. Histologic grade (Bloom-Richardson) 3. TNM (size, node, distant metastasis) 4. Ki-67 index 5. Lympho-vascular invasion 6. Necrosis 7. Tumour border 8. Status of resection margins 9. ER, PR, HER2/neu status 10. In situ components, if present

Overview on ER, PR, HER2 status in breast cancer HER2/neu  overexpressed in 25 – 30%

ER, PR, HER2 status (con’t) Molecular sub-types of breast CA: • Luminal A (ER/PR +, HER2 -) • Luminal B (ER/PR +, HER2 +) • HER2 sub-type (ER/PR -, HER2 +) • Basal-like (ER -, PR -, HER2 -) Perou CM, Sorlie T, Eisen MB et al (2000). Nature 406:747–752

Prognosis of each sub-type of breast CA Hiroo Nakajima et al. World J Surg (2008) 32:2477–2482

ER, PR, HER2 status (con’t) Therapeutic implication : • Luminal A (ER/PR +, HER2 -)  Hormonal therapy • Luminal B (ER/PR +, HER2 +)  Hormonal therapy? + anti-HER2 • HER2 sub-type (ER/PR -, HER2 +)  anti-HER2 • Basal-like (ER -, PR -, HER2 -)  No benefit from either therapy

“Quickscore” for ER-PR IHC Staining intensity - Negative (no staining of any nuclei at high magnification)= 0 - Weak (only visible at high magnification) = 1 - Moderate (readily visible at low magnification) = 2 - Strong (strikingly positive at low magnification) = 3 Quickscore: 0  8 Proportion of positive cells (nuclei) - 0% = 0 - <1% = 1 - 1–10% = 2 - 11–33% = 3 - 34–66% = 4 - 67–100% = 5

Quickscore : What should be the cut off? Harvey JM et al. J Clin Oncol. 1999 May;17(5):1474-81.

Quickscore in ER, PR IHC • Score 0 : no response to endocrine treatment • Score 2 - 3 : 20% response to endocrine treatment • Score 4 - 6 : 50% response to endocrine treatment • Score 7 - 8 : 75% response to endocrine treatment

But many labs use the 10% cut off rule!

HER2/neu Immunohistochemistry

What is known about HER2 and response to Trastuzumab? Guido Sauter et al J Clin Oncol 29. 2009 by American Society of Clinical Oncology

HER2 gene amplication detected by In Situ Hybridization is superior to HER2 protein overexpression detected by IHC in predicting Response to Trastuzumab. Mass R et al. Clinical Breast Cancer 6:240-246, 2005

Does HER2 overexpression defined by IHC predict response to Trastuzumab? YES! If not false-positive Inexperience interpreter Poor fixation Artifact Antigen retrieval techniques

FISH result IHC score 0 1+ 2+ 3+ Total Amplified 4.5% 3.27% 8.6% 83.6% 244 cases Not amplified 49.5% 23.74% 17.22% 9.53% 598 cases Correlation between HER2 FISH and IHC Guido Sauter et al J Clin Oncol 29. 2009 by American Society of Clinical Oncology

How about HER2 status and response to Tamoxifen?

HER2 overexpression is correlated with resistance to Tamoxifen in metastastic breast cancers De Laurentiis M et al. Clin Cancer Res. 2005 Jul 1;11(13):4741-8 ER, PR IHC tests are no longer important in metastatic setting

Does HER2 overexpression predict resistance to Tamoxifen in early breast cancers? Controversial studies: no conclusion yet

Should we trust all these studies? Should we trust all these studies? Why don’t we conduct studies on our own population?

Standard pathology report for benign breast lesions: • Histologic type of lesion + type of proliferation • Diameter • Areas of involvement (unifocal, multifocal, multicentric) • Nuclear grade and growth pattern (for carcinoma in situ) • Presence/absence of micro-invasion (for carcinoma in situ) • Status of resection margin (for carcinoma in situ > 2mm  safe)

Sample of a standardreport Conclusion: • Lumpectomy: Atypical Ductal Hyperplasia (Proliferative lesion with atypia) • Nuclear grade: 3 • Growth pattern: solid type • Areas of involvement: multifocal (3 foci) • Overall size: 0.8 cm • Microinvasion: absent • Resection margins: not involved / negative (6 mm)

Standard pathology report for invasive breast carcinoma • Histologic type • Histologic grade (Bloom-Richardson) • TNM (size, extension, node, distant meta.) • Ki-67 index • Lympho-vascular/perineural invasion • Status of resection margin (> 1 mm  safe) • ER, PR, HER2/neu status • In situ component, if present

Sample of a standardreport Conclusion: Tumorectomy – left breast :  Invasive component: • Type: Invasive ductal adenocarcinoma • Poorly differentiated, Bloom score 8 • Maximal diameter : 1.8 cm • Lymphovascular invasion: present • Resection margins: minimally safe (3 mm from dorsal margin) • Left axillary lymph nodes: 5 lymph nodes found, 2 lymph nodes invaded by carcinoma (2/5) • Ki-67 index : approximately 30% of the tumor • Receptor status: • ER negative (quickscore 0) • PR negative (quickscore 2) • HER2/neu score 2+ TNM (6th edition, 2002) : pT1c pN1a p Mx  In situ component : absent

References and suggested readings • Richard J et al. Benign Breast Disorders. The New England Journal of Medicine. Volume 353:275-285 (July 2005) • Turner NC & Reis-Filho JS (2006). Basal-like breast cancer and the BRCA1 phenotype. Oncogene 25:5846–5853 • Rouzier R et al. (2005). Breast cancer molecular subtypes respond differently to preoperative chemotherapy. Clin Cancer Res 11:5678–585 • Mamatha Chivukula. Evaluation of Morphologic Features to Identify ‘‘Basal-like Phenotype’’ on Core Needle Biopsies of Breast. Appl Immunohistochem Mol Morphol Volume 16, Number 5, October 2008 • E de Azambuja et al. Ki-67 as prognostic marker in early breast cancer: a meta-analysis of published studies involving 12 155 patients. British Journal of Cancer (2007) 96, 1504-1513 • Frédérique Spyratos et al. Correlation between MIB-1 and Other Proliferation Markers: Clinical Implications of the MIB-1 Cutoff Value. Cancer 2002 Apr 15;94(8):2151-9 • Perou CM, Sorlie T, Eisen MB et al (2000). Molecular portraits of human breast tumors. Nature 406:747–752 • Hiroo Nakajima et al. Prognosis of Japanese Breast Cancer Based on Hormone Receptor and HER2 Expression Determined by Immunohistochemical Staining. World J Surg (2008) 32:2477–2482 • Sebastian F et al. Prognostic Value of Lymphangiogenesis and Lymphovascular Invasion in Invasive Breast Cancer. Ann Surg. 2004 August; 240(2): 306–312. • Rosemary R. Millis et al. Ductal in situ component and prognosis in invasive mammary carcinoma. Breast Cancer Research and Treatment 84: 197–198, 2004.

Updates on Breast Diseases: What clinicians need to know from pathologists