Triple-Negative Breast Cancer And its Clinical Implication.

Triple-Negative Breast Cancer

And its Clinical Implication

Background

Definitions and Molecular Features

• Invasive breast cancer was previously identified as a homogeneous group of disease


• Different subgroups exist Patient demographics Clinical behavior Prognosis

Breast Cancer

Basal-like Subtypes

Luminal Subtypes


• Molecular genetics


• Triple-negative breast cancers


• Triple-negative breast cancers

• Lack the clinical manifestations of ER, PR, Her-2 receptors

• Occupy 10-17% of the breast cancer population

Immunostaining for ER


• Immunostaining• Molecular genentics and

cDNA assay


• Basal-like breast cancers

Basal-like breast cancer cells demonstrating EGFR immunostaining


• Resemble myoepithelial cells in basal layer of ductal system


• Possess cytokeratins CK5 CK14 EGFR

• More “progenitor” like in germline


Basal-like Breast Cancers

Triple-Negative Breast Cancers

OverlapNeg for ER, PR, HER2

Possess cytokeratins e.g. EGFR, CK15, CK40

BRCA1 mutation


• Triple-negative breast cancersClinicalNegativity for ER,

PR, HER2

• Basal-like breast cancersBased on cDNA

assays for identification of cytokeratins

CK5, CK14, CK17, epidermal growth factor receptors, etc


• The 2 entities are almost used anonymously in clinical settings

Patient Demographics


• Patient demographics – Younger age of onset (

<50 years old )


• Patient demographics – Larger mean tumour

size– Higher rate of node

positivity

1. Abd El-Rehim DM, Pinder SE, Paish CE et al. Expression of luminal and basal cytokeratins in human breast carcinoma.J. Pathol. 2004; 203; 661–671.

2. Fan C, Oh DS, Wessels L et al. Concordance among geneexpression-based predictors for breast cancer. N. Engl. J. Med.2006; 355; 560–569.


• Patient demographics – Higher histological

grade

1. Fulford LG, Easton DF, Reis-Filho JS et al. Specific morphological features predictive for the basal phenotype in grade 3 invasive ductal carcinoma of breast. Histopathology 2006; 49;22–34.

2. Lakhani SR, Reis-Filho JS, Fulford L et al. Prediction of BRCA1 status in patients with breast cancer using estrogen receptor and basal phenotype. Clin. Cancer Res. 2005; 11; 5175–5180.

3. Livasy CA, Karaca G, Nanda R et al. Phenotypic evaluation of the basal-like subtype of invasive breast carcinoma. Mod. Pathol. 2006; 19; 264–271.

4. Tsuda H, Takarabe T, Hasegawa F, Fukutomi T, Hirohashi S. Large, central acellular zones indicating myoepithelial tumor differentiation in high-grade invasive ductal carcinomas as markers of predisposition to lung and brain metastases. Am. J. Surg. Pathol. 2000; 24; 197–202.

5. Tsuda H, Takarabe T, Hasegawa T, Murata T, Hirohashi S. Myoepithelial differentiation in high-grade invasive ductal carcinomas with large central acellular zones. Hum. Pathol. 1999; 30; 1134–1139


• Patient demographics – More aggressive

clinical behavior

1. Nielsen TO, Hsu FD, Jensen K et al. Immunohistochemical and clinical characterization of the basal-like subtype of invasive breast carcinoma. Clin. Cancer Res. 2004; 10; 5367–5374

2. Abd El-Rehim DM, Pinder SE, Paish CE et al. Expression of luminal and basal cytokeratins in human breast carcinoma. J. Pathol. 2004; 203; 661–671.

3. Fan C, Oh DS, Wessels L et al. Concordance among geneexpression-based predictors for breast cancer. N. Engl. J. Med. 2006; 355; 560–569.

Clinical Implication

• Reason for isolating a subgroup of breast cancer ?


• Clinical implications ?


• Does it affect our way of treating our patients ?


• Let’s utilize a clinical scenario for illustration



• Treatment options

Surgery

• BCT vs Total mastectomy ?

Surgery

• More aggressive clinical behaviour

• Larger tumour size• Higher rate of axillary

LN positivity• Higher histological

grade


• No difference in locoregional recurrence between mastectomy group and BCT with radiation group when multivariate regression was applied

1. Bruce G. Haffty, Qifeng Yang, Michael Reiss, et al. Locoregional Relapse and Distant Metastasis in Conservatively Managed Triple Negative Early-Stage Breast Cancer. J Clin Onc, 2006. 24; 36; 5652-5657

2. Gary M. Freeman, Penny R. Anderson, Tianyu Li, Nicos Nicolaou. Local-Regional Recurrence of Triple Negative Breast Cancer after Breast-Conserving Surgery and Radiation. Cancer. 2009. 115(5): 946-951

3. Parker C.C., Smith M.H., Henderson B.D. Li, Ampil F., Chu Q.D. Breast Conservation Therapy Is a Viable Option for Patients with Triple-Receptor Negative Breast Cancer.


• TNBC is not a sole indicator for / against mastectomy

• Factors which determine BCT / mastectomy :– E.g. multicentricity,

tumour size

Chemotherapy

• Neo-adjuvant Therapy ?

• Adjuvant Therapy ?


• Lack of ER, PR• No role of hormonal

therapy

• Lack Her-2 receptor• No role for current

targeted therapy towards Her-2 receptor


• High chemosensitivity • Higher rate of

achieving complete pathological remission CR ( 36% )

1. Carey LA, Dees EC, Sawyer L, et al. The triple negative paradox: primary tumour chemosensitivity of breast cancer subtypes. Clin Cancer Res. 2007;13(8):2329-2334


• In patients achieving CR, survival similar to patients in non-TNBC group

• Residual disease




Chemotherapy

• Are we giving neo-adjuvant Therapy ?


• Aim– Downstage– Downsize

• To achieve resectability of the tumour

Chemotherapy

• How about adjuvant chemotherapy ?


• St. Gallen consensus recommendations– Tumor size >2 cm– ER and PR negativity– Tumor histologic grade

2 or 3– Age <35 years – Nodal involvement


• Prognosis• Long-term

surveillance


• Poorer prognosis• Higher mortality• Reduced overall

survival and disease-free survival



• Patient demographics – More frequent

haemaogeneous spread

• Lungs• Brain

– Much less spread to lymphatics and bones

1. Fulford LG, Reis-Filho JS, Ryder K et al. Basal-like grade III invasive ductal carcinoma of the breast: patterns of metastasis and long-term survival. Breast Cancer Res. 2007; 9; R4.

2. Hicks DG, Short SM, Prescott NL et al. Breast cancers with brain metastases are more likely to be estrogen receptor negative, express the basal cytokeratin CK5 ⁄ 6, and overexpress HER2 or EGFR. Am. J. Surg. Pathol. 2006; 30; 1097–1104.

3. Rodriguez-Pinilla SM, Sarrio D, Honrado E et al. Prognostic significance of basal-like phenotype and fascin expression in node-negative invasive breast carcinomas. Clin. Cancer Res. 2006; 12; 1533–1539.

4. Tsuda H, Takarabe T, Hasegawa F et al. Large, central acellular zones indicating myoepithelial tumor differentiation in high-grade invasive ductal carcinomas as markers of predisposition to lung and brain metastases. Am. J. Surg. Pathol. 2000; 24; 197–202


• Increased rate of loco-regional recurrence

• Earlier relapse• Shorter post-

recurrence survival

1. Liedte C, Mazouni C, Hess KR, et al. Response to neoadjuvant therapy and long-term survival in patients with triple-negative breast cancer. J Clin Oncol. 2008;26(8);1275-1281

Figures in NTWC

• During the period from 1 Jan 2010 to 31 Dec 2010

• Total no. of 176 breast cancers • 12 cases of triple negative breast cancers

( 6.9% )

Summary

• Triple negative breast cancer• Special breast cancer subgroup• Different patient demographics and different

clinical behaviour• Treatment options• Subgroups of TNBC ?• New therapeutic agents targeted at the surface

molecular markers under development• Direction for the future development of modern

medicine in breast cancer

Triple-Negative Breast Cancer And its Clinical Implication.

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