경희대학교 의과대학·의학전문대학원

(1)

Breast Cancer

• Incidence

– USA(2004)

• 180,510 cases, 40,910 deaths • Most common cancer in women

– one-third of cancer in women

– Korea(2008)

• 한국중앙암등록사업 보고서

– 12,659 명(여자: 12,584명) – 25.6/10만명(여자: 51.1/10만명)

J Clin Oncol 24:2137-2150, 2006 Worldwide annual number of cancer cases & cancer death

(2)

(3)

(4)

Risk Factors of Breast Cancer (1)

• Genetic factor – P53 mutation

• Li-Fraumeni syndrome, 40% of breast cancer

– PTEN mutation

• inherited form, acquired form(10%)

– BRCA1(17q21): 60-80% life time chance – BRCA2(13q12)

– erbB2(HER-2, neu) overexpression • Diet

– Dietary fat

– Increased total caloric – Alcohol intake

Risk Factors of Breast Cancer (2)

• Endocrine factors

– age of menarche, age of menopause

• Length of menstrual life, especially before 1st

full-term pregnancy

– age at first full-term pregnancy

– Maternal nursing – External hormone

• Oral contraceptives, hormone replacement

therapy

• Radiation

– Multiple fluoroscopies

(5)

Gene expression patterns of breast carcinoma

ER(-) PR(-) HER2(-)

HER2(+) ER(+) ER(+)

Low expression

Five subtypes based on gene expression profiling

• Luminal A

– Luminal tumor express cytokeratin 8 & 18 – High level of ER

– Favorable prognosis • Luminal B

– Luminal epithelial origin – Distinct from luminal A • Normal breast-like

– Gene expression profile reminiscent of normal breast epithelium • HER2 amplified

– Amplification of HER2 gene on chromosome 17q • Basal

– ER/PR negative, HER2 negative (triple negative) – Markers of basal/myoepithelial cells

(6)

Survival analysis based on different gene expression

Operable Breast Cancer

• Mastectomy

• Breast conserving treatment

– Lumpectomy+irradiation • Tumor size < 5cm

– Recurrence in breast is not the cause of distant

(7)

Operable Breast Cancer

• Adjuvant therapy

– Prognostic variables • Tumor staging

– Tumor size, regional LN – Microvessel involvement

• Estrogen & progesteron receptor

• Histologic classification

– Poor nuclear grade

• Molecular changes

– erbB2 (HER-2/neu), p53

• Tumor growth rate

– PCNA (Ki67)

Definition of risk categories for operable breast cancer

Low risk Intermediate risk High risk

Node negative AND all of following features: pT  2cm, AND

Grade 1, AND

vascular invasion (-), AND

ER and/or PR (+), AND

HER2/neu gene (-), AND

Age  35

Node negative AND at least one of following features: pT > 2 cm, OR Grade 2-3, OR vascular invasion (+), OR ER & PR (-), OR HER2/neu (+), OR Age < 35

Node positive (1-3 nodes) AND ER and/or PR (+), AND HER2/neu (-) Node positive (1-3 nodes) AND ER & PR(-), OR HER2/neu (+) Node positive ( 4 nodes)

(8)

Choice of treatment modality

Highly endocrine responsive Incompletely endocrine responsive Endocrine non-responsive HER2 (-) ET (consider adding CT according to risk) ET (consider adding CT according to risk) CT HER2 (+) ET + Trastuzumab + CT ET + Trastuzumab + CT Trastuzumab + CT

ET, endocrine treatment; CT, chemotherapy

Adjuvant treatment for operable breast cancer

HER2 status HER2 (-) HER2 (+)

Endocrine response high incomp non high incomp non

Low risk E E Intermed Node (-) E CE CE E C CE +Tr CE +Tr C +Tr Node 1-3 + E CE CE E C high Node 1-3 + C CE +Tr CE +Tr C +Tr > 4 node + CE CE C CE +Tr CE +Tr C +Tr

(9)

Multigene Assay to Predict Recurrence of

Tamoxifen-Treated, Node-Negative Breast Cacner

Soonmyung Paik, MD., NSABP

N Engl J Med 2004;351:2817

16 cancer related genes(selected from 250 candidate genes) 5 reference genes

NSABP trial B-20, B-14(2892 patients) Paraffin block, RT-PCR(Oncotype DX assay)

Adjuvant Therapy

• Chemotherapy

– Cyclophosphamide, methotrexate, 5-FU(CMF) – Anthracycline containing

• doxorubicin, cyclophosphamide (AC)

• doxorubicin, cyclophosphamide, 5-FU (FAC) – Taxane

• AC  taxane • Doxorubicin+taxane

• Hormone therapy • Targeted therapy

(10)

Endocrine Therapy

• Postmenopausal

– Tamoxifen

– Aromatase inhibitor

• Check ovarian function in young postmenopausal women

– Duration: 5-10 years

• Premenopausal

– Tamoxifen alone

– Tamoxifen + ovarian function suppression

• GnRH analogue ( or surgical oophorectomy, ovarian radiation) • Duration: 5 years

Targeted Therapy -

Trastuzumab

• Action mechanisms • Not consider

– Primary tumor < 1 cm, AND – Axillary LN (-), AND

– Endocrine responsive • Duration: 1 year

(11)

Mechanisms of action of trastuzumab

Trastuzumab after Adjuvant chemothx in

HER2-Positive Breast Cancer

(HERA trial)

(12)

Locally advanced breast cancer:

Stage III

• Inoperable

– Chest wall involvement, inflammatory breast cancer,

large matted axillary lymph nodes

• Neoadjuvant chemotherapy

– Response to chemotherapy: 90%

– Reduce the bulk of disease salvage surgery/radiation – Long-term disease-free survival: 30-50%

Metastatic disease

• Metastasis

– Soft tissue, bone, visceral (lung, liver) – 50% of initial relapse occurs > 5 years

• Biopsy should be needed – Median survival: 2 years

• Choice of therapy

– Palliation

• Consider risk/benefit ratio

• Maintain well-being for as long as possible – Local therapy

• Bone metastasis: radiation, strontium 89, bisphosphonates – Systemic therapy

(13)

Metastatic disease

• Endocrine therapy

– Response

• ER+ PR+; 70%, ER+ PR-; 30%, ER- PR-; 10%

– Method

• Castration: surgical, LHRH agonist

• Antiestrogen: tamoxifen

• Aromatase inhibitor: anastrozole, letrozole

• Surgical adrenalectomy • High-dose progestogens • Hypophysectomy

– Non-responder

• Short disease-free interval, rapid progressive visceral disease,

lymphangitic pulmonary disease, intracranial disease

– duration of response in hormone response disease: 3-5 years

Metastatic disease

• Chemotherapy

– Agents:

• anthracyclines, taxanes, gemcitabine, vinca alkaloids,

capecitabine, Navelbine

– Combination vs single agents

• little impact on duration of response or survival – High-dose chemotherapy

• Not recommended outside of research settings

• Trastuzumab(Herceptin)

(14)

Months 0.2 0 0.4 0.6 0.8 1.0 HER-2 FISH (+) Months 0.2 0 0.4 0.6 0.8 1.0 Trast. + CT (n = 176) CT (n = 169) P robabi li ty of s urv iv a l RR = 0.71 p = 0.007 0 10 20 30 40 50 20.0 mo 26.2 mo HER-2 FISH (–) RR = 1.11 p = NS 0 10 20 30 40 50 19.8 mo 24.0 mo Trast. + CT (n = 50) CT (n = 56)