BREAST CANCER 한림대 강동성심병원 혈액종양내과 이정애 1

EPIDEMIOLOGY Risk factors increasing age: rate slows after menopause early menarche, late menopause , nulliparity atypical lobular or ductal hyperplasia(benign breast disease) early exposure to ionizing radiation long-term postmenopausal estrogen-replacement therapy alcohol consumption family history of breast ca.( most important ) - 5 to 10% occur in high-risk families - familial breast ca. syndrome : breast-ovarian cancer synd Li-Fraumeni synd Cowden's ds 2

BIOLOGY BRCA1 and BRCA2 germ line mutation Genetic abnormalities (1) familial breast ca BRCA1 and BRCA2 germ line mutation . 50 to 85 % lifetime risk breast ca, ovarian ca, or both . genetic screening and counseling programs are ongoing (2) sporadic breast ca p53, bcl-2, c-myc, c-myb gene abnormality HER-2/neu 3

DIAGNOSTIC APPROACHES Screening by mammography and physical examination - early diagnosis  25 to 30 % decrease in mortality over age of 50 yrs & probably in btw age of 40-50 yrs American Cancer Society, the National Cancer Institute recommend 1) annual mammography for > 40 yrs 2) high-risk families, with BRCA1 or BRCA2 mutant : at 25 yrs of age or 5 yrs earlier than earliest age at which breast ca diagnosed in family member Standard method for confirming diagnosis fine-needle aspiration or core needle biopsy 4

THERAPY 1. Primary Breast Cancer Local disease without distant spread  curable with local or regional treatment alone but, most pts have subclinical metastasis  distant metastasis ultimately develop 6

1) Local and Regional Treatment  early breast cancer  lumpectomy (wide excision of tumor with preservation of breast) with radiotherapy

2) Axillary Lymph-Node Dissection standard for invasive or large non-invasive tumors (>2.5 cm) Prognosis information - recurrence is higher for histologically positive axillary LNs responsible for morbidity associated with surgery alternative method : Sentinel-lymph-node mapping 7

3) Postop. Adjuvant Therapy (1) Chemotherapy (2) Hormone therapy (3) Radiotherapy Prognostic factors Gold Standard Axillary lymph node status Tumor size Histologic subtype, Histologic or nuclear grade ER and PgR status Potential proliferation marker (S-phase fraction, Ki67, TLI ) c-erbB-2(HER-2/neu)

Axillary LN status and recurrence rate Positive nodes(No.) 10 year recurrence rate(%) 0 20 1-3 47 4-6 59 7-12 69 >13 87 Hormone receptor and response to endocrine therapy Receptor status Response rate(%) ER -, PR - 10 ER -, PR + 33 ER +, PR - 34 ER +, PR + 74

Risk categories for pts with node-negative breast ca. Factors Low Intermediate High (has all listed factors) (at least one factor) Tumor size < 1cm 1-2 cm > 2 cm ER and PgR + - - Grade Grade I Grade 1-2 Grade 2-3 Age > 35 yrs < 35 yrs

(1) Adjuvant Systemic Chemotherapy combination chemotherapy - more effective than single-drug treatment - effects : marked in < 60 yrs ( esp. premenopausal ) - reduce annual risk of death by 20% duration of chemotherapy - usually used combination regimens : FAC, FEC, CMF ( 6 cycles ) AC ( 4 cycles )

(2) Adjuvant Hormone Therapy Tamoxifen - breast ca. is estrogen-dependent - antiestrogenic activity mediated by competitive inhibition of estrogen binding to estrogen receptors - inhibits expression of estrogen-regulated genes including growth factors and angiogenic factors secreted by tumor reduce recur & death in all age group - when to estrogen-receptor-positive tumor - when for about 5 yrs, rather than 1 to 3 yrs ( for more than 5 yrs is no more effective than for 5 yrs )

Adjuvant therapy for node-negative breast ca. (1998 International Consensus) Pt group Low risk Intermediate risk High risk Premenopausal, ER or PgR + None or TMF TMF + CTX CTX + TMF ER and PgR - NA NA CTX Postmenopausal, ER or PgR + None or TMF TMF + CTX TMF + CTX ER and PgR - NA NA CTX Elderly None or TMF TMF TMF ER: estrogen receptor, PgR: progesteron receptor TMF : tamoxifen, CTX : chemotherapy, NA : not applicapable

Adjuvant therapy for node-positive breast ca. (1998 InternationalConsensus) Pt group Minimal/low risk Premenopausal, ER or PgR + CTX + TMF ER and PgR - CTX Postmenopausal, ER or PgR + TMF + CTX Elderly TMF  ER: estrogen receptor, PgR: progesteron receptor  TMF : tamoxifen, CTX : chemotherapy

(3) Adjuvant Radiotherapy (RT) Postmastectomy RT - reduces local recur by 50-75% but this reduction was not accompanied by increased survival so, postop. RT indication only for high risk local recur. pts - large tumors > 5 cm - invading the skin of the breast or chest wall - many (> 4 ) positive axillary LNs

Radiotherapy in high risk premenopausal pt.s 8

4) Preoperative Chemotherapy - large operable tumor - 90% of tumor decrease in size by more than 50% - lumpectomy possible - survival benefit : no apparent advantage as compared with postop. chemotherapy 5) Dose-Intensive and High-Dose Chemotherapy Regimens - ongoing randomized trial should help to determine the efficacy 12

2. Locally Advanced and Inflammatory Breast Ca. 1) Stage III breast ca. tumor > 5 cm in diameter any size with invasion of skin of breast or chest wall any tumors with fixed or matted axillary LNs 2) Inflammatory breast ca. - should treat with preoperative chemotherapy or hormonal therapy - excellent local control achieved in 80 to 90% of pts and 30% pts remain free of cancer after 10 yrs 14

3. Metastatic Breast Cancer clinical course is variable - large variation in growth rate and responsiveness to systemic therapy main goals of treatment - optimal palliation and prolongation of life therapeutic strategy on basis of age, disease-free interval, hormone-receptor status, and extent of disease 15

Metastatic Breast Cancer 1) Hormonal intervention - 20 to 35% response to initial hormonal therapy - 10 to 20% to second-line - 15 to 30% to another Hormonal Therapies for Metastatic Breast Ca. Order of Tx. Premenopausal Postmenopausal First line Antiestrogens or ovarian ablation Antiestrogens (chemical, surgical or postRT) Second line Ovarian ablation after antiestrogens Aromatase inhibitors* ; antiestrgens after ovarian ablation Third Liline Progestins Progestins Forth line Androgens Androgens or estrogens * Aromatase inhibitor: Formestane, Anastrozole(Arimidex), Letrozole(Femara) 16

2) Chemotherapy 40 to 60% response to CMF Metastatic Breast Cancer 2) Chemotherapy - refractory to hormonal therapy 40 to 60% response to CMF - anthracycline-containing combination superior to CMF 50 to 80% response to FAC - new drugs vinorelbine( third-generation vinca alkaloid ) taxanes (paclitaxel and docetaxel) * Combinations of taxanes and anthracyclines responses in 40 to 94% complete remissions in 12 to 41%

Metastatic Breast Cancer Bone - most common site of metastasis cause of substantial morbidity, complication * Bisphosphonate (pamidronate and clodronate) add to chemotherapy or homonal therapy - reduce pain and complication - prolong survival free of bone-related event 18

3) High-Dose Chemotherapy Metastatic Breast Cancer 3) High-Dose Chemotherapy I. single cycle of high-dose combination of cytotoxic drug (usually alkylating agent) bone marrow damage is earliest limiting toxic effect - eliminated by reinfusing autologous hematopoietic stem cell II. 2 to 4 cycles of cytotoxic-drug combination at dose higher than usual but not ablate bone marrow  higher complete remission (40 to 60%) 15 to 25% free of cancer for 3 to 5 yrs 19

CHEMOPREVENTION administration of adj. tamoxifen for 5yrs after primary Tx. - reduce incidence of contralat. breast ca. by 47% - endometrial ca. in twice - increase in thromboembolic event occured predominantly in older than 50 yrs * overall beneficial effect of tamoxifen outweighed adverse effect 20

NOVEL THERAPIES HER-2/neu oncogene overexpressed in 20 to 30% - more aggressive - more resistant to chemotherapy 13% of metastatic breast ca with HER-2/neu - response to monoclonal antibody against extracellular domain of HER-2/neu oncoprotein chemotherapy combined with anti HER-2/neu antibody - increase response rate & prolongation of survival 21