Breast cancer Cancer from breast u From duct

Breast cancer

Cancer from breast u From duct and lobule – Invasive ductal carcinoma(IDC) – Invasive lobular carcinoma u Others – From stroma: sarcoma(Phyllodes) – Squamous cell carcinoma – Lymphoma

Normal Breast u u u u u A. Breast Duct System B. Lobules C. Breast Duct System D. Nipple E. Fat F. Chest Muscle G. Ribs A. Cells lining duct B. Basement membrane C. Open central duct

Invasive ductal carcinoma(IDC) u u u u u A. Breast Duct System B. Lobules C. Breast Duct System D. Nipple E. Fat F. Chest Muscle G. Ribs A. Cells lining duct B. Cancer cells, breaking through the basement membrane C. Basement membrane

Ductal carcinoma in situ(DCIS) u u u A. Breast Duct System B. Lobules C. Breast Duct System D. Nipple E. Fat F. Chest Muscle G. Ribs A. Cells lining duct B. Extra cancer like cells, but aaacontained within duct C. Intact basement membrane D. Open central duct

Invasive lobular carcinoma(ILC) u u u u u A. Breast Duct System B. Lobules C. Breast Duct System D. Nipple E. Fat F. Chest Muscle G. Ribs A. Cells lining lobule B. Cancer cells, breaking through the basement membrane. C. Basement membrane

Lobular carcinoma in situ(LCIS) u u u u u A. Breast Duct System B. Lobules C. Breast Duct System D. Nipple E. Fat F. Chest Muscle G. Ribs A. Cells lining lobule B. Cancer cells, but all contained within the lobules C. Basement membrane

DCIS and LCIS u DCIS – Premalignant change – Turn out to be cancer in ongoing years u LCIS – Not a premalignent change – A sign, which indicate risk of breast ca

Symptoms u In early breast ca – Easily self palpated – Nipple discharge – May accompanied with axillary LN u Late breast ca – Local usually symptomatic – Depends on metastatic sites

Diagnosis tool u Breast sonography – Superior in dense breast, young age u Mammography – Superior in loose(fatty) breast, elder u Cytology – Fine-needle aspiration (FNA) u Biopsy – Incision – Excision

How to describe a breast ca u TNM stage u Tumor morphology – Grade – VLI – PNI u Special receptor – Hormone receptor: ER and PR – Her 2/Neu

TNM u T 1: tumor<2 cm – T 1 mic: <0. 1 cm – T 1 a: 0. 1 -0. 5 cm, T 1 b: 0. 5 -1 cm – T 1 c: 1 -2 cm u T 2: 2 -5 cm u T 3: >5 cm u T 4: chest wall, skin invasion, or inflammatory breast cancer

Inflammatory breast cancer

TNM u. N – N 0: no axilla LAPs – N 1: 1 -3 – N 2: 4 -9 – N 3>10 u M: M 0 or M 1

I IIA IIB IIIA IIIB IIIC T 1 N 0 T 1 N 1 T 2 N 0 T 2 N 1 T 3 N 0 T 1 N 2 T 2 N 2 T 3 N 1 T 3 N 2 T 4 N 0 T 4 N 1 T 4 N 2 N 3

Tumor morphology u Grade – Tubule Formation – Nuclear Pleomorphism – Mitotic Count u Vascular lymphatic invasion(VLI) u Perineural invasion(PNI) – Both indicate aggressive behavior

VLI u u u u A. Veins in breast B. Lymph channels in breast A. Cells lining duct B. Cancer cells, breaking through the basement membrane. C. Broken basement membrane D. Cancer entering a lymph channel. E. Cancer entering a vein. F. Normal breast tissue.

Receptor status u Hormone receptor – Estrogen receptor (%) – Progesterone receptor (%) >10% predict response to hormone tx u Her 2/neu – Associate with invasion, metastasis… – Predict poor prognosis – IHC stain, FISH

The EGFR (erb. B) family Ligands EGF TGF- Amphiregulin No specific ligands Heregulins NRG 2 NRG 3 Heregulins Receptor domain Extracellular Membrane Tyrosine kinase domain Intracellular K K erb. B 1 HER 1 EGFR erb. B 2 HER 2 neu K erb. B 3 HER 3 erb. B 4 HER 4

Current assay of HER 2/neu l Immunohistochemistry ‘ 0’ (negative) ‘ 1+’ (negative) ‘ 2+’ (equivocal) l Fluorescence in situ hybridization (FISH) HER 2 gene no amplification FISH negative HER 2 gene amplification FISH positive ‘ 3+’ (positive)

Treatment u Localized breast cancer – Surgery is mainstay – Halsted, 1882, radical mastectomy u John Hopkins u Metastatic breast cancer – Systemic treatment

Radical mastectomy u A. Entire breast and a chest wall muscle is removed. u LNs in the level 1 (B) and level 2 (C ), and even sometimes more distant lymph node groups (D, E and F) were also removed.

Modified radical mastectomy (MRM) u u MRM = simple mastectomy + ALND A. Entire breast is removed Classically some lymph nodes in the level 1 (B) and level 2 (C ) were removed, called an axillary lymph node dissection.

Breast conserving surgery Also called lumpectomy u RT should be followed u

Surgical evolution u Radical mastectomy – 1885 ~ 1960 s u Modified radical mastectomy: 1970 s u Lumpectomy + RT, 1970 s – NSABP B-06, NEJM 1985 u Lumpectomy vs. MRM – Milan Cancer Institute, NEJM 1977 u Lumpectomy vs. RM

Impact of surgical evolution u Local control: no survival benefit – Local control: RM>MRM>BCT+RT>BCT – Survival no different u Why? u Distant distant metastasis is the main cause “micrometastasis” – Not from local residual dz – Does exist at diagnosis u Adjuvant systemic treatment

Adjuvant systemic treatment u Hypothesis: – Eradicate micrometastasis – From effective tx for overt(macro) metastasis u Chemotherapy u Hormone therapy

Adjuvant chemotherapy u CMF, first generation, 1970 s – Cyclophosphamide – Methotrexate – 5 -FU – Benefit in u Distant recurrence u Survival

Adjuvant chemotherapy u CAF or CEF, 2 nd generation, 1980 s – Cyclophophamide – Adramycin(or Epirubicin) – 5 -FU – More toxic than CMF – CAF better than CMF in high-risk group u Axilla LN+ u LN-, but tumor large or other risk factor

Adjuvant chemotherapy u Incorporate Taxane u TAC, 3 rd generation, mid-1990 s – Taxotere – Adriamycin – Cyclophosphamide – More toxic than CAF – Better than CAF in high-risk group u Need more time to observe

Adjuvant Herceptin u Effective in Her 2+ pts – ICH 3+ – FISH+ u Herceptin + adjuvant chemotherapy – Optimal role to be defined u Concurrent or sequential? u Maintenance ? Duration ?

Adjuvant hormone therapy u In premenopausal woman – Oophorectomy could control metastatic disease u Tamoxifen – Selective estrogen receptor antagonist – Effective in pre- and post-menopausal – Effective in adjuvant setting

Adjuvant hormone therapy u Aromatase inhibitor – Effective in post-menopausal state – Aromatase, in fat tissue, u Convert androgen to estrogen u Main estrogen source in post-menopausal – Exemestane : Aromasin – Letrozole: Femara – Anastrozole: Arimidex u More effective than Tamoxifen

Adjuvant ovarian suppression u Effective in pre-menopausal state u Type – Surgical ablation – RT ablation – Gn. RH analogue: Goserelin, Leupride u Exact role to be defined – Combination with chemotherapy? – Combination with AI or TAM?

Treatment of metastatic dz Usual sites: bone, lung, liver, brain u Incurable u – Goal: live with dz for longest time u Systemic treatment is mainstay – Chemotherapy – Hormone therapy u Palliative local therapy – Radiotherapy – Palliative surgery

Treatment strategy u Principle: – Save your bullet – Right time, right treatment u Why? – Treatment effectiveness only in limited duration – To avoid unnecessary toxicity – Ultimately incurable

Chemotherapy u In general, chemotherapy – Single agent: RR: 20 -30% – Combination: doublet: 40 -60% triplet: 70 -80% u Hormone therapy – Tamoxifen: RR 15 -20% – Aromatase inhibitor: RR 30 -35%

Chemotherapeutic agents u Single agents: – Doxorubicin/Epirubucin – Cyclophosphamide – MTX – 5 -FU – Taxane(Paclitaxel, Docetaxel) – Navelbine – Gemcitabine – BCNU

Chemotherapy regimens u Combination: – Navelbine-HDFL – Paclitaxel-Cisplatin – Doxorubicin-Cyclophosphamide – Gemcitabine-Paclitaxel u Combination C/T provide better RR, but overall survival not different

Example - 1 – 55 y/o woman, ER/PR +/+, – Dz recurred 5 yrs after surgery – Only neck and mediastinum LNs – Slowly progressed clinically(!) Hormone therapy May do RT for symptomatic site

Example - 2 – 45 y/o woman, ER/PR -/– Dz recurred 3 yrs after operation – Only right supraclavicle LNs – Slowly progressed RT alone Observation

Example - 3 – 50 y/o woman, ER/PR +/+ – Back, shoulder, hips pain, 3 m, progress – Massive bone mets over spine, pelvis, shoulder, and ribs Systemic chemotherapy, combination RT for symptomatic sites Bisphonate: Aredia or Zometa

Example - 4 – 55 y/o woman, ER/PR +/+ – Dyspnea progressively – Lung mets bilaterally Systemic chemotherapy, combination

Treatment principle u For visceral organ crisis – Combination chemotherapy – Failure is not allowed (high RR necessary) u For isolated LN or bone mets – Hormone tx (more chance to try) – RT alone in hormone unresponder