Breast cancer

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

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

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

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

How to describe a breast ca TNM stage Tumor morphology Grade VLI PNI Special receptor Hormone receptor: ER and PR Her2/Neu

TNM T1: tumor<2cm T2: 2-5cm T3: >5cm T1mic: <0.1cm T1a:0.1-0.5cm, T1b:0.5-1cm T1c:1-2cm T2: 2-5cm T3: >5cm T4: chest wall, skin invasion, or inflammatory breast cancer

Inflammatory breast cancer

TNM N N0: no axilla LAPs N1:1-3 N2:4-9 N3>10 M: M0 or M1

I T1N0 IIA T1N1 T2N0 IIB T2N1 T3N0 IIIA T1N2 T2N2 T3N1 T3N2 IIIB T4N0 T4N1 T4N2 IIIC N3

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

VLI 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 Hormone receptor Her2/neu Estrogen receptor (%) Progesterone receptor (%) >10% predict response to hormone tx Her2/neu Associate with invasion, metastasis… Predict poor prognosis IHC stain, FISH

The EGFR (erbB) family Ligands Receptor domain Extracellular Membrane NRG2 NRG3 Heregulins EGF TGF- Amphiregulin No specific ligands Ligands Heregulins Receptor domain Extracellular Membrane The epidermal growth factor receptor (EGFR) belongs to a family of four closely related cell surface receptors: EGFR (HER1 or erbB1), erbB2 (HER2/neu), erbB3 (HER3), and erbB4 (HER4).1 These receptors are transmembrane glycoproteins comprising an extracellular ligand-binding domain and an intracellular domain with tyrosine kinase activity.1 Several ligands bind to the EGFR, including EGF and TGF-α. There are no defined ligands for erbB2; erbB3 and erbB4 bind heregulins and neuregulins.1 Dimerization of erbB receptors may occur as follows: EGFR homodimerization EGFR heterodimerization with erbB2 or erbB3 receptors erbB4 heterodimerization with erbB2.1 Dimer formation will dictate the resultant signaling cascade.1 Reference Wells A. Int J Biochem Cell Biol 1999; 31: 637-643. Intracellular Tyrosine kinase domain K K K erbB1 HER1 EGFR erbB2 HER2 neu erbB3 HER3 erbB4 HER4

Current assay of HER2/neu Immunohistochemistry ‘0’ (negative) ‘1+’ (negative) ‘2+’ (equivocal) ‘3+’ (positive) Fluorescence in situ hybridization (FISH) HER2 gene no amplification FISH negative HER2 gene amplification FISH positive

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

Radical mastectomy A. Entire breast and a chest wall muscle is removed. 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) 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. MRM = simple mastectomy + ALND

Breast conserving surgery Also called lumpectomy RT should be followed

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

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

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

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

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

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

Adjuvant Herceptin Effective in Her2+ pts ICH3+ FISH+ Herceptin + adjuvant chemotherapy Optimal role to be defined Concurrent or sequential? Maintenance ? Duration ?

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

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

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

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

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

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

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

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

Example - 1 55y/o woman, ER/PR +/+, Dz recurred 5yrs 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, 3m, progress Massive bone mets over spine, pelvis, shoulder, and ribs Systemic chemotherapy, combination RT for symptomatic sites Bisphosphonate: Aredia or Zometa

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

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