Overview of breast cancer Sun Yat-Sen Cancer Center

Outline 現況 Epidemiology Diagnosis, stage Treatment Surgery Radiation Hormone therapy Chemotherapy

Breast cancer (乳癌) 臺灣乳癌好發年齡在40~50歲之間，較歐美國家的好發年齡約提早十歲。 是世界重要的健康公共議題 台灣地區主要癌症死亡原因。乳癌的發生率為第一位，死亡率是排名第4位的女性癌症。 民國98年，女性及男性乳房惡性腫瘤發生個案數分別占全部惡性腫瘤發生個案數的10.24%及0.06%，女性及男性乳房惡性腫瘤死亡人數占全部惡性腫瘤死亡人數的3.98%及0.03%。發生率的排名於女性為第1位、男性為第32位；死 亡率的排名於女性為第4位、男性為第34位。 民國98年初次診斷為女性及男性 乳房惡性腫瘤者分別為8,926人及48人；當年死因為女性及男性乳房惡性腫瘤 者分別為1,588人及10人。 從1970–1996 之間，乳癌發生率增加2-3倍。 Cancer Registry Annual Report in Taiwan Area 2001 Department of Health, Executive Yuan, ROC 2009 臺灣乳癌好發年齡在40~50歲之間，較歐美國家的好發年齡約提早十歲。

Taiwan: Cancer Registration (year of diagnosis is 2002; a total of 10 hospitals reported 2,174 cases that includes complete follow-up data for five years) USA: National Cancer Database, Survival Report, 2008 (years of diagnosis are 1998-1999 for a total of 299,900 cases that covers complete follow-up data for five years)

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

DCIS and LCIS DCIS（Ductal Carcinoma in situ,管內癌），及 Premalignant change Turn out to be cancer in ongoing years LCIS (Lobular carcinoma is situ,原位小葉癌） 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

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Epidemiology Increases with age, although the rate of increase slows after menopause. Early menarche, late menopause, and nulliparity increase the risk of breast cancer. Atypical lobular or ductal hyperplasia. Other risk factors Early exposure to ionizing radiation long-term postmenopausal estrogen-replacement therapy Alcohol consumption. The most important risk factor is a family history of breast cancer.( 5 to 10%) breast–ovarian cancer syndrome, the Li–Fraumeni syndrome, and Cowden's disease. 家族遺傳性的癌症症候群中，有一名叫Li-Fraumeni syndrome者，其遺傳中之問題基因即是p53。在此症候群中之病人，會罹患多種癌症，尤其是骨骼和肌肉的惡性肉瘤、腎上腺癌、腦瘤、乳癌和白血病等。p53 奇特的一個地方是別的腫瘤抑制基因突變之後都是失去功能，但是有的p53突變卻使它獲得新功能，可以啟動他種基因。由此點看來，p53也可算是一種致癌基因。 Cowden's Disease：在臉部皮膚易有毛髮膜細胞瘤(Trichilemmomas)，多發性角化丘疹，口腔內也有多發性丘疹其形狀似鵝卵石。常伴隨胃腸道息肉、甲狀腺腫瘤、卵巢囊腫和乳房纖維瘤。

Biology BRCA1 and BRCA2 germ-line mutations ( 50 – 85% lifetime risk of breast cancer, ovarian cancer, or both ). In sporadic breast cancer (including p53, bcl-2, c-myc, and c-myb), HER-2/neu and cyclin D1 are overexpressed. Factors that stimulate or inhibit growth and proliferation of breast-cancer cells. Gonadal steroid hormones (estrogens, progestins, and androgens) Growth factors (epidermal growth factor, transforming growth factors and insulin-like growth factors I and II)

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

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

疾病種類 輔助療法 乳癌但無浸潤的情形 包括管內癌（Ductal Carcinoma in situ, DCIS），及原位小葉癌（Lobular carcinoma is situ,LCIS） 不需要 乳癌有浸潤的情形，無淋巴轉移腫瘤小於1mm 。 最大直徑小於1cm浸潤性腺管癌，及浸潤性小葉癌 浸潤性腫瘤，但組織病理預後相對是較好，如髓質癌、黏液素癌、小管癌。腫瘤最大直徑小於3cm。 腫瘤最大直徑大於1cm浸潤性腺管癌，及浸潤性小葉癌。 化療、荷爾蒙療法 浸潤性腫瘤，但組織病理預後相對是較好，如髓質癌、黏液素癌、小管癌。腫瘤最大直徑大於3cm。 乳癌有浸潤的情形且有腋下淋巴轉移 無論腫瘤大小、或病理報告的任何腫瘤

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 Intracellular Tyrosine kinase domain 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. 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

Definition of risk categories for patients with node-negative breast cancer Annals Oncol 2005; 16: 1669-1583 Low risk Node negative AND all of the following features: Pathologic tumour size ≤2cm, AND Grade 1 AND Absence of peritumoural vascular invasion, AND HER2/neu gene neither over-expressed nor amplified, AND Age ≥35 years Intermediate risk Node negative AND at least one of the following features: Pathologic tumour size >2cm, OR Grade 2-3, OR Presence of peritumoural vascular invasion, OR HER2/neu gene over-expressed or amplified, OR Age <35 years Node positive (1-3 nodes involved) AND HER2/neu gene neither over-expressed nor amplified High risk Node positive (1-3 nodes involved) AND HER2/neu gene over-expressed or amplified Node positive (4 or more involved nodes)

Diagnostic Approaches Mammography 25 to 30 % decrease in mortality (>= age of 50 years and probably also in women between the ages of 40 and 50 years. High-risk families ( BRCA1 or BRCA2 mutations) start at 25 years of age 5 years earlier than the earliest age at which breast cancer was diagnosed in a family member The American Cancer Society and the National Cancer Institute recommend annual screening mammography for women older than 40 years who have a standard risk of breast cancer.

Diagnostic Approaches 20years ago, incisional or excisional biopsies were the standard methods for confirming the diagnosis. Today, fine-needle aspiration or core needle biopsy is the standard. Ultrasound-guided core needle biopsy, stereotactic biopsy, and magnetic resonance–directed biopsy have become important diagnostic tools, especially for women with suspicious but nonpalpable breast masses.

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

Radical mastectomy : breast Conserving therapy Equivalent survival with BCT (breast-conserving therapy) as compared to mastectomy. lumpectomy (wide excision of the tumor with preservation of the breast) with radiotherapy is the preferred treatment. Radiotherapy, an integral part of BCT, is inappropriately withheld from some women, especially those older than 65 years. Noninvasive (in situ) ductal and lobular breast cancer can also be treated adequately with lumpectomy and radiotherapy. Early Breast Cancer Trialists' Collaborative Group. N Engl J Med 1995; 333:1444. 36

Individual and Pooled Odds Ratios for Survival at 10 Years in Women with Breast Cancer Treated by Breast-Conserving Therapy as Compared with Mastectomy. Cancer 1977;40:Suppl:574-587 37

Axillary Lymph-Node Dissection Recurrence is higher with positive axillary lymph nodes and increases with each additional positive node. Axillary lymph-node dissection only provides prognostic information most of the morbidity associated with breast surgery. remains the standard of care for all women with invasive breast cancer or large noninvasive tumors (>2.5 cm). Sentinel-lymph-node mapping ( radioactive substance or a blue dye is injected into the area around the tumor) The lower ipsilateral axilla is explored through a small incision and the lymph node that has taken up the dye or radioactive substance is excised. The positive predictive value (100 %), negative predictive value (> 95 %). 38

Adjuvant Radiotherapy Radiotherapy is an integral part of breast-conserving treatment. Administering chemotherapy before radiotherapy resulted in higher survival rates when given postoperatively. Postmastectomy radiotherapy reduces the incidence of local and regional recurrences by 50 to 75 % ( not increase survival). Only for women at high risk for local or regional recurrence ( large tumors invading the skin of the breast, chest wall, positive axillary lymph nodes). Benefit for high-risk premenopausal women. Fewer local and regional recurrences and overall survival was significantly better among the women treated with radiotherapy and chemotherapy. 39

Ten-Year Cancer-free Survival and Overall Survival among Women Treated with Chemotherapy with or without Radiotherapy after Mastectomy Table 2. Ten-Year Cancer-free Survival and Overall Survival among Women Treated with Chemotherapy with or without Radiotherapy after Mastectomy. 40 Hortobagyi, G. N. N Engl J Med 1998;339:974-984 40

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 Benefits both premenopause and postmenopause Benefit is greater in younger as compared to older women. < 50 , polychemotherapy reduced the risk of disease relapse and death by 37 and 30%, respectively. 10 % absolute improvement in 15-year survival (42 versus 32 %). Age 50 to 69, the risk of relapse or death was decreased by 19 and 12 %. 3 % absolute gain in 15-year survival (50 versus 47 %). > age 70 , the benefits of chemotherapy are still uncertain because few studies have included women in this age group. Lancet 2005; 365:1687 46

Early Days: Alkylating Agents and Antimetabolites In 1976, Bonadonna and colleagues from Milan, Italy, reported that postoperative CMF improved DFS and OS in women with node-positive breast cancer At the same time, the NSABP was evaluating adjuvant L-phenylalanine mustard and fluorouracil In Scandinavia, Nissen Meyer was evaluating adjuvant cyclophosphamide CMF, cyclophosphamide, methotrexate, 5-fluorouracil; DFS, disease-free survival; NSABP, National Surgical Adjuvant Breast and Bowel Project; OS, overall survival. I will begin with a brief history of adjuvant therapy in breast cancer. In the early years, we studied alkylating agents and antimetabolites in adjuvant therapy trials. In 1976, Bonadonna and colleagues from Milan, Italy, reported that postoperative cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) improved disease‑free survival and overall survival in women with node‑positive breast cancer. At the same time, the National Surgical Adjuvant Breast and Bowel Project (NSABP) in the United States and Canada was evaluating adjuvant L‑phenylalanine mustard and 5-fluorouracil, and in Scandinavia, Meyer and colleagues were evaluating postoperative adjuvant cyclophosphamide. 47 47

Duration of Chemotherapy CA Cancer J Clin 1995;45:199-226 EBCTCG  Duration of Chemotherapy CA Cancer J Clin 1995;45:199-226 EBCTCG. Lancet 1992;339:71-85 less than 3 months was inferior to treatment for 4 to 6 months Longer than 6 months was no more effective than treatment for four to 6 months. The combinations standard therapy fluorouracil, doxorubicin, and cyclophosphamide (FAC 6 cycles) fluorouracil, epirubicin, and cyclophosphamide (FEC 6 cycles) (AC 4 cycles); and CMF (6 cycles). intermittently at intervals of three to four weeks. Addition of 4 cycles of paclitaxel (duration, 12 to 16 weeks) to 4 cycles of AC improved both disease-free survival and overall survival rates. In premenopausal women Ovarian ablation = combination chemotherapy or tamoxifen. This benefit persists for 15 years after treatment. 48

The choice of regimen Ththere is a modest but significant benefit for anthracycline-containing compared to nonanthracycline-containing adjuvant chemotherapy (CMF). Both premenopausal and postmenopausal women with node-positive breast cancer should consider a taxane-containing chemotherapy regimen. 49

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 GNRH agonists (A) Premenopausal (B) Postmenopausal LH FSH Breast carcinoma Antiestrogen Breast carcinoma Antiestrogen Adrenal Estrogen Estrogen When selecting patients for hormonal therapy, age and receptor status are important considerations. As you can see on the right side of this slide, the preferential hormonal treatments in older postmenopausal women are antiestrogens or inhibitors of the aromatase enzyme. Androstenedione Aromatase inhibitor Adapted with permission from Tellez C, et al. Surg Oncol Clin North Am. 1995;4:751-777. Ovary GNRH = Gonadotropin-releasing hormone; LH = Luteinizing hormone; FSH = Follicle-stimulating hormone. Peripheral aromatization 52 52

Hormone therapy — Adjuvant hormone therapy For presence of ER or progesterone (PgR) receptors. Premenopausal women Surgical removal (or irradiation) of the ovaries Tamoxifen Luteinizing hormone releasing hormone (LHRH) analogs (eg, goserelin [Zoladex®], leuprolide [Lupron®]). For postmenopausal women Tamoxifen or aromatase inhibitors (anastrozole [Arimidex®], letrozole [Femara®], exemestane [Aromasin®]). 53

Tamoxifen hormone therapy EBCTCG The Lancet 2005; 365:1687-1717 ER (+) only 5 yrs of adjuvant tamoxifen reduces the annual breast cancer death rate by 31%, largely irrespective of the use of chemotherapy and of age (<50, 50–69, ≥70 years), progesterone receptor status, or other tumor characteristics. The annual breast cancer mortality rates are similar during years 0–4 and 5–14. The cumulative reduction in mortality is more than twice as big at 15 years as at 5 years 5 years vs 1-2 yrs 2p<0·00001 for recurrence 2p=0·01 for breast cancer mortality 54

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 55

Comparative Toxicity: Tamoxifen and Aromatase Inhibitors ATAC Significantly higher toxicity with tamoxifen vs anastrazole    • Vaginal bleeding or discharge    • Hot flashes    • Endometrial cancer    • Ischemic cerebrovascular events    • Venous thromboembolic events Significantly higher toxicity with anastrozole vs tamoxifen    • Arthralgia    • Fractures 58

Comparative Toxicity: Tamoxifen and Aromatase Inhibitors Significantly higher toxicity with tamoxifen vs exemestane    • Gynecologic symptoms    • Vaginal bleeding    • Muscle cramps    • Thromboembolic events Significantly higher toxicity with exemestane vs tamoxifen    • Arthralgia, Myalgia, Arthritis/osteoarthritis    • Limb pain, Carpal tunnel, Paraesthesia    • Myocardial infarction    • Diarrhea 59

Aromatase inhibitors Upfront therapy (an AI initially instead of tamoxifen) Sequential therapy (switch to an AI after 2-3 years of tamoxifen) Extended therapy (an AI after 5 years of tamoxifen). 60

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?

Concurrent chemotherapy : Sequential chemotherapy Proc Am Soc CLIN Oncol 21: 37a, 2002 (abstr 143) 62

 Does chemotherapy add benefit to tamoxifen for postmenopasual women with ER-positive disease ? Combined chemotherapy and tamoxifen therapy for postmenopausal women with node-positive ER-positive disease. 2000 EBCTCG overview analysis Decreased the annual risk of recurrence and death by 35 and 34%, vs tamoxifen alone. Tamoxifen should be started after chemotherapy is completed, and not given concurrently. The benefit of adding chemotherapy to tamoxifen is less clear for women with ER-positive node-negative are inconclusive 63

Neoajuvant chemotherapy Large operable tumors 90% of primary operable tumors decrease in size by more than 50 %. Lumpectomy a possibility for many women who would otherwise have required a mastectomy. No apparent advantage survival to preoperative chemotherapy as compared with postoperative chemotherapy. 64

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Neoajuvant chemotherapy Emerging data supports a similar degree of benefit from taxanes in the neoadjuvant setting. 4 cycles of induction AC plus vincristine and prednisolone (CAVP); responders were then randomly assigned to continue CAVP for a total of eight courses, or switch to four cycles of docetaxel. The number of pCRs (pathologic complete remission) sequential docetaxel vs CAVP (34 versus 16 %). Initial fail respond to CAVP had a cCR (complete clinical responses) rate of 55% to subsequent docetaxel monotherapy. Significant five-year OS (97 versus 78 %) Presented at the 26th annual San Antonio Breast Cancer Symposiom, San Antonio, TX, December 2003 (abstract 11). 66

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

Chemotherapy regimens Combination: Navelbine-HDFL Paclitaxel-Cisplatin Doxorubicin-Cyclophosphamide Gemcitabine-Paclitaxel/-Trastuzumab/-lapatinib 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

Trastuzumab 20-30 % of breast cancers overexpress the HER-2/neu protein. Preliminary reports support a significant disease-free survival and overall survival benefit from the addition of trastuzumab to anthracyclines and paclitaxel in the adjuvant setting, particularly for women with node-positive breast cancer. Increase in the risk of cardiac events. Trastuzumab at the earliest sign of cardiotoxicity developed in 2 to 3 % over a two year period. Long-term data in the adjuvant setting is lacking.

SUMMARY Surgical resection is required in all invasive breast cancer. Outcomes are similar with mastectomy and breast conserving therapy (lumpectomy plus breast radiation therapy). The status of the axillary lymph nodes provides important prognostic information. Sentinel lymph node dissection is replacing axillary lymph node dissection. there is no information about the long-term outcome (ie, cancer-specific survival). (compare to full axillary node dissection.) With positive sentinel node require a completion axillary node dissection. Adjuvant systemic therapy (chemotherapy, hormone therapy, trastuzumab or a combination) is recommended for node (+), and tumors > 1 cm. Adjuvant hormone therapy is for ER-positive or PR-positive.