Treatment of Breast Cancer Department of Haemato - Oncology MGR Review

Early Stage Breast Cancer Locally Advanced and Inflammatory Cancer Metastatic Disease Locally Recurrent Cancer

Staging Early stage invasive breast cancer - Stage I : tumor size ≤ 2 cm with axillary lymph node negative - Stage II : ipsilateral and mobile axillary node positive tumor size > 2 cm tumor size > 5 cm with node negative Locally advanced cancer : Stage III - extensive axillary nodal disease - supraclavicular nodal involvement - direct tumor extension to the chest wall or skin Inflammatory cancer : Stage III Metastatic breast cancer : Stage IV

Selection of Treatment Modality Lymph node involvement - indication of adjuvant treatment with any nodal involvement Size and extent of tumor - the larger size, the more recurrence - neoadjuvant chemotherapy for large-sized or inflammatory cancer Histology - invasive Vs non-invasive - nuclear grade Hormonal receptor status : ER / PR Molecular changes : overexpression erb2 [ HER-2/neu ], p53 mutation

Early Stage Breast Cancer Locally Advanced and Inflammatory Cancer Metastatic Disease Locally Recurrent Cancer

Surgery Breast conserving therapy [ BCT ] - lumpectomy + RT - almost equal 10Y survival to MRM despite of possibility of recurrence Postlumpectomy irradiation - survival improvement - reduced locoregional recurrence Contraindication for Breast conserving surgery : ABSOLUTE - prior RT to the breast - pregnancy - persistent positive resection margin after reexcision attempts - multicentric disease - diffuse suspicious malignant microcalcifications

Contraindication for Breast conserving surgery : RELATIVE - size > 5 cm : poor cosmetic with too large sized mass removal - history of connective tissue disease : intolerable to RT - 35 y or premenopausal women with a known BRCA 1/2 mutation Margin status after lumpectomy - always need of margin (-) for local control - margin (+)  further surgery : re-excision or masectomy Breast reconstruction

Preoperative Chemotherapy Common indication - locally advanced and large sized-tumor - inflammatory breast cancer  fascilitation of breast conserving therapy rather than masectomy NOT necessarily preferable to postoperative adjuvant chemotherapy

Radiation Therapy Component of Breast conserving therapy - ipsilateral whole-breast irradiation - survival improvement - reduced locoregional recurrence - compelling indication with BCS Early Breast Cancer N Engl J Med 2004; 351:971 Possible avoidance of RT : small ( 65Y)  no benefit of RT despite of increased local recurrence without RT Breast-conserving surgery with or without radiotherapy: pooled-analysis for risks of ipsilateral breast tumor recurrence and mortality J Natl Cancer Inst 2004 Jan 21;96(2): Tamoxifen with or without Breast Irradiation in Women 50 Years of Age or Older with Early Breast Cancer N Engl J Med 2004; 351:971

Postmasectomy RT - larger size (> 5 cm) - axillary lymph node positive - for both premenopausal & postmenopausal  reduction of locoregional recurrence risk  increased disease-free survival  reduced cancer-related mortality

Axillary Lymph Node Management Axillary LN dissection - routine component of early stage invasive cancer treatment - single most important prognostic factor in early stage disease  Need for postmasectomy RT? Adjuvant chemotherapy? Sentinel node biopsy - ipsilateral axllary LN in > 95% - sentinel LN (-)  less than 5% of chance of axillary LN (+)

Adjuvant Systemic Therapy Hormone therapy Chemotherapy Target therapy – Trastuzumab  Administration after definitive local therapy - significant reduced recurrence and cancer-related mortality - indication for all women with node (+) or node (-) with size > 1cm Decision of initial treatment option - chemotherapy Vs hormone therapy ?

Choice of Initial Adjuvant Therapy Concurrent hormone therapy + Chemotherapy : NOT Recommended - Chemotherapy first  Followed by hormone therapy

International Expert Consensus on the Primary Therapy of Early Breast Cancer 2005 St Gallen 2005 Annals of Oncology 16: , 2005

St Gallen 2005: Choice of treatment modalities

Hormone Therapy Action mechanism - negative feedback to estrogen production - blocking estrogen effect  inhibition of hormonal stimulation of cancer cell proliferation  prevention of estrogen-requiring tumor cell growth Response rate - ER (+) PR (+) 70% - ER (+) PR (-) 30% - both negative < 10 % Available options - selective estrogen recptor modulator : tamoxifen - aromatase inhibitor for postmenopausal women : letrozole, anastrozole

§ POSTMENOPAUSAL WOMEN Tamoxifen - standard choice of pre / post-menopausal women - endometrial cancer risk (1%) Non-steroidal third generation aromatase inhibitor for post- menopausal women - anastrozole / letrozole Initial choice of hormone therapy - aromatase inhibitor >> tamoxifen in terms of TTP, contralateral breast cancer incidence - no overall survival benefit Combination hormone therapy - no superior to individual agents

§ PREMENOPAUSAL WOMEN Castration - ovarian function ablation : surgical or medical (LHRH agonist) Tamoxifen Aromatase inhibitor - NOT used for permenopausal women - reduced feedback of estrogen  stimulation of hypothalamus and pituitary gland  stimulation of ovary  increased androgen substrate and aromatase

Adjuvant Chemotherapy Choice of chemotherapy regimen : anthracyclin or taxane– based : combination or single agent therapy Anthracyclin –based regimen >> Non-anthracycline – based regimen Anthracycline Vs Taxane – based regimen ??  Individual approach St. Gallen Breast Cancer Consensus endocrine responsive disease : 4 cycles of AC - endocrine non-responsive or intermediate risk group : anthracycline-containing regimen - higher risk : taxanes

Trastuzumab Trastuzumab [ Herceptin ] - humanized anti-HER2 monoclonal antibody - indication for HER2-overexpressing metastatic breast cancer (20%) Trastuzumab + paclitaxel / anthracycline - significant disease-free survival, overall survival benefit - especially node (+) breast cancer - cardiotoxicity : NYHA Grade III ~ IV cardiotoxicity in 2~3% over a 2Y - combination with paclitaxel rather than anthracycline : more severe cardiotoxicity with anthracycline itself

Early Stage Breast Cancer Locally Advanced and Inflammatory Cancer Metastatic Disease Locally Recurrent Cancer

Locally Advanced Cancer Locally advanced breast cancer - large tumor > 5cm - extensive regional LN involvement - direct involvement of the skin or underlying chest wall - tumors considered inoperable but without distant metastasis - inflammatory breast cancer - TNM stage III Multimodality treatment - neoadjuvant chemotherapy - locoregional therapy : surgery, RT, or both  Increased likelihood of successful breast preservation with large tumor No significant survival benefit

§Induction [ Neoadjuvant ] chemotherapy - Number of total course : NOT established - anthracycline – based regimen : 5-FU + Cyclophosphamide + doxorubicin [ CAF ] or Epirubicin [ FEC ] - taxane : paclitaxel, docetaxel 2003 Proceedings of the Consensus Conference on Neoadjuvant Chemotherapy in Carcinoma of the Breast, April 26 –28, 2003, Philadelphia, Pennsylvania CANCER June 15, cycles of anthracycline – based regimen or taxane  Assessment of response CR / nearly CR  completion of NACT & Definitive locoregional treatmen Lesser response  4 additional chemotherapy with non-cross resistant drugs All 8 cycles of chemotherapy

Induction [ Neoadjuvant ] hormonal therapy - successful downstaging with tamoxifen and aromatase inhibitor - likelihood of pathologic CR : hormone therapy << chemotherapy - survival benefit : NOT established  reserved for elderly women with impaired organ fuction, unwilling to chemotherapy, poor performance

Definitive Locoregional Therapy Following induction chemotherapy : Surgery Vs RT Vs Combination of both Suregery - possible breast conserving surgery with 50~90% of LABC - higher local recurrence rate with neoadjuvant treated women for downstaging Radiation therapy - higher local control rate with RT + surgery than either modality alone in most nonrandomized study Inflammatory cancer – NOT recommended to BCS due to high local recurrence rate

Additional adjuvant chemotherapy - No establised benefit after definitive local treatment with total 8 cycles of preoperative chemotherapy - recommended total 8 cycles of Taxane / Anthracycline-based regimen : all before surgery or split between induction and postoperative therpy Adjuvant trastuzumab - survival benefit for the addition of Herceptin to adjuvant chemotherapy - strongly considered to postoperative trastuzumab with Her2/neu overexpressing LABC Adjuvant Chemotherapy - After Local Therapy

DISEASE PROGRESSION

Early Stage Breast Cancer Metastatic Disease Locally Recurrent Cancer Locally Advanced and Inflammatory Cancer

Locally Recurrent Cancer Definition - reappearance of cancer on the ipsilateral chest wall or preserved breast §Recurrence after Breast-Conserving Therapy - 10~20% within 10Y after BCT - higher in patients without RT as a component of BCT  full re-staging workup to exclude distant metastasis  masectomy - skin involve or inflammatory type of recurrence  initial systemic chemotherapy prior to surgery

§Postmasectomy recurrence Isolated chest wall recurrence  local excision of all gross disease Unresectable chest wall recurrence  systemic chemotherapy : uncertain role No previous immediate postmasectomy chest wall RT  postresection RT recommended Hormone therapy - for hormone receptor-positive disease and not eligible for chemotherapy - addition of trastuzumab – based regimen for Her2 – positive patients

Early Stage Breast Cancer Metastatic Disease Locally Recurrent Cancer Locally Advanced and Inflammatory Cancer

Distant Metastasis Selection of initial therapy - for palliation - therapeutic benefit Vs toxicity estimation Local Vs Systemic treatment - local : surgery, radiation - systemic : endocrine therapy, chemotherapy - generally more effective with local therapy than systemic theray - withhold systemic therapy until completion of local palliative therapy Ex) RT for painful bone metastasis or impending cord compression - combination : RT + hormone therapy

Endocrine therapy Vs Chemotherapy - more likelihood of significant palliation with endocrine therapy : due to lower toxicity profile - slowly growing, no visceral involvement and mininal symptom  endocrine therapy recommended even if hormone receptor negative patient : responsible < 10% - rapidly-growing disease with lung, liver metastasis  better with combination chemotherapy Trastuzumab – Her2/neu overexpression Bisphosphonate – Zolendronate : for lytic bone metastases