• Globally, cancer is one of the top ten leading causes of death. 7.4 million people died of cancer in 2004 and, if current trends continue, 83.2 million more will have died by 2015.• Among women, breast cancer is the most common cause of cancer mortality - 16% of cancer deaths in adult women.• Early detection through mammography screening and adequate follow-up of women with a positive result could significantly reduce mortality from breast cancer.
Less than a quarter of women hadbreast cancer screening
美國乳房篩檢指引For the Early Detection of Breast Cancer Yearly mammograms starting at age 40. A clinical breast exam - about every 3 years for women in their 20s and 30s, and every year for women 40 and older. Women should know how their breasts normally feel and report any breast changes promptly to their health care providers. Breast self-exam is an option for women starting in their 20s. Screening MRI is recommended for women with an approximately 20%-25% or greater lifetime risk of breast cancer, including women with a strong family history of breast or ovarian cancer and women who were treated for Hodgkin disease. American Cancer Society ASCO
Fig. 1 Rate of mammographic breast cancer screening in women over 40 years of age. Breast Cancer Res Treat
篩 檢 使 乳 癌 死 亡 率 下 降Change in breast cancer mortality from 1987 to 2008.
台灣乳癌期別分布 (2006) unknown Stage 0 VI IIIc 5% 6% 9% IIIb5% 3% Stage I IIIa 27% 9% II b 11% II a 25%Stage Stage unkno II a II b IIIa IIIb IIIc VI 0 I wn719 1974 1937 837 704 209 414 398 428 台灣癌症中心資料庫（Taiwan Cancer Database, TCDB）
乳癌切除後乳房重建的比率 20% 60% 17% 3%• In 2005, 212,920 new female breast cancers 57,778 / 212,920 = 27.14%27%• M.D. Anderson cancer center: 45-50%•Taiwan: 7% (KMUH: 45%)
腋下淋巴結SuggestionWho May Avoid ALND Who Should Have ALND• T1 T2, N0 with: • Clinical T3 1. Only 1 or 2 involved SN • Clinical N1 2. Micrometastases • Neoadjuvant therapy 3. ITC • Mastectomy 4. US identified • APBI/Prone radiotherapy metastases but only 2 or less involved SLN 5.Old age 6. Favorable type
Technical considerations in SLNB• Radiotracer No consensus regarding how the procedure• Blue dye injection should be performed.• Preoperative scintigraphic imaging• Intraoperative gamma probe localization
Table 2. Definition of risk categories for patientswith operated breast cancer Annals of Oncology Volume 18 | No. 7 | July 2007
Table 3. Choice of treatment modalities 2007 Annals of Oncology Volume 18 | No. 7 | July 2007
LUMINAL SUBTYPES• Expression Patterns • Clinical Features – luminal A and luminal B. – the most common – luminal ck 8/18, ER, LIV1 subtype, 67% of the and CCND1 tumors. – Fewer than 20% of – Afr. Ame. women less tumors have mutations likely to develop luminal in TP53 A tumors (36%) than any other group of patients – Luminal A has higher (51% to 59%). expression of ER-related genes and lower – luminal B tumors tend to expression of be higher grade proliferative genes
LUMINAL SUBTYPES• Treatment Response and Outcome – luminal B worse prognosis – luminal A tumors adequately treated with endocrine therapy – luminal B tumors may benefit from chemotherapy added to endocrine therapy. Sorlie T 2001 PNAS
HER2 SUBTYPE• Expression Patterns – The HER2-array subtype -the larger group of ER–negative (low expression of ER and related genes) tumors. – overexpression of other genes in the ERBB2 amplicon such as GRB7.4 – 40% to 80% of TP53 mutations – more likely to be grade 3 (P Z .0002)
HER2 SUBTYPE• Clinical Features – no association with age or race and known risk factors. – more likely to be high grade and poorly differentiated, – more than two-fold more likely to involve axillary lymph nodes than luminal A tumors.• Treatment Response and Outcome – poor prognosis with sensitivity to anthracycline and taxane–based neoadj. chemotherapy
hazard ratio, 0.52hazard ratio, 0.65 n engl j med 354;20
BASAL-LIKE BREAST CANCER• Expression Patterns – Mimicked basal epithelial cells of other parts of the body and normal breast myoepithelial cells – strong expression of basal ck 5, 6, and 17 and proliferation related genes. – lack of expression of ER, related gene & HER2 – low expression of BRCA1, – more TP53 mutations & grade III
BASAL-LIKE BREAST CANCER• Clinical Features • Treatment Response and Outcome – most BRCA1 mutations – poor prognosis - poor therapy – 20% of the tumors options or inherent – among premenopausal aggressiveness ? AA women (39%), – sensitive to anthracycline and taxane–based neoadjuvant postmenopausal AA – epidermal growth factor (14%) or non–AAwomen receptor–driven of any age (16%) n engl j med 363;20
Table 2. Thresholdsa for treatment modalities 2009 Annals of Oncology Volume 20 | No. 8 | August 2009
Table 3. Chemoendocrine therapy in patients with ER- positive, HER2-negative disease 2009 Annals of Oncology Volume 20 | No. 8 | August 2009
Table 2. Surrogate definitions of intrinsic subtypes of breast cancer 2011 20 Annals of Oncology Volume 22 | No. 8 | August 2011
Table 3. Systemic treatment recommendations for subtypes 2011 Annals of Oncology Volume 22 | No. 8 | August 2011
Sex hormones - an important role in breast cancer• Bil. oophorectomy - remission of breast ca. in premenopausal women G. Beatson Lancet 1896• 60% of pre. and 75% of postmenopausal patients - estrogen-dependent carcinomas.• the levels of endogenous sex hormones strongly associated with breast cancer risk in postmenopausal women• anti-estrogenic agents – an effective treatment for early breast cancer – to reduce the incidence of contralateral breast cancer – to reduce the primary occurrence of breast cancer
About 5 yrs of tamoxifen vs not in ER+ (or ER-unknown) disease: 15-year probabilities of recurrence and of breast cancer mortality 10 386 women: 20% ER-unknown, 30% node-positive. Error bars are 1SE.
Aromatase & Aromatase inhibitors • Aromatase inhibitors (AIs) – first-line treatment of early & advanced breast cancer.
Results of the ATAC (Arimidex,Tamoxifen, Alone or in Combination) trialafter completion of 5 years’ adjuvanttreatment for breast cancer
• (ER+/PR+/HER2−/cytokeratin 8/18+)• 47 CT, 48 HT• The clinical response rate 66% for CT and 48% for HT (P=0.075).• patients with high Ki67 had a better response with CT (67 versus 42%; P=0.075).. Annals of Oncology 0: 1–6, 2012
Spanish Breast Cancer Research Group (GEICAM) 2006-03 trial
Bedard, P. L. & Cardoso, F. Nat. Rev. Clin. Oncol. 8, 272–279 (2011); published online 1 March2011; doi:10.1038/nrclinonc.2011.19 早期乳癌病人 誰可以不需要接受化學治療 臨床病理因素 新的分子診斷標記
早期乳癌術後輔助化學藥物治療指引 Preferred adjuvant regimens Other adjuvant regimens •TAC • CAF/FAC • CEF/FEC •Dose-dense AC paclitaxel (q2w)• AC docetaxel (q3w) •AC paclitaxel (qw) • AC paclitaxel (q3w) •TC • EC •AC • ATC (q2w) • FEC docetaxel (q3w) Preferred adjuvant regimens for HER2-positive BC •AC paclitaxel + trastuzumab •TCH Other adjuvant regimens for HER2-positive BC •Docetaxel + trastuzumab FEC •Chemotherapy trastuzumab •AC docetaxel + trastuzumab Neoadjuvant •Paclitaxel + trastuzumab CEF + trastuzumabT = docetaxel; A = doxorubicin Adapted from NCCN ClinicalC = cyclophosphamide; F = 5-FU Practice Guidelines, V.1.2009E = epirubicin; TCH = docetaxel, carboplatin, trastuzumab
轉移性乳癌的化學藥物治療指引 Preferred single agents Preferred first-line agents for •Doxorubicin HER2-positive MBC: trastuzumab with •Epirubicin • Paclitaxel ± carboplatin •Liposomal doxorubicin • Docetaxel •Paclitaxel • Vinorelbine •Docetaxel • Capecitabine •Nab-paclitaxel Preferred agents for HER2-positive •Capecitabine MBC after prior trastuzumab •Gemcitabine • Lapatinib + capecitabine •Vinorelbine • Trastuzumab + first-line agents • Trastuzumab + capecitabine Preferred combinations • Trastuzumab + lapatinib • CAF/FAC AT Preferred agents with bevacizumab • FEC CMF • Paclitaxel • AC XT Other combinations • EC GT • Ixabepilone + capecitabineC = cyclophosphamide; A = doxorubicin; F = 5-FU; T = docetaxel or paclitaxelE = epirubicin; M = methotrexate; X = capecitabine; G = gemcitabine Adapted from NCCN Clinical Practice Guidelines, V.1.2010
早期乳癌病人 誰可以不需要接受化學治療 • Challenging - population-wide benefits v.s. accurate individual risk–benefit assessments • In trials, breast cancer regarded as a single disease entity – – anatomical extent of disease at diagnosis – attendant risk of relapseBedard, P. L Nat. Rev. Clin. Oncol. 8, 272–279 (2011)
Efficacy Prior treatment Total AI alone AI + tamoxifen (n=77) (n=21) (n=56)PR 10 (13)* 5 (24)* 5 (9)*SD 6 months 15 (19) 6 (29) 9 (16)CB rate 32% 52% 25%* median duration of 10 months (range 2-20 months) Median TTP : 3 months Median survival: 21 months – 1-year survival rate: 70.4% (95% CI 60.5–82.0) Ingle JN et al. Breast Cancer Res Treat 2004; 88 (Suppl 1): S38, abs 409
Conclusions• Novel mode of action – non-cross resistant with other endocrine therapies法洛 德有不同的作用機轉，與其他抗賀爾蒙藥物無交叉抗性• At least as effective as anastrozole in postmenopausal women with tamoxifen- resistant advanced breast cancer (RCT)法洛德至少與阿美達定有同 樣療效• Well tolerated – low numbers of withdrawals due to adverse events副作用少• Encouraging activity in patients with ABC who have progressed following a non- steroidal AI (Phase 2)在非固醇類芳香酶抑制劑使用無效後使用，仍有療效• Large-scale RCTs to fully determine the role of fulvestrant post non-steroidal Ais 待大型隨機研究證實
TARGETED THERAPY IN BREAST CANCEREarly breast cancer Standards Clinically challenging situations Neoadjuvant setting: New developmentsMetastatic breast cancer New therapy options HER2-negative disease HER2-positive disease: beyond trastuzumab 02.01.2013 120
Treatment concepts in early BC: Today ER and/or PR ER PR and HER2 positive and HER2 positive HER2 negative negative Low risk High riskpN0, G1 pN0, G3 if ≥ pT1b, pN0pN0, G2 + molecular assay pN0 + molecular assaylow risk: high risk• uPA/PAI-1 - uPA/PAI-1• if available/guideline - if available/guidelinesupported: Oncotype supported: OncotypeDX® ; Mammaprint® DX® , Mammaprint® pN+Tamoxifen / AI Chemotherapy Chemotherapy Chemotherapy + Tamoxifen / AI + Trastuzumab ± Tamoxifen / AI Harbeck et al, 2010 02.01.2013 121
The HER2-testing algorithm Patient tumour sample IHC ISH 0 1+ 2+ 3+ - + Retest with Eligible for Eligible for ISH trastuzumab trastuzumab - + Eligible for trastuzumab• If primary ISH testing is used, patients whose tumours overexpress HER2 (i.e. IHC 3+) may not be identified due to the HER2:FISH ratio being <2.0 (e.g. chromosome 17 polysomic cases, Hofmann et al 2007)• ISH-detection mechanism can be fluorescent, chromogenic or silver Hanna & Kwok 2006 ISH, in situ hybridisation
Longterm overall survival advantage with adjuvant trastuzumab: ITT analysis of studies with longer follow-up (update SABCS 09) median follow-up, years No Crossover HERA CTx H 1 year 2 HERA CTx H 1 year Crossover 4 NSABP B-31 / 3 N9831 AC TH H BCIRG 006 AC TH H 5 BCIRG 006 TCH 5 0 1 2 Favouring Advantage without trastuzumab trastuzumab HR Perez et al 2007; Smith et al 2007;EBC, early breast cancer; ITT, intent to treat Gianni et al 2009; Slamon et al 2009
Targeted therapies in HER2+ breast cancer: Trastuzumab, Lapatinib, T-DM1, and Pertuzumab Antibody: Trastuzumab Cytotoxic: IV HER2 DM1 Stable Emtansine linker: MCC P P P P P HER3 Lapatinib Ligand activated Trastuzumab P T-DM1 II Nucleus PertuzumabSpector NL, Blackwell KL. J Clin Oncol 2009;Nelson MH, et al. Ann Pharmacother 2006; Lewis Phillips GD, et al. Cancer Res 2008
Neo-ALTTO: pCR - RatesIn breast In Breast and lymph nodes Baselga et al, S3-3, SABCS 2010; Lancet 2011
EARLY BREAST CANCER – TARGETED THERAPY• Robust data (n>13,000) support the use of one-year adjuvant trastuzumab as standard-of-care in eBC – Concurrent with taxane therapy seems favourable – Small HER2 positive tumors also derive substantial benefit – Older patients derive equal benefit as younger patients – Cardiac dysfunction rate remains low with longer follow-up• Neoadjuvant trastuzumab significantly increases pCR as a surrogate for outcome – standard treatment option in HER2-positive eBC and LABC – second anti-HER2 agent further improves pCR• Current studies further investigating dual HER2 blockade 02.01.2013 Targeted therapy| Prof. Harbeck 126
Targeted therapy| Prof. Harbeck NEW THERAPEUTICS IN HER2-POSITIVE MBC HER2 dimerisation Pertuzumab inhibitor Monoclonal antibody, inhibits HER2 dimerization HER2 ADC T-DM1 Trastuzumab-based ADC, delivers cytotoxic DM1 to HER2 positive tumor cells PI3K inhibitors eg GDC0941 small molecule, selective binding to PI3K isoforms: inhibits PI3K/ Akt pathway Lapatinib Tyrosine kinase reversible inhibitor of EGFR and HER2 tyrosine kinases inhibitors eg Afatinib (BIBW 2992), Neratinib Irreversible Hemmung mehrerer HER Tyrosinkinasen mTOR iInhibitors eg Everolimus small molecule, inhibits mTOR signal transduction pathway HSP 90 inhibitors eg Tanespimycin Antineoplastic antibiotic, inhibits HSP 90 VEGF receptor eg Bevacizumab inhibitors monoclonal antibody, inhibits VEGFADC, antibody-drug conjugate; T-DM1, trastuzumab DM1; PI3K, phosphatidylinositol 3-kinase; EGFR, epidermal growth factor receptor; mTOR, mammaliantarget of rapamycin; HSP, heat-shock protein; VEGF, vascular endothelial growth factor127 02.01.2013
Metastatic Breast Cancer: TARGETED THERAPY• Recent major clinically relevant advances• Biopsy of first metastasis if clinically feasible• HER2-positive disease: – Start targeted therapy as early as possible – Selected ER+ patients: AI + trastuzumab / lapatinib – Trastuzumab+pertuzumab (+docetaxel): new 1stline standard – T-DM1: potential new 2ndline standard – Lapatinib + capecitabine: oral therapy – Trastuzumab beyond progression – Lapatinib + trastuzumab 02.01.2013 Targeted therapy| Prof. Harbeck 128
Metastatic Breast Cancer: TARGETED THERAPY• HER2-negative disease: – Everolimus + Exemestane: after progression on AI – Bevacizumab: first-line option with paclitaxel / capecitabine• Many open clinical questions (in HER2-positive disease) remain: – predictive markers – optimal sequence – drug availability – …• Participation in clinical trials of greatest importance 02.01.2013 Targeted therapy| Prof. Harbeck 129
• The “one size fits all” model should no longer be used in MBC• therapy should be tailored to individual patients according to patient and tumor characteristics, as well as molecular subtypes and targets.• Hormonal therapy, chemotherapy, targeted anti-ErbB2 therapy, antiangiogenic therapy, anti-DNA repair therapy, and many others
N.S. El Saghir et al. / Critical Reviews in Oncology/Hematology xxx (2011)
Fig. 2. Overall management of metastatic breast cancer (MBC).
Triple negative breast cancer• Systemic treatment options – – Cytotoxic chemotherapy with poor Overall survival• targeted approaches – – agents with poly(ADP-ribose) polymerase inhibitory properties • iniparib (BSI-201), olaparib (AZD2281), veliparib (ABT-888),• antiangiogenic agents – – bevacizumab and sunitinib• EGFR blockers – – cetuximab and erlotinib.