Molecular Classification of Breast Cancer

혈액종양내과분과연수강좌 2011 Advances in treatment strategies Breast Cancer 연세의대내과학교실 손주혁

Issues Adjuvant taxanes Avoiding adjuvant chemotherapy Anthracyclines in EBC Adjuvant chemotherapy in older women Bisphosphonate in EBC Trastuzumab in neoadjuvant therapy Adjuvant AIs Molecular targets in MBC Bevacizumab and Eribulin

Early Breast Cancer

Adjuvant chemotherapy is beneficial regardless of age -EBCCTG (194 trials, n=144,939) Lancet 2005

Adjuvant chemotherapy is beneficial regardless of LN status -EBCCTG (194 trials, n=144,939) Lancet 2005

Sequential docetaxel as adjuvant chemotherapy for EBC (TACT) -phase III open-label randomized trial N(+) & high risk N(-) n=4162 Epirubicin 60mg/m2? Lancet 2009

Taxane adjuvant trials Sequential vs concurrent? Lancet 2009

Longer therapy, iatrogenic amenorrhea, and survival in EBC - NSAB B-30 N(+), n=5351 8 vs 4 cycles? NEJM 2010

BCIRG 005 HR=1.002 5 Year DFS; 78.9% vs 78.6% 4 x AC 4 x Docetaxel (100 mg/m 2 ) R Doxorubicin 60 mg/m 2 Cyclophosphamide 600 mg/m 2 6 x TAC (75 mg/m 2 ) N (+), Node HER2 positive (-) n=3298 HER2 ve (FISH) N=3130 350 centers Doxorubicin 50 mg/m 2 Cyclophosphamide 500 mg/m 2 SABCS 2008

Adjuvant Docetaxel for High-Risk, Node Negative Breast Cancer -GEICAM 9805 rimary G CSF prophylaxis

Can some patients avoid adjuvant chemotherapy for EBC? Nature Rev. Clin Oncol 2009

Anthracyclines in the treatment of EBC LN (+), LN (-) patients JCO 2006

Anthracyclines in the treatment of EBC SABCS 2009

Adjuvant chemotherapy in older women NIH consensus 2000

Adjuvant chemotherapy in older women NEJM 2009

Bisphosphonate in EBC (ABCSG 12 Trial) Stage I/II, HR+ BC, >1800 premenopausal women Treat with zometa for 3 years rimary Objectives: DFS after 5 Y Secondary Objectives: RFS and OS at 5 Y, BMD

Bisphosphonate in EBC(AZURE Trial) Treatment duration: 5 yrs atients with stage II/III BC, Stratification: N+/N-, T score, ER status, chemotherapy type, pre/postmenopausal, statins (N = 3360) 174 centers, mostly UK Standard (neo)adjuvant therapy Standard (neo) adjuvant therapy + Zoledronic acid 4 mg 6 doses Q3-4 wks, then 8 doses Q3 mos, then 5 doses Q6 mos rimary endpoint : DFS Secondary endpoints : BMFS, SREs, OS, AEs, predictive biomarkers Interim analysis performed in September 2008 SABCS 2010

Bisphosphonate in EBC(AZURE Trial) Zometa is beneficial to Estrogen-deprived patients? SABCS 2010

Trastuzumab in neoadjuvant therapy (NOAH Trial) Lancet 2010

Adjuvant AI Trials ASCO recommendations 2010

ASCO Recommendations Q 호르몬수용체양성폐경후유방암환자수술후보조요법으로서어떤약을사용하나? ü 재발율을낮추기위해 AI (aromatasi inhibitor) 사용을적극적으로고려해야함. 처음부터혹은 tamoxifen 2~3 년사용후 AI 를사용할수있으며 5 년을넘기진말아야함. Q 호르몬보조요법의사용기간은? ü 처음부터혹은 tamoxifen 5 년사용후에는 AI 를 5 년이상사용하지말아야하고순차적요법으로서 tamoxifen 2~3 년을사용한경우는나머지를 AI 를사용해서 5 년을채우고 AI 부작용으로더이상사용하기어려운경우는 tamoxifen 을써서 5 년을채우는것을반드시고려해야함. Q Tamoxifen 을먼저사용한환자내원시언제 AI 사용을고려하나? ü 2~3 년지나서 AI 로바꾸는것이추천되며 tamoxifen 을 5 년사용후 AI 를사용하는것도가능함. Q AI 를사용해야하는 subgroup 이있는지? ü 특별한 marker 나임상적인군은잘연구되지않았음. 남성유방암은아직 tamoxifen 이표준치료이고 CY2D6 는내분비요법을결정할때추천되지는않지만 CY2D6 기항제 ( 예, paroxetine, fluoxetine) 을사용할때는 tamoxifen 사용시약물간상호작용으로주의를요함

ASCO Recommendations Q 호르몬보조요법의독성및위험성은? ü 임상의사는호르몬보조요법의부작용, 환자의선호도, 그리고환자의기존의질별을고려하여약제를선택해야함. 환자와있을수있는부작용에대해치료전상의해야하며부작용이심해환자가복용을잘못하는경우약제를바꾸는권유해야함. ü 대부분의독성은 mild~moderate 하고중대한독성은드묾. Tamoxifen 의장기독성은잘알려져있지만 AI 는더지켜보아야함. Q 폐경전여성의호르몬치료는? ü 진단당시 re- & perimenopause 환자는 tamoxifen 5 년을사용해야함.

Toxicity Drug 비고 Cardiovascular (ischemic heart disease) Hypercholesterolemia, hypertension AI>Tam AI>Tam small difference small difference Venous thromboembilism (DVT) AI<Tam 1~2% than AI Osteoporosis and bone fracture AI>Tam 2~4% than tamoxifen Musculoskeletal/Arthralgia syndrome AI bone and joint symptom, symmetric pain, stiffness, achiness without evidence of rheumatologic disease; wide spread but incidence unknown; no known intervention. Gynecologic health (endometrial cancer, benign endometrial pathology) Hot flush Vaginal dryness Tam 1% of the patients AI<Tam AI><Tam mixed evidence

Metastatic Breast Cancer

Cross-talk between ER and HER2 & EGFR Estrogen lasma Membrane Non genomic ER mediated response I3K HER2/HER2 or HER1/HER2 SOS RAS RAF AIs 1 ER Nuclear genomic ER mediated response mtor Akt MAK MEK Cytoplasm Fulvestrant 2 ER ER p160k CB ERE Basal Transcription machinery ER Target gene transcription Nucleus

Overcoming resistance to endocrine therapy with signal transduction blockade Serena Di Cosimo et al. Nat Rev Clinical Oncology 2008

Stemke-Hale K et al. Cancer Res 2008

Scientific rationale for combining IGF-1R monoclonal antibody plus mtor inhibitor IGF1R Estrogen lasma Membrane 7 IRS-1 I3K HER2/HER2 or HER1/HER2 Akt AIs 1 ER 5 Everolimus mtor Cytoplasm Fulvestrant 2 ER ER p160k CB ERE Basal Transcription machinery ER Target gene transcription Nucleus

6 Scientific rationale for combining IGF-1R monoclonal antibody plus mtor inhibitor in luminal cancers lasma Membrane IGF1R 7 IRS-1 I3K HER2/HER2 or HER1/HER2 Akt 5 Everolimus mtor Cytoplasm ER ER p160k CB Basal Transcription machinery ERE ER Target gene transcription Nucleus

Trastuzumab ertuzumab On phase III trials Trastuzumab-DM1 EGFR HER2 N H Trastuzumab Reversible EGFR & HER2 dual inhibitor; lapatinib Irreversible EGFR & HER2 dual inhibitor; neratinib

HS90; molecular chaperone for maturation of proteins HS90 inhibitor; tanespimycin have demonstrated anti-tumor activity c trastuzumab in phase I Mikko Taipale et al. Nature Rev Molecular Cell Biology 2010

J Drink lglehart and Daniel Silver NEJM 2009

HR repair HR repair HR repair HR repair Synthetic lethality BRCA1/BRCA2 carrier normal tissue cells Few normal tissue effects DNA repair BRCA1/BRCA2 carrier DNA normal tissue cells repair Base excision DNA repair Homologous recombination (HR) repair AR inhibitor Base excision DNA repair BRCA1/BRCA2 carrier Tumor cells Specific tumor cell killing AR inhibitor Base excision DNA repair

Bevacizumab in MBC FDA NEWS RELEASE For Immediate Release: Dec. 16, 2010 Media Inquiries: Erica Jefferson, 301-796-4988, erica.jefferson@fda.hhs.gov Consumer Inquiries: 888-INFO-FDA FDA begins process to remove breast cancer indication from Avastin label Drug not shown to be safe and effective in breast cancer patients The U.S. Food and Drug Administration announced today that the agency is recommending removing the breast cancer indication from the label for Avastin (bevacizumab) because the drug has not been shown to be safe and effective for that use. The agency is making this recommendation after reviewing the results of four clinical studies of Avastin in women with breast cancer and determining that the data indicate that the drug does not prolong overall survival in breast cancer patients or provide a sufficient benefit in slowing disease progression to outweigh the significant risk to patients. These risks include severe high blood pressure; bleeding and hemorrhage; the development of perforations (or holes ) in the body, including in the nose, stomach, and intestines; and heart attack or heart failure. In July 2010, after reviewing all available data an independent advisory committee, composed primarily of oncologists, voted 12-1 to remove the breast cancer indication from Avastin s label. After careful review of the clinical data, we are recommending that the breast cancer indication for Avastin be removed based on evidence from four independent studies, Janet Woodcock, M.D., director of the FDA s Center for Drug Evaluation and Research. Subsequent studies failed to confirm the benefit observed in the original trial. None of the studies demonstrated that patients receiving Avastin lived longer and patients receiving Avastin experienced a significant increase in serious side effects. The limited effects of Avastin combined with the significant risks led us to this difficult decision. The results of these studies are disappointing. We encourage the company to conduct additional research to identify if there may be select groups of patients who might benefit from this drug.

üsynthetic compound mimics parts of molecule in sea sponge ünon-taxane microtube inhibitor The drug eribulin was inspired by a compound from the sea sponge Halichondria okadai.yasunori Saito

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