Breast Cancer

Breast Cancer

연세 의대 내과학 교실 손 주 혁

혈액종양내과분과 연수강좌 2011 Advances in treatment strategies

Molecular Classification of Breast Cancer

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

Lancet 2009

N(+) & high risk N(-)

n=4162

Epirubicin 60mg/m2 ?

Taxane adjuvant trials

Lancet 2009

Sequential vs concurrent ?

Longer therapy, iatrogenic amenorrhea, and survival in EBC - NSABP B-30

NEJM 2010

N(+) , n=5351

8 vs 4 cycles ?

Node positive HER2–ve (FISH)

N=3130 350 centers

4 x AC → 4 x Docetaxel (100 mg/m

)

Doxorubicin 60 mg/m

Cyclophosphamide 600 mg/m

6 x TAC (75 mg/m

)

Doxorubicin 50 mg/m

Cyclophosphamide 500 mg/m

BCIRG 005

R

N (+), HER2 (-) n=3298

SABCS 2008

HR=1.002 5 Year DFS;

78.9% vs 78.6%

Adjuvant Docetaxel for High-Risk, Node Negative Breast Cancer -GEICAM 9805

Primary G CSF prophylaxis

Can some patients avoid adjuvant chemotherapy for EBC?

Nature Rev. Clin Oncol 2009

Anthracyclines in the treatment of EBC

JCO 2006

LN (+), LN (-) patients

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

Primary Objectives: DFS after 5 Y

Secondary Objectives: RFS and OS at 5 Y, BMD

Bisphosphonate in EBC(AZURE Trial)

Standard (neo)adjuvant therapy

Standard (neo) adjuvant therapy +

then 8 doses Q3 mos, then 5 doses Q6 mos

Patients with stage II/III BC, Stratification:

N+/N-, T score, ER status, chemotherapy type, pre/postmenopausal,

statins (N = 3360)

174 centers, mostly UK

Treatment duration: 5 yrs

Primary endpoint : DFS

Secondary endpoints : BMFS, SREs, OS, AEs, predictive biomarkers Interim analysis performed in September 2008

SABCS 2010

Bisphosphonate in EBC(AZURE Trial)

SABCS 2010

Zometa is beneficial to Estrogen-deprived patients?

Trastuzumab in neoadjuvant therapy

(NOAH Trial)

Lancet 2010

Adjuvant AI Trials

ASCO

recommendations 2010

Adjuvant AI Trials

ASCO

recommendations 2010

ASCO Recommendations

Q 호르몬 수용체 양성 폐경후 유방암환자 수술후 보조요법으로서 어떤 약을 사용하나?

ü 재발율을 낮추기위해 AI (aromatasi inhibitor)사용을 적극적으로 고려해야 함. 처음부 터 혹은 tamoxifen 2~3년 사용후 AI를 사용할 수 있으며 5년을 넘기진 말아야 함.

Q 호르몬 보조요법의 사용기간은?

ü 처음부터 혹은 tamoxifen 5년 사용후에는 AI를 5년이상 사용하지 말아야 하고 순차적 요법으로서 tamoxifen 2~3년을 사용한 경우는 나머지를 AI를 사용해서 5년을 채우고 AI 부작용으로 더 이상 사용하기 어려운 경우는 tamoxifen을 써서 5년을 채우는 것을 반드시 고려해야 함.

Q Tamoxifen 을 먼저 사용한 환자내원시 언제 AI 사용을 고려하나?

ü 2~3년 지나서 AI로 바꾸는 것이 추천되며 tamoxifen을 5년 사용후 AI를 사용하는 것도 가능함.

Q AI를 사용해야하는 subgroup이 있는지?

ü 특별한 marker나 임상적인 군은 잘 연구되지 않았음. 남성유방암은 아직 tamoxifen이

표준치료이고 CYP2D6는 내분비요법을 결정할 때 추천되지는 않지만 CYP2D6 기항

제 (예, paroxetine, fluoxetine)을 사용할 때는 tamoxifen 사용시 약물간 상호작용으로

주의를 요함

Q 호르몬 보조요법의 독성 및 위험성은?

ü 임상의사는 호르몬 보조요법의 부작용, 환자의 선호도, 그리고 환자의 기존의 질별을 고려하여 약제를 선택해야 함. 환자와 있을 수 있는 부작용에 대해 치료전 상의해야 하 며 부작용이 심해 환자가 복용을 잘 못하는 경우 약제를 바꾸는 권유해야 함.

ü 대부분의 독성은 mild~moderate하고 중대한 독성은 드묾. Tamoxifen의 장기 독성은 잘 알려져 있지만 AI는 더 지켜보아야 함.

Q 폐경전 여성의 호르몬 치료는?

ü 진단 당시 Pre- & perimenopause 환자는 tamoxifen 5년을 사용해야 함.

ASCO Recommendations

Toxicity Drug

Cardiovascular (ischemic heart disease)

AI>Tam small difference

Hypercholesterolemia, hypertension

AI>Tam 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)

Tam 1% of the patients

Hot flush AI<Tam

Vaginal dryness AI><Tam mixed evidence

Metastatic Breast Cancer

ER ER

PI3K PI3K

Akt Akt

mTOR mTOR

SOS SOS

RAS RAS

RAF RAF MEK MAPK

P P

P P P

ER ER p160Kp160K CBP

Basal Transcription

machinery Basal Transcription

machinery P

P

P P P

AIs

Estrogen

Plasma Membrane

HER2/HER2 HER1/HER2or

ERE ER Target gene transcription

Cytoplasm

2

Fulvestrant

1

Nucleus

Non genomic ER mediated response

Nuclear genomic ER mediated response

Cross-talk between ER and HER2 & EGFR

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

P P P P

ER ER

PI3K PI3K

Akt Akt

mTOR mTOR

P P

ER ER p160Kp160K CBP

Basal Transcription

machinery Basal Transcription

machinery P

P

P P P

AIs

Estrogen

Plasma Membrane

IGF1R

HER2/HER2 HER1/HER2or

ERE ER Target gene transcription

Cytoplasm

Everolimus

7

5

2

Fulvestrant

1

Nucleus

IRS-1

Scientific rationale for combining IGF-1R monoclonal antibody plus mTOR inhibitor

P P P P

PI3K PI3K

Akt Akt

mTOR mTOR

P P

ER ER p160Kp160K CBP

Basal Transcription

machinery Basal Transcription

machinery P

P

P P P

Plasma Membrane

IGF1R

HER2/HER2 HER1/HER2or

ERE ER Target gene transcription

Cytoplasm

Everolimus

7

5

Nucleus

IRS-1

Scientific rationale for combining IGF-1R monoclonal antibody plus mTOR inhibitor in luminal cancers

6

Trastuzumab Pertuzumab

EGFR HER2

Reversible EGFR & HER2 dual inhibitor; lapatinib Irreversible EGFR & HER2 dual inhibitor; neratinib

Trastuzumab

N H

On phase III trials

Trastuzumab-DM1

HSP90; molecular chaperone for maturation of proteins

HSP90 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

Synthetic lethality

BRCA1/BRCA2 carrier normal tissue cells

normal tissue cells

DNA repair

DNA repair

Base excision DNA repair

Homologous recombination (HR) repair

PARP inhibitor

Base excision

DNA repair HR repair

Few normal tissue effects

HR repair

BRCA1/BRCA2 carrier Tumor cells

HR repair

PARP inhibitor

Base excision DNA repair

Specific tumor cell killing

HR 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.”

The drug eribulin was inspired by a compound from the sea sponge Halichondria okadai.Yasunori Saito

üSynthetic compound mimics parts of molecule in sea sponge

üNon-taxane microtube inhibitor

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