Adjuvant Chemotherapy TNBC & HER2 Subtype

Gun Min Kim Yonsei Cancer Center

Division of Medical Oncology Department of Internal Medicine

Yonsei University College of Medicine gmkim77@yuhs.ac

2015.08.15

mailto:gmkim77@yuhs.ac�

Contents

• HER2 양성 유방암 – Chemotherapy Indication & Regimen – Herceptin – 보험 급여 유의사항

• 삼중 음성 유방암

– Chemotherapy Indication & Regimen – 보험 급여 유의사항

HER2+ BREAST CANCER

Indication

• T ≤ 0.5 cm: No adjuvant chemotherapy • T 0.6 – 1.0 cm: Consider adjuvant chemotherapy with Herceptin (IIA) • T > 1 cm or Node (+): Adjuvant chemotherapy with Herceptin (I)

Node (-)

Node (+)

≤ 0.5cm

0.6-1.0cm

> 1.0cm

No adjuvant CTx or Herceptin

Consider adjuvant CTx + Herceptin

Adjuvant CTx + Herceptin

Learning Points

• Chemotherapy regimen – Anthracycline vs. Non-anthracycline

• Duration of Herceptin – 6 months vs. 1 year vs 2 year – Cardiac monitoring

• Small (

Choice of Chemotherapy Regimen

• Chemotherapy Regimen – Anthracycline-based: AC#4 Taxane#4 + H 1Y – Non-anthracycline-based: TCH#6 H 1Y

NSABP B311 (n=2043)

N98311 (n=1633)

HERA2 (n=5081)

BCIRG-0063 (n=3222)

FINHER4 (n=1010)

A AC#4 Paclitaxel #4

AC#4 Paclitaxel#4 H

Observation

AC#4 Docetaxel#4

Docetaxel#3 FEC#3 ± H

B AC#4 Paclitaxel #4 +H

AC#4 Paclitaxel#4 H

1 Yr of H AC#4 Docetaxel#4 + H

Vinorelbine#3 FEC#3 ± H

C AC#4 Paclitaxel#4 + H

2 Yr of H

Docetaxel+Carboplatin#6 + H

1. N Engl J Med 2005;353:1673-84 2. N Engl J Med 2005;353:1659-72 3. N Engl J Med 2011;365:1273-83 4. N Engl J Med 2006;354:809-20

Cardiac Risk Assessment

J Clin Oncol 30:3792-3799, 2012

B-31: Risk Factors for CHF

Cardiac Monitoring Algorithm

Suter T M et al. JCO 2007;25:3859-3865

Duration of Herceptin

• 3P (Payer/Patient/Physician) vs. Roche

• 1 year vs. 2 years: HERA1 • 1 year vs. 6 months: PHARE2

1. Lancet 2013; 382: 1021–28 2. Lancet Oncol 2013; 14: 741–48

HERA (Median f/u of 8 years)

• 2Y is not superior to 1Y • 1Y of Herceptin: Clear DFS and OS

benefit Standard of Care

Lancet Oncol 2013; 14: 741–48

PHARE (Non-Inferior Study)

• Median 3.5 year f/u: Fail to show 6M is not inferior to 12M

• Despite the higher rates of cardiac events, 12M Standard of Care

Lancet Oncol 2013; 14: 741–48

* Cardiac Event 12M vs. 6M 5.7% vs. 1.9% (p

BCIRG 006

BCIRG-006 (Anthracycline vs. Non-anthracycline)

• The risk–benefit ratio: TCH > AC-TH • Similar Efficacy & Fewer Toxicity • 급여적용은 LN positive만 가능

N Engl J Med 2011;365:1273-83.

Small (

pT1a/bN0 HER2+ Breast Cancer Outcomes

THE AMERICAN JOURNAL OF HEMATOLOGY/ONCOLOGY 2014 Vol 11. No1

Benefits of Herceptin in pT1a/bN0 Breast Cancer

THE AMERICAN JOURNAL OF HEMATOLOGY/ONCOLOGY 2014 Vol 11. No1

APT trial

• Single arm, Phase II study – N=410, 2007-2010 – Node(-) T

보험급여 기준

• T ≤ 0.5 cm: No adjuvant chemotherapy or Herceptin – pN1mi: Node (+)로 Herceptin 급여 청구 가능

• T 0.6 – 1.0 cm: Consider adjuvant chemotherapy

with Herceptin (비급여) – Adjuvant chemotherapy Herceptin (비급여) 1Y

• T > 1 cm or Node (+): Adj CTx with Herceptin 1Y – Adjuvant chemotherapy Herceptin 1Y – AC#4 TH#4 H#14 – TCH#6 H#12 (Node+만 급여)

* Adjuvant Herceptin(급여) 1Y 을 사용하기 위해서는 항암치료를 반드시 시행해야 함.

* Adjuvant Taxane+Herceptin 을 사용하기 위해서는 AC#4를 반드시 시행해야 함.

Herceptin SC

• 적응증 – 유방암에서 IV Herceptin과 동일한 적응증으로 허

가됨 • 용량: Fixed dose 600mg • 투여방법

– 3-5분간 허벅지에 피하주사 • 비용

– 130만원/Vial – 50kg이상의 경우 IV 보다 저렴

• 55kg: IV 2700만원 vs. SC 2300만원 • 45kg: IV 1850만원 vs. SC 2300만원

HannaH Trial

Other Targeted Therapy

• Bevacizumab: No benefit • Lapatinib: No significant benefit

• Currently ongoing trials

– Pertuzumab: APHYNITY – T-DM1: KATHERINE, KAITLIN

Summary (HER2+ BC)

• Chemotherapy Regimen – AC#4 followed by Taxane+Herceptin#4 – TCH (Docetaxel+Carboplatin+Herceptin)#6

• Duration of Herceptin: 1Y

– 3개월 간격 cardiac function monitoring

• Node(-) Small Tumor (≤1cm) – Risk-Benefit 고려 (특히 poor risk feature (1cm size, high histologic grade, HR-,

young age등) 가진 경우

• 보험급여 기준 – T 0.6 – 1.0 cm: Herceptin (비급여) – T > 1 cm or Node (+): Adjuvant CTx with Herceptin 1Y

• AC#4 TH#4 • TCH#6 (Node+만 급여)

– Herceptin SC 허가됨

TRIPLE NEGATIVE BREAST CANCER

Indication

• T < 0.5 cm: No adjuvant chemotherapy • T 0.6 – 1.0 cm: Consider adjuvant chemotherapy (IIA) • T > 1 cm or Node (+): Adjuvant chemotherapy (I)

Node (-)

Node (+)

≤ 0.5cm

0.6-1.0cm

> 1.0cm

No adjuvant CTx

Consider adjuvant CTx

Adjuvant CTx

Regimen ??

Adjuvant Chemotherapy Regimen

CMF ≒ AC

FAC FEC

TAC AC wP

TC

FEC T

AC T

ddAC T

CMF ≒ AC < TC TAC ≒ AC/FEC T < ddAC wP

• No single standard regimen in BC • Anthracycline-based Taxane

Learning Points

• Chemotherapy regimen – Anthracycline (Doxorubicin vs Epirubicin) – Taxane (Paclitaxel vs Docetaxel) – TC / TAC – Dose-dense regimen

• Others – Bevacizumab – PARP inhibitor

Anthracyclines

• Doxorubicin-based – AC (60/600) – FAC (500/50/500)

• Epirubicin-based – EC (90/600) – FEC (600/90/600, 500/100/500)

* AC T regimen은 현재 AC 용법을 사용해야만 보험 급여 적용이 됨

Paclitaxel vs Docetaxel

• ECOG 1199 • N=4950, 1999-2002 • Node(+) or high-risk Node(-) T2/3N0 • 2X2 Factorial design

– AC Paclitaxel Q3W – AC Weekly Paclitaxel – AC Docetaxel Q3W – AC Weekly Docetaxel

J Clin Oncol 2015 33:2353-2360.

ECOG 1199 Long-Term Result

J Clin Oncol 2015 33:2353-2360.

TNBC subtype All Population

TC vs. AC

• US Oncology 9735 • N=510, 1997-2000 • TC#4 vs. AC#4

– T 1cm~7cm – N0 50%, N1 40%, N2

10%

J Clin Oncol 2009 27:1177-1183

TAC vs. FAC

• BCIRG 0011 • N=1491, 1997-1999 • Node (+) BC • T4, N3 제외

• GEICAM 98052 • N=1060, 1999-2003 • High-risk Node(-) BC • T >2cm, ER/PR-, HG

2 or 3, Age

Adjuvant TAC

BCIRG 001 GEICAM 9805

TNBC subgroup (GEICAM 9805)

Lancet Oncol. 2013 Jan;14(1):72-80.

Dose-dense Chemotherapy

• Dose-dense(DD) regimen – DD AC: AC (60/600) 2주 간격 – DD EC: EC (90/600) 2주 간격 – DD Paclitaxel: Paclitaxel 175mg/m2 2주 간격 – Weekly Paclitaxel: Paclitaxel 80mg/m2

• DD regimen vs. Conventional Tx – CALGB 97411 – GIM Phase III2

1. J Clin Oncol 2003 21(8):1431–1439. 2. Lancet 2015; 385: 1863–72

DD Regimen in Adjuvant Setting

CALGB 9741 GIM Phase III

Lancet 2015; 385: 1863–72

DFS of DD Regimen by Subtype

ER(-) Patients ER(+) Patients

Lancet 2015; 385: 1863–72

Meta-analysis of DD regimen

Breast Cancer Res Treat (2015) 151:251–259

ER+ Patients (HR 0.93, 95% CI 0.82–1.05) P=0.25

All Patients

ER(-) Patients

Prophylactic G-CSF in DD AC

• Filgrastim – AC 항암치료 48시간 이후 시작하여 daily G-CSF

투여 (ANC가 nadir 지나서 회복될 때까지) – 단점: Real practice에서 적용하기 어려움, ANC

500이상인 경우 비보험

• Peg-filgrastim – AC 항암치료 24시간 이후에 한번 투여 – 단점: 90만원/V의 고가, 비보험 – Neulasta: original – Neulapeg, Dulastin: generic (60만원/V)

Risk of hospitalization according to chemotherapy regimen

• SEER/Texas Cancer Registry • N=9327 EBC, 2003-2007

J Clin Oncol. 2014 Jul 1;32(19)

보험급여 기준

• T ≤ 0.5 cm: No adjuvant chemotherapy – pN1mi: Node (+)로 청구 가능

• T 0.6 – 1.0 cm: Consider adjuvant chemotherapy

– AC#4, FAC#6, CMF#6

• T > 1 cm or Node (+): Adjuvant chemotherapy – Node (+) BC : AC#4 T#4, TAC#6, TC#4 – Node (-) BC

• T > 1cm: AC#4, TC#4 (T 1~7cm) • T2/3N0: AC#4 weekly paclitaxel#12 • High-risk (T > 2cm or 35세 미만 or HG 2-3 or TNBC): TAC#6

Dose dense regimen 사용은 급여 청구에 문제 없음

Other Therapy

• Bevacizumab: No benefit • Platinum: No data

• Currently ongoing trials

– PARP inhibitor: OlympiA (BRCA+)

Summary (TNBC)

• Chemotherapy Indication – T ≤ 0.5 cm: No adjuvant chemotherapy – T 0.6 – 1.0 cm: Consider adjuvant chemotherapy (IIA) – T > 1 cm or Node (+): Adjuvant chemotherapy (I)

• Chemotherapy Regimen (급여조건)

– Node (-): AC#4, CMF#4 • T2/3N0: AC->weekly paclitaxel • T 1~7cm: TC#4 • High-risk (T > 2cm or 35세 미만 or HG 2-3 or TNBC): TAC#6

– Node (+): AC#4 T#4, TAC#6, TC#4 – Dose-dense regimen 사용 가능 (with prophylactic G-CSF)

• Others

– Bevacizumab: No role in adjuvant setting – Platinum: Benefit in neoadjuvant setting, Adjuvant role? – PARP inhibitor: Current investigating

CASE 1

• F/35 • EBC s/p PM c SLNB

– IDC 0.8cm, LN 0/7 – N3H3, LVI (+) – ER/PR/HER2 -/-/3+ – pT1N0

• Adjuvant therapy?

High risk group consider adjuvant chemotherapy + Herceptin

CASE 2

• F/55 • Adjuvant Herceptin 치료 중 EF 감소

– Baseline EF=55% – 6 Cycle후 EF=45%

• No CHF symptoms • Next Plan?

Herceptin 일시 중단하고 3주후 재평가 EF 회복하면 재투여 고려

CASE 3

• F/40 • EBC s/p PM c ALND

– IDC 2.2cm, LN 2/7 – N3H3, ER/PR/HER2 -/-/- – pT2N1

• Adjuvant chemotherapy regimen?

AC T vs. TAC Weekly paclitaxel vs. docetaxel q3w Dose dense vs. standard

감사합니다.

Adjuvant Chemotherapy �TNBC & HER2 SubtypeContentsHER2+ Breast CancerIndicationLearning PointsChoice of Chemotherapy RegimenCardiac Risk AssessmentB-31: Risk Factors for CHFCardiac Monitoring AlgorithmDuration of HerceptinHERA (Median f/u of 8 years)PHARE (Non-Inferior Study)BCIRG 006BCIRG-006 �(Anthracycline vs. Non-anthracycline)Small (