Newest treatments for all stages of breast cancer including hormonal treatments and

developments in HER2 positive breast cancer

Clifford Hudis, M.D.

Chief, Breast Medicine Service, MSKCC

Professor of Medicine, Weill Cornell Medical College

Immediate Past President, American Society of Clinical Oncology

Cancer in general

300,000,000 Americans

• 560,000 cancer deaths (2/1000/year = 0.2%)

– lung cancer, (160,000)

– colorectal (53,000)

– breast (41,000)

– pancreas (33,000)

– prostate (27,000).

• Mostly age 55 and older.

• Deaths in childhood (0 and 14) are rare (1,500)

Epidemiology

200,000 new cases

Approx 40,000 deaths

Lifetime risk: Approximately 1:8 will develop

breast cancer (cumulative risk)

American Cancer Society. Detailed Guide: Breast Cancer: What are the Key Statistics for

Breast Cancer? Available at: http://www.cancer.org. Accessed Sept. 14, 2009.

Breast Pathology

Breast Carcinoma

In situ

Infiltrating Carcinoma

Ductal Carcinoma In Situ

Lobular Carcinoma In Situ

Infiltrating Ductal, nos (70 - 80%)

Invasive Lobular (5 - 10%)

Others

From: DeVita VT et al. Cancer: Principles and Practice of Oncology. 7th Ed. Philadelphia, Pennsylvania: Lippincott Williams & Wilkins; 2005:1415-1477.

Risk Factors for Breast Cancer

• Gender

• Age

• Race

• Diet high in fat

• Early onset of menses and late menopause

• Late or no pregnancies

• Family history (BRCA1, BRCA2)

• Dense breast tissue

• Alcohol consumption

• Hormone supplementation

American Cancer Society. Breast Cancer Facts and Figures 2005-2006.

Sub-classification of BC: Three Diseases

ER and/or PR (+) ER and PR (-)

HER2

(+)“Triple Positive”

“HER2

positive”

HER2

normal

“Hormone

sensitive”“TNBC”

Sub-classification of BC: Three Diseases

ER and/or PR (+) ER and PR (-)

HER2

(+)“Triple Positive”

“HER2

positive”

HER2

normal

“Hormone

sensitive”“TNBC”

Sub-classification of BC: Three Diseases

ER and/or PR (+) ER and PR (-)

HER2

(+)“Triple Positive”

“HER2

positive”

HER2

normal

“Hormone

sensitive”“TNBC”

Sub-classification of BC: Three Diseases

ER and/or PR (+) ER and PR (-)

HER2

(+)“Triple Positive”

“HER2

positive”

HER2

normal

“Hormone

sensitive”“TNBC”

How Long Should Post-Operative Hormone Therapy Last?

Survival after a Diagnosis of Breast Cancer.

Foulkes WD et al. N Engl J Med 2010;363:1938-1948.

Breast Cancer Recurrences Occur Late

13

SUPPORTING TRIALS

• ATAC – updated at SABCS 2004

• BIG FEMTA

• TEAM (not yet reported)

SUPPORTING TRIALS

• no reported trials

• BIG FEMTA

SUPPORTING TRIALS

• IES – updated at SABCS 2004

• ITA

• ARNO/ABCSG - reported at SABCS 2004

Adjuvant AI Hormonal Therapy Trial Designs

*

* Note that some patients from the original newly diagnosed population

are lost due to recurrence or adverse events prior to randomization

DIRECT COMPARISON

SWITCHING

*

SEQUENCING

EXTENDED ADJUVANTSUPPORTING TRIALS

• MA-17 – updated ASCO 2004

MA.17 Letrozole in the Extended Adjuvant Setting Improved DFS with 5 yrs of Letrozole After 5 yrs of Tamoxifen

Goss. PE. Breast Cancer Res Treat. 2007 October; 105(Suppl 1): 45–53. Epub 2007 Oct 3.

B33: (Stopped Early) Exemestane versus placebo

(intent-to-treat, eligible patients, w/follow-up): DFS

Mamounas E P et al. JCO 2008;26:1965-1971

©2008 by American Society of Clinical Oncology

NSABP B14: Patients Re-randomized After 5 years of

Tamoxifen to Either Placebo or Prolonged Tamoxifen

(10 vs 5 years)

Fisher B et al. JNCI J Natl Cancer Inst 2001;93:684-690

n=117

2

Objectives of ATLAS & aTTom

• Randomise at least 20,000 women

between 10 and 5 years of tamoxifen

(to detect reliably, or refute reliably, a

2-3% improvement in survival)

• Follow-up randomised women for at

least 15 years (because 10 or more

years is needed to see full benefits

from longer tamoxifen*)*Peto R, Five Years of Tamoxifen—or More? JNCI 1996

ECOG, Scottish &

NSABP B-14 1,588

ATLAS 11,646

aTTom 6,953

ALL TRIALS 20,187

20,187 women with ER-positive or ER-unknown disease randomised in 5 trials

of 10 vs 5 years of tamoxifen:

ATLAS, Lancet 2013; 381: 805–16

aTTom: Proc ASCO 2013

San Antonio Breast Cancer Symposium – Cancer Therapy and Research Center at UT Health Science Center – December 4-8, 2012 This presentation is the intellectual property of ATLAS. Contact ATLAS@CTSU.ox.ac.uk for permission to reproduce or distribute.

ATLAS: 6846 women, ER+, 10 vs 5 years tamoxifen RECURRENCE BREAST CANCER MORTALITY

aTTom: 10 vs 5 years of tamoxifen:

Recurrence by treatment ASCO 2013

580 vs 672 recurrences

RR=0.85 (95%CI 0.76-0.95)

p=0.003

Presented ASCO 2013

Concepts to consider •Chronic, relatively steady recurrence risk

•Relatively low rate of mortality

•Time Dependent Effects:

Duration of effect on the rate

Development of resistance

Development of intolerance

•Long term toxicities

•Absolute benefit to the individual

•DRUG-SPECIFIC or DURATION (of any rx)?

ASCO’s CancerLinQ: Big Data

Sledge GW, Hudis CA, Swain SM, et al: ASCO's approach to a learning health care system in oncology. J Oncol Pract 9:145–148, 2013

ASCO’s CancerLinQ prototype

• Development began in June of 2012.

• Completed in eight months.

• Included more than 170,000 de-identified patient records.

• Demonstrated that the full CancerLinQsystem could be a reality.

Kolacevski A, Mann JT, Hauser R, et al: Using Big Data to Track Trends in Medical Practice. Journal of Oncology Practice 11:JOP.2014.001541–70, 2014

Tamoxifen Duration & Survival In CLQ Pilot

Accessed 16 March 2015 at: http://bcove.me/evt9lbbp

Do Young Women Need To Be Made Menopausal?

Hormone Therapy Was The First Targeted Therapy

1896 GT Beatson - Oophorectomy in premenopausal women

1944 A Haddow - Synthetic estrogen

(stilbestrol) as treatment of breast cancer

1952 C Huggins - Adrenalectomy

(1966 Wins Nobel Prize for development of endocrine therapy in prostate cancer)

1958 E Jensen - Characterization of the

estrogen receptor (ER)

TEXT and SOFT Designs

Presented by: Olivia Pagani, MD ASCO 2014

R

A

N

D

O

M

I

Z

E

Tamoxifen+OFS x 5y

Exemestane+OFS x 5y

R

A

N

D

O

M

I

Z

E

Tamoxifen x 5y

Tamoxifen+OFS x 5y

Exemestane+OFS x 5y

Tamoxifen+OFS x 5y

Exemestane+OFS x 5y

Joint Analysis

(N=4690)

• Premenopausal

• ≤12 wks after surgery

• No chemo

OR

• Remain premenopausal

≤ 8 mos after chemo

• Premenopausal

• ≤12 wks after surgery

• Planned OFS

• No planned chemo

OR planned chemo

SUPPRESSION OF OVARIAN

FUNCTION TRIAL (N=3066)

TAMOXIFEN AND EXEMESTANE

TRIAL (N=2672)

OFS=ovarian function suppression

Enrolled: Nov03-Apr11

Median follow-up 5.7 years

TEXT

SOFT

Exemestane+OFS Reduced Recurrence

• 4% absolute improvement in 5-yr freedom from breast cancer for exemestane+OFS

• No significant difference in overall survival

Presented by: Olivia Pagani, MD ASCO 2014

SOFT: Tam vs OS/Tam

Francis P et al, NEJM DOI: 10.1056/NEJMoa1412379

HER Family Receptors

Hudis C. N Engl J Med 2007;357:39-51

H Trastuzumab

Doxorubicin

Cyclophosphamide

Paclitaxel

Docetaxel

Carboplatin

Adjuvant Trastuzumab

NSABP B-31

NCCTG 9831

BCIRG 006

H… x 1 year

H… x 2 years

No therapy

StandardChemoRx

HERA

FinHer PACS 04

H…x9

H…x9

H…x 52

No therapy

Epirubicin

Vinorelbine

Fluorouracil

H…x 52

H…x 52H…x 52

H…x 52

H…x 52

Can We Accelerate?

Is Change In pCR A Reliable Surrogate?

Neoadjuvant Trastuzumab + Pertuzumab

Regimen Duration pCR P value

NEOSPHERE

(N=417)

DH 29%

DP 12 w 24%

DHP 45.8% 0.0141

HP 16.8%

TRYPHAENA

(N=225)

FECHP → DHP 61.6%

FEC → DHP 24 w 57.3%

DCbHP 66.2%

E=epirubicin; C=cyclophosphamide; F=fluorouracil; D=docetaxel;Cb=carboplatin; H=trastuzumab; P=pertuzumab

NeoAdjuvant Approval: Pertuzumab

Unique circumstances?-Significant improvement in pCR-Significant increase in OS (MBC)- Completed, fully powered adjuvant trial-Significant safety experience (MBC & ongoing)

Implications?Is Accelerated Approval a public health benefit? Why?

- Because increased pCR is a leading indicator for OS?- If so, why not give a full year of pertuzumab?(Since that is what APHINITY tests.)

Neoadjuvant Lapatinib TrialsRegimen Duration pCR P value

NSABP B-41

(N=529)

AC → PH 28 w 52.5%

AC → PL 53.2% 0.99

AC → PHL 62% 0.095

NEOALTTO

(N=455)

*PH 18 w 29.5%

*PL 24.7% 0.34

*PHL 51.3% 0.0001

CHERLOB

(N=121)

PH → FEC/H 24 w 25%^

PL → FEC/L 26.3%^ NR

PHL → FEC/HL 46.7%^ 0.019

GEPAR-QUINTO

(620)

EC/H → DH 24 w 30.3%#

EC/L → DL 22.7%# 0.04

A=doxorubicin; E=epirubicin; C=cyclophosphamide; F=fluorouracil; P=paclitaxel q w ; D=docetaxel q 3 w; H=trastuuzmab; L=lapatinib; *In NEOALTTO, 6 w of H or L or HL preceding P; ^ pCR (no invasive tumor breast and nodes); # pCR (no invasive or in situ tumor in breast and nodes; NR=not reported

•Patients with ER or PgR-positive tumors receive endocrine therapy selected accordingly to menopausal status; endocrine therapy will be started

after the end of chemotherapy, will be administered concurrently with targeted therapies and will be planned for at least 5 years

• Radiotherapy if indicated

ALLTO

3-weekly

Trastuzumab

for 52 weeks

Lapatinib

for 52 weeks

Weekly

Trastuzumab (12

weeks)

Lapatinib

+ 3-weekly

Trastuzumab for

52 weeksWashout (6 weeks)

Lapatinib (34

weeks)

Anti-HER2 therapy can overlap chemotherapy

San Antonio Breast Cancer Symposium- Cancer Therapy and Research Center at UT Health Science Center- December 10-14, 2013

Study Design

(APT Trial)

This presentation is the intellectual property of the author/presenter. Contact them at stolaney@partners.org for permission to reprint and or distribute

HER2+

ER+ or ER-

Node Negative

< 3 cm

Enroll

T

P

T

P

T

P

T

P

T

P

T

P

T

P

T

P

T

P

T

P

T

P

T

P

PACLITAXEL 80 mg/m2 + TRASTUZUMAB 2 mg/kg x 12

TT T T T T T T T T T T T

FOLLOWED BY 13 EVERY 3 WEEK DOSES

OF TRASTUZUMAB (6 mg/kg)*

Planned N=400

*Dosing could alternatively be 2 mg/kg IV weekly for 40 weeks

** Radiation and hormonal therapy was initiated after completion of paclitaxel

San Antonio Breast Cancer Symposium- Cancer Therapy and Research Center at UT Health Science Center- December 10-14, 2013

Time (Months)

Dis

ea

se

-Fre

e S

urv

iva

l (P

rob

ab

ility

)

0 12 24 36 48 60

0.0

0.2

0.4

0.6

0.8

1.0

0 12 24 36 48 60

0.0

0.2

0.4

0.6

0.8

1.0

All patientsNumber at risk

406 390 382 307 126 27

Disease-Free Survival

This presentation is the intellectual property of the author/presenter. Contact them at stolaney@partners.org for permission to reprint and or distribute

3-year DFS 95% Conf. Interval

98.7% 97.6% to 99.8%

Poisson p-value: <0.0001

San Antonio Breast Cancer Symposium- Cancer Therapy and Research Center at UT Health Science Center- December 10-14, 2013

Change Is Happening

(Personalization Is Possible)

Anatomy (risk) drives treatment (1990)

Biology (responsiveness) drives treatment (2014)

US Health Spending at 17.7% of GDP is ~50%

Greater than Others (and Still Rising)

Projected US Health Spending 2020 → 20% GDPKehhan SP, Cuckler GI, Sisko AM, Madison AJ, Smith SD, Lizonito JM, Poisal JA and olfe CJ. National Health Expenditure Projections: Modest Annual Growth

Until Coverage Expands And Economic Growth Accelerates. Health Affairs. 2012 Jul;31(7):1600-12.

Higher Spending Does Not Increase Life Expectancy

Health Care Expenditures

and Life Expectancy

(2005)

Fuchs VR, Milstein A. N Engl J Med 2011;364:1985-1987.

Projected family health insurance premium costs and

average household income

Ho

us

eh

old

In

co

me

YearAnnals of Family Medicine: 2012: 10: 156-162

Patients are Bearing More of the Costs

Growing Numbers Of Survivors

From: The State of Cancer Care in America, 2015: A Report by the American Society of Clinical Oncology. Journal of Oncology Practice 11:JOP.2015.003772–113, 2015

Thank You