Department of Oncology & Neurosciences

Stefano IacobelliUniversity “G. d’Annunzio” Chieti-Pescara, ItalyConsorzio CINBO

Medical Management of Breast Cancer

(Early & Advanced)

Factors Influencing Selection of Systemic Therapy for Primary Breast Cancer

OptimalTreatment selection

Risk of recurrenceor death

Benefit from treatment

Tumor characteristics:ER, PR, HER-2

Comorbidities Toxicities

ADVANCED/METSTATIC DISEASE

MBC – Systemic therapy – Selection criteria

Trastuzumab +Endocrine therapy

Trastuzumab +Chemotherapy

Trastuzumab only

IHC 3+ FISH Pos

(15%)

All other cases(85%)

HER 2 status

Endocrine therapy

Long DFS

Age >35 years

Response to previous endocrine therapy

ER+ tumor

Slowly growing disease(soft tissues, skeleton)

Chemotherapy

Short DFS

Age <35 years

Failure to previous endocrine therapy

ER- tumor

Rapidly growing disease

Death from breast cancer in women 30-79 years

Year Death rate

1975: 48.31990: 49.72000: 38.0

Death rate decreased of 24% from 1990 to 2000

NEJM 353: 1784-92, 2005

But also because of the advent of new anticancer drugs, allowing more MBC patients to live longer

Overall survival from time of recurrence (Giordano, Cancer 2004)

Patients divided in 5 groups by year of recurrence

1950s: cyclophosphamide, methotrexate1960s: 5-FU, vinblastine, vincristine1970s: doxorubicin, mitomycin-C, tamoxifen1980s: mitoxantrone, etoposide, aminoglutethimide,

megestrol acetate, goserelin, leuprolide1990s: paclitaxel, docetaxel, vinorelbine, gemcitabine, trastuzumab,

capecitabine, epirubicin, anastrozole, letrozole, exemestane

Survival longer in the more recent groups

5-year OS: from 14% to 44%

New drugs approved by

FDA

TamoxifenAromatase inhibitors

- Inhibitors (anastrozole, letrozole) - Inactivators (exemestane)

Fulvestrant

Progestins

MBC – Endocrine active agents

Proposed Sequence of Endocrine TherapiesPremenopausal Women with ER-Positive Advanced

Breast Cancer

Ooph = oophorectomy; AI = aromatase inhibitor; AIA = aromatase inactivator; MA = megestrol acetate

First-line Tamoxifen + Ooph Ooph + AI/AIA

Second-line Fulvestrant AI/AIA Fulvestrant Tamoxifen

Fourth-line Tamoxifen MAMAMA

Third-line AI/AIA Fulvestrant MA Fulvestrant

EARLY DISEASEEndocrine therapy

Tamoxifen represents the first example of ‘’target therapy’’ for cancer!

EBCTCG, Lancet 2005

Tamoxifen began to be used in clinical trials for MBC in 1971 and has remained “the gold standard” for first-line endocrine therapy for almost 30 yrs.

Second-line drugs were mainly represented by progestins and the first-generation AIs, aminoglutethimide

Recently, new hormonal agents have been developed, particularly novel AIs

AIs

Aromatase Inhibitors

Aromatase

Adrenalglands

ANDROGENS OESTROGENS

(Testosterone, androstenedione)

(Oestradiol, oestrone)

tumourgrowth

Aromatase Inhibitors

ASCO Tech Assessment of Aromatase Inhibitor Adjuvant Therapy 2004

“Adjuvant therapy for postmenopusal women with hormone receptor-positive breast cancer should include an aromatase inhibitor in order to lower the risk of tumor recurrence”

Winer EP, J Clin Oncol 2005

“Treatment option include 5 years of AI or sequential therapy consisting of tamoxifen (for either 2 to 3 yrs) followed by aromatase inhibitors for 2 - 3, to 5 years”

Tamoxifen

Aromatase inhibitor

Control

Extended adjuvant therapy

Switching

Direct comparison (up-front)

ATAC, BIG-1 98

IES, ARNO-95, ITA

MA-17,ABCSG8

Aromatase Inhibitor adjuvant treatment strategies

R

R

R

Overall SurvivalATAC 0.97 (0.84, 1.11)BIG-1 98 0.91 (0.75, 1.11)

Disease-free SurvivalATAC 0.87 (0.78, 0.97)BIG-1 98 0.82 (0.71, 0.95)

Time to Distant RecurrenceATAC 0.86 (0.74, 0.99)BIG-1 98 0.81 (0.67, 0.98)

Favours 5 yrs AI Favours 5 yrs Tam0.70.5 1 1.5

Overall SurvivalABCSG8/ARNO 0.76 (0.51, 1.12)IES 0.85 (0.71, 1.02)ITA 0.56 (0.28, 1.13)

Disease-free SurvivalABCSG8/ARNO 0.60 (0.44, 0.81)IES 0.76 (0.66, 0.88)ITA 0.57 (0.38, 0.85)

0.50.2 2 5Favours AI switch Favours Tam alone1

Up-front

Switching

BIG 1-98: Primary Core Analysis26-Month Median Follow-Up

0 2 5 Years

Tamoxifen

Letrozole

Tamoxifen Letrozole

Letrozole Tamoxifen

A

B

C

D n=1540

n=1548

n=2463

n=2459

8010 pts

Primary core analysis compares letrozole vs tamoxifen monotherapy Tamoxifen: arms A and C Letrozole: arms B and D Excludes events and follow-up beyond switch for C and D Primary endpoint: DFS

Thürlimann et al. N Engl J Med. 2005;353:2747.

RANDOMI

ZE

Patient/Tumor CharacteristicsLetrozole Tamoxifen

Median age (y) 61 61Tumor size >2 cm (%) 36.5 37.7Node+ (%) 41.5 41.2CT given (%) 25.3 25.3ER+/PgR+ (%) 63.5 62.7ER+/PgR– (%) 20.2 20.5ER+/PgR unknown (%) 14.5 14.3

Receptor positivity was a study requirement:99.8% of patients had receptor-positive tumors

CT = chemotherapy. Thürlimann et al. N Engl J Med. 2005;353:2747.

BIG 1-98: DFS At 26 Months

Thürlimann et al. N Engl J Med. 2005;353:2747.

97.797.6

YearlyDFS (%)

95.193.4

90.589.0

86.884.6

84.081.4

No. at risk

38923896

29642926

12611238

892866

40034007

567544

N HR (95% CI) P Value

8010 0.81 (0.70-0.93) 0.003

LETTAM

% o

f p

ts a

live

an

d

dis

ease

-fre

e

Years from randomization

Absolute difference 2.6%

0

20

40

60

80

100

1 2 3 4 5

NPT 1/2.6 x100 = 38 pts!

ATAC Trial

Predefined Adverse Events

0.2 0.4 0.6 0.8 1.0 2.01.5

Hot flushes

Odds ratio (‘Arimidex’/tamoxifen)

In favour of Anastrozole In favour of tamoxifen

Joint disorders

Vaginal bleeding

Vaginal discharge

Endometrial cancer**

Fractures***

Ischaemic cerebrovascular event

Venous thromboembolic events

Deep venous thromboembolic events

*AEs on treatment or within 14 days of discontinuation

**Excludes patients with prior hysterectomy and includes on- and off-therapy AEs

***Fractures occurring at any time prior to recurrence (includes patients no longer receiving treatment) Lancet, 2005

Hadji P, The Breast 2007

Clinical fracture rates in adjuvant AI trials

QALYs: Quality adjusted life years; ICUR: Incremental cost-utility ratio

Both up-front and sequential AI options are cost-effective alternatives to TAM alone, but early switching to EXE appears to be the economically preferred option based on its more favourable cost-utility vs up-front ANA.

Breast Cancer Res Treat 2007

2005 costs/Canada/Markov model

*Drug cost+ FU+adverse events+relapse management

*

Arguments in favour of the switching strategy

First OS advantage demonstration vs tamoxifen*– ITT 15% (-2% – 29%) p = 0.08– ER+/Unknown 17% (0% – 31%) p = 0.05

To minimize the adverse risk of both agents

Limiting the costs of treatment with aromatase inhibitors

*(IES study)

Arguments in favour of the upfront strategy

Contraindication to TAM

Previous therapy with SERMs

Risk of early relapse (adverse prognostic

factors)

Biological rationale (PGR-, HER2+)

Where are we in 2008 with respect to adjuvant chemotherapy for breast

cancer?

Mortality from breast cancer: adjuvant chemotherapyEBCTGG, Lancet 1998

Adjuvant Treatment for Breast Cancer

The most important achievement of medical oncology in terms of lives saved

The ErbB Receptor Familyand Their Ligands

The ErbB Receptor Familyand Their Ligands

Heregulins

EGFTGF-

AmphiregulinBetacellulin

HB-EGF

NRG2NRG3

HeregulinsBetacellulin

ErbB-1 (EGFR) ErbB-2 (HER2/neu) ErbB-3 (HER3) ErbB-4 (HER4)Fernandes et al, 1999. Moghal et al, 1999.

Extracellular Ligand-binding Domain

Tyrosine Kinase Domain

What about patients with HER2+breast cancer?

Trastuzumab in early breast cancer: studies designs of the adjuvant trials

Baselga at al., The Oncologist, 2006

Trastuzumab Adjuvant Trials: Efficacy Results

Trial and arm

N° pts N° events 3-year DFS (%)

HR 95% CI

B31/N9831

AC-TH 1.672 133 87 0.48 0.39-0.59

AC-T 1.679 261 75

BCIRG 006

AC-DH 1.074 128 87 0.61 0.48-0.76

DCarboH 1.075 142 86 0.67 0.54-0.83

AC-D 1.073 192 81

HERA

H 1.703 218 81 0.64 0.54-0.76

Control 1.698 321 74

FinHer

CT+H 115 12 89 0.42 0.21-0.83

CT alone 116 27 78

Neoadjuvant (Primary) Therapy

Pre-clinicalResearch

5-10 yrs

Primary Chemotherapy(End-point = pCR)

3 – 4 months !

ClinicalTrials

3-5 yrs

End Points

(DFS, OS,..)

5-8 yrs

DRUG DEVELOPMENT: A LONG AND EVERMORE EXPENSIVE PROCESS

Adjuvant sytemic chemotherapy:Conclusions

• Highly effective in reducing annual odds of recurrence and death;

• Benefits persist for at least 20 years, probably indefinitely;

• Chemotherapy is administered blindly!! No validated method to predict benefit or efficacy for individual patients exists.

•Prognostic factors

•Predictive factors

Nodal status

Tumor size

Grade

ER/PgR

HER-2

Young age

LVI

ER/PgR

HER-2

(Grade)

Proliferative activity

“Current parameters do not allow us to adequately distinguish patients most likely to benefit from treatment”

a heterogeneous disease!

Breast Cancer

“Histological looks alike” - BCPz 39 a. pre-menopause

CDI 2.2 cm, N (-), G1 ER (±)/PR(+), HER-2 (-)

09/2000: QUART FEC100 x 6 LHRH-Tam

Pz 47 a. pre-menopause

CDI 2.4 cm, N (-), G1 ER (±)/PR(+), HER-2 (-)

12/2003: QUARTFEC100 x 6 LHRH-Tam

09/2005: NED 10/2004: Bone metastases

ERA of Molecular Biology

Only treat those who need treatment

Only treat those who will benefit from treatment

• “omics” technologies for discovery of new

prognostic and predictive markers

• Development of targeted therapies

Genomics

Proteomics

“Molecular signature of cancer”

Gene expression analysis

<1995: Northern Blotting, RNAse protection etc

1 Week: Analyse several genes on 10s of samples

>1995: DNA Microarrays

1 Week: Analyse whole genome on 10s of samples

Courtesy of JA Foekens

BREAST CANCER CLASSIFICATION BREAST CANCER CLASSIFICATION USING GENE EXPRESSION PROFILINGUSING GENE EXPRESSION PROFILING

Breast Cancer

=

At least 4 different diseases!!!

Sorlie T et al, PNAS 2001

Courtesy of Lisa CAREYCourtesy of Lisa CAREY

Basal-like

HER-2+/ER-

Luminal ALuminal B

Normal

The Amsterdam profile

van ‘t Veer et al, Nature 2002

gyui

Training set: 78 patients

Study design

78 breast tumorsPatients < 55 yearsTumor size <5 cmLymph node negative (LN0)No adjuvant therapy

Prognosis reporter genes

Distant metastasis< 5 years (n=34)

NO distant metastasisin 5 years (n=44)

70-gene signature Validation: NEJM / JNCI

50

100

0

25

75

BC – Using the usual selection criteria (St. Gallen)

(100 N-, pre-menopausal pts receiving CT at 5 yrs FU)

83 will be alive even w/o CT

14 will die despite CT

3 will be alive thanks to CT

Using the 70-gene signature

Only 27% of pts will be overtreated

Dutch 70-gene prognosis profile (Agendia)

76-gene signature Veridex / Erasmus MC

- All lymph node-negative patients: untreated and also ER+ patients treated with adjuvant tamoxifen

- Based on global gene expression, frozen tissues

Three major expression profiles70-gene signature Agendia: MammaPrint®

- Lymph node-negative patients <60 years: untreated

- Based on global gene expression, frozen tissues

21-gene signature Genomic Health Inc: OncoType DXTM

- HR+ lymph node-negative patients treated with adjuvant tamoxifen: paraffin-embedded tissues

- Based on 16 candidate genes + 5 control genes: RT-PCR

Commercially available

70-gene signature Agendia: MammaPrint®

~$ 200021-gene signature Genomic Health Inc: OncoType DXTM

~$ 3400

Question: Who is going to pay for such a high-tech test?

Challenge:

How to justify the health economic value for an expensive test that has not been prospectively validated?

EORTC – TransBig Mindact trial

Discordant: 35% Randomized decision making

Both high risk: 55% Both low risk: 10%

6,000 lymph node-negative breast cancer patients

Clinical risk (Adjuvant ! online) and genomic risk (Mammaprint®)

CT No CT

Use clinical risk Use genomic risk

High Low High Low

TAILORx study design

10,000 ER+ / HER2- lymph node-negative breast cancer patients

OncoType DX assayTM

Primary Study Group RS 11-25: ~44%

Secondary Study Group 1 RS < 11: ~29%

Secondary Study Group 2 RS > 25: ~27%

HT alone CT + HT

RANDOMIZE Stratification factors: tumor size, menopausal status, planned

chemo, planned radiation

Hahn & Weinberg, 2002

A Subway Map of Cancer Pathways

BC: targets we want to direct therapy toward

Agent VEGF VEGFR PDGFR EGFR HER-2 c-KIT MAPtau TopoII mTOR

Bevacizumab X

Sunitinib X X X

Lapatinib X X Trastuzumab X

mTOR inhibitors x

Anthracyclines X X

Taxanes X

- E7389 (synthetic analogue of halichondrin B that inhibits the polymerization of tubulin and the assembly of microtubules)

- Trabectedin (tetrahydroisoquinoline alkaloid)

- Tipifarnib (farnesyl-transferase inhibitor)

- RAD001 (mTOR inhibitor)

- XRP9881 (taxane derivatives)

- Vorinostat (histone deacetylase inhibitor)

- BZL101 (aqueous extract of the Scutellaria barbata)

- Dasatinib (dual SRC/ABL kinase inhibitor)

- Ispinesib (Kinesin Spindle Protein Inhibitor)

- Pazopanib (multi-tyrosine kinase inhibitor)

- Ertumaxomab (anti-CD3 x anti-HER-2-neu monoclonal antibody)

- BIBW 2992 (dual, irreversible EGFR- and HER2-inhibitor)

And many more……!!

New biological targeted drugs in BC• Some wonderful successes! (i.e. Trastuzumab);

• Data are still limited, although clinicians are racing ahead of the science;

• Mechanisms of resistance just as important as success;

• Cost of new drugs not affordable in the future;

• Imperative to develop & validate diagnostic tests to predict response in individual patients;

• A pletora of new agents: Imperative to pool data across studies, across disease subtypes, across agents;

• Consensus conference to agree on trial design/endpoints, assessment of biomarkers.

Drug costs (6 courses) in BC

Anthracycline-based regimens (EC, FEC) € 1.400

Anthracycline-based regimens + taxanes € 9.000

Trastuzumab (6 wks) € 2.500

CMF i.v. € 180

Lyposomal anthracyclines + taxanes + Trastuzumab € 12.600

Lyposomal anthracyclines € 7.200

Anticancer therapy is expensive!

Bevacizumab + capecitabine € 21.600Bevacizumab + paclitaxel ± Trastuzumab € 39.600

Thank you for your attention!