OLD AND NEW OLD AND NEW ANTHACYCLINES: ANTHACYCLINES:

A STILL VALID OPTION IN A STILL VALID OPTION IN BREAST CANCER TREATMENTBREAST CANCER TREATMENT

True: Clara Natoli

Anthracyclines are actually the most Anthracyclines are actually the most

discussed drugs in breast cancer discussed drugs in breast cancer

treatmenttreatment

AnthracyclinesAnthracyclinesFarmItalia Research developed anthracyclines in 1960s. They are

derivatives of soil microbe, Streptomyces peucetius (rhodomycin), taken at Castel Del Monte, near Andria.

Doxorubicin was approved by FDA in 1974.

The first trial of epirubicin in humans was published in 1980. Upjohn applied for approval by the FDA in node-positive breast cancer in 1984, but was turned down because of lack of data. However, epirubicin was licensed for use in Europe from around this time.

Patent protection for epirubicin expired in August 2007.

AnthracyclinesAnthracyclinesProposed Mechanisms of ActionProposed Mechanisms of Action

Inhibition of DNA and RNA synthesis by multiple mechanisms, including:Inhibition of topoisomerase II preventing the relaxing of supercolied DNA, thus blocking trascription and replication Single strand DNA breakageIntercalation between DNA base pairsInhibition of proteasome functionChelation of divalent cationsProduction of iron-mediated free O2 radicals able to damage DNA and cell membranesInhibition of angiogenesis

Qu et al, 2001

Anthracyclines have multiple mechanisms ofAnthracyclines have multiple mechanisms ofaction: Topo IIaction: Topo II is only one of them … is only one of them …

What is the role of What is the role of anthracyclinesanthracyclinesin the in the adjuvant adjuvant chemotherapychemotherapyof primary breast cancer?of primary breast cancer?

Oxford Overview, 2000Oxford Overview, 2000Anthracyclines vs. CMFAnthracyclines vs. CMF

unselected node positive breast unselected node positive breast cancer cancer

Absolute differences in mortality is 3% at 5 years and 4% at 10 years

Role of the TaxanesRole of the Taxanes

O

O

O

NH

OH

HO O

OH

OH

H H

OO

O

O

O

O

O

NH

OH

O O

OH

OH

OOO

O

O

H

O

DocetaxelPaclitaxel

O

EBCTCG Meta - analysis 2005-06EBCTCG Meta - analysis 2005-06 Breast cancer mortality Breast cancer mortality

10

0 5 10 0 5 10 0 5 10

50

0

40

30

20

Anthra31.0%

Taxane25.9%

% +

SE

10-y gain 5.1% p < 0.00001

15.3

12.8

10-y gain 4.3% p < 0.00003

10y gain 4.2% p < 0.00001

Years

CMF31.3%

Anthra27.0%

Control36.4%

CMF32.2%

20.5

17.8

19.9

16.5

Peto et al. 2007

No Chemo < CMF < Anthra < Taxanes No Chemo < CMF < Anthra < Taxanes

Even if taxanes are superior to

anthracyclines, it makes sense to try to

combine them with anthracyclines, since

neither group of drugs is effective in

more than a minority of breast cancer

patients

their mechanisms of action are different

they show noncross-resistance

Cochrane Review 2008

A taxane containing regimen should be considered for women with A taxane containing regimen should be considered for women with moderate to high risk of recurrence following assessment of their moderate to high risk of recurrence following assessment of their individual risk of recurrence and comorbiditiesindividual risk of recurrence and comorbidities

Taxanes for adjuvant treatment Taxanes for adjuvant treatment of early breast cancerof early breast cancer

Summary from ASCO 2009Summary from ASCO 2009

Safety of Anthracyclines: CardiotoxicitySafety of Anthracyclines: Cardiotoxicity

• Clinical CHF is rare (< 1%)• In EBCTCG analysis, mortality from

heart disease was 0.08% vs 0.06% per year[1]

• Decrease risk by screening patients

1. EBCTCG. Lancet. 2005;365:1687-1717.

Should we use Anthracyclines Should we use Anthracyclines in the Adjuvant Therapy of in the Adjuvant Therapy of Breast Cancer according to Breast Cancer according to HER2 and Topo2A expression?HER2 and Topo2A expression?

We must still identify reliable predictors ofWe must still identify reliable predictors ofbenefit and resistance to individual drugs tobenefit and resistance to individual drugs toreach the objective of personalized therapyreach the objective of personalized therapy

We believe that …We believe that …

… anthracyclines should still be used in adjuvant chemotherapy (including HER2-positive tumors) because there is insufficient evidence to date supporting

the efficacy of alternative regimens

The Role of Anthracyclines The Role of Anthracyclines

from Adjuvant to from Adjuvant to MetastaticMetastatic

from Metastatic to from Metastatic to AdjuvantAdjuvant

Do anthracyclines workDo anthracyclines workin the metastatic setting?in the metastatic setting?

Principles of Chemotherapy Principles of Chemotherapy for Metastatic Breast Cancerfor Metastatic Breast Cancer

EFFICACYEFFICACY TOXICITYTOXICITY

(RR, TTP, OS)(RR, TTP, OS) (QoL, non-Hem and(QoL, non-Hem andHem. toxicity)Hem. toxicity)

Evaluation of the Therapeutic IndexEvaluation of the Therapeutic Index

Not cure in the vast majority of patients Not cure in the vast majority of patients

The GoalsThe Goals

o improve quality of life improve quality of life

o prolong lifeprolong life

o prevention and palliation of prevention and palliation of

symptomssymptoms

o curecure

Principles of Chemotherapy Principles of Chemotherapy for Metastatic Breast Cancerfor Metastatic Breast Cancer

o prolong lifeprolong life

o improve quality of life improve quality of life

Selection of Chemotherapy Selection of Chemotherapy for Metastatic Breast Cancerfor Metastatic Breast Cancer

Risk of recurrence Risk of recurrence or deathor death

Benefit fromBenefit fromtreatmenttreatment

ToxicitiesToxicities

Tumor biologyTumor biology

ComorbiditiesComorbidities

Optimal treatmentOptimal treatmentselectionselection

Cardiotoxocity is a major Cardiotoxocity is a major clinical handicap limiting clinical handicap limiting the cumulative dose of the cumulative dose of doxorubicin and doxorubicin and epirubicin in the epirubicin in the metastatic settingmetastatic setting

Anthracyclines as single agents or in combination chemotherapy?

Selection of Chemotherapy Selection of Chemotherapy for Metastatic Breast Cancerfor Metastatic Breast Cancer

Efficacy data from randomized studies with Efficacy data from randomized studies with mandated crossover in the monotherapy armmandated crossover in the monotherapy arm

Cardoso et al, J Natl Cancer Inst 2009;101:1174–1181

*

*

**

*

… conventional anthracyclines are limited by cardiac toxicity

PLD has comparable efficacy and significantly improved safety profile compared with conventional doxorubicin in MBC1

◦Significantly less cardiotoxicity

◦Less nausea/vomiting, alopecia, and myelosuppression

Pegylated Liposomal Doxorubicin (PLD)Pegylated Liposomal Doxorubicin (PLD)

1O’Brien et al. Ann Oncol. 2004;15:440-449.

Sparano, J. A. et al. J Clin Oncol; 27:4522-4529 2009

CONSORT diagramCONSORT diagram

International, phase III randomized study

751 patients were randomly assigned to receive either :

docetaxel 75 mg/mdocetaxel 75 mg/m22 (n = 373)

or

PLD 30 mg/mPLD 30 mg/m2 2 followed by docetaxel 60 followed by docetaxel 60 mg/mmg/m22 every 21 days (n = 378) and continued until disease progression or prohibitive toxicity.

Sparano, J. A. et al. J Clin Oncol; 27:4522-4529 2009

Time to progression for PLD plus docetaxel Time to progression for PLD plus docetaxel and docetaxel groupsand docetaxel groups

Adverse Events Adverse Events

Even if no consensus exists and both combination and sequential single-agent chemotherapy are reasonable options as first-line systemic therapy, there is the agreement there is the agreement that, at least in the presence of:that, at least in the presence of: o rapid clinical progressionrapid clinical progressiono life-threatening visceral metastaseslife-threatening visceral metastaseso the need for rapid symptom and/or disease the need for rapid symptom and/or disease controlcontrol

combination chemotherapy, possibly including combination chemotherapy, possibly including anthracyclines and taxanes, should be the first anthracyclines and taxanes, should be the first choicechoice

Cardoso et al, J Natl Cancer Inst 2009;101:1174–1181

European School of Oncology European School of Oncology - Metastatic Breast Cancer Task Force -- Metastatic Breast Cancer Task Force -

SummarySummary Anthracycline-based regimens are still a standard of care

for breast cancer treatment

Retreatment of MBC is effective and PLD is rational choice for retreatment of patients who have received previous anthracyclines

There is currently insufficient evidence:There is currently insufficient evidence:• To replace anthracycline-based adjuvant chemotherapy

with non-anthracycline-based regimens• To support the use of biomarkers HER2 and Topo II to

select chemotherapy regimens