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Cardiotossicità nel carcinoma mammario da inibitori dell’aromatasi

Stefania Gori, Francesca De Iuliis, Simona Duranti, Jennifer Foglietta, Alessandro Inno,Valentina Sini




Aromatase Inhibitors (AIs)

Aromatase Inhibitors


• Third generation AIs, non-steroideal (anastrozole and

letrozole) and steroidal AIs (exemestane) are indicated in estrogen (ER) and/or progesterone (PR) positive Breast Cancer, in the adjuvant, neoadjuvant and metastatic setting.

Therapeutic Indications

• Early ER and/or PR positive BC: as monotherapy for 5 years

(anastrozole or letrozole) [up-front strategy*], sequential administration for 3 or 2 years after 2 or 3 years of tamoxifen [switch strategy**], or letrozole after 5 years of tamoxifen [extended strategy***].

* ATAC (anastrozole) and BIG 1.98 trials


*** MA-17, ABCSG 6a, NSABP-B33 trials

Aromatase Inhibitors (AIs)


Major adjuvant studies comparing third-

generation aromatase inhibitors and tamoxifen

Amir E, JNCI 2011


Tam- and AIs-specific side effects

Tam specific Estrogenic effects

AI specific

High estrogen depletion / lack of estrogenic


Both Tam and AI Anti-estrogenic effects

Decreased Cholesterol Hypercholesterolemia Hot flushes

Increased Bone MD Osteoporosis Mood disturbances Endometrial effects Menopausal arthritis

Carpal-tunnel syndrome

Sexual disfunction

Throembolic effects Vaginal mucosa

Cerebrovasular effects Urinary effects

Adjuvant AIs compliance

Anastrozole1 Exemestane2 Letrozole3 Adverse events leading to

withdrawal (% patients)

12% 11% 13%

1. ATAC trialists’ group. Lancet Oncol 2006;

2. Coombes. NEJM 2004;

3. Coates. J Clin Oncol 2007


Potential cardiovascular effects of AIs

Estrogen deprivation

• Lack of favourable effects on cholesterol and lipids

• Harmful effects on vessel-wall physiology

• Alterations in glucose metabolism and hemostatic variables

Nabholtz, Drug Safety 2006

Interference in adrenal steroidogenesis

• Changes in aldosterone or cortisol levels -> effect on blood

pressure and electrolyte balance

• Impaired cortisol synthesis

• Reduced ability of the hypothalamic-pituitary-adrenal axis to

exert anti-inflammatory effect on the vascular system


Cardiovascular events (Tam vs AIs)

Amir E, JNCI 2011


Cerebrovascular Events (Tam vs AIs)

Amir E, JNCI 2011

*Cerebrovascular disease was an uncommon adverse event: it occurred in 1.4% of patients in the aromatase inhibitor group and in 1.5% of patients in the tamoxifen group (difference in absolute risk = 20.1%, number needed to harm = 2974)


Venous Thrombosis (Tam vs AIs)

Amir E, JNCI 2011

*The incidence of thrombosis was 1.6% and 2.8% in the aromatase inhibitor and tamoxifen groups, respectively (difference in absolute risk = 21.3%, number needed to harm = 279)


AIs and lipid metabolism

(OR = 3.14, 95% CI = 2.78 to 3.55, P < .001)

(OR = 1.71, 95% CI = 1.38 to 2.13, P < .001)

(OR = 1.27, 95% CI = 1.01 to 1.59, P = .04)

Amir E, JNCI 2011

NB: Hypercholesterolemia was assessed formally by only four studies (ITA, BIG1.98, IES, TEAM) and was not graded consistently among those studies!

Overall AIs vs Tam (OR = 2.36, 95% CI = 2.15 to 2.60, P < .001)


Anastrozole Exemestane Letrozole

Total cholesterol +0.37 -3.94 -0.01

Triglycerides +0.28 +2.15 +5.40

LDL-C:HDL-C +4.58 +16.97* +3.39

APO-B:APO-A1 -0.02 +8.98* -0.77

Percentage change from baseline in LEAP study (Weeks after baseline: 24)

McCloskey E, Eur J Cancer 2007

* Significantly different from anastrozole and letrozole

AIs and lipid metabolism


• Trials conducted versus TAM (cardioprotective action!)

• Different grade of inhibition of aromatase different estrogen concentration  different cardiovascular risk profile

• Different action of AIs on lipidic metabolism (LEAP study)

• Higher risk of cardiotoxicity in women previously treated with anthracyclines and/or trastuzumab and/or RT

• Higher risk of cardiotoxicity in women with comorbidities

Considerations on trials variability


• Significant increase of cardiac ischemic events during AIs, but NOT of cardiovascular related deaths.

• Increased incidence of hypercholesterolemia, mostly grade low

Take Home Messages


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