Estrogen suppression was less complete in obese women and was significantly greater with letrozole than with anastrozole across all weight groups.
Obesity is associated with elevated levels of circulating estrogen because steroid precursors are converted to estradiol by aromatase enzymes in adipose tissue. Estrogen exposure is a well-known risk factor for developing breast cancer, and obese women with early stage breast cancer (in particular, those with body-mass index 35 kg/m2) who receive the aromatase inhibitor anastrozole may have greater risk for disease recurrence than women who are of normal weight or who receive tamoxifen. These findings raise concerns that aromatase inhibition as a risk-reduction strategy might be less effective in obese women, and that use of less-potent aromatase inhibitors such as anastrozole might adversely affect clinical outcome. Evidence suggesting that one third-generation aromatase inhibitor is more effective than another has been sparse, although preclinical data have shown that letrozole is more potent than anastrozole at suppressing levels of estradiol and estrone sulfate.
The ALIQUOT (Anastrozole vs. Letrozole, an Investigation of Quality of Life and Tolerability) study was an open-label crossover study of 54 postmenopausal women with hormone receptor-positive breast cancer who were treated with adjuvant aromatase inhibition in the form of 3 months of anastrozole followed by 3 months of letrozole, or the opposite sequence. Plasma estradiol and estrone sulfate levels were measured before and after each course of therapy. Now, the authors have analyzed the data in the context of BMI.
Baseline levels of both forms of estrogen were significantly correlated with BMI; for example, obese women had >2-fold higher estradiol levels than did women with BMI <25. Additionally, suppression of both estrogens was less complete in obese women than in leaner women, and was significantly greater with letrozole than with anastrozole across all weight groups.
Comment: As intriguing as they are, these data fall short of showing that letrozole should be the preferred aromatase inhibitor in the adjuvant setting for all women (or even for any specific weight group). Whether the differences in estrogen suppression with anastrozole or letrozole actually translate into different clinical outcomes cannot be determined from these data. Furthermore, the association between obesity and breast cancer is certainly more complicated than would be indicated by suggesting that estradiol alone is the culprit. Increased levels of insulin, inflammatory mediators, and other proteins all have been implicated as risk factors for breast cancer incidence and recurrence in obese patients.
Source: Journal Watch Oncology and Hematology
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ARYAN'S BLOG 
Cardiovascular morbidity in cancer patients has generated and received mixed reactions, from concern to neglect, from being considered significant to meaningless. Here we join the debate on two of the most commonly used therapeutics in breast cancer patients: trastuzumab and aromatase inhibitors (AIs).
Studies of women with hormone receptor–positive breast cancer comparing AIs and tamoxifen have concluded that AIs are associated with a higher risk of arterial ischemic events. However, this might have been a biased view as tamoxifen improves the cardio-metabolic risk profile and thus might have a lower arterial ischemic risk profile even in comparison with placebo (and not just AIs). Indeed, in randomized controlled trials comparing AIs and placebo, no such signal was noted. The current study of >13,000 postmenopausal breast cancer survivors further attests to this.1Even in time-dependent analyses, there was no increased risk of arterial events with AIs over time. On the contrary, the risk of arterial events, especially cardiac ischemia, seemed to decline after 3 years in tamoxifen users. While based on claims data rather than detailed chart review and verification and adjudication of events, this study still provides reassurance for the use of AIs and the information needed when patients are inquiring about the cardiovascular risk of this therapy, especially considering its chronic treatment dimension.
With regard to the active treatment of breast cancer and women with HER2+ breast cancer, the Ontario Cancer Registry study provides very intriguing information, confirming and challenging some of the current viewpoints.2 First of all, the rate of major cardiac events was highest in the first year after the start of therapy; in fact, it matched the non-cardiac mortality rate, and declined thereafter to the level of the age-matched general population. In conjunction with data on the therapy-related risk further outlined below, these findings support the view that the largest risk is largely confined to the period of adjuvant trastuzumab therapy. Secondly, these dynamics of a “vulnerable first year” were noted in women under 65 years of age. On the contrary, women 65 years of age or older had approximately a three times higher risk of major cardiac events than younger women and remained on a steeper cardiac event rate curve than the general population even after 1 year. In both age groups, non-cardiac death was the main cause of death after 1 year, significantly higher than the incidence of cardiac events combined—a constellation opposite the general population, especially among those 65 years of age and older. Thus, older patients have a higher baseline cardiovascular risk, higher cardiac risk during therapy, and a persistently higher cardiac risk after cancer therapy while the risk remains confined to 1 year in younger patients. Thirdly, over the observed follow-up period of up to 5 years, the hazard ratio of cardiac events roughly doubled from anthracycline therapy to trastuzumab therapy and from trastuzumab therapy to sequential anthracycline/trastuzumab therapy. The latter group also met the threshold for heart failure hospitalization risk.
Thus, as expected, those with combined anthracycline/trastuzumab therapy were at highest cardiac risk; however, what might be surprising is the higher cardiac risk in those on trastuzumab therapy alone, a risk even higher than with anthracycline therapy alone. We do not have detailed information on how long the trastuzumab therapy–related risk persisted, any reversibility dynamics, and if this was noted in women with cardiovascular risk factors and/or disease, essentially unmasking a lower cardiovascular reserve. However, it can likely be extrapolated from the above that even younger patients undergoing trastuzumab need surveillance for at least 1 year, and those with an underlying disease burden even long term. With regard to the follow-up period in this study, it might have been too short to capture all anthracycline-related events. Accordingly, this study is more revealing for trastuzumab than it is for anthracyclines, and it comes at a time when the current recommendation of echocardiograms every 3 months while on trastuzumab therapy is being reconsidered, and details on how much such a monitoring strategy decreases events and at which cost-effectiveness level remain to be defined.
Mixed reactions, but seemingly no reassurance that we can simply forget about cardiotoxicity with trastuzumab therapy.