br Discussion br In most countries
In most countries, the standard adjuvant treatment for patients with HER2+ eBC is chemotherapy combined with one year of trastuzumab, which showed a significant benefit in terms of disease-free survival (DFS) and OS.4 On one hand, a high percentage of these patients will still experience disease progression (about 28.8% at 11-years’ follow-up in the HERA-trial),19 whilst on the other HER2-targeted treatment is associated with potential adverse events, with particular regard to a substantial decrease in left ventricular ejection fraction. Therefore several trials investigated the chance to modify the treatment by reducing the administration of trastuzumab to 6 or 3 months (de-escalation) or by making it more effective with the addition of another HER2-target therapy (escalation) such as Pertuzumab or tyrosine kinase inhibitors (Neratinib, Lapatinib).9 Based on the results of the phase III APHINITY study,10 the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have recently approved Pertuzumab as adjuvant treatment of HER2+ eBC patients at high risk of recurrence. However, the selection of patients, which either would benefit from a treatment escalation or would be eligible for a de-escalation based on their risk-profile and predisposition towards toxicity, still represent a matter of debate. While in most clinical trials (such as in the APHINITY study) risk-profile is based on tumor characteristics (biological features and stage), the assessment of patients’ systemic characteristics such as BMI might represent an additional prognostic and predictive tool.
In our study, we focused on a consecutive series of patients treated at two different institutions who fully completed adjuvant treatment with chemotherapy and Trastuzumab. Although outcome was not significantly different between BMI Bradykinin (acetate) in the whole population of HER2+ tumors, we demonstrated that patients with both BMI>25 and whose tumors were HR- had higher risk of early recurrence (3yDDFS 86.9%, 95% CI: 75.0-97.7%) when compared to pts with HR+ tumors and with BMI<25 (3yDDFS 98%, 95% CI: 94.8-100.0%) and other subgroups (p=0.003). The 3 years-follow up cut-off was selected taking as reference other trials in this setting10 and considering that longer follow-up suggested that the benefit of HER2-targeted therapy is primarily a reduction in early recurrence.14
Previous studies tried to investigate the association between BMI and prognosis, but evidences remain controversial in all subtypes of eBC. In particular, very little is known on the role of overweight and obesity in the HER2+ population, especially after the introduction of adjuvant Trastuzumab.
A recent paper by Martel et al.,18 conducted in the metastatic setting, showed no differences in terms of progression-free survival (PFS) and OS in HER2+ metastatic BC patients. Both univariate and multivariate comparisons between BMI groups resulted not statistically different (adjusted hazard ratio 0.88; 95% CI: 0.66–1.17, p= 0.387).
Regarding HER2+ eBC, Mazzarella et al.17 showed that lack of HR expression distinguishes patients in which BMI correlates with worse outcome from those in which it does not. They noted, in a consecutive series of 1250 patients, a significant correlation between obesity and cumulative incidence of distance metastases in HR-/HER2+ patients (hazard ratio: 2.03, p=0.019, taking only obese patients with BMI≥30 as reference group). These results are consistent with ours. However, patients enrolled in that study were treated before 2005 and none of them had received Trastuzumab in the adjuvant setting.
Gennari et al.20 focused their analysis on high-risk eBC patients treated with chemotherapy, including also 194 HER2+ patients, pointing out no influence on prognosis and thus suggesting that in aggressive biological subtypes, the impact of host factors on patient prognosis is minor. Even in this case, none of the HER2+ patient population had received anti-HER2 therapy.
To the best of our knowledge, our study is the first to investigate the role of BMI and HR expression in a consecutive series of HER2+ eBC patients who completed adjuvant chemotherapy (taxane-based, anthracycline-based or both) and who concluded one year of trastuzumab administration. This treatment homogeneity across subgroups minimize selection bias. Other strengths of our study are represented by long median follow-up (66.2 months) and availability of patient level data which allowed direct measurement of BMI parameters. Limits are the retrospective modality of the study and the small sample size.
In our analysis, consistent with others,17 HR-/HER2+ tumors presented more aggressive features involving a higher AJCC stage (stage II to III, p=0.07) and a trend towards a higher T stage (T3 to T4, 27% vs. 16%, p=0.08). Likewise overweight and obese women were more likely to have larger tumors (T3 to T4, p=0.036), as already reported by other authors.21 Theoretically, this fact could justify the worse prognosis observed in our HR- overweight/obese