Exploring the “obesity paradox” in triple negative breast cancer patients receiving neoadjuvant immunotherapy.

Abstract

e14664 Background: Despite being one of the most aggressive subtypes of breast cancer, triple-negative breast cancer (TNBC) is also the most immunogenic, with immune checkpoint inhibition (ICI) having the most success in this setting [1-5]. Pembrolizumab (pembro; anti-PD-1) is approved for neoadjuvant treatment (NAT) in stage II/III TNBC [5]. At the time of surgical resection after NAT, a pathologic complete response (pCR) is strongly associated with improved long term survival [6-9], and failure to achieve pCR is associated with increased risk of distant recurrence and poor long-term outcomes [9]. Defining mechanistic drivers of ICI response versus resistance is a crucial step towards optimizing ICI use and improving survival. Obesity and its physiologic downstream effects alter the systemic immune landscape and the tumor immune microenvironment [10-13]. Despite obesity being a risk factor for poor outcomes in numerous disease states including cancer, recent studies have described an “obesity paradox” whereby higher body mass index (BMI) is correlated with improved responses to ICI [14-17]. This relationship has not been well defined in breast cancer patients receiving NAT with pembro. We aimed to explore the association between pre-treatment BMI and pCR after NAT with pembro in a diverse cohort of patients with TNBC. Methods: We included patients who received NAT with pembro between 2021 and 2024 from the electronic medical records of NYP network sites (Weill Cornell, Columbia, Queens, Brooklyn, and Westchester). The main endpoint was pCR, and BMI and other variables were compared between patients who achieved pCR (pCR-yes) vs. those who did not (pCR-no). We examined differences in continuous variables using the Wilcoxon rank sum test for two groups or the Kruskal-Wallis test for more than two groups. Results: A total of 75 patients were identified; 23%, 31%, 17%, and 21% were White, Black, Asian, and Hispanic, respectively. The median age was 53. The median pre-treatment BMI in the total population was 26.7 (IQR 24, 31.5). The median pre-treatment BMI was 25 (IQR 23, 29.7), and 28 (IQR 25, 34) in the pCR-no, and pCR-yes groups respectively (p=0.028). The rates of pCR were 43.6%, 32%, 39%, and 60% in the overall population, normal/underweight, overweight, and obese groups respectively (p=0.097). Conclusions: In our cohort of breast cancer patients treated with NAT with pembro, higher BMI was associated with a paradoxical improvement in ICI response. We plan to further investigate this mechanistically with tissue and peripheral blood annotation which we are actively collecting prospectively. We are also evaluating visceral vs. subcutaneous adipose uptake on baseline PET scans in these patients to better understand the tissue dynamics of this paradox.