Table 1.

Systemic therapy concerns and considerations for patients with breast cancer and obesity.

Systemic Treatment	Mechanisms Related to Obesity	Dosing Strategy	Treatment Concerns in Patients with Obesity	Considerations for Patients with Obesity
Chemotherapy	BSA-based dosing strategies may not accurately estimate drug pharmacokinetics in patients with obesity [21] Chemotherapeutic agents can have different pharmacokinetic profiles in patients with obesity (e.g., lipophilic drugs with a high affinity for adipose tissue may have a higher volume of distribution in patients with obesity) [31,130]	BSA-based dosing	Risk of under- or over-dosing using BSA-based dosing formulas, which may lead to decreased efficacy and/or increased toxicity Leads to weight gain and cardiometabolic side effects	Use actual body weight in BSA-based dosing formulas
Endocrine therapy	Increased levels of estrogens due to aromatization of adipose tissue may lead to inadequate estrogen suppression with endocrine therapy [43,44] Dysfunctional adipocytes release adipokines, metabolites, and cytokines, which induce endocrine resistance by activating various signal transduction pathways, modulating apoptosis-related genes, and upregulating aromatase activity [14,45] Adipokines and cytokines have been found to directly diminish the efficacy of endocrine therapy in vitro [45] Increased insulin levels and IGF-1 activate the PI3K/AKT/mTOR and RAS/RAF/MAPK signaling pathway, leading to endocrine resistance [13,46,47] Chronic inflammation results in endocrine therapy resistance through the activation of proinflammatory molecules and reactive oxygen species [45,48,49,50]	Fixed-dose	Increased endocrine-related toxicities and joint symptoms in patients with obesity Leads to cardiometabolic side effects and increased risk of VTE in patients with obesity	Choice of endocrine therapy should be made irrespective of BMI Consider comorbidities and cardiac risk factors when evaluating endocrine therapy choice and duration in the adjuvant setting
Trastuzumab	Further research is needed	Weight-based (IV); fixed-dose (SC)	The first SC dose may be suboptimal Increased risk of cardiotoxicity and other adverse events in patients with obesity	Consideration of a loading dose with SC administration for patients who are overweight and those with obesity
Pertuzumab	Further research is needed	Fixed-dose	NA	Treat irrespective of BMI
Antibody-drug conjugates (T-DM1, fam-trastuzumab deruxtecan)	Further research is needed	Weight-based	Increased toxicity with T-DM1 in patients with obesity	Treat irrespective of BMI
Tyrosine kinase inhibitors (lapatinib, neratinib, tucatinib)	Further research is needed	Fixed-dose	NA	Treat irrespective of BMI
CDK4/6 inhibitors (palbociclib, ribociclib, abemaciclib)	CDK4 and CDK6 help regulate cellular metabolism, including lipid synthesis, oxidative pathways, insulin signaling, glucose regulation, and mitochondrial function [90,91,92,93]	Fixed-dose	NA	Treat irrespective of BMI
mTOR and PI3K inhibitor (everolimus and alpelisib, respectively)	Activation of the PIK3–mTOR pathway results in insulin resistance and altered glucose metabolism [105,106]	Fixed-dose	Associated with dyslipidemia, hyperglycemia (primarily alpelisib)	Obtain serial fasting blood sugars and lipid panels For alpelisib only: Optimize blood glucoses prior to initiation of alpelisib Counsel on healthy lifestyle behaviors and symptoms of hyperglycemia Closely monitor for signs and symptoms of hyperglycemia to allow for the early detection and management of hyperglycemia-related complications
PARP inhibitors (olaparib, talazoparib)	PARP enzymes help regulate metabolic pathways, including carbohydrate and lipid metabolism and adipocyte differentiation [115]	Fixed-dose	NA	Treat irrespective of BMI
Trop-2-directed antibody-drug conjugate (sacituzumab govitecan-hziy)	Further research is needed	Weight-based	NA	Treat irrespective of BMI
Immunotherapy (pembrolizumab)	Excess adipose tissue results in immune system dysfunction [128]	Fixed-dose	NA	Treat irrespective of BMI

BSA = body surface area; VTE = venous thromboembolism; IV= intravenous; SC = subcutaneous; NA = not applicable.