Purpose of Review HER2-targeted therapies have led to improved clinical outcomes in early and advanced breast cancer (BC). We review the long-term cardiotoxicity of HER2-targeted therapy in early and advanced BC, our current knowledge of cardiotoxicity of novel HER2-targeted therapies, and propose a cardiac monitoring (CM) strategy for this population. Recent Findings Long-term data from studies with HER2-targeted therapy in the adjuvant setting have failed to demonstrate an increase in cardiotoxicity over time, and rates of cardiotoxicity seen with novel HER2 agents remain low. Despite over a decade of experience with HER2-targeted therapy, CM in clinical practice is inconsistent in patients with early BC and almost non-existent in advanced BC. Summary Long-term follow-up of clinical trials with HER2-targeted agents in early and advanced BC has failed to demonstrate increased rates of cardiotoxicity over time, attesting to the long-term safety of this class of drugs for the majority of patients, although the long-term cardiac safety of newer HER2 agents in the non-clinical trial setting is largely unknown. We propose CM incorporating clinical history, cardiac imaging, and biomarkers.

Background: A systematic literature review was conducted to summarize first-line (1L) treatments and clinical outcomes among patients with hormone receptor-positive (HR+), human epidermal growth factor 2-positive (HER2+) advanced or metastatic breast cancer (aBC).Methods: Clinical trials and real-world studies (RWS) published between 01/2000-12/ 2020 evaluating clinical outcomes of 1L treatments in adults with HR+/HER2+ aBC were identified through pre-specified searches in Medline, Embase, Cochrane Library, and key conference proceedings. Study and patient characteristics, treatments (anti-HER2 therapy [AHT]+chemotherapy [CT], AHT+endocrine therapy [ET], ET only, and AHT only), treatment strategy (no induction vs. induction and maintenance), and outcomes (e.g., progression-free survival [PFS], overall survival [OS]) were extracted and summarized.Results: Overall, 20 trials and 21 RWS were identified. Among trials, treatments with AHT+CT (70%), AHT+ET (17%), ET only (10%), and AHT only (3%) were evaluated across 30 study arms. Fourteen of these study arms included induction and maintenance treatments, of which induction with AHT+CT (79%), CT only (14%), and AHT only (7%) were evaluated. Median PFS and OS ranged from 2.4-23.7 months and 23.9-66.7 months, respectively, in trials. Among RWS, AHT-based regimens (71%), ET alone (10%), CT alone (5%), or a combination (15%) were evaluated across 41 study arms. Eleven (27%) and 3 (7%) study arms assessed treatments in the induction and maintenance setting and with no induction therapy, respectively, while 27 (66%) could not be evaluated. Induction regimens used included AHT+CT (82%), AHT only (9%), and ET only (9%). Real-world median PFS and OS ranged from 4.8-29.0 months and 26.0-80.4 months, respectively. All studies measured PFS/OS from any 1L treatment initiation for aBC or earlier.Conclusions: There is considerable variation in treatments and clinical outcomes in this patient population. Though most real-world patients with HR+/HER2+ aBC receive AHT-based regimens in the 1L setting, few also receive ET.

Purpose SOLAR-1 investigated alpelisib-fulvestrant (ALP+FLV) in patients with HR+/HER2-, PIK3CA-mutated advanced breast cancer and demonstrated a clinically signi cant increase in all-grade and grade (G) 3-4 hyperglycemia (HG) compared to placebo-fulvestrant. Given high rates of HG, a preventative protocol and identi cation of associated risk factors was implemented. MethodsThis single-center, retrospective study included patients receiving ALP+FLV. One week before ALP initiation, patients started an insulin-sensitizer. Patients had fasting plasma glucose (FPG) levels drawn day 8, 15, 28, then monthly. Primary outcome was incidence of G2-4 HG by day 28. Risk factors assessed included age, BMI, FPG, and hemoglobin A1c. Number of risk factors were compared between patients with and without HG. ResultsSixteen women were included with median age of 59 years. The cohort was 69% White, 25% Black, 75% with BMI > 25kg/m 2 , and 50% with history of diabetes. By day 28, 9 patients (56%) had G2-4 HG, with only 3 (19%) G3 and zero G4. Patients with G2-4 HG had a median of 2 risk factors compared to only 1 if no HG (p=0.03). 5 patients (31%) required a temporary hold of ALP and 3 (19%) required dose reduction due to HG. 13 patients permanently discontinued ALP -9 due to disease progression and 4 from an adverse event (only 1 HG). ConclusionImplementation of a HG prophylaxis protocol with ALP in a single-center study demonstrated fewer G3-4 HG events compared to that seen in SOLAR-1 (19% vs 36.6%).

PurposeSOLAR-1 investigated alpelisib-fulvestrant (ALP+FLV) in patients with HR+/HER2-, PIK3CA-mutated advanced breast cancer and demonstrated a clinically significant increase in all-grade and grade (G) 3-4 hyperglycemia (HG) compared to placebo-fulvestrant. Given high rates of HG, a preventative protocol and identification of associated risk factors was implemented.MethodsThis single-center, retrospective study included patients receiving ALP+FLV. One week before ALP initiation, patients started an insulin-sensitizer. Patients had fasting plasma glucose (FPG) levels drawn day 8, 15, 28, then monthly. Primary outcome was incidence of G2-4 HG by day 28. Risk factors assessed included age, BMI, FPG, and hemoglobin A1c. Number of risk factors were compared between patients with and without HG.ResultsSixteen women were included with median age of 59 years. The cohort was 69% White, 25% Black, 75% with BMI > 25kg/m2, and 50% with history of diabetes. By day 28, 9 patients (56%) had G2-4 HG, with only 3 (19%) G3 and zero G4. Patients with G2-4 HG had a median of 2 risk factors compared to only 1 if no HG (p=0.03). 5 patients (31%) required a temporary hold of ALP and 3 (19%) required dose reduction due to HG. 13 patients permanently discontinued ALP – 9 due to disease progression and 4 from an adverse event (only 1 HG).ConclusionImplementation of a HG prophylaxis protocol with ALP in a single-center study demonstrated fewer G3-4 HG events compared to that seen in SOLAR-1 (19% vs 36.6%). An increase in HG-associated risk factors correlated with a higher incidence of G2-4 HG.