The expansion of the spectrum of human epidermal growth factor receptor 2 (HER2)‐status to HER2‐low, defined as HER2 expression of 1+ by immunohistochemistry (IHC) or 2+ by IHC without gene amplification, has made a major impact in the field of oncology. The HER2‐low expression has emerged as a targetable biomarker, and anti‐HER2 antibody‐drug conjugate trastuzumab deruxtecan has shown significant survival benefit in pretreated metastatic HER2‐low breast cancer (BC). With these recent data, the treatment algorithm for hormone receptor–positive and triple‐negative BC needs to be reconsidered, as approximately half of these BCs are HER2‐low. Although there are different therapeutic agents for hormone receptor–positive and hormone receptor–negative HER2‐low BCs, there is no consensus regarding the sequencing of these agents. In this article, the treatment options for HER2‐low BC are enumerated and a treatment sequencing algorithm based on the current clinical evidence proposed.

e18639 Background: Lung cancer is the second most common cancer and the leading cause of cancer deaths in both sex in the United States (US). Prostate cancer is the most common in men, while in women being breast cancer. America’s Health Rankings (AHR) is a comprehensive assessment of the nation's health on a state-by-state basis to determine state health rankings annually. We aimed to evaluate the association, which has not been investigated, between state-level health disparity as measured by AHR and lung, breast, and prostate cancer incidence and mortality in the US. Methods: We examined lung, breast and prostate cancer incidence and mortality data for 2015-2019 from the United States Cancer Statistics (USCS) database provided by the Centers for Disease Control and Prevention (CDC). Overall state health rankings were obtained from AHR and calculated by an equation using weighted measures in five different categories: 25% Behaviors, 22.5% Community & Environment, 12.5% Policy, 15% Clinical Care, and 25% Outcomes. We extracted 2015-2019 AHR data and further classified state health rankings into quartiles (1st [the healthiest] = rank 1 to 13; 4th [the least healthy] = rank 38 to 50). Associations of cancer incidence and mortality with overall state health rankings were analyzed by negative binomial regressions. Results: From 2015 to 2019, age-adjusted incidence rate per 100,000 population for lung, breast, and prostate cancer were 56.3, 128.0 and 109.8, respectively. Age-adjusted mortality rate per 100,000 population for lung, breast, and prostate cancer were 36.7, 19.9 and 18.9, respectively. Among 50 states we included for analysis, AHR indicated that Hawaii was the healthiest state (No.1) whereas Mississippi was the least healthy state (No. 50) for overall health rankings. States in the 4th quartile of health ranking were significantly associated with greater lung cancer incidence (Rate Ratio [RR]: 1.34 [95% CI, 1.18-1.52]) and mortality (1.50 [1.32-1.71]) than those in the 1st quartile. This was pronounced for age < 65 (Incidence [I]: 1.63 [1.36-1.96]; Mortality [M]: 1.93 [1.51-2.48]), Male (I: 1.48 [1.30-1.67]); M: 1.66 [1.47-1.87]), and Black (I: 1.43 [1.22-1.66]; M: 1.54 [1.32-1.79]). Black women living in states with worse health rankings had higher relative risks of breast cancer incidence (1.14 [1.03-1.26]) and mortality (1.27 [1.05-1.53]). There was no significant association between state health rankings and prostate cancer incidence and mortality in the US. Conclusions: There are significant differences in lung, breast, and prostate cancer incidence and mortality within the US. States with worse health rankings had higher cancer incidence and mortality, and varied by different demographics. Our findings suggests that advanced cancer screening and targeted public health interventions should be prioritized in areas with health disadvantages to improve cancer disparity.

486 Background: UTUC is less common and associated with poorer stage-for-stage prognosis compared to urothelial bladder cancer. AC is regarded as a standard-of-care in high-risk UTUC based on superior disease-free survival compared to observation in the POUT trial, though fewer than 10% of patients in this trial had lymph node involvement.1 CheckMate 274 revealed lesser magnitude of benefit with adjuvant nivolumab in UTUC compared to bladder cancer on post hoc analysis.2 The preferred sequence of perioperative systemic therapy in node positive UTUC remains unclear. Methods: We queried the National Cancer Database for adult patients with clinically node positive (cTanyN1-3M0) UTUC diagnosed between 2004 and 2018. Patients were divided into two groups based on the perioperative treatment strategy - NAC or AC. Patients who did not undergo RNU were excluded from analyses. Fisher’s exact and Mann Whiney U tests were used to compare frequency distributions. Cox Proportional Hazards regression was employed for multivariate analysis of factors associated with overall survival. Models were adjusted for age, sex, race, income, educational level, clinical T stage, insurance status, and the Charlson Comorbidity Index. Results: A total of 862 patients were identified - 362 (42%) underwent NAC while 500 (58%) received AC. No significant differences were noted between the groups regarding age, sex, or insurance status. Patients with cT1-2 UTUC more often received NAC (27.9% vs 11.8%, P <0.001) while those with cT3-4 disease more frequently received AC (38.9% vs 57.4%, p<0.001). Rates of NAC vs AC were not significantly different based on clinical N stage (P = 0.35). Overall survival in the NAC group was significantly longer than the AC group (median of 47.1 vs. 20.2 months, log-rank P < 0.001). On multivariable analysis, only the sequence of perioperative chemotherapy was independently predictive of overall survival (Hazard Ratio of 1.38 for AC, with 95% CI 1.14-1.68, P = 0.001). Conclusions: In this large retrospective analysis of outcomes among patients with clinically node positive UTUC who underwent RNU, NAC was associated with significantly longer overall survival compared to AC. References: 1) Birtle A, Lancet 2020; 2) Bajorin DF, NEJM 2021.