Background: The ASCO Registry was created to analyze the impact of COVID-19 (COVID) on treatment (Tx) and outcomes of patients (pts) with cancer. Vaccination questions were added in 2021, enabling examination of breakthrough cases ? i.e., SARS-CoV-2 infection after vaccination. Methods: The Registry includes pts who test positive for SARS-CoV-2 and have clinically evident cancer receiving Tx or resected cancer on adjuvant Tx <12 months since surgery at the time of the positive test. Practices report data on COVID vaccine type and dates, positive SARS-CoV-2 test date, and subsequent Tx. Breakthrough cases were defined as 1) > 35 days after 1^st Pfizer dose, 2) > 42 days after 1^st Moderna dose, 3) > 14 days after 1^st Janssen dose, or 4) > 42 days after 1^st unknown vaccine dose. Data submission cutoff for all practices was February 2, 2022. Summary statistics and exact binomial 95% confidence intervals (CIs) were calculated. Results: This analysis reports on 231 pts with breakthrough cases. Median age is 68 years and 57% of pts are over age 65. Of 73 pts with non-metastatic solid tumors, 19% were hospitalized. Of 74 with metastatic solid tumors, 39% were hospitalized. Of 75 with B-cell malignancies, 32% were hospitalized. Of 9 with other hematologic malignancies, 56% were hospitalized. While the fraction of patients in the ASCO registry with breakthrough cases who were hospitalized remained fairly constant throughout 2021 (approximately 40%), those with breakthrough cases occurring in the last month of 2021 and early 2022 had a lower hospitalization rate (approximately 20%), which is consistent with less severe cases of COVID-19 in patients infected with the omicron variant (the predominant variant in the US in Dec 2021- Jan 2022) (Table). The majority of breakthrough cases occurred more than 6 months after initial vaccination (71%) and the median time to breakthrough infection from initial vaccination was 7.3 months (IQR: 5.6 ? 9.9). The Registry continues to accrue cases and additional vaccine data; analysis will be updated with most current vaccination data for possible Annual Meeting presentation. Conclusions: Hospitalizations among patients with cancer and breakthrough COVID in the ASCO Registry occur at a high rate, particularly among patients with advanced cancers and hematologic malignancies. This decrease in recent months is likely due to increased incidence of the Omicron variant that resulted in milder COVID symptoms among those infected. A majority of SARS-CoV-2 infections occurring six months or more after vaccination suggests waning vaccine efficacy over time that could be impacted by additional doses.