The US National COVID Cohort Collaborative Consortium Provides Real-World Evidence on Breakthrough COVID-19 Infections in Vaccinated Patients With Cancer

In the US National COVID Cohort Collaborative consortium-vaccinated population of 6,860 breakthrough cases, haematologic malignancies and solid tumours demonstrated significantly higher risks for COVID-19 breakthrough infection and severe outcomes after adjusting for age, sex, race and ethnicity, smoking status, vaccine type, and vaccination date. Patients with recent anticancer treatment showed higher risks of breakthrough infections. The study provides one of the first and the largest real-world evidence at national level on risk for COVID-19 breakthrough infections in patients with cancers, measures the effectiveness of mRNA vaccines in preventing breakthrough infections, and outlines the outcomes of breakthrough cases. The findings are published on 14 March 2022 in the Journal of Clinical Oncology.

Limited evidence exists on the effectiveness of COVID-19 vaccines in patients with cancers. The current public health policies of providing COVID-19 vaccines, including booster doses, to patients with cancers are mainly based on the hypothesis that the benefits of vaccination outweigh their risks.

The authors wrote in the background that the current evidence suggests that, although mRNA-1273 (Moderna) and BNT162b2 (Pfizer–BioNTech) vaccines show more than 90% efficacy in preventing COVID-19 after the second dose, Moderna’s vaccine generates more than double the antibodies than Pfizer’s vaccine. Breakthrough infections are less likely to occur among those vaccinated with Moderna compared with Pfizer, and the rate of hospitalisation was lower among the Moderna-vaccinated cohort versus the Pfizer cohort. This indicates that Moderna’s vaccine may provide better protection for immunocompromised people including patients with cancer. However, corresponding real-world evidence for the population with cancers is still missing.

The National COVID Cohort Collaborative consortium enclave houses the largest harmonised and integrated clinical cohort registry of COVID-19–tested patients in the United States and includes electronic health record data of approximately 7.9 million patients with one (or more) clinical encounters after 1 January 2020 (inpatient or outpatient) from more than 65 US medical centres.

To provide real-world evidence on risks and outcomes of breakthrough COVID-19 infections in vaccinated patients with cancer, the study team used the National COVID Cohort Collaborative; included patients were partially or fully vaccinated with mRNA COVID-19 vaccines and did not have prior SARS-CoV-2 infection record. Risks for breakthrough infection and severe outcomes were analyzed using logistic regression.

A total of 6,860 breakthrough cases were identified, among whom 1,460 (21.3%) were patients with cancer. Solid tumours and haematologic malignancies had significantly higher risks for breakthrough infection (odds ratios [ORs] 1.12, 95% confidence interval [CI] 1.01 to 1.23 and 4.64, 95% CI 3.98 to 5.38) and severe outcomes (ORs 1.33, 95% CI 1.09 to 1.62 and 1.45, 95% CI 1.08 to 1.95) compared with patients without cancer, adjusting for age, sex, race/ethnicity, smoking status, vaccine type, and vaccination date.

Compared with solid tumours, haematologic malignancies were at increased risk for breakthrough infections. Aadjusted OR ranged from 2.07 for lymphoma to 7.25 for lymphoid leukaemia.

Breakthrough risk was reduced after the second vaccine dose for all cancers (OR 0.04, 95% CI 0.04 to 0.05), and for Moderna’s mRNA-1273 compared with Pfizer’s BNT162b2 vaccine (OR 0.66, 95% CI 0.62 to 0.70), particularly in patients with multiple myeloma (OR 0.35, 95% CI 0.15 to 0.72).

Medications with major immunosuppressive effects and bone marrow transplantation were strongly associated with breakthrough risk among the vaccinated population.

The authors concluded that their work provides real-world evidence suggesting that patients with cancer, especially those with haematologic malignancies such as multiple myeloma and lymphoma, were at higher risk of breakthrough infections after mRNA vaccinations and were more likely to develop severe outcomes. The study also provides a baseline for further investigating the efficacy of booster and the breakthroughs and outcomes of variants infections.


Song Q, Bates B, Shao YR, et al. Risk and Outcome of Breakthrough COVID-19 Infections in Vaccinated Patients With Cancer: Real-World Evidence From the National COVID Cohort Collaborative. Journal of Clinical Oncology; Published online 14 March 2022. DOI: 10.1200/JCO.21.02419.