Breast Cancer (BC) and Severe COVID-19 (C-19) Outcomes: A Matched Analysis

Purpose Patients with cancer receiving anticancer treatment have a higher risk of severe COVID-19 (C-19) outcomes. We examine the association between breast cancer (BC), recent treatment (systemic therapy, surgery, radiation), and C-19 outcomes. Methods Retrospective matched cohort study using the Optum® de-identified COVID-19 Electronic Health Record dataset (2007–2022). Patients with C-19 were categorized into: No cancer, BC with recent treatment, and BC without recent treatment and matched based on age, C-19 diagnosis date, and comorbidity score. We evaluated 30-day mortality, mechanical ventilation, intensive care unit (ICU) stay, and hospitalization. A composite outcome including all outcomes was analyzed. Multivariable logistic regression models were used. Results 2200 matched triplets (1:1:10) of patients with BC recently treated, BC not recently treated, and no cancer were included. Rates of adverse outcomes improved in 2021 compared to 2020. Compared to patients without cancer, those with BC recently treated had a similar risk of adverse outcomes, while patients with BC not recently treated had a lower risk of ICU stay and hospitalization. Using the composite variable, BC recently treated had similar outcomes (OR = 1.02; 95%CI 0.93–1.11) to patients without cancer, while BC patients not recently treated had better outcomes (OR = 0.66; 95%CI 0.59–0.74). Among patients with BC, chemotherapy within 3-months was associated with a higher risk of hospitalization (OR = 2.30; 95%CI 1.76–2.99) and composite outcome (OR = 2.11; 95%CI 1.64–2.72). Conclusion Patients with BC have a similar risk of adverse C-19 outcomes compared to patients without cancer. Among patients with BC, recent chemotherapy was associated with a higher risk of hospitalization.


Background
The COVID-19 (C-19) pandemic has had a profound and evolving impact on healthcare systems worldwide.As of June 2023, more than 760 million con rmed cases of C-19 and 6.9 million deaths have been reported globally [1].Older age and comorbid conditions, particularly cardiovascular disease, diabetes, hypertension, and obesity, have been implicated in an increased risk of severe infection and worse C-19 outcomes [2][3][4][5][6][7].Patients with cancer often have compromised immune systems, related to their cancer or cancer treatment, which increases their risk for infection.They also often have multiple comorbid conditions; thus, it is not surprising that several studies have found that patients with cancer have a higher risk of severe C-19 outcomes [8][9][10][11][12].The risk of severe outcomes may vary with cancer type, with studies suggesting that those with hematologic malignancies have a higher risk of poor outcomes related to C-19 infection [10,13,14].Vaccination has been effective in preventing infection and progression to severe disease, although e cacy studies are still ongoing for the various vaccines; in particular, examining how they will fare against recent C-19 variants [15].It has previously been shown that C-19 outcomes in patients with breast cancer (BC) may depend more on presence of medical comorbidities, such as obesity, hypertension, and diabetes, than on the diagnosis and management of breast cancer itself [16].In this study, we examine the association between BC, recent treatment modality, and adverse C-19 outcomes.
This study was granted approval by the MD Anderson Cancer Center Institutional Review Board, which considered the study exempt from obtaining patient informed consent based on its code of regulations.We followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.

Cohort Selection
We identi ed patients with C-19 using diagnosis codes, Healthcare Common Procedure Coding System (HCPCS) codes, Logical Observation Identi ers Names and Codes (LOINC), and laboratory test names as previously described (Supplementary Table-1) [4].We de ned a positive test result for C-19 via polymerase chain reaction, antigen test, or serologic con rmation.We used the earliest collection, test, or result date as the C-19 diagnosis date between 1/1/2020 and 12/20/2021.The last follow-up date was January 20, 2022.
The eligible population included all female patients ≥ 18 years diagnosed with C-19 (n = 561,549).For patients with BC, we used the International Classi cation of Diseases 9th and 10th Revision (ICD-9 and ICD-10) diagnosis codes to identify those who had 2 or more BC diagnosis codes that were at least 30 days apart within 1 year before C-19 diagnosis date (n = 5,571).For controls without cancer, we included those with no cancer diagnosis code within 1 year prior to C-19 diagnosis (n = 528,626).We further categorized patients with BC according to recent (within 3 months prior to C-19 diagnosis) anticancer treatment (surgery, radiation therapy, chemotherapy, immunotherapy, or endocrine therapy), as not recently treated and recently treated.
We matched (1:1:10) patients with BC and controls without cancer based on age, comorbidity score, and date of C-19 diagnosis: Group 1 included patients with BC and recent cancer treatment (referred to as BC recently treated); Group 2 included patients with BC and no recent treatment (BC not recently treated); Group 3 included patients without cancer (non-cancer controls) (eFigure-1).

Outcomes and Covariates
Outcomes of interest included mortality, mechanical ventilation, intensive care unit (ICU) stay, and hospital admission within 30 days of C-19 diagnosis.Death data were obtained from the Social Security Administration Death Master File, including month and year of death; therefore, date of death was set as the 15th of the month.To better capture mortality, we extended follow-up to the next month among patients who were diagnosed with C-19 after the 15th of the month.We identi ed mechanical ventilation using HCPCS codes or ICD-10 procedure codes.ICU stay was de ned as hospitalization in an ICU without mechanical ventilation.
We analyzed the risk of 30-day outcomes using multivariable logistic regression models.Variables in the model were selected based on a backward selection method and clinical relevance and included C-19 diagnosis period, age, race and ethnicity, severe obesity, Charlson-Deyo comorbidity index score, recent skilled nursing facility stay, insurance type, and region.A composite ordinal outcome including all outcomes was evaluated (higher score means more severe outcome: hospitalization = 1, ICU = 2, mechanical ventilation = 3, death = 4).Results are presented as odds ratios (OR) and 95% con dence intervals (CI).
Analyses were conducted using SAS, version 9.4 (SAS Institute), and R, version 4.0.5 (R Foundation for Statistical Computing).All tests were 2 sided, with a statistical signi cance level of P = .05.

Discussion
In this large cohort of patients with C-19 categorized as BC treated, BC not treated, and without cancer, we observed that patients with BC had similar outcomes to the matched non-cancer cohort.Over the last few decades, patients with BC have had improved prognosis and survival due to widespread mammography screening and improved treatment [20].This improvement in outcomes explains the similarities found between patients with BC and controls without cancer.Interestingly, among patients with BC not recently treated, outcomes including ICU stay and hospitalization were better compared to non-cancer controls.This may be related to the good general health of BC survivors or to increased health vigilance of patients with history of cancer without the consequence of potential immunosuppression related to ongoing treatment or active disease.Patients with history of BC have been shown to have similar general health and quality of life compared to controls without cancer [21].This may be related to the "teachable moment" that a diagnosis of cancer may serve with an opportunity to address preventative health strategies for chronic health conditions following acute management of their cancer [22].Among patients with BC, recent treatment with both chemotherapy and immunotherapy (within 3 months of C-19 diagnosis) was associated with a higher rate of both ICU stay and hospitalization compared to those not recently treated.Data evaluating cancer-directed therapy and its association with adverse C-19 outcomes has been mixed with some studies suggesting similar outcomes between patients with cancer and those without cancer [23][24][25] and others suggesting worse outcomes for patients with cancer [8, 12,26,27].The mechanism behind increased susceptibility to worse outcomes in patients receiving chemotherapy or immunotherapy can be postulated -that of a compromised or altered immune system -but it may be that the heterogeneity of cancer types and cancer-directed therapies is leading to mixed data.In our study, patients with breast cancer who had recent chemotherapy or immunotherapy had worse outcomes than patients with breast cancer not recently treated.Interestingly, patients that underwent recent surgery or radiation (within 3 months of C-19 diagnosis) did not have increased risk for adverse C-19 outcomes.Though we had small numbers of patients in the cohort that underwent recent surgery or radiation (4.1% underwent surgery and 4.3% received radiation), these ndings are consistent with prior studies indicating no increased risk of mortality from C-19 after recent cancer surgery or radiation [28,29].
Given that endocrine therapy has a different side effect pro le when compared to immunotherapy and chemotherapy and is most often used in the adjuvant setting to reduce the risk of recurrence following local therapy, we re-grouped patients who were treated with endocrine therapy only into BC patients with no recent treatment.To exclude confounding by patients receiving endocrine therapy for metastatic disease, we adjusted for metastatic disease since we understand that advanced disease could be a factor associated with severity of C-19 as previously reported [4].In this sensitivity analysis, we observed similar results, though attenuated, suggesting that the link between advanced disease and adverse C-19 outcomes in patients with BC may be related to immunosuppressive status or poor performance status.One recent study found no increased risk for C-19 infection in patients with BC treated with chemotherapy, but it did nd an association between metastatic disease and mortality following C-19 infection [23].
As expected, we found that adverse outcomes, speci cally ICU stay, mechanical ventilation and mortality, improved in 2021 when compared to 2020.This positive change stems from increased understanding of C-19 disease and increased availability of treatment and resources.In our cohort, the number of patients with BC who were vaccinated prior to C-19 diagnosis was low, making it di cult to interpret any association between vaccine status and C-19 outcomes.

Limitations
Despite the strength of a large cohort size, this EHR-based study is limited by its reliance on ICD-9 and ICD-10 codes to identify patients with breast cancer, which may lead to false positives.Speci cally, human error in coding may lead to over or underdocumentation of cancer and cancer-related treatment.While a strength of the Optum® COVID-19 data is its geographic diversity of patients in the US, it is limited to capturing patients with

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Table - 3
. Subgroup analysis of 30-day and composite outcomes among patients with breast cancer according to recent systemic treatment a (3 months before COVID-19 diagnosis).
BC: Breast cancer; OR: odds ratio; ICU: intensive care unit.a Variables in model included: C-19 diagnosis period, age, race and ethnicity, severe obesity (BMI>40), Charlson-Deyo comorbidity index score, recent skilled nursing facility stay, insurance type, and region.b Breast cancer treatment included surgery, radiation, chemotherapy, immunotherapy, and endocrine therapy.Abbreviations: BC = breast cancer; OR = odds ratio; CI = con dence interval; ICU = intensive care unit.a Variables in model included: Diagnosis period, age, race and ethnicity, severe obesity (BMI>40), Charles-Deyo comorbidity index score, recent skilled scaled nursing facility stay, insurance type, and region.b No valid estimates because of no event for surgery group.