key: cord-0977330-8bbpujdw authors: Kathuria-Prakash, Nikhita; Antrim, Lauren; Hornstein, Nicholas; Sun, Alexander W.; Kang, Irene M.; Baclig, Nikita V.; Angell, Trevor E.; Lechner, Melissa G.; Wald-Dickler, Noah; In, Gino K. title: Factors Associated with Hospitalization among Breast Cancer Patients with COVID-19: A Diverse Multi-Center Los Angeles Cohort Study date: 2021-12-17 journal: Clin Breast Cancer DOI: 10.1016/j.clbc.2021.12.005 sha: d33be8f2ccf69159591e86baea20d25504932995 doc_id: 977330 cord_uid: 8bbpujdw BACKGROUND: The SARS-CoV-2 virus has infected and killed millions of people worldwide. Breast cancer is the most prevalent cancer in women and few studies have investigated the outcomes of patients with a history of breast cancer and COVID-19. We report the clinical outcomes of patients with invasive breast cancer who tested positive for SARS-CoV-2, including hospitalization and death, and evaluate demographic and cancer-related factors associated with these outcomes. PATIENTS: Patients with a history of invasive breast cancer and positive SARS-CoV-2 test from January 1 to December 31, 2020 at two large, academic Los Angeles health systems were included. METHODS: Retrospective chart review of the electronic medical record was performed. Data for demographic and cancer-related factors were manually abstracted. Relationships between outcomes and clinical variables were evaluated using Fisher's exact test and linear regression analysis. RESULTS: Among a total of 132 patients, 40 (30.3%) were hospitalized, while 11 (8.3%) required intensive care support, and 8 patients (6.1%) died. Older age and presence of one or more additional comorbidities were associated with hospitalization and death (p=0.010, p=0.003, p=0.034, p<0.001). Hispanic/Latinx ethnicity was associated with hospitalization (p=0.047). Cancer treatment was not associated with hospitalization or death. CONCLUSION: In our diverse, multi-center, breast cancer cohort, Hispanic/Latinx ethnicity, older age and presence of other comorbidities were associated with worse outcomes from COVID-19. Breast cancer treatment, including surgery, radiation, systemic therapy, and endocrine therapy, was not associated with hospitalization in our cohort. Further studies are needed to explore the relationship between breast cancer and COVID-19 outcomes. We investigated outcomes of 132 patients with breast cancer and SARS-CoV-2 infection at two Los Angeles health systems. In this study, older age and more comorbidities were associated with COVID-19 hospitalization and death, while Hispanic/Latinx ethnicity was associated with hospitalization. Breast cancer therapies were not associated with hospitalization or death from COVID-19 in our cohort; larger studies are needed to further explore these relationships. was not associated with hospitalization in our cohort. Further studies are needed to explore the relationship between breast cancer and COVID-19 outcomes. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for coronavirus disease 2019 (COVID-19), has caused a global pandemic. Over 258 million people have been infected with SARS-CoV-2 worldwide and over 5.1 million people have died from SARS-CoV-2 related illness 1 . In Los Angeles, over 1.5 million people have been infected and over 27,000 have died from SARS-CoV-2 2 . Older age, male sex, cardiopulmonary disease, obesity, and diabetes mellitus have been extensively studied as risk factors for severe outcomes from COVID-19 3, 4 . In contrast, data evaluating cancer as a risk factor has been mixed and may be specific to cancer type. For example, patients with thyroid cancer do not appear to have increased mortality with COVID-19, while patients with hematologic malignancies do [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] . Breast cancer is the most common cancer in females, affecting 12.9% of women 16 . Yet studies evaluating outcomes of patients with breast cancer and COVID-19 have been limited in scope, with mixed results [17] [18] [19] . Preliminary data from a multi-institutional collaboration reported that 48% of patients with breast cancer, either active or with no evidence of disease (NED), were hospitalized and 9% died, which is significantly higher than the general population 20 . This finding highlights the need for further investigation of COVID-19 outcomes in breast cancer patients and exploration of possible mechanisms driving disease severity in this cohort 21 . Hormones may influence the pathogenesis of COVID-19, although the exact mechanisms are yet to be determined. Peckham and colleagues reported that among a non-cancer population, males with SARS-CoV-2 infection have 3 times the odds of intensive care unit (ICU) admission and 1.39 times the odds of death compared to females 22 . There are multiple proposed mechanisms for this difference including a common enzyme in the androgen receptor signaling pathway and SARS-CoV-2 replication cycle, estrogen receptor expression by most cells in the immune system, and increased production of interferons in females 23-25 . Estrogens, progesterone, and testosterone also are direct signals for immune cell function 25 . Meanwhile, the impact of HER2 targeted therapies, as well as other systemic agents (CDK4/6, PI3K, PD-L1) on COVID-19 outcomes, remains poorly described in breast cancer patients. Therefore, the influence of cancer therapy on COVID-19 outcomes in breast cancer patients is of particular interest. In this retrospective, multi-institutional study, we evaluated how breast cancer-and breast cancer treatment-related factors were associated with COVID-19 hospitalization and mortality at two diverse academic health systems. These results can inform optimal clinical care for breast cancer patients with SARS-CoV-2 and can influence future studies of mechanisms of pathogenesis at the intersection of coronavirus infections and malignancy. This retrospective study enrolled patients based on COVID-19 registries at two major academic health systems in Los Angeles: the University of California Los Angeles (UCLA) Health System and the Los Angeles County-University of Southern California Medical Center (LAC+USC). Patients with a history of invasive breast cancer and a positive SARS-CoV-2 polymerase chain reaction (PCR) or antibody test from January 1, 2020 to December 31, 2020 were eligible for inclusion. Patients with a history of ductal carcinoma in situ (DCIS), lobular carcinoma in situ (LCIS), or Phyllodes tumor without IDC or ILC, as well as those with limited medical records about their cancer, were excluded. The Institutional Review Boards at UCLA (IRB #20-000650) and USC (IRB #HS-20-00401) approved the human subjects research at each institution, respectively. Clinical data was reviewed and abstracted from the electronic medical record for all patients that met eligibility criteria. Variables collected included demographics, body mass index (BMI greater than or less than 25), smoking status, and history of comorbidities (including diabetes, lung, heart, liver, and kidney disease, immunodeficiency, or other malignancy) 26 . Breast cancer-related factors including diagnosis, stage, receptor status, and treatment were also collected. Active cancer was defined by oncology documentation detailing ongoing cancer therapy, including surgery, radiation, or systemic therapy, within 12 months of COVID-19 diagnosis, but not adjuvant endocrine therapy. NED was defined as no evidence of disease per imaging and oncology documentation. Staging was conducted using American Joint Committee on Cancer (AJCC) 8th edition 27 . Systemic regimens were further classified as cytotoxic, HER2 targeted, other targeted therapies (including CDK4/6 inhibitors), or immunotherapy. COVID-19 related outcomes including hospitalization, ICU admission, thromboembolic disease, need for supplemental oxygen, mechanical ventilation, renal replacement therapy, vasopressor support, extracorporeal membrane oxygenation (ECMO), and death were recorded. Treatments received for COVID-19 were also obtained from the EMR. Descriptive statistics were used to evaluate demographic factors, cancer-related factors, and COVID-19 outcomes. The pre-specified primary endpoint of interest was hospitalization rate from COVID-19; the secondary endpoint was death from COVID-19. Associations between COVID-19 related hospitalization and other clinical demographic or cancer-related variables were calculated by Fisher's exact test (categorical variables) or linear regression (continuous variables), with alpha of 0.05. Averages were reported as medians with interquartile range (IQR) as measure of variance. Statistical tests were two-sided. Statistical analysis was conducted using Python. Scipy was used for calculations, pandas for data manipulation, and matplotlib for graphical representation. Table 2 . COVID-19 outcomes are listed in Table 3 . Among all patients, 40 (30.3%) were hospitalized for SARS-CoV-2 infection, and 31 (23.5%) required supplemental oxygen. Eleven patients (8.3%) required ICU admission, 3 (2.3%) required invasive mechanical ventilation, 2 (1.5%) renal replacement therapy, 2 (3.0%) vasopressor therapy, and 1 patient (0.8%) required ECMO. Forty-six (34.8%) received some pharmacologic COVID treatment, including remdesivir, dexamethasone, hydroxychloroquine, azithromycin, convalescent plasma, leronlimab, bamlinivimab, baracitinib, tocilizumab, molnupiravir, or other antibiotics. Among all 132 breast cancer patients, a total of 8 patients (6.1%) died from COVID-19 infection. Outcomes Statistical analysis revealed that breast cancer patients hospitalized for COVID-19 were older than patients who did not require hospitalization [median age 64.5 years (IQR 53.5-79 years) vs. 58 years (IQR 49-67.5 years), p=0.010]. In addition, Hispanic/Latinx patients were more likely to be hospitalized for COVID-19 than non-Hispanic/Latinx [19/47 (40.4%) vs. 21/85 (24.7%), p=0.047]. There was no association between the other minority racial groups (Black/African American, Asian, and other) and hospitalization; when the Hispanic/Latinx cohort was combined with other minority groups, the association with increased hospitalization was no longer apparent. Patients with one or more additional comorbidities were more likely to be hospitalized for COVID-19, compared to those without additional comorbidities [30/74 (40.5%) vs 10/58 (17.2%), p=0.003]. Hospitalization rates were higher among patients with lobular subtype compared to ductal subtype (p=0.034), despite small numbers of patients with lobular histology. There were no other demographic or cancer-related variables that were significantly associated with hospitalization due to COVID-19 (Figure 2) . Patients with breast cancer who died from COVID-19 were significantly older than patients who did not die from COVID-19 [83.5 years (IQR 69.5-94 years) vs. median age 59 years (IQR 49-71 years), p=0.034]. Patients who died from COVID-19 were also more likely to have one or more comorbidities compared to patients who did not die We report the outcomes of patients with a history of breast cancer who tested positive for SARS-CoV-2 at two academic medical centers in Los Angeles. In contrast to other previously reported studies of clinical outcomes among cancer patients with SARS-CoV-2 infection, our study is highlighted by two strengths. First, our study population reflects outcomes from Los Angeles, California, which became the second major epicenter for the COVID-19 pandemic in late 2020, several months after the first epicenter struck New York City 2, 28-30 . This is important to note, as many important COVID-19 therapeutics had been well described and were available to our hospitalized patients at this time. Second, the uniquely diverse racial-ethnic make-up in Los Angeles allows us to comment on the impact of COVID-19 among a large Hispanic/Latinx demographic 13, 31-33 . As such, our motive was to evaluate for associations between demographic and cancer-related variables in connection with hospitalization and death as critical outcomes of COVID-19 in this population. In this analysis, older age and multiple comorbidities were significantly associated with both hospitalization and death from COVID-19; this is consistent with two other studies of breast cancer patients with COVID-19 infection 18, 21 . Unlike other studies among non-cancer patients which reported an association between obese BMI (>30) and worse outcomes from SARS-CoV-2 (including mortality and hospitalization), our cohort did not reflect this, although this may be because our methodology was not designed to address this (BMI was considered a binary variable, greater than or less than 25) 34-36 . However, our study did allow us to query the impact of ethnic diversity; here we found that Hispanic/Latinx ethnicity was significantly associated with hospitalization for COVID-19 in breast cancer patients compared to non-Hispanic/Latinx patients. This trend has also been shown among non-cancer patients, as well as among a cohort of all cancer patients, which found that Hispanic/Latinx persons were 4 times more likely to have COVID-19 compared to White/Caucasian patients 37-40 . To our knowledge, this study is the first to report this association in the breast cancer population. Consistent with other studies of ethnic disparities in COVID-19 outcomes among the general population, we suspect this association may be multifactorial in nature, and warrants further investigation 34, 38 . In contrast to other studies showing increased rates of hospitalization from COVID-19 in Black/African American patients, we did not see this association, likely because of our small population of Black/African Americans, whereas our Hispanic/Latinx population was much larger 9, 41 . Of note, we did not find an association between Hispanic/Latinx (or any race) and death due to COVID-19, although there were only a small number of deaths in our cohort, thus limiting our ability to comment on this specifically. Still, these findings overall suggest the need for continued attention to the Furthermore, the impact of multiple delays in cancer care has led to concerns that untreated malignancy may go unfettered, resulting in progression with advanced disease, or development of resistant malignant clones 42 . In the current study, we did not see any association between any breast cancer therapy (including systemic therapy, surgery, or radiation) within 90 days and increased risk of hospitalization for COVID-19 18, 19 . Again, we are limited by our sample size, and note that only 40 patients in total were hospitalized for COVID-19. Still, this is somewhat counterintuitive, as cytotoxic chemotherapy and radiation are known to be myelosuppressive and surgery as well may predispose to infectious risk 43 . At the same time, we also speculate that many clinicians, when understanding the risk of SARS-CoV-2 infection, were already more careful in only selecting robust patients for cancer therapy and excluding higher risk patients 44 . Given the role of estrogen in enhancing adaptive and humoral immunity, we had hypothesized that patients receiving endocrine therapy would have worse outcomes from COVID-19 24, 25 . However, we did not detect any association between endocrine therapy and either hospitalization or death from COVID-19 infection. In at least one other study, Montopoli et al, also found no association between antiestrogen therapy and COVID-19 outcomes in estrogen-responsive malignancies 45 . Further studies are needed to clarify the interaction between active SARS-CoV-2 infection and breast cancer therapy, to help guide clinicians facing this situation. Until then we advocate that each breast cancer patient should still undergo careful decision-making to assess the risks and benefits with their provider in a personalized approach when infected with SARS- Despite the low number in our cohort, we found that death from COVID-19 was associated with older age and the presence of additional comorbidities in our cohort of breast cancer patients, which has consistently been reported by many COVID-19 studies, as noted above 3, 4, 14 . Among our small sample size, 4 of 8 patients (50.0%) who died had advanced dementia at time of hospitalization, which may have contributed to decisions about goals of care and thereby impacted outcomes; this reflects the challenge of decision-making for frail or highrisk patients in the era of COVID-19 and the debate about how to best utilize health care resources. In addition, all patients who died were noted to be HER2-receptor negative, although we strongly caution against over-interpretation of this finding, again, given the extremely low numbers. Going forward, closer study of the specific variables which may predispose to death from COVID-19 should be more closely examined. Our study has several limitations, including its small sample size and its retrospective nature. As mentioned above, we had a low death rate in our cohort, thus limiting our ability to comment on variables associated with death. Accordingly, there were few patients with metastatic disease, and very few patients who received novel systemic agents, such as PD-L1 based immunotherapy or other targeted agents. Nevertheless, our cohort comprises a relatively homogenous cohort in terms of breast cancer therapy, as nearly all patients were treated with standard approaches for localized or regionally advanced disease, including surgery, radiation, systemic therapy, and endocrine therapy, and thus may provide some clues as to how to view SARS-CoV-2 infection in the context of breast cancer. Furthermore, this multi-institutional cohort also provides an informative perspective with respect to the Hispanic/Latinx breast cancer population, in particular. We recommend larger studies to further investigate these reported relationships. In conclusion, we describe the clinical outcomes of patients with a history of breast cancer from a diverse, multicenter cohort from Los Angeles. Age and the presence of at least one additional comorbidity were significantly associated with hospitalization and death. Hispanic/Latinx ethnicity was associated with hospitalization, but not death. Breast cancer treatments were not associated with hospitalization or death in our cohort.  In a diverse, multicenter cohort of patients with breast cancer who tested positive for SARS-CoV-2, older patients and patients with one or more additional comorbidities were more likely to be hospitalized and die from COVID-19 Potter D, Riffon M, Kakamada S, Miller RS, Komatsoulis GA.

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