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COVID-19 Incidence and Mortality in Patients Operated on for Breast Cancer. Comparison with the General Population.

Published:November 16, 2022DOI:https://doi.org/10.1016/j.clbc.2022.11.002

      Highlights

      • BC patients had higher incidence of COVID-19 infection and mortality compared to control group (13.1% vs 11.7% and 7.1% vs 4.7%)
      • Mortality rates were higher in nursing home patients older than 70 years, and mainly happened during the first six months of the pandemic event.
      • Distant metastases and living in a care home were the only independent predictive factors for COVID-19 mortality in BC patients.

      ABSTRACT

      Background

      Breast Cancer remains the most commonly diagnosed malignancy and the most common cause of cancer-related mortality in women worldwide. Covid-19 mortality in BC patients has been linked to comorbid conditions rather than to cancer treatment itself, although this was not confirmed by a meta-analysis. Also, during Covid-19 outbreaks, a great deal of health care resources are reassigned to critical Covid-19 patients.

      Patients and methods

      During five consecutive trimesters (from 1/12/2020 to 31/3/2021) 2,511 breast cancer (BC) patients older than 20 years from our institution were surveyed. 1,043 of them had received a Covid test and these made our study group, which was conveniently compared with the Covid-19 tested background feminine Catalan population.

      Results

      13.1% of our patients presented with a positive Covid-19 test, whereas confirmed COVID-19 infection amounted to 7.1% of the feminine Catalan tested population. The COVID-19-specific mortality rate was 11.7% (16/137) in the study group, which compares with a 4.7% rate for the overall population. Most deaths occurred in patients over 70.

      Conclusions

      Three clinical factors were significantly associated with Covid-19 mortality in BC, namely lack of hormone therapy, distant metastases, and BC dwelling in nursing homes. BC patients are at a higher risk of Covid-19 infection and mortality in comparison with the reference group without BC.

      Micro Abstract

      1,043 breast cancer patients (BC) had a Covid test and made our study group, which was conveniently compared with the COVID-19 tested background feminine Catalan population.
      Covid-19 incidence and mortality were indeed higher among BC patients, although BC per se without metastases was not linked to increased mortality.
      Metastases and nurse home dwellings were significantly associated with mortality.

      Keywords

      Background

      Some reports in the literature initially suggested that, within the present Covid-19 pandemic crisis

      WHO. WHO Director-General's opening remarks at the media briefing on COVID-19 - 11 March 2020. Geneva: World Health Organization, March 11, 2020. https://www.who.int/dg/speeches/detail/who-director-general-s-opening-remarks-at-the-mediabriefing-on-COVID-19—11-march-2020 (accessed April 20, 2020).

      , patients with a history or with active malignant disease were at higher risk of getting infected, as well as of developing Covid-19-related complications
      • Liang W
      • Guan W
      • Chen R
      • et al.
      Cancer patients in SARS-CoV-2 infection: a nationwide analysis in China.
      • Dai M
      • Liu D
      • Liu M
      • et al.
      Patients with cancer appear more vulnerable to SARS-CoV-2: a multicenter study during the COVID-19 outbreak.
      • Kuderer NM
      • Choueiri TK
      • Shah DP
      • et al.
      Clinical impact of COVID-19 on patients with cancer (CCC19): a cohort study. COVID-19 and Cancer Consortium.
      However, such reports were often limited by short sample size, or by being restricted to a specific geographical area, and therefore their findings could not be easily extrapolated to the general population of cancer patients
      • Kuderer NM
      • Choueiri TK
      • Shah DP
      • et al.
      Clinical impact of COVID-19 on patients with cancer (CCC19): a cohort study. COVID-19 and Cancer Consortium.
      . The notion that cancer patients are at a higher risk for Covid-19 has been further supported by additional research
      • Liang W
      • Guan W
      • Chen R
      • et al.
      Cancer patients in SARS-CoV-2 infection: a nationwide analysis in China.
      • Yu J.
      • Ouyang W.
      • Chua M.L.K.
      • Xie C.
      SARS-CoV-2 transmission in patients with cancer at a tertiary care hospital in wuhan, China.
      • Grasselli G.
      • Zangrillo A.
      • Zanella A.
      • et al.
      Baseline characteristics and outcomes of 1591 patients infected with SARS-CoV-2 admitted to ICUs of the lombardy region.
      • Argenzian M.G.
      • Bruc S.L.
      • Slate C.L.
      • et al.
      Characterization and clinical course of 1000 patients with coronavirus disease 2019 in New York: retrospective case series.
      • Richardson S.
      • Hirsch J.S.
      • Narasimhan M.
      • et al.
      Presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with COVID-19 in the New York city area.
      . On the other hand, it has been shown that cancer patients infected by the SARS-COV2 virus tend to develop an antibody response similar to that of previously healthy subjects
      • Marra A
      • Generali D
      • Zagami P
      • et al.
      Seroconversion in patients with cancer and oncology health care workers infected by SARS-COV-2.
      .
      Breast Cancer (BC) is indeed both the most commonly diagnosed malignancy and the most common cause of cancer-related mortality in women worldwide
      • Bray F
      • Ferlay J
      • Soerjomataram I
      • et al.
      Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.
      . A fresh report suggested that Covid-19 mortality rates in BC patients were related to comorbid conditions, rather than to cancer treatment itself
      • Vuagnat P
      • Frelaut M
      • Ramtohul T
      • et al.
      COVID-19 in breast cancer patients: a cohort at the Institut Curie hospitals in the Paris area.
      , although such results were not confirmed by a subsequent meta-analysis
      • Sheng Z
      • Zhang L
      • Liu X
      • et al.
      Prognosis of COVID-19 in patients with breast cancer: A protocol for systematic review and meta-analysis.
      .
      Also, it is acknowledged that, during Covid-19 outbreaks, a great deal of healthcare resources is reassigned to critical Covid-19 patients
      • Rosenbaum L
      Facing COVID-19 in Italy - ethics, logistics, and therapeutics on the epidemic's front line.
      .
      Singh MK et al.
      • Singh MK
      • Mobeen A
      • Chandra A
      • Joshi S
      • Ramachandran S.
      A meta-analysis of comorbidities in COVID-19: Which diseases increase the susceptibility of SARS-CoV-2 infection?.
      were able to show that basal ACE2 receptor (angiotensin-converting enzyme type 2 receptor) cell expression was significantly increased in several conditions, including leukemia, lung, breast, or cervical cancer, as well as in non-alcoholic fatty liver, psoriasis, and hospital-acquired pneumonia. Increased cell ACE2 receptor expression may enhance viral cell invasion and thus, explain greater susceptibility for SARS-CoV-2 infection in patients with such conditions.
      Furthermore, often patients with malignancies are older, mostly over 60, and sustain significant comorbidities, which in themselves lead to a greater risk of Covid-19-related morbidity and mortality
      • Bialek S
      • Boundy E
      • Bowen V
      • et al.
      CDC. COVID-19 Response Team. Severe outcomes among patients with coronavirus disease 2019 (COVID-19) - United States, February 12-March 16, 2020.
      . Increased Covid-19 mortality rates seem associated with factors such as disease severity, lack of specific treatment, and, perhaps strained medical resources due to increased Covid-19 hospital admissions. Notwithstanding the importance of such factors, there is however some uncertainty regarding other factors that may lead to worsened clinical outcomes in cancer patients.
      We aimed at tracing the characteristics and outcomes of both outpatient and hospital-admitted Covid-19 sufferers with a history or with actively treated BC at our Breast Unit.

      PATIENTS AND METHODS

      Study design

      It was conceived as a unicentric cross-sectional, retrospective analysis.
      As such, it was approved by the Hospital Universitari Mutua de Terrassa Review Board (N° O/21-094) under the consideration that it was dealing with an active population challenge.

      Patients

      The study group included patients aged over 20 with previous or active BC who were tested for Covid-19. Patients with both invasive and in situ tumors were included. These were compared with women from the general population receiving a SARS-CoV-2 test by the Catalan Health Service. The study was meant to span the whole year 2020 and the first trimester of 2021. The actual data collecting time window was from December 1, 2020, to March 30, 2021. Individual subject data were derived from the clinical records of our center, as well as from the online shared clinical record service of the Catalan Health Service and the official population statistical source service. (https://www.idescat.cat/ [Last consulted 10th January 2022]).
      The Breast Unit database was refurbished to include certain Covid-19-related variables, including the SARS-CoV-2 test (CoT), either polymerase chain reaction (PCR) or rapid antigen lateral flow test (RT), date of CoT, patient age at CoT, the reason to test, type of CoT, CoT result, covid signs/symptoms in positive CoT subjects, and mortality, stating if at home or nursing home.

      Statistics

      Qualitative variables were expressed as numbers and percentages, while quantitative variables were expressed as mean value and standard deviation. For comparison of qualitative variables, the Chi-square test or the Fisher's exact test was used, while for comparison of mean values the ANOVA test was used. Statistical significance was set at a p<0.05 value, with a two-tailed approach. Data were subjected to a univariate and multivariate logistic regression analysis using the SPSS statistical software v23.0 (SPSS Inc., Chicago, IL, USA). As the predictive criterion, we considered a dichotomy variable defining mortality after COVID-19. Adequacy of model fitting was measured using the Hosmer–Lemeshow test. The predictive variables eventually used in our logistic regression (LR) model were those variables shown to be statistically significant in the univariate analysis.

      RESULTS

      Of the total 2,511 BC patients older than 20 that were registered in our database, 1,043 (41.5%) received at least one CoT. The total number of CoT was 1,833, 1,180 of which were PCR tests and 653 RT. The reference group included 2,625,958 women with a CoT.

      COVID-19 Incidence

      Confirmed Covid-19 infection amounted to 137 subjects out of 1,043 BC cases (13.1%), whereas confirmed Covid-19 infection amounted to 7.1% of the feminine Catalan tested population, a statistically significant difference (p < 0.001). Table 1 shows the univariate analysis results of COVID-19 comorbidity factors in BC subjects.
      Table 1Comorbidity factors for COVID-19 infection in our group of BC patients
      Covid negativeCovid positivep-value
      N (%)N (%)
      Age0.635
      <50107/121 (88.4)14/121 (11.6%)
      50-69465/532 (87.4)67/532 (12.6%)
      ≥ 70334/390 (85.6)56/390 (14.4%)
      Smoker0.039
      No o ex >10 years679/791 (85.8)112/791 (14.2%)
      yes217/240 (90.4%)23/240 (9.6%)
      Alcohol intake0.058
      No664/773 (85.9%)109/773 (14.1%)
      yes232/258 (89.9%)26/258 (10.1)
      BMI0.067
      < 25320/357 (89.6)37/357 (10.4%)
      ≥ 25534/620 (86.1)86/620 (13.9)
      pTNM0.617
      pTis79/95 (83.2)16/95 (16.8%)
      I408/466 (87.6)58/466 (12.4%)
      IIA196/226 (86.7)30/226 (13.3%)
      IIB102/120 (85)18/120 (15%)
      III*116/130 (89.2)14/130 (10.8%)
      Histologic Diagnosis0.167
      DCIS79/95 (83.2)16/95 (16.8%)
      Invasive Ca827/948 (87.2)121/948 (12.8%)
      Phenotype0.110
      Luminal A319/361 (88.4)42/361 (11.6)
      Luminal B (her2+/-)395/477 (88.4)52/447 (11.6)
      Pure Her235/42 (83.7)7/42 (16.3)
      Triple Negative79/99 (79.8)20/99 (20.2)
      Local recurrence
      No821/946 (86.8)125/946 (13.2)0.397
      Yes84/95 (88.4)11/95 (11.6)
      Distant recurrence0.531
      No863/994 (86.8)131/994 (13.2%)
      Yes43/49 (87.8)6/49 (12.2%)
      Chemotherapy0.472
      No410/473 (86.7)63/473 (13.3)
      Yes496/570 (87)74/570 (13)
      Hormone therapy0.007
      No115/144 (79.9)29/144 (20.1%)
      Yes791/899 (88)108/899 (12.0%)
      Dwelling<0.001
      Home862/979 (88.1)117/979 (11.9)
      Nursing home44/60 (66.7)20/60 (33.3%)
      Months from BC diagnosis0.045
      ≤ 60 months294/326 (90.2)32/326 (9.8%)
      61 to 120 months247/296 (83.5)49/296 (16.5%)
      >120 monts365/421 (86.7)56/421 (13.3%)

      COVID-19 Specific Mortality

      The covid-19-specific mortality rate was 11.7% (16/137) in the study group, which compares with a 4.7% rate for the overall population, a statistically significant difference (p < 0.001).
      Table 2 shows statistically significant factors for Covid-19 mortality according to the univariate analysis. These included age over 70, BMI, tumor phenotype, distant metastases, lack of hormone therapy, and being a resident in a nursing home. Of note, most deaths occurred in non-smokers and abstemious women, both probably related to patient age. Variables that turned out significant in the univariate analysis were used as the base for the multivariate analysis, after which only distant metastases, lack of hormone therapy, and living in a nursing home kept their independent significance (Table 6).
      Table 2COVID-19 mortality related factors
      AliveDeath from COVID-19p-value
      N (%)N (%)
      Age0.022
      <50120/121 (99.2)1/121 (0.8)
      50-69528/532 (99.2)4/532 (0.8)
      ≥70379/390 (97.2)11/390 (2.8)
      Smoker0.024
      No o ex >10 years704/719 (97.9)15/719 (2.1)
      yes311/312 (99.7)1/312 (0.3)
      Alcohol intake0.010
      No757/773 (97.9)13/773 (2.1)
      yes258/258 (100)0/258 (0)
      BMI0.034
      < 25355/357 (99.4)2/357 (0.6)
      ≥ 25606/620 (97.7)14/620 (2.3)
      pTNM0.924
      pTis91/92 (98.9)1/92 (1.1)
      I459/465 (98.7)6/465 (1.3)
      IIA224/227 (98.7)3/227 (1.3)
      IIB118/120 (98.3)2/120 (1.7)
      III*127/130 (97.7)3/130 (2.3)
      Histologic Diagnosis0.564
      DCIS94/95 (98.9)1/95 (1.1)
      Ca Invasive933/948 (98.4)15/948 (1.6)
      Phenotype0.031
      Luminal A355/361 (98.3)6/361 (1.7)
      Luminal B (her2+/-)444/447 (99.3)3/447 (0.7)
      Pure Her241/42 (97.6)1/42 (2.4)
      Triple Negative94/99 (94.9)5/99 (5.1)
      Local recurrence0.436
      No934/948 (98.5)14/948 (1.5)
      Yes93/95 (97.9)2/95 (2.1)
      Distant recurrence0.034
      No982/995 (98.7)13/995 (1.3)
      Yes45/48 (93.5)3/48 (6.5)
      Radiation Therapy0.476
      No174/176 (98.8)2/176 (1.2)
      Yes853/867 (98.4)14/867 (1.6)
      Chemotherapy0.445
      No464/472 (98.3)8/472 (1.7)
      Yes563/571 (98.6)8/571 (1.4)
      Hormone therapy0.015
      No138/144 (95.8)6/144 (4.2)
      Yes889/899 (98.9)10/899 (1.1)
      Dwelling<0.001
      Living place971/979 (99.2)8/979 (0.8)
      Geriatric residence56/64 (87.5)8/64 (2.5)
      Months from BC diagnosis0.145
      ≤ 60 months324/326 (99.4)2/326 (0.6)
      61 to 120 months292/296 (98.6)4/296 (1.4)
      >120 months411/421 (97.6)10/421 (2.4)

      Age and COVID-19 Mortality

      Most COVID-19 deaths occurred beyond 70 years of age, both in the study group and in the reference group, with no statistical difference (P=0.55). As for patients under 70, Covid-19 mortality was 0.8% in the reference group, and 6.3% in the study group, a statistically significant difference (p < 0.001), Table 3.
      Table 3Positive test cases and Mortality in the reference group and in the study group, according to age echelon.
      Reference group*Study group
      AgeConfirmed casesCovid MortalityConfirmed casesCovid Mortality
      YearsN%N%N%N%
      <5094,6526,1740.114/12111.61/147.1
      50-5931,3475,71600,532/247132/326.3
      60-6919,4114,43521,835/28512.32/355.7
      70-7914,0974,11.0617,533/24513.54/3312.1
      80-8916,0737,47.13026,519/119167/2330.4
      ≥9010,86316,54/2615.4
      Overall186.4437.18.7774.7137/104313.11611.7
      *Source: Idescat.Ref

      COVID-19 Mortality time-spread

      Table 4 shows mortality rates at trimestral intervals. It can be seen that Covid-19 mortality occurred mostly during the first two trimesters of 2020 and was significantly higher for the study group (p < 0.001).
      Table 4COVID-19 mortality over five trimesters
      Reference group mortalityStudy cohort mortality
      Overall Control groupNursing homesStudy cohortNursing homes
      TrimesterN%N%N%N%
      First 20201646/1443311.4664/164940.31/147.10/200
      Second 20204806/2968416.23339/904936.911/1668.86/2030
      Third 2020407/429230.9188/149412.60/2100/14**0
      Fourth 20201929/998391.9847/586514.43/634.82/14**14.3
      First 20211724/806412.1530/275819.21/234.30/12**0
      16/1378/20
      **Deaths from the previous trimester subtracted. *Source: Idescat Ref

      COVID-19 Home deaths vs Nursing Home deaths

      The mortality rate for subjects in the study group living in nursing homes was 12.5% (8/64), which was significantly higher than for patients living in their own homes, with a death rate of only 0.8% (8/978). This was a significant difference (p<0.001) both in the univariate and multivariate analyses (Tables 4 and 6).
      Along the first five trimesters, the Covid-19 mortality rate in nursing home residents from the reference population was 26.7%, (5,568/20,818) whereas the corresponding mortality rate for patients with BC was 40% (8/20), a non-statistically significant difference (p =0.181).

      COVID-19 Incidence and Mortality rates in Infiltrating vs In Situ Carcinoma patients

      The rate of Covid-19 infections was 12.8% (121/948) in patients with infiltrating carcinoma (IC), whereas such incidence was 16.8% (16/95) in patients with DCIS; a nonsignificant difference (P=0.167). Covid-19 mortality rate was 1.6% (15/948) in IC patients and 1.1% (1/95) in CDIS patients, also a non-significant difference (p=0.564). On the other hand, both groups were homogeneous when age was considered: a mean of 56.2 ±12 years (range 22-91) for IC patients, and 56±9 years (range 30-86) for DCIS patients. Also, when nursing home dwelling was considered: 6.3% (60/948) for IC patients vs 4.2% (4/95) for DCIS patients (p=0.288).

      COVID-19 Mortality and Adjuvant Hormone Therapy

      Indication of hormone therapy in our patients relies on the individual molecular subtype and only applies to those with tumors expressing estrogen and progestin receptors. BC patients not receiving hormone therapy showed a significantly higher Covid-19 mortality rate than those receiving hormone therapy, both in the univariate and multivariate analysis (4.2% vs 1.1%) (p = 0.015). Tables 1 and 6. More broadly, patients with a positive hormone receptor (HR) status showed a 1% (9/808) mortality rate, while patients with a negative HR status (Pure Her2 and TN subtypes) showed a covid mortality rate of 4.3% (6/140), a statistically significant difference (p = 0.032).

      COVID-19 Mortality and Pandemic Time Window

      Both in BC patients and the reference group, Covid-19 mortality occurred mostly during the first two trimesters of 2020: 27.6% for the reference group and 75.9% for the BC group (p <0.001), Table 4.

      Covid-19-related comorbidity conditions

      Non-BC-related comorbidities in our patient group are displayed in Table 5. It can be seen that hypertension, diabetes mellitus, respiratory diseases, and increased BMI are quite prevalent.
      Table 5Epidemiological and clinical characteristics of BC patients who died from COVID-19
      AgeDwellingHospital admissionTrimesterPresentationDistant metastasesBMIComorbidity
      173homeyes1T20Pneumoniano32.0HBP,TIIDM, Asthma
      287homeyes2T20Pneumoniano25.9None
      390nursing homeno2T20Pneumoniano31.6HBP, TII DM
      479nursing homeno2T20Pneumoniano24.2Heart fail, COPD, R Arthritis
      579nursing homeyes2T20Pneumoniano24.2HBP, TII DM
      688nursing homeyes2T20Pneumoniano27.5HBP, Asthma, TII DM
      780homeyes2T20Pneumoniano40.8HBP, TII DM, heart dis.
      879nursing homeno2T20Pneumoniano29.7HBP, TII DM
      965homeyes2T20Pneumoniano26.2None
      1053homeyes2T20Pneumoniayes29.9Mets
      1141homeyes2T20Pneumoniayes33.7Mets
      1287nursing homeno2T20Pneumoniano27.0HBP
      1359homeyes4T20Pneumoniayes34.4cig. smoker
      1476nursing homeno4T20Pneumoniano32.0dementia
      1585nursing homeno4T20Pneumoniano29.7HBP
      1669homeyes1T21Pneumoniano26.3Recurrent Myeloma
      Mean or %38% nursing home.

      62% home
      38% no admission100% pneumonia19% yes metastasis94% yes morbidity
      Table 6Results from the Multiple regression mortality factors analysis based on significant variables from the univariate analysis
      95% C:I. for EXP (OR)
      ConstantSignificORLowerUpper
      Distant Metastases2,0970.0078.1431,78537,148
      Hormone Therapy-1,3600.0190,2570,0830,797
      Dwelling2,6110.00013,6163,41054,376

      COVID-19 Epidemiological Factors (Table 1)

      Age. The mean age of BC patients with a CoT was 65 ±13(SD) years, with a range of 25-101 years.
      Dwelling. 93.9% of BC patients lived in their own homes, and 6.1% at a nursing home
      Clinical Presentation. Out of the 137 BC with a positive CoT, 16.1% were asymptomatic, 57.7% had mild symptoms, and 26.3% had pneumonia. Of those living at home, 20.5% were admitted to hospital, while of those living in a nursing home 25% were admitted (p =0.421). Hospital admissions amounted to 21.2% of BC patients with a positive CoT.

      DISCUSSION

      Covid-19 hospital admissions have been a matter of debate in our context, especially when elderly patients living in nursing homes were concerned. The overall admission rate in our survey of covid19- positive BC patients was 21%, which compares with the much higher rate of 47% in the study by Vuagnat et al in Paris
      • Vuagnat P
      • Frelaut M
      • Ramtohul T
      • et al.
      COVID-19 in breast cancer patients: a cohort at the Institut Curie hospitals in the Paris area.
      , and 48% in the CCC19 study
      • Kuderer NM
      • Choueiri TK
      • Shah DP
      • et al.
      Clinical impact of COVID-19 on patients with cancer (CCC19): a cohort study. COVID-19 and Cancer Consortium.
      . Notably, only a quarter of Covid-19-infected nursing home BC patients in our study were finally admitted to the hospital.
      The Covid-19 mortality rate in our BC cohort was 11.7%, which is similar to the rate reported by the CCC19 consortium of 9% at 30 days
      • Kuderer NM
      • Choueiri TK
      • Shah DP
      • et al.
      Clinical impact of COVID-19 on patients with cancer (CCC19): a cohort study. COVID-19 and Cancer Consortium.
      . Our mortality rate was higher than the reported cumulative mortality figure for the feminine Catalan population over 20 years of age in the same period, which was 3.6%

      Institut d'estadistica de Catalunya. https://www.idescat.cat. https://www.idescat.cat/novetats/?id=3972. https://www.idescat.cat/pub/?id=covid.

      .
      Covid-19 mortality in patients with BC seems to concentrate mainly on subjects over 70, as already reported
      • Kuderer NM
      • Choueiri TK
      • Shah DP
      • et al.
      Clinical impact of COVID-19 on patients with cancer (CCC19): a cohort study. COVID-19 and Cancer Consortium.
      ,
      • Inwald EC
      • Ortmann O
      • Koller M
      • Zeman F
      • Hofstädter F
      • Evert M
      • Brockhoff G
      • Klinkhammer-Schalke M
      Screeningrelevant age threshold of 70 years and older is a stronger determinant for the choice of adjuvant treatment in breast cancer patients than tumor biology.
      , even though the most hard-hit age tier was for patients over 80. For BC patients under 70, mortality rates were considerably lower, just as has been reported for the general feminine Catalan population

      Institut d'estadistica de Catalunya. https://www.idescat.cat. https://www.idescat.cat/novetats/?id=3972. https://www.idescat.cat/pub/?id=covid.

      . Of the several comorbid conditions considered in epidemiological studies and predictive models, age has been shown the most significant independent factor for Covid-19 infection and mortality compared with the rest: body weight (patients with a BMI over 25 shows significantly higher mortality), hypertension, type II diabetes, cancer, dementia, heart disease, autoimmune disease, or other respiratory conditions such as asthma. Of note, neither cigarette smoking nor alcohol intake was related to increased Covid mortality in BC patients
      • Incerti D
      • Rizzo S
      • Li X
      • Lindsay L
      • Yau V
      • Keebler D
      • Chia J
      • Tsai L.
      Prognostic model to identify and quantify risk factors for mortality among hospitalised patients with COVID-19 in the USA.
      . Other factors unrelated to Covid mortality were the BC stage at the time of operation, local recurrence, and a diagnosis of infiltrating carcinoma versus intraductal carcinoma. Covid-19 mortality in our study group was conspicuously higher for patients living in nursing homes, albeit with no differences when compared with the reference group. These are figures pretty similar to the reported 38.7% rate by a Connecticut study
      Yue Li, PhD, *Helena Temkin-Greener, PhD, * Gao Shan, MS, † and Xueya Cai, PhD† COVID-19 Infections and Deaths among Connecticut Nursing Home Residents.
      and lead us to consider that the fact of being a nursing home resident is in itself the most significant factor for Covid-19 mortality in BC patients.
      Some authors have suggested that Coivid-19 mortality differences are linked to BC-related conditions, such as immunosuppression or metastatic spread
      • Incerti D
      • Rizzo S
      • Li X
      • Lindsay L
      • Yau V
      • Keebler D
      • Chia J
      • Tsai L.
      Prognostic model to identify and quantify risk factors for mortality among hospitalised patients with COVID-19 in the USA.
      In our study, metastatic disease has proved to be the most significant cancer comorbidity factor for Covid-19 mortality. Of note, neither chemotherapy nor the time elapsed between BC diagnosis and Covid-19 infections has been associated with increased mortality, suggesting that patients treated with chemotherapy in our series did not have substantial immunosuppression for long enough to render covid-19 more deadly. Although lack of hormone therapy was a significant variable according to our multivariate analysis, it seems to be related only to the negative hormone receptor status in patients with subtypes Her2 and TN, which are also associated with higher rates of distant metastases.
      In short, BC patients living in their own homes without distant metastases are at the same risk for Covid death as the general population.

      Limitations

      Because ours was a rather short and fixed data collecting time window from December 1, 2020, to March 30, 2021, this has resulted in a rather standard cross-sectional study where any inference may be difficult to apply. Both incidence and prevalence of Covid-19 change as the pandemic evolves and are dependent on the number of patients being considered over time. During that particular time window, some conversion from negative to positive CoT tests might have happened that could have had an impact on our results. Unfortunately, our database does not thoroughly include medical comorbid conditions unrelated to breast cancer that might have influenced covid-19 incidence and mortality results.

      Comment

      According to our multivariate analysis, distant metastases and living in a nursing home are the only independent predictive factors for Covid-19 mortality in BC patients.

      Author Contributions

      "All authors contributed to the study conception and design as well as to Material preparation, data collection, and analysis. The first draft of the manuscript was written by [Carolina Chabrera] and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript."

      Data Availability

      Data from the general population can be found at https://www.idescat.cat/pub/?id=covid.
      Data from our study of patients are not available in the public domain, however, they can be accessed under the request of Doctor Antonio García-Fdez, who is responsible for the database of the Breast Unit at the Hospital Universitari Mútua de Terrassa. ([email protected])

      Ethics approval

      This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of Hospital Universitari Mutua de Terrassa Review Board (Date July 12 2020, N° O/21-094)

      Consent to participate and publication

      All patients gave their written consent shortly before breast surgery so that their anonymized individual data, including those from clinical follow-up, could be used for scientific purposes.

      Statements and Declarations

      The authors have no relevant financial or non-financial interests to disclose.

      Acknowledgments

      We wish to thank Mr. Manel Martori for helping us with the graphic design, to the members of the Breast Unit, and finally to the staff of the Breast Cancer Screening Unit: Cristina, Sandra, and Clara; all of whom were essential contributors to keeping our breast cancer database updated.

      References

      1. WHO. WHO Director-General's opening remarks at the media briefing on COVID-19 - 11 March 2020. Geneva: World Health Organization, March 11, 2020. https://www.who.int/dg/speeches/detail/who-director-general-s-opening-remarks-at-the-mediabriefing-on-COVID-19—11-march-2020 (accessed April 20, 2020).

        • Liang W
        • Guan W
        • Chen R
        • et al.
        Cancer patients in SARS-CoV-2 infection: a nationwide analysis in China.
        Lancet Oncol. 2020; 21: 335-337https://doi.org/10.1016/S1470-2045(20)30096-6
        • Dai M
        • Liu D
        • Liu M
        • et al.
        Patients with cancer appear more vulnerable to SARS-CoV-2: a multicenter study during the COVID-19 outbreak.
        Cancer Discov. 2020; https://doi.org/10.1158/2159–8290.CD-20–0422
        • Kuderer NM
        • Choueiri TK
        • Shah DP
        • et al.
        Clinical impact of COVID-19 on patients with cancer (CCC19): a cohort study. COVID-19 and Cancer Consortium.
        Lancet. 2020 Jun 20; 395 (Epub 2020 May 28): 1907-1918https://doi.org/10.1016/S0140-6736(20)31187-9
        • Liang W
        • Guan W
        • Chen R
        • et al.
        Cancer patients in SARS-CoV-2 infection: a nationwide analysis in China.
        Lancet Oncol. 2020; 21: 335-337https://doi.org/10.1016/S147-2045(20)30096-6
        • Yu J.
        • Ouyang W.
        • Chua M.L.K.
        • Xie C.
        SARS-CoV-2 transmission in patients with cancer at a tertiary care hospital in wuhan, China.
        JAMA Oncol. 2020; https://doi.org/10.1001/jamaoncol.2020.0980
        • Grasselli G.
        • Zangrillo A.
        • Zanella A.
        • et al.
        Baseline characteristics and outcomes of 1591 patients infected with SARS-CoV-2 admitted to ICUs of the lombardy region.
        Italy. J. Am. Med. Assoc. 2020; 323: 1574-1581https://doi.org/10.1001/jama.2020.5394
        • Argenzian M.G.
        • Bruc S.L.
        • Slate C.L.
        • et al.
        Characterization and clinical course of 1000 patients with coronavirus disease 2019 in New York: retrospective case series.
        BMJ. 2020; 369: m1996https://doi.org/10.1136/mbj.m1996
        • Richardson S.
        • Hirsch J.S.
        • Narasimhan M.
        • et al.
        Presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with COVID-19 in the New York city area.
        JAMA. 2020; 323 (2020): 2052-2059https://doi.org/10.1001/jama.2020.6775
        • Marra A
        • Generali D
        • Zagami P
        • et al.
        Seroconversion in patients with cancer and oncology health care workers infected by SARS-COV-2.
        Annals of Oncology. 2020; 32: 113-119
        • Bray F
        • Ferlay J
        • Soerjomataram I
        • et al.
        Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.
        CA Cancer J Clinicians. 2018; 68: 394-424https://doi.org/10.3322/caac.21492
        • Vuagnat P
        • Frelaut M
        • Ramtohul T
        • et al.
        COVID-19 in breast cancer patients: a cohort at the Institut Curie hospitals in the Paris area.
        Breast Cancer Res. 2020; 22: 55https://doi.org/10.1186/s13058-020-01293-8
        • Sheng Z
        • Zhang L
        • Liu X
        • et al.
        Prognosis of COVID-19 in patients with breast cancer: A protocol for systematic review and meta-analysis.
        Medicine (Baltimore). 2020; 99 (Jul 31): e21487https://doi.org/10.1097/MD.0000000000021487
        • Rosenbaum L
        Facing COVID-19 in Italy - ethics, logistics, and therapeutics on the epidemic's front line.
        N Engl JMed: NEJMp2005492,. 2020; (PMID: 32187459)https://doi.org/10.1056/NEJMp2005492
        • Singh MK
        • Mobeen A
        • Chandra A
        • Joshi S
        • Ramachandran S.
        A meta-analysis of comorbidities in COVID-19: Which diseases increase the susceptibility of SARS-CoV-2 infection?.
        Computers in Biology and Medicine Volumen. March 2021; 130 (104219)104219https://doi.org/10.1016/j.compbiomed.2021
        • Bialek S
        • Boundy E
        • Bowen V
        • et al.
        CDC. COVID-19 Response Team. Severe outcomes among patients with coronavirus disease 2019 (COVID-19) - United States, February 12-March 16, 2020.
        MMWR Morb Mortal Wkly Rep. 2020; 69: 343-346https://doi.org/10.15585/mmwr.mm6912e2
      2. Institut d'estadistica de Catalunya. https://www.idescat.cat. https://www.idescat.cat/novetats/?id=3972. https://www.idescat.cat/pub/?id=covid.

        • Inwald EC
        • Ortmann O
        • Koller M
        • Zeman F
        • Hofstädter F
        • Evert M
        • Brockhoff G
        • Klinkhammer-Schalke M
        Screeningrelevant age threshold of 70 years and older is a stronger determinant for the choice of adjuvant treatment in breast cancer patients than tumor biology.
        Breast Cancer Res Treat. 2017; 163 (PMID: 28205042): 119-130https://doi.org/10.1007/s10549-017-4151-6
        • Incerti D
        • Rizzo S
        • Li X
        • Lindsay L
        • Yau V
        • Keebler D
        • Chia J
        • Tsai L.
        Prognostic model to identify and quantify risk factors for mortality among hospitalised patients with COVID-19 in the USA.
        BMJ Open. 2021 Apr 7; 11e047121https://doi.org/10.1136/bmjopen-2020-047121
      3. Yue Li, PhD, *Helena Temkin-Greener, PhD, * Gao Shan, MS, † and Xueya Cai, PhD† COVID-19 Infections and Deaths among Connecticut Nursing Home Residents.
        Facility Correlates JAGS. 2020; 68: 1899-1906