Introduction
Since December 2019, approximately 409 million patients
have been diagnosed with COVID-19.[] The
first case in Turkey was reported on March 11 and the
first death due to COVID-19 occurred on March 15, 2020.[] Nationwide restrictions and lockdown started
in April 2020. Turkish health system never overwhelmed
due to waves of COVID 19 partly because of
the high number of intensive care units (ICU) in the
world. Rarity of hospices or nursing homes, long legacy
of contact tracing, universal healthcare and lockdown policy were the main reasons for low fatality rate (REF).
Vaccination against COVID-19 has started in February
2021 initially with inactivated vaccine and then mRNA
base vaccine. The first peak of COVID-19 was in the
last week of the April and the second peak occurred in
September 2020.
It has been reported that cancer patients have worse
prognosis during this pandemic.[] In addition, patients
with cancer were more likely to have severe disease
and poor prognosis due to anti-tumor treatments,
especially hematological malignancies, lung cancer,
and metastatic cancers. Among all COVID-19 cases,
patients with cancer had a 11.4-28.6% mortality rate
and most of these studies included all solid tumors.[-] In articles including only breast cancer (BC) patients,
the mortality rate in patients has been reported
to be approximately 7%.[-]
Most of the patients with COVID-19 present with
complaints including fever, fatigue, anosmia, cough,
shortness of breath, myalgia, headache, nasal congestion,
and sore throat; however, some patients may remain
asymptomatic.[] Asymptomatic presentation is
reported to be in the range of 17.9-30.8%.[,] Asian
ethnicity, recent cancer diagnosis, hematological malignancies,
male sex, age over 60 years, and elevated Creactive
protein levels were reported to be associated
with increased mortality in cancer patients.[-]
Methods
We conducted a retrospective cohort study of patients
who had COVID-19 and were on treatment for BC at
our medical oncology Breast Health Center between
July 2020 and July 2021. This period covers second
peak of COVID-19 in Istanbul when the delta variant
was the dominant variant in Istanbul. Clinical, pathological,
and treatment characteristics of patients with
BC were recorded from electronic medical records.
The onset of symptoms, method of diagnosis, relation
with most recent anti-cancer therapy, and the severity
of clinical course are collected.
Statistical Analysis
SPSS-22 program was used in statistical analysis. Data
were presented as mean±standard deviation, number
of individuals, and percent. We analyzed patient characteristics
with descriptive statistics. Student's t-test
was used to compare the two normally distributed
quantitative data groups, and the Mann-Whitney U
test was utilized to compare two non-normally distributed
data groups. The qualitative data were compared with Pearson's Chi-square test and Fisher's exact test.
Statistical significance level was set at p<0.05.
Results
Approximately 5000-6000 patients with BC had their
treatments at our center annually. We identified 82 patients
who had COVID-19 while on therapy for BC from
July 2020 to 2021. Clinical and pathological characteristics
of patients are shown in (Table 1). All patients were
female, with a median age of 49 (43-64 years). Majority
of patients 85% (n=70) had early-stage and 15% (n=12)
had advanced BC. 67% (n=55) patients had hormone
receptor-positive/HER-2 negative, 21% (n=17) had
HER-2 positive, and 12% (n=10) had triple-negative
BC. Less than half of the patients had comorbidities.
Most common comorbid diseases were hypothyroidism
(19%, n=13), rheumatological diseases (7%, n=5), and
hypertension (6%, n=5). 63% (n=52) of patients were
on endocrine therapy (ET) when they had COVID-19
diagnosis. Among patients who were on chemotherapy/
targeted therapy (n=16) at the time of COVID-19 diagnosis,
the time from last chemotherapy/targeted therapy
was <7 days in 10% (n=8) of patients. All patients
who were on chemotherapy and/or targeted therapy had
treatment delays up to 2 weeks during COVID-19 infection.
COVID-19 diagnosis was confirmed with Polymerase
chain reaction (PCR) test in 86% (n=71), with
rapid antibody test in 7% (n=6), and chest computed
tomography in 7% (n=6) of patients. 56% (n=46) of the
patients had COVID-19 diagnosis at the emergency department,
17% (n=14) were diagnosed at the pandemic
outpatient clinic, 5% (n=4) were diagnosed in the oncology
ward, and 22% (n=18) had diagnosis at home by
national contact-tracing teams who work 7/24. Clinical
course of COVID-19 was mild in 73% (n=60) and 27%
(n=22) of the patients required hospitalization.
Table 1: Demographic and clinical characteristics of breast cancer patients with COVID-19
Nineteen out of 22 hospitalized patients discharged
with recovery (with a negative PCR test) and three patients
died due to due to COVID-19 and all of them
were heavily pretreated patients for metastatic BC.
Most common symptom was fever (Table 2) for all
patients. The symptomatology differed somewhat between
patients with a mild versus severe COVID-19
course. Patients with a mild course had more myalgia,
fatigue, anosmia, headache, and 15% of them were
asymptomatic compared to those with severe clinical
courses. Metastatic stage (p=0.002) and shorter time
(<7 days) since last chemotherapy (p=0.024) had significant
impact on mortality due to COVID-19 in univariate analysis (Table 3). Mortality due to COVID-19 was
not affected by age, number of symptoms, time since last
chemotherapy/targeted therapy in multivariate analyses.
Table 2: Type and frequency of symptoms due to
COVID-19
Table 3: Impact of clinical factors on mortality due to
COVID 19 (univariate analysis)
Discussion
Patients with cancer are inevitably affected by worldwide
spread of COVID-19 since 2019. All countries
adopted site/region-specific management strategies
and changed their pattern of care during pandemic.
Over time, we had more information on how different
COVID-19 variants affected cancer patients. Retrospective
data shed some light on how COVID-19's
clinical course and potential risk factors for mortality
in cancer patients.
Clinical outcomes and characteristics of BC patients
with COVID-19 have been reported firstly from
China and then from other countries in the world
(Table 4). A multicenter retrospective study aimed to
identify risk factors associated with COVID-19 in 45
BC patients with laboratory-confirmed diagnosis from
seven hospitals in Hubei China. They collected data related
to outcome of COVID-19 in BC patients till April
15, 2020. The median age of the patients was 62, all
were female, 89% had a positive PCR test, and 27% had
a severe clinical course. Five patients were >75 years
old, 60% had comorbid diseases and hypertension was
the most common comorbidity (31%). Three patients
(6.7%) had metastatic disease. Twenty-three patients
(51.5%) were on anti-cancer therapy (systemic and
local) and 33% were receiving anti-cancer treatment
within 1 week of COVID 19 diagnosis. The most common symptom was fever. Four patients required ICU,
3 (6.7%) patients died, all had a severe clinical course.
Age >75 years old, ECOG score were associated with
disease severity in univariate analysis. The impact of
chemotherapy within 7 days of diagnosis was significant
both in univariate and multivariate analyses.[]
Another retrospective study reported clinical, characteristics
and outcomes of 35 BC patients with COVID-
19 infection in the period between January and
May 2020 from 5 hospitals in Wuhan.[] All patients
had laboratory-confirmed COVID-19 diagnosis by
PCR or antibody test. In their study, 55 COVID-19 patients
without cancer and 81 patients with cancer (non-
BC) were also included as control groups. The median
age was 56, the stage of BC (early vs. metastatic) was
not reported and 11% patients had a severe COVID-19
clinical course. Twenty-four patients were symptomatic,
cough was the most common symptom (72.7%),
and fever was present in 6 patients (54.5%). All patients
were female, more than one third of the patients had
comorbidities and hypothyroidism was the most common
comorbidity (15.8%). None of the patients required
ICU admission and all patients were alive at the
time of the analysis. Patients with other types of cancer
were more likely to develop severe/critical disease and
the mortality was 9.9% among them. The number male
patients were higher (0 vs. 38) in the group with other
types of cancer. Symptomatic infection was more common
in patients without cancer and there was no difference
in disease severity and mortality between BC
and non-cancer patients. All COVID 19 patients without
cancer were alive at the time of follow-up date. Age, comorbidities, and abnormal chest computed tomography
findings were significantly associated with disease
severity in the univariate analysis in BC patients.
Age retained its significant impact on disease severity
also in the multivariate analysis.[]
Table 4: Studies reporting the outcome of COVID-19 in breast cancer patients
Two other reports from United States and Europe
were published following these two reports from China.
BC patients with COVID-19 infection were extracted
from a prospective COVID-19 registry at Institute Curie
Hospital from Paris. Seventy-six patients were identified
from March to April 2020. Among 76 patients, 41
had RNA positive test, 18 had radiology-based. And 17
had symptom-based COVID-19 diagnosis. The median
age was 58 (48-68), 17% were older than 70 years of age.
Fever (46%) and cough (37%) were the most common
symptoms. The most common morbidity was hypertension
and two-thirds of the patients had metastatic
disease. Twenty-eight out of 59 patients (47%) needed
hospitalization, four patients required ICU, 45 out of
59 patients recovered. There was limited follow-up for
ten patients at the time of data extraction from the registry.
Four patients among 59 patients (6.7%) died, 3 of
them had positive RNA tests and one patient had only
diagnostic chest computed tomography findings. One
of the patients, who died of COVID-19 infection, had
triple negative early-stage BC and comorbidities including
diabetes mellitus, hypertension, cardiomyopathy, and rheumatoid arthritis. Mortality was higher in
the RNA-positive group at 9.7% (4/41). Age >70 years
and hypertension were associated with the severity of
infection. Authors concluded that risk factors for severe
COVID 19 were similar to the general population and
the mortality was not higher in BC patients. They also
added that the actual number of COVID 19 patients
might be higher due to potential under-declaration of
the infection at the outpatient setting. Kalinsky et al.
reported outcomes of 27 BC patients with COVID-19
in the period between March and April 2020 from
New York. In their retrospective cohort, median age of
BC patients was 56.5 and 19 patients were male. Five
patients (19%) had metastatic disease, seven patients
required hospitalization, none of them required ICU,
and one 87 years-old male patients had died due to
COVID-19 (who also had coronary artery disease and
hypertension). The last received therapy before COVID19
was chemotherapy in 52% of the patients, the
most common symptom was cough (70%), followed by
fever (52%) and shortness of breath (52%). The most
common comorbidity was hypertension (22%).[14,15]
The median age of patients was 49 in our study,
younger than the patients reported from China, France,
and United States. Only three patients were older than
75 years. Most common symptom was fever followed
by myalgia and fatigue similar to other reports. The most common comorbidity was also hypertension in
line with other reports. We reported the number of
COVID19 infected BC patients between July 2020 and
2021. The total number of infected patients within 1
year period can be considered low in comparison to
other reports (Table 4). Other studies reported the
outcome of infected BC patients within 2-5 months of
pandemic. Our study covered the period between the
end of first peak and the whole second peak of COVID
19 in Istanbul. Almost all of the patients were not vaccinated
since elderly patients and healthcare staff were
prioritized and vaccinated first in April 2021.
The number of patients with metastatic BC was low
(15%, n=12) and most patients had COVID-19 while
they were on adjuvant ET (63%, n=52). Patients who
were on chemotherapy or targeted therapy followed
the pandemic isolation and hygienic precautions very
strictly, thus fewer of them had COVID-19 infection.
All of these factors might have an impact on our low
mortality rate. Nevertheless, heavily pretreated metastatic
BC patients who needed hospitalization for their
scheduled chemotherapy or targeted therapy had a severe
clinical course and all three of them died due to
COVID-19. Older age, comorbidities, and hypertension
were not associated with increased mortality in
contrary to other studies. Our study has the highest
number of BC patients with laboratory-based COVID
19 diagnosis. It is important to note that our study did
not have a control group of COVID-19 infected patients
without cancer or patients with cancer other than
BC. Thus, it was not informative about the course of
COVID 19 for other types of cancer. Of note, its retrospective
nature, absence of laboratory and radiological
follow-up data are the other limitations of our study.
COVID-19 pandemic is still ongoing and all of us
including patients with cancer are still at risk. Patients
with BC will be at more risk of getting this infection
like many other cancer patients till pandemic is over.
Any contact history, suspicious clinical symptom, or
sign should be promptly evaluated since COVID infection
might lead to death especially in hospitalized
heavily treated patients with metastatic BC who are on
chemotherapy or targeted treatments.
Conclusion
In this cohort study of patients with BC, most patients
had a mild COVID-19 course. Advanced disease and
chemotherapy within 7 days of diagnosis were the two
risk factors for increased mortality.
Peer-review: Externally peer-reviewed.
Conflict of Interest: All authors declared no conflict of interest.
Ethics Committee Approval: The study was approved
by the Institutional Review Board at Acibadem Altunizade
Hospital (no: 2021-20/08, date: 14/10/2021).
Financial Support: None declared.
Authorship contributions: Concept - A.I.; Design - A. I.,
G.B.; Supervision - G.B., A.S.K.; Funding - None; Materials
- A.I., R.Z., V.B.; Data collection and/or processing - A.
I.; Data analysis and/or interpretation - A.I., G.B.; Literature
search - A.I, G.B.; Writing - A.I., G.B.; Critical review - R.Z.,
V.B., A.S.K.
References
WHO. Coronavirus Disease 2019 (COVID-19) situation
report-119, 2020. Available at: https://www.who.
int/emergencies/diseases/novel-coronavirus-2019/situation-
reports. Accessed Oct 31, 2021.
Worldometer. COVID-19 coronavirus pandemic.
Available at: https://www.worldometers.info/coronavirus.
Accessed Jan 13, 2022.
Guan W, Ni Z, Hu Y, Liang W, Ou C, He J, et al. Clinical
characteristics of coronavirus disease 2019 in
China. N Engl J Med 2020;382:1708-20.
Moghadas SM, Fitzpatrick MC, Sah P, Pandey A,
Shoukat A, Singer BH, et al. The implications of silent
transmission for the control of COVID-19 outbreaks.
Proceedings of the National Academy of Sciences of
the United States of America 2020;117(30):17513-15.
Gosain R, Abdou Y, Singh A, Rana N, Puzanov I, Ernstoff
MS. COVID-19 and Cancer: a Comprehensive
Review. Curr Oncol Rep 2020;22(5):53.
Liang W, Guan W, Chen R, Wang W, Li J, Xu K, et al.
Cancer patients in SARS-CoV-2 infection: a nationwide
analysis in China. Lancet Oncol 2020;21(3):335-7.
Zhang L, Zhu F, Xie L, Wang C, Wang J, Chen R, et al.
Clinical characteristics of COVID-19-infected cancer
patients: a retrospective case study in three hospitals
within Wuhan, China. Ann Oncol 2020;31(7):894-901.
Xia Y, Jin R, Zhao J, Li W, Shen H. Risk of COVID-19
for patients with cancer. Lancet Oncol 2020;21(4):e180.
Russell B, Moss CL, Shah V, Ko TK, Palmer K, Sylva
R, et al; Guy"s Cancer Real World Evidence. Risk of
COVID-19 death in cancer patients: an analysis from
Guy"s Cancer Centre and King"s College Hospital in
London. Br J Cancer 2021;125(7):939-47.
Grasselli G, Zangrillo A, Zanella A, Antonelli M,
Cabrini L, Castelli A, et al; COVID-19 Lombardy
ICU Network. Baseline characteristics and outcomes of 1591 patients infected with SARS-CoV-2 admitted
to ICUs of the Lombardy region, Italy. JAMA
2020;323(16):1574-81.
Wang H, Zhang L. Risk of COVID-19 for patients with
cancer. Lancet Oncol 2020;21(4):e181.
Wei J, Wu M, Liu J, Wang X, Xia P, Peng L, et al. Characteristics
and outcomes of COVID-19 infection in 45
patients with breast cancer: A multi-center retrospective
study in Hubei, China. Breast 2021;59:102-9.
Zhang B, Xie R, Hubert SM, Yu Y, Zhang Y, Lei X,
et al. Characteristics and outcomes of 35 breast cancer
patients infected with COVID-19. Front Oncol
2020;10:570130.
Kalinsky K, Accordino MK, Hosi K, Hawley JE, Trivedi
MS, Crew KD, et al. Characteristics and outcomes
of patients with breast cancer diagnosed with SARSCov-
2 infection at an academic center in New York
City. Breast Cancer Res Treat 2020;182(1):239-42.
Vuagnat P, Frelaut M, Ramtohul T, Basse C, Diakite
S, Noret A, et al; Institut Curie Breast Cancer and
COVID Group. COVID-19 in breast cancer patients: a
cohort at the Institut Curie hospitals in the Paris area.
Breast Cancer Res 2020;22(1):55.
