# COVID-19 in breast cancer patients: A cohort at the Institut Curie hospitals in the Paris area

Perrine Vuagnat, Maxime Frelaut, Toulsie Ramtohul, Clémence Basse, Sarah Diakite, Aurélien Noret, Audrey Bellesoeur, Vincent Servois, Delphine Hequet, Enora Laas, et al.

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Perrine Vuagnat, Maxime Frelaut, Toulsie Ramtohul, Clémence Basse, Sarah Diakite, et al. COVID-19 in breast cancer patients: A cohort at the Institut Curie hospitals in the Paris area. Breast Cancer Research, 2020, 22 (1), 10.1186/s13058-020-01293-8. hal-02844089

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RESEARCH ARTICLE

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# COVID-19 in breast cancer patients: a cohort at the Institut Curie hospitals in the Paris area

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Perrine Vuagnat<sup>1,2,3</sup>, Maxime Frelaut<sup>4</sup>, Toulsie Ramtohul<sup>5</sup>, Clémence Basse<sup>2,3</sup>, Sarah Diakite<sup>2,3</sup>, Aurélien Noret<sup>2,3</sup>, Audrey Bellesoeur<sup>2,3</sup>, Vincent Servois<sup>5</sup>, Delphine Hequet<sup>6</sup>, Enora Laas<sup>6</sup>, Youlia Kirova<sup>7</sup>, Luc Cabel<sup>2,3</sup>, Jean-Yves Pierga<sup>2,3,8</sup>, Institut Curie Breast Cancer and COVID Group, Laurence Bozec<sup>2,3†</sup>, Xavier Paoletti<sup>1,9†</sup>, Paul Cottu<sup>2,3†</sup> and François-Clément Bidard<sup>1,2,3*†</sup>

## Abstract

**Background:** Cancer patients have been reported to be at higher risk of COVID-19 complications and deaths. We report the characteristics and outcome of patients diagnosed with COVID-19 during breast cancer treatment at Institut Curie hospitals (ICH, Paris area, France).

**Methods:** An IRB-approved prospective registry was set up at ICH on March 13, 2020, for all breast cancer patients with COVID-19 symptoms or radiologic signs. Registered data included patient history, tumor characteristics and treatments, COVID-19 symptoms, radiological features, and outcome. Data extraction was done on April 25, 2020. COVID-19 patients were defined as those with either a positive RNA test or typical, newly appeared lung CT scan abnormalities.

**Results:** Among 15,600 patients actively treated for early or metastatic breast cancer during the last 4 months at ICH, 76 patients with suspected COVID-19 infection were included in the registry and followed. Fifty-nine of these patients were diagnosed with COVID-19 based on viral RNA testing (N = 41) or typical radiologic signs: 37/59 (63%) COVID-19 patients were treated for metastatic breast cancer, and 13/59 (22%) of them were taking corticosteroids daily. Common clinical features mostly consisted of fever and/or cough, while ground-glass opacities were the most common radiologic sign at diagnosis. We found no association between prior radiation therapy fields or extent of radiation therapy sequelae and extent of COVID-19 lung lesions. Twenty-eight of these 59 patients (47%) were hospitalized, and 6 (10%) were transferred to an intensive care unit. At the time of analysis, 45/59 (76%) patients were recovering or had been cured, 10/59 (17%) were still followed, and 4/59 (7%) had died from COVID-19. All 4 patients who died had significant non-cancer comorbidities. In univariate analysis, hypertension and age (> 70) were the two factors associated with a higher risk of intensive care unit admission and/or death.

(Continued on next page)

<footnote>* Correspondence: fcbidard@curie.fr</footnote>

<footnote>†Laurence Bozec, Xavier Paoletti, Paul Cottu and François-Clément Bidard contributed equally to this work.</footnote>

<footnote n="1">¹UVSQ, Université Paris-Saclay, Saint Cloud, France</footnote>

<footnote n="2">²Department of Medical Oncology, Institut Curie, Paris, France
Full list of author information is available at the end of the article</footnote>
(Continued from previous page)

**Conclusions:** This prospective registry analysis suggests that the COVID-19 mortality rate in breast cancer patients depends more on comorbidities than prior radiation therapy or current anti-cancer treatment. Special attention must be paid to comorbidities when estimating the risk of severe COVID-19 in breast cancer patients.

**Keywords:** SARS-CoV-2, COVID-19, Breast cancer, Outcome, Survival

## Background

On December 31, 2019, the World Health Organization was informed about cases of pneumonia of unknown cause in Wuhan, China [1]. A novel coronavirus, named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was identified as the cause of coronavirus disease 2019 (COVID-19) [2]. Over the following months, the viral outbreak shifted from China to the rest of the world and was subsequently recognized as a pandemic (http://www.euro.who.int/en/health-topics/health-emergencies/coronavirus-covid-19/news/news/2020/3/who-announces-covid-19-outbreak-a-pandemic). In France, the number of confirmed cases rose during early March: more than 2800 confirmed cases were officially reported on March 13, 2020, when the French hospital emergency response plan, which coordinates all hospitals, was increased to its maximum readiness level (https://www.who.int/docs/default-source/coronaviruse/situation-reports). As of April 24, France is the 6th most severely affected country in the world (in terms of absolute numbers), with more than 21,000 official COVID-19-related deaths (https://www.who.int/docs/default-source/coronaviruse/situation-reports; https://www.who.int/emergencies/diseases/novel-coronavirus-2019/situation-reports). With about 6000 deaths, the Paris area is one of the most severely affected regions in France (https://www.santepubliquefrance.fr/recherche/#search=COVID%2019%20point%20epidemiologique&sort date).

The first report on COVID-19 outcome in cancer patients was published on February 14 [3]: in a series of 18 Chinese patients with a history of cancer and a diagnosis of COVID-19, 7 (39%) had to be treated in the intensive care unit (ICU) and/or died. This seminal retrospective study prompted major concerns about the risk of COVID-19 infection in cancer patients. Further studies confirmed that compared to the Chinese general population, cancer patients are at higher risk of severe COVID-19 symptoms and death [3–5] (https://doi.org/10.2139/ssrn.3558017). Cancer patients with blood, lung, or metastatic cancers were reported to have the highest frequency of severe outcome [4] (https://doi.org/10.2139/ssrn.3558017). These retrospective reports, of limited size and restricted to patients hospitalized in Chinese hospitals, may not be fully transposable to Western healthcare systems, as suggested by a preliminary report on New Yorkers admitted to ICU [6].

Our study reports the COVID-19 features and outcomes experienced by inpatients and outpatients actively treated for breast cancer at Institut Curie hospitals (ICH) in the Paris area, France.

## Methods

### Registry

The prospective COVID-19 registry was approved by the ICH institutional review board, which waived documentation of informed consent due to its observational nature. Starting from March 13, 2020, all proven or suspected COVID-19 cases were prospectively registered. Declaration of all proven or suspected cases was made mandatory by the ICH Director and done by any doctor or nurse to a unique email address, even if RNA test was not done or available. Emails were checked several times a day by a team of 5 doctors; all declared patients were included in the registry on the same day (day 1) and followed up. The standardized follow-up included phone calls to patients which were scheduled at days 8, 14, and 28 and tracked in the central registry. Follow-up calls were initially given by doctors, later joined by other ICH-qualified healthcare workers (such as genetic counselors, who received a training on COVID-19) for patients who had mild symptoms or who were recovering. More frequent and/or longer follow-up was provided whenever medically necessary. Patients hospitalized outside IC hospitals were also registered and prospectively followed. The list of patients who had an RNA test prescribed at ICH was also investigated (with no missing case identified). Data captured in the registry are displayed in Supplementary Methods 1. For this analysis, data were extracted on April 25, 2020. This report was written according to the STROBE checklist.

### Breast cancer care at IC during the SARS-CoV-2 pandemic

Guidance on breast cancer care during the pandemic is detailed in Supplementary Methods 2.

### COVID-19 diagnosis: laboratory tests and radiology

#### SARS-CoV-2 RNA tests

Testing was initially restricted to critically ill patients with COVID-19 symptoms, but subsequently became available to all cancer patients (including outpatients that were under active treatment) with suspected COVID-19 at the end of March 2020. Nasopharyngeal
swabs were analyzed for SARS-CoV-2 RNA by reverse-transcription polymerase chain reaction assays targeting 2 regions of the viral RdRp gene. All assays used in France had to be validated by the French National Reference Center (Institut Pasteur, Paris, France) (https://www.who.int/docs/default-source/coronaviruse/real-time-rt-pcr-assays-for-the-detection-of-sars-cov-2-institute-pasteur-paris.pdf?sfvrsn=3662fcb6_2; https://solidarites-sante.gouv.fr/IMG/pdf/liste-reactifs-diagnostic-rt-pcr.pdf).

## CT scan protocol and image interpretation

Whenever available, CT images were centrally reviewed by two senior radiologists with consensus qualitative and semiquantitative assessment. In accordance with previous reports on COVID-19 imaging [7, 8], the following patterns were sought: ground-glass opacity, crazy paving (ground-glass opacity associated with interlobular septal thickening [9]), focal consolidation, and linear consolidation. To be included in the COVID-19 population, patients with negative or not available RNA test had to display typical and newly acquired (i.e., not pre-existing on the previous CT scan) COVID-19-related lung lesions. The predominant pattern was determined for each examination. The severity (%) of lung involvement was evaluated according to the French Society of Radiology guidelines (http://www.sfrnet.org/portal/actu/news.phtml?id=rc%2forg%2fsfrnet%2fnws%2fNews%2f2020%2f20200316-155630-175). The presence of lung or pleural metastases was assessed by comparison with previous CT scans. Lung radiation therapy sequelae were evaluated by semiquantitative evaluation of confluent radiologic opacities (grade 3 of the Lent-Soma scoring system [10]) affecting the right, left, or middle lobes (no involvement; ≤ 10% of lung volumes; 11–25%; ≥ 26%).

## Statistics

The main study population, “COVID-19 patients,” is defined as those with positive RNA test or for whom RT-PCR result was not available (or pending) but who had suggestive radiologic findings. We also report data on the subgroup of patients who had biological confirmation of COVID-19 status using RT-PCR, referred to as “RNA-positive subgroup,” but did not perform statistical analyses on that subgroup. Main outcome of patients was defined as death or ICU admission. Descriptive and univariate prognostic factor analysis was performed. Two sensitivity analyses were performed: (i) using death only and (ii) using time to death or ICU admission to account for patients with partial follow-up. As sensitivity analyses, prognostic factor analysis of death only was performed. Due to the highly explorative nature of the report and the small number of events, no adjustment for multiple testing was applied and multivariate

analysis was not done. All analyses were performed in SAS v9.4 and R software.

## Results

### COVID-19 diagnosis

From March 13, 2020, to April 25, 2020 (date of data extraction), 76 patients actively treated for breast cancer were included in the ICH COVID-19 registry. For comparison, 15,600 breast cancer patients had at least one consultation or treatment for breast cancer at one of the IC hospitals in the 4 months before lockdown (November 1, 2019, to February 28, 2020). The patient flowchart for the COVID-19 registry is displayed in Fig. 1a. RNA testing was performed in 58 patients, while CT scan was performed in 39 patients. A total of 59 patients were diagnosed with COVID-19, based on either a positive SARS-CoV-2 RNA test (N = 41 patients; “RNA-positive subgroup”) or, in the case of negative or missing RNA test, radiologic findings (N = 18 patients). Seventeen patients only reported symptoms suggestive of COVID-19 that were not confirmed by RNA test and/or lung CT scan. Most patients in the subgroup who underwent both RNA testing and CT scan presented concordant results, as displayed in Fig. 1b.

## Patient history

Breast cancer patient history and comorbidities are shown in Table 1. Ten of the 59 COVID-19 patients (17%) were older than 70. Other notable comorbidities among COVID-19 patients included hypertension (36%), obesity (17%), diabetes (17%), and heart disease (14%). The most frequent comedication in this population was corticosteroids (22%, defined as a daily intake of more than 20 mg equivalent dose of prednisolone, excluding chemotherapy comedications). Reasons for corticosteroid intake were symptomatic brain or leptomeningeal metastasis (10%), epiduritis (5%), other cancer-related symptoms (5%), and autoimmune hepatitis (2%), respectively. All these patients have been under corticosteroids for at least 1 month. About two thirds of COVID-19 patients (and all those treated with corticosteroids) were treated for metastatic breast cancer. As shown in Table 2, ongoing anti-cancer treatments were representative of those currently administered to patients treated for early or metastatic disease, most commonly chemotherapy (49%), followed by endocrine therapy (32%).

## Features at diagnosis

Clinical, laboratory, and radiologic features at diagnosis are displayed in Table 3. Fever and cough were the most common symptoms, observed in 46% and 37% of COVID-19 patients, respectively. Nine of the 59 patients (18%) developed COVID-19 symptoms more than 2 days after being admitted to hospital (IC or elsewhere),
A: Patient flow

<figure><img src="image_3.png" /></figure>

B: Relationship between clinical, laboratory and radiologic features

<figure><img src="image_4.png" /><figcaption>**Fig. 1** Patient flow and COVID-19 testing. **a** Patient flow. **b** Relationship between clinical, laboratory, and radiologic features. Venn diagram focusing on the 30 patients with symptoms and available CT scan and RNA test results. Independence of RNA test and CT scan was rejected (Fisher's exact test, *p* < 0.001)</figcaption></figure>

corresponding to the interval used to define nosocomial in-ections. The mean absolute lymphocyte count was normal
(1.5/mm³). Most patients had no or limited extent of
COVID-19 lung disease, as 25/28 patients (89%) had less
than 25% involvement of their lung volume. Twenty-eight
CT scans were available for central review: the most com-
mon radiologic feature was ground-glass opacities, observed
in 14/28 (50%) of COVID-19 patients with CT scan at diag-
nosis. No significant association was observed between
these characteristics or the presence of lung metastases and
the extent of COVID-19 lung disease. Supplementary Fig-
ure 1 displays, for each COVID-19 patient, the prior radi-
ation therapy fields, radiation therapy sequelae, and extent

of COVID-19 lung disease. There was no association be-
tween prior radiation therapy and the extent of COVID-19
lesions (≤ 10% vs > 10%, Fisher's exact test *p* = 0.69).

**Outcome and prognostic factors**

All patient outcomes were updated 2 days prior to this
analysis. Of the 59 breast cancer patients diagnosed
with COVID-19, 28 (47%) were hospitalized, while 31
(53%) returned home. Twenty-three (82%) of the 28
hospitalized patients received antibiotics, and 3 (11%)
received corticosteroids. No patients received hydroxy-
chloroquine, antiviral, or immunomodulating drugs as
frontline treatment at admission. The use of these
<table><caption>**Table 1** Patients' medical history</caption><thead><tr><th></th><th>COVID-19 patients, N pts/N evaluable (%)</th><th>RNA-positive subgroup, N pts/N evaluable (%)</th></tr></thead><tbody><tr><td><strong>Patient characteristics</strong></td><td></td><td></td></tr><tr><td>Median age (IQR)</td><td>58 (48-68)</td><td>57 (48-68)</td></tr><tr><td>Median BMI (IQR)</td><td>26 (22-30)</td><td>26 (22-29)</td></tr><tr><td>Comorbidities</td><td></td><td></td></tr><tr><td>Age &gt; 70 years old</td><td>10/59 (17%)</td><td>8/41 (20%)</td></tr><tr><td>Obesity (BMI &gt; 30)</td><td>10/59 (17%)</td><td>7/41 (17%)</td></tr><tr><td>Active smokers</td><td>4/59 (7%)</td><td>3/41 (7%)</td></tr><tr><td>Chronic lung disease</td><td>2/59 (3%)</td><td>1/41 (2%)</td></tr><tr><td>Diabetes</td><td>10/59 (17%)</td><td>9/41 (22%)</td></tr><tr><td>Hypertension</td><td>21/59 (36%)</td><td>17/41 (42%)</td></tr><tr><td>Heart disease</td><td>8/59 (14%)</td><td>8/41 (20%)</td></tr><tr><td>Systemic disease</td><td>3/59 (5%)</td><td>3/41 (7%)</td></tr><tr><td>Any of the above</td><td>20/59 (34%)</td><td>13/41 (32%)</td></tr><tr><td>Comedications</td><td></td><td></td></tr><tr><td>Corticosteroids</td><td>13/59 (22%)</td><td>9/41 (22%)</td></tr><tr><td>NSAID</td><td>0/59 (0%)</td><td>0/41 (0%)</td></tr><tr><td>ACE inhibitor/ARB</td><td>15/59 (25%)</td><td>13/41 (32%)</td></tr><tr><td>Anticoagulants</td><td>8/59 (14%)</td><td>5/41 (12%)</td></tr><tr><td>Immunosuppressives</td><td>1/59 (2%)</td><td>1/41 (2%)</td></tr><tr><td><strong>Breast cancer</strong></td><td></td><td></td></tr><tr><td>Subtype</td><td></td><td></td></tr><tr><td>HR+</td><td>39/59 (66%)</td><td>29/41 (70%)</td></tr><tr><td>Triple-negative</td><td>10/59 (17%)</td><td>6/41 (15%)</td></tr><tr><td>HER2+</td><td>10/59 (17%)</td><td>6/41 (15%)</td></tr><tr><td>Clinical setting</td><td></td><td></td></tr><tr><td>Neoadjuvant</td><td>7/59 (12%)</td><td>7/41 (17%)</td></tr><tr><td>Adjuvant</td><td>15/59 (25%)</td><td>15/41 (37%)</td></tr><tr><td>Metastatic, &lt; 3 prior lines</td><td>20/59 (34%)</td><td>11/41 (27%)</td></tr><tr><td>Metastatic, ≥ 3 prior lines</td><td>17/59 (29%)</td><td>8/41 (20%)</td></tr><tr><td>History of radiation therapy</td><td></td><td></td></tr><tr><td>Breast/chest wall irradiation</td><td>36/59 (61%)</td><td>19/41 (46%)</td></tr><tr><td>SCLN irradiation</td><td>29/59 (49%)</td><td>14/41 (34%)</td></tr><tr><td>IMN irradiation</td><td>23/59 (39%)</td><td>11/41 (27%)</td></tr><tr><td>None</td><td>23/59 (39%)</td><td>22/41 (54%)</td></tr><tr><td>Metastatic sites (in metastatic pts)</td><td></td><td></td></tr><tr><td>&lt; 3 sites</td><td>22/37 (60%)</td><td>14/19 (74%)</td></tr><tr><td>≥ 3 sites</td><td>15/37 (41%)</td><td>5/19 (26%)</td></tr><tr><td>Lung/pleural metastases</td><td>16/37 (43%)</td><td>5/19 (26%)</td></tr><tr><td>Bone metastases</td><td>24/37 (65%)</td><td>17/19 (90%)</td></tr><tr><td>Liver metastases</td><td>11/37 (30%)</td><td>5/19 (26%)</td></tr><tr><td>CNS metastases</td><td>7/37 (19%)</td><td>3/19 (16%)</td></tr><tr><td>Other sites</td><td>16/37 (43%)</td><td>7/19 (37%)</td></tr><tr><td><strong>Total</strong></td><td><strong>N = 59</strong></td><td><strong>N = 41</strong></td></tr></tbody></table>

Corticosteroids refer to a chronic daily dose equivalent to ≥ 20 mg of prednisolone (chemotherapy premedication not taken into account). Systemic diseases: 2 patients had a rheumatoid arthritis and 1 patient had an autoimmune hepatitis. BMI body mass index, NSAID non-steroidal anti-inflammatory drugs, ACE angiotensin-converting enzyme, ARB angiotensin II receptor blockers, HR+ hormone receptor-positive, Triple-negative HER2- and hormone receptor-negative, HER2+ HER2-positive, CNS central nervous system, SCLN supraclavicular lymph nodes, IMN internal mammary nodes
<table><caption>**Table 2** Ongoing treatments</caption><thead><tr><th></th><th>COVID-19 patients, N pts/N evaluable (%)</th><th>RNA-positive subgroup, N pts/N evaluable (%)</th></tr></thead><tbody><tr><td><strong>Early breast cancer patients</strong></td><td><strong>N = 22</strong></td><td><strong>N = 22</strong></td></tr><tr><td>Surgery*</td><td>3/22 (14%)</td><td>3/22 (14%)</td></tr><tr><td>Chemotherapy</td><td>8/22 (36%)</td><td>8/22 (36%)</td></tr><tr><td>Epirubicin and cyclophosphamide</td><td>5/22 (23%)</td><td>5/22 (23%)</td></tr><tr><td>Paclitaxel/docetaxel</td><td>2/22 (9%)</td><td>2/22 (9%)</td></tr><tr><td>Radiation therapy</td><td>2/22 (9%)</td><td>2/22 (9%)</td></tr><tr><td>Endocrine therapy</td><td>4/22 (18%)</td><td>4/22 (18%)</td></tr><tr><td>Anti-estrogens</td><td>3/22 (14%)</td><td>3/22 (14%)</td></tr><tr><td>Aromatase inhibitors</td><td>1/22 (4%)</td><td>1/22 (4%)</td></tr><tr><td>Targeted therapy</td><td>3/22 (14%)</td><td>3/22 (14%)</td></tr><tr><td>Trastuzumab</td><td>2/22 (9%)</td><td>2/22 (9%)</td></tr><tr><td>Pertuzumab</td><td>1/22 (4%)</td><td>1/22 (4%)</td></tr><tr><td>Trastuzumab emtansine</td><td>1/22 (4%)</td><td>1/22 (4%)</td></tr><tr><td>None</td><td>6/22 (27%)</td><td>6/22 (27%)</td></tr><tr><td>Pending surgery</td><td>5/22 (23%)</td><td>5/22 (23%)</td></tr><tr><td>Pending radiation therapy</td><td>1/22 (4%)</td><td>1/22 (4%)</td></tr><tr><td>Combination of any treatment</td><td>3/22 (14%)</td><td>3/22 (14%)</td></tr><tr><td><strong>Metastatic breast cancer patients</strong></td><td><strong>N = 37</strong></td><td><strong>N = 19</strong></td></tr><tr><td>Surgery*</td><td>0 (0%)</td><td>0 (0%)</td></tr><tr><td>Chemotherapy</td><td>21/37 (57%)</td><td>10/19 (53%)</td></tr><tr><td>Capecitabine</td><td>7/37 (19%)</td><td>4/19 (21%)</td></tr><tr><td>Paclitaxel/docetaxel</td><td>6/37 (16%)</td><td>3/19 (16%)</td></tr><tr><td>Epirubicin and cyclophosphamide</td><td>1/37 (3%)</td><td>0 (0%)</td></tr><tr><td>Vinorelbine</td><td>2/37 (5%)</td><td>0 (0%)</td></tr><tr><td>Eribulin</td><td>1/37 (3%)</td><td>1/19 (5%)</td></tr><tr><td>Gemcitabine</td><td>2/37 (5%)</td><td>1/19 (5%)</td></tr><tr><td>Carboplatin</td><td>3/37 (8%)</td><td>1/19 (5%)</td></tr><tr><td>Intrathecal chemotherapy</td><td>2/37 (5%)</td><td>2/19 (10%)</td></tr><tr><td>Radiation therapy</td><td>2/37 (5%)</td><td>2/19 (10%)</td></tr><tr><td>Endocrine therapy</td><td>15/37 (40%)</td><td>7/19 (37%)</td></tr><tr><td>Anti-estrogens</td><td>3/37 (8%)</td><td>1/19 (5%)</td></tr><tr><td>Aromatase inhibitors</td><td>11/37 (30%)</td><td>6/19 (32%)</td></tr><tr><td>Selective estrogen receptor degrader</td><td>1/37 (3%)</td><td>0 (0%)</td></tr><tr><td>Targeted therapy</td><td>16/37 (43%)</td><td>7/19 (37%)</td></tr><tr><td>CDK4/6 inhibitor</td><td>9/37 (24%)</td><td>5/19 (26%)</td></tr><tr><td>Trastuzumab</td><td>5/37 (13%)</td><td>2/19 (10%)</td></tr><tr><td>Pertuzumab</td><td>4/37 (11%)</td><td>2/19 (10%)</td></tr><tr><td>Everolimus**</td><td>2/37 (5%)</td><td>0 (0%)</td></tr><tr><td>Immunotherapy</td><td>0 (0%)</td><td>0 (0%)</td></tr><tr><td>Combination of any treatment</td><td>21/37 (57%)</td><td>8/19 (42%)</td></tr><tr><td>None</td><td>1/37 (3%)</td><td>1/19 (5%)</td></tr><tr><td><strong>Total</strong></td><td><strong>N = 59</strong></td><td><strong>N = 41</strong></td></tr></tbody></table>

Listed treatments were those ongoing within 30 days before COVID-19 diagnosis

*Ongoing surgery includes 30 days from surgery

**As recommended, patients stopped everolimus at the beginning of the pandemic
<table><caption>**Table 3** Clinical, laboratory, and radiologic features at first examination</caption><thead><tr><th></th><th>COVID-19 patients, N pts/N evaluable (%)</th><th>RNA-positive subgroup, N pts/N evaluable (%)</th></tr></thead><tbody><tr><td colspan="3"><strong>Clinical examination</strong></td></tr><tr><td>Fever (≥ 38.0 °C)</td><td>27/59 (46%)</td><td>21/41 (51%)</td></tr><tr><td>Cough</td><td>22/59 (37%)</td><td>18/41 (44%)</td></tr><tr><td>Dyspnea</td><td>17/59 (29%)</td><td>10/41 (24%)</td></tr><tr><td>Decreased saturation (&lt; 96%)</td><td>7/59 (12%)</td><td>5/41 (12%)</td></tr><tr><td>GI disorders</td><td>6/59 (10%)</td><td>5/41 (12%)</td></tr><tr><td>Headache</td><td>3/59 (5%)</td><td>3/41 (7%)</td></tr><tr><td>Anosmia/dysgeusia</td><td>5/59 (8%)</td><td>4/41 (10%)</td></tr><tr><td>Possible nosocomial infection</td><td>9/59 (15%)</td><td>8/41 (20%)</td></tr><tr><td colspan="3"><strong>Laboratory parameters</strong></td></tr><tr><td>Neutrophil count: mean (IQR) (G/L)</td><td>4.0 (2.0–5.1), N = 49</td><td>4.3 (2.0–5.0), N = 31</td></tr><tr><td>Lymphocyte count: mean (IQR) (G/L)</td><td>1.5 (0.8–1.9), N = 49</td><td>1.5 (1.3–3.9), N = 31</td></tr><tr><td>LDH &gt; ULN</td><td>11/12 (92%)</td><td>4/4 (100%)</td></tr><tr><td colspan="3"><strong>CT scan available for central review</strong></td></tr><tr><td>Extent of lesions (% of lung volume)</td><td></td><td></td></tr><tr><td>No lesion</td><td>2/28 (7%)</td><td>2/14 (14%)</td></tr><tr><td>&lt; 10%</td><td>11/28 (39%)</td><td>2/14 (14%)</td></tr><tr><td>10–25%</td><td>12/28 (42%)</td><td>8/14 (57%)</td></tr><tr><td>26–50%</td><td>2/28 (7%)</td><td>1/14 (7%)</td></tr><tr><td>51–75%</td><td>1/28 (4%)</td><td>1/14 (7%)</td></tr><tr><td>&gt; 75%</td><td>0/28 (0%)</td><td>0/14 (0%)</td></tr><tr><td>Predominant type of lesion</td><td></td><td></td></tr><tr><td>No lesion</td><td>2/28 (7%)</td><td>2/14 (14%)</td></tr><tr><td>Ground-glass opacities</td><td>14/28 (50%)</td><td>7/14 (50%)</td></tr><tr><td>Crazy paving</td><td>4/28 (14%)</td><td>1/14 (7%)</td></tr><tr><td>Focal consolidation</td><td>7/28 (25%)</td><td>3/14 (22%)</td></tr><tr><td>Linear consolidation</td><td>1/28 (0%)</td><td>1/14 (7%)</td></tr><tr><td>Loco-regional radiation therapy</td><td></td><td></td></tr><tr><td>No radiation therapy</td><td>9/28 (32%)</td><td>8/14 (57%)</td></tr><tr><td>No sequela (0%)</td><td>8/28 (29%)</td><td>4/14 (29%)</td></tr><tr><td>Sequela extent: 1–10% of lung volume</td><td>9/28 (32%)</td><td>2/14 (14%)</td></tr><tr><td>Sequela extent: 11–25% of lung volume</td><td>2/28 (7%)</td><td>0/14 (0%)</td></tr><tr><td>Sequela extent: &gt; 25% of lung volume</td><td>0/28 (0%)</td><td>0/14 (0%)</td></tr></tbody></table>

Nosocomial infection refers to a new infection diagnosed > 2 days after admission to hospital. GI gastrointestinal, ULN upper limit of normal

putative treatments, which were available whenever necessary throughout the patient's stay in hospital, was not always available for patients hospitalized outside ICH.

None of the 17 symptom-only patients had to be hospitalized. The flow of COVID-19 patients during the course disease is shown in Fig. 2. Four patients were transferred to ICU at diagnosis or during hospitalization. As of April 24, 45 (76%) of the 59 COVID-19 patients were considered to be either recovering or cured. The outcome of 10 (17%) patients remains undetermined

(most recent cases with limited follow-up), while 4 (6.7%) patients died: 2 patients were receiving later lines of treatment for metastatic breast cancer (these patients were not transferred to ICU), 1 patient had recently started first-line endocrine therapy combined with palbociclib, and 1 patient was receiving neoadjuvant chemotherapy. Noteworthy, this last patient was treated with an anti-CD80/86 antibody (regulating CTLA-4 signaling). Further details on the history of the four deceased patients are available in Table 4.
<figure><img src="image_5.png" /></figure>

An exploratory analysis of factors associated with either ICU admission or death in the COVID-19 population showed that among all factors listed in Tables 1, 2, and 3, only age > 70 years and hypertension were significantly associated with COVID-19 severity (both *p* < 0.05). More specifically, the ongoing systemic treatment type (Supplementary Table 1), lymphopenia (< 0.5 G/L), neutropenia (< 1 G/L), and use of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers had no significant prognostic impact (all *p* value > 0.6). Age and hypertension remained as prognostic factors in the subgroup of RNA test-positive patients except that hypertension was of borderline significance. Same statistical conclusions were obtained with the analyses of time to death or ICU admission.

## Discussion

The SARS-CoV-2 outbreak is the first viral pandemic affecting cancer patients and oncology teams. To the best of our knowledge, this is the first report on COVID-19 diagnosis, signs, and outcome in breast cancer patients.

While 15,600 patients were actively treated for breast cancer at Institut Curie hospitals over the 4 months prior to the pandemic, only 59 were diagnosed with COVID-19 by either RNA test or CT scan. A recent study estimated that more than 10% of inhabitants of the greater Paris area have been infected by the SARS-CoV-2 virus (https://hal-pasteur.archives-ouvertes.fr/pasteur-02548181). While our study cannot determine the incidence of COVID-19 infection among breast cancer

patients, the small number of diagnosed cases suggests that breast cancer patients do not appear to be at higher risk than the general population. This apparent low incidence could possibly be attributed to much stricter application of social distancing procedures by cancer patients, who had been informed that they may be at higher risk of severe COVID-19 infection. Prophylactic changes implemented in breast cancer care (e.g., postponement of all non-mandatory visits to ICH, changes in medical treatments) may also have contributed to further reduce the risk of SARS-CoV-2 infection. A limitation of our study is that some patients may have been treated by their family physicians or referred to local hospitals, without any notification to ICH. Although no data was available to compare COVID-19 patients to the other breast cancer patients seen at ICH, rates of high BMI and hypertension in our COVID-19 patient cohort were very similar to those reported in a recent prospective large-scale report on French breast cancer patients [11], suggesting that these comorbidities do not increase the risk of COVID-19. Our analyses showed that breast cancer patients have similar clinical and radiologic features of COVID-19 to those previously described in other reports on non-cancer COVID-19 patients. Importantly, we found no trend in favor of a relationship between a history of breast and lymph node radiation therapy, radiation therapy sequela, and radiologic extent of disease or outcome. Thrombotic, cardiovascular, microvascular, and dermatological events were not
<caption>**Table 4** Description of COVID-19-related deaths</caption>

**Patient #1** was a 69-year-old woman with a history of diabetes, hypertension, hypertrophic cardiomyopathy, and rheumatoid arthritis treated by abatacept (a CTLA-4 immunoglobulin). She was diagnosed with stage IIB triple-negative breast cancer in February 2020 and started neoadjuvant chemotherapy (epirubicin and cyclophosphamide) in March. Three days after the first cycle, she was referred to the emergency room (ER) with chest pain, fever, and lung infection (day 1). SARS-CoV-2 infection was diagnosed based on positive RNA PCR and chest CT scan. She was admitted to ICU for acute respiratory distress on day 7, treated with antibiotics, antiviral therapy (chloroquine and lopinavir/ritonavir), and endotracheal intubation and ventilation. She died 19 days later (day 26).

**Patient #2** was a 44-year-old patient with no relevant medical history, diagnosed with de novo stage IV hormone-sensitive breast cancer (node, bone, and hepatic metastases, with 4N cytolysis) in February 2020. She received a first-line combination of CDK4/6 inhibitor, aromatase inhibitor, and complete ovarian function suppression. On day 17 of her first month of treatment, she was referred to the ER for asthenia, dyspnea, grade IV thrombocytopenia (14 G/L), and grade IV neutropenia (0.2 G/L). She was diagnosed with SARS-CoV-2 lung infection complicated by thrombotic microangiopathy, based on positive RNA test, chest CT scan, and laboratory data. She was treated symptomatically, including antibiotics, and was not transferred to ICU due to her metastatic disease and major multiple organ failure. She died 8 days after ER admission.

**Patient #3** was a 78-year-old woman with a history of hypertension. She had been treated since November 2013 for stage IV hormone-sensitive breast cancer (lung and bone metastases). In March 2020, she received two cycles of weekly paclitaxel as second-line chemotherapy. Five days after the last injection, she was referred to the ER with dyspnea and hypoxia. SARS-CoV-2 infection was diagnosed based on a typical chest CT scan with extensive consolidation involving approximately 50% of the lungs. PCR RNA test was negative. Hydroxychloroquine and antibiotics were rapidly initiated on day 1, but the patient was not transferred to ICU due to her limited oncological life expectancy. She died on day 4.

**Patient #4** was an 80-year-old woman treated for metastatic hormone-sensitive breast cancer (bone metastasis only) since February 2016. Since January 2020, after tumor progression, systemic therapies were stopped in favor of best supportive care. She had been hospitalized for tumor-related symptoms since February 2020. In late March, she presented signs of lung infection, followed by acute respiratory distress. Nosocomial SARS-CoV-2 infection was diagnosed based on positive RNA PCR and chest CT scan with ground-glass opacities involving approximately 20% of the lungs. Palliative symptomatic treatments with nasal oxygen therapy were initiated, and the patient died 12 days after onset of the first symptoms.

recorded, as their association with COVID-19 was not fully recognized when the registry was set up.

In terms of COVID-19 outcome, we observed a non-negligible mortality rate of 6.7% (4/59) among breast cancer patients diagnosed with COVID-19, with a higher mortality rate of 9.7% (4/41) in the RNA-positive subgroup. As of April 26, the reported mortality rate among RNA-positive patients in the general population ranges from 18.2% in France to 5.6% in the USA and 3.7% in Germany (https://www.who.int/docs/default-source/coronavirus/situation-reports). However, these percentages reflect more testing policy more than true differences in mortality rates. As in the general population, the true infection and mortality rates could subsequently be

determined by serology tests detecting an immune response to SARS-CoV-2. Nevertheless, on univariate analysis, age and hypertension were associated with disease severity rather than the extent of disease or ongoing cancer therapy. More specifically, we found no statistical relationship between ongoing chemotherapy and outcome. Overall, our data suggest that breast cancer patients share the same risk factors for severe COVID-19 as the general population. Strikingly, the only early breast cancer patient who died was concomitantly treated for a systemic disease by a CTLA-4 signaling modulator, suggesting that breast cancer per se is not a major contributor to COVID-19 mortality. Limitations of this analysis include the limited number of patients, a potential under-declaration due to the difficulty in identifying COVID-19 cases in outpatients who may have been referred to other hospitals. A longer follow-up of this registry may help defining more precisely the outcome of breast cancer patients with COVID-19.

## Conclusions

While lockdown lifting procedures are being discussed in most Western countries, this first report on breast cancer patients suggests that comorbidities (apart from breast cancer) should be the primary focus of attention to define patients at high risk. Further studies devoted to breast cancer patients will help to define breast cancer care for the following months, until preventive treatments, such as a vaccine, have been found.

## Supplementary information

Supplementary information accompanies this paper at https://doi.org/10.1186/s13058-020-01293-8.

### Additional file 1.

### Acknowledgements

Institut Curie Breast Cancer and COVID Group: Aurélia Alimi, Muriel Belotti, Okba Bensaoula, Ophélie Bertrand, Geoffroy Bilger, Etienne Brain, Hervé Brisse, Bruno Buecher, Laetitia Chanas, Caroline Chapus, Isabelle Charles-Massar, Pascal Chérel, Gilles Créhange, Christelle Colas, Hélène Delhomelle, Thomas Frederic-Moreau, Emmanuelle Fourme, Pierre Fumoleau, Marion Gauthier-Villars, Olivier Lantz, Sophie Lassalle, Marine Le Mentec, Florence Ler ebours, Delphine Loirat, Matthieu Minsat, Pauline Moreau, Antoine de Pauw, Maël Priour, Fabien Reyal, Roman Rouzier, Mary Saad, Claire Saule, Clara Seb bag, Dominique Stoppa-Lyonnet, Anne Tardivon, Silvia Takanen, Dominique Vanjak, Marie-Charlotte Villy, Anne Vincent-Salomon, and Mathilde Warcoin.

### Authors' contributions

MF, TR, CB, SD, AN, AB, VS, YK, LC, and JYP contributed to the data collection and interpretation. LB and PC set up the registry and contributed to the data interpretation. LC contributed to the manuscript writing. PV and FCB collected the data, contributed to the analysis, and wrote the manuscript. XP set up the registry, performed the statistical analyses, and contributed to the writing of the manuscript. All authors have read and approved the final manuscript.

### Funding

Institut Curie, Université de Versailles Saint Quentin, and Université Paris-Saclay (no grant number applicable).
**Availability of data and materials**

The datasets generated and analyzed during this study are not publicly available due to French HIPAA (birthdate, admission date, discharge date, date of death), but are available from the corresponding author on reasonable request.

**Ethics approval and consent to participate**

The COVID-19 registry was approved by the Institut Curie institutional review board, which waived documentation of informed consent due to the observational nature of the registry.

**Consent for publication**

Not applicable.

**Competing interests**

The authors declare that they have no competing interests.

**Author details**

¹UVSQ, Université Paris-Saclay, Saint Cloud, France. ²Department of Medical Oncology, Institut Curie, Paris, France. ³Department of Medical Oncology, Institut Curie, Saint Cloud, France. ⁴Department of Drug Development and Innovation, Institut Curie, Paris, France. ⁵Department of Radiology, Institut Curie, Paris, France. ⁶Department of Surgical Oncology, Institut Curie, Paris, France. ⁷Department of Radiation Oncology, Institut Curie, Paris, France. ⁸Université de Paris, Paris, France. ⁹INSERM U900 STAMPM Team, Saint Cloud, France.

Received: 29 April 2020 Accepted: 12 May 2020

Published online: 28 May 2020

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<figure><img src="image_6.png" /></figure>