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A double-edged sword: Prolonged detection of SARS-COV-2 in patients receiving cancer directed therapy

Introduction: SARS-CoV-2 (S-2) infection duration and its impact on patients with cancer and mild to moderate COVID-19 undergoing cancer-directed therapy (CDT), especially in the underserved population, is not well described. We conducted a retrospective study to analyze S-2 positive (+) patients on CDT to describe the S-2 duration and its impact on CDT. Methods:Two hundred ninety-nine patients with cancer were tested with nasopharyngeal (NP) S-2 PCR assay at Columbia University Medical Irving Center (CUIMC), a Minority-NCI Community Oncology site, of which 77 (26%) tested positive. We retrospectively analyzed 26 S-2 (+) patients with mild-to-moderate COVID-19 receiving CDT who consented to the study. NP PCR was repeated every 1 to 2 weeks until 2 successive negative (−) PCRs were obtained prior to restarting CDT. Time to 2 (−) PCR and serology results were recorded. Cycling thresholds (Ct) were obtained for S-2 specific targets and represented an indirect measure of viral load. Results: Demographics of N = 26 patients are: Hispanic (N = 17, 65%), Black (N = 1, 4%), White (N = 7, 27%), and undeclared (N = 1, 4%). Among the tumor histologies represented, gastrointestinal (N = 9, 35%), breast (N = 5, 19%), and sarcoma (N = 3, 12%) were most common. Median time to 2 (−) PCR was 32 days. Twenty patients required greater than 14 days to achieve 2 sequential (−) swabs. CDT was delayed in 21 patients (81%) of whom three experienced disease progression, likely attributed to an interruption in CDT, which was delayed by a mean of 53 days. Interestingly, nine (41%) patients had Ct values greater than 34 for the pan SARS target and seven (32%) patients had Ct values greater than 34 for the SARS-COV-2 target. Sixteen of 16 patients on CDT, tested positive for IgG antibodies at the time of consent, despite protracted viral detectability by NP PCR. Conclusion: Patients receiving CDT appear to have prolonged detectable S-2 by PCR, which can lead to interruption of CDT and POD in patients. We believe and recommend that patients with asymptomatic to mild COVID-19 and aggressive malignancies are at greatest risk for cancer related morbidity and mortality due to CDT cessation and should be considered for continued CDT without interruption. Ct values and serology testing are tools that can help identify those patients on CDT who may be at greatest risk of worsening COVID-19 or of spreading S-2.


Introduction
Severe acute respiratory syndrome coronavirus 2 (SARS-COV-2), which is responsible for coronavirus disease 2019 (COVID-19), has become a worldwide pandemic with over 9 million cases of COVID-19 in the United States (US) and over 230,0 0 0 fatalities at-tributable to the virus as of November 2, 2020 [1 , 2] . Increased risk of morbidity and mortality due to COVID-19 has been observed in patients with cancer likely due to the immunosuppressive nature of the cancer itself, and potentially due to cancer directed therapy (CDT) [3][4][5][6] . As a result, many cancer centers have enacted policies requiring the temporary cessation of chemotherapy in patients with COVID-19. The American Society of Clinical Oncology (ASCO) recommends that all patients who are diagnosed with COVID-19 should cease CDT for risk assessment and that only select COVID-19 positive patients should continue, though the guidelines do not further define key variables in "risk assessment" [7] . The guidelines https://doi.org/10.1053/j.seminoncol.2020. 11.001 0093-7754/© 2020 Elsevier Inc. All rights reserved. recommend a pause in CDT administration for 14 days for a majority of patients and/or until symptom free for 72 hours including a negative test on 2 consecutive nasopharyngeal (NP) polymerase chain reaction (PCR) swabs, which are at least 24 hours apart. The guidelines acknowledge that prioritized COVID-19-positive patients should be considered for reinitiation of CDT, however, definition of these prioritized patients based on risk versus benefit is not clear [7] .
Recent studies however, have indicated conflicting results on whether CDTs actually increase COVID-19 related morbidity and mortality [8] . Outcomes are likely dependent on tumor histology, type of CDT, and severity of COVID-19 symptoms. The impact of treatment delays due to COVID-19 precautions on cancer related outcomes is not well described but is likely to disproportionately affect patients who have aggressive cancer histologic subtypes where uninterrupted treatment is essential for disease control. To date, there is insufficient data to guide decisions regarding specific cancers and their respective treatments in nonhospitalized infected patients and as a result, continuation of CDT in patients with aggressive solid malignancy who are either asymptomatic or mildly symptomatic from COVID-19 presents a challenge for both the treating oncologist and patients. In these patients who appear clinically well with respect to COVID-19, holding CDT risks progression of malignancy-related morbidity and mortality, while continuation of CDT potentially risks worsening of COVID-19 symptoms and the potential epidemiologic consequence of spreading the virus to high risk patients at the medical center or the community at large.
In order to assess the clinical impact of CDT interruption as a result of COVID-19 infection, we conducted a retrospective/prospective cohort study in patients receiving CDT and diagnosed with asymptomatic to mildly symptomatic COVID-19 here at Columbia University Irving Medical center, a National Cancer Institute designated Minority Serving Cancer Center, during the height of the 2020 COVID-19 pandemic.

Methods
We performed a retrospective/prospective cohort study at Columbia University Irving Medical Center (CUIMC), a Minority-NCI Community Oncology Site. Patients who were tested positive for COVID-19 via NP polymerase chain reaction testing (NP PCR) while on CDT were enrolled into the study. NP PCR were performed using the Cepheid infinity or Roche 6800 platforms, which used N2 and ORF1a as SARS-COV-2 specific targets, respectively. Both assays detected the pan SARS specific E-gene. Cycling thresholds (Ct) were also obtained from patients' NP swabs. Consenting patients underwent mandatory repeat NP PCR testing and clinical questionnaires were administered to assess for symptoms. NP PCR testing was performed every 1-2 weeks until 2 successive negative PCRs were obtained, at which time patients were allowed to restart CDT at the discretion of their treating provider. Time to 2 negative PCR was recorded. We performed qualitative enzyme-linked immunosorbent assay for detection of IgG antibodies to SARS-COV-2 using an assay developed at CUIMC [9] . Demographic information and clinical outcome data were also collected from the electronic medical record. Summary statistics such as mean, median, and standard deviation were used to describe the patient cohort.

Results
A total of 299 patients who were undergoing active CDT through the medical oncology program at CUIMC were screened for SARS-CoV-2 by NP PCR assay. Of these, 77 (26%) patients tested positive by NP PCR and had cessation of CDT, of which 26 consented to participate in the study between May 18, 2020 and May 30, 2020. The majority of the study cohort was represented by Black or Latino/Hispanic ethnicity, a group known for increased COVID-19-and cancer-related morbidity and mortality due to healthcare disparities (N = 18; 69%) [10] . The majority of the patient cohort, 15 (58%), had advanced stage IV disease. Our cohort represented patients with distinct cancer histologies who were receiving different cancer directed therapies. See Table 1 for full details.
Overall, 15 patients completed questionnaires regarding symptoms at consent. The most common initial symptom which resulted in COVID-19 testing, was fever. Two subjects (13%) were asymptomatic and screened positive with NP PCR. Six patients were asymptomatic at the time of consent and during the time of CDT cessation. Patients reported a variety of symptoms during their COVID-19 course ( Table 2 ).
We identified prolonged detectable SARS-CoV-2 by NP PCR swab in our patient cohort. It took a mean of 32 days for patients to achieve true negative test as defined by 2 sequential negative swabs 1-2 weeks apart. Twenty patients required greater than 14  days to achieve 2 sequential negative swabs. CDT was delayed in 21 patients (81%) of whom 3 experienced disease progression, likely attributed to an interruption in CDT which was delayed by a mean of 53 days. The viral course for each patient is depicted in Fig. 1 . Table 3 illustrates a summary of studies reporting the duration of viral shedding or time to clearance of SARS-CoV-2 infection in patients without cancer and/or in randomized cohorts. All 3 patients (12%) who experienced disease progression had advanced aggressive malignancies which included metastatic triple negative breast cancer, metastatic pancreas adenocarcinoma, and relapsed refractory multiple myeloma, and for whom CDT was interrupted for 46, 50, and 71 days, respectively. The patient with relapsed refractory multiple myeloma resumed treatment with se-linexor, ixazomib, and dexamethasone despite SARS-COV-2 positivity by NP PCR after an initial CDT interruption of 48 days due to clinical disease progression that required hospitalization. Resumption of CDT despite persistent positive SARS-CoV-2 by NP PCR swab did not result in worsening of clinical COVID-19 related symptoms. The patient's only symptom was fever and dry cough. Confirmed negative SARS-CoV-2 infection by NP PCR swab occurred 2 weeks after initiation of CDT.
A total of 22 patients had available Ct values from their first NP PCR at consent. Notably, 9 (41%) patients had Ct values greater than 34 for the pan SARS target and seven (32%) patients had Ct values greater than 34 for the SARS-COV-2 target. In addition, 4 patients had an undetectable Ct value for the SARS-COV-2 target but a detectable Ct value for the pan SARS target. Thirteen patients had a subsequent Ct value for comparison with a mean number of 17 days between 2 Ct values. For these patients, the initial SARS-COV-2 specific Ct value was 22.3 and the pan SARS Ct value was 31.6 compared to 31.2 and 30.2, respectively on repeat testing.
In our study, all 16 patients who were receiving CDT and underwent serology testing for SARS-CoV-2 IgG antibodies tested positive despite a protracted viral course as detected by NP PCR. The shortest time period between the first positive test by NP PCR and detectable IgG antibodies was 10 days (range 10-69).

Discussion
Our study demonstrates that patients with cancer on active CDT may experience a protracted SARS-CoV-2 viral course putting them at risk for cancer related morbidity and mortality. A majority of our patients required greater than 2 weeks to clear the virus by NP PCR and 3 patients experienced progression of their cancers likely due to treatment interruption. Furthermore, one of our patients who was reinitiated on CDT did not experience worsening COVID-19 and subsequently cleared the virus as tested by NP PCR. Our experience suggests that continuing CDT in aggressive cancer cases where COVID-19 related symptoms are none-to-mild may not result in worsening viral course and clinical outcome. Our findings appear consistent with the UK Coronavirus Cancer Monitoring Project (UKCCMP) study which did not find an increased morbidity or mortality in patients who received chemotherapy within 4 weeks prior to confirm COVID-19, compared to cancer patients who did not receive chemotherapy. The study, however, did not report whether CDT was continued amongst the subset patients who did not require hospitalization, a patient population of focus in our study [8] . Based on our data and experience, we believe that patients with aggressive cancers in whom progression free survival without treatment is estimated to be 6 weeks or less and do not require hospitalization for COVID-19 symptoms should be continued on CDT without pause. This is in opposition to ASCO guidelines which suggest immediate cessation on diagnosis [7] . We recommend that treatment should be continued and patients should be followed closely with weekly clinical assessments via TeleHealth when appropriate, and patients should preferably receive weekly SARS-CoV-2 testing. CDT should be administered in a dedicated COVID-19 infusion unit, which is geographically distant from the site where noninfected cancer patients receive therapy. Given the current increase in SARS-CoV-2 infection rate in the United States and globally, treating oncologists will need to as-sess in real time whether CDT can be administered safely at their locations.
Growing data supports the use of Ct and serology testing in risk benefit assessments to help determine whether CDT can be safely reinitiated [11] . Ct reflects the amount of nucleic acid present and an indirect measure of viral load present in the sample being tested. La Scola et al (2020) evaluated the relationship between Ct of NP PCR tests detecting the SARS-COV-2 E gene, with the ability to isolate virus via cell culture. They found that a Ct of 34 or greater correlated with the inability to isolate virus by cell culture, indicating that the patient is likely not contagious [11] . In our study, nine (41%) patients, two of whom had progression of disease during CDT interruption, with available Ct (E gene target) reported a Ct value of 34 or greater. This suggests that they were likely not at significant risk of worsening infection or spread of the virus if they had continued CDT. Ct values may inform providers as to whether CDT should continue in mildly symptomatic COVID-19 patients with aggressive cancers.
SARS-CoV-2 serology testing may also guide continuation of CDT. A rising Ct value with a positive SARS-CoV-2 antibody titer should provide further assurance in continuation of CDT in patients who are high risk for cancer progression. Our data suggests that CDT and prolonged SARS-CoV-2 detectability by NP PCR does not necessarily prevent development of IgG antibodies as all 16 patients on active CDT tested for serology were positive. Furthermore, the shortest time period between a positive test by NP PCR and detectable SARS-CoV-2-specific IgG antibody was 10 days (range 10-69) in our patients. These results suggest that SARS-CoV-2 antibodies should be tested shortly after patients are confirmed infected by NP PCR. Detection of SARS-CoV-2 antibodies in our patients suggest that CDT may not hinder mounting of an immune response, however, the timing and level of the response is likely to be CDT-specific. PCR cycling thresholds and serology testing may represent powerful tools to help more accurately guide and assure oncologists and patients as to the benefit of continuing CDT and gauging the infectiousness of a patient and their risk of worsening disease or potential spread of the virus to the general community.
The COVID-19 pandemic has had clear ramifications on the way patients with cancer receive care. Patients with cancer represent a vulnerable population and attempts to shield these patients from complications of COVID-19 may have an unexpected impact on cancer related morbidity and mortality. Specifically, delays in CDT in patients who are at high risk for cancer progression due to persistent SARS-COV-2 infection as determined by NP PCR is of significant concern as delay in treatment can be prolonged. Patients with aggressive cancers with asymptomatic or mildly symptomatic COVID-19 can experience a protracted infectious course and the cessation of cancer directed therapy is likely to result in disease progression and a shortened overall survival. We propose that patients with active aggressive malignancies who are diagnosed with mild to asymptomatic COVID-19 in the outpatient setting should continue on CDT without pause given the increased risk of cancerrelated morbidity and mortality. These patients should be monitored closely while on treatment with clinical evaluation, PCR cycling thresholds and serology to assess for worsening SARS-CoV-2 infection.

Conflicts of Interest
None.