Editorial: Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV2), COVID-19 and cancer: three research questions casting a long shadow.

The year 2020 will go into history books as the year of the COVID-19 epidemic. From the Wuhan outbreak in late 2019 to a global pandemics by mid-2020, the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV2) virus has infected over 70 million people and has so far killed over 1.7 million people -- with global numbers still increasing. The emergence of this new viruses is an unprecedented challenge to public health, causing a societal crisis that places billions into lockdown and dramatically impacts on jobs and economies. Healthcare systems take the brunt of the assault, having not only to deal with massive influx of COVID-19 patients but also with profound disruption of prevention, diagnosis and treatment services for other diseases including cancer. In this editorial, we reflect on the already known and unknown interactions between COVID-19, its causal agent SARS-CoV2 and cancer, and we identify three major questions for further research aimed at addressing the long-term impact of COVID-19 on cancer morbidity and mortality in coming months and years.

First question is ‘Are cancer patients at increased risk of mortality from COVID-19?’ Initial small cases series from China and Europe have consistently reported that patients with cancer appeared to be highly susceptible to develop severe forms of COVID-19. It has also been widely suspected that patients receiving potentially immunosuppressive anticancer treatment, in particular those with hematological malignancies, may be more vulnerable to severe infection. These hypotheses have led many care centers to adapt schedules in order to minimize the number of hospital visits and to down-scale standard-of-care treatment regimens. Whereas this situation provides an opportunity to evaluate the costs and benefits of such down-scaling, the call is still out on whether cancer itself and anticancer treatments are risk factors for mortality from COVID-19 [1]. Results of the UK Coronavirus Cancer Monitoring Project (UKCCMP) on 800 cancer patients revealed that mortality from COVID-19 appeared to be principally driven by age, gender and comorbidities -- similar to noncancer patients [2]. This study also failed to identify evidence that cancer patients on cytotoxic chemotherapy or other anticancer treatment were at an increased risk of mortality from COVID-19 compared with those not on active treatment. Further research is definitely needed to evaluate these interactions using larger prospective data series with longer follow-up than the relatively small and time-limited series reported to date. It should be expected that different interactions might occur, depending on cancer type, treatment and patient profile. This research will not only provide for evidence-based decision-making for cancer treatment during the pandemics: it will also give us a magnifying lens into the fine details of personalized medicine, helping us to better understand how specific immune and inflammatory contexts modulate the course of cancer and of anticancer treatment responses.

Second, ‘What will be the magnitude of excess mortality and disease burden caused by disrupted access to prevention, screening, diagnosis and treatment, over and beyond the mortality directly attributable to COVID-19?’ There is overwhelming evidence that the pandemics, and in particular the lockdown periods, have caused major disruptions in cancer healthcare programs, placing additional hurdles on patient's paths of access to rapid diagnosis and treatment. These indirect effects have far-reaching consequences for all cancer patients, independently of their COVID-19 status. Data from several national health services have shown a substantial decrease of urgent referrals and chemotherapy clinics attendance during the spring lockdowns, only partially compensated upon ease of lockdown measures during summer and autumn 2020 [3]. An unknown number of patients have probably postponed visits to family doctors, impairing the chances of rapid action upon early suspicious symptoms. Screening and early detection programs have been severely impacted if not completely halted during significant periods of the year. Access to clinical trials and innovative treatments has been delayed, with loss of chances for patients who could not be included in such trials. There is no doubt that all these effects combined will have a strong measurable impact on short, middle and long-term mortality by cancer, and on other measures of disease burden, such as quality of life, for example, because of more aggressive treatments resulting from delayed diagnosis. Whereas objective numbers will take a decade to emerge through cancer registration, epidemiological models can be developed to predict the magnitude of these effects and, more importantly, to identify points of actions for developing effective mitigation strategies.

The third question is ‘Can SARS-CoV2 and COVID-19 cause a surge in cancers in the future?’ This question is highly speculative but, based on current and rapidly accruing knowledge on the molecular biology of SARS-CoV2 and on the long-term effects of COVID-19, it cannot be overlooked. Two aspects should be considered.

First, ‘Has SARS-CoV2 the potential to be an oncogenic virus?’ Like most viruses, and similar to other known human coronaviruses, the SARS-CoV2 genome encodes structural and nonstructural proteins that hijack host cell regulatory pathways and manipulate them to support sustained viral replication. An extensive proteomics analysis has revealed that among 332 host cell proteins targeted by SARS-CoV2 proteins, 46 were products of genes known as cancer-related and involved in processes, such as cell cycle control, DNA damage response, cell metabolism, innate immune and antiviral cell response, chromatin remodeling and epigenome reprogramming, apoptosis, translation control and RNA processing [4]. In this issue of Current Opinion in Oncology, a review by Cardozo and Hainaut [5] summarizes evidence supporting that two proteins encoded by SARS-CoV viruses, nsp2 and nsp3, directly or indirectly target the p53 pathway, an essential tumor-suppressive mechanism functionally impaired in many cancers. This large repertoire of proteins at the cancer--virus interface underscore that SARS-CoV2 has the potential to cause severe disruption of homeostatic mechanisms that protect cells against neoplastic transformation. Whereas these effects may be of limited impact in a context of transient, time-limited infection, they might cause major damage if sustained over time, that is, in a context of persistent infection. Therefore, it is crucial to precisely evaluate the duration of the SARS-CoV2 infection cycle and to identify cells and tissues in which the virus, or some of its components, may persist in a latent form and thus contribute to increase the risk of transformation in the long-term.

Second, ‘Is the so-called “long-COVID-19 syndrome” a risk factor for cancer?’ A rapidly emerging aspect of the clinical presentation of COVID-19 is the persistence in a fraction of the patients of complex multiorgan long-term effects, such as extreme fatigue, neurological symptoms, tachycardia and persistent respiratory complications [6]. Similar findings in a substantial fraction of the victims of the 2003 SARS outbreak raise alarm on the possible long-term impact on pulmonary health status. Whereas the exact causes of these symptoms still need to be identified, they suggest that acute SARS-CoV2 infection may cause profound tissue scarring as well as long-term dysregulation of immune and inflammation processes. Such conditions may be primers for neoplasia, in particular in the respiratory tract, either as precursor chronic inflammatory diseases or as factors that increase the risk of neoplastic transformation of preexisting or concurrent precancer lesions.

With the rolling out of anti-SARS-CoV2 vaccination programs, one can hope that the pandemics will progressively recede in the year 2021. However, given the large number of people infected and of survivors of severe COVID-19, better knowledge, prediction and management of long-term effects will be mandatory in order to prevent and rapidly diagnose dramatic sequelae, such as cancer. In the meantime, the pandemics is confronting us with a unique opportunity to learn, adapt and transform healthcare systems towards greater resilience in the face of the challenges posed by future societal crises, whether caused by infectious agents or by other economic or environmental factors.

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