The SARS-Cov-2 pandemic in 2020 has caused oncology teams around the world to adapt their practice in the aim of protecting patients. Early evidence from China indicated that patients with cancer, ...and particularly those who had recently received chemotherapy or surgery, were at increased risk of adverse outcomes following SARS-Cov-2 infection. Many registries of cancer patients infected with SARS-Cov-2 emerged during the first wave. We collate the evidence from these national and international studies and focus on the risk factors for patients with solid cancers and the contribution of systemic anti-cancer treatments (SACT-chemotherapy, immunotherapy, targeted and hormone therapy) to outcomes following SARS-Cov-2 infection. Patients with cancer infected with SARS-Cov-2 have a higher probability of death compared with patients without cancer. Common risk factors for mortality following COVID-19 include age, male sex, smoking history, number of comorbidities and poor performance status. Oncological features that may predict for worse outcomes include tumour stage, disease trajectory and lung cancer. Most studies did not identify an association between SACT and adverse outcomes. Recent data suggest that the timing of receipt of SACT may be associated with risk of mortality. Ongoing recruitment to these registries will enable us to provide evidence-based care.
Aneuploidy is associated with poor prognosis in solid tumors. Spontaneous chromosome missegregation events in aneuploid cells promote chromosomal instability (CIN) that may contribute to the ...acquisition of multidrug resistance in vitro and heighten risk for tumor relapse in animal models. Identification of distinct therapeutic agents that target tumor karyotypic complexity has important clinical implications. To identify distinct therapeutic approaches to specifically limit the growth of CIN tumors, we focused on a panel of colorectal cancer (CRC) cell lines, previously classified as either chromosomally unstable (CIN(+)) or diploid/near-diploid (CIN(-)), and treated them individually with a library of kinase inhibitors targeting components of signal transduction, cell cycle, and transmembrane receptor signaling pathways. CIN(+) cell lines displayed significant intrinsic multidrug resistance compared with CIN(-) cancer cell lines, and this seemed to be independent of somatic mutation status and proliferation rate. Confirming the association of CIN rather than ploidy status with multidrug resistance, tetraploid isogenic cells that had arisen from diploid cell lines displayed lower drug sensitivity than their diploid parental cells only with increasing chromosomal heterogeneity and isogenic cell line models of CIN(+) displayed multidrug resistance relative to their CIN(-) parental cancer cell line derivatives. In a meta-analysis of CRC outcome following cytotoxic treatment, CIN(+) predicted worse progression-free or disease-free survival relative to patients with CIN(-) disease. Our results suggest that stratifying tumor responses according to CIN status should be considered within the context of clinical trials to minimize the confounding effects of tumor CIN status on drug sensitivity.
Consolidated evidence suggests spontaneous immunity from SARS-CoV-2 is not durable, leading to the risk of reinfection, especially in the context of newly emerging viral strains. In patients with ...cancer who survive COVID-19 prevalence and severity of SARS-CoV-2 reinfections are unknown.
We aimed to document natural history and outcome from SARS-CoV-2 reinfection in patients recruited to OnCovid (NCT04393974), an active European registry enrolling consecutive patients with a history of solid or haematologic malignancy diagnosed with COVID-19.
As of December 2021, out of 3108 eligible participants, 1806 COVID-19 survivors were subsequently followed at participating institutions. Among them, 34 reinfections (1.9%) were reported after a median time of 152 days (range: 40-620) from the first COVID-19 diagnosis, and with a median observation period from the second infection of 115 days (95% CI: 27-196). Most of the first infections were diagnosed in 2020 (27, 79.4%), while most of reinfections in 2021 (25, 73.5%). Haematological malignancies were the most frequent primary tumour (12, 35%). Compared to first infections, second infections had lower prevalence of COVID-19 symptoms (52.9% vs 91.2%, P = 0.0008) and required less COVID-19-specific therapy (11.8% vs 50%, P = 0.0013). Overall, 11 patients (32.4%) and 3 (8.8%) were fully and partially vaccinated against SARS-CoV-2 before the second infection, respectively. The 14-day case fatality rate was 11.8%, with four death events, none of which among fully vaccinated patients.
This study shows that reinfections in COVID-19 survivors with cancer are possible and more common in patients with haematological malignancies. Reinfections carry a 11% risk of mortality, which rises to 15% among unvaccinated patients, highlighting the importance of universal vaccination of patients with cancer.
The centrosome acts as a centre for microtubule organisation and plays crucial roles in cell polarity, migration, growth and division. Cep131 has recently been described as a basal body component ...essential for cilium formation, but its function in non-ciliogenic cells is unknown. We identified human Cep131 (also known as AZI1) in a screen for regulators of genome stability. We show that centrosomal localisation of Cep131 is cell-cycle-regulated and requires both an intact microtubule network and a functional dynein-dynactin transport system. Cep131 is recruited to centriolar satellites by PCM1, and localised to the centriolar core region by both pericentrin and Cep290. Depletion of Cep131 results in a reduction in proliferation rate, centriole amplification, an increased frequency of multipolar mitosis, chromosomal instability and an increase in post-mitotic DNA damage. These data therefore highlight the importance of human Cep131 for maintaining genomic integrity.
Despite high contagiousness and rapid spread, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to heterogeneous outcomes across affected nations. Within Europe (EU), the United ...Kingdom (UK) is the most severely affected country, with a death toll in excess of 100,000 as of January 2021. We aimed to compare the national impact of coronavirus disease 2019 (COVID-19) on the risk of death in UK patients with cancer versus those in continental EU.
We performed a retrospective analysis of the OnCovid study database, a European registry of patients with cancer consecutively diagnosed with COVID-19 in 27 centres from 27th February to 10th September 2020. We analysed case fatality rates and risk of death at 30 days and 6 months stratified by region of origin (UK versus EU). We compared patient characteristics at baseline including oncological and COVID-19–specific therapy across UK and EU cohorts and evaluated the association of these factors with the risk of adverse outcomes in multivariable Cox regression models.
Compared with EU (n = 924), UK patients (n = 468) were characterised by higher case fatality rates (40.38% versus 26.5%, p < 0.0001) and higher risk of death at 30 days (hazard ratio HR, 1.64 95% confidence interval {CI}, 1.36–1.99) and 6 months after COVID-19 diagnosis (47.64% versus 33.33%; p < 0.0001; HR, 1.59 95% CI, 1.33–1.88). UK patients were more often men, were of older age and have more comorbidities than EU counterparts (p < 0.01). Receipt of anticancer therapy was lower in UK than in EU patients (p < 0.001). Despite equal proportions of complicated COVID-19, rates of intensive care admission and use of mechanical ventilation, UK patients with cancer were less likely to receive anti–COVID-19 therapies including corticosteroids, antivirals and interleukin-6 antagonists (p < 0.0001). Multivariable analyses adjusted for imbalanced prognostic factors confirmed the UK cohort to be characterised by worse risk of death at 30 days and 6 months, independent of the patient's age, gender, tumour stage and status; number of comorbidities; COVID-19 severity and receipt of anticancer and anti–COVID-19 therapy. Rates of permanent cessation of anticancer therapy after COVID-19 were similar in the UK and EU cohorts.
UK patients with cancer have been more severely impacted by the unfolding of the COVID-19 pandemic despite societal risk mitigation factors and rapid deferral of anticancer therapy. The increased frailty of UK patients with cancer highlights high-risk groups that should be prioritised for anti–SARS-CoV-2 vaccination. Continued evaluation of long-term outcomes is warranted.
•Coronavirus disease 2019 (COVID-19) mortality in the United Kingdom (UK) has exceeded that of all other European countries.•Outcomes of UK patients with cancer and COVID-19 may compare unfavourably with European countries.•This is the first study to report detrimental outcomes for UK patients with cancer.•UK patients are older, have more comorbidities and are less likely to have received COVID-19 therapy.•Considering our results, rapid vaccination against severe acute respiratory syndrome coronavirus 2 should be recommended.
Here, we identify coiled-coil domain-containing protein 13 (Ccdc13) in a genome-wide RNA interference screen for regulators of genome stability. We establish that Ccdc13 is a newly identified ...centriolar satellite protein that interacts with PCM1, Cep290 and pericentrin and prevents the accumulation of DNA damage during mitotic transit. Depletion of Ccdc13 results in the loss of microtubule organisation in a manner similar to PCM1 and Cep290 depletion, although Ccdc13 is not required for satellite integrity. We show that microtubule regrowth is enhanced in Ccdc13-depleted cells, but slowed in cells that overexpress Ccdc13. Furthermore, in serum-starved cells, Ccdc13 localises to the basal body, is required for primary cilia formation and promotes the localisation of the ciliopathy protein BBS4 to both centriolar satellites and cilia. These data highlight the emerging link between DNA damage response factors, centriolar and peri-centriolar satellites and cilia-associated proteins and implicate Ccdc13 as a centriolar satellite protein that functions to promote both genome stability and cilia formation.
Intrinsic and acquired drug resistance leads to the eventual failure of cancer treatment regimens in the majority of advanced solid tumours. Understanding drug resistance mechanisms will prove vital ...in the future development of personalised therapeutic approaches. Functional genomics technologies may permit the discovery of predictive biomarkers by unravelling pathways involved in drug resistance and allow the systematic identification of novel therapeutic targets. Such technologies offer the opportunity to develop personalised treatments and diagnostic tools that may improve the survival and quality of life of patients with cancer. However, despite progress in biomarker and drug target discovery, inter-tumour and intra-tumour molecular heterogeneity will limit the effective treatment of this disease. Combining an improved understanding of cancer cell survival mechanisms associated with intra-tumour heterogeneity and drug resistance may allow the selection of patients for specific treatment regimens that will maximise benefit, limit the acquisition of drug resistance and lessen the impact of deleterious side effects.
The COVID-19 pandemic remains a pressing concern to patients with cancer as countries enter the second peak of the pandemic and beyond. It remains unclear whether cancer and its treatment contribute ...an independent risk for mortality in COVID-19.
We included patients at a London tertiary hospital with laboratory confirmed SARS-CoV-2 infection. All patients with a history of solid cancer were included. Age- and sex-matched patients without cancer were randomly selected. Patients with hematological malignancies were excluded.
We identified 94 patients with cancer, matched to 226 patients without cancer. After adjusting for age, ethnicity, and co-morbidities, patients with cancer had increased mortality following COVID-19 (HR 1.57, 95% CI:1.04-2.4,
= 0.03). Increasing age (HR 1.49 every 10 years, 95% CI:1.25-1.8,
< 0.001), South Asian ethnicity (HR 2.92, 95% CI:1.73-4.9,
< 0.001), and cerebrovascular disease (HR 1.93, 95% CI:1.18-3.2,
= 0.008) also predicted mortality. Within the cancer cohort, systemic anti-cancer therapy (SACT) within 60 days of COVID-19 diagnosis was an independent risk factor for mortality (HR 2.30, 95% CI: 1.16-4.6,
= 0.02).
Along with known risk factors, cancer and SACT confer an independent risk for mortality following COVID-19. Further studies are needed to understand the socio-economic influences and pathophysiology of these associations.
Although representing the majority of newly diagnosed cancers, patients with breast cancer appear less vulnerable to COVID-19 mortality compared with other malignancies. In the absence of patients on ...active cancer therapy included in vaccination trials, a contemporary real-world evaluation of outcomes during the various pandemic phases, as well as of the impact of vaccination, is needed to better inform clinical practice.
We compared COVID-19 morbidity and mortality among patients with breast cancer across prevaccination (February 27, 2020-November 30, 2020), Alpha-Delta (December 1, 2020-December 14, 2021), and Omicron (December 15, 2021-January 31, 2022) phases using OnCovid registry participants (ClinicalTrials.gov identifier: NCT04393974). Twenty-eight-day case fatality rate (CFR
) and COVID-19 severity were compared in unvaccinated versus double-dosed/boosted patients (vaccinated) with inverse probability of treatment weighting models adjusted for country of origin, age, number of comorbidities, tumor stage, and receipt of systemic anticancer therapy within 1 month of COVID-19 diagnosis.
By the data lock of February 4, 2022, the registry counted 613 eligible patients with breast cancer: 60.1% (n = 312) hormone receptor-positive, 25.2% (n = 131) human epidermal growth factor receptor 2-positive, and 14.6% (n = 76) triple-negative. The majority (61%; n = 374) had localized/locally advanced disease. Median age was 62 years (interquartile range, 51-74 years). A total of 193 patients (31.5%) presented ≥ 2 comorbidities and 69% (n = 330) were never smokers. In total, 392 (63.9%), 164 (26.8%), and 57 (9.3%) were diagnosed during the prevaccination, Alpha-Delta, and Omicron phases, respectively. Analysis of CFR
demonstrates comparable estimates of mortality across the three pandemic phases (13.9%, 12.2%, 5.3%, respectively;
= .182). Nevertheless, a significant improvement in outcome measures of COVID-19 severity across the three pandemic time periods was observed. Importantly, when reported separately, unvaccinated patients from the Alpha-Delta and Omicron phases achieved comparable outcomes to those from the prevaccination phase. Of 566 patients eligible for the vaccination analysis, 72 (12.7%) were fully vaccinated and 494 (87.3%) were unvaccinated. We confirmed with inverse probability of treatment weighting multivariable analysis and following a clustered robust correction for participating center that vaccinated patients achieved improved CFR
(odds ratio OR, 0.19; 95% CI, 0.09 to 0.40), hospitalization (OR, 0.28; 95% CI, 0.11 to 0.69), COVID-19 complications (OR, 0.16; 95% CI, 0.06 to 0.45), and reduced requirement of COVID-19-specific therapy (OR, 0.24; 95% CI, 0.09 to 0.63) and oxygen therapy (OR, 0.24; 95% CI, 0.09 to 0.67) compared with unvaccinated controls.
Our findings highlight a consistent reduction of COVID-19 severity in patients with breast cancer during the Omicron outbreak in Europe. We also demonstrate that even in this population, a complete severe acute respiratory syndrome coronavirus 2 vaccination course is a strong determinant of improved morbidity and mortality from COVID-19.
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