Prostate cancer is the most common cancer in men in Europe and the United States. The genetic heritability of prostate cancer is contributed to by both rarely occurring genetic variants with higher ...penetrance and moderate to commonly occurring variants conferring lower risks. The number of identified variants belonging to the latter category has increased dramatically in the last 10 years with the development of the genome-wide association study (GWAS) and the collaboration of international consortia that have led to the sharing of large-scale genotyping data. Over 40 prostate cancer GWAS have been reported, with approximately 170 common variants now identified. Clinical utility of these variants could include strategies for population-based risk stratification to target prostate cancer screening to men with an increased genetic risk of disease development, while for those who develop prostate cancer, identifying genetic variants could allow treatment to be tailored based on a genetic profile in the early disease setting. Functional studies of identified variants are needed to fully understand underlying mechanisms of disease and identify novel targets for treatment. This review will outline the GWAS carried out in prostate cancer and the common variants identified so far, and how these may be utilized clinically in the screening for and management of prostate cancer.
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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.
An increased mortality risk was observed in patients with cancer during the first wave of COVID-19. Here, we describe determinants of mortality in patients with solid cancer comparing the first and ...second waves of COVID-19. A retrospective analysis encompassing two waves of COVID-19 (March-May 2020; December 2020-February 2021) was performed. 207 patients with cancer were matched to 452 patients without cancer. Patient demographics and oncological variables such as cancer subtype, staging and anti-cancer treatment were evaluated for association with COVID-19 mortality. Overall mortality was lower in wave two compared to wave one, HR 0.41 (95% CI: 0.30-0.56). In patients with cancer, mortality was 43.6% in wave one and 15.9% in wave two. In hospitalized patients, after adjusting for age, ethnicity and co-morbidities, a history of cancer was associated with increased mortality in wave one but not wave two. In summary, the second UK wave of COVID-19 is associated with lower mortality in hospitalized patients. A history of solid cancer was not associated with increased mortality despite the dominance of the more transmissible B.1.1.7 SARS-CoV-2 variant. In both waves, metastatic disease and systemic anti-cancer treatment appeared to be independent risk factors for death within the combined cancer cohort.
The development of poly (adenosine diphosphate ADP) ribose polymerase (PARP) inhibitors (PARPi) has progressed greatly over the last few years and has shown encouraging results in the BRCA1/2 ...mutation-related cancers. This article attempts to summarize the rationale and theory behind PARPi, the clinical trials already reported, as well as ongoing studies designed to determine the role of PARPi in patients with and without germline mutations of BRCA genes. Future plans for PARPi both as monotherapy and in combination with standard cytotoxics, other biological agents, and as radiosensitizers are also covered. The widening scope of PARPi adds another important targeted agent to the growing list of molecular inhibitors; future and ongoing trials will identify the most effective role for PARPi, including for patients other than BRCA germline mutation carriers.
Introduction
The incidence of immune-related adverse events (irAEs) from immune checkpoint inhibitors (ICI) is well described. However, the impact on emergency care services is not. This study ...investigated the incidence of irAEs out-of-hours, and the management used to mitigate symptoms and side effects.
Methods
This retrospective cohort study reviewed all emergency presentations triaged by the acute oncology team between December 2021 and June 2022, between 5 pm and 9 am. Patients were identified from triage audit sheets and remaining data points were retrieved from electronic health records. Inclusion criteria included all adult patients admitted on an ICI at one tertiary centre.
Results
In 7 months, 970 patients called the acute oncology helpline 11% (n = 109) of patients were on an ICI treatment. After clinical review, 78% (n = 70) resulted in hospital admissions, with length of stay cumulating to 496 bed days. 56% (n = 39) of patients delayed reporting symptoms, ranging between 12 hours and 10 days from symptom onset to seeking support. 49% (n = 34) patients received steroids to manage suspected irAEs. Dexamethasone was the most common steroid used in 71% (n = 24) of patients, and variation was found in prescribed doses.
Conclusions
These results underline the urgent need to address patient and staff education on adverse effects related to ICI. Patients require a comprehensive understanding of the symptoms and importance of prompt reporting. Staff education on recognition and treatment management is needed to reduce variation in practice. Further research is needed to identify barriers in symptom reporting and focus on realtime reporting to reduce the out-of-hours burden on services.
Abstract Introduction The advanced biliary tract cancer (ABC)-02 study established cisplatin and gemcitabine (CisGem) as a reference 1st -line regimen for patients with advanced/metastatic biliary ...tract cancer; patients with bilirubin ⩾1.5 × upper limit of normal (ULN) were excluded and there are few extant data for systemic treatment in the context of elevated bilirubin. Methods Patients with ABC, receiving CisGem with a baseline bilirubin of ⩾1.5×ULN were eligible for this retrospective analysis; response, toxicity and survival data were collected. Results Thirty-three patients of 545 screened; median age 59 years, range 23–79; 58% male, 58% with metastases (79% in the liver) of performance status (PS) 0 (33%), 1 (64%) or 2 (3%) were eligible. The median baseline bilirubin was 55 μmol/L (range 32–286); due to biliary tract obstruction (BTO, 76%) or liver metastases (LM, 24%). Toxicity was comparable to the ABC-02 study; bilirubin normalised in 64% during chemotherapy/follow-up. The median progression-free survival (PFS) was 6.9 months (95% confidence interval (CI): 4.4–9.0) and median overall survival (OS) 9.5 months (95% CI: 5.7–12.8). Patients with BTO had a longer PFS and OS than those with LM (7.0 versus 2.6 months; p = 0.1633 and 9.8 versus 4.4 months, hazard ratio (HR) 0.74; p = 0.465, respectively); not statistically significant (due to small sample size). Normalisation of bilirubin and completion of eight CisGem cycles were associated with longer OS (11.4 versus 2.9 months, HR 0.49; p = 0.08 and 15.2 versus 5.4 months, HR 0.12 p < 0.001, respectively). No difference in OS was shown between the bilirubin percentiles (for either PFS or OS). Conclusion For PS 0-1 patients with ABC and high bilirubin due to luminal disease despite optimal stenting CisGem can be used safely with results similar to those in patients with normal bilirubin.
Rare germline mutations in DNA repair genes are associated with prostate cancer (PCa) predisposition and prognosis.
To quantify the frequency of germline DNA repair gene mutations in UK PCa cases and ...controls, in order to more comprehensively evaluate the contribution of individual genes to overall PCa risk and likelihood of aggressive disease.
We sequenced 167 DNA repair and eight PCa candidate genes in a UK-based cohort of 1281 young-onset PCa cases (diagnosed at ≤60yr) and 1160 selected controls.
Gene-level SKAT-O and gene-set adaptive combination of p values (ADA) analyses were performed separately for cases versus controls, and aggressive (Gleason score ≥8, n=201) versus nonaggressive (Gleason score ≤7, n=1048) cases.
We identified 233 unique protein truncating variants (PTVs) with minor allele frequency <0.5% in controls in 97 genes. The total proportion of PTV carriers was higher in cases than in controls (15% vs 12%, odds ratio OR=1.29, 95% confidence interval CI 1.01–1.64, p=0.036). Gene-level analyses selected NBN (pSKAT-O=2.4×10−4) for overall risk and XPC (pSKAT-O=1.6×10−4) for aggressive disease, both at candidate-level significance (p<3.1×10−4 and p<3.4×10−4, respectively). Gene-set analysis identified a subset of 20 genes associated with increased PCa risk (OR=3.2, 95% CI 2.1–4.8, pADA=4.1×10−3) and four genes that increased risk of aggressive disease (OR=11.2, 95% CI 4.6–27.7, pADA=5.6×10−3), three of which overlap the predisposition gene set.
The union of the gene-level and gene-set-level analyses identified 23 unique DNA repair genes associated with PCa predisposition or risk of aggressive disease. These findings will help facilitate the development of a PCa-specific sequencing panel with both predictive and prognostic potential.
This large sequencing study assessed the rate of inherited DNA repair gene mutations between prostate cancer patients and disease-free men. A panel of 23 genes was identified, which may improve risk prediction or treatment pathways in future clinical practice.
This large sequencing study assessed the rate of inherited DNA repair gene mutations in prostate cancer (PCa) patients and in disease-free men. A total of 23 genes were found to be associated with PCa predisposition or the risk of aggressive disease. These findings have predictive and prognostic potential.
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