Triple negative breast cancer (TNBC) encompasses molecularly different subgroups, with a subgroup harboring evidence of defective homologous recombination (HR) DNA repair. Here, within a phase 2 ...window clinical trial, RIO trial (EudraCT 2014-003319-12), we investigate the activity of PARP inhibitors in 43 patients with untreated TNBC. The primary end point, decreased Ki67, occured in 12% of TNBC. In secondary end point analyses, HR deficiency was identified in 69% of TNBC with the mutational-signature-based HRDetect assay. Cancers with HRDetect mutational signatures of HR deficiency had a functional defect in HR, assessed by impaired RAD51 foci formation on end of treatment biopsy. Following rucaparib treatment there was no association of Ki67 change with HR deficiency. In contrast, early circulating tumor DNA dynamics identified activity of rucaparib, with end of treatment ctDNA levels suppressed by rucaparib in mutation-signature HR-deficient cancers. In ad hoc analysis, rucaparib induced expression of interferon response genes in HR-deficient cancers. The majority of TNBCs have a defect in DNA repair, identifiable by mutational signature analysis, that may be targetable with PARP inhibitors.
Many individuals with multiple or large colorectal adenomas or early-onset colorectal cancer (CRC) have no detectable germline mutations in the known cancer predisposition genes. Using whole-genome ...sequencing, supplemented by linkage and association analysis, we identified specific heterozygous POLE or POLD1 germline variants in several multiple-adenoma and/or CRC cases but in no controls. The variants associated with susceptibility, POLE p.Leu424Val and POLD1 p.Ser478Asn, have high penetrance, and POLD1 mutation was also associated with endometrial cancer predisposition. The mutations map to equivalent sites in the proofreading (exonuclease) domain of DNA polymerases ɛ and δ and are predicted to cause a defect in the correction of mispaired bases inserted during DNA replication. In agreement with this prediction, the tumors from mutation carriers were microsatellite stable but tended to acquire base substitution mutations, as confirmed by yeast functional assays. Further analysis of published data showed that the recently described group of hypermutant, microsatellite-stable CRCs is likely to be caused by somatic POLE mutations affecting the exonuclease domain.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
The genomics of advanced breast cancer (ABC) has been described through tumour tissue biopsy sequencing, although these approaches are limited by geographical and temporal heterogeneity. Here we use ...plasma circulating tumour DNA sequencing to interrogate the genomic profile of ABC in 800 patients in the plasmaMATCH trial. We demonstrate diverse subclonal resistance mutations, including enrichment of HER2 mutations in HER2 positive disease, co-occurring ESR1 and MAP kinase pathway mutations in HR + HER2- disease that associate with poor overall survival (p = 0.0092), and multiple PIK3CA mutations in HR + disease that associate with short progression free survival on fulvestrant (p = 0.0036). The fraction of cancer with a mutation, the clonal dominance of a mutation, varied between genes, and within hotspot mutations of ESR1 and PIK3CA. In ER-positive breast cancer subclonal mutations were enriched in an APOBEC mutational signature, with second hit PIK3CA mutations acquired subclonally and at sites characteristic of APOBEC mutagenesis. This study utilises circulating tumour DNA analysis in a large clinical trial to demonstrate the subclonal diversification of pre-treated advanced breast cancer, identifying distinct mutational processes in advanced ER-positive breast cancer, and novel therapeutic opportunities.
ObjectivesOver two million people in the UK are living with and beyond cancer. A third report diminished quality of life.DesignA review of published systematic reviews to identify effective ...non-pharmacological interventions to improve the quality of life of cancer survivors.Data sourcesDatabases searched until May 2017 included PubMed, Cochrane Central, EMBASE, MEDLINE, Web of Science, the Cumulative Index to Nursing and Allied Health Literature, and PsycINFO.Study selectionPublished systematic reviews of randomised trials of non-pharmacological interventions for people living with and beyond cancer were included; included reviews targeted patients aged over 18. All participants had already received a cancer diagnosis. Interventions located in any healthcare setting, home or online were included. Reviews of alternative therapies or those non-English reports were excluded. Two researchers independently assessed titles, abstracts and the full text of papers, and independently extracted the data.OutcomesThe primary outcome of interest was any measure of global (overall) quality of life.Analytical methodsQuality assessment assessing methdological quality of systematic reviews (AMSTAR) and narrative synthesis, evaluating effectiveness of non-pharmacological interventions and their components.ResultsOf 14 430 unique titles, 21 were included in the review of reviews. There was little overlap in the primary papers across these reviews. Thirteen reviews covered mixed tumour groups, seven focused on breast cancer and one focused on prostate cancer. Face-to-face interventions were often combined with online, telephone and paper-based reading materials. Interventions included physical, psychological or behavioural, multidimensional rehabilitation and online approaches. Yoga specifically, physical exercise more generally, cognitive behavioural therapy (CBT) and mindfulness-based stress reduction (MBSR) programmes showed benefit in terms of quality of life.ConclusionsExercise-based interventions were effective in the short (less than 3–8 months) and long term. CBT and MBSR also showed benefits, especially in the short term. The evidence for multidisciplinary, online and educational interventions was equivocal.
PARTNER is a prospective, phase II-III, randomized controlled clinical trial that recruited patients with triple-negative breast cancer
, who were germline BRCA1 and BRCA2 wild type
. Here we report ...the results of the trial. Patients (n = 559) were randomized on a 1:1 basis to receive neoadjuvant carboplatin-paclitaxel with or without 150 mg olaparib twice daily, on days 3 to 14, of each of four cycles (gap schedule olaparib, research arm) followed by three cycles of anthracycline-based chemotherapy before surgery. The primary end point was pathologic complete response (pCR)
, and secondary end points included event-free survival (EFS) and overall survival (OS)
. pCR was achieved in 51% of patients in the research arm and 52% in the control arm (P = 0.753). Estimated EFS at 36 months in the research and control arms was 80% and 79% (log-rank P > 0.9), respectively; OS was 90% and 87.2% (log-rank P = 0.8), respectively. In patients with pCR, estimated EFS at 36 months was 90%, and in those with non-pCR it was 70% (log-rank P < 0.001), and OS was 96% and 83% (log-rank P < 0.001), respectively. Neoadjuvant olaparib did not improve pCR rates, EFS or OS when added to carboplatin-paclitaxel and anthracycline-based chemotherapy in patients with triple-negative breast cancer who were germline BRCA1 and BRCA2 wild type. ClinicalTrials.gov ID: NCT03150576 .
Ductal carcinoma in situ (DCIS) is widely accepted as a precursor of invasive ductal carcinoma (IDC). Lobular carcinoma in situ (LCIS) is considered a risk factor for invasive lobular carcinoma ...(ILC), and it is unclear whether LCIS is also a precursor. Therefore, it would be expected that similar risk factors predispose to both DCIS and IDC, but not necessarily LCIS and ILC. This study examined associations with risk factors using data from 3075 DCIS cases, 338 LCIS cases, and 1584 controls aged 35–60, recruited from the UK-based GLACIER and ICICLE case-control studies between 2007 and 2012. Analysis showed that breastfeeding in parous women was protective against DCIS and LCIS, which is consistent with research on invasive breast cancer (IBC). Additionally, long-term use of HRT in post-menopausal women increased the risk of DCIS and LCIS, with a stronger association in LCIS, similar to the association with ILC. Contrary to findings with IBC, parity and the number of births were not protective against DCIS or LCIS, while oral contraceptives showed an unexpected protective effect. These findings suggest both similarities and differences in risk factors for DCIS and LCIS compared to IBC and that there may be justification for increased breast surveillance in post-menopausal women taking long-term HRT.
Targeted therapies have yet to have significant impact on the survival of patients with bladder cancer. In this study, we focused on the urea cycle enzyme argininosuccinate synthetase 1 (ASS1) as a ...therapeutic target in bladder cancer, based on our discovery of the prognostic and functional import of ASS1 in this setting. ASS1 expression status in bladder tumors from 183 Caucasian and 295 Asian patients was analyzed, along with its hypothesized prognostic impact and association with clinicopathologic features, including tumor size and invasion. Furthermore, the genetics, biology, and therapeutic implications of ASS1 loss were investigated in urothelial cancer cells. We detected ASS1 negativity in 40% of bladder cancers, in which multivariate analysis indicated worse disease-specific and metastasis-free survival. ASS1 loss secondary to epigenetic silencing was accompanied by increased tumor cell proliferation and invasion, consistent with a tumor-suppressor role for ASS1. In developing a treatment approach, we identified a novel targeted antimetabolite strategy to exploit arginine deprivation with pegylated arginine deiminase (ADI-PEG20) as a therapeutic. ADI-PEG20 was synthetically lethal in ASS1-methylated bladder cells and its exposure was associated with a marked reduction in intracellular levels of thymidine, due to suppression of both uptake and de novo synthesis. We found that thymidine uptake correlated with thymidine kinase-1 protein levels and that thymidine levels were imageable with (18)F-fluoro-L-thymidine (FLT)-positron emission tomography (PET). In contrast, inhibition of de novo synthesis was linked to decreased expression of thymidylate synthase and dihydrofolate reductase. Notably, inhibition of de novo synthesis was associated with potentiation of ADI-PEG20 activity by the antifolate drug pemetrexed. Taken together, our findings argue that arginine deprivation combined with antifolates warrants clinical investigation in ASS1-negative urothelial and related cancers, using FLT-PET as an early surrogate marker of response.
Ductal carcinoma in situ (DCIS) is a non-obligate precursor of invasive ductal breast cancer, and approximately 20% of screen-detected tumours are pure DCIS. Most risk factors for breast cancer have ...similar associations with DCIS and IDC; however, there is limited data on the prevalence of the known high and moderate penetrance breast cancer predisposition genes in DCIS and which women with DCIS should be referred for genetic screening. The aim of this study was to assess the frequency of germline variants in BRCA2, BRCA1, CHEK2, PALB2 and TP53 in DCIS in women aged less than 50 years of age.
After DNA extraction from the peripheral blood, Access Array technology (Fluidigm) was used to amplify all exons of these five known breast cancer predisposition genes using a custom made targeted sequencing panel in 655 cases of pure DCIS presenting in women under the age of 50 years together with 1611 controls.
Case-control analysis revealed an excess of pathogenic variants in BRCA2 (OR = 27.96, 95%CI 6.56-119.26, P = 2.0 × 10
) and CHEK2 (OR = 8.04, 95%CI 2.93-22.05, P = 9.0 × 10
), with weaker associations with PALB2 (P = 0.003), BRCA1 (P = 0.007) and TP53 (P = 0.02). For oestrogen receptor (ER)-positive DCIS the frequency of pathogenic variants was 9% under the age of 50 (14% with a family history of breast cancer) and 29% under the age of 40 (42% with a family history of breast cancer). For ER-negative DCIS, the frequency was 9% (16% with a family history of breast cancer) and 8% (11% with a family history of breast cancer) under the ages of 50 and 40, respectively.
This study has shown that breast tumourigenesis in women with pathogenic variants in BRCA2, CHEK2, PALB2, BRCA1 and TP53 can involve a DCIS precursor stage and that the focus of genetic testing in DCIS should be on women under the age of 40 with ER-positive DCIS.
There is growing evidence of excess peripheral neuropathy in pre-diabetes. We aimed to determine its prevalence, including the impact of diagnostic methodology on prevalence rates, through a ...systematic review conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. A comprehensive electronic bibliographic search was performed in MEDLINE, EMBASE, PubMed, Web of Science and the Cochrane Central Register of Controlled Trials from inception to June 1, 2020. Two reviewers independently selected studies, extracted data and assessed risk of bias. An evaluation was undertaken by method of neuropathy assessment. After screening 1784 abstracts and reviewing 84 full-text records, 29 studies (9351 participants) were included. There was a wide range of prevalence estimates (2%–77%, IQR: 6%–34%), but the majority of studies (n=21, 72%) reported a prevalence ≥10%. The three highest prevalence estimates of 77% (95% CI: 54% to 100%), 71% (95% CI: 55% to 88%) and 66% (95% CI: 53% to 78%) were reported using plantar thermography, multimodal quantitative sensory testing and nerve conduction tests, respectively. In general, studies evaluating small nerve fiber parameters yielded a higher prevalence of peripheral neuropathy. Due to a variety of study populations and methods of assessing neuropathy, there was marked heterogeneity in the prevalence estimates. Most studies reported a higher prevalence of peripheral neuropathy in pre-diabetes, primarily of a small nerve fiber origin, than would be expected in the background population. Given the marked rise in pre-diabetes, further consideration of targeting screening in this population is required. Development of risk-stratification tools may facilitate earlier interventions.
Patients with cancer are at increased risk of hospitalisation and mortality following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. However, the SARS-CoV-2 phenotype ...evolution in patients with cancer since 2020 has not previously been described. We therefore evaluated SARS-CoV-2 on a UK populationscale from 01/11/2020-31/08/2022, assessing case-outcome rates of hospital assessment(s), intensive care admission and mortality. We observed that the SARS-CoV-2 disease phenotype has become less severe in patients with cancer and the non-cancer population. Case-hospitalisation rates for patients with cancer dropped from 30.58% in early 2021 to 7.45% in 2022 while case-mortality rates decreased from 20.53% to 3.25%. However, the risk of hospitalisation and mortality remains 2.10x and 2.54x higher in patients with cancer, respectively. Overall, the SARS-CoV-2 disease phenotype is less severe in 2022 compared to 2020 but patients with cancer remain at higher risk than the non-cancer population. Patients with cancer must therefore be empowered to live more normal lives, to see loved ones and families, while also being safeguarded with expanded measures to reduce the risk of transmission.
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