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Purpose Fear of cancer recurrence (FCR) is common and associated with younger age. This study aimed to explore the prevalence and correlates of FCR amongst younger survivors of early breast cancer. Subjects A total of 218 women aged 18–45 were diagnosed with stage 0–2 breast cancer at least 1 year earlier. Methods The participants completed a web-based survey including a validated measure of FCR and items exploring medical surveillance practices and health care use. Results A total of 70% of participants reported clinical levels of FCR. Higher FCR was associated with higher frequency of unscheduled visits to the GP, higher frequency of breast self-examination and other forms of self-examination for cancer, not having mammograms or ultrasounds or other forms of cancer screening in the past year, more complementary therapy use and the use of counselling and support groups. Conclusions Young women with breast cancer are particularly vulnerable to FCR. The present study provides preliminary evidence that FCR is associated with higher health costs and lower surveillance rates which may compromise health outcomes. Routine screening for FCR in follow-up care is recommended.

Gemcitabine and oxaliplatin have shown single-agent activity in relapsed ovarian cancer. This combination was used to determine response rates, time-to-event efficacy measures, and toxicity in patients with recurrent ovarian cancer. Patients with prior platinum-based chemotherapy who had measurable lesions and/or elevated CA-125 levels were identified as group A (platinum-refractory/platinum-resistant patients) and group B (platinum-sensitive patients). All patients received gemcitabine 1000 mg/m2 on days 1 and 8 and oxaliplatin 130 mg/m2 on day 8 every 21 days for up to eight cycles. Seventy-five patients (21 in group A and 54 in group B), with a median age of 58 years (range, 37–78), were enrolled. A median of six cycles (range, 1–8) was administered. By intent-to-treat analysis, 15 patients with measurable disease achieved partial response for an overall best response rate of 20.0% (9.5% in group A and 24.1% in group B). CA-125 response was observed in 48.4% patients (30.0% in group A and 57.1% in group B). Median time to progressive disease was 7.1 months (95% CI, 5.6–9.0 months) with 5.0 months in group A and 8.3 months in group B. Median overall survival was 17.8 months (95% CI, 12.9–21.3 months) with 9.2 months for group A and 20.0 months for group B. Major grade 3/4 toxicities were neutropenia (61.3%), leukopenia (24.0%), nausea (16.0%), and vomiting (22.7%). We conclude that the combination of oxaliplatin and gemcitabine is active in patients with recurrent ovarian cancer, but the regimen is unsatisfactory for further study due to modest response and relatively high toxicity.

Stable water isotopes from polar ice cores are invaluable high-resolution climate proxy records. Recent studies have aimed to improve our understanding of how the climate signal is stored in the stable water isotope record by addressing the influence of post-depositional processes on the isotopic composition of surface snow. In this study, the relationship between surface snow metamorphism and water isotopes during precipitation-free periods is explored using measurements of snow-specific surface area (SSA). Continuous daily SSA measurements from the East Greenland Ice Core Project site (EastGRIP) during the summer seasons of 2017, 2018 and 2019 are used to develop an empirical decay model to describe events of rapid decrease in SSA linked to snow metamorphism. We find that SSA decay during precipitation-free periods at the EastGRIP site is best described by the exponential equation SSA(t)=(SSA0-22)⋅e-αt+22, and has a dependency on wind speed. The relationship between surface snow SSA and snow isotopic composition is primarily explored using empirical orthogonal function analysis. A coherence between SSA and deuterium excess is apparent during 2017 and 2019, suggesting that processes driving change in SSA also influence snow deuterium excess. By contrast, 2018 was characterised by a covariance between SSA and δ18O highlighting the inter-annual variability in surface regimes. Moreover, we observed changes in isotopic composition consistent with fractionation effects associated with sublimation and vapour diffusion during periods of rapid decrease in SSA. Our findings support recent studies which provide evidence of isotopic fractionation during sublimation, and show that snow deuterium excess is modified during snow metamorphism.

While the processes controlling pore closure are broadly understood, the physical mechanisms driving the associated elemental fractionation remains ambiguous. Previous studies have shown that the pore closure process leads to a depletion in small-sized molecules (e.g. H2, O2, Ar, Ne, He) in ice core bubbles relative to larger-sized molecules like N2. This size-dependent fractionation, identified using ice core δ(O2/N2) records, exhibits a clear anti-correlation with local summer solstice insolation, making δ(O2/N2) a valuable ice core dating tool. Mechanisms controlling this relationship are attributed to the physical properties of deep firn. In this study, we compile δ(O2/N2) records from 15 polar ice cores and show a new additional link between δ(O2/N2) and local surface temperature and/or accumulation rate. Using the Crocus snowpack model, we perform sensitivity tests to identify the response of near-surface snow properties to changes in insolation intensity, accumulation rate, and air temperature. These tests support a mechanism linked to firn grain size, such that the larger the grain size for a given density, the stronger the pore closure fractionation and, hence, the lower the δ(O2/N2) values archived in the ice. Based on both snowpack model outputs and data compilation, our findings suggest that local accumulation rate and temperature should be considered when interpreting δ(O2/N2) as a local insolation proxy.

Accurately identifying patients with high-grade serous ovarian carcinoma (HGSOC) who respond to poly(ADP-ribose) polymerase inhibitor (PARPi) therapy is of great clinical importance. Here we show that quantitative BRCA1 methylation analysis provides new insight into PARPi response in preclinical models and ovarian cancer patients. The response of 12 HGSOC patient-derived xenografts (PDX) to the PARPi rucaparib was assessed, with variable dose-dependent responses observed in chemo-naive BRCA1/2 -mutated PDX, and no responses in PDX lacking DNA repair pathway defects. Among BRCA1 -methylated PDX, silencing of all BRCA1 copies predicts rucaparib response, whilst heterozygous methylation is associated with resistance. Analysis of 21 BRCA1- methylated platinum-sensitive recurrent HGSOC (ARIEL2 Part 1 trial) confirmed that homozygous or hemizygous BRCA1 methylation predicts rucaparib clinical response, and that methylation loss can occur after exposure to chemotherapy. Accordingly, quantitative BRCA1 methylation analysis in a pre-treatment biopsy could allow identification of patients most likely to benefit, and facilitate tailoring of PARPi therapy. Around 10% of high-grade serous ovarian carcinomas (HGSOC) harbor BRCA1 promoter methylation, but it is uncertain how it predicts response to PARP inhibition. Here, the authors show that homozygous BRCA1 methylation predicts response to rucaparib while heterozygous methylation of BRCA1 predicts resistance in HGSOC.

Whole genome duplication is frequently observed in cancer, and its prevalence in our prior analysis of end-stage, homologous recombination deficient high grade serous ovarian cancer (almost 80% of samples) supports the notion that whole genome duplication provides a fitness advantage under the selection pressure of therapy. Here, we therefore aim to identify potential therapeutic vulnerabilities in primary high grade serous ovarian cancer with whole genome duplication by assessing differentially expressed genes and pathways in 79 samples. We observe that MHC-II expression is lowest in tumors which have acquired whole genome duplication early in tumor evolution, and further demonstrate that reduced MHC-II expression occurs in subsets of tumor cells rather than in canonical antigen-presenting cells. Early whole genome duplication is also associated with worse patient survival outcomes. Our results suggest an association between the timing of whole genome duplication, MHC-II expression and clinical outcome in high grade serous ovarian cancer that warrants further investigation for therapeutic targeting. There is high prevalence of whole genome duplication (WGD) in high grade serous ovarian cancer. Here, the authors compare tumours with and without WGD and find that those that acquired WGD early during tumour evolution are associated with worse survival and have the lowest expression of MHC-II.

Adjuvant endocrine therapies such as tamoxifen, goserelin, and oophorectomy improve survival for premenopausal women diagnosed with early-stage breast cancer. However, these treatments often result in menopausal symptoms, sexual dysfunction, permanent infertility, or the need to delay pregnancy. We aimed to quantify the survival gains that premenopausal patients with early-stage breast cancer require to justify the side-effects and inconvenience of adjuvant endocrine treatments. Participants consisted of 102 women who had been diagnosed with early-stage (stage I–II) breast cancer 6–60 months previously, who were aged 40 years or younger at diagnosis, and who had been treated for a minimum of 3 months with endocrine therapy (67 with tamoxifen alone, seven with goserelin alone, and 28 with tamoxifen and goserelin or oophorectomy). 76 patients also received chemotherapy, and 75 received radiotherapy. Participants attended a face-to-face patient-preference interview, in which they were presented with four hypothetical clinical scenarios that were used to quantify the gains in survival rate and life expectancy that women judged necessary to make their endocrine therapy worthwhile. They also completed a questionnaire on standard psychological measures. About half of participants thought that adjuvant endocrine therapy was worthwhile for an absolute gain in survival of 2% from a baseline of either 65% or 85%, and for a gain in life expectancy of 3 months from a baseline of 5 years and of 6 months for a baseline of 15 years. Women who had had more severe endocrine side-effects required larger gains to make endocrine therapy worthwhile (univariate p=0·02, multivariate p=0·04). Modest gains in survival are sufficient to make adjuvant endocrine treatment worthwhile for premenopausal women with early-stage breast cancer. Knowing and incorporating what women think should enhance shared decision-making.

While the introduction of poly-(ADP)-ribose polymerase (PARP) inhibitors in homologous recombination DNA repair (HR) deficient high grade serous ovarian, fallopian tube and primary peritoneal cancers (HGSC) has improved patient survival, resistance to PARP inhibitors frequently occurs. Preclinical and translational studies have identified multiple mechanisms of resistance; here we examined tumour samples collected from 26 women following treatment with PARP inhibitors as part of standard of care or their enrolment in clinical trials. Twenty-one had a germline or somatic BRCA1/2 mutation. We performed targeted sequencing of 63 genes involved in DNA repair processes or implicated in ovarian cancer resistance. We found that just three individuals had a small-scale mutation as a definitive resistance mechanism detected, having reversion mutations, while six had potential mechanisms of resistance detected, with alterations related to BRCA1 function and mutations in SHLD2 . This study indicates that mutations in genes related to DNA repair are detected in a minority of HGSC patients as genetic mechanisms of resistance. Future research into resistance in HGSC should focus on copy number, transcriptional and epigenetic aberrations, and the contribution of the tumour microenvironment.

Whilst next generation sequencing can report point mutations in fixed tissue tumour samples reliably, the accurate determination of copy number is more challenging. The conventional Multiplex Ligation-dependent Probe Amplification (MLPA) assay is an effective tool for measurement of gene dosage, but is restricted to around 50 targets due to size resolution of the MLPA probes. By switching from a size-resolved format, to a sequence-resolved format we developed a scalable, high-throughput, quantitative assay. MLPA-seq is capable of detecting deletions, duplications, and amplifications in as little as 5ng of genomic DNA, including from formalin-fixed paraffin-embedded (FFPE) tumour samples. We show that this method can detect BRCA1, BRCA2, ERBB2 and CCNE1 copy number changes in DNA extracted from snap-frozen and FFPE tumour tissue, with 100% sensitivity and >99.5% specificity.