Circulating tumour DNA (ctDNA) assays conducted on plasma are rapidly developing a strong evidence base for use in patients with cancer. The European Society for Medical Oncology convened an expert ...working group to review the analytical and clinical validity and utility of ctDNA assays. For patients with advanced cancer, validated and adequately sensitive ctDNA assays have utility in identifying actionable mutations to direct targeted therapy, and may be used in routine clinical practice, provided the limitations of the assays are taken into account. Tissue-based testing remains the preferred test for many cancer patients, due to limitations of ctDNA assays detecting fusion events and copy number changes, although ctDNA assays may be routinely used when faster results will be clinically important, or when tissue biopsies are not possible or inappropriate. Reflex tumour testing should be considered following a non-informative ctDNA result, due to false-negative results with ctDNA testing. In patients treated for early-stage cancers, detection of molecular residual disease or molecular relapse, has high evidence of clinical validity in anticipating future relapse in many cancers. Molecular residual disease/molecular relapse detection cannot be recommended in routine clinical practice, as currently there is no evidence for clinical utility in directing treatment. Additional potential applications of ctDNA assays, under research development and not recommended for routine practice, include identifying patients not responding to therapy with early dynamic changes in ctDNA levels, monitoring therapy for the development of resistance mutations before clinical progression, and in screening asymptomatic people for cancer. Recommendations for reporting of results, future development of ctDNA assays and future clinical research are made.
Triple-negative breast cancer (TNBC) is characterised by poor outcomes and a historical lack of targeted therapies. Dysregulation of signalling through the phosphoinositide 3 (PI3)-kinase and AKT ...signalling pathway is one of the most frequent oncogenic aberrations of TNBC. Although mutations in individual genes occur relatively rarely, combined activating mutations in PIK3CA and AKT1, with inactivating mutations in phosphatase and tensin homologue, occur in ∼25%‒30% of advanced TNBC. Recent randomised trials suggest improved progression-free survival (PFS) with AKT-inhibitors in combination with first-line chemotherapy for patients with TNBC and pathway genetic aberrations. We review the evidence for PI3K pathway activation in TNBC, and clinical trial data for PI3K, AKT and mammalian target of rapamycin inhibitors in TNBC. We discuss uncertainty over defining which cancers have pathway activation and the future overlap between immunotherapy and pathway targeting.
The cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor palbociclib, in combination with fulvestrant therapy, prolongs progression-free survival among patients with hormone-receptor-positive, human ...epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer. We report the results of a prespecified analysis of overall survival.
We randomly assigned patients with hormone-receptor-positive, HER2-negative advanced breast cancer who had progression or relapse during previous endocrine therapy to receive palbociclib plus fulvestrant or placebo plus fulvestrant. We analyzed overall survival; the effect of palbociclib according to the prespecified stratification factors of presence or absence of sensitivity to endocrine therapy, presence or absence of visceral metastatic disease, and menopausal status; the efficacy of subsequent therapies after disease progression; and safety.
Among 521 patients who underwent randomization, the median overall survival was 34.9 months (95% confidence interval CI, 28.8 to 40.0) in the palbociclib-fulvestrant group and 28.0 months (95% CI, 23.6 to 34.6) in the placebo-fulvestrant group (hazard ratio for death, 0.81; 95% CI, 0.64 to 1.03; P=0.09; absolute difference, 6.9 months). CDK4/6 inhibitor treatment after the completion of the trial regimen occurred in 16% of the patients in the placebo-fulvestrant group. Among 410 patients with sensitivity to previous endocrine therapy, the median overall survival was 39.7 months (95% CI, 34.8 to 45.7) in the palbociclib-fulvestrant group and 29.7 months (95% CI, 23.8 to 37.9) in the placebo-fulvestrant group (hazard ratio, 0.72; 95% CI, 0.55 to 0.94; absolute difference, 10.0 months). The median duration of subsequent therapy was similar in the two groups, and the median time to the receipt of chemotherapy was 17.6 months in the palbociclib-fulvestrant group, as compared with 8.8 months in the placebo-fulvestrant group (hazard ratio, 0.58; 95% CI, 0.47 to 0.73; P<0.001). No new safety signals were observed with 44.8 months of follow-up.
Among patients with hormone-receptor-positive, HER2-negative advanced breast cancer who had sensitivity to previous endocrine therapy, treatment with palbociclib-fulvestrant resulted in longer overall survival than treatment with placebo-fulvestrant. The differences in overall survival in the entire trial group were not significant. (Funded by Pfizer; PALOMA-3 ClinicalTrials.gov number, NCT01942135 .).
•This ESMO Clinical Practice Guideline provides key recommendations and algorithms for managing metastatic breast cancer.•It covers diagnosis, staging, risk assessment, treatment, disease monitoring, ...palliative care and the patient perspective.•ESMO-MCBS and ESCAT scores are given to describe the levels of evidence for treatment choices.•The authors comprise an international expert group, with recommendations based on available evidence and expert opinion.•In clinical practice, all recommendations provided need to be discussed with patients in a shared decision-making approach.
Basal-like breast cancers form a distinct subtype of breast cancer characterized by the expression of markers expressed in normal basal/myoepithelial cells. Breast cancers arising in carriers of ...germline BRCA1 mutations are predominately of basal-like type, suggesting that BRCA1 dysfunction may play a role in the pathogenesis of sporadic basal-like cancers. We analysed 37 sporadic breast cancers expressing the basal marker cytokeratin 5/6, and age- and grade-matched controls, for downregulation of BRCA1. Although BRCA1 promoter methylation was no more common in basal-like cancers (basal 14% vs controls 11%, P=0.72), BRCA1 messenger RNA expression was twofold lower in basal-like breast cancers compared to matched controls (P=0.008). ID4, a negative regulator of BRCA1, was expressed at 9.1-fold higher levels in basal-like breast cancer (P<0.0001), suggesting a potential mechanism of BRCA1 downregulation. BRCA1 downregulation correlated with the presence of multiple basal markers, revealing heterogeneity in the basal-like phenotype. Finally, we found that 63% of metaplastic breast cancers, a rare type of basal-like cancers, had BRCA1 methylation, in comparison to 12% of controls (P<0.0001). The high prevalence of BRCA1 dysfunction identified in this study could be exploited in the development of novel approaches to targeted treatment of basal-like breast cancer.
Better knowledge of the tumor genomic landscapes has helped to develop more effective targeted drugs. However, there is no tool to interpret targetability of genomic alterations assessed by ...next-generation sequencing in the context of clinical practice. Our aim is to rank the level of evidence of individual recurrent genomic alterations observed in breast cancer based on the ESMO Scale for Clinical Actionability of molecular Targets (ESCAT) in order to help the clinicians to prioritize treatment. Analyses of databases suggested that there are around 40 recurrent driver alterations in breast cancer. ERBB2 amplification, germline BRCA1/2 mutations, PIK3CA mutations were classified tier of evidence IA based on large randomized trials showing antitumor activity of targeted therapies in patients presenting the alterations. NTRK fusions and microsatellite instability (MSI) were ranked IC. ESR1 mutations and PTEN loss were ranked tier IIA, and ERBB2 mutations and AKT1 mutations tier IIB. Somatic BRCA 1/2 mutations, MDM2 amplifications and ERBB 3 mutations were ranked tier III. Seventeen genes were ranked tier IV based on preclinical evidence. Finally, FGFR1 and CCND1 were ranked tier X alterations because previous studies have shown lack of actionability.
Data returned by NASA’s Mars Science Laboratory Curiosity rover showed evidence for abundant secondary materials, including Fe‐oxides, phyllosilicates, and an amorphous component on and below Vera ...Rubin ridge in the Murray formation. We used equilibrium thermochemical modeling to test the hypothesis that altered sediments were deposited as detrital igneous grains and subsequently underwent diagenesis. Chemical compositions of the Murray formations’ altered components were calculated using data returned by the chemistry and mineralogy X‐ray diffraction instrument and the alpha particle X‐ray spectrometer on board Curiosity. Reaction of these alteration compositions with a CO2‐poor and oxidizing dilute aqueous solution was modeled at 25–100 °C, with 10–50% Fe3+/Fetot of the host rock. The modeled alteration assemblages included abundant phyllosilicates and Fe‐oxides at water‐to‐rock ratios >100. Modeled alteration abundances were directly comparable to observed abundances of hematite and clay minerals at a water‐to‐rock ratio of 10,000, for system temperatures of 50–100 °C with fluid pH ranging from 7.9 to 9.3. Modeling results suggest that the hematite–clay mineral assemblage is primarily the result of enhanced groundwater flow compared to the Sheepbed mudstone observed at Yellowknife Bay, and underwent further, localized alteration to produce the mineralogy observed by Curiosity.
Post-treatment detection of circulating tumour DNA (ctDNA) in early-stage triple-negative breast cancer (TNBC) patients predicts high risk of relapse. c-TRAK TN assessed the utility of prospective ...ctDNA surveillance in TNBC and the activity of pembrolizumab in patients with ctDNA detected ctDNA positive (ctDNA+).
c-TRAK TN, a multicentre phase II trial, with integrated prospective ctDNA surveillance by digital PCR, enrolled patients with early-stage TNBC and residual disease following neoadjuvant chemotherapy, or stage II/III with adjuvant chemotherapy. ctDNA surveillance comprised three-monthly blood sampling to 12 months (18 months if samples were missed due to coronavirus disease), and ctDNA+ patients were randomised 2 : 1 to intervention : observation. ctDNA results were blinded unless patients were allocated to intervention, when staging scans were done and those free of recurrence were offered pembrolizumab. A protocol amendment (16 September 2020) closed the observation group; all subsequent ctDNA+ patients were allocated to intervention. Co-primary endpoints were (i) ctDNA detection rate and (ii) sustained ctDNA clearance rate on pembrolizumab (NCT03145961).
Two hundred and eight patients registered between 30 January 2018 and 06 December 2019, 185 had tumour sequenced, 171 (92.4%) had trackable mutations, and 161 entered ctDNA surveillance. Rate of ctDNA detection by 12 months was 27.3% (44/161, 95% confidence interval 20.6% to 34.9%). Seven patients relapsed without prior ctDNA detection. Forty-five patients entered the therapeutic component (intervention n = 31; observation n = 14; one observation patient was re-allocated to intervention following protocol amendment). Of patients allocated to intervention, 72% (23/32) had metastases on staging at the time of ctDNA+, and 4 patients declined pembrolizumab. Of the five patients who commenced pembrolizumab, none achieved sustained ctDNA clearance.
c-TRAK TN is the first prospective study to assess whether ctDNA assays have clinical utility in guiding therapy in TNBC. Patients had a high rate of metastatic disease on ctDNA detection. Findings have implications for future trial design, emphasising the importance of commencing ctDNA testing early, with more sensitive and/or frequent ctDNA testing regimes.
•We report the first study to prospectively assess ctDNA for molecular residual disease (MRD) detection in breast cancer.•Implementation of MRD detection with personalised assays was clinically achievable.•The rapid relapsing nature of high-risk TNBC challenged implementation of MRD detection.•Treatment with pembrolizumab did not result in ctDNA clearance, although assessment was limited by small number of patients.•Recommendations for implementation of MRD detection in future studies are given.
Over-exploitation and habitat degradation are the two major drivers of global environmental change and are responsible for local extinctions and declining ecosystem services. Here we compare the ...top-down effect of exploitation by fishing with the bottom-up influence of habitat loss on fish communities in the most diverse of ecological systems, coral reefs. Using a combination of multivariate techniques and path analyses, we illustrate that the relative importance of coral cover and fishing in controlling fish abundance on remote Fijian reefs varies between species and functional groups. A decline in branching Acropora coral is strongly associated with a decline in abundance of coral-feeding species, and a decrease in coral-associated habitat complexity, which has indirectly contributed to reduced abundance of small-bodied damselfish. In contrast, reduced fishing pressure, brought about by declining human populations and a shift to alternate livelihoods, is associated with increased abundance of some piscivores and fisheries target species. However, availability of prey is controlled by coral-associated habitat complexity and appears to be a more important driver of total piscivore abundance compared with fishing pressure. Effects of both fishing and coral loss are stronger on individual species than functional groups, as variation in the relative importance of fishing or coral loss among species within the same functional group attenuated the impact of either of these potential drivers at the functional level. Overall, fishing continues to have an influence on Fijian fish communities; however, habitat loss is currently the overriding agent of change. The importance of coral loss mediated by climate change is expected to have an increasing contribution to fish community dynamics, particularly in remote locations or where the influence of fishing is waning.
Yields of dryland (rainfed) wheat in Australia have increased steadily over the past century despite rainfall being unchanged, indicating that the rainfall-use efficiency has increased. Analyses ...suggest that at least half of the increase in rainfall-use efficiency can be attributed to improved agronomic management. Various methods of analysing the factors influencing dryland yields and rainfall-use efficiency, such as simple rules and more complex models, are presented and the agronomic factors influencing water use, water-use efficiency, and harvest index of crops are discussed. The adoption of agronomic procedures such as minimum tillage, appropriate fertilizer use, improved weed/disease/insect control, timely planting, and a range of rotation options, in conjunction with new cultivars, has the potential to increase the yields and rainfall-use efficiency of dryland crops. It is concluded that most of the agronomic options for improving rainfall-use efficiency in rainfed agricultural systems decrease water losses by soil evaporation, runoff, throughflow, deep drainage, and competing weeds, thereby making more water available for increased water use by the crop.
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