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  • News & Views |

    Measuring the methylation status of cell-free DNA (cfDNA) in plasma holds great potential for the early, noninvasive detection of cancer. Two recent papers published in Nature Medicine showcase the successful application of cfDNA methylation-based cancer detection to two highly challenging scenarios.

    • Wenyuan Li
    •  & Xianghong Jasmine Zhou
  • News & Views |

    SABR-COMET was the first randomized controlled trial to demonstrate an overall survival benefit with the use of stereotactic ablative body radiotherapy (SABR) for the treatment of oligometastatic cancer. Considering the recently reported long-term follow-up data from SABR-COMET, we review the outcomes and limitations of this study in the context of other emerging information on therapy for oligometastatic disease.

    • Tyler P. Robin
    •  & Jeffrey R. Olsen
  • News & Views |

    Cell-free DNA and proteins are secreted into the bloodstream by multiple types of cancer. In a recently published prospective study involving 10,006 women, such markers were used in a cancer screening approach that incorporated PET–CT as a confirmatory test. Herein, we discuss the implications of these results.

    • Y. M. Dennis Lo
    •  & W. K. Jacky Lam
  • News & Views |

    Lung cancer screening is currently based only on low-dose CT scans; however, novel, more accessible methods that might improve uptake and adherence are eagerly awaited. New liquid biopsy approaches promise to revolutionize cancer screening. Herein, we discuss the opportunities and challenges associated with two such novel assays.

    • Christian Rolfo
    •  & Alessandro Russo
  • News & Views |

    Mature results of the PROfound study demonstrate that the poly(ADP-ribose) polymerase (PARP) inhibitor olaparib prolongs progression-free survival compared with second-generation hormonal therapies in men with metastatic castration-resistant prostate cancer harbouring BRCA1, BRCA2 or ATM mutations. However, a closer look at the efficacy of olaparib on a gene-by-gene basis suggests that its activity is most pronounced in BRCA2-mutant prostate cancers and might not be equally active in all homologous recombination repair-deficient cancers.

    • Emmanuel S. Antonarakis
  • News & Views |

    Bacteria within tumours affect progression and response to therapy; in addition, bacterial DNA can be detected in cell-free plasma. Herein, we discuss evidence showing that intratumoural bacteria are characteristic for each tumour type, and that detection of cell-free bacterial DNA in blood could provide an accurate and non-invasive test for cancer diagnosis.

    • Amiran Dzutsev
    •  & Giorgio Trinchieri
  • News & Views |

    Effective anticancer therapies typically activate antitumour immunity, predominately mediated by T cells in the tumour microenvironment. Here, we discuss the roles of B cells and tertiary lymphoid structures in the context of chemotherapy-induced complement activation, which results in the induction of a B cell subset that modulates T cell function.

    • Catherine Sautès-Fridman
    •  & Lubka T. Roumenina
  • News & Views |

    Evidence of quality of life improvements in patients with advanced-stage cancer has spurred a move towards early integration of palliative care into the outpatient setting. As discussed herein, meaningful and sustained improvements in timely access to palliative care requires commitments to funding, encouraging integration and routinizing referral across care settings. More palliative medicine training positions as well as broader education of clinicians and the public about the benefits of palliative care throughout the disease course are also needed.

    • Jean Mathews
    •  & Camilla Zimmermann
  • News & Views |

    The identification of individuals carrying cancer susceptibility genetic variants could be improved by peridiagnostic cancer genetic testing and cascade testing of the relatives of patients diagnosed with cancer. Herein we discuss two studies that highlight the importance of active involvement of the medical team, both in informing the relatives and offering pre-test telephone genetic counselling.

    • Nora Pashayan
    •  & Clare Turnbull
  • News & Views |

    The survival outcomes of the FLAURA trial support osimertinib as the new first-line standard of care for patients with EGFR-mutated advanced-stage non-small-cell lung cancer in health-care systems that can afford its cost. However, the low crossover rate is a flaw of this study. Knowledge of mechanisms of resistance to provide tailored treatment is the new challenge preventing a continued paradigm shift in this disease.

    • Jordi Remon
    •  & Gilberto Lopes
  • News & Views |

    Developing novel technologies to discriminate malignant tissue from nonmalignant structures and thereby facilitate safe, complete tumour resection is a major priority for advancing oncological neurosurgery. Herein, we discuss a recently reported innovation involving stimulated Raman spectroscopy of intraoperative tissue samples and data interpretation with artificial intelligence, as well as the implications of this approach for neurosurgical oncology.

    • Michael L. Martini
    •  & Eric K. Oermann
  • News & Views |

    In 2018, the SOLO1 trial set a new standard of care with maintenance olaparib substantially extending progression-free survival (PFS) in women with newly-diagnosed BRCA1/2-mutated advanced-stage ovarian cancer. Herein, we summarize trials of first-line poly(ADP-ribose) polymerase (PARP) inhibition beyond BRCA1/2 mutations, including combination strategies, and discuss the optimum use of PARP inhibition in advanced-stage ovarian cancer.

    • Susana N. Banerjee
    •  & Christopher J. Lord
  • News & Views |

    Liu et al. report data from the largest sequencing analysis of tumour material from patients with metastatic melanoma receiving immune-checkpoint inhibitors. These data confirm the correlations between baseline immune infiltrate and treatment response, but also demonstrate inconsistent associations of tumour mutational burden, specific gene mutations and previously described gene expression patterns with clinical outcomes.

    • Jason J. Luke
    •  & Paolo A. Ascierto
  • News & Views |

    Interval invasive breast cancers diagnosed after a normal mammogram but before the next screening examination have a different tumour biology from that of screen-detected breast cancers, and thus are not detected on mammography. Understanding the genetics and biology of interval invasive cancers could inform better approaches to detection.

    • Yiwey Shieh
    • , Elad Ziv
    •  & Karla Kerlikowske
  • News & Views |

    The CHECKMATE-227 trial of nivolumab and ipilimumab presents a potential new frontline chemotherapy-sparing treatment option for patients with PD-L1-positive non-small-cell lung cancer and perhaps, in the future, also for those with PD-L1-negative disease. Indeed, the true predictive value of PD-L1 as well as tumour mutational burden remains to be determined, as neither biomarker segregates clearly with responsiveness.

    • Anne C. Chiang
    •  & Roy S. Herbst
  • News & Views |

    Numerous neoepitope-based vaccination strategies are in testing for clinical use in the treatment of cancer. Rapid identification of immunostimulatory neoantigen targets hastens neoantigen vaccine development. Papers recently published in Nature Biotechnology describe two independent machine-learning-based algorithms that demonstrate improved identification of MHC class II-binding peptides. Herein, we outline the benefits of these algorithms and their implications for future immunotherapies.

    • Tamson V. Moore
    •  & Michael I. Nishimura
  • News & Views |

    The identification of biomarkers and the development of genomics-based assays predictive of outcomes following radiotherapy, in an effort to help guide the treatment of patients with cancer, is an area of increasing research interest. Here, we discuss the validity of one such classifier, ARTIC, in the context of complementary genomic approaches designed to predict both tumour response and the susceptibility of nonmalignant tissues to toxicities resulting from radiotherapy.

    • David Azria
    •  & Barry S. Rosenstein
  • News & Views |

    In the past few years, several studies have addressed the possibility of using immunotherapies to treat patients with mesothelioma. Herein, we discuss two recent trials, one testing the immune-checkpoint inhibitor nivolumab and the other testing a mesothelin-directed therapeutic vaccine, and reflect on the advances and challenges remaining in this research area.

    • Anna K. Nowak
    •  & Patrick M. Forde
  • News & Views |

    BRCA1/2 mutations and poly (ADP-ribose) polymerase (PARP) inhibitors are paradigmatic of synthetic lethal therapy. However, the activity of PARP inhibitors seems to vary considerably across BRCA1/2-mutant cancers and new insights into the tumour-lineage dependency of this synthetic lethal relationship might explain why BRCA1/2 mutations are not tumour-agnostic biomarkers of a response to PARP inhibitors.

    • Nicola J. Curtin
    • , Yvette Drew
    •  & Sweta Sharma-Saha
  • News & Views |

    In the past few years, efforts have been made to combine two approaches — immune-checkpoint inhibition and locally ablative radiation therapy — to treat patients with metastatic non-small-cell lung cancer. Herein we discuss the implications of two studies that support the existence of a systemic therapy augmented by radiotherapy (STAR) effect in this setting.

    • Jordan A. Torok
    •  & Joseph K. Salama
  • News & Views |

    The presence and prognostic relevance of the intratumoural microbiota in pancreatic cancer, and the roles of intratumoural bacteria in oncogenesis and therapeutic response are beginning to be elucidated. The feasibility of characterizing intratumoural microbial communities from paraffin-embedded tissues has now been validated, providing greater opportunities for retrospective research. Prospective studies are also needed to test the efficacy of rational approaches combining microbial modulation with chemotherapy and/or immunotherapy.

    • Joshua C. Leinwand
    •  & George Miller
  • News & Views |

    Five randomized trials have been conducted to prove that shorter duration of trastuzumab treatment (9 weeks or 6 months) can replace the standard duration (1 year). The results of PERSEPHONE, the most recent trial, suggest that the efficacy of a 6-month treatment is non-inferior to that of 1 year, although not for all patients. We discuss these results in the context of current treatment standards.

    • Noam Pondé
    •  & Evandro de Azambuja
  • News & Views |

    An urgent clinical need exists to improve the survival of patients with pancreatic cancer through biomarker-driven therapeutic strategies. Such approaches include the targeting of metastatic pancreatic cancer that harbours germline BRCA mutations with poly(ADP-ribose) polymerase inhibitors as maintenance therapy following platinum-based chemotherapy.

    • Shubham Pant
    • , Anirban Maitra
    •  & Timothy A. Yap
  • News & Views |

    In the TITAN and ENZAMET trials, unprecedented overall survival outcomes were observed in patients with metastatic castration-sensitive prostate cancer receiving an agent targeting the androgen receptor in addition to androgen-deprivation therapy early in the course of their disease. Herein, I discuss both trials in the context of other studies in this disease setting.

    • Fred Saad
  • News & Views |

    The addition of the immune-checkpoint inhibitor nivolumab to first-line therapy with doxorubicin, vinblastine and dacarbazine seems feasible, with no signals of severe additional toxicities emerging. The high response rates and acceptable safety profile might make this combination an appealing alternative in the treatment of patients with high-risk disease.

    • Alvaro J. Alencar
    •  & Craig H. Moskowitz
  • News & Views |

    Researchers from Google AI have presented results obtained using a deep learning model for the detection of lung cancer in screening CT images. The authors report a level of performance similar to, or better than, that of radiologists. However, these claims are currently too strong. The model is promising but needs further validation and could only be implemented if screening guidelines were adjusted to accept recommendations from black-box proprietary AI systems.

    • Colin Jacobs
    •  & Bram van Ginneken
  • News & Views |

    The adoptive transfer of T cells expressing a chimeric antigen receptor (CAR) is an effective therapy for patients with relapsed or refractory CD19+ B cell malignancies, but can cause life-threatening toxicities. Herein we discuss a recent study suggesting that alterations to the design of anti-CD19 CARs can reduce cytokine release and the incidence of treatment-related complications.

    • Alexander I. Salter
    •  & Stanley R. Riddell
  • News & Views |

    In a landmark analysis, investigators of the Multicentric Italian Lung Detection (MILD) trial have confirmed 10-year mortality reductions with lung cancer screening using low-dose helical CT (LDCT). These data complement the reduced lung cancer-specific mortality reported in the National Lung Screening Trial and reinforce the rationale for broad implementation of LDCT screening in high-risk populations.

    • Matthew B. Schabath
    •  & Denise R. Aberle
  • News & Views |

    In recent decades, cancer survival has improved dramatically, resulting in a growing population of cancer survivors with chronic health needs and disease risks. While large epidemiological studies are useful in tracking broad trends in health outcomes of cancer survivors, they lack the level of detail needed to inform the delivery of appropriate clinical care and optimal allocation of resources.

    • Eden R. Brauer
    •  & Patricia A. Ganz
  • News & Views |

    Identification of factors predicting recurrence of breast cancer is a long-standing goal, ranging from classical clinicopathological factors through to immunohistochemical assays of receptor levels and, more recently, the expression levels of several genes. A new paper now explores novel expression markers, especially for late recurrence of oestrogen receptor-positive breast cancer.

    • Jack Cuzick
  • News & Views |

    Glioblastoma remains essentially incurable, and new therapeutic approaches are urgently needed. Now, the findings of three serial tissue-based studies suggest that immune-checkpoint inhibition can modify the glioblastoma microenvironment. Following these encouraging observations, the results of two phase III trials of immune-checkpoint inhibition in newly diagnosed glioblastoma, with larger cohorts of patients, are eagerly anticipated.

    • Michael Weller
    •  & Emilie Le Rhun
  • News & Views |

    Using the example of the recently reported phase III MAIA trial, we emphasize herein the requirement to dig deeper into trial designs and end points to determine their appropriateness for the questions at hand and to assess whether a benefit in terms of the primary end point — even if statistically significant and seemingly clinically meaningful — is sufficient to warrant a change in clinical practice.

    • Prashant Kapoor
    •  & S. Vincent Rajkumar
  • News & Views |

    Inhibition of the NKG2A immune checkpoint restores natural killer cell and T cell effector function in preclinical cancer models. In addition, NKG2A blockade in combination with other therapeutic antibodies is showing encouraging responses in a subset of patients with metastatic colorectal or head and neck cancer. However, established biomarkers of response are lacking, and larger trials are needed to enable firm conclusions to be drawn about whether NKG2A inhibition complements existing immunotherapies.

    • Benjamin C. Creelan
    •  & Scott J. Antonia
  • News & Views |

    Recently published data from the ZUMA-1 and JULIET trials suggest that CD19-directed chimeric antigen receptor (CAR) T cell therapy can provide durable remissions, with a low risk of relapse or progression, in 30–40% of patients with relapsed and/or refractory aggressive large B cell lymphoma. Two-year follow-up of the ZUMA-1 clinical trial has not revealed any unexpected toxicities, but further safety monitoring will be needed.

    • David G. Maloney
  • News & Views |

    The first-in-human study of anti-CD47 antibodies blocking CD47–SIRPα interactions in combination with rituximab in patients with non-Hodgkin lymphoma shows encouraging clinical responses accompanied with mild levels of toxicity. Inhibition of the CD47–SIRPα interaction might provide a generic method of promoting the effects of antitumour antibodies in a variety of cancer types. This reveals, for the first time, an innate immune checkpoint as a bona fide target for therapy.

    • Timo K. van den Berg
    •  & Thomas Valerius
  • News & Views |

    The International Society of Paediatric Oncology (SIOP)–Paediatric Oncology in Developing Countries (PODC) Collaborative Wilms Tumour Africa project delivered treatment in eight centres across five countries in sub-Saharan Africa. Setting up a collaboration like this is easier said than done, and herein we share the lessons we learned along the way.

    • Trijn Israels
    •  & Elizabeth M. Molyneux
  • News & Views |

    In a cohort of 100 patients with neuroendocrine cancer, the use of NETest enabled earlier prediction of tumour progression and resulted in a reduction in the frequency of follow-up procedures. These outcomes are exciting and promising, but limited in value by the heterogeneity of the study cohort and by suboptimal assay sensitivity and specificity.

    • Guido Rindi
    •  & Bertram Wiedenmann
  • News & Views |

    The ESMO Scale for Clinical Actionability of molecular Targets (ESCAT) will be useful as a common language to harmonize discussions in precision oncology and could also guide policy and reimbursement decisions, but it is far from perfect. Herein, we highlight how ESCAT can be further improved to increase its utility in clinical and policy decisions.

    • Bishal Gyawali
    •  & Aaron S. Kesselheim
  • News & Views |

    A minority of patients with gastroesophageal adenocarcinoma derive benefit from immune-checkpoint inhibition (ICI). In a large-cohort phase III study, the nivolumab (1 mg/kg) plus ipilimumab (3 mg/kg) arm (which was based on promising preliminary data from CheckMate 032) was closed owing to unacceptably high levels of mortality and morbidity. Our quest for better biomarkers than programmed cell death 1 ligand 1 (PD-L1) and safer dual ICI strategies must continue.

    • Kazuto Harada
    • , Ahmed A. F. Abdelhakeem
    •  & Jaffer A. Ajani
  • News & Views |

    Chemoprevention for patients with Barrett’s oesophagus remains a controversial topic. Results of the first randomized trial of chemoprevention using a proton pump inhibitor with or without aspirin were recently reported. We highlight strengths and weaknesses in the design of the trial and discuss the clinical implications of the findings.

    • Nisreen S. Husain
    •  & Hashem B. El-Serag
  • News & Views |

    Population-based mammographic screening is widely accepted as an intervention to reduce overall mortality from breast cancer, but at the cost of morbidity due to false positives and substantial overdiagnosis and overtreatment of ultra-low-risk disease, as well as personal and health-economic burdens. Recent data from a modelling study strengthen the rationale for personalized, risk-based screening approaches, now being tested in multiple clinical trials.

    • Laura J. Esserman
    •  & Andrea Z. LaCroix
  • News & Views |

    The approval of blinatumomab based on achievement of undetectable minimal residual disease (MRD) in patients with B cell acute lymphoblastic leukaemia in complete remission is the first of its kind and raises important considerations. This drug might improve outcomes in this setting, although considerable evidence is needed to validate the performance of MRD as a surrogate end point and confirm the hypothesis.

    • Talal Hilal
    •  & Vinay Prasad
  • News & Views |

    A recent clinical trial of a virotherapy approach, consisting of an engineered poliovirus, has provided evidence of apparently durable responses in patients with recurrent glioblastoma. The results of this trial and others indicate that virotherapy might be an effective tool in anticancer immunotherapy. Yet, caution must be exercised until appropriately powered randomized clinical trials truly show efficacy.

    • Pierpaolo Peruzzi
    •  & E. Antonio Chiocca
  • News & Views |

    Comprehensive molecular characterization of infant medulloblastoma has uncovered the high degree of heterogeneity of this disease. Recent results from the SJYC07 study elegantly reveal that risk stratification can be improved if DNA methylation profiling data are incorporated into clinicopathological criteria. Importantly, the delineation of disease subgroups potentially has major clinical implications.

    • Marc Remke
    •  & Vijay Ramaswamy
  • News & Views |

    Platinum-based chemotherapy has long been the mainstay first-line therapy for patients with non-small-cell lung cancer without a targetable driver mutation, but has limited effectiveness. Immunotherapy is drastically changing the treatment landscape for this group and improving survival outcomes, with focus turning to frontline immunotherapy combinations.

    • Cesare Gridelli
    •  & Francesca Casaluce
  • News & Views |

    Accelerated approval enables investigational drugs to reach the US market on the basis of their demonstrated effects in unvalidated surrogate measures, only reasonably likely to predict clinical response. To fulfil the social compromise, regulators should ensure that confirmatory trials testing clinically meaningful end points are already underway at the time of approval.

    • Bishal Gyawali
    •  & Aaron S. Kesselheim
  • News & Views |

    CARMENA, a trial comparing the efficacy of sunitinib alone to that of nephrectomy followed by sunitinib in patients with primary metastatic renal cell carcinoma who require targeted therapy has demonstrated the non-inferiority of systemic therapy alone. The data provided by this and other studies argue for a lesser role of surgery in the management of these patients.

    • Axel Bex
    •  & John Haanen
  • News & Views |

    Developments in the treatment of advanced-stage hepatocellular carcinoma include novel locoregional interventions aiming to induce tumour necrosis and systemic treatments targeting the biological mechanisms of tumour progression, thus aiming to delay progression. These approaches fiercely battle to provide the best survival, but their lack of success to date suggests that they might be better tested as a complementary approach.

    • Marco Sanduzzi-Zamparelli
    •  & Jordi Bruix
  • News & Views |

    PapSEEK, a novel liquid-based cytology test, enabled the highly specific detection of endometrial and ovarian cancer in a retrospective study. Herein, I discuss potential applications of this tool, both for cancer screening of asymptomatic populations and for the early diagnosis of cancer in symptomatic women.

    • Usha Menon
  • News & Views |

    New treatment options for patients with resected stage III melanoma have been established with the publication of the results of four pivotal randomized clinical trials, resulting in three drug approvals, with a forth expected, all within only 4 years. Herein, we put these advances into context.

    • Alexander M. M. Eggermont
    • , Caroline Robert
    •  & Antoni Ribas