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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.