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While anti-PD-1 therapy can be effective in patients with breast cancer, response varies and is often limited by the development of resistance. Here, the authors investigate molecular determinant of response and resistance using multiomic single nucleus sequencing of longitudinal biopsies taken from breast cancer patients on a phase II clinical trial investigating neoadjuvant chemotherapy and pembrolizumab (anti-PD-1).

Eliezer Van Allen is an assistant professor at Harvard Medical School, medical oncologist at Dana-Farber Cancer Institute and associate member of the Broad Institute of MIT and Harvard.

Despite often being poorly immunogenic, some subsets of patients with hormone receptor-positive, HER2-negative (HR + /HER2-) breast cancer benefit from immunotherapy. Here, the authors present a randomised pilot clinical trial comparing a neoadjuvant run-in of either nab-paclitaxel or pembrolizumab (anti-PD-1) monotherapy, followed by the combination, in patients with stage II-III HR + /HER2- breast cancer.

Genomic analyses show that primary germ-cell tumours are highly enriched for chromosomal reciprocal loss of heterozygosity, mutations in KRAS and have high mitochondrial priming, providing insight into chemosensitivity and the evolution of chemoresistance in this disease.

Immune-checkpoint inhibition therapy has achieved success in a subset of patients. Here the authors profiled about 200 relevant metabolites in patient serum samples from three independent immunotherapy trials and found the serum kynurenine/tryptophan ratio increases to be associated with worse overall survival.

Meta-analysis of genome-wide association studies on Alzheimer’s disease and related dementias identifies new loci and enables generation of a new genetic risk score associated with the risk of future Alzheimer’s disease and dementia.

Sequencing analysis of tamoxifen-associated uterine cancers and further in vivo analyses suggest that the drug tamoxifen can activate the PI3K pathway in the absence of oncogenic mutations.

In this Perspective, Reardon et al. explore how integrating machine learning into next-generation sequencing (NGS)-based molecular diagnostic workflows can enhance precision oncology. They discuss the benefits, challenges and responsible implementation of these approaches, highlighting their potential to streamline variant interpretation, maximize clinical insights and support more informed decision-making at the point-of-care.

A randomized phase 2 clinical trial has recently shown no benefit of the combination eribulin and pembrolizumab over pembrolizumab alone in HR + metastatic breast cancer patients (NCT03051659). Here, the authors are reporting the final OS data and biomarker analyses on a subset of samples to analyze molecular correlates

Whole-genome sequence analysis identifies five independent risk loci for Lewy body dementia and demonstrates overlapping genetic architecture with Alzheimer’s and Parkinson’s diseases.

Large genome-wide meta-analysis of clinically diagnosed late-onset Alzheimer’s disease (LOAD) from 94,437 individuals identifies new LOAD risk loci and implicates Aβ formation, tau protein binding, immune response and lipid metabolism.

Whole-exome sequencing (WES) has emerged as a transformative technology for biological discovery, but technical difficulties have so far prevented its widespread clinical use. Here, Eliezer Van Allen and colleagues are able to perform production-scale WES on small amounts of clinically acquired formalin-fixed, paraffin-embedded tumor tissues. Using a newly created WES clinical interpretation algorithm, they apply the complete clinical WES framework prospectively to patients and demonstrate how it can be used to directly affect patient care.

Sarcomatoid and rhabdoid tumours are highly aggressive forms of renal cell carcinoma that are also responsive to immunotherapy. In this study, the authors perform a comprehensive molecular characterization of these tumours discovering an enrichment of specific alterations and an inflamed phenotype.

Neoepitopes derived from intron retention events are processed and presented on MHC I in cancer cell lines.

Existing methods for identifying differential gene expression signatures for clinical case/control analyses with high throughput sequencing data present various challenges. Here, the authors develop BEANIE, a nonparametric statistical method that outperforms existing approaches for simulated and real-world cancer datasets, revealing biologically and clinically relevant insights.

Alterations in the tumour suppressor genes STK11 and/or KEAP1 can identify patients with advanced non-small-cell lung cancer who are likely to benefit from combinations of PD-(L)1 and CTLA4 immune checkpoint inhibitors added to chemotherapy.

By simulating realistic doctor–patient conversations, a framework can be applied to large language models to investigate shortcomings and bias in patient interactions, providing insight before actual clinical deployment.

MutPanning is a new method to detect cancer driver genes that identifies genes with an excess of mutations in unusual nucleotide contexts. Applying this to whole-exome sequencing data from 11,873 tumor–normal pairs identifies 460 driver genes.

To accelerate cancer research that correlates biomarkers with clinical endpoints, methods are needed to ascertain outcomes from electronic health records at scale. Here, the authors train natural language processing to extract outcomes for participants in a precision oncology study.

Single-cell profiling of human prostate cancer and studies in mouse models show that macrophages expressing SPP1 mediate immunotherapeutic resistance through adenosine pathway activation and represent a potential target for future studies.

Analysis of sequencing data from 249 cancer patients with clinically annotated outcomes to immune checkpoint therapy identifies correlates of treatment response. The results highlight complexity in identifying events that generate an immunoresponsive tumor environment.

Analyses of in vivo models, cell lines and patient-derived samples show that apolipoprotein B mRNA-editing catalytic subunit 3B (APOBEC3B) not only restrains lung tumor initiation but also that its upregulation is associated with resistance to targeted therapies. This study highlights the complex and context-dependent role of APOBEC3B in lung cancer.

Shukla and colleagues study the genomic and transcriptomic data of exceptional responders to immunotherapy in renal cell carcinoma and find that such responses could be related to tertiary lymphoid structures, clonal neoantigen load and altered metabolism.

Van Allen and colleagues develop a data-integration framework with an underlying knowledge base supporting clinical decision making and also serving as a hypothesis-generating platform, which the authors benchmark and validate across several retrospective cohorts and a prospective precision oncology trial.

The impact of cisplatin-based chemotherapy on tumor genomes is complex. Here, the authors study matched pre- and post-chemotherapy primary samples in muscle-invasive bladder cancer, finding a cisplatin-based mutational signature, and highlighting the impact of intratumor heterogeneity on survival.

Levi Garraway and colleagues report the identification of somatic mutations of RNF43, which encodes an E3 ubiquitin ligase that negatively regulates Wnt signaling, in over 18% of colorectal adenocarcinomas and endometrial carcinomas.

An interim report from the GAIN/iCat2 study shows that molecular profiling of pediatric solid malignancies clarifies diagnostic classifications and provides opportunities for matched targeted therapy.

Using genetically engineered models, Genovese and colleagues study patterns of convergent evolution in renal cancer, and pinpoint dysregulation of interferon signaling as a means of adaptation to chromosomal instability in metastatic progression.

A biologically informed, interpretable deep learning model has been developed to evaluate molecular drivers of resistance to cancer treatment, predict clinical outcomes and guide hypotheses on disease progression.

A genome-wide association study in large cohorts of patients with different types of cancer treated with immune checkpoint inhibitors identifies genetic variants associated with immune-related adverse events.

Neuroendocrine carcinomas (NECs) arise from different anatomic sites, but have similar histological and clinical features. Here, the authors show that the epigenetic landscape of a range of NECs converges towards a common epigenetic state, while distinct subtypes occur within neuroendocrine prostate cancer contributing to intratumor heterogeneity in clinical samples.

Multiple myeloma (MM) is treated with induction chemotherapy, autologous stem cell transplant (ASCT) and long-term immunomodulatory drug (IMiD) maintenance. Here, the authors show that the presence of clonal haematopoiesis of indeterminate potential (CHIP) at time of ASCT is associated with adverse outcomes in MM patients.

Analysis of fully clinically annotated and sequenced melanoma tumor samples collected before anti-PD1 treatment suggests that determinants of response differ on the basis of previous anti-CTLA4 therapy, and that tumor mutational burden may not be a strong predictor of response across melanoma subtypes.

Sven van der Lee, Julie Williams, Gerard Schellenberg and colleagues identify rare coding variants in PLCG2, ABI3 and TREM2 associated with Alzheimer's disease. These genes are highly expressed in microglia and provide additional evidence that the microglia-mediated immune response contributes to the development of Alzheimer's disease.

Single-cell transcriptomic analysis of metastatic castration-resistant prostate cancer uncovers pervasive coexpression of androgen receptor isoforms and cancer cell–intrinsic and microenvironmental programs of treatment resistance

Ghobrial, Getz and colleagues characterize the changes in the tumor immune microenvironment associated with multiple myeloma progression.

A pooled genetic, transcriptomic and immunopathologic analysis of over 500 tumors from patients with advanced renal cell cancer suggests that response to PD-1 blockade depends on both CD8⁺ T cell infiltration and enrichment of tumor-intrinsic somatic alterations.

In vivo CRISPR screening reveals that loss of Ptpn2 increases the response of tumour cells to immunotherapy and increases IFNγ signalling, suggesting that PTPN2 inhibition may potentiate the effect of immunotherapies that invoke an IFNγ response.

Harmonized analysis of 1,048 melanomas shows different global genomic properties among subtypes and identifies subtype-specific enrichment for secondary driver genes.

Identifying the mutational landscape of tumours from cell-free DNA in the blood could help diagnostics in cancer. Here, the authors present ichorCNA, software that quantifies tumour content in cell free DNA, and they demonstrate that cell-free DNA whole-exome sequencing is concordant with metastatic tumour whole-exome sequencing.

Meta-analysis of exome sequencing data identifies new recurrently mutated driver genes for prostate cancer. Comparison of primary and metastatic tumors further identifies genomic markers for advanced prostate cancer that may inform risk stratification.

Complementary genomic features associated with pathway activation, gene dependency and drug sensitivity are uncovered using REVEALER.

Gad Getz and colleagues analyze mutational patterns in urothelial cancer and find a strong association between mutations in the nucleotide excision repair gene ERCC2 and a distinct mutational signature. They also find that the activity of this signature is associated with smoking, independently of ERCC2 mutational status.

For several cancer types analyzed by The Cancer Genome Atlas project, predictions of patient survival were not substantially improved by using common data mining approaches to combine traditional clinical variables with molecular profiling data.

Studies have identified multiple molecular properties with a biological rationale supporting a role in mediating selective responses to immune-checkpoint inhibitors (ICIs), including loss-of-function mutations in mSWI/SNF chromatin regulators; however, their clinical biomarker relevance is uncertain. Herein, we evaluate emerging concepts, challenges and considerations around translating biology into biomarkers for ICIs in solid tumours setting.