Implementing Genome-Driven Oncology.

Early successes in identifying and targeting individual oncogenic drivers, together with the increasing feasibility of sequencing tumor genomes, have brought forth the promise of genome-driven oncology care. As we expand the breadth and depth of genomic analyses, the biological and clinical complexity of its implementation will be unparalleled. Challenges include target credentialing and validation, implementing drug combinations, clinical trial designs, targeting tumor heterogeneity, and deploying technologies beyond DNA sequencing, among others. We review how contemporary approaches are tackling these challenges and will ultimately serve as an engine for biological discovery and increase our insight into cancer and its treatment.

Author Correction: Tumour lineage shapes BRCA-mediated phenotypes.

An Amendment to this paper has been published and can be accessed via a link at the top of the paper.

Mechanisms of Resistance to Noncovalent Bruton's Tyrosine Kinase Inhibitors.

BACKGROUND: Covalent (irreversible) Bruton's tyrosine kinase (BTK) inhibitors have transformed the treatment of multiple B-cell cancers, especially chronic lymphocytic leukemia (CLL). However, resistance can arise through multiple mechanisms, including acquired mutations in BTK at residue C481, the binding site of covalent BTK inhibitors. Noncovalent (reversible) BTK inhibitors overcome this mechanism and other sources of resistance, but the mechanisms of resistance to these therapies are currently not well understood. METHODS: We performed genomic analyses of pretreatment specimens as well as specimens obtained at the time of disease progression from patients with CLL who had been treated with the noncovalent BTK inhibitor pirtobrutinib. Structural modeling, BTK-binding assays, and cell-based assays were conducted to study mutations that confer resistance to noncovalent BTK inhibitors. RESULTS: Among 55 treated patients, we identified 9 patients with relapsed or refractory CLL and acquired mechanisms of genetic resistance to pirtobrutinib. We found mutations (V416L, A428D, M437R, T474I, and L528W) that were clustered in the kinase domain of BTK and that conferred resistance to both noncovalent BTK inhibitors and certain covalent BTK inhibitors. Mutations in BTK or phospholipase C gamma 2 (PLCγ2), a signaling molecule and downstream substrate of BTK, were found in all 9 patients. Transcriptional activation reflecting B-cell-receptor signaling persisted despite continued therapy with noncovalent BTK inhibitors. CONCLUSIONS: Resistance to noncovalent BTK inhibitors arose through on-target BTK mutations and downstream PLCγ2 mutations that allowed escape from BTK inhibition. A proportion of these mutations also conferred resistance across clinically approved covalent BTK inhibitors. These data suggested new mechanisms of genomic escape from established covalent and novel noncovalent BTK inhibitors. (Funded by the American Society of Hematology and others.).

A view on drug resistance in cancer.

The problem of resistance to therapy in cancer is multifaceted. Here we take a reductionist approach to define and separate the key determinants of drug resistance, which include tumour burden and growth kinetics; tumour heterogeneity; physical barriers; the immune system and the microenvironment; undruggable cancer drivers; and the many consequences of applying therapeutic pressures. We propose four general solutions to drug resistance that are based on earlier detection of tumours permitting cancer interception; adaptive monitoring during therapy; the addition of novel drugs and improved pharmacological principles that result in deeper responses; and the identification of cancer cell dependencies by high-throughput synthetic lethality screens, integration of clinico-genomic data and computational modelling. These different approaches could eventually be synthesized for each tumour at any decision point and used to inform the choice of therapy.

Efficacy of MEK inhibition in patients with histiocytic neoplasms.

Histiocytic neoplasms are a heterogeneous group of clonal haematopoietic disorders that are marked by diverse mutations in the mitogen-activated protein kinase (MAPK) pathway1,2. For the 50% of patients with histiocytosis who have BRAFV600 mutations3-5, RAF inhibition is highly efficacious and has markedly altered the natural history of the disease6,7. However, no standard therapy exists for the remaining 50% of patients who lack BRAFV600 mutations. Although ERK dependence has been hypothesized to be a consistent feature across histiocytic neoplasms, this remains clinically unproven and many of the kinase mutations that are found in patients who lack BRAFV600 mutations have not previously been biologically characterized. Here we show ERK dependency in histiocytoses through a proof-of-concept clinical trial of cobimetinib, an oral inhibitor of MEK1 and MEK2, in patients with histiocytoses. Patients were enrolled regardless of their tumour genotype. In parallel, MAPK alterations that were identified in treated patients were characterized for their ability to activate ERK. In the 18 patients that we treated, the overall response rate was 89% (90% confidence interval of 73-100). Responses were durable, with no acquired resistance to date. At one year, 100% of responses were ongoing and 94% of patients remained progression-free. Cobimetinib treatment was efficacious regardless of genotype, and responses were observed in patients with ARAF, BRAF, RAF1, NRAS, KRAS, MEK1 (also known as MAP2K1) and MEK2 (also known as MAP2K2) mutations. Consistent with the observed responses, the characterization of the mutations that we identified in these patients confirmed that the MAPK-pathway mutations were activating. Collectively, these data demonstrate that histiocytic neoplasms are characterized by a notable dependence on MAPK signalling-and that they are consequently responsive to MEK inhibition. These results extend the benefits of molecularly targeted therapy to the entire spectrum of patients with histiocytosis.

Tumour lineage shapes BRCA-mediated phenotypes.

Mutations in BRCA1 and BRCA2 predispose individuals to certain cancers1-3, and disease-specific screening and preventative strategies have reduced cancer mortality in affected patients4,5. These classical tumour-suppressor genes have tumorigenic effects associated with somatic biallelic inactivation, although haploinsufficiency may also promote the formation and progression of tumours6,7. Moreover, BRCA1/2-mutant tumours are often deficient in the repair of double-stranded DNA breaks by homologous recombination8-13, and consequently exhibit increased therapeutic sensitivity to platinum-containing therapy and inhibitors of poly-(ADP-ribose)-polymerase (PARP)14,15. However, the phenotypic and therapeutic relevance of mutations in BRCA1 or BRCA2 remains poorly defined in most cancer types. Here we show that in the 2.7% and 1.8% of patients with advanced-stage cancer and germline pathogenic or somatic loss-of-function alterations in BRCA1/2, respectively, selective pressure for biallelic inactivation, zygosity-dependent phenotype penetrance, and sensitivity to PARP inhibition were observed only in tumour types associated with increased heritable cancer risk in BRCA1/2 carriers (BRCA-associated cancer types). Conversely, among patients with non-BRCA-associated cancer types, most carriers of these BRCA1/2 mutation types had evidence for tumour pathogenesis that was independent of mutant BRCA1/2. Overall, mutant BRCA is an indispensable founding event for some tumours, but in a considerable proportion of other cancers, it appears to be biologically neutral-a difference predominantly conditioned by tumour lineage-with implications for disease pathogenesis, screening, design of clinical trials and therapeutic decision-making.

Author Correction: HER kinase inhibition in patients with HER2- and HER3-mutant cancers.

The 'Competing interests' statement of this Article has been updated; please see the accompanying Amendment. The original Article has not been corrected online.

HER kinase inhibition in patients with HER2- and HER3-mutant cancers.

Somatic mutations of ERBB2 and ERBB3 (which encode HER2 and HER3, respectively) are found in a wide range of cancers. Preclinical modelling suggests that a subset of these mutations lead to constitutive HER2 activation, but most remain biologically uncharacterized. Here we define the biological and therapeutic importance of known oncogenic HER2 and HER3 mutations and variants of unknown biological importance by conducting a multi-histology, genomically selected, 'basket' trial using the pan-HER kinase inhibitor neratinib (SUMMIT; clinicaltrials.gov identifier NCT01953926). Efficacy in HER2-mutant cancers varied as a function of both tumour type and mutant allele to a degree not predicted by preclinical models, with the greatest activity seen in breast, cervical and biliary cancers and with tumours that contain kinase domain missense mutations. This study demonstrates how a molecularly driven clinical trial can be used to refine our biological understanding of both characterized and new genomic alterations with potential broad applicability for advancing the paradigm of genome-driven oncology.

Pancreaticoduodenectomy After Liver Transplantation: A Single-Center Experience.

BACKGROUND: The aim of this study is to report the feasibility and short-term outcomes of pancreaticoduodenectomy (PD) in patients who have undergone orthotopic liver transplantation (OLT). METHODS: We performed a retrospective review of a prospectively maintained pancreatic surgical database for all patients undergoing pancreaticoduodenectomy (PD) after liver transplant from January 1995 until June 2022. Demographics, indications for pancreatic resection, liver transplant and time from liver transplant to PD were reported. Operative mortality and morbidity were recorded within 90 days of surgery. Continuous variables were recorded as mean and range, while categorical variables were summarized using frequency and percentage. Postoperative complications within 90 days from PD were graded based on Clavien-Dindo classification with major complication recorded as grade IIIa or higher. Additionally, a comprehensive literature review was performed. RESULTS: A total of 916 patients who underwent PD at our institution between January 1995 and June 2022 were identified, and 9 patients had previous OLT. Five patients were females and 4 males with a mean age of 65 years (range 51-78). Average body mass index (BMI) was 30.8. Two patients had major complications, and three patients had minor complications. No clinically relevant POPF, PPH or DGE were observed. One patient died within 90 days from PD due to ischemic biliary pancreatic limb causing intrabdominal sepsis. CONCLUSION: Although uncommon, PD after OLT is feasible with acceptable outcomes at high volume institutions and if performed by experienced surgeons.

Criminal Records and Licensure in Five Allied Health Professions: Is There Evidence of a Disparate Impact on Historically Marginalized Groups?

CONTEXT: In health care, licensing is pervasive. Restrictions on applicants with criminal records may have a disparate impact on historically marginalized groups. There is bipartisan interest in evaluating whether occupational licensing requirements are too strict. METHODS: The authors analyze how 12 representative states (California, Colorado, Connecticut, Delaware, Florida, Illinois, Missouri, New York, Ohio, Pennsylvania, South Dakota, and Texas) respond when people with criminal records apply for a license for five entry-level allied health professions (dental hygienist, occupational therapy assistant, physical therapy assistant, radiologic technologist, and respiratory therapist). FINDINGS: With one exception for one allied health profession, all states require their licensing boards to consider past serious criminal convictions. A majority of states require the conviction to be substantially related to the scope of professional duties for it to provide a basis for disqualification. Most states make it difficult for applicants with criminal records to determine whether they may obtain a license. CONCLUSIONS: State licensing boards have considerable discretion in handling applicants with a criminal record. The trend is toward fewer restrictions, but more could be done to increase the transparency of state licensing board guidelines, practices, and procedures-particularly in the states that still rely on a "good moral character" test.