T3N0 Rectal Cancer: Radiation for All, None, or Some?

The optimal management of T3N0 rectal cancer is an area of active debate that has withstood multiple decades of research. In this comprehensive review, we delve into the many nuances that come with treating T3N0 rectal cancer, particularly examining the role and evolution of radiation therapy. We review both the historical paradigms and latest advances in treatment and highlight the significance of precise preoperative staging.

Asparagine Dependency Is a Targetable Metabolic Vulnerability in TP53-Altered Castration-Resistant Prostate Cancer.

TP53 tumor suppressor is frequently altered in lethal, castration-resistant prostate cancer (CRPC). However, to date there are no effective treatments that specifically target TP53 alterations. Using transcriptomic and metabolomic analyses, we have shown here that TP53-altered prostate cancer exhibits an increased dependency on asparagine (Asn) and overexpresses Asn synthetase (ASNS), the enzyme catalyzing the synthesis of Asn.

Anki Tagger: A Generative AI Tool for Aligning Third-Party Resources to Preclinical Curriculum.

Using large language models, we developed a method to efficiently query existing flashcard libraries and select those most relevant to an individual's medical school curricula.

A Genome-Wide CRISPR Activation Screen Identifies PRRX2 as a Regulator of Enzalutamide Resistance in Prostate Cancer.

Unlabelled: Androgen receptor (AR) pathway inhibitors are the mainstay treatment for advanced prostate cancer, but resistance to therapy is common. Here, we used a CRISPR activation screen in metastatic castration-sensitive prostate cancer cells to identify genes that promote resistance to AR inhibitors. Activation of the TGFβ target gene paired-related homeobox2 (PRRX2) promoted enzalutamide resistance.

PARP Inhibition in Advanced Prostate Cancer.

In May 2020, the poly(ADP-ribose) polymerase (PARP) inhibitors rucaparib and olaparib were Food and Drug Administration approved for the management of metastatic castration-resistant prostate cancers. Rucaparib was approved for tumors that harbor alterations in BRCA1 and BRCA2 following progression on chemotherapy and androgen receptor-directed therapy, whereas olaparib was approved for tumors that harbor alterations in a broader range of DNA damage repair genes following progression on androgen receptor-directed therapy. Loss-of-function mutations in genes such as BRCA1 and BRCA2 increase reliance on PARP-mediated mechanisms of DNA repair, and inhibition of this pathway results in the accumulation of lethal levels of DNA damage.

Activated ALK Cooperates with N-Myc via Wnt/β-Catenin Signaling to Induce Neuroendocrine Prostate Cancer.

Neuroendocrine prostate cancer (NEPC) is an aggressive subtype of prostate cancer with poor prognosis, and there is a critical need for novel therapeutic approaches. NEPC is associated with molecular perturbation of several pathways, including amplification of . Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase involved in the pathogenesis of neuroblastoma and other malignancies where it cooperates with N-Myc.

Early-onset metastatic and clinically advanced prostate cancer is a distinct clinical and molecular entity characterized by increased TMPRSS2-ERG fusions.

Background: Men with early-onset prostate cancer are at increased risk for cancer-related mortality, yet the prevalence and spectrum of molecular alterations in this patient population is unknown. Here, we analyze comprehensive genomic profiling data to characterize the molecular drivers of early-onset prostate cancer in patients with clinically advanced and metastatic disease.

Methods: Next-generation sequencing was ordered as a part of routine clinical care for 10,189 patients with prostate cancer between 02/2013 and 03/2020 using commercially available comprehensive genomic profiling.

Genomic Profiling of Prostate Cancers from Men with African and European Ancestry.

Purpose: African American (AFR) men have the highest mortality rate from prostate cancer (PCa) compared with men of other racial/ancestral groups. Differences in the spectrum of somatic genome alterations in tumors between AFR men and other populations have not been well-characterized due to a lack of inclusion of significant numbers in genomic studies.

Experimental Design: To identify genomic alterations associated with race, we compared the frequencies of somatic alterations in PCa obtained from four publicly available datasets comprising 250 AFR and 611 European American (EUR) men and a targeted sequencing dataset from a commercial platform of 436 AFR and 3018 EUR men.

Small-Molecule MYC Inhibitors Suppress Tumor Growth and Enhance Immunotherapy.

Small molecules that directly target MYC and are also well tolerated in vivo will provide invaluable chemical probes and potential anti-cancer therapeutic agents. We developed a series of small-molecule MYC inhibitors that engage MYC inside cells, disrupt MYC/MAX dimers, and impair MYC-driven gene expression. The compounds enhance MYC phosphorylation on threonine-58, consequently increasing proteasome-mediated MYC degradation.

Clinical and Immunological Implications of Frameshift Mutations in Lung Cancer.

Introduction: Presently, programmed death ligand 1 is the most commonly used biomarker to predict response to immune checkpoint inhibitors (ICIs) in NSCLC. Owing to its several limitations, there is continuous search for more precise and reliable markers. Frameshift mutations by insertion or deletion (fsindels) are suggested to induce more immunogenic tumor-specific neoantigens, conferring better response to ICIs.

BRAF internal deletions and resistance to BRAF/MEK inhibitor therapy.

BRAF and MEK inhibitors have improved clinical outcomes in advanced, BRAF -mutated melanomas. Acquired resistance occurs in most patients, with numerous and diverse drivers. We obtained pretreatment and progression biopsies from a patient who progressed on dabrafenib and trametinib.

Correlation Between Molecular Subclassifications of Clear Cell Renal Cell Carcinoma and Targeted Therapy Response.

Background: Vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR)-directed therapies are the standard of care in metastatic clear cell renal cell carcinoma (mccRCC) but are not used based on molecular subclassifications of ccRCC.

Objective: To determine if an association exists between genomic alterations (GAs) detected by comprehensive genomic profiling (CGP) in the course of clinical care and the response to anti-VEGF receptor (VEGFR) and anti-MTOR pathway targeted therapies in a cohort of patients with treated mccRCC.

Design, Setting, And Participants: CGP, using a Clinical Laboratory Improvement Amendments-certified platform, was performed on 31 formalin-fixed, paraffin-embedded tissue specimens (84% from cytoreductive nephrectomies) obtained from patients with metastatic renal cell carcinoma who had received VEGFR and/or mTOR inhibitors.

Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden.

Background: High tumor mutational burden (TMB) is an emerging biomarker of sensitivity to immune checkpoint inhibitors and has been shown to be more significantly associated with response to PD-1 and PD-L1 blockade immunotherapy than PD-1 or PD-L1 expression, as measured by immunohistochemistry (IHC). The distribution of TMB and the subset of patients with high TMB has not been well characterized in the majority of cancer types.

Methods: In this study, we compare TMB measured by a targeted comprehensive genomic profiling (CGP) assay to TMB measured by exome sequencing and simulate the expected variance in TMB when sequencing less than the whole exome.

Clinical Benefit in Response to Palbociclib Treatment in Refractory Uterine Leiomyosarcomas with a Common Alteration.

Background: Uterine leiomyosarcoma (uLMS) responds poorly to conventional chemotherapeutic agents, and personalized therapies have yet to be systematically explored. Comprehensive genomic profiling (CGP) can identify therapeutic targets and provide insight into the biology of this highly aggressive tumor. We report a case of uLMS treated with the CGP-matched therapy palbociclib, a CDK4/6 inhibitor, with sustained clinical benefit in this rare and deadly malignancy.

Targeted Next Generation Sequencing Identifies Markers of Response to PD-1 Blockade.

Therapeutic antibodies blocking programmed death-1 and its ligand (PD-1/PD-L1) induce durable responses in a substantial fraction of melanoma patients. We sought to determine whether the number and/or type of mutations identified using a next-generation sequencing (NGS) panel available in the clinic was correlated with response to anti-PD-1 in melanoma. Using archival melanoma samples from anti-PD-1/PD-L1-treated patients, we performed hybrid capture-based NGS on 236-315 genes and T-cell receptor (TCR) sequencing on initial and validation cohorts from two centers.

Characterization of 298 Patients with Lung Cancer Harboring MET Exon 14 Skipping Alterations.

Background: The hepatocyte growth factor receptor gene (MET) exon 14 skipping (METex14) has recently been described a potential driver alteration in lung cancer targetable by mesenchymal-to-epithelial transition factor (MET) tyrosine kinase inhibitors (TKIs).

Methods: Well-validated hybrid capture-based comprehensive genomic profiling was performed at the request of individual treating physicians.

Results: Of 11,205 lung cancers profiled by comprehensive genomic profiling, 298 (2.

Comprehensive Genomic Profiling Identifies a Subset of Crizotinib-Responsive ALK-Rearranged Non-Small Cell Lung Cancer Not Detected by Fluorescence In Situ Hybridization.

Introduction: For patients with non-small cell lung cancer (NSCLC) to benefit from ALK inhibitors, sensitive and specific detection of ALK genomic rearrangements is needed. ALK break-apart fluorescence in situ hybridization (FISH) is the U.S.

Comprehensive Genomic Profiling Identifies Frequent Drug-Sensitive EGFR Exon 19 Deletions in NSCLC not Identified by Prior Molecular Testing.

Purpose: Reliable detection of drug-sensitive activating EGFR mutations is critical in the care of advanced non-small cell lung cancer (NSCLC), but such testing is commonly performed using a wide variety of platforms, many of which lack rigorous analytic validation.

Experimental Design: A large pool of NSCLC cases was assayed with well-validated, hybrid capture-based comprehensive genomic profiling (CGP) at the request of the individual treating physicians in the course of clinical care for the purpose of making therapy decisions. From these, 400 cases harboring EGFR exon 19 deletions (Δex19) were identified, and available clinical history was reviewed.

Comprehensive Genomic Profiling of Renal Cell Carcinoma at Initial Diagnosis and Putative Local Recurrence.

In the context of metastatic renal cell carcinoma, it would typically be assumed that the site of recurrence is derived from the original tumor. Through the use of comprehensive genomic profiling in a case of localized disease with a subsequent recurrence in the renal fossa, we determined that the latter was a wholly distinct tumor. The original tumor harbors mutations in PBRM1, while the second harbors mutations in KDM5C.

STUMP un"stumped": anti-tumor response to anaplastic lymphoma kinase (ALK) inhibitor based targeted therapy in uterine inflammatory myofibroblastic tumor with myxoid features harboring DCTN1-ALK fusion.

Background: Recurrent, metastatic mesenchymal myxoid tumors of the gynecologic tract present a management challenge as there is minimal evidence to guide systemic therapy. Such tumors also present a diagnostic dilemma, as myxoid features are observed in leiomyosarcomas, inflammatory myofibroblastic tumors (IMT), and mesenchymal myxoid tumors. Comprehensive genomic profiling was performed in the course of clinical care on a case of a recurrent, metastatic myxoid uterine malignancy (initially diagnosed as smooth muscle tumor of uncertain malignant potential (STUMP)), to guide identify targeted therapeutic options.

Activation of MET via diverse exon 14 splicing alterations occurs in multiple tumor types and confers clinical sensitivity to MET inhibitors.

Unlabelled: Focal amplification and activating point mutation of the MET gene are well-characterized oncogenic drivers that confer susceptibility to targeted MET inhibitors. Recurrent somatic splice site alterations at MET exon 14 (METex14) that result in exon skipping and MET activation have been characterized, but their full diversity and prevalence across tumor types are unknown. Here, we report analysis of tumor genomic profiles from 38,028 patients to identify 221 cases with METex14 mutations (0.