Fidelity of Next-Generation Sequencing to Predict Human Epidermal Growth Factor 2 Overexpression Across Solid Tumors.

Purpose: Human epidermal growth factor 2 (HER2/ERBB2) has recently become a pan-tumor-agnostic target after the approval of trastuzumab deruxtecan for solid tumors with HER2 overexpression (3+). HER2 positivity is currently assessed by immunohistochemistry (IHC) and/or amplification through in situ hybridization (ISH), owing to the fact that HER2 overexpression is secondary to HER2 gene amplification in many cases. Outside of breast/gastroesophageal cancer, the optimal IHC scoring method to assess overexpression across solid tumors remains undefined.

Association of heightened host and tumor immunity with prolonged duration of response to checkpoint inhibition across solid tumors.

Cancer immunotherapy is a beneficial therapy for many cancer types, but predictive pan-tumor biomarkers for clinical benefit are suboptimal. Our study, employing DNA and RNA based analysis, investigated the role of predicted neoantigens in the benefits of immunotherapy within a cohort of 88 patients of European descent with advanced solid tumors. Patients who had a prolonged (> 12 months) duration of immunotherapy exhibited heightened immune responses, characterized by increased levels of predicted neoantigens with strong HLA binding potential, elevated cytotoxic marker levels, and enhanced T cell activity.

Optimization of a human induced pluripotent stem cell-derived sensory neuron model for the in vitro evaluation of taxane-induced neurotoxicity.

Human induced pluripotent stem cell-derived sensory neuron (iPSC-dSN) models are a valuable resource for the study of neurotoxicity but are affected by poor replicability and reproducibility, often due to a lack of optimization. Here, we identify experimental factors related to culture conditions that substantially impact cellular drug response in vitro and determine optimal conditions for improved replicability and reproducibility. Treatment duration and cell seeding density were both found to be significant factors, while cell line differences also contributed to variation.

Germline predictors for bevacizumab induced hypertensive crisis in ECOG-ACRIN 5103 and BEATRICE.

Background: Bevacizumab is a beneficial therapy in several advanced cancer types. Predictive biomarkers to better understand which patients are destined to benefit or experience toxicity are needed. Associations between bevacizumab induced hypertension and survival have been reported but with conflicting conclusions.

Cytochrome P450 Oxidoreductase (POR) Associated with Severe Paclitaxel-Induced Peripheral Neuropathy in Patients of European Ancestry from ECOG-ACRIN E5103.

Purpose: Paclitaxel is a widely used anticancer therapeutic. Peripheral neuropathy is the dose-limiting toxicity and negatively impacts quality of life. Rare germline gene markers were evaluated for predicting severe taxane-induced peripheral neuropathy (TIPN) in the patients of European ancestry.

A non-coding GWAS variant impacts anthracycline-induced cardiotoxic phenotypes in human iPSC-derived cardiomyocytes.

Anthracyclines, widely used to treat breast cancer, have the potential for cardiotoxicity. We have previously identified and validated a germline single nucleotide polymorphism, rs28714259, associated with an increased risk of anthracycline-induced heart failure. We now provide insights into the mechanism by which rs28714259 might confer increased risk of cardiac damage.

Passage number affects differentiation of sensory neurons from human induced pluripotent stem cells.

Induced pluripotent stem cells (iPSCs) are a valuable resource for neurological disease-modeling and drug discovery due to their ability to differentiate into neurons reflecting the genetics of the patient from which they are derived. iPSC-derived cultures, however, are highly variable due to heterogeneity in culture conditions. We investigated the effect of passage number on iPSC differentiation to optimize the generation of sensory neurons (iPSC-dSNs).

The impact of SBF2 on taxane-induced peripheral neuropathy.

Taxane-induced peripheral neuropathy (TIPN) is a devastating survivorship issue for many cancer patients. In addition to its impact on quality of life, this toxicity may lead to dose reductions or treatment discontinuation, adversely impacting survival outcomes and leading to health disparities in African Americans (AA). Our lab has previously identified deleterious mutations in SET-Binding Factor 2 (SBF2) that significantly associated with severe TIPN in AA patients.

BRE12-158: A Postneoadjuvant, Randomized Phase II Trial of Personalized Therapy Versus Treatment of Physician's Choice for Patients With Residual Triple-Negative Breast Cancer.

Purpose: Patients with triple-negative breast cancer (TNBC) with residual disease after neoadjuvant chemotherapy (NAC) have high risk of recurrence with prior data suggesting improved outcomes with capecitabine. Targeted agents have demonstrated activity across multiple cancer types. BRE12-158 was a phase II, multicenter trial that randomly allocated patients with TNBC with residual disease after NAC to genomically directed therapy versus treatment of physician choice (TPC).

Association of Circulating Tumor DNA and Circulating Tumor Cells After Neoadjuvant Chemotherapy With Disease Recurrence in Patients With Triple-Negative Breast Cancer: Preplanned Secondary Analysis of the BRE12-158 Randomized Clinical Trial.

Importance: A significant proportion of patients with early-stage triple-negative breast cancer (TNBC) are treated with neoadjuvant chemotherapy. Sequencing of circulating tumor DNA (ctDNA) after surgery, along with enumeration of circulating tumor cells (CTCs), may be used to detect minimal residual disease and assess which patients may experience disease recurrence.

Objective: To determine whether the presence of ctDNA and CTCs after neoadjuvant chemotherapy in patients with early-stage TNBC is independently associated with recurrence and clinical outcomes.