A phase Ib/II study of eribulin in combination with cyclophosphamide in patients with advanced breast cancer.

PURPOSE: We hypothesized that eribulin combined with cyclophosphamide (EC) would be an effective combination with tolerable toxicity for the treatment of advanced breast cancer (ABC). METHODS: Patients with histologically confirmed metastatic or unresectable ABC with any number of prior lines of therapy were eligible to enroll. In the dose escalation cohort, dose level 0 was defined as eribulin 1.1 mg/m2 and cyclophosphamide 600 mg/m2, and dose level 1 was defined as eribulin 1.4 mg/m2 and cyclophosphamide 600 mg/m2. Eribulin was given on days 1 and 8 and cyclophosphamide on day 1 of a 21-day cycle. In the dose expansion cohort, enrollment was expanded at dose level 1. The primary objective was clinical benefit rate (CBR), and secondary objectives were response rate (RR), duration of response (DOR), progression-free survival (PFS), and safety. RESULTS: No dose-limiting toxicities were identified in the dose escalation cohort (n = 6). In the dose expansion cohort, an additional 38 patients were enrolled for a total of 44 patients, including 31 patients (70.4%) with hormone receptor-positive (HR +)/HER2- disease, 12 patients (27.3%) with triple-negative breast cancer (TNBC), and 1 patient (2.3%) with HR + /HER2 + disease. Patients had a median age of 56 years (range 33-82 years), 1 prior line of hormone therapy (range 0-6), and 2 prior lines of chemotherapy (range 0-7). CBR was 79.5% (35/44; 7 partial response, 28 stable disease) and the median DOR was 16.4 weeks (range 13.8-21.1 weeks). Median PFS was 16.4 weeks (95% CI: 13.8-21.1 weeks). The most common grade 3/4 adverse event was neutropenia (47.7%, n = 21). Fourteen of 26 patients (53.8%) with circulating tumor cell (CTC) data were CTC-positive ([Formula: see text] 5 CTC/7.5 mL) at baseline. Median PFS was shorter in patients who were CTC-positive vs. negative (13.1 vs 30.6 weeks, p = 0.011). CONCLUSION: In heavily pretreated patients with ABC, treatment with EC resulted in an encouraging CBR of 79.5% and PFS of 16.4 weeks, which compares favorably to single-agent eribulin. Dose reduction and delays were primarily due to neutropenia. The contribution of cyclophosphamide to eribulin remains unclear but warrants further evaluation. NCT01554371.

Advancing immunotherapy in gastroesophageal cancer through rational combinations and biomarkers.

The impact of checkpoint inhibitors on gastroesophageal cancer treatment has been tremendous in the last 2 years. KEYNOTE-590, CHECKMATE 649 and CheckMate 648 are landmark trials that have introduced immunotherapy to the field as first-line therapy, leading to a paradigm change for advanced esophageal and gastric cancer. Chemotherapy in combination with immunotherapy is now the standard of care for first-line treatment of locally advanced or metastatic adenocarcinoma of the esophagus, esophagogastric junction and stomach. Several new targets and treatments are available for gastroesophageal cancer that are based on the characterization of cancer cells and the tumor microenvironment. Biomarker-based therapy selection is critical to optimize outcomes and minimize toxicities, as well as give insight into the optimal timing and sequence of a patient's treatment course.

Doctors have found a better treatment for advanced esophageal and stomach cancer. They combined two types of medicines called immune checkpoint inhibitors and chemotherapy. This made more people respond to the treatment and live longer without the cancer getting worse. They use a test called PD-L1 Combined Positive Score to see if the treatment will work but, when looking at the results, there remain challenges and new treatments and tests are still needed for these cancers.

Reshaping Treatment Paradigms for Advanced Renal Cell Cancer Patients and Improving Patient Management : Optimal Management for Renal Cell Cancer Patients.

OPINION STATEMENT: The treatment of renal cell carcinoma (RCC) is one of the great success stories in the field of oncology, which was revolutionized with the development of therapies aimed at disrupting crucial pathways. Tumor biology of RCC has provided insight into the disease through elucidation of the role of vascular endothelial growth-factor (VEGF) and the mammalian target of rapamycin (mTOR). Targeted agents against VEGF and mTOR, as well as agents targeting relevant immunomodulatory pathways, have shown clinical benefit for advanced disease. The targeted agents are highly effective in achieving a response and survival, particularly in high-risk patients. These include the vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs) axitinib and cabozantinib, and programmed cell death 1 protein (PD-1) immune checkpoint inhibitors (ICI) nivolumab and pembrolizumab. There is a wealth of evidence investigating different therapeutic options and combinations for first-line treatment of advanced RCC including the CheckMate 214 study, KEYNOTE-426, JAVELIN Renal 101, and CheckMate 9ER. Dual ICI and combination agents targeting the programmed cell death protein 1/programmed cell death protein ligand 1 (PD1/PDL1) and VEGF, began to demonstrate superiority over previously accepted standards in advanced clear-cell RCC. Data from a number of clinical studies are available to help physicians with evidence-based decisions for the sequence of second-line and future treatments for patients with progressive RCC. In this review, we focus on essentials for clinicians treating patients with clear-cell RCC.

CDK4/6 inhibitors: mechanisms of resistance and potential biomarkers of responsiveness in breast cancer.

Hormone receptor (HR)-positive, HER2-negative tumors represent the most common form of metastatic breast cancer (MBC), and endocrine therapy has been the mainstay treatment for several decades. Recently, a novel drug class called CDK4/6 inhibitors in combination with endocrine therapy have remarkably improved the outcome of patients with HR-positive, HER2-negative MBC by targeting the cell cycle machinery and overcoming aspects of endocrine resistance. Several potential cell-cycle-specific and nonspecific mechanisms of resistance to CDK4/6 inhibitors have been reported in recent studies. This review discusses potential resistance mechanisms to CDK4/6 inhibitors, the use of biomarkers to guide treatment for HR-positive, HER2-negative MBC and possible approaches to overcome resistance to CDK4/6 inhibitors.

Approximately 70% of breast cancers are hormone receptor (HR)-positive. A CDK4/6 inhibitor combined with endocrine therapy is the first-line standard of care for patients with HR-positive, HER-2 negative advanced breast cancer. Markers to predict the efficacy of CDK4/6 inhibitors in HR-positive, HER2-negative advanced breast cancer are limited. In this review, we summarize the use of CDK4/6 inhibitors in breast cancer, as well as possible approaches to overcome resistance to CDK4/6 inhibitors.

Optimal Treatment for Patients with Oligometastatic Prostate Cancer.

Oligometastatic prostate cancer (PCa) can be defined as cancer with a limited number of metastases, typically fewer than 5 lesions, and involves lesions contained within the axial versus the appendicular skeleton. Patients can present with de novo oligometastatic, oligorecurrent, or oligoprogressive PCa. Oligometastatic PCa patients demonstrate considerable improvements in survival outcomes, with a better prognosis than patients with extensive metastatic disease. However, the management of patients that present with nonsymptomatic oligometastatic PCa remains difficult. In the oligometastatic setting, the benefit of local therapies such as prostatectomy and radiotherapy on survival outcomes is an intriguing topic; however, their impact on oncological outcomes is still unknown.

A diagnostic host response biosignature for COVID-19 from RNA profiling of nasal swabs and blood.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes coronavirus disease-19 (COVID-19), has emerged as the cause of a global pandemic. We used RNA sequencing to analyze 286 nasopharyngeal (NP) swab and 53 whole-blood (WB) samples from 333 patients with COVID-19 and controls. Overall, a muted immune response was observed in COVID-19 relative to other infections (influenza, other seasonal coronaviruses, and bacterial sepsis), with paradoxical down-regulation of several key differentially expressed genes. Hospitalized patients and outpatients exhibited up-regulation of interferon-associated pathways, although heightened and more robust inflammatory responses were observed in hospitalized patients with more clinically severe illness. Two-layer machine learning-based host classifiers consisting of complete (>1000 genes), medium (<100), and small (<20) gene biomarker panels identified COVID-19 disease with 85.1-86.5% accuracy when benchmarked using an independent test set. SARS-CoV-2 infection has a distinct biosignature that differs between NP swabs and WB and can be leveraged for COVID-19 diagnosis.

The DNA damaging revolution.

Poly(ADP-ribose) polymerase (PARP) is a nuclear enzyme that plays a critical role in the repair of single-strand DNA damage via the base excision repair pathway. PARP inhibitors have substantial single-agent antitumor activity by inducing synthetic lethality. They have also emerged as promising anticancer targeted therapies, especially in tumors harboring deleterious germline or somatic breast cancer susceptibility gene (BRCA) mutations. PARP inhibition produces single-strand DNA breaks, which may be repaired by homologous recombination, a process partially dependent on BRCA1 and BRCA2. The PARP inhibitors olaparib, veliparib, talazoparib, niraparib, and rucaparib have predominantly been studied in patients with breast or ovarian cancers associated with deleterious germline mutations in BRCA1 and BRCA2. Ongoing clinical trials are evaluating the role of PARP inhibitors alone and in combination with other therapies, including selective inhibitors against key targets involved in the DNA damage response. In this review we summarize the use of PARP inhibitors in various tumor types, as well as possible approaches for overcoming resistance to PARP inhibitors.

Strategic Combinations to Prevent and Overcome Resistance to Targeted Therapies in Oncology.

Recent advances in the understanding of underlying molecular signaling mechanisms of cancer susceptibility and progression have led to an increase in the use of targeted therapies for cancer treatment. Despite improvements in survival with new treatment options in oncology, resistance to therapy is a major obstacle to the long-term effectiveness of targeted agents in metastatic cancer treatment, culminating in insensitivity to treatment and tumor outgrowth. Adaptive resistance can play an important role in primary and upfront resistance to therapy as well as in secondary or acquired resistance. By focusing on colorectal and breast tumors, we discuss how therapeutic combinations based on specific drivers of tumor biology can be used to overcome resistance. We present how monitoring tumor dynamics over time may allow early adaptation of treatment. Breast cancer is the most common malignancy in women worldwide, and the majority of these cancers are sensitive to endocrine therapy (ET) blocking the production of or response to estrogen. However, primary and acquired resistance limits efficacy. Recent combinations of agents targeted to pathways that drive tumor growth resistance with ET have resulted in remarkable improvements in disease response and control, improving survival in some settings. In this review, we summarize adaptive resistance mechanisms, approaches to combination strategies, and dynamic tumor monitoring to improve efficacy and overcome resistance. We provide examples of combination therapy to enhance the efficacy of targeted therapies in breast and colorectal tumors.