Christina S. Baik

Emerging molecular biomarkers—blood-based strategies to detect and monitor cancer

There is an urgent need for blood-based, noninvasive molecular tests to assist in the detection and diagnosis of cancers in a cost-effective manner at an early stage, when curative interventions are still possible. Additionally, blood-based diagnostics can classify tumors into distinct molecular subtypes and monitor disease relapse and response to treatment. Increasingly, biomarker strategies are becoming critical to identify a specific patient subpopulation that is likely to respond to a new therapeutic agent. The improved understanding of the underlying molecular features of common cancers and the availability of a multitude of recently developed technologies to interrogate the genome, transcriptome, proteome and metabolome of tumors and biological fluids have made it possible to develop clinically applicable and cost-effective tests for many common cancers. Overall, the paradigm shift towards personalized and individualized medicine relies heavily on the increased use of diagnostic biomarkers and classifiers to improve diagnosis, management and treatment. International collaborations, involving both the private and public sector will be required to facilitate the development of clinical applications of biomarkers, using rigorous standardized assays. Here, we review the recent technological and scientific advances in this field.

Aerodigestive fistula formation as a rare side effect of antiangiogenic tyrosine kinase inhibitor therapy for thyroid cancer

BACKGROUND In the past decade, targeted therapy with antiangiogenic drugs has become standard of care for most types of metastatic, progressive thyroid cancer. While these drugs were thought initially to be less toxic than traditional chemotherapy, they can have rare but serious and fatal toxicities. Once such toxicity that has been reported in other tumor types is upper airway fistula formation, which can be life-threatening. SUMMARY Here, we describe three patients treated with antiangiogenic tyrosine kinase inhibitors at two academic institutions who developed aerodigestive fistula. All three patients had risk factors for fistula formation, which included external beam radiation and/or large tumor with invasion of the tracheal wall. CONCLUSIONS Fistula formation is a known but rare side effect of antiangiogenic tyrosine kinase inhibitors. Knowledge of the risk factors that may predispose thyroid cancer patients to this serious adverse event is vital prior to prescribing antiangiogenics. Particular caution should be observed when using these drugs in patients undergoing radiation therapy or surgery, or in patients whose tumor is invading vital structures of the neck, as they may be at higher risk of developing this rare complication. In these patients, antiangiogenic tyrosine kinase inhibitors should be used cautiously, patients should be aware of the risk, and physicians should monitor patients for symptoms of fistula.

Systemic therapy of brain metastases: non-small cell lung cancer, breast cancer, and melanoma.

Brain metastases (BM) occur frequently in many cancers, particularly non-small cell lung cancer (NSCLC), breast cancer, and melanoma. The development of BM is associated with poor prognosis and has an adverse impact on survival and quality of life. Commonly used therapies for BM such as surgery or radiotherapy are associated with only modest benefits. However, recent advances in systemic therapy of many cancers have generated considerable interest in exploration of those therapies for treatment of intracranial metastases.This review discusses the epidemiology of BM from the aforementioned primary tumors and the challenges of using systemic therapies for metastatic disease located within the central nervous system. Cumulative data from several retrospective and small prospective studies suggest that molecularly targeted systemic therapies may be an effective option for the treatment of BM from NSCLC, breast cancer, and melanoma, either as monotherapy or in conjunction with other therapies. Larger prospective studies are warranted to further characterize the efficacy and safety profiles of these targeted agents for the treatment of BM.

Targeted Therapy for Brain Metastases in EGFR-Mutated and ALK-Rearranged Non-Small-Cell Lung Cancer

Approximately half of all patients with non–small-cell lung cancer (NSCLC) develop brain metastases (BM) during the course of their disease, leading to significant challenges in treatment. Molecular targeted tyrosine kinase inhibitors have proven effective for patients with activating mutations in the epidermal growth factor receptor gene and chromosomal rearrangements involving the anaplastic lymphoma kinase gene. Despite their efficacy in systemic disease control, their effectiveness in patients with BM is not well established. In this article, we review recent data on the use of epidermal growth factor receptor and anaplastic lymphoma kinase tyrosine kinase inhibitors for treatment of patients with NSCLC and BM. These data highlight the potential for meaningful disease control within the central nervous system and the inherent challenges in treating patients with NSCLC and BM.

Estrogen Signaling in Lung Cancer: An Opportunity for Novel Therapy

Lung cancer is the leading cause of cancer death in U.S. and represents a major public health burden. Epidemiologic data have suggested that lung cancer in women may possess different biological characteristics compared to men, as evidenced by a higher proportion of never-smokers among women with lung cancer. Emerging data indicate that female hormones such as estrogen and progesterone play a significant role in lung carcinogenesis. It has been reported that estrogen and progesterone receptors are expressed in lung cancer cell lines as well as in patient-derived tumors. Hormone related risk factors such as hormone replacement therapy have been implicated in lung carcinogenesis and several preclinical studies show activity of anti-estrogen therapy in lung cancer. In this review, we summarize the emerging evidence for the role of reproductive hormones in lung cancer and implications for lung cancer therapy.

Combination of stereotactic ablative body radiation with targeted therapies

Recent advances allow safe and effective delivery of ablative doses of radiation with stereotactic precision to tumours, resulting in very high levels of tumour control. Parallel advances in the understanding of tumour biology enable delivery of systemic drugs that selectively antagonise biological pathways in the tumour and surrounding microenvironment. Data is emerging that these treatments have synergistic effects that might further increase therapeutic efficacy, and they are therefore being increasingly used in combination, primarily in metastatic or recurrent disease. In this Review we summarise the biological rationale and clinical data for both sterotactic ablative radiotherapy (SABR) and targeted therapies, and the emerging experience with combination of these treatments. We describe potential pathways of cooperation in both tumour and normal tissue between SABR and targeted drugs, and, because fatal toxicities have been reported, we outline clinical precautions.

Phase 1b Trial of the Toll-Like Receptor 8 Agonist, Motolimod (VTX-2337), Combined with Cetuximab in Patients with Recurrent or Metastatic SCCHN

Purpose: As Toll-like receptors (TLR) are key mediators of immune responses, TLR agonists may be important for augmenting the efficacy of therapies for squamous cell carcinoma of the head and neck (SCCHN). Motolimod (VTX-2337), a selective small-molecule agonist of TLR8, stimulates natural killer (NK) cells, dendritic cells, and monocytes. A phase Ib clinical trial assessed the safety and antitumor activity of motolimod in combination with cetuximab in patients with SCCHN. Correlative biomarkers of immune activity were explored. Experimental Design: Thirteen patients with recurrent or metastatic SCCHN were enrolled in this open-label, dose–escalation study using a standard 3 + 3 design. Doses of motolimod (2.5, 3.0, or 3.5 mg/m2) were given on days 1, 8, and 15, in combination with fixed weekly doses of cetuximab in 28-day cycles. Results: There were no protocol-defined dose-limiting toxicities, drug-related deaths, or evidence of synergistic toxicities between motolimod and cetuximab. Clinical tolerability at the 3.5 mg/m2 dose level was not optimal for repeated dosing and 3.0 mg/m2 was identified as the MTD. Two patients achieved partial responses for an overall response rate of 15%. Five patients had disease stabilization equating to a disease control rate of 54%. Statistically significant increases in plasma cytokines and in the frequency and activation of circulating NK cells were observed. Conclusions: Motolimod can be safely administered in combination with cetuximab with an acceptable toxicity profile. Encouraging antitumor activity and robust pharmacodynamic responses were observed. Motolimod is being further investigated in a phase II trial in patients with SCCHN (ClinicalTrials.gov ID: NCT01836029). Clin Cancer Res; 23(10); 2442–50. ©2016 AACR.

Non-steroidal anti-inflammatory drugs and small cell lung cancer risk in the VITAL study.

Few studies have examined the association between non-steroidal anti-inflammatory drug (NSAID) use and risk of small cell lung cancer (SCLC); among them, findings are mixed. Recently, we found that use of NSAIDs was differentially associated with lung cancer risk by histology. Here, we examine, more comprehensively, the association between individual NSAIDs and SCLC risk. 75,546 residents of western Washington State, ages 50-76, completed a baseline questionnaire in 2000-2002 and reported on their use of individual NSAIDs over the past 10 years. NSAID use was categorized as non-users, low (<4 days/week or <4 years), and high (≥4 days/week and ≥4 years). 111 SCLC were identified through linkage to a population-based cancer registry. Multivariable-adjusted Cox proportional hazards models including strong adjustment for smoking were used to estimate hazard ratios (HR) and 95% confidence intervals (95% CI). Compared to non-use, high use of regular-strength aspirin was associated with an elevated risk of SCLC (HR 1.78, 95% CI: 1.05-3.02; P-trend=0.03). Findings for low-dose aspirin were elevated but did not reach statistical significance. Use of non-aspirin NSAIDs was not associated with SCLC risk. Our findings provide further indication of heterogeneity in the association between aspirin and lung cancer morphologies. Large, prospective studies with comprehensive assessments of NSAID use and smoking history and data on both men and women, are needed in order to better understand the association between use of aspirin and SCLC.

Prediagnostic Nonsteroidal Anti-Inflammatory Drug Use and Lung Cancer Survival in the VITAL Study

Introduction: Inflammation is important for lung oncogenesis. Use of nonsteroidal anti-inflammatory drugs (NSAIDs) has been shown to improve colorectal cancer survival. However, few studies have examined the association in lung cancer patients. Methods: The VITamins And Lifestyle (VITAL) cohort includes Washington State residents, aged 50 to 76 years, who completed a baseline questionnaire between 2000 and 2002. Participants responded on the frequency and duration of use of individual NSAIDs in the previous 10 years. Subjects of this study were 785 members of the cohort, who were identified with incident lung cancer from baseline through 2007 through linkage to a population-based cancer registry. Participants were followed for lung cancer death through linkage to state records of death through 2009. Adjusted proportional hazards models estimated hazard ratios (HR) and 95% confidence intervals (CI) for the association between NSAIDs and lung cancer death. Results: Five hundred and twenty-two participants (66%) died from lung cancer. Relative to nonuse, high (≥ 4 days/week and ≥ 4 years) prediagnostic use of regular-strength or low-dose aspirin (HR 0.99, 95% CI: 0.74–1.33 and HR 0.89, 95% CI: 0.67–1.17, respectively) or total nonaspirin NSAIDs (HR 1.20, 95% CI: 0.79–1.83) did not reduce lung cancer death. However, high use of ibuprofen was associated with a 62% increased risk of lung cancer death (HR 1.62, 95% CI: 1.01–2.58). Conclusions: Long-term, prediagnostic NSAID use does not improve lung cancer survival overall. Use of ibuprofen may reduce survival from lung cancer. Our results underscore the need for further study of the mechanisms of action for individual NSAIDs with regard to cancer survival.

Targeting BRAF‐Mutant Non‐Small Cell Lung Cancer: From Molecular Profiling to Rationally Designed Therapy

This review provides a comprehensive overview of the clinical characteristics and prognostic implications for patients with BRAF‐mutant non‐small cell lung cancer and discusses therapeutic strategies that leverage experience from BRAF‐mutant metastatic melanoma. Practical considerations for oncologists are discussed, including considerations for molecular profiling and management of potential toxicities associated with targeted agents.