Positron emission tomography of tumour [18F]fluoroestradiol uptake in patients with acquired hormone-resistant metastatic breast cancer prior to oestradiol therapy

Purpose Whereas anti-oestrogen therapy is widely applied to treat oestrogen receptor (ER) positive breast cancer, paradoxically, oestrogens can also induce tumour regression. Upregulation of ER expression is a marker for oestrogen hypersensitivity. We, therefore, performed an exploratory study to evaluate positron emission tomography (PET) with the tracer 16 alpha-[F-18] fluoro-17 beta-oestradiol (F-18-FES) as potential marker to select breast cancer patients for oestradiol therapy. Methods Eligible patients had acquired endocrine-resistant metastatic breast cancer that progressed after >= 2 lines of endocrine therapy. All patients had prior ER-positive histology. Treatment consisted of oestradiol 2 mg, three times daily, orally. Patients underwent F-18-FES-PET/CT imaging at baseline. Tumour F-18-FES-uptake was quantified for a maximum of 20 lesions and expressed as maximum standardised uptake value (SUVmax). CT-scan was repeated every 3 months to evaluate treatment response. Clinical benefit was defined as time to radiologic or clinical progression >= 24 weeks. Results F-18-FES uptake, quantified for 255 lesions in 19 patients, varied greatly between lesions (median 2.8; range 0.6-24.3) and between patients (median 2.5; range 1.1-15.5). Seven (37 %) patients experienced clinical benefit of oestrogen therapy, eight progressed (PD), and four were non-evaluable due to side effects. The positive and negative predictive value PPV/NPV) of F-18-FES-PET for response to treatment were 60 % (95 % CI: 31-83 %) and 80 % (95 % CI: 38-96 %), respectively, using SUVmax >1.5. Conclusion F-18-FES-PET may aid identification of patients with acquired antihormone resistant breast cancer that are unlikely to benefit from oestradiol therapy

Clinical utility of circulating tumor DNA as a response and follow-up marker in cancer therapy

Response evaluation for cancer treatment consists primarily of clinical and radiological assessments. In addition, a limited number of serum biomarkers that assess treatment response are available for a small subset of malignancies. Through recent technological innovations, new methods for measuring tumor burden and treatment response are becoming available. By utilization of highly sensitive techniques, tumor-specific mutations in circulating DNA can be detected and circulating tumor DNA (ctDNA) can be quantified. These so-called liquid biopsies provide both molecular information about the genomic composition of the tumor and opportunities to evaluate tumor response during therapy. Quantification of tumor-specific mutations in plasma correlates well with tumor burden. Moreover, with liquid biopsies, it is also possible to detect mutations causing secondary resistance during treatment. This review focuses on the clinical utility of ctDNA as a response and follow-up marker in patients with non-small cell lung cancer, melanoma, colorectal cancer, and breast cancer. Relevant studies were retrieved from a literature search using PubMed database. An overview of the available literature is provided and the relevance of ctDNA as a response marker in anti-cancer therapy for clinical practice is discussed. We conclude that the use of plasma-derived ctDNA is a promising tool for treatment decision-making based on predictive testing, detection of resistance mechanisms, and monitoring tumor response. Necessary steps for translation to daily practice and future perspectives are discussed

Actionability of on-target ALK Resistance Mutations in Patients With Non-Small Cell Lung Cancer:Local Experience and Review of the Literature

Introduction Non-small cell lung cancer (NSCLC) patients with Anaplastic Lymphoma Kinase (ALK) gene fusions respond well to ALK inhibitors but commonly develop on-target resistance mutations. The objective of this study is to collect clinical evidence for subsequent treatment with ALK inhibitors. Patients and methods Local experience with on-target ALK resistance mutations and review of the literature identified 387 patients with ALK inhibitor resistance mutations. Clinical benefit of mutation-inhibitor combinations was assessed based on reported response, progression-free survival and duration of treatment. Furthermore, this clinical evidence was compared to previously reported in vitro sensitivity of mutations to the inhibitors. Results Of the pooled population of 387 patients in this analysis, 239 (62%) received at least one additional line of ALK inhibition after developing on-target resistance to ALK inhibitor therapy. Clinical benefit was reported for 177 (68%) patients, but differed for each mutation-inhibitor combination. Agreement between in vitro predicted sensitivity of six published models and observed clinical benefit ranged from 64 to 87%. The observed clinical evidence for highest probability of response in the context of specific on-target ALK inhibitor resistance mutations is presented. Conclusion Molecular diagnostics performed on tissue samples that are refractive to ALK inhibitor therapy can reveal new options for targeted therapy for NSCLC patients. Our comprehensive overview of clinical evidence of drug actionability of ALK on-target resistance mechanisms may serve as a practical guide to select the most optimal drug for individual patients

Positron emission tomography of tumour [F-18] fluoroestradiol uptake in patients with acquired hormone-resistant metastatic breast cancer prior to oestradiol therapy

Purpose Whereas anti-oestrogen therapy is widely applied to treat oestrogen receptor (ER) positive breast cancer, paradoxically, oestrogens can also induce tumour regression. Upregulation of ER expression is a marker for oestrogen hypersensitivity. We, therefore, performed an exploratory study to evaluate positron emission tomography (PET) with the tracer 16 alpha-[F-18] fluoro-17 beta-oestradiol (F-18-FES) as potential marker to select breast cancer patients for oestradiol therapy. Methods Eligible patients had acquired endocrine-resistant metastatic breast cancer that progressed after >= 2 lines of endocrine therapy. All patients had prior ER-positive histology. Treatment consisted of oestradiol 2 mg, three times daily, orally. Patients underwent F-18-FES-PET/CT imaging at baseline. Tumour F-18-FES-uptake was quantified for a maximum of 20 lesions and expressed as maximum standardised uptake value (SUVmax). CT-scan was repeated every 3 months to evaluate treatment response. Clinical benefit was defined as time to radiologic or clinical progression >= 24 weeks. Results F-18-FES uptake, quantified for 255 lesions in 19 patients, varied greatly between lesions (median 2.8; range 0.6-24.3) and between patients (median 2.5; range 1.1-15.5). Seven (37 %) patients experienced clinical benefit of oestrogen therapy, eight progressed (PD), and four were non-evaluable due to side effects. The positive and negative predictive value PPV/NPV) of F-18-FES-PET for response to treatment were 60 % (95 % CI: 31-83 %) and 80 % (95 % CI: 38-96 %), respectively, using SUVmax >1.5. Conclusion F-18-FES-PET may aid identification of patients with acquired antihormone resistant breast cancer that are unlikely to benefit from oestradiol therapy

Molecular imaging of estrogen receptors

For patients with estrogen receptor (ER) positive breast cancer, endocrine therapy plays a major role in both the adjuvant and palliative setting. For adequate treatment decision-making it is crucial to obtain up-to-date information on the ER-status of the tumor(s), since ER-expression is the sole predictor for response to endocrine therapy. Moreover, ER-status can change during the course of disease in up to 30% of the patients, and therefore treatments based on the ER-status of the primary tumor may be inadequate. Positron emission tomography (PET) imaging of ER-expression by use of the tracer 16α-[18F]fluoro-17β-oestradiol (FES) can give functional information about the ER-status of all lesions within the body. The aim of this thesis is to address the clinical potential of the FES-PET technique in breast and ovarian cancer patients

Current and upcoming approaches to exploit the reversibility of epigenetic mutations in breast cancer

DNA methylation and histone modifications are important epigenetic modifications associated with gene (dys) regulation. The epigenetic modifications are balanced by epigenetic enzymes, so-called writers and erasers, such as DNA (de)methylases and histone (de)acetylases. Aberrant epigenetic alterations have been associated with various diseases, including breast cancer. Since aberrant epigenetic modifications are potentially reversible, they might represent targets for breast cancer therapy. Indeed, several drugs have been designed to inhibit epigenetic enzymes (epi-drugs), thereby reversing epigenetic modifications. US Food and Drug Administration approval has been obtained for some epi-drugs for hematological malignancies. However, these drugs have had very modest anti-tumor efficacy in phase I and II clinical trials in breast cancer patients as monotherapy. Therefore, current clinical trials focus on the combination of epi-drugs with other therapies to enhance or restore the sensitivity to such therapies. This approach has yielded some promising results in early phase II trials. The disadvantage of epi-drugs, however, is genome-wide effects, which may cause unwanted upregulation of, for example, pro-metastatic genes. Development of gene-targeted epigenetic modifications (epigenetic editing) in breast cancer can provide a novel approach to prevent such unwanted events. In this context, identification of crucial epigenetic modifications regulating key genes in breast cancer is of critical importance. In this review, we first describe aberrant DNA methylation and histone modifications as two important classes of epigenetic mutations in breast cancer. Then we focus on the preclinical and clinical epigenetic-based therapies currently being explored for breast cancer. Finally, we describe epigenetic editing as a promising new approach for possible applications towards more targeted breast cancer treatment