The AURORA pilot study for molecular screening of patients with advanced breast cancer–a study of the breast international group

Several studies have demonstrated the feasibility of molecular screening of tumour samples for matching patients with cancer to targeted therapies. However, most of them have been carried out at institutional or national level. Herein, we report on the pilot phase of AURORA (NCT02102165), a European multinational collaborative molecular screening initiative for advanced breast cancer patients. Forty-one patients were prospectively enroled at four participating centres across Europe. Metastatic tumours were biopsied and profiled using an Ion Torrent sequencing platform at a central facility. Sequencing results were obtained for 63% of the patients in real-time with variable turnaround time stemming from delays between patient consent and biopsy. At least one clinically actionable mutation was identified in 73% of patients. We used the Illumina sequencing technology for orthogonal validation and achieved an average of 66% concordance of substitution calls per patient. Additionally, copy number aberrations inferred from the Ion Torrent sequencing were compared to single nucleotide polymorphism arrays and found to be 59% concordant on average. Although this study demonstrates that powerful next generation genomic techniques are logistically ready for international molecular screening programs in routine clinical settings, technical challenges remain to be addressed in order to ensure the accuracy and clinical utility of the genomic data.info:eu-repo/semantics/publishe

Temsirolimus Is Highly Effective as Third-Line Treatment in Chromophobe Renal Cell Cancer

We report unexpectedly high efficacy of temsirolimus as third-line treatment in a patient with metastatic chromophobe renal cell carcinoma. After failure of two sequentially administered tyrosine kinase inhibitors, treatment with temsirolimus resulted in a prolonged partial remission of 14 months, and the response is still continuing. Up to now, no data from randomized clinical studies have been published addressing the question of efficacy of temsirolimus as third-line treatment after failure of tyrosine kinase inhibitors. The case presented here implies that temsirolimus could be a viable option for patients with metastatic chromophobe renal cell carcinoma

Efficacy of temsirolimus in metastatic chromophobe renal cell carcinoma

<p>Background: Renal cell carcinoma (RCC) is a histopathologically and molecularly heterogeneous disease with the chromophobe subtype (chRCC) accounting for approximately 5% of all cases. The median overall survival of advanced RCC has improved significantly since the advent of tyrosine kinase inhibitors and mammalian target of rapamycin (mTOR) inhibitors. However, high-quality evidence for the use of new generation tyrosine kinase inhibitors in patients with advanced chRCC is lacking. Few published case reports have highlighted the use of temsirolimus in chRCC.</p> <p>Case presentation: Here, we report the case of a 36-year-old Caucasian woman with metastatic chRCC with predominantly skeletal metastases who was refractory to sunitinib who demonstrated a durable clinical response to temsirolimus lasting 20 months. We review the available evidence pertaining to the use of new generation molecularly targeted agents, in particular mTOR inhibitors in chRCC and discuss their emerging role in the management of this disease which would aid the oncologists faced with the challenge of treating this rare type of RCC.</p> <p>Conclusion: Conducting randomised clinical trials in this rarer sub-group of patients would be challenging and our case report and the evidence reviewed would guide the physicians to make informed decision regarding the management of these patients.</p&gt

Phase I trial combining temozolomide plus lapatinib for the treatment of brain metastases in patients with HER2-positive metastatic breast cancer: the LAPTEM trial

Background Brain metastases (BMs) pose a clinical challenge in breast cancer (BC). Lapatinib or temozolomide showed activity in BM. Our study assessed the combination of both drugs as treatment for patients with HER2-positive BC and BM. Methods Eighteen patients were enrolled, with sixteen of them having recurrent or progressive BM. Any type of previous therapy was allowed, and disease was assessed by gadolinium (Gd)-enhanced magnetic resonance imaging (MRI). The primary end points were the evaluation of the dose-limiting toxicities (DLTs) and the determination of the maximum-tolerated dose (MTD). The secondary end points included objective response rate, clinical benefit and duration of response. Results The lapatinib-temozolomide regimen showed a favorable toxicity profile because the MTD could not be reached. The most common adverse events (AEs) were fatigue, diarrhea and constipation. Disease stabilization was achieved in 10 out of 15 assessable patients. The estimated median survival time for the 16 patients with BM reached 10.94 months (95% CI: 1.09-20.79), whereas the median progression-free survival time was 2.60 months [95% confidence interval (CI): 1.82-3.37]. Conclusions The lapatinib-temozolomide combination is well tolerated. Preliminary evidence of clinical activity was observed in a heavily pretreated population, as indicated by the volumetric reductions occurring in brain lesion

Patient-centric trials for therapeutic development in precision oncology

An enhanced understanding of the molecular pathology of disease gained from genomic studies is facilitating the development of treatments that target discrete molecular subclasses of tumours. Considerable associated challenges include how to advance and implement targeted drug-development strategies. Precision medicine centres on delivering the most appropriate therapy to a patient on the basis of clinical and molecular features of their disease. The development of therapeutic agents that target molecular mechanisms is driving innovation in clinical-trial strategies. Although progress has been made, modifications to existing core paradigms in oncology drug development will be required to realize fully the promise of precision medicine

KRAS driven expression signature has prognostic power superior to mutation status in non-small cell lung cancer

KRAS is the most frequently mutated oncogene in non-small cell lung cancer (NSCLC). However, the prognostic role of KRAS mutation status in NSCLC still remains controversial. We hypothesize that the expression changes of genes affected by KRAS mutation status will have the most prominent effect and could be used as a prognostic signature in lung cancer. We divided NSCLC patients with mutation and RNA-seq data into KRAS mutated and wild type groups. Mann-Whitney test was used to identify genes showing altered expression between these cohorts. Mean expression of the top five genes was designated as a "transcriptomic fingerprint" of the mutation. We evaluated the effect of this signature on clinical outcome in 2,437 NSCLC patients using univariate and multivariate Cox regression analysis. Mutation of KRAS was most common in adenocarcinoma. Mutation status and KRAS expression were not correlated to prognosis. The transcriptomic fingerprint of KRAS include FOXRED2, KRAS, TOP1, PEX3 and ABL2. The KRAS signature had a high prognostic power. Similar results were achieved when using the second and third set of strongest genes. Moreover, all cutoff values delivered significant prognostic power (p < 0.01). The KRAS signature also remained significant (p < 0.01) in a multivariate analysis including age, gender, smoking history and tumor stage. We generated a "surrogate signature" of KRAS mutation status in NSCLC patients by computationally linking genotype and gene expression. We show that secondary effects of a mutation can have a higher prognostic relevance than the primary genetic alteration itself

Interobserver Agreement of PD-L1/SP142 Immunohistochemistry and Tumor-Infiltrating Lymphocytes (TILs) in Distant Metastases of Triple-Negative Breast Cancer: A Proof-of-Concept Study. A Report on Behalf of the International Immuno-Oncology Biomarker Working Group

Patients with advanced triple-negative breast cancer (TNBC) benefit from treatment with atezolizumab, provided that the tumor contains 651% of PD-L1/SP142-positive immune cells. Numbers of tumor-infiltrating lymphocytes (TILs) vary strongly according to the anatomic localization of TNBC metastases. We investigated inter-pathologist agreement in the assessment of PD-L1/SP142 immunohistochemistry and TILs. Ten pathologists evaluated PD-L1/SP142 expression in a proficiency test comprising 28 primary TNBCs, as well as PD-L1/SP142 expression and levels of TILs in 49 distant TNBC metastases with various localizations. Interobserver agreement for PD-L1 status (positive versus negative) was high in the proficiency test: the corresponding scores as percentages showed good agreement with the consensus diagnosis. In TNBC metastases, there was substantial variability in PD-L1 status at the individual patient level. For one in five patients, the chance of treatment was essentially random, with half of the pathologists designating them as positive and half negative. Assessment of PD-L1/SP142 and TILs as percentages in TNBC metastases showed poor and moderate agreement, respectively. Additional training for metastatic TNBC is required to enhance interobserver agreement. Such training, focusing on metastatic specimens, seems worthwhile, since the same pathologists obtained high percentages of concordance (ranging from 93% to 100%) on the PD-L1 status of primary TNBCs

Oestrogen and zoledronic acid driven changes to the bone and immune environments: potential mechanisms underlying the differential anti-tumour effects of zoledronic acid in pre- and post-menopausal conditions

Late stage breast cancer commonly metastasises to bone and patient survival averages 2–3 years following diagnosis of bone involvement. One of the most successful treatments for bone metastases is the bisphosphonate, zoledronic acid (ZOL). ZOL has been used in the advanced setting for many years where it has been shown to reduce skeletal complications associated with bone metastasis. More recently, several large adjuvant clinical trials have demonstrated that administration of ZOL can prevent recurrence and improve survival when given in early breast cancer. However, these promising effects were only observed in post-menopausal women with confirmed low concentrations of circulating ovarian hormones. In this review we focus on potential interactions between the ovarian hormone, oestrogen, and ZOL to establish credible hypotheses that could explain why anti-tumour effects are specific to post-menopausal women. Specifically, we discuss the molecular and immune cell driven mechanisms by which ZOL and oestrogen affect the tumour microenvironment to inhibit/induce tumour growth and how oestrogen can interact with zoledronic acid to inhibit its anti-tumour actions

The path to a better biomarker: Application of a risk management framework for the implementation of PD-L1 and TILs as immuno-oncology biomarkers in breast cancer clinical trials and daily practice

Immune checkpoint inhibitor therapies targeting PD-1/PD-L1 are now the standard of care in oncology across several hematologic and solid tumor types, including triple negative breast cancer (TNBC). Patients with metastatic or locally advanced TNBC with PD-L1 expression on immune cells occupying 651% of tumor area demonstrated survival benefit with the addition of atezolizumab to nab-paclitaxel. However, concerns regarding variability between immunohistochemical PD-L1 assay performance and inter-reader reproducibility have been raised. High tumor-infiltrating lymphocytes (TILs) have also been associated with response to PD-1/PD-L1 inhibitors in patients with breast cancer (BC). TILs can be easily assessed on hematoxylin and eosin\u2013stained slides and have shown reliable inter-reader reproducibility. As an established prognostic factor in early stage TNBC, TILs are soon anticipated to be reported in daily practice in many pathology laboratories worldwide. Because TILs and PD-L1 are parts of an immunological spectrum in BC, we propose the systematic implementation of combined PD-L1 and TIL analyses as a more comprehensive immuno-oncological biomarker for patient selection for PD-1/PD-L1 inhibition-based therapy in patients with BC. Although practical and regulatory considerations differ by jurisdiction, the pathology community has the responsibility to patients to implement assays that lead to optimal patient selection. We propose herewith a risk-management framework that may help mitigate the risks of suboptimal patient selection for immuno-therapeutic approaches in clinical trials and daily practice based on combined TILs/PD-L1 assessment in BC. \ua9 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley &amp; Sons, Ltd