An important tool to evaluate the performance of a dose-finding design is the nonparametric optimal benchmark that provides an upper bound on the performance of a design under a given scenario. A fundamental assumption of the benchmark is that the investigator can arrange doses in a monotonically increasing toxicity order. While the benchmark can be still applied to combination studies in which not all dose combinations can be ordered, it does not account for the uncertainty in the ordering. In this article, we propose a generalization of the benchmark that accounts for this uncertainty and, as a result, provides a sharper upper bound on the performance. The benchmark assesses how probable the occurrence of each ordering is, given the complete information about each patient. The proposed approach can be applied to trials with an arbitrary number of endpoints with discrete or continuous distributions. We illustrate the utility of the benchmark using recently proposed dose-finding designs for Phase I combination trials with a binary toxicity endpoint and Phase I/II combination trials with binary toxicity and continuous efficacy.
While there is recognition that more informative clinical endpoints can support better decision-making in clinical trials, it remains a common practice to categorize endpoints originally measured on a continuous scale. The primary motivation for this categorization (and most commonly dichotomization) is the simplicity of the analysis. There is, however, a long argument that this simplicity can come at a high cost. Specifically, larger sample sizes are needed to achieve the same level of accuracy when using a dichotomized outcome instead of the original continuous endpoint. The degree of “loss of information” has been studied in the contexts of parallel-group designs and two-stage Phase II trials. Limited attention, however, has been given to the quantification of the associated losses in dose-ranging trials. In this work, we propose an approach to estimate the associated losses in Phase II dose-ranging trials that is free of the actual dose-ranging design used and depends on the clinical setting only. The approach uses the notion of a nonparametric optimal benchmark for dose-finding trials, an evaluation tool that facilitates the assessment of a dose-finding design by providing an upper bound on its performance under a given scenario in terms of the probability of the target dose selection. After demonstrating how the benchmark can be applied to Phase II dose-ranging trials, we use it to quantify the dichotomization losses. Using parameters from real clinical trials in various therapeutic areas, it is found that the ratio of sample sizes needed to obtain the same precision using continuous and binary (dichotomized) endpoints varies between 70% and 75% under the majority of scenarios but can drop to 50% in some cases.
Among protein oxidative damages, di-tyrosine bridges formation has been evidenced in many neuropathological diseases. Combining oxidative radical production by gamma radiolysis with very performant chromatographic separation coupled to mass spectrometry detection, we brought into light new insights of tyrosine dimerization. Hydroxyl and azide radical tyrosine oxidation leading to di-tyrosine bridges formation was studied for different biological compounds: a full-length protein (Δ25-centrin 2), a five amino acid peptide (KTSLY) and free tyrosine. We highlighted that both radicals generate high proportion of dimers even for low doses. Surprisingly, no less than five different di-tyrosine isomers were evidenced for the protein and the peptide. For tyrosine alone, at least four distinct dimers were evidenced. These results raise some questions about their respective role in vivo and hence their relative toxicity. Also, as di-tyrosine is often used as a biomarker, a better knowledge of the type of dimer detected in vivo is now required.
ERBB2 and ERBB3 somatic gain-of-function mutations, which may be targeted by anti-ERBB2 therapies, were reported by high-throughput sequencing studies in 1% and 2% of invasive breast cancers respectively. Our study aims to determine ERBB2 and ERBB3 mutations frequencies in grade 3 and/or ERBB2-positive invasive lobular breast carcinomas (ILC). All the 529 ILC surgically-excised registered at Institut Curie in the years 2005 to 2008 were reviewed. Thirty-nine grade 3 ERBB2-negative ILC and 16 ERBB2-positive ILC were retrieved and subjected to Sanger sequencing of the ERBB2 and ERBB3 activation mutation hotspots (ERBB2: exons 8, 17, 19, 20, 21; ERBB3: exons 3, 6, 7, 8). Among the 39 grade 3 ERBB2-negative ILC, six tumors were found to have at least one detectable ERBB2 activating mutation (incidence rate: 15%, 95%CI [4%-27%]). No ERBB2 mutation was found among the 16 ERBB2-positive ILC. No ERBB3 mutation was found in any of the 55 ILC. ERBB2 mutations were statistically associated with solid ILC features (p=0.01). Survival analyses showed no significant prognostic impact of ERBB2 mutations. Our study demonstrates that high grade ERBB2-negative ILC display a high frequency of ERBB2 mutations, and should be subjected to systematic genetic screening.
We present a pooled analysis of predictive and prognostic values of circulating tumour cells (CTC) and circulating endothelial cells (CEC) in two prospective trials of patients with inflammatory breast cancer (IBC) treated with neoadjuvant chemotherapy combined with neoadjuvant and adjuvant bevacizumab.
As a result of recent progress in detection techniques, circulating tumor DNA (ctDNA) and circulating tumor cells (CTC) can now be accurately detected in the blood of most cancer patients. While these new biomarkers can provide a better understanding of key biological mechanisms underlying cancer growth and dissemination, they also open up a wide range of possible clinical applications in medical oncology, radiation oncology and surgical oncology. In this review, we summarize the results obtained with ctDNA and CTC together with their potential future clinical applications in the field of surgical oncology, with particular focus on the perioperative setting of various types of cancer. These applications include, but are not limited to, cancer screening, early diagnosis, prognostic assessment, evaluation and management of preoperative systemic or local therapies, post-surgical detection of minimal residual disease and early detection of cancer relapse.
Circulating tumor cells (CTCs) are rare tumor cells and have been investigated as diagnostic, prognostic and predictive biomarkers in many types of cancer. Although CTCs are not currently used in clinical practice, CTC studies have accumulated a high level of clinical validity, especially in breast, lung, prostate and colorectal cancers. In this review, we present an overview of the current clinical validity of CTCs in metastatic and non-metastatic disease, and the main concepts and studies investigating the clinical utility of CTCs. In particular, this review will focus on breast, lung, colorectal and prostate cancer. Three major topics concerning the clinical utility of CTC are discussed-(1) treatment based on CTCs used as liquid biopsy, (2) treatment based on CTC count or CTC variations, and (3) treatment based on CTC biomarker expression. A summary of published or ongoing phase II and III trials is also presented.
Paired primary breast cancers and metachronous metastases after adjuvant treatment are reported to differ in their clonal composition and genetic alterations, but it is unclear whether these differences stem from the selective pressures of the metastatic process, the systemic therapies, or both. We sought to define the repertoire of genetic alterations in breast cancer patients with metastatic disease who had not received local or systemic therapy. Up to two anatomically distinct core biopsies of primary breast cancers and synchronous distant metastases from nine patients who presented with metastatic disease were subjected to high-depth whole-exome sequencing. Mutations, copy number alterations and their cancer cell fractions, and mutation signatures were defined using state-of-the-art bioinformatics methods. All mutations identified were validated with orthogonal methods. Genomic differences were observed between primary and metastatic deposits, with a median of 60% (range 6%-95%) of shared somatic mutations. Although mutations in known driver genes including , and were preferentially clonal in both sites, primary breast cancers and their synchronous metastases displayed spatial intratumor heterogeneity. Likely pathogenic mutations affecting epithelial-to-mesenchymal transition-related genes, including , and (), were found to be restricted to or enriched in the metastatic lesions. Mutational signatures of trunk mutations differed from those of mutations enriched in the primary tumor or the metastasis in six cases. Synchronous primary breast cancers and metastases differ in their repertoire of somatic genetic alterations even in the absence of systemic therapy. Mutational signature shifts might contribute to spatial intratumor genetic heterogeneity. .
Recent clinical results support the use of new immune checkpoint blockers (ICB), such as anti-PD-1 (e.g. nivolumab and pembrolizumab) and anti-PD-L1 antibodies. Radiological evaluation of ICB efficacy during therapy is challenging due to tumor immune infiltration. Changes of circulating tumor DNA (ctDNA) levels during therapy could be a promising tool for very accurate monitoring of treatment efficacy, but data are lacking with ICB.
Squamous cell carcinoma of the anal canal (SCCA) is a rare HPV-associated cancer with limited sensitivity to standard chemotherapy. In a phase 2 study, nivolumab, an anti PD-1 immune checkpoint inhibitor, demonstrated significant efficacy as single-agent therapy in metastatic SCCA patients. Nevertheless, imaging assessment by standard RECIST criteria of the efficacy of immune therapy can be difficult in some patients due to tumor immune cell infiltration, and biomarkers of treatment efficacy are needed. We have previously developed a quantitative droplet digital PCR (ddPCR) technique to detect HPV circulating tumor DNA (HPV ctDNA), with excellent sensitivity and specificity. Here, we report, for the first time, the kinetics of HPV ctDNA during therapy in a patient with metastatic SCCA, who obtained sustained partial response to single-agent nivolumab. We observed an early and very significant decrease of HPV ctDNA during therapy from the baseline level of 3713 copies/ml plasma to 564 copies/ml plasma at 4 weeks, and 156 copies/ml at 6 weeks, followed by a plateau. This observation provides proof-of-concept that HPV ctDNA can be used as a noninvasive early dynamic biomarker to monitor the efficacy of new immunotherapy agents.
Chemoradiotherapy (CRT) is the current standard of care for patients diagnosed with locally advanced anal squamous cell carcinoma (ASCC), but some patients develop local and/or distant relapse during follow-up. This study was designed to monitor human papillomavirus (HPV) circulating tumor DNA (ctDNA) levels during CRT in patients with ASCC. We analyzed samples from patients with HPV16- or HPV18-positive locally advanced ASCC. Blood samples were collected before and after CRT. HPV16 or HPV18 ctDNA detection was performed by droplet digital-PCR. HPV ctDNA was detected before CRT in 29 of 33 patients with stages II-III ASCC [sensitivity: 88%; 95% confidence interval (CI), 72-95]; ctDNA positivity rate was associated with tumor stage (64% and 100% in stages II and III, respectively; = 0.008). Among ctDNA-positive patients at baseline, ctDNA levels were higher in N than in N tumors (median 85 copies/mL, range = 8-9,333 vs. 32 copies/mL, range = 3-1,350; = 0.03). ctDNA detection at baseline had no significant prognostic impact. After CRT, three of 18 (17%) patients displayed residual detectable HPV ctDNA; ctDNA detection after CRT was strongly associated with shorter disease-free survival ( < 0.0001). This is the first proof-of-concept study assessing the prognostic value of ctDNA after CRT in locally advanced ASCC. In most patients, HPV ctDNA can be detected before CRT and becomes undetectable during CRT. In this study, we show that residual ctDNA levels after CRT are associated with very poor outcome. .
Recent technological developments enable the detection and quantification of circulating tumour DNA in the blood, with potentially major clinical implications, particularly for cancers treated with curative intent. Circulating tumour DNA has a potential impact before, during and after treatment. If limitations of this approach remain, requiring further development, it is important to know the principles and applications in view of the potential impact on the clinical practice. In this review, we will discuss the current detection methods, then the place of circulating tumour DNA in oncology and more particularly in radiotherapy.
Disseminated tumor cells (DTCs) collect in the bone marrow and indicate micrometastatic spread. We previously reported that DTCs could be a predictive factor for the efficacy of regional node irradiation (internal mammary nodes [IMNs]/supra- and infraclavicular nodes [SCNs]). In this article, we report the long-term results (>10 years) on the impact of DTC status in early stage breast cancer.
Droplet digital polymerase chain reaction (ddPCR) is a highly sensitive quantitative polymerase chain reaction (PCR) method based on sample fractionation into thousands of nano-sized water-in-oil individual reactions. Recently, ddPCR has become one of the most accurate and sensitive tools for circulating tumor DNA (ctDNA) detection. One of the major limitations of the standard ddPCR technique is the restricted number of mutations that can be screened per reaction, as specific hydrolysis probes recognizing each possible allelic version are required. An alternative methodology, the drop-off ddPCR, increases throughput, since it requires only a single pair of probes to detect and quantify potentially all genetic alterations in the targeted region. Drop-off ddPCR displays comparable sensitivity to conventional ddPCR assays with the advantage of detecting a greater number of mutations in a single reaction. It is cost-effective, conserves precious sample material, and can also be used as a discovery tool when mutations are not known a priori.
Human papillomavirus (HPV) is found in 90% of squamous cell carcinomas of the anal canal (SCCA). We investigated the clinical validity of HPV circulating tumor DNA (ctDNA) detection in patients enrolled in the Epitopes-HPV02 trial that demonstrated the efficacy of docetaxel, cisplatin, and 5-FU as first-line chemotherapy in advanced SCCA.
The heterogeneity of metastatic breast cancer (MBC) necessitates novel biomarkers allowing stratification of patients for treatment selection and drug development. We propose to use the prognostic utility of circulating tumor cells (CTCs) for stratification of patients with stage IV disease.