Jean-Louis Merlin

BACKGROUND Hot flashes are frequent and distressing adverse effects of adjuvant hormone therapy (HT) in women with non-metastatic, hormone receptor–positive breast cancer, negatively affecting health-related quality of life (HRQoL) and potentially treatment adherence. Non-pharmacological approaches, including hypnosis, have shown promising but inconsistent results. Digitally delivered guided self-hypnosis with therapist support may provide a scalable, low-risk option, but its efficacy for hot flashes in this population has not been evaluated. OBJECTIVE The primary objective is to evaluate the effect of daily guided self-hypnosis sessions, delivered via a digital solution, on the reduction of hot flashes in patients with non-metastatic breast cancer receiving adjuvant HT. The secondary objectives are to evaluate adherence to the programme, HRQoL, sleep quality, satisfaction with care, and usability of the digital tool. METHODS HYBOU is a pilot, prospective, single-centre, open-label, randomized controlled trial with two parallel arms, conducted at the Institut de Cancérologie de Lorraine, France. Women aged ≥18 years with non-metastatic breast cancer receiving adjuvant HT, with or without a cyclin-dependent kinase 4/6 inhibitor, and experiencing ≥50 hot flashes per week or ≥7 per day will be randomized 1:1 to standard care or to standard care plus digital guided self-hypnosis. The intervention is a 3-week programme delivered through the HypnoCare-solution®, in which participants practise self-hypnosis daily for approximately 20 minutes. It addresses 3 themes introduced sequentially, one per week: pleasant coolness, body-temperature regulation, and anxiety and stress management, with weekly telephone or teleconsultation contact with a hypnotherapist. The primary outcome is the weekly Hot Flash Score (HFS), derived from daily hot flash frequency and severity (graded 1-4), assessed over a baseline week (the 7 days before randomization) and the week preceding day 28. Secondary outcomes are adherence, HRQoL (European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30), sleep quality (Pittsburgh Sleep Quality Index), satisfaction with care, and usability of the digital tool (System Usability Scale). A total of 76 evaluable participants (38 per arm) are required; 91 participants will be pre-included to account for patients not meeting inclusion criteria at randomization. RESULTS The study received a favourable opinion from the French ethics committee (Comité de Protection des Personnes Ile de France III) on September 11, 2024. The first participant was enrolled on December 20, 2024. Recruitment is planned over 30 months and is expected to end on June 20, 2027, within an overall project duration of 40 months. Results are not yet available. CONCLUSIONS HYBOU will evaluate a digitally delivered, multi-thematic guided self-hypnosis programme with weekly therapist support for hot flash management during adjuvant HT for breast cancer. If effective, the findings will inform the design of a larger multicentre confirmatory trial. CLINICALTRIAL ClinicalTrials.gov NCT06552091 (prospectively registered on August 12, 2024); French national authorisation number (ID-RCB) 2024-A01105-42

Isocitrate dehydrogenase (IDH) variants can lead to the development and/or progression of various solid tumors and hematological malignancies. IDH testing can guide diagnosis, prognosis, and therapeutic choice and typically relies on NGS, IHC, or PCR-based assays. Here, we evaluated the analytical performance of the Idylla IDH1-2 mutation assay for IDH variant detection using 70 fixed samples from patients with solid tumors and 36 DNA extracts from patients with acute myeloid leukemias previously characterized by NGS +/− IHC. Idylla IDH1-2 mutation assay gave 98.1% of valid results with an overall agreement, sensitivity, and specificity of 97.1%, 96.2%, and 98.1%, respectively, compared to NGS. Using commercial DNA standards, the limit of detection of the assay was 1.6% and 0.5% for IDH1 R132H and IDH2 R172K variants, respectively. Based on these data, the Idylla IDH1-2 mutation assay represents a fast and reliable alternative to detect IDH hotspot variants in solid tumors and hematological malignancies using either fixed tissue sections or DNA extracts. Particular attention, however, is needed for the interpretation of cases with cycle of quantification values of the internal controls over 35, for which a variant with low allelic frequency could be missed due to low DNA quantity or quality.

Based on immunohistochemistry (IHC) and in situ hybridization (ISH), HER2-low breast cancers (BC) subtype—defined as IHC1+ or IHC2+/ISH− tumors—emerged and represent more than half of all BC. We evaluated the performance of NGS for integrated molecular characterization of HER2-low BC, including identification of actionable molecular targets, copy number variation (CNV), and microsatellite instability (MSI) analysis. Thirty-one BC specimens (11 HER2+, 10 HER2−, and 10 HER2-low) were routinely analyzed using IHC and ISH, and were selected and analyzed using NGS for gene mutations including ESR1, PIK3CA, AKT1, ERBB2, TP53, BRCA1, and BRCA2, CNV, and MSI. CNV values for the ERBB2 gene were significantly (p < 0.001) different between HER2+, and either HER2-low or HER2− tumors with mean values of 7.8 (SD = 6.8), 1.9 (SD = 0.3), and 2.0 (SD = 0.3), respectively. Using 3.25 as the cutoff value, 96.8% overall concordance of HER2 status was achieved between IHC and NGS compared to IHC and ISH. Using NGS, gene mutations and amplifications were detected in 68% (21/31) and 19% (6/31) of the cases, respectively. One case of MSI was detected in a HER2-negative and ISH unamplified case. Beside IHC, NGS allows the identification of HER2-low subtype simultaneously, with the detection of multiple actionable gene mutations being helpful for molecular board treatment selection.

The predominant forms of breast cancer (BC) are hormone receptor-positive (HR+) tumors characterized by the expression of estrogen receptors (ERs) and/or progesterone receptors (PRs). Patients with HR+ tumors can benefit from endocrine therapy (ET). Three types of ET are approved for the treatment of HR+ BCs and include selective ER modulators, aromatase inhibitors, and selective ER downregulators. ET is the mainstay of adjuvant treatment in the early setting and the backbone of the first-line treatment in an advanced setting; however, the emergence of acquired resistance can lead to cancer recurrence or progression. The mechanisms of ET resistance are often related to the occurrence of mutations in the ESR1 gene, which encodes the ER-alpha protein. As ESR1 mutations are hardly detectable at diagnosis but are present in 30% to 40% of advanced BC (ABC) after treatment, the timeline of testing is crucial. To manage this resistance, ESR1 testing has recently been recommended; in ER+ HER2− ABC and circulating cell-free DNA, so-called liquid biopsy appears to be the most convenient way to detect the emergence of ESR1 mutations. Technically, several options exist, including Next Generation Sequencing and ultra-sensitive PCR-based techniques. In this context, personalization of ET through the surveillance of ESR1 mutations in the plasma of HR+ BC patients throughout the disease course represents an innovative way to improve the standard of care.

Background: With more than 15,000 new cases /year in France and 2,000 deaths, cutaneous melanoma represents approximately 4% of incidental cancers and 1.2% of cancer related deaths. In locally advanced (stage III) or resectable metastatic (stage IV) melanomas, medical adjuvant treatment is proposed and recent advances had shown the benefit of anti-PD1/PDL1 and anti-CTLA4 immunotherapy as well as anti-BRAF and anti-MEK targeted therapy in BRAF V600 mutated tumors. However, the recurence rate at one year is approximately 30% and justify extensive research of predictive biomarkers. If in metastatic disease, the follow-up of circulating tumor DNA (ctDNA) has been demonstrated, its interest in adjuvant setting remains to be precised, especially because of a lower detection rate. Further, the definition of a molecular response could prove useful to personalized treatment. Methods: PERCIMEL is an open prospective multicentric study executed through collaboration of the Institut de Cancérologie de Lorraine (non-profit comprehensive cancer center) and 6 French university and community hospitals. A total of 165 patients with resected stage III and IV melanoma, eligible to adjuvant imunotherapy or anti-BRAF/MEK kinase inhibitors will be included. The primary endpoint is the presence of ctDNA, 2 to 3 weeks after surgery, defined as mutated ctDNA copy number calculated as the allelic fraction of a clonal mutation relative to total ctDNA. Secondary endpoints are recurrence-free survival, distant metastasis-free survival and specific survival. We will follow ctDNA along treatment, quantitatively through ctDNA mutated copy number variation, qualitatively through the presence of cfDNA and its clonal evolution. Relative and absolute variations of ctDNA during follow-up will be also analyzed. PERCIMEL study aims at provide scientific evidence that ctDNA quantitative and qualitative variations can be used to predict the recurrence of patients with melanoma treated with adjuvant immunotherapy or kinase inhibitors, thus defining the notion of molecular recurrence.

Human solid malignancies harbour a heterogeneous set of cells with distinct genotypes and phenotypes. This heterogeneity is installed at multiple levels. A biological diversity is commonly observed between tumours from different patients (inter-tumour heterogeneity) and cannot be fully captured by the current consensus molecular classifications for specific cancers. To extend the complexity in cancer, there are substantial differences from cell to cell within an individual tumour (intra-tumour heterogeneity, ITH) and the features of cancer cells evolve in space and time. Currently, treatment-decision making usually relies on the molecular characteristics of a limited tumour tissue sample at the time of diagnosis or disease progression but does not take into account the complexity of the bulk tumours and their constant evolution over time. In this review, we explore the extent of tumour heterogeneity with an emphasis on ITH and report the mechanisms that promote and sustain this diversity in cancers. We summarise the clinical strikes of ITH in the management of patients with cancer. Finally, we discuss the current material and technological approaches that are relevant to adequately appreciate ITH.