Therapeutic De-escalation Research Articles

Advancements in Managing Pure Ductal Carcinoma In Situ: An 18-Year Artificial Intelligence-Aided Analysis of 998 Patients

IntroductionThe integration of artificial intelligence (AI) in oncological diseases has opened new avenues for early cancer detection, accurate risk assessments, and personalized treatment protocols. The objective of our study was to describe the shift in the treatment indications and prognosis of ductal carcinoma in situ (DCIS) in a prospective cohort of 998 patients managed over 18 years at a single University Hospital in France. MethodsThis analysis included all patients managed for DCIS at the University Hospitals of Strasbourg between January 14, 2002, and December 18, 2019, from the prospective SENOMETRY cohort, which initially included 9599 patients with both in situ and invasive breast cancer. Data were analyzed using Onconum, an AI-based natural language processing tool, to extract structured information from medical records. ResultsThe incidence of DCIS remained stable at 65 new cases per year. The mean age at diagnosis increased from 55 years in 2002 to 61 years in 2019. There was a significant rise in high-grade DCIS (DIN3) cases from 25% to 35%. The re-excision rate decreased from 57% in 2002 to 18% in 2019. Most DCIS cases were managed with breast-conserving surgeries (682), while total mastectomies accounted for 385 cases. Sentinel lymph node biopsy was performed in 39% of cases, primarily in high-grade and multifocal DCIS. Specific mortality was 0%, with a recurrence rate of 2.2%, predominantly invasive and occurring earlier in high-grade DCIS. Discussion: Over 18 years, there has been a notable shift in the clinicopathological characteristics of DCIS, with an increase in patient age at diagnosis and higher histopathological grades. Therapeutic management evolved significantly, with reduced surgical margins and fewer adjuvant treatments, while maintaining low and stable recurrence rates. AI significantly enhanced data extraction and analysis efficiency, contributing to better clinical decision-making. ConclusionThe study confirms the possibility of therapeutic de-escalation in DCIS, supported by AI-driven data analysis, allowing individualized treatment approaches and leading to optimized patient outcomes.

Patients with ulcerative colitis who have normalized histology are clinically stable after de-escalation of therapy

We have previously demonstrated that histological normalization in ulcerative colitis (UC) is associated with superior maintenance of remission outcomes. This single-center, retrospective case-control study assessed outcomes after the therapeutic de-escalation in UC patients who have achieved histologic normalization. A total of 111 patients were included, of which 24 underwent de-escalation, and 87 patients without therapeutic changes. The most commonly withdrawn therapy was aminosalicylates (50%), followed by immunomodulators (37.5%), and biologics (12.5%). Fourteen patients remained on therapies after de-escalation, including aminosalicylate (9/14), immunomodulators (3/14), and biologics (3/14), while 10 patients were not on any therapy immediately after withdrawal. Median follow-up was 43 months in the de-escalation group and 47 months in the control. The rates of clinical, endoscopic, and histologic recurrence were not significantly different between the two groups, nor was the proportion of patients who subsequently required additional therapies after withdrawal (P = 0.133). Clinical and endo-histologic recurrence rates were the lowest in patients who withdrew immunomodulators (0% and 14.3%, respectively). We demonstrate the clinical stability of therapeutic withdrawal in UC patients with histologic normalization.

De-escalating therapy in inflammatory bowel disease: Results from an observational study in clinical practice

Background and objectivesCombination therapy with an immunomodulator (IMM) and an anti-TNF is commonly recommended in Crohn's disease (CD) and ulcerative colitis (UC) patients. However, little is known about relapse rates after therapeutic de-escalation. This study aimed to evaluate the risk of relapse in a cohort of UC and CD patients with long-standing clinical remission after discontinuation of IMM or anti-TNF and to identify predictive factors for relapse. MethodsThis retrospective study included patients with UC or CD on combination therapy and clinical remission for at least 6 months. IMM or anti-TNF was stopped upon physician decision. Primary objective was to evaluate the relapse rates after discontinuation of IMM or anti-TNF and to analyze predictors of relapse. ResultsThe study included 88 patients, 48 patients (54.5%) discontinued IMM and 40 (45.5%) anti-TNF. During follow-up, relapse rates were 16.7% and 52.5% in the IMM discontinuation group and anti-TNF discontinuation group, respectively (p<0.001). Multivariate analysis showed that anti-TNF discontinuation (HR=3.01; 95% CI=1.22–7.43) and ileal CD location (HR=2.36; 95% CI=1.02–5.47) were predictive factors for relapse while inflammatory CD phenotype was a protective factor (HR=0.32; 95% CI=0.11–0.90). Reintroduction of anti-TNF upon relapse was effective and safe. ConclusionAnti-TNF discontinuation led to significantly higher relapse rates compared to IMM discontinuation in UC and CD patients on combination therapy. Anti-TNF discontinuation and ileal CD location were identified as predictive factors for relapse while inflammatory CD phenotype was a protective factor. Retreatment after anti-TNF discontinuation was effective and safe.

Trifluridine/Tipiracil Based Chemoradiation in locally Advanced Rectal Cancer: The Phase I/II TARC Trial

BackgroundOptimizing functional outcomes and securing long-term remissions are key goals in managing patients with locally advanced rectal cancer. In this proof-of-concept study, we set out to further optimize neoadjuvant therapy by integrating the radiosensitizer trifluridine/tipiracil and explore the potential of cell free tumor DNA (ctDNA) to monitor residual disease. MethodsAbout 10 patients were enrolled in the phase I dose finding part which followed a 3 + 3 dose escalation design. Tipiracil/trifluridine was administered concomitantly to radiotherapy. ctDNA monitoring was performed before and after chemoradiation with patient-individualized digital droplet PCRs. ResultsNo dose-limiting toxicities were observed at the maximum tolerated dose level of 2 × 35 mg/m² trifluridine/tipiracil. There were 9 grade 3 adverse events, of which 8 were hematologic with anemia and leukopenia. Chemoradiation yielded a pathological complete response in 1 out of 8 assessable patients, downstaging in nearly all patients, and 1 clinical complete response referred for watchful waiting. Three of 4 assessable patients with residual tumor cells at pathological assessment remained liquid biopsy positive after chemoradiation, but 1 turned negative. ConclusionIn this exploratory phase I trial, the novel combination of neoadjuvant trifluridine/tipiracil and radiotherapy proved to be feasible, tolerable, and effective. However, the application of liquid biopsy as a potential marker for therapeutic de-escalation in the neoadjuvant setting requires additional research and prospective validation.The trial was registered at ClinicalTrials.gov: NCT04177602.

Deciphering the spatial landscape and plasticity of immunosuppressive fibroblasts in breast cancer

Although heterogeneity of FAP+ Cancer-Associated Fibroblasts (CAF) has been described in breast cancer, their plasticity and spatial distribution remain poorly understood. Here, we analyze trajectory inference, deconvolute spatial transcriptomics at single-cell level and perform functional assays to generate a high-resolution integrated map of breast cancer (BC), with a focus on inflammatory and myofibroblastic (iCAF/myCAF) FAP+ CAF clusters. We identify 10 spatially-organized FAP+ CAF-related cellular niches, called EcoCellTypes, which are differentially localized within tumors. Consistent with their spatial organization, cancer cells drive the transition of detoxification-associated iCAF (Detox-iCAF) towards immunosuppressive extracellular matrix (ECM)-producing myCAF (ECM-myCAF) via a DPP4- and YAP-dependent mechanism. In turn, ECM-myCAF polarize TREM2+ macrophages, regulatory NK and T cells to induce immunosuppressive EcoCellTypes, while Detox-iCAF are associated with FOLR2+ macrophages in an immuno-protective EcoCellType. FAP+ CAF subpopulations accumulate differently according to the invasive BC status and predict invasive recurrence of ductal carcinoma in situ (DCIS), which could help in identifying low-risk DCIS patients eligible for therapeutic de-escalation.

De-escalating therapy in inflammatory bowel disease: Results from an observational study in clinical practice

Background and objectivesCombination therapy with an immunomodulator (IMM) and an anti-TNF is commonly recommended in Crohn's disease (CD) and ulcerative colitis (UC) patients. However, little is known about relapse rates after therapeutic de-escalation. This study aimed to evaluate the risk of relapse in a cohort of UC and CD patients with long-standing clinical remission after discontinuation of IMM or anti-TNF and to identify predictive factors for relapse. MethodsThis retrospective study included patients with UC or CD on combination therapy and clinical remission for at least 6 months. IMM or anti-TNF was stopped upon physician decision. Primary objective was to evaluate the relapse rates after discontinuation of IMM or anti-TNF and to analyze predictors of relapse. ResultsThe study included 88 patients, 48 patients (54.5%) discontinued IMM and 40 (45.5%) anti-TNF. During follow-up, relapse rates were 16.7% and 52.5% in the IMM discontinuation group and anti-TNF discontinuation group, respectively (p<0.001). Multivariate analysis showed that anti-TNF discontinuation (HR=3.01; 95% CI=1.22–7.43) and ileal CD location (HR=2.36; 95% CI=1.02–5.47) were predictive factors for relapse while inflammatory CD phenotype was a protective factor (HR=0.32; 95% CI=0.11–0.90). Reintroduction of anti-TNF upon relapse was effective and safe. ConclusionAnti-TNF discontinuation led to significantly higher relapse rates compared to IMM discontinuation in UC and CD patients on combination therapy. Anti-TNF discontinuation and ileal CD location were identified as predictive factors for relapse while inflammatory CD phenotype was a protective factor. Retreatment after anti-TNF discontinuation was effective and safe.

LESS: Single-arm study to de-escalate adjuvant endocrine therapy duration in post-menopausal women with HR+ HER2- early-stage breast cancer at very low risk of metastasis.

TPS615 Background: Adjuvant Endocrine Therapy (ET) is the cornerstone treatment of localized hormone-receptor positive (HR+) breast cancer, with demonstrated benefits on overall survival (30-40% relative decrease in mortality) but also on the risk of local and contralateral relapse (43-50% relative decrease). While the relative benefit of 5 years of ET is identical for small tumors as compared to larger ones, the absolute benefit is much lower, and the risk-benefit ratio becomes questionable given the frequent and impactful side effects of ET which are associated with non-adherence. If recent trials tested longer durations as compared to 5 years for high-risk cancers, older trials have tested shorter durations. Five years appeared at that time as the gold standard because of optimal benefit-risk ratios of tamoxifen among rather high-risk patients. However, shorter treatments of 2-3 years were already associated with substantial benefits and may be enough for very low risk patients. The purpose of this study is to demonstrate that adjuvant ET limited to 2 years of aromatase inhibitor (AI) in postmenopausal women at very low risk of recurrence as determined with a MammaPrint and BluePrint Ultra Low Risk Luminal test result can ensure very high survival without metastatic relapse and allows a reduction of side effects and a better quality of life. Methods: LESS (NCT05297617) is a prospective, national, multicenter, single-arm, interventional, non-threshold crossing phase II study evaluating a therapeutic de-escalation that limits adjuvant ET to 2 years of AI. Approximately 696 post-menopausal patients with an invasive unilateral, HR+, HER2-negative, without indication of adjuvant chemoT and genomically-assessed MammaPrint/BluePrint UltraLow risk Luminal A breast cancer tumors, will be enrolled. LESS will include two sub cohorts: the majority of patients with Grade 2, pT1c-2, pN0/N1mic tumors, and up to 80 patients ≥65 years with Grade 1, pT1, pN0 and Ki67&lt;10% tumors. The primary endpoint is distant metastasis free survival (DMFS) defined as the time from date of registration to date of first event of distant recurrence, death, or second primary non-breast invasive cancer. Secondary endpoints include the assessment of quality of life parameters and psychological aspects related to this de-escalation. The null hypothesis (H0) that, in the study population after 2 years of adjuvant AI, DMFS at 5 years is lower or equal to 94.5% will be tested against the alternative - that it is above 94.5%. For an expected DMFS of 96.7% under the alternative hypothesis, a total of 37 DMFS events are required in order to provide approximately 85% power at a one-sided significance level of 0.05 to reject H0 using a logrank test. The 1st patient was included in October 2022, initiating the 2-year inclusion period and 10 years FU per patient. Clinical trial information: NCT05297617 .

In-silico analysis of TCGA data showing multiple POLE-like favourable subgroups overlapping with TP53 mutated endometrial cancer: Implications for clinical practice in low and middle-income countries

IntroductionThe Cancer Genome Atlas cohort of endometrial carcinoma (TCGA-UCEC) includes almost 40% TP53-mutants encompassing missense and truncated variants. TCGA revealed ‘POLE’, characterized by POLE gene bearing exonuclease domain mutation (EDM), as the prognostically best molecular profile. The worst profile was characterized by TP53-mutated Type 2 cancer requiring adjuvant therapy having cost implications in low-resource settings. We aimed to find more ‘POLE-like’ favourable subgroups by searching TCGA cohort, especially within TP53 mutated risk group, that could eventually avoid adjuvant treatment in resource-poor settings. MethodOur study was an in-silico survival analysis performed on the TCGA-UCEC dataset using SPSS statistical package. TP53 and POLE mutations, microsatellite instability (MSI), time-to-event and clinicopathological parameters were compared among 512 endometrial cancer cases. Deleterious POLE-mutations were identified by Polyphen2. Progression free survival was studied using Kaplan-Meier plots keeping original ‘POLE’ as comparator. ResultIn presence of wild type (WT)-TP53, other deleterious POLE-mutations behaved like POLE-EDM. Only truncated and not missense TP53 benefitted from POLE/MSI overlap. However, TP53 missense mutation, Y220C, was found to be as favourable as ‘POLE’. Overlapping POLE, MSI and WT-TP53 also performed favourably. Truncated TP53 overlapped with POLE and/or MSI, TP53 Y220C alone and, WT-TP53 overlapped with POLE and MSI both, were named ‘POLE-like’ for prognostically behaving like the comparator ‘POLE’. ConclusionObesity being a lesser frequent event in low and middle-income countries (LMICs), relative proportion of women with lower BMI and Type 2 endometrial cancers may be high. Identification of ‘POLE-like’ groups may facilitate therapeutic de-escalation in some TP53-mutated cases - a novel option. Instead of 5% (POLE-EDM), potential beneficiary would then comprise 10% (POLE-like) of TCGA-UCEC.

¿Qué debe irradiarse tras tratamiento sistémico primario?

The indications for primary chemotherapy (PTC) in breast cancer patients have widened in recent years. This therapeutic paradigm shift has led to a rethinking of the surgical approach to the axilla and a challenge in defining the indications for adjuvant loco-regional radiotherapy. Therapeutic decision-making was initially extrapolated and based on evidence from randomized studies in the context of primary surgery.The scenario of nodal involvement at diagnóstico is particularly controversial. To reduce the morbidity arising from complete axillary lymphadenectomy (AL), the trend over the last decade has been towards therapeutic de-escalation at the axillary level.

Abstract 2217: Novel risk stratification utilizing NanoString for HPV+ head and neck cancer patients

Abstract Incidence of human papillomavirus positive (HPV+) head and neck squamous cell carcinoma (HNSCC) has dramatically increased in the U.S. surpassing cervical cancer since 2012. Among HNSCC, HPV+ HNSCC patients have a favorable prognosis; however, approximately 20-30% suffer recurrence. Given the morbidity of current therapy, therapeutic de-escalation for HPV+ HNSCC is being explored in many clinical trials but is hampered by absence of accurate molecular classifiers to identify tumors at high and low risk of recurrence. Being able to risk stratify patients can help with therapeutic decisions, maintain high cure rates and decrease treatment associated complications. We assemble a NanoString panel to capture our recently developed NF-κB RNA signature that can distinguish patients requiring aggressive therapy from patients who are appropriate for reduced intensity treatment. Our custom gene set can select HPV+ head and neck cancer patients that may benefit from therapy de-escalation. Several advantages of using a NanoString technology, including smaller amounts of patient samples and less processing time that allow real-time patient-specific results. This makes our Nanostring panel suitable to be used in clinic to identify HPV+ head and neck cancer patients for therapeutic de-escalation without compromising their survival. Citation Format: Sulgi Kim, Travis Schrank, Aditi Kothari, Hina Rehmani, Jason Tasoulas, Xue Li, Wendell Yarbrough, Natalia Isaeva. Novel risk stratification utilizing NanoString for HPV+ head and neck cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2217.

Physicians' Opinion on Intraoperative Radiotherapy as a Therapeutic De-Escalation Option in Older Women with Early Breast Cancer.

Intraoperative radiotherapy (IORT) is a therapeutic de-escalation option in older women with low-risk early breast cancer (EBC). A qualitative study was implemented to describe EBC physicians' points of view on IORT as a de-escalation option. Recorded face-to-face and telephone semi-structured interviews were conducted among diverse physicians from seven French comprehensive cancer centers. Interview transcripts were grouped as corpus to construct a typology. Thematic analysis was performed. Positions toward IORT were contrasted between the 16 participating physicians. Five fully supported IORT as a de-escalation option, four were not in favor, and seven had a more reserved or neutral opinion. Points of divergence concerned treatment efficacy, treatment duration, side effects and sequelae, psychological impact, compliance with adjuvant endocrine therapy, logistical constraints, financial cost, and availability of other techniques of partial breast irradiation. Physicians in favor of IORT emphasized direct benefits for the patient, and those against pointed the lack of specific guidelines, risk of lost opportunity in older women with long life expectancy, and challenges of shared decision making. Despite national policies to preserve cancer patients' quality of life and increase their participation in medical decision making, therapeutic de-escalation using IORT is not consensual among physicians. Further efforts are needed to promote patient-centered care.

Towards adaptive structuring of the lupologist’s consultation to transform the care pathway of systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a complex autoimmune disease, which can be clinically heterogeneous in the same patient over the disease process and has an unpredictable evolution. Although its prevalence is increasing, SLE remains a rare disease with frequent extra-articular manifestations managed by multiple specialists. Among these, the internist is a key player in the overall coordination of the care pathway. The dramatic improvement in the short-term prognosis of SLE observed over the past few decades has favoured the emergence of more chronic disease-associated morbidities, especially infectious, cardiovascular and/or related to sequelae, notably renal. Thus, every lupologist is confronted with the difficulty of having to address, in an educational, individualised but also systematic way, a certain number of key items on which the short-, medium- and long-term medical future of patients who develop SLE at a relatively young age depend. In recent years, in addition to the creation of a network of reference centres and the drafting of regularly updated national therapeutic guidelines and therapeutic education programs, international consensus about the factors to consider in SLE patients has been reached, including the definition of therapeutic objectives according to a treat-to-target (T2T) strategy. However, the translation of these new objectives/paradigms in real-life has encountered a number of difficulties. As part of a multidisciplinary team involving SLE patients, we developed practical tools in the form of CHECKLISTs addressing the problems of refractory SLE (D2T), the management of comorbidities and toxicities (BASICs), and, more recently, therapeutic de-escalation with a shared medical decision (T2U). It appears that there is an opportunity to transform the care pathway of SLE patients by allowing the implementation of these tools within adaptive structuring of the consultation, which has the advantage of defining a starting point within the care pathway as a common denominator for lupologists, regardless of their specialty or where they work.

Determination of biomarkers associated with neoadjuvant treatment response focusing on colibactin-producing Escherichia coli in patients with mid or low rectal cancer: a prospective clinical study protocol (MICARE)

IntroductionThe management of mid and low rectal cancer is based on neoadjuvant chemoradiotherapy (CRT) followed by standardised surgery. There is no biomarker in rectal cancer to aid clinicians in foreseeing...

Criteria Associated with Treatment Decisions in Juvenile Idiopathic Arthritis with a Focus on Ultrasonography: Results from the JIRECHO Cohort.

The treatment of children with juvenile idiopathic arthritis (JIA) to prevent disability is a major challenge in paediatric rheumatology. The presence of synovitis, which is difficult to detect in children, is associated with structural damage. Musculoskeletal ultrasonography (MSUS) can be used in patients with JIA to reveal subclinical synovitis. The primary aim was to determine whether the use of MSUS was associated with therapeutic modification in patients with JIA. The secondary aim was to identify other factors associated with therapeutic decisions. We conducted an observational study based on the JIRECHO multi-centre cohort, which was developed to provide a systematic MSUS follow-up for patients with JIA. Follow-up occurred every 6months and included clinical and MSUS examinations. We included children who underwent MSUS of the elbows, wrists, second metacarpophalangeal joints, knees and ankles, which was performed by expert sonographers. Clinical and biological data, disease activity scores and information on therapeutics were collected. A total of 185 visits concerning 112 patients were recorded. Three groups were defined according to the therapeutic decision: escalation (22%, n = 40), de-escalation (14%, n = 26) or stable (64%, n = 119). In the "therapeutic escalation" group: the presence of ultrasonographic synovitis in B-mode and the presence of grade 2 or 3 synovitis in B-mode were not significantly more frequent than in the "stable therapeutic or de-escalation" group (80% versus 65%, p = 0.06; 33% versus 19%, p = 0.06), and the patient's and physician's visual analogue scale (VAS) scores, the clinical JADAS and the C-reactive protein level were significantly higher, but only physician's VAS score remained in the model of logistic regression. In the "therapeutic de-escalation" group: there was no difference in the presence of US synovitis compared with the "stable therapeutic or escalation" group (62% versus 69%, p = 0.48). Even though US synovitis tended to be more frequent in patients with therapeutic escalation, the study did not show that the presence of synovitis in MSUS was statistically associated with therapeutic modifications in patients with JIA. Treatment remained stable despite the presence of US synovitis.

Thyroid cancers in children and adolescents in France: Incidence, survival and clinical management over the 2000-2018 period.

Thyroid cancer is the first cause of endocrine malignancy among children. Over the past decades, an increase in the incidence rates (IR) has been observed around the world. Our study aimed to describe epidemiology, therapeutic management and survival rates of children and adolescents with thyroid cancer in France. A population-based study was conducted between 2000 and 2018 in children and adolescents less than 17 years with a diagnostic of thyroid cancer. A total of 774 thyroid cancers were included: 579 papillary (PTC), 83 follicular (FTC), and 111 medullary carcinomas (MTC). PTC are more frequent in females and in adolescents whereas MTC mainly concerned children, mostly with a familial predisposition. Almost all patients underwent thyroidectomy, completed for most patients with PTC and FTC by radioiodine therapy. Cervical dissection was performed more frequently in patients having PTC and MTC compared to those with FTC. Between 2000 and 2018, thyroid cancers IR in children fluctuated between 1.3 and 3.2 per million, without any significant trend. The median follow-up time was 11.3 years in children, and 5.7 years in adolescents. The 5year-OS was greater than 98.5%. Population-based studies are crucial for better understanding and delineation of best management of rare diseases as thyroid cancers in pediatric and adolescent population. Considering the very favorable survival, a stratification should be proposed between cases at low risk and cases at high risk of relapse, in order to consider a strategy of therapeutic de-escalation in the most favorable cases.

Accelerated Partial Breast Irradiation: An Opportunity for Therapeutic De-escalation.

Partial breast irradiation (PBI) has been demonstrated to have comparable outcomes to whole breast irradiation based on multiple randomized trials with long-term follow-up. However, despite the strength of the data available, PBI remains underutilized despite being an appropriate option for many women diagnosed with early-stage breast cancer. This is significant, as PBI offers the potential to reduce toxicities and shorten treatment duration without impacting outcomes; in addition, for low-risk patients, PBI alone is being investigated as an alternative to endocrine therapy alone. Modern PBI can be delivered with multiple techniques, and advances in treatment planning have allowed for improved therapeutic ratios compared with earlier techniques; one such approach is utilizing stereotactic body radiation therapy approaches allowing for smaller target margins and therefore lower breast doses. Moving forward, studies are ongoing evaluating the use of radiation alone including PBI as compared with endocrine therapy alone, with prospective studies evaluating stereotactic body radiation therapy.

147P Blind validation of an AI-based tool for predicting distant relapse from breast cancer HES stained slides

147P Blind validation of an AI-based tool for predicting distant relapse from breast cancer HES stained slides

Cancer de l’endomètre de stade localisé : la perspective d’une désescalade thérapeutique guidée par la classification moléculaire

In Europe, endometrial cancer is the fourth most common cancer among women. The majority of patients are diagnosed at a localized stage. For these patients, the standard of care is based on an hysterectomy with salpingo oophorectomy±lymph node staging. Through the assessment of histopathologic features, risk groups are determined: low, intermediate, high-intermediate, and high risk. Adjuvant strategies are guided by these risk groups. While the prognosis of low-risk and high-risk is well known, that of intermediate and high-intermediate risk is more heterogeneous, and the therapeutic index of adjuvant treatments is more questionable. Several trials (PORTEC [Post Operative Radiation Therapy in Endometrial Carcinoma] I, GOG [Gynecologic Oncology Group] 99, ASTEC [A Study in the Treatment of Endometrial Cancer] EN.5, PORTEC II, Sorbe et al trial) have assessed observation, vaginal cuff brachytherapy and/or pelvic external beam radiotherapy in this population. Vaginal cuff brachytherapy reduces the local recurrence rate, and pelvic external beam radiotherapy the pelvic recurrence rate. However, no benefit in terms of overall survival or occurrence of distant metastases is highlighted. Compared to observation, brachytherapy and above all external beam radiotherapy are associated with an increased morbidity, and with a decreased quality of life. In order to improve the therapeutic ratio and to optimize medico-economic decisions, therapeutic de-escalation strategies, based on the molecular profiles, are emerging in clinical trials, and in the recommendations for the management of intermediate and high-intermediate risk endometrial cancers. The four main molecular profiles highlighted by the genomic analyzes of The Cancer Genome Atlas (TCGA) – POLE (polymerase epsilon) mutation, non-specific molecular profile, MMR (MisMatch repair) deficiency, and p53 mutation – but also the quantification of lymphovascular space invasion (absent, focal or substantial), and the assessment of L1CAM (L1 cell adhesion molecule) overexpression represent growing concerns. Thus, the use of molecular-integrated risk profile to determine the best adjuvant treatment represent a major way to personalize adjuvant treatment of endometrial cancers, with therapeutic de-escalation opportunity for around half of the high-intermediate risks. However, in the absence of prospective data, inclusion in clinical trials assessing molecular profile-based treatment remains the best therapeutic opportunity.

CIC-DUX4 sarcomas.

CIC-DUX4 sarcoma (CDS) is a high-grade undifferentiated round cells sarcoma that belongs to the undifferentiated round cell sarcomas family. It represents less than one percent of sarcomas, defining a rarest among rare malignancies. It affects young adults, displaying soft tissue mass. Considered very aggressive, a high proportion of cases display an advanced disease with lung metastasis at diagnosis. Here we discuss recent progress in molecular characterization of CDS, the main tracks of CDS biology and the current and future prospects of therapeutic approaches. CDS is characterized by a specific oncogenic translocation CIC::DUX4 that induce ETV4 overexpression. Patients with CDS show an aggressive clinical course and have a significantly unfavorable outcome compared to Ewing sarcoma. As of today, there is a lack of consensus on whether they should be treated with an Ewing-like approach, as currently done by most sites, or regarded as high-grade soft tissue sarcoma (STS). Anyway, when feasible, combination regimens including anthracycline and alkylating agents should be favored and patients should not benefit from a therapeutic de-escalation. Overall, registration within clinical trials and prospective registries is recommended. Overall, CDS showed a poor prognosis regardless of the patterns of treatment that warrant biological studies to better understand the disease.

76P How to explain current reluctance against therapeutic de-escalation: Results of the exploratory qualitative phase of the mixed method research program CARTE therapy in older women with early breast cancer in France

Intraoperative radiotherapy (IORT) as a therapeutic de-escalation option is in France still limited and not recommended in national guidelines. In context of CARTE research program, a qualitative study was implemented among physiciansto better understand reluctance toward de-escalation treatment.