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Background The long-term survival of germline retinoblastoma patients is decreased due to the risk of second primary tumors (SPTs) that occur years after the diagnosis of retinoblastoma. This risk is related to genetic predisposition and other factors, such as the treatment of retinoblastoma by external beam radiotherapy (EBRT). Procedure We studied the incidence, risk factors, and prognosis of specific craniofacial SPTs developed within the margins of radiation field in a cohort of 209 patients with germline retinoblastoma treated with EBRT at our institution between 1977 and 2010. Clinical characteristics, survival, incidence, and histology of craniofacial SPTs were recorded. Results Fifty-three of the 209 patients developed 60 distinct craniofacial SPTs in irradiated field with a median time from EBRT of 16.9 years (4-35) and a median follow-up of 24.8 years (5.3-40). Osteosarcoma (33.3%) and undifferentiated sarcoma (23.3%) were the more prevalent histological entities. Benign tumors (16.7%) also occurred. The cumulative incidence of craniofacial SPTs reached 32.6% at 35 years after EBRT, and the median survival after diagnosis was five years. In our series, irradiation under 12 months of age, bilateral EBRT, or previous treatment of retinoblastoma with chemotherapy did not significantly increase the risk of craniofacial SPTs. Conclusions This work presents a strong argument to avoid EBRT in the management of retinoblastoma and emphasizes the high risk and poor prognosis of specific craniofacial SPTs. This study also points to the question of the need and benefits of special programs for early detection of craniofacial SPTs in survivors of irradiated germline retinoblastoma.

Background After treatment of primary ocular uveal melanoma (UM), up to 50% of patients will develop metastases, mostly in the liver. Systemic treatments do not provide any overall survival benefit for these patients and surgery remains the most effective therapy for selected patients. Radiofrequency ablation (RFA) alone or in combination with surgery is frequently used to spare hepatic parenchyma. When patients relapse after treatment of their first metastases, and when the liver recurrence is limited, new local liver treatment is questionable. Methods A total of 14 patients with liver metastases from uveal melanoma (LMUM) were retrospectively evaluated. All patients had a complete first liver resection and a second treatment with RFA. Overall survival, recurrence-free interval after the first and the second treatment was evaluated. Results Treatment of hepatic recurrence was percutaneous RFA for ten patients and per-operative RFA for four patients associated with new metastasectomy. The median time to onset of LMUMs after ocular UM treatment was 50 months, and the median time to recurrence of hepatic metastasis after the first liver treatment was 20 months. The overall survival was 70% at five years and 35% at ten years. The recurrence-free interval was 50% and 56% at two years after the first and the second treatment, respectively. Conclusion Prolonged survival can be achieved by exclusive and iterative local treatment combining surgery and RFA in a small proportion of patients with a first recurrence of isolated LMUM.

Background and purposeFew data are available concerning the safety of bevacizumab (B) in combination with locoregional radiation therapy (RT). The objective of this study was to evaluate the 5-year late toxicity of concurrent B and RT in non-metastatic breast cancer.Materials and methodsThis multicentre prospective study included non-metastatic breast cancer patients enrolled in phase 3 clinical trials evaluating B with concurrent RT versus RT alone. All patients received neoadjuvant or adjuvant chemotherapy and normofractionated breast or chest wall RT, with or without regional lymph node RT. B was administered at an equivalent dose of 5 mg/kg once a week for 1 year. The safety profile was evaluated 1, 3 and 5 years after completion of radiotherapy.ResultsA total of 64 patients were included between November 2007 and April 2010. Median follow-up was 60 months (12-73) and 5-year late toxicity data were available for 46 patients. The majority of tumours were triple-negative (68.8%), tumour size ConclusionConcurrent B and locoregional RT are associated with acceptable 5-year toxicity in patients with non-metastatic breast cancer. No grade ≥3 toxicity was observed.

Patients with liver metastases of uveal melanoma (LMUM) die from their metastatic evolution within 2 years. We established a nomogram to choose a treatment adapted to life expectancy. From 2002 to 2013, we reviewed 224 patients with LMUM selected by liver MRI. A nomogram was developed based on a Cox model. The predictive performance of the model was assessed according to the C-statistic, Kaplan&ndash, Meier curve, and calibration plots. The median follow-up was 49.2 months (range, 0.6&ndash, 70.9). The survival rates at 6, 12, and 24 months were 0.88 (0.95 CI [0.84&ndash, 0.93]), 0.68 (0.95 CI [0.62&ndash, 0.75]), and 0.26 (0.95 CI [0.21&ndash, 0.33]), respectively. The four factors selected for the nomogram with a worse prognosis were: A disease-free interval between the UM and LMUM groups of less than 6 months (HR = 3.39, 0.95 CI [1.90&ndash, 6.05]), more than 10 LMUM (HR = 3.95, 0.95 CI [1.97&ndash, 4.43]), a maximum LMUM of more than 1200 mm2 (HR = 2.47, 0.95 CI [1.53&ndash, 3.98]), and a lactate dehydrogenase (LDH) value greater than 1.5 (HR = 3.72, 0.95 CI [2.30&ndash, 6.00]). The model achieved relatively good discrimination and calibration (C-statistic 0.71). This nomogram could be useful for decision-making and risk stratification for therapeutic options.

Background Vascular anomalies (VA) may cause severe tracheomalacia in some cases. Chronic upper airway obstruction (UAO) is the most common symptom. Increased pulmonary pressure and cardiac dysfunction have been described in patients with chronic UAO, but not in infants with VA. Aim The aim of this study was to evaluate myocardial strain in infants with VA. Method Demographics characteristics, respiratory symptoms, and the percentage of tracheal obstruction measured on CT were collected. Left and right ventricle (LV, RV) systolic function were measured with speckle tracking longitudinal strain (LS) analysis. Pulmonary artery pressure was evaluated on tricuspid regurgitation (TR) jet and quantified by end-systolic eccentricity index (EI). Conclusion Of 15 cases, 6 had tracheal obstruction 50%. LS LV and RV was significantly reduced in cases with obstruction > 50% compared to those with 50%. There are no significant data for TR and EI. Results In cases with VA with severe tracheomalacia RV and LV myocardial strain is reduced, suggesting myocardial impairment. Further studies with larger sample size are needed to confirm these data and investigate cardiac function. Association with lung function test may be investigated too.

Introduction Patients affected by esophageal atresia (EA) often faced airway problems, due to multifactorial dynamics (tracheomalacia, gastroesophageal reflex disorder, etc.). The aim of this study was to longitudinally evaluate the lung function test (LFT) in those infants to explore how the LFT modifies at mid-term follow-up. Methods Retrospective evaluation of lung functions in infants treated for EA (2010–2017) was performed at three time points: 6 months, 12 months, and 24 months. Tidal volume (Vt), respiratory rate (RR), and time to peak tidal expiratory flow as a percentage of total expiratory time (tPTEF/te) were analyzed. ANOVA test was used as appropriate. Results During the study period 172 patients were treated for EA. Of those 50 infants (28%) underwent LFT at 6 months, 30 at 12 months, and 11 at 24 months. Tracheomalacia was present in 20 infants (42%). Both Vt (6,79 ml/kg vs 7,82 ml/kg vs 8,37 ml/kg—p = 0,001) and RR (49,7 a/min vs 40,6 a/min vs 34,0 a/min—p = 0,020) significantly improved, while there was no significant difference for tPTEF/te (0,25 vs 0,26 vs 0,29—p = 0,62) despite the data showing an improvement trend. Conclusion The preliminary data suggest that, although EA patients may present impaired LTF in early infancy, lung function seems to improve over time, showing normal pulmonary function test at 24 months. The presence of selection bias and the retrospective nature of the study limit our result. Nonetheless, evaluation of lung function is warranted in EA infants to early detect respiratory symptoms, ideally reducing the impact on short- and long-term pulmonary outcomes.

Context Advance care planning is essential to enable informed medical decisions to be made and to reduce aggressiveness in end-of-life (EOL) care. Objectives This study aimed to explore whether a question prompt list (QPL) adapted to French language and culture could promote discussions, particularly on prognosis and EOL issues, among advanced cancer patients attending outpatient palliative care (PC) consultations. Methods In this multicenter randomized study, patients assigned to the intervention arm received a QPL to help them prepare for the next consultation one month later. The main inclusion criteria were advanced cancer patients referred to the PC team with an estimated life expectancy of less than one year. The primary endpoint was the number of questions raised, globally and by topic. The secondary objectives were the impact of the QPL on psychological symptoms, quality of life, satisfaction with care, and coping styles at two months. Results Patients (n = 71) in the QPL arm asked more questions (mean 21.8 vs. 18.2, P = 0.03) than patients in the control arm (n = 71), particularly on PC (5.6 vs. 3.7, P = 0.012) and EOL issues (2.2 vs. 1, P = 0.018) but not on prognosis (4.3 vs. 3.6, not specified). At two months, there was no change in anxiety, depression, or quality of life in either arm; patient satisfaction with doctors' technical skills was scored higher (P = 0.024), and avoidance coping responses were less frequent (self-distraction, P = 0.015; behavioral disengagement, P = 0.025) in the QPL arm. Conclusion Questions on PC and EOL issues in outpatient PC consultations were more frequent, and patient satisfaction was better when a QPL was made available before the consultation.

To analyse long-term overall survival, relapse-free survival and late toxicities in a series of 675 patients treated between 1999 and 2003, with a median follow-up of 132 months.The cohort included low-risk patients and a selection of "favourable-intermediate" risk patients. All patients were homogeneously treated using an intraoperative dynamic planning prostate brachytherapy technique, with loose 125 iodine seeds. Hormone therapy, consisting most often of an anti-androgen alone, was given in 393 patients (58%).The 10-year overall survival was 92% (95% confidence interval [CI]: 90-94) without a significant difference between the low and the select intermediate-risk groups (P=0.17). The 10-year relapse-free survival rate for the entire cohort was 82% (95% CI: 79-85), and was significantly higher in the low-risk group than in the intermediate one (87 vs 71%; P0.0001). Twenty-six percent of the relapses observed in this series occurred after more than 10 years of follow-up. The 10-year cumulative incidence of grade 3-4 urinary toxicity (whatever the delay and the recovery) was 5.78%. The cumulative incidence of grades 3-4 rectal toxicity in the present series was 1.65% at 10 years. As for sexual toxicity, 61% of our patients retained an erectile capacity at 10 years (with or without oral medication), with age being a major factor.With a median follow-up of more than 11 years, this series appears to confirm the excellent long-term results of low-dose rate prostate brachytherapy, both in terms of survival and in terms of toxicity.

Purpose: To report the results of a randomised study comparing the efficacy of Hydrosorb® versus control (water based spray) in the topical treatment of grade 1 and 2 radiation dermatitis in population of patients treated for early stage breast cancer (BC) with normo fractionated radiotherapy (RT). Patients and Methods: Breast cancer patients with grade 1-2 radio-induced dermatitis during normo fractionated postoperative radiotherapy were eligible (according to the CTCAE v3 scale). They were randomised to receive either Hydrosorb® (A) or water based spray (B). The primary endpoint was local treatment failure defined as interruption of radiotherapy because of skin radiotoxicity or and/or change of local cares for skin alteration. Secondary endpoints were the evaluation of skin colorimetry, pain, and quality of life. Pain was assessed according to two classes with a VAS cut-off of 2. Results: Two-hundred seventy eight patients were enrolled (A = 142, B = 136). There were 186 successfully treated patients (82 in Hydrosorb® arm, and 74 in the control arm). There were 60 "failures" in the Hydrosorb® arm, and 62 in the control arm (p = 0.72), but mostly without interruption of the radiotherapy. Twenty-four patients stopped the radiotherapy treatment for local cares (16 in Hydrosorb®, arm and 8 in control arm). No risk factors were associated with failure to local treatment. The average absolute reduction of colorimetric levels between day 28 and day 0 was 4 in the Hydrosorb®, and 4.2 in the water spray groups, respectively (p = 0.36). Forty-eight patients in the Hydrosorb® arm had a VAS > 2 versus 51 patients in the placebo arm, i.e. 34% and 38%, respectively (p = 0.45). A significant reduction of pain was observed on D7 (p = 0.04) and D21 (p = 0.01) in the Hydrosorb® arm. Sixty patients in the Hydrosorb® arm and 55 patients in the placebo arm had moderately to severely altered quality of life (p = 0.76). Conclusions: The present study showed no significant difference between Hydrosorb® and simple water spray in the treatment of acute radio-induced dermatitis even if there was a trend to an improvement in pain at the first weeks after the treatment. Systematic prevention measures and modern breast cancer radiotherapy techniques now allow excellent tolerability, but the place of topical treatment to optimize this tolerability has yet to be defined. Citation Format: Bazire L, Fromentin I, Diallo A, de Lalande B, Pernin V, Dendale R, Fourquet A, Savignoni A, Kirova Y. Hydrosorb® versus control (water based spray) in the management of radio-induced skin toxicity: Results of multicentre controlled randomized trial. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-12-16.

BACKGROUND: The benefit of chemotherapy for patients with estrogen receptor(ER)+ HER2- breast cancers is an ongoing question. The evaluation of the tumor's proliferation by Ki67 may guide the indication but no consensual predictive cut-off has been set yet. MATERIALS AND METHODS: This study included women with a first ER+HER2- invasive breast cancer treated by primary surgery between 2003 and 2008. Data was collected prospectively. Ki67 cut-off was sequentially set each 1% from 5% to 30%. For each threshold, the interaction between Ki67 and adjuvant chemotherapy was integrated in a multivariate Cox model to determine when it became statistically significant in predicting distant-disease free survival (DDFS). Using different Ki67 cut-offs, we also compared DDFS of patients who had or not an indication of chemotherapy, depending on whether they actually received it or not. RESULTS: Among the 3221 breast cancers, median Ki67 was 10%, with a mean of 15% (S.D = 14). Ki67 was an independent prognosis factor whether the cut-off was set to 14% or to 20% (p CONCLUSION: In ER+ HER2- breast cancers, a Ki67 level of expression >= 20% was predictive of benefit from adjuvant chemotherapy. A threshold at 14% was not as discriminant. Based on this large cohort study, we recommend the use of a cut-off at 20% to decide whether patientes with ER positive tumors should receive chemotherapy or not/. Citation Format: Rouzier R, Rossi L, Lerebours F, Savignoni A, Falcou M-C, Bonneau C, Pierga J-Y, Guinebretière J-M. Ki67 cut-off point to predict the benefit of adjuvant chemotherapy in ER+ HER2- breast cancer patients. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-07-63.

Background: There is a lack of information as to which molecular processes, present at diagnosis, favor tumour escape from standard-of-care treatments in cervical cancer (CC). RAIDs consortium (www.raids-fp7.eu), conducted a prospectively monitored trial, [BioRAIDs (NCT02428842)] with the objectives to generate high quality samples and molecular assessments to stratify patient populations and to identify molecular patterns associated with poor outcome. Methods: Between 2013-2017, RAIDs collected a prospective CC sample and clinical dataset involving 419 participant patients from 18 centers in seven EU countries. Next Generation Sequencing has so far been carried out on a total of 182 samples from 377 evaluable (48%) patients, allowing to define dominant genetic alterations. Reverse phase protein expression arrays (RPPA) was applied to group patients into clusters. Activation of key genetic pathways and protein expression signatures were tested for associations with outcome. Findings: At a median FU of 22 months, progression-free survival rates of this FIGO stage IB1-IV population, treated predominantly (87%) by chemoradiation, were 65*4% [CI95%: 60*2-71.1]. Dominant oncogenic alterations were seen in PIK3CA (40%), while dominant suppressor gene alterations were seen in KMT2D (15%) and KMT2C (16%). Cumulative frequency of loss-of-function (LOF) mutations in any epigenetic modulatorgene alteration was 47% and it was associated with PIK3CA gene alterations in 32%. Patients with tumours harbouring alterations in both pathways had a significantly poorer PFS. A new finding was the detection of a high frequency of gains of TLR4 gene amplifications (10%), as well as amplifications, mutations, and non-frame-shift deletions of Androgen receptor (AR) gene in 7% of patients. Finally, RPPA protein expression analysis defined three expression clusters. Interpretation: Our data suggests that patient population may be stratified into four different treatment strategies based on molecular markers at the outset. Funding: European Union's Seventh Program grant agreement No 304810. Declaration of Interest: All authors declared: No conflict of interest. Ethical Approval: Ethical review was conducted according to national requirements and in accordance with the Declaration of Helsinki. All tumour and serum samples and clinical data were registered in a common database using a unique barcode system assuring data privacy.

Palbociclib, ribociclib, and abemaciclib have been investigated in combination with aromatase inhibitors as first-line therapy for metastatic hormone receptor-positive breast cancer (PALOMA-2, MONALEESA-2 and MONALEESA-7, MONARCH-3 trials, respectively); pivotal trials led to absolute median progression-free survival (PFS) gain of about 15 months. We aimed to estimate, for each trial, the statistical power to demonstrate a significant gain in overall survival (OS). Power was calculated with Freedman’s formula. Given the allocation ratio and the number of events, power was computed as a function of hazard ratio. We focused on four specific hazard ratio values (0.94, 0.89, 0.81, and 0.77), which are estimated to correspond to absolute 3, 6, 12, and 15 months gain in OS, respectively. For these calculations, the type I error rate was stated at 5% with a two-sided test, and we assumed that the risk of death was constant over time. PALOMA-2 and MONALEESA trials have an almost similar power despite different allocation ratios, while MONARCH-3 has a more limited power. Overall, the power of the four trials to demonstrate a statistically significant improvement in OS is less than 70% if the prolongation in median OS is ≤12 months, whatever the OS data maturity. This analysis shows that OS results are jeopardized by limited powers, and a meta-analysis might be required to demonstrate OS benefit. Conversely, if a significant OS improvement is observed in some but not at all trials, this discrepancy might be more attributable to chance than to a truly different drug efficacy.

Introduction Dans le cadre d’une etude retrospective de patients atteints d’un cancer et exposes au cours de leur suivi a des dispositifs medicaux implantables (DMI), nous nous interessons a l’analyse de l’impact d’une exposition dependante du temps sur le risque de deces. Les modeles comme le modele de Cox ou exponentiel par morceaux (Em) font l’hypothese que le risque instantane d’evenement a l’instant t ne depend que de l’exposition a t et non des expositions recues jusqu’a t−. Le modele WCE (« Weighted Cumulative Exposure ») permet de prendre en compte les expositions passees et d’en etudier l’effet cumule en estimant une courbe ponderant les valeurs de ces expositions [1] . Ce modele est semi-parametrique, comme le modele de Cox et contrairement au modele Em qui suppose une fonction de risque instantane de base constante par morceaux. Il permet le calcul d’hazard ratios associes a differentes trajectoires d’expositions. Methodes L’objectif de ce travail est de comparer, a l’aide de simulations, le modele WCE au modele de Cox et au modele Em avec : – application de differentes courbes de ponderation definissant l’influence des expositions passees sur le risque instantane a l’instant t, allant d’une influence faible (ce cas de figure se rapprochant de l’hypothese faite par les modeles de Cox et Em) a une influence importante ; – le taux de censure variant entre 0 % et 80 % ; – la fonction de risque instantane de base des temps d’evenements qui est soit issue d’une loi uniforme, soit parametree par une fonction constante par morceaux. Dans ce dernier cas, deux modeles Em ont ete appliques, correctement et incorrectement specifies. La metrique utilisee pour les modeles de Cox et Em est le biais entre l’effet estime par ces modeles et la vraie valeur de l’effet de l’exposition a l’instant t sur le risque instantane a t ; la metrique utilisee pour le modele WCE est l’ecart moyen entre les courbes de poids estimees et la vraie courbe de ponderation. Suite aux resultats de ces simulations, le modele le plus interessant a ete applique aux donnees de l’etude retrospective. Resultats Le modele WCE est performant quel que soit le niveau d’influence des expositions passees sur le risque instantane d’evenement. Les modeles de Cox et Em surestiment l’effet de l’exposition recue a l’instant t lorsque les expositions passees ont une influence importante. Nous avons donc applique le modele WCE aux donnees de l’etude. Aucun effet significatif de l’effet cumule des expositions aux differents types de DMI sur le risque de deces n’a pu etre mis en evidence. Conclusion Le modele WCE semble etre approprie lorsqu’il n’existe pas de connaissance a priori sur la dynamique de l’exposition etudiee. Il reste cependant plus complexe a interpreter qu’un modele de Cox et il est par consequent preferable d’utiliser ce dernier lorsque qu’il existe une connaissance clinique fiable de l’absence d’effet cumule des expositions passees.

Background: Trastuzumab was introduced a decade ago and has improved outcomes for HER2-positive breast cancer. We investigated the factors predictive of pathological complete response (pCR), prognostic factors for disease-free survival (DFS), and interactions between pCR and DFS after neoadjuvant treatment. Methods: We identified 287 patients with primary HER2-positive breast cancers given neoadjuvant chemotherapy (NAC) between 2002 and 2011. Univariate and multivariate analyses of clinical and pathological factors associated with pCR and DFS were performed. Results: pCR rates differed between patients receiving neoadjuvant trastuzumab treatment or not (47.7% versus 19.3%, P

Purpose To report the efficacy of Hydrosorb® versus control (water based spray) as topical treatment of grade 1–2 radiodermatitis in patients (pts) treated for early stage breast cancer (BC) with normo fractionated radiotherapy (RT). Patients and methods BC pts were randomized to receive either Hydrosorb® (A) or water based spray (B). The primary endpoint was local treatment failure defined as interruption of RT because of skin radiotoxicity or change of local care because of skin alteration. Secondary endpoints were: evaluation of skin colorimetry, pain, quality of life. Results Two-hundred seventy-eight pts were enrolled. There were 186 successfully treated pts. There were 60 "failures" in the Hydrosorb® arm, and 62 in the control arm ( p =0.72), but mostly without interruption of the RT. Twenty-four pts stopped RT for local care. The average absolute reduction of colorimetric levels between day 28 and day 0 was 4 in the Hydrosorb®, and 4.2 in the water spray groups, respectively ( p =0.36). Forty-eight patients in the Hydrosorb® arm had a VAS >2 versus 51 pts in the placebo arm, i.e. 34% and 38%, respectively ( p =0.45). A significant reduction of pain was observed on D 7 and D 21 in the Hydrosorb® arm. Conclusions The present study showed no significant difference between Hydrosorb® and simple water spray in the treatment of acute radio-induced dermatitis even if there was a trend to an improvement in pain at the first weeks after the treatment. Systematic prevention measures and modern breast cancer radiotherapy techniques now allow excellent tolerability, but the place of topical treatment to optimize this tolerability has yet to be defined. It seems that the most important part of the skin care is the prevention of skin reactions using new adapted techniques, as well as strict hygiene.

Summary Introduction To describe the results of retinoblastoma treatment from 1995–2009 in a single institution. Material and methods Retrospective review of the charts of patients treated for retinoblastoma. Clinical characteristics at diagnosis, treatments and outcomes in terms of survival and ocular preservation are described. Results During the study period 826 children were referred for retinoblastoma and 730 were managed in our institution. Four hundred and eleven children presented with unilateral retinoblastoma and 319 with bilateral retinoblastoma. Median follow-up is of 93 months. Global survival is 98.5% of children, 10 children presented with second tumors, 11 children died (6 of tumor-related causes). Of the 411 children with unilateral retinoblastoma enucleation was needed at diagnosis for 324 (78.8%). Conservative treatments were attempted for 87 patients (21.2%) and ocular preservation obtained for 65 patients (74% of eyes). Three hundred and nineteen patients presented with bilateral retinoblastoma. Three hundred and ten could be treated conservatively for at least one eye. Initial intravenous chemotherapy was necessary for 75% of them. Ocular preservation without external beam radiation was possible for 221 patients (70%). The use of EBR decreased significantly after 2004 (9.1% of eyes vs 25.1%: P Discussion Management and treatment of retinoblastoma are complex, adapted to the extent of the disease. Survival is good. Enucleation is still required for extensive ocular disease, especially for unilateral patients. Intravenous chemotherapy allows good tumor control and eye preservation and decrease the need of EBR. Conclusions Retinoblastoma treatment with intravenous chemotherapy and ocular adjuvant therapies is very effective on the local tumor control and eye preservation.

International audience; Retinoblastoma (Rb) results from biallelic inactivation of the RB1 gene. Hereditary Rb patients i. e germline carriers of a RB1 mutation also have a risk of developing subsequent malignant neoplasms (SMN) such as os-teosarcomas. This SMN risk is maximized by external beam radiotherapy treatments (EBRT), which is why these treatments are now avoided. Nevertheless, EBRT is still a matter of great concern, as EBRT-treated patients are in their adulthood and SMNs remain the major cause of death for patients. To decipher the relationship between RB1 genotype and SMN development in EBRT treated patients, we conducted a retrospective study in a cohort of 160 irradiated hereditary Rbs with fully resolved RB1 mutational status. Median follow-up was 22 years [1-51] and median age of patients was 27 years old [7-53]. Among these 160 Rb patients, 120 did not develop any SMN (75%) and 40 developed SMNs (25%). The age at which EBRT is given (i.e. before or after the age of 12 months) was not correlated to SMN development (p = 0.6). We didn't find any difference in RB1 mutation type between patients with or without SMN, neither could we detect any linkage between mutation type and SMN location, SMN type and age at diagnosis. Interestingly, among 13 carriers of a RB1 low penetrance mutation, 3 of them developed sarcomas, a rare tumor that cannot be attributed to the general population. Our study cannot explain why a RB1 mutation leads or not to a SMN but demonstrated that EBRT patients with a low penetrance mutation remain at risk of SMN and should be cautiously monitored.