Body Image Concerns in Adolescent and Young Adult Oncology Patients within Six Months of Upfront Diagnosis.

This cross-sectional study described prevalent body image (BI) concerns among adolescents and young adults (AYAs) with neoplasms who received treatment at a quaternary care children's hospital. Thirty-two AYAs, aged 15-39 years, completed questionnaires assessing BI within six months of diagnosis. The most frequently endorsed questionnaire items included the following: desire for increased physical fitness (62.5%), self-consciousness about hair (45.2%), weight dissatisfaction (40.6%), lack of strength (37.5%), wearing loose clothing to hide one's body (37.5%), decreased agility (34.4%), shape dissatisfaction (32.2%), and self-perception of too much body fat (31.3%). Awareness of AYA BI concerns during treatment may generate early intervention targeting this complex issue.

Reducing Unnecessary Oophorectomies for Benign Ovarian Neoplasms in Pediatric Patients.

Importance: Although most ovarian masses in children and adolescents are benign, many are managed with oophorectomy, which may be unnecessary and can have lifelong negative effects on health. Objective: To evaluate the ability of a consensus-based preoperative risk stratification algorithm to discriminate between benign and malignant ovarian pathology and decrease unnecessary oophorectomies. Design, Setting, and Participants: Pre/post interventional study of a risk stratification algorithm in patients aged 6 to 21 years undergoing surgery for an ovarian mass in an inpatient setting in 11 children's hospitals in the United States between August 2018 and January 2021, with 1-year follow-up. Intervention: Implementation of a consensus-based, preoperative risk stratification algorithm with 6 months of preintervention assessment, 6 months of intervention adoption, and 18 months of intervention. The intervention adoption cohort was excluded from statistical comparisons. Main Outcomes and Measures: Unnecessary oophorectomies, defined as oophorectomy for a benign ovarian neoplasm based on final pathology or mass resolution. Results: A total of 519 patients with a median age of 15.1 (IQR, 13.0-16.8) years were included in 3 phases: 96 in the preintervention phase (median age, 15.4 [IQR, 13.4-17.2] years; 11.5% non-Hispanic Black; 68.8% non-Hispanic White); 105 in the adoption phase; and 318 in the intervention phase (median age, 15.0 [IQR, 12.9-16.6)] years; 13.8% non-Hispanic Black; 53.5% non-Hispanic White). Benign disease was present in 93 (96.9%) in the preintervention cohort and 298 (93.7%) in the intervention cohort. The percentage of unnecessary oophorectomies decreased from 16.1% (15/93) preintervention to 8.4% (25/298) during the intervention (absolute reduction, 7.7% [95% CI, 0.4%-15.9%]; P = .03). Algorithm test performance for identifying benign lesions in the intervention cohort resulted in a sensitivity of 91.6% (95% CI, 88.5%-94.8%), a specificity of 90.0% (95% CI, 76.9%-100%), a positive predictive value of 99.3% (95% CI, 98.3%-100%), and a negative predictive value of 41.9% (95% CI, 27.1%-56.6%). The proportion of misclassification in the intervention phase (malignant disease treated with ovary-sparing surgery) was 0.7%. Algorithm adherence during the intervention phase was 95.0%, with fidelity of 81.8%. Conclusions and Relevance: Unnecessary oophorectomies decreased with use of a preoperative risk stratification algorithm to identify lesions with a high likelihood of benign pathology that are appropriate for ovary-sparing surgery. Adoption of this algorithm might prevent unnecessary oophorectomy during adolescence and its lifelong consequences. Further studies are needed to determine barriers to algorithm adherence.

Fluorescent-guided surgery and the use of indocyanine green sentinel lymph node mapping in the pediatric and young adult oncology population.

BACKGROUND: Technetium-99 (99m Tc) lymphoscintigraphy with blue dye injection is an accepted method for sentinel lymph node (SLN) mapping, but blue dye has known adverse effects, and injection of 99m Tc may increase time under anesthesia for pediatric patients. Indocyanine green (ICG) may serve as an adjunct to assist with visibility and identification of SLNs. We hypothesized that sensitivity of ICG was similar to blue dye in SLN biopsies. METHODS: Thirty patients (36 procedures with 96 total specimens) underwent preoperative intradermal injection of 99m Tc, followed by intradermal injection of isosulfan blue and ICG. Test characteristics of blue dye, ICG, and 99m Tc included sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). RESULTS: ICG had a sensitivity of 87% and PPV of 83% for detection of 99m Tc-hot lymph nodes; blue dye had a sensitivity of 44% and PPV of 97%. For detection of pathologically confirmed lymph nodes, ICG had a sensitivity of 84% and a positive predictive value (PPV) of 91%. 99m Tc had a sensitivity of 82% and a PPV of 94%. ICG had no significant difference in odds of being positive in pathology-confirmed lymph nodes compared to 99m Tc (odds ratio [OR], 0.818; 95% confidence interval [CI], 0.3-2.172; p = .823) and had higher odds than isosulfan blue (OR, 0.025, 95% CI, 0.001-0.148; p < .001). CONCLUSION: This study established the efficacy of ICG as an adjunct to SLNB in the pediatric and young adult population. ICG was safe, more efficacious than blue dye, and may obviate the need for lymphoscintigraphy in selected patients resulting in reduced time under anesthesia.

Atypical Presentation of Granulosa Cell Tumor in an Adolescent: A Case Report.

BACKGROUND: Granulosa cell tumors (GCTs) frequently present with elevated levels of estrogen and inhibin. Most diagnoses in the pediatric and adolescent population are juvenile-type GCTs; adult-type GCTs in this population are rare. CASE: We describe a 14-year-old female who presented with a large adnexal mass and clinical hyperandrogenism. Laboratory evaluation revealed elevated levels of free and total testosterone, low-normal estradiol, and mildly elevated alpha-fetoprotein (AFP). Other tumor markers, including inhibin, were within normal limits. Intraoperative assessment with unilateral oophorectomy, pathology, and imaging resulted in a diagnosis of a stage IA adult-type GCT. SUMMARY AND CONCLUSION: GCTs often result in elevated estrogen and inhibin B levels; however, this case demonstrates that non-classic elevations in testosterone and normal inhibin levels should not eliminate concern for a GCT, particularly in the setting of a large ovarian mass.

Nirogacestat, a γ-Secretase Inhibitor for Desmoid Tumors.

BACKGROUND: Desmoid tumors are rare, locally aggressive, highly recurrent soft-tissue tumors without approved treatments. METHODS: We conducted a phase 3, international, double-blind, randomized, placebo-controlled trial of nirogacestat in adults with progressing desmoid tumors according to the Response Evaluation Criteria in Solid Tumors, version 1.1. Patients were assigned in a 1:1 ratio to receive the oral γ-secretase inhibitor nirogacestat (150 mg) or placebo twice daily. The primary end point was progression-free survival. RESULTS: From May 2019 through August 2020, a total of 70 patients were assigned to receive nirogacestat and 72 to receive placebo. Nirogacestat had a significant progression-free survival benefit over placebo (hazard ratio for disease progression or death, 0.29; 95% confidence interval, 0.15 to 0.55; P<0.001); the likelihood of being event-free at 2 years was 76% with nirogacestat and 44% with placebo. Between-group differences in progression-free survival were consistent across prespecified subgroups. The percentage of patients who had an objective response was significantly higher with nirogacestat than with placebo (41% vs. 8%; P<0.001), with a median time to response of 5.6 months and 11.1 months, respectively; the percentage of patients with a complete response was 7% and 0%, respectively. Significant between-group differences in secondary patient-reported outcomes, including pain, symptom burden, physical or role functioning, and health-related quality of life, were observed (P≤0.01). Frequent adverse events with nirogacestat included diarrhea (in 84% of the patients), nausea (in 54%), fatigue (in 51%), hypophosphatemia (in 42%), and maculopapular rash (in 32%); 95% of adverse events were of grade 1 or 2. Among women of childbearing potential receiving nirogacestat, 27 of 36 (75%) had adverse events consistent with ovarian dysfunction, which resolved in 20 women (74%). CONCLUSIONS: Nirogacestat was associated with significant benefits with respect to progression-free survival, objective response, pain, symptom burden, physical functioning, role functioning, and health-related quality of life in adults with progressing desmoid tumors. Adverse events with nirogacestat were frequent but mostly low grade. (Funded by SpringWorks Therapeutics; DeFi ClinicalTrials.gov number, NCT03785964.).

Pediatric and Young Adult Image-Guided Percutaneous Bone Biopsy-A New Standard of Care?

BACKGROUND: There are no consensus guidelines regarding the use of percutaneous needle biopsy for the diagnosis of soft tissue and bone tumors. The aim of this study was to understand the efficacy of image-guided percutaneous biopsy for pediatric patients with soft tissue and bony masses, the role of intraoperative image guidance, and diagnostic accuracy. PATIENTS AND METHODS: A retrospective institutional chart review was performed on patients who underwent percutaneous biopsy of soft tissue or bone tumors between 2007 and 2017. Data collected included preoperative imaging, type of biopsy, demographics, insurance status, number of samples taken, and pathologic results. RESULTS: One hundred forty-one children and young adults underwent 169 biopsies. Female patients received 48.2% of biopsies. The mean age was 14.3 ± 7.0 years. Core needle biopsies made up 89.4% of procedures, while 10.6% were fine needle aspirate. The mean number of samples per patient was 3.6 ± 2.5. All patients had imaging guidance, with computed tomography used in 44.7% of patients, 9.9% using fluoroscopy, 7.1% using ultrasound for guidance, and 53 (37.6%) patients had more than one modality. Diagnostic specimens were obtained in 97.9% of biopsies. The most common overall pathology was osteoid osteoma. The most common malignant tumors were osteosarcoma and Ewing's sarcoma. CONCLUSION: Image-guided percutaneous biopsy is a safe and effective method of obtaining accurate tissue samples in children and young adults with soft tissue or bone masses. LEVEL OF EVIDENCE: Level 4-Study of diagnostic test.

Strategies for the Treatment of Infantile Soft Tissue Sarcomas With BCOR Alterations.

BCOR alterations are described in ultra-rare infantile soft tissue sarcomas including primitive myxoid mesenchymal tumor of infancy and undifferentiated round cell sarcoma (URCS). Previous reports often describe dismal outcomes. Thus, we undertook a retrospective, multi-institutional study of infants with BCOR -rearranged soft tissue sarcomas. Nine patients aged 6 weeks to 15 months were identified. One tumor carried a BCOR :: CCNB3 fusion, whereas 7 tumors harbored internal tandem duplication of BCOR , including 4 cases classified as primitive myxoid mesenchymal tumor of infancy, 1 case as URCS, and 2 cases characterized by a "hybrid morphology" in our evaluation. Four patients underwent upfront surgery with residual disease that progressed locally after a median of 2.5 months. Locoregional recurrences were observed in hybrid patients, and the URCS case recurred with brain metastases. Complete radiographic responses after chemotherapy were achieved in patients treated with vincristine/doxorubicin/cyclophosphamide alternating with ifosfamide/etoposide, vincristine/doxorubicin/cyclophosphamide alternating with cyclophosphamide/etoposide (regimen I), and ifosfamide/carboplatin/etoposide. Seven patients received radiotherapy. With a median of 23.5 months off therapy, 8 patients are with no evidence of disease. In our study, observation was inadequate for the management of untreated postsurgical residual disease. Tumors demonstrated chemosensitivity with anthracycline-based regimens and ifosfamide/carboplatin/etoposide. Radiotherapy was required to achieve durable response in most patients.

Comorbidity Burden in a Cohort of Adolescent and Young Adult Patients Diagnosed with Central Nervous System Tumors and Sarcomas.

Purpose: Adolescent and young adult (AYA) oncology patients experience unique biological, behavioral, and socioeconomic challenges, for which provision of care must be tailored. AYAs with central nervous system (CNS) tumors and sarcomas represent a vulnerable population with worse outcomes and potential for serious sequelae from intense multimodal therapy. Comorbidity burden impacts treatment tolerance, adherence, and efficacy, yet has been understudied among these high-risk AYA patients. Methods: Utilizing a validated AYA oncology comorbidity index, we (1) measured comorbid conditions present at diagnosis in AYA-aged patients with CNS tumors and sarcomas and (2) compared baseline comorbidity burden across ascending AYA age groups (15-19, 20-29, and 30-39 years) and with pediatric patients (10-14 years). Results: The cohort included 131 AYAs and 50 pediatric patients. Mean comorbidity score significantly differed between pediatric (0.8) and AYA (1.7) patients, and across ascending age subgroups (0.8 [10-14] < 1.2 [15-19] < 1.7 [20-29] < 2.5 [30-39]). AYAs were significantly more likely than pediatric patients to have ≥2 or ≥3 comorbidities (47% vs. 18%, 24% vs. 6%), with increasing prevalence across ascending age subgroups. Frequency of overweight/obese status, smoking/substance use, obstetric/gynecologic conditions, and cardiovascular comorbidities increased with age. In multivariate analyses adjusting for sex, tumor type, and race, age remained a significant predictor of comorbidity score. Conclusions: AYAs with CNS tumors or sarcomas have a high burden of baseline comorbidities, which increase with age at diagnosis, conferring susceptibility to treatment-related toxicity and mortality. Improving the prognosis for AYAs requires appropriate identification of pre-existing comorbidities and tailoring therapeutic and supportive care accordingly.

Molecularly Defined Subsets of Ewing Sarcoma Tumors Differ in Their Responses to IGF1R and WEE1 Inhibition.

PURPOSE: Targeted cancer therapeutics have not significantly benefited patients with Ewing sarcoma with metastatic or relapsed disease. Understanding the molecular underpinnings of drug resistance can lead to biomarker-driven treatment selection. EXPERIMENTAL DESIGN: Receptor tyrosine kinase (RTK) pathway activation was analyzed in tumor cells derived from a panel of Ewing sarcoma tumors, including primary and metastatic tumors from the same patient. Phospho-RTK arrays, Western blots, and IHC were used. Protein localization and the levels of key markers were determined using immunofluorescence. DNA damage tolerance was measured through PCNA ubiquitination levels and the DNA fiber assay. Effects of pharmacologic inhibition were assessed in vitro and key results validated in vivo using patient-derived xenografts. RESULTS: Ewing sarcoma tumors fell into two groups. In one, IGF1R was predominantly nuclear (nIGF1R), DNA damage tolerance pathway was upregulated, and cells had low replication stress and RRM2B levels and high levels of WEE1 and RAD21. These tumors were relatively insensitive to IGF1R inhibition. The second group had high replication stress and RRM2B, low levels of WEE1 and RAD21, membrane-associated IGF1R (mIGF1R) signaling, and sensitivity to IGF1R or WEE1-targeted inhibitors. Moreover, the matched primary and metastatic tumors differed in IGF1R localization, levels of replication stress, and inhibitor sensitivity. In all instances, combined IGF1R and WEE1 inhibition led to tumor regression. CONCLUSIONS: IGF1R signaling mechanisms and replication stress levels can vary among Ewing sarcoma tumors (including in the same patient), influencing the effects of IGF1R and WEE1 treatment. These findings make the case for using biopsy-derived predictive biomarkers at multiple stages of Ewing sarcoma disease management.

Small cell carcinoma of the ovary hypercalcemic type (SCCOHT): A review and novel case with dual germline SMARCA4 and BRCA2 mutations.

Small cell carcinoma of the ovary hypercalcemic type (SCCOHT) is a rare and aggressive disease. While classically linked to mutations in SMARCA4, we describe a case in a patient with both SMARCA4 and BRCA2 germline mutations. We describe her disease presentation, histopathology and treatment with adjuvant systemic chemotherapy, interval hyperthermic intraperitoneal chemotherapy, high dose chemotherapy with stem cell rescue, and maintenance with a poly-ADP-ribose polymerase inhibitor (PARPi). Additionally, we share spatial transcriptomics completed on original tumor.

GIST presenting as refractory iron-deficiency anaemia in paediatric patient.

Gastrointestinal stromal tumours (GISTs) are very rare gastrointestinal (GI) mesenchymal tumours affecting only 0.02 children/million/year below the age of 14 years. We reported a 9-year-old girl presented to emergency department with pallor and haemoglobin of 50 g/L. Extensive workup for anaemia suggested iron-deficiency anaemia secondary to GI loss. Ultimately after blood transfusion of packed cells, she was discharged with a haemoglobin of 92 g/L with iron supplementation. Upper endoscopy showed incidental antral nodularity with biopsy proven helicobacter gastritis and an isolate 3-4 cm suspicious mass in the lesser curvature. Abdomen imaging confirmed the gastric mass in addition to two lesions, one retroperitoneal and one paraspinal. She undergone open laparotomy with complete surgical resection of the gastric and retroperitoneal masses with histological confirmation of GIST and paraganglioma. This case emphasises the importance of proper examination of the stomach at endoscopy and to illustrate that although anaemia is common in paediatric age group it may be reflect serious medical condition even in normal looking child.

Chemotherapy-induced thrombocytopenia in Ewing sarcoma: Implications and potential for romiplostim supportive care.

BACKGROUND: Maintaining dose-dense, interval-compressed chemotherapy improves survival in patients with Ewing sarcoma but is limited by myelosuppression. Romiplostim is a thrombopoietin receptor agonist that may be useful in the treatment of chemotherapy-induced thrombocytopenia (CIT). METHODS: Patients aged between 3 and 33 years with Ewing sarcoma from 2010 to 2020 were reviewed. CIT was defined as a failure to achieve 75,000 platelets per microliter by day 21 after the start of any chemotherapy cycle. Fisher's exact test was used for univariate analysis and Pearson's correlation coefficient was used for the association between continuous variables. RESULTS: Twenty-seven out of 42 patients (64%) developed isolated CIT, delaying one to four chemotherapy cycles per patient. CIT occurred during consolidation therapy in 24/27(88.9%) and with ifosfamide/etoposide cycles in 24/27 (88.9%). Univariate analysis failed to identify risk factors for CIT. The use of radiation approached significance (p-value = .056). Ten patients received romiplostim. The median starting dose was 3 µg/kg (range 1-5). Doses were escalated weekly by 1-2 to 4-10 µg/kg and continued throughout chemotherapy. A higher romiplostim dose was associated with a higher change in average platelet counts from baseline, r = .73 (p = .04). No romiplostim-related adverse events were identified aside from mild headache. CONCLUSIONS: CIT is the primary reason for the inability to maintain treatment intensity in Ewing sarcoma. The concurrent use of romiplostim with chemotherapy was safe and feasible, and efficacy was associated with higher romiplostim doses.

Comparison of 0.3-mSv CT to Standard-Dose CT for Detection of Lung Nodules in Children and Young Adults With Cancer.

BACKGROUND. CT is the imaging modality of choice to identify lung metastasis. OBJECTIVE. The purpose of this study was to evaluate the performance of reduced-dose CT for the detection of lung nodules in children and young adults with cancer. METHODS. This prospective study enrolled patients 4-21 years old with known or suspected malignancy who were undergoing clinically indicated chest CT. Study participants underwent an additional investigational reduced-dose chest CT examination in the same imaging encounter. Separated deidentified CT examinations were reviewed in blinded fashion by three independent radiologists. One reviewer performed a subsequent secondary review to match nodules between the standard- and reduced-dose examinations. Diagnostic performance was computed for the reduced-dose examinations using the clinical examinations as the reference standard. Intraobserver agreement and interobserver agreement were calculated using Cohen kappa. RESULTS. A total of 78 patients (44 male patients and 34 female patients; mean age, 15.2 ± 3.8 [SD] years) were enrolled. The mean estimated effective dose was 1.8 ± 1.1 mSv for clinical CT and 0.3 ± 0.1 mSv for reduced-dose CT, which is an 83% dose reduction. Forty-five of the 78 (58%) patients had 162 total lung nodules (mean size, 3.4 ± 3.3 mm) detected on the clinical CT examinations. A total of 92% of nodules were visible on reduced-dose CT. The sensitivity and specificity of reduced-dose CT for nodules ranged from 63% to 77% and from 80% to 90%, respectively, across the three reviewers. Intraob-server agreement between clinical CT and reduced-dose CT was moderate to substantial for the presence of nodules (κ = 0.45-0.67) and was good to excellent for the number of nodules (κ = 0.68-0.84) and nodule size (κ = 0.69-0.86). Interobserver agreement for the presence of nodules was moderate for both reduced-dose (κ = 0.53) and clinical (κ = 0.54) CT. A median of one nodule was present on clinical CT in patients with a falsely negative reduced-dose CT examination. CONCLUSION. Reduced-dose CT depicts more than 90% of lung nodules in children and young adults with cancer. Reviewers identified the presence of nodules with moderate sensitivity and high specificity. CLINICAL IMPACT. CT performed at a 0.3-mSv mean effective dose has acceptable diagnostic performance for lung nodule detection in children and young adults and has the potential to reduce patient dose or expand CT utilization (e.g., to replace radiography in screening or monitoring protocols). TRIAL REGISTRATION. ClinicalTrials.gov NCT03681873.

Targeting EYA3 in Ewing Sarcoma Retards Tumor Growth and Angiogenesis.

EWSR1/FLI1, the most common fusion gene in Ewing sarcoma, upregulates expression of the Eyes Absent 3 (EYA3) transactivator-phosphatase protein. The purpose of this study was to investigate molecular and cellular mechanisms through which EYA3 might promote Ewing sarcoma tumor growth and to determine whether the EYA3 tyrosine phosphatase activity represents a viable therapeutic target. We used genetic and pharmacologic modulation of EYA3 in cell line-based xenografts to examine how loss of EYA3 tyrosine phosphatase activity affects tumor growth and angiogenesis. Molecular mechanisms were evaluated in vivo and in vitro through analyses of tumor tissue and multicellular tumor spheroids. Our results show that both loss of EYA3 in Ewing sarcoma cells and pharmacologic inhibition of the EYA3 tyrosine phosphatase activity inhibit tumor growth and tumor angiogenesis. EYA3 regulates levels of VEGFA in Ewing tumors, as well as promoting DNA damage repair and survival of Ewing sarcoma tumor cells. Target engagement is demonstrated in tumor tissue through elevated levels of the EYA3 substrate H2AX-pY142 upon loss of EYA3 or with Benzarone treatment. The efficacy of EYA3 tyrosine phosphatase inhibition in attenuating tumor growth and angiogenesis is corroborated in an Ewing sarcoma patient-derived tumor xenograft. Together, the results presented here validate EYA3 as a target for the development of novel Ewing sarcoma therapeutic strategies, and set the stage for evaluating the efficacy of combining the antiangiogenic and anti-cell survival effects of EYA3 inhibition with cytotoxic chemotherapy.

FOXF1 is required for the oncogenic properties of PAX3-FOXO1 in rhabdomyosarcoma.

The PAX3-FOXO1 fusion protein is the key oncogenic driver in fusion positive rhabdomyosarcoma (FP-RMS), an aggressive soft tissue malignancy with a particularly poor prognosis. Identifying key downstream targets of PAX3-FOXO1 will provide new therapeutic opportunities for treatment of FP-RMS. Herein, we demonstrate that Forkhead Box F1 (FOXF1) transcription factor is uniquely expressed in FP-RMS and is required for FP-RMS tumorigenesis. The PAX3-FOXO1 directly binds to FOXF1 enhancers and induces FOXF1 gene expression. CRISPR/Cas9 mediated inactivation of either FOXF1 coding sequence or FOXF1 enhancers suppresses FP-RMS tumorigenesis even in the presence of PAX3-FOXO1 oncogene. Knockdown or genetic knockout of FOXF1 induces myogenic differentiation in PAX3-FOXO1-positive FP-RMS. Over-expression of FOXF1 decreases myogenic differentiation in primary human myoblasts. In FP-RMS tumor cells, FOXF1 protein binds chromatin near enhancers associated with FP-RMS gene signature. FOXF1 cooperates with PAX3-FOXO1 and E-box transcription factors MYOD1 and MYOG to regulate FP-RMS-specific gene expression. Altogether, FOXF1 functions downstream of PAX3-FOXO1 to promote FP-RMS tumorigenesis.

Active and Protected: Developing a "Safer Sex" Handout for Adolescents and Young Adults with Cancer.

There is a critical need to engage adolescents and young adults (AYAs) with cancer in conversations regarding "safer" sexual activity during treatment. Many providers, however, report lacking the knowledge and/or tools to engage in these discussions. This article describes the experience of one pediatric institution in assessing and addressing provider barriers to safer sexual activity discussions among AYAs with cancer. Feedback from patients and providers resulted in an educational handout detailing recommendations regarding safer sex practices for AYAs with cancer. Handout adoption, acceptability, appropriateness, and feasibility are described alongside barriers to assist other institutions seeking to develop similar interventions.

Tazemetostat in advanced epithelioid sarcoma with loss of INI1/SMARCB1: an international, open-label, phase 2 basket study.

BACKGROUND: Epithelioid sarcoma is a rare and aggressive soft-tissue sarcoma subtype. Over 90% of tumours have lost INI1 expression, leading to oncogenic dependence on the transcriptional repressor EZH2. In this study, we report the clinical activity and safety of tazemetostat, an oral selective EZH2 inhibitor, in patients with epithelioid sarcoma. METHODS: In this open-label, phase 2 basket study, patients were enrolled from 32 hospitals and clinics in Australia, Belgium, Canada, France, Germany, Italy, Taiwan, the USA, and the UK into seven cohorts of patients with different INI1-negative solid tumours or synovial sarcoma. Patients eligible for the epithelioid sarcoma cohort (cohort 5) were aged 16 years or older with histologically confirmed, locally advanced or metastatic epithelioid sarcoma; documented loss of INI1 expression by immunohistochemical analysis or biallelic SMARCB1 (the gene that encodes INI1) alterations, or both; and an Eastern Cooperative Oncology Group performance status score of 0-2. Patients received 800 mg tazemetostat orally twice per day in continuous 28-day cycles until disease progression, unacceptable toxicity, or withdrawal of consent. The primary endpoint was investigator-assessed objective response rate measured according to the Response Evaluation Criteria in Solid Tumors, version 1.1. Secondary endpoints were duration of response, disease control rate at 32 weeks, progression-free survival, overall survival, and pharmacokinetic and pharmacodynamic analyses (primary results reported elsewhere). Time to response was also assessed as an exploratory endpoint. Activity and safety were assessed in the modified intention-to-treat population (ie, patients who received one or more doses of tazemetostat). This trial is registered with ClinicalTrials.gov, NCT02601950, and is ongoing. FINDINGS: Between Dec 22, 2015, and July 7, 2017, 62 patients with epithelioid sarcoma were enrolled in the study and deemed eligible for inclusion in this cohort. All 62 patients were included in the modified intention-to-treat analysis. Nine (15% [95% CI 7-26]) of 62 patients had an objective response at data cutoff (Sept 17, 2018). At a median follow-up of 13·8 months (IQR 7·8-19·0), median duration of response was not reached (95% CI 9·2-not estimable). 16 (26% [95% CI 16-39]) patients had disease control at 32 weeks. Median time to response was 3·9 months (IQR 1·9-7·4). Median progression-free survival was 5·5 months (95% CI 3·4-5·9), and median overall survival was 19·0 months (11·0-not estimable). Grade 3 or worse treatment-related adverse events included anaemia (four [6%]) and weight loss (two [3%]). Treatment-related serious adverse events occurred in two patients (one seizure and one haemoptysis). There were no treatment-related deaths. INTERPRETATION: Tazemetostat was well tolerated and showed clinical activity in this cohort of patients with advanced epithelioid sarcoma characterised by loss of INI1/SMARCB1. Tazemetostat has the potential to improve outcomes in patients with advanced epithelioid sarcoma. A phase 1b/3 trial of tazemetostat plus doxorubicin in the front-line setting is currently underway (NCT04204941). FUNDING: Epizyme.