A retrospective collection of diagnostic data from the desmoid tumor research foundation natural history study.

Background: Desmoid tumors are a benign sarcoma diagnosed in 4-5 patients per million each year. The Desmoid Tumor Research Foundation (DTRF) launched the patient registry and natural history study (NHS) in 2017. This is a retrospective analysis of diagnostic data collected, tumor location, rates of misdiagnosis, how genetics testing is being incorporated into clinical practice, and additional clinical trial participation. Methods: The NHS launched September 2017 and contains 15 surveys covering diagnostics, disease, treatment, care management, and quality of life. Current reporting as of December 31, 2020, contains 619 participants or legally authorized representatives for which a subset have completed the surveys on desmoid tumor diagnoses. Results: Survey analysis documents that the most prevalent tumor locations were intra-abdominal 35.5% (220), joint / extremities 21.2% (131), and chest wall 14.7% (91). The majority of participants, 68.2%, reported that they had unifocal tumors (199/292), 19.5% reported that they had multifocal desmoid tumors (57). Biopsy procedures were the primary method of diagnosis according to 57.2% (167/292) of the participants, with needle biopsy comprising 19.8% (33/167). Biopsy as the primary method of diagnosis was most prevalent in tumors of the head and neck (18/26, 69.2%), chest wall (32/47, 68.1%) joint /extremities (50/90, 55.6%), and abdominal tumors (27/51, 52.9%). Additionally, imaging methods (CT, MRI) were the primary method of diagnosis in 22.6% (66/292) and surgical resection 14.4% (42/292). Misdiagnosis is common for this tumor type, as 41.0% (119/290) participants reported an incorrect initial diagnosis. The reported incorrect diagnoses are described in the table. Genetic testing is not standard of care for desmoid tumors but is increasing in practice. A total of 78 participants (28%) of 282 participants report they had genetic testing (germline or somatic) of their tumor tissue. The majority of those participants, 65.4% (51/78), reported having Familial Adenomatous Polyposis (FAP). Of the participants that had genetic testing, 89.0% live in the United States. 10.5% of participants (37/353) have reported having participated in clinical trials. The majority of participants (317/368, 86.1%) are willing to participate in other studies in the future, with 77.4% (285/368) willing to donate specimens for biomarker studies. Conclusions: Participants with desmoid tumors report many methods of diagnosis for their diverse tumor locations, high rates of misdiagnosis, and increased rates of genetic mutation testing. Data collection through the DTRF NHS is ongoing.

Background: The Desmoid Tumor Research Foundation (DTRF) launched the natural history study (NHS) in 2017. At this time, there are no standard-of-care options for this rare sarcoma. The treatments, clinical descriptors, and the patient reported outcomes to pharmacologic agents are described here within. Methods: The web-based natural history study launched September 2017 in collaboration with the National Organization of Rare Disorders. It contains 15 surveys covering diagnostics, disease, treatment, care management, and quality of life. Treatment types included in the DTRF NHS were pharmacology, surgery, radiation, high-intensity focused ultrasound (HiFU), and active surveillance (watch and wait). Results: While surgery was once the primary intervention for desmoid tumor patients, the NHS participants reported that 47.6% had received active surveillance or no systemic treatment at diagnosis. This is most common for desmoid tumors located in abdominal wall (54/103; 52.4%). There were 87 reported cases of complete surgical resection, 38 incomplete resections, and 23 bowel resections. 9 amputations were reported; 8 participants reported recurrent disease following the removal of the limb. The non-surgical interventions, such as radiation and HiFU, were mostly described for participants with chest wall tumors (15 pts) and joints/extremities (10 pts). Many options for systemic therapies were described including sorafenib (44/284; 15.5%), sulindac (36/284; 12.7%), and anti-hormonal agents tamoxifen and toremifene (34/285; 10.9%) were described. Targeted agents, such as gamma secretase inhibitor, pazopanib, and sorafenib, were greater in the United States than the non-US country participants (21% vs 9%). Multiple lines of treatments were reported by 81 participants, surgery is greatest as the first intervention for all tumor locations (49/81, 60%), with the exception of those with head/neck tumors who received chemotherapy (6/11, 55%). Analysis has started to evaluate the efficacy of systemic treatments from these NHS data. The table describes the participant reported outcomes of anti-hormonal agents, chemotherapeutics, non-steroidal anti-inflammatories, and targeted agents. Both chemotherapies and targeted agents were reported to have 38.1% response rates from the participants with 34.3% and 23.8% of participants reported progressive disease on therapy, respectively. Conclusions: Desmoid tumor NHS study participants reported the use of many treatment modalities demonstrating a range of frequency of use by tumor location and efficacy. Data collection through the DTRF NHS is ongoing.

Background: Desmoid tumor (DT) is a rare disease characterized by histologically monoclonal fibroblastic proliferation. DT does not have metastatic spread potentially but can be infiltrative and locally aggressive and decrease patients’ quality of life. Although current treatment guidelines recommend active surveillance as initial therapy, systemic therapy should be considered in rapidly progressing or symptomatic patients. Systemic treatments for DT include hormonal blockade, cytotoxic chemotherapy, and tyrosine-kinase inhibitors. In this real-life study, we aimed to evaluate the efficacy of sorafenib in patients with progressing or symptomatic DT. Methods: The clinical, pathological, and treatment data of the patients were retrospectively evaluated. Also, prognostic parameters for overall survival were assessed. We used SPSS v.25 for statistical analysis. Kaplan-Meier and Cox-regression analysis were used for survival analysis. Results: Seventeen patients were included in the study. The ratio of female/male patients was 2.4, and the median age was 32 (range,14-65). Four (23.5%) patients had Gardner syndrome. The rates of extra-abdominal and ?ntra-abdominal tumor locations were 64.7% and 35.3%, respectively. The median follow-up duration before sorafenib was 6±0.84 years. Before sorafenib, 15 patients had underwent surgical resection. Four (23.5%) patients received adjuvant radiotherapy. All patients received median two-line systemic therapy, and four (23.5%) patients had received chemotherapy. The median treatment duration of sorafenib was 23.4±2.2 months. One- and two-year progression-free survival ratios were 94.1% and 80.7%, respectively. Grade 3-4 toxicities were observed in six (35.2%) of the patients. In univariate analysis, we found that gender (p = 0.012), ECOG performance status (p = 0.032), and history of Gardner syndrome (p = 0.021) were statistically significant prognostic factors for progression-free survival. However, there was no statistically significant between extra-abdominal and ?ntra-abdominal tumor locations (p = 0.56). Conclusions: In the study, we observed that sorafenib was an effective treatment option for previously treated advanced desmoid tumors. Despite a small number of patients, we detected that male gender, poor ECOG performance status, and history of Gardner syndrome were negative prognostic factors for progression-free survival.

Background: Abdominal desmoid tumors are locally aggressive, non-metastatic tumors that develop mainly in Familial adenomatous polyposis (FAP) patients, within the mesentery or abdominal wall. Understanding and implications of treatment regimens are evolving. We aimed to assess course, treatment and outcomes of FAP and non-FAP abdominal desmoids and their related genetic alterations. Methods: Retrospective cohort study. Demographics, tumor characteristics, oncological and surgical history, complications, genetic-testing and mortality data were retrieved from two tertiary referral centers. Results: Sixty-two patients were identified (46 FAP, 16 non-FAP) with a median follow up of 72.4 months. Thirty-eight patients (61.3%) underwent surgical procedures: twelve urgent and 26 elective. Out of 33 tumor resections, 39.4% recurred. Hormonal therapy, COX-inhibitors, chemotherapy, imatinib and sorafenib were used in 35(56.4%), 30(48.4%), 18(29.1%), 7(11.3%) and 8(12.9%) of patients, respectively, with 2 years progression-free survival of 67.8%, 57.7%, 38.4%, 28.5%, respectively. Only 1/9 patients treated with sorafenib had disease progression after a median follow up of 6.8 months. Forty-one patients (66.1%) suffered complications: bowel obstruction (30.6%), hyperalimentation (14.5%), ureteral obstruction (12.9%), perforation (11.3%), abscess formation (3.2%) and spinal cord compression (3.2%). Two patients died. Non-FAP patients presented with three renal-cell carcinomas and one germ-cell tumor and carried pathogenic mutations in CHEK2, BLM, ERCC5, MSH6 and PALB2. Conclusions: Abdominal desmoids are mostly FAP-related and are associated with severe outcomes. We report a group of non-FAP abdominal desmoids that includes patients with additional cancer-related gene alterations. This interesting group should undergo genetic consultation and be further explored.

Background: DF rare locally aggressive fibroblastic non-metastasizing tumor, with an unpredictable course. Its management remains challenging, there is a current shift in standard of care from large surgical resection (SR) to active surveillance (AS). Most of DF display somatic mutation of CTNNB1, with three major hotpots: S45F, T41A and S45P. The poor prognosis of S45F is a matter of debate (Timbergen et al. Ann Surg 2019). Methods: ALTITUDES (NCT02867033) is a nationwide prospective registry of DF, diagnosed from January 2016 to December 2020 and confirmed by central pathological review. CTNNB1 mutations were identified by NGS. Primary endpoint was event-free survival (including disease progression or relapse). We have selected pts managed by AS, SR or systemic treatments as front-line. Pt undergoing R2 resection and then managed by follow-up were part of AS group. Prognostic factors were assessed using univariate and multivariate Cox Model. Results: From the 630-pts enrolled in ALTITUDES, 500 (79.3%) were eligible for the present analysis. Exclusion criteria were diagnosis before 2016 in 13 pts, multiple DF in 33 pts, 39 pts without CTNNB1 mutation analysis, and 45 pts receiving other treatments. The study population included 349 females (69.8%), the median age was 40 years (range 1-89). Abdominal wall was the predominant primary site: 161 pts (32.2%). In 430 (86.0%) cases, there was a CTNNB1 mutation, including, S45F in 56 cases (11.2%). In 70 cases (14.0%), we did not identify CTNNB1 mutation. The front-line managements were AS in 361 pts (72.2%), SR with R0/R1 margins in 57 cases (11.4%) and systemic treatments in 82 pts (16.5%). The median follow-up was 23 months (Range, 0.4-55). Overall, progression or relapse occurred in 128 pts (25.6%). We observed a significant EFS-difference between treatment groups, both in univariate and multivariate analysis with, compared to AS, a better outcome in patients with SR and worse outcome in patients who had received a systemic treatment (p = 0.01 in multivariate analysis). The risk of event was significantly associated with the tumor size, with a HR = 1.46 in tumors larger than 50 mm compared to smaller tumors (95%CI, 1.01-2.10, p = 0.04). We did not observe any significant association between the CTNNB1 mutational status and the outcome: compared to patients with another mutation, the hazard ratio associated with a S45F mutation was HR = 0.84 (95%CI, 0.48-1.46, p = 0.53) in multivariate analysis. Age, gender, location (abdominal wall versus other) were not associated with EFS. Conclusions: In this large prospective study, S45F was not an independent poor prognostic factor in DF. Size and front-line treatment drive both the outcome. The understanding and prediction of natural course of DF require further studies.

Background: In recent years evidence of long term stabilization and spontaneous regression of primary sporadic DT resulted in a paradigm shift towards more conservative approaches. We present herein the results of an observational study aimed at prospectively assess the behavior of primary sporadic DT initially managed by active surveillance and its relation to CTNNB1 mutational status. Methods: This is an Italian prospective, multicenter, observational study (NCT 02547831) to evaluate primary sporadic DT behavior in patients (pts) >16 years with primary naive or incompletely resected and measurable disease, at any site, with CTNNB1 mutational status available. Pts were assessed by contrast enhanced MRI or CT scan at baseline, at 3, 6, 9, 12 months, then every 6 months until the third year. Tumor changes were assessed by RECIST. In case of dimensional or symptomatic progression active treatment could be proposed on an individualized basisCTNNB1 mutational status was obtained in all patients by Sanger and deep sequencing was performed in wild-type cases. Primary end-point was progression-free survival (PFS) at 3 yrs. Treatment-free survival (TFS) was also analyzed. PFS and TFS were calculated using survival analysis methods, including Kaplan-Meier plots, log-rank test for survival curves comparison, and Cox proportional-hazard multivariable regression (age, size, anatomic site and CTNNB1 mutational status). Results: From April 2013 to February 2018 108 pts were included (82% female, 18% male); median age was 39 (interquartile range, IQR 34-48) and median size 50 mm (IQR, 40-80 mm). Tumor location was: 4/108 (4%) = head&neck, 25/108 (23%) = trunk, 59/108 (55%) = abdominal wall, 3/108 (3%) = intra-abdominal, 17/108 (16%) = extremities. CTNNB1 mutations were as follow: T41A 54/108 (50%), S45F 13/108 (12%), WT 20/108 (19%), other mutations 21/108 (19%). At a m-FU of 32.3 months, the 3-year PFS was 54.5% (95% CI, 44.9%-66.1%). 42/108 (39%) pts showed a RECIST progression, with equal distribution among the different anatomic sites. None of the variables analyzed were associated to PFS. Spontaneous regression was initially observed in 27/108 (25%) patients, while it followed dimensional progression in another 33/108 (30%). 35/108 (32%) pts received active treatment, 18/42 (43%) after RECIST progression and 17/66 (26%) after symptomatic progressions. TFS at 36 months was 65.9% (95% CI, 57.3%-75.9%). S45F mutation, larger tumor size and extremity location were associated to a shorter TFS. No dimensional or symptomatic progression were observed after 36 months of FU. Conclusions: Active surveillance was marked by spontaneous regressions in 60/108 (55%) pts. An active treatment was needed in 32%. If no events occur after 3 yrs of FU, more relaxed FU schedules can be considered given the low risk of subsequent progression. Attention should be paid to patients with DT located to the extremity and/or carrying a S45F mutation.