Rhabdoid Tumor Predisposition Syndrome: A Historical Review of Treatments and Outcomes for Associated Pediatric Malignancies

Abstract

Rhabdoid tumor predisposition syndrome (RTPS) is a rare disorder associated with malignant rhabdoid tumor of the kidney (RTK), atypical teratoid rhabdoid tumor (ATRT), and/or other extracranial, extrarenal rhabdoid tumors (EERT), and these pediatric malignancies are difficult to treat. Presently, most of the information regarding clinical manifestations, treatment, and outcomes of rhabdoid tumors comes from large data registries and case series. Our current understanding of treatments for patients with rhabdoid tumors may inform how we approach patients with RTPS. In this manuscript, we review the genetic and clinical features of RTPS and, using known registry data and clinical reports, review associated tumor types ATRT, RTK, and EERT, closing with potential new approaches to treatment. We propose collaborative international efforts to study the use of SMARC (SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin)-targeting agents, high-dose consolidative therapy, and age-based irradiation of disease sites in RTPS.

1. Introduction

Rhabdoid tumor predisposition syndrome (RTPS) was first proposed in 1999 as a rare autosomal dominant condition associated with increased risk of malignant rhabdoid tumor of the kidney (RTK), brain (atypical teratoid rhabdoid tumor or ATRT), and other sites (liver and soft tissues, also known as extracranial, extrarenal rhabdoid tumors or EERT).^1,2 In this setting, ATRT (65%) is more common than extracranial rhabdoid tumors (ERT).^3–6 Here, we review the genetic basis of RTPS and associated molecular classification, clinical presentation, available data on treatments of individual associated tumors, clinical outcomes, and genetic testing and screening, and promising future directions are discussed.

2. Genetic Basis of RTPS

Rhabdoid cells were so-named because of their histological resemblance to rhabdomyoblasts, but modern diagnosis now relies on the presence of biallelic loss of SMARC sub-families: SMARCB1 (also known as INI1; RTPS1) located at chromosome 22q11, or SMARCA4 (also known as BAF47/BRG1; RTPS2) located at chromosome 19p13.^4–6 Subsequent loss of the associated protein disrupts nucleosome remodeling and affects chromatin-based promoters that regulate the cell cycle, leading to malignancy.^4,7–9 Germline mutations in SMARCB1 (RTPS1), typically de novo, account for over one-third of rhabdoid tumors. Genetic diagnosis of RTPS involves clinical assessment and a immunohistochemical result indicating SMARCB1/SMARCA4 deficiency, in addition to screening for somatic mutations.⁹ Gonadal mosaicism is thought to often account for inherited rhabdoid tumors,^8,10–12 but unusual reports of gain-in-function of SMARCB1 resulting in a similar phenotype have also been reported.¹³ Case reports have found that not only do patients with synchronous rhabdoid tumors have varied methylation profiles, but also patients with metachronous rhabdoid tumors arising from RTPS, in which different DNA methylation patterns and copy number aberrations have been observed; these findings indicate that RTPS leads to non-clonal formation of rhabdoid tumors.^14,15

Recent studies have characterized over 300 patients with ATRT and described prognostic molecular subdivisions (ATRT-SHH, ATRT-TYR, and ATRT-MYC) associated with the location of the tumor, average age of the patient, and specific genetic mutations. More recently, ATRT samples were evaluated from a cohort of 325 patients from the Hospital for Sick Children in Toronto and 65 patients from the Children’s Oncology Group (COG) study ACNS0333, and results validated the molecular subgroupings and revealed that the 16% of patients with germline mutations had a four-year OS (overall survival) of only 20%.^18,19 There have been conflicting data between the COG study, EU-RHAB registry, and St. Jude Children’s Research Hospital with regards to whether the ATRT-SHH¹⁹ or ATRT-TYR^20,21 subgroup has a better prognosis; recent work demonstrates that ATRT-SHH may be further subdivided into three molecular subgroups associated with differing overall survivals.²² As a result, genomic subtyping may be helpful for prognosticating outcomes in RTPS and rhabdoid tumor variants.^23,24

3. Clinical Presentation and Outcomes of RTPS

RTPS1 is characterized by early onset rhabdoid tumors and will be the focus of this review; RTPS2 only accounts for 2% of patients with RTPS and is associated with small cell carcinoma of the ovary, hypercalcemic type (SCCOHT).^4–6,25,26 Individuals with mutations at these loci are also at heightened risk for other tumors including schwannomas, malignant peripheral nerve sheath tumors, cribriform neuroepithelial tumors, meningiomas, and others.⁶

Familial penetrance of RTPS1 may be as high as 90% by five years of age.²⁷ The median age of diagnosis of a rhabdoid tumor in patients with RTPS is between four and seven months, as opposed to the typical age of diagnosis for patients with ATRT, RTK, and EERT arising sporadically, which are 18–30,^20,27 13,²⁷ and 13–17²⁷ months, respectively. In a retrospective study by the European Rhabdoid Registry (EU-RHAB), 66% of patients (n = 42) diagnosed with a rhabdoid tumor within 28 days of their birth had germline SMARCB1 or SMARCA4 mutations.²⁵ An update on EU-RHAB data of 90 patients with germline mutations demonstrated a five-year OS of 20% and EFS (event-free survival) of 15%, with significant negative prognostic factors including age less than one year, presence of ERTs versus ATRT, metastatic disease, and presence of synchronous tumors.^28,29 In a retrospective study from St. Jude, 53 patients with ATRT were sequenced, and a third of patients were identified as having germline mutations.²¹

Synchronous tumors arise in a third of patients with RTPS and are often detected at an advanced stage. St. Jude reported on 21 children with multiple rhabdoid tumors, two-thirds of which were diagnosed synchronously, with similar numbers of patients with RTK.³⁰ The majority of the patients had germline SMARCB1 abnormalities; while ATRT-SHH molecular subtype was most common among patients with ATRT, methylation analysis of the non-ATRT tumors found the vast majority clustered into a MYC subgroup. All patients died of tumor progression. A review from our group in 2018 of concurrent ATRT and EERTs described 32 cases; 20 were positive for SMARCB1 germline mutations.³¹ The most common synchronous site was the kidney, and OS was 13%. Four long-term survivors (mean EFS of seven years) had tumors all located in extracranial sites, with RTK in three; all four received high-dose chemotherapy (HDC) with autologous stem cell rescue (ASCR) with gross total resection (GTR) of at least one tumor (two had GTR of both), and three patients received irradiation. Molecular profiling of three patients with synchronous ATRT and RTK revealed two had a SMARCB1 deletion and the third had a frameshift variant; the RTK were all identified as the MYC subtype, and one ATRT was classified as ATRT-SHH and one as ATRT-TYR.^10,27 Following use of GTR, adjuvant Rhabdomyosarcoma Study (IRS) III) sarcoma-styled chemotherapy, triple intrathecal chemotherapy (IT), and consolidation with triple HDC/ASCR, one patient was reported to be three years off therapy with no evidence of disease (NED), one passed away approximately 2 years after diagnosis with progression in the lungs and brain, and the third died over a year after diagnosis with retroperitoneal progression. Commonalities among successful approaches to patients with multiple rhabdoid tumors include aggressive combination of surgery, chemoradiation, including IRS-III-based chemotherapy, and potential to consider HDC/ASCR.

4. Tumor Types Associated with RTPS

4.1. Atypical Teratoid Rhabdoid Tumor (ATRT)

Primary CNS ATRT was first unequivocally described in 1987 as “a malignant rhabdoid tumor of the CNS,” with the histologic diagnosis clarified by the National Cancer Institute in 2001.¹⁶ Several ATRT registries published their findings between 1995 and 2015 (Table 1). These reports sought to determine the prognostic roles of GTR, timing and extent of radiation therapy, and role and type of chemotherapy. Findings showed that ATRT was chemotherapy-responsive and the duration of response could be stratified by age. Furthermore, benefits were observed with the greatest extent of resection,³² using HDC/ASCR as a radiation-sparing strategy, and focal irradiation where possible.^33–35 We highlight that the Canadian ATRT registry reported over half the long-term survivors from this series were treated with HDC/ASCR, suggesting a subgroup that may be able to be spared irradiation.³⁵ There was lack of benefit with maintenance therapy,³⁶ and overall use of early and aggressive therapy to increase EFS was recommended.³⁷ More recently, the largest prospective registry trial to date was published from European centers between 2009 and 2017, which included 143 patients, and results demonstrated that HDC/ASCR had no significant impact on survival while certain clinical factors such as younger age at diagnosis and molecular subgroup (ATRT-TYR) did.²⁰

TABLE 1.

Summary of outcomes for selected atypical teratoid rhabdoid tumor (ATRT) treatment regimens

Study/Group	ATRT patients	Induction chemotherapy	GTR	IT	RT	HDC +/− ASCR	EFS	OS	Positive prognostic factors
Canadian ATRT Registry20–22	50	Per CCG-9921 (cisplatin, vincristine, etoposide, cyclophosphamide, ifosfamide, carboplatin with maintenance), IRS-III (VAC/VDC, cisplatin ± AMD, etoposide), ICE, HS-II	30%	23%	52%	45%	Median 5.5 months	Median 14 months	GTR, HDC/ASCR
US ATRT Registry19	42	Per CCG-99703 (cisplatin, vincristine, etoposide, cyclophosphamide, HD carboplatin, TT), CCG-9921 or IRS-III	48%	38%	31%	31%	Median 10 months	Median 16.75 months	GTR, irradiation, HDC/ASCR, age 3 years or older
European ATRT Registry23	19	VDC/ICE +/− actinomycin-D, maintenance	26%	68%	47%	63%	Median 14 months; Two-year 29%	Two-year 50%	Irradiation (47% received up-front, additional 26% at progression)
Head Start (HS) I and II27	13	Cisplatin, vincristine, etoposide, cyclophosphamide, ± HD methotrexate	38%	0%	31%	54%	Three-year 23%	Three-year 23%	GTR (or at least 90% resected), methotrexate
Dana Farber32	20	IRS-III with temozolomide instead of dacarbazine	55%	100%	75%	0%	Two-year 53%	Two-year 70%	GTR, posterior fossa tumors
Head Start III28	19	HS-II styled + cycles with temozolomide	47%	0%	0%	16%	Three-year 21%	Three-year 26%	-
COG ACNS033333	65	HS-II styled	38%	0%	62%	65%	Four-year 37%	Four-year 43%	Tumors non-contiguous between infra- and supra-tentorial locations, non-spinal tumors
EU-RHAB15	143	Doxorubicin, ICE, VAC, ± HD Carbo/TT	34%	100%	87%	24%	Five-year 30%	Five-year 35%	Age 1 year or older, ATRT-TYR subgroup

Abbreviations: AMD (doxorubicin, dacarbazine), ASCR (autologous stem cell rescue), ATRT (atypical teratoid rhabdoid tumor), COG (Children’s Oncology Group), EFS (event free survival), GTR (gross total resection), HD or HDC (high-dose chemotherapy), ICE (ifosfamide, carboplatin, etoposide), IRS (Intergroup Rhabdomyosarcoma Study), IT (intrathecal chemotherapy), OS (overall survival), RT (radiation therapy), TT (thiotepa), VAC (vincristine, actinomycin D, cyclophosphamide), VDC (vincristine, doxorubicin, cyclophosphamide).

“Head Start” I and II (HS-I and HS-II) identified 13 patients with ATRT from 1992 to 2002 (Table 1).³⁸ These results demonstrated the prognostic significance of GTR, which was again demonstrated by the Children’s Cancer Group (CCG, now COG) study CCG-99703, conducted from 1998 to 2004.³⁹ “Head Start” III (HS-III) was conducted from 2003 to 2009 and enrolled 19 patients with ATRT but was limited by toxicity-related deaths.⁴⁰ Two groups evaluated the addition of tandem transplantation; in the first cohort of six children, researchers unfortunately found neurocognitive impairment in four survivors who were NED, three of whom were spared irradiation.⁴¹ The second group evaluated 37 patients between 1984 to 2003, and found survival benefit with the inclusion of irradiation versus chemotherapy alone.⁴² The Dana Farber Cancer Institute modified IRS-III from 2004 to 2006 for 20 children with SMARCB1 mutations and concluded that older age and extent of resection influenced survival while irradiation and anthracyclines trended towards benefit.⁴³

Results of the largest to-date prospective clinical trial for ATRT patients, COG study ACNS0333, included 65 children.⁴⁴ Following surgery, patients received three cycles of chemotherapy, second-look surgery, and three tandem transplants with ASCR. Patients with non-metastatic disease and above 6 or 12 months of age received “sandwich” irradiation after induction. Seventeen percent had germline mutations of SMARCB1 (two of whom survived event-free). The four-year EFS and OS was 35% and 40% for children under 36 months, respectively, which represent statistically significant improvements. There was no impact of tumor location, metastatic disease, extent of resection, age at diagnosis, or delayed craniospinal irradiation. Significant toxicity was observed with ACNS0333, which involved four deaths; however, performing radiation at the end of treatment may reduce the number of treatment-related deaths.

Although a definitive strategy is still lacking, these data collectively encourage an aggressive multimodal therapeutic approach to patients with ATRT, with pursuit of GTR, anthracycline-based chemotherapy, and irradiation encouraged but with due consideration given to radiation-sparing regimens in the youngest patients and improved selection of patients that would benefit from HDC/ASCR.

4.2. Rhabdoid Tumor of the Kidney (RTK) and Extracranial, Extrarenal Rhabdoid Tumor (EERT)

The RTK (also known as malignant RTK or MRTK) and EERT types constitute subsets of ERT, for which there are more data specific to the treatment of RTKs. RTK was distinguished from Wilms tumors in 1978 as an aggressive tumor that often metastasizes to the lungs and is highly lethal, with a median survival below one year and five-year OS of around 20%.^9,45 SMARCB1 mutations are characteristic with segmental duplications.⁷ RTK represents a small portion of both renal (2%) and RTPS tumors (9%) and often presents with greater chance of tumor rupture.^4,45–47 Patients with RTK have often been treated according to EU-RHAB protocol chemotherapy cassettes; children under 18 months can also receive carboplatin/thiotepa HDC with ASCR.⁴⁸ Inclusion of regular CNS imaging for early detection of metastatic spread may improve survival.^45,49,50

There are data to suggest patients with EERTs have better survival than those with RTK, and this may be related to the fact that germline mutations in SMARCB1, an adverse prognostic marker in EU-RHAB, are found in less patients with EERT than RTK.²⁸ In 2013, a systematic review and meta-analysis on 167 patients with primary EERT demonstrated that complete resection was significantly associated with improved prognosis.⁵¹ A series of 78 children with ERTs found a three-year OS of 27% and EFS of 21% with use of irradiation prognostic for EFS.⁵² Another study of 18 children with rhabdoid tumors found the five-year OS of the EERT group was significantly higher than that for those with ATRT and RTK, and survival was associated with GTR (p <0.001).⁵³

Traditionally, patients with RTKs were treated using protocols for Wilms tumors with poor results.⁴⁵ The first formal evaluation of RTK took place in 1989 during the third National Wilms Tumor Studies (NWTS-3) (Table 2).^45,54,55 When all the NWTS studies were studied together, older age was shown to positively influence survival.⁵⁶ In 2006, NWTS-5 was discontinued for lack of efficacy.^45,55 The International Society for Pediatric Oncology (SIOP) retrospectively studied 107 patients from 1993 to 2005 and found that while RTK tumor volume appeared to decrease with neoadjuvant chemotherapy, there was no correlation between survival and pre-operative reduction in tumor size.⁴⁷

TABLE 2.

Summary of outcomes for selected rhabdoid tumor of the kidney (RTK) treatment regimens

Study/Group	RTK Patients	Chemotherapy	RT (%)	GTR (%)	ASCR (%)	Composite OS (%)	Composite EFS (%)	Positive prognostic factors
NWTS-354	111	Actinomycin D versus vincristine versus AV versus AVD	70	44	0	21	19	Lower stage disease, younger age at diagnosis, GTR
COG AREN032145	36	UH-1 Protocol (VDC, etoposide, carboplatin)	-	-	0	Four-year: 39	-	N/A
SIOP47	107	Pre-operative AV versus AVD plus post-operative chemotherapy	35	NR	0	Five-year: 26	Five-year: 22	Older age at diagnosis
GPOH57	58	SIOP9/GPOH or SIOP2001/GPOH (AV or AVD) versus SIOP93–01/GPOH (AV or AVD or ECIA)	36	64	19	Two-year: 39	Two-year: 37	Older age at diagnosis, radiotherapy
Children’s Hospital Los Angeles60	21	Varied. VDC (62%) versus other therapies	38	71	19	Five-year: 38 ± 11	Five-year: 38 ± 11	Older age at diagnosis, GTR, treatment after 2002
Beijing Children’s Hospital46	32 of 53 ERT	Varied. UH-1 Protocol versus other therapies	13	88	0	Three-year: 17	Three-year: 17	GTR, radiotherapy, use of anthracyclines; N.B. EFS reflects 53 ERT patients
EU-RHAB28	30 of 100 ERT	VAC, ICE, doxorubicin, HD carboplatin, TT	56	53	21	Five-year: 46 ± 5	Five-year: 35 ± 5	Radiotherapy, GTR, localized disease; N.B. All tabulations reflect 100 ERT patients
Li 202188	14	ICE versus IE versus VDC versus AVCP	21	93	0	Four-year: 42%	-	Older age at diagnosis

Abbreviations: ASCR (autologous stem cell rescue), AV (actinomycin, vincristine), AVCP (doxorubicin, vincristine, cyclophosphamide, cisplatin), AVD (actinomycin, vincristine, doxorubicin), COG (Children’s Oncology Group), ECIA (etoposide, carboplatin, ifosfamide, doxorubicin), EFS (event free survival), ERT (extracranial rhabdoid tumor), EU-RHAB (European Rhabdoid Registry), GPOH (Gesellschaft für Pädiatrische Onkologie und Hämatologie), GTR (gross total resection), ICE (ifosfamide, carboplatin, etoposide), NWTS (National Wilms’ Tumor Study Group), NR (not reported), OS (overall survival), RT (radiation therapy), RTK (rhabdoid tumor of kidney), SIOP (International Society of Paediatric Oncology), TT (thiotepa), VAC (vincristine, actinomycin D, cyclophosphamide), VDC (vincristine, doxorubicin, cyclophosphamide).

A retrospective analysis by the German group GPOH of 58 patients treated between 1991 and 2014 studied the benefit of irradiation in patients with RTK.⁵⁷ Two-year EFS with no radiotherapy was 15.4% versus 66.7% (p <0.001) with radiotherapy in patients with stage II–IV disease. The study concluded that irradiation is necessary for RTK treatment even in infantile disease, but that HDC/ASCR had no effect on survival outcomes.⁵⁸ In line with the GPOH, the European Paediatric Soft Tissue Sarcoma Study Group reported poor outcomes in patients with ERT treated with Ewing sarcoma-styled chemotherapy, surgical resection, and irradiation.⁵⁹ A retrospective study between 1983 and 2012 at the Children’s Hospital Los Angeles compared pre-2002 with post-2002 regimens, including 10 patients with RTK and 11 with other systemic rhabdoid tumors, and found better outcomes with modern regimens, concluding that younger age had poorer prognosis but that intensive chemotherapy, irradiation, aggressive resection, and metastasectomy conferred a survival benefit.⁶⁰ Survival benefit with HDC/ASCR was proposed, as four stage III/IV patients who received it achieved long-term survival with a median of three years follow-up.

Between 2006 and 2015, COG study AREN0321 was performed using the neoadjuvant UH-1 regimen, but the treatment regimen did not significantly impact survival in patients with RTK compared with NWTS with toxicity-related deaths occurring in four patients.⁴⁵ This was corroborated in a retrospective study between 2007 and 2017 from Beijing Children’s Hospital, in which UH-1 was evaluated in 53 patients with ERTs, 32 of whom had RTK.⁴⁶ However, they found that excellent local control significantly improved OS.

EU-RHAB treated 100 patients between 2009 and 2020, 30 of whom had RTK.²⁸ GTR and irradiation were significantly prognostic, but HDC/ASCR and maintenance chemotherapy were not. Germline mutation in SMARCB1 was an adverse prognostic marker. Using these data, the authors proposed two risk categories for rhabdoid tumors: standard (localized disease with GTR and no germline mutations) and high-risk (either metastatic, no GTR, or germline mutation present). In 2014, a German group compared neoadjuvant AV versus AVD (actinomycin, vincristine +/− doxorubicin) in 37 patients with RTK with no difference in OS between the two groups, although the AVD cohort had more partial responses.⁶¹ Most recently, a retrospective review of 14 children with high-risk renal (including nine RTK) and INI-1-deficient tumors found that the use of VDC (vincristine, doxorubicin, cyclophosphamide) alternating with ICE (ifosfamide, carboplatin, etoposide) was tolerable, even in patients with solitary kidneys, and 8 of 14 achieved first clinical remission, with a median follow-up time of 3.3 years in the survivors.⁶²

We conclude from this data that patients with ERTs, including RTK and EERTs, are best treated with aggressive GTR, including metastases if feasible, and chemoradiation, including VDC/ICE-styled chemotherapy. Similar to ATRT, inclusion of HDC/ASCT may require refined subgroup selection.

5. Targeted Therapies

Several studies on targeted treatments for rhabdoid tumors have been published over the past decade (Table 3). Initial attempts began with the discovery of cell cycle dysregulation secondary to loss of SMARCB1.^45,63,64 For a comprehensive review of targeted therapies specifically being tested in ATRT, the reader is directed to the referenced review article.⁶⁵ The cyclin-dependent kinase 4/6 (CDK4/6) inhibitor ribociclib was tested in a phase I trial in 11 patients with malignant rhabdoid tumors but did not demonstrate efficacy.⁶⁶ Alisertib, an aurora kinase A (cell cycle-regulated kinase) inhibitor, was studied in RTs.^67–69 In a phase II trial, 8 of 30 patients with recurrent ATRT achieved stable disease for greater than six months though alisertib was not found to have a statistically significant impact in EFS or OS.⁶⁹

TABLE 3.

Selected novel agents with reported data in rhabdoid tumors

Author/Trial	Drug	Target	Patients	Outcome
Geoerger et al. 2017/NCT0174787666	ribociclib	CDK4/6	15	2/13 (15%) ATRT and 0/2 (0%) ERT with SD
Upadhyaya et al. 2023/SJATRT69	alisertib	aurora kinase A	30	8/30 (27%) ATRT with SD, 1/30 (3%) with PR
Chi et al. 2022/NCT0260193772	tazemetostat	EZH2	47	2/6 (33%) ATRT with PR, 0/21 ERT with PR
Chi et al. 2023/APEC1621C71	tazemetostat	EZH2	12	1/8 (13%) ATRT with 0/4 (0%) ERT with SD
Blay et al. 2019/: AcSé Pembrolizumab81	pembrolizumab	PD-1	3	1/3 (33%) ERT with PR
Jelinic et al. 201882	various	PD-1	4	Case series with 3 CR and 1 PR
Geoerger et al. 2020/NCT0254160483	atezolizumab	PD-L1	6	1/3 (33%) ERT with PR, 0/3 (0%) ATRT with PR

Abbreviations: ATRT (atypical teratoid rhabdoid tumor), CDK (cyclin-dependent kinase), ERT (extracranial rhabdoid tumor), EZH2 (Enhancer of zeste homolog 2), PD-1 (programmed cell death protein 1), PD-L1 (programmed cell death ligand 1), PR (partial response), SD (stable disease).

SMARCB1/A4-loss leads to dependency on PRC2 and its enzymatic subunit EZH2,⁷⁰ so efforts have been made to inhibit EZH2 in SMARC-deficient tumors. Twenty patients with tumors with loss of SMARCB1/A4 or mutations in EZH2 were treated with EZH2-inhibitor tazemetostat. Five patients reported prolonged disease stabilization for greater than six months, four of which had SMARCB1 loss.⁷¹ In a multicenter study, 109 patients with relapsed or refractory INI1-deficient tumors received tazemetostat monotherapy; responses were observed in 5 of 21 ATRT patients.⁷² Sixty-two patients with advanced epithelioid sarcoma with loss of INI1/SMARCB1 were enrolled in a phase II study of tazemetostat with 9 of 62 exhibiting an objective response.⁷³ Recent work has explored resistance patterns to tazemetostat in vivo, including acquired mutations in cell cycle proteins that can be overcome with simultaneous aurora kinase B inhibition in mice.⁷⁴

It is possible that decreased expression of SWI/SNF complex members may lead to increased cytotoxic T-cell activity⁷⁵ and PD-L1 expression,⁷⁶ which could theoretically lead to therapeutic gain in SMARC-deficient cancers treated with immune checkpoint inhibition. Case reports combining chemotherapy plus checkpoint inhibition have shown individual success in SMARC-deficient tumors.^77–80 In a phase II study, there was a partial response in one of three patients with rhabdoid tumors given pembrolizumab.⁸¹ There were three complete responses and one partial response in a selected case series of SCCOHT patients that received anti-PD-1 immunotherapy, three of whom had a deleterious mutation in SMARCA4 or loss of SMARCA4 expression.⁸² Atezolizumab was used to treat three patients with rhabdoid tumors and three with ATRT, and the study found one partial response in the only rhabdoid tumor patient with high PD-L1 expression.⁸³ As a result, SMARC-deficient cancers are being targeted with nivolumab plus ipilimumab as well as atezolizumab plus a TIGIT (tyrosine-based inhibition motif domain) inhibitor in two ongoing clinical trials (NCT04416568, NCT05286801). Other approaches have included the use of autologous dendritic cell vaccines in seven children with ATRT with three long-term responses⁸⁴ and histone deacetylase (HDAC) inhibition via panobinostat, which did not have a therapeutic effect on seven patients with rhabdoid tumors.⁸⁵ Future approaches that strive to better understand the biology of the disease, investigate combination epigenetic therapy to overcome EZH2 resistance and combination checkpoint and EZH2 strategies (NCT05407441), and apply novel chimeric antigen receptor (CAR) T-cell strategies (NCT02932956)⁸⁶ will be informative, and continued progress through international collaborations will be important to follow.

6. Recommendations for Testing and Screening in RTPS

Young patients presenting with RTPS-related tumor(s), especially in advanced stages upon detection, and/or a concerning family history should have germline testing for RTPS and genetic counseling.^8,9 In addition, the parents and siblings should be screened in event of detection of a pathogenic variant in the proband. The rare instance of a non-de novo germline variant is inherited in an autosomal dominant pattern and thus the risk of a sibling being affected by an inherited variant is 50%, not accounting for incomplete penetrance. Any affected healthy individuals should be offered surveillance.

Early identification of tumors in patients with confirmed RTPS mandates surveillance from birth.^4,27 The most recent proposals for screening diagnosis of patients with suspected RTPS1 and RTPS2 were made by the European Society of Pediatric Oncology (SIOPE) in 2021.^6,27 Early whole-body magnetic resonance imaging (MRI) is recommended with central nervous system imaging every four to six weeks until the age of six months, at which point imaging every two to three months becomes more reasonable.^6,27 Individuals affected by RTPS1 may undergo decreased surveillance at the age of five when tumor risk decreases significantly outside of the risk of schwannomatosis;⁸⁷ thereafter, yearly whole-body MRI and physical examination every six months is typically sufficient. However, patients with RTPS2 should continue to be screened for SCCOHT by ultrasound until their mid-40s. Risk prevention is the main management strategy for patients with RTPS as standardized treatment for rhabdoid tumors remains unestablished and reliant on treatment strategies for individual tumors such as ATRT and RTK. Given the high mortality rates in rhabdoid tumors and negative prognosis associated with RTPS, development of more effective treatment regimens is crucial.

7. Conclusion

From the first description of RTK in 1978, ATRT in 1987, and RTPS in 1999, therapy for all three has evolved significantly. Though standardized treatments are lacking, outcomes have improved with aggressive multimodal strategies and concurrent improvements in supportive care. Progress has been made in sparing young children with ATRT of CNS irradiation and, conversely, institution of abdominal irradiation for young children with RTK. Based on available data for patients with RTPS who developed concurrent ATRT and RTK, common prognostic variables appear to be aggressive chemotherapy regimens, extent of surgical resection, irradiation where possible, and careful consideration of HDC/ASCR. The chemotherapy of choice remains in question, but aggressive, dose-compressed regimens used to treat sarcoma are typical, with VDC/ICE gaining favor for RTK. The next generation of treatments will potentially incorporate agents that are active in the SMARC pathway based on preliminary data and active clinical trials.

Based on the data assembled, we suggest the inclusion of aggressive sarcoma-like chemotherapy, efforts toward GTR of the primary tumors, age-based irradiation of all disease if unable to irradiate the CNS, and the incorporation of targeted agents. These hypotheses can be answered by proposing international efforts focused upon collaborations to treat RTPS which should include alliances among cooperative groups across the world to ensure that as many patients are captured as possible, the broadening of existing rhabdoid registries to be inclusive, and the early involvement of advocacy groups and forums to ensure that providers and families are aware of any such opportunities to enroll.

Abbreviations:

ATRT

Atypical Teratoid Rhabdoid Tumor

ASCR

Autologous Stem Cell Rescue

AV

Actinomycin D and Vincristine

AVD

Actinomycin D, Vincristine, and Doxorubicin

CAR

Chimeric Antigen Receptor

CCG

Children’s Cancer Group

CI

Confidence Interval

COG

Children’s Oncology Group

CR

Complete Response

EERT

Extracranial Extrarenal Rhabdoid Tumor

EFS

Event Free Survival

ERT

Extrarenal Rhabdoid Tumors

EU-RHAB

European Rhabdoid Registry

GPOH

Gesellschaft für Pädiatrische Onkologie und Hämatologie

GTR

Gross Total Resection

HDC

High-Dose Chemotherapy

HS

Head Start

ICE

Ifosfamide, Carboplatin, Etoposide

IRS

Intergroup Rhabdomyosarcoma Study

IT

Intrathecal Chemotherapy

MRI

Magnetic Resonance Imaging

MRTK

Malignant Rhabdoid Tumor of the Kidney

NED

No Evidence of Disease

NWTS

National Wilms Tumor Studies

OS

Overall Survival

PR

Partial Response

RTs

Rhabdoid Tumors

RTK

Rhabdoid Tumor of the Kidney

RTPS

Rhabdoid Tumor Predisposition Syndrome

SCCOHT

Small Cell Carcinoma of the Ovary, Hypercalcemic Type

SIOP

International Society for Pediatric Oncology

SIOPE

European Society of Pediatric Oncology

SMARC

SWI/SNF-Related, Matrix-Associated, Actin-Dependent Regulator of Chromatin

TIGIT

Tyrosine-Based Inhibition Motif Domain

UH-1

VDC (see below) Plus Etoposide and Carboplatin

VDC

Vincristine, Doxorubicin, Cisplatin