CLINICAL CANCER RESEARCH | REVIEW

Small-Cell Carcinoma of the Ovary, Hypercalcemic

Type–Genetics, New Treatment Targets, and Current
Management Guidelines A C

Marc Tischkowitz , Sidong Huang , Susana Banerjee5, Jennifer Hague2, William P.D. Hendricks6,
1,2 3,4

David G. Huntsman7, Jessica D. Lang6, Krystal A. Orlando8,9, Amit M. Oza10, Patricia Pautier11,
Isabelle Ray-Coquard12, Jeffrey M. Trent6, Michael Witcher13, Leora Witkowski14, W. Glenn McCluggage15,
Douglas A. Levine16, William D. Foulkes13,14,17,18, and Bernard E. Weissman8,9

ABSTRACT
◥
Small-cell carcinoma of the ovary, hypercalcemic type with hypercalcemia. SCCOHT primarily affects females under
(SCCOHT) is a rare and highly aggressive ovarian malignancy. In 40 years of age who usually present with symptoms related to a

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almost all cases, it is associated with somatic and often germline pelvic mass. SCCOHT is an aggressive cancer, with long-term
pathogenic variants in SMARCA4, which encodes for the survival rates of 30% in early-stage cases. Although various
SMARCA4 protein (BRG1), a subunit of the SWI/SNF chromatin treatment approaches have been proposed, there is no consensus
remodeling complex. Approximately 20% of human cancers possess on surveillance and therapeutic strategy. An international group
pathogenic variants in at least one SWI/SNF subunit. Because of of multidisciplinary clinicians and researchers recently formed
their role in regulating many important cellular processes the International SCCOHT Consortium to evaluate current
including transcriptional control, DNA repair, differentiation, cell knowledge and propose consensus surveillance and therapeutic
division, and DNA replication, SWI/SNF complexes with mutant recommendations, with the aim of improving outcomes. Here,
subunits are thought to contribute to cancer initiation and we present an overview of the genetics of this cancer, provide
progression. Fewer than 500 cases of SCCOHT have been updates on new treatment targets, and propose management
reported in the literature and approximately 60% are associated guidelines for this challenging cancer.

Introduction
Small-cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is
1
Department of Medical Genetics, National Institute for Health Research Cam- a rare and aggressive cancer which mainly occurs in adolescents and
bridge Biomedical Research Centre, University of Cambridge, Cambridge, young women. It represents less than 0.01% of all ovarian malignan-
United Kingdom. 2East Anglian Medical Genetics Unit, Cambridge University
cies (1), with fewer than 500 cases reported to date in the medical
Hospitals NHS Trust, Cambridge, United Kingdom. 3Department of Biochemis-
try, McGill University, Montreal, Quebec, Canada. 4The Rosalind & Morris Good- literature. The clinical and pathologic aspects of this tumor were
man Cancer Research Centre, McGill University, Montreal, Quebec, Canada. 5The initially described by Scully in 1979 (2). In describing these neoplasms,
Royal Marsden NHS Foundation Trust and Institute of Cancer Research, London, he noted: (i) the characteristic morphologic appearance of small
United Kingdom. 6Translational Genomics Research Institute, Division of Inte- hyperchromatic cells with scant cytoplasm and brisk mitotic activity,
grated Cancer Genomics, Phoenix, Arizona. 7BC Cancer, Vancouver, British (ii) the occurrence in young females, and (iii) the presence of hyper-
Columbia, Canada. 8Department of Pathology and Laboratory Medicine, Uni-
calcemia. Although the mechanism underlying the commonly
versity of North Carolina, Chapel Hill, North Carolina. 9Lineberger Comprehen-
sive Cancer Center, University of North Carolina, Chapel Hill, North Carolina. observed serum hypercalcemia is not well established, one study found
10
Princess Margaret Cancer Centre, University of Toronto, Toronto, Ontario, that in four of seven cases, the tumor cells expressed parathyroid
on Berard,
Canada. 11Gustave Roussy, Villejuif, France. 12Centre Anti cancereux Le hormone-related protein (3). It has long been postulated that some
& University Claude Bernard Lyon, GINECO Group, Lyon, France. 13The Lady cases could be familial (4) and in 2014, multiple groups discovered
Davis Institute of the Jewish General Hospital, Department of Oncology, McGill that SCCOHT is characterized by both germline and somatic delete-
University, Montreal, Canada. 14Department of Human Genetics, McGill Univer-
rious mutations (henceforth termed pathogenic variants, PV) in
sity, Montreal, Quebec, Canada. 15Department of Pathology, Belfast Health and
Social Care Trust, Belfast, United Kingdom. 16Gynecologic Oncology, Laura and SMARCA4 (5–8). Studies have shown that SMARCA4 appears as the
Isaac Perlmutter Cancer Center, NYU Langone Health, New York, New York. only recurrently mutated gene in SCCOHT (6–8). Therefore, PVs in
17
Department of Medical Genetics, Jewish General Hospital, McGill University, SMARCA4 likely serve as the driver mutation for almost all cases of
Montreal, Quebec, Canada. 18Department of Medical Genetics and Cancer SCCOHT (8). The discovery of SMARCA4 PVs in >95% of SCCOHTs
Research Program, Research Institute of the McGill University Health Centre, has been the first step in the development and implementation of
McGill University, Montreal, Quebec, Canada.
potential targeted treatment options (9). With these discoveries in
Corresponding Authors: Marc Tischkowitz, University of Cambridge, mind we brought together international experts and formed the
Cambridge CB2 0QQ, United Kingdom. Phone: 4401-2232-16446; E-mail: International SCCOHT Consortium (ISC) consisting of researchers,
mdt33@cam.ac.uk; and Bernard E. Weissman, University of North Carolina at
clinical scientists, and clinicians. We held the first symposium on
Chapel Hill, 450 West Drive, 31-321 LCCC, CB #7295, Chapel Hill, NC 27599-7295.
Phone: 1 91-9966-7533; E-mail: weissman@med.unc.edu SCCOHT in London in July 2018 to lay out the current state of
knowledge regarding genetics and consider potential treatment tar-
Clin Cancer Res 2020;26:3908–17
gets. There have been 2–3 monthly follow-up conference calls since
doi: 10.1158/1078-0432.CCR-19-3797 then to foster collaborative research and to develop a consensus
2020 American Association for Cancer Research. guideline for the diagnosis and management of SCCOHT.

AACRJournals.org | 3908
 SCCOHT, Management Guidelines, and New Treatment Targets

SWI/SNF Chromatin Remodeling this term is well established in the literature. SCCOHT is the proto-
typical ovarian neoplasm composed predominantly or exclusively of
Complex small round cells with scant cytoplasm (so-called “small round blue
Recent sequencing studies have identified mutations in subunits of cell tumor”). Because of the wide range of differential diagnoses of the
the SWI/SNF chromatin remodeling complexes in over 20% of human various neoplasms in this broad group, pathologists commonly strug-
cancers (10). Multiple configurations of the SWI/SNF complex exist, gle with these tumors due to overlapping morphology and IHC (18). In
each consisting of approximately 15 proteins (11). With several iso- diagnosing the various tumor types, IHC and molecular studies are of
forms existing for many of these proteins, theoretically, 100 or more value (19). While typical SCCOHT is part of the differential diagnosis
different combinations may exist (12). While all SWI/SNF complexes of a small round blue cell tumor, the large cell variant of SCCOHT may
contain one of the two mutually exclusive ATPase subunits, be confused with other neoplasms composed of large cells (Fig. 1).
SMARCA4 (BRG1) or SMARCA2 (BRM), functional differences Older studies investigated the immunophenotype of SCCOHT to try to
appear among them (13). This is likely due to the differential complex elucidate the histogenesis but were inconclusive. The neoplastic cells
compositions and the cell type in which they exist, as some SWI/SNF are sometimes focally positive with epithelial membrane antigen,
subunits specifically target certain genomic regions and transcription broad spectrum cytokeratins, calretinin, and CD10 (20), while desmin,
factors (14). Depending on the cell type and timepoint in development, S100, and inhibin are consistently negative. Occasional neoplasms are
these complexes can both repress and activate gene expression (15). focally positive with neuroendocrine markers. Most cases also exhibit
Thus, SWI/SNF alterations play important and varied roles in driving diffuse nuclear positivity with an antibody against the N-terminal of

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tumorigenesis. WT1 (20); this may be of some diagnostic use, although many other
tumors, including some in the differential diagnosis of SCCOHT, are
also positive. While estrogen receptor and progesterone receptor have
Normal SMARCA4 Functions not been widely investigated in SCCOHT, these neoplasms invariably
SMARCA4 is involved in a plethora of cellular processes including do not stain using antibodies directed against hormone receptors.
transcriptional regulation, DNA damage repair, differentiation, and The discovery of SMARCA4 mutations in almost all SCCOHT
mitosis, all of which may contribute to SCCOHT phenotypes. As a part tumors resulted in the development of a SMARCA4 (also known as
of the diverse SWI/SNF (BAF, PBAF, and ncBAF) chromatin remo- BRG1) antibody, which is highly useful in the diagnosis of this
deling complexes, SMARCA4 utilizes energy from ATP hydrolysis to neoplasm and distinction from its many mimics (21). One of the
mobilize nucleosomes and remodel chromatin. This remodeling original publications describing germline and somatic SMARCA4
activity commonly makes DNA accessible for loading of transcrip- mutations in these neoplasms showed loss of SMARCA4 nuclear
tional regulators or repressors. Thus, SMARCA4 is normally found at immunoreactivity in 51 of 54 (94%) cases (8). Subsequent studies
promoters and enhancers of actively transcribed genes. Because showed that over 95% of these neoplasms exhibit loss of nuclear
SCCOHTs do not possess complex genomes, transcriptional and immunoreactivity with this marker, making it an important diagnostic
epigenetic deregulation induced by SMARCA4 loss, which remains tool, although not all cases are negative (22, 23). Occasional tumors
to be uncovered, likely play a central role in driving tumorigenic exhibit loss of SMARCB1 (INI1), or loss of SMARCA2 (BRM) IHC
pathways. staining with retention of SMARCA4 (BRG1; ref. 7). Dual loss of
SMARCA4 and SMARCA2 (the latter is a subunit of the SWI/SNF
complex mutually exclusive with SMARCA4) occurs in many
Clinical Management SCCOHT (23); SMARCA2 loss occurs through epigenetic inactivation
The clinical management of SCCOHT has varied widely, although as mutations or deletions rarely occur in human tumors and have not
some clinical guidelines have previously been published (16). Outcome been demonstrated in SCCOHT (23–27). Potentially consistent with
remains poor, with estimated long-term survival reported as 33% in this notion, treatment with epigenetic inhibitors such as DNMTi or
stage I disease, and 10%–20% overall. The ISC here present consensus histone deacetylase inhibitor (HDACi), leads to reexpression of
guidelines for the diagnosis and management of women and their SMARCA2 in cancer cell lines (23, 28).
families affected by this condition, summarized in Table 1. We discuss It should be stressed that SMARCA4 loss through mutations,
potential strategies in diagnosis, genetic counseling, surveillance, and deletions, and other mechanisms is observed in several other tumor
treatment for SCCOHT as well as many issues arising from the lack of types; for example, 10%–37% of primary non–small cell lung cancers
established data on this very rare malignancy. The Consortium (NSCLC) exhibit loss of IHC expression of SMARCA4 (29–32). Dual
unreservedly recommends further research to explore the effectiveness loss of SMARCA4 and SMARCA2 is also found in SMARCA4-
of current recommendations for this rare cancer. We also recommend deficient thoracic sarcomas (33), undifferentiated and dedifferentiated
conducting all work in liaison with specialist support groups, such as endometrial carcinomas, and rare undifferentiated uterine sarco-
the Small Cell Ovarian Cancer Foundation, that provide psychosocial mas (23, 34). Although the diagnosis of SCCOHT can usually be
support and advocacy for affected families. (8) made on the basis of morphology and loss of SMARCA4 staining,
SMARCA4 tumor sequencing could be considered in problematic
cases of suspected SCCOHT with the minimum requirements to cover
SCCOHT Pathology and Diagnosis all exons and splice sites. SMARCA4 sequencing can help to distinguish
SCCOHT is currently classified as a miscellaneous neoplasm in the SCCOHT from other cancers with SMARCA4 loss when combined
2014 World Health Organization (WHO) Classification of Tumors of with histologic features, or in the context of few other somatic
Female Reproductive Organs (17). The discovery of recurrent mutations, which is much more frequently observed in SCCOHTs
SMARCA4 mutations has resulted in alternative terminologies such compared with most other tumors with SMARCA4 loss.
as malignant rhabdoid tumor of the ovary (8) and SMARCA4-defi- The age range at diagnosis is quite wide and has ranged from
cient ovarian neoplasm being proposed. However, the term SCCOHT 7 months to 56 years, with an average age of 23.9 years (35). In one
will be retained in the upcoming 2020 WHO classification given that study, 26 of 60 patients (43%) had a germline SMARCA4 PV, including

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 Tischkowitz et al.

Table 1. Summary of the ISC guidelines.

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a
Contact members of the ISC if patients want to contribute to international research efforts.
b
The role of cytoreductive surgery is not well defined for SCCOHT, but may be considered before initiating chemotherapy or at the time of recurrence in cases where
residual disease appears completely resectable (such as in referral cases where attempted cytoreduction was never performed).

all patients diagnosed before the age of 15 years. Women with germline mutations have been reported previously (6–8, 33, 36). The penetrance
PVs present at a significantly younger age than those without (P ¼ of these PVs remains uncertain, and interpretation of risk is compli-
0.02; ref. 36). We recommend caution in diagnosing SCCOHT in cated by our observation that germline PVs are often paternally
females under 10 or over 50 years of age and although one publication inherited, with only two known cases caused by a de novo SMARCA4
reported a SCCOHT in a 71-year-old female, the lack of modern PV (37, 38). While SMARCA4 PVs occur across the entire gene, with
diagnostic markers used (immunostaining or SMARCA4 mutation no obvious predilection for certain domains, loss of function variants
analysis), makes the validity of this diagnosis unclear (9). Given the in some exons may not be pathogenic for SCCOHT due to their lack of
importance of establishing a correct diagnosis and the wide differential expression in transcripts expressed in the ovary (39). Furthermore, we
diagnosis (18), we strongly recommend an expert opinion from a do not know whether individuals with a germline SMARCA4 PV
specialist gynecologic pathologist and SMARCA4 IHC staining to associated with SCCOHT possess an increased risk for development of
establish the diagnosis in an ovarian neoplasm in which SCCOHT is other types of cancers.
considered in the differential diagnosis and where a firm diagnosis of The risk of cancer in females with germline SMARCA4 PVs remains
an alternative neoplasm cannot be established. At present, most uncertain but may be considerable. Only one publication reports a
pathology laboratories do not perform SMARCA4 IHC. female with a SMARCA4 germline mutation who remained cancer-free
past her sixth decade (36). On the other hand, there is likely to be
ascertainment bias in the literature, resulting in overestimation of
Genetic Counseling and Screening in
cancer risk. Prospective studies will be needed to provide more
Patients and at-risk Family Members accurate cancer risk estimates. Thus, one of the top priorities of this
Germline and somatic SMARCA4 PVs causing SCCOHT are gen- Consortium effort is the establishment of an international registry of
erally nonsense or frameshift, although in-frame indels and missense patients with SCCOHT to facilitate follow-up of families and provide

3910 Clin Cancer Res; 26(15) August 1, 2020 CLINICAL CANCER RESEARCH
 SCCOHT, Management Guidelines, and New Treatment Targets

A B

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C D

Figure 1.
A, SCCOHT is composed of predominantly diffuse arrangement of cells with follicle-like structures. B, On higher power, the tumor cells have hyperchromatic nuclei
and scant cytoplasm. C, Large cell variant of SCCOHT composed of tumor cells with abundant eosinophilic cytoplasm. D, There is loss of nuclear immunoreactivity
with SMARCA4 (BRG1) with a positive internal control in the form of nuclear staining of endothelial cells.

opportunities for participation in research and clinical trials. Please see with a left-sided SCCOHT in 2011. This suggests that the remaining
https://smallcellovariancancer.com/contact-us/ for more details. ovary in females with SCCOHT and a germline SMARCA4 PV is also at
The Consortium recommends referral of all patients with SCCOHT risk. Therefore, we recommend discussion of risk-reducing removal of
to a clinical genetics service or provider, with an offer for testing for the other ovary if a germline SMARCA4 PV is detected. SMARCA4
germline SMARCA4 PVs (Table 1). It is important to use a clinical variants are inherited in an autosomal dominant manner. All at-risk
laboratory that offers full gene sequencing, including copy number relatives of those with SCCOHT due to a germline SMARCA4 PV
calling, as PVs are typically scattered throughout the gene, and whole- should receive genetic counseling and be offered predictive testing,
or partial-gene deletions have been reported previously (40). The which should be covered by personal or national health insurance.
incidence of germline pathogenic PVs could be high (up to 43%), Males with germline SMARCA4 PVs will not develop SCCOHT,
and the family history is not generally informative, especially if the but their daughters will have a 50% chance of inheriting the PV.
germline PV was inherited from the proband's father (36). There are Confidence in the pathogenicity of a germline variant can be enhanced
several different approaches to genetic testing for diagnostic confir- by either IHC showing loss of SMARCA4 protein expression in the
mation and with the increasing use of matched tumor-normal tumor or by identifying a second PV in the tumor.
sequencing, both germline and somatic mutations can be identified.
If no SMARCA4 mutation is detected, the diagnosis of SCCOHT
should be reconsidered, along with sequencing of other related genes as Surveillance for at-risk Family Members
a SMARCB1 mutation has been reported in one case of SCCOHT (41). This remains controversial considering the lack of proven efficacy
When there is a confirmed diagnosis of SCCOHT (appropriate and the potential risks including a false sense of security, risk of false
histologic findings plus loss of SMARCA4 expression), germline positive screens, and the potential exclusion of effective risk-reducing
testing is strongly recommended, regardless of somatic testing. surgery. Although early detection methods using imaging offer
We have recently identified a molecularly confirmed second pri- an appealing alternative to risk-reducing bilateral salpingo-
mary SCCOHT in the right ovary of a young woman initially diagnosed oophorectomy (RRBSO), this approach remains unproven and has

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 Tischkowitz et al.

been ineffective to date for other more common ovarian malignan- effective (36). However, these nonrandomized studies may suffer
cies (42, 43). While RRBSO performed prior to malignant transfor- from selection bias. Early-stage patients will more likely meet the
mation may prove more effective, its benefits for females at high risk criteria for HDC, which requires a complete response to initial
for SCCOHT also remain unproven. Determining the optimal age for chemotherapy, with the expectation of improved outcomes compared
RRBSO is extremely challenging considering the early age of disease with patients with more advanced stage disease (16). Although
onset and the uncertain penetrance of germline SMARCA4 PVs (36). SCCOHT is often chemosensitive initially, a substantial risk for relapse
RRBSO has been offered, on a highly selective basis, to females with persists and the effectiveness of additional chemotherapy is limited.
germline SMARCA4 PVs, typically for siblings in an affected fami- Reported options for chemotherapy in the recurrent setting include
ly (42, 44). Counseling for such a procedure needs sensitivity, including combinations of cyclophosphamide, doxorubicin, and vincristine, or
a discussion of surgical-based risks, onset of surgical menopause, carboplatin in combination with paclitaxel and topotecan (47). Sub-
estrogen replacement therapy, and reproductive preservation options sequent responses are often short-lived, emphasizing the need for
including oocyte cryopreservation and preimplantation genetic diag- more clinical trials.
nosis. RRBSO should be only be considered with extreme caution
where a germline SMARCA4 PVs is identified incidentally during
genetic testing for another indication and where there is no personal or
Identification of SCCOHT Therapeutic
family history of SCCOHT as the penetrance for these variants remains Candidates
uncertain. There are no published studies that suggest any form of To date, a paucity of approved or investigational agents exists for

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surveillance can prevent death from SCCOHT and therefore we do not SWI/SNF-mutant tumors. For SCCOHT specifically, there is no
recommend it. The similarities identified between rhabdoid tumors agreed standard of care and the usual care management includes
and SCCOHT (45) suggest that infant carriers of SMARCA4 PVs may surgery, platinum-based chemotherapy plus HDC with stem cell
be at risk for both. However, the risk of SMARCA4-related rhabdoid rescue, and consideration of radiation in select cases (36). Under
tumors is likely confined to very young children because of its absence the current usual care, SCCOHT portends a poor outcome, with
in children older than 46 months (36). We recommend the develop- approximately 30% survival, even following early diagnosis. Clin-
ment of standard guidelines for the care of unaffected individuals with ical trials have not yet been performed in patients with SCCOHT as
germline SMARCA4 PVs. a single entity, in large part because of the rarity of the disease,
In certain cases, testing other cancers by sequencing and/or IHC for although some genetic basket studies have included patients with
SMARCA4 can help to determine pathogenicity. Testing female SCCOHT. This means that most efforts have focused on identi-
relatives over the age of 60 years may also help to better estimate fying effective targeted treatment strategies that can translate
penetrance and cancer risk. Classifications of variants (46), particularly rapidly into clinical trials. Cancer therapeutic approaches aimed
variants of uncertain significance, will require periodic review because at restoring expression of inactivated tumor suppressor genes, such
they are likely to change over time. as TP53, RB1, or BRCA1, have not proven successful. Therefore,
targeted drug development for SCCOHT has focused on several
Recommendations for Oncological approaches, including exploiting known synthetic lethal interac-
tions of SMARCA4 loss and identifying novel targets through
Management unbiased genetic screens. We discuss the most promising results
Given the lack of prospective studies, treatment recommendations from mainly preclinical studies below (summarized in Fig. 2
are based on small case series and management strategies remain and Table 2).
heterogeneous. Despite the absence of data, the general principles of
primary cytoreductive surgery for epithelial ovarian cancer apply to Epigenetic therapeutics
patients with SCCOHT, with the goal of complete surgical resection Because tumor suppressor loss is not directly druggable, most
leaving no visible disease. A multimodal approach including radical investigators have searched for therapeutic vulnerabilities by exploit-
surgery, chemotherapy, and radiotherapy after discussion at an in- ing the concomitant changes in gene expression and signaling path-
person or virtual multidisciplinary tumor board is essential (47). ways. Cancer cells are often dependent on these alterations induced
Fertility-sparing surgery may be considered in comprehensively sur- by tumor suppressor loss, resulting in a targetable synthetic lethali-
gically staged Stage IA patients without germline SMARCA4 PVs if ty (49, 50). For example, suppression of SMARCA2 is synthetically
they desire future pregnancies, although radical surgery for all patients lethal with SMARCA4 loss in NSCLC cells (30, 51, 52) likely driven by
remains the norm. paralogous subunit compensation. However, SMARCA2 is currently
Adjuvant chemotherapy is recommended for all stages, generally undruggable and cancer cells with SMARCA4/2 dual loss, such as
cisplatin- and etoposide-based combination regimens (e.g., BEP: SCCOHT and most lung adenocarcinomas are unlikely to respond to
bleomycin, etoposide, and cisplatin; VPCBAE: vinblastine, cisplatin, SMARCA2 inhibition.
cyclophosphamide, bleomycin, doxorubicin, and etoposide; and The best developed therapeutic target comes from studies dem-
PAVEP: cisplatin, doxorubicin, and etoposide cyclophosphamide). onstrating that SWI/SNF complexes oppose the repressor function
For patients in whom initial surgery is not feasible (e.g., stage IV of PRC1 and PRC2 in regulating gene expression (24, 26). SWI/SNF
disease, unresectable disease, and medically unfit patient), adminis- loss leads to elevated PRC2 activity with a concomitant increase in
tration of chemotherapy and interval cytoreductive surgery may be H3K27me3 levels, providing a viable approach for treatment inter-
considered on an individual basis. High-dose chemotherapy (HDC) ventions. Indeed, SMARCA4-deficient cancer cells display sensi-
with autologous stem cell transplantation rescue following a complete tivity to suppression of enhancer of zeste homolog 2 (EZH2;
response to initial chemotherapy, with or without surgery, may also be refs. 53–55), the catalytic subunit of PRC2. In SCCOHT cells,
considered (48). Recently updated survival data suggest that multi- EZH2 inhibitors induce reexpression of SMARCA2 (53, 56) and
modality therapy including surgery and multi-agent chemotherapy neuronal-like proteomic signatures, as well as potently inhibiting
with possible stem cell transplantation and radiotherapy are most growth of SCCOHT cell line xenografts (55). The only trial

3912 Clin Cancer Res; 26(15) August 1, 2020 CLINICAL CANCER RESEARCH
 SCCOHT, Management Guidelines, and New Treatment Targets

PRC2 SWI/SNF
GSK126 SMARCA4/2 Palbociclib
EZH2 RB CDK4/6 Abemaciclib
Tazemetostat
Cyclin D1 Ribociclib

BRD4 JQ1
H3K27me3 H3K4me3 H3/4KAc OTX015

Proliferation
Repressed gene Activated gene Survival

Vorinostat

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Panobinostat
Seclidemstat LSD1 HDAC Quisinostat NUCLEUS
Trichostatin A

CYTOPLASM

RTKs
SCCOHT cells MHCI PD-L1 Ponatinib
(FGFR)

Nivolumab
Pembrolizumab

TCR PD-1

T-cell activation

Figure 2.
Graphic summary of SCCOHT therapeutic candidates and their corresponding drugs. Agents that are being tested in clinical trials available to patients with SCCOHT
are underlined. See Table 2 for more details.

(NCT02601950) to include patients with SCCOHT by name are EPZ-6438 in vitro and further reduces tumor growth in vivo (56).
investigating the most studied EZH2 inhibitor, tazemetostat (EPZ- While HDACi may offer an attractive treatment option for patients
6438), and early results from these phase I/II trials reported on 2 with SCCOHT, a single case report did not find efficacy with this
patients with SCCOHT, 1 with stable disease and 1 with a partial approach (58). A phase I trial (NCT03895684) of seclidemstat, a
response after treatment. A tazemetostat trial sponsored by the NCI lysine-specific demethylase inhibitor, will open specifically for
was recently suspended because of observations of secondary SWI/SNF-mutant gynecologic cancers, with an emphasis on
lymphomas. Of interest, one report has shown that growth inhi- SCCOHT, ovarian clear cell carcinomas, and endometrial carcinomas
bition of SMARCA4-deficient NSCLC appears primarily dependent that show SMARCA4 or ARID1A mutation or loss. Following dose
on a noncatalytic role of EZH2 for stabilizing the PRC2 complex, escalation with the single agent, combination with pembrolizumab will
which current EZH2 inhibitors do not target (54). be examined.
Targeting other histone modification complexes has also shown In addition to targeting EZH2 and HDAC, bromodomain and extra-
promise for treatment of patients with SCCOHT. HDACi have been terminal motif containing protein inhibitors (BETi) have been explored
clinically approved for the treatment of several hematologic malig- in SCCOHT models, based on previous studies showing the dependency
nancies but have proved less effective for solid tumors (57). Several of SMARCA4-mutant esophageal cancer models for BET protein
studies have shown that HDACis in the context of SCCOHT result in BRD4 (59) and the coregulation of an oncogenic network by BRD4
reexpression of SMARCA2, which strongly suppresses growth of and SMARCA4 in acute leukemia (60). Consistent with these findings,
SCCOHT cells (23, 56). One of these reports also showed in vivo SCCOHT cells were highly sensitive to BETi JQ1 and OTX015, the latter
sensitivity of SCCOHT cells to the HDACi quisinostat (56). They of which showed strong antitumor activities in an orthotopic xenograft
further demonstrated that quisinostat acts synergistically with model of SCCOHT (61). In addition to BRD4, other BET proteins have

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 Tischkowitz et al.

Table 2. Potential treatments and trials for SCCOHT.

Activities against
SCCOHT Clinical trial available
Class Target Drug In vitro In vivo FDA-approved application for SCCOHT Reference

Epigenetic therapeutics EZH2 GSK126 þ þ (55)

Tazemetostat þ þ Phase II NCT02601950 (53, 55)
LSD1 Seclidemstat n.a. n.a. Phase I, NCT03895684 (77)
HDAC Vorinostat þ n.a. Cutaneous T-cell lymphoma (56)
Panobinostat þ n.a. Multiple myeloma (56)
Quisinostat þ þ (56)
Trichostatin A þ n.a. (23)
BET proteins JQ1 þ n.a. (61)
OTX015 þ þ (61)
Kinase inhibitors Multi-kinases Ponatinib þ þ ALL, CML (63)
CDK4/6 Palbociclib þ þ Breast cancer Phase II, NCT03297606 (66)
Abemaciclib þ n.a. (66)
Ribociclib þ n.a. (66)

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Immunotherapies PD-1 Pembrolizumab n.a. þ Multiple cancers Phase II, NCT03012620 (70)
PD-1 Nivolumab n.a. þ Multiple cancers (70)
Abbreviations: LSD1, lysine-specific histone demethylase 1; n.a., not accessed.

been linked to SWI/SNF function. Inactivation of another key SWI/SNF regulation of cyclin D1, limiting CDK4/6 kinase activity in
subunit SMARCB1, also known as INI1 or SNF5, occurs in synovial SCCOHT cells and leading to in vitro and in vivo susceptibility
sarcomas and rhabdoid tumors as well as in a small fraction of to CDK4/6 inhibitors. Thus, their findings indicated that CDK4/6
SCCOHTs. Recent evidence suggests that both synovial sarcomas and inhibitors, approved for a breast cancer subtype addicted to CDK4/
rhabdoid tumors require a noncanonical SWI/SNF complex (ncBAF, as 6 activation, could be repurposed to treat SCCOHT. They also
opposed to BAF and PBAF), carrying BRD9 as an essential subunit, for observed this synthetic lethal interaction between SMARCA4-loss
their survival (10). Supporting this, CRISPR-knockout screens uncov- and CDK4/6 inhibition in SMARCA4-deficient NSCLC despite
ered BRD9 as a therapeutic target in these cancers (62). However, their differences in tissue of origin and mutation landscape (67).
pharmacologic inhibition of BRD9 did not recapitulate this phenotype, Given that SMARCA4 loss occurs in a variety of other cancer types,
indicating ncBAF function requires protein domains beyond the BRD9 this common druggable vulnerability, shared by SCCOHT and
bromodomain. While these studies suggest that BRD9 inhibitors may NSCLC, may also be effective for targeting other SMARCA4-
prove effective for the treatment of patients with SCCOHT, Michel and deficient tumors. Furthermore, patients may also benefit from the
colleagues showed that BRD9 forms complexes with SMARCA4 but not antitumor immunity triggered by CDK4/6 inhibition as recently
SMARCB1 (10). Therefore, the effects of BRD9 inhibition on SCCOHT shown by others (68, 69). The Canadian Profiling and Targeted
remain untested. Currently, there is no available clinical study to Agent Utilization Trial (NCT03297606), a pan-Canadian phase II
investigate the effect of BETi in patients with SCCOHT. basket trial matching patients with cancer with different genetic
variants to appropriate targeted treatments, has recently approved a
Kinase inhibitors new match to treat SMARCA4-mutant tumors with the CDK4/6
Functional genetic screening approaches have proven to be a pow- inhibitor palbociclib based on the above findings (66, 67). Patients
erful tool to uncover novel drug targets in cancers. In this context, the with SCCOHT will be included in this new trial arm.
kinome is often chosen because pharmacologic inhibitors targeting
kinases identified from the screens are often available, providing the Immunotherapies
highest chance of clinical implementation. Using an arrayed kinome- Although the low mutation burden of SCCOHT would not predict
focused siRNA screen, Lang and colleagues showed sensitivity of responsiveness to immune checkpoint blockade (ICB) based on
SCCOHT cell lines in culture and in xenografts, as well as PDX models neoantigen burden alone, programmed cell death protein 1 (PD-1)
to the clinically available multi-targeted tyrosine kinase inhibitor pona- inhibitors including pembrolizumab have shown substantial and
tinib (63). They also implicated a dependence upon FGFR signaling durable responses in selected patients with recurrent SCCOHT after
as the underlying mechanism for this sensitivity (56). These results prior treatment with cytotoxic chemotherapy and also immediately
coincide with similar observations in rhabdoid tumors where reexpres- following radiation treatment (70). In addition, 1 patient, known to
sion of SMARCB1 resulted in decreased expression of FGFR1 and these authors, showed near complete treatment response to CDK4/6
FGFR2, as well as the relative in vitro and in vivo sensitivity of rhabdoid inhibition in combination with ICB (see comment above). Further-
tumor cell lines to receptor tyrosine kinase inhibitors ponatinib and more, preclinical data from SWI/SNF-mutant melanoma (71) and
BGJ-398 (64, 65). Ponatinib is FDA-approved for the use in leukemias clear cell renal carcinoma (72) models demonstrate a causal connec-
and warrants further investigation in SCCOHT. tion between loss of SWI/SNF components such as PBRM1 and
Using a pooled short hairpin RNA screening approach also sensitivity to ICB. Although these reports focus upon loss of the
targeting human kinome, Xue and colleagues found that SCCOHT PBRM1 subunit, Pan and colleagues showed loss of this subunit in
cells are highly sensitive to cyclin-dependent kinase4/6 (CDK4/6) SCCOHT cells (73). Rhabdoid tumors, also with low mutation burden,
inhibition (66). They showed that SMARCA4 loss causes down- have recently been shown to have high infiltration of immune cells; this

3914 Clin Cancer Res; 26(15) August 1, 2020 CLINICAL CANCER RESEARCH
 SCCOHT, Management Guidelines, and New Treatment Targets

immunogenicity is linked to endogenous retrovirus expression upon identification of germline PVs. Because surveillance is unproven,
induced by SMARCB1 loss (74). Indeed, several recent reports support we recommend RRBSO for unaffected adult females with germline
the efficacy of these inhibitors in patients with rhabdoid PVs in the context of a positive family history. Given the lack of defined
tumors (75, 76). Checkpoint blockade responses in SWI/SNF- guidelines for the management of women with SCCOHT, we recom-
mutant cancers may be associated with overexpression of immune- mend aggressive cytoreductive surgery followed by adjuvant combi-
stimulatory genes (71, 72). Given the similarity between SCCOHT and nation therapy with a cisplatin- and etoposide-based regimen. HDC
rhabdoid tumors, similar mechanisms may be in place underlying the with stem cell rescue for individuals who have a complete clinical
response of SCCOHT to PD-1 inhibitor. A French phase II basket trial response may be considered (36, 48). Patients with progressive or
AcSe program with pembrolizumab (NCT03012620) is currently open recurrent disease should enroll in a clinical trial or consider nonstan-
for women with rare ovarian tumors including relapsed SCCOHT. dard therapy based on the latest data that may come from case reports
While further investigation will define the utility of checkpoint inhi- and limited source material.
bitors in SCCOHT, mechanistic understanding remains limited on the SCCOHT is an excellent example of a cancer where the develop-
basis of the complex nature of modeling immune cell interactions in ment of novel therapies targeting the cancer vulnerabilities induced by
the available SCCOHT models, where the cell of origin is not yet the driver mutation is possible. The key message for patients and
defined. A phase II trial including pembrolizumab in combination family members it to remain in contact with disease experts who have
with initial chemotherapy for advanced disease (stage II to IV) is due knowledge of the latest clinical trials, seek consultation from academic
to start in France in 2020. referral centers, and request input from members of the ISC, https://

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As more clinical trials become available for patients with SCCOHT, www.smallcellovarian.org/consortium.html. The landscape of treat-
we suggest that immunotherapy be the first choice for treatment when ments for SCCOHT will continually change as we improve patient
eligibility requirements permit. After initial therapy, as described outcomes and work toward prevention and cure for this rare and
previously, immunotherapy appears to be the most promising non- aggressive malignancy. International prospective multicenter pro-
standard therapy based on activity in selected patients reported to date tocols with collection of data are urgently needed to be considered
and data from other related tumor types. The addition of CDK 4/6 for both first-line and relapsed disease in this particularly rare
inhibitors and epigenetic therapies also have some favorable reported condition.
outcomes to date on the basis of very limited, and mostly unpublished,
case reports. We hope that additional viable options will become Disclosure of Potential Conflicts of Interest
available as more preclinical and translational research is reported. S. Banerjee reports receiving speakers bureau honoraria from AstraZeneca,
Tesaro/GlaxoSmithKline, Roche, and Seattle Genetics. No potential conflicts of
interest were disclosed by the other authors.
Conclusions
Acknowledgments
In the six years since the discovery of SMARCA4 mutations in We acknowledge support from The Eve Appeal research charity who funded the
SCCOHT, this cancer has been transformed from being a little studied, SCCOHT Symposium held on July 5, 2018 in London, United Kingdom that led to the
poorly understood cancer for which there was no rational therapeutic formation of the International SCCOHT Consortium. This was made possible with
options, to a tumor which is now the focus of much research. This is the support and generosity of families affected by SCCOHT including Linda, Mike,
leading to the discovery of multiple potential treatments, meaning that and Mark Butcher and their extended family and friends in memory of Angela; The
there is now a need to carefully evaluate and prioritize the best Louise Hartley Memorial Fund and the Hartley Family in memory of Louise; The
family and friends of Emma Houlston and Matt Lees; and the family and friends of
candidate drugs for future trials. The rarity of SCCOHT creates Ailsa Renshaw. We are grateful for assistance from Inga Plaskoncinska and input from
challenges in the identification and management of affected patients. Maren Petersen of the Small Cell Ovarian Cancer Foundation, founded in memory of
The true number of women affected worldwide remains unknown, Stephanie Petersen. M. Tischkowitz was funded by the European Research Council
creating barriers to rapidly and systematically identify eligible indivi- under the European Union's Seventh Framework Programme (FP/2007–2013)/ERC
duals for new treatments or clinical trials. We have begun establishing Grant Agreement n.310018 and Cancer Research UK (CanGene-CanVar Catalyst
an international registry of well-characterized patients with, or at-risk Award C61296/A27223). S. Huang is supported by CIHR grants MOP-130540
and PJT-156233. J.M. Trent, B.E. Weissman, J.D. Lang, W.P. Hendricks, and
for, SCCOHT. The collation of high quality clinical and epidemiologic D.G. Huntsman receive support from the U.S. NCI grant R01CA195670. A.M. Oza
data will allow us to better understand this disease and act as a catalyst was supported by Princess Margaret Cancer Foundation and Ontario Institute Cancer
to improve translational research and the overall outcome for patients Research Ovarian Translational Research Initiative. D.A. Levine was supported by
with SCCOHT. U.S. DOD grant W81XWH-15-1-0429. W.D. Foulkes was funded by the Canadian
Females with germline PVs in SMARCA4 likely have a clinically Institutes of Health Research (FDN- 148390). These guidelines have been endorsed by
important risk of SCCOHT up to the age of approximately 60 years, the European Reference Network GENTURIS.
particularly in the context of a positive family history. Genetic testing
for germline SMARCA4 PVs is recommended for all affected indivi- Received November 25, 2019; revised February 4, 2020; accepted March 6, 2020;
duals with SCCOHT with cascade testing of at-risk family members published first March 10, 2020.

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