SMARCA4-deficient ovarian cancer is an uncommon and highly aggressive disease that follows a rapid clinical course. This malignancy presents unique challenges for diagnosis and treatment. It primarily affects a younger demographic, setting it apart from other ovarian malignancies that are more common in older women.
The Role of the SMARCA4 Gene
The SMARCA4 gene contains instructions for a tumor-suppressing protein called BRG1. This protein is a central component of the SWI/SNF chromatin remodeling complex, which manages how DNA is packaged inside a cell’s nucleus. By altering chromatin structure, the SWI/SNF complex controls which genes are turned on or off, regulating cell growth, differentiation, and DNA repair.
When the SMARCA4 gene is mutated or absent, the resulting protein is non-functional or not produced. This deficiency impairs the SWI/SNF complex, leading to widespread dysregulation of gene expression. Without this regulatory system, cell division becomes uncontrolled, permitting cells to grow and multiply, forming a tumor.
This genetic deficiency defines a rare cancer known as Small Cell Carcinoma of the Ovary, Hypercalcemic Type (SCCOHT). Inactivating mutations in the SMARCA4 gene are identified in most SCCOHT cases, making it a monogenic disease driven by alterations in a single gene. Unlike many cancers that accumulate numerous mutations, SCCOHT has a simple genome, with the loss of SMARCA4 being the principal driver. The absence of the SMARCA4 protein is the hallmark used to identify this tumor.
Clinical Presentation and Diagnosis
The symptoms of this cancer often relate to a pelvic mass and can include non-specific abdominal pain, bloating, or a feeling of fullness. A distinct feature is the age of the patients, who are adolescents and young women with a median age at diagnosis around 24 years. This contrasts with more common ovarian cancers that affect post-menopausal women.
A second distinguishing feature is the frequent occurrence of hypercalcemia, an abnormally high level of calcium in the blood. This condition is seen in approximately two-thirds of patients and gives the cancer its “hypercalcemic type” name. The elevated calcium is caused by the tumor secreting a substance similar to parathyroid hormone. Symptoms of hypercalcemia, such as frequent urination or confusion, are less commonly reported by patients at diagnosis.
The diagnostic process begins when symptoms prompt a clinical examination, which may reveal a large pelvic mass. Imaging studies, such as an ultrasound or a CT scan, are used to visualize the mass and determine its size and extent. A biopsy is then performed to obtain a tissue sample for analysis by a pathologist.
A definitive diagnosis is made using a laboratory test on the tumor tissue called immunohistochemistry (IHC). This technique uses antibodies to detect the presence or absence of specific proteins. In SCCOHT cases, IHC staining shows a complete loss of the SMARCA4 (BRG1) protein in cancer cells, while surrounding healthy cells retain it as an internal control. This finding is highly specific for SCCOHT, distinguishing it from other tumors, and genetic testing may also identify the specific SMARCA4 mutation.
Standard Treatment Modalities
The standard of care involves an intensive, multi-modal treatment plan. While no single protocol is universally agreed-upon, recommendations are based on case series and institutional experience. The approach begins with surgery, followed by systemic chemotherapy and sometimes radiation, even for early-stage disease.
The surgical goal is complete cytoreduction, which means removing all visible tumor. The extent of the surgery depends on the disease’s spread and may include:
- Unilateral salpingo-oophorectomy (removal of the affected ovary and fallopian tube)
- Total hysterectomy (removal of the uterus)
- Bilateral salpingo-oophorectomy (removal of both ovaries and fallopian tubes)
- Omentectomy (removal of the omentum)
- Removal of any extra-ovarian tumors
- Peritoneal biopsies to fully stage the cancer
Following surgery, adjuvant treatment is recommended for all patients. This consists of high-dose, multi-agent chemotherapy, which is generally platinum-based and includes drugs like cisplatin and etoposide. Common combination regimens include BEP (bleomycin, etoposide, and cisplatin) or PAVEP (cisplatin, doxorubicin, cyclophosphamide, and etoposide).
In some cases, treatment plans incorporate high-dose chemotherapy with autologous stem cell transplantation, which allows for more potent doses of chemotherapy. Radiation therapy to the pelvis or other affected areas may also be considered as part of the initial treatment or for managing recurrent disease. This combination of therapies aims to improve outcomes.
Emerging and Targeted Therapies
Research into the cancer’s genetic weakness has led to new therapeutic strategies that move beyond standard chemotherapy. These treatments are designed to exploit the tumor’s dependence on cellular pathways that become active after SMARCA4 is lost. Many are being evaluated in clinical trials at specialized cancer centers.
The most developed targeted approach involves EZH2 inhibitors. In healthy cells, the SWI/SNF complex (containing SMARCA4) and the PRC2 complex (containing EZH2) work in opposition to regulate gene expression. When SMARCA4 is lost, this balance is disrupted, and cancer cells can become dependent on EZH2 activity for survival. EZH2 inhibitors, such as tazemetostat, block EZH2 function, which can suppress tumor growth in SMARCA4-deficient cells.
Other targeted agents are also showing promise. CDK4/6 inhibitors, a class of drugs approved for certain breast cancers, are effective in preclinical models of SCCOHT. The loss of SMARCA4 makes cancer cells susceptible to these drugs, which work by halting the cell cycle. The CDK4/6 inhibitor palbociclib is being investigated for patients with SMARCA4-mutant tumors.
Immunotherapy, specifically immune checkpoint inhibitors, represents another avenue of investigation. These drugs, such as pembrolizumab, help the body’s own immune system recognize and attack cancer cells. Although SCCOHT has a low number of genetic mutations, some patients with recurrent disease have shown durable responses. Research is ongoing to identify which patients are most likely to benefit.
Hereditary Risk and Family Considerations
A diagnosis has important considerations for the patient’s family, as the SMARCA4 mutation can be inherited. It is necessary to distinguish between a somatic mutation, which occurs only in the tumor and is not inherited, and a germline mutation. A germline mutation is present in every cell of a person’s body and can be passed to their children.
Studies show that between one-third and one-half of SCCOHT cases are associated with a germline SMARCA4 mutation, meaning the predisposition was inherited. The mutation is passed down in an autosomal dominant pattern, so a person only needs one copy of the mutated gene to have an increased risk. A child of an individual with a germline mutation has a 50% chance of inheriting it.
All patients diagnosed with SCCOHT are recommended to undergo genetic counseling and testing to determine if their mutation is germline. If a germline mutation is found, predictive testing can be offered to first-degree relatives. Identifying family members who carry the mutation allows for discussions about potential risk-reducing strategies. These discussions may include difficult decisions about preventive surgery, which must be weighed against the cancer’s early age of onset, as the exact lifetime risk for carriers is not fully understood.