Epidemiology and survival

Watch to learn about sarcoma and its prognosis

Boehringer Ingelheim in collaboration with the Sarcoma Alliance. Filmed in 2022.

Incidence

Sarcomas are rare tumors, accounting for approximately 1% of adult cancers.¹ Sarcomas are primarily classified into bone tumors (~15–20%) and STS or soft tissue sarcomas (~80%).² Liposarcomas (LPSs) are the most common type of STS, accounting for 15–20% of all STSs.³ LPSs are defined as malignant adipocytic tumors and arise in the body’s fat cells.³ Dedifferentiated liposarcoma (DDLPS) is a histologic subtype that represents 15–20% of LPSs.³

Survival

Overall five-year survival in STS ranges from 56%-65%.^4,5 The five-year survival rate for STS depends on the stage at diagnosis; it is 81% for patients with localized disease and declines to 16% for patients with distant metastases.⁴ Survival can also vary by tumor site, ranging from 14% in STS of the heart to 90.2% in STS of the skin.⁵

Histologic grade is the most important prognostic factor for STS and is predictive of distant metastasis and disease-specific survival (DSS). In a retrospective study of 1,240 patients with non-metastatic STS from the French Federation of Cancer Centers Sarcoma Group (FNCLCC), the 5-year metastasis-free survival rate was 91% for grade 1 tumors, 71% for grade 2 tumors, and 43% for grade 3 tumors.^6,7 

Another prognostic factor to consider for STS is histologic type, with LPS being the most common accounting for up to 25% of all diagnosed patients.^8,9 The prognosis of patients diagnosed with the LPS subtype is poor, with median overall survival of 8-12 months and median progression-free survival of 2.0-4.4 months.¹⁰ One particular subtype of LPS, dedifferentiated liposarcoma (DDLPS), is known to be the most aggressive type associated with very poor outcomes.^8,11,13

Five-year survival of patients with STS

Presentation and diagnosis

STS presentation varies, making it difficult to diagnose or predict tumor behavior.¹¹ Diagnosis should thus be carried out by a multidisciplinary team with expertise and experience in sarcoma.¹⁴ Diagnostic evaluation includes clinical history and examination, proper imaging, and tissue biopsy.^13-15

Morphologic diagnosis based on microscopic evaluation remains the gold standard for sarcoma diagnosis.¹⁴ The pathologic diagnosis should be made according to the WHO Classification of Tumors and Soft Tissue and Bone. Given the prognostic value of tumor grade, grading should also be done based on FNCLCC system, NCI system, or another appropriate grading system.^12,14

In the approach to LPS in particular, diagnostic challenges are common because some of its subtypes often coexist in the same site, with the tumors located most frequently in the extremities or retroperitoneum.⁸ At initial diagnosis, 15% of LPS patients present with metastatic disease while almost 50% of patients develop metastasis during the course of their disease.¹⁰ Ninety percent of patients diagnosed with DDLPS present with primary tumors at diagnosis; however, those who initially have well-differentiated liposarcoma (WDLPS) may eventually transition into DDLPS, making it difficult to distinguish between the two neoplasms.⁸ Histological patterns are similar between these subtypes and other malignancies such as undifferentiated pleomorphic sarcoma and spindle cell sarcoma, so misdiagnosis may occur and lead to further treatment delays.¹³ Imaging modalities such as PET/CT scans are used to aid in distinguishing DDLPS from other neoplasms, and are used to identify potential sites for biopsy to confirm the diagnosis.^14,16

Molecular characterization of tumors is an important advancement in the diagnosis and treatment of STS.¹¹ These testing methods are mostly based on fluorescence in situ hybridization (FISH), polymerase chain reaction (PCR), or next-generation sequencing (NGS).¹⁴ Histological hallmarks in LPS/DDLPS may be similar to those in other LPS types, so FISH testing is often utilized as a diagnostic adjunct to microscopic evaluation to help confirm the diagnosis.¹⁷

Clinical management

Treatment options for STS, especially for advanced/metastatic disease, are dependent on multiple factors such as histologic subtype, location, disease status, performance status, and patient preference.^15,18 Surgical resection is advised for localized tumors, while cytotoxic anthracycline-based chemotherapy (e.g., doxorubicin) is the main treatment option for patients that present with late-stage disease.¹⁴ However, despite being the cornerstone of treatment, systemic chemotherapy is associated with poor outcomes, low overall response rates, progressive disease, and a high risk of toxicity.^6,19-22 Patients diagnosed with high-grade disease such as DDLPS are still advised surgical resection for localized tumors; however, recurrence rates remain high at 40%-80%.^16,17

Compared to monotherapy, combination therapy with systemic chemotherapy was reported to have slightly improved response rates and survival outcomes. Only <20% of patients had a favorable response to initial first- and second-line treatment, and most patients with advanced STS discontinue second-line treatment because of disease progression.^14,16,18 

Combination therapy with doxorubicin and ifosfamide is the recommended standard line of treatment for patients with advanced/metastatic DDLPS. Combination therapy results in a higher ORR of 12%-18.5% compared to 7.5% with doxorubicin monotherapy.¹⁶ Despite this improvement, treatment with doxorubicin is associated with cardiotoxicity, and long-term treatment predisposes patients to the development of other chronic diseases such as coronary artery disease.^23,24

Clinical management of STS patients, especially those with advanced/metastatic disease, continues to be a challenge because treatment options are limited and may even pose additional difficulties on top of an already burdensome condition.⁶

Recent advances in the treatment of STS

Potential targeted therapies in STS

Novel biomarkers are currently being identified as potential therapeutic targets for STS, to address the unmet needs of patients and limited treatment options that are available. Ongoing studies on these biomarkers will aid in the development of treatments with improved clinical efficacy, improving survival rates especially for patients with advanced/metastatic disease (with known estimated median 5-year survival rates of only 30%).²⁵ 

At present, studies have shown that the molecular targets vary among STS types and patients with the same subtype may even possess varying degrees of mutational heterogeneity.²⁵

Selected histologic subtypes and corresponding molecular targets in STS²⁵

Targeted therapies produce significant tumor responses by disrupting molecular pathways that drive oncogenesis, with the use of monoclonal antibody therapy, immune checkpoint inhibitors, and small molecule therapies. Preliminary studies have shown that tumors with high PD-L1 expression were found to benefit from such treatment, unblocking immune inhibition via PD-1/PD-L1 bridging and enhancing CD8 + CTLs tumor cell killing. Though these treatments have lead to remarkable clinical responses, they are effective in a rather low percentage of cancer patients based on current data. Therefore, the identification of biomarkers for selecting patients that are most likely to respond to treatment is of great importance and may be correlated to prognosis for certain STS subtypes.²⁵

Role of MDM2 and p53 in STS

The tumor suppressor gene p53 is known as the “guardian of the genome” because it induces gene transcription that may result in either apoptosis or cell repair in response to cellular stress/damage in normal physiologic conditions.²⁶ Inactivation of the tumor suppressor activity of p53 through mutations, deletions, or inhibitor overactivity leads to tumor proliferation.²⁷

MDM2 is a negative regulator that helps ensure stability of physiologic functions in healthy cells and serves as the primary cellular inhibitor of p53.^26-28 When amplified, MDM2 results in excessive inhibition of p53 activity, which removes its tumor-suppressing effects and allows malignant cells to evade apoptosis and maintain their proliferative state.^27,28 

More than 90% of patients diagnosed with well-differentiated or dedifferentiated liposarcoma had wild-type p53 with MDM2 amplification.¹⁰ MDM2 is a critical component of DDLPS tumorigenesis, with amplification reported to be more prominent in dedifferentiated areas as opposed to well-differentiated areas.^17,29 Because outcomes remain poor despite first-line treatment with combination chemotherapy,¹⁶ studies are currently underway to evaluate anti-MDM2 therapy and its potential clinical benefits especially for patients with advanced/metastatic disease.²⁹