Personalizing Sarcoma treatment with comprehensive genomic profiling

Avishek Roy

Scientific Liaison Manager
4baseCare

Sarcomas are rare diseases with a high mortality rate, accounting for around 1% of all adult cancers. These are a heterogeneous category of rare cancers with over 80 subtypes identified to date. Sarcomas have multiple genomic alterations, including copy number changes, point mutations, insertions and deletions, and fusions. Specific driver molecular abnormalities have been found in a considerable proportion of soft tissue sarcomas (STS), which account for up to 40% of all sarcomas. As a result, thorough RNA and DNA sequence analysis is critical for both diagnostic and therapeutic decision-making. Therefore, incorporating comprehensive genomic profiling (CGP) into sarcoma treatment might lead to more accurate diagnosis and sub-classification of this diverse and rare disease, as well as personalized matching of patients to targeted therapies.

Currently, the diagnosis of sarcoma is based on morphology through immunohistochemistry (IHC) and clinicopathological correlation. However, advances in next-generation sequencing (NGS) technology have led to the discovery of genetic events in these mesenchymal tumors, which has opened up new options for molecularly targeted therapy and immunotherapy, in addition to improving our understanding of biology. Precision oncology medicine not only enables a better diagnosis in sarcomas but also allows for the identification of better therapeutic targets for different subtypes of sarcomas. Imatinib and other tyrosine kinase inhibitors in gastrointestinal stromal tumors, neurotrophic tyrosine receptor (NTRK) kinase inhibitors in infantile fibrosarcoma, and crizotinib in inflammatory myofibroblastic tumors are all examples of targeted therapy that have had considerable success in sarcomas. As a result, sarcoma treatment has shifted from conventional chemotherapy-based therapies to modern targeted therapy.

Overall survival (OS) in metastatic sarcoma patients remains poor. Using a commercially available CGP panel, a single-institution study by Hay et al (2020) evaluated the profiling outcomes of 392 samples from sarcoma patients. 75.3% of sarcoma patients were effectively interrogated by CGP. Bone sarcomas had a lower passing rate of 65.3%, compared to 76.7% for soft tissue sarcomas. The effectiveness of profiling was also linked to the site of the biopsy. Bone biopsy specimens passed 52.8% of the time, compared to 61.1% for lung and 80.1% for the abdomen. In 25% of evaluable patients, CGP influenced physician treatment choices, which was linked to increased progression-free survival (PFS).

Groisberg and colleagues, conducted a systematic analysis of potentially druggable alterations in sarcomas based on comprehensive genomic profiling (CGP) performed in the course of clinical care and evaluated clinical response in patients receiving molecularly matched therapies. They reported that 95 out of 102 patients (93%) had at least one genomic alteration identified with a mean of six mutations per patient. Of the 95 biopsy samples with identifiable genomic alterations, the most commonly affected genes were TP53 (31.4%), CDK4 (23.5%), MDM2 (21.6%), RB1 (18.6%), and CDKN2A/B (13.7%). Of the 102 patients in the cohort, forty (39%) had either no reported mutation (7%) or no actionable mutation (32%). The remaining 62 (61%) patients all had a potentially actionable alteration. In 14 (14%) of the patients, there was a change that may be targeted with an approved sarcoma drug. This was either an off-target effect of pazopanib or imatinib and included five patients with PDGFR (1 GIST), four with FGFR, three with KIT (2 GIST), and two with KDR gene aberrations.   A total of 46 patients (45%) had a change that might be treated with an off-label medicine. Sixty-one patients (60%) had a change that may be targeted by a treatment now in clinical trial, and fifty-eight patients (57%) had a change that could be a prospective target for a therapy in preclinical research.A total of 36 patients (35%) had a primary site biopsied and sent for next-generation sequencing (NGS), whereas 66 patients (65%) had a metastatic site biopsied and sent for NGS. Of the 102 patients, 38 patients presented with metastatic disease. The most common histologies were Leiomyosarcoma (18.6%; 8 uterine and 11 non-uterine), dedifferentiated liposarcoma (11%), osteosarcoma (11%), well-differentiated liposarcoma (7%), carcinosarcoma (6%), and rhabdomyosarcoma (6%).

The field of immunotherapy is in an expansive mode in the treatment of cancer. Some of the most promising strategies involve deregulating the immune system through immune checkpoint blockade (ICBs) and rewiring the immune system using cell transfer technology with re-infusion of ex vivo expanded TILs or genetically engineered T lymphocytes.

The diverse and rare biology that underlies STS has historically contributed to the often painstakingly slow and inefficient development of effective new therapies. Outcomes for patients with STS remain poor. However, a growing understanding of the molecular pathology of some STS subtypes has yielded important therapeutic breakthroughs. The dramatic and increasingly far-reached impacts that modern immunotherapies have had on cancer management present a tremendous opportunity in sarcoma treatment.

The authors aimed to see if CGP could aid with the diagnosis and treatment of sarcomas, given the effectiveness of targeted therapy in other diseases. Using CGP, they identified that 61% of their patients have a potentially actionable mutation that may be addressed with an off-label or experimental treatment in a clinical study. Based on these findings, the researchers conclude that NGS and actionable alterations, rather than histologic subtypes, must guide future sarcoma research. Since targeted treatment for sarcomas is scarce, however, they have shown that there are several targets with unique therapeutic promise. The authors believe that personalization will determine future therapy in oncology, and a tailored strategy would be especially beneficial for a rare and diverse tumor-like sarcoma. Thus precision oncology medicine is a way forward that will help to revolutionize the way cancer is diagnosed and treated.