Impact of O6-methylguanine-DNA Methyltransferase (MGMT) Promoter Methylation and MGMT Expression on Dacarbazine Treated Sarcoma Patients (MGMT)

Sarcomas comprise a group of rare malignancies that are challenging to treat. Incidence of sarcoma is 15,000 annually in the U.S. [1] with a high case fatality rate. Up to one fourth of patients with sarcomas present with metastatic disease, and up to one half of patients who present with locally advanced disease develop metastases despite surgical resection and radiotherapy. Standard chemotherapies (doxorubicin, ifosfamide; gemcitabine and docetaxel) have modest activity with single-agent and combination response rates of 10%-20% and 17%- 40%, respectively .

For patients with primary soft tissue sarcomas, surgery with or without radiotherapy can offer a cure, but nearly half of patients recur and eventually die, with an estimated median survival of 12 to 15 months . As a result, treatment of metastatic or unresectable disease with cytotoxic agents is often given for palliative rather than curative purposes. These cytotoxic agents often incorporate anthracycline- or gemcitabine-based regimens as a first line treatment. Other agents such as dacarbazine and ifosfamide, only show clinical improvement in overall response rate and progression free survival (PFS), without significant benefit in overall survival. Moreover, despite superior PFS observed with these conventional cytotoxic therapies, they are fraught with severe toxicities and attendant high costs, a burden for both patients and health care systems. Until recently, a limited number of drugs have been available for these patients. Doxorubicin and ifosfamide are agents with well established activity that, given sequentially or in combination, constitute the standard treatment of advanced STS. Dacarbazine (DTIC) also is a drug with some classically known activity. The results obtained by using these standard agents, however, remain disappointing, with a median overall survival (OS) close to 12 months.

In the Randomized Phase II Study Comparing Gemcitabine Plus Dacarbazine Versus Dacarbazine Alone in Patients With Previously Treated Soft Tissue Sarcoma, the A Spanish Group for Research on Sarcomas Study showed The combination of gemcitabine and DTIC is active and well tolerated in patients with STS, providing in this phase II randomized trial superior progression-free survival and overall survival than DTIC alone. This regimen constitutes a valuable therapeutic alternative for these patients.

Recent phase III clinical trials have confirmed the efficacy of dacarbazine in the leiomyosarcoma subgroup.

So, despite new drugs such as eribulin, trabectedin, or immunotherapy, dacarbazine remains still one of the most important drugs in the therapeutic landscape of sarcomas, registering in aeterogeneous cases series including liposarcomas and leiomiosarcomas a m PFS 2 ms and a m OS 12 ms , with 10% RR and 60% DCR approximately.