Researchers at MD Anderson Cancer Center believe that including clinical genomic profiling into sarcoma management could result in more precise diagnosis and subclassification of the disease.
Researchers at MD Anderson Cancer Center believe that including clinical genomic profiling (CGP) into sarcoma management could result in more precise diagnosis and subclassification of the disease, based on results from a retrospective, observational, phase I study published in Oncotarget.
Recurrent and metastatic sarcomas are a rare and heterogeneous group of diseases. With more than 70 subtypes, even making a correct diagnosis is a challenge. Moreover, only about 25% of patients respond to the cytotoxic agents typically used to treat these advanced sarcomas.
“Overall survival continues to be poor in metastatic sarcoma as a group. With small numbers and large diversity of subtypes, even the prospect of initiating and accruing a study in this population is daunting,” lead author Roman Groisberg, MD, and his colleagues at MD Anderson wrote. “Given the success of targeted therapy in other diseases, we sought to discover if CGP could aid in diagnosis and treatment of sarcomas as a whole. Using CGP we discovered that 61% of our patients had a potentially actionable mutation which could be targeted with either an off-label or an investigational therapeutic available in a clinical trial.”
Groisberg et al determined that 95 of 102 patients in the study had least 1 genomic alteration, with a mean of 6 alterations per patient. Amino acid substitutions were the most common alterations (49%), followed by amplifications (31%). The most commonly altered genes were TP53 (31.4%), CDK4 (23.5%), MDM2 (21.6%), RB1 (18.6%), and CDKN2A/B (13.7%).
Forty patients (39%) had no reported mutation (7%) or no actionable mutation (32%); the remaining 62 (61%) patients all had a potentially actionable alteration.
Fourteen patients (14%) had an alteration that could be targeted with an approved drug in sarcoma (on-label). This was either an off-target effect of pazopanib (Votrient) or imatinib (Gleevec), and included 5 patients with PDGFR (1 GIST), 4 with FGFR, 3 with KIT (2 GIST), and 2 with KDR gene aberrations.
Forty-six patients (45%) had an alteration that could be targeted with an off-label drug. Sixty-one patients (60%) had an alteration that could be targeted by a drug currently in clinical trial, and fifty-eight (57%) had an alteration that is a potential target for a drug currently in preclinical development.
The researchers noted that very high numbers of patients with dedifferentiated liposarcoma (100%), well-differentiated liposarcoma (100%), and carcinosarcoma (83%) had actionable mutations.
To identify genomic alterations that could be targets for therapy, researchers conducted a systemic analysis based on CGP “performed in the course of clinical care and evaluated clinical response in patients receiving molecularly matched therapies.”
Researchers defined “actionable gene alteration” as any gene alteration or pathway component of a gene alteration that is either directly targeted by an approved or investigational drug.
Researchers evaluated records of patients treated at the Investigational Therapeutics Department, the phase I clinical trials program at MD Anderson. All patients had advanced or metastatic relapsed or refractory sarcoma, or did not have any other standard care therapies available when they presented for clinical trials.
Thirty-six patients had primary site biopsies and were sent for next-generation sequencing (NGS) while 66 patients had a metastatic site sent for NGS. Thirty-eight 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%).
“Based on our findings, we believe that future studies in sarcomas should be guided by next-generation sequencing [NGS] and actionable alterations rather than histologic subtypes,” the researchers wrote. “Sarcomas are lacking in development of targeted therapy, but we demonstrate that there are myriad targets with novel therapeutic potential. We believe that personalization will shape future therapy in oncology. A rare and heterogeneous neoplasm like sarcoma would especially benefit from such a personalized approach.”
Groisberg R, Hong DS, Holla V, et al. Clinical genomic profiling to identify actionable alterations for investigational therapies in patients with diverse sarcomas [published online April 5, 2017]. Oncotarget. doi: 10.18632/oncotarget.16845.