Sounding the Alarm on Leiomyosarcoma Recurrence: Role of Circulating Tumor DNA

In this issue of Clinical Cancer Research, Madanat-Harjuoja and colleagues could clearly demonstrate that patients with advanced leiomyosarcoma (LMS) with high levels of circulating tumor DNA (ctDNA) prior to start of chemotherapy treatment had a significantly worse overall survival and outcome compared with patients with low ctDNA levels (1).

Soft-tissue sarcomas (STS) are a heterogeneous group of mesenchymal neoplasms, with over 150 histologic subtypes and even greater genetic diversity within these subtypes. LMS arise from smooth muscle anywhere in the body, most commonly visceral or blood vessel muscular walls within the uterus, retroperitoneum, and extremities. Despite surgical resection, high-grade LMS is prone to metastatic recurrences. Clinical trials of adjuvant systemic therapy for high-risk disease, particularly in the uterus and retroperitoneum, have failed to demonstrate meaningful impact. In addition, the prognosis of patients with unresectable or metastatic LMS remains poor with limited activity of conventional cytotoxic chemotherapies, targeted therapies, and immunotherapies. Together with patient advocacy organizations, including Sarcoma Patients EuroNet (SPAEN) in Europe, and the National LeioMyoSarcoma Foundation (NLMSF) in the United States, we jointly developed a position paper that identified 12 research fields and key topics in LMS patient care, to prioritize future clinical and basic science efforts to close these research gaps (2).

We highlighted ctDNA investigation as one of these key research fields, as ctDNA could serve as an accessible biomarker of prognosis, a sensitive marker of minimal residual disease after surgery, a tool to inform choice and timing of therapy, and a measure of response to therapy (Fig. 1). Historically, sensitivity of ctDNA analysis for sarcomas has been limited, but with improved next-generation sequencing technology including matched tumor and blood sequencing, and the ability to detect amplification products or fusions, ctDNA is becoming more applicable for a wider range of sarcoma subtypes (3). Arshad and colleagues reported on a series of 73 patients with metastatic LMS who underwent ctDNA testing (4). Fifty-nine patients were found to have genomic alterations, including TP53 (65%), BRAF (13%), CCNE (13%), EGFR (12%), PIK3CA (12%), FGFR1 (10%), RB1 (10%), KIT (8%), and PDGFRA (8%). Less frequent alterations were also identified in RAF1, ERBB2, MET, PTEN, TERT, APC, and NOTCH1. Overall, potentially targetable mutations were found in 40% of patients, and 5% were also found to have germline TP53 mutations. To further investigate the utility of ctDNA in LMS, a pilot study is ongoing through the Sarcoma Alliance for Research through Collaboration (SARC) cooperative group to evaluate ctDNA as a biomarker of relapse-free survival, and response to chemotherapy in patients with localized LMS (NCT04925089).

Having this background in mind, the article in the present issue of Clinical Cancer Research entitled “Circulating Tumor DNA is Associated with Response and Survival in Patients with Advanced Leiomyosarcoma” by Madanat-Harjuoja and colleagues is of special interest (1). The study cohort analyzed in this article consisted of patients who had previously been enrolled in the prospective SARC021 study, an open-label, randomized, phase III, multicenter trial that compared treating patients with STS with either doxorubicin alone or with the combination of doxorubicin plus evofosfamide (5). All patients included in the present analysis (n = 98) had a diagnosis of LMS confirmed by central pathology. Madanat-Harjuoja and colleagues found that ctDNA was detectable in 49% of patients prior to chemotherapeutic treatment and in 25% of patients after two cycles of chemotherapy. Detection of pretreatment ctDNA was associated with a significant lower overall survival [HR = 1.55; 95% confidence interval (CI): 1.03–2.31; P = 0.03] and a significantly lower likelihood of objective response (OR = 0.21; 95% CI, 0.06–0.59; P = 0.005). After two cycles of chemotherapy, patients who continued to have detectable levels of ctDNA experienced a significantly worse overall survival (HR = 1.77; 95% CI, 1–3.14; P = 0.05) and were unlikely to experience an objective response (OR = 0.05; 95% CI, 0–0.39; P = 0.001). In this article, the authors have provided the largest cohort of patients with LMS evaluated for the presence of ctDNA while undergoing treatment with chemotherapy and, for the first time, identified a significant association between the detection of ctDNA with outcome and the likelihood of experiencing an objective treatment response, especially when measured after the initiation of chemotherapy.

In summary, Madanat-Harjuoja and colleagues could clearly show that patients with advanced LMS who had high levels of ctDNA prior to start of chemotherapy treatment and after receiving two chemotherapy cycles had a significantly worse overall survival than patients with low ctDNA levels. Moreover, patients with low ctDNA were significantly more likely to experience an objective response receiving additional cycles of chemotherapy. The present analysis nicely demonstrates a bench-to-bedside approach that ctDNA may be used for risk stratification in future clinical trials for patients with LMS and by providers and their patients to help to decide on the utility of chemotherapeutic treatment known to bear a significant risk of toxicity. These results suggest that liquid biopsy assays could be used to inform treatment decisions by identifying patients who are likely or unlikely to benefit from chemotherapy. These encouraging results certainly justify setting up a prospective, more comprehensive clinical trial of liquid biopsies in this rare and challenging disease.

B. Kasper reports personal fees from Ayala, Bayer, Blueprint, GSK, PharmaMar, and Springworks outside the submitted work. B.A. Wilky reports personal fees from Springworks, Deciphera, Adaptimmune, Daiichi Sankyo, Epizyme, and Adcendo outside the submitted work.