bims-myxlip 2021-12-19 papers

Issue of 2021‒12‒19
three papers selected by
Laura Mannarino
Humanitas Research

J Surg Oncol. 2022 Jan;125(1): 17-27

The evolution of adjuvant/neoadjuvant trials for resectable localized sarcoma.

Mai-Kim Gervais, Dario Callegaro, Alessandro Gronchi.

Soft-tissue sarcomas are rare tumors arising from mesenchymal tissues. As a heterogeneous group comprising more than 50 types, the development of clinical trials remains challenging. Decision-making for neoadjuvant or adjuvant chemotherapy and radiation therapy is based on the available evidence of contemporary trials and multidisciplinary clinical judgment.

Keywords: chemotherapy; clinical trials; extremity sarcoma; immunotherapy; radiotherapy; retroperitoneal sarcoma

DOI: https://doi.org/10.1002/jso.26745

Cancer Res. 2021 Dec 13. pii: canres.1222.2021. [Epub ahead of print]

Integrated molecular characterization of patient-derived models reveals therapeutic strategies for treating CIC-DUX4 sarcoma.

Marianna Carrabotta, Maria Antonella Laginestra, Giorgio Durante, Caterina Mancarella, Lorena Landuzzi, Alessandro Parra, Francesca Ruzzi, Lisa Toracchio, Alessandra De Feo, Veronica Giusti, Michela Pasello, Alberto Righi, Pier-Luigi Lollini, Emanuela Palmerini, Davide Maria Donatii, Maria Cristina Manara, Katia Scotlandi.

Capicua-double homeobox 4 (CIC-DUX4)-rearranged sarcomas (CDS) are extremely rare, highly aggressive primary sarcomas that represent a major therapeutic challenge. Patients are treated according to Ewing sarcoma (EWS) protocols, but CDS-specific therapies are strongly needed. In this study, RNA sequencing was performed on patient samples to identify a selective signature that differentiates CDS from EWS and other fusion-driven sarcomas. This signature was used to validate the representativeness of newly generated CDS experimental models - patient-derived xenografts (PDX) and PDX-derived cell lines - and to identify specific therapeutic vulnerabilities. Annotation analysis of differentially expressed genes and molecular gene validation highlighted an HMGA2/IGF2BP/IGF2/IGF1R/AKT/mTOR axis that characterizes CDS and renders the tumors particularly sensitive to combined treatments with trabectedin and PI3K/mTOR inhibitors. Trabectedin inhibited IGF2BP/IGF2/IGF1R activity, but dual inhibition of the PI3K and mTOR pathways was required to completely dampen downstream signaling mediators. Proof-of principal efficacy for the combination of the dual AKT/mTOR inhibitor NVP-BEZ235 (dactolisib) with trabectedin was obtained in vitro and in vivo using CDS PDX-derived cell lines, demonstrating a strong inhibition of local tumor growth and multiorgan metastasis. Overall, the development of representative experimental models (PDXs and PDX-derived cell lines) has helped to identify the unique sensitivity of the CDS to AKT/mTOR inhibitors and trabectedin, revealing a mechanism-based therapeutic strategy to fight this lethal cancer.

DOI: https://doi.org/10.1158/0008-5472.CAN-21-1222

Front Oncol. 2021 ;11 732525

Clinical Utility of Circulating Tumor DNA in Advanced Rare Cancers.

Hitomi Sumiyoshi Okuma, Kan Yonemori, Yuki Kojima, Maki Tanioka, Kazuki Sudo, Emi Noguchi, Susumu Hijioka, Keiko Wakakuwa, Ken Kato, Akihiro Hirakawa, Aya Kuchiba, Takashi Kubo, Hitoshi Ichikawa, Akihiko Yoshida, Yasushi Yatabe, Kenichi Nakamura, Hiroyuki Mano, Noboru Yamamoto, Yasuhiro Fujiwara.

Purpose: Patients with advanced/relapsed rare cancers have few treatment options. Analysis of circulating tumor DNA in plasma may identify actionable genomic biomarkers using a non-invasive approach.Patients and Methods: Rare cancer patients underwent prospective plasma-based NGS testing. Tissue NGS to test concordance was also conducted. Plasma DNA alterations were assessed for incidence, functional impact, therapeutic implications, correlation to survival, and comparison with tissue NGS.
Results: Ninety-eight patients were analyzed. Diseases included soft-tissue sarcoma, ovarian carcinoma, and others. Mean turn-around-time for results was 9.5 days. Seventy-six patients had detectable gene alterations in plasma, with a median of 2.8 alterations/patient. Sixty patients had a likely pathogenic alteration. Five received matched-therapy based on plasma NGS results. Two developed known resistance mutations while on targeted therapy. Patients with an alteration having VAF ≥5% had a significantly shorter survival compared to those of lower VAF. Tissue NGS results from eleven of 22 patients showed complete or partial concordance with plasma NGS.
Conclusion: Plasma NGS testing is less invasive and capable of identifying alterations in advanced rare cancers in a clinically meaningful timeframe. It should be further studied as a prospective enrollment assay in interventional studies for patients with rare advanced stage cancers.
Clinical Registration: [https://www.umin.ac.jp/ctr/index-j.htm], identifier UMIN000034394.

Keywords: CtDNA (circulating tumor DNA); precision medicine; rare cancer; soft tissue sarcoma; targeted therapy

DOI: https://doi.org/10.3389/fonc.2021.732525