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- Osteosarcoma pathogenesis leads the way to new target treatmentsPublication . Fernandes, Isabel; Alvim, Cecilia; Brás, Raquel; Esperança Martins, Miguel; Costa, LuisOsteosarcoma (OS) is a rare condition with very poor prognosis in a metastatic setting. Basic research has enabled a better understanding of OS pathogenesis and the discovery of new potential therapeutic targets. Phase I and II clinical trials are already ongoing, with some promising results for these patients. This article reviews OS pathogenesis and new potential therapeutic targets.
- HERVs establish a distinct molecular subtype in stage II/III colorectal cancer with poor outcomePublication . Golkaram, Mahdi; Salmans, Michael L.; Kaplan, Shannon; Vijayaraghavan, Raakhee; Martins, Marta; Khan, Nafeesa; Garbutt, Cassandra; Wise, Aaron; Yao, Joyee; Casimiro, Sandra; Marques, Catarina; Macedo, Daniela; Costa, Ana Lúcia; Alvim, Cecilia; Mansinho, André; Filipe, Pedro; Marques da Costa, Pedro; Fernandes, Afonso; Borralho, Paula; Ferreira, Cristina; Aldeia, Fernando; Malaquias, João; Godsey, Jim; So, Alex; Pawlowski, Traci; Costa, Luis; Zhang, Shile; Liu, LiColorectal cancer (CRC) is one of the most lethal malignancies. The extreme heterogeneity in survival rate is driving the need for new prognostic biomarkers. Human endogenous retroviruses (hERVs) have been suggested to influence tumor progression, oncogenesis and elicit an immune response. We examined multiple next-generation sequencing (NGS)-derived biomarkers in 114 CRC patients with paired whole-exome and whole-transcriptome sequencing (WES and WTS, respectively). First, we demonstrate that the median expression of hERVs can serve as a potential biomarker for prognosis, relapse, and resistance to chemotherapy in stage II and III CRC. We show that hERV expression and CD8+ tumor-infiltrating T-lymphocytes (TILs) synergistically stratify overall and relapse-free survival (OS and RFS): the median OS of the CD8-/hERV+ subgroup was 29.8 months compared with 37.5 months for other subgroups (HR = 4.4, log-rank P < 0.001). Combing NGS-based biomarkers (hERV/CD8 status) with clinicopathological factors provided a better prediction of patient survival compared to clinicopathological factors alone. Moreover, we explored the association between genomic and transcriptomic features of tumors with high hERV expression and establish this subtype as distinct from previously described consensus molecular subtypes of CRC. Overall, our results underscore a previously unknown role for hERVs in leading to a more aggressive subtype of CRC.
- Genomic profiling of sarcomas: a promising weapon in the therapeutic arsenalPublication . Brás, Raquel; Lopez-Presa, Dolores; Esperança Martins, Miguel; Alvim, Cecilia; Gallego Páez, Lina Marcela; Costa, Luis; Fernandes, IsabelSarcomas are rare malignant mesenchymal neoplasms, and the knowledge of tumor biology and genomics is scarce. Chemotherapy is the standard of care in advanced disease, with poor outcomes. Identifying actionable genomic alterations may offer effective salvage therapeutic options when previous lines have failed. Here, we report a retrospective cohort study of sarcoma patients followed at our center and submitted to comprehensive genomic profiling between January 2020 and June 2021. Thirty patients were included, most (96.7%) with reportable genomic alterations. The most common alterations were linked to cell cycle regulation (TP53, CDKN2A/B, and RB1 deletions and CDK4, MDM2, and MYC amplifications). Most patients (96.7%) had microsatellite stability and low tumor mutational burden (≤10 muts/megabase (Mb); median 2 Muts/Mb). Two-thirds of patients had actionable mutations for targeted treatments, including five cases with alterations amenable to targeted therapies with clinical benefit within the patient's tumor type, ten cases with targetable alterations with clinical benefit in other tumor types, and five cases with alterations amenable to targeting with drugs under investigation in a clinical trial setting. A significant proportion of cases in this study had actionable genomic alterations with available targeted drugs. Next-generation sequencing is a feasible option for identifying molecular drivers that can provide therapeutic options for individual patients. Molecular Tumor Boards should be implemented in the clinical practice to discuss genomic findings and inform clinically relevant targeted therapies.
- Prognostic factors for patients treated with abirateronePublication . Alvim, Cecilia; Mansinho, André; Paiva, Rita S.; Brás, Raquel; Semedo, Patrícia M.; Lobo-Martins, Soraia; da Ponte, Carolina B.; Macedo, Daniela; Ribeiro, Maria Leonor; dos Reis, José P; Fernandes, Isabel; Costa, LuisAim: To evaluate prostate-specific antigen response (PSAr) defined as a ≥50% decrease in PSA concentration from the pretreatment value, as a prognostic factor in patients with metastatic castration-resistant prostate cancer (mCRPC) treated with abiraterone acetate (AA). Methods: Retrospective evaluation of patients with mCRPC treated with AA. Results: 124 patients were identified. Median overall survival and progression-free survival for patients achieving PSAr versus patients without PSAr were 29.3 versus 9.7 months and 17.0 versus 5.2 months, respectively. Multivariate analysis confirmed that PSAr correlated with better overall survival (hazard ratio: 0.19; 95% CI: 0.10-0.38; p < 0.001) and progression-free survival (hazard ratio: 0.24; 95% CI: 0.14-0.41; p < 0.001). Conclusion: PSAr can be utilized as prognostic and predictive factors in mCRPC patients treated with AA.