bims-preonc 2025-01-19 papers

Issue of 2025–01–19
four papers selected by
Ankita Daiya, OneCell Diagnostics Inc.

Ann Lab Med. 2025 Jan 13.

Prognostic Value of Residual Circulating Tumor DNA in Metastatic Pancreatic Ductal Adenocarcinoma.

Hongkyung Kim, Jinho Lee, Mi Ri Park, Zisun Choi, Seung Jung Han, Dongha Kim, Saeam Shin, Seung-Tae Lee, Jong Rak Choi, Seung Woo Park.

Background: Circulating tumor DNA (ctDNA) is a potential biomarker in pancreatic ductal adenocarcinoma (PDAC). However, studies on residual ctDNA in patients post-chemotherapy are limited. We assessed the prognostic value of residual ctDNA in metastatic PDAC relative to that of carbohydrate antigen 19-9 (CA19-9).
Methods: ctDNA analysis using a targeted next-generation sequencing panel was performed at baseline and during chemotherapy response evaluation in 53 patients. Progression-free survival (PFS) and overall survival (OS) were first evaluated based on ctDNA positivity at baseline. For further comparison, patients testing ctDNA-positive at baseline were subdivided based on residual ctDNA into ctDNA responders (no residual ctDNA post-chemotherapy) and ctDNA non-responders (residual ctDNA post-chemotherapy). Additional survival analysis was performed based on CA19-9 levels.
Results: The baseline ctDNA detection rate was 56.6%. Although clinical outcomes tended to be poorer in patients with baseline ctDNA positivity than in those without, the differences were not significant. Residual ctDNA post-chemotherapy was associated with reduced PFS and OS. The prognosis of ctDNA responders was better than that of non-responders but did not significantly differ from that of ctDNA-negative individuals (no ctDNA both at baseline and during post-chemotherapy). Compared with ctDNA responses to chemotherapy, a ≥ 50% decrease in the CA19-9 level had less effect on both PFS and OS based on hazard ratios and significance levels. ctDNA could be monitored in half of the patients whose baseline CA19-9 levels were within the reference range.
Conclusions: Residual ctDNA analysis post-chemotherapy is a promising approach for predicting the clinical outcomes of patients with metastatic PDAC.

Keywords: Biomarkers; CA19-9; Circulating tumor DNA; Neoplasm metastasis; Pancreatic ductal adenocarcinoma; Prognosis; Residual neoplasm

DOI: https://doi.org/10.3343/alm.2024.0345

J Cancer Res Clin Oncol. 2025 Jan 16. 151(1): 37

Exploiting somatic oncogenic driver alterations in a patient with Li-Fraumeni syndrome- paving the path towards precision medicine: a case report.

Carolin Seeling, Sonja Dahlum, Ralf Marienfeld, Vera Jan, Brigitte Rack, Uwe Gerstenmaier, Ambros J Beer, Regine Mayer-Steinacker, Wolfgang Thaiss, Thomas F E Barth, Thomas Seufferlein, Nadine T Gaisa, Stephan Stilgenbauer, Wolfgang Janni, Reiner Siebert, Hartmut Döhner, Verena I Gaidzik.

BACKGROUND: Li-Fraumeni syndrome (LFS) is an autosomal dominant tumor predisposition syndrome characterized by a high familial incidence of various malignancies. It results from pathogenic/likely pathogenic heterozygous constitutional variants of the TP53 gene. Due to impaired DNA damage repair, conventional cytotoxic therapies or radiotherapy should be avoided whenever feasible to mitigate the high incidence of treatment-related secondary malignancies in these patients. However, there is limited evidence supporting the effectiveness of targeted therapy approaches in LFS patients.
CASE PRESENTATION: We present the case of a woman with breast cancer and subsequent osteosarcoma, both treated with surgery and chemotherapy. Constitutional genetic germline testing identified a pathogenic TP53 variant in line with the clinical features of Li-Fraumeni syndrome. Subsequent molecular analysis of the osteosarcoma tissue revealed homozygous loss of the CDKN2A gene locus, warranting treatment with CDK4/6 inhibitor palbociclib. Palbociclib therapy was discontinued after one year with no evidence of disease. One year later, ovarian cancer was diagnosed, with molecular analysis indicating interstitial heterozygous loss of the BRCA2 gene locus, providing a rationale for targeted therapy with the PARP inhibitor olaparib.
CONCLUSIONS: In the era of accessible and comprehensive genetic and phenotypic tumor profiling, this case study of a patient with Li-Fraumeni syndrome underscores the success of precision oncology in harnessing additional somatic oncogenic driver alterations. Furthermore, it emphasizes the indispensable role of an interdisciplinary molecular tumor board, enhancing the awareness of molecular profiling and targeted therapies in patients with rare cancer susceptibility disorders.

Keywords: Case report; Molecular tumor board - Li-Fraumeni syndrome; Precision oncology; Targeted therapy

DOI: https://doi.org/10.1007/s00432-024-06077-7

Cancer. 2025 Jan 15. 131(2): e35707

Olaparib as treatment for platinum-sensitive relapsed ovarian cancer by BRCA mutation and homologous recombination deficiency: Phase 2 LIGHT study final overall survival analysis.

Ying L Liu, Cara A Mathews, Fiona Simpkins, Karen A Cadoo, Diane Provencher, Colleen C McCormick, Adam C ElNaggar, Alon D Altman, Lucy Gilbert, Destin Black, Nashwa Kabil, Rosie N Taylor, Alan Barnicle, Jiefen Y Munley, Carol Aghajanian.

BACKGROUND: LIGHT (oLaparib In HRD-Grouped Tumor types; NCT02983799) prospectively evaluated olaparib treatment in patients with platinum-sensitive relapsed ovarian cancer (PSROC) assigned to cohorts by known BRCA mutation (BRCAm) and homologous recombination deficiency (HRD) status: germline BRCAm (gBRCAm), somatic BRCAm (sBRCAm), HRD-positive non-BRCAm, and HRD-negative. At the primary analysis, olaparib treatment demonstrated activity across all cohorts, with greatest efficacy in terms of objective response rate and progression-free survival observed in the g/sBRCAm cohorts. The authors report final overall survival (OS).
METHODS: In this phase 2, open-label, noncomparative study, patients with PSROC and one or more prior line of platinum-based chemotherapy were assigned to cohorts by BRCAm and HRD status. OS was a secondary end point. Tumors were analyzed using Myriad BRACAnalysis CDx and MyChoice CDx assays; HRD-positive tumors were defined using a genomic instability score of ≥42.
RESULTS: Of 272 enrolled patients, 271 received olaparib and 270 met the inclusion criteria for the efficacy analysis. At data cutoff, 18-month OS rates in the gBRCAm, sBRCAm, HRD-positive non-BRCAm, and HRD-negative cohorts were 86.4%, 88.0%, 78.6%, and 59.6%, respectively. No new safety signals were observed. In a post hoc analysis, patients on treatment for >18 months were most frequently present in g/sBRCAm cohorts (31.0%).
CONCLUSIONS: Olaparib treatment continued to demonstrate benefit across all cohorts. Consistent with the primary analysis, the highest OS rates were observed in the BRCAm cohorts, regardless of g/sBRCAm. In patients without a BRCAm, a higher OS rate was observed in the HRD-positive non-BRCAm than the HRD-negative cohorts. These results highlight the importance of biomarker testing in this treatment setting.

Keywords: carcinoma; genomic instability; mutation; olaparib; ovarian epithelial; ovarian neoplasms; platinum; poly(ADP‐ribose) polymerase inhibitors

DOI: https://doi.org/10.1002/cncr.35707

Target Oncol. 2025 Jan 13.

Second-Line Treatment Options for Patients with Metastatic Triple-Negative Breast Cancer: A Review of the Clinical Evidence.

José Ángel García-Saenz, Álvaro Rodríguez-Lescure, Josefina Cruz, Joan Albanell, Emilio Alba, Antonio Llombart.

Metastatic triple-negative breast cancer has a poor prognosis and poses significant therapeutic challenges. Until recently, limited therapeutic options have been available for patients with advanced disease after failure of first-line chemotherapy. The aim of this review is to assess the current evidence supporting second-line treatment options in patients with metastatic triple-negative breast cancer. Evidence was reviewed from controlled clinical trials in which eribulin, vinorelbine, capecitabine, gemcitabine, gemcitabine plus carboplatin, fam-trastuzumab-deruxtecan, sacituzumab govitecan, olaparib, and talazoparib were used in the second-line treatment for metastatic breast cancer, either as study drugs or as comparators. The benefit of treatment was evaluated using the European Society for Medical Oncology-Magnitude of Clinical Benefit Scale. Based on the evidence review, sacituzumab govitecan was identified as the preferred second-line treatment option for patients with metastatic triple-negative breast cancer, supported by clinical evidence and consensus across international clinical guidelines. Olaparib and talazoparib are of use in patients with human epidermal growth factor receptor 2-negative metastatic breast cancer and germline BRCA1/2 mutations. Exploratory data for fam-trastuzumab-deruxtecan suggest a survival benefit in human epidermal growth factor receptor 2-low, hormone-receptor-negative patients, but further solid evidence is required. Other chemotherapies with lower European Society for Medical Oncology-Magnitude of Clinical Benefit Scale scores may continue to be useful in highly selected patients.

DOI: https://doi.org/10.1007/s11523-024-01125-1