Title: Validation of a cisplatin response predictor in carboplatin-treated metastatic breast cancer patients

Background: Cisplatin and carboplatin are widely used platinum-based chemotherapies in breast cancer, particularly in triple negative breast cancer, but their use is often limited by toxicity and variable efficacy. A cisplatin Drug Response Predictor (DRP) based on a 205-gene mRNA signature has previously demonstrated clinical utility in liposomal cisplatin-treated metastatic breast cancer (MBC) patients (DOI 10.1200/JCO.2023.41.16_suppl.3130) and in non-small cell lung cancer (NSCLC) patients treated with cisplatin (PMID 29566065). In this study, the clinical relevance of the DRP was assessed in MBC patients receiving carboplatin and gemcitabine.

Methods: The cisplatin DRP was applied to tumor gene expression data from 20 MBC patients treated with carboplatin and gemcitabine within a Danish MBC cohort (DBCG) (PMID 31654283), and the scores were scaled from 0 to 100 using the full DBCG cohort (n=803) as background population. Time to progression (TTP) was used as the clinical endpoint and associations between DRP scores and TTP were evaluated using Cox proportional hazards models. A one-sided significance level of 0.05 was used for statistical testing.

Results: The median TTP in the carboplatin and gemcitabine-treated patients (n = 20) was 2.1 months, and patients had received a median of four prior lines of therapy. The DRP score was significantly associated with TTP when modeled as a continuous covariate using Cox regression (one-sided p-value = 0.03). A 50-point difference in DRP score corresponded to a hazard ratio (HR) of 0.31 (upper 95% confidence bound = 0.86, p = 0.03, one-sided), indicating a lower risk of progression in patients with a higher DRP score. The estimated median TTP was 6.5 months for patients with a DRP score of 75, compared to 2.1 months for those with a score of 25. Conclusion: The previously validated cisplatin DRP was significantly associated with clinical outcomes in carboplatin-treated MBC patients, supporting its applicability to carboplatin in addition to cisplatin. A 50-point increase in DRP score (75 versus 25) was estimated to extend the median TTP by 4.4 months. This difference in median TTP is clinically relevant in the context of advanced BC, given the short median TTP and the heavily pretreated status of the patients.

References:

Dorte Nielsen et al. “Predictive biomarker for cisplatin in prospective phase 2 of liposomal cisplatin in metastatic breast cancer.” JCO 41, 3130-3130(2023). DOI:10.1200/JCO.2023.41.16_suppl.3130

Buhl, Ida Kappel et al. “Molecular prediction of adjuvant cisplatin efficacy in Non-Small Cell Lung Cancer (NSCLC)-validation in two independent 3 cohorts.” PloS one vol. 13,3 e0194609. 22 Mar. 2018, doi:10.1371/journal.pone.0194609

Christensen, Troels Dreier, et al. “Prediction of Fulvestrant Efficacy in Patients with Advanced Breast Cancer: Retrospective-Prospective Evaluation of the Predictive Potential of a Multigene Expression Assay.” Breast Cancer, vol. 27, no. 2, 25 Oct. 2019, pp. 266–276, https://doi.org/10.1007/s12282 019-01017-7

All authors and affiliations

Bent Ejlertsen (presenting author): Ejlertsen, B. (1)

Beatrice Hahn: Hahn, B. (2)

Troels Dreier Christensen: Christensen, T.D. (3)

Jan Nart: Nart, J. (2)

Jacob Hansen Niklassen: Niklassen, J.H. (2)

Ib Jarle Christensen: Christensen, I.J. (4)

Thomas Jensen: Jensen, T. (5)

Anker Hansen: Hansen, A. (5)

Anna Sofie Buhl Rasmussen: Rasmussen, A.S.B. (6)

Ida Kappel Buhl: Buhl, I.K. (2)

Ulla Hald Buhl: Buhl, U.H. (7)

Peter Buhl Jensen: Jensen, P.B. (7)

Steen Knudsen: Knudsen, S. (5)

1: Department of Oncology, Rigshospitalet, Copenhagen, Denmark

2: Science, Aida Oncology, Copenhagen, Denmark

3: Department of Oncology, Herlev and Gentofte Hospital, Herlev, Denmark

4: Department of Pathology, Herlev and Gentofte Hospital, Herlev, Denmark

5: Allarity Therapeutics, Hørsholm, Denmark

6: Paediatric Oncology, Rigshospitalet, Copenhagen, Denmark

7: Chosa Oncology, Copenhagen, Denmark

Contact information

Peter Buhl Jensen (CHOSA Oncology, CEO): peter@chosa.bio