Clinical outcomes of patients with metastatic breast cancer enrolled in phase I clinical trials

Eur J Cancer. 2021 Nov;157:40-49. doi: 10.1016/j.ejca.2021.07.037. Epub 2021 Aug 31.


Background: Next-generation phase I clinical trials (Ph1s) investigating targeted therapy (TT) and immunotherapy (IO) led to consistent improvements in outcomes of patients with cancer . Ph1s are mainly designed to enrol patients with different tumour types; hence, scant information on characteristics and outcomes of specific tumours is available. The aim of our study is to evaluate the outcomes of patients with metastatic breast cancer (BC) enrolled in Phs1 testing TT, IO and combinations.

Material and methods: We retrospectively collected data on clinical characteristics and outcomes of all patients with metastatic BC treated in Ph1s from 2014 to 2019 at our Institution. The primary end-points were progression-free survival (PFS) and overall survival (OS). The secondary objectives were overall response rate (ORR), disease control rate (DCR) and 90-day mortality rate. Univariate and multivariate analyses were performed to assess the impact of different variables.

Results: One hundred fifty-one patients with metastatic BC were treated, including 70 (46%) with hormone receptor-positive (HR+), 18 (12%) with HER2+ and 63 (42%) with triple-negative (TN) BC. The median age was 52.4 years (26.9-77.9). Patients with TNBC were less pretreated than patients with HR+ and HER2+ subtypes. Patients with HR+ tumours were preferentially included in TT rather than IO trials (97% vs. 2.9%, P < 0.001). In 148 patients evaluable for tumour response, DCR and ORR were 51.4% and 18.9%, respectively. Higher response rates have been observed in patients treated with TT (TT vs. IO: 23.5% vs. 3.0%, P = 0.008) and in the HER2+ or TN subtypes (HER2+ vs. TN vs. HR+: 33.3% vs. 24.2% vs. 10.3%, P = 0.032). Improved median PFS was observed in patients treated with TT (P < 0.001), aged ≥ 65 years (P = 0.001) and having fewer than 3 metastatic sites (P = 0.026). Patients with HR+ and HER2+ subtypes presented a numerically higher median PFS than those with TNBC (3.65 vs. 3.58 vs. 2.28 months, P = 0.053). Median OS was longer in HR+ and HER2+ subtypes than that in TNBC (20 vs. 16 vs. 10 months, P = 0.007). Variables independently associated with improved OS were fewer than three metastatic sites (P = 0.014) and a baseline lactate dehydrogenase lower than upper limit of normal (P < 0.001).

Conclusion: Our study provides novel insights on the landscape of metastatic breast cancer metasta treated in Ph1s. Patients with TNBC still have poor outcomes, reinforcing the need to better translate preclinical findings into the clinical context. TT-based trials-mainly biomarker-driven-are associated with improved outcomes, suggesting that future IO trials have to be guided by meaningful biomarkers. Finally, patients with low tumour burden can have significant benefit, underling the importance to enrol patients in earlier lines of treatment to maximise the benefit.

Keywords: Biomarkers; Breast cancer; Immunotherapy; Phase I trials; Targeted therapy.

Publication types

  • Clinical Trial, Phase I
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / mortality
  • Breast Neoplasms / pathology
  • Female
  • Humans
  • Immune Checkpoint Inhibitors / therapeutic use
  • Middle Aged
  • Molecular Targeted Therapy
  • Neoplasm Metastasis
  • Receptor, ErbB-2 / analysis
  • Retrospective Studies


  • Immune Checkpoint Inhibitors
  • ERBB2 protein, human
  • Receptor, ErbB-2