Elsevier

European Journal of Cancer

Volume 136, September 2020, Pages 43-51
European Journal of Cancer

Original Research
Effect of dose-dense adjuvant chemotherapy in hormone receptor positive/HER2-negative early breast cancer patients according to immunohistochemically defined luminal subtype: an exploratory analysis of the GIM2 trial

https://doi.org/10.1016/j.ejca.2020.05.007Get rights and content

Highlights

  • Dose-dense chemotherapy improves outcome in hormone receptor-positive breast cancer.

  • Differences in dose-dense effect according to luminal subtype are still unknown.

  • In the Gruppo Italiano Mammella 2 trial, there was no interaction between luminal subtype and treatment.

  • Yet, only the luminal B cohort derived survival benefit from dose-dense schedule.

  • No benefit from dose-dense chemotherapy was observed in the luminal A-like cohort.

Abstract

Background

Luminal A-like and luminal B-like subtypes have different sensitivity to (neo)adjuvant chemotherapy, but their role in predicting dose-dense (DD) efficacy in the high-risk setting is unknown. In this exploratory analysis of the Gruppo Italiano Mammella 2 (GIM2) trial, we investigated DD efficacy according to luminal-like subtypes.

Methods

Patients with node-positive early breast cancer were randomised to receive either DD or standard-interval (SI) anthracycline-based chemotherapy followed by paclitaxel. In our analysis, luminal A-like cohort was identified as having a Ki67 < 20% and a progesterone receptor (PgR) ≥ 20%; luminal B-like cohort as having a Ki67 ≥ 20% and/or a PgR < 20%.

Results

Out of 2003 patients enrolled in the GIM2 trial, 412 had luminal A-like and 638 luminal B-like breast cancer. After a median follow-up of 7.9 years, disease-free survival (DFS) was 80.8% (95% confidence interval [CI] 76.4–84.5) and 70.5% (66.5–74.2) in luminal A-like and luminal B-like cohorts; overall survival (OS) was 91.6% (88.2–94.1) and 85.1% (81.7–87.9), respectively. We found no significant interaction between treatment and luminal subtype (interaction p = 0.603 and 0.535 for DFS and OS, respectively). When DD efficacy was investigated separately in each cohort, luminal-B like cohort appeared to benefit more from the DD schedule both in terms of DFS (unadjusted hazard ratio [HR] 0.72 [95% CI 0.54–0.96]) and OS (unadjusted HR 0.61 [95% CI 0.40–0.94]), compared with the luminal A-like cohort (unadjusted HR for DFS 0.89 [95% CI 0.59–1.33]; unadjusted HR for OS 0.83 [95% CI 0.45–1.54]).

Conclusions

No significant interaction between luminal-like subtype and treatment was observed. Patients in the luminal B-like cohort seemed to benefit more from DD schedule.

Introduction

The efficacy of adjuvant chemotherapy in patients with hormone receptor positive (HR+) breast cancer has been questioned for decades [1]. The Early Breast Cancer Trialist Cooperative Group (EBCTCG) meta-analysis published in 2012 showed that the relative magnitude of the benefit of modern chemotherapy is similar irrespective of hormone receptor status and given endocrine therapy [2]. However, because the HR+ population is heterogeneous with respect to sensitivity to chemotherapy [[3], [4], [5], [6]], identification of patients who may most benefit from this approach remains a matter of controversy.

In stage I–II disease, the classification of HR+ breast cancer into luminal A-like and luminal B-like subtypes, based on the immunohistochemical evaluation of the progesterone receptor (PgR) and the proliferation marker Ki67, has allowed to identify two subgroups of HR+ breast cancer patients with different prognosis and different sensitivity to chemotherapy [[6], [7], [8], [9]].

In the high-risk setting, chemotherapy effect within luminal-like subtypes has been poorly investigated. High-risk early breast cancer is preferentially treated with dose-dense (DD) adjuvant chemotherapy, which has been proved to be superior to standard-interval (SI) chemotherapy both in terms of DFS and OS [10]. Although randomised clinical trials found no correlation of the efficacy of DD chemotherapy with neither hormone receptors status nor Ki67 expression [[11], [12], [13], [14], [15], [16], [17], [18], [19]], the potential interaction between luminal-like subtypes and DD effect has never been specifically investigated.

The Gruppo Italiano Mammella (GIM) 2 trial is one of the largest studies that investigated the efficacy of DD chemotherapy as adjuvant treatment of high-risk early breast cancer patients [20]. Considering the follow-up of nearly 8 years and the large proportion of HR+ tumours, the GIM2 trial provides a unique opportunity to investigate whether patients with different luminal-like breast cancer subtypes benefit differently from DD chemotherapy.

Section snippets

Study design and procedures

The full description of the GIM2 trial has been previously reported [20]. Briefly, this was a multicentre, open-label, randomised phase III trial, which enrolled patients with invasive early breast cancer with metastasis in at least one axillary lymph node. The study aimed to establish whether fluorouracil, epirubicin and cyclophosphamide (FEC) followed by paclitaxel (FEC-P) regimen would improve disease-free survival compared with the same regimen without fluorouracil (EC-P), and whether the

Results

Between April 24, 2003 and July 3, 2006, 2003, patients were randomised to either DD or SI chemotherapy in the GIM2 trial. Of 2003 patients, 1050 had HR+, HER2-negative/HER2-unknown breast cancer and could therefore be classified into the luminal A-like (n = 412; 39.2%) and luminal B-like (n = 638; 60.7%) cohorts. Out of 412 patients in the luminal A-like cohort, 176 were randomised to SI chemotherapy and 236 to DD chemotherapy, whereas 336 and 302 patients with luminal B-like disease were

Discussion

To our knowledge, this is the first study investigating the efficacy of DD adjuvant chemotherapy in patients with HR+ breast cancer according to IHC-defined luminal subtypes. We found no significant interaction between treatment efficacy and subtypes in the 1050 node-positive, HR+ and HER2-negative/HER2-unknown breast cancer patients enrolled in the GIM2 trial. Yet, when treatments were compared separately in each subtype, it seems to argue a trend for a greater benefit of DD chemotherapy in

Conclusion

Although this exploratory analysis of the GIM2 trial showed no interaction between luminal subtype and treatment, our findings suggest that luminal B-like subtype might benefit more from DD adjuvant chemotherapy. Our results are merely exploratory and need to be externally validated.

Conflict of interest statement

L.D.M. declares honoraria from Roche, Pfizer, Ipsen, Eli Lilly, Eisai, Novartis, Takeda and MSD and Seattle Genetics; a consulting and advisory role for Roche and Eli Lilly and fees for travel, accommodation and expenses from Roche, Pfizer and Celgene outside the submitted work. M.L. served as a consultant for Teva and received speaker honoraria from Theramex outside the submitted work. O.G. received personal fees from Celgene, Eisai, Pfizer, Amgen, Eli Lilly and Novartis; travel and

Acknowledgements

This work was partially supported by grant from Ministero della Salute 5X1000 2015 (Italy) and Associazione Italiana per la Ricerca sul Cancro (AIRC).

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