Beyond failure of endocrine-based therapies in HR+/HER2 negative advanced breast cancer: What before chemotherapy? A
Rosalba Torrisi1, Riccardo Gerosa2, Chiara Miggiano2
1Humanitas Research Hospital IRCCS, Medical Oncology and Hematology Unit, Viale Manzoni 56, Rozzano, MI 20089, Italy.
Abstract:
Despite the impressive improvements achieved by endocrine therapy and CDK4/6 inhibitors (CDK4/6i) and the forthcoming availability of alternative endocrine manipulations and targeted therapies, hormone-receptor positive/HER2 negative (HR+/HER2-) advanced breast cancer (ABC) is almost inevitably destined to become endocrine- refractory. At this time chemotherapy has been recently challenged and partly replaced by new targeted options as antibody-drug conjugated (ADCs). Trastuzumab-deruxtecan has been proven meaningfully superior to chemotherapy either in 1st and later lines after progression to CDK4/6i in HER2-low ABC and results with other ADCs as Sacituzumab Govitecan and Datopotamab-deruxtecan are promising, but the definition of cross-resistance between these drugs sharing either antibody or payload is crucial before implementing them in a useful sequence. While PARP inhibitors are the standard 2nd line in patients with gBRCA mutation, it is not still known whether patients with mutations of PALB2 or of other homologous recombinant defect (HRD)-related genes will benefit of the same treatment. On the other hand, the results obtained with immune checkpoint inhibitors (ICIs) in HR+ /HER2-ABC contrarily to the early setting are disappointing up to now, but investigations of ICIs in combination with other targeted drugs which may increase immune response and the search for better markers of activity are under way. Moreover the anticipation in upfront treatment of ADCs or PARPi in patients with features of putative endocrine resistance and/or of less sensitiviy to CDK4/6i and the choice of therapy in patients recurring during or soon after adjuvant CDK4/6i and olaparib represent further challenges for the future.
Insights
Hormone-receptor positive advanced breast cancer often becomes endocrine-resistant. Antibody-drug conjugates show promise, but sequencing and resistance mechanisms require further study for optimal treatment strategies.
Area of Science:
- Oncology
- Pharmacology
- Genetics
Background:
- Hormone-receptor positive/HER2 negative (HR+/HER2-) advanced breast cancer (ABC) frequently develops endocrine resistance despite current therapies like endocrine therapy and CDK4/6 inhibitors.
- Chemotherapy is being increasingly replaced by novel targeted therapies, including antibody-drug conjugates (ADCs).
Purpose of the Study:
- To review the current landscape and future challenges in treating HR+/HER2- ABC, focusing on emerging targeted therapies and resistance mechanisms.
- To discuss the efficacy and sequencing of antibody-drug conjugates (ADCs), PARP inhibitors, and immune checkpoint inhibitors (ICIs) in advanced breast cancer.
Main Methods:
- Review of recent clinical trial data and emerging therapeutic strategies for HR+/HER2- advanced breast cancer.
- Analysis of resistance patterns and cross-resistance potential among novel targeted agents like ADCs.
- Evaluation of the role of PARP inhibitors in specific genetic mutation profiles and the potential of ICIs in combination therapies.
Main Results:
- ADCs such as trastuzumab-deruxtecan demonstrate superiority over chemotherapy in HER2-low ABC, with other ADCs showing promise.
- PARP inhibitors are established for BRCA-mutated patients, but their benefit in other homologous recombination defect (HRD) gene mutations is under investigation.
- Immune checkpoint inhibitors (ICIs) have shown disappointing results in HR+/HER2- ABC to date, but combination strategies are being explored.
Conclusions:
- The management of endocrine-refractory HR+/HER2- ABC is evolving with the advent of ADCs and other targeted agents.
- Defining cross-resistance between ADCs and optimizing the sequencing of novel therapies are critical future challenges.
- Further research is needed to elucidate the role of PARP inhibitors in broader HRD populations and to improve the efficacy of ICIs in this setting.
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