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The Place of Chemotherapy in The Evolving Treatment Landscape for Patients With HR-positive/HER2-negative MBC

  • Author Footnotes
    # All authors contributed to this review article. All authors have read and approved the final manuscript.
    Chris Twelves
    Correspondence
    Address for correspondence: Chris Twelves, Professor of Clinical Cancer Pharmacology and Oncology, Leeds Institute of Medical Research, St James's University Hospital, Beckett Street Leeds, West Yorkshire LS9 7TF, UK
    Footnotes
    # All authors contributed to this review article. All authors have read and approved the final manuscript.
    Affiliations
    Clinical Cancer Pharmacology and Oncology, Leeds Institute of Medical Research, University of Leeds and Leeds Teaching Hospitals Trust Leeds
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  • Author Footnotes
    # All authors contributed to this review article. All authors have read and approved the final manuscript.
    Rupert Bartsch
    Footnotes
    # All authors contributed to this review article. All authors have read and approved the final manuscript.
    Affiliations
    Department of Medicine 1, Division of Oncology, Medical University of Vienna, Austria
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  • Noa Efrat Ben-Baruch
    Correspondence
    Address for correspondence: Chris Twelves, Professor of Clinical Cancer Pharmacology and Oncology, Leeds Institute of Medical Research, St James's University Hospital, Beckett Street Leeds, West Yorkshire LS9 7TF, UK
    Affiliations
    Department of Oncology, Kaplan Medical Center, Rehovot, Israel
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  • Simona Borstnar
    Correspondence
    Address for correspondence: Chris Twelves, Professor of Clinical Cancer Pharmacology and Oncology, Leeds Institute of Medical Research, St James's University Hospital, Beckett Street Leeds, West Yorkshire LS9 7TF, UK
    Affiliations
    Division of Medical Oncology, Institute of Oncology, Ljubljana, Slovenia
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  • Luc Dirix
    Correspondence
    Address for correspondence: Chris Twelves, Professor of Clinical Cancer Pharmacology and Oncology, Leeds Institute of Medical Research, St James's University Hospital, Beckett Street Leeds, West Yorkshire LS9 7TF, UK
    Affiliations
    Medical Oncology, Sint-Augustinus Hospital, Antwerp, Belgium
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  • Petra Tesarova
    Correspondence
    Address for correspondence: Chris Twelves, Professor of Clinical Cancer Pharmacology and Oncology, Leeds Institute of Medical Research, St James's University Hospital, Beckett Street Leeds, West Yorkshire LS9 7TF, UK
    Affiliations
    First Faculty of Medicine and General Teaching Hospital, Charles University, Prague, Czech Republic
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  • Constanta Timcheva
    Correspondence
    Address for correspondence: Chris Twelves, Professor of Clinical Cancer Pharmacology and Oncology, Leeds Institute of Medical Research, St James's University Hospital, Beckett Street Leeds, West Yorkshire LS9 7TF, UK
    Affiliations
    Medical Oncology MHAT “Nadezhda”, Sofia, Bulgaria
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  • Lyudmila Zhukova
    Correspondence
    Address for correspondence: Chris Twelves, Professor of Clinical Cancer Pharmacology and Oncology, Leeds Institute of Medical Research, St James's University Hospital, Beckett Street Leeds, West Yorkshire LS9 7TF, UK
    Affiliations
    Loginov Moscow Clinical Scientific Center, Moscow, Russia
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  • Xavier Pivot
    Correspondence
    Address for correspondence: Chris Twelves, Professor of Clinical Cancer Pharmacology and Oncology, Leeds Institute of Medical Research, St James's University Hospital, Beckett Street Leeds, West Yorkshire LS9 7TF, UK
    Affiliations
    ICANS – Strasbourg Europe Cancerology Institute, Strasbourg, France
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  • Author Footnotes
    # All authors contributed to this review article. All authors have read and approved the final manuscript.
Open AccessPublished:October 25, 2021DOI:https://doi.org/10.1016/j.clbc.2021.10.007

      Abstract

      Endocrine therapy (ET) for the treatment of patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR-positive/HER2-negative) metastatic breast cancer (MBC) has changed markedly over recent years with the emergence of new ETs and the use of molecularly targeted agents. Cytotoxic chemotherapy continues, however, to have an important role in these patients and it is important to maximize its efficacy while minimizing toxicity to optimize outcomes. This review examines current HR-positive/HER2-negative MBC clinical guidelines and addresses key questions around the use of chemotherapy in the face of emerging therapeutic options. Specifically, the indications for chemotherapy in patients with HR-positive/HER2-negative MBC and the choice of optimal chemotherapy are discussed.

      Keywords

      Introduction

      In Europe, breast cancer incidence continues to increase and, despite falling mortality
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      , MBC still causes more cancer-related deaths than any other cancer in women
      World Health Organization
      . Outcomes for patients with advanced disease outcomes remain poor, and treatment is essentially “palliative” despite recent advances
      World Health Organization
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      . Molecular phenotypes, specifically HR and HER2 status, are predictive (i.e., driving treatment decisions) and prognostic (i.e., correlated with course of disease). HR-positive/HER2-negative disease comprises ∼60-70% of all MBC
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      Until recently, single-agent ET was standard of care first-line treatment for patients with HR-positive/HER2-negative MBC
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      Hormone receptor-positive, HER2-negative metastatic breast cancer: redrawing the lines.
      ,
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      4th ESO-ESMO international consensus guidelines for advanced breast cancer (ABC 4)†.
      . Tamoxifen has been largely replaced by the aromatase inhibitors (AIs; letrozole, anastrozole and exemestane) in postmenopausal patients
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      REACHAUT: First-line (1L) ribociclib (RIB) + endocrine therapy (ET) in HR+, HER2- metastatic breast cancer (MBC) in the real-world setting.
      .
      The 2020 European School of Oncology (ESO)–European Society for Medical Oncology (ESMO) 5th International Consensus Guidelines for Advanced Breast Cancer (ABC 5) recommend first-line treatment of patients with HR-positive/HER2-negative MBC using ET and a CDK4/6i, regardless of menopausal status and previous ET therapy (Figure 1). The key exception is patients with impending or current visceral crisis
      • Cardoso F
      • Senku E
      • Costa A
      • et al.
      4th ESO-ESMO international consensus guidelines for advanced breast cancer (ABC 4)†.
      . This is defined as “severe organ dysfunction as assessed by signs and symptoms, laboratory studies, and rapid progression of disease.” Importantly, “visceral crisis is not the mere presence of visceral metastases but implies important visceral compromise leading to a clinical indication for a more rapidly efficacious therapy, particularly since another treatment option at progression will probably not be possible
      • Cardoso F
      • Senku E
      • Costa A
      • et al.
      4th ESO-ESMO international consensus guidelines for advanced breast cancer (ABC 4)†.
      .”
      Figure 1
      Figure 1Overview of the ABC 5 guidelines
      • Cardoso F
      • Senku E
      • Costa A
      • et al.
      4th ESO-ESMO international consensus guidelines for advanced breast cancer (ABC 4)†.
      *Visceral crisis implies severe organ dysfunction as assessed by signs and symptoms, laboratory studies and rapid progression of disease. Visceral crisis is not the mere presence of visceral metastases but implies significant organ compromise leading to a clinical indication for the most rapidly effective therapy. For premenopausal women, for whom ET was decided, OFS/OFA combined with additional ET is the preferred choice. Single-agent tamoxifen is the only available ET option for premenopausal women who decline OFS/OFA, but the panel believes it is a less effective option. OFA=ovarian function ablation; OFS=ovarian function suppression.
      Guidelines highlight the continuing role of chemotherapy, as an alternative to a CDK4/6i and ET, as first-line systemic treatment and following progression on a CDK4/6i and ET. They do not, however, definitively answer questions such as “When is chemotherapy best used?” or “What is the preferred hierarchy/sequence of chemotherapy options
      • Cardoso F
      • Senku E
      • Costa A
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      4th ESO-ESMO international consensus guidelines for advanced breast cancer (ABC 4)†.
      ,
      • Partridge AH
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      • Carey LA
      • et al.
      Chemotherapy and targeted therapy for women with human epidermal growth factor receptor 2-negative (or unknown) advanced breast cancer: American society of clinical oncology clinical practice guideline.
      ?” These are the clinically relevant questions that we address.
      This review focuses on the role of chemotherapy in patients with HR-positive/HER2-negative MBC. The efficacy of CDK4/6i–ET combinations may mean fewer such patients receive chemotherapy first line, and that when they do eventually receive chemotherapy, they receive fewer lines of chemotherapy. Optimal, evidence-based use of chemotherapy is, therefore, essential. Many cytotoxics are “active” in patients with MBC but cross-trial Phase II data comparisons are unsatisfactory. Accordingly, we prioritize randomized chemotherapy trials with survival endpoints. We do not address re-treatment with the same cytotoxic, nor the emerging role of targeted therapy with poly(adenosine diphosphate-ribose) polymerase inhibitors, which are not specifically applicable to this patient group.

      First-line Treatment of Patients With HR-positive/HER2-negative MBC

      CDK4/6i and ET Combinations: The New Gold Standard

      Research on HR-positive tumor resistance mechanisms showed that upregulation of molecules involved in cell cycle regulation and advancement through the G1-to-S checkpoint often occurs, presenting attractive therapeutic targets
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      .
      CDK4/6i–ET combinations enhance efficacy and delay the emergence of endocrine resistance
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      . Table 1 summarizes Phase III studies underpinning regulatory approvals of CDK4/6i–ET combinations. These combinations consistently maintain disease control for ∼2 years (Table 1)
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      Updated results from MONALEESA-2, a phase III trial of first-line ribociclib plus letrozole versus placebo plus letrozole in hormone receptor-positive, HER2-negative advanced breast cancer.
      ,
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      Ribociclib plus endocrine therapy for premenopausal women with hormone-receptor-positive.
      ,
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      MONARCH 3 final PFS: a randomized study of abemaciclib as initial therapy for advanced breast cancer.
      with increasing evidence of overall survival (OS) benefits
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      MONARCH 3 final PFS: a randomized study of abemaciclib as initial therapy for advanced breast cancer.
      ,
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      • Bardia A
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      Overall survival with ribociclib plus endocrine therapy in breast cancer.
      . While such studies have mostly been conducted in postmenopausal women
      • Finn RS
      • Martin M
      • Rugo HS
      • et al.
      Palbociclib and letrozole in advanced breast cancer.
      ,
      • Hortobagyi GN
      • Stemmer SM
      • Burris HA
      • et al.
      Updated results from MONALEESA-2, a phase III trial of first-line ribociclib plus letrozole versus placebo plus letrozole in hormone receptor-positive, HER2-negative advanced breast cancer.
      ,
      • Goetz MP
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      MONARCH 3: abemaciclib as initial therapy for advanced breast cancer.
      ,
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      Phase III randomized study of ribociclib and fulvestrant in hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: MONALEESA-3.
      , progression-free survival (PFS) and OS were also significantly prolonged by adding ribociclib to ET in pre- and perimenopausal women
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      Ribociclib plus endocrine therapy for premenopausal women with hormone-receptor-positive.
      .
      Table 1Studies of CDK4/6is + ET in patients with HR-positive/HER2-negative MBC
      • Finn RS
      • Martin M
      • Rugo HS
      • et al.
      Palbociclib and letrozole in advanced breast cancer.
      • Hortobagyi GN
      • Stemmer SM
      • Burris HA
      • et al.
      Updated results from MONALEESA-2, a phase III trial of first-line ribociclib plus letrozole versus placebo plus letrozole in hormone receptor-positive, HER2-negative advanced breast cancer.
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      • Im S-A
      • Colleoni M
      • et al.
      Ribociclib plus endocrine therapy for premenopausal women with hormone-receptor-positive.
      ,
      • Johnston S
      • Martin M
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      • et al.
      MONARCH 3 final PFS: a randomized study of abemaciclib as initial therapy for advanced breast cancer.
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      • Lu Y-S
      • Bardia A
      • et al.
      Overall survival with ribociclib plus endocrine therapy in breast cancer.
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      MONARCH 3: abemaciclib as initial therapy for advanced breast cancer.
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      MONARCH 2: abemaciclib in combination with fulvestrant in women With HR+/HER2- advanced breast cancer who had progressed while receiving endocrine therapy.
      Study and

      first author
      Line of treatmentTreatment

      groups
      YearPhaseMenopausal statusRR, %Median PFS, monthsMedian OS, monthsSerious AEs, %
      PALOMA-2

      Finn/Rugo6, 41
      FirstPalbociclib–letrozole vs placebo–letrozole2016/2019IIIPostmenopausal42.1 vs 34.727.6 vs 14.5NR23.6 vs

      15.3
      MONARCH 3

      Johnston/Goetz34, 36
      FirstAbemaciclib–anastrozole/letrozole vs placebo–anastrozole/letrozole2017/2019IIIPostmenopausal48.2 vs 34.528.2 vs 14.8NR27.5 vs 14.9
      MONALEESA-7

      Tripathy/Im18,35
      FirstRibociclib–letrozole/anastrozole or ribociclib–tamoxifen vs placebo–letrozole/anastrozole or placebo–tamoxifen2018/2019IIIPre- or perimenopausal41 vs 3023.8 vs 13NR vs 40.918 vs 12
      MONALEESA-2

      Hortobagyi
      • Hortobagyi GN
      • Stemmer SM
      • Burris HA
      • et al.
      Updated results from MONALEESA-2, a phase III trial of first-line ribociclib plus letrozole versus placebo plus letrozole in hormone receptor-positive, HER2-negative advanced breast cancer.
      FirstRibociclib–

      letrozole vs

      placebo–letrozole
      2018IIIPostmenopausal42.5 vs 28.725.3 vs 16.0NR25.4 vs 15.5
      MONALEESA-3

      Slamon/Slamon37, 46
      FirstRibociclib–fulvestrant vs placebo–fulvestrant2018/2020IIIPostmenopausal40.9 vs 28.733.6 vs 19.2NR vs 45.128.6 vs 16.6*
      Second14.6 vs 9.140.2 vs 32.5
      PALOMA-3 Cristofanilli/Turner/Turner47–49Second and later linePalbociclib–fulvestrant vs placebo–fulvestrant2015/2016/2018IIIAny10.4 vs 6.311.2 vs 4.634.9 vs 28.013 vs 17
      MONARCH 2

      Sledge/Sledge50, 51
      Second and later lineAbemaciclib–fulvestrant vs placebo–fulvestrant2017/2019IIIPostmenopausal48.1 vs 21.316.4 vs 9.346.7 vs 37.322.4 vs 10.8
      *Safety data from first- and second-line patients. AEs = adverse events; NR = not reached; OS = overall survival; PFS = progression-free survival; RR = response rate; vs = versus.
      Optimal CDK4/6i use, including choice of agent, remains under debate. In the ABC 5 guidelines there was, however, the highest level of consensus that “a CDK4/6 inhibitor combined with ET is the standard of care for patients with ER-positive /HER2-negative ABC (advanced breast cancer), since it achieves a substantial PFS benefit, significantly increases OS and either maintains or improves QoL
      • Cardoso F
      • Senku E
      • Costa A
      • et al.
      4th ESO-ESMO international consensus guidelines for advanced breast cancer (ABC 4)†.
      ,
      • Partridge AH
      • Rumble RB
      • Carey LA
      • et al.
      Chemotherapy and targeted therapy for women with human epidermal growth factor receptor 2-negative (or unknown) advanced breast cancer: American society of clinical oncology clinical practice guideline.
      .” A recent meta-analysis of 8 randomized controlled trials, including 4,580 patients with MBC, confirmed that the addition of 1 of 3 currently approved CDK4/6is to ET prolonged PFS (hazard ratio [HR] 0.55; 95% confidence interval [CI]: 0.50–0.60; P<.01) and OS (HR 0.75; 95% CI: 0.67–0.85; P<.01)
      • Xie N
      • Qin T
      • Ren W
      • et al.
      Efficacy and safety of cyclin-dependent kinases 4 and 6 inhibitors in HR+/HER2- advanced breast cancer.
      . The magnitude of benefit from this approach is consistent across patient subgroups
      • Finn RS
      • Martin M
      • Rugo HS
      • et al.
      Palbociclib and letrozole in advanced breast cancer.
      • Hortobagyi GN
      • Stemmer SM
      • Burris HA
      • et al.
      Updated results from MONALEESA-2, a phase III trial of first-line ribociclib plus letrozole versus placebo plus letrozole in hormone receptor-positive, HER2-negative advanced breast cancer.
      • Tripathy D
      • Im S-A
      • Colleoni M
      • et al.
      Ribociclib plus endocrine therapy for premenopausal women with hormone-receptor-positive.
      ,
      • Goetz MP
      • Toi M
      • Campone M
      • et al.
      MONARCH 3: abemaciclib as initial therapy for advanced breast cancer.
      ,
      • Awada A
      • Gligorov J
      • Jerusalem G
      • et al.
      CDK4/6 inhibition in low burden and extensive metastatic breast cancer: summary of an ESMO Open-Cancer Horizons pro and con discussion.
      ,
      • Di Leo A
      • O'Shaughnessy J
      • Sledge Jr, GW
      • et al.
      Prognostic characteristics in hormone receptor-positive advanced breast cancer and characterization of abemaciclib efficacy.
      and no significant efficacy differences have been observed between the approved CDK4/6is
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      • Qin T
      • Ren W
      • et al.
      Efficacy and safety of cyclin-dependent kinases 4 and 6 inhibitors in HR+/HER2- advanced breast cancer.
      . Their adverse event (AE) profiles do, however, differ. Although usually asymptomatic, hematologic toxicities (particularly neutropenia) occur more often with palbociclib and ribociclib; gastrointestinal AEs are more frequent with abemaciclib
      • Finn RS
      • Martin M
      • Rugo HS
      • et al.
      Palbociclib and letrozole in advanced breast cancer.
      ,
      • Hortobagyi GN
      • Stemmer SM
      • Burris HA
      • et al.
      Updated results from MONALEESA-2, a phase III trial of first-line ribociclib plus letrozole versus placebo plus letrozole in hormone receptor-positive, HER2-negative advanced breast cancer.
      ,
      • Johnston S
      • Martin M
      • Di Leo A
      • et al.
      MONARCH 3 final PFS: a randomized study of abemaciclib as initial therapy for advanced breast cancer.
      ,
      • Goetz MP
      • Toi M
      • Campone M
      • et al.
      MONARCH 3: abemaciclib as initial therapy for advanced breast cancer.
      ,
      • Rugo HS
      • Finn RS
      • Diéras V
      • et al.
      Palbociclib plus letrozole as first-line therapy in estrogen receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer with extended follow-up.
      ,
      • Farooq F
      • Cohen JA.
      Efficacy and toxicity of CDK 4/6 inhibitors in breast cancer: Systematic review and meta-analysis of the phase III clinical trials.
      . Similarly, the preferred ET partner is unclear; preliminary data from the PARSIFAL trial showed no PFS difference between palbociclib added to first-line fulvestrant or letrozole in patients with endocrine-sensitive disease
      • Llombart-Cussac A
      • Pérez-García JM
      • Bellet M
      • et al.
      PARSIFAL: A randomized, multicenter, open-label, phase II trial to evaluate palbociclib in combination with fulvestrant or letrozole in endocrine-sensitive patients with estrogen receptor (ER)[+]/HER2[-] metastatic breast cancer.
      .
      To what extent the greater “activity” of ET when combined with CDK4/6is should encourage their use where clinicians currently choose chemotherapy is unclear. Palbociclib plus ET improved PFS compared with capecitabine as first-line therapy in premenopausal women with HR-positive/HER2-negative MBC, but this study was confounded by ET-treated patients receiving exemestane and leuprolide, whereas capecitabine was given without ovarian suppression
      • Park YH
      • Kim T-Y
      • Kim GM
      • et al.
      Palbociclib plus exemestane with gonadotropin-releasing hormone agonist versus capecitabine in premenopausal women with hormone receptor-positive, HER2-negative metastatic breast cancer (KCSG-BR15-10): a multicentre, open-label, randomised, phase 2 trial.
      . A second Phase III trial, for which preliminary data are available, compared palbociclib in combination with either exemestane or fulvestrant to capecitabine in postmenopausal women with HR-positive/HER2-negative disease that had progressed on an AI. There was no difference in the primary endpoints of median PFS between (i) palbociclib plus fulvestrant and capecitabine (7.5 and 10 months, respectively) or (ii) palbociclib plus either fulvestrant or exemestane and capecitabine in patients with ESR1 wild type tumors (8.0 and 10.6 months, respectively). ET plus palbociclib was, however, generally better tolerated than capecitabine
      • Martín M
      • Zielinski CC
      • Ruiz-Borrego M
      • Carrasco E.
      Abstract GS2-07: Results from PEARL study (GEICAM/2013-02_CECOG/BC.1.3.006): A phase 3 trial of Palbociclib (PAL) in combination with endocrine therapy (ET) versus Capecitabine (CAPE) in hormonal receptor (HR)-positive/human epidermal growth factor receptor (HER) 2-negative metastatic breast cancer (MBC) patients (pts) whose disease progressed on aromatase inhibitors (AIs).
      .

      Anthracycline and Taxane Chemotherapy

      While CDK4/6is represent a significant advance for first-line treatment of women with HR-positive/HER2-negative MBC disease, chemotherapy is important in those with visceral crisis
      • Cardoso F
      • Senku E
      • Costa A
      • et al.
      4th ESO-ESMO international consensus guidelines for advanced breast cancer (ABC 4)†.
      . For such patients, chemotherapy is usually preferred because of the need for “the most rapidly efficacious therapy
      • Cardoso F
      • Senku E
      • Costa A
      • et al.
      4th ESO-ESMO international consensus guidelines for advanced breast cancer (ABC 4)†.
      .” Response rates (RRs) are, however, high with CDK4/6i–ET combinations so the role of chemotherapy in this setting may diminish. Interestingly, in a 2003 Cochrane analysis of randomized trials comparing chemotherapy and single-agent ET, the assumption of earlier response with chemotherapy than with ET was not supported
      • Wilcken N
      • Hornbuckle J
      • Ghersi D.
      Chemotherapy alone versus endocrine therapy alone for metastatic breast cancer.
      .
      Real-world European and United States (US) studies report chemotherapy use as first-line systemic treatment for MBC in 1-quarter to 1-half of patients with HR-positive/HER2-negative MBC
      • Lobbezoo DJ
      • van Kampen RJW
      • Voogd AC
      • et al.
      In real life, one-quarter of patients with hormone receptor-positive metastatic breast cancer receive chemotherapy as initial palliative therapy: a study of the Southeast Netherlands Breast Cancer Consortium.
      • D'Alonzo A
      • Bighin C
      • Puglisi F
      • et al.
      Trends in the choice of first line treatment for hormone - responsive (HR+), human epidermal growth factor receptor - 2 negative (HER2-) metastatic breast cancer (MBC) patients (pts): Results of a multicentric Italian observational study.
      • Swallow E
      • Zhang J
      • Thomason D
      • et al.
      Real-world patterns of endocrine therapy for metastatic hormone-receptor-positive (HR+)/human epidermal growth factor receptor-2-negative (HER2-) breast cancer patients in the United States: 2002-2012.
      • Watanabe J
      • Hayashi T
      • Tadokoro Y
      • et al.
      Clinical pattern of primary systemic therapy and outcomes of estrogen receptor-positive, HER2-negative metastatic breast cancer: a review of a single institution.
      . Such variation is unlikely to reflect differences in the proportion of patients with visceral crisis, suggesting significant variation in practice despite the consistency of guidelines. Interestingly, in a large UK regional cancer center the proportion of patients with HR-positive/HER2-negative MBC receiving chemotherapy first line already fell from >30% to <20% between 2012 and 2017, before the CDK4/6i era
      • Twelves C
      • Cheeseman S
      • Sopwith W
      • et al.
      Systemic treatment of hormone receptor positive, human epidermal growth factor 2 negative metastatic breast cancer: retrospective analysis from Leeds Cancer Centre.
      . For patients with HR-positive/HER2-negative MBC requiring first-line chemotherapy, ABC 5 guidelines recommend single-agent anthracyclines or taxanes, especially if they were not administered in the (neo)adjuvant setting
      • Cardoso F
      • Senku E
      • Costa A
      • et al.
      4th ESO-ESMO international consensus guidelines for advanced breast cancer (ABC 4)†.
      . There is no clear recommendation for one over the other
      • Cardoso F
      • Senku E
      • Costa A
      • et al.
      4th ESO-ESMO international consensus guidelines for advanced breast cancer (ABC 4)†.
      ,
      • Partridge AH
      • Rumble RB
      • Carey LA
      • et al.
      Chemotherapy and targeted therapy for women with human epidermal growth factor receptor 2-negative (or unknown) advanced breast cancer: American society of clinical oncology clinical practice guideline.
      ,
      National Comprehensive Cancer Network
      . Taxanes are used more frequently first line, even following their (neo)adjuvant administration, particularly if there has been ≥1 year of disease-free survival. Less often, anthracyclines may be considered provided the maximum cumulative dose has not been reached with (neo)adjuvant therapy and there are no cardiac contraindications
      • Cardoso F
      • Senku E
      • Costa A
      • et al.
      4th ESO-ESMO international consensus guidelines for advanced breast cancer (ABC 4)†.
      .
      In a 2004 Cochrane review, anthracycline-containing regimens extended time to progression (TTP) (HR 0.84; 95% CI: 0.77–0.91) and increased tumor RRs (odds ratio 1.33; 95% CI: 1.21–1.48) compared with those without an anthracycline
      • Lord S
      • Ghersi D
      • Gattellari M
      • et al.
      Antitumour antibiotic containing regimens for metastatic breast cancer.
      . A subsequent review in 2015 concluded that first-line treatment with a taxane improved OS (P=.03), but not TTP
      • Ghersi D
      • Wilcken N
      • Simes J
      • Donoghue E.
      Taxane-containing regimens for metastatic breast cancer.
      . RRs and PFS, but not OS or quality of life (QoL), were improved with anthracycline/taxane combinations compared with either alone in a Phase III trial
      • Sledge GW
      • Neuberg D
      • Bernardo P
      • et al.
      Phase III trial of doxorubicin, paclitaxel, and the combination of doxorubicin and paclitaxel as front-line chemotherapy for metastatic breast cancer: an intergroup trial (E1193).
      .
      For women at increased cardiac risk, pegylated liposomal doxorubicin (PLD) is an alternative to a standard anthracycline. In a randomized Phase III clinical trial, PFS and OS were similar with PLD and doxorubicin, but there was significantly less cardiotoxicity with PLD. Alopecia, nausea, vomiting and neutropenia were more frequent with doxorubicin but palmar-plantar erythrodysesthesia, stomatitis and mucositis were more frequent with PLD
      • O'Brien ME
      • Wigler N
      • Inbar M
      • et al.
      Reduced cardiotoxicity and comparable efficacy in a phase III trial of pegylated liposomal doxorubicin HCl (CAELYX/Doxil) versus conventional doxorubicin for first-line treatment of metastatic breast cancer.
      . In a systematic review and meta-analysis, docetaxel and paclitaxel had similar efficacy in patients with MBC; paclitaxel regimens were less toxic, especially in older patients and when administered weekly
      • Qi WX
      • Shen Z
      • Lin F
      • et al.
      Paclitaxel-based versus docetaxel-based regimens in metastatic breast cancer: a systematic review and meta-analysis of randomized controlled trials.
      . Taxanes can cause acute hypersensitivity reactions despite pre-medication; such reactions are not seen with nanoparticle albumin-bound (nab)-paclitaxel. In a Phase III trial, nab-paclitaxel significantly improved RRs and TTP compared with standard paclitaxel (P=.001 and P=.006, respectively); Grade 4 neutropenia was also significantly less frequent (9% versus 22%, respectively; P<.001)
      • Gradishar WJ
      • Tjulandin S
      • Davidson N
      • et al.
      Phase III trial of nanoparticle albumin-bound paclitaxel compared with polyethylated castor oil-based paclitaxel in women with breast cancer.
      . Grade 3 sensory neuropathy was significantly more frequent with nab-paclitaxel but improved over the course of a few weeks
      • Gradishar WJ
      • Tjulandin S
      • Davidson N
      • et al.
      Phase III trial of nanoparticle albumin-bound paclitaxel compared with polyethylated castor oil-based paclitaxel in women with breast cancer.
      . Therefore, nab-paclitaxel is most often used in patients who experience hypersensitivity to a conventional taxane despite pre-medication.
      Single-agent capecitabine or vinorelbine are alternatives in patients unsuitable for, unwilling to take, or previously exposed to an anthracycline or taxane
      • Cardoso F
      • Senku E
      • Costa A
      • et al.
      4th ESO-ESMO international consensus guidelines for advanced breast cancer (ABC 4)†.
      . Patients keen to reduce alopecia may prefer them, especially if scalp cooling is not possible
      • Cardoso F
      • Senku E
      • Costa A
      • et al.
      4th ESO-ESMO international consensus guidelines for advanced breast cancer (ABC 4)†.
      ,
      • Mayer EL
      • Burstein HJ.
      Chemotherapy for metastatic breast cancer.
      . In a preliminary report of a recent first-/second-line (patients had ≤1 prior chemotherapy for advanced or MBC) Phase III trial of eribulin versus weekly paclitaxel there appeared to be no difference in PFS or OS between the 2 agents. Peripheral neuropathy was significantly more frequent with weekly paclitaxel, occurred earlier and lasted longer; however, the nature and severity of neuropathy were deemed similar in both treatment groups
      • Liu MC
      • William DW
      • Frith AE
      • et al.
      Randomized phase III trial of eribulin (E) versus standard weekly paclitaxel (P) as first- or second-line therapy for locally recurrent or metastatic breast cancer (MBC).
      . Although not approved in the European Union (EU) or United States (US) in the first-line metastatic treatment, this trial suggests eribulin is effective in this setting.
      Although ABC 5 guidelines recommend single-agent anthracyclines and taxanes, combination chemotherapy is a “reasonable option
      • Cardoso F
      • Senku E
      • Costa A
      • et al.
      4th ESO-ESMO international consensus guidelines for advanced breast cancer (ABC 4)†.
      ." The addition of capecitabine to docetaxel improved OS in anthracycline pretreated patients; toxicity was, however, problematic although QoL was maintained
      • O'Shaughnessy J
      • Miles D
      • Vukelja S
      • et al.
      Superior survival with capecitabine plus docetaxel combination therapy in anthracycline-pretreated patients with advanced breast cancer: phase III trial results.
      . Combination chemotherapy should, however, be reserved for patients with rapid clinical progression, life-threatening visceral metastases or requiring rapid symptom and/or disease control
      • Cardoso F
      • Senku E
      • Costa A
      • et al.
      4th ESO-ESMO international consensus guidelines for advanced breast cancer (ABC 4)†.
      . In a 2009 Cochrane review of first-line chemotherapy for MBC, combination regimens significantly improved survival compared with single-agent taxane (P<.00001), but not single-agent anthracycline (P=.15) regimens; combinations were, however, associated with increased toxicity
      • Carrick S
      • Parker S
      • Thornton CE
      • et al.
      Single agent versus combination chemotherapy for metastatic breast cancer.
      .

      Second- and Later-line Treatment of Patients With HR-positive/HER2-negative MBC

      Continuing ET and Overcoming Resistance

      For patients receiving first-line ET-based treatment remaining free of visceral crisis, further lines of ET (with or without targeted therapy) are appropriate
      • Matutino A
      • Joy AA
      • Brezden-Masley C
      • et al.
      Hormone receptor-positive, HER2-negative metastatic breast cancer: redrawing the lines.
      ,
      National Comprehensive Cancer Network
      ,
      • Hurvitz SA
      • Pietras RJ.
      Rational management of endocrine resistance in breast cancer: a comprehensive review of estrogen receptor biology, treatment options, and future directions.
      . Response to first-line ET predicts response to subsequent lines of ET
      • Hurvitz SA
      • Pietras RJ.
      Rational management of endocrine resistance in breast cancer: a comprehensive review of estrogen receptor biology, treatment options, and future directions.
      ,
      • Cheung KL
      • Willsher PC
      • Pinder SE
      • et al.
      Predictors of response to second-line endocrine therapy for breast cancer.
      . Cross-resistance between pharmacologically similar ETs is likely, so second-line ET is usually one with a different mechanism of action
      • Hurvitz SA
      • Pietras RJ.
      Rational management of endocrine resistance in breast cancer: a comprehensive review of estrogen receptor biology, treatment options, and future directions.
      ,
      • Cheung KL
      • Willsher PC
      • Pinder SE
      • et al.
      Predictors of response to second-line endocrine therapy for breast cancer.
      . It is unclear how CDK4/6i treatment changes tumor biology
      • Spring LM
      • Wander SA
      • Zangardi M
      • Bardia A.
      CDK 4/6 inhibitors in breast cancer: current controversies and future directions.
      , but Rb gene loss may facilitate CDK4/6i resistance
      • McCartney A
      • Migliaccio I
      • Bonechi M
      • et al.
      Mechanisms of resistance to CDK4/6 inhibitors: potential implications and biomarkers for clinical practice.
      . In the PALOMA-3 trial, however, although Rb mutations only emerged in palbociclib-treated patients, their frequency was low (4.7%)
      • O'Leary B
      • Cutts RJ
      • Liu Y
      • et al.
      The genetic landscape and clonal evolution of breast cancer resistance to palbociclib plus fulvestrant in the PALOMA-3 trial.
      . Other potential resistance mechanisms remain under investigation, including signaling pathway alterations
      • D'Souza A
      • Spicer D
      • Lu J.
      Overcoming endocrine resistance in metastatic hormone receptor-positive breast cancer.
      . Data are emerging around the efficacy of combining a CDK4/6i with a different ET partner after disease progression
      • Mayer E
      • Wander SA
      • Regan MM
      • et al.
      Abstract OT3-05-11: Palbociclib after CDK inhibitor and endocrine therapy (PACE): A randomized phase II study of fulvestrant versus palbociclib plus fulvestrant, with and without avelumab, for CDK inhibitor pre-treated HR+/HER2- metastatic breast cancer.
      ,
      • Bardia A
      • Hurvitz SA
      • DeMichele A
      • et al.
      Triplet therapy (continuous ribociclib, everolimus, exemestane) in HR+/HER2− advanced breast cancer postprogression on a CDK4/6 inhibitor (TRINITI-1): Efficacy, safety, and biomarker results.
      . Furthermore, 15-20% of patients may acquire ET resistance because of HR loss or mutations making re-biopsy before second-line treatment selection reasonable
      • AlFakeeh A
      • Brezden-Masley C.
      Overcoming endocrine resistance in hormone receptor-positive breast cancer.
      .
      Everolimus, a PI3K/protein kinase B/mammalian target of rapamycin signaling inhibitor, combined with ET is effective as second-line treatment and beyond
      • Baselga J
      • Campone M
      • Piccart M
      • et al.
      Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer.
      • Kornblum N
      • Zhao F
      • Manola J
      • et al.
      Randomized phase ii trial of fulvestrant plus everolimus or placebo in postmenopausal women with hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer resistant to aromatase inhibitor therapy: results of PrE0102.
      • Bachelot T
      • Bourgier C
      • Cropet C
      • et al.
      Randomized phase II trial of everolimus in combination with tamoxifen in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer with prior exposure to aromatase inhibitors: a GINECO study.
      • Royce ME
      • Osman D.
      Everolimus in the Treatment of Metastatic Breast Cancer.
      . Following first-line, single-agent, non-steroidal AI treatment, the addition of everolimus to exemestane significantly increased RR (9.5% versus 0.4%; P<.001) and PFS (10.6 months versus 4.1 months; HR 0.36; 95% CI: 0.27–0.47; P<.001)
      • Baselga J
      • Campone M
      • Piccart M
      • et al.
      Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer.
      . Combining everolimus with fulvestrant or tamoxifen also significantly improved PFS in patients with AI-resistant MBC
      • Kornblum N
      • Zhao F
      • Manola J
      • et al.
      Randomized phase ii trial of fulvestrant plus everolimus or placebo in postmenopausal women with hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer resistant to aromatase inhibitor therapy: results of PrE0102.
      ,
      • Bachelot T
      • Bourgier C
      • Cropet C
      • et al.
      Randomized phase II trial of everolimus in combination with tamoxifen in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer with prior exposure to aromatase inhibitors: a GINECO study.
      . Everolimus added to ET has not significantly improved OS in clinical trials; it does, however, substantially increase toxicity
      • Piccart M
      • Hortobagyi GN
      • Campone M
      • et al.
      Everolimus plus exemestane for hormone-receptor-positive, human epidermal growth factor receptor-2-negative advanced breast cancer: overall survival results from BOLERO-2†.
      , raising the question of whether exemestane plus everolimus is better tolerated and/or more effective than chemotherapy. Compared with capecitabine, the efficacy of exemestane plus everolimus was very similar; Grade 3–4 AEs were more frequent with capecitabine, but serious AEs were more frequent with everolimus plus exemestane
      • Jerusalem G
      • de Boer RH
      • Hurvitz S
      • et al.
      Everolimus plus exemestane vs everolimus or capecitabine monotherapy for estrogen receptor–positive, HER2-negative advanced breast cancer: The BOLERO-6 randomized clinical trial.
      .
      PIK3CA mutations occur in ∼35% of breast cancers and are particularly prevalent in patients with HR-positive/HER2-negative cancers
      • Mollon L
      • Aguilar A
      • Anderson E
      • et al.
      Abstract 1207: A systematic literature review of the prevalence of PIK3CA mutations and mutation hotspots in HR+/HER2- metastatic breast cancer.
      . In the Phase III SOLAR-1 trial, addition of alpelisib to fulvestrant in patients with MBC and PIK3CA mutations who had received at least one prior ET significantly increased PFS (11.0 months versus 5.7 months; HR 0.65; 95% CI: 0.50–0.85; P<.001)
      • André F
      • Ciruelos EM
      • Rubovszky G.
      Alpelisib (ALP) + fulvestrant (FUL) for advanced breast cancer (ABC): Results of the Phase 3 SOLAR-1 trial.
      . Again, the addition of alpelisib significantly increased toxicity; 25.0% and 4.2% of patients discontinued alpelisib and placebo, respectively. Preliminary results of the Phase II BYLieve trial suggest combining alpelisib with fulvestrant is effective in patients with PIK3CA-mutated, HR-positive, HER2-negative cancers who have progressed on a CDK4/6i and AI; median PFS was 7.3 months and RR was 17.4%
      • Rugo HS
      • Lerebours F
      • Ciruelos E
      • et al.
      Alpelisib (ALP) + fulvestrant (FUL) in patients (pts) with PIK3CA-mutated (mut) hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2–) advanced breast cancer (ABC) previously treated with cyclin-dependent kinase 4/6 inhibitor (CDKi) + aromatase inhibitor (AI): BYLieve study results.
      . These results will likely affect clinical guidelines and practice.

      Post-anthracycline and Taxane Chemotherapy

      For patients who become refractory to endocrine therapy, and/or experience visceral crisis necessitating a rapid response, chemotherapy remains the preferred option
      • Mayer EL
      • Burstein HJ.
      Chemotherapy for metastatic breast cancer.
      . Following an anthracycline and a taxane, ABC 5 guidelines advise capecitabine, vinorelbine or eribulin for patients not requiring combination chemotherapy; gemcitabine, platinum agents, a different taxane and liposomal anthracyclines are alternatives
      • Cardoso F
      • Senku E
      • Costa A
      • et al.
      4th ESO-ESMO international consensus guidelines for advanced breast cancer (ABC 4)†.
      . The 2014 American Society of Clinical Oncology (ASCO) guidelines include ixabepilone as a post-capecitabine option, but it is not approved in Europe
      • Partridge AH
      • Rumble RB
      • Carey LA
      • et al.
      Chemotherapy and targeted therapy for women with human epidermal growth factor receptor 2-negative (or unknown) advanced breast cancer: American society of clinical oncology clinical practice guideline.
      . The ABC 5 guidelines do not specifically address combination chemotherapy in this patient group previously treated with an anthracycline and a taxane. Nevertheless, the greater toxicity of combinations, with limited or no additional efficacy and survival benefit, discourages this approach
      • Martín M
      • Ruiz A
      • Muñoz M
      • et al.
      Gemcitabine plus vinorelbine versus vinorelbine monotherapy in patients with metastatic breast cancer previously treated with anthracyclines and taxanes: final results of the phase III Spanish Breast Cancer Research Group (GEICAM) trial.
      .
      MBC heterogeneity, variability in patient characteristics and lack of head-to-head comparisons mean guidelines lack a clear hierarchy for sequencing chemotherapies
      • Miglietta F
      • Dieci MV
      • Griguolo G
      • et al.
      Chemotherapy for advanced HER2-negative breast cancer: Can one algorithm fit all?.
      ,
      • Kalinowski L
      • Saunus JM
      • McCart Reed AE
      • Lakhani SR
      Breast cancer heterogeneity in primary and metastatic disease.
      . We will pay particular attention to randomized trials in patients previously treated with an anthracycline and a taxane, but such trials do not exist in patients previously treated with a CDK4/6i. Emerging real-world data suggest, however, that chemotherapy may be less effective in these patients
      • Chainitikun S
      • Long JP
      • Rodriguez-Bautista R
      • et al.
      The efficacy of first-line chemotherapy in endocrine-resistant hormone receptor-positive (HR+), human epidermal growth factor receptor 2- negative (HER2-) metastatic breast cancer (MBC).
      .

      Eribulin

      Eribulin targets microtubules but differs from other antimicrotubule agents due to its unique interaction with tubulin, inhibiting microtubule growth with no apparent effect on depolymerization
      • Kuznetsov G
      • Towle MJ
      • Cheng H
      • et al.
      Induction of morphological and biochemical apoptosis following prolonged mitotic blockage by halichondrin B macrocyclic ketone analog E7389.
      . Eribulin is approved as second- (EU) or third-line treatment of patients with MBC, following treatment with an anthracycline and a taxane. ASCO guidelines suggest preferential use of eribulin after anthracyclines/taxanes may optimize survival compared with other recommended cytotoxics
      • Partridge AH
      • Rumble RB
      • Carey LA
      • et al.
      Chemotherapy and targeted therapy for women with human epidermal growth factor receptor 2-negative (or unknown) advanced breast cancer: American society of clinical oncology clinical practice guideline.
      . This is supported by Phase III trials, subgroup analyses and real-world data
      • Cortes J
      • O'Shaughnessy J
      • Loesch D
      • et al.
      Eribulin monotherapy versus treatment of physician's choice in patients with metastatic breast cancer (EMBRACE): a phase 3 open-label randomised study.
      • Kaufman PA
      • Awada A
      • Twelves C
      • et al.
      Phase III open-label randomized study of eribulin mesylate versus capecitabine in patients with locally advanced or metastatic breast cancer previously treated with an anthracycline and a taxane.
      • Pivot X
      • Ah Im S
      • Guo M
      • Marmé F
      Subgroup analysis of patients with HER2-negative metastatic breast cancer in the second-line setting from a phase 3, open-label, randomized study of eribulin mesilate versus capecitabine.
      • Cortes J
      • Hudgens S
      • Twelves C
      • et al.
      Health-related quality of life in patients with locally advanced or metastatic breast cancer treated with eribulin mesylate or capecitabine in an open-label randomized phase 3 trial.
      • Jacot W
      • Heudel P-E
      • Fraisse J
      • et al.
      Real-life activity of eribulin mesylate among metastatic breast cancer patients in the multicenter national observational ESME program.
      • Twelves C
      • Cortes J
      • Vahdat L
      • et al.
      Efficacy of eribulin in women with metastatic breast cancer: a pooled analysis of two phase 3 studies.
      • Cortes J
      • Twelves C.
      Impact of the number of prior chemotherapy regimens on outcomes for patients with metastatic breast cancer treated with eribulin: A post hoc pooled analysis.
      • Yuan P
      • Hu X
      • Sun T
      • et al.
      Eribulin mesilate versus vinorelbine in women with locally recurrent or metastatic breast cancer: A randomised clinical trial.
      .
      Three Phase III studies have evaluated eribulin in patients with anthracycline/taxane pretreated HR-positive/HER2-negative MBC. Study 305/EMBRACE involved patients with 2-5 prior chemotherapy regimens, including an anthracycline and a taxane. Eribulin significantly extended median OS (13.1 versus 10.6 months; P=.041), which was the primary endpoint; the RR for eribulin was 12% (versus 5% with treatment of physician's choice [TPC]; P=.002) and PFS was similar between treatment groups
      • Cortes J
      • O'Shaughnessy J
      • Loesch D
      • et al.
      Eribulin monotherapy versus treatment of physician's choice in patients with metastatic breast cancer (EMBRACE): a phase 3 open-label randomised study.
      . This study underpinned approval of eribulin in the third-line setting. Study 301 compared eribulin with capecitabine, yielding similar RRs (11.0% versus 11.5%, respectively) and PFS (4.1 and 4.2 months, respectively; P=.30). Significant OS benefit with eribulin was not seen (15.9 months versus 14.5 months, respectively; P=.056)
      • Kaufman PA
      • Awada A
      • Twelves C
      • et al.
      Phase III open-label randomized study of eribulin mesylate versus capecitabine in patients with locally advanced or metastatic breast cancer previously treated with an anthracycline and a taxane.
      . Further analysis of the trial data requested by European regulators extended the eribulin label to second line in patients with HER2-negative disease, based on OS benefit versus capecitabine in those patients
      • Pivot X
      • Ah Im S
      • Guo M
      • Marmé F
      Subgroup analysis of patients with HER2-negative metastatic breast cancer in the second-line setting from a phase 3, open-label, randomized study of eribulin mesilate versus capecitabine.
      . In a subgroup analysis of patients in Study 301 with HER2-negative disease, eribulin prolonged OS from 13.5 to 15.9 months (HR 0.84; P=.03)
      • Twelves C
      • Awada A
      • Cortes J
      • et al.
      Subgroup analyses from a phase 3, open-label, randomized study of eribulin mesylate versus capecitabine in pretreated patients with advanced or metastatic breast cancer.
      . Finally, a recently published Chinese Phase III trial in a population similar to EMBRACE achieved its primary endpoint of superior PFS with eribulin versus vinorelbine (HR 0.80; 95% CI: 0.65–0.98; P=.036); RRs were higher with eribulin and there were fewer discontinuations from treatment-emergent AEs, but no significant OS difference
      • Yuan P
      • Hu X
      • Sun T
      • et al.
      Eribulin mesilate versus vinorelbine in women with locally recurrent or metastatic breast cancer: A randomised clinical trial.
      .
      Eribulin has a safety profile that is generally considered acceptable, the most common AEs being neutropenia, alopecia, leukopenia, peripheral neuropathy and nausea
      • Kaufman PA
      • Awada A
      • Twelves C
      • et al.
      Phase III open-label randomized study of eribulin mesylate versus capecitabine in patients with locally advanced or metastatic breast cancer previously treated with an anthracycline and a taxane.
      . Importantly, QoL was similar with eribulin and capecitabine; more specifically, QoL mirrored the known toxicities of both agents
      • Cortes J
      • Hudgens S
      • Twelves C
      • et al.
      Health-related quality of life in patients with locally advanced or metastatic breast cancer treated with eribulin mesylate or capecitabine in an open-label randomized phase 3 trial.
      . Namely, patients receiving eribulin reported more systemic side effects from chemotherapy but less gastrointestinal toxicity compared with capecitabine
      • Cortes J
      • Hudgens S
      • Twelves C
      • et al.
      Health-related quality of life in patients with locally advanced or metastatic breast cancer treated with eribulin mesylate or capecitabine in an open-label randomized phase 3 trial.
      .
      Eribulin is approved in the US in patients who have received ≥2 prior lines of chemotherapy for MBC, but after one line of chemotherapy in the EU. A series of combined analyses of Study 305/EMBRACE and Study 301 have investigated further how eribulin may best be used. One such analysis in patients who had received ≥1 prior chemotherapies for MBC confirmed the survival benefit with eribulin used according to its EU approval
      • Pivot X
      • Marmé F
      • Koenigsberg R
      • et al.
      Pooled analyses of eribulin in metastatic breast cancer patients with at least one prior chemotherapy.
      . Another evaluated whether eribulin was best used sooner or later, after an anthracycline and a taxane
      • Cortes J
      • Twelves C.
      Impact of the number of prior chemotherapy regimens on outcomes for patients with metastatic breast cancer treated with eribulin: A post hoc pooled analysis.
      ; patients who had received ≤3 prior chemotherapies for locally advanced/MBC had longer median OS with eribulin (15.3 and 13.2 months, respectively; P=.01)
      • Cortes J
      • Twelves C.
      Impact of the number of prior chemotherapy regimens on outcomes for patients with metastatic breast cancer treated with eribulin: A post hoc pooled analysis.
      .
      Recently, a further pooled, hypothesis-generating post hoc analysis showed eribulin to be efficacious in patients with locally advanced/MBC, irrespective of the location of metastases at baseline. A nominally significant difference in OS in favor of patients randomized to eribulin versus control was seen in patients with bone, lymph node and chest wall/breast/skin metastases at baseline. A difference in OS was also seen in patients with liver metastases randomized to eribulin versus control (13.4 months versus 11.3 months, respectively; HR 0.84; 95% CI: 0.72-0.97). The PFS improvement seen in the Chinese trial with eribulin compared with vinorelbine was also predominantly manifest in less heavily pretreated patients (HR 0.69; 95% CI: 0.53-0.91)
      • Yuan P
      • Hu X
      • Sun T
      • et al.
      Eribulin mesilate versus vinorelbine in women with locally recurrent or metastatic breast cancer: A randomised clinical trial.
      .
      A network meta-analysis of 7 trials investigating eribulin versus other chemotherapies used as second- or later-line treatment in locally advanced or MBC examined the data from 7 clinical trials, including Study 305/EMBRACE and Study 301
      • Zhao Q
      • Hughes R
      • Neupane B
      • et al.
      Network meta-analysis of eribulin versus other chemotherapies used as second- or later-line treatment in locally advanced or metastatic breast cancer.
      . Results showed that second- or later-line patients treated with eribulin had statistically longer OS versus TPC (HR 0.81; credible interval [CrI]: 0.66-0.99) or gemcitabine + vinorelbine (HR 0.62; CrI: 0.42-0.90) and statistically longer PFS versus TPC (HR 0.76; CrI: 0.640.90), but statistically shorter PFS versus capecitabine + ixabepilone (HR 1.40; CrI: 1.17-1.67) and capecitabine + utidelone (HR 1.61; CrI: 1.23-2.12)
      • Zhao Q
      • Hughes R
      • Neupane B
      • et al.
      Network meta-analysis of eribulin versus other chemotherapies used as second- or later-line treatment in locally advanced or metastatic breast cancer.
      . TPC involved administration of any single-agent, licensed chemotherapy, hormonal, or biological treatment, radiotherapy or symptomatic treatment alone
      • Zhao Q
      • Hughes R
      • Neupane B
      • et al.
      Network meta-analysis of eribulin versus other chemotherapies used as second- or later-line treatment in locally advanced or metastatic breast cancer.
      . The results of this network meta-analysis, supports randomized trial evidence that eribulin can provide an overall OS benefit compared with standard treatments
      • Twelves C
      • Cortes J
      • Vahdat L
      • et al.
      Efficacy of eribulin in women with metastatic breast cancer: a pooled analysis of two phase 3 studies.
      ,
      • Zhao Q
      • Hughes R
      • Neupane B
      • et al.
      Network meta-analysis of eribulin versus other chemotherapies used as second- or later-line treatment in locally advanced or metastatic breast cancer.
      .
      In a real-world French national cohort of 16,703 patients with MBC, OS was significantly longer with eribulin than other chemotherapies in the HER2-negative population (n = 4,617) across all treatment lines, including second line (14.98 versus 10.51 months, respectively; P=.0113)
      • Jacot W
      • Heudel P-E
      • Fraisse J
      • et al.
      Real-life activity of eribulin mesylate among metastatic breast cancer patients in the multicenter national observational ESME program.
      .
      These data may support eribulin as preferred chemotherapy in patients with HR-positive/HER2-negative MBC following an anthracycline and a taxane. Use earlier in the course of the disease, for example, as second- or third-line treatment appears beneficial, but would require a high-quality randomized trial or prospective data to reach the threshold for level 1 evidence
      • Burns PB
      • Rohrich RJ
      • Chung KC.
      The levels of evidence and their role in evidence-based medicine.
      .

      Capecitabine

      The oral prodrug capecitabine is preferentially converted enzymatically to 5-fluorouracil in cancer cells. It is approved for treatment of patients with MBC as a single agent or in combination. A randomized Phase II trial evaluated capecitabine in patients with anthracycline-pretreated MBC versus 3-weekly paclitaxel; RRs, median TTP and OS were comparable
      • Talbot DC
      • Moiseyenko V
      • Van Belle S
      • et al.
      Randomised, phase II trial comparing oral capecitabine (Xeloda) with paclitaxel in patients with metastatic/advanced breast cancer pretreated with anthracyclines.
      . Similarly, first-line capecitabine and weekly paclitaxel (both plus bevacizumab) achieved similar OS
      • Zielinski C
      • Láng I
      • Inbar M
      • et al.
      Bevacizumab plus paclitaxel versus bevacizumab plus capecitabine as first-line treatment for HER2-negative metastatic breast cancer (TURANDOT): primary endpoint results of a randomised, open-label, non-inferiority, phase 3 trial.
      . Two randomized Phase II trials also suggested capecitabine was at least as effective as intravenous (i.v.) or oral cyclophosphamide, methotrexate and 5-fluorouracil based on RR, PFS and OS in the first-line MBC setting
      • Stockler MR
      • Harvey VJ
      • Francis PA
      • et al.
      Capecitabine versus classical cyclophosphamide, methotrexate, and fluorouracil as first-line chemotherapy for advanced breast cancer.
      ,
      • Oshaughnessy JA
      • Blum J
      • Moiseeyenko V
      • et al.
      Randomized, open-label, phase II trial of oral capecitabine (Xeloda) vs. a reference arm of intravenous CMF (cyclophosphamide, methotrexate and 5-fluorouracil) as first-line therapy for advanced/metastatic breast cancer.
      .
      Study 301, which compared eribulin with capecitabine, is discussed above. RRs for eribulin and capecitabine (11.0% versus 11.5%, respectively) and PFS (4.1 and 4.2 months, respectively; P=.30) were similar with eribulin and capecitabine
      • Kaufman PA
      • Awada A
      • Twelves C
      • et al.
      Phase III open-label randomized study of eribulin mesylate versus capecitabine in patients with locally advanced or metastatic breast cancer previously treated with an anthracycline and a taxane.
      . OS with eribulin was not significantly superior to that of capecitabine (15.9 months versus 14.5 months, respectively; P=.056)
      • Kaufman PA
      • Awada A
      • Twelves C
      • et al.
      Phase III open-label randomized study of eribulin mesylate versus capecitabine in patients with locally advanced or metastatic breast cancer previously treated with an anthracycline and a taxane.
      . However, in a subgroup of patients with HER2-negative disease, OS appeared inferior with capecitabine compared with eribulin (13.5 and 15.9 months, respectively; HR 0.84; P=.03)
      • Twelves C
      • Awada A
      • Cortes J
      • et al.
      Subgroup analyses from a phase 3, open-label, randomized study of eribulin mesylate versus capecitabine in pretreated patients with advanced or metastatic breast cancer.
      .
      In patients with anthracycline/taxane pretreated HR-positive/HER2-negative MBC, capecitabine monotherapy was primarily evaluated in non-randomized Phase II trials (Table 2)
      • Blum JL
      • Jones SE
      • Buzdar AU
      • et al.
      Multicenter phase II study of capecitabine in paclitaxel-refractory metastatic breast cancer.
      • Blum JL
      • Dieras V
      • Lo Russo PM
      • et al.
      Multicenter, Phase II study of capecitabine in taxane-pretreated metastatic breast carcinoma patients.
      • Fumoleau P
      • Largillier R
      • Clippe C
      • et al.
      Multicentre, phase II study evaluating capecitabine monotherapy in patients with anthracycline- and taxane-pretreated metastatic breast cancer.
      • Reichardt P
      • Von Minckwitz G
      • Thuss-Patience PC
      • et al.
      Multicenter phase II study of oral capecitabine (Xeloda(")) in patients with metastatic breast cancer relapsing after treatment with a taxane-containing therapy.
      ; RRs and PFS were similar and toxicities predictable
      • Blum JL
      • Jones SE
      • Buzdar AU
      • et al.
      Multicenter phase II study of capecitabine in paclitaxel-refractory metastatic breast cancer.
      ,
      • Blum JL
      • Dieras V
      • Lo Russo PM
      • et al.
      Multicenter, Phase II study of capecitabine in taxane-pretreated metastatic breast carcinoma patients.
      . Additionally, a limited number of Phase III studies have incorporated capecitabine as the control arm in this patient population, reflecting it as a standard treatment in this setting
      • Baselga J
      • Zamangi C
      • Gómez P
      • Bermejo B.
      RESILIENCE: A Phase III randomized, double-blind, trial comparing sorafenib plus capecitabine versus placebo plus capecitabine in the treatment of locally advanced or metastatic HER2-negative breast cancer.
      • Miller KD
      • Chap LI
      • Holmes FA
      • et al.
      Randomized Phase III trial of capecitabine compared with bevacizumab plus capecitabine in patients with previously treated metastatic breast cancer.
      • Sparano JA
      • Vrdoljak E
      • Rixe O
      • et al.
      Randomized phase III trial of ixabepilone plus capecitabine versus capecitabine in patients with metastatic breast cancer previously treated with an anthracycline and a taxane.
      • Zhang P
      • Sun T
      • Zhang Q
      • et al.
      Utidelone plus capecitabine versus capecitabine alone for heavily pretreated metastatic breast cancer refractory to anthracyclines and taxanes: a multicentre, open-label, superiority, phase 3, randomised controlled trial.
      • Park IH
      • Im S-A
      • Jung KH
      • et al.
      Randomized Open Label Phase III Trial of Irinotecan Plus Capecitabine versus Capecitabine Monotherapy in Patients with Metastatic Breast Cancer Previously Treated with Anthracycline and Taxane: PROCEED Trial (KCSG BR 11-01).
      • Martin M
      • Campone M
      • Bondarenko I
      • et al.
      Randomised phase III trial of vinflunine plus capecitabine versus capecitabine alone in patients with advanced breast cancer previously treated with an anthracycline and resistant to taxane.
      . For example, in the RESILIENCE Phase III trial in patients treated with capecitabine PFS was 5.5 months, OS was 18.9 months and ORR was 13.5%
      • Reichardt P
      • Von Minckwitz G
      • Thuss-Patience PC
      • et al.
      Multicenter phase II study of oral capecitabine (Xeloda(")) in patients with metastatic breast cancer relapsing after treatment with a taxane-containing therapy.
      . In a number of other trials where capecitabine was the control arm, the RR ranged from 9.1% to 33.3% and OS between 11.7 and 20.4 months but PFS was more consistant, ranging from 4.17 to 4.7 months. This heterogeneity in outcomes emphasizes the limitations of cross-trial comparisons
      • Miller KD
      • Chap LI
      • Holmes FA
      • et al.
      Randomized Phase III trial of capecitabine compared with bevacizumab plus capecitabine in patients with previously treated metastatic breast cancer.
      • Sparano JA
      • Vrdoljak E
      • Rixe O
      • et al.
      Randomized phase III trial of ixabepilone plus capecitabine versus capecitabine in patients with metastatic breast cancer previously treated with an anthracycline and a taxane.
      • Zhang P
      • Sun T
      • Zhang Q
      • et al.
      Utidelone plus capecitabine versus capecitabine alone for heavily pretreated metastatic breast cancer refractory to anthracyclines and taxanes: a multicentre, open-label, superiority, phase 3, randomised controlled trial.
      • Park IH
      • Im S-A
      • Jung KH
      • et al.
      Randomized Open Label Phase III Trial of Irinotecan Plus Capecitabine versus Capecitabine Monotherapy in Patients with Metastatic Breast Cancer Previously Treated with Anthracycline and Taxane: PROCEED Trial (KCSG BR 11-01).
      • Martin M
      • Campone M
      • Bondarenko I
      • et al.
      Randomised phase III trial of vinflunine plus capecitabine versus capecitabine alone in patients with advanced breast cancer previously treated with an anthracycline and resistant to taxane.
      .
      Table 2Chemotherapy Monotherapy After Anthracycline and/or Taxane Treatment for MBC
      • Cortes J
      • O'Shaughnessy J
      • Loesch D
      • et al.
      Eribulin monotherapy versus treatment of physician's choice in patients with metastatic breast cancer (EMBRACE): a phase 3 open-label randomised study.
      • Kaufman PA
      • Awada A
      • Twelves C
      • et al.
      Phase III open-label randomized study of eribulin mesylate versus capecitabine in patients with locally advanced or metastatic breast cancer previously treated with an anthracycline and a taxane.
      • Yuan P
      • Hu X
      • Sun T
      • et al.
      Eribulin mesilate versus vinorelbine in women with locally recurrent or metastatic breast cancer: A randomised clinical trial.
      • Talbot DC
      • Moiseyenko V
      • Van Belle S
      • et al.
      Randomised, phase II trial comparing oral capecitabine (Xeloda) with paclitaxel in patients with metastatic/advanced breast cancer pretreated with anthracyclines.
      • Blum JL
      • Jones SE
      • Buzdar AU
      • et al.
      Multicenter phase II study of capecitabine in paclitaxel-refractory metastatic breast cancer.
      • Blum JL
      • Dieras V
      • Lo Russo PM
      • et al.
      Multicenter, Phase II study of capecitabine in taxane-pretreated metastatic breast carcinoma patients.
      • Fumoleau P
      • Largillier R
      • Clippe C
      • et al.
      Multicentre, phase II study evaluating capecitabine monotherapy in patients with anthracycline- and taxane-pretreated metastatic breast cancer.
      • Reichardt P
      • Von Minckwitz G
      • Thuss-Patience PC
      • et al.
      Multicenter phase II study of oral capecitabine (Xeloda(")) in patients with metastatic breast cancer relapsing after treatment with a taxane-containing therapy.
      • Meier CR
      • Illiger H-J
      • Steder M
      • et al.
      Weekly vinorelbine versus docetaxel for metastatic breast cancer after failing anthracycline treatment.
      • Pajk B
      • Cufer T
      • Canney P
      • et al.
      Anti-tumor activity of capecitabine and vinorelbine in patients with anthracycline- and taxane-pretreated metastatic breast cancer: findings from the EORTC 10001 randomized phase II trial.
      • Perez EA
      • Lerzo G
      • Pivot X
      • et al.
      Efficacy and safety of ixabepilone (BMS-247550) in a phase II study of patients with advanced breast cancer resistant to an anthracycline, a taxane, and capecitabine.
      First authorYearPhaseNRR, %mPFS, monthsmOS, months
      Capecitabine
      Kaufman
      • Kaufman PA
      • Awada A
      • Twelves C
      • et al.
      Phase III open-label randomized study of eribulin mesylate versus capecitabine in patients with locally advanced or metastatic breast cancer previously treated with an anthracycline and a taxane.
      2015III55411.54.214.5
      Fumoleau
      • Fumoleau P
      • Largillier R
      • Clippe C
      • et al.
      Multicentre, phase II study evaluating capecitabine monotherapy in patients with anthracycline- and taxane-pretreated metastatic breast cancer.
      2004II126284.9
      Median time to progression
      15.2
      Reichardt
      • Reichardt P
      • Von Minckwitz G
      • Thuss-Patience PC
      • et al.
      Multicenter phase II study of oral capecitabine (Xeloda(")) in patients with metastatic breast cancer relapsing after treatment with a taxane-containing therapy.
      2003136153.5
      Median time to progression
      10.1
      Talbot
      • Talbot DC
      • Moiseyenko V
      • Van Belle S
      • et al.
      Randomised, phase II trial comparing oral capecitabine (Xeloda) with paclitaxel in patients with metastatic/advanced breast cancer pretreated with anthracyclines.
      200222363.0
      Median time to progression
      7.6
      Blum
      • Blum JL
      • Dieras V
      • Lo Russo PM
      • et al.
      Multicenter, Phase II study of capecitabine in taxane-pretreated metastatic breast carcinoma patients.
      200174268.3
      Median duration of response
      12.2
      Blum
      • Blum JL
      • Jones SE
      • Buzdar AU
      • et al.
      Multicenter phase II study of capecitabine in paclitaxel-refractory metastatic breast cancer.
      1999162208.1
      Median duration of response
      12.8
      Vinorelbine
      Yuan
      • Yuan P
      • Hu X
      • Sun T
      • et al.
      Eribulin mesilate versus vinorelbine in women with locally recurrent or metastatic breast cancer: A randomised clinical trial.
      2019III26616.92.812.5
      Pajk
      • Pajk B
      • Cufer T
      • Canney P
      • et al.
      Anti-tumor activity of capecitabine and vinorelbine in patients with anthracycline- and taxane-pretreated metastatic breast cancer: findings from the EORTC 10001 randomized phase II trial.
      2008II2412.54.211.0
      Meier
      • Meier CR
      • Illiger H-J
      • Steder M
      • et al.
      Weekly vinorelbine versus docetaxel for metastatic breast cancer after failing anthracycline treatment.
      2008II62182.8*9.3
      Eribulin
      Yuan
      • Yuan P
      • Hu X
      • Sun T
      • et al.
      Eribulin mesilate versus vinorelbine in women with locally recurrent or metastatic breast cancer: A randomised clinical trial.
      2019III26430.72.813.4
      Kaufman
      • Kaufman PA
      • Awada A
      • Twelves C
      • et al.
      Phase III open-label randomized study of eribulin mesylate versus capecitabine in patients with locally advanced or metastatic breast cancer previously treated with an anthracycline and a taxane.
      2015III55411.04.115.9
      Cortes
      • Cortes J
      • O'Shaughnessy J
      • Loesch D
      • et al.
      Eribulin monotherapy versus treatment of physician's choice in patients with metastatic breast cancer (EMBRACE): a phase 3 open-label randomised study.
      2011III508123.713.1
      Ixabepilone
      Perez128
      Patients previously treated with an anthracycline, taxane and capecitabine. mOS = median overall survival; mPFS = median progression-free survival; RR = response rate.
      2007II12611.53.18.6
      a Median time to progression
      b Median duration of response
      c Patients previously treated with an anthracycline, taxane and capecitabine.mOS = median overall survival; mPFS = median progression-free survival; RR = response rate.
      Finally, real-world data suggest that outcomes may be better with capecitabine than vinorelbine (median OS 188 and 102 days, respectively; P<.0001), but these were non-randomized so do not carry the weight of a randomized clinical trial
      • Verma S
      • Wong SN
      • Trudeau M
      • et al.
      Survival differences observed in metastatic breast cancer patients treated with capecitabine when compared with vinorelbine after pretreatment with anthracycline and taxane.
      . These data provide support for capecitabine in patients with HR-positive/HER2-negative MBC after an anthracycline and a taxane
      • Kaufman PA
      • Awada A
      • Twelves C
      • et al.
      Phase III open-label randomized study of eribulin mesylate versus capecitabine in patients with locally advanced or metastatic breast cancer previously treated with an anthracycline and a taxane.
      ,
      • Twelves C
      • Awada A
      • Cortes J
      • et al.
      Subgroup analyses from a phase 3, open-label, randomized study of eribulin mesylate versus capecitabine in pretreated patients with advanced or metastatic breast cancer.
      ,
      • Blum JL
      • Jones SE
      • Buzdar AU
      • et al.
      Multicenter phase II study of capecitabine in paclitaxel-refractory metastatic breast cancer.
      • Blum JL
      • Dieras V
      • Lo Russo PM
      • et al.
      Multicenter, Phase II study of capecitabine in taxane-pretreated metastatic breast carcinoma patients.
      • Fumoleau P
      • Largillier R
      • Clippe C
      • et al.
      Multicentre, phase II study evaluating capecitabine monotherapy in patients with anthracycline- and taxane-pretreated metastatic breast cancer.
      • Reichardt P
      • Von Minckwitz G
      • Thuss-Patience PC
      • et al.
      Multicenter phase II study of oral capecitabine (Xeloda(")) in patients with metastatic breast cancer relapsing after treatment with a taxane-containing therapy.
      ,
      • Miller KD
      • Chap LI
      • Holmes FA
      • et al.
      Randomized Phase III trial of capecitabine compared with bevacizumab plus capecitabine in patients with previously treated metastatic breast cancer.
      • Sparano JA
      • Vrdoljak E
      • Rixe O
      • et al.
      Randomized phase III trial of ixabepilone plus capecitabine versus capecitabine in patients with metastatic breast cancer previously treated with an anthracycline and a taxane.
      • Zhang P
      • Sun T
      • Zhang Q
      • et al.
      Utidelone plus capecitabine versus capecitabine alone for heavily pretreated metastatic breast cancer refractory to anthracyclines and taxanes: a multicentre, open-label, superiority, phase 3, randomised controlled trial.
      • Park IH
      • Im S-A
      • Jung KH
      • et al.
      Randomized Open Label Phase III Trial of Irinotecan Plus Capecitabine versus Capecitabine Monotherapy in Patients with Metastatic Breast Cancer Previously Treated with Anthracycline and Taxane: PROCEED Trial (KCSG BR 11-01).
      • Martin M
      • Campone M
      • Bondarenko I
      • et al.
      Randomised phase III trial of vinflunine plus capecitabine versus capecitabine alone in patients with advanced breast cancer previously treated with an anthracycline and resistant to taxane.
      • Verma S
      • Wong SN
      • Trudeau M
      • et al.
      Survival differences observed in metastatic breast cancer patients treated with capecitabine when compared with vinorelbine after pretreatment with anthracycline and taxane.
      . Advantages of capecitabine include oral dosing and minimal alopecia
      • Joy AA
      • Gosh M
      • Fernandes R
      • Clemons MJ.
      Systemic treatment approaches in her2-negative advanced breast cancer-guidance on the guidelines.
      .

      Vinorelbine

      Vinorelbine is a vinca alkaloid and microtubule-stabilizing agent, available as i.v. and oral formulations; it is approved for MBC in the EU, but not the US, after an anthracycline. In the first-line setting, disease control rates with oral vinorelbine and weekly paclitaxel were similar; neutropenia was more common with vinorelbine, but significant alopecia was much more frequent with paclitaxel
      • Aapro M
      • Ruiz-Borrego M
      • Hegg R
      • et al.
      Randomized phase II study evaluating weekly oral vinorelbine versus weekly paclitaxel in estrogen receptor-positive, HER2-negative patients with advanced breast cancer (NorBreast-231 trial).
      . An early randomized trial demonstrated OS benefit in patients with anthracycline-refractory MBC with vinorelbine compared with melphalan; the latter is, however, no longer clinically relevant and the trial was conducted in the pre-taxane era
      • Jones S
      • Winer E
      • Vogel C
      • et al.
      Randomized comparison of vinorelbine and melphalan in anthracycline-refractory advanced breast cancer.
      . In a Phase II trial in patients with anthracycline pretreated MBC, progression occurred more frequently with vinorelbine than weekly docetaxel as did Grade 3–4 toxicities, especially hematologic toxicity
      • Meier CR
      • Illiger H-J
      • Steder M
      • et al.
      Weekly vinorelbine versus docetaxel for metastatic breast cancer after failing anthracycline treatment.
      .
      The Chinese Phase III trial that showed inferior PFS and RR (but not OS) with vinorelbine versus eribulin was discussed above
      • Yuan P
      • Hu X
      • Sun T
      • et al.
      Eribulin mesilate versus vinorelbine in women with locally recurrent or metastatic breast cancer: A randomised clinical trial.
      . In a mostly anthracycline/taxane pretreated HR-positive/HER2-negative MBC population, a Phase III trial evaluated PLD with the comparator being vinorelbine for most (85%) patients. There were no significant PFS and OS differences between PLD and comparator
      • Keller AM
      • Mennel RG
      • Georgoulias VA
      • et al.
      Randomized phase III trial of pegylated liposomal doxorubicin versus vinorelbine or mitomycin C plus vinblastine in women with taxane-refractory advanced breast cancer.
      . In the other Phase III trial directly comparing vinorelbine with another single-agent cytotoxic, vinorelbine had inferior PFS to eribulin
      • Yuan P
      • Hu X
      • Sun T
      • et al.
      Eribulin mesilate versus vinorelbine in women with locally recurrent or metastatic breast cancer: A randomised clinical trial.
      . A randomized Phase II trial of i.v. vinorelbine and capecitabine concluded their antitumor activity was similar
      • Pajk B
      • Cufer T
      • Canney P
      • et al.
      Anti-tumor activity of capecitabine and vinorelbine in patients with anthracycline- and taxane-pretreated metastatic breast cancer: findings from the EORTC 10001 randomized phase II trial.
      . The efficacy of metronomic, oral vinorelbine compared with classical regimens is being investigated
      • Langkjer ST
      • Kenholm J
      • Jensen JD
      • et al.
      The NAME trial: a direct comparison of classical oral Navelbine versus Metronomic Navelbine in metastatic breast cancer.
      . Randomized trial data do not, therefore, support vinorelbine as preferred chemotherapy in patients with HR-positive/HER2-negative MBC after an anthracycline and a taxane.

      Gemcitabine

      Gemcitabine is an antimetabolite approved, combined with paclitaxel, in patients who have previously received an anthracycline (unless clinically contraindicated). In a first-line, randomized, Phase III study in women aged ≥60 single-agent gemcitabine had significantly inferior TTP, OS and independently assessed RR compared with epirubicin
      • Feher O
      • Vodvarka P
      • Jassem J
      • et al.
      First-line gemcitabine versus epirubicin in postmenopausal women aged 60 or older with metastatic breast cancer: a multicenter, randomized, phase III study.
      .
      In anthracycline/taxane pretreated HR-positive/HER2-negative MBC, gemcitabine has not been evaluated as a single agent in randomized trials; it cannot, therefore, be considered a preferred option in this setting.

      Platinum-based Regimens

      There is increasing use of platinum-based regimens in patients with triple-negative breast cancer. A Cochrane review concluded, however, that outside of this subgroup there is a lack of survival benefit and excess toxicity with such regimens
      • Egger SJ
      • Willson ML
      • Morgan J
      • et al.
      Platinum-containing regimens for metastatic breast cancer.
      . For patients with anthracycline/taxane pretreated HR-positive/HER2-negative MBC platinum-based regimens are not, therefore, a preferred option.

      Ixabepilone

      Ixabepilone is the first epothilone cytotoxic and causes cell death by stabilizing microtubule dynamics
      • Thomas ES
      • Gomez HL
      • Li RK
      • et al.
      Ixabepilone plus capecitabine for metastatic breast cancer progressing after anthracycline and taxane treatment.
      . It is approved in the US (but not in the EU) in patients resistant or refractory to anthracyclines, taxanes and capecitabine. A Phase II study of 126 patients administered prior anthracycline, taxane and capecitabine chemotherapy showed an RR of 11.5% with PFS of 3.1 months with ixabepilone
      • Perez EA
      • Lerzo G
      • Pivot X
      • et al.
      Efficacy and safety of ixabepilone (BMS-247550) in a phase II study of patients with advanced breast cancer resistant to an anthracycline, a taxane, and capecitabine.
      . The only Grade 3-4 treatment-related AEs occurring in >10% of patients were peripheral sensory neuropathy (14%) and fatigue/asthenia (13%)
      • Perez EA
      • Lerzo G
      • Pivot X
      • et al.
      Efficacy and safety of ixabepilone (BMS-247550) in a phase II study of patients with advanced breast cancer resistant to an anthracycline, a taxane, and capecitabine.
      .
      In patients with HR-positive/HER2-negative MBC randomized trials have not compared ixabepilone with other single-agent chemotherapies. Ixabepilone cannot, therefore, be considered a preferred option.

      Antibody Drug Conjugates

      Looking to the future, there is the prospect of new and effective therapies for patients with HR-positive/HER2-negative MBC in the form of antibody drug conjugates (ADCs). Specifically, sacituzumab govitecan (SG), an ADC composed of a humanized anti-Trop-2 monoclonal antibody coupled with the cytotoxic SN-38
      • Kalinsky K
      • Diamond JR
      • Vahdat LT
      • et al.
      Sacituzumab govitecan in previously treated hormone receptor-positive/HER2-negative metastatic breast cancer: final results from a phase I/II, single-arm.
      . Patients treated with SG achieved an ORR of 31.5%, median PFS of 5.5 months (95% CI: 3.6–7.6) and median OS of 12 months (95% CI: 9.0–18.2) in a subgroup of patients with HR-positive/HER2-negative MBC
      • Kalinsky K
      • Diamond JR
      • Vahdat LT
      • et al.
      Sacituzumab govitecan in previously treated hormone receptor-positive/HER2-negative metastatic breast cancer: final results from a phase I/II, single-arm.
      . A second ADC, trastuzumab deruxtecan is a novel HER2-targeted ADC with a topoisomerase I inhibitor payload
      • Modi S
      • Park H
      • Murthy RK
      • et al.
      Antitumor activity and safety of trastuzumab deruxtecan in patients With HER2-low-expressing advanced breast cancer: results from a phase Ib study.
      . In a Phase Ib study in patients with HER2-low MBC the ORR was 37.0% and median duration of response of 10.4 months
      • Modi S
      • Park H
      • Murthy RK
      • et al.
      Antitumor activity and safety of trastuzumab deruxtecan in patients With HER2-low-expressing advanced breast cancer: results from a phase Ib study.
      . Both ADCs are being evaluated versus TPC choice in ongoing Phase III trials
      ClinicalTrials.gov
      ,
      ClinicalTrials.gov
      Study of Trastuzumab Deruxtecan (T-DXd) vs Investigator’s Choice Chemotherapy in HER2-low,.
      .
      While promising, these ADCs remain investigational in patients with HR-positive/HER2-negative MBC and can be recommended only in the context of clinical trials.

      Summary: Future Directions and Outstanding Questions

      ET combined with CDK4/6is is standard of care for patients with HR-positive/HER2-negative MBC, with many patients receiving successive lines of ET; combination with targeted agents that can circumvent resistance are increasingly important
      • Augereau P
      • Patsouris A
      • Bourbouloux E
      • et al.
      Hormonoresistance in advanced breast cancer: a new revolution in endocrine therapy.
      . Chemotherapy continues, however, to have a key role. The perceived greater likelihood of rapid response to chemotherapy than ET has made it valuable in patients with visceral crisis
      • Cardoso F
      • Senku E
      • Costa A
      • et al.
      4th ESO-ESMO international consensus guidelines for advanced breast cancer (ABC 4)†.
      ,
      • Partridge AH
      • Rumble RB
      • Carey LA
      • et al.
      Chemotherapy and targeted therapy for women with human epidermal growth factor receptor 2-negative (or unknown) advanced breast cancer: American society of clinical oncology clinical practice guideline.
      . Patients initially treated with single-agent and/or combination ET become resistant, so optimal use of chemotherapy is key. Across successive lines of treatment an average of 20-40% of patients die without receiving further treatment
      • Twelves C
      • Cheeseman S
      • Sopwith W
      • et al.
      Systemic treatment of hormone receptor positive, human epidermal growth factor 2 negative metastatic breast cancer: retrospective analysis from Leeds Cancer Centre.
      , so it is important they have the opportunity to receive effective chemotherapy.
      Guidelines recommend anthracycline- and taxane-based regimens as preferred first-line chemotherapy options, with single, sequential agents preferred over combinations
      • Cardoso F
      • Senku E
      • Costa A
      • et al.
      4th ESO-ESMO international consensus guidelines for advanced breast cancer (ABC 4)†.
      ,
      • Partridge AH
      • Rumble RB
      • Carey LA
      • et al.
      Chemotherapy and targeted therapy for women with human epidermal growth factor receptor 2-negative (or unknown) advanced breast cancer: American society of clinical oncology clinical practice guideline.
      . The heterogeneity of both patients and disease, and the paucity of direct comparisons between single-agent cytotoxics, means few recommendations exist regarding specific chemotherapies and their optimal sequencing following an anthracycline and a taxane
      • Miglietta F
      • Dieci MV
      • Griguolo G
      • et al.
      Chemotherapy for advanced HER2-negative breast cancer: Can one algorithm fit all?.
      ,
      • Kalinowski L
      • Saunus JM
      • McCart Reed AE
      • Lakhani SR
      Breast cancer heterogeneity in primary and metastatic disease.
      . The choice of treatment is determined by multiple factors including not only efficacy but also toxicity, performance status, comorbidities and patient preference
      • Cardoso F
      • Senku E
      • Costa A
      • et al.
      4th ESO-ESMO international consensus guidelines for advanced breast cancer (ABC 4)†.
      ,
      • Partridge AH
      • Rumble RB
      • Carey LA
      • et al.
      Chemotherapy and targeted therapy for women with human epidermal growth factor receptor 2-negative (or unknown) advanced breast cancer: American society of clinical oncology clinical practice guideline.
      .
      In the evidence-based medicine era it is, however, incumbent on us to use the best data available when making treatment decisions. Although there is a lack of robust comparative data between chemotherapy agents in later lines of treatment, randomized clinical trial data, supplemented by real-world evidence, most convincingly support eribulin as the preferred chemotherapy
      • Partridge AH
      • Rumble RB
      • Carey LA
      • et al.
      Chemotherapy and targeted therapy for women with human epidermal growth factor receptor 2-negative (or unknown) advanced breast cancer: American society of clinical oncology clinical practice guideline.
      , which remains the only cytotoxic agent to have demonstrated an OS benefit in this setting
      • Cortes J
      • O'Shaughnessy J
      • Loesch D
      • et al.
      Eribulin monotherapy versus treatment of physician's choice in patients with metastatic breast cancer (EMBRACE): a phase 3 open-label randomised study.
      . Of the other frequently used cytotoxics, evidence supporting its use is stronger for capecitabine than vinorelbine or navelbine.

      Funding

      Medical writing support was provided by Virgo Health and was funded by Eisai Europe Limited. This manuscript represents the opinions of the authors and not their employers or Eisai Europe Limited.

      Acknowledgements

      Not applicable.

      Disclosures

      Chris Twelves, Honoraria, travel: Daiichi-Sankyo, EISAI, MSD Oncology, Pfizer, Re-imbursed travel, advisory boards, speaker bureau support: EISAI, Daiichi-Sankyo, Pfizer, Roche, AstraZeneca, Rupert Bartsch, Honoraria: Accord, AstraZeneca, BMS, Celgene, Eli Lilly, Novartis, Pfizer, Pierre-Fabre, Roche, Sandoz, Advisory role: AstraZeneca, Celgene, Daiichi-Sankyo, EISAI, Eli Lilly, MSD, Novartis, Pfizer, Pierre-Fabre, Puma, Roche, Samsung, Research support: Daiichi-Sankyo, MSD, Novartis, Roche, Noa Efrat Ben-Baruch, Honoraria, speaker bureau, consultancy, travel: AstraZeneca, Dexcel, Eli Lilly, Novartis, Pfizer, Roche, Consultant: Dexcel, Simona Borstnar, Honoraria: Amgen, BMS, Eli Lilly, Krka, Novartis, Pfizer, Roche, Consultant: Amgen, AstraZeneca, Eli Lilly, Novartis, Pfizer, Roche, Luc Dirix, None, Lyudmila Zhukova, Board of directors: RUSSCO, Honoraria: AstraZeneca, Biocad, BMS, Eli Lilly, GSK, MSD, Novartis, Pfizer, Roche, Sanofi, Consultant: AstraZeneca, Biocad, Eli Lilly, Roche, Research support: AstraZeneca, Biocad, Eli Lilly, GSK, MSD, Novartis, Pfizer, Roche, Sanofi, Petra Tesarova, Honoraria: Accord, EISAI, Eli Lilly, Novartis, Pfizer, Roche, Constanta Timcheva, Honoraria: Astellas, AstraZeneca, Novartis, Pfizer, Roche, Servier, Travel support: Pfizer, Roche, Servier, Advisory board member: Astellas, BMS, Pfizer, Servier, Clinical trial participation: AstraZeneca, Novartis, Pfizer, Roche Xavier Pivot, None.

      Ethics Approval

      Not applicable.

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