Brain Metastases in HER2-Positive Breast Cancer: Current and Novel Treatment Strategies
Abstract
:Simple Summary
Abstract
1. Introduction
2. Prevention of Brain Metastases
2.1. Trastuzumab
2.2. Trastuzumab–Pertuzumab
2.3. Ado-Trastuzumab-Emtansine (T-DM1)
2.4. Lapatinib
2.5. Novel Agents
Neratinib
3. Systemic Therapy in the Treatment of Brain Metastases
3.1. Trastuzumab
3.2. Trastuzumab-Pertuzumab
3.3. Ado-Trastuzumab-Emtansine (T-DM1)
3.4. Lapatinib
3.5. Novel Agents
3.5.1. Trastuzumab Deruxtecan
3.5.2. Neratinib
3.5.3. Tucatinib
3.5.4. Pyrotinib
3.5.5. Margetuximab
3.6. Combination of Systemic Therapy with Radiotherapy
3.6.1. Trastuzumab
3.6.2. T-DM1
3.6.3. Lapatinib
4. Challenges and Open Questions
5. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Anti-HER2 Agent | Study | Type of Study | Population | Treatment | Reported Outcomes Related to BM |
---|---|---|---|---|---|
Trastuzumab | |||||
RegistHER, Brufsky et al., 2011 [6] | Prospective observational | Newly diagnosed HER2+ MBC | Trastuzumab versus no trastuzumab | Time to BM progression OS | |
Olson et al., 2013 [14] | Meta-analysis | RCTs with adjuvant 1 year trastuzumab reporting BM as first event of metastasis | Trastuzumab versus no trastuzumab | Incidence of BM as first metastatic site Time to BM OS | |
Dawood et al., 2008 [15] | Retrospective | HER2 + MBC with BM | Trastuzumab versus no trastuzumab | Time to BM OS after BM | |
Pertuzumab | |||||
CLEOPATRA, Swain et al., 2014 [16] | Phase III | HER2+ MBC, first-line | Trastuzumab + docetaxel +/− pertuzumab | Incidence of BM as first metastatic site Time to BM OS | |
PATRICIA, Lin et al., 2021 [17] | Phase II | HER2+ MBC, progressing BM after RT | Pertuzumab + high dose trastuzumab | ORR, DOR, CBR | |
RePer, Gamucci et al., 2019 [18] | Retrospective | HER2+ MBC, first-line | Trastuzumab + pertuzumab + taxane | ORR, OS | |
Esin et al., 2019 [19] | Retrospective | HER2+ MBC, First-line, trastuzumab naïve | Trastuzumab + pertuzumab + taxane | PFS, OS | |
PHEREXA, Urruticoechea et al., 2017 [20] | Phase III | HER2+ MBC | Trastuzumab + capecitabine +/− pertuzumab | PFS, OS | |
T-DM1 | |||||
EMILIA, Krop et al., 2015 [21] | Phase III | HER2+ MBC, previous trastuzumab+taxane | T-DM1 versus Capecitabine + Lapatinib | CNS progression OS | |
KAMILLA, Montemurro et al., 2020 [22] | Phase III | HER2+ MBC | T-DM1 | ORR, PFS, OS | |
Bartsch et al., 2015 [23] | Retrospective | HER2+ MBC with BM | T-DM1 | ORR, PFS, OS | |
Fabi et al., 2018 [24] | Retrospective | HER2+ MBC with BM | T-DM1 | ORR, PFS, OS | |
Jacot et al., 2016 [25] | Retrospective | HER2+ MBC with BM | T-DM1 | ORR, PFS, OS | |
Trastuzumab deruxtecan | |||||
DESTINY Breast01, Modi et al., 2020 [26] | Phase II | HER2+ MBC, previous T-DM1 | Trastuzumab deruxtecan | ORR, PFS, OS | |
Jerusalem et al., 2020 [27] | |||||
Lapatinib | |||||
CEREBEL, Pivot et al., 2015 [28] | Phase III | HER2+ MBC | Lapatinib/capecitabine versus trastuzumab/capecitabine | Incidence of BM Time to first relapse in the CNS BM progression | |
EGF105084, Lin et al., 2009 [29] | Phase II | HER2+ MBC with BM, previous trastuzumab | Lapatinib monotherapy | ORR, PFS, OS | |
Blackwell et al., 2010 [30] | Phase III | HER2+ MBC | Lapatinib +/− trastuzumab | ORR, PFS, OS | |
LANDSCAPE, Bachelot et al., 2013 [31] | Phase II | HER2+ MBC with previously untreated BM | Lapatinib + capecitabine | Objective CNS response, PFS | |
Metro et al., 2011 [32] | Retrospective | HER2+ MBC | Lapatinib + capecitabine | BM progression OS | |
Sutherland et al., 2010 [33] | Prospective observational | HER2+ MBC | Lapatinib + capecitabine | ORR, PFS | |
Neratinib | |||||
TBCRC022, Freedman et al., 2019 [34] | Phase II | HER2+ MBC with BM, with/without previous lapatinib | Neratinib + capecitabine | ORR, PFS, OS | |
NALA, Saura et al., 2020 [35] | Phase III | HER2+ MBC | Neratinib/capecitabine versus Lapatinib/capecitabine | Intervention for BM Time to intervention for BM | |
NEfERT-T, Awada et al., 2016 [36] | Phase III | HER2+ MBC | Neratinib/paclitaxel versus Trastuzumab/paclitaxel | Incidence BM Time to BM Time to BM progression | |
Tucatinib | |||||
HER2CLIMB, Lin et al., 2020 [37] | Phase III | HER2+ MBC previous trastuzumab, pertuzumab T-DM1 | Trastuzumab/capecitabine +/− tucatinib | ORR, PFS, OS | |
Metzger et al., 2020 [38] | Phase I | HER2+ MBC with BM | Trastuzumab + tucatinib | ORR, CBR, PFS | |
Borges et al., 2018 [39] | Phase I | HER2+ MBC | T-DM1 + Tucatinib | ORR, PFS | |
Pyrotinib | |||||
PHENIX, Jiang et al., 2019 [40] | Phase III | HER2+ MBC | Pyrotinib + capecitabine | PFS | |
Lin et al., 2020 [41] | Prospective Observational | HER2+ MBC | Pyrotinib +/− combination | ORR, PFS | |
Combination with radiotherapy | |||||
Trastuzumab | Chargari et al., 2011 [42] | Prospective Observational | HER2+ MBC with BM | WBRT + trastuzumab | ORR, OS Time to BM progression |
T-DM1 | |||||
Geraud et al., 2017 [43] | Retrospective | HER2+ MBC with BM | T-DM1 + SRS or WBRT | Local control, ORR | |
Stumpf et al., 2019 [44] | Retrospective | HER2+ MBC with BM | T-DM1 + SRS | Toxicity | |
Lapatinib | |||||
Lin et al., 2013 [45] | Phase I | HER2+ MBC with BM | Lapatinib + RT | ORR | |
Parsai et al., 2019 [46] | Retrospective | HER2+ MBC with BM | Lapatinib + SRS | Local control, OS | |
Kim et al., 2019 [47] | Retrospective | HER2+ MBC with BM | Lapatinib + SRS | Local control, ORR, BM-progression rate | |
Christodoulou et al., 2017 [48] | Phase II | HER2+ MBC with BM | Lapatinib + WBRT | Objective response |
Clinicaltrials.Gov Identifier | Title | Phase | N | Population | Treatment Arms | Primary Endpoint |
---|---|---|---|---|---|---|
Brain MRI Screening or Monitoring | ||||||
NCT03881605 | Routine MRI Screening Versus Symptom-directed Surveillance for BM among Patients with TNBC and HER2-positive MBC: A Single-center Randomized Pilot Study. | N/A | 50 | TNBC and HER2-positive MBC without symptoms of BM or known asymptomatic BM at study entry. | Arm A: MRI of the brain at baseline, 4 months, 8 months and 12 months. Arm B: Imaging of the brain will take place only if patients develop symptoms that are suggestive of brain metastases. | Feasibility of screening program (secondary endpoints related to BM outcomes) |
NCT03617341 | Brain Monitoring for High Risk of BM in MBC. | N/A | 200 | HER2-positive unresectable or MBC with no prior systemic palliative treatment and without symptomatic BM at screening | Arm A: Brain MRI will be taken at the time of initial diagnosis, first- and second-line treatment failure. | Incidence rates of BM in high-risk patients |
NCT04030507 | Screening MRI of the Brain in Patients with MBC Managed with First/Second Line Chemotherapy or Inflammatory BC Managed with Definitive Intent: A Prospective Study. | N/A | 214 | BC irrespective of subtype | No intervention arm: No initial MRI screening will be conducted. Experimental arms: 1. Inflammatory breast cancer managed with curative intent: Initial screening MRI and every 6 months for two years. 2. HR+ or HER2+ metastatic BC: Initial MRI and at first systemic progression after study entry. 3. TNBC: Initial MRI and at first systemic progression after study entry. | Neurologic quality of life at 12 months (HR+/HER2- or HER2+ MBC) incidence of symptomatic BM (TNBC). incidence of BM for patients with (inflammatory BC managed with curative intent). |
Combination with Local Treatments (Surgery or Radiotherapy) | ||||||
NCT04582968 | A Phase Ib/II Pilot Study of Pyrotinib Plus Capecitabine Combined with Brain Radiotherapy in HER2-positive BC with BM. | Ib/II | 47 | HER2-positive MBC with measurable BM. | Arm A: Pyrotinib plus capecitabine combined with fractionated stereotactic radiotherapy (FSRT) or WBRT. | Safety and tolerability of pyrotinib Plus capecitabine combined with brain radiotherapy (phase Ib part). Intracranial local tumor control rate (Phase II part). |
NCT01494662 | A Phase II Trial of HKI-272 (Neratinib), Neratinib and Capecitabine, and T-DM1 for Patients with HER2-Positive BC and BM. | II | 168 | HER2-positive MBC with BM. Cohort 1: Patients with progressive BM. Cohort 2: Patients who are candidates for craniotomy. Cohort 3a: Lapatinib naïve. Cohort 3b: Prior lapatinib treatment Cohort 4a: Previously untreated BM. Cohort 4b: Progressive BM. Cohort 4c: Progressive BM and prior T-DM1. | Cohort 1: Neratinib. Cohort 2: Neratinib + Surgery. Cohort 3a and 3b: Neratinib + Capecitabine. Cohort 4a, 4b and 4c: Neratinib + T-DM1. | ORR in the CNS by composite response criteria in cohort 1. |
Systemic Treatment (Monotherapy or Combination) | ||||||
NCT03190967 | Phase I/II Study of T-DM1 Alone Versus T-DM1 and Metronomic Temozolomide in Secondary Prevention of HER2-Positive BC BM Following Stereotactic Radiosurgery. | I/II | 125 | HER2-positive BC with BM for which standard curative measures do not exist or are no longer effective. | Arm A: T-DM1 (3.6 mg/kg IV every 21 days) + Temozolomide (30, 40 or 50 mg/m2 daily for the phase I). | Maximum Tolerated dose of TMZ when used in combination with T-DM1 (phase I). Median time to progression (phase II). |
NCT04512261 | TOPAZ: Single Arm, Open Label Phase 1b/2 Study of Tucatinib in Combination with Pembrolizumab Additionally, TrastuZumab in Patients with HER2-Positive BC BM. | Ib/II | 33 | HER2-positive MBC with untreated or previously treated and progressing CNS disease. | Arm A: Tucatinib + pembrolizumab + trastuzumab. | 24-week CNS DCR. Recommended dose of tucatinib in combination with pembrolizumab and trastuzumab. |
NCT03765983 | Phase II Trial of GDC-0084 in Combination With Trastuzumab for Patients with HER2-Positive BC BM. | II | 47 | HER2-positive metastatic breast cancer with: Cohort A: Unequivocal evidence of new and/or progressive BM. Cohort B: New and/or progressive BM with clinical indication for resection. | GDC-0084 (45 mg orally once daily) + trastuzumab (8 mg/kg intravenously loading dose; followed by 6 mg/kg IV every 3 weeks thereafter) | ORR in the CNS (RANO-BM criteria). |
NCT04752059 | Phase II Study of Trastuzumab Deruxtecan (T-DX; DS-8201a) in HER2-positive BC with Newly Diagnosed or Progressing BM. | II | 15 | HER2-positive MBC with newly diagnosed BM or BM progressing after prior local therapy and measurable disease (RANO-BM criteria). | Trastuzumab deruxtecan 5.4 mg/kg i.v. on day 1 once every three weeks. | Response rate of BM according to RANO-BM criteria. |
NCT04760431 | Anti-HER2 TKI Versus Pertuzumab in Combination with Trastuzumab and Taxane as First-Line in HER2-positive BC with Active BM: A Phase II, Multicenter, Double-blind, Randomized Clinical Trial. | II | 120 | Patients of HER2-positive BC with a documented CNS recurrence/progression during or after trastuzumab. | Arm A: Trastuzumab, taxanes and pertuzumab. Arm B: Trastuzumab, taxanes and pyrotinib. | Intracranial ORR. |
NCT04158947 | A Randomized Study of HER2-positive BC with Active Refractory BM Treated with Afatinib in Combination with T-DM1 Versus T-DM1 Alone. | I/II | 130 | Patients with HER2-positive BC with documented CNS recurrence/progression during or after anti-HER2 therapy (trastuzumab and/or lapatinib, pyrotinib, tucatinib). | Arm A: T-DM1 and afatinib (Phase I dose escalation starting at 20 mg/day). Arm B: T-DM1. | Safety and tolerability of T-DM1 and afatinib to determine the recommended Phase II dose (RP2D) ORR. |
NCT04739761 | An Open-Label, Multinational, Multicenter, Phase 3b/4 Study of Trastuzumab Deruxtecan in Patients with or without Baseline BM with Previously Treated Advanced/Metastatic HER2-Positive BC (DESTINY-Breast12). | IIIb/IV | 500 | HER2-positive MBC Cohort 1: No evidence of BM. Cohort 2: Untreated BM not needing immediate local therapy, or previously treated stable or progressing BM. | Arm A: Trastuzumab deruxtecan 5.4 mg/kg, every 3 weeks. | ORR in participants without BM at baseline (Cohort 1). PFS in participants with BM at baseline (Cohort 2). |
NCT04639271 | A Single-arm, Open-label Study Of Pyrotinib Combined with Trastuzumab Additionally, Abraxane in Patients with BM from HER2-positive MBC. | II | 100 | HER2-positive MBC with measurable BM. | Arm A: Pyrotinib Plus Trastuzumab Additionally, Abraxane. | ORR of intracranial lesions PFS of intracranial lesion. |
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Garcia-Alvarez, A.; Papakonstantinou, A.; Oliveira, M. Brain Metastases in HER2-Positive Breast Cancer: Current and Novel Treatment Strategies. Cancers 2021, 13, 2927. https://doi.org/10.3390/cancers13122927
Garcia-Alvarez A, Papakonstantinou A, Oliveira M. Brain Metastases in HER2-Positive Breast Cancer: Current and Novel Treatment Strategies. Cancers. 2021; 13(12):2927. https://doi.org/10.3390/cancers13122927
Chicago/Turabian StyleGarcia-Alvarez, Alejandro, Andri Papakonstantinou, and Mafalda Oliveira. 2021. "Brain Metastases in HER2-Positive Breast Cancer: Current and Novel Treatment Strategies" Cancers 13, no. 12: 2927. https://doi.org/10.3390/cancers13122927