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Real-World Outcomes in Patients With Brain Metastases Secondary to HER2-Positive Breast Cancer: An Australian Multi-centre Registry-based Study

      Abstract

      Background

      The development of brain metastases occurs commonly in HER2-positive metastatic breast cancer and is associated with a poorer prognosis. The advent of HER2-targeted therapy has improved overall survival, but the benefit in patients with brain metastases is unclear, as these patients are often excluded from clinical trials. This study aimed to explore real-world outcomes in patients with brain metastases in HER2-positive MBC.

      Materials & Methods

      Data was extracted from the TABITHA registry, which consists of patient data collected prospectively from 16 Australian sites from 24th February 2015 to 31st October 2021. Data analysed included characteristics of brain metastases, treatment received and survival outcomes.

      Results

      A total of 135 (37%) of 361 patients with HER2-positive MBC were diagnosed with brain metastases during their clinical course, including 45 (12%) with brain metastases at time of MBC diagnosis. 61 (45%) had ≥4 brain lesions. The most common local therapy given was whole brain radiation therapy (WBRT) (36%) followed by multi-modality treatment with both surgery and radiation therapy (27%). The majority of patients received first-line HER2-targeted treatment with trastuzumab and pertuzumab followed by second-line trastuzumab emtansine (T-DM1) but third-line therapy was heterogenous. The median overall survival in patients who developed brain metastases was significantly shorter than those who did not develop brain metastases (58.9 vs. 96.1 months, P = .02).

      Conclusion

      Real-world patients diagnosed with brain metastases in HER2-positive MBC have a relatively poor prognosis, despite advances in HER2-targeted treatment. As the range of HER2-targeted treatment expands, it is important to pursue clinical trials that focus on patients with brain metastases.

      Keywords

      Introduction

      HER2-positive metastatic breast cancer (MBC) is associated with an increased risk of developing brain metastases, with an incidence of up to 50%.
      • Brufsky AM
      • Mayer M
      • Rugo HS
      • et al.
      Central nervous system metastases in patients with HER2-positive metastatic breast cancer: incidence, treatment, and survival in patients from registHER.
      ,
      • Pasquier D
      • Darlix A
      • Louvel G
      • et al.
      Treatment and outcomes in patients with central nervous system metastases from breast cancer in the real-life ESME MBC cohort.
      The incidence of brain metastases in HER2-positive MBC is rising due to enhanced detection with improved imaging technology and improved control of extracranial disease.
      • Hadjipanteli A
      • Doolan P
      • Kyriacou E
      • Constantinidou A.
      Breast cancer brain metastasis: the potential role of MRI beyond current clinical applications.
      Nevertheless, the true incidence of brain metastases is likely to be underestimated as routine screening is currently not recommended due to a lack of benefit in overall survival.
      • Cardoso F
      • Paluch-Shimon S
      • Senkus E
      • et al.
      5th ESO-ESMO international consensus guidelines for advanced breast cancer (ABC 5).
      A number of HER2-targeted agents have emerged over the last decade and contributed to substantial improvement in survival. The addition of the HER2-targeted agent pertuzumab to trastuzumab and taxane-based chemotherapy has demonstrated survival benefit and is now considered standard first-line treatment for HER2-positive MBC.
      • Swain SM
      • Miles D
      • Kim SB
      • et al.
      Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA): end-of-study results from a double-blind, randomised, placebo-controlled, phase 3 study.
      Trastuzumab emtansine, a HER2-targeted antibody-drug conjugate has also demonstrated survival benefit when used in the second-line treatment setting.
      • Diéras V
      • Miles D
      • Verma S
      • et al.
      Trastuzumab emtansine versus capecitabine plus lapatinib in patients with previously treated HER2-positive advanced breast cancer (EMILIA): a descriptive analysis of final overall survival results from a randomised, open-label, phase 3 trial.
      ,
      • Verma S
      • Miles D
      • Gianni L
      • et al.
      Trastuzumab emtansine for HER2-positive advanced breast cancer.
      However, the optimal treatment strategy for patients with brain metastases remains unclear as most systemic therapy and some HER2-targeted agents such as trastuzumab have limited penetrance and anti-tumour activity in the central nervous system.
      • Lampson LA.
      Monoclonal antibodies in neuro-oncology: Getting past the blood-brain barrier.
      Treatment of brain metastases include local therapy such as surgery or radiation therapy, in combination with systemic therapy.
      Patients with brain metastases continue to have poorer prognosis, with reduced survival and suboptimal quality of life. Moreover, patients with brain metastases often have poor performance status and as those with untreated brain metastases are traditionally excluded from clinical trials, the outcomes for this cohort of patients are largely unknown. The treatment landscape of HER2-positive MBC continues to evolve, with the development of novel agents such as trastuzumab deruxtecan and oral tyrosine kinase inhibitors including tucatinib, which appear to have a higher rate of intracranial activity.
      • Jerusalem G
      • Park YH
      • Yamashita T
      • et al.
      138O CNS metastases in HER2-positive metastatic breast cancer treated with trastuzumab deruxtecan: DESTINY-Breast01 subgroup analyses.
      ,
      • Lin NU
      • Borges V
      • Anders C
      • et al.
      Intracranial efficacy and survival with tucatinib plus trastuzumab and capecitabine for previously treated HER2-positive breast cancer with brain metastases in the HER2CLIMB trial.
      However, it remains important to understand current clinical practices and patient outcomes including treatment efficacy and toxicity profile in routine care. The aim of this registry-based study is to evaluate the real-world outcomes of patients with brain metastases secondary to HER2-positive MBC including survival and treatment patterns across various sites in Australia.

      Materials and Methods

      Study Population

      The Treatment of Advanced Breast Cancer in the HER2 Positive Australian patient (TABITHA) registry is a prospective registry that was established in 2015 and includes data from consecutive patients with HER2-positive MBC across 16 sites in Australia, including metropolitan, regional, private and public centres. Patients with HER2-positive MBC were identified at each participating site and data were extracted from local medical records. Eligible patients had histological confirmation of HER2-positive MBC and were commenced on first or second-line therapy on or after 24th February 2015. Patients were not excluded based on age or performance status.

      Data Collection

      Data collected in the TABITHA registry include patient characteristics such as age, performance status, date of diagnosis of MBC, tumour characteristics such as hormone receptor status, sites of metastases, characteristics of brain metastases, treatment patterns and date of death. In this study, data was extracted and analysed for patients diagnosed with HER2-positive MBC from 24th February 2015 to 31st October 2021.

      Ethics Approval

      Ethics approval for data collection and use of de-identified patient data was obtained from the Human Research Ethics Committee (HREC) at each participating site and from Melbourne Health HREC, which oversees the TABITHA registry.

      Statistical Analysis

      Data analysis was performed using the SAS software. The comparisons of patient characteristics were performed using the Chi square method. Statistical significance is defined with a P value ≤ .05. Overall survival analyses were performed using the Kaplan-Meier method. The stratified log rank test was used to compare survival across different groups.

      Results

      Patient Characteristics

      Between the 24th February 2015 and 31st October 2021, 361 patients with HER2-positive MBC were enrolled into the TABITHA registry. The mean age of patients at the time of enrolment was 57.6 years. A total of 341 (95%) patients had an ECOG performance status of 0 to 1 at time of enrolment. The median follow-up period from diagnosis of HER2-positive MBC was 30.8 months.
      As illustrated in Figure 1, 135 (37%) of patients were diagnosed with brain metastases during their course of MBC, of which 45 (33%) were found to have brain metastases at time of initial MBC diagnosis whereas 90 (67%) developed brain metastases after the initial MBC diagnosis. A total of 78% of patients who did not have brain metastases at MBC diagnosis were subsequently found to have brain metastases at the time of first disease progression. Within the subset of patients who had brain metastases at initial MBC diagnosis, 5 (11%) had leptomeningeal disease. Notably, 16 (12%) patients had isolated intracranial metastases without extracranial disease at initial MBC diagnosis, of which 11 (69%) presented with symptomatic brain metastases.
      Figure 1
      Figure 1The development of brain metastases in patients with HER2-positive MBC in the TABITHA registry Abbreviation: BM = brain metastases.
      As summarised in Table 1, over 60% of patients who developed brain metastases after MBC diagnosis had concurrent visceral disease and were significantly more likely to have liver and bone metastases compared to patients who never developed brain metastases.
      Table 1Characteristics of Patients With HER2-Positive MBC (n = 361)
      CharacteristicPatients Diagnosed With HER2-Positive MBC (n = 361)
      All Patients (n = 361)BM at MBC Diagnosis (n = 45)BM After MBC Diagnosis (n = 90)Never Developed BM (n = 226)P value a) BM at MBC diagnosis vs. Never developed BM b) BM after MBC diagnosis vs. Never developed BM
      Mean age at diagnosis57.654.355.659.1a) P = .03, b) P = .04
      ECOG status at diagnosisa) P = .19, b) P = .07
       0 - 1341 (95%)45 (100%)88 (98%)207 (92%)
       2 - 420 (5%)0 (0%)2 (2%)17 (8%)
      Oestrogen receptor (ER) statusa) P = .98, b) P = .45
       Positive209 (58%)26 (58%)55 (61%)128 (57%)
       Negative137 (38%)18 (40%)31 (34%)88 (39%)
       Unknown15 (4%)1 (2%)4 (4%)10 (4%)
      Site of extracranial metastases
       Bone186 (52%)22 (49%)55 (61%)109 (8%)a) P = .94, b) P = .04
       Liver127 (35%)13 (29%)42 (47%)72 (32%)a) P = .70, b) P = .01
       Lung136 (38%)11 (24%)33 (37%)92 (41%)a) P = .04, b) P = .51
      Abbreviation: MBC = metastatic breast cancer, BM = brain metastases

      Characteristics of Brain Metastases

      As described in Table 2, approximately half of all patients diagnosed with brain metastases had multiple lesions with bilateral involvement. Sixty-one (45%) patients had ≥4 brain lesions. Brain metastases were most commonly located in the cerebral hemispheres (67%) and cerebellum (53%). Twenty (15%) patients had extensive involvement with leptomeningeal disease. Sixty-eight (50%) patients were diagnosed with asymptomatic brain metastases via imaging such as CT and MRI whereas the remainder were diagnosed on clinical history. Of those with leptomeningeal disease, 16 (80%) presented with symptomatic brain metastases.
      Table 2Characteristics of Brain Metastases (n = 135)
      Characteristic of Brain MetastasesTotal (%)
      Number of lesions
       1 – 374 (55%)
       ≥461 (45%)
      Laterality
       Unilateral68 (50%)
       Bilateral67 (50%)
      Detection method
       Clinical65 (48%)
       Imaging – CT38 (28%)
       Imaging - MRI30 (22%)
       Other2 (1%)
      Structure involved
       Cerebral hemisphere91 (67%)
       Cerebellum72 (53%)
       Brainstem14 (10%)
      Leptomeningeal disease
       Yes20 (15%)
       No115 (85%)

      Treatment Patterns

      The common modalities of local treatment of brain metastases are summarised in Figure 2. One hundred and thirteen (84%) patients with brain metastases received local therapy. Forty-nine (36%) of patients were treated with whole brain radiation therapy (WBRT) alone. Twenty-two (16%) patients received stereotactic radiosurgery (SRS) alone. Thirty-six (27%) patients received multimodality treatment with a combination of surgical resection and radiation therapy including WBRT or SRS. Six (4%) patients underwent surgical resection only. Patients with intracranial disease alone without extracranial disease were more likely to receive multi-modal local therapy including surgical resection combined with radiation therapy, only 4 (25%) patients received WBRT alone. Seventeen (85%) patients with leptomeningeal disease received WBRT alone. Despite local treatment of brain metastases, 72 (64%) patients developed intracranial progression, of which 8 (11%) received further surgery and 17 (24%) received further radiotherapy.
      Figure 2
      Figure 2Local treatment of brain metastases in HER2-positive MBC (n = 135) Abbreviations: WBRT = whole brain radiation therapy; SRS = stereotactic radiosurgery.
      As summarised in Table 3, the presence of brain metastases at MBC diagnosis did not impact on the type of first-line systemic therapy received. Overall, the majority of patients (70%) received first-line HER2-targeted therapy with trastuzumab and pertuzumab. Sixty-one (17%) patients received trastuzumab alone. Ten (3%) patients received trastuzumab emtansine (T-DM1). Thirty-four (9%) patients did not receive HER2-targeted therapy. Overall, paclitaxel was the most common first-line chemotherapy agent used. Thirteen (29%) patients with brain metastases at MBC diagnosis did not receive first-line chemotherapy.
      Table 3HER2-Targeted Agent and Chemotherapy Used in the First-line Treatment Setting
      Patients diagnosed with HER2-positive MBC (n = 361)
      All patients (n = 361)Brain metastases at MBC diagnosis (n = 45)No brain metastases at MBC diagnosis (n = 316)P value
      Type of HER2 therapy
       Trastuzumab only62 (17%)7 (16%)55 (17%).67
       Trastuzumab & pertuzumab253 (70%)31 (69%)222 (70%).61
       T-DM110 (3%)3 (7%)7 (2%).12
       None34 (9%)4 (9%)30 (9%)1.00
       Other
      n = 1 lapatinib, n = 1 pertuzumab alone.
      2 (1%)0 (0%)2 (1%)
      n = 1 lapatinib, n = 1 pertuzumab alone.
      1.00
      Type of chemotherapy
       Paclitaxel156 (43%)21 (47%)135 (43%).53
       Docetaxel81 (22%)9 (20%)72 (23%).68
       Nab-paclitaxel23 (6%)1 (2%)22 (7%).22
       Other
      Include cyclophosphamide & doxorubicin, capecitabine, carboplatin, gemcitabine, nab-paclitaxel.
      36 (10%)1 (2%)35 (11%).06
       None65 (18%)13 (29%)52 (16%).04
      low asterisk n = 1 lapatinib, n = 1 pertuzumab alone.
      ^ Include cyclophosphamide & doxorubicin, capecitabine, carboplatin, gemcitabine, nab-paclitaxel.
      The duration of first-line chemotherapy given in conjunction with HER2-targeted therapy was significantly shorter in the cohort of patients with brain metastases at MBC diagnosis, compared to those who did not have brain metastases at MBC diagnosis (3.1 vs. 5.1 months, P = .01). However, the duration of first-line HER2-targeted therapy did not significantly differ between these 2 groups (15.8 vs. 22 months, P = .23).
      Within the cohort of patients with isolated intracranial metastases and no extracranial disease, 3 (19%) did not receive HER2-targeted therapy or chemotherapy and 4 (25%) received HER2-targeted therapy only, without chemotherapy.
      The presence of leptomeningeal disease did not impact on the type of first-line systemic therapy given and did not alter the duration of first-line chemotherapy (3.4 vs. 4.9 months, P = 0.05) or first-line HER2-targeted therapy (16.8 vs. 20.9 months, P = .81).
      The Sankey diagram (Fig. 3) illustrates the pattern of change in HER2-targeted therapy in subsequent lines of treatment upon disease progression in patients with brain metastases at MBC diagnosis. The most common first-line HER2 targeted therapy used was trastuzumab with pertuzumab, with which 14 (35%) had durable responses with stable disease at last follow up and remained on first-line HER2-targeted therapy for a median duration of 26 months. The most common second-line HER2-targeted therapy used was T-DM1 but the selection of HER2-targeted therapy in the third-line treatment setting was heterogeneous, including 2 patients who were enrolled on clinical trial (10%).
      Figure 3
      Figure 3Treatment pattern of HER2-targeted therapy used in patients who had brain metastases at MBC diagnosis* *Not included: n = 5, no HER2-targeted therapy used Abbreviations: T-DM1 = trastuzumab emtansine; ICI = immune checkpoint inhibitor; PD = disease progression; SD = stable disease; 1L= first line treatment; 2L= second line treatment; 3L= third line treatment.

      Survival Outcomes

      As demonstrated in Figure 4, patients who developed brain metastases any time during their clinical course had a significantly shorter overall survival of 58.9 months versus 96.1 months for those who were never diagnosed with brain metastases (HR 0.66; 95% CI, 0.47-0.93; P = .02). Patients diagnosed with brain metastases after MBC diagnosis also had a significantly reduced overall survival, compared to those who were never diagnosed with brain metastases (52.6 vs. 96.1 months; HR 0.79, 95% CI 0.65-0.95, P = .01). The presence of brain metastases at MBC diagnosis did not significantly reduce overall survival, compared to those who never developed brain metastases (82.4 vs. 96.1 months; HR 0.81, 95% CI 0.46-1.45, P = .48). There was no significant difference in median overall survival of patients with intracranial disease alone, compared to those with both intracranial and extracranial disease (HR 0.48; 95% CI, 0.15-1.51; P = 0.19). The presence of leptomeningeal disease did not significantly reduce overall survival (58.9 vs. 62.8 months; HR 1.18, 95% CI 0.58-2.41; P = .64).
      Figure 4
      Figure 4Median overall survival of patients who developed brain metastases any time during clinical course versus patients who never developed brain metastases. Abbreviation: OS = overall survival.

      Discussion

      To our knowledge, this is the first Australian study to explore patient outcomes and treatment patterns in those with brain metastases secondary to HER2-positive MBC. The advent of HER2-targeted therapy has transformed the treatment landscape of HER2-positive MBC. The use of HER2-targeted therapy in the treatment of HER2-positive MBC became standard practice after a key clinical trial demonstrated additional survival benefit offered by trastuzumab when used in conjunction with chemotherapy.
      • Slamon DJ
      • Leyland-Jones B
      • Shak S
      • et al.
      Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2.
      Over the last decade, newer HER2-targeted agents including pertuzumab and T-DM1 have become available, demonstrating survival benefit in the clinical trial setting.
      • Swain SM
      • Miles D
      • Kim SB
      • et al.
      Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA): end-of-study results from a double-blind, randomised, placebo-controlled, phase 3 study.
      ,
      • Verma S
      • Miles D
      • Gianni L
      • et al.
      Trastuzumab emtansine for HER2-positive advanced breast cancer.
      However, many of these key clinical trials excluded patients with untreated brain metastases. Therefore, the degree of benefit offered by various HER2-targeted agents in this group of patients is unclear and highlights the importance of evaluating the outcomes of this patient subset in a real-world setting.
      There is no consensus with regard to the optimal local treatment strategy for patients with brain metastases secondary to HER2-positive MBC. In our study, one third of patients with brain metastases received surgical resection alone or in conjunction with radiation therapy. The uptake of SRS was approximately 30%, which is higher than previously reported internationally, where WBRT is favoured.
      • Hurvitz SA
      • O'Shaughnessy J
      • Mason G
      • et al.
      Central nervous system metastasis in patients with HER2-positive metastatic breast cancer: patient characteristics, treatment, and survival from SystHERs.
      ,
      • Witzel I
      • Laakmann E
      • Weide R
      • et al.
      Treatment and outcomes of patients in the brain metastases in breast cancer Network Registry.
      The discrepancy in the pattern of radiation treatment may be explained by inconsistent access to and lack of expertise in SRS. This is supported by retrospective data from the United Kingdom, which demonstrated an increasing use of SRS as initial radiation therapy from 2018, compared to the decade prior.
      • Bentley R
      • O'Cathail M
      • Aznar-Garcia L
      • Crosby V
      • Wilcock A
      • Christian J.
      Defining patterns of care in the management of patients with brain metastases in a large oncology centre: a single-centre retrospective audit of 236 cases.
      In Australia, access to SRS is similar for patients residing in regional and metropolitan locations, which potentially explains the higher uptake of SRS compared to international data.
      • Ong WL
      • Kang TMJ
      • Ratnayake G
      • et al.
      Stereotactic radiosurgery for managing brain metastases in Victoria, 2012-2017.
      Currently, the European Society of Medical Oncology (ESMO) favours the use of SRS over WBRT in patients with up to 10 brain metastases.
      • Cardoso F
      • Paluch-Shimon S
      • Senkus E
      • et al.
      5th ESO-ESMO international consensus guidelines for advanced breast cancer (ABC 5).
      ,
      • Stavrou E
      • Winer EP
      • Lin NU.
      How we treat HER2-positive brain metastases.
      Although hippocampal-sparing WBRT may reduce cognitive dysfunction, there is no randomised data to recommend its use over SRS.
      • Brown PD
      • Gondi V
      • Pugh S
      • et al.
      Hippocampal avoidance during whole-brain radiotherapy plus memantine for patients with brain metastases: phase III Trial NRG oncology CC001.
      The use of SRS mitigates long-term cognitive impairment that is associated with WBRT, which may develop up to 6 months after radiotherapy and creates substantial morbidity in MBC patients who in our study, had a median survival of 58 months.
      • Brown PD
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      • Ballman KV
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      Effect of radiosurgery alone vs radiosurgery with whole brain radiation therapy on cognitive function in patients with 1 to 3 brain metastases: a randomized clinical trial.
      ,
      • Chang EL
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      • Hess KR
      • et al.
      Neurocognition in patients with brain metastases treated with radiosurgery or radiosurgery plus whole-brain irradiation: a randomised controlled trial.
      Treatment patterns in patients with brain metastases secondary to HER2-positive MBC in the real-world setting are seldom explored. Despite strong evidence to support the use of dual HER2 blockade, trastuzumab alone is the most common first-line HER2-targeted therapy used in patients with brain metastases across various international studies.
      • Hurvitz SA
      • O'Shaughnessy J
      • Mason G
      • et al.
      Central nervous system metastasis in patients with HER2-positive metastatic breast cancer: patient characteristics, treatment, and survival from SystHERs.
      ,
      • Witzel I
      • Laakmann E
      • Weide R
      • et al.
      Treatment and outcomes of patients in the brain metastases in breast cancer Network Registry.
      In our study, the presence of brain metastases at MBC diagnosis did not impact on the first-line HER2-targeted therapy received, in contrast to the findings from a study in the United States, in which first-line trastuzumab and pertuzumab was more commonly used in patients who did not have brain metastases at MBC diagnosis while lapatinib was more commonly used in those diagnosed with brain metastases.
      • Hurvitz SA
      • O'Shaughnessy J
      • Mason G
      • et al.
      Central nervous system metastasis in patients with HER2-positive metastatic breast cancer: patient characteristics, treatment, and survival from SystHERs.
      In our study, over one third of patients with brain metastases at MBC diagnosis had a durable response to first-line pertuzumab and trastuzumab and remained on this treatment for many months. However, treatment patterns are heavily influenced by access to HER2-targeted therapy. Despite T-DM1 having greater intracranial activity and prolonging survival when given in a clinical trial setting, its funding is restricted to the second-line setting.
      • Diéras V
      • Miles D
      • Verma S
      • et al.
      Trastuzumab emtansine versus capecitabine plus lapatinib in patients with previously treated HER2-positive advanced breast cancer (EMILIA): a descriptive analysis of final overall survival results from a randomised, open-label, phase 3 trial.
      ,
      • Verma S
      • Miles D
      • Gianni L
      • et al.
      Trastuzumab emtansine for HER2-positive advanced breast cancer.
      ,
      • Krop IE
      • Lin NU
      • Blackwell K
      • et al.
      Trastuzumab emtansine (T-DM1) versus lapatinib plus capecitabine in patients with HER2-positive metastatic breast cancer and central nervous system metastases: a retrospective, exploratory analysis in EMILIA.
      Similarly, lapatinib is infrequently used as first-line treatment in Australia despite its ability to penetrate the BBB due to restricted access and poor tolerance secondary to gastrointestinal toxicities.
      • Bachelot T
      • Romieu G
      • Campone M
      • et al.
      Lapatinib plus capecitabine in patients with previously untreated brain metastases from HER2-positive metastatic breast cancer (LANDSCAPE): a single-group phase 2 study.
      Compliance with funding and prescription restrictions in Australia was variable in our study, as some patients continued treatment with pertuzumab beyond disease progression. Similar practices were identified in another Australian study, in which 36% of patients received trastuzumab that was non-adherent to restrictions in the 2000s, before trastuzumab become more widely available in 2015.
      • Daniels B
      • Lord SJ
      • Kiely BE
      • et al.
      Use and outcomes of targeted therapies in early and metastatic HER2-positive breast cancer in Australia: protocol detailing observations in a whole of population cohort.
      ,
      • Daniels B
      • Girosi F
      • Tervonen H
      • et al.
      Adherence to prescribing restrictions for HER2-positive metastatic breast cancer in Australia: a national population-based observational study (2001-2016).
      This highlights the ongoing challenge of accessing HER2-targeted therapy to improve patient outcomes in a cost-effective manner.
      In our study, treatment selection was heterogeneous in the third-line setting and beyond, which reflects the lack of evidence to guide treatment sequencing. Many patients continued with the same HER2-targeted therapy despite disease progression, concurrently with local treatment options including radiation therapy or change in the chemotherapy backbone. Approximately 20% of patients with brain metastases did not receive further therapy upon disease progression due to decline of functional status secondary to progressive disease. This illustrates that early treatment intensification with both local and systemic therapy is important and time-sensitive. More recently, the newer HER2-targeted agents tucatinib and trastuzumab deruxtecan (T-DXd) have demonstrated prolonged progression-free survival, with significant intracranial activity in those with progressive HER2-positive MBC.
      • Jerusalem G
      • Park YH
      • Yamashita T
      • et al.
      138O CNS metastases in HER2-positive metastatic breast cancer treated with trastuzumab deruxtecan: DESTINY-Breast01 subgroup analyses.
      ,
      • Lin NU
      • Borges V
      • Anders C
      • et al.
      Intracranial efficacy and survival with tucatinib plus trastuzumab and capecitabine for previously treated HER2-positive breast cancer with brain metastases in the HER2CLIMB trial.
      ,
      • Modi S
      • Saura C
      • Yamashita T
      • et al.
      Trastuzumab Deruxtecan in previously treated HER2-positive breast cancer.
      The current ESMO guidelines recommend the use of tucatinib or T-DXd as preferred HER2-targeted therapy in the third-line treatment setting and may be considered in the second-line setting if available.
      • Gennari A
      • André F
      • Barrios CH
      • et al.
      ESMO Clinical Practice Guideline for the diagnosis, staging and treatment of patients with metastatic breast cancer.
      However, both agents are not currently funded in Australia.
      The development of brain metastases is historically associated with poorer prognosis and is often associated with high disease burden.
      • Pasquier D
      • Darlix A
      • Louvel G
      • et al.
      Treatment and outcomes in patients with central nervous system metastases from breast cancer in the real-life ESME MBC cohort.
      ,
      • Martin AM
      • Cagney DN
      • Catalano PJ
      • et al.
      Brain metastases in newly diagnosed breast cancer: a population-based study.
      Patients with brain metastases at MBC diagnosis received significantly shorter duration of first-line chemotherapy in conjunction with HER2-targeted therapy, compared to those who did not have brain metastases at MBC diagnosis. Consistent with international data, patients in our study who developed brain metastases any time during their clinical course had significantly reduced overall survival compared to those who never developed brain metastases in our study. However, there is marked heterogeneity in the brain metastases cohort. In our study, patients who developed brain metastases after first-line treatment had an inherently poor prognosis as most had concurrent visceral metastases and had significantly shorter overall survival compared to those who never developed brain metastases. Moreover, many patients developed intracranial progression despite local treatment and required further surgery or radiotherapy. Contrastingly, the presence of brain metastases at MBC diagnosis did not significantly reduce overall survival, when compared to those who never developed brain metastases. This finding may be driven by the favourable prognosis in the few patients with isolated intracranial disease at MBC diagnosis, who received aggressive local therapy with durable treatment response. Internationally, the reported median overall survival in patients who develop brain metastases secondary to HER2-positive MBC ranges from 12 to 48 months, which is much lower than reported in our study.
      • Hurvitz SA
      • O'Shaughnessy J
      • Mason G
      • et al.
      Central nervous system metastasis in patients with HER2-positive metastatic breast cancer: patient characteristics, treatment, and survival from SystHERs.
      ,
      • Witzel I
      • Laakmann E
      • Weide R
      • et al.
      Treatment and outcomes of patients in the brain metastases in breast cancer Network Registry.
      ,
      • Martin AM
      • Cagney DN
      • Catalano PJ
      • et al.
      Brain metastases in newly diagnosed breast cancer: a population-based study.
      ,
      • Niwińska A
      • Murawska M
      • Pogoda K.
      Breast cancer brain metastases: differences in survival depending on biological subtype, RPA RTOG prognostic class and systemic treatment after whole-brain radiotherapy (WBRT).
      This discrepancy in overall survival internationally may be secondary to inherent differences in the study populations recruited. Moreover, access to HER2-targeted agents varies internationally and may be limited by financial affordability in under-resourced countries. Nonetheless, outcomes in patients with brain metastases have substantially improved in past decades, as overall survival was typically less than 6 months prior to the advent of the HER2-targeted therapy.
      • Nussbaum ES
      • Djalilian HR
      • Cho KH
      • Hall WA.
      Brain metastases. Histology, multiplicity, surgery, and survival.
      Isolated brain metastases in MBC were uncommon in our study as only 16 patients had intracranial disease alone. This group of patients received aggressive local therapy with both surgical resection and radiation therapy. Overall survival was similar in patients with intracranial disease alone compared to those with both intracranial and extracranial disease but this analysis is limited by the small number of patients in this cohort in our study. Few studies in the current literature explore outcomes in patients with isolated intracranial metastases secondary to MBC, as most are limited by small sample sizes. Some studies suggest that this cohort of patients have a favourable prognosis when early intensive local therapy is delivered with curative intent.
      • Berghoff AS
      • Bago-Horvath Z
      • Ilhan-Mutlu A
      • et al.
      Brain-only metastatic breast cancer is a distinct clinical entity characterised by favourable median overall survival time and a high rate of long-term survivors.
      The role of systemic therapy in this subgroup of patients is unclear but overall, systemic therapy is favoured as intracranial disease is likely associated with microscopic extracranial metastases not detected by conventional imaging.
      • Niwińska A.
      Brain metastases as site of first and isolated recurrence of breast cancer: the role of systemic therapy after local treatment.
      Leptomeningeal disease was uncommon and did not impact upon survival in our study but this analysis was limited by the small sample size of only 20 patients in this cohort. The reported median overall survival for this subset of patients ranged from 3 to 7 months.
      • Buszek SM
      • Chung C.
      Radiotherapy in leptomeningeal disease: a systematic review of randomized and non-randomized trials. systematic review.
      ,
      • Morikawa A
      • Jordan L
      • Rozner R
      • et al.
      Characteristics and outcomes of patients with breast cancer with leptomeningeal metastasis.
      The poor outcomes in this group may be attributed to limited treatment options, as the mainstay of local therapy remains to be WBRT and these patients are routinely excluded from clinical trials.
      The role of screening for brain metastases in HER2-positive MBC remains controversial.
      • Hadjipanteli A
      • Doolan P
      • Kyriacou E
      • Constantinidou A.
      Breast cancer brain metastasis: the potential role of MRI beyond current clinical applications.
      ,
      • Komorowski AS
      • Warner E
      • MacKay HJ
      • Sahgal A
      • Pritchard KI
      • Jerzak KJ.
      Incidence of brain metastases in nonmetastatic and metastatic breast cancer: is there a role for screening?.
      Currently, screening is not recommended due to the lack of a proven survival benefit.
      • Gennari A
      • André F
      • Barrios CH
      • et al.
      ESMO Clinical Practice Guideline for the diagnosis, staging and treatment of patients with metastatic breast cancer.
      In our study, most patients developed brain metastases early at the time of first disease progression, with most having asymptomatic lesions diagnosed on imaging. Moreover, most clinical trials mandate imaging to screen for brain metastases prior to enrolment. Brain metastases may be amenable to intensive local therapy when detected early, which may improve prognosis and reduce morbidity. Given the recent development of more potent HER2-targeted agents, the role of screening should be re-visited.
      The findings from our study are limited by incomplete data as some patients from the TABITHA registry were lost to follow up. Further, data regarding clinician rationale for specific treatment selection was not collected. The small sample size of patients in certain subgroups, such as those with brain metastases at MBC diagnosis and isolated brain metastases, limits our ability to explore outcomes in these subgroups.

      Conclusion

      The TABITHA registry has provided an opportunity to explore real-world outcomes and treatment patterns in patients with brain metastases secondary to HER2-positive MBC, a unique cohort that is historically otherwise excluded from key clinical trials. The treatment landscape of HER2-positive MBC continues to evolve with the development of new HER2-targeted agents, that may offer greater intracranial activity. Nevertheless, many questions remain unanswered regarding optimal treatment in patients with brain metastases. There is a pressing need to improve prognosis in patients with brain metastases in the era of new HER2-targeted agents and this can only be achieved via clinical trials that focus on this cohort of patients.

      Clinical Practice Points

      • Patients with untreated brain metastases secondary to HER2-positive MBC are traditionally excluded from clinical trials hence outcomes and treatment patterns in this group are largely unknown.
      • Real-world patients with brain metastases secondary to HER2-positive MBC had significantly shorter prognosis compared to those who did not develop brain metastases. However, overall survival in this group of real-world patients with brain metastases are higher than reported in other international studies.
      • The presence of brain metastases at initial diagnosis of HER2-positive MBC did not impact on the type of HER2-targeted therapy received, despite agents such as T-DM1 offer greater intracranial activity. Access to HER2-targeted therapy is limited by funding restrictions.
      • Although newer HER2-targeted agents such as T-DXd may offer greater intracranial activity, optimal treatment in patients with brain metastases remain unclear.
      • There is a pressing need to improve prognosis in patients with brain metastases, which can only be achieved via clinical trials that focus on this cohort of patients.

      Acknowledgments

      The authors thank BioGrid Australia, Roche, and Astra Zeneca for financial support of the TABITHA registry.

      Disclosure

      Vanessa Wong has received honorarium from Amgen and Janssen. Richard de Boer has received honorarium from AstraZeneca, Gilead, Novartis, Roche and Genesis Care. Belinda Yeo has been part of the advisory board for Novartis, Amgen, Genentech, Roche, AstraZeneca and Merck. She has received speaker fees from Roche, Novartis, Eisai, Myriad, Specialised Therapeutics and Gilead and has received travel grants from Roche and Novartis. Angelyn Anton has received honorarium from Amgen, Janssen, MSD. Her affiliated institution has received funding from Amgen, AstraZeneca, Astellas Pharma, Bayer and Mundipharma. Louise Nott has been part of the advisory board for Bristol Myers Squibb, Merck and Roche. She has received grants from MSD, Roche, Bristol Myer Squibb, Celgene and Amgen. Peter Gibbs has received institutional research support from Roche. Sheau Wen Lok's affiliated institution has received funding from Roche. Iris Tung, Cristina Moldovan, Laeeq Malik, Sally Greenberg, Frances Barnett, Ian M Collins, Janine Lombard, Michelle Nottage, Arvind Sahu and Javier Torres declare they have no conflicts of interest.

      Appendix. Supplementary materials

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