Current state of clinical trials in breast cancer brain metastases

Abstract

Background

Breast cancer brain metastases (BCBM) are the final frontier in neuro-oncology for which more efficacious therapies are required. In this work, we explore clinical trials in BCBM, and determine the shortcomings in the development of new BCBM therapies to shed light on potential areas for enhancement.

Methods

On July 9, 2018, we searched ClinicalTrials.gov for all interventional and therapeutic clinical trials involving BCBM, without limiting for date or location. Information on trial characteristics, including phase, status, start and end dates, study design, primary endpoints, selection criteria, sample size, experimental interventions, results, and publications were collected and analyzed.

Results

Fifty-three trials fulfilled the selection criteria. Median trial duration across phases ranged between 3 and 6 years. More than half of the trials were conducted in the United States. Although 94% of the trials were in early phases (I-II), 20% of patients were in phase III trials. Two phase III trials were anteceded by phase II trials that were non-randomized; one reported positive results. Approximately one-third of the trials were completed, whereas 23% of trials were terminated early; mostly due to inadequate enrollment. Only 13% of all trials and 22% of completed trials had published results directly linked to their primary outcomes.

Conclusions

The low number of trials and accrual numbers, the lack of diversity, and the scarcity of published results represent the main troubles in clinical BCBM research. Optimization of BCBM trials is necessary to achieve effective therapies.

Brain metastases are amongst the possible complications of systemic breast cancer. It is estimated that 15–20% of patients with breast cancer develop brain metastases during the course of their disease.^1,2 However, the incidence is likely much higher given that brain metastases are found in 30% of post-mortem autopsies of patients with primary breast cancer.^2,3 Some subtypes of breast cancer, such as HER2-positive, triple-negative, or basal-like breast cancer have higher incidence of brain metastases compared to estrogen receptor-positive subtypes.4–6 In most cases, though, brain involvement occurs in the late stage of the disease; patients will already have lung, liver, and/or bone involvement by the time brain metastasis is diagnosed.⁷ Unfortunately, brain metastasis portends a dismal prognosis,⁸ as it is often associated with progressive neurological impairments that worsen quality of life and limit life expectancy.

Development of brain metastases is a multifaceted process that may take 2–3 years from the initial cancer diagnosis.⁹ It requires the invasion of primary breast cancer cells into surrounding tissue and vessels, trafficking through the circulatory system, and colonization in the brain parenchyma.^2,10 The addition of antibodies to chemotherapeutic regimens has improved survival outcomes for patients with HER2 positive breast cancer. However, the unique ability of breast cancer cells to cross the blood–brain barrier (BBB) coupled with the BBB-limited penetration of antibodies may result in reduced drug delivery and increase in the incidence of brain metastases.¹¹

Despite understanding some of the molecular underpinnings behind the development of breast cancer brain metastases (BCBM), there have been minimal developments of new drugs that can capitalize on this information. The current therapeutic landscape for BCBM lacks optimal results: treatment options are limited to surgical resection, whole-brain radiation therapy, stereotactic radiosurgery, chemotherapy and targeted therapy.^12–14 The BBB and the lack of sufficient investment are some of the many potential reasons for the lack of progress in developing new therapies for BCBM. Survival outcomes and clinical benefits continue to rely on the discovery of novel therapeutic regimens. Nevertheless, the establishment of an effective strategy to critically analyze and evaluate new therapies as well as present patients with BCBM the opportunity to participate in clinical trials is equally important. This will allow us to generate valuable data, stop investment in ineffective therapies, and push for the approval of productive interventions.

In this work, we present an overview of clinical trials on BCBM, explore their characteristics, and extrapolate conclusions on whether goals of therapies are being met.

Materials and Methods

Search Strategy and Selection Criteria

ClinicalTrials.gov is a large clinical trial registry that adds a high number of trial entries, weekly. Its submission process necessitates providing detailed information on trial profile and history and description of registered protocols. The ability to conduct analysis and extrapolate conclusions on clinical trials’ data from the registry has been previously elaborated on.^15–17

On July 9, 2018, we searched ClinicalTrials.gov for all clinical trials involving BCBM, without limiting for date or location. Following an elimination schema similar to Vanderbeek et al.,¹⁸ 27 trials were removed as they were non-interventional and non-therapeutic studies and/or clinical trials that do not list BCBM in the title or as a condition treated. Nine trials were further determined to be diagnostic or non-therapeutic despite being listed as “interventional” and were excluded (Fig. 1).

Fig. 1.

Clinical trial selection process.

Data Collection

Information was acquired from the final data set on trial characteristics, including: phase (I, I/II, II, II/III, III), status (completed, active, recruiting, not recruiting, suspended, terminated, etc.), BCBM classification (newly diagnosed, progressive, recurrent, both), start and end dates, primary endpoints, selection criteria, sample size, study design, experimental interventions, location, results, and publication.

Trial history of changes was obtained using the ClinicalTrials.gov archives site. To comply with Section 801 in the Food and Drug Administration Amendments Act of 2007,¹⁹ trial duration was defined by the study start date and the primary completion date. Endpoints were classified as based on objective response rate, clinical benefit rate, disease control rate, efficacy, progression-free survival, safety and toxicity, overall survival, and/or pharmacokinetics/pharmacodynamics.

Retrieving Publications

Trial publications were obtained using the ClinicalTrials.gov registry number (NCTID). NCTID identifiers were searched for on the Pubmed/Medline and Embase/Scopus records to locate publications. If the trial was published, the NCTID identifier was included as part of the original paper and the paper will appear in the search result. Associated publications were collected and reviewed by two investigators (J.F., D.K.) to identify publications reporting on primary results.

Results

Trial Characteristics

Only 53 trials met our criteria. Table 1 shows trial characteristics by phase. About 60% of the trials (32 trials) were for newly diagnosed or progressive BCBM; 5 trials were for newly diagnosed BCBM exclusively. Only 1 trial (2%) targeted recurrent BCBM. Six trials (11%) recruited both newly diagnosed/progressive and recurrent BCBM, and 14 trials (26%) did not specify the classification. Brain metastatic lesions were defined based on the RECIST guideline version 1.1.²⁰ Trials that allowed patients that received prior systemic treatment necessitated a washout period before enrollment. This washout period ranged from one week to six months in some trials.

Table 1.

Clinical trials in breast cancer brain metastases as found in ClinicalTrials.gov as of July 9, 2018 (n = 53)

	Phase I	Phase I/II	Phase II	Phase II/III	Phase III	Total
Number of Trials	6 (11%)	6 (11%)	38 (72%)	1 (2%)	2 (4%)	53 (100%)
Trial Status
Completed	3	-	14	-	1	18 (34%)
Active, not recruiting	1	-	3	-	-	4 (8%)
Recruiting	1	2	9	-	1	13 (25%)
Not yet recruiting	-	1	-	-	-	1 (2%)
Enrolling by invitation	-	-	-	1	-	1 (2%)
Terminated	1	2	9	-	-	12 (23%)
Withdrawn	-	1	2	-	-	3 (6%)
Unknown status	-	-	1	-	-	1 (2%)
Estimated Enrollment
0–10	1	2	7	-	-	10 (19%)
11–50	5	2	18	-	-	25 (47%)
51–100	-	1	6	1	-	8 (15%)
>100	-	1	7	-	2	10 (19%)
BCBM Classification
Newly diagnosed/progressive	4	3	25	-	-	32 (60%)
Recurrent	-	-	1	-	-	1 (2%)
Both	1	-	4	1	-	6 (11%)
Not specified/other	1	3	8	-	2	14 (26%)
Breast Cancer Subtype
HER2—positive	5	3	13	-	-	21 (40%)
HER2—negative	-	-	1	-	-	1 (2%)
Triple negative (ER-, PR-, HER2-)	-	-	3	-	-	3 (6%)
Unspecified	1	3	21	1	2	28 (53%)
Required Prior Therapy
WBRT and/or SRS	-	1	5	-	-	6 (11%)
Chemotherapy	1	-	7	-	1	9 (17%)
No treatment	1	-	2	-	1	4 (8%)
No Requirement of Prior Therapy	4	5	24	1	-	34 (64%)
Results Provided	1	1	10	-	-	12 (23%)
Linked Publication	-	-	6	-	1	7 (13%)
Trial Location
North America (US/Canada)	4	5	21	-	-	30 (57%)
Europe/UK/Russia	2	1	8	1	-	12 (23%)
Asia/Australia	-	-	5	-	-	5 (9%)
Intercontinental	-	-	4	-	2	6 (11%)

WBRT: whole brain radiation therapy, SRS: stereotactic radiosurgery.

Trial duration was available for all 6 phase I trials, 6 phase I/II trials, 38 phase II trials, 1 phase II/III trial, and 2 phase III trials. One phase I trial, 2 phase I/II trials, and 9 phase II trials were terminated. One phase I/II trial and 2 phase II trials were withdrawn. Median trial duration including and not including terminated/withdrawn studies was 39 and 42 months for phase I trials, 34 and 67 months for phase I/II trials, 38.5 and 42 months for phase II trials, and 42 months for phase III trials, respectively. The trial duration for the phase II/III trial was 72 months. As of July 9, 2018, 18 trials (34%) are yet to reach their primary completion date.

Trials were mostly in the early stages: 11% were phase I, 11% were phase I/II, and 72% were phase II (Table 1, Fig. 2A). Phase II trials accounted for the most patients enrolled (66.4%) (Fig. 2B). Although patients enrolled in phase III trials constituted approximately 20% of all patient enrollments, only 4% of the trials were in phase III. No phase IV trial was detected.

Fig. 2.

Distribution of trials (A) and patients (B) among phases.

More than half of the trials were conducted in North America (30 trials, 57%). Europe, including UK and Russia, was the location of 23% of the trials, whereas Asia, including Australia, constituted 9%. Close to 11% of the trials were conducted intercontinentally. Of the terminated trials, 8 trials were being conducted in North America, 2 in Europe, 1 in Asia, and 1 was of an intercontinental setting.

Twelve trials (23%) were terminated early. The major reason for termination was inadequate recruitment (9 trials). Other reasons included lack of funding (1 trial), feasibility (1 trial), and operational issues (1 trial). The median trial duration for terminated studies across all phases was 18 months (range 9 to 48 months).

Trial Results and Publication

Of all, only 7 trials (13%) had publications linked to their identification number (Table 2).21–27 Twelve trials (23%) provided results on ClinicalTrials.gov, of which only 2 had published their findings. Of the 18 completed trials, only 4 trials (22%) were published, even after 100 months of trial initiation (Fig. 3). Of the 7 published trials, median time from trial initiation to completion date and from trial initiation to publication date was 34 months and 50 months, respectively.

Table 2.

Clinical findings of published trials in breast cancer brain metastases, as of July 9, 2018 (n = 7)

Authors	Year	Trial	NCTID	Phase	Number Enrolled	Inclusion Criteria	Primary Outcome	Result
Van Swearingen et al.21	2018	A Study Of Everolimus, Trastuzumab And Vinorelbine In HER2-Positive Breast Cancer Brain Metastases	NCT01305941	II	32	Histologically- confirmed HER2- positive BCBM after receipt of intracranial radiation therapy.	Response Rate	The combination of everolimus, vinorelbine, and trastuzumab did not meet the pre-specified intracranial response endpoint.
Cortés et al.22	2017	A Study of Etirinotecan Pegol (NKTR- 102) Versus Treatment of Physician’s Choice (TPC) in Patients With Metastatic Breast Cancer Who Have Stable Brain Metastases and Have Been Previously Treated With an Anthracycline, a Taxane, and Capecitabine	NCT02915744	III	220	Histologically- confirmed BCBM for whom cytotoxic chemotherapy is indicated. Patients must have brain metastases that are non-progressing and have had prior therapy.	Overall Survival	Significant improvement in survival in BCBM patients with etirinotecan pegol. Survival rates at 12 months were 44.4% for etirinotecan pegol versus 19.4% for treatment of physician’s choice.
Freedman et al.23	2016	HKI-272 for HER2-Positive Breast Cancer and Brain Metastases	NCT01494662	II	168	HER2-positive BCBM with no limit to the number of previous lines of therapy. No prior therapy with neratinib is allowed	Response Rate	Neratinib (HKI-272) had low activity and did not meet the threshold for success.
Cortés et al.24	2015	Lux-Breast 3; Afatinib Alone or in Combination With Vinorelbine in Patients With Human Epidermal Growth Factor Receptor 2 (HER2) Positive Breast Cancer Suffering From Brain Metastases	NCT01441596	II	121	Patients with HER2- positive BCBM recurrence and/or progression during or after a HER2 inhibitor-based therapy	Progression Free Survival	No difference in patient benefit. Adverse events were frequent and afatinib-containing treatments seemed to be less well tolerated.
Wu et al.25	2015	Bevacizumab With Etoposide and Cisplatin in Breast Cancer Patients With Brain and/or Leptomeningeal Metastasis	NCT01281696	II	40	Histologically- confirmed BCBM that progress or develop new lesions with or without prior therapy	Response Rate	Out of 5 patients, 3 patients improved neurologically without evidence of systemic progression; one patient was neurologically stable but progressed systemically; and one patient exhibited both neurologic and systemic progression.
Cao et al.26	2015	Radiation Therapy With or Without Temozolomide in Treating Women With Brain Metastases and Breast Cancer	NCT00875355	II	100	Patients who have unresectable breast cancer or are refusing surgery and have brain metastases. No prior brain radiotherapy	Response Rate	No significant improvement in local control and survival.
Bachelot et al.27	2013	Lapatinib Ditosylate and Capecitabine in Treating Patients With Stage IV Breast Cancer and Brain Metastases	NCT00967031	II	45	Patients with HER2- positive BCBM who did not receive prior therapy with lapatinib or capecitabine.	Response Rate	An objective response was noted in two-thirds of patients, with about a fifth having a volumetric reduction of greater than 80%.

Fig. 3.

Cumulative incidence of publications for primary clinical trial results.

Analysis of Phase I and I/II Trials

There were 6 phase I trials (11%) and 6 phase I/II trials (11%). Of these, 9 trials included outcomes on safety/toxicity, 7 were dose escalation studies, and 3 included a pharmacokinetics and/or pharmacodynamics endpoint. Five trials were randomized. There were 8 trials that targeted participants with HER2-positive breast cancer only. One trial required participants who had received whole brain radiation therapy, one trial required participants to have received at least one line of chemotherapy, while another trial required patients who had not received any treatment (Table 1).

The average observed sample size for phase I and I/II trials—excluding terminated and withdrawn trials—was 48.8 patients. Observed enrollment met or exceeded planned sample size in 6 trials. Two trials could not meet the planned sample size (41 vs 50 patients; and 35 vs 39 patients). Three trials were terminated. Reasons included: inadequate enrollment, discontinuation of drug, sponsor revision and assessment of feasibility. One trial was withdrawn for major revision of protocol.

Analysis of Phase II Trials

Approximately 72% of the conducted BCBM trials were phase II trials (n = 38). Most of the trials followed the single group assignment (68%), and measured objective response rate as the primary outcome (61%). Only 6 trials (16%) were randomized, whereas 37 trials (97%) were unblinded (Table 3). Thirteen phase II trials targeted patients with HER2-positive breast cancer, 1 trial was specified for patients with HER2-negative breast cancer, and 3 trials were for patients with triple negative breast cancer (Table 1).

Table 3.

Primary outcomes of Phase II clinical trials (n = 38)

	Number	Percent
Interventional Model
Single Group Assignment	26	68.4
Parallel Assignment	10	26.3
Not Specified	2	5.3
Treatment Allocation
Non-randomized	10	26.3
Randomized	6	15.8
Not Specified	22	57.9
Masking
Open Label	37	97.4
Not Specified	1	2.6
Primary Endpoint
Progression-free Survival	7	18.4
Objective Response Rate	23	60.5
Disease Control Rate	1	2.6
Clinical Benefit Rate	3	7.9
Relapse Rate	1	2.6
Safety / Toxicity	2	5.3
Efficacy	1	2.6

The average observed sample size for phase II trials—excluding terminated and withdrawn trials—was 80.8 patients. Observed enrollment met planned sample size in 13 trials and exceeded it in 7 trials. In 6 trials, enrollment number fell short of the planned sample size; reasons were not cited. One trial did not specify the planned sample size, thus comparison could not be drawn.

Six of the 38 trials had published results related to their primary outcomes (Table 2). One trial (NCT00967031) reported a positive outcome when using lapatinib ditosylate and capecitabine in treating patients with BCBM. Objective response was noted in two-thirds of patients, with about a fifth having a volumetric reduction of greater than 80%.²⁷ Another trial revealed that the combination of everolimus, vinorelbine, and trastuzumab (NCT01305941) was not effective in treating patients with BCBM.²¹ Neratinib (NCT01494662), a tyrosine kinase inhibitor, had low activity in patients with BCBM and failed to instigate a positive response.²³ Afatinib and afatinib-containing regimens (NCT01441596) exhibited multiple adverse events, like diarrhea and neutropenia.²⁴ Bevacizumab with etoposide and cisplatin (NCT01281696) showed promising efficacy in patients with breast cancer who had leptomeningeal spread; however, only five patients were followed up.²⁵ Whole brain radiotherapy combined with temozolomide (NCT00875355) was not effective in improving neither survival nor response rate in patients with BCBM.²⁶

Analysis of Phase III Trials

All phase III trials (n = 2) were randomized controlled trials. The average observed sample size for phase III trials was 359 patients. Observed enrollment met planned sample size in one trial (350 patients) and exceeded planned sample size in another trial (368 vs 360 patients). The 2 trials use overall survival as the primary outcome.

Only 1 of the 2 trials had published its results (NCT02915744). It reported a positive outcome using etirinotecan pegol (NKTR-102) versus treatment of physician’s choice in patients with BCBM that have been previously treated with anthracycline, taxane, and capecitabine.²² The other trial (efaproxiral; NCT00083304)—although completed—did not provide results or publications.

As the overall rate of success in phase III trials was low, we queried ClinicalTrials.gov and PubMed/Medline for the phase II trials that preceded using the same drug and indication (Table 4). Both trials had antecedent phase II studies: one used progression-free survival as the primary outcome, while the other used overall response rate. Both of the antecedent trials were single-arm trials. The average time from the start of phase II till the completion of phase III averaged 7.9 years (range 7.1 to 8.7 years).

Table 4.

Details of Phase III trials (n = 2) and associated Phase II trials

Intervention	Phase IIII NCTID	Indication	Phase III Status	Phase III Completion Date	N (III)	Endpoint (III)	Result	Preceding Phase II?	Phase II NCTID	N (II)	Endpoint (II)	Randomized?	Start of Phase II to End of Phase III (months)
Etirinotecan pegol	NCT02915744	Non- progressing brain metastases	Recruiting	August 2019	350	Overall Survival	Improvement in survival	Yes†	NCT01663012	20	Progression- Free Survival	No	85
Efaproxiral	NCT00083304	Not specified	Completed	June 2007	368	Overall Survival	-	Yes	NCT00004202	51	Overall Response Rate	No	104

†Phase II study was based on the treatment of high grade gliomas

Discussion

The dismal survival associated with BCBM warrants the development of novel and conceptually targeted treatments. The effectiveness of new therapy depends on meticulously designing clinical trials, effectively enrolling and retaining patients, and publishing results in major outlets. Extensive participation in clinical trials is essential so that BCBM loses its ‘end-stage disease’ perception.

Low Number of Trials

Only 53 trials—as of July 9, 2018—have been found to be interventional and therapeutic. In comparison to other brain tumors, a recent study was capable of collecting 417 therapeutic clinical trials for glioblastoma multiforme.¹⁸ The low number of clinical trials targeting BCBM can be attributed to a variety of factors. The presence of brain metastases is considered by many as an exclusion criterion since it entails a poor prognosis, with a median survival that ranges from 2 to 25.3 months despite treatment.^9,14 In addition, the ability to cross the BBB makes metastatic breast cancer cells difficult to target.²⁸ Current existing treatments are facing challenges in evading the BBB.²⁹ Furthermore, more than 11% of the existing clinical trials focus on the diagnosis and prevention of brain metastases, without attempting to treat. This may deter sponsors and researchers from investing in risky trials that can produce negative results.

More than one-third of the current ongoing trials in BCBM are set to be completed within the next 10 years. The rise in the number of clinical trials lately can be attributed to the advancement in neuroimaging modalities that can detect brain metastases,³⁰ which would have gone unnoticed in the past. This allows the tracking of targeted therapies and the objective measure of tumor response and outcomes. Previously, the inability to detect brain metastases caused lower incidence rates,³¹ and thus BCBM research would not have been prioritized.

Our results show that BCBM clinical trial activity in many nations has been scarce. BCBM clinical trials from our dataset that include African nations, for example, are nil. The lack of infrastructure and resources can be good reasons. However, in sub-Saharan Africa alone, breast cancer is responsible for one in four diagnosed cancers and one in five cancer deaths in women,³² who usually present with late-stage onset of breast cancer. In Eastern Mediterranean nations, breast cancer is the most frequently diagnosed female malignant disease; affected patients are at least a decade younger than patients in the US or Europe, and exhibit a more advanced stage of disease at first presentation.³³ The lack of diversity can prevent the access of some patients with BCBM to new therapies. It has been shown that different ethnicities respond differently to different treatments,³⁴ thus wider inclusion is crucial for better and more precise outcomes.

Inadequate Accrual

About 75% of the terminated trials in BCBM were due to inadequate recruitment. Aside from patient preferences; strict eligibility criteria, trial location, and lack of adequate marketing to reach consumers can be possible reasons. In addition, uncertainty among likely participants, along with an overall lack of awareness as a result of ineffective enrolling approaches, contributes to lack of recruitment. Traditional recruiting methods have been ineffective in terms of increasing the pools of participants.³⁵ Even with the extensive use of media and communication terminals, nearly two-thirds of all clinical trials are delayed as a result of recruitment issues.³⁶

Adopting innovative approaches for patient recruitment in BCBM trials is necessary. Employing advanced analytic tools to scan electronic health records for eligible patients in health centers have shown to save time and significantly increase recruitment rate in an ongoing clinical trial.³⁷ We also believe that physicians can be more involved in the recruitment process. It has been shown that patients are more likely to participate in a clinical trial if it is recommended by their physician.³⁸ Furthermore, releasing recruitment messages that often appear in commercials in multiple languages can improve overall recruitment numbers and increase the diversity of the pool of participants. As the numbers of patients enrolled increase, more data will be generated, and the industry will be pushed to sponsor more BCBM trials.

Trial Design Inefficiencies

The current governing system in clinical trials does not stop inefficient treatments early in development, leading to maldistribution of patients among trials. Although phase III trials constituted only 4% of the total number of trials, they accrued 20% of the total number of patients. Failure in phase III may mean that patients were subjected to futile therapies.¹⁸ In addition; better designs of trials, consistency of endpoints, lack of randomization, and comparison to a historical control have been reported to be possible sources for overestimation of treatment effects.³⁹

With more than 60% of phase II trials having objective response rate as the primary endpoint, there is hope that positive results will show sponsors direct therapeutic effects and encourage them to support more trials in BCBM. Of note, close to 75% of phase I and I/II trials included safety/toxicity as an endpoint. Early-phase trials, with their limited number of patients, can also help us understand whether the treatment is able to affect the tumor or not. Understanding the pharmacodynamics and pharmacokinetics along with establishing optimum dosing lays the foundation to conduct better phase II and III trials in the future.

Trial Duration and Lack of Published Results

After completing a phase I trial in BCBM, the time from the start of phase II till the completion of phase III averages 7.9 years. Still, only 7 of the 53 trials had publications on the primary outcomes of their studies. Moreover, only 4 of the 18 completed trials were published. Some trials will never reach publication for indefinite reasons,⁴⁰ with a significant number potentially due to obtaining negative results and/or a lack of interest either by the editors or the authors.⁴¹ However, publishing negative results is important to comprehend the reasons of failure and for similar designs and/or therapies not to be replicated in the future. Besides, patients who enrolled in the trial deserve to know its results, and abstaining from providing results will decrease available information and create ordeals for researchers and sponsors as they seek to find a cure for BCBM.

Designing a clinical trial and obtaining the necessary support and approval to conduct it is a lengthy process; however, better time management will result in the elimination of inefficiencies. A master protocol, for example, will screen patients for various biomarkers and assign them to trials for drugs that are most likely to be effective.^42,43 Hence, multiple drugs can be tested at once and chances for better patient outcomes can be achieved.

Therapeutic Benefit and Future Directions

Two trials showed positive outcomes. Bachelot et al.²⁷ reported that lapatinib ditosylate and capecitabine improve response rate and lead to a decrease in the volume of brain metastases. Out of 45 recruits, 29 patients (64%) had an objective central nervous system response of 65.9%; all were partial responses. Nevertheless, the phase II trial was non-randomized with a single-group assignment. In addition, 49% of patients had adverse events: 20% of patients suffered from diarrhea and 20% developed hand-foot syndrome. In a phase III trial, Cortes et al.²² demonstrated that etirinotecan pegol prolonged survival in patients with BCBM. Etirinotecan pegol is a long-acting topoisomerase-I inhibitor that has been suggested to exhibit anti-tumor activity.^44,45 Interestingly, this inhibitor did not improve overall survival when compared to treatment of physician’s choice in patients with heavily pre-treated advanced breast cancer.⁴⁶ Still, patients who presented with a history of brain metastases and were treated by etirinotecan pegol had a significant reduction in the risk of death (HR 0.51; P < 0.01) versus treatment of physician’s choice.²² Moreover, the median overall survival for patients with BCBM was 10 months with etirinotecan pegol versus 4.8 months with treatment of physician’s choice.²² This emphasizes the importance of screening thoroughly and diversifying recruits in clinical trials to achieve better and more precise outcomes.

A recent phase I trial using tucatinib (HER2-specific tyrosine kinase inhibitor) with capecitabine and trastuzumab to treat patients with advanced HER2-positive metastatic breast cancer showed preliminary anti-tumor activity and acceptable toxicity.⁴⁷ Although not the focus of the trial, patients with brain metastases responded to the treatment regimen. This supports further exploration in patients with BCBM, who are frequently excluded from clinical trials.

Zacharakis et al.⁴⁸ reported the case of a patient with chemorefractory HER2+ metastatic breast cancer who was treated with tumor-infiltrating lymphocytes (TILs) reactive against mutant versions of four proteins—SLC3A2, KIAA0368, CADPS2 and CTSB. Adoptive transfer of these mutant-protein-specific TILs in conjunction with interleukin-2 and checkpoint blockade mediated the complete durable regression of metastatic breast cancer. Their finding presents a new immunotherapeutic approach for the treatment of patients with BCBM.

Recent advances in melanoma brain metastases can be insightful for developing similar therapeutic approaches in BCBM. Checkpoint blockade immunotherapy and BRAF^V600-targeted therapy trials demonstrated dramatic improvements in overall survival.⁴⁹ A recent phase II clinical trial of nivolumab combined with ipilimumab had clinically meaningful intracranial efficacy, concordant with extracranial activity, in patients with melanoma who had untreated brain metastases.⁵⁰ These findings have generated substantial promise for revolutionizing the management of patients with advanced melanoma.⁵¹ Similar strategies in patients with metastatic breast cancer to the brain, who are usually excluded from trials, can prove to be beneficial for these patients. Moreover, exploring the unique molecular features of brain metastases can allow the formulation of better targeted treatments.

Limitations

This study focused on trials that explored patients with BCBM, exclusively. We took ample precautions to avoid any bias or improper analyses by having two authors (J.F. and D.K.) revise all trials identified and the trial selection steps. Some data might be registered incorrectly and/or not up-to-date and/or missing in ClinicalTrials.gov, as described by Cihoric et al.⁴¹ Nevertheless, this analysis is distinctive and imperative as it paints a realistic image of the current status of BCBM trials and offers researchers and clinicians the opportunity to reflect upon future BCBM therapies.

Conclusion

We believe that preserving continuous flow of new treatments for BCBM is necessary. Therefore, addressing the inadequacies in past and current BCBM clinical trials is vital. The low number of trials and accrual numbers, and lack of diversity and result publication constitute major hurdles in BCBM research. Proper management of resources and time through an organized system that stops inefficient therapies and route for the advancement of effective ones is needed. Optimization of the research portfolio of BCBM is warranted.

Funding

This work was supported by: NIH grants R35CA197725 (M.S.L.), R01NS87990 (M.S.L., I.V.B.), R01NS093903 (M.S.L.), and 1R01NS096376-01A1 (A.U.A.).

Conflict of Interest: None declared

Authorship statement. JF and MSL conceived the study. JF, DK and MSL were involved in the study design. JF and DK were involved in the data collection process. All authors were involved in data analysis and preparation of the manuscript. MSL is the guarantor of the study.