HER2-positive Breast Cancer Brain Metastases Research Articles

Analysis of Breast Cancer Brain Metastases Reveals an Enrichment of Cyclin-Dependent Kinase 12 Structural Rearrangements in Human Epidermal Growth Factor Receptor 2-Positive Disease.

Genomic alterations have been identified in patients with breast cancer brain metastases (BCBMs), but large structural rearrangements have not been extensively studied. We analyzed the genomic profiles of 822 BCBMs and compared them with 11,988 local, breast-biopsied breast cancers (BCs) and 15,516 non-CNS metastases (Non-CNS M) derived from formalin-fixed paraffin-embedded material using targeted capture sequencing. Nine genes with structural rearrangements were more prevalent within BCBMs as compared with local BCs and Non-CNS M (adjusted-P < .05) and displayed a prevalence of >0.5%. The most common rearrangements within BCBMs involves cyclin-dependent kinase 12 (CDK12; 3.53%) as compared with the local BC (0.86%; adjusted-P = 7.1 × 10-8) and Non-CNS M specimens (0.68%; adjusted-P = 3.7 × 10-10). CDK12 rearrangements had a significantly higher frequency within human epidermal growth factor receptor 2 (HER2)-positive BCBMs (14.59%) compared with HER2-positive BCs (7.80%; P = 4.6 × 10-3) and HER2-positive Non-CNS M (7.87%; P = 4.8 × 10-3). The most common structural rearrangements involve CDK12 with the higher prevalence in HER2-positive BCBMs. These data support more detailed investigation of the role and importance of CDK12 rearrangements in BCBMs.

Association Between 18F-FDG PET Activity and HER2 Status in Breast Cancer Brain Metastases

PurposeThe objective of this study was to evaluate whether uptake on 18F-fluorodeoxyglucose (18F-FDG) PET could help differentiate HER2-positive from HER2-negative breast cancer brain metastases.MethodsIn this retrospective, cross-sectional study of a cohort of 14 histologically proven breast cancer brain metastases, we analyzed both preoperative 18F-FDG PET/CT and HER2 status of the resected/biopsied brain specimens. The maximum standardized uptake values (SUVmax) of the lesions were normalized to contralateral normal white matter and compared using Mann–Whitney U tests.ResultsThe study cohort was comprised of 12 women with breast cancer with a mean age of 59 years (range: 43–76 years) with a total of 14 distinct brain metastatic lesions. The SUVmax ratio of HER2-positive breast cancer brain metastases was significantly greater than that of HER2-negative lesions (3.98 vs 1.79, U = 38.00, p = 0.008).ConclusionThe SUVmax ratio may help to identify the HER2 status of breast cancer brain metastases, if validated prospectively.

CTNI-08. TUCATINIB, TRASTUZUMAB, AND CAPECITABINE WITH STEREOTACTIC RADIOSURGERY IN PATIENTS WITH BRAIN METASTASES FROM HER-2 POSITIVE BREAST CANCER (TUTOR): A MULTICENTER PHASE 1 CLINICAL TRIAL

Abstract BACKGROUND 20-40% of HER-2-positive breast cancer patients develop brain metastases (BMs), which are frequently tackled with stereotactic radiosurgery (SRS). Tucatinib, an oral HER-2 selective tyrosine kinase inhibitor (TKI), has demonstrated efficacy for HER-2-positive breast cancer in combination with capecitabine and trastuzumab. We hypothesize that a combinatorial approach for HER-2 positive breast cancer BMs (BCBM) will lead to better long-term control of BMs and systemic disease. METHODS This is an in-progress, prospective, single-arm, multicenter, phase 1 clinical trial that aims to determine the safety of combination of tucatinib, capecitabine, and trastuzumab with SRS in patients with HER-2 positive BCBM. Patients with age 18-80 years, ECOG 0-2, normal organ function, and up to 10 newly-diagnosed BMs are enrolled at six US centers. Any number of prior systemic therapies are allowed, except tucatinib and capecitabine. The primary endpoint of the study is the maximum tolerated dose (MTD) of tucatinib with SRS. This de-escalation study starts tucatinib at a dose level of 300 mg BID. Dose level -1 is 250 mg BID and level -2 is 200 mg BID. Upto 40 patients will be enrolled based on a 3 + 3 design. We plan to expand the cohort at MTD to 40 patients to assess the safety and efficacy of the combination. Secondary endpoints include efficacy as determined by response rate, intracranial PFS, extracranial PFS, and overall survival. Patients are administered oral tucatinib with SRS, followed by oral tucatinib for two weeks which is the dose-limiting toxicity (DLT) period. This is followed by tucatinib, trastuzumab, and capecitabine until progression or intolerable toxicity. DLTs are defined by Grade 3 or 4 thrombocytopenia, grade 4 anemia, grade 4 neutropenia lasting more than seven days, febrile neutropenia, and any non-hematologic toxicity of grade 3 or greater (excluding alopecia). The trial started enrollment in February 2023. Trial Information: NCT05553522.

Engineering CAR-NK cell derived exosome disguised nano-bombs for enhanced HER2 positive breast cancer brain metastasis therapy

HER2-positive breast cancer brain metastasis (HER2+ BCBM) is a refractory malignancy with a high recurrence rate and poor prognosis. The efficacies of conventional treatments, including radiation and the FDA-approved drug trastuzumab, are compromised due to their significant obstacles, such as limited penetration through the blood-brain barrier (BBB), off-target effects on HER2+ tumor cells, and systemic adverse reactions, ultimately resulting in suboptimal therapeutic outcomes. In order to address these challenges, a novel biomimetic nanoplatform was created, which consisted of a combination of chimeric antigen receptor-natural killer (CAR-NK) cell-derived exosomes (ExoCAR), and a nanobomb (referred to as Micelle). This nanoplatform, known as ExoCAR/T7@Micelle, was designed to enhance the effectiveness of antitumor treatment by disrupting ferroptosis defense mechanisms. Due to the transferrin receptor binding peptide (T7) modification and CAR expression on the exosome surface, the nanoplatform successfully traversed the blood-brain barrier and selectively targeted HER2+ breast cancer cells. Moreover, integration of the reactive oxygen species (ROS) -amplified and photodynamic therapy (PDT)-based nanobomb facilitated the spatiotemporal release of the cargos at specific sites. Upon systemic administration of ExoCAR/T7@Micelle, mice with orthotopic HER2+ BCBM demonstrated a robust antitumor response in vivo, leading to a significant extension in survival time. Furthermore, histological analyses and blood index studies revealed no discernible side effects. Collectively, this study is the first to indicate the possibility of HER2+ BCBM therapy with a CAR-NK cell-derived biomimetic drug delivery system.

464P Developing a prognostic risk stratification model and treatment options for HER2-positive breast cancer brain metastasis

464P Developing a prognostic risk stratification model and treatment options for HER2-positive breast cancer brain metastasis

JS06.5.A TUCATINIB, TRASTUZUMAB, AND CAPECITABINE WITH STEREOTACTIC RADIOSURGERY IN PATIENTS WITH BRAIN METASTASES FROM HER-2 POSITIVE BREAST CANCER (TUTOR): A MULTICENTER PHASE 1 CLINICAL TRIAL

Abstract BACKGROUND 20-40% of HER-2-positive breast cancer patients develop brain metastases (BMs), for which stereotactic radiosurgery (SRS) is used for local disease control. Tucatinib, an oral HER-2-selective tyrosine kinase inhibitor (TKI), has been demonstrated to be safe and efficacious in HER-2-positive breast cancer in combination with capecitabine and trastuzumab. The synergism between these three drugs and radiation may potentially enhance DNA damage, causing increased apoptosis. We hypothesize that this 3-drug therapy, in combination with SRS in patients with HER-2 positive breast cancer BM (BCBM), may be safe and provide superior long-term control of intracranial and systemic disease. METHODS This is a prospective, single-arm, multicenter, ongoing, phase 1 clinical trial that aims to determine the safety of the combination therapy in patients with HER-2 positive BCBM. Patients aged 18-80 years, ECOG score 0-2, normal organ function, and up to 10 newly-diagnosed BMs are being enrolled at six centers in the US. Any number of prior systemic therapies are allowed, except tucatinib and capecitabine. Key exclusion criteria include leptomeningeal metastases documented by MRI or CSF evaluation, evidence of intra-tumoral or peri-tumoral hemorrhage, and BMs within 5 mm of the optic chiasm/nerve. The primary study endpoint is maximum tolerated dose (MTD) of tucatinib with SRS. This de-escalation study starts tucatinib at a dose level of 300 mg twice daily (BID). Dose level -1 is 250 mg BID, and dose level -2 is 200 mg BID. Up to 40 patients will be enrolled in this study based on a 3 + 3 design. We plan to expand the cohort at MTD to total of 40 patients to assess the safety and efficacy of drug combination. Secondary endpoints include efficacy as determined by response rate, intracranial progression-free survival (PFS), extracranial PFS, and overall survival. Neurocognitive outcomes are being assessed by Hopkins Verbal Learning Test, Controlled Oral Word Association, Trail Making Test Part A and B, and Grooved Pegboard Test. Acute and late toxicity is assessed using CTCAE v5.0. Quality of life is assessed by Functional Assessment of Cancer Therapy, including Brain Tumor module (FACT-Br). Patients are administered oral tucatinib with SRS as per the treating radiation oncologist, followed by oral tucatinib for two weeks which is the dose-limiting toxicity (DLT) period. This is followed by tucatinib, trastuzumab, and capecitabine until progression or intolerable toxicity. DLTs are defined by Grade 3 or 4 thrombocytopenia, grade 4 anemia, grade 4 neutropenia lasting more than seven days, febrile neutropenia, and any non-hematologic toxicity of grade 3 or greater (excluding alopecia). RESULTS Patient enrollment started in February 2023. CONCLUSION Findings from this trial will demonstrate the safety and efficacy of this combination treatment in BCBM (Clinical Trial Information: NCT05553522).

Construction of a prognostic hierarchical model for patients with HER2 positive breast cancer with brain metastases.

e13030 Background: Brain metastasis occurs in about 50% of advanced HER2-positive breast cancer patients. In clinical practice, we need accurate model to predict the patients’ survival time. According to survival time, we can arrange reasonable treatment strategy for HER2 positive breast cancer with brain metastases. Methods: The study recruited HER2-positive breast cancer brain metastasis (BCBM) patients who attended the Fifth Medical Center of PLA General Hospital from June 2003 to June 2022.All statistics were performed using SPSS version 22.0 and R version 3.4.3 software. Results: This study included 300 patients with HER2-positive BCBM. The median age at Brain Metastases diagnosis was 48.5 years, and the median Brain Metastases Overall Survival time (BMOS) was 18.0 months (95% CI: 14.6-21.4). A single-factor analysis of BMOS revealed that age, number of brain metastasis lesions, number of extracranial lesions during BCBM, radiotherapy after BCBM, anti-HER2 therapy after BCBM, and survival prognosis after BCBM were associated with survival prognosis after diagnosis of BCBM. According to a multi-factor analysis, the age, the number of brain metastases, radiotherapy after BCBM, and anti-HER2 therapy after BCBM were all independent factors influencing survival after diagnosis of BCBM. Different independent prognostic factors comprised the patient hierarchical evaluation model. Patients' warning scores range from 0 to 7. We divided the patients into three groups with obvious differences in prognosis： Low- intermediate-risk (score≥1), stroke group (score≥3) and high-risk group (score≥6). The patient prognosis was worse when the warning score was high. The results of Kaplan-Meier survival curve analysis showed significant prognosis differences between the three groups of patients (P &lt; 0.0001). The mean Area Under Curve of the receiver operating characteristic curve for 1-yeasr, 2-year, and 3-year prognosis prediction was 0.69,0.71, and 0.67, respectively. For low-risk patients, the prognosis was significantly improved by using any anti-HER2 medications (P&lt;0.05). Trastuzumab + Pertuzumab can significantly improve the prognosis of patients at intermediate risk (P&lt;0.001, HR=0.24,95%CI: 0.13-0.43). Patients in the intermediate-risk group received both anti-HER2 medication and combined radiotherapy significantly prolonged BMOS in patients who received only drug therapy or radiotherapy (P=0.0132). Conclusions: A survival and prognostic stratification model was constructed based on the clinicopathological characteristics and treatment pattern of a large cohort of HER2-positive breast cancer patients with brain metastases, and the patients were divided into the low-risk group, intermediate-risk group and high-risk group. The optimal individualized treatment strategy was recommended according to different groups.

Pyrotinib maleate for the treatment of brain metastases from HER2-positive solid tumours: A real-world study.

e13041 Background: Pyrotinib maleate is a small molecule, irreversible inhibitor of HER1, HER2 and HER4 tyrosine kinases developed in China. A number of clinical studies have confirmed the good efficacy in treating patients with HER2-positive solid tumours and HER2-positive breast cancer brain metastases. In this study, we ulteriorly explore the curative effect and safety of pyrotinib in HER2-positive solid tumours brain metastases treatment. Methods: Clinical data from 53 patients with HER2-positive solid tumor brain metastases enrolled were compiled and analyzed. The impact of whether pyrrolizidine was combined with chemotherapy, a large molecule TKI, and intracranial local radiotherapy on PFS and intracranial PFS in the enrolled patients is somewhat outlined. Results: From June 2021 to December 2022, according to 53 patients with HER2-positive solid tumor brain metastases availably measured intracranial metastases meeting RECIST 1.1 criteria at baseline, with the dosing regimen based on pyrotinib and the combination or intracranial radiation therapy following the clinician's choice. The recorded patients included 49 patients with breast cancer, 2 patients with lung adenocarcinoma, and 1 patient with gastric cancer. A total of 37 patients were HER2-positive by immunohistochemistry, 4 patients were HER-positive by genetic testing, 9 patients were HER2-positive by fluorescence in situ hybridization, and the remaining 3 patients had unknown HER2 status. A total of 27 patients had one or more radiation treatments for intracranial metastases, 39 patients with treatment regimens combining chemotherapy with pyrotinib, and 19 patients with combination of large molecule TKI. The selected 53 patients base in the study, had disease progression due to new intracranial metastases or enlarged intracranial metastases in 42. The mPFS was 12 months for all patients and 13 months for intracranial metastases. Further collated analysis has shown there was no significant difference in mPFS between subgroups according to age, method of HER2 detection, lines of therapy, whether or not combined with chemotherapy, and possibility of combining with large molecule TKI therapy. There was a remarkable difference in PFS between the combined intracranial radiation therapy group and the non-combined intracranial radiation therapy group (14.6 months vs. 11.4 months, p = 0.042). There was also a significant variance in intracranial PFS between the combined intracranial radiation treatment group and the non-combined intracranial radiation treatment group (15.8 months vs. 12.0 months, p = 0.023). Conclusions: Pivotally, pyrotinib has shown good clinical efficacy in patients with HER2-positive solid tumor brain metastases. The results of this study suggest that early intervention with intracranial local radiation therapy is utterly essential for HER2-positive patients with brain metastases at baseline.

Tyrosine kinase inhibitors in HER2-positive breast cancer brain metastases: A systematic review and meta-analysis.

Small tyrosine kinase inhibitors (TKIs) show activity against breast cancer brain metastases (BCBM) of the human epidermal growth factor receptor 2 (HER2)-positive subtype. This meta-analysis aimed to objectively explore the efficacy and safety of TKIs. Electronic databases were searched for relevant clinical trials. We conducted a pairwise meta-analysis, pooled analysis, and estimated summary survival curves to compare survival outcomes following TKIs therapy for BCBM patients using Stata version 16.0 or R x64 4.0.5. Thirteen clinical trials involving 987 HER2-positive BCBM patients were analyzed. A trend of longer progression-free survival (PFS) was observed in the TKI-containing arm compared to the non-TKI-containing arm (hazard ratio = 0.64, 95% confidence interval [CI]: 0.35-1.15, p = 0.132), although the difference is not statistically significant. Summary survival curves reported the summary median PFS and overall survival were 7.9 months and 12.3 months. Subgroup analysis revealed that TKIs combined with capecitabine (TKI + Cap) regimens resulted in improved survival outcomes. Tucatinib may be more effective in BCBM patients. The main grade 3-5 adverse events (AEs) were diarrhea (22%, 95% CI: 14%-32%), neutropenia (11%, 95% CI: 5%-18%), hepatic toxicity (7%, 95% CI: 1%-16%), and sensory neuropathy (6%, 95% CI: 2%-12%). TKIs therapy improved the survival outcomes of HER2-positive BCBM patients, especially when combined with capecitabine and tolerable AEs. We also identified the clinical value of tucatinib, which appears to be the most favorable TKI drug for BCBM patients.

Abstract P1-11-03: VRN101099, Brain Permeable HER2 Kinase Inhibitor, Shows the Anti-tumor Activity in Preclinical Models of HER2-positive Cancers

Abstract The brain is a common target organ for breast cancer metastasis, and the risk of brain metastasis is usually high for patients with HER2-positive breast cancer. While T-DXd showed positive results in HER2-positive breast cancer brain metastasis (BCBM), its activity and blood-brain barrier (BBB) permeability in active BCBM need to be further validated (TUXEDO-1 included 15 patients with active brain metastasis). Tucatinib plus Trastuzumab and Capecitabine triplet showed efficacy in patients with brain metastasis, but Tucatinib alone has poor BBB penetration. There is still an unmet medical need for active HER2-positive BCBM. VRN101099 is a highly selective kinase inhibitor of HER2 (Eurofins scanMAX Kinase Profiling, S-score (35) of 0.01). VRN101099 has single- to double-digit nanomolar (IC50) cellular potency in HER2-dependent cancer cells, and Ba/F3 cells expressing HER2 wild type or mutations with selectivity over wildtype EGFR. VRN101099 inhibited proliferation of BT474 with 3.6 nM IC50 but HaCaT with 829.2 nM IC50. VRN101099 binds HER2 kinase by forming a covalent bond to the Cys805 and its irreversible inhibition resulted in a longer target resident time than Tucatinib, confirmed by in vitro washout experiments. Robust in vivo activity of VRN101099 was observed in HER2-positive BT474 xenograft models. Moreover, once daily oral administration of VRN101099 significantly regressed intracranial BT474 tumor, demonstrating greater efficacy than twice daily oral administration of Tucatinib. These results were well explained by the superior brain to plasma exposure of VRN101099 to Tucatinib. Also, VRN101099 showed high exposure in the target organ, the fat pad, which potentiated better clinical translation. These anti-tumor efficacies are correlated with pharmacodynamic responses, as confirmed by decreased HER2, AKT, and ERK phosphorylation. In summary, VRN101099 is a brain penetrant, orally bioavailable, irreversible, and highly selective inhibitor of HER2 with therapeutic potential in HER2-positive BCBM. These data support the clinical development of VRN101099 in HER2-driven cancers. Citation Format: Yikyung Ko, Jihye yoo, Hong-ryul Jung, Hyerim Lim, YeongDeok Lee, Se Hyuk Kim, Dong Guk Shin, Serin Cho, Myung hoe Heo, Haelee Kim, Ha Yeon Cho, Ah Reum Han, Eunhwa Ko, Hwan Geun Choi, Deakwon Kim, Sunghwan Kim. VRN101099, Brain Permeable HER2 Kinase Inhibitor, Shows the Anti-tumor Activity in Preclinical Models of HER2-positive Cancers [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-11-03.

Association of Relative Cerebral Blood Volume from Dynamic Susceptibility Contrast-Enhanced Perfusion MR with HER2 Status in Breast Cancer Brain Metastases

With the development of HER2-directed therapies, identifying non-invasive imaging biomarkers of HER2 expression in breast cancer brain metastases has become increasingly important. The purpose of this study was to investigate whether relative cerebral blood volume (rCBV) from dynamic susceptibility contrast-enhanced (DSC) perfusion MR could help identify the HER2 status of breast cancer brain metastases. With IRB approval for this HIPAA-compliant cross-sectional study and a waiver of informed consent, we queried our institution's electronic medical record to derive a cohort of 14 histologically proven breast cancer brain metastases with preoperative DSC perfusion MR and HER2 analyses of the resected/biopsied brain specimens from 2011-2021. The rCBV of the lesions was measured and compared using Mann-Whitney tests. Receiver operating characteristic analyses were performed to evaluate the performance of rCBV in identifying HER2 status. The study cohort was comprised of 14 women with a mean age of 56 years (range: 32-81 years) with a total of 14 distinct lesions. The rCBV of HER2-positive breast cancer brain metastases was significantly greater than the rCBV of HER2-negative lesions (8.02 vs 3.97, U=48.00, p=0.001). rCBV differentiated HER2-positive lesions from HER2-negative lesions with an area under the curve of 0.98 (standard error=0.032, p<0.001). The accuracy-maximizing rCBV threshold (4.8) was associated with an accuracy of 93% (13/14), a sensitivity of 100% (7/7), and a specificity of 86% (6/7). rCBV may assist in identifying the HER2 status of breast cancer brain metastases, if validated in a large prospective trial.

Pyrotinib combining with radiotherapy on breast cancer with brain metastasis.

With the extensive application of anti-human epidermal growth factor receptor-2 (HER2) targeted therapy, the prognosis of HER2-positive breast cancer brain metastasis (BCBM) has been improved greatly. Due to the lack of prospective randomized controlled studies; however, the treatment of active brain metastasis (BM) remains a difficulty in clinic. Based upon the retrospective studies, an effective approach of radiotherapy combined with pyrotinib in HER2-positive BCBM treatment was investigated in present research. In all, 29 patients who had active BM in HER2-positive breast cancer (BC) and underwent whole-brain radiotherapy (WBRT) combined with pyrotinib from January 2019 to May 2021 were enrolled. The progression-free survival (PFS), overall survival (OS), clinical benefit rate (CBR), objective response rate (ORR), and drug-related adverse events (AEs) were analyzed among patients undergoing WBRT combined with concurrent or sequence pyrotinib + capecitabine. After the systematic treatments using WBRT combined with pyrotinib + capecitabine, the mPFS and mOS of BM patients were 6.5 months and 15.5 months, respectively. PFS (7.2 vs 6.2 months, p = 0.038) and OS (19.0 vs 14.0 months, p = 0.014) were longer after sequence treatments than those after concurrent treatment. The central nervous system (CNS) ORR of sequence treatment was superior to that of concurrent treatment (80.4% vs 58.6%, p < 0.05). Vomiting (17.2%) and diarrhea (10.3%) were the most common adverse reactions ⩾ grade 3. WBRT combined with pyrotinib is safe and effective for the treatments of active BM in HER2-positive BC. WBRT combined with sequence pyrotinib + capecitabine is more effective and less toxic than concurrent treatment. Therefore, sequence treatment is potentially a preferred regimen for patients with active BM in HER2-positive BC. The size and number of BM lesions, presence or absence of hepatic metastasis, and combination mode of radiotherapy and targeted therapy are independent risk factors for active BM prognosis.

281MO Quality of life and neurocognitive function in patients with active brain metastases of HER2-positive breast cancer treated with trastuzumab-deruxtecan: Secondary endpoint analysis of the prospective single-arm phase II TUXEDO-1 trial

Maintaining quality-of-life (QoL) and neurocognitive function is a main goal in the setting of brain metastases (BM) in HER2-positive breast cancer (BC) patients (pts). TUXEDO-1 investigated QoL and neurocognitive function during trastuzumab-deruxtecan (T-DXd) therapy in HER2-positive BC BM pts. TUXEDO-1 is a prospective, open-label, single-arm phase II trial and enrolled adult HER2-positive BC pts with newly diagnosed BM or progressive BM with no immediate need for local therapy. T-DXd was administered every three weeks at standard dose until disease progression, unacceptable side-effects or consent withdrawal. A secondary endpoint of the trial was QoL and pts completed the EORTC QLQ-C30 questionnaire at cycle 1, 3, 5 and every 9 weeks thereafter. A final assessment was performed at first survival follow-up three months after end-of-treatment. Linear mixed-effect models were used to analyze changes in QoL scores (sub-domains global QoL score, cognitive/emotional/physical function scores; scores range from 0-100) over time (slope). TUXEDO-1 is registered with EU Clinical Trials Register (EudraCT 2020-000981-41) and ClinicalTrials.gov (NCT04752059) and enrollment is closed. Fifteen pts (14 females, 1 male; 12/15 luminal B) were enrolled and received at least one dose of T-DXd. Median age at inclusion was 69 (range 30-76) years. Pts received a median of two (range 1-5) prior systemic therapies for metastatic BC and 9/15 (60%) pts received prior local therapy (whole brain radiotherapy, stereotactic radiotherapy or neurosurgery) for BM. Neurologic symptoms at inclusion were present in 6/15 (40%) of pts. Median follow-up time was 11 months. The QLQ-C30 global QoL (slope -0.13 per follow-up visit, p=0.953), the physical (0.52, p=0.363), emotional (-0.24, p=0.835) as well as the cognitive functioning scores (-0.79, p=0.429) were all maintained over the duration of T-DXd therapy. TUXEDO-1 showed maintained QoL and neurocognitive function during T-DXd therapy in HER2-positive BC BM pts. Our data support first-line systemic therapy with T-DXd in pts with active BM.

Comparative Efficacy of Tyrosine Kinase Inhibitors and Antibody-Drug Conjugates in HER2-Positive Metastatic Breast Cancer Patients with Brain Metastases: A Systematic Review and Network Meta-Analysis.

Simple SummaryComparisons between the efficacy of tyrosine kinase inhibitors (TKIs) and antibody–drug conjugates (ADCs) in treating HER2-positive breast cancer brain metastasis (BCBM) patients have not previously been conducted. We performed a systematic review and Bayesian-based network meta-analysis to pool the estimates of progression-free survival, overall survival, and incidence of central nervous system (CNS) disease progression. The current study indicated that both T-DXd and T-DM1 presented better efficacy than TKIs regarding survival outcomes. Treatments containing neratinib or T-DM1 tended to rank the best in reducing the recurrent rate of CNS. Our study provides more evidence for the clinical decision making for patients with HER2-positive BCBM. More high-quality studies with standardized entry criteria and comparable CNS-related endpoints are warranted in the future.HER2-positive breast cancer brain metastasis (BCBM) is an important clinical problem. A systematic review and network meta-analysis were conducted to compare the efficacy of tyrosine kinase inhibitors (TKIs) and antibody–drug conjugates (ADCs), two categories of emerging agents in this field. We implemented a comprehensive literature search of PubMed, Embase, the Cochrane Library, ClinicalTrials.gov, and abstracts of oncology conferences. A network meta-analysis following Bayesian approaches was performed. Pooled hazard ratios (HRs) and odds ratios (ORs) with credible intervals (CrIs) were calculated to estimate progression-free survival (PFS), overall survival (OS), and the incidence of central nervous system (CNS) disease progression. Sixteen studies were included. Pairwise comparisons of PFS showed salient divergency between T-DXd and the physician’s choice of treatment (HR 0.17; 95% CrI 0.03–0.82) or afatinib (HR 0.14; 95% CrI 0.02–1.00). T-DXd and T-DM1 ranked first regarding PFS and OS, respectively, followed by TKI-containing regimens. The incidence of CNS disease progression was analyzed separately according to baseline BCBM status, among which neratinib-containing regimens were most likely to rank the best. In conclusion, ADCs including T-DXd and T-DM1 showed better efficacy than TKIs in the survival outcomes for HER2-positive BCBM patients. Treatments based on neratinib or T-DM1 revealed favorable results in reducing the recurrent rate of CNS.

Homogeneity of antibody-drug conjugates critically impacts the therapeutic efficacy in brain tumors.

SUMMARYGlioblastoma multiforme (GBM) is the most aggressive and fatal disease of all brain tumor types. Most therapies rarely provide clinically meaningful outcomes in the treatment of GBM. Although antibody-drug conjugates (ADCs) are promising anticancer drugs, no ADCs have been clinically successful for GBM, primarily because of poor blood-brain barrier (BBB) penetration. Here, we report that ADC homogeneity and payload loading rate are critical parameters contributing to this discrepancy. Although both homogeneous and heterogeneous conjugates exhibit comparable in vitro potency and pharmacokinetic profiles, the former shows enhanced payload delivery to brain tumors. Our homogeneous ADCs provide improved antitumor effects and survival benefits in orthotopic brain tumor models. We also demonstrate that overly drug-loaded species in heterogeneous conjugates are particularly poor at crossing the BBB, leading to deteriorated overall brain tumor targeting. Our findings indicate the importance of homogeneous conjugation with optimal payload loading in generating effective ADCs for intractable brain tumors.

Evolving management of HER2+ breast cancer brain metastases and leptomeningeal disease.

Patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer are at a particularly high risk of breast cancer brain metastasis (BCBM) and leptomeningeal disease (LMD). Improvements in systemic therapy have translated to improved survival for patients with HER2-positive BCBM and LMD. However, the optimal management of these cases is rapidly evolving and requires a multidisciplinary approach. Herein, a team of radiation oncologists, medical oncologists, neuro-oncologists, and breast surgeon created a review of the evolving management of HER2-positive BCBM and LMD. We assess the epidemiology, diagnosis, and evolving treatment options for patients with HER2-positive BCBM and LMD, as well as the ongoing prospective clinical trials enrolling these patients. The management of HER2-positive BCBM and LMD represents an increasingly common challenge that involves the coordination of local and systemic therapy. Advances in systemic therapy have resulted in an improved prognosis, and promising targeted therapies currently under prospective investigation have the potential to further benefit these patients.

Abstract P2-13-15: VRN101396, a brain-permeable HER2 inhibitor, shows the anti-tumor activity in preclinical HER2-positive cancer models

Abstract Breast cancer (BC) is the second most common cancer associated with brain metastasis (BM) and among patients with breast cancer brain metastasis (BCBM), human epidermal growth factor receptor 2 (HER2)-positive breast cancer is most likely to develop BM. The overall prognosis of HER2-positive BCBM remains dismal with median survival time after BM of less than a year. Drugs like T-DM1, T-DXd and Tucatinib are reported to deliver a progression-free survival benefit in HER2-positive BCBM patients, but there are still unmet needs for a drug that crosses the blood brain barrier more effectively. We develop VRN101396, a brain penetrant, orally available, and irreversible small molecule inhibitor targeting HER2 to offer a new therapeutic option for the treatment of HER2-positive BCBM. VRN101396 potently inhibits catalytic activity of HER2 but spares wild-type EGFR. In HER2-positive breast cancer cell lines BT474 and SK-BR3 and gastric cancer cell line NCI-N87, VRN101396 inhibited the cell proliferation and phosphorylation of HER2 with single- or double-digit nanomolar IC50 values while inhibiting wild type EGFR with an IC50 value of &amp;gt;100 nM. In both subcutaneous and intracranial efficacy mouse models, once-daily oral dose of VRN101396 significantly inhibited tumor growth and achieved tumor regression. In N87 subcutaneous xenograft model, VRN101396 alone showed superior efficacy to the combination of Tucatinib and Trastuzumab. Additionally, in intracranial xenograft model, VRN101396 showed superior efficacy to Tucatinib. Pharmacokinetics of VRN101396 displayed higher brain exposure than tucatinib and lapatinib, indicating better target engagement in the brain. Pharmacodynamic analysis revealed that VRN101396 reduced phosphorylation of HER2, HER3, AKT, and ERK compared to vehicle group after administration up to 24 hours. In conclusion, VRN101396 is a therapeutic candidate for the treatment of HER2-positive BC, BCBM and gastric cancer. Citation Format: Hong-ryul Jung, Sunghwan Kim, Jihye Yoo, Chan mi Park, Somi Lee, Hyoju Lee, Youngyi Lee, Jinhee Park, Kyungah Seo, Dong-Hyuk Seo, Eunhwa Ko, Jung Beom Son, Deakwon Kim, Hwan Geun Choi, Nam Doo Kim. VRN101396, a brain-permeable HER2 inhibitor, shows the anti-tumor activity in preclinical HER2-positive cancer models [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-13-15.

Performance of enhancement on brain MRI for identifying HER2 overexpression in breast cancer brain metastases

PurposeTo investigate whether enhancement on MRI could help identify HER2 overexpression in breast cancer brain metastases. MethodsWe derived a cohort of 38 histologically proven breast cancer brain metastases with preoperative contrast-enhanced brain MRI and HER2 fluorescent in-situ hybridization of the resected/biopsied brain specimens from 2018 to 2021. Enhancement of the lesions was measured and compared using t-tests. Receiver operating characteristic and logistic regression analyses were performed to evaluate the performance of MRI enhancement in identifying HER2 overexpression. ResultsThe study cohort was comprised of 29 women with a mean age of 55 years (range: 31–81 years) with a total of 38 distinct lesions. The HER2-positive subcohort was comprised of 17 patients, while the HER2-negative subcohort was comprised of 13 patients. The percent signal intensity change (PSIC) of HER2-positive breast cancer brain metastases was significantly greater than that of HER2-negative lesions (310 v. 153, P = 0.002). The PSIC differentiated HER2-positive lesions from HER2-negative lesions with an area under the curve of 0.88 (P < 0.001). In a model controlling for lesion size, lesion location, tumor grade, patient age, scanner magnetic field strength, and contrast agent, the PSIC had an accuracy of 92% (35/38), sensitivity of 96% (23/24), and specificity of 86% (12/14) in differentiating HER2-positive lesions from HER2-negative lesions. ConclusionEnhancement on MRI may assist in identifying HER2 overexpression in breast cancer brain metastases, if validated prospectively.

Trastuzumab Emtansine (T-DM1) and stereotactic radiation in the management of HER2+ breast cancer brain metastases

BackgroundDue to recent concerns about the toxicity of trastuzumab emtansine (T-DM1) with stereotactic radiation, we assessed our institutional outcomes treating HER2-positive breast cancer brain metastases (BCBM) with T-DM1 and stereotactic radiation.MethodsThis is a single institution series of 16 patients with HER2-positive breast cancer who underwent 18 stereotactic sessions to 40 BCBM from 2013 to 2019 with T-DM1 delivered within 6 months. The Kaplan-Meier method was used to calculate overall survival (OS), local control (LC), distant intracranial control (DIC), and systemic progression-free survival (sPFS) from the date of SRS. A neuro-radiologist independently reviewed follow-up imaging.ResultsOne patient had invasive lobular carcinoma, and 15 patients had invasive ductal carcinoma. All cases were HER2-positive, while 10 were hormone receptor (HR) positive. Twenty-four lesions were treated with stereotactic radiosurgery (SRS) to a median dose of 21 Gy (14–24 Gy). Sixteen lesions were treated with fractionated stereotactic radiation (FSRT) with a median dose of 25 Gy (20-30Gy) delivered in 3 to 5 fractions. Stereotactic radiation was delivered concurrently with T-DM1 in 19 lesions (48%). Median follow up time was 13.2 months from stereotactic radiation. The 1-year LC, DIC, sPFS, and OS were 75, 50, 30, and 67%, respectively. There was 1 case of leptomeningeal progression and 1 case (3%) of symptomatic radionecrosis.ConclusionsWe demonstrate that stereotactic radiation and T-DM1 is well-tolerated and effective for patients with HER2-positive BCBM. An increased risk for symptomatic radiation necrosis was not noted in our series.

Favourable outcome of patients with breast cancer brain metastases treated with dual HER2 blockade of trastuzumab and pertuzumab.

Background:Dual human epidermal growth factor receptor 2 (HER2) blockade with trastuzumab and pertuzumab (TP) is a standard therapy of metastatic and localized HER2-positive breast cancer (BC), but its activity in breast cancer brain metastases (BCBM) is unknown.Methods:Patients with HER2-positive BCBM were identified from the Vienna Brain Metastasis Registry and clinical data including patient characteristics, therapies and overall survival (OS) were obtained. Patients were grouped into ‘TP’, ‘other-HER2-targeted therapy’ and ‘no-HER2-targeted therapy’ according to received first-line systemic therapy after diagnosis of BCBM. Radiological re-assessment of intracranial lesions was performed in patients treated with TP as systemic first-line therapy according to RANO response criteria for brain metastases (BM).Results:A total of 252 HER2-positive BC patients with BM were available for this analysis. Patients treated with TP as systemic first-line therapy after diagnosis of BM had a significantly longer OS compared with treatment with other-HER2-targeted therapy and no-HER2-targeted therapy (44 versus 17 versus 3 months, p < 0.001; log-rank test). Among radiologically re-assessed patients treated with TP as systemic first-line therapy after diagnosis of BM, 5/14 patients (35.7%) had complete intracranial remission (CR), 8/14 patients (57.1%) partial intracranial remission (PR), 1/14 patients (7.1%) stable intracranial disease (SD) and 0/14 patients (0.0%) progressive intracranial disease (PD) as best response resulting in an intracranial objective response rate (iORR) of 92.9% and an intracranial clinical benefit rate (iCBR) of 100.0%.Conclusion:First-line therapy with dual HER2-inhibition of TP after BM diagnosis was associated with the longest median OS times in patients with BCBM.