Impact of systemic disease on CNS disease control after stereotactic radiosurgery to breast cancer brain metastases (The SYBRA Study).

The objective of the study is to assess impact of systemic disease (SD) status on overall survival and brain metastasis (BM) control, adopting a novel landmark approach to categorize SD among breast cancer (BC) patients. This single institution retrospective study included BCBM patients who have received stereotactic radiosurgery (SRS) to brain. Separate endpoints [CNS failure-free survival (cFFS), overall survival (OS)] were analyzed from each Landmark (LM): LM1 (3-months), LM2 (6-months). Patients were categorized into early and non-early progression (EP, NEP) groups depending on SD status before LMs. Median survivals from LM were assessed with Kaplan Meier plots, compared with Log-Rank test. EP was associated with worse median cFFS and OS vs NEP in both LM analyses (cFFS- LM1: 3.6 vs. 9.7 months, p = 0.0016; LM2: 2.3 vs. 12.5 months, p < 0.0001; OS- LM1: 3.6 vs. 24.3 months, p < 0.0001; LM2: 5.3 vs. 30.2 months, p < 0.0001). In multivariate analyses, EP was associated with shorter cFFS [LM1: Hazard Ratio (HR) with 95% confidence interval (CI) 3.16, 1.46-6.83, p = 0.0034; LM2: 5.32, 2.33-12.15, p = <0.0001] and shorter OS (LM1: HR with 95% CI 4.28, 1.98-9.12, p = 0.0002; LM2: 7.40, 3.10-17.63, p = <0.0001) vs NEP. Early systemic disease progressions after 1st SRS to brain is associated with worse cFFS and OS in patients with BCBM.

A Phase I Trial of Alpelisib Combined With Capecitabine in Patients With HER2-Negative Metastatic Breast Cancer.

BACKGROUND: Alpelisib is an oral α-specific class I PI3K inhibitor approved in combination with fulvestrant for the treatment of PIK3CA-mutated hormone receptor-positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) metastatic breast cancer. The tolerability of this drug with the oral chemotherapy capecitabine is unknown. PATIENTS AND METHODS: This phase I trial evaluated the dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of alpelisib (250 mg or 300 mg daily for 3-weeks) with capecitabine (1000 mg/m2 twice daily for 2-weeks followed by a 1-week rest period) in patients with metastatic HER2-negative breast cancer, regardless of PIK3CA mutation status. RESULTS: Eighteen patients were treated with alpelisib-capecitabine. Half of the patients had HR+ breast cancer, and 16 had prior systemic therapy for metastatic disease. The MTD of alpelisib was 250 mg daily in combination with capecitabine 1000 mg/m2 twice daily. DLTs included hyperglycemia, QTc prolongation, fatigue, and chest pain. The most common grade 3 adverse event (AE) was hyperglycemia (28%). No grade 4 AEs were observed. Three patients discontinued therapy due to an AE. One-third of patients required dose reduction of both alpelisib and capecitabine. Four patients experienced a partial response and 8 patients experienced stable disease. The median progression-free survival was 9.7 months (95% CI 2.8-13.5 months) and median overall survival was 18.2 months (95% CI 7.2-35.2 months). Twelve patients had PIK3CA mutation testing completed, of these 2 had known or likely deleterious PIK3CA mutation. CONCLUSION: This study provides safety data for an oral combination therapy of alpelisib-capecitabine and defines tolerable doses for further study.

Atopy improves survival and decreases risk of brain metastasis in cutaneous melanoma.

Importance: Development of new therapies in melanoma has increased survival, and as a result more patients are living to develop brain metastasis (BrM). Identifying patients at increased risk of BrM is therefore of significant public health importance. Objective: To determine whether history of atopy is associated with improved survival or reduced incidence of BrM in cutaneous melanoma. Design: A retrospective cohort study conducted from June 2022 to March 2024. Setting: Population-based in states with Surveillance, Epidemiology and End Results (SEER) supported cancer registries. Participants: Individuals (≥65 years) diagnosed with cutaneous melanoma between January 1, 2008 and December 31, 2017 that are participants in traditional Medicare. Exposures: Individuals were compared that had history of atopy (allergic rhinitis, atopic dermatitis, asthma, and/or allergic/atopic conjunctivitis) diagnosed prior to melanoma diagnosis, ascertained using ICD-9 or ICD-10 codes in Medicare claims. Main Outcomes and Measures: Primary endpoints were diagnosis with a BrM or death during the follow-up period. Associations between atopy and endpoints were assessed using cox proportional hazards models to estimate hazard ratios (HR) and p-values. Results: A total of 29,956 cutaneous melanoma cases were identified (median age 76, 60% male and 97% non-Hispanic White). Overall, 7.1% developed BrM during follow up. Among the 35% that had history of atopy, the most common condition was atopic dermatitis (19%). After adjustment for demographic and prognostic factors, atopy was associated with a 16% decrease in death (HR=0.84 [95%CI:0.80-0.87], pFDR<0.001). Among those with non-metastatic disease at time of diagnosis, atopy conferred a 15% decrease in cumulative incidence BrM (HR=0.85 [95%CI: 0.76-0.94], pFDR=0.006), with a 25% decrease associated with atopic dermatitis (HR=0.75 [95%CI:0.65-0.86], pFDR<0.001). Among those with metastatic disease at diagnosis (any metastatic site), only those who received immune checkpoint inhibitors had a survival benefit associated with atopy (HR=0.31, [95%CI:0.15-0.64], p=0.001 vs HR=1.41, [95%CI:0.87-2.27], p=0.165). Conclusions and Relevance: Atopy, particularly atopic dermatitis, was significantly associated with improved survival and decreased incidence of BrM. The improved survival associated with these conditions in the context of immunotherapy suggests that these conditions in the elderly may identify those with more robust immune function that may be more responsive to treatment.

Unique genomic alterations in the circulating tumor DNA of patients with solid tumors brain metastases.

Background: Although serum circulating tumor DNA (ctDNA) is routine, data from patients with brain metastases (BrMs) is limited. We assessed genomic alterations in ctDNA from patients with solid tumor BrMs in 3 groups: Isolated BrMs with stable extracranial disease (iCNS), concurrent brain and extracranial progression (cCNS), and extracranial progression with no active BrMs (eCNS). We also compared ctDNA alterations between patients with and without BrMs. Methods: Patients with a Guardant360 ctDNA profile with (n = 253) and without BrMs (n = 449) from the Duke Molecular Registry between January 2014 and December 2020 were identified. Actionable alterations were defined as FDA-recognized or standard-of-care biomarkers. Disease status was determined via investigator assessment within 30 days of ctDNA collection. Results: Among the 253 patients with BrMs: 29 (12%) had iCNS, 160 (63%) cCNS, and 64 (25%) eCNS. Breast (BC; 12.0%) and non-small cell lung cancer (NSCLC; 76.4%) were the most common tumor types. ESR1 (60% vs 25%, P < .001) and BRCA2 (17% vs 5%, P = .022) were more frequent in BC BrMs. In NSCLC BrMs, EGFR alterations were most frequent in the iCNS group (iCNS: 67%, cCNS: 40%, eCNS:37%, P = .08) and in patients with BrMs (36% vs 17%, P < .001). Sequencing from both brain tissue and ctDNA were available for 8 patients; 7 (87.5%) had identical alterations. Conclusions: This study illustrates the feasibility of detecting alterations from ctDNA among patients with BrMs. A higher frequency of actionable mutations was observed in ctDNA in patients with BrMs. Additional studies comparing ctDNA and alterations in BrMs tissue are needed to determine if ctDNA can be considered a surrogate to support treatment decisions.

Triple Negative Breast Cancer and Brain Metastases.

The treatment of metastatic breast cancer (MBC) has improved over the past decade, however prognosis continues to be mitigated by the fact that about 1 in 5 patients with MBC will develop brain metastases (BrM) during their metastatic disease course. 1 This number is even higher for patients with triple-negative breast cancer (TNBC), with studies showing as high as 40% of patients developing BrM. 2, 3 Studies have shown that TNBC portends a worse survival after a diagnosis of BrM compared with non-TNBC subtypes. 4 Given the unique location and biologic properties of BrM, treatment options have historically been limited. Challenges to the treatment of TNBC BrM include a lack of targeted therapies and difficulties in delivery of drug to the brain past the blood-brain barrier (BBB). Herein, we will review the advances in local and systemic therapies to most effectively treat patients with TNBC BrM, including therapies on the horizon currently in clinical trials.

National Cancer Institute Collaborative Workshop on Shaping the Landscape of Brain Metastases Research: challenges and recommended priorities.

Brain metastases are an increasing global public health concern, even as survival rates improve for patients with metastatic disease. Both metastases and the sequelae of their treatment are key determinants of the inter-related priorities of patient survival, function, and quality of life, mandating a multidimensional approach to clinical care and research. At a virtual National Cancer Institute Workshop in September, 2022, key stakeholders convened to define research priorities to address the crucial areas of unmet need for patients with brain metastases to achieve meaningful advances in patient outcomes. This Policy Review outlines existing knowledge gaps, collaborative opportunities, and specific recommendations regarding consensus priorities and future directions in brain metastases research. Achieving major advances in research will require enhanced coordination between the ongoing efforts of individual organisations and consortia. Importantly, the continual and active engagement of patients and patient advocates will be necessary to ensure that the directionality of all efforts reflects what is most meaningful in the context of patient care.

Efficacy of a Dual-Epitope Dendritic Cell Vaccine as Part of Combined Immunotherapy for HER2-Expressing Breast Tumors.

Previous work from our group and others has shown that patients with breast cancer can generate a T cell response against specific human epidermal growth factor 2 (HER2) epitopes. In addition, preclinical work has shown that this T cell response can be augmented by Ag-directed mAb therapy. This study evaluated the activity and safety of a combination of dendritic cell (DC) vaccination given with mAb and cytotoxic therapy. We performed a phase I/II study using autologous DCs pulsed with two different HER2 peptides given with trastuzumab and vinorelbine to a study cohort of patients with HER2-overexpressing and a second with HER2 nonoverexpressing metastatic breast cancer. Seventeen patients with HER2-overexpressing and seven with nonoverexpressing disease were treated. Treatment was well tolerated, with one patient removed from therapy because of toxicity and no deaths. Forty-six percent of patients had stable disease after therapy, with 4% achieving a partial response and no complete responses. Immune responses were generated in the majority of patients but did not correlate with clinical response. However, in one patient, who has survived >14 y since treatment in the trial, a robust immune response was demonstrated, with 25% of her T cells specific to one of the peptides in the vaccine at the peak of her response. These data suggest that autologous DC vaccination when given with anti-HER2-directed mAb therapy and vinorelbine is safe and can induce immune responses, including significant T cell clonal expansion, in a subset of patients.

Available Systemic Treatments and Emerging Therapies for Breast Cancer Brain Metastases.

OPINION STATEMENT: In 2023, breast cancer brain metastases (BCBrM) remain a major clinical challenge gaining well-deserved attention. Historically managed with local therapies alone, systemic therapies including small molecule inhibitors and antibody-drug conjugates (ADCs) have shown unprecedented activity in recent trials including patients with brain metastases. These advancements stem from efforts to include patients with stable and active BCBrM in early- and late-phase trial design. Tucatinib added to trastuzumab and capecitabine improves intracranial and extracranial progression-free survival and overall survival in stable and active human epidermal growth factor receptor 2 (HER2+)-positive brain metastases. Trastuzumab deruxtecan (T-DXd) has both shown impressive intracranial activity in stable and active HER2+ BCBrMs challenging historical thinking of ADCs' inability to penetrate the central nervous system (CNS). T-DXd has shown potent activity in HER2-low (immunohistochemistry scores of 1+ or 2+, non-amplified by fluorescence in situ hybridization) metastatic breast cancer and will be studied in HER2-low BCBrM as well. Novel endocrine therapies including oral selective estrogen downregulators (SERDs) and complete estrogen receptor antagonists (CERANs) are being studied in hormone receptor-positive BCBrM clinical trials due to robust intracranial activity in preclinical models. Triple-negative breast cancer (TNBC) brain metastases continue to portend the worst prognosis of all subtypes. Clinical trials leading to the approval of immune checkpoint inhibitors have enrolled few BCBrM patients leading to a lack of understanding of immunotherapies contribution in this subgroup. Data surrounding the use of poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors in patients with germline BRCA mutation carriers with CNS disease is hopeful. ADCs including those targeting low-level HER2 expression and TROP2 are under active investigation in triple-negative BCBrMs.

Durable responses in patients with HER2+ breast cancer and leptomeningeal metastases treated with trastuzumab deruxtecan.

Leptomeningeal metastases (LM) are a devastating complication of HER2 + metastatic breast cancer (MBC), with no effective treatments. In a case series of 8 patients with heavily pretreated HER2 + MBC and progressing LM, all 8 patients (100%) derived clinical benefit from Trastuzumab deruxtecan (TDXd), and 4 patients (50%) had an objective partial response based on formal neuroradiology MRI reads using the EORTC/RANO-LM Revised-Scorecard. T-DXd warrants further study in LM in HER2 + MBC and solid tumors where T-DXd may be active.

Current drug development and trial designs in neuro-oncology: report from the first American Society of Clinical Oncology and Society for Neuro-Oncology Clinical Trials Conference.

Successful drug development for people with cancers of the CNS has been challenging. There are multiple barriers to successful drug development including biological factors, rarity of the disease, and ineffective use of clinical trials. Based upon a series of presentations at the First Central Nervous System Clinical Trials Conference hosted by the American Society of Clinical Oncology and the Society for Neuro-Oncology, we provide an overview on drug development and novel trial designs in neuro-oncology. This Review discusses the challenges of therapeutic development in neuro-oncology and proposes strategies to improve the drug discovery process by enriching the pipeline of promising therapies, optimising trial design, incorporating biomarkers, using external data, and maximising efficacy and reproducibility of clinical trials.

The Enduring Effects of COVID for Cancer Care: Learning from Real-Life Clinical Practice.

For three years, COVID-19 has circulated among our communities and around the world, fundamentally changing social interactions, health care systems, and service delivery. For people living with (and receiving treatment for) cancer, pandemic conditions presented significant additional hurdles in an already unstable and shifting environment, including disrupted personal contact with care providers, interrupted access to clinical trials, distanced therapeutic encounters, multiple immune vulnerabilities, and new forms of financial precarity. In a 2020 perspective in this journal, we examined how COVID-19 was reshaping cancer care in the early stages of the pandemic and how these changes might endure into the future. Three years later, and in light of a series of interviews with patients and their caregivers from the United States and Australia conducted during the pandemic, we return to consider the potential legacy effects of the pandemic on cancer care. While some challenges to care provision and survivorship were unforeseen, others accentuated and amplified existing problems experienced by patients, caregivers, and health care providers. Both are likely to have enduring effects in the "post-pandemic" world, raising the importance of focusing on lessons that can be learned for the future.

Phase I Study and Cell-Free DNA Analysis of T-DM1 and Metronomic Temozolomide for Secondary Prevention of HER2-Positive Breast Cancer Brain Metastases.

PURPOSE: Preclinical data showed that prophylactic, low-dose temozolomide (TMZ) significantly prevented breast cancer brain metastasis. We present results of a phase I trial combining T-DM1 with TMZ for the prevention of additional brain metastases after previous occurrence and local treatment in patients with HER2+ breast cancer. PATIENTS AND METHODS: Eligible patients had HER2+ breast cancer with brain metastases and were within 12 weeks of whole brain radiation therapy (WBRT), stereotactic radiosurgery, and/or surgery. Standard doses of T-DM1 were administered intravenously every 21 days (3.6 mg/kg) and TMZ was given orally daily in a 3+3 phase I dose escalation design at 30, 40, or 50 mg/m2, continuously. DLT period was one 21-day cycle. Primary endpoint was safety and recommended phase II dose. Symptom questionnaires, brain MRI, and systemic CT scans were performed every 6 weeks. Cell-free DNA sequencing was performed on patients' plasma and CSF. RESULTS: Twelve women enrolled, nine (75%) with prior SRS therapy and three (25%) with prior WBRT. Grade 3 or 4 AEs included thrombocytopenia (1/12), neutropenia (1/12), lymphopenia (6/12), and decreased CD4 (6/12), requiring pentamidine for Pneumocystis jirovecii pneumonia prophylaxis. No DLT was observed. Four patients on the highest TMZ dose underwent dose reductions. At trial entry, 6 of 12 patients had tumor mutations in CSF, indicating ongoing metastatic colonization despite a clear MRI. Median follow-up on study was 9.6 m (2.8-33.9); only 2 patients developed new parenchymal brain metastases. Tumor mutations varied with patient outcome. CONCLUSIONS: Metronomic TMZ in combination with standard dose T-DM1 shows low-grade toxicity and potential activity in secondary prevention of HER2+ brain metastases.

Cisplatin with veliparib or placebo in metastatic triple-negative breast cancer and BRCA mutation-associated breast cancer (S1416): a randomised, double-blind, placebo-controlled, phase 2 trial.

BACKGROUND: Poly(ADP-ribose) polymerase (PARP) inhibitors are effective in germline BRCA1 or BRCA2 (BRCA1/2) mutation-associated metastatic breast cancer. However, studies evaluating PARP inhibitors plus platinum-based chemotherapy in germline BRCA1/2-wildtype triple-negative breast cancer are scarce. A large proportion of germline BRCA1/2-wildtype triple-negative breast cancer shows homologous recombination deficiency (HRD), resulting in a BRCA-like phenotype that might render sensitivity to PARP inhibitors. The S1416 trial assessed the efficacy of cisplatin combined with the PARP inhibitor veliparib in three predefined groups of metastatic breast cancer: germline BRCA1/2-mutated, BRCA-like, and non-BRCA-like. METHODS: S1416 was a randomised, double-blind, placebo-controlled, phase 2 trial conducted at 154 community and academic clinical sites across the USA. Eligible patients aged 18 years or older had metastatic or recurrent triple-negative breast cancer or germline BRCA1/2-associated metastatic or recurrent breast cancer, an Eastern Cooperative Oncology Group performance status of 0-2, and had received up to one line of chemotherapy for metastatic disease. Patients were randomly assigned (1:1) via the National Clinical Trials Network open interactive system with dynamic balancing on number of previous cytotoxic regimens for metastatic disease to receive intravenous cisplatin (75 mg/m2, day 1) combined with either veliparib or matching placebo (300 mg orally twice a day, days 1-14) on a 21-day cycle. Investigators, patients, and the sponsors were masked to treatment assignment; the study statisticians were unmasked. Central testing after ran domisation classified patients as having mutated or wildtype germline BRCA1/2. A biomarker panel established a priori was used to classify patients with wildtype germline BRCA1/2 into BRCA-like and non-BRCA-like phenotype groups, with BRCA-like status based on at least one of the biomarkers: genomic instability score (≥42), somatic BRCA1/2 mutations, BRCA1 promoter methylation, or non-BRCA1/2 homologous recombination repair germline mutations. The primary endpoint was investigator-assessed progression-free survival, analysed separately for the three predefined biomarker groups with a prespecified α value for each analysis. Efficacy analyses were done by intention to treat and included all eligible patients. Safety analyses of toxicities attributed to treatment included all patients who received at least one dose of veliparib or placebo. The study is ongoing and registered with ClinicalTrials.gov, NCT02595905. FINDINGS: Between July 7, 2016, and June 15, 2019, 335 patients were enrolled and randomly assigned. 320 patients (n=162 to cisplatin plus veliparib, all women; and n=158 to cisplatin plus placebo, 157 women and one man) were eligible for efficacy evaluation. 247 patients were classified into the three biomarker groups: germline BRCA1/2-mutated (n=37), BRCA-like (n=101), and non-BRCA-like (n=109). 73 patients could not be classified due to missing biomarker information. Median follow-up was 11·1 months (IQR 5·6-20·8). In the germline BRCA1/2-mutated group, median progression-free survival was 6·2 months (95% CI 2·3-9·2) in the cisplatin plus veliparib group and 6·4 months (4·3-8·2) in the cisplatin plus placebo group (HR 0·79 [95% CI 0·38-1·67]; log-rank p=0·54). In the BRCA-like group, median progression-free survival was 5·9 months (95% CI 4·3-7·8) in the cisplatin plus veliparib group versus 4·2 months (2·3-5·0) in the cisplatin plus placebo group (HR 0·57 [95% CI 0·37-0·88]; p=0·010). In the non-BRCA-like group, median progression-free survival was 4·0 months (95% CI 2·5-4·7) in the cisplatin plus veliparib group versus 3·0 months (2·2-4·4) in the cisplatin plus placebo group (HR 0·89 [95% CI 0·60-1·33]; p=0·57). The most common grade 3 or worse adverse events attributed to treatment were neutropenia (71 [46%] of 155 patients in the cisplatin plus veliparib group vs 29 [20%] of 147 in the cisplatin plus placebo group), leukopenia (42 [27%] vs 11 [7%]), anaemia (35 [23%] vs 12 [8%]), and thrombocytopenia (29 [19%] vs four [3%]). Serious adverse events attributed to treatment occurred in 48 (31%) patients in the cisplatin plus veliparib group and 53 (36%) patients in the cisplatin plus placebo group. Treatment-related adverse events led to death in one patient in the cisplatin plus veliparib group (sepsis) and one patient in the cisplatin plus placebo group (acute kidney injury due to cisplatin plus heart failure from previous doxorubicin exposure). INTERPRETATION: The addition of veliparib to cisplatin significantly improved progression-free survival in patients with BRCA-like metastatic triple-negative breast cancer, but not in patients with non-BRCA-like metastatic breast cancer. PARP inhibitors combined with platinum-based chemotherapy should be explored further in BRCA-like triple-negative breast cancer. FUNDING: National Cancer Institute and National Institute of General Medical Sciences (US National Institutes of Health); AbbVie; Myriad Genetics; the Biomarker, Imaging, and Quality of Life Studies Funding Program (awarded by the National Cancer Institute); and The University of Kansas Cancer Center.

Brain metastasis as the first and only metastatic relapse site portends worse survival in patients with advanced HER2 + breast cancer.

PURPOSE: Current systemic therapy guidelines for patients with HER2 + breast cancer brain metastases (BCBrM) diverge based on the status of extracranial disease (ECD). An in-depth understanding of the impact of ECD on outcomes in HER2 + BCBrM has never been performed. Our study explores the implications of ECD status on intracranial progression-free survival (iPFS) and overall survival (OS) after first incidence of HER2 + BCBrM and radiation. METHODS: A retrospective analysis was performed of 151 patients diagnosed with initial HER2 + BCBrM who received radiation therapy to the central nervous system (CNS) at Duke between 2008 and 2021. The primary endpoint was iPFS defined as the time from first CNS radiation treatment to intracranial progression or death. OS was defined as the time from first CNS radiation or first metastatic disease to death. Systemic staging scans within 30 days of initial BCBrM defined ECD status as progressive, stable/responding or none (isolated brain relapse). RESULTS: In this cohort, > 70% of patients had controlled ECD with either isolated brain relapse (27%) or stable/responding ECD (44%). OS from initial metastatic disease to death was markedly worse for patients with isolated intracranial relapse (median = 28.4 m) compared to those with progressive or stable/responding ECD (48.8 m and 71.5 m, respectively, p = 0.0028). OS from first CNS radiation to death was significantly worse for patients with progressive ECD (16.9 m) versus stable/responding (36.6 m) or isolated intracranial relapse (28.4 m, p = 0.007). iPFS did not differ statistically based on ECD status. Receipt of systemic therapy after first BCBrM significantly improved iPFS (HR 0.45, 95% CI: 0.25-0.81, p = 0.008) and OS (HR: 0.43 (95% CI: 0.23-0.81); p = 0.001). CONCLUSION: OS in patients with HER2 + isolated BCBrM was inferior to those with concurrent progressive or stable/responding ECD. Studies investigating initiation of brain-penetrable HER2-targeted therapies earlier in the disease course of isolated HER2 + intracranial relapse patients are warranted.

Preclinical and Clinical Efficacy of Trastuzumab Deruxtecan in Breast Cancer Brain Metastases.

PURPOSE: Brain metastases can occur in up to 50% of patients with metastatic HER2-positive breast cancer. Because patients with active brain metastases were excluded from previous pivotal clinical trials, the central nervous system (CNS) activity of the antibody-drug conjugate trastuzumab deruxtecan (T-DXd) is not well characterized. EXPERIMENTAL DESIGN: We studied how T-DXd affects growth and overall survival in orthotopic patient-derived xenografts (PDX) of HER2-positive and HER2-low breast cancer brain metastases (BCBM). Separately, we evaluated the effects of T-DXd in a retrospective cohort study of 17 patients with stable or active brain metastases. RESULTS: T-DXd inhibited tumor growth and prolonged survival in orthotopic PDX models of HER2-positive (IHC 3+) and HER2-low (IHC 2+/FISH ratio < 2) BCBMs. T-DXd reduced tumor size and prolonged survival in a T-DM1-resistant HER2-positive BCBM PDX model. In a retrospective multi-institutional cohort study of 17 patients with predominantly HER2-positive BCBMs, the CNS objective response rate (ORR) was 73% (11/15) while extracranial response rate was 45% (5/11). In the subset of patients with untreated or progressive BCBM at baseline, the CNS ORR was 70% (7/10). The median time on treatment with T-DXd was 8.9 (1.3-16.2) months, with 42% (7/17) remaining on treatment at data cutoff. CONCLUSIONS: T-DXd demonstrates evidence of CNS activity in HER2-positive and HER2-low PDX models of BCBM and preliminary evidence of clinical efficacy in a multi-institution case series of patients with BCBM. Prospective clinical trials to further evaluate CNS activity of T-DXd in patients with active brain metastases are warranted. See related commentary by Soffietti and Pellerino, p. 8.

Systemic Therapy Approaches for Breast Cancer Brain and Leptomeningeal Metastases.

OPINION STATEMENT: Brain metastasis arising from breast cancer is associated with a poor prognosis. Various systemic chemotherapy and targeted therapies which are effective against breast cancer often fail to provide benefits against brain metastasis. This is mainly due to limited penetration of the therapies across the blood-brain barrier, and divergent evolution of brain metastasis compared to the primary tumor. Thus, brain metastasis is typically treated upfront with local therapies, such as surgery and radiation, followed by systemic therapies. Systemic therapies with CNS permeability are favored in patients with brain metastasis. This paper reviews various systemic therapy options for breast cancer brain metastasis.

Comprehensive Analysis of the Immunogenomics of Triple-Negative Breast Cancer Brain Metastases From LCCC1419.

Background: Triple negative breast cancer (TNBC) is an aggressive variant of breast cancer that lacks the expression of estrogen and progesterone receptors (ER and PR) and HER2. Nearly 50% of patients with advanced TNBC will develop brain metastases (BrM), commonly with progressive extracranial disease. Immunotherapy has shown promise in the treatment of advanced TNBC; however, the immune contexture of BrM remains largely unknown. We conducted a comprehensive analysis of TNBC BrM and matched primary tumors to characterize the genomic and immune landscape of TNBC BrM to inform the development of immunotherapy strategies in this aggressive disease. Methods: Whole-exome sequencing (WES) and RNA sequencing were conducted on formalin-fixed, paraffin-embedded samples of BrM and primary tumors of patients with clinical TNBC (n = 25, n = 9 matched pairs) from the LCCC1419 biobank at UNC-Chapel Hill. Matched blood was analyzed by DNA sequencing as a comparison for tumor WES for the identification of somatic variants. A comprehensive genomics assessment, including mutational and copy number alteration analyses, neoantigen prediction, and transcriptomic analysis of the tumor immune microenvironment were performed. Results: Primary and BrM tissues were confirmed as TNBC (23/25 primaries, 16/17 BrM) by immunohistochemistry and of the basal intrinsic subtype (13/15 primaries and 16/19 BrM) by PAM50. Compared to primary tumors, BrM demonstrated a higher tumor mutational burden. TP53 was the most frequently mutated gene and was altered in 50% of the samples. Neoantigen prediction showed elevated cancer testis antigen- and endogenous retrovirus-derived MHC class I-binding peptides in both primary tumors and BrM and predicted that single-nucleotide variant (SNV)-derived peptides were significantly higher in BrM. BrM demonstrated a reduced immune gene signature expression, although a signature associated with fibroblast-associated wound healing was elevated in BrM. Metrics of T and B cell receptor diversity were also reduced in BrM. Conclusions: BrM harbored higher mutational burden and SNV-derived neoantigen expression along with reduced immune gene signature expression relative to primary TNBC. Immune signatures correlated with improved survival, including T cell signatures. Further research will expand these findings to other breast cancer subtypes in the same biobank. Exploration of immunomodulatory approaches including vaccine applications and immune checkpoint inhibition to enhance anti-tumor immunity in TNBC BrM is warranted.