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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.
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Neoplasias Encefálicas , Neoplasias da Mama , Humanos , Feminino , Prognóstico , Receptor ErbB-2 , Estudos Retrospectivos , Neoplasias Encefálicas/radioterapia , Doença Crônica , RecidivaRESUMO
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.
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Neoplasias Encefálicas , Neoplasias da Mama , Neoplasias de Mama Triplo Negativas , Humanos , Feminino , Neoplasias da Mama/patologia , Hibridização in Situ Fluorescente , Trastuzumab , Receptor ErbB-2 , Neoplasias Encefálicas/tratamento farmacológico , Capecitabina , Prognóstico , Neoplasias de Mama Triplo Negativas/tratamento farmacológicoRESUMO
Up to half of all patients with metastatic human epidermal growth factor receptor 2-positive (HER2+) breast cancer will eventually acquire brain metastases (BrMs), which are associated with reduced overall survival and decreased quality of life. Although the median overall survival was previously less than a year, novel systemic treatments have significantly extended life expectancy in patients with HER2+ breast cancer BrMs. The current first-line standard of care for all patients with HER2+ metastatic breast cancer, regardless of BrMs status, is dual HER2 antibody therapy with pertuzumab/trastuzumab plus a taxane. Second-line systemic therapy has recently evolved, with the option of trastuzumab deruxtecan (T-DXd) or tucatinib in combination with trastuzumab and capecitabine. T-DXd has shown dramatically superior progression-free survival in comparison with trastuzumab emtansine (T-DM1) in patients with stable BrMs in the second-line setting. Patients who have untreated or locally treated/progressive BrMs may benefit from a regimen with robust intracranial response rates, such as tucatinib in combination with trastuzumab and capecitabine. Third-line therapy and beyond includes multiple options that require careful selection, with the patient's BrMs status, comorbidities, and performance status taken into account. In this review, we focus on current management and evolving strategies for the treatment of patients with HER2+ breast cancer BrMs.
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Neoplasias Encefálicas , Neoplasias da Mama , Ado-Trastuzumab Emtansina , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/etiologia , Neoplasias da Mama/patologia , Capecitabina/uso terapêutico , Feminino , Humanos , Qualidade de Vida , Receptor ErbB-2/metabolismo , Trastuzumab/uso terapêuticoRESUMO
BACKGROUND: Although metastatic breast cancer (MBC) remains incurable, advances in therapies have improved survival. Using a contemporary dataset of de novo MBC patients, we explore how overall (OS) and cancer-specific survival (CSS) changed over time. METHODS: All patients with de novo MBC from 1988 to 2016 were selected from Surveillance, Epidemiology, and End Results (SEER) 18. Unadjusted OS and CSS were estimated by Kaplan-Meier method and stratified by disease characteristics. Cox proportional hazards models determined factors associated with survival. RESULTS: 47,034 patients were included, with median OS of 25 months and CSS of 27 months. Survival steadily improved over time (1988: 1-year OS 62%, CSS 65%; 2015: 1-year OS 72%, CSS 74%). Patients with triple-negative breast cancer (TNBC) had the worst prognosis and were most likely to die from MBC [versus human epidermal growth factor receptor 2 (HER2)+ and hormone receptor (HR)+/HER2-]. Those with ≥ 4 sites of metastatic disease were also more likely to die from MBC with nearly identical OS and CSS (5-year OS 9%, CSS 9%), when compared with those with 1 site (5-year OS 31%, CSS 35%). After adjustment, improved CSS was associated with bone-only disease [hazard ratio (HR) 0.88, 95% confidence interval (CI) 0.83-0.94], while TNBC (versus HER2+: HR 3.12, 95% CI 2.89-3.36) and > 3 sites of metastatic disease (versus 1 site: HR 3.24, 95% CI 2.68-3.91) were associated with worse CSS (all p < 0.001). CONCLUSIONS: Accurate prognostic estimates are essential for patient care. As treatments for patients with MBC have expanded, OS and CSS have improved, and more patients, particularly with limited distant disease or favorable tumor subtypes, are also dying from non-MBC causes.
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Neoplasias da Mama , Neoplasias de Mama Triplo Negativas , Neoplasias da Mama/terapia , Feminino , Humanos , Prognóstico , Modelos de Riscos Proporcionais , Neoplasias de Mama Triplo Negativas/terapiaRESUMO
PURPOSE: Brain metastases (BM) are a complication of advanced breast cancer (BC). Histology of melanoma BM offers prognostic value; however, understanding the microenvironment of breast cancer brain metastases (BCBM) is less characterized. This study reports on four histological biomarkers, gliosis, immune infiltrate, hemorrhage, necrosis, and their prognostic significance in BCBM. METHODS: A biobank of 203 human tissues from patients who underwent craniotomy for BCBM was created across four academic institutions. Degree of gliosis, immune infiltrate, hemorrhage, and necrosis were identified and scored via representative H&E stain (0-3+). Overall survival (OS) was estimated using the Kaplan-Meier method. Cox proportional hazards regression evaluated prognostic value of the biomarkers in the context of standard clinical characteristics. RESULTS: BCBM subtype (available for n = 158) was 36% Her2+, 26% hormone receptor (HR)+/Her2- 38% HR-/Her2- (triple negative, TN). Gliosis was observed in 82% (116/141) of BCBM, with immune infiltrate 44% (90/201), hemorrhage 82% (166/141), and necrosis 87% (176/201). Necrosis was significantly higher in TNBC (p < 0.01). Presence of gliosis, immune infiltrate, and hemorrhage correlated with improved OS (p = 0.03, p = 0.03, p = 0.1), while necrosis correlated with inferior OS (p = 0.01). Improved OS was associated with gliosis in TN (p = 0.02), and immune infiltrate (p = 0.001) and hemorrhage (p = 0.07) in HER2+. In a multivariable model for OS, incorporating these biomarkers with traditional clinical variables improved the model fit (p < 0.001). CONCLUSION: Gliosis confers superior prognosis in TNBC BM; immune infiltrate and hemorrhage correlate with superior prognosis in HER2+ BCBM. Understanding the metastatic microenvironment of BCBM refines prognostic considerations and may unveil novel therapeutic strategies.
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Neoplasias Encefálicas/secundário , Neoplasias Encefálicas/cirurgia , Craniotomia/métodos , Neoplasias de Mama Triplo Negativas/patologia , Adulto , Idoso , Bancos de Espécimes Biológicos , Biomarcadores Tumorais/imunologia , Neoplasias Encefálicas/imunologia , Feminino , Humanos , Pessoa de Meia-Idade , Prognóstico , Análise de Sobrevida , Neoplasias de Mama Triplo Negativas/imunologia , Microambiente TumoralRESUMO
INTRODUCTION: Most patients with breast cancer have early-stage hormone receptor (HR)-positive, human epidermal growth factor receptor-2 (HER2)-negative disease. Even though the prognosis for most of these patients is good, there is a need to identify patients at risk for poor outcomes and to develop strategies to mitigate this risk. AREAS COVERED: The addition of immunotherapy to standard neoadjuvant chemotherapy represents a promising option for select patients with HR-positive early breast cancer. Three randomized clinical trials have shown favorable results to date. In this review, we discuss the findings of I-SPY2, CheckMate 7FL (NCT04109066), and KEYNOTE-756 (NCT03725059). EXPERT OPINION: Despite the promising results of these trials, there are unanswered questions that need to be considered before incorporating neo/adjuvant immunotherapy in the treatment paradigm of early-stage HR-positive breast cancer. One example of an unanswered question is patient selection. Because the regimens used in these protocols are associated with long-term toxicities, identifying the patients who are more likely to derive a benefit from these agents, such as through the use of biomarkers, is critical. A second example is the optimal integration of adjuvant therapies that improve invasive disease-free survival, such as abemaciclib and ribociclib, which are not safely administered concurrently with immunotherapy.
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Neoplasias da Mama , Humanos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/imunologia , Feminino , Terapia Neoadjuvante/efeitos adversos , Inibidores de Checkpoint Imunológico/uso terapêutico , Imunoterapia , Receptor ErbB-2/antagonistas & inibidores , Receptor ErbB-2/metabolismo , Ensaios Clínicos Controlados Aleatórios como Assunto , Estadiamento de NeoplasiasRESUMO
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 (nâ =â 253) and without BrMs (nâ =â 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%, Pâ <â .001) and BRCA2 (17% vs 5%, Pâ =â .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%, Pâ =â .08) and in patients with BrMs (36% vs 17%, Pâ <â .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.
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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.
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PURPOSE: We explored the efficacy of PARP inhibition with or without programmed death ligand-1 (PD-L1) blockade as chemotherapy-free maintenance therapy for advanced triple-negative breast cancer (aTNBC) sensitive to platinum-based chemotherapy. PATIENTS AND METHODS: In the phase II non-comparative DORA trial (NCT03167619), patients with ongoing stable disease (SD) or complete/partial response (CR/PR) to first- or second-line platinum-based chemotherapy for TNBC (≤10% estrogen/progesterone receptor expression) were randomized 1:1 to receive olaparib 300 mg twice daily with or without durvalumab 1,500 mg on day 1 every 4 weeks. The primary objective was to compare progression-free survival (PFS) versus a historical control of continued platinum-based therapy. RESULTS: 45 patients were randomized (23 to olaparib alone, 22 to the combination; 3 with estrogen/progesterone receptor expression 1%-10%). At 9.8 months' median follow-up, median PFS from randomization was 4.0 [95% confidence interval (CI), 2.6-6.1] months with olaparib and 6.1 (95% CI, 3.7-10.1) months with the combination, both significantly longer than the historical control (P = 0.0023 and P < 0.0001, respectively). Clinical benefit rates (SD ≥24 weeks or CR/PR) were 44% (95% CI, 23%-66%) and 36% (95% CI, 17%-59%) in the monotherapy and combination arms, respectively. Sustained clinical benefit was seen irrespective of germline BRCA mutation or PD-L1 status, but tended to be associated with CR/PR to prior platinum, particularly in the olaparib-alone arm. No new safety signals were reported. CONCLUSIONS: PFS was longer than expected with both regimens. A patient subset with wild-type BRCA platinum-sensitive aTNBC had durable disease control with chemotherapy-free maintenance.
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Anticorpos Monoclonais , Neoplasias Ovarianas , Piperazinas , Neoplasias de Mama Triplo Negativas , Feminino , Humanos , Neoplasias Ovarianas/genética , Antígeno B7-H1/genética , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/genética , Platina/efeitos adversos , Receptores de Progesterona/genética , Ftalazinas , Estrogênios , Recidiva Local de Neoplasia/tratamento farmacológicoRESUMO
BACKGROUND: The predictive and prognostic value of the recurrence score (RS) has emphasized the importance of tumor biology and has reduced the prognostic implications of limited nodal burden in post-menopausal women with HR+/HER2-invasive breast cancer (IBC). It is unclear whether routine axillary staging has a continued role in the management of small, clinically node negative (cN0) HR+/HER2- IBC. We sought to estimate the association of RS with pN stage. METHODS: Patients >50yo diagnosed with cN0, HR+/HER2- IBC (2015-2019) with an available RS were identified from the National Cancer Database. The clinicopathologic characteristics and rates of pN-stage (pN0, pN1, pN2/3) were compared for RS of ≤25 vs. >25. RESULTS: The median patient age was 64.1 (IQR 58-69) and the majority (75%) of tumors displayed ductal histology. Most (81.6%) were cT1 on presentation and pT1 (74.7%) on final pathology. There were 130,568 (86.2%) with a RS â≤ â25 and 20,879 (13.8%) with a RS â> â25. On final pathology, 128,995 (85.2%) were pN0 and 21,991 (14.5%) pN1. Of the pN1, 2699 (12.3%) yielded a RS â> â25. There were 461 (0.3%) patients with pN2-pN3 disease. Of those, 57 (12.4%) had RS â> â25. CONCLUSION: In our analysis, pN0 and pN1 tumors are biologically similar by gene expression assay in postmenopausal patients with similar proportions of high RS. These data support the notion that tumor biology examined via RS may have more prognostic and predictive value than metastatic dissemination to limited lymph nodes. These findings support the ongoing evaluation of routine axillary staging in postmenopausal patients with HR+/HER2- IBC.
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Axila , Neoplasias da Mama , Recidiva Local de Neoplasia , Estadiamento de Neoplasias , Pós-Menopausa , Humanos , Feminino , Pessoa de Meia-Idade , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Idoso , Recidiva Local de Neoplasia/epidemiologia , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Metástase Linfática , Linfonodos/patologia , Prognóstico , Estudos RetrospectivosRESUMO
Tumor mutational burden (TMB) correlates with tumor neoantigen burden, T cell infiltration, and response to immune checkpoint inhibitors in many solid tumor types. Based on data from the phase II KEYNOTE-158 study, the anti-PD-1 antibody pembrolizumab was granted approval for treating patients with advanced solid tumors and TMB ≥ 10 mutations per megabase. However, this trial did not include any patients with metastatic breast cancer; thus, several questions remain unanswered about the true role of TMB as a predictive biomarker of benefit to immune checkpoint inhibitor therapy in breast cancer. In this review, we will discuss the challenges and opportunities in establishing TMB as a predictive biomarker of benefit to immunotherapy in metastatic breast cancer.
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The rise of cyclin-dependent kinase (CDK)4/6 inhibitors has rapidly reshaped treatment algorithms for hormone receptor (HR)-positive metastatic breast cancer, with endocrine treatment (ET) plus a CDK4/6-inhibitor currently representing the standard of care in the first line setting. However, treatment selection for those patients experiencing progression while on ET + CDK4/6-inhibitors remains challenging due to the suboptimal activity or significant toxicities of the currently available options. There is also a paucity of data regarding the efficacy of older regimens, such as everolimus + exemestane, post-CDK4/6 inhibition. In this setting of high unmet need, several clinical trials of novel drugs have recently reported encouraging results: the addition of the AKT-inhibitor capivasertib to fulvestrant demonstrated a significant improvement in progression-free survival (PFS); the oral selective estrogen receptor degrader (SERD) elacestrant prolonged PFS compared to traditional ET in a phase 3 trial, particularly among patients with detectable ESR1 mutations; finally, PARP inhibitors are available treatment options for patients with pathogenic BRCA1/2 germline mutations. Overall, a plethora of novel endocrine and biologic treatment options are finally filling the gap between first-line ET and later line chemotherapy. In this review article, we recapitulate the activity of these novel treatment options and their potential role in future treatment algorithms.
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Background: Data supporting high tumor mutational burden (TMB-H) as a lone biomarker for an immune-responsive tumor microenvironment (TME) in metastatic breast cancer (MBC) are weak, yet tumor agnostic approval in TMB-H advanced tumors provides immune checkpoint inhibition (ICI) as a clinical option. We evaluated concurrent predictors of immune-responsive and non-responsive TME within MBC. Methods: Tumor samples from patients with MBC (N=5621) were analyzed by next-generation sequencing of DNA (592-gene panel or whole exome) and RNA (whole transcriptome) at Caris Life Sciences (Phoenix, AZ). TMB-H threshold was set to ≥ 10 muts/Mb. PDL-1 was evaluated using SP142 antibody. Gene expression profiling and RNA deconvolution were used to estimate immune and stromal cell population abundance in the TME, and transcriptomic signature of immunotherapy response (T cell-inflamed score). Results: 461 (8.2%) TMB-H MBC samples were identified. Consistent with prior studies, TMB-H tumors exhibited significant dMMR/MSI-H enrichment (7 vs. 0%, p<0.0001) and PD-L1+ expression (36 vs. 28%, p<0.05) compared to TMB-L. Across all samples, T cell-inflamed scores were weakly correlated with TMB. TMB-H was not associated with significantly increased immune responsive cell types (CD8+ T-cells, NK cells, or B cells) or immune response gene signatures (e.g. antigen presentation), yet positive trends were observed, while immunosuppressive fibroblasts were significantly decreased in TMB-H tumors (0.84-fold change compared to TMB-L, P<0.05). HR+/HER2- breast cancer was the only subtype in which TMB-H tumors exhibited increased T cell-inflamed scores vs. TMB-L. Concurrent PD-L1+ or dMMR/MSI-H with TMB-H was associated with high T cell-inflamed scores in both HR+/HER2- and TNBC. Among several associated biomarkers, B2M mutations and CD274 amplifications were positively associated with T-cell inflamed scores in TMB-H tumors; CDH1 and ERBB2 mutations were negatively associated. Conclusion: High TMB alone does not strongly correlate with immune infiltrate or immune-related gene signatures in MBC. TMB-H predicts T-cell inflamed signature compared to TMB-L in HR+/HER2- tumors only. Along with MSI-H and PD-L1+, several biomarkers, including B2M mutation and CD274 amplification, may help predict ICI benefit amongst TMB-H tumors. Co-occurring biomarkers within TMB-H breast cancer warrant evaluation in larger cohorts for response or resistance to ICI to develop composite predictive biomarkers in MBC.
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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.
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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.
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Neoplasias Encefálicas , Neoplasias da Mama , Imunoconjugados , Humanos , Feminino , Estudos Retrospectivos , Estudos de Coortes , Estudos Prospectivos , Receptor ErbB-2/uso terapêutico , Trastuzumab/efeitos adversos , Neoplasias da Mama/patologia , Camptotecina/uso terapêutico , Imunoconjugados/uso terapêutico , Neoplasias Encefálicas/mortalidade , Resultado do TratamentoRESUMO
INTRODUCTION: The majority of the over 250,000 new cases of invasive breast cancer diagnosed in the United States are driven by hormone receptor signaling (HR+). Since 2015, cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) have become the standard in combination with endocrine therapy (ET) for patients facing HR+ metastatic disease. AREAS COVERED: There are now three approved agents in the HR+ metastatic setting such as abemaciclib, ribociclib, and palbociclib. Due to the almost doubling of progression-free survival (PFS) and improvement in overall survival (OS) in the metastatic setting, studies were conducted to examine the benefit of adding CDK4/6i in the adjuvant setting for those patients at high risk for recurrence. Despite negative results of PALLAS (palbociclib) in this setting, monarchE (abemaciclib) showed an improvement in invasive disease-free survival (IDFS) and distant recurrence-free survival (DRFS) at the 3-year time point for patients with high-risk tumor characteristics leading to its approval. Herein, we discuss the data, the population studied and for which abemaciclib is approved as well as safety, tolerability, and dose reductions for practical management of these patients. EXPERT OPINION: Abemaciclib is appropriate and beneficial for those patients with high-risk, node-positive, hormonally driven, human epidermal growth factor receptor 2 negative (HER2-) breast cancer.
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Aminopiridinas , Benzimidazóis , Neoplasias da Mama , Aminopiridinas/uso terapêutico , Benzimidazóis/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Feminino , Humanos , Inibidores de Proteínas Quinases/uso terapêutico , Receptor ErbB-2/metabolismoRESUMO
BACKGROUND: We sought to identify characteristics of metastatic breast cancer (MBC) patients who may benefit most from primary tumor resection. METHODS: Recursive partitioning analysis (RPA) was used to categorize non-surgical patients with de novo MBC in the NCDB (2010-2015) into 3 groups (I/II/III) based on 3-year overall survival (OS). After bootstrapping (BS), group-level profiles were applied, and the association of surgery with OS was estimated using Cox proportional hazards models. RESULTS: All patients benefitted from surgery (median OS, surgery vs no surgery): 72.7 vs 42.9 months, 47.3 vs 30.4 months, 23.8 vs 14.4 months (all p < 0.001) in BS-groups I, II, and III, respectively. After adjustment, surgery remained associated with improved OS (HR 0.52, 95% CI 0.50-0.55). The effect of surgery on OS differed quantitatively across groups. CONCLUSION: Prognostic groups may inform the degree of benefit from surgery, with the greatest benefit seen in those with the most favorable survival.
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Neoplasias da Mama/cirurgia , Mastectomia/estatística & dados numéricos , Seleção de Pacientes , Adulto , Idoso , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Tomada de Decisão Clínica/métodos , Feminino , Seguimentos , Humanos , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Medição de Risco/métodos , Medição de Risco/estatística & dados numéricos , Resultado do TratamentoRESUMO
BACKGROUND: Controversy exists regarding the optimal sequence of chemotherapy among women with operable node-negative breast cancers with high-risk tumor biology. We evaluated national patterns of neoadjuvant chemotherapy (NACT) use among women with early-stage HER2+, triple-negative (TNBC), and high-risk hormone receptor-positive (HR+) invasive breast cancers. METHODS: Women ≥18 years with cT1-2/cN0 HER2+, TNBC, or high recurrence risk score (≥31) HR+ invasive breast cancers who received chemotherapy were identified in the National Cancer Database (2010-2016). Cochran-Armitage and logistic regression examined temporal trends and likelihood of undergoing NACT versus adjuvant chemotherapy based on patient age and molecular subtype. RESULTS: Overall, 96,622 patients met study criteria; 25% received NACT and 75% underwent surgery first, with comparable 5-year estimates of overall survival (0.90, 95% CI 0.892-0.905 vs 0.91, 95% CI 0.907-0.913). During the study period, utilization of NACT increased from 14% to 36% and varied according to molecular subtype (year*molecular subtype p < 0.001, p-corrected < 0.001). Women with HER2+ (OR 4.17, 95% CI 3.70-4.60, p < 0.001, p-corrected < 0.001) and TNBC (OR 3.81, 95% CI 3.38-4.31, p < 0.001, p-corrected < 0.001) were more likely to receive NACT over time, without a change in use among those with HR+ disease (OR 1.58, 95% CI 0.88-2.87, p = 0.13, p-corrected = 0.17). CONCLUSION: Among women with early-stage triple-negative and HER2+ breast cancers, utilization of NACT increased over time, a trend that correlates with previously reported improved rates of pCR and options post-neoadjuvant treatment with residual disease. Future research is needed to better understand multidisciplinary decisions for NACT and implications for breast cancer patients.
Assuntos
Neoplasias da Mama , Neoplasias de Mama Triplo Negativas , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/patologia , Quimioterapia Adjuvante , Feminino , Humanos , Masculino , Terapia Neoadjuvante , Neoplasia Residual/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/patologiaRESUMO
PURPOSE: APOBEC mutagenesis underlies somatic evolution and accounts for tumor heterogeneity in several cancers, including breast cancer (BC). In this study, we evaluated the characteristics of a real-world cohort for time-to-treatment discontinuation (TTD) and overall survival on CDK4/6 inhibitors (CDK4/6i) plus endocrine therapy (ET) and immune checkpoint inhibitors. METHODS: Comprehensive genomic profiling results from 29,833 BC samples were analyzed for tumor mutational burden and APOBEC signatures. For clinical outcomes, a deidentified nationwide (United States-based) BC Clinico-Genomic Database (CGDB) was evaluated with log-rank and Cox models. Patients with hormone receptor-positive (HR+) human epidermal growth factor receptor 2-negative (HER2-) BC who received first-line ET and CDK4/6i were included. Eligible patients from Mayo Clinic and Duke University were HR+ HER2- BC with sequencing data between September 2013 and July 2020. RESULTS: Of 29,833 samples sequenced, 7.9% were APOBEC+ with a high rate in invasive lobular carcinoma (16.7%) and in metastatic tumors (9.7%) relative to locally biopsied BC (4.3%; P < .001). In CGDB, 857 patients with HR+ HER2- BC received ET plus CDK4/6i in the first line. APOBEC+ patients had significantly shorter TTD on ET plus CDK4/6i than APOBEC- patients, 7.8 (95% CI, 4.3 to 14.6) versus 12.4 months (95% CI, 11.2 to 14.1; hazard ratio, 1.6; 95% CI, 1.03 to 2.39; P = .0036). Clinical benefit to immune checkpoint inhibitors was observed in HR+ HER2-, APOBEC+, tumor mutational burden-high patients, with four of nine CGDB patients (TTD 0.3-11.3 months) and four of six patients in Duke/Mayo cohorts (TTD 0.9-40.5 months) with a TTD of ≥ 3 months. CONCLUSION: APOBEC+ HR+ HER2- patients had shorter TTD on first-line ET plus CDK4/6i relative to APOBEC- patients. Further research is needed to optimize the treatment of APOBEC+ HR+ HER2- BC and to investigate the efficacy of immunotherapeutic strategies in this population.
Assuntos
Desaminases APOBEC , Neoplasias da Mama , Receptores de Estrogênio , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica , Biomarcadores Tumorais/metabolismo , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Inibidores de Checkpoint Imunológico , Receptores de Estrogênio/genética , Estados Unidos , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Desaminases APOBEC/genética , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genéticaRESUMO
The development of breast cancer (BC) brain metastases (BrM) is a common complication of advanced disease, occurring in up to half of the patients with advanced disease depending on the subtype. The management of BCBrM requires complex multidisciplinary care including local therapy, surgical resection and/or radiotherapy, palliative care, and carefully selected systemic therapies. Significant progress has been made in the human epidermal growth factor receptor 2-positive (HER2+) BCBrM population due to novel brain penetrable systemic therapies. Increased inclusion of patients with BCBrM in clinical trials using brain-penetrant systemic therapies recently led to the first FDA approval of a HER2-directed therapy specifically in the BCBrM population in the last year. Advances for the treatment of HR+/HER2- and TNBC BCBrM subgroups continue to evolve. In this review, we will discuss the diagnosis and multidisciplinary care of BCBrM. We focus on recent advances in neurosurgery, radiation therapy, and systemic treatment therapies with intracranial activity. We also provide an overview of the current clinical trial landscape for patients with BCBrM.