RESUMEN
Importance: The absolute benefit of chemotherapy for all patients with stage I triple-negative breast cancer (TNBC) is unclear, and biomarkers are not currently available for selecting patients with an excellent outcome for whom neoadjuvant or adjuvant chemotherapy may have negligible benefit. High levels of stromal tumor-infiltrating lymphocytes (sTILs) are associated with favorable survival in TNBC, but data solely in stage I TNBC are lacking. Objective: To examine the outcomes of patients of all ages with stage I TNBC solely and who received neither neoadjuvant nor adjuvant chemotherapy, according to centrally reviewed sTIL levels at prespecified cutoffs. Design, Setting, and Participants: This cohort study used the Netherlands Cancer Registry to identify patients diagnosed with stage I TNBC between January 1, 2005, and December 31, 2015, who were not treated with chemotherapy. Only patients who did not receive neoadjuvant and/or adjuvant chemotherapy were selected. The clinical data were matched with their corresponding pathology data provided by the Dutch Pathology Registry. Data analysis was performed between February and October 2023. Main Outcomes and Measures: The primary end point was breast cancer-specific survival (BCSS) at 5, 10, and 15 years for the prespecified sTIL level cutoffs of 30%, 50%, and 75%. Hematoxylin and eosin-stained slides were used for central review of histologic subtype, grade, and lymphovascular invasion. The International Immuno-Oncology Biomarker Working Group guidelines were used to score the sTIL levels; these levels were determined for 1041 patients. Results: A total of 4511 females with stage I TNBC (mean [SD] age at diagnosis, 64.4 [11.1] years; median follow-up, 11.4 [95% CI, 10.9-11.9] years) were included. Most tumors (952 [91.5%]) were invasive carcinomas of nonspecial histologic subtype. Most patients (548 [52.6%]) had pT1cN0 tumors. Median (range) sTIL level was 5% (1%-99%). A total of 775 patients (74.4%) had sTIL levels below 30%, 266 (25.6%) had 30% or greater, 203 (19.5%) had 50% or greater, and 141 (13.5%) had 75% or greater. Patients with pT1abN0 tumors had a more favorable outcome vs patients with pT1cN0 tumors, with a 10-year BCSS of 92% (95% CI, 89%-94%) vs 86% (95% CI, 82%-89%). In the overall cohort, sTIL levels of at least 30% were associated with better BCSS compared with sTIL levels less than 30% (96% and 87%, respectively; hazard ratio [HR], 0.45; 95% CI, 0.26-0.77). High sTIL levels of 50% or greater were associated with a better outcome than low sTIL levels of less than 50% (HR, 0.27; 95% CI, 0.10-0.74) in patients with pT1C tumors, with a 10-year BCSS of 95% increasing to 98% with sTIL levels of 75% or greater. Conclusions and Relevance: Results of this study showed that patients with stage I TNBC and high level of sTILs who did not receive neoadjuvant or adjuvant chemotherapy had excellent 10-year BCSS. The findings further support the role of sTILs as integral biomarkers in prospective clinical trials of therapy optimization for this patient population.
RESUMEN
Multiplexed imaging offers a powerful approach to characterize the spatial topography of tissues in both health and disease. To analyze such data, the specific combination of markers that are present in each cell must be enumerated to enable accurate phenotyping, a process that often relies on unsupervised clustering. We constructed the Pan-Multiplex (Pan-M) dataset containing 197 million distinct annotations of marker expression across 15 different cell types. We used Pan-M to create Nimbus, a deep learning model to predict marker positivity from multiplexed image data. Nimbus is a pre-trained model that uses the underlying images to classify marker expression across distinct cell types, from different tissues, acquired using different microscope platforms, without requiring any retraining. We demonstrate that Nimbus predictions capture the underlying staining patterns of the full diversity of markers present in Pan-M. We then show how Nimbus predictions can be integrated with downstream clustering algorithms to robustly identify cell subtypes in image data. We have open-sourced Nimbus and Pan-M to enable community use at https://github.com/angelolab/Nimbus-Inference.
RESUMEN
PURPOSE: To evaluate efficacy of pembrolizumab across multiple cancer types harboring different levels of Whole-Genome Sequencing (WGS)-based tumor mutational load (TML; total of non-synonymous mutations across the genome) in patients included in the Drug Rediscovery Protocol (NCT02925234). PATIENTS AND METHODS: Patients with solid, treatment-refractory, microsatellite-stable tumors were enrolled in cohort A: breast cancer TML 140-290, cohort B: tumor-agnostic cohort TML 140-290, and cohort C: tumor-agnostic cohort TML >290. Patients received pembrolizumab 200 mg every three weeks. Primary endpoint was clinical benefit (CB: objective response or stable disease (SD) ≥16 weeks). Pre-treatment tumor biopsies were obtained for WGS and RNA-sequencing. RESULTS: Seventy-two evaluable patients with 26 different histotypes were enrolled. CB rate was 13% in cohort A (3/24 with partial response (PR)), 21% in cohort B (3/24 with SD, 2/24 with PR), and 42% in cohort C (4/24 with SD, 6/24 with PR). In cohort C, neoantigen burden estimates and expression of inflammation and innate immune biomarkers were significantly associated with CB. Similar associations were not identified in cohort A and B. In cohort A, CB was significantly associated with mutations in the chromatin remodeling gene PBRM1, while in cohort B, CB was significantly associated with expression of MICA/MICB and butyrophilins. CB and clonal TML were not significantly associated. CONCLUSION: While in cohort A pembrolizumab lacked activity, cohort B and cohort C met the study's primary endpoint. Further research is warranted to refine selection of patients with tumors harboring lower TMLs and may benefit from a focus on innate immunity.
RESUMEN
OBJECTIVE: This study aims to evaluate the response to and surgical benefits of neoadjuvant endocrine therapy (NET) in ER+/HER2-breast cancer patients who are clinically high risk, but genomic low risk according to the 70-gene signature (MammaPrint). METHODS: Patients with ER+/HER2-invasive breast cancer with a clinical high risk according to MINDACT, who had a genomic low risk according to the 70-gene signature and were treated with NET between 2015 and 2023 in our center, were retrospectively analyzed. RECIST 1.1 criteria were used to assess radiological response using MRI or ultrasound. Surgical specimens were evaluated to assess pathological response. Two breast cancer surgeons independently scored the eligibility of breast conserving therapy (BCS) pre- and post- NET. RESULTS: Of 72 included patients, 23 were premenopausal (100% started with tamoxifen of which 4 also received OFS) and 49 were postmenopausal (98% started with an aromatase inhibitor). Overall, 8 (11%) showed radiological complete response. Only 1 (1.4%) patient had a pathological complete response (RCB-0) and 68 (94.4%) had a pathological partial response (RCB-1 or RCB-2). Among the 26 patients initially considered for mastectomy, 14 (53.8%) underwent successful BCS. In all 20 clinical node-positive patients, a marked axillary lymph node was removed to assess response. Four out of 20 (20%) patients had a pathological complete response of the axilla. CONCLUSION: The study showed that a subgroup of patients with a clinical high risk and a genomic low risk ER+/HER2-breast cancer benefits from NET resulting in BCS instead of a mastectomy. Additionally, NET may enable de-escalation in axillary treatment.
Asunto(s)
Antineoplásicos Hormonales , Neoplasias de la Mama , Terapia Neoadyuvante , Receptor ErbB-2 , Receptores de Estrógenos , Tamoxifeno , Humanos , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/cirugía , Neoplasias de la Mama/terapia , Femenino , Terapia Neoadyuvante/métodos , Persona de Mediana Edad , Estudios Retrospectivos , Receptor ErbB-2/metabolismo , Receptor ErbB-2/análisis , Adulto , Receptores de Estrógenos/metabolismo , Receptores de Estrógenos/análisis , Antineoplásicos Hormonales/uso terapéutico , Anciano , Tamoxifeno/uso terapéutico , Mastectomía Segmentaria/métodos , Inhibidores de la Aromatasa/uso terapéutico , Imagen por Resonancia Magnética , Resultado del TratamientoRESUMEN
Importance: The association of tumor-infiltrating lymphocyte (TIL) abundance in breast cancer tissue with cancer recurrence and death in patients with early-stage triple-negative breast cancer (TNBC) who are not treated with adjuvant or neoadjuvant chemotherapy is unclear. Objective: To study the association of TIL abundance in breast cancer tissue with survival among patients with early-stage TNBC who were treated with locoregional therapy but no chemotherapy. Design, Setting, and Participants: Retrospective pooled analysis of individual patient-level data from 13 participating centers in North America (Rochester, Minnesota; Vancouver, British Columbia, Canada), Europe (Paris, Lyon, and Villejuif, France; Amsterdam and Rotterdam, the Netherlands; Milan, Padova, and Genova, Italy; Gothenburg, Sweden), and Asia (Tokyo, Japan; Seoul, Korea), including 1966 participants diagnosed with TNBC between 1979 and 2017 (with follow-up until September 27, 2021) who received treatment with surgery with or without radiotherapy but no adjuvant or neoadjuvant chemotherapy. Exposure: TIL abundance in breast tissue from resected primary tumors. Main Outcomes and Measures: The primary outcome was invasive disease-free survival [iDFS]. Secondary outcomes were recurrence-free survival [RFS], survival free of distant recurrence [distant RFS, DRFS], and overall survival. Associations were assessed using a multivariable Cox model stratified by participating center. Results: This study included 1966 patients with TNBC (median age, 56 years [IQR, 39-71]; 55% had stage I TNBC). The median TIL level was 15% (IQR, 5%-40%). Four-hundred seventeen (21%) had a TIL level of 50% or more (median age, 41 years [IQR, 36-63]), and 1300 (66%) had a TIL level of less than 30% (median age, 59 years [IQR, 41-72]). Five-year DRFS for stage I TNBC was 94% (95% CI, 91%-96%) for patients with a TIL level of 50% or more, compared with 78% (95% CI, 75%-80%) for those with a TIL level of less than 30%; 5-year overall survival was 95% (95% CI, 92%-97%) for patients with a TIL level of 50% or more, compared with 82% (95% CI, 79%-84%) for those with a TIL level of less than 30%. At a median follow-up of 18 years, and after adjusting for age, tumor size, nodal status, histological grade, and receipt of radiotherapy, each 10% higher TIL increment was associated independently with improved iDFS (hazard ratio [HR], 0.92 [0.89-0.94]), RFS (HR, 0.90 [0.87-0.92]), DRFS (HR, 0.87 [0.84-0.90]), and overall survival (0.88 [0.85-0.91]) (likelihood ratio test, P < 10e-6). Conclusions and Relevance: In patients with early-stage TNBC who did not undergo adjuvant or neoadjuvant chemotherapy, breast cancer tissue with a higher abundance of TIL levels was associated with significantly better survival. These results suggest that breast tissue TIL abundance is a prognostic factor for patients with early-stage TNBC.
Asunto(s)
Linfocitos Infiltrantes de Tumor , Neoplasias de la Mama Triple Negativas , Adulto , Humanos , Persona de Mediana Edad , Adyuvantes Inmunológicos , Colombia Británica , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/patología , Recurrencia Local de Neoplasia/inmunología , Recurrencia Local de Neoplasia/patología , Estudios Retrospectivos , Neoplasias de la Mama Triple Negativas/inmunología , Neoplasias de la Mama Triple Negativas/mortalidad , Neoplasias de la Mama Triple Negativas/patología , Neoplasias de la Mama Triple Negativas/terapiaRESUMEN
BACKGROUND: Due to the abundant usage of chemotherapy in young triple-negative breast cancer (TNBC) patients, the unbiased prognostic value of BRCA1-related biomarkers in this population remains unclear. In addition, whether BRCA1-related biomarkers modify the well-established prognostic value of stromal tumor-infiltrating lymphocytes (sTILs) is unknown. This study aimed to compare the outcomes of young, node-negative, chemotherapy-naïve TNBC patients according to BRCA1 status, taking sTILs into account. METHODS: We included 485 Dutch women diagnosed with node-negative TNBC under age 40 between 1989 and 2000. During this period, these women were considered low-risk and did not receive chemotherapy. BRCA1 status, including pathogenic germline BRCA1 mutation (gBRCA1m), somatic BRCA1 mutation (sBRCA1m), and tumor BRCA1 promoter methylation (BRCA1-PM), was assessed using DNA from formalin-fixed paraffin-embedded tissue. sTILs were assessed according to the international guideline. Patients' outcomes were compared using Cox regression and competing risk models. RESULTS: Among the 399 patients with BRCA1 status, 26.3% had a gBRCA1m, 5.3% had a sBRCA1m, 36.6% had tumor BRCA1-PM, and 31.8% had BRCA1-non-altered tumors. Compared to BRCA1-non-alteration, gBRCA1m was associated with worse overall survival (OS) from the fourth year after diagnosis (adjusted HR, 2.11; 95% CI, 1.18-3.75), and this association attenuated after adjustment for second primary tumors. Every 10% sTIL increment was associated with 16% higher OS (adjusted HR, 0.84; 95% CI, 0.78-0.90) in gBRCA1m, sBRCA1m, or BRCA1-non-altered patients and 31% higher OS in tumor BRCA1-PM patients. Among the 66 patients with tumor BRCA1-PM and ≥ 50% sTILs, we observed excellent 15-year OS (97.0%; 95% CI, 92.9-100%). Conversely, among the 61 patients with gBRCA1m and < 50% sTILs, we observed poor 15-year OS (50.8%; 95% CI, 39.7-65.0%). Furthermore, gBRCA1m was associated with higher (adjusted subdistribution HR, 4.04; 95% CI, 2.29-7.13) and tumor BRCA1-PM with lower (adjusted subdistribution HR, 0.42; 95% CI, 0.19-0.95) incidence of second primary tumors, compared to BRCA1-non-alteration. CONCLUSIONS: Although both gBRCA1m and tumor BRCA1-PM alter BRCA1 gene transcription, they are associated with different outcomes in young, node-negative, chemotherapy-naïve TNBC patients. By combining sTILs and BRCA1 status for risk classification, we were able to identify potential subgroups in this population to intensify and optimize adjuvant treatment.
Asunto(s)
Neoplasias Primarias Secundarias , Neoplasias de la Mama Triple Negativas , Humanos , Femenino , Adulto , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/genética , Adyuvantes Inmunológicos , Etnicidad , Biomarcadores , Proteína BRCA1/genéticaRESUMEN
T cell-excluded tumors are less responsive to immunotherapies. In this issue of Immunity, Taifour et al. show that secretion of the cytokine Chi3l1 by tumor cells induces T cell exclusion via neutrophil extracellular trap (NET) formation. Chi3l1 depletion stimulates T cell infiltration and synergizes with PD-1 blockade.
Asunto(s)
Neoplasias , Linfocitos T , Humanos , Neoplasias/terapia , Inmunoterapia , CitocinasRESUMEN
Immune checkpoint inhibitors (ICI) have become a cornerstone in medical oncology, with evolving therapeutic strategies and applications. These monoclonal antibodies, designed to enhance immune responses, have revealed a spectrum of immune-related adverse events (irAEs). While many irAEs exhibit favorable responses to corticosteroid or immunosuppressive therapy, most ICI-related endocrinopathies necessitate lifelong replacement therapy and pose significant clinical challenges. Adrenal insufficiency (AI), a noteworthy endocrine irAE, can manifest as primary AI (PAI) or secondary AI (SAI), resulting from adrenal or pituitary gland dysfunction, respectively. ICI-induced AI, albeit relatively infrequent, occurs in 1-2% of patients receiving single-agent anti-Programmed Death-1/Programmed Death-Ligand 1 (PD-1/PD-L1) or Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4) therapies and in a higher range of 4-9% when ICIs are used in combinations. Recognizing and addressing ICI-induced PAI is crucial, as it often presents with acute and potentially life-threatening symptoms, especially considering the expanding use of ICI therapy. This review provides an updated overview of ICI-induced PAI, exploring its clinical, diagnostic, and radiological aspects.
Asunto(s)
Enfermedad de Addison , Antineoplásicos Inmunológicos , Neoplasias , Humanos , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Antineoplásicos Inmunológicos/efectos adversos , Neoplasias/terapia , Enfermedad de Addison/inducido químicamente , Enfermedad de Addison/tratamiento farmacológico , Anticuerpos Monoclonales/uso terapéuticoRESUMEN
BACKGROUND: Checkpoint inhibitor (CPI) immunotherapies have provided durable clinical responses across a range of solid tumor types for some patients with cancer. Nonetheless, response rates to CPI vary greatly between cancer types. Resolving intratumor transcriptomic changes induced by CPI may improve our understanding of the mechanisms of sensitivity and resistance. METHODS: We assembled a cohort of longitudinal pre-therapy and on-therapy samples from 174 patients treated with CPI across six cancer types by leveraging transcriptomic sequencing data from five studies. RESULTS: Meta-analyses of published RNA markers revealed an on-therapy pattern of immune reinvigoration in patients with breast cancer, which was not discernible pre-therapy, providing biological insight into the impact of CPI on the breast cancer immune microenvironment. We identified 98 breast cancer-specific correlates of CPI response, including 13 genes which are known IO targets, such as toll-like receptors TLR1, TLR4, and TLR8, that could hold potential as combination targets for patients with breast cancer receiving CPI treatment. Furthermore, we demonstrate that a subset of response genes identified in breast cancer are already highly expressed pre-therapy in melanoma, and additionally we establish divergent RNA dynamics between breast cancer and melanoma following CPI treatment, which may suggest distinct immune microenvironments between the two cancer types. CONCLUSIONS: Overall, delineating longitudinal RNA dynamics following CPI therapy sheds light on the mechanisms underlying diverging response trajectories, and identifies putative targets for combination therapy.
Asunto(s)
Neoplasias de la Mama , Melanoma , Humanos , Femenino , Melanoma/tratamiento farmacológico , Inmunoterapia/efectos adversos , Terapia Combinada , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Microambiente Tumoral/genéticaRESUMEN
PURPOSE: Treatment advancements have improved life expectancy for adolescents and young adults (AYAs) with an uncertain and/or poor cancer prognosis (UPCP) and change clinical practice. This improved survival requires a different approach and specific expertise to meet the needs of this group. The aim of this study is to explore the health care experiences of AYAs with a UPCP. METHODS: We conducted a multicenter qualitative study using semi-structured interviews and elements of the grounded theory by Corbin and Strauss. RESULTS: Interviews were conducted with 46 AYAs with a UPCP. They were on average 33.4 years old (age range 23-44), and most of them were woman (63%). Additionally, five AYAs with a UPCP participated as AYA research partners in two focus groups. They were on average 31.8 years old and four of them were woman. AYAs with a UPCP reported four pillars for a satisfied healthcare experience: (1) trust, (2) tailored communication, (3) holistic empathic open attitude, and (4) care being offered (pro-)actively. They reported both optimal and suboptimal experiences about distrust based on a delay in diagnostic trajectory, lack of tailored communication and discussion of sensitive topics, preference for a holistic approach, and struggles with finding the way to get additional healthcare support. CONCLUSION: For AYAs with a UPCP, it is important that both age-specific issues and issues related to the UPCP are understood and addressed; however, this seems not yet optimally implemented in clinical practice. This emphasizes the importance of providing this patient group with tailored care incorporating both aspects. Healthcare professionals need to be supported with training and tools to understand the healthcare needs of AYAs with a UPCP. AYAs can be empowered to take more control over their own healthcare needs.
Asunto(s)
Neoplasias , Femenino , Humanos , Adolescente , Adulto Joven , Adulto , Neoplasias/terapia , Personal de Salud , Investigación Cualitativa , Atención a la Salud , PronósticoRESUMEN
BACKGROUND: Despite major improvements in treatment of HER2-positive metastatic breast cancer (MBC), only few patients achieve complete remission and remain progression free for a prolonged time. The tumor immune microenvironment plays an important role in the response to treatment in HER2-positive breast cancer and could contain valuable prognostic information. Detailed information on the cancer-immune cell interactions in HER2-positive MBC is however still lacking. By characterizing the tumor immune microenvironment in patients with HER2-positive MBC, we aimed to get a better understanding why overall survival (OS) differs so widely and which alternative treatment approaches may improve outcome. METHODS: We included all patients with HER2-positive MBC who were treated with trastuzumab-based palliative therapy in the Netherlands Cancer Institute between 2000 and 2014 and for whom pre-treatment tissue from the primary tumor or from metastases was available. Infiltrating immune cells and their spatial relationships to one another and to tumor cells were characterized by immunohistochemistry and multiplex immunofluorescence. We also evaluated immune signatures and other key pathways using next-generation RNA-sequencing data. With nine years median follow-up from initial diagnosis of MBC, we investigated the association between tumor and immune characteristics and outcome. RESULTS: A total of 124 patients with 147 samples were included and evaluated. The different technologies showed high correlations between each other. T-cells were less prevalent in metastases compared to primary tumors, whereas B-cells and regulatory T-cells (Tregs) were comparable between primary tumors and metastases. Stromal tumor-infiltrating lymphocytes in general were not associated with OS. The infiltration of B-cells and Tregs in the primary tumor was associated with unfavorable OS. Four signatures classifying the extracellular matrix of primary tumors showed differential survival in the population as a whole. CONCLUSIONS: In a real-world cohort of 124 patients with HER2-positive MBC, B-cells, and Tregs in primary tumors are associated with unfavorable survival. With this paper, we provide a comprehensive insight in the tumor immune microenvironment that could guide further research into development of novel immunomodulatory strategies.
Asunto(s)
Neoplasias de la Mama , Femenino , Humanos , Neoplasias de la Mama/patología , Receptor ErbB-2/metabolismo , Linfocitos T Reguladores , Trastuzumab , Pronóstico , Protocolos de Quimioterapia Combinada Antineoplásica , Microambiente TumoralRESUMEN
Immune checkpoint blockade (ICB) is currently approved for patients with triple-negative breast cancer (TNBC), whereas responses to ICB are also observed in a small subgroup of Estrogen Receptor (ER)-positive breast cancer. The cut-off for ER-positivity (≥1%) is based on likelihood of endocrine treatment response, but ER-positive breast cancer represents a very heterogeneous group. This raises the question whether selection based on ER-negativity should be revisited to select patients for ICB treatment in the context of clinical trials. Stromal tumor-infiltrating lymphocytes (sTILs) and other immune parameters are higher in TNBC compared to ER-positive breast cancer, but it is unknown whether lower ER levels are associated with more inflamed tumor microenvironments (TME). We collected a consecutive series of primary tumors from 173 HER2-negative breast cancer patients, enriched for tumors with ER expression between 1 and 99% and found levels of stromal TILs, CD8 + T cells, and PD-L1 positivity in breast tumors with ER 1-9% and ER 10-50% to be comparable to tumors with ER 0%. Expression of immune-related gene signatures in tumors with ER 1-9% and ER 10-50% was comparable to ER 0%, and higher than in tumors with ER 51-99% and ER 100%. Our results suggest that the immune landscape of ER low tumors (1-9%) and ER intermediate tumors (10-50%) mimic that of primary TNBC.
RESUMEN
The clinical successes of immune checkpoint blockade (ICB) in advanced cancer patients have recently spurred the clinical implementation of ICB in the neoadjuvant and perioperative setting. However, how neoadjuvant ICB therapy affects the systemic immune landscape and metastatic spread remains to be established. Tumors promote both local and systemic expansion of regulatory T cells (Tregs), which are key orchestrators of tumor-induced immunosuppression, contributing to immune evasion, tumor progression and metastasis. Tregs express inhibitory immune checkpoint molecules and thus may be unintended targets for ICB therapy counteracting its efficacy. Using ICB-refractory models of spontaneous primary and metastatic breast cancer that recapitulate the poor ICB response of breast cancer patients, we observed that combined anti-PD-1 and anti-CTLA-4 therapy inadvertently promotes proliferation and activation of Tregs in the tumor, tumor-draining lymph node and circulation. Also in breast cancer patients, Treg levels were elevated upon ICB. Depletion of Tregs during neoadjuvant ICB in tumor-bearing mice not only reshaped the intratumoral immune landscape into a state favorable for ICB response but also induced profound and persistent alterations in systemic immunity, characterized by elevated CD8+ T cells and NK cells and durable T cell activation that was maintained after treatment cessation. While depletion of Tregs in combination with neoadjuvant ICB did not inhibit primary tumor growth, it prolonged metastasis-related survival driven predominantly by CD8+ T cells. This study demonstrates that neoadjuvant ICB therapy of breast cancer can be empowered by simultaneous targeting of Tregs, extending metastasis-related survival, independent of a primary tumor response.
Asunto(s)
Neoplasias de la Mama , Activación de Linfocitos , Linfocitos T Reguladores , Humanos , Neoplasias de la Mama/inmunología , Neoplasias de la Mama/terapia , Linfocitos T Reguladores/inmunología , Terapia Neoadyuvante , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Células Asesinas Naturales/inmunología , Células Mieloides/inmunología , Metástasis de la Neoplasia , Animales , Ratones , Linfocitos T CD8-positivos/inmunologíaRESUMEN
OPINION STATEMENT: In approximately 15-20% of the patients diagnosed with breast cancer, it comprises the triple negative (TN) subtype, which until recently lacked targets for specific treatments and is known for its aggressive clinical behavior in patients with metastatic disease. TNBC is considered the most immunogenic breast cancer subtype due to higher levels of tumor infiltrating lymphocytes (TILs), tumor mutational burden and PD-L1 expression, providing a rationale for immunotherapy. The addition of pembrolizumab to chemotherapy as first-line treatment resulted in significantly improved PFS and OS for PD-L1 positive mTNBC, leading to FDA approval. However, response rate of ICB in unselected patients is low. Ongoing (pre)clinical trials aim to further optimize ICB efficacy and widen its application beyond PD-L1 positive breast tumors. Novel immunomodulatory approaches to induce a more inflamed tumor microenvironment include dual checkpoint blockade, bispecific antibodies, immunocytokines, adoptive cell therapies, oncolytic viruses, and cancer vaccines. Preclinical data for these novel strategies seems promising, but solid clinical data to further support its application for mTNBC is awaited. Biomarkers capturing the degree of immunogenicity such as but not limited to TILs, CD8 T cell levels, and IFNg signatures could support deciding which therapeutic strategy is most appropriate for which patient. Given 1) the accumulating therapy options for patients with metastatic disease and 2) the heterogeneity of mTNBC from inflamed to immune-desert tumors, the challenge is to work towards immunomodulatory strategies for specific subgroups of patients with TNBC to enable personalized (immuno)therapy for patients with metastatic disease.
Asunto(s)
Neoplasias de la Mama Triple Negativas , Humanos , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Antígeno B7-H1/metabolismo , Inmunoterapia/métodos , Biomarcadores de Tumor/metabolismo , Inmunomodulación , Microambiente TumoralRESUMEN
Invasive lobular breast cancer (ILC) is the second most common histological breast cancer subtype, but ILC-specific trials are lacking. Translational research revealed an immune-related ILC subset, and in mouse ILC models, synergy between immune checkpoint blockade and platinum was observed. In the phase II GELATO trial ( NCT03147040 ), patients with metastatic ILC were treated with weekly carboplatin (area under the curve 1.5 mg ml-1 min-1) as immune induction for 12 weeks and atezolizumab (PD-L1 blockade; triweekly) from the third week until progression. Four of 23 evaluable patients had a partial response (17%), and 2 had stable disease, resulting in a clinical benefit rate of 26%. From these six patients, four had triple-negative ILC (TN-ILC). We observed higher CD8+ T cell infiltration, immune checkpoint expression and exhausted T cells after treatment. With this GELATO trial, we show that ILC-specific clinical trials are feasible and demonstrate promising antitumor activity of atezolizumab with carboplatin, particularly for TN-ILC, and provide insights for the design of highly needed ILC-specific trials.
Asunto(s)
Carcinoma Lobular , Neoplasias de la Mama Triple Negativas , Humanos , Antígeno B7-H1 , Carboplatino/uso terapéutico , Carcinoma Lobular/tratamiento farmacológico , Carcinoma Lobular/patología , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/patologíaRESUMEN
Alpelisib is a specific oral PI3K inhibitor used combined with fulvestrant for the treatment of patients with HR+/HER2-/PIK3CA-mutated metastatic breast cancer. Adverse drug reactions with alpelisib are common, including hyperglycemia and rash. Here we describe extraordinary and life-threatening reactions beyond skin rash in two patients with progressive PIK3CA-mutated metastatic cancer in whom alpelisib was initiated. Case-A (vaginal cancer): After 10 days on treatment, she developed dry eyes, generalized rash and itching. Alpelisib was interrupted and symptomatic treatment initiated. Because of an initial tumor response, a rechallenge was done. Ninety minutes after a reduced dose of alpelisib, she developed an anaphylactic reaction with angioedema, hypotension, and skin rash. Case-B (breast cancer): After 11 days on treatment, she developed skin rash and alpelisib was interrupted. At re-initiation, she felt tingles in her face and ears and some skin erythema. Given the mild rash, a second rechallenge with premedication was performed. Ninety minutes after a reduced dose of alpelisib, she developed a type-1 allergic reaction with angioedema, tingles, and skin rash. In both cases, a type-1 allergic reaction was diagnosed and symptomatic treatment was initiated, alpelisib was permanently discontinued and the patients fully recovered the next week(s). This report underlines the critical importance to consider type-I allergic reactions in the differential diagnosis in cases of rash associated with alpelisib. Even if a reaction develops after days on treatment, a type-I allergic reaction cannot be excluded. A rechallenge can be dangerous and should always be well contemplated or even avoided.
Asunto(s)
Anafilaxia , Neoplasias de la Mama , Exantema , Femenino , Humanos , Receptor ErbB-2/uso terapéutico , Anafilaxia/inducido químicamente , Anafilaxia/tratamiento farmacológico , Fosfatidilinositol 3-Quinasas , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Exantema/inducido químicamente , Exantema/tratamiento farmacológico , Fosfatidilinositol 3-Quinasa Clase I/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéuticoRESUMEN
Around 40-50% of all triple-negative breast cancer (TNBC) patients achieve a pathological complete response (pCR) after treatment with neoadjuvant chemotherapy (NAC). The identification of biomarkers predicting the response to NAC could be helpful for personalized treatment. This systematic review provides an overview of putative biomarkers at baseline that are predictive for a pCR following NAC. Embase, Medline and Web of Science were searched for articles published between January 2010 and August 2022. The articles had to meet the following criteria: patients with primary invasive TNBC without distant metastases and patients must have received NAC. In total, 2045 articles were screened by two reviewers resulting in the inclusion of 92 articles. Overall, the most frequently reported biomarkers associated with a pCR were a high expression of Ki-67, an expression of PD-L1 and the abundance of tumor-infiltrating lymphocytes, particularly CD8+ T cells, and corresponding immune gene signatures. In addition, our review reveals proteomic, genomic and transcriptomic markers that relate to cancer cells, the tumor microenvironment and the peripheral blood, which also affect chemo-sensitivity. We conclude that a prediction model based on a combination of tumor and immune markers is likely to better stratify TNBC patients with respect to NAC response.
Asunto(s)
Terapia Neoadyuvante , Neoplasias de la Mama Triple Negativas , Humanos , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/genética , Neoplasias de la Mama Triple Negativas/metabolismo , Proteómica , Linfocitos Infiltrantes de Tumor , Biomarcadores/metabolismo , Microambiente TumoralRESUMEN
A substantial fraction of early-stage triple-negative breast cancer (eTNBC) is characterized by high levels of stromal tumor-infiltrating lymphocytes (sTIL) and has a good prognosis even without systemic treatment, highlighting the importance of an endogenous anticancer immune response. Still, a considerable proportion of patients with eTNBC need some "therapeutical push" to kick-start this immune response. Exploiting this immune response with immune-checkpoint inhibition (ICI), in combination with chemotherapy, has made its way into standard of care in eTNBC. Major challenges in the near future include finding those patients with eTNBC who can be treated with ICI alone or with a reduced chemotherapy backbone. Exploring the optimal duration of ICI and finding biomarkers to predict response will be key to enable personalized implementation of ICI in patients with eTNBC. For patients who currently do not respond effectively to ICI plus chemotherapy, challenges lie in finding new immunomodulatory therapies and developing response-guided neoadjuvant approaches.
Asunto(s)
Neoplasias de la Mama Triple Negativas , Humanos , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Linfocitos Infiltrantes de Tumor , Terapia Neoadyuvante , InmunoterapiaRESUMEN
Immune checkpoint blockade (ICB) has heralded a new era in cancer therapy. Research into the mechanisms underlying response to ICB has predominantly focused on T cells; however, effective immune responses require tightly regulated crosstalk between innate and adaptive immune cells. Here, we combine unbiased analysis of blood and tumors from metastatic breast cancer patients treated with ICB with mechanistic studies in mouse models of breast cancer. We observe an increase in systemic and intratumoral eosinophils in patients and mice responding to ICB treatment. Mechanistically, ICB increased IL-5 production by CD4+ T cells, stimulating elevated eosinophil production from the bone marrow, leading to systemic eosinophil expansion. Additional induction of IL-33 by ICB-cisplatin combination or recombinant IL-33 promotes intratumoral eosinophil infiltration and eosinophil-dependent CD8+ T cell activation to enhance ICB response. This work demonstrates the critical role of eosinophils in ICB response and provides proof-of-principle for eosinophil engagement to enhance ICB efficacy.