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INTRODUCTION: Cyclin-dependent-kinase 4/6(CDK4/6) inhibitors are widely used as a first-line systemic treatment for patients with hormone receptor-positive, human epidermal growth factor receptor-2 negative metastatic breast cancer. Although many patients with metastatic breast cancer require palliative radiotherapy (RT), there are limited data on the safety of combining a CDK4/6 inhibitor with palliative RT. CASE REPORT: Presented is a case of acute high-grade radiation dermatitis with low-dose palliative RT following administration of palbociclib. A 49-year-old woman with newly diagnosed hormone receptor-positive invasive ductal carcinoma of the left breast presented with lytic bone lesions in the left femur and lumbar spine. The patient initiated treatment with goserelin, tamoxifen, and palbociclib. She underwent prophylactic surgical fixation of the left femur and received post-operative RT encompassing the entire surgical nail (30 Gy/10 fractions) and palliative RT to the lumbar spine for pain relief (20 Gy/5 fractions). During cycle 4, palbociclib was stopped 3 days prior to the start of RT to reduce the risk of toxicity risk. However, 16 days after starting RT, she developed painful erythematous papules and bullae with moist desquamation on the left groin and lumbar spine. MANAGEMENT & OUTCOME: Her symptoms were managed with topical Aquaphor-lidocaine, silver sulfadiazine, and aluminum acetate soaks. Dermatitis subsided to dry desquamation within 2 weeks. The patient denied late toxicity at 11 months follow-up. DISCUSSION: Larger retrospective or prospective studies are needed to further elucidate the safety of combined CDK4/6 inhibitors and RT. In the meantime, special precautions are warranted in patients receiving combined therapy.
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Neoplasias de la Mama , Dermatitis , Humanos , Femenino , Persona de Mediana Edad , Estudios Retrospectivos , Piridinas/efectos adversos , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/radioterapia , Neoplasias de la Mama/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Dermatitis/tratamiento farmacológico , Dermatitis/etiología , Inhibidores de Proteínas Quinasas/uso terapéuticoRESUMEN
Germline genetic evaluation is indicated for all patients with epithelial ovarian cancer (EOC). For testing to have clinical utility, results must be documented within the electronic medical record (EMR) and accessible to providers at the point of care, which can be challenging in the context of current EMR limitations and genetic testing processes. We examined the receipt of genetics services and EMR capture of genetic testing results in patients with EOC. We conducted a retrospective chart review to examine germline genetic evaluations among patients with EOC seen by a gynecologic or medical oncologist at the University of Pennsylvania in 2016. EMRs were reviewed to determine: (1) if patients were referred for genetic evaluation; (2) if genetic testing was performed; (3) if results were documented in office notes, scanned third-party test reports, and/or the EMR problem list; (4) if provider notes correctly listed the variant classification. Overall, 413 (62%) of patients had documented genetic testing. Genetic testing was documented in almost all provider notes (96%) and the majority of scanned EMR reports (64%). Pathogenic variants were found in 119 (29%) individuals; the majority (70%) had genetic testing documented within EMR problem lists. Provider notes were highly accurate in describing variant classification. In this study, genetic testing was performed and documented in the EMR for most EOC patients. Approximately one-third of those tested did not have scanned test reports specifying variant found, limiting the utility of test results for cascade testing and therapeutic decisions.
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OBJECTIVE: Platinum-resistant, high-grade serous ovarian cancer (HGSOC) has limited treatment options. Preclinical data suggest that poly(ADP-ribose) polymerase inhibitors (PARPi) and ataxia telangiectasia and Rad3-related kinase inhibitors (ATRi) are synergistic. CAPRI (NCT03462342) is an investigator-initiated study of olaparib plus ceralasertib in recurrent HGSOC. Herein, we present results from the platinum-resistant cohort. METHODS: A Simon 2-stage design was utilized. Platinum-resistant HGSOC patients received ceralasertib 160 mg orally daily, days 1-7 and olaparib 300 mg orally twice daily, days 1-28 of a 28-day cycle until toxicity or progression. Primary endpoints were toxicity and efficacy including objective response rate (ORR) by RECIST. Secondary endpoint was progression-free survival (PFS). The null hypothesis (≤5% ORR) would be rejected if there were ≥ 1 responses in 12 patients. RESULTS: Fourteen PARPi-naïve patients were evaluable for toxicity; 12 were evaluable for response. Three had BRCA1 mutations (1 germline, 2 somatic). Adverse events possibly related to treatment were primarily grade (G) 1/2. G3 toxicities included nausea (14.3%), fatigue (7.1%), anorexia (7.1%), and anemia (7.1%). No objective responses occurred. Best response was stable disease in 9 patients and progressive disease in three. Five patients had a ≥ 20% to <30% reduction in disease burden, including 3 with BRCA1 mutations. Three of 11 patients (27%; 2 with BRCA1 mutations) evaluable by Gynecologic Cancer Intergroup criteria had >50% CA-125 decline, including 2 with CA-125 normalization. Median PFS was 4.2 months overall (90% CI:3.5-8.2) and 8.2 months (3.6 months-not determined) for patients with BRCA1 mutations. CONCLUSIONS: Olaparib plus ceralasertib is well-tolerated. No objective responses occurred, though a signal of activity was seen particularly in disease associated with BRCA1. Further evaluation of this combination should include alternate dosing strategies in genomically-selected populations.
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Indoles/efectos adversos , Morfolinas/efectos adversos , Recurrencia Local de Neoplasia/tratamiento farmacológico , Neoplasias Ováricas/tratamiento farmacológico , Ftalazinas/administración & dosificación , Piperazinas/administración & dosificación , Pirimidinas/efectos adversos , Sulfonamidas/efectos adversos , Administración Oral , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Proteínas de la Ataxia Telangiectasia Mutada/antagonistas & inhibidores , Proteína BRCA1/genética , Esquema de Medicación , Resistencia a Antineoplásicos , Femenino , Humanos , Indoles/administración & dosificación , Imagen por Resonancia Magnética , Persona de Mediana Edad , Morfolinas/administración & dosificación , Recurrencia Local de Neoplasia/mortalidad , Recurrencia Local de Neoplasia/patología , Neoplasias Ováricas/diagnóstico , Neoplasias Ováricas/genética , Neoplasias Ováricas/mortalidad , Ovario/diagnóstico por imagen , Ovario/patología , Ftalazinas/efectos adversos , Piperazinas/efectos adversos , Inhibidores de Poli(ADP-Ribosa) Polimerasas/administración & dosificación , Inhibidores de Poli(ADP-Ribosa) Polimerasas/efectos adversos , Supervivencia sin Progresión , Inhibidores de Proteínas Quinasas , Pirimidinas/administración & dosificación , Criterios de Evaluación de Respuesta en Tumores Sólidos , Sulfonamidas/administración & dosificación , Tomografía Computarizada por Rayos XRESUMEN
Next-generation or massively parallel sequencing has transformed the landscape of genetic testing for cancer susceptibility. Panel-based genetic tests evaluate multiple genes simultaneously and rapidly. Because these tests are frequently offered in clinical settings, understanding their clinical validity and utility is critical. When evaluating the inherited risk of breast and ovarian cancers, panel-based tests provide incremental benefit compared with BRCA1/2 genetic testing. For inherited risk of other cancers, such as colon cancer and pheochromocytoma-paraganglioma, the clinical utility and yield of panel-based testing are higher; in fact, simultaneous evaluation of multiple genes has been the historical standard for these diseases. Evaluating inherited risk with panel-based testing has recently entered clinical practice for prostate and pancreatic cancers, with potential therapeutic implications. The resulting variants of uncertain significance and mutations with unclear actionability pose challenges to service providers and patients, underscoring the importance of genetic counseling and data-sharing initiatives. This review explores the evolving merits, challenges, and nuances of panel-based testing for cancer susceptibility.
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Predisposición Genética a la Enfermedad , Pruebas Genéticas/métodos , Mutación , Neoplasias/genética , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Humanos , MasculinoRESUMEN
PURPOSE: Women with Li-Fraumeni syndrome (LFS), a cancer predisposition syndrome caused by germline mutations in TP53, have an over 50% risk of developing breast cancer by age 70. Patients with LFS are at risk for radiation-induced malignancies; however, only small case series have prior investigated radiation risks in the treatment of breast cancer. We therefore aimed to investigate the risk of malignancy in breast cancer patients with LFS following adjuvant radiotherapy. METHODS: A single-institution retrospective chart review was conducted for female breast cancer patients with confirmed germline TP53 mutation. The frequency of radiation-induced malignancies in LFS patients was compared to non-LFS breast cancer cases reported in the Penn Medicine Cancer Registry via statistical analyses. RESULTS: We identified 51 female LFS breast cancer patients with 74 primary diagnoses. Fifty-seven% had a history of breast cancer only, and 25% had breast cancer as their presenting diagnosis of LFS. LFS-associated breast cancers were predominantly invasive ductal carcinoma (48%) and HER2+ (58%). Twenty patients underwent adjuvant radiotherapy with a median follow-up of 12.5 (2-20) years. Of 18 patients who received radiation in a curative setting, one (6%) patient developed thyroid cancer, and one (6%) patient developed sarcoma in the radiation field. This risk for radiation-induced malignancy associated with LFS was higher for both sarcoma and thyroid cancer in comparison with the control cohort. CONCLUSIONS: We found a lower risk of radiation-induced secondary malignancies in LFS breast cancer patients than previously reported in the literature (33% risk of radiation-induced sarcoma). These findings suggest that LFS may not be an absolute contraindication for radiotherapy in breast cancer. The potential risk for locoregional recurrence without radiotherapy must be weighed against the long-term risk for radiation-induced malignancies in consideration of adjuvant radiotherapy for LFS breast cancer patients.
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Neoplasias de la Mama/radioterapia , Carcinoma Ductal de Mama/radioterapia , Carcinoma Lobular/radioterapia , Síndrome de Li-Fraumeni/complicaciones , Recurrencia Local de Neoplasia/radioterapia , Neoplasias Inducidas por Radiación/etiología , Radioterapia Adyuvante/efectos adversos , Adolescente , Adulto , Neoplasias de la Mama/patología , Carcinoma Ductal de Mama/patología , Carcinoma Lobular/patología , Femenino , Estudios de Seguimiento , Mutación de Línea Germinal , Humanos , Metástasis Linfática , Persona de Mediana Edad , Recurrencia Local de Neoplasia/patología , Neoplasias Inducidas por Radiación/patología , Pronóstico , Estudios Retrospectivos , Tasa de Supervivencia , Proteína p53 Supresora de Tumor/genética , Adulto JovenRESUMEN
The landscape of genetic testing for breast cancer susceptibility has transformed dramatically over the last decade and a half. Traditionally, the process of genetic testing resided fully within a medical infrastructure, from identification of appropriate testing candidates to gene selection to risk mitigation recommendations. More recently, decreasing costs, advancing technology, and a growing understanding of therapeutic implications of certain genetic test results have led to more widespread uptake of testing that increasingly involves broad multigene panels. Germline genetic testing for breast cancer susceptibility can now be obtained through one of three approaches: through clinical care; a direct-to-consumer (DTC) approach that is entirely consumer-driven; or a hybrid, patient-initiated, provider-mediated model. Increased access to testing has led to extensive dialogue about the best way to conduct testing and act on results. Points of discussion include: selection of appropriate candidates for genetic testing; optimal composition of genes on panels; informed consent; safe return of results; privacy; and legal protections for those found to have relevant pathogenic or likely pathogenic variants. As more individuals undergo genetic testing, a growing population of individuals with inherited breast cancer predisposition informs optimal management of cancer risk and also highlights unanswered questions. This article aims to review the current state of genetic testing for inherited breast cancer susceptibility including testing approaches, the legal, ethical and social landscape, and selected contemporary management issues.
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Neoplasias de la Mama , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/genética , Femenino , Asesoramiento Genético , Predisposición Genética a la Enfermedad , Pruebas Genéticas , HumanosRESUMEN
BACKGROUND: Biological differences between BRCA-associated breast cancer and sporadic breast cancer may warrant different adjuvant chemotherapy (ACRx) recommendations despite similar phenotypic features. A 21-gene expression profile (Oncotype DX) generates a prognostic recurrence score (RS) that predicts the ACRx benefit in patients with hormone receptor-positive breast cancer. No reports describe assay results for BRCA-associated breast cancer. METHODS: A review of Memorial Sloan Kettering Cancer Center databases identified 4908 patients with hormone receptor-positive, node-negative breast cancer who underwent Oncotype DX testing between July 2006 and March 2014. BRCA1/BRCA2 carriers (cases) were identified and matched (1:2) by age at diagnosis and tumor size to noncarrier controls. Two-sample nonparametric tests were used to compare the baseline characteristics, RSs, and risk stratification between BRCA1 and BRCA2 patients. Conditional logistic regression was used to assess these differences by mutational status. RESULTS: Fifty mutation-associated cases (19 BRCA1 cases and 31 BRCA2 cases) and 100 controls who were well matched for age (P = .9) and tumor size (P = .6) were included. BRCA1 and BRCA2 carriers had similar median RSs (P = .6) and risk category stratification (P = .3). The median RS was higher for cases versus controls (24 vs 16; P < .0001). Risk stratification also differed by mutational status (P = .0002). Cases had more high-risk disease (28% vs 7%) and intermediate-risk disease (56% vs 36%) and less low-risk disease (16% vs 57%). Cases were more likely than controls to receive ACRx (74% vs 46%; P = .002). CONCLUSIONS: Germline BRCA-associated hormone receptor-positive breast cancer may be associated with intrinsically less favorable biology. Few affected carriers have RS indicating a clear absence of benefit from ACRx. The increased use of ACRx and benefit from ACRx in BRCA carriers may mitigate otherwise inferior outcomes.
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Neoplasias de la Mama/genética , Genes BRCA1 , Genes BRCA2 , Predisposición Genética a la Enfermedad/epidemiología , Mutación de Línea Germinal , Recurrencia Local de Neoplasia/genética , Adulto , Anciano , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Neoplasias de la Mama/terapia , Estudios de Cohortes , Bases de Datos Factuales , Supervivencia sin Enfermedad , Femenino , Perfilación de la Expresión Génica , Humanos , Modelos Logísticos , Persona de Mediana Edad , Análisis Multivariante , Recurrencia Local de Neoplasia/epidemiología , Pronóstico , Estudios Retrospectivos , Medición de Riesgo , Tasa de Supervivencia , Estados Unidos , Adulto JovenRESUMEN
The demonstrated efficacy of pharmacologic antiestrogen therapy in treating hormone receptor-positive breast cancer has changed the landscape of treatment for the majority of women with metastatic disease, providing them with a well-tolerated therapeutic alternative to surgical oophorectomy and chemotherapy. A multitude of clinical trials have evaluated the various endocrine agents alone or in combination. Studies have established ovarian suppression as key for the management of premenopausal metastatic breast cancer patients, and aromatase inhibitor therapy as first-line treatment for their postmenopausal counterparts. Fulvestrant (Faslodex, AstraZeneca) has also been found to be efficacious and has been studied in the first-line and second-line settings. De novo and acquired endocrine therapy resistance represent a major challenge to the ongoing treatment of patients with hormone receptor-positive disease; strategies to circumvent or delay resistance, including the use of combination endocrine therapy and endocrine therapy with agents targeting various growth-factor signaling pathways, represent an active area of investigation. This review provides a summary of the various landmark trials that have established our current standards of practice in the management of patients with hormone receptor-positive metastatic breast cancer. A discussion of future directions and ongoing studies is also provided.
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Antineoplásicos Hormonales/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Femenino , HumanosRESUMEN
Germline pathogenic variants (PVs) in the BRCA1 and BRCA2 genes confer elevated risks of breast, ovarian, and other cancers. Lynch syndrome (LS) is associated with increased risks of multiple cancer types including colorectal and uterine cancers. Current cancer risk mitigation strategies have focused on pharmacologic risk reduction, enhanced surveillance, and preventive surgeries. While these approaches can be effective, they stand to be improved on because of either limited efficacy or undesirable impact on quality of life. The current review summarizes ongoing investigational efforts in cancer risk prevention strategies for patients with germline PVs in BRCA1, BRCA2, or LS-associated genes. These efforts span radiation, surgery, and pharmacology including vaccine strategies. Understanding the molecular events involved in the premalignant to malignant transformation in high-risk individuals may ultimately contribute significantly to novel prevention strategies.
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Proteína BRCA1 , Proteína BRCA2 , Neoplasias Colorrectales Hereditarias sin Poliposis , Predisposición Genética a la Enfermedad , Humanos , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Neoplasias Colorrectales Hereditarias sin Poliposis/prevención & control , Proteína BRCA1/genética , Proteína BRCA2/genética , Femenino , Síndromes Neoplásicos Hereditarios/genética , Síndromes Neoplásicos Hereditarios/prevención & control , Mutación de Línea GerminalRESUMEN
BACKGROUND: Germline heterozygous TP53 pathogenic variants (PVs) cause Li Fraumeni Syndrome (LFS, OMIM#151623). TP53 PVs at lower-than-expected variant allele frequencies (VAF) may reflect postzygotic mosaicism (PZM) or clonal hematopoiesis (CH); however, no guidelines exist for workup and clinical management. PATIENTS AND METHODS: Retrospective analysis of probands who presented to an academic cancer genetics program with a TP53 PV result on germline genetic testing. RESULTS: Twenty-one of 125 unrelated probands (17 %) were found to harbor a TP53 PV with VAF<30 % or a designation of "mosaic". A diagnosis of PZM was made in nine (43 %) due to a clinical phenotype consistent with LFS with (n = 8) or without (n = 1) positive ancillary tissue testing. Twelve patients (57 %) were diagnosed with presumed CH (pCH) due to a diagnosis of a myeloproliferative neoplasm, negative ancillary tissue testing, clinical phenotype not meeting LFS criteria, no cancer, and/or no first cancer age<50. Of the 19 patients with biological offspring, nine had either partial or complete offspring testing, all negative. CONCLUSIONS: Determining the etiology of low VAF TP53 PVs requires ancillary tissue testing and incorporation of clinical phenotype. Discerning PZM versus CH is important to provide optimal care and follow-up.
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Pruebas Genéticas , Mutación de Línea Germinal , Síndrome de Li-Fraumeni , Mosaicismo , Proteína p53 Supresora de Tumor , Humanos , Pruebas Genéticas/métodos , Proteína p53 Supresora de Tumor/genética , Femenino , Masculino , Síndrome de Li-Fraumeni/genética , Estudios Retrospectivos , Adulto , Persona de Mediana Edad , Adulto Joven , AdolescenteRESUMEN
Importance: Agents targeting programmed death ligand 1 (PD-L1) have demonstrated efficacy in triple-negative breast cancer (TNBC) when combined with chemotherapy and are now the standard of care in patients with PD-L1-positive metastatic disease. In contrast to microtubule-targeting agents, the effect of combining platinum compounds with programmed cell death 1 (PD-1)/PD-L1 immunotherapy has not been extensively determined. Objective: To evaluate the efficacy of atezolizumab with carboplatin in patients with metastatic TNBC. Design, Setting, and Participants: This phase 2 randomized clinical trial was conducted in 6 centers from August 2017 to June 2021. Interventions: Patients with metastatic TNBC were randomized to receive carboplatin area under the curve (AUC) 6 alone or with atezolizumab, 1200 mg, every 3 weeks until disease progression or unacceptable toxic effects with a 3-year duration of follow-up. Main Outcome and Measures: The primary end point was investigator-assessed progression-free survival (PFS). Secondary end points included overall response rate (ORR), clinical benefit rate (CBR), and overall survival (OS). Other objectives included correlation of response with tumor PD-L1 levels, tumor-infiltrating lymphocytes (TILs), tumor DNA- and RNA-sequenced biomarkers, TNBC subtyping, and multiplex analyses of immune markers. Results: All 106 patients with metastatic TNBC who were enrolled were female with a mean (range) age of 55 (27-79) years, of which 12 (19%) identified as African American/Black, 1 (1%) as Asian, 73 (69%) as White, and 11 (10%) as unknown. Patients were randomized and received either carboplatin (n = 50) or carboplatin and atezolizumab (n = 56). The combination improved PFS (hazard ratio [HR], 0.66; 95% CI, 0.44-1.01; P = .05) from a median of 2.2 to 4.1 months, increased ORR from 8.0% (95% CI, 3.2%-18.8%) to 30.4% (95% CI, 19.9%-43.3%), increased CBR at 6 months from 18.0% (95% CI, 9.8%-30.1%) to 37.5% (95% CI, 26.0%-50.6%), and improved OS (HR, 0.60; 95% CI, 0.37-0.96; P = .03) from a median of 8.6 to 12.6 months. Subgroup analysis showed PD-L1-positive tumors did not benefit more from adding atezolizumab (HR, 0.62; 95% CI, 0.23-1.65; P = .35). Patients with high TILs (HR, 0.12; 95% CI, 0.30-0.50), high mutation burden (HR, 0.50; 95% CI, 0.23-1.06), and prior chemotherapy (HR, 0.59; 95% CI, 0.36-0.95) received greater benefit on the combination. Patients with obesity and patients with more than 125 mg/dL on-treatment blood glucose levels were associated with better PFS (HR, 0.35; 95% CI, 0.10-1.80) on the combination. TNBC subtypes benefited from adding atezolizumab, except the luminal androgen receptor subtype. Conclusions and Relevance: In this randomized clinical trial, the addition of atezolizumab to carboplatin significantly improved survival of patients with metastatic TNBC regardless of PD-L1 status. Further, lower risk of disease progression was associated with increased TILs, higher mutation burden, obesity, and uncontrolled blood glucose levels. Trial Registration: ClinicalTrials.gov Identifier: NCT03206203.
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Anticuerpos Monoclonales Humanizados , Neoplasias de la Mama Triple Negativas , Humanos , Femenino , Persona de Mediana Edad , Anciano , Masculino , Carboplatino/uso terapéutico , Neoplasias de la Mama Triple Negativas/patología , Antígeno B7-H1/inmunología , Glucemia , Ligandos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Biomarcadores , Progresión de la Enfermedad , Obesidad , ApoptosisRESUMEN
PURPOSE: To develop recommendations for germline mutation testing for patients with breast cancer. METHODS: An ASCO-Society of Surgical Oncology (SSO) panel convened to develop recommendations based on a systematic review and formal consensus process. RESULTS: Forty-seven articles met eligibility criteria for the germline mutation testing recommendations; 18 for the genetic counseling recommendations. RECOMMENDATIONS: BRCA1/2 mutation testing should be offered to all newly diagnosed patients with breast cancer ≤65 years and select patients >65 years based on personal history, family history, ancestry, or eligibility for poly(ADP-ribose) polymerase (PARP) inhibitor therapy. All patients with recurrent breast cancer who are candidates for PARP inhibitor therapy should be offered BRCA1/2 testing, regardless of family history. BRCA1/2 testing should be offered to women who develop a second primary cancer in the ipsilateral or contralateral breast. For patients with prior history of breast cancer and without active disease, testing should be offered to patients diagnosed ≤65 years and selectively in patients diagnosed after 65 years, if it will inform personal and family risk. Testing for high-penetrance cancer susceptibility genes beyond BRCA1/2 should be offered to those with supportive family histories; testing for moderate-penetrance genes may be offered if necessary to inform personal and family cancer risk. Patients should be provided enough pretest information for informed consent; those with pathogenic variants should receive individualized post-test counseling. Variants of uncertain significance should not impact management, and patients with such variants should be followed for reclassification. Referral to providers experienced in clinical cancer genetics may help facilitate patient selection and interpretation of expanded testing, and provide counseling of individuals without pathogenic germline variants but with significant family history.Additional information is available at www.asco.org/breast-cancer-guidelines.
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Neoplasias de la Mama , Oncología Quirúrgica , Humanos , Femenino , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Neoplasias de la Mama/cirugía , Pruebas Genéticas , Proteína BRCA1/genética , Proteína BRCA2/genética , Recurrencia Local de Neoplasia/genética , Mutación de Línea Germinal , Medición de Riesgo , Células Germinativas/patología , Predisposición Genética a la EnfermedadRESUMEN
Despite the success of immune checkpoint inhibition (ICI) in treating cancer, patients with triple-negative breast cancer (TNBC) often develop resistance to therapy, and the underlying mechanisms are unclear. MHC-I expression is essential for antigen presentation and T-cell-directed immunotherapy responses. This study demonstrates that TNBC patients display intratumor heterogeneity in regional MHC-I expression. In murine models, loss of MHC-I negates antitumor immunity and ICI response, whereas intratumor MHC-I heterogeneity leads to increased infiltration of natural killer (NK) cells in an IFNγ-dependent manner. Using spatial technologies, MHC-I heterogeneity is associated with clinical resistance to anti-programmed death (PD) L1 therapy and increased NK:T-cell ratios in human breast tumors. MHC-I heterogeneous tumors require NKG2A to suppress NK-cell function. Combining anti-NKG2A and anti-PD-L1 therapies restores complete response in heterogeneous MHC-I murine models, dependent on the presence of activated, tumor-infiltrating NK and CD8+ T cells. These results suggest that similar strategies may enhance patient benefit in clinical trials. SIGNIFICANCE: Clinical resistance to immunotherapy is common in breast cancer, and many patients will likely require combination therapy to maximize immunotherapeutic benefit. This study demonstrates that heterogeneous MHC-I expression drives resistance to anti-PD-L1 therapy and exposes NKG2A on NK cells as a target to overcome resistance. This article is featured in Selected Articles from This Issue, p. 201.
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Neoplasias de la Mama Triple Negativas , Humanos , Animales , Ratones , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/genética , Inmunoterapia/métodos , Células Asesinas Naturales , Linfocitos T CD8-positivos , Antígeno B7-H1/metabolismoRESUMEN
Combinations of immune checkpoint inhibitors (ICI, including anti-PD-1/PD-L1) and chemotherapy have been FDA approved for metastatic and early-stage triple-negative breast cancer (TNBC), but most patients do not benefit. B7-H4 is a B7 family ligand with proposed immunosuppressive functions being explored as a cancer immunotherapy target and may be associated with anti-PD-L1 resistance. However, little is known about its regulation and effect on immune cell function in breast cancers. We assessed murine and human breast cancer cells to identify regulation mechanisms of B7-H4 in vitro. We used an immunocompetent anti-PD-L1-sensitive orthotopic mammary cancer model and induced ectopic expression of B7-H4. We assessed therapy response and transcriptional changes at baseline and under treatment with anti-PD-L1. We observed B7-H4 was highly associated with epithelial cell status and transcription factors and found to be regulated by PI3K activity. EMT6 tumors with cell-surface B7-H4 expression were more resistant to immunotherapy. In addition, tumor-infiltrating immune cells had reduced immune activation signaling based on transcriptomic analysis. Paradoxically, in human breast cancer, B7-H4 expression was associated with survival benefit for patients with metastatic TNBC treated with carboplatin plus anti-PD-L1 and was associated with no change in response or survival for patients with early breast cancer receiving chemotherapy plus anti-PD-1. While B7-H4 induces tumor resistance to anti-PD-L1 in murine models, there are alternative mechanisms of signaling and function in human cancers. In addition, the strong correlation of B7-H4 to epithelial cell markers suggests a potential regulatory mechanism of B7-H4 independent of PD-L1. SIGNIFICANCE: This translational study confirms the association of B7-H4 expression with a cold immune microenvironment in breast cancer and offers preclinical studies demonstrating a potential role for B7-H4 in suppressing response to checkpoint therapy. However, analysis of two clinical trials with checkpoint inhibitors in the early and metastatic settings argue against B7-H4 as being a mechanism of clinical resistance to checkpoints, with clear implications for its candidacy as a therapeutic target.
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Inmunoterapia , Neoplasias de la Mama Triple Negativas , Inhibidor 1 de la Activación de Células T con Dominio V-Set , Inhibidor 1 de la Activación de Células T con Dominio V-Set/genética , Inhibidor 1 de la Activación de Células T con Dominio V-Set/metabolismo , Animales , Humanos , Ratones , Femenino , Línea Celular Tumoral , Inmunoterapia/métodos , Neoplasias de la Mama Triple Negativas/inmunología , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/patología , Neoplasias de la Mama Triple Negativas/genética , Neoplasias de la Mama Triple Negativas/terapia , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Neoplasias de la Mama/inmunología , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Neoplasias de la Mama/genética , Antígeno B7-H1/metabolismo , Antígeno B7-H1/antagonistas & inhibidores , Células Epiteliales/metabolismo , Células Epiteliales/inmunología , Células Epiteliales/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacosRESUMEN
PURPOSE: Addition of ataxia telangiectasia and Rad3-related kinase inhibitors (ATRi) to PARP inhibitors (PARPi) overcomes PARPi resistance in high-grade serous ovarian cancer (HGSOC) cell and mouse models. We present the results of an investigator-initiated study of combination PARPi (olaparib) and ATRi (ceralasertib) in patients with acquired PARPi-resistant HGSOC. PATIENTS AND METHODS: Eligible patients had recurrent, platinum-sensitive BRCA1/2 mutated or homologous recombination (HR)-deficient (HRD) HGSOC and clinically benefited from PARPi (response by imaging/CA-125 or duration of maintenance therapy; > 12 months first-line or > 6 months ≥ second-line) before progression. No intervening chemotherapy was permitted. Patients received olaparib 300 mg twice daily and ceralasertib 160 mg daily on days 1 to 7 of a 28-day cycle. Primary objectives were safety and objective response rate (ORR). RESULTS: Thirteen patients enrolled were evaluable for safety and 12 for efficacy; 62% (n = 8) had germline BRCA1/2 mutations, 23% (n = 3) somatic BRCA1/2 mutations, and 15% (n = 2) tumors with positive HRD assay. Prior PARPi indication was treatment for recurrence (54%, n = 7), second-line maintenance (38%, n = 5) and first-line treatment with carboplatin/paclitaxel (8%, n = 1). There were 6 partial responses yielding an ORR of 50% (95% confidence interval, 0.15-0.72). Median treatment duration was 8 cycles (range 4-23+). Grade (G) 3/4 toxicities were 38% (n = 5); 15% (n = 2) G3 anemia, 23% (n = 3) G3 thrombocytopenia, 8% (n = 1) G4 neutropenia. Four patients required dose reductions. No patient discontinued treatment due to toxicity. CONCLUSIONS: Combination olaparib and ceralasertib is tolerable and shows activity in HR-deficient platinum-sensitive recurrent HGSOC that benefited and then progressed with PARPi as the penultimate regimen. These data suggest that ceralasertib resensitizes PARPi-resistant HGSOCs to olaparib, warranting further investigation.
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Antineoplásicos , Neoplasias Ováricas , Animales , Femenino , Humanos , Ratones , Antineoplásicos/uso terapéutico , Proteínas de la Ataxia Telangiectasia Mutada/genética , Proteína BRCA1/genética , Proteína BRCA2/genética , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Recombinación Homóloga , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/genética , Neoplasias Ováricas/patología , Ftalazinas , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéuticoRESUMEN
Purpose: Treatments are limited for metastatic melanoma and metastatic triple-negative breast cancer (mTNBC). This pilot phase I trial (NCT03060356) examined the safety and feasibility of intravenous RNA-electroporated chimeric antigen receptor (CAR) T cells targeting the cell-surface antigen cMET. Experimental Design: Metastatic melanoma or mTNBC subjects had at least 30% tumor expression of cMET, measurable disease and progression on prior therapy. Patients received up to six infusions (1 × 10e8 T cells/dose) of CAR T cells without lymphodepleting chemotherapy. Forty-eight percent of prescreened subjects met the cMET expression threshold. Seven (3 metastatic melanoma, 4 mTNBC) were treated. Results: Mean age was 50 years (35-64); median Eastern Cooperative Oncology Group 0 (0-1); median prior lines of chemotherapy/immunotherapy were 4/0 for TNBC and 1/3 for melanoma subjects. Six patients experienced grade 1 or 2 toxicity. Toxicities in at least 1 patient included anemia, fatigue, and malaise. One subject had grade 1 cytokine release syndrome. No grade 3 or higher toxicity, neurotoxicity, or treatment discontinuation occurred. Best response was stable disease in 4 and disease progression in 3 subjects. mRNA signals corresponding to CAR T cells were detected by RT-PCR in all patients' blood including in 3 subjects on day +1 (no infusion administered on this day). Five subjects underwent postinfusion biopsy with no CAR T-cell signals seen in tumor. Three subjects had paired tumor tissue; IHC showed increases in CD8 and CD3 and decreases in pS6 and Ki67. Conclusions: Intravenous administration of RNA-electroporated cMET-directed CAR T cells is safe and feasible. Significance: Data evaluating CAR T therapy in patients with solid tumors are limited. This pilot clinical trial demonstrates that intravenous cMET-directed CAR T-cell therapy is safe and feasible in patients with metastatic melanoma and metastatic breast cancer, supporting the continued evaluation of cellular therapy for patients with these malignancies.
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Melanoma , Neoplasias de la Mama Triple Negativas , Humanos , Persona de Mediana Edad , ARN/metabolismo , Linfocitos T , Inmunoterapia Adoptiva/efectos adversos , Melanoma/terapia , Neoplasias de la Mama Triple Negativas/terapiaRESUMEN
BACKGROUND: Breast cancer is the most common female cancer worldwide. Effective therapies including doxorubicin and trastuzumab have improved survival, but are associated with a substantial risk of cardiovascular disease. Mechanisms underlying cancer treatment-induced cardiotoxicity (CTC) are poorly understood and have largely focused on cardiomyocyte damage, although other cellular populations in the heart such as the cardiac endothelium, may play an important role in cardiac damage. We treated a breast tumor-bearing mouse model with doxorubicin and trastuzumab to investigate the role of the cardiac endothelium in the development of CTC. METHODS: Immune compromised mice were inoculated in the 4th mammary fat pad with human breast cancer cells overexpressing HER2 (BT474). When tumors were palpable, mice were treated weekly with doxorubicin (5 mg/kg) and trastuzumab (4 mg/kg). The cardiac phenotype of mice was assessed by echocardiography and histological evaluation of the heart. Cardiac vascular damage was assayed by in vivo permeability assays and primary cultures of murine cardiac endothelial cells were used to assay doxorubicin toxicity in vitro. RESULTS: The growth of BT474 breast tumors in Balb/c Nude mice was suppressed upon treatment with doxorubicin and trastuzumab. Mice treated for 4 months with doxorubicin and trastuzumab maintained body weights, but demonstrated an echocardiographic phenotype consistent with preserved left ventricular (LV) ejection fraction, decreased LV mass and increased filling pressures (E/e'). Histological staining with Masson's trichrome and Picrosirius red showed extensive fibrosis and increased collagen deposition in the ventricular myocardium surrounding blood vessels of treated mice compared to untreated mice. Evans blue permeability assays demonstrated increased cardiac vasculature permeability while primary cardiac endothelial cells exposed to doxorubicin in vitro showed increased cell death as compared to lung or liver endothelial cells. CONCLUSIONS: An orthotopic mouse model of human breast cancer in Nude mice treated with doxorubicin and trastuzumab resulted in a cardiac vascular defect accompanied by preserved LV ejection fraction, decreased LV mass, suggesting mild diastolic dysfunction and cardiac remodeling consistent with subclinical cardiotoxicity. Our data suggest that cardiac endothelium is more sensitive to doxorubicin therapy as compared to other organ endothelium and cardiac endothelial damage may correlate with breast cancer treatment-induced cardiotoxicity.
RESUMEN
BACKGROUND[18F]FluorThanatrace ([18F]FTT) is a radiolabeled poly (adenosine diphosphate-ribose) polymerase inhibitor (PARPi) that enables noninvasive quantification of PARP with potential to serve as a biomarker for patient selection for PARPi therapy. Here we report for the first time to our knowledge noninvasive in vivo visualization of drug-target engagement during PARPi treatment.METHODSTwo single-arm, prospective, nonrandomized clinical trials were conducted at the University of Pennsylvania from May 2017 to March 2020. PARP expression in breast cancer was assessed in vivo via [18F]FTT PET before and after initiation of PARPi treatment and in vitro via [125I]KX1 (an analog of [18F]FTT) binding to surgically removed breast cancer.RESULTSThirteen patients had baseline [18F]FTT PET. Nine of these then had resection and in vitro evaluation of [18F]FTT uptake with an analog and uptake was blocked with PARPi. Of the other 4 patients, 3 had [18F]FTT PET uptake, and all had uptake blocked with treatment with a therapeutic PARPi. Initial in vivo [18F]FTT tumor uptake ranged from undetectable to robust. Following initiation of PARPi therapy, [18F]FTT uptake was not detectable above background in all cases. In vitro tumor treatment with a PARPi resulted in 82% reduction in [125I]KX1 binding.CONCLUSION[18F]FTT noninvasively quantifies PARP-1 expression. Early results indicate ability to visualize PARPi drug-target engagement in vivo and suggest the utility of further study to test [18F]FTT PET as a predictive and pharmacodynamic biomarker.TRIAL REGISTRATIONClinicalTrials.gov identifiers NCT03083288 and NCT03846167.FUNDINGMetavivor Translational Research Award, Susan G. Komen for the Cure (CCR 16376362), Department of Defense BC190315, and Abramson Cancer Center Breakthrough Bike Challenge.
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Neoplasias de la Mama/diagnóstico por imagen , Neoplasias Hepáticas/diagnóstico por imagen , Ganglios Linfáticos/diagnóstico por imagen , Poli(ADP-Ribosa) Polimerasa-1/metabolismo , Inhibidores de Poli(ADP-Ribosa) Polimerasas/metabolismo , Radiofármacos , Neoplasias de la Columna Vertebral/diagnóstico por imagen , Adulto , Anciano , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Femenino , Humanos , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/secundario , Ganglios Linfáticos/metabolismo , Persona de Mediana Edad , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Tomografía Computarizada por Tomografía de Emisión de Positrones , Neoplasias de la Columna Vertebral/tratamiento farmacológico , Neoplasias de la Columna Vertebral/metabolismo , Neoplasias de la Columna Vertebral/secundarioRESUMEN
Carriers of a pathogenic/likely pathogenic (P/LP) BRCA1/BRCA2/ATM/PALB2 variant are at increased risk of pancreatic ductal adenocarcinoma (PDAC), yet current guidelines recommend surveillance only for those with a family history of PDAC. We aimed to investigate outcomes of endoscopic ultrasound (EUS)-based PDAC surveillance in BRCA1/BRCA2/ATM/PALB2 carriers without a family history of PDAC. We performed a retrospective analysis of all P/LP BRCA1/BRCA2/ATM/PALB2 carriers who underwent EUS at a tertiary care center. Of 194 P/LP BRCA1/BRCA2/ATM/PALB2 carriers who underwent EUS, 64 (33%) had no family history of PDAC and had at least 1 EUS for PDAC surveillance. These individuals underwent 143 total EUSs, were predominantly female (72%), and BRCA2 carriers (73%), with the majority having a personal history of cancer other than PDAC (67%). The median age at time of first EUS was 62 years [interquartile range (IQR), 53-67 years] and a median of 2 EUSs (IQR 1-3) were performed per patient, with a median of 3 years (IQR 2-4.5 years) between the first and last EUS for those with more than 1 EUS. Pancreatic abnormalities were detected in 44%, including cysts in 27%, and incidental luminal abnormalities in 41%. Eight percent developed a new pancreatic mass or cyst during surveillance, 2 individuals developed PDAC, and no serious complications resulted from surveillance. After discussion of the risks, limitations, and potential benefits, PDAC surveillance can be considered in BRCA1/BRCA2/ATM/PALB2 carriers without a family history of PDAC; however, the effectiveness of PDAC surveillance in this population requires further study. PREVENTION RELEVANCE: BRCA1/BRCA2/ATM/PALB2 carriers have increased pancreatic ductal adenocarcinoma (PDAC) risk, yet are typically not eligible for PDAC surveillance in the absence of PDAC family history. Herein we describe outcomes of PDAC surveillance in BRCA1/BRCA2/ATM/PALB2 carriers without a family history of PDAC, showing that PDAC surveillance can be considered in this high-risk group.