RESUMO
SMARCA4 gene encodes BRG1 , a member of the SWItch/sucrose non-fermentable protein family involved in epigenetic transcriptional regulation of important cellular processes. In the uterine corpus, SMARCA4 / BRG1 deficiency is associated with a novel class of undifferentiated uterine sarcomas, characterized by younger age onset, rhabdoid histology, focal phyllodiform architecture, high-risk pathologic findings, and dismal prognosis. Herein, we report a case of a 34-year-old Asian woman with a SMARCA4 / BRG1 -deficient uterine tumor fulfilling the clinicopathologic features of an undifferentiated uterine sarcoma. However, the tumor exhibited several unique features that have not been previously emphasized, including (1) conspicuous phyllodiform architecture recapitulating conventional adenosarcoma, (2) rhabdoid tumor cells forming cords and keratin-positive cohesive epithelial islands, and (3) cooccurrence with a spatially distinct and discrete endometrial complex atypical hyperplasia from the rest of the proliferation. By immunohistochemistry, the tumor cells were diffusely positive for synaptophysin, whereas BRG1 was lost. Pertinent molecular findings included frameshift mutations in the SMARCA4 gene, mutations in histone modification and chromatin remodeling genes, including KMT2C , ARID1B , KAT6A , and NCOR1 , and mutations in Wnt signaling involving APC and CTNNB1 . Copy number gain in MDM2 and CDK4 were also identified. The tumor mutation burden was intermediate (6.8/MB) and it was microsatellite stable. On balance, our case exhibited morphologic and molecular features that overlap with (1) an undifferentiated uterine sarcoma, (2) an adenosarcoma with sarcomatous overgrowth, and (3) a mixed adenosarcoma and undifferentiated endometrial carcinoma. These hybrid features further expand the molecular-morphologic spectrum of SMARCA4 / BRG1 -deficient uterine neoplasms.
Assuntos
Adenossarcoma , DNA Helicases , Proteínas Nucleares , Fatores de Transcrição , Neoplasias Uterinas , Humanos , Feminino , DNA Helicases/genética , DNA Helicases/deficiência , Fatores de Transcrição/genética , Fatores de Transcrição/deficiência , Proteínas Nucleares/genética , Proteínas Nucleares/deficiência , Adulto , Adenossarcoma/patologia , Adenossarcoma/genética , Neoplasias Uterinas/patologia , Neoplasias Uterinas/genética , Imuno-Histoquímica , Carcinoma/patologia , Carcinoma/genéticaRESUMO
BACKGROUND: The objective of this study was to evaluate the safety and efficacy of nab-paclitaxel, trastuzumab, and pertuzumab as neoadjuvant therapy (NAT) in patients with human epidermal growth factor receptor 2 HER2+ breast cancer (HER2+ BC) to determine pathologic complete response (pCR), invasive disease-free survival (iDFS), and overall survival. METHODS: Forty-five patients with HER2+ BC Stages II-III were to be enrolled from 2013 to 2017. Patients were treated with weekly nab-paclitaxel (100 mg/m2 intravenously), weekly trastuzumab (4 mg/kg loading dose, then 2 mg/kg), and six cycles of pertuzumab (840 mg loading dose, then 420 mg intravenously day 1 every 21 days). RESULTS: Median follow-up was 60 months (95% CI, 32.3-55.6) and pCR was 29/45 (64%). The 5-year iDFS for patients who achieved pCR (N = 29) was 96.3% (95% CI, 76.5-99.5) and non-pCR patients (N = 16) was 74.3% (95% CI, 39.1-91.0). The 5-year overall survival (N = 45) was 94.1% (95% CI, 77.6-98.5). Based on hormonal status, the 5-year iDFS for HR+ pCR patients (N = 14) was 92.3% (95% CI, 56.6-98.9) and for HR- (N = 15) was 100% (p = .3). CONCLUSIONS: This anthracycline/carboplatin-free regimen with nab-paclitaxel achieved a pCR rate of 64% in patients with HER2+ BC. The 5-year iDFS in patients with and without pCR was 96.3% and 74.3%, respectively. The pCR rate is comparable with docetaxel, carboplatin, trastuzumab, and pertuzumab therapy in the NAT setting, but with fewer treatment-associated toxicities. This finding suggests the possibility of safe avoidance of anthracyclines and carboplatin as components of NAT in patients with HER2+ BC.
Assuntos
Neoplasias da Mama , Humanos , Feminino , Trastuzumab/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Terapia Neoadjuvante/efeitos adversos , Estudos Prospectivos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Paclitaxel , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Carboplatina , Antraciclinas/uso terapêuticoRESUMO
BACKGROUND: Hyperglycemia is recognized as a common adverse event for patients receiving alpelisib but has been little studied outside of clinical trials. We report the frequency of alpelisib-associated hyperglycemia in a real-world setting and evaluate proposed risk factors. PATIENTS AND METHODS: We retrospectively identified patients with PIK3CA-mutated, hormone receptor-positive, metastatic breast cancer who initiated treatment with alpelisib plus fulvestrant between August 2019 and December 2021. Ordinal logistic regression evaluated 5 characteristics (diabetes, prediabetes, body mass index [BMI], age, and Asian ancestry) as independent risk factors for ALP-associated hyperglycemia grades 2-4. Risk of error from multiple hypothesis testing was controlled using the false discovery rate method. RESULTS: The study included n = 92 subjects, all but 1 female, mean age 59.9 (+11.9) years with 50% non-Hispanic White, 15% Hispanic/Latino, 13% Asian, 9% African/Black, and 13% other/unknown. In total 34% of patients had diabetes, 10% had pre-diabetes, and 56% had normoglycemia. Thirty-six percent were obese, 32% were overweight, 25% were normal weight, and 7% were lean. Frequency of grades 1-4 hyperglycemia in current subjects (64.1%) was similar to hyperglycemia reported in the SOLAR-1 trial (63.7%). Our subjects' risk of grades 2-4 hyperglycemia was independently increased by pre-existing diabetes (Odds ratio 3.75, 95% CI, 1.40-10.01), pre-diabetes (6.22, 1.12-34.47), Asian ancestry (7.10, 1.75-28.84), and each unit of BMI above 20 (1.17, 1.07-1.28). CONCLUSION: While receiving alpelisib, patients of Asian ancestry, as well as patients with pre-existing hyperglycemia and/or BMI above 20, should be closely monitored for hyperglycemia. The mechanism underlying the current association of alpelisib-associated hyperglycemia with Asian ancestry is independent of BMI and merits further study. The high incidence of hyperglycemia resulted in a change in practice to include consultation with a diabetes nurse educator or endocrinologist at the start of alpelisib.
Assuntos
Neoplasias da Mama , Hiperglicemia , Estado Pré-Diabético , Humanos , Feminino , Pessoa de Meia-Idade , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Fulvestranto/uso terapêutico , Estado Pré-Diabético/induzido quimicamente , Estado Pré-Diabético/tratamento farmacológico , Estudos Retrospectivos , Receptor ErbB-2/uso terapêutico , Hiperglicemia/induzido quimicamente , Hiperglicemia/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêuticoRESUMO
BACKGROUND: This trial evaluated the safety and efficacy of ipatasertib in combination with carboplatin, carboplatin/paclitaxel, or capecitabine/atezolizumab in patients with metastatic triple-negative breast cancer (mTNBC). METHODS: Eligibility criteria were mTNBC, RECIST 1.1 measurable disease, no prior use of platinum for metastatic disease (Arms A and B), and no prior exposure to immune checkpoint inhibitor (Arm C). Primary endpoints were safety and RP2D. Secondary endpoints were progression-free survival (PFS), response rate, and overall survival. RESULTS: RP2D for Arm A (n = 10) was ipatasertib 300 mg daily, carboplatin AUC2, and paclitaxel 80 mg m-2 days 1, 8, and 15 every 28 days. RP2D for Arm B (n = 12) was ipatasertib 400 mg daily and carboplatin AUC2 days 1, 8, and 15 every 28 days. RP2D for Arm C (n = 6) was likely ipatasertib 300 mg 21 days on 7 days off, capecitabine 750 mg m-2, twice a day, 7 days on 7 days off, and atezolizumab 840 mg days 1 and 15 every 28 days. The most common (≥10%) grade 3-4 AEs at RP2D for Arm A (N = 7 at RP2D) were neutropenia (29%), diarrhea (14%), oral mucositis (14%), and neuropathy (14%); Arm B had diarrhea (17%) and lymphopenia (25%); and Arm C had anemia, fatigue, cognitive disturbance, and maculopapular rash (17% each). Overall responses at RP2D were 29% Arm A, 25% Arm B, and 33% Arm C. PFS was 4.8, 3.9, and 8.2 months for patients on Arms A, B, and C, respectively. CONCLUSIONS: Continuous dosing of ipatasertib with chemotherapy was safe and well-tolerated. Further study is warranted in understanding the role of AKT inhibition in treatment of TNBCs. TRIAL REGISTRATION: NCT03853707.
Assuntos
Neoplasias de Mama Triplo Negativas , Humanos , Carboplatina , Capecitabina/efeitos adversos , Neoplasias de Mama Triplo Negativas/patologia , Paclitaxel , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversosRESUMO
Currently there is a limited understanding for the optimal combination of immune checkpoint inhibitor and chemotherapy for patients with metastatic triple-negative breast cancer (mTNBC). Here we evaluate the safety, efficacy, and immunogenicity of a phase I trial for patients with mTNBC treated with pembrolizumab plus doxorubicin. Patients without prior anthracycline use and 0-2 lines of prior systemic chemotherapies received pembrolizumab and doxorubicin every 3 weeks for 6 cycles followed by pembrolizumab maintenance until disease progression or intolerance. The primary objectives were safety and objective response rate per RECIST 1.1. Best responses included one complete response (CR), five partial responses (PR), two stable disease (SD), and one progression of disease (PD). Overall response rate was 67% (95% CI 13.7%, 78.8%) and clinical benefit rate at 6 months was 56% (95% CI 21.2%, 86.3%). Median PFS was 5.2 months (95% CI 4.7, NA); median OS was 15.6 months (95% CI 13.3, NA). Grade 3-4 AEs per CTCAE 4.0 were neutropenia n = 4/10 (40%), leukopenia n = 2/10 (20%), lymphopenia n = 2/10 (20%), fatigue n = 2/10 (20%), and oral mucositis n = 1/10 (10%). Immune correlates showed increased frequencies of circulating CD3 + T cells (p = 0.03) from pre-treatment to cycle 2 day 1 (C2D1). An expansion of a proliferative exhausted-like PD-1 + CD8 + T cell population was identified in 8/9 patients, and exhausted CD8 + T cells were significantly expanded from pre-treatment to C2D1 in the patient with CR (p = 0.01). In summary, anthracycline-naïve patients with mTNBC treated with the combination of pembrolizumab and doxorubicin showed an encouraging response rate and robust T cell response dynamics.Trial registration: NCT02648477.
Assuntos
Neoplasias de Mama Triplo Negativas , Humanos , Neoplasias de Mama Triplo Negativas/patologia , Doxorrubicina/uso terapêutico , Anticorpos Monoclonais Humanizados/efeitos adversos , Antraciclinas/uso terapêutico , Progressão da Doença , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversosRESUMO
The goal of immunotherapy is to mobilize the immune system to kill cancer cells. Immunotherapy is more effective and, in general, the prognosis is better, when more immune cells infiltrate the tumor. We explore the question of whether the spatial distribution rather than just the density of immune cells in the tumor is important in forecasting whether cancer recurs. After reviewing previous work on this issue, we introduce a novel application of maximum entropy to quantify the spatial distribution of discrete point-like objects. We apply our approach to B and T cells in images of tumor tissue taken from triple negative breast cancer patients. We find that the immune cells are more spatially dispersed in good clinical outcome (no recurrence of cancer within at least 5 years of diagnosis) compared to poor clinical outcome (recurrence within 3 years of diagnosis). Our results highlight the importance of spatial distribution of immune cells within tumors with regard to clinical outcome, and raise new questions on their role in cancer recurrence.
Assuntos
Recidiva Local de Neoplasia , Neoplasias de Mama Triplo Negativas , Humanos , Imunoterapia , Física , Linfócitos TRESUMO
BACKGROUND: Triple-negative breast cancer (TNBC) has a high recurrence risk and poor clinical outcomes. Associations between metabolic syndrome (MetS) risk components and mortality in postmenopausal women with TNBC were examined in the Women's Health Initiative. METHODS: Five hundred forty-four postmenopausal women were diagnosed with nonmetastatic TNBC. Baseline risk components included a high waist circumference (≥88 cm), high blood pressure, hypercholesterolemia, and diabetes. Groups were categorized by the number of MetS risk components: none, 1 or 2, or 3 or 4. Hazard ratios (HRs) and 95% confidence intervals (CIs) across groups were computed with multivariable adjusted Cox models. Outcomes included breast cancer-specific mortality and breast cancer overall mortality (breast cancer followed by death from any cause). Variables in the multivariable model included age at TNBC diagnosis; race/ethnicity; income; education; clinical/observational trial status; history of oral contraceptive, hormone, and/or statin use; cancer stage; and chemotherapy and/or radiation treatment status. RESULTS: Of the 544 participants with TNBC, 33% had no MetS risk components (n = 178), 59% had 1 or 2 risk components (n = 323), and 8% had 3 or 4 risk components (n = 43). After a median follow-up from diagnosis of 8.3 years, multivariable results showed that women with 3 or 4 risk components had a nonsignificantly higher risk of breast cancer mortality (HR, 2.05; 95% CI, 0.94-4.47 trend P = .114) and a significantly higher risk of overall mortality (HR, 2.13; 95% CI, 1.22-3.71; trend P = .006) versus women with 0 risk components. CONCLUSIONS: Postmenopausal women with TNBC and 3 or 4 MetS risk components have a nonsignificantly higher breast cancer mortality risk and a significantly higher overall mortality risk, likely because of negative influences of metabolic risk factors on several causes of death.
Assuntos
Síndrome Metabólica , Neoplasias de Mama Triplo Negativas , Feminino , Humanos , Síndrome Metabólica/epidemiologia , Síndrome Metabólica/mortalidade , Pós-Menopausa , Fatores de Risco , Neoplasias de Mama Triplo Negativas/diagnóstico , Neoplasias de Mama Triplo Negativas/mortalidade , Saúde da MulherRESUMO
BACKGROUND: In this phase II clinical trial, we evaluated the efficacy of the nonanthracycline combination of carboplatin and nab-paclitaxel in early stage triple-negative breast cancer (TNBC). PATIENTS AND METHODS: Patients with newly diagnosed stage II-III TNBC (n = 69) were treated with neoadjuvant carboplatin (area under the curve 6) every 28 days for four cycles plus nab-paclitaxel (100 mg/m2 ) weekly for 16 weeks. Pathological complete response (pCR) and residual cancer burden (RCB) were analyzed with germline mutation status, tumor-infiltrating lymphocytes (TILs), TNBC molecular subtype, and GeparSixto immune signature (GSIS). RESULTS: Sixty-seven patients were evaluable for safety and response. Fifty-three (79%) patients experienced grade 3/4 adverse events, including grade 3 anemia (43%), neutropenia (39%), leukopenia (15%), thrombocytopenia (12%), fatigue (7%), peripheral neuropathy (7%), neutropenia (16%), and leukopenia (1%). Twenty-four patients (35%) had at least one dose delay, and 50 patients (72%) required dose reduction. Sixty-three (94%) patients completed scheduled treatment. The responses were as follows: 32 of 67 patients (48%) had pCR (RCB 0), 10 of 67 (15%) had RCB I, 19 of 67 (28%) had RCB II, 5 of 67 (7%) had RCB III, and 1 of 67 (2%) progressed and had no surgery. Univariate analysis showed that immune-hot GSIS and DNA repair defect (DRD) were associated with higher pCR with odds ratios of 4.62 (p = .005) and 4.76 (p = .03), respectively, and with RCB 0/I versus RCB II/III with odds ratio 4.80 (p = .01). Immune-hot GSIS was highly correlated with DRD status (p = .03), TIL level (p < .001), and TNBC molecular subtype (p < .001). After adjusting for age, race, stage, and grade, GSIS remained associated with higher pCR and RCB class 0/I versus II/III with odds ratios 7.19 (95% confidence interval [CI], 2.01-25.68; p = .002) and 8.95 (95% CI, 2.09-38.23; p = .003), respectively. CONCLUSION: The combination of carboplatin and nab-paclitaxel for early stage high-risk TNBC showed manageable toxicity and encouraging antitumor activity. Immune-hot GSIS is associated with higher pCR rate and RCB class 0/1. This study provides an additional rationale for using nonanthracycline platinum-based therapy for future neoadjuvant trials in early stage TNBCs. Clinical trial identification number: NCT01525966 IMPLICATIONS FOR PRACTICE: Platinum is an important neoadjuvant chemotherapy agent for treatment of early stage triple-negative breast cancer (TNBC). In this study, carboplatin and nab-paclitaxel were well tolerated and highly effective in TNBC, resulting in pathological complete response of 48%. In univariate and multivariate analyses adjusting for age, race, tumor stage and grade, "immune-hot" GeparSixto immune signature (GSIS) and DNA repair defect (DRD) were associated with higher pathological complete response (pCR) and residual cancer burden class 0/1. The association of immune-hot GSIS with higher pCR holds promise for de-escalating neoadjuvant chemotherapy for patients with early stage TNBC. Although GSIS is not routinely used in clinic, further development of this immune signature into a clinically applicable assay is indicated.
Assuntos
Terapia Neoadjuvante , Neoplasias de Mama Triplo Negativas , Albuminas , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carboplatina/uso terapêutico , Humanos , Paclitaxel/efeitos adversos , Resultado do Tratamento , Neoplasias de Mama Triplo Negativas/tratamento farmacológicoRESUMO
LESSONS LEARNED: The combination of enobosarm and pembrolizumab was well tolerated and showed a modest clinical benefit rate of 25% at 16 weeks. Future trials investigating androgen receptor-targeted therapy in combination with immune checkpoint inhibitors are warranted. BACKGROUND: Luminal androgen receptor is a distinct molecular subtype of triple-negative breast cancer (TNBC) defined by overexpression of androgen receptor (AR). AR-targeted therapy has shown modest activity in AR-positive (AR+) TNBC. Enobosarm (GTx-024) is a nonsteroidal selective androgen receptor modulator (SARM) that demonstrates preclinical and clinical activity in AR+ breast cancer. The current study was designed to explore the safety and efficacy of the combination of enobosarm and pembrolizumab in patients with AR+ metastatic TNBC (mTNBC). METHODS: This study was an open-label phase II study for AR+ (≥10%, 1+ by immunohistochemistry [IHC]) mTNBC. Eligible patients received pembrolizumab 200 mg intravenous (IV) every 3 weeks and enobosarm 18 mg oral daily. The primary objective was to evaluate the safety of enobosarm plus pembrolizumab and determine the response rate. Peripheral blood, tumor biopsies, and stool samples were collected for correlative analysis. RESULTS: The trial was stopped early because of the withdrawal of GTx-024 drug supply. Eighteen patients were enrolled, and 16 were evaluable for responses. Median age was 64 (range 36-81) years. The combination was well tolerated, with only a few grade 3 adverse events: one dry skin, one diarrhea, and one musculoskeletal ache. The responses were 1 of 16 (6%) complete response (CR), 1 of 16 (6%) partial response (PR), 2 of 16 (13%) stable disease (SD), and 12 of 16 (75%) progressive disease (PD). Response rate (RR) was 2 of 16 (13%). Clinical benefit rate (CBR) at 16 weeks was 4 of 16 (25%). Median follow-up was 24.9 months (95% confidence interval [CI], 17.5-30.9). Progression-free survival (PFS) was 2.6 months (95% CI, 1.9-3.1) and overall survival (OS) was 25.5 months (95% CI, 10.4-not reached [NR]). CONCLUSION: The combination of enobosarm and pembrolizumab was well tolerated, with a modest clinical benefit rate of 25% at 16 weeks in heavily pretreated AR+ TNBC without preselected programmed death ligand-1 (PD-L1). Future clinical trials combining AR-targeted therapy with immune checkpoint inhibitor (ICI) for AR+ TNBC warrant investigation.
Assuntos
Neoplasias de Mama Triplo Negativas , Adulto , Idoso , Idoso de 80 Anos ou mais , Anilidas , Anticorpos Monoclonais Humanizados , Humanos , Pessoa de Meia-Idade , Receptores Androgênicos , Neoplasias de Mama Triplo Negativas/tratamento farmacológicoRESUMO
BACKGROUND: Alteration of the PI3K/AKT/mTOR pathway is a common genomic abnormality detected in triple-negative breast cancer (TNBC). Everolimus acts synergistically with eribulin in TNBC cell lines and xenograft models. This phase I trial was designed to test the safety and tolerability of combining eribulin and everolimus in patients with metastatic TNBC. METHODS: The primary objective of this study was to evaluate the safety and toxicities of the combination. Patients with metastatic TNBC who had up to four lines of prior chemotherapies were enrolled. The combination of eribulin and everolimus was tested using three dosing levels: A1 (everolimus 5 mg daily; eribulin 1.4 mg/m2 days 1 and 8 every 3 weeks), A2 (everolimus 7.5 mg daily; eribulin 1.4 mg/m2, days 1 and 8 every 3 weeks), and B1 (everolimus 5 mg daily; eribulin 1.1 mg/m2 days 1 and 8 every 3 weeks). RESULTS: Twenty-seven patients with median age 55 years were enrolled. Among 8 evaluable patients who received dose level A1, 4 had dose-limiting toxicities (DLTs). Among 3 evaluable patients treated with dose level A2, 2 had DLTs. Among 12 evaluable patients who received dose level B1, 4 had DLTs. The DLTs were neutropenia, stomatitis, and hyperglycemia. Over the study period, 59% had a ≥ grade 3 toxicity, 44% had ≥ grade 3 hematologic toxicities, and 22% had grade 4 hematologic toxicities. The most common hematological toxicities were neutropenia, leukopenia, and lymphopenia. Thirty-three percent had grade 3 non-hematologic toxicities. The most common non-hematological toxicities were stomatitis, hyperglycemia, and fatigue. The median number of cycles completed was 4 (range 0-8). Among 25 eligible patients, 9 patients (36%) achieved the best response as partial response, 9 (36%) had stable disease, and 7 (28%) had progression. The median time to progression was 2.6 months (95% CI [2.1, 4.0]), and median overall survival (OS) was 8.3 months (95% CI [5.5, undefined]). CONCLUSION: Eribulin 1.1 mg/m2 days 1 and 8 every 3 weeks with everolimus 5 mg daily was defined as the highest dose with acceptable toxicity (RP2D). The combination is safe, and efficacy is modest. A post hoc analysis showed that participants that used dexamethasone mouthwash stayed on treatment for one additional cycle. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02120469. Registered 18 April 2014.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Relação Dose-Resposta a Droga , Esquema de Medicação , Everolimo/administração & dosagem , Everolimo/efeitos adversos , Fadiga/induzido quimicamente , Feminino , Furanos/administração & dosagem , Furanos/efeitos adversos , Humanos , Estimativa de Kaplan-Meier , Cetonas/administração & dosagem , Cetonas/efeitos adversos , Pessoa de Meia-Idade , Neutropenia/induzido quimicamente , Estomatite/induzido quimicamente , Neoplasias de Mama Triplo Negativas/genéticaRESUMO
BACKGROUND: Gene expression profiling of rare cancers has proven challenging due to limited access to patient materials and requirement of intact, non-degraded RNA for next-generation sequencing. We customized a gene expression panel compatible with degraded RNA from formalin-fixed, paraffin-embedded (FFPE) patient cancer samples and investigated its utility in pathway activity profiling in patients with metaplastic breast cancer (MpBC). METHODS: Activity of various biological pathways was profiled in samples from nineteen patients with MpBC and 8 patients with invasive ductal carcinoma with triple negative breast cancer (TNBC) phenotype using a custom gene expression-based assay of 345 genes. RESULTS: MpBC samples of mesenchymal (chondroid and/or osteoid) histology demonstrated increased SNAI1 and BCL2L11 pathway activity compared to samples with non-mesenchymal histology. Additionally, late cornified envelope and keratinization genes were downregulated in MpBC compared to TNBC, and epithelial-to-mesenchymal transition (EMT) and collagen genes were upregulated in MpBC. Patients with high activity of an invasiveness gene expression signature, as well as high expression of the mesenchymal marker and extracellular matrix glycoprotein gene SPARC, experienced worse outcomes than those with low invasiveness activity and low SPARC expression. CONCLUSIONS: This study demonstrates the utility of gene expression profiling of metaplastic breast cancer FFPE samples with a custom counts-based assay. Gene expression patterns identified by this assay suggest that, although often histologically triple negative, patients with MpBC have distinct pathway activation compared to patients with invasive ductal TNBC. Incorporation of targeted therapies may lead to improved outcome for MpBC patients, especially in those patients expressing increased activity of invasiveness pathways.
Assuntos
Carcinoma Ductal de Mama/genética , Receptores de Fatores de Crescimento/metabolismo , Transdução de Sinais/genética , Transcriptoma/genética , Neoplasias de Mama Triplo Negativas/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Proteína 11 Semelhante a Bcl-2/metabolismo , Carcinoma Ductal de Mama/patologia , Estudos de Coortes , Transição Epitelial-Mesenquimal/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Pessoa de Meia-Idade , Osteonectina/genética , Fenótipo , Prognóstico , RNA-Seq/métodos , Fatores de Transcrição da Família Snail/metabolismo , Neoplasias de Mama Triplo Negativas/patologiaRESUMO
BACKGROUND: Triple negative breast cancer (TNBC) is aggressive with limited treatment options upon recurrence. Molecular discordance between primary and metastatic TNBC has been observed, but the degree of biological heterogeneity has not been fully explored. Furthermore, genomic evolution through treatment is poorly understood. In this study, we aim to characterize the genomic changes between paired primary and metastatic TNBCs through transcriptomic and genomic profiling, and to identify genomic alterations which may contribute to chemotherapy resistance. METHODS: Genomic alterations and mRNA expression of 10 paired primary and metastatic TNBCs were determined through targeted sequencing, microarray analysis, and RNA sequencing. Commonly mutated genes, as well as differentially expressed and co-expressed genes were identified. We further explored the clinical relevance of differentially expressed genes between primary and metastatic tumors to patient survival using large public datasets. RESULTS: Through gene expression profiling, we observed a shift in TNBC subtype classifications between primary and metastatic TNBCs. A panel of eight cancer driver genes (CCNE1, TPX2, ELF3, FANCL, JAK2, GSK3B, CEP76, and SYK) were differentially expressed in recurrent TNBCs, and were also overexpressed in TCGA and METABRIC. CCNE1 and TPX2 were co-overexpressed in TNBCs. DNA mutation profiling showed that multiple mutations occurred in genes comprising a number of potentially targetable pathways including PI3K/AKT/mTOR, RAS/MAPK, cell cycle, and growth factor receptor signaling, reaffirming the wide heterogeneity of mechanisms driving TNBC. CCNE1 amplification was associated with poor overall survival in patients with metastatic TNBC. CONCLUSIONS: CCNE1 amplification may confer resistance to chemotherapy and is associated with poor overall survival in TNBC.
Assuntos
Ciclina E/genética , Amplificação de Genes , Perfilação da Expressão Gênica/métodos , Proteínas Oncogênicas/genética , Neoplasias de Mama Triplo Negativas/genética , Adulto , Idoso , Ciclina E/metabolismo , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Predisposição Genética para Doença/genética , Humanos , Pessoa de Meia-Idade , Proteínas Oncogênicas/metabolismo , Prognóstico , Análise de Sobrevida , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/metabolismo , Sequenciamento do ExomaRESUMO
Introduction: Low grade serous ovarian carcinoma (LGSOC) is a rare subtype of ovarian cancer (OC) that is challenging to treat due to its relative chemoresistance. Given that LGSOC patients often recur in the peritoneal cavity, novel intraperitoneal (IP) chemotherapy should be explored. Pressurized intraperitoneal aerosolized chemotherapy (PIPAC) is a method that has demonstrated peritoneal disease control in cancers with peritoneal metastases. Methods: NCT04329494 is a US multicenter phase 1 trial evaluating the safety of PIPAC in recurrent ovarian, uterine, and GI cancers with peritoneal metastases. This analysis describes the outcomes of a sub-cohort of four LGSOC patients treated with IP cisplatin 10.5 mg/m2, doxorubicin 2.1 mg/m2 PIPAC q4-6 weeks. Primary endpoints included dose-limiting toxicities (DLT) and incidence of adverse events (AE). Secondary endpoints were progression free survival (PFS) and treatment response based on radiographic, intraoperative, and pathological findings. Results: Four patients with LGSOC were enrolled of which three were heavily pretreated. Median prior lines of therapy was 5 (range 2-10). Three patients had extraperitoneal metastases, and two patients had baseline partial small bowel obstructive (SBO) symptoms. Median age of patients was 58 (38-68). PIPAC completion rate (≥2 PIPACs) was 75%. No DLTs or Clavien-Dindo surgical complications occurred. No G4/G5 AEs were observed, and one G3 abdominal pain was reported. One patient had a partial response after 3 cycles of PIPAC and completed an additional 3 cycles with compassionate use amendment. Two patients came off study after 2 cycles due to extraperitoneal progressive disease. One patient came off study after 1 cycle due to toxicity. Median decrease in peritoneal carcinomatosis index between cycles 1 and 2 was 5.0%. Ascites decreased in 2 out of 3 patients who had ≥2 PIPACs. Median PFS was 4.3 months (1.7-21.6), median overall survival was 11.6 months (5.4-30.1), and objective response rate was 25%. Conclusion: PIPAC with cisplatin/doxorubicin is well tolerated in LGSOC patients without baseline SBO symptoms. IP response was seen in 2 out of 3 patients that completed ≥2 PIPAC cycles. Further study of PIPAC for patients with recurrent disease limited to the IP cavity and with no partial SBO symptoms should be considered.
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Medication-related osteonecrosis of the jaw (MRONJ) in cancer patients presents a considerable challenge in management. Current management is primarily based on interventions in a limited number of cases assessing a single approach. Medical management typically is reported to include antimicrobial therapy with or without surgery. Advances in the understanding of pathogenesis have led to the investigation of additional medical interventions for early-stage necrosis. We present 3 patients with advanced-stage MRONJ of the maxilla using combined medical modalities including antimicrobial therapy, photobiomodulation therapy, pentoxifylline, vitamin E, and synthetic parathyroid hormone. All patients had a good outcome and avoided surgical intervention. We also report biological and functional imaging that may assist in more effective diagnosis and management of MRONJ. The 3 patients reported suggest that combined medical management should be considered in all cases of MRONJ (including stage III) prior to determining if surgical intervention is required. Functional imaging with a technetium bone scan or positron emission tomography scan correlated with diagnosis and confirmed resolution in patients. We present 3 challenging MRONJ patients that were effectively managed with a combined medical and nonsurgical therapy that demonstrated good clinical outcomes avoiding surgical interventions.
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Patients receiving allogeneic hematopoietic stem cell transplant may experience graft-versus-host disease (GVHD) in which donor immune cells cause an immune reaction in host tissues. Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) vaccines are highly effective in prevention of severe coronavirus-2019 (COVID-19) disease, but the vaccine can result in immune activation and GVHD. Herein, we report 4 cases of oral manifestations that may have been stimulated by COVID-19 or vaccination with Pfizer or Moderna vaccines. We believe this study is the first to report oral changes driven by an inflammatory/immune mechanism leading to oral symptomatic cGVHD. The clinical impact of this study is early recognition and appropriate management of oral symptomatic cGVHD following COVID-19 disease or SARS-CoV-2 vaccination.
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Histologic and genetic mutation information from racially and ethnically diverse populations is warranted to better inform future cancer predisposition and promote health equity. A single institutional, retrospective capture of patients with gynecologic conditions and genetic susceptibilities to malignant neoplasms of the breast or ovaries was performed. This was achieved with manual curation of the electronic medical record (EMR) from 2010-2020 with the use of ICD-10 code searches. Among 8983 consecutive women identified with gynecologic conditions, 184 were diagnosed with pathogenic/likely pathogenic (P/LP) germline BRCA (gBRCA) mutations. Median age was 54 (22-90). Mutations included insertion/deletion (majority frameshift, 57.4%), substitution (32.4%), large structural rearrangement (5.4%), and alteration in splice site/intronic sequence (4.7%). A total of 48% were non-Hispanic White, 32% Hispanic or Latino, 13% Asian, 2% Black, and 5% Other. The most common pathology was high grade serous carcinoma (HGSC, 63%), followed by unclassified/high grade carcinoma (13%). Additional multigene panels led to the detection of 23 additional BRCA-positive patients with germline co-mutations and/or variants of uncertain significance in genes functionally involved in DNA repair mechanisms. Hispanic or Latino and Asian individuals comprised 45% of patients with concomitant gynecologic condition and gBRCA positivity in our cohort, confirming that germline mutations are represented across racial and ethnic groups. Insertion/deletion mutations, the majority of which led to a frameshift change, occurred in approximately half of our patient cohort, which may have prognostic implication for therapy resistance. Prospective studies are needed to unravel the significance of germline co-mutations in gynecologic patients.
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Carcinoma , Mutação em Linhagem Germinativa , Humanos , Feminino , Pessoa de Meia-Idade , Promoção da Saúde , Estudos Retrospectivos , MutaçãoRESUMO
Glucocorticoids, which are administered with chemotherapy, cause hyperglycemia. Glycemic variability among breast cancer patients without diabetes is not well known. A retrospective cohort study was conducted involving early-stage breast cancer patients without diabetes who received dexamethasone prior to neoadjuvant or adjuvant taxane chemotherapy between August 2017-December 2019. Random blood glucose levels were analyzed, and steroid-induced hyperglycemia (SIH) was defined as a random glucose level of >140 mg/dL. A multivariate proportional hazards model was used to identify the risk factors of SIH. Out of 100 patients, the median age was 53 years (IQR: 45-63.5). A total of 45% of patients were non-Hispanic White, 28% Hispanic, 19% Asian, and 5% African American. The incidence of SIH was 67%, and glycemic fluctuations were highest in those with glucose levels of >200 mg/dL. Non-Hispanic White patients represented a significant predictor for time to SIH, with a hazard ratio of 2.5 (95% CI: 1.04, 5.95, p = 0.039). SIH was transient in over 90% of the patients, and only seven patients remained hyperglycemic after glucocorticoid and chemotherapy completion. Pretaxane dexamethasone-induced hyperglycemia was observed in 67% of the patients, with the greatest glycemic lability in those patients with blood glucose levels of >200 mg/dL. The non-Hispanic White patients had a higher risk of developing SIH.
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Prognosis of metastatic triple negative breast cancer (mTNBC) remains poor despite recent advances in therapeutic options. Trastuzumab deruxtecan (T-DXd) has shown promising efficacy in patients with human epidermal growth factor receptor 2 (HER2)-low breast cancer, which is defined by immunohistochemistry (IHC) 1+ or 2+ and lack of HER2 amplification by fluorescence in situ hybridization (FISH) testing. The purpose of the study is to evaluate the safety and initial evidence of efficacy of intratumoral administration of CF33-hNIS-anti-PD-L1 (CHECKvacc) against mTNBC. Oncolytic virus CHECKvacc intratumoral injection is currently undergoing investigation in patients with mTNBC as a single agent (NCT05081492). The patient was enrolled on the clinical trial CHECKvacc for the Treatment of Metastatic Triple Negative Breast Cancer, received a single dose of CHECKvacc, and discontinued the study due to lack of immediate response. We report a case of a patient with mTNBC who was heavily pretreated and presented with extensive dermal metastasis. Two dermal metastasis biopsies in 2021 showed HER2 0 by IHC. The patient received a single dose of CHECKvacc and discontinued the study due to lack of immediate response. Twenty-five days later, the patient received treatment with T-DXd, and her tumor regressed significantly. The patient's disease-free survival was 10 months (December 2021-October 2022). The sequential treatment with intratumoral injection of CHECKvacc followed by T-DXd may have significant clinical activity in select patients with heavily pretreated mTNBC. ClinicalTrials.gov NCT05081492.
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Triple-negative breast cancer (TNBC) and ovarian carcinomas (OvCas) with BRCA1 promoter methylation (BRCA1meth) respond more poorly to alkylating agents compared to those bearing mutations in BRCA1 and BRCA2 (BRCAmut). This is a conundrum given the biologically equivalent homologous recombination deficiency (HRD) induced by these genetic and epigenetic BRCA perturbations. We dissected this problem through detailed genomic analyses of TNBC and OvCa cohorts and experimentation with patient-derived xenografts and genetically engineered cell lines. We found that despite identical downstream genomic mutational signatures associated with BRCA1meth and BRCAmut states, BRCA1meth uniformly associates with poor outcomes. Exposure of BRCA1meth TNBCs to platinum chemotherapy, either as clinical treatment of a patient or as experimental in vivo exposure of preclinical patient derived xenografts, resulted in allelic loss of BRCA1 methylation and increased BRCA1 expression and platinum resistance. These data suggest that, unlike BRCAmut cancers, where BRCA loss is a genetically "fixed" deficiency state, BRCA1meth cancers are highly adaptive to genotoxin exposure and, through reversal of promoter methylation, recover BRCA1 expression and become resistant to therapy. We further found a specific augmented immune transcriptional signal associated with enhanced response to platinum chemotherapy but only in patients with BRCA-proficient cancers. We showed how integrating both this cancer immune signature and the presence of BRCA mutations results in more accurate predictions of patient response when compared to either HRD status or BRCA status alone. This underscores the importance of defining BRCA heterogeneity in optimizing the predictive precision of assigning response probabilities in TNBC and OvCa.
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Carcinoma , Neoplasias Ovarianas , Neoplasias de Mama Triplo Negativas , Proteína BRCA1/genética , Proteína BRCA1/metabolismo , Proteína BRCA2/genética , Proteína BRCA2/metabolismo , Epigenômica , Feminino , Genômica , Humanos , Mutação/genética , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Platina/farmacologia , Platina/uso terapêutico , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/metabolismoRESUMO
Cyclin-dependent kinase 4/6 inhibitors are the standard of care for hormone receptor-positive metastatic breast cancer. This retrospective study reports on genomic biomarkers of CDK 4/6i resistance utilizing genomic data acquired through routine clinical practice. Patients with HR+ MBC treated with palbociclib, ribociclib, or abemaciclib and antiestrogen therapy were identified. Patients were grouped into early (<6 months); intermediate (6−24 months for 0−1 lines; 6−9 months for ≥2 lines); or late progressors (>24 months for 0−1 lines; >9 months PFS for ≥2 lines). NGS and RNA sequencing data were analyzed in association with PFS, and survival analysis was stratified by prior lines of chemotherapy. A total of 795 patients with HR+ MBC treated with CDK 4/6i were identified. Of these, 144 (18%) patients had genomic data and 29 (3.6%) had RNA data. Among the 109 patients who received CDK4/6i as 1st- or 2nd-line therapy, 17 genes showed associations with PFS (p-value ≤ 0.15 and HR ≥ 1.5 or HR < 0.5). Whole transcriptome RNAseq was analyzed for 24/109 (22%) patients with 0−1 prior lines of therapy and 56 genes associated with PFS (HR ≥ 4 or HR ≤ 0.25 and FDR ≤ 0.15). In this retrospective analysis, genomic biomarkers including FGFR1 amplification, PTEN loss, and DNA repair pathway gene mutations showed significant associations with shorter PFS for patients receiving CDK4/6 inhibitor therapy.