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Mpox, caused by infection with Monkeypox virus, usually presents as a mild, self-limited illness in immunocompetent persons that resolves within 2-4 weeks. Serious complications have been reported when mpox lesions involve vulnerable anatomic sites, such as the eye, and in those with substantial immunosuppression. We describe a patient with advanced human immunodeficiency virus infection and sustained viral shedding of mpox with ocular involvement, which resulted in vision loss.
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BACKGROUND: Neoadjuvant therapy aims to preoperatively downstage breast cancer patients. We evaluated nodal upstaging in clinically node-negative (cN0) patients receiving neoadjuvant chemotherapy (NAC) and neoadjuvant endocrine therapy (NET). METHODS: cN0 patients undergoing neoadjuvant therapy from 2009 to 2018 were reviewed. Univariate and multivariate analyses evaluated rates of nodal upstaging. RESULTS: A total of 228 cN0 patients with a mean age of 55 years underwent neoadjuvant therapy for Stage I-III invasive carcinoma. Subtypes included ER+/HER2- = 93 (40%), HER2+ = 61 (27%), and triple negative (TNBC) = 74 (33%). Among ER+/HER2- patients, 65 (70%) underwent NET. Overall, 49 patients (21%) were upstaged due to occult nodal disease. Factors associated with higher rates of occult nodal disease included advanced stage on initial presentation (P = .008), larger presenting tumor size (P = .009), low/intermediate tumor grade (P = .025), and ER+/HER2- subtype (P < .001); incidence of occult nodal disease by subtype included: ER+/HER2- = 37%, HER2+ = 15%, TNBC = 8%. Patients experiencing a breast pCR had a significantly lower rate of nodal upstaging compared to those with residual tumor (4% vs. 96%, P < .001). On multivariate analysis, ER+/HER- patients exhibited higher risk of occult nodal disease when compared to patients with HER2+ (odds ratio [OR] = 3.4, 95% CI, 1.2-9.8, P = .003) and TNBC (OR = 5.7, 95% CI, 1.7-19.6, P = .003). Comparing NAC vs. NET in ER+/HER2- patients showed no difference in rates of occult nodal disease (39% vs. 35%, P = .13). CONCLUSIONS: ER+/HER2- subtype carries higher risk for occult nodal disease after neoadjuvant therapy; NAC versus NET in these patients does not affect nodal upstaging.
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Antineoplásicos Hormonais/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Neoplasia Residual/patologia , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/metabolismo , Adulto , Idoso , Neoplasias da Mama/metabolismo , Feminino , Humanos , Linfonodos/patologia , Metástase Linfática , Pessoa de Meia-Idade , Terapia Neoadjuvante , Invasividade NeoplásicaRESUMO
Breast cancers exhibit intratumoral heterogeneity associated with disease progression and therapeutic resistance. To define the sources and the extent of heterogeneity, we performed an in-depth analysis of the genomic architecture of three chemoradiation-naïve breast cancers with well-defined clinical features including variable ER, PR, ERBB2 receptor expression and two distinct pathogenic BRCA2mut genotypes. The latter included a germ line carrier and a patient with a somatic variant. In each case we combined DNA content-based flow cytometry with whole exome sequencing and genome wide copy number variant (CNV) analysis of distinct populations sorted from multiple (4-18) mapped biopsies within the tumors and involved lymph nodes. Interrogating flow-sorted tumor populations from each biopsy provided an objective method to distinguish fixed and variable genomic lesions in each tumor. Notably we show that tumors exploit CNVs to fix mutations and deletions in distinct populations throughout each tumor. The identification of fixed genomic lesions that are shared or unique within each tumor, has broad implications for the study of tumor heterogeneity including the presence of tumor markers and therapeutic targets, and of candidate neoepitopes in breast and other solid tumors that can advance more effective treatment and clinical management of patients with disease.
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Neoplasias da Mama/genética , Carcinoma Ductal de Mama/genética , Evolução Molecular , Aneuploidia , Biomarcadores Tumorais , HumanosRESUMO
AIM: To present the pre-specified analyses of >5-years follow-up of the Phase III ALTTO trial. PATIENTS AND METHODS: 8381 patients with stage I-III HER2 positive breast cancer randomised to chemotherapy plus 1-year of trastuzumab (T), oral lapatinib (L; no longer evaluated), trastuzumab followed by lapatinib (TâL), and lapatinib + trastuzumab (L+T). The primary endpoint was disease-free survival (DFS). A secondary analysis examined DFS treatment effects by hormone receptor status, nodal status and chemotherapy timing; time to recurrence; overall survival (OS) and safety (overall and cardiac). RESULTS: At a median follow-up of 6.9 years, 705 DFS events for L+T versus T were observed. Hazard Ratio (HR) for DFS was 0.86 (95% CI, 0.74-1.00) for L+T versus T and 0.93 (95% CI, 0.81-1.08) for TâL versus T. The 6-year DFS were 85%, 84%, and 82% for L+T, TâL, and T, respectively. HR for OS was 0.86 (95% CI, 0.70-1.06) for L+T versus T and 0.88 (95% CI, 0.71-1.08) for TâL versus T. The 6-year OS were 93%, 92%, and 91% for L+T, TâL, and T, respectively. Subset analyses showed a numerically better HR for DFS in favour of L+T versus T for the hormone-receptor-negative [HR 0.80 (95% CI, 0.64-1.00; 6-yr DFS% = 84% versus 80%)] and the sequential chemotherapy [HR 0.83 (95% CI, 0.69-1.00; 6-yr DFS% = 83% versus79%)] subgroups. CONCLUSION: T+L did not significantly improve DFS and OS over T alone, both with chemotherapy, and, therefore, cannot be recommended for adjuvant treatment of early-stage HER2-positive breast cancer. TRIAL REGISTRATION: clinicaltrials.gov Identifier NCT00490139.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Quimioterapia Adjuvante/mortalidade , Terapia Neoadjuvante/mortalidade , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/patologia , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Taxa de Sobrevida , Adulto JovemRESUMO
BACKGROUND: A collision tumor is a rare entity consisting of 2 histologically distinct tumor types (benign or malignant) in the same anatomic location. This can occur from a tumor-to-tumor metastasis or as a result of 2 adjacent intracranial tumors colliding and growing together. To our knowledge, this is the first reported case of collision tumor with confirmed meningioma and uterine adenocarcinoma. Multiple mechanisms have been proposed for the facilitative growth of collision tumors, including local epigenetic signaling. Clinically, it is important to consider collision tumors in the differential diagnosis of a rapidly growing intracranial lesion in the setting of systemic cancer to provide optimal surgical and postoperative management. CASE DESCRIPTION: A 78-year-old, right-handed woman with a known 10-year history of stable meningioma presented for evaluation of a right sphenoid wing lesion. She had recently completed treatment of uterine papillary serous carcinoma with no evidence of disease on follow-up imaging. On presentation, there was significant progression of the meningioma resulting in brain compression and right third nerve palsy. The patient underwent urgent resection of the lesion. Pathology demonstrated a collision tumor with a combination of metastatic uterine papillary serous carcinoma and meningioma. CONCLUSIONS: It is important to consider a collision tumor when a patient with a benign intracranial lesion presents with rapid progression, even in the context of a systemic cancer that rarely metastasizes to the brain. Appropriate histopathologic assessment is crucial in these cases and can have a significant impact on treatment plan and prognosis.
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Adenocarcinoma/patologia , Adenocarcinoma/secundário , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/secundário , Meningioma/patologia , Neoplasias Uterinas/patologia , Adenocarcinoma/cirurgia , Idoso , Neoplasias Encefálicas/cirurgia , Progressão da Doença , Evolução Fatal , Feminino , Humanos , Imageamento por Ressonância Magnética , Meningioma/complicações , Meningioma/cirurgia , Síndromes de Compressão Nervosa/etiologia , Síndromes de Compressão Nervosa/patologia , Nervo Oculomotor/patologia , Doenças do Nervo Oculomotor/patologia , Neoplasias Uterinas/cirurgiaAssuntos
Colo Sigmoide/patologia , Neoplasias do Colo/diagnóstico , Plasmocitoma/diagnóstico , Idoso de 80 Anos ou mais , Biópsia , Neoplasias do Colo/patologia , Diagnóstico Diferencial , Humanos , Obstrução Intestinal , Masculino , Plasmocitoma/patologia , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Tomografia Computadorizada por Raios XRESUMO
BACKGROUND AND OBJECTIVES: Neoadjuvant endocrine therapy (NET) for ER+ breast cancer can downstage primary tumors. We evaluated NET efficacy in node-positive patients. METHODS: Node-positive patients undergoing NET for ER+ breast cancer from 2012 to 2019 were reviewed. Primary endpoints included rates of axillary lymphadenectomy (ALND), pathologic complete response (pCR), and final nodal staging. RESULTS: Thirty-nine patients were included. Before NET, all were clinically node-positive (cN1 = 36, 94%; cN2 = 2, 5%; cN3 = 1, 3%; Stage II = 23, 59%, Stage III = 16, 41%). After NET, nine (23%) had clinically persistent axillary disease necessitating ALND. The remaining 30 (77%) underwent sentinel lymph node biopsy (SLNB). Of these, 25 (83%) were SLNB+ on frozen section, undergoing immediate ALND. Five patients were negative on frozen section: one had a confirmed axillary pCR, and four had residual nodal disease on permanent pathology. One underwent delayed ALND, and for the remaining three patients, decision was made to forgo ALND. Final overall axillary staging was: N0 (pCR) = 1, 3%, pN1mic = 1, 3%, pN1 = 20, 51%, pN2 = 12, 30%, pN3 = 5, 13%; Stage II = 16, 41%, Stage III = 23, 59%. CONCLUSIONS: While NET is reported to downstage primary tumors, downstaging of the axilla was unsuccessful in the majority of patients.
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Longitudinal analysis of circulating tumor DNA (ctDNA) has shown promise for monitoring treatment response. However, most current methods lack adequate sensitivity for residual disease detection during or after completion of treatment in patients with nonmetastatic cancer. To address this gap and to improve sensitivity for minute quantities of residual tumor DNA in plasma, we have developed targeted digital sequencing (TARDIS) for multiplexed analysis of patient-specific cancer mutations. In reference samples, by simultaneously analyzing 8 to 16 known mutations, TARDIS achieved 91 and 53% sensitivity at mutant allele fractions (AFs) of 3 in 104 and 3 in 105, respectively, with 96% specificity, using input DNA equivalent to a single tube of blood. We successfully analyzed up to 115 mutations per patient in 80 plasma samples from 33 women with stage I to III breast cancer. Before treatment, TARDIS detected ctDNA in all patients with 0.11% median AF. After completion of neoadjuvant therapy, ctDNA concentrations were lower in patients who achieved pathological complete response (pathCR) compared to patients with residual disease (median AFs, 0.003 and 0.017%, respectively, P = 0.0057, AUC = 0.83). In addition, patients with pathCR showed a larger decrease in ctDNA concentrations during neoadjuvant therapy. These results demonstrate high accuracy for assessment of molecular response and residual disease during neoadjuvant therapy using ctDNA analysis. TARDIS has achieved up to 100-fold improvement beyond the current limit of ctDNA detection using clinically relevant blood volumes, demonstrating that personalized ctDNA tracking could enable individualized clinical management of patients with cancer treated with curative intent.
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Neoplasias da Mama/sangue , Neoplasias da Mama/tratamento farmacológico , DNA Tumoral Circulante/análise , Terapia Neoadjuvante , Neoplasia Residual/sangue , Neoplasia Residual/tratamento farmacológico , Bioensaio , Neoplasias da Mama/genética , DNA Tumoral Circulante/sangue , DNA Tumoral Circulante/genética , Feminino , Humanos , Mutação/genética , Estadiamento de Neoplasias , Neoplasia Residual/genética , Curva ROC , Padrões de Referência , Análise de Sequência de DNARESUMO
LESSONS LEARNED: Dual epidermal growth factor receptor (EGFR)-directed therapy with erlotinib and panitumumab in combination with gemcitabine was superior to gemcitabine and erlotinib, but the clinical relevance is uncertain given the limited role of gemcitabine monotherapy.A significantly longer overall survival was observed in patients receiving the dual EGFR-directed therapy.The dual EGFR-directed therapy resulted in increased toxicity. BACKGROUND: Gemcitabine is active in patients with advanced pancreatic adenocarcinoma. The combination of erlotinib, an oral epidermal growth factor receptor (EGFR) inhibitor, and gemcitabine was shown to modestly prolong overall survival when compared with gemcitabine alone. The North Central Cancer Treatment Group (now part of Alliance for Clinical Trials in Oncology) trial N064B compared gemcitabine plus erlotinib versus gemcitabine plus combined EGFR inhibition with erlotinib and panitumumab. METHODS: Eligible patients with metastatic adenocarcinoma of the pancreas were randomized to either gemcitabine 1,000 mg/m2 on days 1, 8, and 15 of a 28-day cycle with erlotinib 100 mg p.o. daily (Arm A) or the same combination with the addition of panitumumab 4 mg/kg on days 1 and 15 of a 28-day cycle (Arm B). The primary endpoint of the trial was overall survival. Secondary endpoints included progression-free survival, the confirmed response rate, and toxicity. Comparison between arms for the primary endpoint was done with a one-sided log-rank test, and a p value less than .20 was considered statistically significant. Response rate comparison was done with Fisher's exact test. All other reported p values are two-sided. RESULTS: A total of 92 patients were randomized, 46 to each arm. The median overall survival was 4.2 months in Arm A and 8.3 months in Arm B (hazard ratio, 0.817; 95% confidence interval [CI], 0.530-1.260; p = .1792). The progression-free survival was 2.0 months in Arm A and 3.6 months in Arm B (hazard ratio, 0.843; 95% CI, 0.555-1.280; p = .4190). A partial confirmed response was seen in 8.7% of patients on Arm A and 6.5% on Arm B (p = .9999). No patients had a complete response. Grade 3 and higher nonhematologic toxicities were more common in patients on Arm B compared with those on Arm A (82.6% vs. 52.2%; p = .0018). CONCLUSION: Dual EGFR-directed therapy resulted in a significant prolongation of overall survival in patients with advanced adenocarcinoma of the pancreas but was associated with substantially increased toxicities. Dual EGFR-directed therapy in combination with gemcitabine alone cannot be recommended for further study, as single-agent gemcitabine is no longer considered an appropriate therapy for otherwise fit patients with metastatic pancreatic cancer.
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Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Desoxicitidina/análogos & derivados , Cloridrato de Erlotinib/uso terapêutico , Neoplasias Pancreáticas/tratamento farmacológico , Panitumumabe/uso terapêutico , Adenocarcinoma/mortalidade , Adenocarcinoma/patologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Desoxicitidina/farmacologia , Desoxicitidina/uso terapêutico , Cloridrato de Erlotinib/farmacologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Panitumumabe/farmacologia , Análise de Sobrevida , Gencitabina , Neoplasias PancreáticasRESUMO
BACKGROUND: Elevated PD-L1 expression on tumor cells, a context associated with an adaptive immune response, has been linked to the total burden of copy number variants (CNVs) in aneuploid tumors, to microsatellite instability (MSI), and to specific genomic driver lesions, including loss of PTEN, MYC amplification, and activating mutations in driver oncogenes such as KRAS and PIK3CA. Triple-negative breast cancers (TNBCs) typically have high levels of CNVs and diverse driver lesions in their genomes. Thus, there is significant interest in exploiting genomic data to develop predictive immunotherapy biomarkers for patients with TNBC. METHODS: Whole tissue samples from 55 resected TNBCs were screened by immunohistochemistry (IHC) for PD-1 and PD-L1 by using validated antibodies and established scoring methods for staining of tumor and non-tumor cells. In parallel, we interrogated biopsies from each resection with DNA content flow cytometry and sorted the nuclei of diploid, tetraploid, and aneuploid cell populations. CNVs were mapped with CNV oligonucleotide arrays by using purified (>95%) tumor populations. We generated whole exome data for 12 sorted tumor samples to increase the resolution within loci of interest and to incorporate somatic mutations into our genomic signatures. RESULTS AND CONCLUSIONS: PD-L1 staining was detected on tumor cells in 29 out of 54 (54%) evaluable cases and was associated with increased overall survival (P = 0.0024). High levels of PD-1 and PD-L1 (IHC ≥4) were present in 11 out of 54 (20%) and 20 out of 54 (37%) cases with staining of PD-L1 primarily on tumor cells for 17 out of 20 (85%) cases. The latter included tumors with both high (>50) and low (<20) numbers of CNVs. Notably, homozygous deletion of PTEN (n = 6) or activating mutation in PIK3CA (n = 1) was not associated with increased expression of either immune checkpoint activator in TNBC. In contrast, two treatment-naïve cases with EGFR driver amplicons had high PD-L1 tumor staining. High mutational load and predicted neoepitopes were observed in MSI+ and high CNV burden TNBCs but were not associated with high PD-L1 expression on tumor cells. Our results challenge current models of genomic-based immunotherapy signatures yet suggest that discrete genomic lesions may complement existing biomarkers to advance immune checkpoint therapies for patients with TNBC.
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Antígeno B7-H1/genética , Biomarcadores Tumorais/genética , Variações do Número de Cópias de DNA/genética , Receptor de Morte Celular Programada 1/genética , Neoplasias de Mama Triplo Negativas/genética , Idoso , Aneuploidia , Classe I de Fosfatidilinositol 3-Quinases/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Genoma Humano/genética , Humanos , Estimativa de Kaplan-Meier , Linfócitos do Interstício Tumoral/patologia , Instabilidade de Microssatélites , Pessoa de Meia-Idade , Mutação , PTEN Fosfo-Hidrolase/genética , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Neoplasias de Mama Triplo Negativas/patologia , Sequenciamento do ExomaRESUMO
BACKGROUND: The appropriate management of the axilla among women undergoing neoadjuvant therapy is in evolution. METHOD: A retrospective review of a prospective database of women with breast cancer who underwent neoadjuvant systemic therapy using endocrine/chemotherapy (NE/CT) from 2002 to 2015 was performed. RESULTS: We reviewed 253 women: triple negative breast cancer (30%), ER+HER2- (44%) breast cancer and HER2+ (25%) disease. The mean age was 55 years (SD = 12). 197 patients were analyzed based on their axillary disease. 33 patients (35%) who had clinical N1-3 disease prior to neoadjuvant therapy had no axillary metastases at definitive surgery. There were no significant differences in overall survival or local/regional recurrence between patients who underwent axillary lymph node dissection (ALND), sentinel lymph node biopsy (SLNB), or SLNB+ALND (p = 0.05061 and p = 0.33). CONCLUSION: SLNB is a viable technique in patients with breast cancer undergoing NE/CT. Patients with pre-neoadjuvant therapy proven axillary disease may be a candidate for SLNB as opposed to planned ALND with good multidisciplinary review of their response and localization of previously positive lymph nodes.
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Neoplasias da Mama/cirurgia , Terapia Neoadjuvante , Biópsia de Linfonodo Sentinela , Adulto , Idoso , Idoso de 80 Anos ou mais , Axila , Neoplasias da Mama/patologia , Feminino , Humanos , Excisão de Linfonodo , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Estudos Retrospectivos , Taxa de Sobrevida , Resultado do TratamentoRESUMO
The amplification of chromosome 9p24.1 encoding PD-L1, PD-L2, and JAK2 has been reported in multiple types of cancer and is associated with poor outcome, upregulation of PD-L1, and activation of the JAK/STAT pathway. We have developed a novel fluorescence in situ hybridization assay which combines 3 probes mapping to 9p24.1 with a commercial chromosome 9 centromere (CEN9) probe for detection of the JAK2/9p24.1 amplification. JAK2 fluorescence in situ hybridization was compared with array-based comparative genomic hybridization in 34 samples of triple negative breast cancer tumor. By array-based comparative genomic hybridization, 15 had 9p24.1 copy-number gain (log2ratio>0.3) and 19 were classified as non-gain (log2ratio≤0.3). Copy-number gain was defined as JAK2/CEN9 ratio ≥1.1 or average JAK2 signals≥3.0. Twelve of 15 samples with copy-number gain by array-based comparative genomic hybridization were also detected by fluorescence in situ hybridization. Eighteen of 19 samples classified as copy-number non-gain by array-based comparative genomic hybridization were concordant by array-based comparative genomic hybridization. The sensitivity and specificity of the fluorescence in situ hybridization assay was 80% and 95%, respectively (P=0.02). The sample with the highest level of amplification by array-based comparative genomic hybridization (log2ratio=3.6) also scored highest by fluorescence in situ hybridization (ratio=8.2). There was a correlation between the expression of JAK2 and amplification status (Mean 633 vs 393, P=0.02), and there was a trend of association with PD-L1 RNA expression (Mean 46 vs 22, P=0.11). No significant association was observed between PD-L1 immunohistochemistry expression and copy-number gain status. In summary, the novel array-based comparative genomic hybridization assay for detection of chromosome 9p24.1 strongly correlates with the detection of copy-number gain by array-based comparative genomic hybridization. In triple negative breast cancer, this biomarker may identify a relevant subset of patients for targeted molecular therapies.
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Antígeno B7-H1/genética , Biomarcadores Tumorais/análise , Hibridização in Situ Fluorescente/métodos , Janus Quinase 2/genética , Neoplasias de Mama Triplo Negativas/genética , Adulto , Idoso , Biomarcadores Tumorais/genética , Feminino , Amplificação de Genes , Humanos , Pessoa de Meia-Idade , Neoplasias de Mama Triplo Negativas/diagnósticoRESUMO
Harmful mutations of the BRCA tumor suppressor genes result in a greater lifetime risk for malignancy-breast and ovarian cancers in particular. An increased risk for male breast, fallopian tube, primary peritoneal, pancreatic, prostate, and colon cancers also has been reported. The BRCA gene is inherited in an autosomal dominant pattern and tends to be highly penetrant; thus, there is an increased incidence of these cancers in affected families. Compared with sporadic tumors, BRCA-associated malignancies have unique manifestations, clinical features, and pathologic profiles. Manifestation at an early patient age, high-grade tumors, and an aggressive clinical course are common features of BRCA-associated malignancies. Understanding the behavior of these cancers aids in identification of affected individuals and families, who can then make informed decisions regarding their future health. Enhanced screening, prophylactic surgery, and chemoprevention are options for managing cancer risk factors in these individuals. Imaging has an important role in the screening, evaluation, staging, and follow-up of BRCA-associated malignancies. Supplemental screening of BRCA mutation carriers often begins at an early age and is critical for early and accurate cancer diagnoses. The authors review the etiopathogenesis and imaging features of BRCA-associated malignancies, the importance of a multidisciplinary approach to determining the diagnosis, and the treatment of patients who have these mutations to improve their outcomes. © RSNA, 2017.
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Diagnóstico por Imagem , Genes BRCA1 , Genes BRCA2 , Neoplasias/diagnóstico por imagem , Neoplasias/genética , Neoplasias/terapia , Predisposição Genética para Doença , Humanos , Fatores de RiscoRESUMO
Background: Preclinical evidence indicates that increased insulin-like growth factor receptor-1 (IGF1R) signaling interferes with the action of trastuzumab suggesting a possible mechanism of trastuzumab resistance. Thus, we evaluated IGF1R prevalence, relationship with demographic data, and association with disease-free survival (DFS) of patients randomized to chemotherapy alone (Arm A) or chemotherapy with sequential (Arm B) or concurrent trastuzumab (Arm C) in the prospective phase III HER2+ adjuvant N9831 trial.Experimental Design: IGF1R protein expression was determined in tissue microarray sections (three cores per block; N = 1,197) or in whole tissue sections (WS; N = 537) using IHC (rabbit polyclonal antibody against IGF1R ß-subunit). A tumor was considered positive (IGF1R+) if any core or WS had ≥1+ membrane staining in >0% invasive cells. Median follow-up was 8.5 years.Results: Of 1,734 patients, 708 (41%) had IGF1R+ breast tumors. IGF1R+ was associated with younger age (median 48 vs. 51, P = 0.007), estrogen receptor/progesterone receptor positivity (78% vs. 35%, P < 0.001), nodal positivity (89% vs. 83%, P < 0.001), well/intermediate grade (34% vs. 24%, P < 0.001), tumors ≥2 cm (72% vs. 67%, P = 0.02) but not associated with race or tumor histology. IGF1R did not affect DFS within arms. Between Arms A and C, patients with IGF1R+ and IGF1R- tumors had DFS HRs of 0.48 (P ≤ 0.001) and 0.68 (P = 0.009), respectively (Pinteraction = 0.17). Between Arms A and B, patients with IGF1R+ and IGF1R- tumors had DFS HRs of 0.83 (P = 0.25) and 0.69 (P = 0.01), respectively (Pinteraction = 0.42).Conclusions: In contrast to preclinical studies that suggest a decrease in trastuzumab sensitivity in IGF1R+ tumors, our adjuvant data show benefit of adding trastuzumab for patients with either IGF1R+ and IGF1R- breast tumors. Clin Cancer Res; 23(15); 4203-11. ©2016 AACR.
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Neoplasias da Mama/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/genética , Receptores de Somatomedina/genética , Trastuzumab/administração & dosagem , Adulto , Idoso , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Intervalo Livre de Doença , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Receptor ErbB-2/genética , Receptor IGF Tipo 1 , Receptores de Estrogênio/genética , Receptores de Progesterona/genética , Trastuzumab/efeitos adversosAssuntos
Adenocarcinoma Mucinoso/tratamento farmacológico , Receptores ErbB/genética , Cloridrato de Erlotinib/administração & dosagem , Análise de Sequência de DNA/métodos , Neoplasias Uretrais/tratamento farmacológico , Adenocarcinoma Mucinoso/genética , Idoso , Cloridrato de Erlotinib/uso terapêutico , Amplificação de Genes , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Metástase Neoplásica , Medicina de Precisão , Regulação para Cima , Neoplasias Uretrais/genéticaRESUMO
DNA focused panel sequencing has been rapidly adopted to assess therapeutic targets in advanced/refractory cancer. Integrated Genomic Profiling (IGP) utilising DNA/RNA with tumour/normal comparisons in a Clinical Laboratory Improvement Amendments (CLIA) compliant setting enables a single assay to provide: therapeutic target prioritisation, novel target discovery/application and comprehensive germline assessment. A prospective study in 35 advanced/refractory cancer patients was conducted using CLIA-compliant IGP. Feasibility was assessed by estimating time to results (TTR), prioritising/assigning putative therapeutic targets, assessing drug access, ascertaining germline alterations, and assessing patient preferences/perspectives on data use/reporting. Therapeutic targets were identified using biointelligence/pathway analyses and interpreted by a Genomic Tumour Board. Seventy-five percent of cases harboured 1-3 therapeutically targetable mutations/case (median 79 mutations of potential functional significance/case). Median time to CLIA-validated results was 116 days with CLIA-validation of targets achieved in 21/22 patients. IGP directed treatment was instituted in 13 patients utilising on/off label FDA approved drugs (n = 9), clinical trials (n = 3) and single patient IND (n = 1). Preliminary clinical efficacy was noted in five patients (two partial response, three stable disease). Although barriers to broader application exist, including the need for wider availability of therapies, IGP in a CLIA-framework is feasible and valuable in selection/prioritisation of anti-cancer therapeutic targets.
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Testes Diagnósticos de Rotina/métodos , Resistência a Medicamentos , Genômica/métodos , Neoplasias/diagnóstico , Neoplasias/tratamento farmacológico , Humanos , Estudos ProspectivosRESUMO
Therapeutic radiotherapy rarely causes sarcoma, and this occurs years after completion of the intended treatment. In treating breast carcinoma, careful planning in the application of modern radiotherapeutic techniques usually can shield the heart and pericardium. We report a rare case of angiosarcoma of the pericardium, which presented in a 41-year-old woman as constrictive pericarditis 8 years after irradiation for cancer of the left breast. To our knowledge, this is only the 2nd report of angiosarcoma of the pericardium after radiotherapy.
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Neoplasias da Mama/radioterapia , Carcinoma Papilar/radioterapia , Hemangiossarcoma/complicações , Pericardite Constritiva/etiologia , Neoplasias Pleurais/complicações , Lesões por Radiação/complicações , Adulto , Biópsia , Neoplasias da Mama/diagnóstico , Carcinoma Papilar/diagnóstico , Feminino , Hemangiossarcoma/diagnóstico , Humanos , Pericardite Constritiva/diagnóstico , Neoplasias Pleurais/diagnóstico , Lesões por Radiação/diagnóstico , Tomografia Computadorizada por Raios XRESUMO
BACKGROUND: Women with benign breast disease (BBD) have an increased risk of developing breast cancer (BC). Nearly 30% of all BCs develop in women with prior BBD. Information regarding features of the expected number of BCs after BBD would enhance individualized surveillance and prevention strategies for these women. In the current study, the authors sought to characterize BCs developing in a large cohort of women with BBD. METHODS: The current study cohort included 13,485 women who underwent breast biopsy for mammographic or palpable concerns between 1967 and 2001. Biopsy slides were reviewed and classified as nonproliferative disease, proliferative disease without atypia, or atypical hyperplasia. BCs were identified by follow-up questionnaires, medical records, and Tumor Registry data. BC tissues were obtained and reviewed. RESULTS: With median follow-up of 15.8 years, 1273 women developed BC. The majority of BCs were invasive (81%), of which 61% were ductal, 13% were mixed ductal/lobular, and 14% were lobular. Approximately two-thirds of the BC cases were intermediate or high grade, and 29% were lymph node positive. Cancer characteristics were similar across the 3 histologic categories of BBD, with a similar frequency of ductal carcinoma in situ, invasive disease, tumor size, time to invasive BC, histologic type of BC, lymph node positivity, and human epidermal growth factor receptor 2 positivity. Women with atypical hyperplasia were found to have a higher frequency of estrogen receptor-positive BC (91%) compared with women with proliferative disease without atypia (80%) or nonproliferative disease (85%) (P = .02). CONCLUSIONS: A substantial percentage of all BCs develop in women with prior BBD. The majority of BCs after BBD are invasive tumors of ductal type, with a substantial number demonstrating lymph node positivity. Of all the BCs in the current study, 84% were estrogen receptor positive. Prevention therapy should be strongly encouraged in higher-risk women with BBD.
Assuntos
Biomarcadores Tumorais/análise , Biópsia/métodos , Neoplasias da Mama/patologia , Mama/patologia , Linfonodos/patologia , Lesões Pré-Cancerosas/patologia , Adulto , Idoso , Biópsia com Agulha de Grande Calibre , Doenças Mamárias/patologia , Neoplasias da Mama/diagnóstico por imagem , Carcinoma Ductal de Mama/patologia , Carcinoma Intraductal não Infiltrante/patologia , Carcinoma Lobular/patologia , Estudos de Coortes , Feminino , Humanos , Hiperplasia/diagnóstico , Metástase Linfática/diagnóstico , Mamografia , Pessoa de Meia-Idade , Gradação de Tumores , Receptor ErbB-2/análise , Receptores de Estrogênio/análise , Receptores de Progesterona/análise , Medição de Risco , Fatores de RiscoRESUMO
BACKGROUND: Lapatinib (L) plus trastuzumab (T) improves outcomes for metastatic human epidermal growth factor 2-positive breast cancer and increases the pathologic complete response in the neoadjuvant setting, but their role as adjuvant therapy remains uncertain. METHODS: In the Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization trial, patients with centrally confirmed human epidermal growth factor 2-positive early breast cancer were randomly assigned to 1 year of adjuvant therapy with T, L, their sequence (TâL), or their combination (L+T). The primary end point was disease-free survival (DFS), with 850 events required for 80% power to detect a hazard ratio (HR) of 0.8 for L+T versus T. RESULTS: Between June 2007 and July 2011, 8,381 patients were enrolled. In 2011, due to futility to demonstrate noninferiority of L versus T, the L arm was closed, and patients free of disease were offered adjuvant T. A protocol modification required P ≤ .025 for the two remaining pairwise comparisons. At a protocol-specified analysis with a median follow-up of 4.5 years, a 16% reduction in the DFS hazard rate was observed with L+T compared with T (555 DFS events; HR, 0.84; 97.5% CI, 0.70 to 1.02; P = .048), and a 4% reduction was observed with TâL compared with T (HR, 0.96; 97.5% CI, 0.80 to 1.15; P = .61). L-treated patients experienced more diarrhea, cutaneous rash, and hepatic toxicity compared with T-treated patients. The incidence of cardiac toxicity was low in all treatment arms. CONCLUSION: Adjuvant treatment that includes L did not significantly improve DFS compared with T alone and added toxicity. One year of adjuvant T remains standard of care.