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1.
Cancer ; 119(9): 1736-43, 2013 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-23361892

RESUMO

BACKGROUND: Intraoperative radiation therapy (IORT) allows delivery of high-dose radiation at the time of lumpectomy, potentially sparing adjuvant daily radiation. A phase 2 study of pre-excision IORT was performed for early-stage breast cancer. METHODS: Patients ≥ 48 years of age with invasive ductal carcinoma, ≤ 3 cm, and clinically node-negative were eligible for this study, which was approved by institutional review board. Ultrasound was used to select electron energy and cone size to cover the tumor plus 1.5- to 2.0-cm lateral margins and 1-cm-deep margins (90% isodose). Fifteen Gy was delivered with a Mobetron irradiator, and immediate needle-localized partial mastectomy followed. Local event results were updated using the Kaplan-Meier method. RESULTS: A total of 53 patients received IORT alone. Median age was 63 years, and median tumor size was 1.2 cm. Of these, 81% were positive for estrogen receptor or progesterone receptor, 11% were positive for human epidermal growth factor receptor 2, and 15% were triple-negative. Also, 42%, 49%, and 9% would have fallen into the Suitable, Cautionary, and Unsuitable groups, respectively, of the American Society of Therapeutic Radiation Oncology consensus statement for accelerated partial breast irradiation. Median follow-up was 69 months. Ipsilateral events occurred in 8 of 53 patients. The 6-year actuarial rate of ipsilateral events was 15% (95% confidence interval = 7%-29%). The crude event rate for Suitable and Cautionary groups was 1 of 22 (5%) and 7 of 26 (27%), respectively. Overall survival was 94.4%, and breast cancer-specific survival was 100%. CONCLUSIONS: The rate of local events in this study is a matter of concern, especially in the Cautionary group. On the basis of these findings, pre-excision IORT, as delivered in this study, may not provide adequate local control for less favorable early-stage breast cancers.


Assuntos
Neoplasias da Mama/radioterapia , Neoplasias da Mama/cirurgia , Idoso , Idoso de 80 Anos ou mais , Terapia Combinada , Feminino , Humanos , Cuidados Intraoperatórios , Pessoa de Meia-Idade
2.
Oncologist ; 17(12): 1496-503, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23006498

RESUMO

PURPOSE: This phase I study assessed the toxicity and safety of combining daily lapatinib with radiation therapy. Sequential tumor biopsies were obtained to evaluate changes in biomarkers, such as epidermal growth factor receptor (EGFR) and human EGFR-2 (HER2) signaling pathways. METHODS: Eligibility for this dose-escalation study included unresectable and locally recurrent or chemotherapy-refractory and locally advanced breast cancer, and adequate organ function. Patients underwent three serial biopsies: at baseline, after 1 week of lapatinib alone, and after 1 week of lapatinib and radiation. Endpoints included determination of toxicity, maximum tolerated dose, and analysis of the effect of lapatinib with or without radiation on EGFR and HER2 signaling pathways by immunohistochemistry. RESULTS: Doses of lapatinib up to 1,500 mg/day were well tolerated. Toxicity of grade 3 or more was limited to radiation dermatitis and pain. Out of 19 patients treated, in field responses per response evaluation criteria in solid tumors criteria were complete in four patients and partial in six patients. Serial biopsies were obtained in 16 patients with no complications. Total Her2 was relatively unchanged while phospho-Her2, phospho-Akt, and phospho-ERK showed variable responses to both lapatinib alone and dual therapy with lapatinib and radiation. CONCLUSIONS: The combination of lapatinib and radiation was well tolerated in this patient cohort. Overall local response rates were comparable to those reported in other studies in this patient population. Biopsies were safely performed at all time points. Inhibition of HER2 and downstream signaling pathways was identified, although no strong correlation with response was seen.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/radioterapia , Quinazolinas/uso terapêutico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/análise , Biópsia/métodos , Estudos de Coortes , Receptores ErbB/genética , Receptores ErbB/metabolismo , Feminino , Humanos , Imuno-Histoquímica , Lapatinib , Dose Máxima Tolerável , Pessoa de Meia-Idade , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Transdução de Sinais
3.
Ann Surg Oncol ; 18(4): 939-45, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21061074

RESUMO

BACKGROUND: Multiple partial breast radiotherapy techniques are available. We have previously presented the technical details of our procedure of delivering partial breast irradiation with a single fraction of intraoperative radiotherapy (IORT) targeting the tumor in situ prior to partial mastectomy. This study details our completed, single-institution trial. MATERIALS AND METHODS: An IRB-approved, DSMB-monitored phase II trial was performed with the following inclusion criteria: women age ≥48, ultrasound-visible invasive ductal cancers <3 cm, clinically negative axillary nodes. IORT was delivered using mobile electron irradiator, at least a 1.5-cm radial and 1-cm deep margin; patients received 15 Gy and immediately underwent partial mastectomy. Ipsilateral breast recurrence was classified as true/marginal, elsewhere in the breast or nodal basin. Kaplan-Meier methods were used to estimate survival functions and exact 95% confidence intervals are reported. RESULTS: Between 2003 and 2007, 71 women underwent IORT (median follow-up: 3.5 years). For patients with tumor-involved or close margins, additional therapy was required: 7 patients, total mastectomy; 11, whole breast radiation. Four women experienced invasive ipsilateral breast failures (1 new primary, 3 margin recurrences) for a 3-year local control rate of 49 of 53 (94.8%; 95% confidence interval 92.4% [95% CI] 84.2­98.3%), actuarial three-year in breast recurrence was 8% (95% CI 2­18%), and breast cancer-specific survival was 100%. CONCLUSIONS: Intraoperative radiotherapy delivered to an in situ tumor is feasible, but our local control rate at 3.5 years is concerning. Possible changes to this technique to improve local control rates include better preoperative imaging (MRI), routine intraoperative ultrasound, and improved IORT delivery (larger cone, increased dose).


Assuntos
Neoplasias da Mama/radioterapia , Neoplasias da Mama/cirurgia , Mastectomia , Recidiva Local de Neoplasia/radioterapia , Recidiva Local de Neoplasia/cirurgia , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/patologia , Feminino , Seguimentos , Humanos , Cuidados Intraoperatórios , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Dosagem Radioterapêutica , Radioterapia Adjuvante , Taxa de Sobrevida , Resultado do Tratamento
4.
Mol Cell Biol ; 26(17): 6412-24, 2006 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-16914727

RESUMO

HER4 expression in human breast cancers correlates with a positive prognosis. While heregulin inhibits the growth of HER4-positive breast cancer cells, it does so by undefined mechanisms. We demonstrate that heregulin-induced HER4 activity inhibits cell proliferation and delays G(2)/M progression of breast cancer cells. While investigating pathways of G(2)/M delay, we noted that heregulin increased the expression of BRCA1 in a HER4-dependent, HER2-independent manner. Induction of BRCA1 by HER4 occurred independently of the cell cycle. Moreover, BRCA1 expression was elevated in HER4-postive human breast cancer specimens. Heregulin stimulated c-Jun N-terminal kinase (JNK), and pharmacologic inhibition of JNK impaired heregulin-enhanced expression of BRCA1 and mitotic delay; inhibition of Erk1/2 did not. Knockdown of BRCA1 with small interfering RNA in a human breast cancer cell line interfered with HER4-mediated mitotic delay. Heregulin/HER4-dependent mitotic delay was examined further with an isogenic pair of mouse mammary epithelial cells (MECs) derived from mice harboring homozygous LoxP sites flanking exon 11 of BRCA1, such that one cell line expressed BRCA1 while the other cell line, after Cre-mediated excision, did not. BRCA1-positive MECs displayed heregulin-dependent mitotic delay; however, the isogenic BRCA1-negative MECs did not. These results suggest that heregulin-mediated growth inhibition in HER4-postive breast cancer cells requires BRCA1.


Assuntos
Proteína BRCA1/metabolismo , Receptores ErbB/metabolismo , Mitose/efeitos dos fármacos , Neuregulina-1/farmacologia , Animais , Proteína BRCA1/deficiência , Proteína BRCA1/genética , Neoplasias da Mama/patologia , Células Epiteliais/citologia , Células Epiteliais/efeitos dos fármacos , Receptores ErbB/genética , Éxons/genética , Fase G2/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células HeLa , Humanos , Glândulas Mamárias Animais/citologia , Camundongos , Proteína Quinase 8 Ativada por Mitógeno/metabolismo , Proteína Quinase 9 Ativada por Mitógeno/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptor ErbB-2/metabolismo , Receptor ErbB-4 , Células Tumorais Cultivadas
5.
Clin Cancer Res ; 13(8): 2329-34, 2007 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-17438091

RESUMO

PURPOSE: Gene expression analysis identifies several breast cancer subtypes. We examined the relationship of neoadjuvant chemotherapy response to outcome among these breast cancer subtypes. EXPERIMENTAL DESIGN: We used immunohistochemical profiles [human epidermal growth factor receptor 2-positive (HER2+)/hormone receptor-negative for HER2+/estrogen receptor-negative (ER-), hormone receptor and HER2- for basal-like, hormone receptor-positive for luminal] to subtype a prospectively maintained data set of patients with breast cancer treated with neoadjuvant anthracycline-based (doxorubicin plus cyclophosphamide, AC) chemotherapy. We analyzed each subtype for clinical and pathologic response to neoadjuvant chemotherapy and examined the relationship of response to distant disease-free survival and overall survival. RESULTS: Of the 107 patients tested, 34 (32%) were basal-like, 11 (10%) were HER2+/ER-, and 62 (58%) were luminal. After neoadjuvant AC, 75% received subsequent chemotherapy and all received endocrine therapy if hormone receptor-positive. The chemotherapy regimen and pretreatment stage did not differ by subtype. Clinical response to AC was higher among the HER2+/ER- (70%) and basal-like (85%) than the luminal subtypes (47%; P < 0.0001). Pathologic complete response occurred in 36% of HER2+/ER-, 27% of basal-like, and 7% of luminal subtypes (P = 0.01). Despite initial chemosensitivity, patients with the basal-like and HER2+/ER- subtypes had worse distant disease-free survival (P = 0.04) and overall survival (P = 0.02) than those with the luminal subtypes. Regardless of subtype, only 2 of 17 patients with pathologic complete response relapsed. The worse outcome among basal-like and HER+/ER- subtypes was due to higher relapse among those with residual disease (P = 0.003). CONCLUSIONS: Basal-like and HER2+/ER- subtypes are more sensitive to anthracycline-based neoadjuvant chemotherapy than luminal breast cancers. Patients that had pathologic complete response to chemotherapy had a good prognosis regardless of subtype. The poorer prognosis of basal-like and HER2+/ER- breast cancers could be explained by a higher likelihood of relapse in those patients in whom pathologic complete response was not achieved.


Assuntos
Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Adulto , Idoso , Neoplasias da Mama/mortalidade , Feminino , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Receptor ErbB-2/análise , Receptores de Estrogênio/análise , Receptores de Progesterona/análise , Análise de Sobrevida
6.
Mol Endocrinol ; 21(8): 1861-76, 2007 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-17505063

RESUMO

Unlike the proliferative action of other epidermal growth factor (EGF) receptor family members, HER4/ErbB4 is often associated with growth-inhibitory and differentiation signaling. These actions may involve HER4 two-step proteolytic processing by intramembraneous gamma-secretase, releasing the soluble, intracellular 80-kDa HER4 cytoplasmic domain, s80HER4. We demonstrate that pharmacological inhibition of either gamma-secretase activity or HER4 tyrosine kinase activity blocked heregulin-dependent growth inhibition of SUM44 breast cancer cells. We next generated breast cell lines stably expressing GFP-s80HER4 [green fluorescent protein (GFP) fused to the N terminus of the HER4 cytoplasmic domain, residues 676-1308], GFP-CT(HER4) (GFP fused to N terminus of the HER4 C-terminus distal to the tyrosine kinase domain, residues 989-1308), or GFP alone. Both GFP-s80HER4 and GFP-CTHER4 were found in the nucleus, but GFP-s80HER4 accumulated to a greater extent and sustained its nuclear localization. s80HER4 was constitutively tyrosine phosphorylated, and treatment of cells with a specific HER family tyrosine kinase inhibitor 1) blocked tyrosine phosphorylation; 2) markedly diminished GFP-s80HER4 nuclear localization; and 3) reduced signal transducer and activator of transcription (STAT)5A tyrosine phosphorylation and nuclear localization as well as GFP-s80HER4:STAT5A interaction. Multiple normal mammary and breast cancer cell lines, stably expressing GFP-s80HER4 (SUM44, MDA-MB-453, MCF10A, SUM102, and HC11) were growth inhibited compared with the same cell line expressing GFP-CTHER4 or GFP alone. The s80HER4-induced cell number reduction was due to slower growth because rates of apoptosis were equivalent in GFP-, GFP-CTHER4-, and GFP-s80HER4-expressing cells. Lastly, GFP-s80HER4 enhanced differentiation signaling as indicated by increased basal and prolactin-dependent beta-casein expression. These results indicate that surface HER4 tyrosine phosphorylation and ligand-dependent release of s80HER4 are necessary, and s80HER4 signaling is sufficient for HER4-dependent growth inhibition.


Assuntos
Proliferação de Células , Citoplasma/fisiologia , Receptores ErbB/fisiologia , Inibidores do Crescimento/fisiologia , Glândulas Mamárias Humanas/citologia , Glândulas Mamárias Humanas/metabolismo , Fragmentos de Peptídeos , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Linhagem Celular Tumoral , Feminino , Humanos , Glândulas Mamárias Humanas/enzimologia , Neuregulina-1/antagonistas & inibidores , Neuregulina-1/fisiologia , Fragmentos de Peptídeos/fisiologia , Estrutura Terciária de Proteína , Receptor ErbB-4
7.
Cancer Res ; 66(12): 6412-20, 2006 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-16778220

RESUMO

ERBB4/HER4 (referred to here as ERBB4) is a unique member of the epidermal growth factor receptor (EGFR) family of receptor tyrosine kinases. In contrast to the other three members of the EGFR family (i.e., EGFR, ERBB2/HER2/NEU, and ERBB3), which are associated with aggressive forms of human cancers, ERBB4 expression seems to be selectively lost in tumors with aggressive phenotypes. Consistent with this observation, we show that ERBB4 induces apoptosis when reintroduced into breast cancer cell lines or when endogenous ERBB4 is activated by a ligand. We further show that ligand activation and subsequent proteolytic processing of endogenous ERBB4 results in mitochondrial accumulation of the ERBB4 intracellular domain (4ICD) and cytochrome c efflux, the essential and committed step of mitochondrial regulated apoptosis. Our results indicate that 4ICD is functionally similar to BH3-only proteins, proapoptotic members of the BCL-2 family required for initiation of mitochondrial dysfunction through activation of the proapoptotic multi-BH domain proteins BAX/BAK. Similar to other BH3-only proteins, 4ICD cell-killing activity requires an intact BH3 domain and 4ICD interaction with the antiapoptotic protein BCL-2, suppressed 4ICD-induced apoptosis. Unique among BH3-only proteins, however, is the essential requirement of BAK but not BAX to transmit the 4ICD apoptotic signal. Clinically, cytosolic but not membrane ERBB4/4ICD expression in primary human breast tumors was associated with tumor apoptosis, providing a mechanistic explanation for the loss of ERBB4 expression during tumor progression. Thus, we propose that ligand-induced mitochondrial accumulation of 4ICD represents a unique mechanism of action for transmembrane receptors, directly coupling a cell surface signal to the tumor cell mitochondrial apoptotic pathway.


Assuntos
Apoptose/fisiologia , Neoplasias da Mama/patologia , Receptores ErbB/metabolismo , Sequência de Aminoácidos , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Citocromos c/metabolismo , Receptores ErbB/biossíntese , Humanos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Modelos Moleculares , Dados de Sequência Molecular , Neuregulina-1/farmacologia , Fragmentos de Peptídeos/metabolismo , Estrutura Terciária de Proteína , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Receptor ErbB-4 , Homologia de Sequência de Aminoácidos , Proteína Killer-Antagonista Homóloga a bcl-2/metabolismo
8.
BMC Genomics ; 8: 258, 2007 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-17663798

RESUMO

BACKGROUND: The epidermal growth factor receptor (EGFR/HER1) and its downstream signaling events are important for regulating cell growth and behavior in many epithelial tumors types. In breast cancer, the role of EGFR is complex and appears to vary relative to important clinical features including estrogen receptor (ER) status. To investigate EGFR-signaling using a genomics approach, several breast basal-like and luminal epithelial cell lines were examined for sensitivity to EGFR inhibitors. An EGFR-associated gene expression signature was identified in the basal-like SUM102 cell line and was used to classify a diverse set of sporadic breast tumors. RESULTS: In vitro, breast basal-like cell lines were more sensitive to EGFR inhibitors compared to luminal cell lines. The basal-like tumor derived lines were also the most sensitive to carboplatin, which acted synergistically with cetuximab. An EGFR-associated signature was developed in vitro, evaluated on 241 primary breast tumors; three distinct clusters of genes were evident in vivo, two of which were predictive of poor patient outcomes. These EGFR-associated poor prognostic signatures were highly expressed in almost all basal-like tumors and many of the HER2+/ER- and Luminal B tumors. CONCLUSION: These results suggest that breast basal-like cell lines are sensitive to EGFR inhibitors and carboplatin, and this combination may also be synergistic. In vivo, the EGFR-signatures were of prognostic value, were associated with tumor subtype, and were uniquely associated with the high expression of distinct EGFR-RAS-MEK pathway genes.


Assuntos
Neoplasias da Mama/genética , Receptores ErbB/fisiologia , Perfilação da Expressão Gênica , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/farmacologia , Receptores ErbB/antagonistas & inibidores , Humanos , MAP Quinase Quinase Quinases/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo
9.
Cancer Res ; 65(8): 3404-9, 2005 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-15833875

RESUMO

Advanced prostate cancer invariably recurs despite androgen deprivation therapy. The androgen receptor (AR) likely plays a key role in this progression and in the continued survival and proliferation of prostate cancer cells in the low androgen environment. Cross-talk with growth factor receptors, such as epidermal growth factor receptor (EGFR) family, has been postulated as a potential mechanism to activate AR in recurrent prostate cancer. We have investigated the role of HER-2/neu (ErbB-2) tyrosine kinase in AR function by characterizing the effect of inhibiting endogenous HER-2 activity in LNCaP cells. We used two independent methods, expression of intracellular single-chain antibody against HER-2 and treatment with a novel dual EGFR/HER-2 kinase inhibitor GW572016 (lapatinib). Expression of intracellular HER-2 antibody scFv-5R and treatment with GW572016 inhibited HER-2 signaling. This HER-2 inhibition led to impairment of AR-mediated functions, such as androgen-stimulated growth and the induction of endogenous prostate-specific antigen (PSA) mRNA and protein. Androgen-stimulated recruitment of AR and histone acetylation at the androgen responsive enhancer of the PSA gene, detected by chromatin immunoprecipitation analysis, were impaired by HER-2 inhibition. GW572016 was more potent in its ability to inhibit PSA expression and AR recruitment and histone acetylation than the EGFR-selective kinase inhibitor ZD1839 (gefitinib), consistent with the HER-2 kinase playing the major role in AR regulation. These results show that HER-2 signaling is required for optimal transcriptional activity of AR in prostate cancer cells and suggest that HER-2 inhibition may provide a novel strategy to disrupt AR function in prostate cancer.


Assuntos
Antagonistas de Receptores de Andrógenos , Neoplasias da Próstata/metabolismo , Receptor ErbB-2/antagonistas & inibidores , Acetilação/efeitos dos fármacos , Androgênios/fisiologia , Linhagem Celular Tumoral , Cromatina/efeitos dos fármacos , Cromatina/genética , Imunoprecipitação da Cromatina , Di-Hidrotestosterona/farmacologia , Receptores ErbB/antagonistas & inibidores , Gefitinibe , Histonas/metabolismo , Humanos , Fragmentos de Imunoglobulinas/biossíntese , Fragmentos de Imunoglobulinas/genética , Fragmentos de Imunoglobulinas/imunologia , Lapatinib , Masculino , Antígeno Prostático Específico/antagonistas & inibidores , Antígeno Prostático Específico/biossíntese , Antígeno Prostático Específico/genética , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/enzimologia , Neoplasias da Próstata/genética , Quinazolinas/farmacologia , Receptor ErbB-2/imunologia , Receptores Androgênicos/genética , Receptores Androgênicos/metabolismo , Receptores Androgênicos/fisiologia , Elementos de Resposta , Transcrição Gênica/efeitos dos fármacos , Transcrição Gênica/fisiologia
10.
J Clin Oncol ; 23(1): 30-40, 2005 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-15545661

RESUMO

PURPOSE: We compared radiotherapy (RT) delivery and locoregional control in patients with node-positive breast cancer randomly assigned on Cancer and Leukemia Group B 9344 to receive adjuvant doxorubicin/cyclophosphamide (AC) with patients assigned to receive AC followed by paclitaxel (AC+T). METHODS: Eligible patients were randomly assigned to receive adjuvant AC versus AC+T chemotherapy. RT was required if breast-conserving surgery was performed but was elective after mastectomy. Information about RT delivery was retrospectively collected. Cumulative incidence of locoregional recurrence (LRR), use of elective RT, and RT delivery were compared between treatment arms. RESULTS: For patients treated with breast-conserving surgery and RT, the 5-year cumulative incidence of isolated LRR was 9.7% in the AC arm and 3.7% in the AC+T arm (P = .04) and of LRR as any component of failure was 12.9% versus 6.1%, respectively (P = .04). Although LRR rates in patients who did not receive postmastectomy RT were lower in the AC+T arm, the difference was not statistically significant. Despite the lack of protocol guidelines, RT use did not differ between arms, nor did RT dose, treatment interruption, or completion. CONCLUSION: Despite the delay to RT during additional chemotherapy, adjuvant AC+T afforded better local control than AC alone in patients treated with breast-conserving therapy. Addition of paclitaxel did not adversely affect delivery or ability to tolerate RT, as indicated by similar rates of completion of timely, full-dose RT between arms.


Assuntos
Antineoplásicos Fitogênicos/administração & dosagem , Neoplasias da Mama/terapia , Paclitaxel/administração & dosagem , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Quimioterapia Adjuvante , Terapia Combinada , Ciclofosfamida/administração & dosagem , Doxorrubicina/administração & dosagem , Procedimentos Cirúrgicos Eletivos , Feminino , Humanos , Mastectomia , Mastectomia Segmentar , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Radioterapia/métodos , Estudos Retrospectivos
11.
Int J Radiat Oncol Biol Phys ; 64(1): 168-75, 2006 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-16198507

RESUMO

PURPOSE: Whole breast radiotherapy (RT) followed by a tumor bed boost typically spans 5-6 weeks of treatment. Interest is growing in RT regimens, such as concomitant boost, that decrease overall treatment time, lessening the time/cost burden to patients and facilities. METHODS AND MATERIALS: Computed tomography (CT) scans from 20 cases were selected for this retrospective, dosimetric study to compare three different techniques of concomitant boost delivery: (1) standard tangents plus an electron boost, (2) intensity-modulated RT (IMRT) tangents using custom compensators plus an electron boost, and (3) IMRT tangents plus a conformal photon boost. The equivalent uniform dose model was used to compare the plans. RESULTS: The average breast equivalent uniform dose value for the three techniques (standard, IMRT plus electrons, and IMRT plus photons) was 48.6, 47.9, and 48.3, respectively. The plans using IMRT more closely approximated the prescribed dose of 46 Gy to the whole breast. The breast volume receiving >110% of the dose was less with the IMRT tangents than with standard RT (p = 0.037), but no significant difference in the maximal dose or other evaluated parameters was noted. CONCLUSION: Although the IMRT techniques delivered the prescribed dose with better dose uniformity, the small improvement seen did not support a goal of improved resource use.


Assuntos
Neoplasias da Mama/radioterapia , Radioterapia de Intensidade Modulada/métodos , Adulto , Idoso , Neoplasias da Mama/diagnóstico por imagem , Estudos de Avaliação como Assunto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Dosagem Radioterapêutica , Estudos Retrospectivos , Tomografia Computadorizada por Raios X
12.
Am J Surg ; 191(6): 827-9, 2006 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-16720159

RESUMO

BACKGROUND: Retrieval of fewer than 10 lymph nodes at axillary dissection (ALND) for breast cancer can represent anatomic variation or inadequate dissection. We postulated that despite aggressive ALND, a lower lymph node count is more frequent after neoadjuvant chemotherapy. METHODS: Patients who received neoadjuvant chemotherapy followed by ALND were compared with patients who received surgery first. All patients received a level I and II ALND at a single institution by one of the breast surgeons. The number of nodes retrieved at ALND was dichotomized into categories (< 10 and > or = 10), and compared using Fisher exact test. RESULTS: A total of 143 neoadjuvant and 170 surgery-first patients were studied. Patients treated with neoadjuvant chemotherapy were significantly more likely to have fewer than 10 lymph nodes retrieved at ALND than were the surgery-first patients (19/143 or 13% vs. 6/170 or 4%, P = .003). CONCLUSIONS: A low lymph node count is more common in patients after treatment with neoadjuvant chemotherapy and should not be assumed to represent an incomplete ALND.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Linfonodos/patologia , Terapia Neoadjuvante , Invasividade Neoplásica/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Axila , Neoplasias da Mama/cirurgia , Feminino , Humanos , Excisão de Linfonodo/métodos , Linfonodos/cirurgia , Metástase Linfática/patologia , Metástase Linfática/prevenção & controle , Mastectomia/métodos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Probabilidade , Prognóstico , Estudos Prospectivos , Biópsia de Linfonodo Sentinela , Estatísticas não Paramétricas , Resultado do Tratamento
13.
Cancer Res ; 63(22): 7807-14, 2003 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-14633707

RESUMO

Oncogenic forms of the small GTPase Ras increase the resistance of cells to killing by ionizing radiation (IR). Although not all of the signaling pathways for radioresistance are well defined, it is now clear that Ras-dependent signaling pathways involved in radioresistance include those mediated by phosphatidylinositol 3'-kinase (PI3-K) and Raf. Nevertheless, PI3-K and Raf together are not sufficient to reconstitute all of the resistance conferred by Ras, indicating that other effectors must also contribute. We show here that Ras-driven autocrine signaling through the epidermal growth factor receptor (EGFR) also contributes to radioresistance in Ras-transformed cells. Conditioned media (CM) collected from RIE-1 rat intestinal epithelial cells expressing oncogenic Ras increased the survival of irradiated cells. Ras-CM contains elevated levels of the EGFR ligand transforming growth factor alpha (TGF-alpha). Both Ras-CM and TGF-alpha stimulated EGFR phosphorylation, and exogenous TGF-alpha mimicked the effects of Ras-CM to increase radioresistance. Blocking EGFR signaling with the EGFR/HER-2 kinase inhibitor (KI) GW572016 decreased the postradiation survival of irradiated Ras-transformed cells and normal cells but had no effect on the survival of unirradiated cells. Ras-CM and TGF-alpha also increase PI3-K activity downstream of the EGFR and increase postradiation survival, both of which are abrogated by GW572016. Thus, Ras utilizes autocrine signaling through EGFR to increase radioresistance, and the EGFR KI GW572016 acts as a radiosensitizer. The observation that Ras-transformed cells can be sensitized to killing by ionizing radiation with GW572016 demonstrates that EGFR KIs could potentially be used to radiosensitize tumors in which radioresistance is dependent on Ras-driven autocrine signaling through EGFR.


Assuntos
Receptores ErbB/fisiologia , Genes ras/fisiologia , Tolerância a Radiação/fisiologia , Animais , Linhagem Celular Transformada , Meios de Cultivo Condicionados , Células Epiteliais/metabolismo , Células Epiteliais/fisiologia , Células Epiteliais/efeitos da radiação , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase , Fosforilação , Tolerância a Radiação/genética , Ratos , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Fator de Crescimento Transformador alfa/farmacologia
14.
Cancer Res ; 62(14): 4142-50, 2002 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-12124353

RESUMO

Cells transformed by the oncogenic small GTPase, Ras, display a radioresistant phenotype in response to ionizing radiation (IR). To determine the mechanisms by which Ras mediates radioresistance in epithelial cells, we assessed the importance of three major survival pathways that can be activated by Ras [phosphatidylinositol 3-kinase (PI3-K)>Akt, nuclear factor kappaB (NF-kappaB), and Raf>mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK)>extracellular signal-regulated kinase] as necessary or sufficient for Ras-mediated radioresistance in matched pairs of RIE-1 rat intestinal epithelial cells expressing oncogenic Ras or empty vector (RIE-Ras and RIE-vector). Inhibiting PI3-K with LY294002 sensitized RIE-1 cells to IR in a dose-dependent manner, indicating that PI3-K is necessary for radioresistance, whereas inhibition of NF-kappaB with the super-repressor IkappaBalpha had little effect on survival. Expression of either the constitutively active catalytic subunit of PI3-K, p110alpha-CAAX, or the Ras effector domain mutant 12V/40C, which retains binding to PI3-K but is impaired in binding to other Ras effectors, was sufficient to confer partial radioresistance. Expression of either a constitutively active form of the serine/threonine kinase Raf-1 or the Ras effector domain mutant 12V/35S, which retains binding to Raf but is impaired in binding to other Ras effectors, was also sufficient to confer partial radioresistance. Surprisingly, however, even complete inhibition of MEK activity by using U0126 resulted in no change in post-IR survival whatsoever. Thus, whereas Raf contributes to Ras-mediated radioresistance, this is accomplished through a MEK-independent pathway. Taken together, these results indicate that multiple pathways, including both PI3-K-dependent and Raf-dependent but MEK-independent signaling, are required for Ras-mediated radioresistance in epithelial cells. Finally, we demonstrate that Ras-mediated radioresistance can be uncoupled from Ras-mediated transformation, in that PI3-K is required for radioresistance but not transformation, whereas MEK and NF-kappaB are required for transformation but not radioresistance in RIE-1 epithelial cells.


Assuntos
Sistema de Sinalização das MAP Quinases/fisiologia , Fosfatidilinositol 3-Quinases/fisiologia , Proteínas Proto-Oncogênicas c-raf/fisiologia , Tolerância a Radiação/fisiologia , Proteínas ras/fisiologia , Animais , Células Epiteliais/fisiologia , Células Epiteliais/efeitos da radiação , Intestinos/citologia , Intestinos/fisiologia , Intestinos/efeitos da radiação , Proteínas Quinases JNK Ativadas por Mitógeno , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação/efeitos da radiação , Isoformas de Proteínas , Ratos , Proteínas Quinases p38 Ativadas por Mitógeno
15.
Cancer Res ; 64(13): 4585-92, 2004 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-15231670

RESUMO

Although mutated forms of ras are not associated with the majority of breast cancers (<5%), there is considerable experimental evidence that hyperactive Ras can promote breast cancer growth and development. Therefore, we determined whether Ras and Ras-responsive signaling pathways were activated persistently in nine widely studied human breast cancer cell lines. Although only two of the lines harbor mutationally activated ras, we found that five of nine breast cancer cell lines showed elevated active Ras-GTP levels that may be due, in part, to HER2 activation. Unexpectedly, activation of two key Ras effector pathways, the extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase and phosphatidylinositol 3'-kinase/AKT signaling pathways, was not always associated with Ras activation. Ras activation also did not correlate with invasion or the expression of proteins associated with tumor cell invasion (estrogen receptor alpha and cyclooxygenase 2). We then examined the role of Ras signaling in mediating resistance to matrix deprivation-induced apoptosis (anoikis). Surprisingly, we found that ERK and phosphatidylinositol 3'-kinase/AKT activation did not have significant roles in conferring anoikis resistance. Taken together, these observations show that Ras signaling exhibits significant cell context variations and that other effector pathways may be important for Ras-mediated oncogenesis, as well as for anoikis resistance, in breast cancer. Additionally, because ERK and AKT activation are not strictly associated with Ras activation, pharmacological inhibitors of these two signaling pathways may not be the best approach for inhibition of aberrant Ras function in breast cancer treatment.


Assuntos
Anoikis/fisiologia , Neoplasias da Mama/patologia , Proteínas ras/fisiologia , Anoikis/genética , Neoplasias da Mama/enzimologia , Neoplasias da Mama/genética , Linhagem Celular Tumoral , Ciclo-Oxigenase 2 , Receptor alfa de Estrogênio , Regulação Neoplásica da Expressão Gênica , Humanos , Isoenzimas/biossíntese , Isoenzimas/genética , Isoenzimas/metabolismo , Sistema de Sinalização das MAP Quinases/fisiologia , Proteínas de Membrana , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Invasividade Neoplásica , Fosfatidilinositol 3-Quinases/metabolismo , Prostaglandina-Endoperóxido Sintases/biossíntese , Prostaglandina-Endoperóxido Sintases/genética , Prostaglandina-Endoperóxido Sintases/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Proteínas Proto-Oncogênicas c-akt , Receptor ErbB-2/biossíntese , Receptor ErbB-2/genética , Receptor ErbB-2/fisiologia , Receptores de Estrogênio/biossíntese , Transdução de Sinais/fisiologia , Proteínas ras/genética
16.
J Clin Oncol ; 21(8): 1431-9, 2003 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-12668651

RESUMO

PURPOSE: Using a 2 x 2 factorial design, we studied the adjuvant chemotherapy of women with axillary node-positive breast cancer to compare sequential doxorubicin (A), paclitaxel (T), and cyclophosphamide (C) with concurrent doxorubicin and cyclophosphamide (AC) followed by paclitaxel (T) for disease-free (DFS) and overall survival (OS); to determine whether the dose density of the agents improves DFS and OS; and to compare toxicities. PATIENTS AND METHODS: A total of 2,005 female patients were randomly assigned to receive one of the following regimens: (I) sequential A x 4 (doses) --> T x 4 --> C x 4 with doses every 3 weeks, (II) sequential A x 4 --> T x 4 --> C x 4 every 2 weeks with filgrastim, (III) concurrent AC x 4 --> T x 4 every 3 weeks, or (IV) concurrent AC x 4 --> T x 4 every 2 weeks with filgrastim. RESULTS: A protocol-specified analysis was performed at a median follow-up of 36 months: 315 patients had experienced relapse or died, compared with 515 expected treatment failures. Dose-dense treatment improved the primary end point, DFS (risk ratio [RR] = 0.74; P =.010), and OS (RR = 0.69; P =.013). Four-year DFS was 82% for the dose-dense regimens and 75% for the others. There was no difference in either DFS or OS between the concurrent and sequential schedules. There was no interaction between density and sequence. Severe neutropenia was less frequent in patients who received the dose-dense regimens. CONCLUSION: Dose density improves clinical outcomes significantly, despite the lower than expected number of events at this time. Sequential chemotherapy is as effective as concurrent chemotherapy.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/cirurgia , Quimioterapia Adjuvante , Ciclofosfamida/administração & dosagem , Doxorrubicina/administração & dosagem , Esquema de Medicação , Feminino , Filgrastim , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Humanos , Pessoa de Meia-Idade , Análise Multivariada , Paclitaxel/administração & dosagem , Modelos de Riscos Proporcionais , Proteínas Recombinantes , Análise de Sobrevida , Resultado do Tratamento
17.
Am J Surg ; 190(4): 595-7, 2005 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-16164929

RESUMO

BACKGROUND: In patients with breast cancer who choose mastectomy with immediate reconstruction, the sentinel lymph node (SLN) status on permanent histology may complicate treatment if a metastasis is found. The purpose of this study was to determine how performing an SLN biopsy (SLNB) before the definitive operation would influence subsequent surgical procedures. METHODS: Our SLN database was searched for patients who underwent staged SLNB with subsequent mastectomy between 2001 and 2004. RESULTS: Twenty-five patients with 27 breast cancers underwent SLNB before mastectomy. Of them, 9 of 27 (33%) were node positive. All 9 patients underwent modified radical mastectomy. Three node-positive patients did not undergo immediate reconstruction. Of the remaining 6 node-positive patients, 5 underwent reconstruction with autologous tissue rather than a tissue expander. In contrast, 6 of 16 (37%) node-negative patients underwent reconstruction with a tissue expander. CONCLUSIONS: Staged SLNB assists in selecting the appropriate operation in patients who are considering immediate reconstruction.


Assuntos
Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/patologia , Carcinoma Intraductal não Infiltrante/patologia , Carcinoma Lobular/patologia , Biópsia de Linfonodo Sentinela/métodos , Adulto , Idoso , Axila , Neoplasias da Mama/terapia , Carcinoma Ductal de Mama/terapia , Carcinoma Intraductal não Infiltrante/terapia , Carcinoma Lobular/terapia , Feminino , Humanos , Excisão de Linfonodo , Metástase Linfática , Mamoplastia , Mastectomia , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Radioterapia Adjuvante
18.
Semin Radiat Oncol ; 12(4): 341-51, 2002 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-12382192

RESUMO

Therapy directed against specific biologic targets has long been used in the treatment of breast cancer; the estrogen receptor is a validated prognostic and therapeutic target, and antiestrogen therapy has been used effectively for decades. Recently, scientific progress and increased comprehension of mechanisms of breast cancer pathogenesis have led to the proliferation of both potential molecular targets and new therapeutic agents. The success of traztuzumab (Herceptin, Genentech, South San Francisco, CA), an anti-HER2 antibody, has spurred the development of other biologically directed therapeutics. In this overview, I discuss three targets relevant to breast cancer (the epidermal growth factor receptor family, angiogenesis, and NF-kappa B), and therapeutic approaches directed against these targets are discussed.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Apoptose/efeitos dos fármacos , Neoplasias da Mama/terapia , Fator de Crescimento Epidérmico/antagonistas & inibidores , Neoplasias da Mama/irrigação sanguínea , Neoplasias da Mama/metabolismo , Fator de Crescimento Epidérmico/metabolismo , Feminino , Humanos , NF-kappa B/antagonistas & inibidores , Neovascularização Patológica/prevenção & controle
19.
Semin Radiat Oncol ; 13(1): 22-30, 2003 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-12520461

RESUMO

Growing evidence suggests that epidermal growth factor family receptors (HERs) play a significant role in radiation response. EGFR expression levels and activation by ligand correlate with radioresistance, and exogenous HER2 expression alters radiation response. Preclinical studies of anti-EGFR anti-HER2 antibodies, and kinase inhibitors that inhibit EGFR, both EGFR and HER2, or all 4 family members show potential for clinical radiosensitization. Early-phase clinical trials of the anti-EGFR antibody, C225, prove the combination of C225 and radiotherapy to be well tolerated and promising. A phase 3 randomized trial in head and neck cancer is underway, and clinical investigation of other HER inhibitors is in progress. The mechanisms(s) of radiation response modulation by HERs appear complex and diverse. Signal transduction initiated by receptor activation promotes survival and proliferation after ionizing radiation, and HER inhibitors affect cellular responses to ionizing radiation (IR) in diverse ways, including inducing apoptosis, cell cycle arrest, and impeding DNA repair. HER signaling and inhibition also affect tumor-stroma interactions, particularly angiogenesis and endothelial survival after IR. Further investigation of the radiation response modulation by EGFR family members and their inhibitors will lead to optimization of this promising therapeutic approach.


Assuntos
Fator de Crescimento Epidérmico/uso terapêutico , Receptores ErbB/efeitos dos fármacos , Receptores ErbB/fisiologia , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/fisiopatologia , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/fisiologia , Humanos , Receptores Proteína Tirosina Quinases/efeitos dos fármacos , Receptores Proteína Tirosina Quinases/fisiologia , Ativação Transcricional/efeitos dos fármacos , Ativação Transcricional/fisiologia
20.
Int J Radiat Oncol Biol Phys ; 58(2): 344-52, 2004 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-14751502

RESUMO

PURPOSE: Two members of the epidermal growth factor receptor family, EGFR and HER2, have been implicated in radioresistance in breast cancer and other malignancies. To gauge the potential clinical utility of targeting both EGFR and HER2 to control growth and radiosensitize human breast cancers, we examined the effect of a dual EGFR/HER2 inhibitor, GW572016, on the proliferation and radiation response of either EGFR- or HER2-overexpressing human breast cancer cell lines. METHODS AND MATERIALS: Primary human breast cancer cell lines that endogenously overexpress EGFR or HER2 and luminal mammary epithelial H16N2 cells stably transfected with HER2 were evaluated for the effect of GW572016 on inhibition of ligand-induced or constitutive receptor phosphorylation, proliferation, radiosensitization, and inhibition of downstream signaling. RESULTS: GW572016 inhibited constitutive and/or ligand-induced EGFR or HER2 tyrosine phosphorylation of all five cell lines, which correlated with the antiproliferative response in all but one cell line. GW572016 radiosensitized EGFR-overexpressing cell lines, but HER2-overexpressing cells were unable to form colonies after brief exposure to GW572016 even in the absence of radiation, and thus could not be evaluated for radiosensitization. One cell line was resistant to the antiproliferative and radiosensitizing effects of GW572016, despite receptor inhibition. Exploration of potential mechanisms of resistance in SUM185 cells revealed failure of GW572016 to inhibit downstream ERK and Akt activation, despite inhibition of HER2 phosphorylation. In contrast, sensitive HER2-overexpressing cell lines demonstrated inhibition of both ERK and Akt phosphorylation. CONCLUSION: GW572016 potently inhibits receptor phosphorylation in either EGFR- or HER2-overexpressing cell lines and has both antiproliferative and radiosensitizing effects. Resistance to GW572016 was not due to a lack of receptor inhibition, but rather with a lack of inhibition of ERK and Akt, suggesting that measurement of inhibition of crucial signaling pathways may better predict response than inhibition of receptor phosphorylation. The SUM185 cell line provides a valuable model for studying mechanisms of resistance of EGFR/HER2 inhibitor therapy.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Receptores ErbB/antagonistas & inibidores , Proteínas de Neoplasias/antagonistas & inibidores , Quinazolinas/farmacologia , Receptor ErbB-2/antagonistas & inibidores , Neoplasias da Mama/metabolismo , Neoplasias da Mama/radioterapia , Divisão Celular/efeitos dos fármacos , Divisão Celular/efeitos da radiação , Linhagem Celular Tumoral/efeitos dos fármacos , Linhagem Celular Tumoral/efeitos da radiação , Resistencia a Medicamentos Antineoplásicos , Receptores ErbB/metabolismo , Feminino , Humanos , Lapatinib , Proteínas de Neoplasias/metabolismo , Fosforilação , Tolerância a Radiação , Receptor ErbB-2/metabolismo , Transdução de Sinais/efeitos dos fármacos , Ensaio Tumoral de Célula-Tronco
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