RESUMO
Luminal breast cancer (BrCa) has a favorable prognosis compared with other tumor subtypes. However, with time, tumors may evolve and lead to disease progression; thus, there is a great interest in unraveling the mechanisms that drive tumor metastasis and endocrine resistance. In this review, we focus on one of the many pathways that have been involved in tumor progression, the fibroblast growth factor/fibroblast growth factor receptor (FGFR) axis. We emphasize in data obtained from in vivo experimental models that we believe that in luminal BrCa, tumor growth relies in a crosstalk with the stromal tissue. We revisited the studies that illustrate the interaction between hormone receptors and FGFR. We also highlight the most frequent alterations found in BrCa cell lines and provide a short review on the trials that use FGFR inhibitors in combination with endocrine therapies. Analysis of these data suggests there are many players involved in this pathway that might be also targeted to decrease FGF signaling, in addition to specific FGFR inhibitors that may be exploited to increase their efficacy.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Fatores de Crescimento de Fibroblastos/fisiologia , Receptores de Fatores de Crescimento de Fibroblastos/fisiologia , Receptores de Esteroides/fisiologia , Transdução de Sinais/fisiologia , Animais , Inibidores da Aromatase/uso terapêutico , Neoplasias da Mama/química , Neoplasias da Mama/terapia , Linhagem Celular Tumoral , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Receptor alfa de Estrogênio/análise , Feminino , Fatores de Crescimento de Fibroblastos/genética , Amplificação de Genes , Humanos , Camundongos , Mutação , Receptor Cross-Talk/fisiologia , Receptores de Fatores de Crescimento de Fibroblastos/antagonistas & inibidores , Receptores de Fatores de Crescimento de Fibroblastos/genéticaRESUMO
PURPOSE OF REVIEW: The article reviews the consequences of estrogen deprivation during endocrine therapy for breast cancer and provides an update on alternative therapies for the management of symptoms. RECENT FINDINGS: Endocrine therapy has progressed substantially in recent years, and its use is recommended for all breast cancer patients expressing hormone receptors. The main adverse events of this treatment can be controlled with medications and nonpharmacological measures. Antidepressants are effective in controlling vasomotor symptoms. Vaginal discomfort can be treated with local lubricants and pelvic floor physiotherapy, which may help in sexual dysfunction. Pathophysiological mechanisms of musculoskeletal symptoms during aromatase inhibitors treatment are not well understood, but some studies evaluating treatment with duloxetine, yoga, and acupuncture have shown some benefits. For prevention of bone loss, patients with risk factors should be offered bisphosphonates or denosumab. Individualization of treatment is crucial. Consideration should be given to therapy effects on quality of life, and strategies for controlling associated symptoms should be offered.
Assuntos
Antineoplásicos Hormonais/efeitos adversos , Inibidores da Aromatase/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Antagonistas de Estrogênios/efeitos adversos , Doenças Ósseas Endócrinas/terapia , Neoplasias da Mama/química , Ensaios Clínicos como Assunto , Feminino , Fogachos/terapia , Humanos , Doenças Musculoesqueléticas/terapia , Receptores de Estrogênio/análiseRESUMO
PURPOSE: Brain metastases (BM) occur in 15-35% of patients with metastatic breast cancer, conferring poor prognosis and impairing quality of life. Clinical scores have been developed to classify patients according to their prognosis. We aimed to check the utility of the Breast Graded Prognostic Assessment (B-GPA) and its modified version (mB-GPA) and compare them in routine clinical practice. METHODS: This is an ambispective study including all patients with breast cancer BM treated in a single cancer comprehensive center. We analyzed the overall survival (OS) from BM diagnosis until death. The Kaplan-Meier method and Cox proportional hazard regression model were used in the analyses. ROC curves were performed to compare both scores. RESULTS: We included 169 patients; median age was 50 years. HER2-positive and triple negative patients were 33.7% and 20.7%, respectively. At the last follow-up, 90% of the patients had died. Median OS was 12 months (95% confidence interval 8.0-16.0 months). OS was worse in patients with > 3 BM and in patients with triple negative subtype. CONCLUSIONS: In our series, we confirm that B-GPA and mB-GPA scores correlated with prognosis. ROC curves showed that B-GPA and mB-GPA have similar prognostic capabilities, slightly in favor of mB-GPA.
Assuntos
Neoplasias Encefálicas/mortalidade , Neoplasias Encefálicas/secundário , Neoplasias da Mama/mortalidade , Neoplasias da Mama/química , Neoplasias da Mama/classificação , Neoplasias da Mama/patologia , Intervalos de Confiança , Feminino , Humanos , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Prognóstico , Modelos de Riscos Proporcionais , Qualidade de Vida , Curva ROC , Receptor ErbB-2 , Neoplasias de Mama Triplo Negativas/mortalidade , Neoplasias de Mama Triplo Negativas/patologiaRESUMO
PURPOSE: Endocrine therapy is a mainstay for the treatment of hormone receptor-positive breast cancer (BC); however, only a fraction of patients experience a pronounced response to antagonists of estrogen signaling. There is a need to identify predictors for efficacy of this treatment. METHODS: This study included 138 patients with newly diagnosed metastatic BC, who received upfront endocrine therapy. Archival biopsy specimens were tested for CCND1 and FGFR1 gene amplification and mRNA expression by PCR-based methods. RESULTS: CCND1 and FGFR1 amplification was detected in 24 (17.9%) and 28 (20.9%) of 134 evaluable cases, respectively; 9 carcinomas had concurrent alterations of these two genes. Presence of amplification in at least one locus was more common in tumors of higher grade (p = 0.018) and was associated with higher Ki-67 proliferation index (p = 0.036). CCND1 gene amplification was associated with shorter progression-free survival (PFS) in patients receiving aromatase inhibitors (AI) [16.0 months vs. 32.4 months, HR = 3.16 (95% CI 1.26-7.93), p = 0.014]. FGFR1 status did not significantly affect PFS of AI-treated women; however, objective response to AI was observed less frequently in FGFR1-amplified BC as compared to cases with normal FGFR1 copy number [2/15 (13.3%) vs. 22/46 (47.8%), p = 0.031]. Meanwhile, CCND1/FGFR1 gene status did not influence the outcome of tamoxifen-treated patients. CONCLUSION: Presence of CCND1 and/or FGFR1 amplification is associated with worse outcomes of AI therapy in patients with metastatic BC.
Assuntos
Inibidores da Aromatase/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Ciclina D1/genética , Amplificação de Genes , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/química , Neoplasias da Mama/patologia , Proliferação de Células , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Estimativa de Kaplan-Meier , Antígeno Ki-67/metabolismo , Pessoa de Meia-Idade , Intervalo Livre de Progressão , RNA Mensageiro/metabolismo , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Tamoxifeno/uso terapêutico , Resultado do TratamentoRESUMO
Previous studies have reported a close relationship between type V collagen (Col V) and tumor invasion and motility in both breast cancer (BC) and lung cancer (LC). The present work aims to determine whether the extracellular-matrix (ECM)-defined microenvironment influences patient clinical outcome and investigate to which extent histological patterns of Col V expression in malignant cells have a prognostic effect in patients. To that end, we examined the expression of Col V in the tissues of 174 primary tumors (MM, N = 82; LC, N = 41; and BC, N = 46) by immunohistochemistry. We found: (1) diffuse strong green birefringence in membrane and cytoplasm individualizing malignant cells in MM; (2) a focal and weak birefringence mainly in cytoplasmic membrane involving groups of malignant cells in LC and BC; (3) higher average H-score of Col V in MM than in LC and BC samples; (4) a direct correlation between Col V histologic pattern and TNM stage IV, status and median overall survival; (5) patients with LC in TNM stage I, and Col V ≤ 41.7 IOD/mm2 had a low risk of death and a median survival time more than 20 months; (6) patients with MM in TNM stage IV and Col V > 41.7 IOD/mm2 presented a high risk of death and a median survival time of just 20 months. These findings suggest that high levels of Col V individualizing malignant cells, as observed in MM, and low levels grouping malignant cells, as observed in LC and BC, confers different immune-privileged tissue microenvironment for tumor invasion with impact on prognosis of the patients.
Assuntos
Neoplasias da Mama/química , Movimento Celular , Colágeno Tipo V/análise , Matriz Extracelular/química , Neoplasias Pulmonares/química , Mesotelioma Maligno/química , Microambiente Tumoral , Idoso , Neoplasias da Mama/imunologia , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Matriz Extracelular/patologia , Feminino , Humanos , Imuno-Histoquímica , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Mesotelioma Maligno/imunologia , Mesotelioma Maligno/patologia , Pessoa de Meia-Idade , Invasividade Neoplásica , Estadiamento de Neoplasias , Microambiente Tumoral/imunologiaRESUMO
Objective: Clinical guidelines recommend the use of endocrine therapy (ET) in advanced hormone receptor positive (HR+) human epidermal growth factor receptor type 2 negative (HER2-) breast cancer (BC) patients in the absence of visceral disease or ET resistance. Furthermore, studies indicate similar response and survival rates using ET or cytotoxic chemotherapy (CT).Methods: Herein, we assessed clinical characteristics, type of systemic therapy and survival rates of advanced HR + HER2-BC patients in our database.Results: A total of 172 advanced HR + HER2-BC patients were treated at our institution between 1997 and 2019. Sixty percent received first-line ET (4% received combined ET). Median age of this subset was 55 years (range: 30-86). Similarly, the median age of patients that received CT was 54 years (range: 21-83). Over time, 30% of patients received ET in the 2000-2005 period; this increased to 70% in the 2016-2019 period (p = .045). Overall survival (OS) was 97 months and 51 months for patients treated with ET or CT, respectively (p = .002).Conclusions: To the best of our knowledge this is the first study assessing the use of ET in Chilean advanced HR + HER2-BC patients. Several patients in our institution receive CT without indication. The increase in ET usage over time can be attributed to better and faster immunohistochemical detection methods for Estrogen Receptor (ER), changes in educational and government policies, and a wider variety of ET options. Finally, clinical trials have failed to demonstrate a substantial benefit of CT over ET in this setting.
Assuntos
Antineoplásicos Hormonais/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/química , Neoplasias da Mama/mortalidade , Feminino , Humanos , Pessoa de Meia-Idade , Receptor ErbB-2/análise , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Estudos Retrospectivos , Adulto JovemRESUMO
PURPOSE: Patients presenting with lymphovascular space invasion (LVSI) had an absolute decrease in survival. In our present study, the potential roles of LVSI on tumor characteristics was explored to predict the difference in the prognosis of ER and HER2 positive T1 tumors. METHODS: A total of 142 breast cancer patients diagnosed with ER+ and HER2+ tumors whose tumor size was ≤ 2 cm were included in this analysis. One hundred forty-two patients were divided into four groups, group 1 (lymph nodes+ and LVSI+), group 2 (lymph nodes+ and LVSI-), group 3 (lymph nodes- and LVSI+), group 4 (lymph nodes- and LVSI-). Univariate and multivariate Cox proportional hazard models were used to identify independent prognostic factors and calculate the HR and 95% CI. Kaplan-Meier and Cox regression models were used to test the prognostic significance. RESULTS: LVSI positivity was significantly associated with patient age, menopausal status, tumor size, lymph node status, Ki67, PR, and tumor grade. In the univariate and multivariate model, LVSI, PR, and Ki67 were significantly associated with DFS, and LVSI, lymph node status, PR, and Ki67 were significantly associated with OS. LVSI was significantly related to increased risk of DFS and OS only in the PR-negative and low-positive subgroups. It was a prognostic factor for DFS but not for OS in women with low Ki67 and was associated with DFS and OS in high-Ki67 tumors. Furthermore, patients who presented with only LVSI had a significantly worse survival rate than those with lymph node metastasis without LVSI in small tumors. CONCLUSION: The presence of LVSI was highlighted as a variable significant to survival. In further clinical practice, patients with LVSI may need more intensive treatment in certain populations.
Assuntos
Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Receptor ErbB-2 , Receptores de Estrogênio , Adulto , Fatores Etários , Idoso , Neoplasias da Mama/química , Capilares/patologia , Quimioterapia Adjuvante , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Antígeno Ki-67 , Metástase Linfática , Vasos Linfáticos/patologia , Menopausa , Pessoa de Meia-Idade , Gradação de Tumores , Invasividade Neoplásica , Prognóstico , Modelos de Riscos Proporcionais , Estudos Prospectivos , Receptores de Progesterona , Carga Tumoral , Adulto JovemRESUMO
Women of Latin American origin in the United States are more likely to be diagnosed with advanced breast cancer and have a higher risk of mortality than non-Hispanic White women. Studies in U.S. Latinas and Latin American women have reported a high incidence of HER2 positive (+) tumors; however, the factors contributing to this observation are unknown. Genome-wide genotype data for 1,312 patients from the Peruvian Genetics and Genomics of Breast Cancer Study (PEGEN-BC) were used to estimate genetic ancestry. We tested the association between HER2 status and genetic ancestry using logistic and multinomial logistic regression models. Findings were replicated in 616 samples from Mexico and Colombia. Average Indigenous American (IA) ancestry differed by subtype. In multivariate models, the odds of having an HER2+ tumor increased by a factor of 1.20 with every 10% increase in IA ancestry proportion (95% CI, 1.07-1.35; P = 0.001). The association between HER2 status and IA ancestry was independently replicated in samples from Mexico and Colombia. Results suggest that the high prevalence of HER2+ tumors in Latinas could be due in part to the presence of population-specific genetic variant(s) affecting HER2 expression in breast cancer. SIGNIFICANCE: The positive association between Indigenous American genetic ancestry and HER2+ breast cancer suggests that the high incidence of HER2+ subtypes in Latinas might be due to population and subtype-specific genetic risk variants.
Assuntos
Neoplasias da Mama/química , Neoplasias da Mama/etnologia , Hispânico ou Latino/genética , Receptor ErbB-2/análise , Adulto , Idoso , Povo Asiático/etnologia , Povo Asiático/estatística & dados numéricos , População Negra/etnologia , População Negra/estatística & dados numéricos , Neoplasias da Mama/genética , Colômbia/etnologia , Feminino , Humanos , Indígenas Norte-Americanos , Indígenas Sul-Americanos , América Latina/etnologia , Modelos Lineares , Modelos Logísticos , México/etnologia , Pessoa de Meia-Idade , Peru/etnologia , Receptor ErbB-2/genética , Receptores de Estrogênio/sangue , Receptores de Progesterona/sangue , Estados Unidos , População Branca/etnologia , População Branca/estatística & dados numéricos , Adulto JovemRESUMO
OBJECTIVE: The aim of this analysis is to evaluate the relative weight of different epidemiological risk factors on the development of different breast cancer subtypes (i.e. luminal, Her2+ overexpressed or triple negative). METHODS: De-identified datasets of female participants recruited within the Prostate, Lung, Colorectal, and Ovarian (PLCO) trial were accessed. Multivariate Cox regression analysis was utilized to assess factors affecting the development of breast cancer (regardless of subtype). Additional multivariate analyses were conducted to assess factors affecting the development of the three principal subtypes of breast cancer (ER+/Her2- breast cancer; Her2 overexpressed breast cancer and ER-/Her2- breast cancer). RESULTS: A total of 73,570 eligible participants were evaluated in the current analysis of which 2370 participants subsequently developed breast cancer. The following factors were associated with a higher risk of ER+/Her2- breast cancer: white race (P < 0.001), nulliparity (P < 0.001), higher body mass index (P = 0.003), prior exposure to hormone treatment (P = 0.004) and breast cancer in first-degree female relatives (P < 0.001). The following factors were associated with a higher risk of Her2 overexpressed breast cancer: prior exposure to hormone treatment (P = 0.002) and breast cancer in first-degree female relatives (P = 0.001). The following factors were associated with a higher risk of ER-/Her2- breast cancer: black race (P = 0.013), younger age (P = 0.017) and breast cancer in first-degree female relatives (P 0.023). CONCLUSIONS: There is considerable heterogeneity in risk factors among patients with different subtypes of breast cancer. In particular, factors associated with high estrogen levels seem to be associated with luminal breast cancer rather than other breast cancer subtypes.
Assuntos
Neoplasias da Mama/etiologia , Idoso , Neoplasias da Mama/química , Ensaios Clínicos como Assunto , Feminino , Humanos , Pessoa de Meia-Idade , Pós-Menopausa , Modelos de Riscos Proporcionais , Receptor ErbB-2/análise , Receptores de Estrogênio/análise , Fatores de RiscoRESUMO
PURPOSE: Mounting studies have investigated the clinicopathological and prognostic value of hypoxia-inducible factor-1α (HIF-1α) in breast cancer (BC), yet conclusions remain controversial. Therefore, we conducted this meta-analysis to clarify this issue. METHODS: All relevant studies were searched using Cochrane Library, Web of Science, PubMed, and EMBASE online databases. Pooled odds ratios (ORs) and hazard ratios (HRs) with 95% confidence intervals (CIs) were applied to evaluate the clinicopathological and prognostic value of HIF-1α, respectively. Subgroup analysis and sensitivity analysis were performed to investigate heterogeneity and stability of the results. Begg's funnel plot and Egger's test were used to examine publication bias. RESULTS: A total of 31 eligible studies including 5177 subjects were enrolled. Of these, 25 studies assessed the prognostic role of HIF-1α and included 4546 individuals. Twenty-three studies involving 3277 individuals evaluated the clinicopathological significance of HIF-1α. High expression level of HIF-1α was correlated with poor overall survival (OS) (HR = 1.59, 95% CI = 1.40-1.80, P < 0.001), disease-free survival (DFS) (HR = 1.87, 95% CI = 1.53-2.28, P < 0.001), relapse-free survival (HR = 1.36, 95% CI = 1.07-1.73, P = 0.001), and cancer-specific survival (HR = 1.55, 95% CI = 1.10-2.19, P = 0.012). Pooled data from studies using multivariate survival analysis also showed that HIF-1α expression was associated with worse OS (HR = 1.59, 95% CI = 1.32-1.92, P < 0.001) and DFS (HR = 1.60, 95% CI = 1.39-1.84, P < 0.001). Additionally, high HIF-1α expression was associated with advanced tumor-node-metastasis stage, positive lymph-node status, negative ER status, ductal type, advanced histologic grade, high Ki67 expression, and strong VEGF expression. CONCLUSION: HIF-1α might serve as an independent prognostic biomarker and a promising therapeutic target for BC. Future large-scale prospective randomized trials are needed to confirm our findings.