ER positive (ER+) and HER2 negative (HER2-) breast cancers are routinely treated based on estrogen dependence. CDK4/6 inhibitors in combination with endocrine therapy have significantly improved the progression-free survival of patients with ER+/HER2- metastatic breast cancer. Gene expression profiling in ER+/HER2- models was used to define the basis for the efficacy of CDK4/6 inhibitors and develop a gene expression signature of CDK4/6 inhibition. CDK4/6 inhibition robustly suppressed cell cycle progression of ER+/HER2- models and complements the activity of limiting estrogen. Chronic treatment with CDK4/6 inhibitors results in the consistent suppression of genes involved in cell cycle, while eliciting the induction of a comparable number of genes involved in multiple processes. The CDK4/6 inhibitor treatment shifted ER+/HER2- models from a high risk (luminal B) to a low risk (luminal A) molecular-phenotype using established gene expression panels. Consonantly, genes repressed by CDK4/6 inhibition are strongly associated with clinical prognosis in ER+/HER2- cases. This gene repression program was conserved in an aggressive triple negative breast cancer xenograft, indicating that this is a common feature of CDK4/6 inhibition. Interestingly, the genes upregulated as a consequence of CDK4/6 inhibition were more variable, but associated with improved outcome in ER+/HER2- clinical cases, indicating dual and heretofore unknown consequence of CDK4/6 inhibition. Interestingly, CDK4/6 inhibition was also associated with the induction of a collection of genes associated with cell growth; but unlike suppression of cell cycle genes this signaling was antagonized by endocrine therapy. Consistent with the stimulation of a mitogenic pathway, cell size and metabolism were induced with CDK4/6 inhibition but ameliorated with endocrine therapy. Together, the data herein support the basis for profound interaction between CDK4/6 inhibitors and endocrine therapy by cooperating for the suppression of cell cycle progression and limiting compensatory pro-growth processes that could contribute to therapeutic failure.

En 2016, environ 53 070 patients ont reçu un diagnostic d'adénocarcinome canalaire pancréatique (PDA) aux États-Unis et la plupart d'entre eux mourront de leur maladie dans les 5 ans. Le registre belge du cancer rapporte une incidence estimée à 1200 nouveaux cas par an. La survie globale à 5 ans pour toutes stades confondus a marginalement augmenté au cours des 50 dernières années, passant de 2 à 6%, malgré l'imagerie, les soins périopératoires et l'amélioration des techniques chirurgicales.La chirurgie reste la seule chance de guérison, cependant, seulement 10-15% des patients nouvellement diagnostiqués sont jugés éligibles pour une chirurgie. Même s'il existe peu d'autres modalités de traitement efficaces qui puissent considérablement prolonger la survie globale, la plupart des patients finiront par mourir de métastases au foie, au poumon et / ou au péritoine, les sites de propagation les plus courants. Les patients, les cliniciens et les chercheurs restent frustrés par le manqué d’outils thérapeutiques et des nouvelles stratégies sont nécessaires pour comprendre et mieux prendre en charge cette maladie.Le terme «cancer» engendre un sentiment de peur et colère, en particulier quand on est confronté au diagnostic dévastateur de cancer du pancréas. En plus, une réaction commune est de personnifier le cancer comme une entité maléfique qui doit être combattue pour sauver la vie du patient. Les armes pour cette bataille comprennent le scalpel d'un chirurgien, la chimiothérapie, la radiothérapie, les thérapies ciblées, les immunothérapies, les approches holistiques et la foi religieuse. Mais nous avons trop souvent oublié ou sous-estimé la contribution de la recherche translationnelle pour la médecine de précision, pour mieux adapter les thérapies et éviter les toxicités inutiles.Dans un sens biologique, qu'est-ce qu'un cancer du pancréas ou un cancer? Le cancer est une maladie génétique, soumise à un phénomène évolutif avec ses propres règles, contraintes et caractéristiques prévisibles qui mènent finalement à un phénotype unique.La stratégie "one size fits all" dans la PDA a souvent échoué dans les essais de nouveaux médicaments dans une population non sélectionnée.Cette thèse est une contribution modeste et authentique à une approche plus personnalisée du PDA, de l'acquisition tissulaire, à l'analyse de biomarqueurs tissulaires, à une analyse moléculaire plus profonde afin de mieux comprendre cette maladie mortelle et de proposer l'intégration de biomarqueurs dans le developpement d’etudes cliniques guides par les analyses moléculaires. / Doctorat en Sciences / info:eu-repo/semantics/nonPublished

Introduction Recent advances in microarray technology have allowed more understanding of the complex molecular biology of breast cancer. The traditional prognostic information afforded by hormone receptor status and pathology variables is being supplemented and superseded by gene signatures predictive of risk of recurrence and response to treatments. Approximately 75% of breast cancers are oestrogen receptor positive (ER+) and can be treated by drugs that block oestrogen production such as letrozole. However not all ER+ tumours respond and even those that initially respond can develop resistance. Treating patients with neoadjuvant letrozole affords a unique opportunity to sample the same tumour in vivo at different time points reducing any potential inter-patient and inter-tumour variability. The molecular effects of drugs can be assessed long before clinical outcome is apparent. Underlying genetic differences or characteristics of the patient, tumour or sample may affect the molecular response to treatment. This project set out to use sequential patient-matched samples to evaluate molecular changes in breast tumours in the presence or absence of endocrine treatment in different subtypes, defined by histology or mutation status and to assess molecular variation between primary tumour and nodal metastasis. Methods RNA was extracted and processed to generate whole transcriptome Illumina Beadarray gene expression data from four unique cohorts of patients. Clinical data on treatments, recurrence and survival was collected from medical records. The first cohort compared 25 breast cancer patients with matched samples at diagnosis and at surgery, 14-35 (median 23) days later, with no intervening treatment; with 36 patients treated with neoadjuvant letrozole. A PCR assay to detect 8 known PIK3CA mutations and assessment of PTEN status was performed at both the primary and secondary event in a second cohort of 120 patients with endocrine treated disease who relapsed with either recurrence, lymph node metastases, a new second primary or progression of disease on primary endocrine therapy. The third cohort compared the molecular response to neoadjuvant letrozole in 14 patients with invasive lobular cancer (ILC) and 14 patients with invasive ductal cancer (IDC). A fourth cohort of women with node positive disease at diagnosis were assessed for variations in gene expression profiles between primary tumour and synchronous metastatic axillary lymph nodes (68 samples from 31 patients). Results The genomic profile of the no intervening treatment cohort did not differ significantly. Some changes in inflammatory genes were evident. This reassures us that changes seen during treatment are truly due to drug effect. This validates the use of a second biopsy to explore prediction of response. PIK3CA mutation status is maintained in the majority of patients with endocrine resistant disease and changed in only 15.7%. Where there was a change in PIK3CA this was significantly more likely to be a second primary breast cancer rather than a recurrence or progression of the primary cancer. PTEN status was also maintained in most patients. This does not support the theory that acquisition of a PIK3CA mutation is responsible for developing endocrine resistance. Novel PI3K inhibitor drugs may still be suitable in endocrine-resistant disease if activation of the pathway develops by other mechanisms. Consistent with previous studies, significant molecular differences were observed between ILC and IDC pre-treatment. Over half of these molecular differences were maintained after 3 months of letrozole. However, changes over time in individual tumours in response to letrozole were highly consistent in both ILC and IDC. When comparing primary with synchronous metastatic nodes only 39% of tumours clustered together with their matched primary or node. The molecular subtype of the node was often a poorer prognosis than the primary. There were also differences in subtype between nodes in a small cohort of patients with 2 involved nodes. Conclusions We have demonstrated that neoadjuvant window studies are a valid model for assessment of drug effects and evaluated differences in histology and mutation status. Endocrine resistance in breast cancer is rarely related to acquisition of PIK3CA mutations. Synchronous lymph node metastases can differ greatly from their matched primary. These findings are highly relevant when considering prescribing (neo)/adjuvant therapy and have significantly improved our understanding of breast cancer as we strive towards personalised medicine.

Base teórica: Nas últimas décadas, o prognóstico do câncer inicial da mama tem sido baseado nas características clínicas das pacientes e em aspectos histológicos dos tumores. Nos últimos anos, subtipos moleculares de carcinoma de mama foram identificados através de estudos de perfil genético por “DNA microarray”. Esta nova classificação pode melhorar a avaliação prognóstica, porém ainda não está disponível e é de alto custo. A possibilidade de identificar subtipos moleculares através de métodos mais simples e de menor custo é particularmente importante em países com recursos limitados. A identificação de subtipos do câncer de mama é particularmente importante pelas implicações clínicas e pelas opções de tratamento. Métodos: Uma coorte retrospectiva de 71 pacientes consecutivas com carcinoma primário de mama de estágio clínico I e II, tratadas no Serviço de Mastologia do HCPA entre os anos de 1993 e 1997 com um seguimento mínimo de 5 anos.Foram revisados dados sobre características clínicas, histopatológicas, evolução clínica e desfechos apresentados no período. Foi realizada uma análise imunoistoquímica de blocos representativos dos tumores, avaliando-se o Receptor Estrogênico (RE), o Receptor de Progesterona (RP), o HER2, o Ki-67, o Bcl-2, o p53, o p63 e o CK8. Os objetivos foram determinar a prevalência do perfil molecular nesta população e em seus desfechos clínicos. Resultados: 39 tumores (54,9 %) foram luminal A; 15 tumores (21,1%) foram luminal B; 15 tumores (21,1) foram basais ou triplo negativos e somente 2 tumores (2,8%) foram HER2. Não houve diferença no prognóstico entre os subtipos de câncer de mama: luminal A (RH positivo e HER2 negativo); luminal B (RH positivo e HER2 positivo); HER2 (HER2 positivo) e basal (RH negativo, HER2 negativo) em relação à sobrevida livre de doença e à sobrevida global, embora apresentassem uma forte correlação com a diferenciação e com o grau tumoral. Provavelmente, isto se deve ao pequeno número de pacientes e ao prognóstico de pacientes com estágios iniciais da doença. Conclusões: Nossos resultados sugerem que é possível identificar os subtipos do câncer de mama pela análise imunoistoquímica de RE, RP e HER2, e que a adição de outros marcadores não melhora a estimativa de prognóstico. O perfil molecular pode ser um instrumento valioso para o manejo do câncer de mama em países com recursos limitados. / Background: In the last decades, prognostic evaluation of initial breast cancer is mostly based on patients’ clinical and tumoral histological features. Recently, molecular subtypes of invasive breast cancer were recognized through DNA microarray profiling studies. This new classification can potentially improve the prognostic evaluation but this technology is still not widely available and it’s too expensive. The possibility of identifying the molecular subtypes through simpler and cheaper methods is promising especially in countries with limited resorts. The identification of breast cancer subtypes is particularly important because it has clinical implications and for treatment options. Methods: A retrospective cohort of 71 consecutive patients with pathologic stage I or II primary breast carcinomas, treated in the HCPA Breast Unit, between 1993 and 1997 with a minimum follow up of 5 years , was studied. Histological and clinical features as well as clinical outcome and survival were reviewed. Immunohistochemical analysis was carried out in representative blocks of tumors with antibodies against Estrogen Receptor (ER),Progesterone Receptor (PR), Human Epidermal Growth Receptor – type 2 (HER2), Ki-67, Bcl-2, p53, p63 and CK8. The endpoints were to determine the prevalence the molecular portrait in this population and its clinical outcomes. Results: 39 tumors (54,9 %) were Luminal A, 15 tumors (21,1%) were Luminal B, 15 tumors (21,1) were Basal or triple negative and only 2 tumors (2,8%) were HER2. There was no prognostic difference among the breast cancer subtypes: luminal A (HR-positive and HER2 negative); luminal B (HR positive and HER2 positive); HER2 overexpressing (HER2 positive) and basal (HR negative, HER2 negative) relating to disease-free and overall survival, although there was a robust correlation with tumor grade and differentiation. This is probably related to limited number of patients in this study and prognosis of initial-stage patients. Conclusions: Our results suggest that it is possible to identify breast cancer subtypes by immunohistochemical analysis of ER, EP, HER2, and that the addition of other markers didn’t improve the prognosis estimates. The molecular profile may be a very useful instrument for breast cancer managing in countries with limited resorts.

Base teórica: Nas últimas décadas, o prognóstico do câncer inicial da mama tem sido baseado nas características clínicas das pacientes e em aspectos histológicos dos tumores. Nos últimos anos, subtipos moleculares de carcinoma de mama foram identificados através de estudos de perfil genético por “DNA microarray”. Esta nova classificação pode melhorar a avaliação prognóstica, porém ainda não está disponível e é de alto custo. A possibilidade de identificar subtipos moleculares através de métodos mais simples e de menor custo é particularmente importante em países com recursos limitados. A identificação de subtipos do câncer de mama é particularmente importante pelas implicações clínicas e pelas opções de tratamento. Métodos: Uma coorte retrospectiva de 71 pacientes consecutivas com carcinoma primário de mama de estágio clínico I e II, tratadas no Serviço de Mastologia do HCPA entre os anos de 1993 e 1997 com um seguimento mínimo de 5 anos.Foram revisados dados sobre características clínicas, histopatológicas, evolução clínica e desfechos apresentados no período. Foi realizada uma análise imunoistoquímica de blocos representativos dos tumores, avaliando-se o Receptor Estrogênico (RE), o Receptor de Progesterona (RP), o HER2, o Ki-67, o Bcl-2, o p53, o p63 e o CK8. Os objetivos foram determinar a prevalência do perfil molecular nesta população e em seus desfechos clínicos. Resultados: 39 tumores (54,9 %) foram luminal A; 15 tumores (21,1%) foram luminal B; 15 tumores (21,1) foram basais ou triplo negativos e somente 2 tumores (2,8%) foram HER2. Não houve diferença no prognóstico entre os subtipos de câncer de mama: luminal A (RH positivo e HER2 negativo); luminal B (RH positivo e HER2 positivo); HER2 (HER2 positivo) e basal (RH negativo, HER2 negativo) em relação à sobrevida livre de doença e à sobrevida global, embora apresentassem uma forte correlação com a diferenciação e com o grau tumoral. Provavelmente, isto se deve ao pequeno número de pacientes e ao prognóstico de pacientes com estágios iniciais da doença. Conclusões: Nossos resultados sugerem que é possível identificar os subtipos do câncer de mama pela análise imunoistoquímica de RE, RP e HER2, e que a adição de outros marcadores não melhora a estimativa de prognóstico. O perfil molecular pode ser um instrumento valioso para o manejo do câncer de mama em países com recursos limitados. / Background: In the last decades, prognostic evaluation of initial breast cancer is mostly based on patients’ clinical and tumoral histological features. Recently, molecular subtypes of invasive breast cancer were recognized through DNA microarray profiling studies. This new classification can potentially improve the prognostic evaluation but this technology is still not widely available and it’s too expensive. The possibility of identifying the molecular subtypes through simpler and cheaper methods is promising especially in countries with limited resorts. The identification of breast cancer subtypes is particularly important because it has clinical implications and for treatment options. Methods: A retrospective cohort of 71 consecutive patients with pathologic stage I or II primary breast carcinomas, treated in the HCPA Breast Unit, between 1993 and 1997 with a minimum follow up of 5 years , was studied. Histological and clinical features as well as clinical outcome and survival were reviewed. Immunohistochemical analysis was carried out in representative blocks of tumors with antibodies against Estrogen Receptor (ER),Progesterone Receptor (PR), Human Epidermal Growth Receptor – type 2 (HER2), Ki-67, Bcl-2, p53, p63 and CK8. The endpoints were to determine the prevalence the molecular portrait in this population and its clinical outcomes. Results: 39 tumors (54,9 %) were Luminal A, 15 tumors (21,1%) were Luminal B, 15 tumors (21,1) were Basal or triple negative and only 2 tumors (2,8%) were HER2. There was no prognostic difference among the breast cancer subtypes: luminal A (HR-positive and HER2 negative); luminal B (HR positive and HER2 positive); HER2 overexpressing (HER2 positive) and basal (HR negative, HER2 negative) relating to disease-free and overall survival, although there was a robust correlation with tumor grade and differentiation. This is probably related to limited number of patients in this study and prognosis of initial-stage patients. Conclusions: Our results suggest that it is possible to identify breast cancer subtypes by immunohistochemical analysis of ER, EP, HER2, and that the addition of other markers didn’t improve the prognosis estimates. The molecular profile may be a very useful instrument for breast cancer managing in countries with limited resorts.

Base teórica: Nas últimas décadas, o prognóstico do câncer inicial da mama tem sido baseado nas características clínicas das pacientes e em aspectos histológicos dos tumores. Nos últimos anos, subtipos moleculares de carcinoma de mama foram identificados através de estudos de perfil genético por “DNA microarray”. Esta nova classificação pode melhorar a avaliação prognóstica, porém ainda não está disponível e é de alto custo. A possibilidade de identificar subtipos moleculares através de métodos mais simples e de menor custo é particularmente importante em países com recursos limitados. A identificação de subtipos do câncer de mama é particularmente importante pelas implicações clínicas e pelas opções de tratamento. Métodos: Uma coorte retrospectiva de 71 pacientes consecutivas com carcinoma primário de mama de estágio clínico I e II, tratadas no Serviço de Mastologia do HCPA entre os anos de 1993 e 1997 com um seguimento mínimo de 5 anos.Foram revisados dados sobre características clínicas, histopatológicas, evolução clínica e desfechos apresentados no período. Foi realizada uma análise imunoistoquímica de blocos representativos dos tumores, avaliando-se o Receptor Estrogênico (RE), o Receptor de Progesterona (RP), o HER2, o Ki-67, o Bcl-2, o p53, o p63 e o CK8. Os objetivos foram determinar a prevalência do perfil molecular nesta população e em seus desfechos clínicos. Resultados: 39 tumores (54,9 %) foram luminal A; 15 tumores (21,1%) foram luminal B; 15 tumores (21,1) foram basais ou triplo negativos e somente 2 tumores (2,8%) foram HER2. Não houve diferença no prognóstico entre os subtipos de câncer de mama: luminal A (RH positivo e HER2 negativo); luminal B (RH positivo e HER2 positivo); HER2 (HER2 positivo) e basal (RH negativo, HER2 negativo) em relação à sobrevida livre de doença e à sobrevida global, embora apresentassem uma forte correlação com a diferenciação e com o grau tumoral. Provavelmente, isto se deve ao pequeno número de pacientes e ao prognóstico de pacientes com estágios iniciais da doença. Conclusões: Nossos resultados sugerem que é possível identificar os subtipos do câncer de mama pela análise imunoistoquímica de RE, RP e HER2, e que a adição de outros marcadores não melhora a estimativa de prognóstico. O perfil molecular pode ser um instrumento valioso para o manejo do câncer de mama em países com recursos limitados. / Background: In the last decades, prognostic evaluation of initial breast cancer is mostly based on patients’ clinical and tumoral histological features. Recently, molecular subtypes of invasive breast cancer were recognized through DNA microarray profiling studies. This new classification can potentially improve the prognostic evaluation but this technology is still not widely available and it’s too expensive. The possibility of identifying the molecular subtypes through simpler and cheaper methods is promising especially in countries with limited resorts. The identification of breast cancer subtypes is particularly important because it has clinical implications and for treatment options. Methods: A retrospective cohort of 71 consecutive patients with pathologic stage I or II primary breast carcinomas, treated in the HCPA Breast Unit, between 1993 and 1997 with a minimum follow up of 5 years , was studied. Histological and clinical features as well as clinical outcome and survival were reviewed. Immunohistochemical analysis was carried out in representative blocks of tumors with antibodies against Estrogen Receptor (ER),Progesterone Receptor (PR), Human Epidermal Growth Receptor – type 2 (HER2), Ki-67, Bcl-2, p53, p63 and CK8. The endpoints were to determine the prevalence the molecular portrait in this population and its clinical outcomes. Results: 39 tumors (54,9 %) were Luminal A, 15 tumors (21,1%) were Luminal B, 15 tumors (21,1) were Basal or triple negative and only 2 tumors (2,8%) were HER2. There was no prognostic difference among the breast cancer subtypes: luminal A (HR-positive and HER2 negative); luminal B (HR positive and HER2 positive); HER2 overexpressing (HER2 positive) and basal (HR negative, HER2 negative) relating to disease-free and overall survival, although there was a robust correlation with tumor grade and differentiation. This is probably related to limited number of patients in this study and prognosis of initial-stage patients. Conclusions: Our results suggest that it is possible to identify breast cancer subtypes by immunohistochemical analysis of ER, EP, HER2, and that the addition of other markers didn’t improve the prognosis estimates. The molecular profile may be a very useful instrument for breast cancer managing in countries with limited resorts.

Introduction Breast cancer is the most common cancer among women in Sweden and world-wide. Immunohistochemical (IHC) expression of oestrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and Ki-67 is routinely performed for diagnostic and prognostic purposes. Based on these biomarkers tumours are divided into subtypes: Luminal A, Luminal B, HER2-enriched and triple negative breast cancer (TNBC). There is evidence that tumour associated macrophages (TAMs) have a crucial role in tumour development. To identify TAMs the antibody CD163 can be used in immunohistochemical staining. Aim The aim of the study was to investigate differences in density of CD163+ macrophages among different subtypes of breast cancer. Material and method Formalin-fixed paraffin-embedded (FFPE) breast cancer tissue from the Biobank of Region Värmland was used. Tissue was de-identified before analysis. Groups were formed based on immunohistochemical expression of ER, PR and HER2, with the exclusion of the Luminal B group. Tissue was stained with CD163. Analysis was performed semi-quantitatively. The border between tumour and healthy tissue was assessed as well as the intra-tumoral tissue. Results At the tumour border, density of CD163+ macrophages was found to be lower in the Luminal group compared to both the HER2-enriched and TNBC.Within intra-tumoral tissue, the density of CD163+ macrophages was found to be lower in the Luminal compared to the HER2-enriched group. Conclusion The density of CD163+ macrophages is higher in HER-enriched and TNBC tumours compared to Luminal A breast cancer tumours.

Thesis (M.Med. (Radiation Oncology)) -- University of Limpopo, 2022 / Background Breast cancer is known to be a heterogeneous disease that demands patient centered care. Establishing the clinicopathological characteristics of breast cancer patients is a vital step in an effort to individualize their treatment. Aim The aim is to evaluate the clinicopathologic features of the different subtypes of breast cancer when classified according to immunohistochemistry markers in women attending Pietersburg hospital. Methods A retrospective review of medical records of women treated at Pietersburg hospital between 2010 and 2011 was done. Data collection was extracted on a customized data collection sheet. Chi square was used to determine association between clinicopathologic features and molecular subtypes. Analysis of variants was used to assess association between molecular types and age. Results The mean age of the population was 55.3 years (+/-14 standard deviation). The majority of patients were in stage III (46.9%) and IV (33.5%). The ER, PR, HER2/neu positive rate was 50.6%, 30% and 14,3 % respectively with a negative rate of 13,4%, 19,5% and 23,4% respectively. ER, PR and HER2/neu was unknown in 18%, 19, 5% and 23,4% respectively. The most common molecular subtype was luminal A (53,6%) followed by triple negative (27.2%), HER2/neu (11, 4%) and luminal B (7. 9%).There was no association between the subtypes and tumour stage (p=0.578).The rate of distant metastasis was similar across the subtypes being 37,9%,35%, 32,4% and 31,9% in HER2/neu, luminal B ,luminal A and TNBC, respectively. All four molecular subtypes had high rate of axillary lymph node involvement (p=0.886) Luminal A had the least percentage of high grade tumours with TNBC having the highest. Five-year overall survival for the cohort was 25, 6% with luminal A and B having a better 5 year overall survival of 27,2% and 25% respectively, whereas HER2/neu and TNBC had lower 5 year OS of 24% and 23,3%. Conclusion The findings of this study suggest that luminal A subtype is the most predominant and the majority might benefit from hormonal therapy. However, some patients could not be classified due to missing IHC marker test results. The outcome across all four subtypes is poor and more effort should be put towards improving the diagnosis and treatment individualization and follow-up in these patients.

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In Brazil, an incidence of the disease increases and the number of new cases of breast cancer can be attributed to the increase in life expectation of women and changes related to reproductive factors and lifestyle. Objectives: The aim of this study was to analyze the literature on breast cancer risk factors and knowledge about the disease and to identify associations between risk factors and triple-negative breast cancer. Methods: Two scientific articles were developed for publication. The first article deals with an integrative review on the knowledge of breast cancer and its risk factors in Latin American studies. The second article deals with a cross-sectional study on lifestyle risk factors and triple-negative breast cancer, performed with 236 women diagnosed with invasive breast cancer in the state of Paraiba. Results: In the integrative review, of 47 studies selected, 27 were about risk of breast cancer and 20 were about knowledge or awareness. The main risk factors identified by the authors were obesity and overweight, old age, family history of breast cancer, nulliparity and menopause. The articles on knowledge focused in early diagnosis of breast cancer and breast self-examination was the most investigated method of detection. The cross - sectional study showed that smoking and obesity had associations with the triple- negative subtype of breast cancer. Women who smoked sometime in their lives had 3.70 (OR = 0.270, 95% CI: 0.10-0.68, p = 0.006) times less likely to have a triple-negative subtype. Patients with obesity had 3,514 (95% CI: 1.23 - 10.03; p = 0.019) more likely to have the triple-negative subtype when compared to the Luminal A subtype. Conclusions: The literature on breast cancer risk factors presents a better methodological outline and theoretical basis than the literature on the knowledge of the disease. Smoking is associated with lower chances of having triple-negative breast cancer, while obesity is associated with a higher chance of developing this type of breast cancer. / Introdução: O câncer de mama é o tipo de neoplasia que mais causa mortes entre as mulheres nos países em desenvolvimento. No Brasil, a incidência da doença é elevada no Nordeste do país e o aumento no número de casos novos pode ser atribuído às mudanças relacionadas aos fatores reprodutivos e do estilo de vida. Objetivos: Esta dissertação teve como objetivo analisar a literatura sobre os fatores de risco do câncer de mama e o conhecimento sobre a doença e identificar associações entre fatores de risco e o câncer de mama do tipo triplo-negativo. Métodos: Foram desenvolvidos dois artigos científicos para publicação. O primeiro artigo trata-se de uma revisão integrativa sobre o conhecimento da neoplasia mamária e seus fatores de risco em estudos Latino americanos. O segundo artigo trata-se de um estudo transversal sobre fatores de risco do estilo de vida e o câncer de mama triplo-negativo, realizado com 236 mulheres diagnosticadas com câncer de mama invasivo no estado da Paraíba. Resultados: Na revisão integrativa da literatura foram selecionados 47 artigos, dos quais 27 eram sobre fatores de risco do câncer de mama e 20 eram sobre conhecimento ou consciência sobre a doença. Os principais fatores de risco identificados pelos autores foram obesidade e sobrepeso, idade avançada, historia familiar de câncer de mama, nuliparidade e menopausa. Os artigos sobre conhecimento destacaram o diagnóstico precoce da neoplasia mamária e o autoexame foi o método de detecção mais investigado. O estudo transversal mostrou que tabagismo e obesidade tiveram associações com o subtipo triplo-negativo do câncer de mama. As mulheres que já fumaram alguma vez na vida tiveram 3.70 (OR= 0.270; 95% CI: 0.10-0.68; p= 0.006) vezes menos chances de ter o subtipo triplo-negativo. Pacientes com obesidade tiveram 3.514 (95% CI: 1.23- 10.03; p= 0.019) mais chances de ter o subtipo triplo-negativo quando comparadas com o subtipo Luminal A. Conclusões: A literatura sobre fatores de risco do câncer de mama apresenta melhor delineamento metodológico e fundamentação teórica do que a literatura sobre o conhecimento da doença. O tabagismo está associado a menores chances de ter o câncer de mama triplo-negativo, enquanto que a obesidade está associada a maiores chances de desenvolver esse tipo de câncer de mama.

Gastric cancer is a leading cause of cancer death worldwide. Systemic treatment comprising chemotherapy and targeted therapy is the standard of care in advanced/metastatic gastric cancer. Comprehensive molecular characterization of gastric adenocarcinomas by the TCGA Consortium and ACRG has resulted in the definition of distinct molecular subtypes. These efforts have in parallel built a basis for the development of novel molecularly stratified treatment approaches. Based on this molecular characterization, an increasing number of specific genomic alterations can potentially serve as treatment targets. Consequently, the development of promising compounds is ongoing. In this review, key molecular alterations in gastric and gastroesophageal junction cancers will be addressed. Finally, the current status of the translation of targeted therapy towards clinical applications will be reviewed.