By: Marta Aldehuela, Paula Sáez & Cecilia Carmona
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 BREAST CANCER By: Marta Aldehuela, Paula Sáez & Cecilia Carmona.
What it is Causes
Chemical and biological symptoms
Article 1 (New medicine) Article 2 (Advances on targeting it) Cecilia: In 2004 around 500 000 women died because of breast cancer. We’ve all heard about it, but do we really know what breast cancer is? (Music) Welcome to another episode of Sassy Science, today we are going to talk about breast cancer. I’m Cecilia Carmona and I’m joined by Paula Sáez and Marta Aldehuela, two experts of this type of cancer that are going to tell us about it. (Music) Before getting deep into this topic, some background information. Breast cancer is a malignant tumour that starts in the cells of the breast. A malignant tumour is a group of cancer cells that can grow into surrounding tissues or spread to distant areas of the body. The disease occurs almost entirely in women, but men can get it, too. But Marta Aldehuela, an oncologist specialised in breast cancer is going to tell us more about its causes. Marta: So first of all thank you Cecilia for having me in this podcast. Breast cancer is so common that is very important to know about it. Familiar background of breast cancer multiply the risk of having it by two or even three. Some gene mutations in specific genes are associated with a very high risk of having this cancer. Reproductive factors include having the period very early o the menopause very late, also having your first child at an advanced age. In the other hand breastfeeding lowers the risk. Some hormones increase the risk of having breast cancer like oral contraceptives or treatments that substitute hormones. But above all, 21% of the deaths by breast cancer are due to alcohol consumption, overweight and obesity and lack of physical activity. Early detection to improve the prognosis and survival of breast cancer is the most important thing in the fight against cancer. Cecilia: As far as I know, at the beginning you may not feel any symptoms. Maybe a lump has appeared in your breast but is not easily seen or it may cause changes that you can’t notice on your own. Right, Marta? Marta: Yes Cecilia, normally, a strange area turns up on a screening mammogram, which is an X-ray of the breast, this leads to further testing. In some cases, however, the first sign of breast cancer is a new lump or mass in the breast that you or your doctor can feel. A lump that is hard, without a define shape and painless is more likely to be cancer. But sometimes they can be tender, soft, and rounded. So it's important to have anything unusual checked by your doctor. But there are more unusual changes in the breast that can be a symptom of breast cancer. Cecilia: Oh it would be really interesting if you could tell us about the most common symptoms because I’m sure that many people are wondering about it. Marta: Sure, you may have breast cancer if there is:
That’s why it’s important that you get any breast changes checked by a doctor. Cecilia: Thank you Marta. But don’t worry guys, because science and medicine are very advanced nowadays. What I’m trying to say is, yes breast cancer sucks but there is light at the end of the tunnel. Our next guest will be reviewing two articles from the end of last year which have a crucial role on breast cancer oncology. Paula: I’m Paula Sáez and I have the honor to bring light to this topic. Cecilia: A new drug, commercialized in Spain, turns out to be the therapy that expands patients’ life expectancy the most. Paula: This treatment is specialized on a specific type of cancer named HER2. This cancer is caused by the protein HER2, hence the name. This protein is naturally created by our bodies. Its function is to help the development and growth of some cells, called epithelial cells. But, the excessive production of these proteins makes the epithelial cells multiply faster than normal ones and this is what triggers cancer. Marta: Keep in mind, this cancer is the deathliest one because it spreads from the original tumor to the rest of the body very quickly. Paula: You are right Marta. That’s why the CLEOPATRA study has developed an antibody called Pertuzumab. Pertuzumab blocs the cellular transmission and stops the growth of cancerous cells. This treatment is applied along with the traditional one. The two antibodies work complementarily which ensures a more complete eradication of the HER. Spanish oncologists have had a very important role in this study as 9 Spanish centers have collaborated in the project, including oncologists like Miguel Martín president of GEICAM, the Spanish group of investigation of breast cancer. Another of the Spanish specialists which worked in the CLEOPATRA study, Eva Ciruelos, said that this is very close of converting HER2 cancer from a deadly disease to a chronic one as the innovative therapy reduced the risk of death in a 32%. For more information on Pertuzumab, visit www.roche.com the web of the lab which developed it. I repeat: www.roche.com (Music rise) Cecilia: Scientists have found the weakness of triple-negative breast cancer Paula: To start with, what is a triple-negative breast cancer? Well basically is “the other cancer”. There are four types of cancer. One stimulated by estrogens, another by progesterone and the HER2 explained before. And finally, everything other than that, which means a cancer negative to the three signs, the triple-negative breast cancer. Marta: That is why there are very little effective treatments as there is really nothing to target. Paula: Well at least there wasn’t until now! A research carried out by the Welcome Trust Sanger Institute in Britain has identified a gene which is key to this type of cancer. The gene is called BCL11A, and it has been found to be very active in triple negative cancers. They carried out experiments in human and mice cells. What they found is 1. When this gen was inactivated, no mice developed tumors and 2. When adding an active BCL11A to cells, made them behave as cancer cells. The experiments led them to suggest that the novel gene is in charge of triple-negative breast cancer development. This study is very important because with further research we might find new treatments. (Music) Cecilia: So that’s all for today, first I have to thank Marta and Paula for being here with us sharing their knowledge, and then I have to thank you, all of you that are every week listening to our podcasts and sharing them. For further information on breast cancer you can visit www.breastcancer.org. (Music) REFERENCES
ORIGINAL ARTICLES El nuevo anticuerpo, comercializado este año en España, se convierte en la terapia que aporta más tiempo de vida a las pacientes con el tumor en fase metastásica
Madrid, 28 septiembre 2014 Los datos finales del estudio fase III CLEOPATRA han confirmado que el nuevo anticuerpo Pertuzumab (Perjeta®) aporta la mayor tasa de supervivencia obtenida hasta la fecha en cáncer de mama metastásico.  Concretamente, en primera línea de tratamiento de pacientes que no han recibido tratamiento previo para el cáncer de mama HER2 positivo metastásico, este fármaco, añadido a Trastuzumab y a la quimioterapia Docetaxel, consiguió que vivieran una mediana de 56,5 meses, es decir 15,7 meses más que aquellas que recibieron esta misma pauta pero sin Pertuzumab (mediana de supervivencia global (SG): 56,5 meses versus 40,8 meses). Estos resultados se acaban de presentar en el Simposio Presidencial del Congreso de la Sociedad Europea de Oncología Médica (ESMO), que estos días se celebra en Madrid. Desde que hace más de una década y media irrumpiera Herceptin® (Trastuzumab), ningún fármaco había aportado un incremento de la supervivencia tan relevante como Pertuzumab en las pacientes con cáncer de mama HER2 positivo. “Los datos demuestran la gran eficacia de esta combinación, con un beneficio muy grande de la supervivencia global. Este es, sin duda, un resultado de supervivencia muy difícil de encontrar si tenemos en cuenta que es un anticuerpo utilizado como primera opción y que estas mujeres luego reciben múltiples terapias”, explica la doctora Eva Ciruelos, oncóloga del Hospital 12 de Octubre de Madrid y una de las especialistas españolas que ha participado en el estudio CLEOPATRA. Los resultados difundidos en ESMO están, según esta experta, “muy cerca de lo que podemos entender en oncología como concepto de cronicidad en un tumor que ha hecho metástasis. Son cifras de supervivencia prácticamente inéditas en la oncología en enfermedad avanzada. Hay patologías no oncológicas consideradas crónicas en las que la tasa de supervivencia se aproxima a lo que revela este estudio”. Control de la enfermedad Los primeros resultados de esta investigación, publicados en New England Journal of Medicine en 2012, ya mostraron una mejora muy significativa en el análisis final de supervivencia libre de progresión. Concretamente, supuso un aumento de 6 meses con una mediana de SLP que alcanzó los 18,5 meses para las pacientes que recibieron Perjeta®, Herceptin® y quimioterapia frente a los 12,4 meses de aquellas que recibieron solo Herceptin® y quimioterapia. Con respecto al perfil de seguridad, los datos presentados en Madrid confirman también el buen perfil de tolerabilidad asociado al uso de la combinación de anticuerpos. Según la doctora Ciruelos, “el origen de las principales toxicidades está en las quimioterapias utilizadas. Un seguimiento tan prolongado, cercano a los 50 meses, nos ha permitido observar que no hay una incidencia elevada de problemas cardiacos por añadir Pertuzumab al tratamiento”. Una actualización de los datos del estudio también mostraron que:
Fármaco con acento español Nunca antes en el desarrollo clínico de un fármaco para el cáncer de mama la oncología española había tenido un peso tan grande. El estudio CLEOPATRA, en el que han participado nueve centros españoles, es, en palabras de la doctora Ciruelos, “el mejor ejemplo de la confianza que una compañía como Roche ha tenido en la investigación clínica de los oncólogos de este país. Especialistas como el doctor Joan Albanell, José Baselga, Javier Cortés y Ana Lluch, han estado implicados desde la etapa preclínica y los ensayos fase I y II, que fueron los que pusieron sobre la pista la necesidad de combinar el nuevo anticuerpo con Trastuzumab para conseguir la mayor eficacia”. En España, el pasado mes de junio, el Ministerio de Sanidad, Servicios Sociales e Igualdad autorizó su financiación para combinarse con el estándar de tratamiento (Herceptin® + docetaxel) en mujeres con cáncer de mama localmente recidivante irresecable o metastásico HER2 positivo que no han recibido tratamiento previo anti-HER2 o quimioterapia para la enfermedad avanzada.  La combinación de los dos anticuerpos proporciona un bloqueo más completo de las vías de señalización del HER implicadas en la proliferación y supervivencia de las células cancerígenas dependientes de HER2. Un 15-20% de los tumores de mama son HER2 positivo. Acerca del estudio CLEOPATRA El estudio CLEOPATRA (CLinical Evaluation Of Pertuzumab And TRAstuzumab) es un estudio internacional, fase III, doble diego, randomizado y controlado con placebo en el que han participado un total de 250 centros de 19 países (entre ellos España con nueve hospitales) y 808 mujeres con cáncer de mama HER2 positivo metastásico no tratadas previamente o que habían recaído tras recibir tratamiento adyuvante o neoadyuvante con Trastuzumab. Para evaluar eficacia y seguridad, se compararon dos pautas: la combinación de Pertuzumab y Herceptin® más la quimioterapia docetaxel frente al estándar (Herceptin® + quimioterapia). Acerca de Perjeta® Terapia personalizada que actúa sobre el receptor HER2, una proteína que se encuentra en cantidades elevadas en la parte exterior de las células tumorales HER2 positivo. Pertuzumab es el primero de una nueva generación de agentes dirigidos denominados Inhibidores de la Heterodimerización del HER2 (HDI por sus siglas en inglés). Previene que el receptor HER2 dimerice (se una) al receptor HER3. De este modo, Pertuzumab bloquea la transmisión celular de señales, pudiendo así inhibir el crecimiento de las células cancerosas o conducir a su muerte. La unión del Pertuzumab a HER2 también podría inducir al sistema inmunitario a destruir las células cancerosas. Pertuzumab se une a un epitopo diferente que Herceptin en el receptor HER2, por lo tanto, presentan mecanismos de acción complementarios que se traducen en un bloqueo más completo de las vías de señalización del HER implicadas en la proliferación y supervivencia de las células cancerígenas dependientes de HER2. BCL11A is a triple-negative breast cancer gene with critical functions in stem and progenitor cells (nature communications)Walid T. Khaled, Song Choon Lee, John Stingl, Xiongfeng Chen, H. Raza Ali, Oscar M. Rueda, Fazal Hadi, Juexuan Wang, Yong Yu, Suet-Feung Chin, Mike Stratton, Andy Futreal,Nancy A. Jenkins, Sam Aparicio, Neal G. Copeland, Christine J. Watson, Carlos Caldas &Pentao Liu AbstractTriple-negative breast cancer (TNBC) has poor prognostic outcome compared with other types of breast cancer. The molecular and cellular mechanisms underlying TNBC pathology are not fully understood. Here, we report that the transcription factor BCL11A is overexpressed in TNBC including basal-like breast cancer (BLBC) and that its genomic locus is amplified in up to 38% of BLBC tumours. Exogenous BCL11A overexpression promotes tumour formation, whereas its knockdown in TNBC cell lines suppresses their tumourigenic potential in xenograft models. In the DMBA-induced tumour model, Bcl11a deletion substantially decreases tumour formation, even in p53-null cells and inactivation of Bcl11a in established tumours causes their regression. At the cellular level, Bcl11a deletion causes a reduction in the number of mammary epithelial stem and progenitor cells. Thus, BCL11A has an important role in TNBC and normal mammary epithelial cells. This study highlights the importance of further investigation of BCL11A in TNBC-targeted therapies. 9 January 2015 Novel breast cancer gene found (welcome trust sager institute)BCL11A is active in difficult-to-treat triple-negative breast cancer Tumour size in mice is reduced when BCL11A activity is inhibited in human, Triple-Negative Breast Cancer cells 4T1, SUM159 and MSA231. Control (red) is no inhibitory RNA, compared to inhibitory RNA1 (blue; shRNA1) or inhibitory RNA2 (green; shRNA2) [doi: 10.1038/ncomms6987] A new study identifies a gene that is especially active in aggressive subtypes of breast cancer. The research suggests that an overactive BCL11A gene drives triple-negative breast cancer development and progression. The research, which was done in human cells and in mice, provides new routes to explore targeted treatments for this aggressive tumour type. There are many types of breast cancers that respond differently to treatments and have different prognoses. Approximately one in five patients is affected by triple-negative breast cancer; these cancers lack three receptor proteins that respond to hormone therapies used for other subtypes of breast cancer. In recent years it has become apparent that the majority of triple-negative tumours are of the basal-like subtype. Although new treatments are being explored, the prognosis for triple-negative cancer is poorer than for other types. To date, only a handful of genomic aberrations in genes have been associated with the development of triple-negative breast cancer. The team looked at breast cancers from almost 3000 patients. Their search had a particular focus: they examined changes to genes that affect the behaviour of stem cells and developing tissues, because other work they have done suggests that such genes, when mutated, can often drive cancer development. Among these was BCL11A. "Our understanding of genes that drive stem cell development led us to search for consequences when these genes go wrong," says Dr Pentao Liu, senior author on the study, from the Wellcome Trust Sanger Institute. "BCL11A activity stood out because it is so active in triple-negative cancers. "It had all the hallmarks of a novel breast cancer gene." Higher activity of the BCL11A gene was found in approximately eight out of ten patients with basal-like breast cancer and was associated with a more advanced grade of tumour. In cases where additional copies of the BCL11A gene were created in the cancer, the prospects for survival of the patient were diminished. " BCL11A stood out because it is so active in many triple-negative cancers: it has all the hallmarks of a novel breast cancer gene. " Dr Pentao Liu "Our gene studies in human cells clearly marked BCL11A as a novel driver for triple-negative breast cancers," says Dr Walid Khaled, joint first author on the study from the Wellcome Trust Sanger Institute and University of Cambridge. "We also showed that adding an active human BCL11A gene to human or mouse breast cells in the lab drove them to behave as cancer cells. "As important, when we reduced the activity of BCL11A in three samples of human triple-negative breast cancer cells, they lost some characteristics of cancer cells and became less tumorigenic when tested in mice. So by increasing BCL11A activity we increase cancer-like behaviour; by reducing it, we reduce cancer-like behaviour." When BCL11A was inactivated in an experimental system in mice, no mice developed tumours in the mammary gland, whereas all untreated animals developed tumours. The team also showed that BCL11A is required for normal development of breast stem cells and progenitors, which are thought to be the cells that, when mutated, give rise to basal-like breast cancer. "This exciting result identifies a novel breast cancer gene in some of the more difficult-to-treat cases," says Professor Carlos Caldas, Professor of Cancer Medicine and Director of the Cambridge Breast Cancer Research Unit at the University of Cambridge, and Head of Breast Cancer Functional Genomics at Cancer Research UK Cambridge Institute. "It builds on our work to develop a comprehensive molecular understanding of breast cancer that will inform clinical decisions and treatment choices. "Finding a novel gene that is active in cancer should also help in the search for new treatments." The team propose that BCL11A is a strong candidate for development of a possible targeted treatment. |
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