Personalised Medicine at a Glance: Breast Cancer

Personalised Medicine at a Glance: Breast Cancer
For patients, policy makers and other non-medical professionals

This text was prepared by ESMO for the European Alliance for Personalised Medicine – January 2015

Even in tumours that arise in the same organ, there are many different subtypes. Thanks to advances in molecular medicine, we are increasingly able to distinguish between them. Care of women with breast cancer is being improved by tailoring treatment to the molecular characteristics of individual tumours, as well as to the size and spread of the cancer and the patient’s menopausal status.

Around 3.8 million women in Europe have breast cancer. The number of cases is rising because of earlier detection through mammography and because the population is ageing. Breast cancer is the leading cause of cancer deaths among European women. Even so, the chances that an individual woman with breast cancer will die of the disease is falling. This is partly due to the fact that cancers are identified at an earlier and more curable stage, and partly due to advances in treatment.

The personalisation of breast cancer care is a major factor in improving outcomes. This approach starts with screening. Women from families with a history of breast cancer are at higher risk of developing the disease themselves. This is particularly so if women carry the BRCA1 or BRCA2 gene mutation which means that cells do not repair DNA as effectively as normal. Women with a family history of breast (and ovarian) cancer can be tested for BRCA mutations and need to have more frequent screening.
Video resource: How personalised medicine will affect breast cancer patients

M.Piccart warns that since treatment still relies on the evaluation of critical targets in the tumour (e.g. hormone receptors, HER2 overexpression), and the tests to identify them are very delicate, it is mandatory that they are assessed in labs which meet very strict quality criteria. Science is moving rapidly: patients are invited to search for clinical trial opportunities where their tumour can be profiled in a deeper way which will lead them to access smart targeted drugs.

May 2013
Tailoring breast cancer treatment

If a tumour is found, the tailoring of care to a woman’s particular circumstances moves to the next stage. Among the critical factors that determine the nature of treatment are the type of cell that has become malignant and the size of the tumour and its grade, i.e. the extent to which the cells differ from normal when viewed under a microscope. But perhaps of greatest importance is whether or not the cancer has spread within the breast or to lymph nodes in the armpit or to nodes and organs elsewhere in the body. Spread to sites in the body that are distant from the primary tumour is termed metastasis (and the secondary cancers are called metastases).

Although chemotherapy is sometimes given to shrink otherwise inoperable tumours, initial treatment for most women with breast cancer is surgery. Where possible, the tumour and a surrounding margin of tissue will be removed while healthy breast tissue is conserved, i.e. by a lumpectomy operation rather than mastectomy.

Existing or potential spread of the cancer within and close to the breast can be managed by radiotherapy. But if there are metastases elsewhere in the body, systemic cytotoxic chemotherapy is frequently required. This form of therapy kills rapidly dividing cells. But it does not distinguish between cells that are proliferating quickly because they are cancerous and cells in the bone marrow and gastrointestinal tract that divide rapidly as part of their healthy function. Increased risk of infection, and nausea and vomiting are frequent side-effects. If cytotoxic chemotherapy can safely be avoided in some patients, they can be spared these toxicities.

Treatement based on the molecular characteristics of breast cancer

Increasingly, the molecular characteristics of the individual patient’s tumour are being taken into account when deciding on treatment. To truly match therapy to the patient, the biological factors that drive tumour growth in specific cases need to be identified.

Because breast tissue is designed to respond to hormonal changes in the woman’s body, many – but not all – breast tumours express oestrogen receptors and grow in response to their activation. Around thirty years ago, doctors showed that the growth of breast tumours that are oestrogen receptor positive (ER+) could be prevented or delayed by using anti-oestrogen drugs such as tamoxifen and the aromatase inhibitors. These were the first targeted drugs in breast cancer; indeed, they were probably the first targeted drugs in any area of cancer medicine. Presence of the progesterone receptor on tumour cells can also be used to select the most appropriate treatment. In some women with hormone-receptor positive cancers, endocrine therapy alone is sufficient to minimise the risk of cancer spread. In others, it is used together with cytotoxic agents or other targeted therapies.

More recently, other drivers of tumour growth have been identified. A particularly aggressive subtype of breast cancer has a gene abnormality that causes tumour cells to overexpress the human epidermal growth factor receptor HER2. Once this became clear, pharmacologists developed antibodies that would block the receptor. Trastuzumab was the first such agent. They also developed small molecule drugs that act within the cell to block downstream growth signalling caused by receptor activation. Lapatinib is an example

In women with HER2-positive breast cancer who have had all detectable tumour removed by surgery, anti-HER2 drugs roughly halve the risk that the cancer will recur. If the cancer does return, anti-HER2 drugs can again be used. But it is important to note that even if the HER2 target is present on the tumour cells, there is no guarantee that an anti-HER2 drug will benefit a specific patient. We urgently need biomarkers that predict the sensitivity or resistance of individual tumours to drugs directed against the HER2 receptor. The same is true with drugs that target the oestrogen receptor.

As well as the molecular characteristics mentioned above, several other markers have proven validity in distinguishing between more and less aggressive breast cancers, and so in personalising treatment according to individual risk. Ki67, a molecular marker that relates to the speed of cancer cell proliferation, and uPA-PA11, a marker of the risk that cancer cells will invade healthy tissue, are two examples. The predictive value of many other markers is being investigated and it is hoped that their collective use will enable us to obtain a “genetic fingerprint” for a specific tumour, allowing therapy to be fine-tuned to the individual patient.

Though their use holds great promise, the multiplicity of potential molecular markers is daunting. A further layer of complexity arises from the fact that the mechanisms responsible for tumour growth can change with time even within a particular patient. So a cancer that is HER2 positive when the primary is first discovered may have become HER2 negative on recurrence. Repeated evaluation of the tumour may be required if we are to achieve the ultimate aim of personalised medicine, i.e. ensuring that the right drug is given to the right patient at the right time.

Capecitabine Improves HER2-Negative Breast Cancer Survival After Post-Op Residual Disease

Capecitabine Improves HER2-Negative Breast Cancer Survival After Post-Op Residual Disease
HER2-negative patients who do not have a complete pathological response after neoadjuvant chemotherapy and surgery may benefit from adjuvant capecitabine

Date: 10 Dec 2015
Author: By Lynda Williams, Senior medwireNews Reporter
Topic: Anti-Cancer Agents & Biologic Therapy / Breast Cancer, Early Stage

medwireNews: Treatment with capecitabine significantly improves survival for HER2-negative breast cancer patients who have residual disease after neoadjuvant chemotherapy and surgery, phase III trial results suggest.

The CREATE-X study was discontinued after the planned interim analysis demonstrated that the addition of the 5-fluorouracil prodrug to postoperative chemotherapy met the primary endpoint of significantly improved disease-free survival compared with no capecitabine.

The 2-year rate of disease-free survival was 87.3 versus 80.5% with a hazard ratio [HR] of 0.688, reported Masakazu Toi, from Kyoto University Hospital in Japan and director of the Japan Breast Cancer Research Group, and co-authors at the San Antonio Breast Cancer Symposium in Texas, USA.

Overall survival was also significantly improved with capecitabine treatment, with 2-year rates of 96.2% versus 93.9% for no capecitabine, and a HR of 0.658.

The study included 902 HER2-negative patients who were randomly assigned to receive hormone therapy where appropriate and either eight cycles of capecitabine, at a twice-daily dose of 1250 mg/m2 for 2 weeks followed by 1 week off treatment, or no additional chemotherapy.

Grade 3 or 4 adverse events reported in the capecitabine arm of the study included hand–foot syndrome (11%), neutropenia (9%), diarrhoea (3%) and fatigue (1%) but all symptoms were described by the researchers as “controllable”.

Masakazu Toi commented on the results in a press release: “These data are exciting, because the side effects of the treatment were manageable and the benefit of capecitabine treatment was clear.”

The authors conclude: “The benefit to risk balance of the addition of 8 cycles of [capecitabine] to standard adjuvant therapy seems to be satisfied. This evidence might allow the development of personalized individualized treatment based on the response to primary systemic therapy.”

Reference

Toi M, Lee S-J, Lee ES, et al. Abstract S1-07. A phase III trial of adjuvant capecitabine in breast cancer patients with HER2-negative pathologic residual invasive disease after neoadjuvant chemotherapy (CREATE-X, JBCRG-04). Reported atSan Antonio Breast Cancer Symposium; San Antonio, Texas, USA: 8–12 December 2015.

Los Avances en Cáncer Gástrico SEOM

Los Avances en Cáncer Gástrico
Miércoles, 09 de Diciembre de 2015 14:35

El cáncer gástrico es un problema sanitario de primer orden. Hoy en día representa la 5ª causa de muerte por cáncer en el hombre y la 6ª en la mujer, con más de 56.000 fallecimientos anuales en Europa. En las últimas décadas se ha producido una disminución en su incidencia en países occidentales aunque con un incremento relativo en la frecuencia de los adenocarcinomas localizados en el cardias y la unión esofagogástrica.

Los pacientes que debutan con estadios precoces se tratan con cirugía curativa y suelen recibir quimioterapia perioperatoria o bien quimiorradioterapia adyuvante. Sin embargo, muchos de ellos recaen, de modo que la proporción de largos supervivientes no supera el 25%. Cuando la enfermedad se detecta en estadio localmente avanzado o metastásico (lo que ocurre en dos terceras partes), el pronóstico es desfavorable, con medianas de supervivencia en torno a los 12 meses. El objetivo del tratamiento en este contexto es principalmente paliativo.

Pero en las últimas décadas hemos asistido a notables avances en el tratamiento de esta enfermedad que han permitido mejorar el pronóstico en todos los estadios y vislumbrar un aumento de la supervivencia en el futuro:

- En los años ´90 se demostró que la quimioterapia mejoraba la supervivencia y calidad de vida en pacientes con enfermedad metastásica (en comparación con el tratamiento sintomático exclusivo).
- A principios del año 2000, por medio de metaanálisis de estudios aleatorizados, se confirmó que la poliquimioterapia es superior al empleo de agentes únicos en términos de respuestas y supervivencia, a expensas de un aumento de la toxicidad.
- El esquema de referencia desde entonces es la combinación de cisplatino y 5-fluorouracilo en infusión continua.
- Estudios posteriores han demostrado que ambos fármacos pueden ser sustituidos por agentes menos tóxicos, oxaliplatino y capecitabina, respectivamente (2008).
- Los tripletes con docetaxel o epirrubicina (DCF, EOX) son superiores a los dobletes en pacientes seleccionados sin comorbilidades (2006).
- La quimiorradioterapia adyuvante (5FU-LV en esquema de Macdonald, 2001) y la quimioterapia perioperatoria (ECF en esquema MAGIC, 2006) reducen el riesgo de recidiva y mejoran la supervivencia tras la resección quirúrgica en estadios localizados.
- La adición de trastuzumab (primer anticuerpo monoclonal aprobado en esta patología) en pacientes con sobreexpresión de HER2 (HER2+++ o FISH+) mejora significativamente los resultados de la quimioterapia (cisplatino y fluoropirimidinas) en enfermedad avanzada. Por ello, debe determinarse la sobreexpresión de HER2 en todos los pacientes con cáncer gástrico avanzado (2010).
- La quimioterapia de segunda línea (con taxanos o irinotecán) es activa y mejora la supervivencia en pacientes seleccionados (2011).
- Ramucirumab es un fármaco antiangiogénico (antagonista del VEGFR-2) que se ha aprobado recientemente en esta enfermedad. Cuando se emplea sólo o asociado a la quimioterapia (paclitaxel) aumenta la supervivencia en el tratamiento de segunda línea (2014).

NHS England and NICE plans to reform Cancer Drugs Fund

NHS England and NICE Have Begun a Consultation on a New Cancer Drugs Fund
Consultation now open on plans to reform Cancer Drugs Fund

Date: 01 Dec 2015
Topic: Bioethics, legal and economic issues

NICE announced on 19 November 2015 that a 12-week consultation has started on draft proposals outlining new arrangements for the Cancer Drugs Fund (CDF). It will enable patients to receive new treatments that can't yet be recommended for routine use but which have genuine promise, while real world evidence is collected for up to two years on how well the drugs work in practice.

The proposals are aimed at providing patients with access to promising new medicines while the evidence is still emerging, in a financially sustainable way.

They are intended to create a system that captures data and information on new medicines and other technologies to develop a more robust evidence base.

The proposal is that the CDF will become a ‘managed access’ fund for new cancer drugs to give early access to those drugs which appear promising but which have currently uncertain evidence bases which are insufficient to support a recommendation for routine commissioning. The new scheme would operate from April 2016.

All new cancer drugs will normally receive a clear ‘yes’ (baseline commissioning), ‘maybe’ (CDF funding for time limited period), or ‘no’ funding decision within 90 days of market authorisation.

The new CDF will collect important information on longer-term benefits which may not be available at the time of licensing, as the chief executive of NICE, Sir Andrew Dillon, explained:

“Our joint proposals will ensure that the Cancer Drugs Fund is used to provide patients with promising medicines at a cost which reflects the uncertainty about their effectiveness and cost effectiveness and at the same time, generate additional data to help the NHS make a longer term decision on whether and how to use them.”

Simon Stevens, Chief Executive of NHS England, said: “Over the next five years we're likely to see many new cancer drugs coming on to the worldwide market - some of which will be major therapeutic breakthroughs, and some of which will turn out to offer little extra patient benefit but at enormous cost.

"The new Cancer Drugs Fund offers a route for sorting out the wheat from the chaff, so that patients in England get faster access to the genuinely most promising new treatments. For those drug companies willing to price their products affordably while sharing transparent information about 'real world' patient benefit, the new CDF will offer a new fast-track route to NHS funding.”

The original CDF was established in 2011 to fund cancer drugs in England that are not currently approved by NICE. The current CDF runs until April 2016.

The proposal issued on 19 November for public consultation outlines a new system, fully integrated into the NICE appraisal process, where the CDF becomes a transitional fund – with clear criteria for entry and exit.

This is in line with the recommendation of the recently published independent Cancer Taskforce report, which proposed that the new CDF should operate with NHS England and NICE.

It’s proposed that from April 2016, all new cancer drugs will be referred to NICE for appraisal. Cancer drugs would normally receive draft guidance from NICE before market authorisation, and final guidance normally within 90 days of market authorisation being granted.

The outcome of each initial NICE appraisal will be a recommendation falling into one of the following three categories:

Recommended for routine use
Not recommended for routine use
Recommended for use within the CDF

At the end of the period for use within the CDF, the drug will go through a short NICE appraisal, using the additional evidence.

The drug will then attract either a NICE positive recommendation, at which point it would move out of the CDF into routine commissioning. Alternatively, it will receive a NICE negative recommendation, meaning it would move out of the CDF and become available only on the basis of individual patient funding requests.

The consultation will run for 12 weeks until 11 February 2016.