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World Cancer Day 2022

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Over the past decade HealthPad has published ~30 Commentaries on significant developments in cancer therapies. On this World Cancer Day, we would like to share our contribution, to show how scientific knowledge and therapies have progressed to improve the lives of people living with cancer. The genesis of the HealthPad platform owes a lot to Professor Hani Gabra, a cancer expert who, together with many of his colleagues, believe that it is important to provide people with easy and convenient access to premium information to help them make informed medical and lifestyle choices and improve patients’ treatment journeys.

In addition to our Commentaries, HealthPad has built a unique and exclusive premium cancer content library of >1,100 videos, which address peoples’ frequently asked questions across several cancer pathways. The videos have been contributed by leading oncologists and scientists from world renowned medical institutions across the world and can be accessed anytime, anywhere, anyhow.

We reconfirm HealthPad’s commitment in helping to make cancer less scary by empowering people with the knowledge we have gathered and shared in our Commentaries.

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4 years, 3 months ago

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Will behavioural techniques improve breast cancer outcomes?

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Cancer

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behavioural techniques

breast cancer

breast cancer treatment

cancer research

commentary

The burden of breast cancer throughout the world is significant and increasing
Research has shown that a cheap pill (anastrozole) halves postmenopausal women’s risk of breast cancer and continues to be effective seven years after women stop taking the drug
Anastrozole has fewer side-effects and is more effective than comparable treatments
Government watchdogs both in the UK and US recommend anastrozole
But the uptake of the drug in the UK is relatively low
Doctors are not prescribing anastrozole and women are not availing themselves of the drug
The UK’s NHS should employ new behavioural techniques to influence and change doctors’ and patients’ decisions and increase the uptake of anastrozole to reduce the burden of breast cancer

Will behavioural techniques improve breast cancer outcomes?

Being a woman and growing older are two unavoidable risk factors for breast cancer. Indeed, most breast cancers are found in women who are 50 years or older. Despite significant advances in diagnoses and treatments, breast cancer is one of the rapidly increasing cancers among women and a significant cause of cancer-related morbidity and mortality worldwide. Breast cancer alone accounts for 30% of all new cancer diagnoses among females and has become a major 21st century health challenge.

Study shows long term benefits of a cheap breast cancer pill

Research findings reported in the December 2019 edition of The Lancet and also presented at the December 2019 San Antonio Breast Cancer Symposium in Texas, show that a cheap pill, anastrozole, if taken once a day for 5 years, not only halves postmenopausal women’s risk of breast cancer, but continues to be effective seven years after stopping treatment, which for the first time, suggests a long-term benefit.

Relatively low uptake

The UK’s NHS watchdog, the National Institute for Health and Care Excellence (NICE), suggests that hundreds of thousands of healthy older women should take anastrozole to cut their risk of breast cancer and recommends that the drug is offered to postmenopausal women at moderate to high risk of breast cancer unless they have severe osteoporosis. However, evidence suggests that some doctors in the UK are not prescribing anastrozole and some women are not availing themselves of the drug despite its demonstrated clinical benefits and the fact that anastrozole is supported by NICE.

Jack Cuzick, the lead author of The Lancet 2019 paper, who is Professor of Epidemiology and the Director of the Wolfson Institute of Preventive Medicine at Queen Mary University, London, is concerned because although anastrozole is, “An agent that looks really effective with minimal side-effects and is available on the NHS in the UK; its uptake has been quite low with only a tenth of eligible women receiving it”. Cuzick’s concerns are echoed by Delyth Jane Morgan, Chief Executive of the charity Breast Cancer Now, who said: "It is worrying to hear that anastrozole may not be being offered to all that could benefit. We need to understand the extent of this potential issue. It's essential that we raise awareness of this option among doctors and patients".

In this Commentary

Part 1 of this Commentary explores some of the reasons for the relatively low uptake of anastrozole. Part 2 describes new behavioural techniques, which could be cheaply and easily employed by health systems to increase the uptake of anastrozole and dent the burden of breast cancer. Also the Commentary: (i) describes breast cancer, (ii) provides some epidemiological facts of the disease, (iii) estimates the cost to treat breast cancer in the UK, (iv) describes hormone receptor positive breast cancer, (v) explains how anastrozole works and (vi) reports the findings of The Lancet 2019 study.

Part 1

Breast cancer

Cancer is a group of diseases that cause cells in your body to change and spread out of control. Most types of cancer cells eventually form a lump or mass called a tumour and are named after the part of your body where the tumour originates.

Breast cancer is characterized by the presence of cancer cells in the tissue or ducts of your breast. Most breast cancers begin either in the breast tissue made up of glands for milk production, called lobules, or in the ducts that connect the lobules to the nipple. The remainder of the breast is made up of fatty, connective and lymphatic tissues. Advanced breast cancer refers to cancer that has spread outside of your breast to lymph nodes and/or distant locations in your body, often invading your vital organs.

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Epidemiology of breast cancer

Breast cancer is a common malignancy. Although more and more women are surviving the disease, each year in the UK there are over 55,000 new breast cancer cases: which equates to over 1,000 diagnosed each week. In the US, there are some 250,000 new breast cancer cases diagnosed each year: nearly 5,000 a week. Between 1993 and 2016 the incidence of breast cancer in the UK increased by 24%. Over a similar period, breast cancer incidence in the US declined, but an increasing trend of some 1.1% was observed among American Asians. In China, between 2000 to 2013, breast cancer increased at an annual rate of around 3.5%. Breast cancer rates in China are higher in urban areas than in rural areas: the higher the population density, the higher the rate. It is not altogether clear why breast cancer incidence is increasing. Experts suggest that breast cancer is a complicated disease with a variety of causes. Most cases of the disease are not linked to a family history. Around 5% of people diagnosed with breast cancer have inherited a faulty BRCA1 or BRCA2 gene. However, if you have a faulty gene, it does not mean that you will automatically develop breast cancer, but you are at higher risk. Out of every 100 women with a faulty gene, between 40 and 85 will develop breast cancer in their lifetime. Optimal therapy for breast cancer often requires several different treatment modalities including surgery, radiation, chemotherapy and hormone therapy (see below).

Cost of breast cancer treatment in the UK

The cost of treating breast cancer in the UK is significant and rising. Findings of research on the treatment costs of breast cancer published in the August 1999 edition of The Breast estimated that the average cost per case of breast cancer in the UK to be £7,247 (US$9,418). Although the estimate is dated, it provides a guide. With 55,000 new cases of breast cancer diagnosed each year, the annual cost of treating the newly diagnosed alone, would be about £0.4bn (US$0.52bn). According to the UK charity Breast Cancer Now, an estimated 840,000 women living in the UK have been diagnosed with breast cancer and the charity predicts that this figure will increase to 1.2m over the next decade. Thus, ceteris paribus, we can assume that the current annual cost of treating breast cancer in the UK is significantly higher than £0.4bn and this figure is expected to increase substantially by 2030.

Hormones and hormone therapy

Hormones are chemical messengers secreted directly into your bloodstream, which carry them to organs and tissues of your body to exercise their functions. Oestrogen and progesterone are steroid hormones produced by the ovaries in premenopausal women and by some other tissues, including fat and skin, in both premenopausal and postmenopausal women. These hormones play a critical role in regulating reproduction. Oestrogen promotes the development and maintenance of female sex characteristics and the growth of long bones. Progesterone plays a role in the menstrual cycle and pregnancy.

Similar hormones are produced artificially either for use in oral contraceptives or to treat menopausal and menstrual disorders. Oestrogen and progesterone also promote the growth of some breast cancers, which are called hormone-sensitive (or hormone-dependent) breast cancers. Hormone-sensitive breast cancer cells contain proteins called hormone receptors, which become activated when hormones bind to them. The activated receptors cause changes in the expression of specific genes that can stimulate cell growth.

Anastrozole is a hormone therapy (also called hormonal therapy and endocrine therapy), which slows or stops the growth of hormone-sensitive tumours by either blocking the body’s ability to produce hormones or by interfering with the effects of hormones on breast cancer cells. Anastrozole blocks a process called aromatisation, which changes sex hormones called androgens into oestrogen. This happens mainly in the fatty tissues, muscle and the skin and needs a particular enzyme called aromatase.

Prescribing anastrozole

Anastrozole belongs to a group of drugs called aromatase inhibitors, which are specifically designed to treat postmenopausal women diagnosed with hormone-receptor-positive, early-stage breast cancer. It is most often prescribed as an adjuvant therapy (after surgery) to decrease the risk of your cancer returning but can also be used in the neoadjuvant setting (prior to surgery) to decrease the size of your cancer in the breast. Hormone blocking therapy is also used to treat breast cancer that has recurred or spread. Most hormone blocking therapy drugs such as anastrozole are taken daily in pill form.

Anastrozole also may be given to reduce the risk of breast cancer in women who have not had breast cancer but have an increased risk of developing it because of their family history. Most experts suggest that your breast cancer risk should be higher than average for you to consider taking anastrozole as a preventative strategy. If your cancer is hormone receptor negative, then anastrozole will not be of any benefit, because these cancers do not need oestrogen to grow and usually such cancer cells do not stop growing when treated with hormones that block oestrogen from binding.

Reasons for the relatively low uptake of anastrozole

There are at least three probably reasons for the relatively low uptake of anastrozole. These include: (i) doctors becoming so used to prescribing the gold standard tamoxifen as an adjuvant hormone therapy, (ii) doctors wanting to be convinced about anastrozole’s long term benefits, and (iii) doctors wanting assurance about anastrozole’s minimal side effects.

Tamoxifen

Tamoxifen is the oldest and most-prescribed aromatase inhibitor and for the past three decades has become the standard of care as the adjuvant treatment of postmenopausal women with hormone-responsive early breast cancer. The drug reduces the risk of breast cancer returning by 40% to 50% in postmenopausal women and by 30% to 50% in premenopausal women. Notwithstanding, over the past two decades a new generation of aromatase inhibitors have been developed, and anastrozole is one of these. How does anastrozole compare with the gold standard tamoxifen?

Tamoxifen and anastrozole compared

Findings of two long-term comparative clinical studies undertaken in North America and Europe involving over 1,000 women with oestrogen receptor positive advanced breast cancer, showed that anastrozole is better than tamoxifen for: (i) increasing the time before the cancer returns in those who experience recurrence, (ii) reducing the risk of the cancer spreading to other parts of the body and (iii) reducing the risk of a new cancer developing in the other breast.

Significantly, studies have shown that anastrozole avoids two of tamoxifen's more serious side-effects: an increased risk of developing a blood-clotting disease and an increased risk of developing womb cancer. Anastrozole can make bones weaker and so it is not recommended for women with osteoporosis and also it can cause stiff joints, hot flushes and vaginal dryness, which clinicians need to recognize and manage. But overall, the benefits of anastrozole over tamoxifen were maintained without a detrimental impact on quality of life. However, anastrozole is not a therapy for premenopausal women because it blocks the hormone oestrogen and in effect creates a drug-induced menopause.

Part 2

Increasing the uptake of anastrozole

For healthcare systems to function effectively and efficiently we expect doctors and patients to behave rationally and make effective and efficient decisions. Traditionally, the rational choice model, which is predicated upon the belief that all human beings (including doctors and patients) act rationally in their own self-interest, has been used to influence people to behave in desirable ways. However, evidence suggests that, despite the well-founded theory and sound evidence to support it, the rational choice approach does not appear to work that well in practice.

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A newer theory to explain peoples’ choices and behaviours

A newer approach to influencing behaviour, which builds on decades of research by Nobel prize-winning psychologist Daniel Kahneman, and described in a book published in 2008 entitled Nudge, by Nobel Prize winning economist Richard Thaler and Harvard Law School professor Cass Sunstein, suggests that no choice is ever presented in a neutral way and people - including doctors and patients - are susceptible to biases that can lead them to make suboptimal decisions. The authors suggest that many decisions and consequent behaviours are made automatically rather than after a considered rational decision. And this applies to decisions about your health.

Policymakers have been quick to latch onto the possibilities of these new behavioural techniques. Following the publication of Thaler and Sunstein’s book in 2008, President Obama set up a “Nudge Unit” in the White House and the UK Government, under Prime Minister David Cameron, set up the Behavioural Insights Team, popularly known as the Nudge Unit, in 10 Downing Street, and other governments around the world have since followed suit.

Nudges

Nudges are particular types of interventions, which are used to change peoples’ behaviour and improve outcomes at lower cost than traditional tools across a range of policy areas. Nudge techniques have been used in healthcare to influence behaviour and decision making to improve patient outcomes. For instance, the behavioural analysis of the decision-making that leads to a patient taking one drug instead of another. A research paper published in 2015 by the UK’s Health Foundation entitled “Behavioural insights in healthcare” suggests that health messages are often inconsistent and confusing to patients and framing them using social comparison via descriptive social norms (pointing out what is commonly done) or using injunctive norms (pointing out what is approved of) has been demonstrated to change patients’ behaviour and thereby have the potential to improve patient outcomes.

Information design

Behavioural techniques suggest that more attention should be given to the design of health information because the design and the way information is presented can influence and change doctors' and patients’ behaviour. Clinical guidelines, patients’ checklists and decision aids can all be improved in terms of text and language (e.g. the use of “plain English” and behaviourally specific, concrete statements and presentation of risk) and appearance (e.g. colour, visual stimuli, images etc).

HealthPad advocates that health information can have significantly more influence on the choices that doctors and patients make and on their behaviour simply by presenting critical information in a video format. Over the past few decades people have moved away from consuming information in written and audio formats to consuming information predominantly in a visual format.

Shift to consuming information in video format

Consider the following as being indicative of this shift. 82% of Twitter’s 330m average monthly users consume information in video format. The video channel You Tube has over a billion users and more than 500m hours of video are watched on the channel each day. 72 hours of video are uploaded to You Tube every 60 seconds, and more video content is uploaded onto the channel in 30 days than the major US television networks have created in 30 years. To further put things into perspective, in 2017, 56 exabytes (equivalent to 1bn gigabytes) of internet video content was consumed on a monthly basis, and this figure is expected to more than quadruple to 240 exabytes per month by 2022.

Today, almost all industries, with the exception of healthcare, use video formats to communicate and the overwhelming majority of people who have consumed information in video format say it has influenced their choices and changed their behaviour. With video becoming the most significant influence on consumer decisions, it seems reasonable to suggest that more health information needs to be communicated in a video format if it is to influence and change doctors’ and patients’ behaviours in order to improve medical outcomes, increase the quality of care and slow and prevent chronic lifetime diseases.

Prompts cues reminders and audits

Prompts, cues and reminders have been demonstrated to be generally effective “nudges” that can successfully change the behaviour of healthcare providers and consumers, as well as being relatively inexpensive and easy to administer. Audit and feedback “nudges” are also effective. A set of best practices derived from systematic review evidence suggests that various nudge-type interventions (notably information design and presentation) may offer new ways to enhance choices and change behaviour.

Takeaways

The burden of breast cancer is huge and increasing globally. Research has demonstrated that a cheap pill, anastrozole, halves postmenopausal women’s risk of the disease and continues to be effective seven years after women stop taking the drug. We suggest that healthcare systems should consider using new behavioural techniques to influence and change doctors' and patients’ decisions to increase the uptake of anastrozole to help reduce the burden of breast cancer. Evidence suggests that nudge-type interventions, if suitably applied, can influence and change the behaviour of doctors and patients and thereby contribute to the reduction of the burden of breast cancer. However, given the newness of these techniques the quality of evidence available about their impact is relatively thin and patchy. Notwithstanding, this suggests a need for more quality evaluation and synthesised evidence of nudge-type interventions, their behaviour change potential and their impact on reducing the burden of breast cancer and other chronic lifetime diseases.

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4 years, 6 months ago

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A new comprehensive gene-based breast cancer prediction device

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Cancer

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CanRisk is a new online gene-based health-risk evaluation algorithm for detecting breast cancer
It identifies people with different levels of risk of breast cancer, not just those at high risk
As the infotech and biotech revolutions merge expect authority in medicine to be transferred to algorithms
CanRisk has the potential to provide a cheap, rapid, non-invasive, highly sensitive and accurate diagnosis before symptoms present
Breast cancer is the most common cancer in women worldwide and is the 5^th most common cause of death from cancer in women
Currently mammography screening, which has a sensitivity between 72% and 87%, is the gold standard for preventing and controlling breast cancer
For every death from breast cancer that is prevented by screening, it is estimated there will be three false-positive cases that are detected and treated unnecessarily
Lack of resources do not support breast cancer screening in many regions of the world where the incidence rates of the disease are rapidly increasing
In the near-term expect interest in the CanRisk algorithm to increase

A new comprehensive gene-based breast cancer prediction device

A new online gene-based health-risk evaluation device called CanRisk has the potential to identify women with different levels of risk of breast cancer; not just women who are at high risk. Predicated on a comprehensive algorithm, CanRisk is one of several innovations currently in development, which include novel methods for predicting the recurrence of breast cancer, a new class of molecules that aim to halt or destroy breast cancer, and liquid biopsies, which determine the presence and recurrent risk of the disease through the detection of tumour cells in peoples’ blood.

Although over the past two decades there have been significant improvements in the detection and treatment of breast cancer, the disease remains the most common cancer in women worldwide, with some 1.7m new cases diagnosed each year, which account for about 25% of all cancers in women and it is the fifth most common cause of death from cancer in women, with over 0.52m deaths each year.

Game changer for breast cancer

Findings of CanRisk were reported in the January 2019 edition of Genetics in Medicine. Findings of a less comprehensive version of the device’s algorithm were published in the July 2016 edition of the same journal. Commenting on the 2019 study, Antonis Antoniou, Professor of Cancer Risk Prediction at the University of Cambridge and lead author of the two studies said: "This is the first time that anyone has combined so many elements into one breast cancer prediction tool. It could be a game changer for breast cancer and help doctors to tailor the care they provide depending on their patients' level of risk”.

When fully developed and approved, CanRisk will be well positioned to provide a cheap, rapid, non-invasive, highly sensitive and accurate diagnostic test to detect breast cancer early in people with diverse levels of risk. This might be expected to provide an alternative to the current gold standard population-based mammography screening and assist in making a significant dent in the vast and escalating global burden of the disease.

In this Commentary

This Commentary describes the algorithm that drives CanRisk, which benefits from the increasing availability of vast and growing amounts of genomic and other personal data and significant advances in genomic sequencing technologies. The confluence of these two phenomena facilitates and enhances the quality and speed of data analysis and drives the development of new and innovative diagnostic and prognostic cancer technologies. The fact that CanRisk is based on UK data and its algorithm is available to researchers globally, presents a potential opportunity for medical research organizations in emerging regions of the world where the burden of breast cancer is increasing. The Commentary briefly describes the heterogeneous nature of breast cancer and highlights some of its complexities and risk factors. Originally perceived as a Western disease, breast cancer is growing rapidly in Asia and other regions of the world where it tends to be detected late and managed less effectively. Developed economies prevent and manage breast cancer through well-established population-based mammography screening programs. Because of the lack of resources, such screening programs are not widely available in low to middle income countries (LMIC). As the infotech and biotech revolutions merge expect authority in medicine to be transferred to Big Data algorithms such as CanRisk. This not only could provide an alternative to gold standard mammography screening, but also provide a cheap and effective device for use in developing nations where the burden of breast cancer is significant and increasing.

CanRisk: a world first

CanRisk, developed by members of the Centre for Cancer Genetic Epidemiology at the University of Cambridge, UK, takes advantage of discoveries in both cancer genomics and epidemiology and aims to become a popular device used by primary care physicians, in consultation with their patients, to effectively assess patients’ diverse levels of risk of developing breast cancer. The device is predicated on an algorithm called BOADICEA (the Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm). This is the world’s first polygenic breast cancer risk model and the only one to-date, which is available to the international research community. Also, it is the first breast cancer risk model to incorporate pathology data and population-specific cancer incidences in risk calculations. The algorithm accounts for over 300 genetic risk factors, including BRCA1, [BReast CAncer gene] BRCA2, PALB2, CHEK2, and ATM, which are genes that have been found to impact a person’s chances of developing breast cancer. The device uses a Polygenic Risk Score (PRS) based on 313 single-nucleotide polymorphisms (SNPs), [SNPs, pronounced ‘snips’, are the most common types of genetic variation in people. Each SNP represents a difference in a single DNA building block and is called a nucleotide] which explains 20% of breast cancer polygenic variance. CanRisk also includes a residual polygenic component, which accounts for other genetic/familial effects; known lifestyle/hormonal/reproductive risk factors and mammographic density [Dense breast tissue can make it harder to evaluate mammographic results and may also be associated with an increased risk of breast cancer].

Authority increasingly being transferred to algorithms

Over the past two decades we have increasingly learnt to accept the authority of Big Data algorithms. For example, without question we expect algorithms to give us directions, tell us what movies to watch, who to date, what clothes to wear, where to go on holiday, what flight to take, what hotel to stay in and where to eat. We are comfortable with algorithms assigning us our credit rating, limiting our overdraft and capping our payments. Furthermore, we are beginning to accept the authority of algorithms in medicine. For example, we are gradually replacing the authority of primary care doctors with algorithms that can diagnose common diseases more accurately and more cost effectively.

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In December 2018, for the first time in history, the US FDA approved an algorithm to diagnose patients without a doctor’s interpretation. The algorithm, called IDx-DR, detects diabetic retinopathy by analysing images of the back of the eye. Indeed, we are living on the cusp of history when the twin revolutions of information technology and biotechnology are merging and providing the basis for us to transfer authority in medicine to algorithms. In the next two decades, it seems reasonable to assume that it will become common practice to accept the authority of algorithms such as CanRisk, which will inform us that we are suffering from a medical condition long before we present any signs or symptoms.

Increasing supply of data

CanRisk takes advantage of the fact that genetic and other risk factor data are becoming more easily available in clinical practice through electronic health records, biometric sensors that convert biological processes into electronic information, which computers can store and analyse, cost-effective high speed, high capacity genomic sequencing technologies, and efforts such as the 100,000 Genomes Project. A UK Government sponsored initiative completed in December 2018, which collected, stored and analysed data from the genomes and medical records of 85,000 NHS England patients affected by cancer or rare disease. Genomics England, which is wholly owned by the UK’s Department of Health, was set up in 2003 to deliver the project. Because CanRisk solely is based on UK population data, its findings are likely to be more applicable to similarly developed Western populations, and less so to populations in other regions of the world. This provides a potential opportunity for international organizations interested in early breast cancer diagnosis.

International sequencing projects

The UK’s genomes project is part of a much larger rapidly growing and dynamic global genomics market comprised of data and gene sequencing technologies. 100,000 genomes have been the goal of several other nations interested in improving their healthcare - and lowering costs - by carrying out precision medicine based on insights from sequencing data. Currently the global genomics market is estimated to be about US$19bn and projected to reach US$41bn by 2025. The market is driven by increasing government funding, the consequent rise in the number of genomics projects, decreasing gene sequencing costs, growing application areas of genomics and the entry and fast growth of commercial players.

China has become the world’s leader in genomic sequencing. In 2010, the Beijing Genomics Institute (BGI) in Shenzhen was understood to be hosting a higher sequencing capacity than that of the entire US. While most government projects aim to sequence 100,000 genomes, China’s sequencing program is set to sequence 1m human genomes, which include subgroups of 50,000 people, each with specific conditions such as cancer or metabolic disease. The data will also include cohorts from different regions of China, which will facilitate “the analysis of different genetic backgrounds of subpopulations”.

Revolution in genome sequencing

The first human genome project began in 1990, took 13 years and about US$1bn to complete. The last two decades have seen a revolution in genome sequencing with dramatic increases in its speed and efficiency coupled with massive reductions in cost. Genomic sequencing has proved its usefulness as a diagnostic and prognostic tool. Today it is possible to get your genome sequenced for around US$1,000 in a few days and delivered by post from firms such as Dante Labs and 24 Genetics in Europe, and Veritas Genetics and Sure Genomics in the US.

Breast cancer

Returning to breast cancer. It is important to note that the disease is not one, but a group of conditions that manifest themselves with maladies in the same organ. Breasts are comprised of three main parts: lobules, which produce milk; ducts, which carry milk to the nipples; and fibrous and fatty connective tissue, which hold everything together. The type of breast cancer depends on which cells in the breast mutate, but most breast cancers begin in the ducts or lobules. Some mutated cells in the breast may never spread, however, most breast cancers tend to be invasive and may present with a number of different characteristics in terms of hardness and shape, which can provide some indication of their likely progression. Breast cancer can spread outside the breast through blood and lymph vessels. Further, there are significant differences in breast cancer at the genetic level. A study published in the April 2012 edition of Nature compared the genetic makeup of breast cancer tumour samples with their other characteristics for some 2,000 women, for whom information about the tumour characteristics had been meticulously recorded; and identified at least 10 distinct sub-types of breast cancer, each with its own unique characteristics. Although the study contributed to how breast cancer is diagnosed, classified and treated, in practice certain characteristics of these tumours were already known and tested for: most notably cellular receptors for estrogen, and progesterone, which are the two most significant steroid hormones responsible for various female characteristics. Their presence or absence generally suggests the potential utility of additional medication to accompany surgery, radiotherapy and chemotherapy.

Despite population screening and advanced therapies breast cancer remains a killer disease

Let us briefly consider breast cancer in the world’s most advanced and wealthiest nation: the US. Although there have been significant improvements in the detection and treatment of breast cancer in the US; still about 1 in 8 American women will develop an invasive type of the disease over the course of her lifetime. In 2019, an estimated 268,600 new cases of invasive breast cancer are expected to be diagnosed in the US, along with 62,930 new cases of non-invasive (in situ) breast cancer. Breast cancer death rates for women in the US are higher than those for any other cancer, besides lung cancer. As of January 2019, there were more than 3.1m women with a history of breast cancer in the US. Although breast cancer death rates in the US have been decreasing over the past three decades and women under 50 have experienced larger decreases, still some 41,760 are expected to die in 2019 from the disease. About 2,670 new cases of invasive breast cancer are expected to be diagnosed in men in the US in 2019 where a man’s lifetime risk of breast cancer is about 1 in 883.

Breast cancer challenges in Singapore

There are also breast cancer challenges in wealthy non-Western developed economies such as Singapore. Over the past four decades, the incidence of breast cancer in Singapore has more than doubled: from 25 to 65 per 100,000 women. Breast cancer is not just the most common cancer for Singaporean women, accounting for one in three cancers in women, but it is also the top killer. Data reported in the country’s Cancer Registry showed that 2,105 women died of the disease between 2011 and 2015. Notwithstanding, Singapore has extensive awareness-raising programs; population-wide mammography screening; excellent, multi-disciplinary primary and long-term care and improving palliative care, which have contributed to a significant increase in the survival rates of breast cancer patients. However, a substantial proportion of Singaporean women still appear to have a patchy knowledge of aspects of the disease, which leads to comparatively low participation rates in the nation’s breast cancer screening services, and this contributes to late presentation of the disease when it is more difficult to cure and more challenging to treat.

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Breast cancer growing rapidly in Asia

Breast cancer was once largely confined to developed Western countries and Australasia, but it has now become the most common cancer in Asia. Although Asian data on breast cancer are patchy, an Economist Intelligence Unit report, suggests that, “since the 1990s, increases in the incidence of breast cancer in Asia, as measured by age-standardised rates (ASRs), is four to eight times that of the global average”. Indeed, as younger cohorts of Asian women age and adopt Western diets and lifestyles (particularly fertility patterns, such as later first childbirth and shorter breast feeding), breast cancer incidence rates in Asia look set to converge with the much higher ones in the West. Further, in LMIC breast cancer is increasing at a more rapid rate than in the West and has become a significant healthcare challenge: 50% of breast cancer cases and 58% of deaths from the disease occur in LMIC.

The significance of early detection

The good news is that if caught in its early stages, breast cancer can be treated effectively, with high survival rates. The average 5-year survival rate for women with invasive breast cancer is 90%. The average 10-year survival rate is 83%. If the cancer is located only in the breast, the 5-year survival rate of women with breast cancer is 99%. In all types of the disease early detection is the cornerstone of breast cancer control.

Gold standard breast cancer mammography screening

The current gold standard for preventing and controlling breast cancer is population-based mammography screening. This is a non-invasive process that uses an x-ray of the breast to look for disease in women who do not have symptoms. The method has reasonable sensitivity (72%–87%) that increases with age and allows for the early detection of breast cancer, which helps increase survival, especially in women between 50 and 70. Notwithstanding, mammograms are not pleasant as the breast is squashed between two metal plates and further some women may find mammograms embarrassing.

Success of population-based mammography screening

Following a landmark Swedish study that began in 1977 mammography screening has been adopted in more than 26 developed countries worldwide. Findings of the study, reported in a 1989 edition of the Journal of Epidemiology and Community Health, suggested that mortality from breast cancer dropped 31% after screening of women aged 39 to 74. More recent findings of the UK screening program published in the June 2013 edition of the British Journal of Cancer, suggested mortality rates from breast cancer were reduced by 20% in the screened group compared to the unscreened group across all age groups. A study published in 2018 in Cancer, which tracked 52,438 Swedish women aged 40-69 from 1977 to 2015, suggested that regular mammograms contributed to a 60% decrease in breast cancer death during the first 10-years of diagnosis, and a 47% reduced risk within 20-years. Research has shown that mammography has relatively little benefit for women under 50.

Diverging views about mammography screening

Despite evidence to support the benefits of population-based mammography screening, there are diverging views among healthcare professionals about the impact of several decades of high levels of screening. Some argue that traditional mammography screening stretches finite resources and is not cost-effective because the majority of people who undergo screening do not have cancer and may never go on to develop it. Others suggest that there are significant uncertainties about the magnitude of the harms from mammography screening especially associated with false positives (a test result, which wrongly indicates that breast cancer is present).

Challenges of mammography screening

The sensitivity of mammography is between 72% and 87%, but is higher in women over 50 and in women with fatty rather than dense breasts. Dense breast tissue can make it harder to evaluate results of a mammogram. According to the Marmot review, for every death from breast cancer that is prevented by screening, it is estimated there will be three over-diagnosed or false-positive cases that are detected and treated unnecessarily. The chance of having a false positive result after one mammogram ranges from 7% to 12%, depending on age (younger women are more likely to have false positive results). After 10 yearly mammograms, the chance of having a false positive is about 50-60%. The more mammograms a woman has, the more likely it is she will have a false positive result. This makes it difficult for doctors to weigh and communicate the benefits and risks of mammography screening programs and fuels interest in innovations such as CanRisk.

Takeaways

Mammography screening for breast cancer is not 100% accurate. Further, knowhow, trained healthcare professionals and significant resources are required to effectively implement and manage a well-organized and sustainable breast cancer screening program that targets the right population group and ensures effective coordination and quality of actions across the whole continuum of care. These attributes tend to exist only in developed wealthy countries. CanRisk, and other innovative breast cancer early diagnostic devices under development, offer the potential for cheap, rapid, reliable and exquisitely accurate diagnosis that can be easily used in primary care settings throughout the world. In time, as authority in medicine passes to algorithms, expect these new and innovative devices to replace mammography screening in wealthy countries and quickly become devices of choice in developing economies and significantly dent the vast and rapidly growing global burden of breast cancer.

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After 20 years of the cancer drug Herceptin is less more?

HealthPad

Directory:

Cancer

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advanced breast cancer

15 to 20% of breast cancer patients suffer a type of the disease that could benefit from the drug Herceptin
Herceptin is very effective and normally administered for 12-months but it is expensive and can cause heart damage
New research has found that the treatment period for Herceptin could be reduced from 12-months to 6 without compromising outcomes
A 6-month course would reduce the cost of the drug, increase access and potentially reduce the number of patients suffering debilitating side effects
The research findings reignited broader concerns about the sustainability of cancer care and the competing interests of patients, producers and providers
Herceptin’s patents are expiring and biosimilars are entering the market which is expected to lower costs and increase access

After 20 years of the cancer drug Herceptin is less more?

Findings of a phase III clinical study funded by UK government grants and presented at the June 2018 meeting of the American Society of Clinical Oncology (ASCO) suggest that the time a patient needs to spend on Herceptin, (chemical name trastuzumab), a drug widely used to treat an aggressive form of breast cancer, could be halved from 12 to 6 months. This would save insurers, governments, healthcare providers and patients significant sums of money and possibly reduce the incidence of side effects, which can include heart problems.

In this Commentary

This Commentary: (i) summarizes the findings of the clinical study and some expert reactions to it and (ii) describes the different subtypes of breast cancer and the drug trastuzumab. The Commentary also broaches a broader concern about the escalating costs of life-saving or life-extending cancer therapies, which show no sign of either slowing or reversing. According to ASCO, in the US, newly approved cancer drugs cost on average US$10,000 per month, with some costing as much as US$30,000 per month. This causes financial hardship for many American patients and their families. In the UK, which has a large devolved public healthcare system, cancer therapies are a postcode lottery because medicines that patients receive depend on whether their local healthcare provider can afford them. In emerging economies, where the prevalence of breast cancer is rising, only a privileged few breast cancer patients have access to trastuzumab. Notwithstanding, patients should gain some comfort from Herceptin’s patents expiring and biosimilar versions of trastuzumab entering the market, which is expected to make the drug cheaper and more accessible.

Breast cancer and HER2

Breast cancer is a heterogenic disease and biomolecular changes in breast cancer involve the expression of genes. The disease is classified according to the 4 subtypes of genes expressed: (i) luminal A, which accounts for 51 to 61% of all breast cancer patients, (ii) luminal B, which accounts for 14 to 16%, (iii) basal-like, which accounts for 11-20% and (iv) the HER2 subtype, which accounts for 15 to 20% of all breast cancer patients and is the focus of this Commentary. Each subtype has different clinical features, different prognoses and different responses to therapies. HER2 protein overexpression is the result of amplification of the HER2 gene and is associated with aggressive tumour growth and consequent high rates of recurrence and mortality in patients. HER2-positive breast cancer is not inherited but is a somatic genetic mutation, which occurs after conception and therefore the new DNA does not enter the eggs or sperm.

Trastuzumab the first gene targeted drug

Trastuzumab was first approved by the US Food and Drug Administration (FDA) in 1998 and became the first FDA-approved therapeutic antibody targeted to a specific cancer-related molecular marker. The FDA recommended that the drug should be administered for 12 months. Robert Leonard, formerly Professor of Cancer Studies at Imperial College London, UK, and a consultant medical oncologist specialising in breast cancer at the BUPA Cromwell Hospital, the London Clinic and the London Oncology Clinic describes HER2 positive breast cancer and trastuzumab: see video below. “We like to talk about targeted therapies since we’ve learnt more about the basic biology of cancer, which uses subtle techniques of investigation including biological and immunological profiling of cancers. We now have the ability for new molecules to target specific abnormalities in cancer cells and these can be effective in sublimating standard breast cancer treatments. A good example are Herceptin and Lapatinib, both of which target the HER2 pathway, which is a very important pathway in breast cancer,” says Leonard.

Trastuzumab and advanced breast cancer

Trastuzumab’s approval followed 4 randomized clinical studies involving more than 8,000 patients with stages II or III HER2-positive breast cancers. These showed that when trastuzumab was administered for a period of 12 months in combination with or after chemotherapy agents, it potentiated the efficacy of chemo- and immunotherapy; reduced the risk of breast cancer recurrence by approximately 50% and significantly improved survival. In 2000, trastuzumab's use for advanced breast cancer was approved in Europe and has since been approved in a number of countries outside Europe. In 2002 the UK government’s watchdog, the National Institute for Health and Clinical Excellence (NICE), endorsed the use of trastuzumab for advanced HER2 breast cancer.

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Trastuzumab and early stage breast cancer
Shortly afterwards, trastuzumab expanded its use to early stage HER2 breast cancer. Findings of 2 papers in the October 2005 edition of the New England Journal of Medicine (NEJM), suggested that following initial interventions, a 12-month course of trastuzumab in combination with other agents, could also be a lifesaver for those still in the early stages of breast cancer because it reduced the risk of recurrence and death of patients by 46% compared with chemotherapy alone. In this respect trastuzumab has been viewed as a possible “cure” for early stage breast cancer. Based on these findings, trastuzumab’s approval was extended for the treatment of early stage HER2 cancers. Commenting on the 2 studies in the same edition of the NEJM Gabriel Hortoboagyi, a breast cancer specialist from MD Anderson Cancer Center in Huston, USA, said, “the results reported in this issue of the Journal are not evolutionary but revolutionary. . . . . . trastuzumab and the two reports in this issue will completely alter our approach to the treatment of breast cancer.” In September 2013, a time-saving subcutaneous formulation of trastuzumab was approved in Europe, which can be administered in just 2 to 5 minutes, rather than the standard 30 to 90 minutes intravenously.

Was the 12 months treatment time a “guess”?
After regulatory approval in 1998 and following some subsequent clinical studies, a 12-month regimen for trastuzumab became the standard of care. Notwithstanding, some oncologists view the 12-month treatment period as a “guess”, and some smaller trials have questioned the duration of treatment.

Clinical study and the 2018 ASCO Meeting

The study presented at the 2018 ASCO meeting is the largest and most significant study to-date, which suggests that the treatment time for trastuzumab could be halved. The randomized clinical study followed 4,088 women with early-stage breast cancer across 152 sites in the UK for a median of more than 5 years: 2043 received trastuzumab for 6 months and 2045 received the drug for 12 months. The disease-free survival rate at 4 years was 89.4% with 6 months of therapy and 89.8% with 12 months of therapy. In addition, 4% of patients on the shorter treatment dropped out due to cardiac toxicity versus 8% of those treated for a year. Across both groups, cardiac function recovered within a few months following treatment with trastuzumab but patients in the 6-month group recovered more rapidly.

Helena Earl, Professor of Clinical Cancer Medicine at the University of Cambridge, UK and the study’s lead investigator is confident that the study will, “mark the first steps towards reduction of treatment duration for many women with HER2-positive breast cancer." According to Richard Schilsky, ASCO’s Chief Medical Officer, “There’s no reason to not immediately change practice. The findings are persuasive”.

Expert reaction to the study

Although oncologists view the study’s findings as “persuasive”, changing the length of treatment time for trastuzumab might not occur quickly. Generally, clinicians appear hesitant to immediately support a shorter duration of trastuzumab as a new standard of care. Some believe that since so few women have died or relapsed after being treated with trastuzumab, longer follow-up may be required to make sure the findings hold up before guidelines are changed.

“My guess is that people will continue to aim for a year of treatment' because of lingering concerns that longer use is better, as a smaller previous study suggested,” says Harold Burstein, a breast cancer expert at the Dana-Farber Cancer Institute in Boston, USA. However, Burstein is mindful that a shorter treatment regimen might increase access to trastuzumab for patients in emerging economies where the prevalence of breast cancer is increasing but where many women cannot afford a 12-month treatment course of the drug. Other experts suggest that the study’s findings are significant for women who suffer the toxic effects of trastuzumab.

Jennifer Litton, a breast cancer specialist at MD Anderson Cancer Center points to another issue the ASCO study raises. She suggests the study’s findings show just how important it can be to study drugs that are already on the market. “It's really important that we continue to have public funding for clinical trials, so we can continue to ask all of these questions for our patients. Scaling back treatment whenever possible is important to patients,” says Litton.

Industry response
A spokesperson for Roche Genentech, Herceptin's developers, suggested that the ASCO study should be viewed along with several smaller studies, which conclude that the optimum duration for trastuzumab is 12 months. The goal of the treatment, “is to provide people with the best chance for a cure.” Courtney Aberbach, a spokesperson for Genentech, which was acquired by Roche, in March 2009 for US$$46.8bn, suggested that previous studies had not found that a shorter duration worked as well as the longer one. She said the 12-month course was still the only regimen approved for early-stage disease by the FDA and recommended by several international organizations that issue treatment guidelines.

The HERA Trial
Industry views are influenced by a clinical study sponsored by Roche in the expectation that the 12-month trastuzumab treatment period could be doubled. Referred to as the HERA trial, the study was conducted by France's Institut National du Cancer and reported at the 2012 meeting of the European Society for Medical Oncology (ESMO). HERA was an international multi-centre, phase III randomized study involving 5,102 women with early HER2-positive breast cancer. After finishing primary therapy with surgery, chemotherapy and radiotherapy, they were randomly assigned to trastuzumab therapy every 3 weeks for 1 year, 2 years or observation.

In April 2012, when the study’s findings were presented at the ESMO meeting, the overall survival rate of the 24-month treatment cohort versus the 12-month cohort was comparable. The principal conclusion of the study was that 12-month treatment remains the standard of care for HER2 positive early breast cancer patients. Results also suggested that shortening treatment of trastuzumab to 6 months may offer a worse result than a 12-month course of treatment. While the study’s findings meant that Roche missed an opportunity to expand sales of trastuzumab on the back of a longer recommended treatment period, they were also a relief to the company, which had faced the risk of losing significant sales revenues from trastuzumab had a shorter treatment period turned out to be as effective as the current standard of 12-months.

Unsustainable of cancer care

Cancer treatment has always been expensive, but the costs of newer molecular targeted therapies, such as trastuzumab, have escalated, which significantly reduces access for a lot of breast cancer patients to efficacious drugs. According to a 2015 study by the US National Bureau of Economic Research, each year between 1995 and 2013 the prices of cancer drugs increased 10%. This finding led some health professionals to suggest that cancer therapies are becoming “unsustainable”. In England, NICE has come under intense criticism from patient groups for rejecting numerous cancer drugs for use on the NHS because they were not judged to be cost effective. The UK’s Cancer Drugs Fund, which was set up in 2011 to plug gaps in NHS funding for cancer drugs, overspent its allocated budget by 35% between 2013 and 2015. The debate of the rising cost of cancer therapies is exacerbated by the revenues generated by cancer drugs for big pharmaceutical companies. For example, in 2017 Roche-Genentech recorded annual sales of US$6.8bn for Herceptin alone, which some analysts suggested was driven partly by the duration of the treatment and partly by strong sales growth of the drug in Brazil and China.

When vast revenues from the sale of drugs are mentioned there is negative reaction directed at giant pharmaceutical companies. In their defence drug producers stress the vast costs of developing new drugs and the tenure of patents, which limit the time drug companies have to recoup R&D costs before copycats are introduced into the market. According to the most recent report from the Tufts Center for the Study of Drug Development, and published in the May 2016 edition of the Journal of Health Economics; the cost of developing a medicine from invention to pharmacy shelves is estimated to be some US$2.7bn. Patents protect drugs for 20 years after the initial invention. This exclusivity is designed to promote a balance between new drug innovation and greater public access to drugs, which result from copycat versions. Notwithstanding, big pharmaceutical companies stress that it can take 8 to 12 years after invention to accumulate enough data to get a drug past the FDA.

Biosimilars

For 20 years now Roche-Genentech has benefited from its 90% market share of the HER2-positive global breast cancer market. Notwithstanding, the main EU patent for Herceptin expired in 2014 and is due to expire in the US in 2019. Already, the market has experienced the entry of biosimilar versions of trastuzumab, which are expected to be cheaper and therefore extend patient access to the drug. Biosimilars are not to be confused with generic drugs. Regulators require biosimilars to be “highly similar” to the “reference product” but not exact copies of the biologic medicine. Biologic medicines are comprised of large complex molecules, which may be composed of living material. Here we provide some examples of the biosimilar versions of trastuzumab, which are coming onto the market.

Trastuzumab biosimilars

In December 2017, a biosimilar version of trastuzumab was approved by the FDA and is marketed in the US as Ogivri. Approval of Ogivri was based on a review of evidence that included extensive structural and functional characterization, animal study data, human pharmacokinetic and pharmacodynamic data, clinical immunogenicity data and other clinical safety and effectiveness data, which demonstrated that Ogivri is biosimilar to trastuzumab. In 2018, Merck Sharp and Dohme (MSD) launched Ontruzan, in the UK, which is Europe’s first biosimilar to Herceptin. Clinical studies have shown Ontruzan to be similar to trastuzumab in terms of its structure, biological activity and efficacy, safety and immunogenicity profile. Studies also showed that in early breast cancer, breast pathologic complete response rates were 51.7% with Ontruzant and 42% with Herceptin, while overall response rates were 96.3% and 91.2% respectively. Mylan and Biocon have launched a biosimilar version of trastuzumab called Canmab in India, and Celltrion, has launched Herzuma, another biosimilar version of trastuzumab in South Korea. According to Mark Verrill, head of the Department of Medical Oncology at the Newcastle upon Tyne Hospitals NHS Foundation Trust, UK, “The launch of biosimilar trastuzumab provides a high-quality treatment alternative for patients, while offering significant potential savings for health providers and patients.”

Takeaways

The clinical study presented at the June 2018 meeting of ASCO suggested that the treatment time for trastuzumab could be reduced from 12 months to 6 without compromising outcomes. This would significantly reduce the cost of trastuzumab and thereby make the drug available to more breast cancer patients. Although the study’s findings are “persuasive” there is a reticence among clinicians to reduce the treatment time of trastuzumab. The ASCO study throws light on the challenges to reconcile the competing interests of patients, healthcare providers and drug companies. While pharmaceutical companies spend billions on R&D they are challenged to reconcile the demands of shareholders and society. Public funds for medical research, while important, are limited especially at a time of relatively slow economic growth and fiscal constraint. Given that there does not appear to be any credible suggestion to curtail the vast and escalating cost of cancer care more generally, the current situation, which incentivises giant pharmaceutical companies to invest in R&D with 20-year patents, appears to be a formula that will prevail for some time to come, and patients will have to wait significant lengths of time before they get access to biosimilars.

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Breast cancer and harmful BRCA gene mutations

HealthPad

Directory:

Cancer

Tags:

gynaecological cancers

mammography

ovarian cancer

Each year about 1.7m women are diagnosed with breast cancer worldwide and over 0.5m die from the condition
Between 5% and 10% of these breast cancers result from harmful gene mutations
BRCA1 and BRCA2 gene mutations are the most common cause of hereditary breast cancer
45% to 85% of women with a BRCA mutation will develop breast cancer in their lifetime compared to 12% of women in the general population
Most women do not know if they have a harmful BRCA mutation
Testing for the BRCA gene is now affordable, fast and accessible
Surgical interventions of women with BRCA mutations can significantly reduce their risk of developing breast cancer and substantially increase cancer survival
Genetic test results for breast cancer are fraught with uncertainty because testing reveals the likelihood of developing cancer rather than a certain fate
Research suggests that BRCA test results are not being clearly communicated to women
Best practice demands that expert counselors discuss genetic testing and help interpret results

Breast cancer and harmful BRCA gene mutations

Few things frighten women more than discovering a lump in one of her breasts The standard treatment: surgery, followed by radio- and chemotherapy, can be disfiguring, painful, sometimes unsuccessful, and the impact of the disease is felt by far more individuals than just those who have the diagnosis.The good news is that over the past 30 years breast cancer survival rates in most developed countries have been improving, largely due to screening, earlier diagnosis and improved treatments. The bad new is that in most developed countries it is twice as likely for a woman to be diagnosed with breast cancer than 60 years ago.

Harmful BRCA genes mutations

5 to 10% of breast cancers are thought to be due to gene mutations, and harmful BRCA mutations account for 20 to 25% of these. Women who inherit the BRCA1 mutations have a 60 to 90% risk of developing breast cancer in their lifetime, and those who inherit BRCA2 mutations increase their risk of breast cancer by 45 to 85%, compared to 12% of women in the general population. Most women do not know if they carry the harmful BRCA mutation, but if they discover they do, many elect to have a bilateral mastectomy. This is a significant procedure with potential risks and side effects, but can reduce your mortality risk by about 50%.

The gold standard screening for breast cancer is an x-ray picture of the breast (mammography), but increasingly women are turning to genetic testing as their awareness of the harmful BRCA mutations increase, and genetic testing becomes more accessible and affordable. However, results from these tests are not straightforward, and often not communicated well. This can increase the anxiety in women with suspected breast cancer, and make them elect to have unnecessary interventions and procedures.

This Commentary describes how advanced genetic testing together with expert counselling help women improve their management of breast cancer.

Breast Cancer

Cancer is a group of diseases that cause cells in your body to change and grow out of control: they mutate. Most types of cancer cells eventually form a lump or mass called a tumor, and are named after the part of the body where the tumor originates, e.g. “breast cancer”, although this convention is changing with the development of targeted personalized medicine. The exact cause of breast cancer is unknown, but the overwhelming majority result from some combination of environment, lifestyle, and genes. Breast cancer affects about 1 in 8 women at some point during their life, usually after the menopause, and is the most common cancer in women. The majority of breast cancers begin in the parts of the breast tissue that are made up of glands for milk production, called lobules, and ducts that connect the lobules to the nipple. The remainder of the breast is made up of fatty, connective, and lymphatic tissue. Most invasive breast cancers (those that have spread from where they started) are found in women 55 and older. Women with a family history of the disease have an increased risk of getting breast cancer. Each year about 1.7m women are diagnosed with breast cancer worldwide, and over 0.5m die from the condition. However in developed economies more and more women survive the disease. In the US, for instance, the average 5-year survival rate for people with breast cancer is 89%. The 10-year rate is 83%, and the 15-year rate is 78%. Other developed countries have similar success rates. What makes breast cancer fatal is if it spreads to the bones, lungs, liver and other organs. Early detection in order to improve breast cancer outcomes remains the cornerstone of the condition’s management. Although breast cancer is thought to be a disease of the developed world, it is increasing rapidly in emerging countries where the majority of cases present later and die earlier than women in developed countries: almost 50% of breast cancer cases and 58% of deaths occur in emerging economies. This is because women generally have relatively poor knowledge of the risk factors, symptoms and methods for early detection. Also, they experience cancer fatalism, believe in alternative medicine, and lack of autonomy in decision making, which often results in delays in seeking or avoidance of evidence-based medicine.

Mammography

Mammography, which has long been the mainstay of breast cancer detection, is a specific type of breast imaging that uses low-dose x-rays to detect small changes in the breast before there are any other signs or symptoms of the disease when it is most treatable. Mammography is noninvasive, relatively inexpensive, and has reasonable sensitivity (72–88%), which increases with age. It can also be used to detect and diagnose breast disease in women experiencing symptoms such as a lump, pain, or nipple discharge. If breast cancer is found at an early stage, there is an increased chance for breast-conserving surgery and a better prognosis for long-term survival. Most developed countries operate breast-screening programs, which regularly provides mammography for women between certain ages.

Advances in mammography

In recent years, mammography has undergone increased scrutiny for false positives and excessive biopsies, which increase radiation dosage, cost and patient anxiety. In response to these challenges, new forms of mammography screening have been developed, including; low dose mammography, digital mammography, computer-aided detection, tomosynthesis, which is also called 3-D mammography, automated whole breast ultrasound, molecular imaging and MRI. Notwithstanding, there is increasing awareness of subpopulations of women for whom mammography has reduced sensitivity. More recently, women have turned to genetic testing to gain a better understanding of their risk of inherited breast cancer.

Genes

Every cell in your body contains genes. These contain the genetic code for your body, which not only determines the color of your eyes and hair etc., but also provides information that affects how the cells in your body behave: for example, how they grow, divide and die. Information in your genes is inherited from both parents, and you pass on this information to your children. A change in your genetic code that affects the function of a gene is called a mutation. Many inherited gene mutations do not have any effect on your health, but some do; the BRCA1 and BRCA2 mutations account for 20 to 25% of all inheritable female breast cancers and 15% of ovarian cancers.

BRCA genes

In normal cells, BRCA genes are tumor suppressor genes that assist in preventing cancer developing by making proteins that help to keep cells from growing abnormally. Mutated versions of BRCA genes cannot stop abnormal growth, and this can lead to cancer. Mutated BRCA genes have a higher prevalence in certain ethnic groups, such as those of Ashkenazi Jewish descent.

In the video below Professor Robert Leonard, a medical oncologist and an authority on breast cancer, describes how BRCA genes are influential in breast and ovarian cancer risk. BRCA1 runs in families and may also increase a woman’s risk of developing fallopian tube and peritoneal cancers. BRCA2 also runs in families, and is more breast cancer-specific, but a less commonly inherited abnormality. Both or either of these genes may not be detectably abnormal even in a family with a strong inherited pattern of breast cancer, but there is a significant possibility that you will find them in people with a family history of breast and ovarian cancer. Breast and ovarian cancers associated with BRCA mutations tend to develop at younger ages than their non-hereditary counterparts.

Enhanced risk when family members have cancer

In December 2013, the US Preventive Services Task Force recommended that women who have family members with breast, ovarian, fallopian tube, or peritoneal cancer be evaluated to see if they have a familial history that is associated with an increased risk of a harmful mutation in one of the BRCA genes. Compared to women without a family history of cancer, risk of breast cancer is about 2 times higher for women with a close female relative who has been diagnosed with cancer; nearly 3 times higher for women with two relatives, and nearly 4 times higher for women with three or more relatives. Risk is further increased when the affected relative was diagnosed at a young age. Notwithstanding, the Preventive Services Task Force recommends against BRCA testing for women with no family history of cancer.

The Angelina Jolie effect

The Hollywood actress and filmmaker Angelina Jolie lost her grandmother and aunt to breast cancer and her mother to ovarian cancer. After discovering that she carried a maternally inherited pathogenic BRCA1 mutation, and being told that she had an 87% chance of developing breast cancer, and a 50% chance of ovarian cancer, Jolie elected to have her breasts, ovaries and fallopian tubes removed. After surgery her risk of developing breast cancer in later life fell to 5%.

In May 2013, Jolie described her decision in a New York Times (NYT) article, “I am writing about it now because I hope that other women can benefit from my experience . . . . . Cancer is still a word that strikes fear into people’s hearts, producing a deep sense of powerlessness. But today it is possible to find out through a blood test whether you are highly susceptible to breast and ovarian cancer, and then take action.”

Over testing of by low-risk women

Findings published in December 2016 in the British Medical Journal suggest that tests for the BRCA genes shot up by 64% following Jolie’s article. Researchers analysed data on US health insurance claims from more than 9m women between 18 and 64, and suggested that in just 2 weeks following Jolie’s NYT disclosure, 4,500 additional BRCA tests were carried out, which cost the US healthcare system some US$13.5m. Interestingly, increased testing rates were not accompanied by a corresponding increase in mastectomy rates, which suggests that additional testing did not identify new BRCA mutations. Thus, the Angela Jolie effect might have encouraged over-testing among low-risk women.

Mindful of her influence on women’s decisions, in 2015 Jolie wrote another NYT article in which she attempted to correct her earlier support for radical risk reduction surgery for women carriers of BRCA mutations. She said that because surgery worked for her, it is not necessarily the optimal therapeutic pathway for all women, and stressed that non-surgical treatments could be more appropriate.

Traditional genetic testing for breast cancer risk was slow and expensive

Genetic testing to detect BRCA mutations has been available since 1996, but for many years it was under-used because of its scarcity, high cost, and the length of time it took to produce a result. The rapid development and plummeting costs of genetic testing, and a 2013 US Supreme Court ruling, which invalidated the patents held by Myriad Genetics Inc., which restricted BRCA testing, have resulted in the growth and accessibility of genetic testing.

BRCA testing is not straightforward

There are hundreds of mutations in the BRCA1 and BRCA2 genes that can cause cancer. Several different tests are available, including tests that look for a known mutation in one of the genes (i.e., a mutation that has already been identified in another family member), and tests that check for all possible mutations in both genes. Commercial laboratories usually charge between US$450 and US$5,000 to carry out BRCA testing, depending on whether you are being tested for only a specific area(s) of a gene known to be abnormal or if hundreds of areas are being examined within multiple genes. Tests that use traditional technology take several months to report findings. This means that even if a woman is tested at the time of diagnosis, she might not know the results before she has to decide on treatment.

Importance of regulated testing laboratories

Testing for the BRCA genes usually involves a blood sample taken in a doctor’s clinic and sent to a commercial laboratory. In 1988, the US Congress passed the Clinical Laboratory Improvement Amendments (CLIA) to ensure quality standards, and the accuracy and reliability of results across all testing laboratories. Since then, all legitimate genetic testing in the US is undertaken in CLIA-approved facilities. During testing for BRCA mutations, the genes are separated from the rest of the DNA, and then scanned for abnormalities. Unlike other clinical screening such as HIV tests and colonoscopies, which provide a simple positive or negative result; genetic testing is fraught with uncertainty because it reveals the likelihood of developing cancer rather than a certain fate.

BRCA1 and BRCA2 genetic test results

A positive BRCA test result indicates that you have inherited a known harmful mutation in the BRCA1 or BRCA2 gene. This means that you have an increased risk of developing breast and ovarian cancers, but it does not mean that you will actually develop cancer. Some women who inherit a harmful BRCA mutation will never develop cancer. A positive test result may create anxiety and compel clinicians to perform further tests and women to undergo premature and unnecessary clinical interventions, other women in a similar situation will opt for regular screening.

The potential benefits of a true negative result include a sense of relief regarding your future risk of cancer, learning that your children are not at risk of inheriting the family's cancer susceptibility, and that a range of interventions may not be required. However, a negative result sometimes can be difficult to interpret because its meaning partly depends on your family’s history of cancer, and whether a BRCA mutation has been identified in a blood relative. Further, scientists continue to discover new BRCA1 and BRCA2 mutations, and have not yet identified all potentially harmful ones. Therefore, it is possible that although you have a “negative” test result you might have a harmful BRCA1 or BRCA2 mutation, which has not been identified.

Counselling

Because of these uncertainties and the agonising choices women with suspected breast cancer face, health providers in most developed countries recommend counselling as part of breast cancer treatment pathways. In the video below Dr John Green, a medical oncologist knowledgeable about the influence of inherited BRCA gene mutations on treatment options underlines the importance of expert genetic counselling to help women navigate their therapeutic pathways. Counselling is performed by a health professional experienced in cancer genetics, and usually includes the psychological risks and benefits of genetic tests, a hereditary cancer risk assessment based on a person’s personal and family medical history; a description of the tests, their technical accuracy and appropriateness, medical implications of a positive or a negative test result, the possibility of uncertain or ambiguous test results, cancer risk-reducing treatment options, and the risk of passing on a mutation to children. Because people are more aware of the genetic mutations linked to breast cancer, the demand for genetic testing and counselling have increased, and in some instances it is challenging for genetic counsellors to keep pace with demand.

The context in which genetic tests are carried out

A 2017 study published in the Journal of Clinical Oncology suggests that genetic test results for breast cancer are not being clearly communicated to women, and this could cause them to opt for treatments that are more aggressive than they actually need. To reduce this possibility the Royal Marsden NHS Trust Hospital in London has introduced the Mainstreaming Cancer Genetics programme. Since 2014 the Marsden has employed genetic counseling and used laboratories with enhanced genetic testing capabilities. This reduces processing time and costs, helps to meet the increased demand for rapid, accurate and affordable BRCA testing, and helps women make critical decisions about their treatment options.

“There were two main problems with the traditional system for gene testing. Firstly, gene testing was slow and expensive, and secondly the process for accessing gene testing was slow and complex,” says Nazneen Rahman, Professor and Head of Cancer Genetics at the UK’s Institute for Cancer Research in London. “We used new DNA sequencing technology to make a fast, accurate, affordable cancer gene test, which is now used across the UK. We then simplified test eligibility and brought testing to patients in the cancer clinic, rather than making them have another appointment, often in another hospital,” says Rahman.

The Marsden is now offering tests to three times more patients a year than before the program started. The new pathway is faster, with results arriving within 4 weeks, as opposed to the previous 20-week waiting period. According to Rahman, “Many other centres across the country and internationally are adopting our mainstream gene testing approach. This will help many women with cancer and will prevent cancers in their relatives.”

Takeaways

The history of cancer is punctuated with overzealous interventions, many of which have had to be modified once it has been demonstrated that they could cause more harm than good.

As advanced genetic testing becomes affordable and more accessible it is important that their results are interpreted with the help of genetic counsellors in a broader familial context in order to help women make painfully difficult decisions about their treatment.

Migration to next generation genetic testing technologies has many benefits, but it also introduces challenges, which arise from, the choice of platform and software, and the need for enhanced bio-informatics analysts, which are in scarce supply. An efficient, cost-effective accurate mutation detection strategy and a standardized, systematic approach to the reporting of BRCA test results are central for diagnostic laboratories wishing to provide a service during a time of increasing demand and downward pressure on costs.