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UK scientists have discovered three new genetic changes that increase the risk of breast cancer in men, in the world’s largest genetic study of the causes of male breast cancer to date.

Researchers, largely funded by Breast Cancer Now, identified three common variations in DNA that predispose men to developing breast cancer, bringing the total known number to five.

All three genetic variants are known to be linked to female breast cancer but scientists at The Institute of Cancer Research, London, and Queen’s University Belfast found the changes to have a greater effect on breast cancer risk in men than in women.

The study involved 1,380 men with breast cancer, primarily from the Breast Cancer Now Male Breast Cancer Study based at The Institute of Cancer Research (ICR). The team found that three genetic changes, called rs9371545, rs554219 and rs78540526, increased the risk of developing breast cancer in men by approximately 47, 45 and 61 per cent respectively.

The researchers then analysed over 170 SNPs known to affect risk in women, finding significant overlap in the genetic risk factors for the disease in men. The results suggest male and female breast cancer may have a very similar genetic basis ? a discovery which could in future lead to new preventive treatments for men and women.

The study also found that men at the highest genetic risk were almost four times more likely to develop breast cancer than those at lowest risk.

‘Major step forward’

Breast Cancer Now described the discovery as a “major step forward in our understanding of male breast cancer”, calling for greater awareness of the disease in men and for research into the shared genetic causes of male breast cancer and the most common form in women (ER+), to develop risk-reducing drugs and other interventions to prevent more cases among those at increased risk.

The study was funded by Breast Cancer Now and Queen’s University Belfast, and is published in the Journal of the National Cancer Institute.

While breast cancer in men is very rare, around 370 men are diagnosed with the disease every year in the UK, and around 80 men lose their lives each year.

There are a number of different treatments for breast cancer in men depending on the features of the tumour, including surgery, hormone therapy, radiotherapy, chemotherapy and targeted drugs – all of which were first developed to treat the disease in women.

More than 95 per cent of all breast cancers in men are oestrogen receptor (ER) positive ? compared to up to 80 per cent of cases in women ? meaning that they contain proteins called oestrogen receptors and can be stimulated to grow by the hormone.

Shared genetic causes in men and women

Men with a strong family history of breast cancer among female relatives are known to be at greater risk, and around 10 per cent of male cases are caused by mutations in the BRCA2 gene. But the exact causes of the disease in men are not yet understood, and, for year

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We provided the first conclusive evidence that the basic cause of cancer is damage to DNA. The discovery changed scientific opinion dramatically and marked a turning point for cancer research.

Until that point, scientists had assumed carcinogens caused cancer by acting on proteins, rather than genes.

Nuclei of tumour cells stained with a blue dye and two markers of DNA damage resulting from irradiation
Nuclei of tumour cells stained with a blue dye and two markers of DNA damage resulting from irradiation. Credit: Dr Susanne Gatz from the ICR's Sarcoma Molecular Pathology Team.

Research conducted here at The Institute of Cancer Research in the 1950 and 60s provided the first conclusive evidence indicating that damage to DNA is the root cause of cancer.

Cancer cells replicate at an accelerated rate, often ignoring the normal controls on cell division and growth. Proteins within cells regulate growth and division, and were widely assumed to be the targets for cancer-causing chemicals. However, research conducted at the ICR by Professor Philip Lawley and Professor Peter Brookes showed that cancer is caused by damage not to proteins but to DNA.

Mustard gas
Their discovery was made through working on mustard gas – which was known to cause cancer. In 1960, Professors Lawley and Brookes published a paper which showed that mustard gas reacted with both pure DNA and with the DNA of mice when injected into tumours.

In 1964, Professors Lawley and Brookes published their second classic paper. This used radiolabelled poly-aromatic hydrocarbons (PAHs), which are among the chemicals that give cigarettes their cancer-causing properties. They found a direct correlation between a PAH’s ability to induce tumours when applied to mouse skin, and the degree to which it bound to DNA. There was no correlation with the degree to which the PAH bound to proteins. It was this finding that showed that cancer was caused by chemicals damaging DNA rather than proteins.

'A turning point'
This discovery marked a turning point for cancer research, and is the basis of all modern cancer research and treatment. It explains why some cancers can be inherited, enabling people with a particularly high risk of developing certain cancers to be identified. It has also changed the way that scientists search for new cancer drugs, allowing personalised treatments to be developed that target the specific genetic defects in an individual’s cancer.

Quantitative Systems Pharmacology (QSP) is an exciting discipline within pharmaceutical development that is showing significant interest from our pharmaceutical clients seeking to gain valuable insights to improve their R&D efficiency and productivity.

QSP involves combining mechanistic models with the PK/PD of a therapeutic agent and the large volumes of readily available, quantitative experimental drug data.

Why QSP?

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QSP is increasingly used in drug development to guide research and to aid with critical decision-making.

Optimal use of integrated QSP models can:

Assist with target feasibility and selection
Provide insights into Mechanisms of Action (MOA)
Enable scenario analysis and testing of different drug profiles
Help accelerate drug development and the discovery of new drugs
Areas of Focus
At Physiomics, our core capabilities include creating integrated QSP models. We have worked with clients to develop QSP models using generic literature and to create hybrid models by integrating them with our proprietary Virtual TumourTM technology.

Recent examples of our QSP work:
1. Scenario Testing

We identified a published model of interest to our client and coded it up to perform further analysis, such as:

For which parameters is calibration data realistically available
What is the sensitivity of the model to key parameters
How do key output parameters behave over time as other parameters are perturbed.

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Example of parameter sensitivity analysis. Optimal level of inhibitions for two targets (x and y axis) for maximum synergy (z axis).
2. Combining Virtual TumourTM with Mechanistic Model

Having identified a relevant literature model for our client, we were able to code it up and hybridize with Virtual TumourTM to assess the following:

How does a complex literature model compare with in-house models or hybrids in predicting TGI
Which model is most biologically plausible given the predicted behaviour of their parameters

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Combining Virtual Tumour with a MAPK/ERK pathway model (Kirouac et al 2017).
Why Partner With Us?
At Physiomics, our team of scientific consultants create integrated QSP models and rigorously test them to provide valuable insights for our clients.

Our clients range from global pharmaceuticals to biotech companies and smaller commercial and not-for profit clients.

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A vaccine for HER2-positive breast cancers that is being tested in a clinical trial at Duke Cancer Institute is part of an effective, two-drug strategy for enlisting the immune system to fight tumors, according to a Duke-led study in Clinical Cancer Research, a journal of the American Association for Cancer Research.

The vaccine was developed at Duke and targets the HER2 protein, which is the driver of HER2-positive breast cancer and the cause of about 20 percent of all breast cancer cases.

While the vaccine works to a degree on its own, the tumor can still activate backup strategies for survival. But when combined with existing immune checkpoint inhibitors, the one-two punch proves highly effective, the researchers found.

"This study supports the development of vaccines targeting tumor driver and resistance genes, which we think is critical in establishing effective anti-tumor immune responses," said study leader Zachary Hartman, Ph.D., an assistant professor in the departments of Surgery and Pathology at Duke University School of Medicine.

Hartman and colleagues found that vaccine-induced HER2-specific T-cells were essential for immune responses. Additionally, it was more effective to elicit the T-cells early in tumor development—a finding that has implications for clinical trial designs that typically enroll patients after standard therapies have failed.

Treatment with the investigational vaccine was significantly enhanced when combined with the checkpoint inhibitor drug pembrolizumab. When used alone, pembrolizumab has shown limited benefit for HER2-positive breast cancers.

By working in tandem, the vaccine primes the immune system and the checkpoint inhibitor then rallies the T-cells to action, resulting in pronounced tumor reduction and long-term tumor-free survival.

"The basic premise is that the immune checkpoint inhibitors work fantastic if the body has already triggered an immune response, but they don't work well in the absence of that," said H. Kim Lyerly, M.D., a professor in the departments of Surgery, Immunology and Pathology at Duke University School of Medicine and an author of this study.

"Our vaccine initiates the anti-tumor response, and in combination with the checkpoint inhibitors, works beautifully," Lyerly said.

An investigational #vaccine to treat HER2-positive #breastcancer has been shown to be highly effective when combined with existing immune checkpoint inhibitors. The two-drug strategy results in pronounced tumour reduction & long-term tumour-free survival

AI capable of detecting prostate cancer with ‘near perfect’ accuracy

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Near 4 years early detection to cancer before patient shows signs

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A computer algorithm which helps radiographers interpret ultrasound images could improve radiotherapy treatment for patients with prostate cancer, a new study suggests.

The new algorithm helps radiographers – who are experts in interpreting scans – to quickly locate the prostate in ultrasound scans, which can be time consuming to interpret on their own.

Importantly the algorithm, described in a new study led by scientists at The Institute of Cancer Research and our partner hospital The Royal Marsden and published in the journal Radiotherapy and Oncology, could help radiographers less familiar with ultrasound use the technology to deliver more accurate radiotherapy for prostate cancer.

A safe, effective way to improve radiotherapy

New radiotherapy techniques aim to deliver large doses of radiation in fewer sessions overall, which can be more effective and convenient for patients than smaller doses delivered more often.

Larger radiation doses kill more cancer cells and mean patients need fewer visits to hospital, but treatment also needs to be as accurate as possible to limit damage to healthy tissue.

Radiotherapy is usually guided by X-ray images taken during a CT scan or CAT scan, which are used to build 3D images of metallic markers that are implanted into the prostate.

Ultrasound, which does not require markers, could be as effective, and because ultrasound is safer than X-rays, it has the advantage that it can be used throughout treatment, ensuring the prostate stays in the correct position throughout treatment.

The algorithm helps computer software to compare and match ultrasound scans taken at the planning stage and during treatment, so radiographers could reposition the patient to account for the movement of the prostate inside the body.

In the study, which was funded by Cancer Research UK, the algorithm was used retrospectively on ultrasound scans for 32 patients with prostate cancer treated at The Royal Marsden.

Three technicians then used the scans to select the regions around the prostate to target with radiotherapy.

The algorithm reduced differences in the regions selected by the different technicians and increased the accuracy of radiotherapy targeting, and reduced the time required.

We've lost many vital research hours to the coronavirus crisis but the need for our work continues to grow. Please help us kick-start our research to make up for lost time in discovering smarter, kinder and more effective cancer treatments, and to ensure cancer patients don't get left behind.

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Paving the way for more widespread ultrasound use to guide radiotherapy

In the future, the team hopes to develop machine learning techniques to help radiographers who are unfamiliar with ultrasound, enabling them to more easily acquire high quality images and interpret them in real-time. This could make ultrasound a safe, easy and reliable way to guide radiotherapy treatment for the prostate cancer.

Stu

Some of the most promising advances in cancer treatment have centered on immunotherapies that rev up a patient's immune system to attack cancer. But immunotherapies don't work in all patients, and researchers have been searching for ways to increase their effectiveness.

Now, researchers at Washington University School of Medicine in St. Louis have combined two immunotherapy strategies into a single therapy and found, in studies in human cells and in mice, that the two together are more effective than either alone in treating certain blood cancers, such as leukemia.

Evidence also suggests that the new approach could be safer than one of the most recent cellular immunotherapies to be approved by the FDA, called CAR-T cell therapy, in which the immune system's T cells are engineered to target tumor cells. Cell-based immunotherapies are most commonly used against blood cancers but can be harnessed against some solid tumors as well, such as prostate and lung tumors and melanoma.

The study appears online in the journal Blood.

In the new research, the scientists have harnessed the technology used to engineer CAR-T cells and, instead of modifying specialized immune cells called T cells, they have used similar technology to alter different immune cells called natural killer (NK) cells. The resulting immunotherapy combines the benefits of both strategies and may reduce the side effects that are sometimes seen in CAR-T cell therapy. In some patients, for example, CAR-T cell therapy causes a cytokine storm, a life-threatening overreaction of the immune system.

Immunotherapies show great promise for cancer therapy, but we need to make them more effective and more safe for more patients. This combined approach builds on the treatment strategy that we developed for leukemia patients using natural killer cells. We can supercharge natural killer cells to enhance their ability to attack cancer cells. And at the same time, we can use the genetic engineering approaches of CAR cell therapy to direct the natural killer cells to a tumor target that would normally be overlooked by NK cells. It fundamentally changes the types of cancer that NK cells could be used to treat, both additional blood cancers and potentially solid tumors as well."

Todd A. Fehniger, MD, PhD, professor of medicine and co-senior author

In past work, Fehniger and his colleagues showed that they could collect a patient's own NK cells, expose the cells to a specific recipe of chemical signals that prime the cells to attack tumors, and then return the primed cells to patients for therapy. This chemical exposure is a sort of basic training for the cells, according to the investigators, preparing the NK cells to fight the cancer. When the cells are then returned to the body, they remember their training, so to speak, and are more effective at targeting the tumor cells. Because their training has given the NK cells a memory of what to do when they encounter tumor cells, the researche

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