In a paper published in the journal Biomolecules, UK and Chinese researchers report their creation of a biomedical compound that has the potential to stop breast cancer metastasis.
The scientists from the Chemistry and Biochemistry Departments at the University of Liverpool and Nanjing Medical School in China have discovered a possible way to block proteins produced by cancer cells that promote metastasis – the chief impediment to successful cancer treatment.
Prof Philip Rudland from the University of Liverpool explained: “As a general rule, cancer that has spread is treated with chemotherapy, but this treatment can rarely be given without severely harming or becoming toxic to the patient. The importance of our work was to identify a specific and important target to attack, without toxic side effects.”
The University’s research team have in the past discovered that specific proteins are involved in the metastatic process; these proteins are different from those involved in the production of the primary tumour. One such example is a protein called ‘S100A4’, and is the protein chosen by the research team to target for the identification of chemical inhibitors of metastasis, using model systems of cells from the highly metastatic and incurable hormone receptor-free breast cancer.
Using these model systems, researchers at the University’s Department of Biochemistry discovered a novel compound that can specifically block the interaction of this metastasis-inducing protein S100A4 with its target inside the cell. Researchers in the Department of Chemistry then synthesised a simpler chemical and connected it to a warhead which stimulates cells’ normal protein-degrading machinery. This compound now works at very low doses to inhibit properties associated with metastasis, an improvement of over 20 000-fold on the original unarmed inhibitor, with virtually no toxic side effects. Moreover, in collaboration with Chinese researchers at Nanjing Medical School, they have shown that this compound inhibits metastasis in similar metastatic tumours in mice, suggesting a potential therapeutic role.
Dr Gemma Nixon, Senior Lecturer in Medicinal Chemistry at the University of Liverpool said: “This is an exciting breakthrough in our research. We now hope to take the next steps, and repeat this study in a large group of animals with similar metastatic cancers so that the efficacy and stability of the compounds can be thoroughly investigated and if necessary improved by further design and syntheses, prior to any clinical trials.”
“Significantly, this particular protein we’re investigating occurs in many different cancers, which could mean this approach may be valid for many other commonly occurring human cancers.”
A new study by researchers in the UK and Israel has investigated how to improve breast cancer genetic tests for Ashkenazi Jewish women. By analysing genetic samples from women from Ashkenazi Jewish backgrounds, they were able to correctly adjust the risk estimates from commercially available genetic screening tests, giving a more accurate result. They detail their technique in the journal Genetics in Medicine.
New forms of genetic tests can tell women their personal risk of developing breast cancer. However, previous research has shown they are not accurate for many Black, Asian or Ashkenazi Jewish women, or women with a mixed ethnic background.
The study focuses on tiny genetic variations called Single Nucleotide Polymorphisms (SNPs) – which, depending on the unique combination of them, can increase or decrease the risk of breast cancer.
This information is used to produce a Polygenic Risk Score (PRS), which can inform women whether they are at low, average, or high risk of developing breast cancer in the next 10 years. PRS are becoming more widely available through commercial companies and research studies on the NHS breast screening programme.
Current PRSs were developed from large-scale genome studies which predominantly collected genetic data from mainstream White European populations. As a result, the accuracy of a PRS for an individual will depend on how closely their genetic material resemble those of the people whose data was used to develop the risk score.
This means that while commercially available PRS can accurately predict breast cancer risk for mainstream White European women, they often exaggerate this risk for Black, Asian or Ashkenazi Jewish women, or women with a mixed ethnic background.
In this new study, researchers compared two available PRS based on two SNPs – SNP142 and the commercial SNP78 – and analysed their accuracy for women of Ashkenazi Jewish ancestry.
The findings showed that these PRS tests inaccurately predicted Ashkenazi Jewish women to be at higher risk of developing breast cancer.
After adjusting the test for Ashkenazi Jewish ancestry, the researchers were able to generate a more accurate prediction of breast cancer risk for these women.
The research team used genetic information from Ashkenazi Jewish women in both Manchester and Israel, with data from the Predicting the Risk of Cancer at Screening (PROCAS) study conducted in Greater Manchester, a Manchester regional genetics database, and the Breast Cancer in Northern Israel (BCINIS) study.
Professor Evans said: “Polygenic Risk Scores (PRS) are a major component of accurate breast cancer risk prediction and have great potential to improve personalised screening methods. However, it is clear from our findings that you cannot simply apply current PRS developed using genetic data from individuals of white European ancestry to those from Ashkenazi Jewish backgrounds.
“A test result which exaggerates a woman’s risk of the disease could lead to undue stress or concern and unnecessary screening and preventative measures that they don’t need. Future PRS for Ashkenazi Jewish women should be based on their genetic data to provide a more accurate risk prediction.
“This study is an important step forward in our continued research into breast cancer genetic testing for people of different ethnic backgrounds to improve equity. More accurate and personalised PRS are required to avoid further increasing health inequalities and so patients can receive high-quality screening, care, and treatments.”
Dense breast tissue, which contains a higher proportion of fibrous tissue than fat, is a risk factor for breast cancer and also makes it more difficult to identify cancer on a mammogram. Many US states have enacted laws that require women with dense breasts to be notified after a mammogram, so that they can choose to undergo supplemental ultrasound screening to improve cancer detection. A recent study published by Wiley online in CANCER, a peer-reviewed journal of the American Cancer Society, evaluated the results of such additional screening to determine its benefits and harms to patients.
Although supplemental ultrasound screening may detect breast cancers missed by mammography, it requires additional imaging and may lead to unnecessary breast biopsies among women who do not have breast cancer. Therefore, it is important to use supplemental ultrasound only in women at high risk of mammography screening failure – in other words, women who develop breast cancer after a mammogram shows no signs of malignancy.
Brian Sprague, PhD, of the University of Vermont Cancer Center, and his colleagues evaluated 38 166 supplemental ultrasounds and 825 360 screening mammograms without supplemental ultrasounds during 2014–2020 at 32 US imaging facilities within three regional registries of the Breast Cancer Surveillance Consortium.
The team found that 95.3% of supplemental ultrasounds were performed in women with dense breasts. In comparison, 41.8% of mammograms without additional screening were performed in women with dense breasts.
Among women with dense breasts, a high risk of interval invasive breast cancer was present in 23.7% of women who underwent ultrasounds, compared with 18.5% of women who had mammograms without additional imaging.
The findings indicate that ultrasound screening was highly targeted to women with dense breasts, but only a modest proportion of these women were at high risk of mammography screening failure. A similar proportion of women who received only mammograms were at high risk of mammography screening failure.
“Among women with dense breasts, there was very little targeting of ultrasound screening to women who were at the highest risk of a mammography screening failure. Rather, women with dense breasts undergoing ultrasound screening had similar risk profiles to women undergoing mammography screening alone,” said Dr Sprague. “In other words, many women at low risk of breast cancer despite having dense breasts underwent ultrasound screening, while many other women at high risk of breast cancer underwent mammography alone with no supplemental screening.”
Clinicians can consider other breast cancer risk factors beyond breast density to identify women who may be appropriate for supplemental ultrasound screening. Publicly available risk calculators from the Breast Cancer Surveillance Consortium are available that also consider age, family history, and other factors (https://www.bcsc-research.org/tools).
Breast cancer cells. Image by National Cancer Institute
In what could be a long-missing piece in the puzzle of breast cancer, researchers have identified the molecular sparkplug that ignites cases of the disease currently unexplained by the classical model of breast-cancer development. The team reported their work inNature.
“We have identified what we believe is the original molecular trigger that initiates a cascade culminating in breast tumour development in a subset of breast cancers that are driven by oestrogen,” said study senior investigator Peter Park, Harvard Medical School professor.
The researchers said as many as one-third of breast cancer cases may arise through the newly identified mechanism.
The study also shows that the sex hormone oestrogen is the culprit behind this molecular dysfunction because it directly alters a cell’s DNA.
Most, though not all, breast cancers are fuelled by hormonal fluctuations. The prevailing view of oestrogen’s role in breast cancer is that it acts as a catalyst for cancer growth because it stimulates the division and proliferation of breast tissue, a process that carries the risk for cancer-causing mutations. The new work, however, shows that oestrogen causes mischief in a far more direct manner.
“Our work demonstrates that oestrogen can directly induce genomic rearrangements that lead to cancer, so its role in breast cancer development is both that of a catalyst and a cause,” said study first author Jake Lee.
While the findings does not have immediate therapy applications, it could lead to tests that can track treatment response and could help doctors detect the return of tumours in patients with a history of certain breast cancers.
Birth of a cancer cell
When DNA breaks in the process of cell division, the breaks usually get swiftly mended by the molecular machinery that guards the integrity of the genome. However, every now and then, the repair of broken DNA gets botched, causing chromosomes to get misplaced or scrambled inside a cell.
Many human cancers arise in this manner during cell division, when chromosomes get rearranged and awaken dormant cancer genes that can trigger tumour growth.
One such chromosomal scramble can occur when a chromosome breaks, and a second copy of the broken chromosome is made before the break gets fixed.
Then, in what ends up being a botched repair attempt, the broken end of one chromosome is fused to the broken end of its sister copy rather than to its original partner. The resulting new structure is a misshapen, malfunctioning chromosome.
During the next cell division, the misshapen chromosome is stretched between the two emerging daughter cells and the chromosome “bridge” breaks, leaving behind shattered fragments that contain cancer genes to multiply and get activated.
It has been known since the 1930s that certain human cancers, including some breast cancers, arise when a cell’s chromosomes get rearranged in this way. Cancer experts can often identify this particular aberration in tumour samples by using genomic sequencing. Yet, a portion of breast cancer cases do not harbour this mutational pattern, raising the question: What is causing these tumours?
These ‘cold’ intrigued study authors Park and Lee, who searched for answers by analysing the genomes of 780 breast cancers obtained from patients diagnosed with the disease. They expected to find the classical chromosomal disarray in most of the tumour samples, but many of the tumour cells bore no trace of this classic molecular pattern.
Instead of the classic misshapen and improperly patched-up single chromosome, they saw that two chromosomes had fused, suspiciously near ‘hot spots’ where cancer genes are located.
Just as in McClintock’s model, these rearranged chromosomes had formed bridges, except in this case, the bridge contained two different chromosomes. This distinctive pattern was present in one-third (244) of the tumours in their analysis.
Lee and Park realised they had stumbled upon a new mechanism by which a ‘disfigured’ chromosome is generated and then fractured to fuel the mysterious breast cancer cases.
A new role for oestrogen in breast cancer?
When the researchers zoomed onto the hot spots of cancer-gene activation, they noticed that these areas were curiously close to oestrogen-binding areas on the DNA.
Oestrogen receptors are known to bind to certain regions of the genome when a cell is stimulated by oestrogen. The researchers found that these oestrogen-binding sites were frequently next to the zones where the early DNA breaks took place.
This offered a strong clue that oestrogen might be somehow involved in the genomic reshuffling that gave rise to cancer-gene activation.
Lee and Park followed up on that clue by exposing breast cancer cells to oestrogen and then used CRISPR gene editing to make cuts to the cells’ DNA.
As the cells mended their broken DNA, they initiated a repair chain that resulted in the same genomic rearrangement Lee and Park had discovered in their genomic analyses.
Oestrogen is already known to fuel breast cancer growth by promoting the proliferation of breast cells. However, the new observations cast this hormone in a different light. They show oestrogen is a more central character in cancer genesis because it directly alters how cells repair their DNA.
The findings suggest that oestrogen-suppressing drugs such as tamoxifen work in a more direct manner than simply reducing breast cell proliferation.
“In light of our results, we propose that these drugs may also prevent oestrogen from initiating cancer-causing genomic rearrangements in the cells, in addition to suppressing mammary cell proliferation,” Lee said.
The study could lead to improved breast cancer testing. For instance, detecting the genomic fingerprint of the chromosome rearrangement could alert oncologists that a patient’s disease is coming back, Lee said.
A similar approach to track disease relapse and treatment response is already widely used in cancers that harbour critical chromosomal translocations, including certain types of leukaemia.
More broadly, the work underscores the value of DNA sequencing and careful data analysis in deepening the biology of cancer development, the researchers said.
“It all started with a single observation. We noticed that the complex pattern of mutations that we see in genome sequencing data cannot be explained by the textbook model,” Park said. “But now that we’ve put the jigsaw puzzle together, the patterns all make sense in light of the new model. This is immensely gratifying.”
In a move bringing it closer in line with other organisations’ breast cancer screening guidelines, The United States Preventative Task Force (USPSTF) has released a draft statement recommending mammography every other year (biennially) from ages 40 to 74.
These recommendations are not applicable to women with a genetic marker or syndrome linked to increased breast cancer risk, a history of high-dose chest radiotherapy at a young age, or previous breast cancer or a high-risk breast lesion on previous biopsies.
According to the USPSTF, “new and more inclusive science about breast cancer in people younger than 50 has enabled us to expand our prior recommendation and encourage all women to get screened in their 40s. We have long known that screening for breast cancer saves lives, and the science now supports all women getting screened, every other year, starting at age 40.”
South African cancer screening guidelines typically closely follow American ones, according to an article by Lipschitz in the South African Journal of Radiology. Many countries had not recommended screening at the ages of 40–50 due to fears of overdiagnosis.
The UPSTF made particular attention the fact that black women are 40% more likely to die of breast cancer than white women, and have a high rate of aggressive cancers at young ages.
The recommendations are not without criticism. Biennial screenings are not seen as worth it by Desountis et al., as it leaving two years between tests leaves too much time for a tumour to grow.
Debra Monticciolo, MD, of Massachusetts General Hospital in Boston, and a member of the Society of Breast Imaging’s board of directors, told MedPage Today that she was “disappointed” with the decision to recommend biennial scans.
“Even if you look at their own data,” Monticciolo said, “annual screening results in more deaths averted, no matter what type of screening program you put in those models.”
Regarding the ongoing debated about continued screening in women ages 75 and older, and supplemental screening for those with dense breasts, the UPSTF found there was not enough evidence for a recommendation.
Triple-negative breast cancer (TNBC) is the most aggressive and deadly form of breast cancer with limited treatment options and a high probability of recurrence. Researchers from the University of Frieburg discovered that coordinated differentiation and changes in the metabolism of breast cancer stem cells make them invisible for the immune system. Counteracting the metabolic change with the drug zolendronate could make immunotherapy using gamma delta T cells more efficient against TNBC. The research team was led by Prof Dr Susana Minguet and published in Cancer Immunology Research.
TNBC cells hide from gamma delta T cells
Gamma delta T cells recognise and kill cells that produce stress-induced molecules and phosphoantigens, a common characteristic of cancer cells. Because gamma delta T cells work differently to other types of T cells, they are being investigated as an alternative to existing immunotherapies. In the current study, the researchers tested the effect of gamma delta T cells on TNBC using isolated cancer cells and a recently developed mouse model that closely replicates the tumour properties found in human patients.
While the gamma delta T cells worked well against isolated breast cancer stem cells from patients, they had a much weaker effect in the mouse model. This was due to adaptations of the cancer cells that let them stay unnoticed by the immune system, the researchers found. These adaptations included the downregulation of the so-called mevalonate pathway: a metabolic pathway that leads to the production of phosphoantigens – one of the classes of molecules that gamma T cells recognise. This escape mechanism likely also happens in patients with TNBC: analysis of public patient databases showed that reduced expression of key molecules of the mevalonate pathway correlate with a worse prognosis.
The immune evasion of TNBC cells is reversible
This newly discovered escape mechanism can be counteracted by the drug zolendronate, which is FDA-approved for the treatment of osteoporosis and bone metastasis. When the researchers treated the escapist cells with zolendronate, the gamma T cells became a lot more efficient in clearing the cancer. “Our findings explain why current clinical trials using gamma delta T cells are not resulting in the expected success,” Minguet summarises. “We found a possible pharmacological-based approach to revert immune escape, which paves the way for novel combinatorial immunotherapies for triple negative breast cancer.”
Breast cancer cells. Image by National Cancer Institute
A new international study has for the first time, identified that beta-blockers could significantly enhance the therapeutic effect of anthracycline chemotherapy in triple negative breast cancer (TNBC) by reducing metastasis. The results are published in Science Translational Medicine.
Anthracyclines are a class of drugs used in chemotherapy to treat many cancers, including TNBC.
Monash University researchers have previously shown in a clinical trial that beta blockers are linked with reduced metastasis. However, until now, it was unclear how beta-blockers would interact with common cancer treatments.
In this new study, the team used mouse models of cancer and analysed large-scale patient clinical data, in collaboration with the Cancer Registry of Norway, to discover that anthracycline chemotherapy on its own, in the absence of a beta-blocker, induces nerve growth in tumours.
However, adding a beta blocker to chemotherapy inhibited nerve fibre activity in tumours and stopped the cancer from coming back after treatment.
Lead author Dr Aeson Chang said the findings reveal an unanticipated insight into why chemotherapy treatment does not always work as it should.
“We set out to build on previous studies that have shown beta-blockers can halt the stress response experienced by cancer patients at the time of diagnosis and stop the cancer from spreading.
In this new study, not only did we discover the biological effect of beta-blockers when used alongside anthracycline chemotherapy, we also discovered why they are effective,” said Dr Chang.
“In mouse models of TNBC, we found that anthracycline chemotherapy was able to increase sympathetic nerve fibre activity in tumours. Activation of these stress neurons can help tumour cells spread and, fortunately, we found that beta blockers could stop this effect. Our hope is that this exciting discovery will pave the way for further research and, ultimately, lead to improved outcomes for patients.”
Senior author, Professor Erica Sloan, who has been exploring the use of beta-blockers as a novel strategy to slow cancer progression for a number of years, said the study provides important clues about why beta-blockers may help improve the clinical management of TNBC.
“While many patients will be cured by treatment, unfortunately, in some patients the cancer may return – this study has helped us understand why. Our findings show that anthracycline chemotherapy supports the growth of nerves, which can support cancer relapse. This is important, as it tells us that targeting nerves using a beta blocker can improve response to treatment,” said Professor Sloan.
“Beta blocker use has been consistently linked to reduced metastatic relapse and cancer-specific survival in TNBC patients. However, the lack of understanding of how beta blockers improve chemotherapy – which is a core component of the standard treatment for TNBC – has limited the translation of these findings into the cancer clinic,” said Professor Sloan.
“We believe this study presents an exciting opportunity to further explore the use of beta-blockers as a novel strategy in the treatment of TNBC.”
New research indicates that for patients with breast cancer, the cancer’s stage and receptor status can help clinicians predict whether and when cancer might recur after initial treatment. The findings are published in the journal cancer CANCER.
For the study, Heather Neuman, MD, MS, of the University of Wisconsin, and her colleagues analysed data on 8007 patients with stage I–III breast cancer who participated in nine clinical trials from 1997–2013 and received standard of care therapy.
Time to first cancer recurrence varied significantly between cancers with different receptors – including oestrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). Within each receptor type, cancer stage influenced time to recurrence.
Risk of recurrence was highest and occurred earliest for ER−/PR−/HER2− (triple negative) tumours. Patients with these tumours diagnosed at stage III had a 5-year probability of recurrence of 45.5%. Risk of recurrence was lowest for ER+/PR+/HER2+ (triple positive) tumours. Patients with these tumours diagnosed at stage III had a 5-year probability of recurrence of 15.3%.
Based on their findings, the investigators developed follow-up recommendations by cancer stage and receptor type. For example, patients with the lowest risk should be seen by their oncology team once annually over five years, whereas those with the highest risk should be seen once every three months over five years.
“Our developed follow-up guidelines present an opportunity to personalize how we deliver breast cancer follow-up care,” said Dr Neuman. “By tailoring follow-up based on risk, we have the potential to have a strong, positive impact on both survivors and their oncology providers by improving the quality and efficiency of care.”
Radiotherapy is an important part of breast cancer treatment but can lead to cancer-related fatigue and negatively impact patients’ health-related quality of life. Fortunately, latest research by has revealed exercise may make radiotherapy more tolerable for patients, offering benefits for their emotional, physical and social wellbeing.
Researchers at Edith Cowan University (ECU) included 89 women in the study, with 43 completing a home-based 12-week program, consisting of a weekly exercise regime of one to two resistance training sessions and an accumulated 30–40 minutes of aerobic exercise. The 46 controls did not participate in the exercise regime.
The results, published in Breast Cancer, showed that patients who exercised recovered from cancer-related fatigue quicker during and after radiotherapy compared to the control group and saw a significant increase in health-related quality of life post radiotherapy with no reported adverse effects.
Study supervisor Professor Rob Newton said this showed home-based resistance and aerobic exercise during radiotherapy is safe, feasible and effective in accelerating recovery from cancer-related fatigue and improving health-related quality of life.
“A home-based protocol might be preferable for patients, as it is low-cost, does not require travel or in-person supervision and can be performed at a time and location of the patient’s choosing,” he said.
“These benefits may provide substantial comfort to patients.”
Important changes observed
Australia’s current national guidelines for cancer patients recommend moderately intense aerobic exercise for 30 minutes per day, five days a week, or vigorously intense aerobic exercise for 20 minutes a day for three days a week.
They also call for 8–10 strength-training exercises with 8–12 repetitions per exercise, for two-to-three days per week.
However, study lead Dr Georgios Mavropalias said benefits were still observed with less exercise.
“The amount of exercise was aimed to increase progressively, with the ultimate target of participants meeting the national guideline for recommended exercise levels,” he said.
“However, the exercise programmes were relative to the participants’ fitness capacity, and we found even much smaller dosages of exercise than those recommended in the national guidelines can have significant effects on cancer-related fatigue and health-related quality of living during and after radiotherapy.”
The study also found participants good adherence to exercise programmes once they started. The exercise group reported significant improvements in mild, moderate and vigorous physical activity up to 12 months after the supervised exercise programme finished.
“The exercise programme in this study seems to have induced changes in the participants’ behaviour around physical activity,” Dr Mavropalias said.
“Thus, apart from the direct beneficial effects on reduction in cancer-related fatigue and improving health-related quality of life during radiotherapy, home-based exercise protocols might result in changes in the physical activity of participants that persist well after the end of the program.”
A new study reported in the journal Cancer reconsiders guidelines for when to start screening with mammograms if a woman has a first degree relative who was diagnosed with breast cancer.
Women with a first-degree family relative diagnosed with breast cancer, who are otherwise at average risk, are often advised to get screened 10 years earlier than the relative’s diagnosis age. However, there is little evidence to support the long-standing recommendation.
UC Davis Comprehensive Cancer Center researcher Diana Miglioretti joined Danielle Durham, with the Department of Radiology at University of North Carolina at Chapel Hill, and five other researchers on the study. They analysed data from the Breast Cancer Surveillance Consortium on screening mammograms conducted from 1996–2016 to evaluate when screenings should begin for women with a family history of breast cancer.
More than 300 000 women were included in the national study. Researchers compared cumulative 5-year breast cancer incidence among women with and without a first-degree family history of breast cancer by relative’s age at diagnosis and screening age.
“The study concluded that a woman with a relative diagnosed at or before age 45 may wish to consider, in consultation with her doctor, initiating screening 5–8 years earlier than their relative’s diagnosis age, rather than a decade earlier. That puts them at a risk that is equal to that of an average-risk woman who is age 50, which is the most recommended age for starting mammograms,” said Durham.
BRCA gene mutation carriers may benefit from starting screenings earlier. Women ages 30–39 with more than one first-degree relative diagnosed with breast cancer may wish to consider genetic counselling.
Increasing the age for initiating screening could reduce the potential harms of starting breast cancer screenings too early. These include increased radiation exposure and false positive results that require women to return to the clinic for diagnostic imaging and possibly invasive procedures, but do not result in a breast cancer diagnosis. The earlier a woman starts receiving mammograms, the more screenings they will undergo over their lifetime – and that increases the chances of experiencing these harms.
“Mammography also may not perform as well in younger women because they are more likely to have dense breasts which increase the difficulty of finding cancer on the images and results in more false-positives,” Miglioretti said.
