Tag: breast cancer

Categories : CancerTags :

Oestrogen May Trigger Breast Cancer, Not Just Fuel it

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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 in Nature.

“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.”

Source: Harvard Medical School

Categories : Cancer Lab Tests and ImagingTags :

US Task Force to Recommend Earlier Start to Breast Cancer Screening

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Photo by National Cancer Institute on Unsplash

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.”

The UPSTF has posted the new recommendations on its website for comment.

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.

Categories : CancerTags :

Osteoporosis Drug Zolendronate Could also Help Fight Breast Cancer

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Killer T cells about to destroy a cancer cell.

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.”

Source: University of Freiburg

Categories : CancerTags :

Beta Blockers Plus Chemotherapy Cut Metastasis in Triple Negative Breast Cancer

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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.”

Source: Monash University

Categories : CancerTags :

Breast Cancer Stage and Receptor Type Predict Recurrence

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Photo by National Cancer Institute on Unsplash

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.”

Source: Wiley

Categories : Cancer ExerciseTags :

Exercise Improves Quality of Life in Breast Cancer Radiotherapy

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Tired woman after exercise
Photo by Ketut Subiyanto on Pexels

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.”

Source: Edith Cowan University

Categories : CancerTags :

Earlier Mammograms for Family History of Breast Cancer may be Unnecessary

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Woman receiving mammogram
Source: National Cancer Institute

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.

Source: University of California – Davis Health

Categories : Cancer ExerciseTags :

Trial to Investigate Exercise with Neodjuvant Chemotherapy for Breast Cancer

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Woman receiving mammogram
Source: National Cancer Institute

The prognosis for breast cancer has improved, allowing more and more women to be cured with a combination of surgery, radiotherapy and medical treatment. A new trial led by Karolinska Institutet will investigate whether combining neoadjuvant chemotherapy with exercise will improve the outcomes of breast cancer patients.

Neoadjuvant chemotherapy (NACT) is increasingly used in breast cancer. The main benefit of NACT is its ability to downstage large tumours with a view to treatment by breast-conserving surgery, although there is a non-significant increase in the local recurrence rate. The best proof of NACT efficacy is pathological complete response (pCR), ie the absence of invasive tumour on post-NACT on surgical histopathology.

“While it is known that physical exercise can help patients to better tolerate often harsh cancer treatments, it is an emerging area of research to understand if and how exercise exerts anti-tumour effects and improves oncological outcomes”, explained Jana de Boniface, principal investigator of the trial and associate professor in the Breast Surgery Group, Department of Molecular Medicine and Surgery.

The Neo-ACT trial opened for recruitment in September 2022, and it is estimated that inclusion may be completed in December 2025.

Source: Karolinska Institutet

Categories : CancerTags :

Inflammatory Breast Cancer More Likely to Metastasise to the Brain

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Source: National Cancer Institute

Higher rates of brain metastases in patients with inflammatory breast cancer, a rare subtype of breast cancer, have been observed in studies, but detailed information is lacking. Now, a new study published in CANCER indicates that patients inflammatory breast cancer face a higher risk that their cancer will metastasise to the brain.

To provide insights into the incidence and risk factors for brain metastases in this patient population, Laura E.G. Warren, MD, and colleagues analysed data on 372 patients with stage III inflammatory breast cancer and 159 with stage IV inflammatory breast cancer. 

Over a median follow-up of five years, the incidence of brain metastases at one, two, and five years was 5%, 9%, and 18% among patients who presented with stage III disease, and 17%, 30%, and 42% among those with stage IV disease. Patients with triple-negative breast cancer faced a particularly high risk, and when they did experience brain metastases, their survival time was shorter than those with hormone receptor–positive or HER2-positive breast cancer who experienced brain metastases. Higher risks of brain metastases were also seen in patients whose cancer had metastasised to other parts of the body besides the brain, especially when this occurred at a young age. 

“The relatively high incidence of brain metastases seen in the study population highlights the need for future research on the potential role for surveillance brain imaging for high-risk patients. There is an open, phase II, single arm study at Dana-Farber Cancer Institute examining this question,” said Dr. Warren. “It also emphasises the need to obtain brain imaging in patients with inflammatory breast cancer presenting with neurologic symptoms given the high incidence of brain metastases in this population.” Most patients in this study who were diagnosed with brain metastases had neurologic symptoms, but because some patients may have undetected, asymptomatic brain metastases, the true incidence in patients with inflammatory breast cancer is likely even higher than what Dr Warren and her colleagues observed. 

An accompanying editorial notes that when considering whether to implement routine brain imaging tests in patients with inflammatory breast cancer, it will be important to determine whether earlier detection of brain metastases leads to improvements in both survival and quality of life.

Source: Wiley

Categories : CancerTags :

A Clue to Breast Cancer Survivors’ Cognitive Problems

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Woman receiving mammogram
Source: National Cancer Institute

Why breast cancer survivors experience troubling cognitive problems is a long-standing mystery, and for which inflammation is one possible culprit. A new long-term study of older breast cancer survivors published in the Journal of Clinical Oncology adds evidence to this link.

Higher levels of the inflammatory marker C-reactive protein (CRP) were related to older breast cancer survivors reporting cognitive problems in the new study.

“Blood tests for CRP are used routinely in the clinic to determine risk of heart disease. Our study suggests this common test for inflammation might also be an indicator of risk for cognitive problems reported by breast cancer survivors,” said study lead author Judith Carroll, an associate professor at UCLA. 

The Thinking and Living with Cancer (TLC) Study is one of the first long-term efforts to examine the potential link between chronic inflammation and cognition in breast cancer survivors 60 and older, who make up a majority of the nearly 4 million breast cancer survivors in the United States. Previous research has focused largely on younger women and women immediately after therapy, making it difficult to draw conclusions about CRP’s role in long-term cognitive problems among older breast cancer survivors.   

In TLC, teams of researchers from around the country talked to, and obtained blood samples from, hundreds of breast cancer survivors and women without cancer up to six times over the course of five years. The study was motivated by hearing from survivors and advocates that cognitive problems are one of their major worries. 

“Cognitive issues affect women’s daily lives years after completing treatment, and their reports of their own ability to complete tasks and remember things was the strongest indicator of problems in this study,” said co-senior study author Dr Jeanne Mandelblatt, a professor of oncology at Georgetown University who is the lead of the TLC study.   

“Being able to test for levels of inflammation at the same time that cognition was being rigorously evaluated gave the TLC team a potential window into the biology underlying cognitive concerns,” said Elizabeth C. Breen, a professor emerita of psychiatry and biobehavioral sciences at the Cousins Center for Psychoneuroimmunology at UCLA, who also served as co-senior study author. 

The women’s cognition was evaluated through a commonly used questionnaire. The study found higher CRP levels among survivors were predictive of lower reported cognitive function among breast cancer survivors. There was no similar relationship between CRP levels and reported cognition in the women without cancer. 

Cognitive performance, as measured by standardised neuropsychological tests, failed to show a link between CRP and cognition. The authors say this may indicate women are more sensitive to differences in their everyday cognitive function, self-reporting changes that other tests miss.

The authors said their study supports the need for research on whether interventions that can lower inflammation – including increased physical activity, better sleep, and anti-inflammatory medications – may prevent or reduce cognitive concerns in older breast cancer survivors. 

Source: EurekAlert!