Tag: breast cancer

Categories : CancerTags :

Researchers Halt Aspirin Trial to Prevent Breast Cancer Recurrence

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Source: National Cancer Institute

A large randomised trial was halted after preliminary analysis found that taking aspirin after treatment for breast cancer did not reduce the risk of disease recurrence.

Laboratory studies had previously shown that aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs) reduced breast cancer growth and invasion. Non-steroidal anti-inflammatory drugs (NSAIDs) display anticancer activity through the inhibition of the COX-2 enzyme, triggering processes such as apoptosis, a reduction in proliferation and inhibition of carcinogenesis.  Several observational studies have shown a reduced risk of breast cancer mortality among regular aspirin users. 

There was a 25% higher risk of invasive recurrence in patients who took aspirin for a median of 18 months, but not statistically different from placebo (P = 0.1258). The aspirin group had an excess of all disease-related events, including death, local and distant recurrence/progression, and new primary tumours.

The results are in line with similar trials that ended while the Aspirin after Breast Cancer (ABC) trial was ongoing, Wendy Y. Chen, MD, of Dana-Farber Cancer Institute in Boston, said during a presentation at the American Society of Clinical Oncology (ASCO) Plenary Series.

“In this double-blind, placebo-controlled randomised trial, there was no benefit of aspirin 300 milligrams daily in terms of breast cancer invasive disease-free survival,” reported Dr Chen. “Although follow-up was short, the futility bound was clearly crossed. We had reached 50% of the events, and there was a numerically higher number of events in the aspirin arm. Therefore, it was unlikely that even with further follow-up there wouldn’t be any benefit associated with aspirin.”

“Although inflammation may still play a key role in cancer, it’s important to remember that aspirin may have different effects in other cancers, such as colon, or in different settings, such as primary versus secondary prevention,” she added.

Though the trial was well designed, enrolled the right population and with adequate dosing. the trial was stopped early for futility, commented Angela DeMichele, MD, of the Abramson Cancer Center at the University of Pennsylvania.

“The direction and magnitude [of the difference in events] highly preclude the possibility that there would have been a benefit with more follow-up,” said Dr DeMichele. “Although it was not statistically significant, we cannot rule out the possibility of a potential increase in breast cancer recurrence from the use of aspirin.”

“For patients and providers at this time, aspirin should not be used simply to prevent breast cancer recurrence,” she continued. “For those situations in which there are other options, decisions about aspirin use for other indications should definitely include an individualised risk/benefit discussion between physician and patient.”

The results underscore the need for prospective, randomised clinical trials to validate the effects of interventions from observational studies, she concluded.

The ABC trial involved patients under 70 with HER2-negative, high-risk breast cancer. The study randomised 3021 participants to 300 mg of aspirin daily or matching placebo for 5 years, with the primary endpoint being invasive disease-free survival. 

Dr Chen further noted that three clinical trials of aspirin or NSAID treatment ended while the ABC trial was ongoing. The Canadian-led MA.27 trial of an aromatase inhibitor plus celecoxib ended due to toxicity in the celecoxib arm. The randomised REACT trial of celecoxib in HER2-negative breast cancer showed no difference in disease-free survival after more than 6 years of follow-up.

The ASPREE trial tested low-dose aspirin on all-cause mortality in healthy older patients, and results showed a trend to increased all-cause mortality and significantly higher cancer mortality in the aspirin arm. 
During the post-presentation discussion, an audience member asked whether the results definitively ruled out a late benefit of aspirin, given that most patients had HR-positive disease wherein late relapse is not uncommon.

“It’s always frustrating when a study is closed early, and it was done in this case after we had reached 50% of the expected benefits,” said Chen. “There was an increase [in clinical events]. Not a statistically significant increase, but it was bordering on statistical significance. In order for aspirin to have a benefit, it would mean that in the second half, there would need to be a significantly decreased risk. It would basically need to flip and that would be biologically difficult to imagine.”

“I think it’s fair to say that this study doesn’t say definitively that there’s harm, but as for the likelihood of a benefit of aspirin, that would be extremely unlikely,” she said.

Source: MedPage Today

Categories : CancerTags :

Metformin Ineffective in Most Breast Cancers

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Breast cancer cells. Image source: National Cancer Institute on Unsplash

Researchers have found that the diabetes drug metformin, once hoped to hold enormous promise in treating breast cancer, does not prevent or stop the spread of the most common forms of the disease but may still have potential in HER2-positive breast cancer.

The randomised, double-blind trial enrolled 3600 patients who received two pills a day of either placebo or metformin. Overall, researchers found the addition of metformin to standard breast cancer treatments did not improve outcomes in the two most common types of breast cancer, hormone receptor-positive or negative.

“The results tell us that metformin is not effective against the most common types of breast cancer and any off-label use of this drug for the treatment of these common types of breast cancer should be stopped,” said Pamela Goodwin, a professor in the department of medicine at the University of Toronto’s Temerty Faculty of Medicine.

Prof Goodwin presented the findings at the 2021 San Antonio Breast Cancer Symposium.

While metformin was found not to be effective in treating the most common forms of breast cancer, there was evidence that use of metformin for five years might lead to a reduction in deaths from HER2-positive breast cancer, a less aggressive subtype which makes up about 20% of all breast cancers.

“Metformin is not beneficial for use in most common breast cancers, but in the cases of HER2 positive breast cancer, our findings suggest it may be beneficial,” said Prof Goodwin. “These results need to be replicated in future research before metformin is used as a breast cancer treatment, however, it could provide an additional treatment option for HER2-positive breast cancer,” she added

Previous studies suggested metformin may also reduce the risk of development and increase survival of some cancers, including breast cancer.

Metformin was theorised to slow breast cancer growth by improving patient metabolism, notably insulin levels, leading to reduced cancer cell growth, or that it might impact cancer cells directly.

Next steps would be to prospectively test the impact of metformin in patients with HER2-positive breast cancer in a randomised clinical trial. 

Source: University of Toronto

Categories : CancerTags :

Anti-diabetes Drug under Development May Also Treat Breast Cancer

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Source: NCI

A new study has shown that a small molecule inhibitor drug, with the unwieldy designation of PF05175157, originally developed to treat diabetes by Pfizer, may help in the treatment of breast cancer by blocking a key enzyme. 

The findings from the Yale Cancer Center-led study were reported at the 2021 San Antonio Breast Cancer Symposium in San Antonio, Texas.

“Our research shows the preclinical, anti-cancer activity using PF05175157 may lead us to bring this drug back into the clinic to help treat patients with breast cancer,” said lead study author Julia Foldi, MD, PhD, a clinical fellow at Yale Cancer Center and Smilow Cancer Hospital. “More studies are needed, but our initial data looks very promising.”

Cancer cells are characterised by altered metabolism. In this study, the Yale team identified new metabolic vulnerabilities in cancer cells that are based on a loss of enzyme diversity. They found that an enzyme called acetyl-CoA-carboxylase-1 (ACC1), is critical for the survival of breast cancer cells. The ACC1 enzyme is the key initial step in fatty acid synthesis. Fatty acids are building blocks of the various types of lipids and fat that are the critical ingredients of cell membranes and play an important role in energy generation in cells. The team’s analysis demonstrated that blocking ACC1 using PF05175157 can inhibit the growth of breast cancer cells grown in mice and also in patient-derived cancer models.

“We are currently testing this drug in combination with other approved breast cancer drugs to see if it could improve their activity, with the hope to bring the most promising combinations to the clinic to help patients with breast cancer,” added Lajos Pusztai, MD, DPhil, Professor of Medicine (Medical Oncology), Director of Breast Cancer Translational Research at Yale Cancer Center, and senior author of the study.

Source: Yale Cancer Center

Categories : Cancer Obstetrics & GynaecologyTags :

After a Pregnancy, Natural Killer Cells Suppress Tumours

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Source: Anna Hecker on Unsplash

After a pregnancy, breast cells call in Natural Killer T (NKT) cells as reinforcements to prevent tumours from arising, according to a study published in Cell Reports. This finding from the lab of Associate Professor Camila dos Santos at Cold Spring Harbor Laboratory (CSHL) illuminates a new way in which pregnancy reduces the risk of breast cancer.

Two lines of defence exist in the immune system: the innate response, which involves immune cells that attack any foreign molecule they encounter, and the adaptive response, which consists of immune cells that respond specifically to calls for help. NKT cells are a unique subset of cells that are present throughout the body which can participate in both responses. 

CSHL graduate student Amritha Varshini Hanasoge Somasundara said that after a pregnancy: “There is an increase in this specific [NKT] cell type, and only in the mammary gland. We don’t see the expansion everywhere else in the body, even though NKT cells are present everywhere else in the body.”

The team sought to uncover the reason behind the larger number of NKT cells were doing in the breast tissue. Hanasoge discovered that in mice, breast epithelial cells, which line lactation ducts, produce a specific protein called CD1d after pregnancy. If the cells did not present CD1d, no increase in NKT cells was seen in the tissue; the epithelial cells became cancerous and grew into tumours. Hanasoge and dos Santos think that CD1d molecules are calling in NKT cells to monitor the epithelial cells in the breast tissue after pregnancy. If they become cancerous, the NKT cells can quickly kill them to prevent tumour growth.

The team’s findings establish a novel link between pregnancy and the immune system in preventing breast cancer. They want to know how these findings can be translated into humans and what other factors may influence an abundance of NKT cells in breast tissue, such as aging and menopause, which are both associated with increased breast cancer risk.

Discussing the results, Associate Professor dos Santos said: “One of the hypotheses that we are working on now is: do pregnancies later on in life bring in the same expansion of the same subtypes of immune cells as pregnancies that took place early in life?”

Source: Cold Spring Harbor Laboratory

Categories : CancerTags :

Older Antipsychotic Drugs Linked to Breast Cancer

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Source: National Cancer Institute

A number of commonly prescribed older antipsychotic drugs, and some newer ones, are associated with a significant increase in risk of breast cancer, according to a new study.  The findings are published online in the Journal of Clinical Psychopharmacology.

Previous research uncovered the link between antipsychotic drug use, prescribed for a wide array of mental health problems, and breast cancer risk. This study compared newer antipsychotics to older drugs, and examined how the drugs affect prolactin levels, which have been associated with breast cancer. However, many antipsychotics elevate prolactin levels and can produce side effects such as menstrual cycle irregularities, abnormal breast milk production and abnormal breast tissue growth.

“Many women with psychiatric illnesses such as schizophrenia and bipolar disorder will take antipsychotics for decades, and they are essential to keeping symptoms in check,” said first author Tahir Rahman, MD. “But both older antipsychotic medicines and some newer drugs raise levels of prolactin and increase the risk of breast cancer, which is concerning. Our study confirms findings from a smaller European study that advised women and their doctors to first try drugs that don’t affect prolactin levels. We agree with that advice and believe psychiatrists should start to monitor prolactin levels in their patients taking antipsychotics.”

Antipsychotic drugs were classified into three categories, based on their established effects on prolactin. Category 1 included drugs associated with high prolactin levels, such as haloperidol, paliperidone and risperidone. Category 2 had mid-range effects and included iloperidone, lurasidone and olanzapine. Category 3 had low-effect drugs such as aripiprazole, asenapine, brexpiprazole, cariprazine, clozapine, quetiapine and ziprasidone.

Comparing the three drug categories to anticonvulsant drugs and lithium, the relative risk of breast cancer was 62% higher for women who took Category 1 drugs and 54% higher for those taking Category 2 drugs, whereas Category 3 antipsychotics were not associated with any increase in breast cancer risk.

“Certain drugs are known to elevate prolactin, and the women taking those drugs were more likely to have breast cancer,” Dr Rahman said. “But we didn’t detect any increased risk in women taking antipsychotics that don’t raise prolactin levels.”

In mouse models, prolactin can help weaken systems keeping precancerous lesions from becoming breast cancer. In humans, prolactin levels tend to be lower in women who have had more children at a younger age than in women who have fewer children or wait until they are older to do so.

In this study using data collected from 2012 through 2016, the research team performed a retrospective, observational study of breast cancer risk in women ages 18 through 64 who took antipsychotics.

The researchers identified which patients were treated for breast cancer during a 12-month period and matched that information to patients taking antipsychotic drugs. Of the 540 737 women in the database taking antipsychotics, only 914 were identified as having breast cancer – a significant number of whom were taking drugs known to increase prolactin.

“Antipsychotic medications can be lifesaving for patients who have psychotic episodes where they experience symptoms such as hallucinations and delusions,” Dr Rahman said. “In recent years, the drugs have been approved to treat other conditions, too, including depression and bipolar disorder. As those high-prolactin agents are used more widely, the number at risk could increase. We’ve been advising against using these high-prolactin agents in women who already have breast cancer, but we’d like to investigate whether keeping prolactin levels lower even might prevent some of these cancers.”

In another recent study, the antipsychotic drug aripiprazole did not increase prolactin levels in women and that a few women who began the study with high prolactin levels experienced decreases in prolactin levels after 12 weeks of treatment.

Those findings, combined with preclinical evidence of the anticancer effects of some antipsychotics, have inspired Dr Rahman and colleagues to propose repurposing some antipsychotic drugs in the fight against breast cancer.

“We don’t want to alarm patients taking antipsychotic drugs for life-threatening mental health problems, but we also think it is time for doctors to track prolactin levels and vigilantly monitor their patients who are being treated with antipsychotics,” Dr Rahman said.

Source: Washington University School of Medicine

Categories : Diseases, Syndromes and ConditionsTags :

Tamoxifen Found to be Ineffective in Fungal Meningitis Trial

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Photomicrograph of a sample extracted from a lesion that revealed the presence of Cryptococcus neoformans. Credit: CDC

In a disappointing outcome, a clinical trial has shown that tamoxifen, a promising candidate to improve survival for a deadly form of fungal meningitis, is ineffective. The trial was conducted by University of Oxford researchers and published in eLife.

The study finds that adding tamoxifen, a breast cancer drug, to standard antifungal treatment was no faster in clearing fungal infection from the spinal fluid of people with meningitis. More patients who received tamoxifen had evidence of heart conduction disturbances, rates of severe side effects were similar.

Cryptococcal meningitis is a leading cause of death in people with HIV, but also affects those without HIV, regardless of whether they are immunocompromised. Most infections are caused by a fungus called Cryptococcus neoformans (C. neoformans) and occur in low-income tropical settings. The gold-standard treatment is a combination of three drugs: flucytosine and amphotericin B initially, followed by fluconazole. Yet, even on this gold-standard therapy, a third of patients die within 10 weeks of being diagnosed. Moreover, the drug flucytosine is severely restricted by availability and cost, meaning it is rarely used where the disease burden is highest.

Co-first author Nguyen Thi Thuy Ngan, Clinician at the Oxford University Clinical Research Unit (OUCRU): ‘Tamoxifen has shown antifungal activity against various yeasts in the lab; we subsequently showed that it acts synergistically with amphotericin against two-thirds of clinical Cryptococcus isolates from our archive. As a well-understood, off-patent, cheap and widely available medicine, it was a promising candidate for treating cryptococcal meningitis.’

Co-first author Nhat Thanh Hoang Le, Biostatistician at OUCRU, added: ‘We designed a randomised trial to determine whether using these drugs in combination could improve the speed of clearance of Cryptococcus from patients with meningitis with and without HIV.’

The trial involved 50 patients, 40 with HIV. Of the patients, 24 were assigned to receive a standard anti-fungal treatment of amphotericin B and fluconazole plus tamoxifen, and 26 received the standard anti-fungal treatment only. Researchers measured the Early Fungicidal Activity (EFA) for both groups – how quickly C. neoformans amounts declined in a patient’s spinal fluid in the two weeks following treatment.

Based on their prior work, the team were hoping for better EFA for patients receiving tamoxifen, but there was no detectable difference in EFA.

The only observed difference was increased heart toxicity in the tamoxifen group. Lab studies had shown that a tamoxifen dose five to 10 times higher than that used routinely in breast cancer would be needed to have an antifungal effect. However, high doses of tamoxifen cause QT prolongation, which can cause cardiac arrest. While there was one sudden death in the tamoxifen group in this study, this occurred after the period of tamoxifen administration and it was not associated with an abnormal heart rhythm.

Senior author Professor Jeremy Day, Professor of Infectious Diseases, Oxford University, said: “Despite its apparent anti-cryptococcal effect and synergy with other drugs, tamoxifen does not increase the rate of clearance of yeast from spinal fluid in people with meningitis and is unlikely to result in clinical benefit.

“Our results show the importance of small-scale trials such as this for rapidly evaluating repurposable drugs and preventing the time and cost of a larger clinical study that is likely to fail. However, sadly this does mean that we urgently still need new, specific anti-cryptococcal drugs to be developed, and we also need to ensure that existing, available treatments are made accessible and affordable.”

Source: Oxford University

Categories : CancerTags :

Nut Consumption Linked to Long-term Breast Cancer Survival

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Photo by Pavel Kalenik on Unsplash

In a study of breast cancer survivors, the consumption of nuts was linked with reduced risks of breast cancer recurrence or death.

Researchers examined data for 3449 breast cancer survivors from the Shanghai Breast Cancer Survival Study who completed a dietary assessment five years after diagnosis. Of the participants, there were 374 deaths during a median follow-up of 8.27 years after the dietary assessment. Among 3274 survivors who did not have a previous recurrence at the time of their dietary assessment, 209 developed breast cancer-specific events, including recurrence, metastasis, or breast cancer mortality.

There was a dose-response pattern in the relationship between nut consumption and risk of breast cancer recurrence or death, with those consuming the highest amounts having the lowest risks. Also, the association was stronger for survivors who had earlier stages of breast cancer than for those who had later stages.

The findings were published in the International Journal of Cancer.

Source: Wiley

Categories : CancerTags :

Link Between High Cholesterol and Breast Cancer Explained

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Source: National Cancer Institute

While chronically high cholesterol levels are linked to increased risks of breast cancer and worse outcomes in most cancers, the link had not been fully understood until now.

In a study published in Nature Communications, researchers identify the mechanisms at work, describing how breast cancer cells utilise cholesterol to develop stress tolerance, preventing them from dying as they migrate from the original tumour site.

“Most cancer cells die as they try to metastasise – it’s a very stressful process,” said senior author Donald P. McDonnell, Ph.D., professor in the departments of Pharmacology and Cancer Biology and Medicine at Duke University School of Medicine. “The few that don’t die have this ability to overcome the cell’s stress-induced death mechanism. We found that cholesterol was integral in fueling this ability.”

McDonnell and colleagues built on earlier research in their lab focusing on the link between high cholesterol and oestrogen-positive breast and gynaecological cancers. Those studies found that cancers fueled by the oestrogen hormone benefitted from derivatives of cholesterol that act like oestrogen, stoking cancer growth.

But a paradox emerged for estrogen-negative breast cancers. These cancers are not oestrogen dependent, but high cholesterol is still associated with worse disease, which indicates the possible effect of a different mechanism.

In the current study using cancer cell lines and mouse models, the Duke researchers found that migrating cancer cells gobble cholesterol in response to stress. Most die.

However, those that live emerge with a super-power that makes them able to withstand ferroptosis, a natural process in which cells succumb to stress. These stress-impervious cancer cells then proliferate and readily metastasise.

Other tumours beside ER-negative breast cancer cells use this process. including melanoma. And the mechanisms identified could be targeted by therapies.

“Unraveling this pathway has highlighted new approaches that may be useful for the treatment of advanced disease,” McDonnell said. “There are contemporary therapies under development that inhibit the pathway we’ve described. Importantly, these findings yet again highlight why lowering cholesterol — either using drugs or by dietary modification — is a good idea for better health.”

Source: Duke University

Categories : CancerTags :

Many Breast Cancer Patients Don’t Discuss Cannabis Use with Docs

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Photo by Crystalweed Cannabis on Unsplash

About half of US adults with breast cancer use cannabis as an adjunct to cancer treatment for symptom and side effect management. However, most don’t discuss their use of cannabis with their physicians, according to a new study.

Pain, fatigue, nausea, and other difficulties often arise from cancer and its treatment, and some patients turn to cannabis for relief of their symptoms. However, many physicians feel that they lack the necessary knowledge to discuss cannabis with their patients. Such knowledge is especially important now that cannabis use is becoming more widespread.

In a study published in CANCER, researchers reported the results of an anonymous online survey to examine cannabis use among adults who were diagnosed with breast cancer within five years and were members of the Breastcancer.org and Healthline.com online health communities.

The findings revealed that:

  • Of the 612 participants, 42% reported using cannabis for relief of symptoms, including pain, insomnia, anxiety, stress, and nausea/vomiting. Among those who used cannabis, 75% reported that it was extremely or very helpful at relieving their symptoms.
  • Nearly half (49%) of participants who used cannabis believed that medical cannabis can be used to treat cancer itself; however, its effectiveness against cancer is unclear.
  • Among those using cannabis, 79% had used it during treatment, which included systemic therapies, radiation, and surgery.
  • Participants reported using a wide range of different cannabis products known to vary in quality and purity.
  • Half of participants sought information on medical cannabis, and websites and other patients were ranked as the most helpful sources of information. Physicians ranked low on the list.
  • Among those who sought information on cannabis use for medical purposes, most were unsatisfied with the information they received.
  • Most participants believed cannabis products to be safe and were unaware that the safety of many products is untested.

“Our study highlights an important opportunity for providers to initiate informed conversations about medical cannabis with their patients, as the evidence shows that many are using medical cannabis without our knowledge or guidance,” said lead author Marisa Weiss, MD, of Breastcancer.org and Lankenau Medical Center near Philadelphia, Pennsylvania. “Not knowing whether or not our cancer patients are using cannabis is a major blind spot in our ability to provide optimal care, and as healthcare providers, we need to do a better job of initiating informed conversations about medical cannabis with our patients to make sure their symptoms and side effects are being adequately managed while minimising the risk of potential adverse effects, treatment interactions, or non-adherence to standard treatments due to misinformation about the use of medical cannabis to treat cancer.”

Dr Weiss added that patients should never use cannabis as an alternative to standard cancer treatment, and clinicians should inform patients about the safe and effective use of cannabis as an adjunct to their cancer treatment plan.

Source: Wiley

Categories : CancerTags :

Radiation after Breast-conserving Surgery Reduces Cancer Recurrence

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Source: National Cancer Institute

A long-term follow up analysis of a trial has shown that breast radiation following lumpectomy significantly reduces incidence of ipsilateral breast recurrence (IBR) for “low risk” DCIS.

NRG-RTOG 9804 is a clinical study conducted by the National Cancer Institute National Clinical Trials Network group NRG Oncology. These results were recently published in JCO.

IBR occurs at a rate of 5-10% after breast-conserving surgery. The NRG-RTOG 9804 study enrolled 636 women with a median age of 58 between December 1999 and July 2006. Patients were randomised to breast radiation (RT) or observation (OBS) treatment groups. All patients who participated in the trial underwent annual mammography and specified clinical exam intervals. For this analysis, the median follow up time was 13.9 years.

Analysis focused on the long-term cumulative incidence of IBR, the primary endpoint in the study. The study hypothesised that radiation would significantly reduce IBR from 6% to 3.5% at 5 years, assuming that the reduction in IBR from RT would be less than previous trials that included higher grades and larger sizes of DCIS. With long-term follow-up, cumulative incidence of IBR remained statistically significantly lower with RT, as compared to OBS. At 10 and 15 years, the cumulative incidence of IBR with OBS was 9.2% and 15.1%, respectively, and was 1.5% and 7.1%, respectively, with RT. The 10 and 15 year invasive IBR incidence, respectively, was 0.4% and 5.4%  with RT; 4.3%  and 9.5% with OBS. A total of 52 IBRs were observed; 14 in the RT arm and 38 in the OBS arm.

No statistically significant differences in mastectomy, distant metastasis, overall or disease-free survival were seen between the two treatment arms.

“Since IBR risk continues to increase through at least 15 years, with radiation conferring both a delay and decrease in this risk, the data presented support the decision to treat patients who wish to minimise their IBR and particularly the invasive cancer risk long term. Factors such as age, life expectancy, and willingness (if oestrogen receptor–positive) to take antioestrogen therapy should be taken into consideration in this patient-doctor shared decision,” stated lead author Beryl McCormick, MD, of the Memorial Sloan Kettering Cancer Center.

Source: NRG Oncology