Cholesterol byproduct hijacks immune cells to spread breast cancer

High cholesterol levels have been associated with breast cancer spreading to other sites in the body, but doctors and researchers don’t know the cause for the link. A new study by University of Illinois researchers found that the culprit is a byproduct of cholesterol metabolism that acts on specific immune cells so that they facilitate the spread of the cancer instead of stopping it.

The study, published in the journal Nature Communications, identifies new potential drug targets that could inhibit the creation or actions of the dangerous cholesterol byproduct, a molecule called 27HC.

Breast cancer impacts roughly 1 in 8 women. We’ve developed fairly good strategies for the initial treatment of the disease, but many women will experience metastatic breast cancer, when the breast cancer has spread to other organs, and at that point we really don’t have effective therapies. We want to find what drives that process and whether we can target that with drugs,” said Erik Nelson, a professor of molecular and integrative physiology who led the study.

Nelson’s group fed mice with breast cancer tumors a diet high in cholesterol. The researchers confirmed that high levels of cholesterol increased tumor growth and metastasis, and that mice treated with cholesterol-lowering drugs called statins had less metastasis. Then they went further, specifically inhibiting the enzyme that makes 27HC during cholesterol metabolism.

By inhibiting the enzyme that makes 27HC, we found a suppressor effect on breast cancer metastasis. This suggests that a drug treatment targeting this enzyme could be an effective therapeutic,” said Amy Baek, a postdoctoral researcher at Illinois and the first author of the paper.

The researchers also saw unusual activity among specific immune cells – certain types of neutrophils and T-cells – at metastatic sites high in 27HC.

Normally, your body’s immune system has the capacity to attack cancer,” Nelson said, “but we found that 27HC works on immune cells to fool them into thinking the cancer is fine. It’s hijacking the immune system to help the cancer spread.”

See a video of Nelson describing the study on YouTube.

Because 27HC acts through the immune system, and not on the breast cancer itself, the researchers believe their findings have broad applicability for solid tumors. They performed experiments looking at colon cancer, lung cancer, melanoma and pancreatic cancer, and found that 27HC increased metastasis for all the tumor types, suggesting that a treatment targeting 27HC could be effective across multiple cancer types.

The researchers are working to further understand the pathway by which 27HC affects the immune cells. With clinical partners at Carle Foundation Hospital in Urbana, the team is working to establish whether 27HC has the same pathway in human patients as in mice.

We hope to develop small-molecule drugs to inhibit 27HC,” Nelson said. “In the meantime, there are good cholesterol-lowering drugs available on the market: statins. Cancer patients at risk for high cholesterol might want to talk to their doctors about it.

Baek et al. The cholesterol metabolite 27 hydroxycholesterol facilitates breast cancer metastasis through its actions on immune cells. Nature Communications 8, Article number: 864 (2017) doi:10.1038/s41467-017-00910-z [Article]

Advertisements

Breast cancer patients on opioids less likely to stick to vital treatment

A new study has found a troubling lack of adherence to a potentially lifesaving treatment regimen among breast cancer patients who take opioids to manage their pain.

The treatment, adjuvant endocrine therapy, commonly known as hormone therapy, is used to prevent the cancer from returning after surgery, chemotherapy or radiation therapy. Opioid use, however, was “significantly associated” with both failure to adhere to the hormone therapy and a higher risk of death, the study found.

Overall, the study found “really suboptimal” adherence to hormone therapy among the women on opioids, said researcher Rajesh Balkrishnan, PhD, of the University of Virginia School of Medicine’s Department of Public Health Sciences. “It’s not a big secret that the U.S. uses more opioids than any other country in the world,” he said. “Clearly there has to be better management of opioids in the elderly cancer population.”

One researcher cautioned that the opioid crisis sweeping the country may be causing doctors to become too cautious about prescribing the powerful drugs, even when appropriate and much needed. “A lot of doctors feel worried about prescribing them,” said researcher Leslie Blackhall, MD, a pain-management expert at the UVA Health System. “People feel judged for prescribing them.”

Breast Cancer and Opioids

Up to 60 percent of breast cancer survivors suffer chronic pain related to their treatment, the study notes. Survivors often face 10 years of adjuvant endocrine therapy to keep the cancer from coming back – a long time to comply with any treatment regimen, but especially if suffering poorly managed pain.

To better understand the relationship between opioid use and the hormone therapy, the researchers looked at treatment adherence among more than 10,000 women, with an average age of 72.3, using the National Cancer Institute’s expansive SEER database. They found that women who were younger, single and had more advanced cancer all were more likely to be on opioids, as were women with depression.

Women who received chemotherapy and breast cancer surgery were more likely to take opioids, but this was not the case for women receiving radiation therapy. This may be because of new, more targeted radiation therapy that causes less pain, the researchers hypothesized.

Using Opioids Safely

Researcher Virginia LeBaron, PhD, of the UVA School of Nursing, is a former medical oncology staff nurse and palliative care nurse practitioner. “These results underscore the importance of a balanced approach to the utilization of prescription opioid medications,” she said. “By balanced approach, I mean that it is critically important we ensure that prescription opioid medications are accessible to cancer patients who need them, but at the same time we must ensure we have appropriate systems in place to mitigate risk and reduce potential harms related to these medications.”

The researchers have published their findings in the scientific journal Breast Cancer Research and Treatment. Blackhall noted that the article is intended to foster dialogue and spur additional research. For example, clinical trials might compare opioids with non-opioids for managing cancer pain or identify patient subgroups that would most benefit from certain approaches to pain management. “This study was really just a way to bring attention to the problem and the need to provide better care for patients,” she said.

Tan et al. Opioid use among female breast cancer patients using different adjuvant endocrine therapy regimens. Breast Cancer Res Treat. 2017;165(2):455-465 [Abstract]

Breast cancer patients can use antiperspirants during radiotherapy

Women undergoing daily radiation therapy for breast cancer are commonly told they should not use antiperspirant for fear that it could cause greater radiation damage to the skin, but a new study from the Perelman School of Medicine at the University of Pennsylvania shows that advice is not based on sound science.

While they found that about eight out of every 10 patients reported their doctors told them not to use antiperspirants and roughly the same number of doctors say they routinely make that recommendation, their study also showed there was no difference in the radiation skin dose absorbed by these patients with or without these deodorants. They published their findings in Radiotherapy and Oncology this month.

Going without antiperspirants entirely for a 3-6 week course of radiotherapy can have a negative impact on a patient’s quality-of-life,” said the study’s lead author Brian C. Baumann, MD, who recently completed his residency in Radiation Oncology at Penn and is a member of Penn’s Leonard Davis Institute of Health Economics. He is also currently an assistant professor of Radiation Oncology at Washington University in St. Louis. “Our study suggests that antiperspirants can be safely used during breast radiotherapy without risking increased skin side effects.”

The study tackled two key areas. First, it established that it’s still common practice for physicians to advise breast cancer patients to avoid antiperspirants during radiotherapy. Second, it debunked the myth that the use of these antiperspirants increases the amount of radiation the skin receives, thus causing more damage to the skin.

For the first part of the study, researchers utilized OncoLink, an online cancer service dedicated to patient and provider education that is run by Penn’s Radiation Oncology unit. They developed a survey to find out what percentage of providers still tell their patients not to use antiperspirants, and what percentage of patients say they received that advice. Of the 105 doctors and nurses who responded and said they regularly manage radiation dermatitis for their patients, 86 of them (82 percent) said they regularly tell patients not to use antiperspirants during their course of radiation treatment. On the patient side, 92 women responded who said they have received radiotherapy for breast cancer, 73 of whom (79 percent) say their healthcare providers advised them to avoid using deodorant for the duration of their treatment.

While the sample size of the survey is relatively small, the percentage of patients who received the advice to avoid antiperspirants and the percentage of providers who routinely offer this advice was very similar. We cannot make any conclusions about the exact prevalence of this recommendation, but we think the results strongly suggest that the recommendation remains popular,” Baumann said.

The advice persists despite a lack of scientific evidence. Trials have not shown antiperspirant use leads to higher skin side effects during breast radiation therapy, but those trials do not appear to have changed clinical practice. Baumann says that shows providers either do not know about these studies or they are skeptical of the results.

There can be a discrepancy between the ways we measure skin toxicity in clinical trials versus the problems patients report to their healthcare providers,” Baumann said. “The current skin toxicity scoring system has important limitations. It does not take pain or itching into account, for example, so it is possible that the studies may have missed a clinically meaningful effect because of the limitations of the measurement tool.” Researchers addressed that discrepancy in the second part of this study as they sought to find out if antiperspirants really do increase the surface dose of radiation on the skin. For this portion, researchers used optically stimulated luminescent dosimeters (OSLDs) – a common device for measuring the amount of surface radiation absorbed with each dose. They used three squares of paper: one with nothing on it, one with a thick coating of standard antiperspirant, and one with a thick coating of extra-strength antiperspirant. They placed the squares of paper in the beam’s path and measured the absorbed radiation dose with OSLDs.

We found no significant difference in surface dose with or without antiperspirant,” Baumann said.
Baumann’s team also moved the beam to four different angles, but found it did not lead to different results.
These antiperspirants also contain aluminum zirconium tetrachlorohydrex glycine, a common metal found in antiperspirants. The standard deodorants contain 15 percent of it, while the extra strength contains 25 percent.

We specifically wanted to know if the radiation could hit that metal and scatter, sending radiation off target and into other, healthy parts of the skin, but any difference in surface dose we found was within the margin of error,” Baumann said.

This study shows providers should be more liberal in letting patients use antiperspirants during radiation treatment, which may improve patient quality-of-life.”

Baumann et al. Avoiding antiperspirants during breast radiation therapy: Myth or sound advice? Radiother Oncol. 2017;S0167-8140(17)30432-2. doi: 10.1016/j.radonc.2017.06.021 [Abstract]

Balance, gait negatively impacted after chemotherapy treatment

A single chemotherapy treatment can result in a significant negative impact on walking gait and balance, putting patients at an increasing risk for falls, according to a new study involving breast cancer patients conducted by researchers at The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC – James). Up to 60 percent of patients experience chemotherapy-induced peripheral neuropathy (CIPN), nerve damage that impacts feeling in the hands or feet; however, when and to what extent this damage impacts functional abilities has been largely unknown.

This new study is the first to objectively measure the functional abilities of cancer patients during and after taxane-based chemotherapy. Researchers followed 33 patients with stage I-III breast cancer, assessing functional performance (standing balance and gait) and patient-reported outcomes at five timepoints spanning before treatment began up to three months post-treatment completion.

Researchers observed a 28 percent increase in side-to-side sway (medial-lateral) after just one chemotherapy treatment. That increased to 48 percent with cumulative chemotherapy exposure. Patients also demonstrated a 5 percent reduction in walking speed after three cycles of chemotherapy.

This is not simply a quality of life concern – CIPN can impact a patient’s ability to receive treatment at all, limiting the potential for a cure. For patients who have great difficulty with neuropathy, we often have to modify their treatment regimen to make it tolerable – sometimes the therapy has to be ceased entirely,” says Maryam Lustberg, MD, MPH, senior author of the study and director of breast cancer survivorship services at the OSUCCC – James. “We need to make these treatments more tolerable to patients so they can get the full benefit of the treatments.”

Lustberg and her colleagues report that taxane exposure is also associated with worsened sensory symptoms and poorer postural control. There was also an association between patients’ balance and self-reported sensory symptoms.

Significant Clinical Problem

CIPN leads to pain, falls and difficulty walking as well as performing activities of daily living. Although symptoms can improve with time, up to 30 percent of patients have persistent symptoms that last at least six months.

Researchers say the study provides initial support for the feasibility and potential utility of implementing objective measures of physical function into the oncology clinic.

Cancer survivors are at a significant increased risk for falls, and the incidence rate of falling after chemotherapy is a serious concern for survivors’ long-term quality of life,” adds Lustberg. “Our study provides new insights on how taxane-based chemotherapy can impact fundamental aspects of patient function. These new insights can help us develop better strategies to help patients combat these challenges and, in some cases, choose a different therapy to treat the disease but with reduced side effects.”

The OSUCCC – James is expanding this research to assess CIPN in colorectal cancer patients receiving taxane-based chemotherapy.

Integrating Gait, Balance Testing Into Clinical Practice

Study co-author Ajit Chaudhari, PhD, associate professor of physical therapy, orthopedics, mechanical engineering and biomedical engineering at The Ohio State University Wexner Medical Center says the study was an important first step in achieving better long-term outcomes after cancer and provides a new tool for integrating gait and balance screening into clinical care.

We have created an easy-to-use clinical tool that has strong potential to quickly help clinicians identify patients – very early on – who are developing a chemotherapy reaction that impacts gait and balance,” says Chaudhari. “It’s no longer good enough for someone to just ‘survive’ cancer because many patients have decades of life ahead of them. It is critical to do everything we can to make the rest of their lives as productive and enjoyable as they want it to be.

Monfort et al. Gait, balance, and patient-reported outcomes during taxane-based chemotherapy in early-stage breast cancer patients. Breast Cancer Res Treat. 2017; doi: 10.1007/s10549-017-4230-8 [Abstract]

Recovering Latina breast cancer patients report big gaps in ‘survivorship’ care

Breast cancer patients in one of the United States’ largest and fastest-growing ethnic minority groups are likely to experience numerous gaps in care following their primary treatment, research from Oregon State University suggests.

Seventy-four Latina women who had breast cancer participated in the “survivorship” care research, recruited through support groups and health fairs. The subjects, ages 30 to 75, took part in semi-structured focus groups that used a question guide crafted by a task force of academic researchers and community partners such as the American Cancer Society. Approximately half of the women were low-income, uninsured or publicly insured.

Results indicate numerous gaps and unmet needs in Latinas’ survivorship care experiences, including problems with finances, continuity of care, unmet needs for information, and symptom management,” said Carolyn Mendez-Luck, an assistant professor in OSU’s College of Public Health and Human Sciences and one of the authors of the study.

The California Breast Cancer Research Program provided primary funding for the research. Results were recently published in Public Health Nursing. Optimal survivorship care, according to the Institute of Medicine, includes the prevention of recurrence, new cancer and late effects of cancer treatment; the monitoring or surveillance for cancer and medical, mood and social issues; interventions for the effects of cancer and its treatment; and coordination among specialists and primary care providers to ensure all health needs are met.

Many survivors experience persisting symptoms including fatigue, pain, depression and sleep disturbance, but until recent years, survivorship has been relatively neglected in education, clinical practice and research,” Mendez-Luck said.

People of Mexican, Cuban, Puerto Rican, and Central and South American descent comprise 17.6 percent of the U.S. population, and about 10 percent of the women in the Hispanic/Latino population will develop breast cancer at some point in their lifetime.

Latina women are more likely to be diagnosed at later stages than non-Hispanic whites and also face linguistic and cultural barriers to diagnosis and treatment, including modesty; spiritual beliefs that cancer is God’s punishment; de-prioritizing their own health care in favor of their roles as mother and wife; and passivity in interactions with health care providers out of respect for their authority.

In addition, there are often financial hurdles – more than 25 percent of Latina women live in poverty and lack health insurance.

Understanding the cultural context in which women receive care is important,” Mendez-Luck said.
Women in the study sample expressed confusion and anxiety associated with a lack of information regarding future surveillance and treatment once primary care concluded. Many were unsure who was to be in charge of their treatment in the future, what the right schedule was for follow-up examinations, what self-care activities were recommended, and what to expect regarding their physical and psychological well-being.

Among the women in our focus groups, survivorship care plans were scarce,” Mendez-Luck said. “The vast majority of participants reported never having heard of them, or associated them with a completely different meaning – making a plan for how their families could carry on after they were gone.
The research also showed that depending on the person, “survivor” could have negative or positive connotations.

Negative perceptions included feelings that being identified as a cancer survivor was depressing, victimizing and stigmatizing,” Mendez-Luck said. “Also, that thinking about the cancer could potentially contribute to an increased likelihood of a recurrence, either by ‘tempting fate’ or from the stress brought on by negative thinking.

Positive views, the professor noted, included feeling special, strong, and blessed by God. Many survivors felt they had a special purpose for living, often including a mission to serve others.

A survivorship care plan is meant to be this living document for you and your care providers, a document a patient can follow through this entire process of what’s going on with the cancer and what she can do to stay healthy and reduce the chances that the cancer will return,” Mendez-Luck said. “It makes the patient truly a partner in her own care with health providers. But that’s not happening, clearly, at least not for these women. There’s an enormous opportunity there for improvement.

Tisnado et al. Perceptions of Survivorship Care among Latina Women with Breast Cancer in Los Angeles County. Public Health Nursing, 2016; DOI: 10.1111/phn.12299 [Abstract]

Long-term outcomes of preventing premature menopause during chemotherapy

Compared with receiving chemotherapy alone, women with breast cancer who also received the hormonal drug triptorelin to achieve ovarian suppression had a higher long-term probability of ovarian function recovery, without a statistically significant difference in pregnancy rate or disease-free survival, according to a study published in JAMA.

The majority of young women with invasive breast cancer are candidates to receive both chemotherapy and endocrine therapy. Loss of ovarian function and impaired fertility are possible consequences of anticancer treatments. Fertility concerns can affect treatment decisions of young women with breast cancer. Whether the administration of luteinizing hormone-releasing hormone analogues (LHRHa) during chemotherapy is a reliable strategy to preserve ovarian function is controversial owing to both the lack of data on long-term ovarian function and pregnancies and the safety concerns about the potential negative interactions between endocrine therapy and chemotherapy, according to background information in the article.

Lucia Del Mastro, M.D., of the Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy and colleagues randomly assigned 281 premenopausal women (median age, 39 years) with stage I to III hormone receptor-positive or hormone receptor-negative breast cancer to receive chemotherapy alone (control group) or chemotherapy plus triptorelin (LHRHa group). The trial was conducted at 16 Italian sites. Women were enrolled between October 2003 and January 2008; last annual follow-up was June 2014. Median follow-up was 7.3 years.

The 5-year cumulative incidence estimate of menstrual resumption was 73 percent among the 148 patients in the LHRHa group and 64 percent among the 133 patients in the control group. Eight pregnancies (5-year cumulative incidence estimate of pregnancy, 2.1 percent) occurred in the LHRHa group and 3 (5-year cumulative incidence estimate of pregnancy, 1.6 percent) in the control group. Five-year disease-free survival was 80.5 percent in the LHRHa group and 84 percent in the control group. This increased but statistically nonsignificant risk appeared specific to the patients with hormone receptor-negative tumors.

The authors write that these results, together with the findings of another study (POEMS-SWOG S0230), “indicate that, in addition to fertility preservation strategies such as embryo and oocyte cryopreservation, temporary ovarian suppression with LHRHa is an option to preserve ovarian function in premenopausal women with early stage breast cancer receiving adjuvant chemotherapy.”

Lambertini et al. Ovarian Suppression With Triptorelin During Adjuvant Breast Cancer Chemotherapy and Long-term Ovarian Function, Pregnancies, and Disease-Free Survival. A Randomized Clinical Trial. JAMA. 2015;314(24):2632-2640. doi:10.1001/jama.2015.17291 [Abstract]

Acupuncture reduces hot flashes in breast cancer survivors

Findings also highlight acupuncture’s ability to induce a stronger placebo effect than oral medications.

Acupuncture may be a viable treatment for women experiencing hot flushes as a result of estrogen-targeting therapies to treat breast cancer, according to a new study from researchers at the Perelman School of Medicine at the University of Pennsylvania. Hot flashes are particularly severe and frequent in breast cancer survivors, but current FDA-approved remedies for these unpleasant episodes, such as hormone replacement therapies are off-limits to breast cancer survivors because they include estrogen. The results of the study are published in the Journal of Clinical Oncology.

Though most people associate hot flashes with menopause, the episodes also affect many breast cancer survivors who have low estrogen levels and often undergo premature menopause, following treatment with chemotherapy or surgery,” said lead author Jun J. Mao, MD, MSCE, associate professor of Family Medicine and Community Health. “These latest results clearly show promise for managing hot flashes experienced by breast cancer survivors through the use of acupuncture, which in previous studies has also been proven to be an effective treatment for joint pain in this patient population.”

Hot flashes are brief episodes of flushing, sweating, racing heartbeat and sensations of heat. Precisely how hot flushes arise isn’t known, though they are closely associated with decreased estrogen levels.

In the trial, the research team enrolled 120 breast cancer survivors, all of whom reported experiencing multiple hot flashes per day. Participants were randomized into four different interventions that would analyze how effectively an acupuncture technique known as electroacupuncture – in which embedded needles deliver weak electrical currents – reduces incidents of hot flushes as compared to the epilepsy drug gabapentin, which was previously shown to be effective in reducing hot flashes for these patients. For an eight-week period, participants received gabapentin (900 mg) daily, gabapentin placebo daily, electroacupuncture (twice per week for two weeks, then once weekly), or “sham” electroacupuncture, which involves no actual needle penetration or electrical current.

After the eight-week treatment period, the subjects in the electroacupuncture group showed the greatest improvement in a standard measure of hot flush frequency and severity, known as the hot flash composite score (HFCS). They were followed by the group that had received the “sham acupuncture” treatment. The gabapentin pill group reported less improvement than the sham acupuncture group, and the placebo pill group placed last.

In addition to reporting the greatest reductions in hot flash frequency/severity, both acupuncture groups reported fewer side effects than either of the pill groups.

The Penn researchers surveyed the subjects sixteen weeks after treatment ended, and found that the electroacupuncture and sham electroacupuncture groups had enjoyed a sustained, and even slightly increased, abatement of hot flashes. The pill-placebo patients also reported a slight improvement in symptoms, whereas the gabapentin pill group reported a worsening.

Compared to its sham version, electroacupuncture produced a 25 percent greater reduction in HFCS, suggesting that it really could work better – though the modest size of the study precluded a statistically definitive conclusion. However, the study did show with confidence that the sham acupuncture procedure worked better than a placebo pill at relieving hot flushes, presumably by creating a stronger expectation of benefit.

Acupuncture is an exotic therapy, elicits the patient’s active participation, and involves a greater patient-provider interaction, compared with taking a pill,” Mao said. “Importantly, the results of this trial show that even sham acupuncture – which is effectively a placebo – is more effective than medications. The placebo effect is often dismissed as noise, but these results suggest we should be taking a closer look at how we can best harness it.”

The sham acupuncture procedure also seemed to create a strikingly lower experience of adverse side effects, which were virtually absent in this group. Only one woman reported an episode of drowsiness from the sham acupuncture, whereas the placebo pill recipients reported eight adverse events such as headache, fatigue, dizziness and constipation.

Some have questioned whether acupuncture has a biological effect apart from the power of suggestion. There is evidence from prior studies that it can boost bloodstream levels of endorphins and related painkilling, mood-elevating molecules more directly than via suggestion. Studies also have found that traditional acupuncture works differently than sham acupuncture in the brain. But for patients, that issue may be moot if they can enjoy dramatic improvements in their quality of life, especially compared to no improvement if they receive no treatment.

Mao et al. Electroacupuncture Versus Gabapentin for Hot Flashes Among Breast Cancer Survivors: A Randomized Placebo-Controlled Trial. J Clin Oncol. 2015; doi: 10.1200/JCO.2015.60.941 [Abstract]