Ask the Expert: Breast Cancer, Diet and Exercise

Cancer Connect

CancerConnect partnered with Dana-Farber to engage with breast cancer expert, Jennifer A. Ligibel, MD, of the Susan F. Smith Center for Women’s Cancers at Dana-Farber. Dr. Ligibel guest-moderated a question-and-answer session on “Breast Cancer, Diet and Exercise.”

Dr. Ligibel has authored several papers on the role of lifestyle factors and breast cancer, including a recent study on the impact of exercise on reducing drug-related joint pain. She is also an assistant professor of medicine at Dana-Farber.

Join us in the Breast Cancer Community on CancerConnect to view the entire Ask the Expert session with Dr. Ligibel.

Question about lifestyle factors, breast cancer and depression: Are there any ‘lifestyle’ type of factors—diet/nutrition, that might help with anxiety, depression (I didn’t seem to have these issues until after my breast cancer diagnosis)?

Dr. Ligibel:There are many studies that show that exercise has a positive impact on anxiety and depression. Studies suggest that fairly modest amounts of exercise can improve mood. We generally recommend that women start slowly and check with their physicians before starting an exercise program, but research suggests that moderate physical activity, such as walking, is safe for most breast cancer survivors and can have many positive health effects.

Although information is more limited in cancer survivors, there is also evidence that weight loss can have a positive effect on depression in women.

Question about health benefits of green tea or tumeric: What do you think of the health benefits of green tea, specifically Matcha green tea? Also, what about tumeric?

Dr. Ligibel:There is a lot of interest in the health benefits of specific supplements, but not much evidence that these products have any benefits for cancer survivors. Green tea has been studied as a potential nausea-preventing intervention, but the results of these studies have been mixed. Some preliminary results from animal studies have suggested health benefits of turmeric, but it is too early to know whether either of these supplements will eventually be shown to be beneficial for cancer survivors.

It is important to note that green tea and turmeric are foods rather than medications, like most supplements. This means that they are not regulated by the FDA. Companies that produce them can make all kinds of health claims, as long as they include the statement that the claims are not supported by the FDA. This can be confusing for patients, as many of these products are marketed as “cancer-fighting”.

Question about Optimal Types of Fat: I’m a 9-year breast cancer survivor. I’ve seen studies which favor a low fat diet to reduce the risk of breast cancer and recurrence. These studies do not specify types of fat. Do they look at or compare trans fats, fat from meat, dairy and processed foods, fats from nuts, seeds, olive oil, coconut oil, etc? I am mostly vegetarian and my diet is actually fairly high in fat since my protein comes from nuts, seeds and some eggs. What is your sense about high fat vs low fat and if the types of fats consumed contribute to higher or lower risk? I’d like to believe that healthy fats are not risk factors! Thank you.

Dr. Ligibel:The study that showed that eating a low fat diet reduced the risk of breast cancer recurrence, called the Women’s Interventional Nutrition Study or “WINS”, was largely conducted in the 1990’s, when there was not as much of a focus on different types of fat. Thus there is unfortunately not a lot of evidence to provide an answer for your question about the impact of different types of fat on breast cancer recurrence rates. However, in the years since the WINS study was conducted, research in other disease such as heart disease, has shown that all fats are not equal in terms of the impact that they have on a person’s risk of developing different diseases. There is also evidence from population studies that suggest that individuals who consume healthy fats seem to be at lower risk of some kinds of cancers, although we can’t determine if there is a cause and effect relationship between the types of fats a person eats and their risk of cancer from this kind of study.

A number of on-going studies are looking at whether there is a “best” diet for breast cancer survivors, but evidence is not conclusive at this point. Some evidence suggests that keeping weight in a good range might be more important than specific dietary ingredients. The National Heart, Lung and Blood Institute, a group that prepares many of the recommendations about weight and diet for the US population, currently supports the use of a number of diets to maintain a healthy weight.

Thus there is no simple answer to your question, but if your diet is successful in keeping your weight in a good range, it is likely a reasonable plan for you to continuing following.

Question about Exercise and Health Benefits: I have a very physically demanding job where I move at a great clip outdoors for at least 3-4 hours each day. When I am done work I have no energy for formal exercise, especially since BC treatment and Tamoxifen, just stretching or a little Yoga. Is this enough?

Dr. Ligibel:Studies have shown that physical activity, no matter how it is achieved is linked to better outcomes in breast cancer. Sometimes it is hard to know how much activity a person is doing as part of a work day, so one way to make sure that you are doing enough exercise is to wear a pedometer to track the distance you walk each day as part of your job and during your leisure time. You should aim for 10,000 steps per day. If you are accomplishing this much walking during your average work day, you are likely achieving enough physical activity to provide health benefits.

Question about Weight Loss: I am taking Anastrozole. It is very difficult to lose weight. Do you have any suggestions as to offsetting the effects of this medication on weight loss? What should the majority of the diet include and what should be omitted in order to lose weight?

Dr. Ligibel:There are many reasons why woman with breast cancer gain weight or have difficulty in losing it after breast cancer diagnosis. Some women go through menopause as a result of chemotherapy or other cancer treatments. The average women who undergoes a “normal” menopausal (not due to cancer treatment) will gain 5-10 pounds in the years after her menstrual cycles stop. This weight gain can be even greater when it occurs suddenly as a result of breast cancer treatment. Many women also feel fatigued as a result of their breast cancer therapy and become less physical active. Studies have shown that weight gain is not increased in women taking tamoxifen or anastrozole, but it is harder to study the effects of these drugs on a woman’s ability to lose weight.

Regardless of the reasons for weight gain, weight loss requires calorie reduction. This can be accomplished in many ways. A diet that is low in fat and high in fruits and vegetables has been a standard for weight loss for many years, but low carbohydrate, vegetarian, low glycemic index and Mediterranean diets can also be used to lose weight. Many people find keeping a journal of what you eat and drink as a first step to understanding your eating patterns. You might be surprised by “hidden” calories you are consuming. Some people also find a structured meal plan to be helpful when starting a weight loss program. Commercial programs can also be useful to teach you how to recognize where your calories re coming from and create new eating patterns.

Question about Diet/Exercise Resources: Do you have any recommendations for books or resources that would be a good guide to helping with navigating the best things to do for nutrition/exercise after breast cancer?

Dr. Ligibel:The American Cancer Society has developed a set of diet and nutrition guidelines for cancer survivors that is available on its web site.

The American Society of Clinical Oncology has also made Obesity and Cancer one of its primary initiatives this year and will be releasing a set of materials about weight, nutrition, and diet for cancer survivors in the next few weeks. This materials will be available in print and online through the website.

Question about Neuropathy: Can diet or exercise help neuropathy from chemo?

Dr. Ligibel:There is not a lot of evidence that diet or exercise can help neuropathy from chemotherapy. There are studies looking at glutamine, a supplement, but this product seems to work best while an individual is receiving chemotherapy treatments. On-going studies are looking at acupuncture as a potential treatment for chemotherapy-induced neuropathy.

Question about Prevention: What should we tell our daughters, sisters, mothers, wives, girlfriends about diet/exercise to help them prevent breast cancer?

Dr. Ligibel:There is a lot of evidence that a “healthy” lifestyle—keeping your weight in a healthy range, exercising regularly, and consuming a diet that is higher in fruits and vegetables and lower in fat—could reduce the risk of developing breast and other cancers. This doesn’t mean that these behaviors are 100% effective in preventing breast cancer or that people who don’t do any of these things will necessarily develop breast cancer, but the evidence does suggest that maintaining a healthy lifestyle should be part of a cancer prevention strategy.

General nutrition and physical activity recommendations from the American Cancer Society for Cancer Prevention include the following:

1. Stay Active: perform at least 150 minutes of moderate-intensity aerobic exercise each week, such as walking at a brisk pace

2. Consume a healthy diet that is low in fat and high in fruits, vegetables and fiber

3. Maintain your weight in a healthy range and attempt weight loss if you are overweight or obese

4. Limit alcohol to no more than 1 drink per day for women and 2 drinks per day for men

Question about Immune System: My questions are three-fold: First- does boosting the immune system help prevent breast cancer? Second, Is there a diet that boosts the immune system (I am a vegetarian)? And, lastIy, I just read something about a study showing that a vegetarian diet is linked to poor health—what does this mean to me as a breast cancer survivor?

Dr. Ligibel:There is a lot that we do not know about the biology that links nutrition and exercise to breast cancer. Some scientists have hypothesized that the immune system may play a role in this connection, but there is little conclusive evidence. Similarly there is not much known about how specific foods or supplements affect the immune system, so I would not recommend a particular diet to enhance the immune system.

Finally, vegetarian diets can be very healthy, as long as they contain a good balance of essential nutrients. It can be hard to consume enough protein, for example, for individuals who maintain a vegetarian diet. As long as you ensure that you consume a balanced diet, there is no reason why a vegetarian diet would be unhealthy. If you have specific concerns regarding your diet, I would recommend meeting with an oncology nutrition specialist.

Question about Diet/Exercise to help with fatigue: I have metastatic breast cancer—been on multiple treatments for what seems like forever. I am grateful to be alive but am beginning to feel what I assume are the cumulative effects of all of my treatments. Are there any recommendations for food or exercise that might help with my fatigue?

Dr. Ligibel:There is unfortunately very little information about the role of diet and exercise in patients with advanced breast cancer. However, exercise has been shown to be an effective way to reduce fatigue in many studies performed in women with early-stage cancer undergoing chemotherapy. There have been a few small studies of moderate-intensity exercise in women with advanced cancer that suggest that exercise is safe and may have benefits. I would recommend asking your doctor about starting an exercise program. As long as he or she is supportive of this, I would recommend slowing starting to exercise. It is important to set reasonable goals, and begin slowly. If you have not been exercising at all, even just walking around the block once per day can be a good start. Build up the time that you spend exercise each week, and you will likely begin to see some benefits in terms of your energy level.

Question about Weight Loss: I was diagnosed with Stage 4 Inflammatory Breast Cancer last July at the age of 31. I am currently on maintenance treatment and need to lose about 40-50 pounds. I lost a lot of my strength during treatment and I am a pretty picker eater who hates to cook. The thought of having to lose that much weight is so overwhelming even though I know it will help to decrease recurrence. Can you tell me what 2 or 3 things (whether nutrition or exercise related or both) that I can start with?

Dr. Ligibel:It can be daunting to know where to figure out where to start when you would like to lose a lot of weight. We find that people are most successful when they start with an attainable goal. Studies have shown that smaller amount of weight loss, 5-10% of your starting body weight, can have many benefits, even if people can’t lose 50 pounds.

I would recommend that you start with keeping track of what you eat for a week. Look for “hidden” calories like soft drinks, alcoholic beverages or juices, which are high in calories and not filling. Processed foods and sweets are also very high in calories with less nutritional value. Try to limit the amount of these you consume.

Start slowly with exercise if you have not been active. Make a plan to start with walking at a moderate pace for 10-15 minutes three times per week and gradually increase to every day, and then for longer periods of time.

Joining a group program (like Weight Watchers) can also be helpful for some people, or working with a weight loss “buddy”, a person with whom you can explore low calorie recipes and exercise, works for some people.

Question about Maca: I am taking Femara for ER & PR + stage III breast cancer. Is it safe to take Maca to help manage side effects of the AI?

Dr. Ligibel:There is unfortunately no safety data for this supplement for women with breast cancer.

Question about Soy: My question concerns tamoxifen, nutrition and products that contain soy. I was diagnosed 1/19/12 with invasive ductal carcinoma PR+ ER+ HER2+ and received bilateral lumpectomies, No lymph node involvement either side, 16 taxol/herception weekly infusions, 33 radiation rounds, 4 A/C, and the year’s course of Herceptin. I have been taking tamoxifen for the last year and a half and have read conflicting information about soy products. Although my hot flashes have subsided a bit, they do keep wake me up at night. I realized that many protein rich yogurts and nutrition bars have traces of soy in them. I considered soy as a supplement initially but decided against it, since the research appeared to be “”out”” on the final word (soy mimics estrogen but does it tend to promote my type of estrogen-driven cancer?). What are your thoughts on how much soy is “”good”” or harmful in contributing to recurrence? I appreciate your opinion. ”

Dr. Ligibel:There is a lot that we do not know about the relationship between soy and estrogen-driven breast cancers. Early studies showed that high doses of soy led to breast cancer formation in lab experiments, but it is not clear whether this amount of soy was remotely similar to what a woman could consume through diet. A number of recent reports looking at diet patterns in women in Asia and the US suggested that the risk of breast cancer recurrence was not increased by soy intake. Although there are some difficulties in using this information to completely conclude that soy intake is “safe” for breast cancer survivors, most experts at this point feel fairly confident that some soy intake in the diet is unlikely to be dangerous for breast cancer survivors. This means that it is likely not necessary to be reading food labels to avoid products containing soy, but I would personally stop short of endorsing soy as a supplement for a breast cancer survivor.

Question about Foods to Avoid: Are there any specific foods we should stay away from specifically if you are positive to estrogen?

Dr. Ligibel:There is a lot of debate regarding the use of soy products in women with an estrogen-positive breast cancer (please refer to the prior question regarding soy). Other foods also contain phytoestrogens, which are plant-based substances that are similar in structure to hormonal estrogen but come from plant sources. There is not a lot of definitive evidence about the risks or benefits of any of these products in women with breast cancer, but as a general rule, the moderate amounts of most of these substances in foods are considered safe.

Therefore, I would not say that there is good evidence that any food needs to be avoided for women with breast cancer, but soy products, flax seed, and alcoholic beverages (which also increase estrogen in some situations) should be taken in moderation.

Stomach Cancer: How Immunotherapy and Targeted Therapy are Changing Treatment

The approval of a targeted therapy and an immunotherapy drug for some patients with advanced stomach cancer reflects recent new approaches to this difficult-to-treat cancer that hasn’t had many therapeutic advances in recent years.

Stomach cancer, uncommon in the United States but a leading cause of cancer death globally, causes few definitive symptoms in early stages and is usually diagnosed too late for curative therapy. The main treatment for stomach cancer is surgery to remove the tumor, combined with chemotherapy, which can be given before or after surgery. Radiation therapy may also be used in combination with surgery or chemotherapy.

Investigators led by Dana-Farber's Adam Bass, MD, led to the identification of four subtypes of stomach cancers.

Unlike many other types of cancer, stomach cancer research has seen few developments leading to precision therapies that can home in on molecular weak points to halt or shrink tumors. One such therapy, approved in 2010, targets a protein, HER2, that is over-expressed on the surface of about 20 to 25 percent of stomach cancers. The drug trastuzumab (Herceptin) was approved for use with chemotherapy in patients with HER2-overexpressing metastatic cancer of the stomach or gastroesophageal junction – the area where the stomach and esophagus meet. Other drugs that target HER2, such as lapatinib (Tykerb), pertuzumab (Perjeta), and trastuzumab emtansine (Kadcyla), are now being studied in clinical trials.

Immunotherapy drugs, which help the patient’s immune system seek out and destroy tumor cells, have proven very effective for some patients with advanced melanoma, non-small cell lung cancer, kidney cancer, and other cancer types. In September 2017, the U.S. Food and Drug Administration (FDA) approved pembrolizumab (Keytruda) for people with certain advanced cancers of the stomach or the gastroesophageal junction.

The approval applies to patients with advanced cancers, called adenocarcinomas, that have come back or continued to grow after having at least two previous treatments. The cancer cells must also test positive for the PD-L1 protein, which allows some cells to escape attack by the immune system. The FDA also approved a new lab test to check these cancers for the PD-L1 protein and determine whether the patient is likely to benefit from cancer drugs known as immune checkpoint inhibitors.

Pembrolizumab has also been approved to treat any type of tumor that is so-called MSI-High, meaning its cells exhibit microsatellite instability. A small percentage of stomach cancers have this characteristic.

In an effort to diagnose stomach cancer earlier, researchers are looking at known risk factors, such as mutations that run in certain families that increase the risk of the disease, although these are rare.

The strongest known risk factor for stomach cancer is infection with the H. pylori bacterium, which is found in about 50 percent of the world’s population. H. pylori infection causes chronic inflammation and increases the risk of developing ulcers and stomach cancer. However, most people whose stomachs harbor the bug don’t develop cancer.

Studies are being conducted to see whether antibiotic treatment of people who are chronically infected by H pylori will help prevent stomach cancer. Some studies have found that treating this infection may prevent precancerous stomach abnormalities, but more research is needed.

Another research effort, which has led to the identification of four subtypes of stomach cancers, highlights the complexity of the disease, and may eventually lead to more precise treatments. Investigators led by Adam Bass, MD, reported that analysis of 295 samples of stomach cancers revealed four groups that had distinct features and types of molecular alterations.

Bass, who directs the Center for Esophageal and Gastric Cancer at Dana-Farber, says that grouping the cancers this way will help researchers enroll patients in clinical trials that test drugs aimed at targeting their specific stomach cancer subtype.

How Can Bioinformatics Help Advance Precision Cancer Care?

Chris Sander PhD

Chris Sander, PhD, director of the cBio Center at Dana-Farber. Sander is co-founder of the computational biology field and a leader in applying its methods to cancer research.

Scattered amongst the letters of genetic code in a tumor cell are telltale mutations and DNA alterations that spur its malignant activity. But there are billions of letters of code and each patient’s cancer is different, with its own particular genetic changes. These changes may dictate how it behaves, how aggressively the cancer progresses, and it may spell out which molecular weaknesses might be successfully attacked with treatments.

Technology like the OncoPanel platform of Dana-Farber’s Profile research program can rapidly decipher the DNA code of 400 cancer-related genes in an individual’s tumors, detecting mutations, missing or extra copies of genes, and other changes. But it’s a process that generates massive volumes of digital data – data which mean nothing until processed and analyzed. Only then, may researchers and oncologists be able to prescribe a precision treatment to target the specific mutation. This is the goal of precision cancer medicine, but it’s often a needle in a haystack search.

Dana-Farber’s Chris Sander, PhD, founded and directs the new cBio Center at DFCI, along with Ethan Cerami, PhD, who leads the Knowledge Systems Group in the Center, to help researchers mine the genomic data, using a user-friendly web-based tool they developed called cBioPortal for 

The cBio Portal software digests the data and presents it in diverse visual formats that help investigators detect patterns of abnormalities across groups of patients and cancer types.

With cBioPortal, a researcher can tap into the Profile tumor base of nearly 8,000 genomic tumor profiles and rapidly compare the mutation pattern in one patient’s tumor to those of hundreds of other patients. Some cancers with certain mutations might have an approved drug targeting those changes; finding the same mutations in other tumor types may lead to new trials of that drug. “We will be able to use cancer genomics to define groups of patients who might be eligible for new kinds of genomically informed clinical trials,” says Sander.

The cBioPortal analysis tools can also help scientists sift genomic data for clues to why a few patients in a clinical trial had dramatic responses to a drug that had little benefit for the majority of other patients. The cause of this “exceptional response” may be a previously undiscovered mutation that made the tumor vulnerable to the drug – and cBioPortal analysis of genomic profile data may help scientists discover it.

The Center’s Knowledge Systems Group has also devised a clinically oriented tool called MatchMiner. “Clinicians use it to recruit patients for clinical trials,” Cerami explains. “They look in the Profile database for patients whose tumors’ mutations match targeted drugs in available clinical trials, and they can have MatchMiner notify them when appropriate new patients are identified.”

The scientists are now working on tools to enable oncologists and patients to sit down together and use MatchMiner to search for clinical trials of drugs targeted to their cancer’s specific mutation pattern.

Six Things to Do When You Learn You Have Cancer.

A cancer diagnosis can put even the most organized person into a state of disarray. That’s not surprising, because it’s normal to feel overwhelmed and out of control in the face of such stress. But there are steps you can take to ensure you’re best prepared for the road ahead. Don’t forget to:

Slow down and give yourself a chance to cope. Set aside time for yourself and your loved ones. It’s easy to feel isolated when you put up a strong front, so keep the lines of communication open with your family, friends, and doctors. Try to gain strength from one another by expressing your emotions honestly and openly.
Learn what services and programs are available. Many patients don’t take full advantage of support and resources simply because they haven’t had a chance to learn what’s out there. The National Cancer Institute offers advice for finding support resources in the general community. At Dana-Farber, patients and their loved ones can leaf through their patient handbook or talk with a concierge in the Shapiro Center for Patients and Families to learn about available programs (they can also call a concierge at 617-632-3750).
Accept help from others. Make a list of ways that friends and family can help, and suggest specific tasks. Friends or family members who assist with the day-to-day challenges of living with cancer can review the helpful advice and tips in Dana-Farber’s downloadable caregiver booklets.
Beth Overmoyer with patientLearn more about your cancer. Gather basic information about your diagnosis, to the extent that you feel comfortable. Take notes when your doctor or nurse explains something, or ask a loved one to do so. If you have questions before an appointment, write them down and ask them when you meet with your cancer care team. At Dana-Farber, you can research more about a cancer diagnosis with help from a trained volunteer or staff member in the Eleanor and Maxwell Blum Patient and Family Resource Center.
Step back and think about how you are coping. Everyone reacts to a cancer diagnosis in his or her own way, so it may help to turn to strategies that have helped you manage and reduce stress in the past. Ideas to consider: Practice relaxation techniques or attend a yoga class (both available through Dana-Farber’s Zakim Center). Rely on your preferred spiritual support. Start (or continue) an exercise routine. At most cancer centers, you can let your doctor or nurse know if you are feeling particularly stressed and they can help you make an appointment with one of our social workers.
Connect with others in your situation. Talking with someone who has previously dealt with cancer can be a great help. Dana-Farber’s One-to-One program links trained volunteer cancer survivors with those who are facing it for the first time. Similarly, CancerConnect offers an online forum where patients and family members can connect with cancer patients, doctors, survivors, family members, and friends for advice, support, and guidance.

Scientists find mutation driving pediatric brain tumors.

A type of low-grade but sometimes lethal brain tumor in children has been found, in many cases, to contain an unusual mutation that may help to classify, diagnose and guide the treatment of the tumors, report scientists at Dana-Farber Cancer Institute.

The researchers led a study of pediatric low-grade gliomas, samples of which were collected through an international consortium organized by brain tumor specialists at Dana-Farber/Children’s Hospital Cancer Center. Their findings are being published online by the Proceedings of the National Academy of Sciences (PNAS) the week of April 29.

Low-grade gliomas are the most common type of pediatric brain tumors, diagnosed in about 1,000 young patients annually in the United States. There are about 30 distinct types of these tumors, which arise from specialized cells called glia in the brain. Low-grade gliomas are generally slow-growing, said Keith Ligon, MD, PhD, a senior author of the study, but they behave unpredictably and can be life-threatening.

The investigators focused on diffuse low-grade gliomas, so-called because they lack a tumor mass but spread throughout the brain. As a result, diffuse gliomas often recur after surgery and are more likely to evolve into lethal glioblastomas than are non-diffuse low-grade tumors. “Many of these patients do well, but it’s hard to generalize, as the tumors are difficult to diagnose and study because without better tools pathologists can’t name them consistently,” explained Ligon, who in addition to being a researcher is also a neuropathologist. The research was undertaken in hopes of identifying a common genetic alteration that could be used to better define and design treatments for them.

The researchers analyzed DNA from 45 tissue samples collected from seven institutions in collaboration with Rameen Beroukhim, MD, PhD, a Dana-Farber genome biologist and co- senior author of the study. They looked for mutations caused by extra or missing copies of DNA code in the tumor genomes.

One alteration stood out: a gene called MYBL1, a transcription factor important for controlling other genes, was rearranged and missing a part of its genetic message in nearly 30 percent of the diffuse tumors categorized as grade 2 in terms of aggressiveness. The scientists went on to show that the mutated version of MYBL1 can cause tumors in mice. Previously MYBL1 was not known to cause cancer, but a closely related gene, MYB, is one of the oldest “proto-oncogenes” — a normal gene that can become a cancer-causing gene.

“The creation of these truncated genes, reminiscent in structure of the viral oncogene, is a potential driver for this type of tumor,” said Lori Ramkissoon, PhD, co-first author along with Peleg Horowitz, MD, PhD, a neurosurgery resident, both of Dana-Farber. “It gives us something to follow up on and investigate the function of this gene. It may lead to a specific test for diagnosing these tumors, and we will also try to determine whether patients who have this mutation do better or worse than those lacking the mutation.”

The paper’s other authors include investigators and clinicians from Dana-Farber; the Broad Institute; Brigham and Women’s Hospital; Boston Children’s Hospital; Stanford University School of Medicine; Children’s Cancer Hospital, Cairo, Egypt; University of Texas South Western Medical Center, Dallas; Hospital for Sick Children, Toronto; Children’s National Medical Center, Washington; Johns Hopkins University School of Medicine; and the University of Calgary.

Source: Dana-Farber/Children’s Hospital Cancer Center


Targeting cancers’ ‘addiction’ to cell-cycle proteins shuts down tumors in mice.

In what they say is a promising and highly selective treatment strategy, scientists at Dana-Farber Cancer Institute have safely shut down breast cancer and a form of leukemia in mice by targeting abnormal proteins to which the cancers are “addicted,” according to a new study.

Even though the investigators genetically silenced the proteins or blocked them with a drug in normal as well as cancerous tissues, the animals remained healthy, they report in the Oct. 16 issue of the journal Cancer Cell.

The experiments targeted two related proteins, cyclin D1 and cyclin D3, that control cells’ growth cycle. Many types of cancer have abnormal amounts of the proteins, spurring the cells to grow too rapidly and form tumors. Peter Sicinski, MD, PhD, the paper’s senior author, said that the new results show that the cancers’ addiction to these proteins is an Achilles’ heel that can be safely targeted with an inhibitor drug that halts cancer growth or causes cancer cells to die.

Based on the results, the Dana-Farber scientists are planning a clinical trial, using an experimental cyclin-inhibiting drug called PD0332991 that has already been tested in a form of lymphoma.

“It was impressive to find that you could target a single cyclin protein and completely clear the leukemia and the mouse remained healthy,” said Yoon Jong Choi, PhD, the study’s lead author. “We’re excited because we think this approach is very promising” as a potential treatment for some cancer types, she added.

Some of the experimental mice had been engineered to develop a type of breast cancer driven by the ErbB2 oncogene. Others were modified to develop a type of T-cell acute lymphoblastic leukemia (T-ALL) that is driven by an abnormal pathway known as Notch1. In one experiment, human T-ALL cells were infused into mice that then developed the disease.

Blocking cyclin D1 in the mice drove the breast cancer cells into a kind of permanent retirement called senescence, an irreversible halt to their growth cycle. Inhibiting cyclin D3 in the T-ALL leukemia mice caused the cancer cells to self-destruct — a programmed death process called apoptosis.

In addition to these tests with mouse cancers, the scientists found that the cyclin-D-inhibiting drug had similar effects on human blood cancer cells in the laboratory.

Cyclin proteins act as “checkpoint” guards to control cell’s cycle of rest, growth and division. The D-cyclins determine when a cell begins making DNA in preparation for dividing to form new cells. In many types of cancer, an excess of cyclins allows cells to grow too fast and form tumors. Abnormal cyclins D1, D2 and D3 are found in breast, lung, endometrial, pancreatic, and testicular cancers and in multiple myeloma and other blood cancers.

In a key report in Nature in 2001, Sicinski showed that mice engineered to lack cyclin D1 were resistant to developing breast cancer. It wasn’t known for many years, however, whether knocking out cyclin D1 could halt an established cancer, or if breast cancer needed the protein long-term.

Also unknown was whether normal cells could get along without cyclin D1: If not, treating cancer by targeting the protein might be too dangerous.

To test these questions, Choi and her Dana-Farber colleagues developed a strain of mice with cyclin D proteins that could be inactivated at any time by treating the mice with the drug tamoxifen.

“By generating these ‘conditional’ knockout mice, we could address these questions for the first time,” said Choi. The effect was global, affecting all the body cells, not just those that were cancerous. When the cyclin D proteins were turned off using this technique, the addicted cancer cells shut down while normal cells were unaffected.

The authors say the results show that blocking cyclin D “represents a highly selective anticancer strategy that specifically targets cancer cells without significantly affecting normal tissues.”

Other authors of the report include Xiaoyu Li, MD, PhD, a co-first author, and Harald von Boehmer, MD, PhD, of Dana-Farber, and Andrew L. Kung, MD, PhD, formerly at Dana-Farber and now at Columbia University.

Source: Dana-Farber cancer institute.



Dana-Farber compounds or creates medication tailored for individual patients.

News of unclean facilities and lax safety standards at the New England Compounding Center in Framingham has cast a public spotlight on compounding — a critical, but not widely known, sector of the pharmaceutical industry. To learn more about compounding, its role in cancer treatment, and its use at Dana-Farber, DFCI Online spoke recently with Sylvia Bartel, RPh, MHP, the Institute’s vice president of Pharmacy Services.


What is pharmaceutical compounding?

It’s the preparation of sterile products used to treat patients intravenously. Such medications could be chemotherapy agents, antiemetics (which prevent nausea and vomiting), support medications, or vaccines.

Does Dana-Farber’s pharmacy do compounding?

Yes. The dose of chemotherapy a patient receives is based on his or her height, weight, and individual health circumstances. Because those factors vary from patient to patient and visit to visit, we prepare patient-specific doses on-site.

What are the main types of medications compounded here?

In general, they’re chemotherapy agents and biotherapies (drugs that stimulate the body’s immune system defenses) that treat a patient’s cancer. We also prepare antiemetics, as well as intravenous fluid solutions that could contain potassium or magnesium to prevent the depletion of these nutrients in patients receiving chemotherapy.

Does Dana-Farber use products from the New England Compounding Center?

The only products we’ve purchased from the New England Compounding Center are two topical solutions (agents applied to tissue) used in gynecologic procedures.

What is done to ensure the safety of products compounded here?

We have numerous safeguards to ensure the proper preparation of sterile products. We train and monitor our staff in correct preparation techniques. We routinely test staff members’ sterile technique and the work environment for microbial growth. We’ve implemented a series of quality-control checks and report regularly to the Institute’s Infection Control Committee.

What specific safety precautions are in place?

We follow USP 797, a set of regulations developed by the United States Pharmacopeial Convention, a scientific organization that sets standards for the purity of medicines. The standards govern the preparation of sterile products in “clean rooms” where dust and foreign matter is kept below certain levels. Products are prepared within biological safety cabinets within the clean rooms. Before entering a clean room, the staff washes their hands and put on special clothing, much like that used in an operating room. Clean rooms undergo specific cleaning procedures on a daily, weekly, and monthly basis, and we routinely test surfaces from to ensure there is no microbial growth.

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Source: Dana-Farber cancer institute.

Researchers identify three subtypes of high-grade serous ovarian cancer.

Findings may indicate how patients will respond to treatment

New research led by Dana-Farber Cancer Institute scientists may soon enable doctors to determine which patients with high-grade serous ovarian cancer (HGSOC) – the most common cancer of the ovary – are most likely to benefit from a certain class of drugs.

Using technology able to pick out abnormalities in single units of the genetic code, the researchers sorted tumor samples from HGSOC patients into three subtypes based on the extent of a particular kind of genetic damage within the cells. Patients in the subtype with the highest levels of damage – representing one-third to one-half of all HGSOC patients – were the slowest to develop resistance to platinum chemotherapy treatment such as carboplatin. Overall, these patients lived longer without having their disease worsen than more did patients in the two other groups.

“Our findings suggest that, for the first time, we can determine which patients have the best chance of responding to specific categories of drugs for high-grade serous ovarian cancer,” says Dana-Farber’s Ursula Matulonis, MD, one of the senior authors of the study, which has been published online by the journal Clinical Cancer Research. “For this disease, one of the most difficult to treat of all gynecologic cancers, the study is an important step forward.”

J. Dirk Iglehart, MD, of Dana-Farber and Brigham and Women’s Hospital, is the paper’s other senior author, and Zhigang Wang, MD, PhD, of Dana-Farber, is the first author.

HGSOC cells have a high degree of “genomic instability,” their nuclei littered with large numbers of extra or missing chromosomes or chromosome fragments. One of the consequences of this havoc is a process known as loss of heterozygosity (LOH). LOH occurs in cells that lack the usual complement of two normal copies of each gene, having instead a normal and mutant copy of certain genes. When the normal gene in these mismatched pairs becomes inactive or mutated, the cell has no normal copy of the gene left – and is said to have lost heterozygosity.

In the study, investigators used single nucleotide polymorphism (SNP) arrays – technology that reads the elements of the genetic code one by one – to probe HGSOC tissue samples for instances of LOH. The samples tested fell neatly into three groups based on the patterns of LOH within them.

One of these groups was distinguished by a high level of LOH and a deleted segment of chromosome 13. When researchers reviewed the medical records of patients in this group, they found the patients were slow to develop resistance to chemotherapy drugs.

“Patients with the greatest burden of LOH had the longest progression-free survival – the period of time after treatment when their disease is not advancing,” says Wang. “This is the group which stands to derive the most from treatment with certain classes of drugs.”

LOH hampers cancer cells’ ability to survive, rendering the cells particularly dependent on proteins that repair damaged chromosomes. Drugs that target those repair proteins, including a class of agents known as PARP inhibitors, may be especially effective against HGSOC cells with high levels of LOH, the study authors assert.

The authors also found that LOH patterns in HGSOC were similar to those in triple-negative breast cancer, a form of breast cancer also characterized by a high level of chromosomal instability. The discovery suggests that agents effective in treating HGSOC might be effective against this type of breast cancer as well, the authors claim.