DCIS: Can We Lower the Tamoxifen Dose?

Today’s brief missive is directed at those who have a “pre-cancer” of the breast; more specifically, we ask Can use a lower dose of a drug (tamoxifen) for those with non-invasive breast cancers such as ductal carcinoma in situ (DCIS), lobular carcinoma in situ (LCIS), and atypical ductal hyperplasia (ADH)?

Non-invasive Breast Cancer

Daily use of low-dose (5 mg) tamoxifen (multiple brands) for a shorter-than-usual treatment period (3 years) for patients with ductal carcinoma in situ (DCIS) and other forms of noninvasive breast cancer halved the recurrence of new breast cancer events in comparison with placebo, a new Italian study (TAM-01 clinical trial) indicates.

Tamoxifen is typically prescribed post surgery at a dosage of 20 mg/day for 5 years for DCIS and these other conditions, said lead study author Andrea De Censi, MD, of the National Hospital EO Ospedali Galliera – SC Oncologia Medica in Genoa, Italy.

Tamoxifen was developed in the 1960s, but the minimal effective dose has never been established, he said during a press briefing here at San Antonio Breast Cancer Symposium (SABCS) 2018, where the study was presented.

De Censi and colleagues hypothesized that a reduced dose and a shorter duration would be effective. That idea was based on a 2003 study from this same Italian group, which showed that 5 mg of tamoxifen was comparable to 20 mg in reducing breast cancer proliferation, as measured by Ki-67 level.

Lower Dose Tamoxifen Pills

In the new 500-patient trial, 5.5% patients in the low-dose tamoxifen arm (n = 14 of 253) had either experienced disesase recurrence or had new disease, including invasive disease, compared with 11.3% in the placebo arm (n = 28 of 247). The median follow-up was 5.1 years.

With the low dose, rates of occurrence of two worrisome side effects of tamoxifen — endometrial cancer (which is rare), and deep vein thrombosis (DVT)/pulmonary embolism (PE) — were not different from the rate seen among the patients taking placebo, reported De Censi. Menopausal symptoms, the other common side effect, were not worsened, with the exception of hot flashes, in which the drug had a borderline effect.

But…

Prescribing low-dose tamoxifen involves a twist, De Censi explained. A 5-mg pill is not currently available, so patients need to take a 10-mg pill every other day. In a press statement at the meeting, De Censi said that the new results are “practice changing.”

“Tamoxifen 10 mg every other day is applicable in practice [starting] from tomorrow,” he told reporters.

Added the conference session moderator: “Looking at these data, especially for the ADH and LCIS patients, I would definitely give lower doses of tamoxifen,” she said, explaining that the data were most compelling for those two groups.

I’m Dr. Michael Hunter. I’m Dr. Hunter and I thank you for joining me today. Please click the Wellness! title above to explore more. Thank you.

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I received an undergraduate degree from Harvard, a medical degree from Yale, and completed a residency in radiation oncology at the University of Pennsylvania. I have been blessed to be named a “top doctor” in Seattle Magazine, US News & World Report, Seattle Metropolitan Magazine, 425 Magazine, and WA magazine. On multiple occasions, readers of the Kirkland Advertiser have voted me the top doctor (in any field) in the region. I help individuals with cancer at Evergreen Hospital, just outside Seattle. And now the small print: Any information provided herein is not to serve as a individualized advice, and I encourage you to check in with a valued health care provider. Thank you.

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Medscape reference

Chemo Brain: Why?

Today’s blog is not directed at most of you. But we will turn to a topic important to anyone who has received chemotherapy, or cares for (or about) someone who has received the drugs.

So-called chemo brain is becoming increasingly common as cancer therapies increasingly allow patients to live many years beyond their diagnoses. Alas, the cognitive side effects of cancer treatment be debilitating and long-lasting. Many of my patients cannot return immediately to work, and children may struggle academically.

Now comes a study published in the 06 December 2018 issue of cell. Researchers at Stanford (go Cardinal!) have identified some of the reasons for chemo brain, and point to a solution.

Inside the Brain’s White Matter

In addition to neurons, which transmit nerve impulses, the brain’s white matter contains other cells that help the neurons function. The research focused on three types of those cells: oligodendrocytes, which produce and maintain myelin, the fatty insulating sheath around nerve fibers; astrocytes, which link neurons to their blood supply, promote proper connections between neurons and maintain the neurons’ environment; and microglia, immune cells that can engulf and destroy foreign invaders in the brain, as well as sculpt neural circuitry.

Comparing post-mortem frontal lobe brain tissue from children who had and had not received chemotherapy, the researchers showed that there were far fewer oligodendrocyte lineage cells in the brains of the chemotherapy-treated children.

The Study: Injecting Mice with Chemotherapy and Examining their Brains

To figure out what was happening to these cells, the researchers injected young mice with methotrexate at levels designed to replicate human exposures during cancer treatment. The mice received three doses at weekly intervals. Four weeks later, the researchers compared the mice’s brains to those of mice that had not received the drug.

Methotrexate chemotherapy was found to damage the brain’s populations of oligodendrocyte precursor cells. Normally, these cells can quickly divide to replace any that are lost, but after methotrexate was administered, this self-renewal process did not happen correctly. More precursor cells than normal were starting down the path of maturation to oligodendrocytes, but they were getting stuck in an intermediate, immature state. The same problem was seen in mice brains six months after methotrexate was administered.

Transmission electron microscopy of the mouse brains after methotrexate administration revealed deficiencies in the thickness of the myelin insulation around nerve fibers, similar to changes in the brains of humans who have received chemotherapy. Mice exposed to methotrexate also exhibited behavioral problems after four weeks that were similar to humans with chemo brain, including motor impairment (slower movement of their forepaws), signs of anxiety on an “open field” test used to assess how threatened the animal feels in an unsheltered environment, and impaired attention and short-term memory function, evidenced by the inability to discern between novel and familiar objects — a symptom that persisted for six months after methotrexate was given.

The researchers injected oligodendrocyte precursor cells from healthy animals into the brains of animals that had received methotrexate to see if the cells’ maturation problems were caused by some aspect of the brain environment after chemotherapy. The precursor cells still began maturing at higher-than-normal rates but did not get stuck partway through the maturation process, indicating that the brain environment was partly responsible for the cells’ abnormal maturation.

Microglial Activation

Further study showed that microglia, the brain’s immune cells, were persistently activated after methotrexate exposure for at least six months. The activated microglia caused problems for astrocytes, the cells that help neurons get nutrients and function properly. Administering a drug that selectively depleted microglia to mice that had been treated with methotrexate reversed many of the cognitive symptoms of chemo brain and reversed the abnormalities in maturation of oligodendrocyte precursor cells, activation of astrocytes and myelin thickness.

More research is needed to understand exactly how the different cell types are signaling to each other, as well as when and how medications could be best deployed against chemo brain. I’m Dr. Michael Hunter. Explore more here: Two Major Cancer Risk Factors

I received an undergraduate degree from Harvard, a medical degree from Yale, and completed a residency in radiation oncology at the University of Pennsylvania. I have been blessed to be named a “top doctor” in Seattle Magazine, US News & World Report, Seattle Metropolitan Magazine, 425 Magazine, and WA magazine. On multiple occasions, readers of the Kirkland Advertiser have voted me the top doctor (in any field) in the region. I help individuals with cancer at Evergreen Hospital, just outside Seattle. And now the small print: Any information provided herein is not to serve as a individualized advice, and I encourage you to check in with a valued health care provider. Thank you.

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Stanford Research on So-Called Chemo Brain

Breast Cancer Relapse: New Clues

Today, I wanted to chat less about wellness, and turn to breast cancer; more specifically, to a generally favorable type driven by estrogen. Why might some patients with this entity relapse, while most do not?

A large genomic analysis has linked certain DNA mutations to a high risk of relapse in estrogen receptor positive breast cancer, while other mutations were associated with better outcomes, according to researchers from Washington University School of Medicine in St. Louis, the Baylor College of Medicine and the University of British Columbia. The study appears Sept. 4 in the journal Nature Communications.

Why might this finding be important? The knowledge could help predict which patients are most likely to have their cancer return and spread, and could help guide treatment decisions. It also opens the door to developing more aggressive treatments for patients with the newly identified high-risk mutations.

The researchers analyzed tumor samples from more than 2,500 patients with estrogen receptor positive breast cancer, one of the most common forms of the disease. These cancer cells have receptors that bind to the hormone estrogen in the nucleus of the cell and drive tumor growth.

Management options

Estrogen receptor positive (ER +) breast cancer patients have a number of treatment options that block the estrogen receptor to stop tumor growth. Such hormonal therapies are effective and less toxic than traditional chemotherapy and radiation. But some tumors develop resistance to these treatments, mutating in ways that fuel growth independent of the presence of estrogen. These types of mutations are of great interest because they are responsible for the majority of deaths due to breast cancer.

Why recurrence?

The new study confirmed past work showing that relatively common mutations in genes called MAP3K1 and TP53 had opposite effects on tumor aggressiveness. Patients with MAP3K1 mutations did well, while those with TP53 mutations were likely to have a recurrence. The study also identified three genes — DDR1, PIK3R1 and NF1 — with relatively uncommon mutations that were associated with cancer recurrence and spreading.

Going forward, these genes will likely be included in gene panel tests, particularly when clinical trials are developed that target these mutations. Scientists now have enough healthy genomes sequenced to be able to compare, on a broad population level, normal genomes to cancer genomes and use big data bioinformatics methods to pull out the mutations likely to be driving cancer, even in old samples that can’t be directly compared with healthy DNA from the same patient. This study illustrates that continuing breast cancer gene sequencing may yield information that may help with establishing prognosis, and give us new targets for treatment. I’m Dr. Michael Hunter.

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_________________________

I received an undergraduate degree from Harvard, a medical degree from Yale, and completed a residency in radiation oncology at the University of Pennsylvania. I have been blessed to be named a “top doctor” in Seattle Magazine, US News & World Report, Seattle Metropolitan Magazine, 425 Magazine, and WA magazine. On multiple occasions, readers of the Kirkland Advertiser have voted me the top doctor (in any field) in the region. I help individuals with cancer at Evergreen Hospital, just outside Seattle. And now the small print: Any information provided herein is not to serve as a individualized advice, and I encourage you to check in with a valued health care provider.

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https://www.sciencedaily.com/releases/2018/09/180904114708.htm

Stage IV Breast Cancer: Some Good News

I recently had a patient who presented with Stage IV (cancer associated with spread to distant sites such as the lungs, liver, bone, or brain). Given her cancer is associated with HER2 over-expression, I wondered what her long-term odds of survival would be. A retrospective study provides some answers:

For those who are found to have distant spread of cancer at initial diagnosis, patients with HER2-positive breast cancer treated with HER2-directed therapy had a median overall survival of 5.5 years. And for the 13 percent of patients who achieved a no evidence of disease status, the 5 year progression-free survival odds were an amazing 100 percent! Amazingly, the results held at the ten year mark.

For the unfortunate group of patients who did not achieve a no evidence of disease status, the 5 year progression free survival rate was 12 percent, and the overall survival rate 45 percent. By ten years, these numbers dropped to 0% for progression free survival, and only 4 percent for overall survival.

Now, some details… The results were the product of an analysis of 483 patients diagnosed between 1998 and 2015 at M.D. Anderson Cancer Center and Yale. All patients received Herceptin (trastazumab), and 20 percent also received pertuzumab as first-line therapy.

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Thank you.

_________________________

I received an undergraduate degree from Harvard, a medical degree from Yale, and completed a residency in radiation oncology at the University of Pennsylvania. I have been blessed to be named a “top doctor” in Seattle Magazine, US News & World Report, Seattle Metropolitan Magazine, 425 Magazine, and WA magazine. On multiple occasions, readers of the Kirkland Advertiser have voted me the top doctor (in any field) in the region. I help individuals with cancer at Evergreen Hospital, just outside Seattle. And now the small print: Any information provided herein is not to serve as a individualized advice, and I encourage you to check in with a valued health care provider.

Oncologist 2018 Aug 23;[EPub Ahead of Print], Y Wong, AS Raghavendra, C Hatzis, JP Irizarry, T Vega, N Horowitz, CH Barcenas, M Chavez-MacGregor, V Valero, D Tripathy, L Pusztai, RK Murthy

Breast Cancer: Are You Over 70?

The 21-gene recurrence score (RS), known as OncoType Dx is a fabulous way of interrogating the breast cancer genome to ask some simple, but critical questions: Are you a secretly aggressive cancer? Would you respond to chemotherapy or not? While the test can be invaluable for select patients with hormone receptor positive breast cancer, the OncoType has not been validated in an older cohort with estrogen receptor-positive breast cancer.

The study

Now comes a study of the US Surveillance, Epidemiology, and End Results (SEER) database with available OncoType Recurrence Scores. Researchers evaluated women with estrogen receptor-positive breast cancer ages 18 to 69 and those 70 years of age and older from 2004 to 2014. They presented their results in the Journal of Geriatric Oncology earlier this month.

The results

Among patients with a high-risk recurrence score, chemotherapy was associated with a decreased risk of death in the younger group, but not the older group.

My take

Older women are less likely to have OncoType testing (8 percent versus 18 percent), but when tested, older patients have a similar distribution of Recurrence Scores as do the younger women. However, while being in the high-risk group was prognostic irrespective of age, chemotherapy was not associated with an improved survival for the older population. I’m Dr. Michael Hunter.

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_________________________

I received an undergraduate degree from Harvard, a medical degree from Yale, and completed a residency in radiation oncology at the University of Pennsylvania. I have been blessed to be named a “top doctor” in Seattle Magazine, US News & World Report, Seattle Metropolitan Magazine, 425 Magazine, and WA magazine. On multiple occasions, readers of the Kirkland Advertiser have voted me the top doctor (in any field) in the region. I help individuals with cancer at Evergreen Hospital, just outside Seattle. And now the small print: Any information provided herein is not to serve as a individualized advice, and I encourage you to check in with a valued health care provider.

Breast Cancer: Can THIS Lower Your Risk?

I hope you are having a great day. Here in Seattle, we are looking at sunny and a temperature of 71F (22C). While we have largely focused on wellness (including musings on the benefits of meditation and of sex), today I want to talk a bit about a recent study from researchers from the University of California, San Diego (USA). I am often asked about vitamins and cancer risk reduction, and to be frank, most studies have not shown a benefit to taking vitamins, at least with respect to cancer risk reduction; here, I am a big advocate of getting our cancer-fighting nutrients through diet.

A lower risk of breast cancer is found among older women who have greater levels of vitamin D, according to a study from the University of California, San Diego.

While the study doesn’t prove cause and effect, it’s the latest among many that find those with higher levels of vitamin D have lower risks of various diseases. It was recently published in the journal PLOS ONE, and can be found at j.mp/vitdbcancer.

Women with the highest levels of vitamin D in the blood had 20 percent of breast cancer risk as those with the lowest levels.

Researchers used data from two randomized clinical trials with a total of 3,325 participants, and another study with 1,713 participants. All participants were women 55 and older. Their blood was examined between 2002 and 2017 for the main form of vitamin D in the blood. 25(OH)D. This was correlated with any diagnosis of breast cancer.

Over the course of the studies, 77 new cases of breast cancer were diagnosed. Participants with blood levels above 60 nanograms per milliliter had just 20 percent of the risk, compared to those those with less than 20 ng/ml.

But…

The official recommended level of vitamin D is set at 20 ng/ml by the National Academy of Medicine, an advisory body to the president and Congress on health issues. The issue remains hotly debated, in part because the evidence at this point is mostly associational, not causal.

“Increasing vitamin D blood levels substantially above 20 ng/ml appears to be important for the prevention of breast cancer,” co-author Sharon McDonnell, an epidemiologist and biostatistician for GrassrootsHealth, said in a statement.

Garland said the study was limited to postmenopausal breast cancer, and mainly included white women. So more research is needed on whether high vitamin D levels might protect against premenopausal breast cancer, including other ethnic groups,

To reach the recommended blood level of vitamin D, Garland said daily supplements of 4,000 to 6,000 international units are required. This can also be achieved at low latitudes, such as in Southern California, by wearing minimal clothing in the sun for 10 to 15 minutes per day.

The National Academy of Medicine recommends 400 IU of vitamin D3 daily for infants; 600 IU for those 1 to 70 years, and 800 IU for those over 70.

Other studies have examined the correlation of various diseases with exposure to sunshine, which the body uses to produce vitamin D. The studies found lower incidences of various diseases with lower latitudes, and higher levels at higher levels. When charted, this association produces a curve that’s called the “vitamin D smile.”

Not So Fast…

Now, should you run out and start taking a ton of vitamin D? We have no evidence that doing so will reduce your risk of breast cancer. Everything in moderation. For me, that means a sojourn to Hawaii in February, as we can make 5,000 IU in 10 to 15 minutes of “reasonable” sun: That means 8 to 10 in the morning, after 4 in the afternoon. No sunburns, please! I’m Dr. Michael Hunter, and I thank you for letting me ramble a bit on this sunny and glorious Seattle Tuesday!

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_________________________

I received an undergraduate degree from Harvard, a medical degree from Yale, and completed a residency in radiation oncology at the University of Pennsylvania. I have been blessed to be named a “top doctor” in Seattle Magazine, US News & World Report, Seattle Metropolitan Magazine, 425 Magazine, and WA magazine. On multiple occasions, readers of the Kirkland Advertiser have voted me the top doctor (in any field) in the region. I help individuals with cancer at Evergreen Hospital, outside Seattle. Any information provided herein is not to serve as a substitute for the good judgment of your valued health care provider. Thank you.

References

Primary source

Vitamin D and Breast Cancer

Breast Cancer: Omega-3 Fatty Acids for Side Effects

While I have spent the last several days blogging about mindfulness (and meditation in particular), today I want to talk about a challenging problem for many women with breast cancer. The vast majority of breast cancer feeds off the “female” hormone estrogen; that is, they tend to be hormone receptor positive (estrogen- and/or progesterone receptor positive).

For women who have completed menopause, we often offer pills that target the estrogen creation pathway, using drugs known as aromatase inhibitors. Unfortunately, about half of patients will experience associated pain in bones, joints, or muscles. This prompts many to simply quit this prognosis-improving drug. Researchers recently used a retrospective analysis of the use of omega-3 fatty acids to see whether it could reduce pain. Here’s what they found:

Omega-3 fatty acids significantly reduced pain among very overweight women who take aromatase inhibitors (AIs) for breast cancer.

The findings are potentially good news because, among postmenopausal women with hormone receptor–positive breast cancer, aromatase inhibitors can prolong survival but are often discontinued because of often severe joint pain.

The new results come from the Southwest Oncology Group (SWOG) Study S0927, a 24-week randomized controlled trial of omega-3 fatty acids versus placebo (inert pill) for aromatase inhibitor-related bone pain. The original results were disappointing, showing no difference in pain reduction between the treatment and placebo groups.

However, researchers suspected that heavier women were benefitting from the therapy. So, in the new study, they divided the women into two groups by weight. Among the 249 participants, 139 had a body mass (BMI) less than 30 (56%) and 110 had a BMI of 30 or higher (44%).

Joint-specific symptoms were also significantly lower at 24 weeks (compared to baseline) in the omega-3 fatty acid group  — but only in women with a BMI of 30 or more, said Shen.

The study results must be confirmed in a prospective trial in order for omega-3 fatty acids to be fully deemed beneficial. Still, seems wonderful that we may have a new tool for dealing with pain associated with aromatase inhibitor use among obese women.

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_________________________

I received an undergraduate degree from Harvard, a medical degree from Yale, and completed a residency in radiation oncology at the University of Pennsylvania. I have been blessed to be named a “top doctor” in Seattle Magazine, US News & World Report, Seattle Metropolitan Magazine, 425 Magazine, and WA magazine. Readers of the Kirkland Advertiser have voted me the top doctor (in any field) in the region. I help individuals with cancer at Evergreen Hospital, outside Seattle. Any information provided herein is not to serve as a substitute for the good judgment of your valued health care provider. Thank you.