What are BRCA mutations?

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Angelina Jolie has put personalized medicine in the spotlight. Her mother died at age 56 following a 10 year battle with cancer. Jolie recently published a powerful New York Times op ed piece revealing her personal journey after testing positive for a BRCA mutation and her subsequent decision to have risk-reducing removal of her breasts and ovaries. In today’s blog, we turn to the basics of BRCA mutations. What are they, and what are the risks they pose?

BRCA stands for BReast CAncer susceptibility gene. We have BRCA1 and BRCA2, initially discovered by Dr. Claire King at the University of Washington, Seattle. You and I have BRCA genes; in fact we all do. They are tumor suppressor genes that help to keep your cells’ genetic material stable and to prevent cells from growing uncontrollably.

Among women, BRCA mutations (changes) have been associated with a marked increase in the risk of breast and ovarian cancer, often at an early age. On average, the risk of breast cancer increases from 12% (for the average woman in the USA) to about 60% or more among those with a BRCA mutation. The lifetime risk for ovarian cancer increases too, from about 1.4% in the general population to as much as 40%.

Unfortunately, there is more. BRCA1 mutations also increase the risk of cervix, uterus, colon, and pancreas cancer. And BRCA2 mutations also increase the risk of stomach, gallbladder, pancreas, and bile duct tumors as well as melanoma. Among men, BRCA mutations can increase the risk of male breast cancer, with BRCA1 mutations also associated with a higher risk of testicular cancer, and BRCA2 mutations increasing the risk for prostate cancer.

Genetic counseling can be remarkably informative. We will discuss who should consider BRCA testing in a future blog. Thank you. I’m Dr. Michael Hunter.

The small print: Anything stated here is for general use only, and should not be construed as medical advice for an individual. Please check with your health care provider with any questions or concerns.

Hot flashes in Cancer: Neutraceuticals for Treatment

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Over several blogs, I look forward to reviewing the biology of hot flashes, causes, and management tools. Today, let’s take a moment to look at neutraceutical medicines. Neutraceuticals include herbal medicines such as black cohosh and homeopathic herbs. The category also includes vitamins, and phytoestrogens (including soy and flaxseed). Historically, studies have been challenged by lack of standardization for the interventions. Let’s turn to some of these potential remedies for hotflashes.

Black cohosh: This herb is derived from the North American periwinkle plant, and has been well-studied for hot flashes among women with breast cancer, but not very much for symptoms linked to prostate cancer management. It acts on serotonin receptors, but does not have estrogen-like actions. While some historic trials showed effectiveness, modern trials do not show it to work among women without cancer. Some studies show it helps women who are on tamoxifen, but check with your doctor before you considering using it.

St. Johns’ wort: My review leads me to believe that this intervention does not work well. In addition, it can interact with some specific medicines.

Homeopathic herbs: While some observational trials have shown benefit, two randomized, controlled trials have not found homeopathic herbs to be effective against hot flashes, compared to placebo. We do not have high level evidence to suggest you should use this approach.

Vitamins: Vitamin E is one of the most investigated vitamins used to reduce hot flashes. First of all, some women should take caution: Heart disease, high blood pressure, and high blood pressure can present problems. There is some concern about inducing cancer, too. My read: Vitamin E may reduce hot flash incidence by 1 or 2 per day. Folic acid may help alleviate hot flashes, but more studies are needed.

Flax Seed: This rich source of lignans (a class of phytoestrogens) has been investigated in 3 prospective, randomized trials. There appears to be no benefit for women, and no good data for men.

Red clover: A randomized trial showed no benefit among women. No good data for men.

Soy isoflavones: A systematic review of 19 randomized studies (meta-analysis) suggests that soy may reduce hot flashes more than a placebo for women. The median dose was 54 mg per day. We don’t have much data about prostate cancer-related hot flashes and soy among men, but what is available is a bit conflicting.

Well, that’s it for today. Going forward, we’ll turn to other potential interventions. For now, I suggest exercise, and looking for triggers (for example, caffeine, heat, stress, alcohol, and spicy foods). I’m Dr. Michael Hunter.

Tamoxifen for 10 years has benefits

breast cancer tumor anatomy

 

Ten years of anti-estrogen treatment with tamoxifen appears to be better than the more standard 5 years in reducing the risk for breast cancer recurrence and death due to the disease. A trial conducted in the United Kingdom (aTTom, of adjuvant Tamoxifen Treatment offers more?) confirms the results from another international trial, the ATLAS (Adjuvant Tamoxifen, Longer Against Shorter). We saw the ALTAS results in late 2012. Now comes this new study, in which nearly 7,000 women received 5 years of tamoxifen and were then randomly assigned to either stop treatment or continue treatment to 10 years. The longer treatment group had fewer breast cancer recurrences (28% versus 32%), compared to the shorter use group. The risk of death dropped from 24% to 21% as well.

So what’s the downside? Well, there was an increase in endometrial (uterus) cancer in the long-term use group. In the longer treatment group, 1.1% died of endometrial cancer, compared to 0.6% in the shorter use group. Still, it is estimated that for every endometrial cancer death that occurs as a side of effect of long-term tamoxifen, there would be 30 deaths from breast cancer prevented. In addition, many women experience side effects such as hot flashes (and less commonly, vaginal discharge and dryness; joint pain). Perhaps not surprisingly, only 75% were continuing to take their tamoxifen as prescribed by the end of the study.

Who needs to pay close attention to these results? Premenopausal women with hormone receptor positive breast cancer might be the key group. In conclusion, while daily tamoxifen for 5years if the current worldwide standard for the treatment of hormone receptor-positve breast cancer (and reduces the risk of death), we now know that extending treatment beyond 5 years has benefits (that appear to outweigh the risks for most women). We often switch away from tamoxifen (to an aromatase inhibitor drug) for women who past menopause.

Breakthrough for eye melanoma

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For the first time, a systemic treatment has been found to be effective for a rare form of melanoma that affects the eye. This cancer is known as uveal melanoma, and it is one of the most challenging cancers to treat. Now comes an exciting report from the 2013 Annual Meeting of the American Society of Clinical Oncology pointing to a practice-changing development. A drug known as a MEK inhibitor appears to improve clinical outcomes for advanced disease. With the use of the drug Selumetinib, 50% of patients had some tumor shrinkage, and 15% had major tumor shrinkage. In the control arm (treatment with temozolomide), not a single patient had significant tumor shrinkage. The bottom line? This is the first study any systemic therapy has been shown to work among patients with ocular melanoma.

But… the drug will probably not be on the market for a couple of years. In this context, if you have advanced uveal melanoma, ask about clinical trials in which you might participate. I’m Dr. Michael Hunter

Addendum: MEK is a molecule that is activated by something called BRAF. When BRAF is mutated (changed) in melanoma, it directly activates MEK and unleashs a host of negative effects.

Gene flaws linked to black women’s greater breast cancer risk

African American young woman

We have long known that African-American women who have breast cancer have a higher risk of death from the disease. Now, we have learned that gene flaws that raise the risk of breast cancer are surprisingly common among blacks who have the disease. A study reported today found that roughly 1 in 5 of these women have BRCA mutations, a problem we typically associate with women of Eastern European Jewish descent. These findings may help to explain why black women have higher rates of breast cancer at young ages, in addition to a higher risk of breast cancer-related death. Dr. Jane Churpek, the study leader, was very surprised by the results.

The study included 249 black breast cancer patients from the Chicago area. Many had breast cancer at a young age, and half had a family history of the disease. Here’s where the investigators went beyond the usual genetic testing: All patients had complete gene sequencing for all 18 known breast cancer risk genes rather than the usual tests that simply try to find a few specific mutations in BRCA genes. The results? Gene flaws were found in 56, or 22% of study participants; 46 involved BRCA1 or BRCA2, and the rest were less commonly mutated genes. Among black women with “triple negative” (estrogen receptor negative, progesterone receptor negative, HER2 negative), or the worst subtype of breast cancer, 30% had harmful mutations.

To me, the results point to the fact that too few African-American women have been included in genetic studies in the past. We really had no clue about the extent of mutations among this population. And if a parent has a BRCA mutation, children have a 50% chance of getting the gene. Today, we have more knowledge about the specifics of the gene problem among African American women with breast cancer. I’m Dr. Michael Hunter.

Physical activity after a breast cancer diagnosis

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I always counsel my patients about the role of physical activity in recovery. Almost inevitably, they are surprised that I ask them not to run a marathon, or work out for hours at the gym. In fact, I suggest doing what our grandparents did: WALK! So why do I focus on physical activity? Even light exercise may reduce the risk of death from breast cancer. In the Nurses’ Health Study, the greatest benefit occurred among women who did the equivalent of walking 3 to 5 hours per week at an average pace. In fact, there was little evidence of a link between increased benefit and greater energy expenditure. In addition, several studies have associated physical activity (after a breast cancer diagnosis) with improved quality of life. (http://jama.jamanetwork.com/article.aspx?articleid=200955#REF-JOC50040-4)

Physical activity can also reduce the risk of getting breast cancer. An expert panel of the International Agency for Research on Cancer of the World Health Organization estimated a 20% to 40% decrease in the risk of developing breast cancer among the most physically active women, regardless of menopausal status, type, or intensity of activity. (www.ncbi.nlm.nih.gov/pubmed/12119660) 

Physical activity has been linked to lower levels of circulating ovarian hormones, which may explain the association between physical activity and lower risk of breast cancer. Lower estrogen levels among physically active women with breast cancer could potentially improve survival, although we still need more data. However, irrespective of the amount of benefit in the breast cancer arena, why would you not want to lower your risk of other cancers, heart attack, stroke, diabetes, and maybe even dementia?

Erlotinib targeted therapy approved for metastatic lung cancer

Metastatic lung cancer is cancer that originated in the lungs and has spread to distant organs. It tends to go wherever the blood goes, including the liver, the bones, elsewhere in the lungs, and the brain. It is, alas, not curable. Still, chemotherapy and targeted therapies offer the possibility of improved quality of life, and can lengthen life as well. Hot off the press is news that the US FDA has approved a targeted therapy (erlotinib, also known as Tarceva) for the treatment of patients whose cancers have spread and who in addition have tumors that have something known as an epidermal growth factor receptor EGFR) mutation. Let’s take a closer look at this fascinating EGFR protein. There is a family of glycoproteins that poke out of the cell surface like antennae. We call them HER1, HER2, HER3, and HER4. In some patients with lung cancer, the HER1 is over expressed; there are too many of them. When the growth signal hits the EGFR receptor, it causes it to join arms with other HER family members, fueling the growth of the cell. Erlotinib (a pill) targets the EGFR.

On May 14, 2013, the US Food and Drug Administration (FDA) approved the use of a drug that targets the EGFR receptor. Here’s why the FDA took the step: A randomized, multicenter trial compared erlotinib (86 patients) to the more commonly used combination of a platinum chemotherapy drug with another drug (we call this a platinum doublet). All patients had to have an EGFR mutation.

The majority of the patients were female (72%), Caucasian (99%), never-smokers (69%), and had adenocarcinoma histology (93%). The median progression free survival (half of patients had progression by this point, half did not) was 5.2 months in the platinum doublet chemotherapy arm, and 10.4 months in the erlotinib arm. And the survival was a bit better with erlotinib, too: 22.9 months versus 19.5 months. The majority of the patients in the platinum-based chemotherapy arm (82%) subsequently received an EGFR tyrosine kinase inhibitor following investigator-determined disease progression.

What’s the downside of erlotinib? The most frequent (greater than or equal to 30%) adverse reactions of any grade in the erlotinib arm were rash, diarrhea, asthenia, cough, dyspnea and decreased appetite. The most frequent (greater than or equal to 5%) grade 3-4 (bad) adverse reactions in the erlotinib arm were rash and diarrhea. The recommended daily dose of erlotinib for NSCLC is 150 mg taken orally at least one hour before or two hours after the ingestion of food. Treatment should continue until disease progression or unacceptable toxicity.

Thank you for visiting. I’m Dr. Michael Hunter.

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Coming later this month: Understand Lung Cancer in 60 Minutes, an e-book for IPad.