Femara for Breast Cancer: October News and Research

October has been hopping with news and research about the aromatase inhibitor Femara (letrozole) for breast cancer. Today we'll share the five latest studies and the headlines about them. Links may be found on the Femara (letrozole) page of our website.

Femara more effective than tamoxifen

The big story this month was an October 21 study in The Lancet Oncology which compared 8 year recurrence and survival rates for postmenopausal women taking Femara, tamoxifen or a sequential combination of both for early-stage, hormone-receptor positive breast cancer. The study is known as the Breast International Group (BIG) 1-98 study. The New York Times, The Telegraph (UK), US News and World Report/HealthDay and Medical News Today all ran stories.

According to the study, Femara alone resulted in a reduction in breast cancer recurrence and death compared to tamoxifen alone. Sequential use of tamoxifen and Femara, in any order, did not improve outcome compared to Femara alone, "but might be useful strategies when considering an individual patient's risk of recurrence and treatment tolerability."

Femara improves response to chemotherapy before surgery

Not all of the October Femara studies made headlines. An October 16 study in Breast Cancer Research and Treatment evaluated the addition of Femara to chemotherapy before surgery for postmenopausal women with locally advanced breast cancer. For women with hormone-receptor positive breast cancer, the addition of Femara to chemotherapy improved clinical and pathological response rates with "acceptable toxicity" compared to chemotherapy alone.

Femara reduces bone mineral density

Not all Femara news this month was good. An October 14 Annals of Oncology study evaluated bone loss in women in the BIG 1-98 study discussed above. It found that Femara use was associated with a reduction in bone mineral density, whether used alone or in sequence with tamoxifen, when compared to the use of tamoxifen alone. In fact, the "sequential schedules were as detrimental for bone density" as taking Femara alone.

Zometa improves bone mineral density for women taking Femara

There may be a way to reduce the risk of bone loss associated with Femara. An October 10 study in the journal Cancer compared the immediate use of Zometa (zoledronic acid) with the delayed use in postmenopausal women with early breast cancer taking Femara for 5 years. The trial is known as Z-FAST. The Los Angeles Times and Medical News Today covered the study.

According to the study, taking Zometa (zoledronic acid) with Femara "upfront," from the beginning, "significantly and progressively" increases bone mineral density, compared with a delayed start of Zometa. The authors also found that "long-term coadministration of letrozole and zoledronic acid is well tolerated."

Another study evaluated the data from the Z-FAST trial. Whereas the October 10 Cancer study looked at bone mineral density at 5 years, an October 17 study in Clinical Breast Cancer evaluated the data at month 12. It also found that immediate use of Zometa prevented bone loss and increased bone mineral density, "regardless of BMD [bone mineral density] at baseline."

These are only the five most recent studies on Femara (letrozole) for breast cancer. For two years of news and research, plus overviews and FDA information, please check the Femara (letrozole) page of our LATESTBreastCancer.com website. From the home page, click the Treatments tab and search for 'Femara' in the search box on the top right of the page.

We'll continue to follow developments in breast cancer research. Links are added to our website daily and interesting findings are highlighted here. Please stay tuned.

Herceptin for Small, Early-Stage Breast Cancer: Does Tumor Size Matter?

When it comes to Herceptin for HER2 positive breast cancer, does tumor size matter? What if the tumor is very small? Should Herceptin still be considered? Today we'll share the latest research on Herceptin (trastuzumab) for women with small, node-negative, HER2 positive breast cancer.

Clinical Breast Cancer: HER2 positive breast cancer has a higher risk of recurrence than other breast cancers

A July 15 Clinical Breast Cancer study from MD Anderson compared the risk of recurrence for women with different breast cancer subtypes. All of the women had small (less than 2cm), node-negative breast cancer. None were treated with chemotherapy or Herceptin.

The study found that women with HER2 positive breast cancer had a greater risk of recurrence than women with hormone-receptor positive breast cancer. Triple-negative breast cancer also had a greater risk than hormone-receptor positive breast cancer, but the difference was not as high as with the HER2 group.

Cancer (6/16): Herceptin plus chemotherapy beneficial for tumors 2cm or less

A June 16 study in Cancer from the Memorial Sloan-Kettering Cancer Center compared recurrence rates for women treated with and without Herceptin plus chemotherapy for small (2cm or less), node-negative, HER2 positive breast cancer. Based on their comparison, the authors concluded, "Women with small, node-negative, HER2+ primary breast cancers likely derive significant benefit from adjuvant trastuzumab with chemotherapy."

Cancer (9/1): Herceptin reduces recurrence after lumpectomy for tumors 5cm or less

A September 1 study in Cancer from the Memorial Sloan-Kettering Cancer Center compared localregional recurrence rates (LRR) for women treated with or without Herceptin after lumpectomy (breast conserving surgery) and radiation. All women had node-negative, HER2 positive breast cancer measuring 5cm or less.

According to the conclusion, "Even among women with lower risk breast cancer, the relatively high locoregional failure rates associated with positive HER2 status could be reduced markedly with adjuvant trastuzumab chemotherapy." Within 3 years, there was a 10% recurrence rate for women not treated with Herceptin compared to a 1% rate with Herceptin.

Internal Medicine News: Uncertainty for tumors less than 1cm

An August 16 Internal Medicine News article discussed the uncertainty about Herceptin for women with very small (less than 1cm), node-negative, HER2 positive breast cancer.

Although studies such as the July 15 Clinical Breast Cancer study above suggest a higher risk of recurrence for small, HER2 positive breast cancer, an American Society of Clinical Oncology (ASCO) presentation suggested that for women with very small tumors (1cm or less), the risk of recurrence may be so low that the benefit of Herceptin may not be worth the risk of cardiovascular disease.

Nonetheless, Dr. Gabriel Hortobagyi from MD Anderson was quoted to say he discusses Herceptin and chemotherapy with anyone with HER2 positive breast cancer, regardless of tumor size.


For more on Herceptin for HER2 positive breast cancer, including two-years worth of news, research and overviews, please visit the Hercetpin (trastuzumab) page of our website. From the home page of our site, click the "Treatments" tab and search for "Herceptin" in the box in the top right corner.

Radiation Therapy for Breast Cancer: Three New Studies

What's new in breast cancer radiation therapy news? Last week we added three studies on radiation to the LATESTBreastCancer.com database and website. Topics include postmastectomy radiation, radiation of the axilla and heart related side-effects.

Radiation after mastectomy reduces recurrence rates in women with large breast tumors

An August 20 study from MD Anderson in the International Journal of Radiation Oncology, Biology Physics examined recurrence rates of 162 patients with clinically T3N0 tumors who were treated with neoadjuvant (before surgery) chemotherapy and mastectomy. 'T3' means the tumors were larger than 5 cm. 'N0' means there was no lymph node involvement. (For some of the patients, pathological evaluation later revealed lymph node involvement.)

The study revealed that women who also received postmastectomy radiation were less likely to experience a local-regional recurrence (LRR) than those who did not receive radiation. Postmastectomy radiation reduced recurrence rates in women with and without lymph node involvement. Accordingly, the authors suggested that postmastectomy radiation be considered for women with T3N0 breast cancer.

Whole breast radiation is sufficient to prevent lymph node recurrence after sentinel lymph node procedure

An August 31 study in Cancer from the Memorial Sloan-Kettering Cancer Center evaluated the effectiveness of whole breast irradiation in preventing lymph node recurrence in 326 women with positive sentinel lymph nodes (SLNs) who did not undergo axillary lymph node dissection. Instead of removing all lymph nodes in the axilla area, only the sentinel lymph nodes were removed. 93% received some sort of radiation therapy.

After 4 years, 3 of the 326 women experienced a lymph node recurrence. Two of them received radiation in the standard supine (face-up) position. One did not receive radiation at all. There was no lymph node recurrence among the 66 who received radiation in the prone (face-down) position.

The authors concluded that regional control was high (99% at 4 years) in women with low-volume sentinel lymph node disease, "regardless of whether the axilla was irradiated." They noted,

"Whole-breast radiation alone, including in the prone position, is sufficient treatment after breast-conserving surgery for select patients with tumor-containing SLNs who omit axillary dissection."

Risk of cardiovascular disease after radiation is greater in older women with left-side breast cancer

An August 30 study in Cancer Epidemiology, Biomarkers & Prevention evaluated the risk of cardiovascular disease in 806 women over 65 with early stage breast cancer.

As a group, radiotherapy was not associated with a greater risk of cardiovascular disease. However, among women who received radiation, those who were treated for cancer of the left breast had a significantly increased risk of cardiovascular disease compared to those with right-side breast cancer.

The authors concluded that laterality (the side of treatment) "is critical to understanding the effect of" radiotherapy on cardiovascular disease. "As some irradiation to the heart is unavoidable, . . . continued effort is required to minimize such exposures, especially in older women with left-sided tumors."

To see all the latest news and research on radiation therapy for breast cancer, please visit the LATESTBreastCancer.com website. Click on the "Treatments" tab and search for "radiation" or "postmastectomy".

Media Headlines from the 2011 Breast Cancer Symposium

Breast Cancer Symposium 2011 is underway in San Francisco this week. Today we'll share the media coverage of some of the presentations.

Medical News Today: "Young Women With Early Breast Cancer Have Similar Survival With Breast Conservation, Mastectomy"

More young women under 40 with breast cancer are choosing mastectomy over breast conserving surgery (lumpectomy), in part because of concerns about recurrence. Two presentations suggest that there is no survival difference between women treated with a mastectomy and those treated with a lumpectomy plus radiation.

US News and World Report wrote about both studies. The first, presented a few days ahead of the Symposium, evaluated medical records of 628 women aged 21 to 40. Local recurrence and survival rates were similar for women treated with mastectomy and women treated with lumpectomy.

According to Medical News Today, the second study reviewed the records of nearly 15,000 women under 40 with breast cancer. Overall survival was similar between women treated with mastectomy and those treated with lumpectomy plus radiation. When women were matched with others with similar cancer characteristics, such as tumor size and lymph node involvement, there was no difference in overall survival.

HemOnc Today: "New tool may help predict breast-cancer-associated lymphedema"

On September 8, HemOnc Today shared a Brazilian study of a model to predict lymphedema before axillary lymph node dissection. The statistical model "demonstrated more than 70% accuracy for predicting the 5-year risk for developing lymphedema after lymph node removal during breast cancer surgery."

Dr. Jose Bevilacqua, a study author, noted that the model used "readily available clinical factors," such as age, BMI and number of chemotherapy cycles, for a "quick and easy estimation of individual risks of developing lymphedema after axillary lymph node surgery in women with breast cancer."

Drugs.com: "Syndax Pharmaceutical's Positive Phase 2 Data Supports Potential for Entinostat in Advanced Breast Cancer"

On September 6, Drugs.com printed a press release from Syndax about a positive phase 2 study of entinostat for advanced breast cancer.

For post-menopausal women with estrogen-receptor positive metastatic breast cancer, entinostat plus Aromasin (exemestane) improved progression-free survival and overall survival compared to placebo plus Aromasin.

A phase 3 trial is planned for early 2012.

US News and World Report: "Annual Breast Exams, Mammograms Still Key to Detecting Breast Cancer"

There's more fuel in the screening mammography debate. On September 6, US News and World Report/HealthDay covered a study from Michigan which reviewed breast cancer detection and treatment records from almost 6,000 women with breast cancer.

Overall, breast cancer detected by palpitation (feel) tended to be later-stage and more likely to be treated with a mastectomy and chemotherapy compared to breast cancer detected by mammography.

For women under 50, 48% of breast cancers were detected by mammography and 46% by palpitation. Dr. Andrew Seidman, an official of the American Society of Clinical Oncology (ASCO), said, "Undoubtedly, this area will continue to remain an area of controversy for some, but certainly women in this age group would be well-served to know about this data."


Not every study we add to the LATESTBreastCancer.com website and database makes media headlines. Next week, we'll highlight some new research which is under the media radar. Please stay tuned.

Soy Vey! Is Soy Safe for Breast Cancer Survivors or Not?

Is soy safe for breast cancer survivors? Traditionally, caution was advised. Then, a big study in April suggested that survivors needn't worry about soy consumption. Now, a new study raises concerns again. Today we'll share the latest research on soy for breast cancer survivors.

Links to all of the studies, news stories and overviews discussed below may be found on the soy page of the LATESTBreastCancer.com website. If the link does not take you directly to the soy page, please click the "Treatments" tab, then search for "soy" in the search box in the top right corner.

A little biology

The issue for breast cancer survivors involves the isoflavones in soy. Isoflavones are phytoestrogens, or an estrogen-like compounds found in plants. They act like weak estrogens and are able to bind to estrogen receptors in cells. For women with estrogen receptor positive breast cancer, there is some concern about the estrogen-like behavior of isoflavones in soy.

April 2011 study: Dietary soy is safe after breast cancer

An April 5 presentation to the American Association for Cancer Research caused quite a media stir, with headlines in the Los Angeles Times ("Soy: Breast cancer survivors can eat soy foods without risk, study finds") and Consumer Reports Health ("No need to avoid soy after breast cancer").

The study analyzed soy consumption data from 18,000 breast cancer survivors in China and America followed for an average of more than 9 years. According to the study conclusion, "Soy food consumption was not associated with an increased risk of mortality or cancer recurrence among breast cancer survivors."

On the positive side, this data represented a large number of women over a long period of time. On the other hand, the study has not yet been published in a medical journal or subject to critical peer review. Also, the study conclusions relate to dietary soy not soy supplements.

August 2011 study: Soy supplements may affect aromatase inhibitor activity

An August 10 study from The Netherlands published in Toxicology examined the effects of the soy isoflavone genistein on estrogen dependent breast cancer cells. In the study, genistein induced tumor cell growth and increased aromatase expression and activity. The data suggested that soy-based supplements "might affect the efficacy of breast cancer treatment with aromatase inhibitors." The authors caution,

Considering the high number of breast cancer patients using soy supplements to treat menopausal symptoms, the increasing risk for adverse interactions with breast cancer treatment is of major concern and should be considered with care.

NAMS 2011 Isoflavones Report: More studies are needed

The North American Menopause Society (NAMS) issued a comprehensive report on soy isoflavones for menopausal symptoms (link to full report). It provides a thorough review of the biology of soy and the recent research on hot flashes, breast safety and bone health. With respect to use after a breast cancer diagnosis, the report notes,

Specific recommendations regarding soy or isoflavone
consumption by breast cancer survivors cannot be made at
this time; studies in human subjects indicate a null or
protective effect, whereas cell culture and rodent studies
indicate potential for risk. Further studies are needed. (p. 739)

Interestingly, the report discusses human studies from both China and the United States which support the safety of soy after breast cancer. (p. 740) Nevertheless, it does not recommend soy due to safety concerns in cells and animals.

NAMS is not alone in recommending caution when using soy after breast cancer. The National Institutes of Health National Center for Complementary and Alternative Medicine webpage on soy notes,

Soy's possible role in breast cancer risk is uncertain. Until more is known about soy's effect on estrogen levels, women who have or who are at increased risk of developing breast cancer or other hormone-sensitive conditions (such as ovarian or uterine cancer) should be particularly careful about using soy and should discuss it with their health care providers.

The American Cancer Society publishes a similar warning,

The isoflavones in soy have weak estrogen-like activity, and it is unclear how they might affect the growth of estrogen receptor-positive breast cancers. Some researchers suggest they may act as anti-estrogens and reduce cancer growth, while others suggest their estrogen-like activity could cause cancer to grow faster. Until this issue is resolved, many oncologists recommend that people taking tamoxifen or aromatase inhibitors and people with estrogen-sensitive breast tumors should avoid adding large amounts of soy, including soy supplements or isoflavones, to their diets.

At LATESTBreastCancer.com, we'll continue to follow and share the latest research on soy for breast cancer survivors. Any new developments will be added to the LATESTBreastCancer.com website and highlighted here. Please stay tuned.

The Importance of Radiation for Triple-Negative Breast Cancer

Radiation therapy, which is standard treatment for many breast cancers, may be especially important for triple-negative breast cancer.

Triple-negative breast cancer, by definition estrogen-receptor, progesterone-receptor and HER2 negative, does not have as many treatment options as other breast cancers. Hormonal therapy and Herceptin (trastuzumab) for HER2 positive cancer are not effective.

Two recent studies highlighted the importance of radiation for triple-negative breast cancer.

Lumpectomy plus radiation better than mastectomy alone

A July 20 study in the Journal of Clinical Oncology found that women with small, node-negative, triple-negative breast cancer treated with mastectomy alone had a "significant increased risk" of local-regional recurrence compared to women treated with lumpectomy (breast conserving surgery) plus radiation. The authors noted that future studies are warranted to investigate the benefit of radiation after mastectomy in triple-negative breast cancer.

After mastectomy, chemotherapy plus radiation better than chemotherapy alone

Almost on cue, an August 16 study in Radiotherapy and Oncology evaluated the benefit of radiation after mastectomy in triple-negative breast cancer. (Link may be found on the postmastectomy radiotherapy (PMRT) page of our website.)

For women with early-stage triple-negative breast cancer treated with a mastectomy, chemotherapy plus radiation was "more effective" than chemotherapy alone. Recurrence rates and overall survival rates were significantly better in the group treated with radiation.

In both studies, women with triple-negative breast cancer treated with radiation fared better than those not treated with radiation.

Triple-negative breast cancer is a special situation. At our LATESTBreastCancer.com website, subscribers may create a profile based on their personal diagnosis to see the latest breast cancer news and research applicable to them. Our goal is to make internet research more efficient, and less overwhelming, for women with breast cancer.

Breast Cancer News (8/12): Insomnia and anemia

Feeling tired? Insomnia and anemia are problems for many breast cancer patients, and both cause fatigue. Today we'll look at the latest breast cancer research on insomnia and anemia.

Insomnia in breast cancer patients and survivors

Three recent studies and a Reuters news story addressed insomnia in breast cancer patients and survivors. All may be found on the mastectomy page of the LATESTBreastCancer.com website.

Insomnia before and after surgery for early-stage cancer

An August 8 Journal of Clinical Oncology study from Canada periodically assessed insomnia in early-stage cancer patients from before surgery to 18 months later. Before surgery, insomnia levels were high. Women with breast or gynecologic cancers had higher rates than men with prostate cancer.

Over time, insomnia declined, but remained pervasive even 18 months later. The authors suggest that "[e]arly intervention strategies, such as cognitive-behavioral therapy, could prevent the problem from becoming more severe and chronic."

Carol Enderlin, a sleep researcher not involved in either study, told Reuters the findings indicate that sleep is "a really big problem for cancer patients." She advised patients to report changes in sleep before the problems become more severe. "When people are faced with stress, when they are faced with challenges, they do much better on a good night's sleep," she said. "It's very important, never more so than with cancer patients."

Insomnia, fatigue and depression after treatment for early breast cancer

Also on August 8, a Journal of Clinical Oncology study from UCLA assessed fatigue, sleep disturbance and depression among women who completed surgery, radiation and/or chemotherapy for early breast cancer. More than 60% reported "clinically significant problems with fatigue and sleep, and 25% reported elevated depressive symptoms." Women treated with chemotherapy reported higher levels of all symptoms. The authors associated the symptoms with elevated blood levels of markers of inflammation, suggesting that inflammatory signaling contributes to fatigue.

Insomnia may be due to arm and shoulder pain from breast cancer treatment

A June study from Norway in Sleep Medicine evaluated insomnia a median of 4 years and again 7 years after surgery and radiation for stage II/III breast cancer. Arm and shoulder pain at 4 years was significantly associated with insomnia at 4 and 7 years on simple analysis. In multivariate analysis, however, only the use of sleep aids remained associated with insomnia at 4 years. Only insomnia at 4 years remained associated with insomnia at 7 years. Nevertheless, the authors concluded that arm and shoulder problems, particularly pain, are factors to consider in breast cancer survivors with insomnia.

Anemia develops immediately after treatment for advanced cancer

One potential side effect of chemotherapy is anemia, a low red blood cell count. An August 3 study in Breast Cancer Research and Treatment analyzed the blood of advanced breast cancer patients one hour after chemotherapy with Adriamycin (doxorubicin) or Taxol (paclitaxel). Just one hour after chemotherapy, anemia and oxidative stress were already evident. The authors conclude that this is a new perspective on the aggravation of chronic anemia in women with advanced breast cancer.

Please check back Monday for the weekend breast cancer research news update. Until then, all the latest news and research for any breast cancer test or treatment option may be found on the LATESTBreastCancer.com website anytime.

Opening Up the Potential of Peptide Drugs -- A New Delivery Method

Results from the DoD's Era of Hope Conference

Scientists are teasing apart the molecular causes of breast cancer so that they can develop more targeted drugs. But applying this new model of personalized, targeted treatment depends as much on developing new technologies to deliver drugs as developing the active components of the drugs.

Why is drug delivery is so critical? To explain, today we'll look at research results presented yesterday at the Era of Hope conference in Orlando, which featured research funded by the Department of Defense's Breast Cancer Research Program (BCRP). Today I spoke to Dr. Gene Bidwell of the University of Mississippi Medical Center who presented findings on a new "thermally-targeted" approach to delivering peptide drugs. (Press releases from the conference can be found here.)

Dr. Bidwell's research was performed in an animal model and is years away from the bedside. But it is an exciting approach. It also underscores several larger trends in cancer research and future treatment. So let me explain the context and relevance before describing his new system.

First, peptides. What are they? The term "peptide" simply refers to a small protein. While a typical protein is a chain of hundreds of amino acids, peptides are tens or teens. Dr. Bidwell's H1 peptide, the focus of this research, is 16 amino acids long.

Peptides have the potential to be fabulous drugs. Most of the molecular activity in cells is about proteins interacting with other proteins. So peptides (being proteins themselves) are a natural in terms of interacting with, changing or inhibiting proteins gone awry.

In addition, today we have machines that make peptides to order. You just type in any series of amino acids you want, and out pops the peptide. So researchers can make a peptide, try it out, adjust it a bit (maybe switch one of the 16 amino acids), make that one, try that out and iterate little by little to create the perfect drug. This process is called "rational drug design."

Today, some drugs are large proteins called monoclonal antibodies (for example, Herceptin), which work well if the target lies on the surface of the tumor cell. But most drugs are "small molecules" -- chemicals.

Pharmaceutical companies make enormous collections (libraries) of millions of random chemicals that they then robotically test. The process of finding a good small molecule drug is literally like throwing the entire library against a wall (actually against the molecule they're targeting) and seeing which "stick," or attach to that molecule. If one or more do stick, they still have to figure out if it sticks such that it interrupts the molecule's function. If not, they move on. This process doesn't allow the research team to iterate small changes to perfect the drug nearly as easily as with peptides. So there are big advantages to peptides in terms of a rational drug design approach.

But today there are no peptide cancer drugs. Why? First, small peptides degrade in the bloodstream. So they need to be attached to another molecule (sometimes just larger peptides) for protection until they arrive at the tumor. Second, peptides need to get inside tumor cells to do their thing. That doesn't happen naturally.

Many research teams are trying to solve this problem and Dr. Bidwell's research provides a great and an exciting example. He created a three part peptide drug. All three parts are peptides. Together create a larger and more stable molecule. It's really tricky. Here's how it works.

- The first part is the peptide drug itself, called H1. It targets a growth signaling protein in cancer cells called c-Myc.

- The second part is called elastin-like peptide (ELP). The ELP enables the drug to remain soluble and stable in the bloodstream. But right at the tumor site a mild heat is applied (according to Dr. Bidwell, "about 5-10 degrees hotter than body temperature... like a high fever") using ultrasound. The focused heat changes the shape of the ELP, and causes the drug to aggregate and accumulate where it's needed.

- The third part is called cell-penetrating peptide (CPP). When the drug aggregates at the tumor cell, the CPP provides entry into the cells.

This is a powerful approach. All three parts of the drug have distinct functions. Mild heat is used to aggregate the drug to where it's needed at the tumor and to avoid exposure of other tissues.

According to Dr. Bidwell, there are other approaches being developed to deliver peptides to breast tumors, including synthetic polymers and liposomes. But those aren't thermally-targeted, which provides not only stability, but also (potentially) increased effectiveness and fewer side effects.

So cross your fingers. Let's hope that Dr. Bidwell's thermally-targeted delivery mechanism, or a variant of it, will open up the full potential of next-generation peptide drugs against cancer. And thanks again to Dr. Bidwell for taking the time to speak with me today.

HER2 Part 7: DNAarray HER2 PRO

Bottom line: CombiMatrix's DNAarray HER2 PRO test offers a more complete picture of HER2 amplification than FISH and can avoid some false negatives. It also shows other important chromosomal problems beyond HER2.

Understanding a breast tumor's HER2 status is critical for treatment planning. But what to do if a pathology report describes HER2 status as "equivocal" (FISH result between 1.8 and 2.2; IHC result of 2+) or if IHC and FISH results contradict one another and so are "discordant?" Inconclusive HER2 results happen about 10-15% of the time. So this is not a rare situation.

As a side note: HER2 testing guidelines for gastic cancer now require dual IHC and FISH testing, an acknowledgement of both the importance of, and concerns over current HER2 testing methods.

In the past few blogs we've written about newer tests based on technologies different than the ones used in IHC and FISH that can be used to make the determination. Today we'll discuss CombiMatrix's DNAarray HER2 PRO.

First, what does this test "look at?" The answer: the entire chromosome 17 in breast tumor cells in your biopsy sample. The HER2 gene is on chromosome 17. But FISH also looks at chromosome 17. So what's the difference?

It's pretty simple. FISH looks at a specific gene (HER2) by attaching ("hybridizing"... the "H" in FISH) fluorescent molecules to it ("fluorescence" is the "F" in FISH). The more HER2 DNA there is, due to gene amplification, the brighter the fluorescence that's emitted.

FISH determines whether the HER2 gene has been amplified by comparing the amount of fluorescence at the HER2 gene with the amount at a different part of the chromosome that FISH also targets. So the pathologist looks at two points on the chromosome using a fluorescence microscope.

If the amount of fluorescence at the HER2 gene is much greater than the amount at the centromere (pronounced sen'-tro-mere and more technically called CEP17), then the assumption is that the gene has been amplified. So the test is all about the ratio of fluorescence emitted at two different know points on chromosome 17. Pretty tricky.

Now DNAarray HER2 PRO. As previously mentioned, it looks at many more points on the chromosome using a technology you might have heard of in the news called a "DNA microarray" or "DNA chip." The generic term for the DNAarray test is array-based Comparative Genomic Hybridization, or aCGH. You don't have to know this. But I didn't want anyone to be confused if they happened to come across the term.

aCGH uses somewhat similar technology to FISH, but by using the DNA chip, it can simultaneously look at hundreds or thousands of points on the chromosome using fluorescence hybridization, not two. The chip is analyzed using an automated instrument. No one looks through a microscope, as with FISH.

Next question: Why does it matter to look at the whole chromosome? Mainly because one potential problem of FISH is that it can give a false negative result. This is a situation where the test says the tumor is HER2 negative even though there is amplification. This can occur if BOTH the HER2 gene and the centromere are amplified. Remember, FISH looks at the ratio between the two. If both are amplified, the amount of fluorescence signal could be about the same but the reason would be that they are BOTH amplified, NOT that neither is amplified! And centromere amplification is relatively common.

Second, and this goes beyond the issue of HER2, tumors that are more aggressive tend to have bigger problems than just HER2 gene amplification. They tend to have amplification elsewhere, changes in the numbers of chomosomes and other problems that can be summed up as "chromosomal chaos." Chromosomal chaos is easily visualized using aCGH. And if the DNAarray test shows big chromosomal problems on chromosome 17, then there's little doubt that the same thing has happened on other chromosomes. Knowing this, and thus that the tumor is aggressive, might alter treatment decisions.

DNAarray HER2 PRO costs $1,500. Reimbursement not certain, as it is with IHC and FISH. But for patients who either don't have a clear-cut HER2 status or who might be willing to pay for a high-tech method that might provide additional insights into the tumor's characteristics, then it's worth a look.

HER2 Part 6: Agendia's TargetPrint Test

Bottom line: TargetPrint is a quantitative mRNA test that can be used as a second opinion to IHC or FISH testing or as a first line test to measure HER2, ER and PR.

There are three situations where it would be reasonable to consider some of the next generation, "non-standard-of-care" tests, like TargetPrint, that assess a breast tumor's HER2 status:

1) The first situation is when a basic IHC (immunohistochemistry) test like Dako's HercepTest gives an "equivocal" result (a score of 2+). Today FISH is most commonly used in this case. But other tests could be considered. Or multiple different tests could be used.

2) The second situation is where neither IHC or FISH deliver a clear positive or negative result, or if they give conflicting ("discordant") results.

3) Finally, if a tumor is designated HER2-negative but the disease is progressing faster than expected, then consider rechecking with another kind of test.

Agendia's TargetPrint test looks quantitatively at the amount of HER2 mRNA in tumor cells. This is different than standard IHC tests (like Dako's HercepTest) that look at the amount of protein on the tumor cell surface semi-quantitatively, or FISH tests (like Abbott's' PathVysion or Dako's HER2 FISH PharmDx) that look at the amount of DNA amplification.

Why might looking at mRNA be useful? Consider the biology. Within the cancer cells, a portion of chromosome 17 (home of the HER2 gene) is being amplified. Instead of the normal double helix of chromosome 17 DNA, the cell has aberrantly made many double helixes. There are too many HER2 genes so the cell naturally produces too much HER2 mRNA. These HER2 mRNAs float around the cell and are used to creates too many HER2 proteins.

In theory, the amount of DNA amplification, mRNA and protein should coincide. But biology is complex and scientists always have an imperfect picture of what's going on inside of the cell. In addition, there are strengths and weaknesses associated with different tests and lab techniques. Some tests are more subject to laboratory error, for example. So the idea of using different techniques to measure different aspects of biology (DNA, mRNA and proteins) and to cross check one against the other is a reasonable strategy.

In addition, analyzing mRNA as a means of understanding what's happening inside cancer cells has become important in recent years. mRNA analysis is the basis of Genomic Health's popular Oncotype Dx test and Agendia's better known test, MammaPrint test, both for assessing recurrence risk. So it is a growing diagnostic approach.

Back to TargetPrint. Yes, it analyzes HER2. But it also analyzes estrogen receptor (ER) and progesterone receptor (PR), also by looking at mRNA. Normally both are analyzed by IHC. Several recent studies show that ER testing is far from perfect. For example, a Yale study that just came out this week found that 10-20% of patients who are told they have ER-negative tumors really have ER-positive tumors. Another recent study found that patients test negative for ER by IHC more often on Fridays and Saturdays! So, as mentioned before, IHC is subject to lab and lab technician variability.

TargetPrint costs $1200 and it is covered by Medicare.

The Breast Cancer News Update: June 24

In the news today the FDA says silicone implants appear to be safe. Also, a possible shortage of a mainstay breast cancer chemotherapy, and the possibility of a topical gel form of tamoxifen that might eliminate side effects that keep some patients from using the drug.

Silicon Implants: So Far So Good

Silicone breast implants were banned in 1992 based on health concerns but then were reintroduced into the market in 2006. Yesterday FDA officials claimed that, based on research performed since 2006, their decision to reintroduce the products seems to have been the right one. The research was performed by the manufacturers. Last year 60% of breast implants were silicone-based rather than saline-based. You can find all of these stories on our Breast Implant page.

A Possible Shortage of Taxol (paclitaxel)

Taxol is one of the most commonly used breast cancer chemotherapeutics. It's used to treat early stage, locally advanced and metastatic disease. A report from About.com claims that some hospitals are finding it difficult to get enough of the drug. The degree of the shortage is unclear, as is the reason. Find the article on our Taxol page.

Tamoxifen the Gel

Researchers at Northwestern University are conducting a clinical trial of a gel form of tamoxifen that might very well avoid some of the major side effects of the tablet: namely, blood clots, uterine cancer and hot flashes. In theory, a gel would concentrate the drug in the breast and minimize exposure to the rest of the body. This could be very good news, especially for the many women at high risk who choose not to take the drug based on their concerns about these side effects. The article does not say when the drug might be available assuming positive trial results. The article will be the first News Article listed on LatestBreastCancer.com's Tamoxifen page.

Next update: Monday June 27. Enjoy the weekend!

HER2 Part 5: The HERmark test

Note: This is the blog of LATESTBreastCancer.com, where you can get personalized information about the latest in breast cancer treatment.


Bottom line: HERmark is a powerful new test for patients who need to resolve an unclear HER2 result.

There are situations in which the standard ways of analyzing HER2 fail to provide a clear positive or negative result, leaving it uncertain as to whether or not to prescribe Herceptin (trastuzumab).

If this describes your situation, realize that it is critical that you accurately determine your tumor's HER2 status. Patients who are HER2-positive have a significantly worse prognosis. On the other hand, Herceptin is a powerful drug that essentially neutralizes the survival disadvantage caused to HER2 overexpression. In other words, if your tumor will respond to Herceptin, you need to know that.

So regarding HER2 testing, there are two situations to avoid. The first is wrongly diagnosing a patient as HER2-negative and not giving her Herceptin. The second is wrongly diagnosing a patient as HER2-positive and subjecting her to possible side effects without providing any benefit.

Today there isn't enough clinical evidence to recommend using HERmark instead of IHC. There might be in the future. So in what situation might a patient consider asking about HERmark?

1) If IHC gives an "equivocal" result (a score of 2+). Today FISH is commonly used in these cases, but HERmark is another option. Given the importance of knowing HER status with certainty, another reasonable but more expensive option in this situation might be "do both."

2) If neither IHC or FISH deliver a clear positive or negative result, or if they give conflicting ("discordant") results.

3) If a patient is determined to be HER2-negative but their disease is progressing more rapidly than expected, then consider rechecking HER2 with HERmark to make sure that the situation can't be reversed with Herceptin.

So how does HERmark differ from IHC and FISH? Remember that IHC analyzes the amount of HER2 protein on tumor cells in a "semi-quantitative" way. FISH looks at amplification of the HER2 gene, which is what causes the overabundance of HER2 protein.

HERmark, like IHC, looks at the protein. It actually looks at total HER2 protein and it looks at the extent to which HER2 proteins are paired up with each other ("homodimers"). To quantitatively assess both, it uses a method that is more sophisticated than IHC. So you get more quantitative information about HER2 status. For example, instead of knowing that your HER2 result was a "3", you might see that it was barely a three (really almost a 2). Or you might see that it was a strong 3. This might make a difference with regard to treatment approach or decisions about the value of additional HER2 testing. The point is, IHC only delivers 4 results: 0+, 1+, 2+ and 3+. HERmark tells you the real, numerical result.

As I mentioned, HERmark also does something tricky. Remember that HER2 only sends a grow signal when it is paired with either another HER2 (called a "homodimer") or with a different HER (called a "heterodimer"). HERmark tells you to what extent HER2 is found as active homodimers on the cell.

Today, the company that developed HERmark doesn't emphasize the homodimer information on the lab report. I spoke to someone at the company--Dr. Weidong Huang, an MD/PhD in their clinical research group--about this. Apparently the homodimer information isn't yet providing much value beyond the quantitative total HER2 information in the test report. The company is developing next-generation versions of the test that will look at all of the possible HER2 pairings and Dr. Weidong believes that those tests could provide key information that could bear upon treatment strategy in the future.

In a nutshell, HERmark is a powerful option for patients who need to resolve an unclear HER2 result. This is no small issue, given the importance of correctly identifying patients who will receive a drug as potent as Herceptin. The technology behind the test has strong validation. The company that developed the test, Monogram Biosciences (South San Francisco, CA) was recently purchased by LabCorp, the largest testing lab in the United States. So the experts at LabCorp obviously see great promise in the HERmark technology.

A few other details: the test takes seven days to perform, it requires a standard FFPE breast biopsy sample (FFPE is an acronym describing the way biopsy samples are most commonly stored), and it is performed at a single lab in South San Francisco. The price is $3,350. Assistance with insurance reimbursement is provided by the company.

Thanks to Dr. Weidong Huang and Bruce Nita, both of whom work for Monogram Biosciences (LabCorp).

HER2 Part 2: What Goes Wrong in Breast Cancer?

If you have "HER2-positive" breast cancer, then there's a huge overabundance of HER2 molecules on surface your breast tumor cells.

To paint a clearer picture, there are normally about 10,000-20,000 HER2 molecules on a breast cell. On a HER2 positive breast cancer cell, there are 1-2 million... so a 100-fold increase.

Having this many extra HER2 cells on the cell surface ready and waiting to pair up with other HER molecules upon their binding with EGF very simply sends a much louder "grow" signal inside the cell and into the nucleus. The cell grows faster and divide more often. They have one of the key characteristics of cancer cells: rapid, uncontrolled growth.

Why are there so many HER2 molecules on the cell surface? We have to look into the nucleus at the world of DNA. DNA is a long filamentous molecule. It's packaged as chromosomes (23 pairs, one from mom and one from dad, so 46 total). And it contains messages called genes that provide the code for making specific proteins. On chromosome 17 sits one of the 20,000 human genes that code human life. It is the gene that makes the HER2 protein.

In an earlier blog we talked about the fact that everything that goes awry in cancer cells, including uncontrolled growth, blood vessel formation, cell mobility, etc.... everything is due to gene mutations and problems with DNA repair.

Well, one of the general kinds of mutations that occur when a cell is having problems keeping its DNA pristine is called gene amplification. In gene amplification, one section of a very long DNA molecule starts creating extra copies of itself. The extra copies remain attached to the main strand. Visualize this as a long rope where in one section, there is a big bulge of extra rope strands. Rampant gene amplification is a common characteristic in cancer cells.

In HER2 positive cancer cells, a specific gene amplification occurs at the part of chromosome 17 where the HER2 gene sits. This results in many extra copies of the HER2 gene that in turn produce an overabundance of HER2 proteins that lodge themselves in the cell membrane, poised to send too much grow signal inside the cell.

So the answer to the question in today's title is: "Gene amplification on chromosome 17 that results in up to a 100-fold overabundance of HER2 growth factor receptor."

Next: Drugs that Target HER2

HER2 Part 1: Know the Molecule

For about a fourth of breast cancers, a molecule called HER2 plays a key role in both the cause of the disease and its treatment. For the next few days, we'll cover what HER2 is, its involvement in breast cancer, how it's targeted by drugs, and how HER2-positive patients are identified.

The methods for identifying HER2-positive patients are under scrutiny. One often-cited study states that up to 20% of HER2 test results could be inaccurate. If these inaccuracies result in inappropriate use or non-use of Herceptin (trastuzumab) and other powerful HER2-targeted drugs, then the impact on patient survival and unwanted side effects could be significant. So we'll also look at some new tests that might be able to help better identify HER2-positive patients, including TargetPrint (Agendia), HERmark (Monogram Biosciences/LabCorp), and DNAarray HER2 Pro (CombiMatrix Diagnostics).

First, HER2... Let's step back to biology for a minute. You need to know just a couple things before we discuss treatments and tests.

We know that cancer is a disease in which cells grow out of control because molecules involved in normal growth control "go haywire." Normal growth control in healthy breast cells looks like this: small signalling molecules called growth factors attach to antenna-like molecules called growth factor receptors on the outside of breast cells. These antenna molecules span the cell membrane. When a signal molecule attaches to the part outside the cell, the molecule transmits the signal to the part that sits inside the cell. There, it passes the signal on to a series of signal transducer molecules that work like a relay team, carrying the signal deeper inside the cell and eventually into the nucleus, the home of the cell's genes. When the signal arrives inside the nucleus, it "tells" still more molecules to turn on genes that produce proteins involved in cell growth. With these proteins active, the cell grows and divides.

For breast cells, Epidermal Growth Factor, or EGF, is a key growth factor. EGF targets a family of four similar growth factor receptors (antennae) called HER1, HER2, HER3 and HER4. In the often confusing world of molecule naming, proteins often have more than one name. HER1 is more often called EGFR (Epidermal Growth Factor Receptor). HER, by the way, stands for Human Epidermal growth factor Receptor. And HER2 is also called HER2/neu as well as ErbB2. Sorry. Not much we can do about that...

Finally, let's paint a clearer picture of how HER2 and its family members work. In a word, they work in pairs. When EGF attached to a HER family member, it doesn't cause the growth signal to be transmitted into the cell instantly. Instead, EGF binding cause HER receptors of all four types to want to link up with one another. It could be two HER2s. Or it could be other pairings like a HER2 with a HER3 (see diagram). When pairing occurs, it changes the shape of both of the paired HER molecules, and this causes each HER molecule to activate it's companion inside the cell. It's these activated, paired HERs that transmit signal to the relay team of signal transducer molecules.

Next: What goes wrong with HER2 in breast cancer?

April Breast Cancer News for Patients

Last week, LatestBreastCancer.com highlighted April news for women who completed breast cancer treatment. Today, we'll look at recent breast cancer news for current patients.

Let's start with breast cancer drugs. For those taking aromatase inhibitors, Bloomberg Business Week ran a story about the launch of a generic version of Femara (letrozole). There's been a lot of activity on our Halaven (eribulin) news page. In March, the National Comprehensive Cancer Network (NCCN) added Halaven to its guidelines as a preferred single agent option for metastatic disease. In April, Halaven made its international debut in the UK, Japan, Norway, Sweden and Denmark.

Breast cancer side effects are always a concern. For those considering a double mastectomy, US News and World Report covered a story about patient satisfaction twenty years later. For women who have breast cancer while pregnant, The Huffington Post addressed the safety of diagnostic mammography, surgery and chemotherapy during pregnancy.

I really like news about taking care of yourself while receiving breast cancer treatment. This month, The Los Angeles Times provided beauty tips for women undergoing chemotherapy. The story can be found on our Adriamycin (doxorubicin) news page. Also, FOX News revealed the four types of exercise that help patients most.

I look forward to continuing to cover news for breast cancer patients. As always, I welcome feedback about topics that interest you most. I'll keep you posted.

Listening to patients: Experiences researching treatments online

During the development of LATESTBreastCancer, we heard feedback via face-to-face interviews, usability testing, or online surveys from nearly 100 breast cancer patients and survivors. We always asked about their experience searching for treatment information online. Everyone found the experience challenging to some degree. The main complaints were:

1. QUALITY: How can I trust the information, or the source of a link?

2. TIMELINESS: How do I know a link is showing me the most up-to-date information? Even if a Web page is only a few months old, is that the most recent information?

3. RELEVANCE: How do know if the information pertains to me? As many people said, "There are different types of breast cancer and you need to find information that's relevant to you."

4. UNKNOWNS: Search engines work well if you're searching for a known. But if your question is "What's out there that I should know about?" then search engines comes up very short.

LATESTBreastCancer's "database model" solves all four of these problems. By "database model" what I mean is that we maintain our own database of links and treatment information that's automatically identified on the Web, but manually reviewed and organized so it can be much more precisely searched by patients.

1. QUALITY: We only put information and links in our database that comes from established, high quality Web sites.

2. TIMELINESS: When you see a list of links on our site, you know it's every link we've come across--all of the info available--in reverse chronological order.

3. RELEVANCE: When you subscribe, we use your medical profile to filter out information that isn't relevant to you and greatly streamline your research.

4. UNKNOWNS: Our Web site shows the full universe of breast cancer treatment options. Everything of even potential relevance to a patient is listed on our site.

If you need to use Google to research a complex topic then you're at a big disadvantage. In most other aspects of life where people have to make important decisions, there are Web site that allow them to perform methodical research by accessing the most up-to-date data. This includes buying a car (edmunds.com), buying or selling a house (zillow.com), buying a new computer (cnet.com) or making investments and financial plans (schwab.com). Note that all of these sites are databases.

But today when people have to research the latest treatment information so that they can have a well-informed discussion with their doctor, they either need to use content sites like WebMD with articles that can be out of date or incomplete, or they need to use Google, which gives them much too much disorganized information of variable quality and relevance.

So the dissatisfaction of our breast cancer patient and survivor interviewees about their experience searching for treatment information are spot on. We think the time is now for a sane, methodical way to research the most important topic a woman might ever have to learn about.