Herceptin Plus Chemotherapy for HER2 Positive Breast Cancer: The Latest Data in the Hunt for the Best Combination

Herceptin (trastuzumab) is the treatment of choice for women with HER2 positive breast cancer. By itself, it is associated with a risk of heart damage. What happens when it is combined with chemotherapy? Which drug combinations are best in terms of effectiveness and side-effects?

Today we'll share the two most recent studies on Herceptin in combination with chemotherapy. Both evaluated chemotherapy combinations with and without anthracyclines, such as Adriamycin and Ellence. Links may be found on the Herceptin (trastuzumab) page of our website.

TCH better than AC-T plus H as adjuvant therapy

An October 6 study in The New England Journal of Medicine evaluated the risks and benefits of Herceptin plus chemotherapy as adjuvant (after surgery) therapy for women with early-stage, HER2 positive breast cancer. The Los Angeles Times and US News and World Report/HealthDay covered the study.

The 3,222 women in the study were divided into three groups. One received Adriamycin (doxorubicin) and Cytoxan (cyclophosphamide) followed by Taxotere (docetaxel) (AC-T). One received AC-T plus 52 weeks of Herceptin (AC-T plus H). The last received Taxotere, Paraplatin (carbobplatin) and 52 weeks of Herceptin (TCH).

In terms of effectiveness, the AC-T plus H and TCH groups had similar disease-free and overall survival rates, and both were superior to the group that did not receive Herceptin.

In terms of side-effects, the AC-T plus H group experienced "significantly higher" rates of congestive heart failure and cardiac dysfunction than the TCH group. There were seven cases of leukemia in the AC-T plus H group and one in the TCH group.

The authors concluded that the addition of one year of Hercpetin significantly improved disease-free and overall survival. The risk-benefit ratio favored the TCH combination over AC-T plus H, "given its similar efficacy, fewer acute toxic effects, and lower risks of cardiotoxicity and leukemia."

PH-FECH better than TCH as neoadjuvant therapy

A September 27 study in Cancer evaluated Herceptin plus chemotherapy as neoadjuvant (before surgery) treatment. This time, TCH came out on the bottom.

The 300 HER2 positive women were treated with either Taxol (paclitaxel) and Herceptin followed by 5-FU, Ellence (epirubicin), Cytoxan and Herceptin (PH-FECH) or Taxotere, Paraplatin and Herceptin (TCH).

Patients in the PH-FECH group experienced a higher rate of pathological complete response (pCR), meaning tumor disappearance. They also had a lower risk of recurrence and death compared to the TCH group.

In terms of side-effects, there was "no significant difference" in heart damage. However, the authors noted that the women in the PH-FECH group had "fewer cardiac comorbidities at baseline," meaning they had a lower risk of heart damage when the study started.

The authors concluded that the type of neoadjuvant therapy is predictive of pCR rate. "Although TCH is active, PH-FECH shows a higher pCR rate and RFS [relapse-free survival] advantage."

At LATESTBreastCancer.com, we'll continue to monitor research on Herceptin plus chemotherapy. Today's studies are only the two most recent. For two-years worth of news and research, please visit the Herceptin page under the Treatments tab of our website.

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.

Breast Cancer News (8/11): Cardiotoxicity

Breast cancer treatment side effects are in the news again. Earlier this week, we shared the recent research on nausea and thromboembolic events. Today we'll review the latest studies on cardiotoxicity, the heart damage caused by some breast cancer treatments. As always, the news stories and studies discussed below may be found on the treatment pages of the LATESTBreastCancer.com website.

Herceptin-induced cardiotoxicity in elderly patients

The big story was a small study from Spain in the Annals of Oncology which assessed the cardiotoxicity of Herceptin (trastuzumab) in women older than 70. Twelve of the 45 women in the study developed Herceptin-related cardiotoxicity. According to Medical News Today, "Earlier clinical trials in younger, healthier women revealed a slightly lesser rate."

Cardiotoxicity was more prevalent in women with cardiovascular risk factors. It developed in 33% of the women with cardiac disease and 33.3% of the women with diabetes. By contrast, only 9.1% of those without cardiac disease and 6.1% of those without diabetes developed heart damage.

The cardiotoxicity induced by Herceptin was reversible in most. According to US News and World Report, "When the women with heart problems stopped taking Herceptin, all but one recovered fully and five were able to re-start treatment with the drug."

In conclusion, Dr. Cesar Serrano, who conducted the study, was quoted in Medical News Today, "We think that it is reasonable to refer elderly breast cancer patients to a cardiologist if one or more cardiovascular risk factors are present before or during treatment with trastuzumab. Moreover, a closer surveillance of early symptoms and cardiac function is highly recommended."

Exercise and Adriamycin-related cardiotoxicity

Can aerobic exercise prevent or reduce the heart damage associated with
Adriamycin (doxorubicin)? Researchers from the NASA Johnson Space Center asked that very question in a review in Circulation, a journal of the American Heart Association. To lay the preliminary groundwork, the authors reviewed the molecular mechanisms of chemotherapy-induced cardiotoxicity and the effects of exercise on heart tissue. Their early findings "have implications for future research regarding the application and effectiveness of exercise and doxorubicin treatment in humans."

Sutent and the risk of congestive heart failure

Sutent (sunitinib) is approved for renal cell carcinoma and gastrointestinal stromal tumors, and is in clinical trials for breast cancer. A Journal of Clinical Oncology review of phase II and phase III trials found Sutent to be associated with an increased risk of congestive heart failure in cancer patients.

A story and video from TheDoctorsChannel.com provides more detail. The review included 16 studies of renal cell carcinoma and other cancers, involving almost 7,000 patients. Patients treated with Sutent had about a 3-fold higher relative risk of developing high-grade congestive heart failure. The authors concluded that "clinicians need to be aware of the risk of CHF with sunitinib treatment to provide early intervention and balance therapeutic benefit with this potentially life-threatening adverse effect."

Tomorrow, we'll review the latest breast cancer research on another treatment side effect - insomnia. Please stay tuned.

Breast Cancer News (8/3): Mammography, Hercpetin and the NCCN Guide for Patients

Today in breast cancer news, we'll highlight a study on the radiation damage caused by screening mammography, two studies on the neoadjuvant (before surgery) use of Herceptin and the new patient-friendly guidelines from the National Comprehensive Cancer Network (NCCN).

DNA damage from screening mammography

Once concern in the screening mammography debate is the exposure to radiation. A July 29 study in the International Journal of Radiation Biology assessed mammography induced DNA damage, in the form of double-strand breaks, in cells of women with high and low risk of breast cancer. DNA double-strand breaks were induced by mammography in all patients, and the effects were "exacerbated" in high-risk patients. The researchers concluded, "These findings may lead us to re-evaluate the number of views performed in screening using a single view (oblique) in women whose mammographic benefit has not properly been proved such as the 40-49 and HR [high risk] patients."

Neoadjuvant use of Herceptin

Herceptin (trastuzumab) is used to treat HER2 positive breast cancer. This week, two studies addressed the use of Herceptin in the neoadjuvant setting, to shrink tumors before surgery.

A July 25 study in the Journal of Clinical Oncology found that the neoadjuvant combination of Herceptin plus chemotherapy resulted in a high rate of pathological complete response (pCR), "defined as no residual invasive tumor in breast and lymphatic tissue." Women with pCR who continued Herceptin after surgery had "an improved long-term outcome." On the other hand, patients "without a pCR had an increased risk for relapse and death."

A July 25 review of five trials (515 patients) in Breast (Edinburgh, Scotland) found the addition of Herceptin to chemotherapy in the "neoadjuvant setting improves the probability of achieving higher pCR with no additional toxicity."

NCCN Guidelines for Breast Cancer Patients

For doctors, the NCCN publishes Clinical Practice Guidelines in Oncology, which outline a recommended standard of care for the treatment of cancer. This week, the NCCN released a patient-friendly version for breast cancer called the NCCN Guidelines for Patients. It's a terrific starting point for the newly diagnosed, covering breast cancer development, detection, staging, and standard-of-care treatment options by type. It even addresses side effects, complementary therapy and caregiver issues.

Our website, LATESTBreastCancer.com, is an additional resource for breast cancer patients. Patients may explore the latest news and research on the standard-of-care treatment options mentioned in the NCCN Guidelines and up-and-coming tests and treatment options in development. In addition, subscribers may personalize their research to their pathology reports to see the test and treatment options applicable to them.

The Breast Cancer News Update: July 25

Today in breast cancer research news, we'll look at recent studies on Herceptin plus chemotherapy and Ellence plus Taxotere for early breast cancer, the Doxil shortage, and a study on the risk of recurrence after a trauma or surgery. Links to the study abstracts may be found on the treatment pages of the LATESTBreastCancer.com website.

Herceptin benefits confirmed in long-term follow-up

In 2006, Herceptin (trastuzumab) received FDA approval in combination with chemotherapy for the treatment of early, HER2 positive breast cancer based on two large trials - the North Central Cancer Treatment Group (NCCTG) and National Surgical Adjuvant Breast and Bowel Project (NSABP). This week, a Journal of Clinical Oncology study published four-year follow-up data which confirmed the benefit of Herceptin. Consistent disease-free survival and overall survival advantages were observed during "the longest follow-up reported to date." "The clinical benefits continue to outweigh the risks of adverse effects."

Ellence followed by Taxotere is better than Ellence alone

Chemotherapy drugs may be given alone or in combination with other chemotherapy drugs. This week, a "relatively small" phase III trial in the Journal of Clinical Oncology compared survival, toxicity and quality of life of six cycles of Ellence (epirubicin) alone to three cylces of Ellence followed by three cycles of Taxotere (docetaxel) for women with postmenopausal, node-positive, early breast cancer. Both disease-free survival and five-year survival rates were better in the Ellence plus Taxotere arm. Ellence plus Taxotere was associated with "greater toxicity," but there was no difference in quality of life during follow-up.

TheDoctorsChannel.com published a detailed video on this study for medical professionals. A link to the video may be found under the news tab on the Taxotere page of the LATESTBreastCancer.com website.

Chemotherapy drug Doxil is in short supply

Doxil (PLD), a chemotherapy approved for ovarian cancer, is in clinical trial or used off-label for breast cancer. It's a formulation of Adriamycin (doxorubicin) believed to reduce its cardiotoxicity, or heart-related side effects. According to Reuters, Johnson & Johnson has announced a Doxil shortage and advised doctors not to start new patients on Doxil. New supplies will not be shipped until late August.

Trauma or surgery after breast cancer not associated with increased risk of recurrence

According to a recent Annals of Oncology study, "Several lines of evidence suggest that cytokines released as a result of wound healing might reactivate dormant breast cancer metastases." To test this, British researchers examined recurrence rates 2 to 24 months after a non-cancer related trauma or surgery. They concluded that "[t]rauma was not associated with an increased rate of breast cancer recurrence in the 24-month window after the event in this large study." (Emphasis added.)

Please check back tomorrow for more breast cancer research news updates. Until then, all the latest news and research on any breast cancer test or treatment option may be found on our website anytime.

The Breast Cancer News Update: July 19

Herceptin (trastuzumab) is the treatment of choice for HER2 positive breast cancer. Today, we'll look at the latest news and research on Herceptin for metastatic patients. All of the news and research discussed below can be found on the Herceptin (trastuzumab) page of the LATESTBreastCancer.com website.

Herceptin improves survival in patients with brain metastasis

On July 18, Medical News Today covered a Clinical Cancer Research study which examined the survival benefit of three treatment options - Herceptin, chemotherapy and surgery - for breast cancer patients with brain or central nervous system metastasis. Each option was associated with a "significant improvement in overall survival." Overall survival averaged 17.5 months with Herceptin compared to 3.8 months without, 16.4 months with chemotherapy compared to 3.7 months without, and 20.3 months with surgery compared to 11.3 months without. According to Adam Brufsky, M.D., Ph.D., the lead researcher, "We clearly now know that these women should get trastuzumab and potentially chemotherapy, even if cancer spreads to the brain."

Herceptin after previous progression while on Herceptin

The continued use of Herceptin in metastatic patients whose cancer has previously progressed while on Herceptin is controversial. This month, two studies addressed the use of Herceptin beyond progression.

Overall survival analysis of Herceptin plus Xeloda

A July 7 phase III study from Germany in the European Journal of Cancer evaluated the overall survival benefit of Herceptin plus Xeloda (capecitabine) to treat HER2 positive metastatic breast cancer which had previously progressed on Herceptin. Preliminary study results showed a "significantly improved overall response rate and time to progression." However, "final overall survival analysis" did not demonstrate a significant survival benefit.

Post-hoc anaylsis, or looking back at the data for patterns, revealed that patients who continued anti-HER2 treatment with Herceptin or Tykerb (lapatinib) as third-line therapy, after a second progression while on Herceptin, experienced "better post-progression survival than those not receiving this targeted treatment." Post-progression survival in this group averaged 18.8 months compared to 13.3 months for those who did not receive third-line anti-HER2 treatment.

Clinical benefit of Herceptin plus Afinitor

A July 5 Journal of Clinical Oncology phase I/II study evaluated the combination of Herceptin plus Afinitor (everolimus) for patients with HER2 positive breast cancer who had progressed while on Herceptin-based therapy. 7 of 47 patients (15%) experienced a partial response. 9 of 47 (19%) experienced "persistent stable disease" lasting 6 months or longer. Combined, this reflects a clinical benefit of 34%. The authors concluded that the addition of the mTOR inhibitor Afinitor to Herceptin "results in clinical benefit and disease response."

According to a July 8 EurekAlert! press release about the study, "MD Anderson researchers are recruiting HER-2 positive breast cancer patients for BOLERO-3, a randomized multi-center trial of a regimen including the two agents and a chemotherapy drug (vinorelbine)."

Please check back tomorrow for more breast cancer news and research updates from LATESTBreastCancer.com

The Breast Cancer Update: July 1

Today in breast cancer news, we'll wrap up the week's big story by looking at what's next for Avastin. We'll also look at a UK decision to deny cost coverage for Tykerb or Herceptin plus hormone therapy for some metastatic patients and surgical scar treatment and prevention advice.

What's next for Avastin?

There's been a great deal of activity on the LATESTBreastCancer.com Avastin (bevacizumab) news page this week. Earlier this week, an FDA advisory panel held hearings on the risks and benefits of Avastin for metastatic breast cancer. In the end, the panel voted 6-0 against the use of Avastin for breast cancer. The FDA Commissioner will make the final decision, which will likely follow the panel's recommendation.

So, what's next for Avastin?

First, because Avastin will still be available for other cancers, doctors may continue to prescribe it off-label for metastatic breast cancer. At a cost of about $8,000 a month, the real question is if insurance will continue to pay.

According to the New York Times, Medicare will continue to cover Avastin for metastatic breast cancer even if the FDA revokes approval. This may eventually change, but such a change in policy "would take at least a year and involve public input." Representatives from several private insurance companies indicated that they would review coverage after the FDA final decision. A UnitedHealthcare representative told the New York Times that it would continue to base chemotherapy coverage on National Comprehensive Cancer Network (NCCN) guidelines.

A Reuters story noted that Roche is "undeterred" and is planning another breast cancer trial for early 2012. The new trial will include a biomarker to try to identify which patients may benefit from Avastin.

Both the New York Times and Reuters mentioned that Europe expanded its approval for Avastin for breast cancer to allow it to be combined with a second type of chemotherapy, Xeloda (capecitabine). Avastin "can be used for breast cancer in more than 80 countries."

UK won't pay for Tykerb or Herceptin plus hormone therapy for some patients

In foreign regulatory news, Bloomberg reports that the UK National Institute for Health and Clinical Excellence has denied cost coverage for Tykerb (lapatinib) or Herceptin (trastuzumab) in combination with aromatase inhibitor therapy for older, HER2 positive, metastatic patients. Unlike the recent Avastin hearing, the UK decision was based on a cost/benefit analysis. Both Tykerb and Herceptin have previously been approved in the UK for use in "certain other patients."

Breast cancer surgical scar prevention and treatment

According to a recent Cure Today article, surgical scars "can be managed and minimized." Breast surgeries, such as breast conserving surgery (lumpectomy) and mastectomy, are "associated with a high incidence of scarring." The International Advisory Panel on Scar Management recommends silicone gel sheeting be used as the "first-line preventative measure" for the first month after surgery. For more severe cases, intralesional corticosteroid injections are recommended as second-line treatment. Pressure wrapping may also be an option. In some cases, surgical excision may be necessary.

Please check back on Monday for more breast cancer news updates from LATESTBreastCancer.com. You may find all the news and research on any breast cancer test or treatment option, including complementary therapies on our website anytime.

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).

The Breast Cancer News Update: June 1

Today in breast cancer news, there were two studies about beta-blocker use and an overview of the chemotherapy side-effect neutropenia.

Beta-blocker use associated with breast cancer survival

Late yesterday, Reuters Health covered two Journal of Clinical Oncology studies which found an association between beta-blocker use and breast cancer survival.

In the first study, from MD Anderson, breast cancer patients who took beta-blockers, mainly metoprolol and atenolol, seemed to "fare better." Even though there were no differences in the tumors after surgery, three years later, 87 percent of the women on beta-blockers were alive and cancer free, compared to 77 percent women not on beta-blockers. The findings were "even more striking" for women with triple-negative breast cancer.

The second study, from Ireland, found that women who took the beta-blocker propranolol in the year before diagnosis were less likely to present with advanced breast cancer and had a "significantly lower" risk of mortality than those who took no beta-blockers. However, the use of the beta-blocker atenolol did not appear to confer similar benefits.

Although beta-blockers are inexpensive and readily available, both of these studies are considered early. Further research is needed to identify or confirm a causal relationship.

Neutropenia from chemotherapy

Today, Cure Today published an overview of chemotherapy side-effect neutropenia, or low white blood cell count. Because neutropenia results in a compromised immune system, the article recommended that patients "take precautions to prevent infections," such as washing hands, avoiding crowds, sick people and raw or uncooked foods. Medications such as granulocyte colony stimulating factors (G-CSFs) and antibiotics were also addressed. The latest news and research on Neulasta (pegfilgrastim) and Neupogen (filgrastim), two forms of G-CSFs, can be found on our website, LATESTBreastCancer.com.

Please check back tomorrow for more daily breast cancer news updates.

HER2 Part 3: Drugs that Target HER2

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

For patients with HER2 over-expressing breast cancer, it is critical to target the HER protein. Here we'll look at an array of HER2 targeted drugs: current, new and future. If you're a patient with metastatic disease whose disease is progressing following Herceptin treatment, accessing one of these newer drugs through a clinical trial might be a reasonable option.

Herceptin (trastuzumab). "The big standard." The first drug to target HER2. Approved in 1998. Currently used for patients with all stages of HER2+ breast cancer. Picture how it works: Herceptin is a very large monoclonal antibody protein. It attaches to HER2 on the portion of the molecule that sits outside the cell. By binding to it, Herceptin effectively "flags" the cancer cell for destruction by the body's own immune system. Herceptin also seems to inhibit HER2 growth signaling more conventionally. But attracting an immune system attack is the primary way the drug works (also called, by pharma nerds, "mechanism of action" or MOA).

Tykerb (lapatinib). "The little newcomer." The second HER2 drug. Unlike Herceptin, Tykerb is a very small molecule that inhibits not only HER2 but also EGFR (HER1). Also unlike Herceptin, Tykerb attaches to EGFR and HER2 inside the cell. HER2 and EGFR still pair up with other members of the HER family, but because of Tykerb binding, the grow signal is never sent to other molecules in the "relay chain." Tykerb is used in patients with metastatic disease if they progress after using Herceptin. The other key point about Tykerb is that because it is a very small molecule, it can travel from the bloodstream into the brain, and it seems to reduce brain metastases in HER2 positive patients.

T-DM1. "Targeted AND chemotherapy." A modified version of Herceptin (trastuzumab). In this case "T" (trastuzumab) is attached to another molecule called "DM1" which is a traditional chemotherapeutic. How about this for tricky: the trastuzumab portion of the drug attaches to HER2 outside the cell. When it does, it causes HER2 to get pulled inside the cell, where there (and only there) the chemotherapy portion of the drug is released and kills the cell. So the chemotherapy only kills HER2-laden cancer cells and isn't released where it could do damage to other cells. T-DM1 appears to be doing well in clinical trials and is generating excitement.

OmniTarg (pertuzumab). "Separate, you two!" Remember that to send the grow signal inside the cell, HER family molecules on the cell membrane have to pair up. Well, Genentech has created a drug that inhibits this pairing ("dimerization"). Pertuzumab is a large monoclonal antibody like Herceptin. Like Herceptin, it binds to HER2 outside the cell. But it binds to a different part of the molecule than Herceptin, effectively inhibiting HER2 from pairing up with EGFR (HER1), HER3 and probably HER2 as well. No pairing, no growth signal. Lone HER2s just float around the cell membrane doing nothing. Cancer cell growth and proliferation slows or halts (in theory).

afatinib and neratinib "Same but (maybe) better." These two drugs are in clinical trials. They both work much like Tykerb, but they might end up being more potent and thus more effective. Like Tykerb, both are small molecules, both are taken orally as tablets, and both attach to HER2 inside the cell to inhibit growth signaling. But unlike Tykerb, they are so-called "irreversible" inhibitors of HER2. They bind and then stay attached to HER2. Tykerb is a "reversible" inhibitor that binds but sometimes detaches.

To find clinical trials for these drugs, you can go to clinicaltrials.gov. Or, better yet, try out a newer, easier-to-use site called BCTrials.org. This site provides personalized info about available clinical trials. It's sponsored by UC San Francisco.

Next: How doctors determine if you're HER2 positive

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?

The Breast Cancer News Daily Update: May 6

It's Friday. Today we'll cover the morning breast cancer news and highlight the noteworthy abstracts from medical research publications we added to our database this week.

First the news.

This morning, The Telegraph (UK) reported that tamoxifen only reduces risk of breast cancer in about half of the women who take it for breast cancer prevention.

The screening mammography discussion continued today with a Reuters story about the impact of the US Preventative Services Task force recommendation against mammograms for women in their 40s on minority women. According to the report, "minority women are more likely to develop breast cancer in their forties than white women."

In prognostic testing, Irish and American researchers compared the OncotypeDX test to the PAM50 test. According to the story in Medical News Today, the tests predicted similar risk for those with high and low risk. For those with intermediate risk, the PAM50 identified more patients who would not benefit from chemotherapy.

Also in prognostic testing, French researchers reported that baseline circulating tumor cell (CTC) counts are prognostic at baseline for metastatic patients, and that CTC changes during treatment, "may be an early indicator of chemotherapy efficiency."

This week, we added a few interesting abstracts from breast cancer research medical publications to our database.

Researchers in Chicago reviewed hospital and emergency room admission records to see which 5-HT(3) RA class drugs for chemotherapy-related nausea and vomiting were most effective. They concluded that breast cancer patients on cyclophosphamide-based chemotherapy had "a significantly lower risk" of hospital-related nausea and vomiting if they started and continued taking palonosetron (brand name Aloxi).

The Annals of Plastic Surgery published a study that found "nearly 1 in 5" healthy breasts removed during a contralateral prophylactic mastectomy contained a malignant or pre-malignant lesion. Risk factors for finding a malignancy in a healthy breast included "a lobular histology in the original specimen" and patient age over 54.

In the UK, a study in The British Journal of Cancer found clinical benefit in continuing trastuzumab (brand name Herceptin) beyond disease progression in patients with locally advanced or metastatic HER2 positive disease.

Please check back Sunday evening for a recap of the weekend breast cancer news. As always, at LATESTBreastCancer.com we welcome any and all feedback. We want to know what interests you most.