New, effective and less toxic therapeutic option for patients with HER2-positive brea

[News]

Patients with HER2-positive breast cancer, a particularly aggressive form of breast cancer, now have a new, effective and less toxic therapeutic option.

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['lizbeth]

That's what I love about this option, kills the cancer cell, and you get to keep your hair. It seems like such a petty thing. But I miss my beautiful thick hair. I can't wait for a world where chemo becomes obsolete!

[gdpawel]

I've heard from breast cancer patients who were bumped from the T-DM1 clinical trial because of disease progression, which meant that their cancer was growing despite the drug. Bumped off the trial because of disease progression? Wonder how many more patients there were like this?

Response rates (how much a tumor decreased in size) can be inflated when excluding patients during clinical trials (evaluable patients). Patients not considered "evaluable" are often those who do not get the benefit of an entire treatment plan. The response rate is calculated after removing patients, who die or have been excluded, from the calculation. This inflates the response rate.

But clinical oncologists want to publish their papers. They need to report on the outcomes of their experiments, but if they had to wait for survival data, it could take years until all the data was aggregated. That wouldn't bode well for them to participate in pharma-sponsored trials in the future.

Response rates give clinical oncologists the opportunity to take a more optimistic look at therapies that have limited success. They can describe results as being complete remission, partial remission or simply clinical improvement.

If they treat all patients for three weeks, they can fairly evaluate the efficacy of a compound, which takes that lone (on average) before it can be regarded as effective. If they disregard all patients who die or were excluded after onset of therapy, and include only those treated three weeks or more, they can improve their data.

To justify their existence, they have to publish papers. That's what they do.

http://cancerfocus.org/forum/showthread.php?t=3768

Progression-free survival (PFS) is the length of time during and after treatment in which a patient is living with a disease that does not get worse. Time to progression (TTP) is a measure of time after a disease is diagnosed (or treated) until the disease starts to get worse.

In the Annals of Oncology, it states that clinical investigators seem to be frequently using PFS and TTP interchangeably in cancer. Such use of terms may lead to confusion when results of different trials are compared.

Clinical trials virtually always have progression-free survival as a primary endpoint. Without imaging studies, one can't get accurate time to progression data. So tests are performed for the benefit of drug companies seeking new drug approval, for clinical investigators seeking contracts and publications, and for clinicians seeking an easy way to make clinical decisions.

The final arbiter of clinical approval is overall survival. Progression-free survival does not address the patient's quality of life during what little additional months of some serious side effects that can be experienced. And drug response is not even a reliable predictor of overall survival. Overall survival is based on death from any cause like side effects of treatment and effects on survival after relapse.

[schoonder]

Overall Survival was an end-point in Emilia trial, it favored participants in T-DM1 arm, people in the lapatinib and Xeloda arm were offered the option to receive trastuzumab emtansine
http://www.roche.com/media/media_rel...012-10-01b.htm

[gdpawel]

Dr. Kimberly L. Blackwell from Duke University, presented results of the EMILIA study in HER2-positive metastatic breast cancer where T-DM1 was compared to treatment with the combination of Xeloda and Tykerb. The study included nearly 1,000 women whom had received prior treatment with Herceptin and a taxane.

The EMILIA study found that trastuzumab emtansine (T-DM1) can improve progression-free survival in "some" women with metastatic breast cancer. The final arbiter of clinical approval is overall survival. Median overall survival for patients treated with T-DM1 was not reached. Drug response is not a reliable predictor of overall survival. Median progression-free survival was longer in patients treated with T-DM1 than in those treated with the standard therapy (9.6 vs 6.4 months). The difference reached is statistically significant?

For patients with high levels of GPNMB (fully human monoclonal antibody CR011 directed against glycoprotein NMB) as well as triple negative breast cancer, the response rate was 36%, compared with no responses in the control group. In this group, a statistically significant progression-free survival benefit is currently observed (p=0.0032), the researchers say.

['lizbeth]

It still feels like a step away from chemotherapy. Once a drug is approved then someone is going to try to improve upon it. And the best part is, if they fudged the numbers - it will be easier for the next up & coming treatment to show a significant improvement. In the meantime, it has been helpful for some women.

So GDP, what is the next up & coming breast cancer treatment?

[gdpawel]

What's up and coming in breast cancer treatment is not "breast" cancer treatment. I was telling someone on another cancer board about the way doctors are now starting (or at least should be looking) to consider the biology of the tumor cell along with the site of the tumor when determining treatment. There are no breast cancer drugs or lung cancer drugs or ovarian cancer drugs. They are learning that the same proteins and pathways are involved in many types of cancer.

I mentioned on the other thread here about Perjeta (pertuzumab) that functions by preventing dimerization of HER-2 with the other members of the human epidermal growth factor family, HER-1, HER-3 and HER-4. It is the failure to completely inhibit all the kinase family members that limits efficacy of these drugs. And even Perjeta showed only modest antitumor activity until they found more comprehensive blockade of HER signaling family when used with Herceptin.

It's going to take sequential application of anticancer drugs to enhance cell death. One of the truest breakthroughs comes with metabolomics, that finds the most active combinations to inhibit the cross-talk between pathway (horizontal inhibition) over drug combinations that target the same pathway at different downstream points (vertical inhibition). Laying siege to cancer cells' supply lines may cast a wider net than targeted therapies aimed at rare oncogenic mutations.

Altering cancer metabolism is not just about energy supply, but also directly affects gene expression through regulating chromatin, the protein packaging around spools of DNA by opening or closing a spool to raise or lower the activity level of a gene in that area, and close the loop between metabolism and genetics. It is now widely acknowledged that cancer metabolism is a main player in cancer and developing anti-metabolism treatments should be a main focus of researchers and pharmaceutical companies.

Perjeta is one of a number of new targeted drugs in breast cancer therapy. And metabolomics is a newly emerging field of "omics" research concerned with comprehensive characterization of the "small molecule" metabolites in biological systems (i.e. PECAM-1 and T-DM1 + Perjeta).

['lizbeth]

You are right, of course. And I've told others the same - that soon the term "breast cancer' will be obsolete.

I should drop the term myself and help move science along, eh?

The better question, GDP, is what drugs can we expect to cross over from research of other initial cancer sites? Prostate, colorectal cancers, ovarian?

I looked at PECAM-1 and read it has a function of getting rid of old neutrophils. This is interesting to me because my hubby has large granular lymphocytosis and has an almost non existant neutrophil count. I suspect that my breast cancer came from his cancer, but my body responds in a different way. I know that it seemed to hijack my immune system, but it didn't affect my neutrophil count. I just feel it used something in my system to evade destruction.

[gdpawel]

One example of the cross over from research of other initial cancer sites (because the same proteins and pathways are involved in many types of cancer), has been that KRAS gene variations or mutations are linked to ovarian cancer. Because many cancer cells use similar pathways, the same drug could be used to treat one person's lung cancer and another person's ovarian cancer, as long as each tumor contained similar targets.

The HER2 gene (typically known as the Herceptin gene) is also known as epidermal growth factor receptor (EGFR) type 2. The EGFR gene is found in a number of lung cancers. Herceptin may show clinical response with the presence of a mutation in the HER2 kinase domain in patients with lung cancer. You remember Tykerb? It is an inhibitor of the tyrosine kinase domains of HER1 and HER2. It has antitumor activity not only against HER1 (EGFR) but also HER2 (EGFR type 2).

Researchers have found that Herceptin (HER2-drug) can sensitize ovarian cancer cells to EGFR-targeted therapeutics. However, ovarian cancer cells that are not growth inhibited by Herceptin are still responsive to it. They found that responsiveness to alternative HER-targeted inhibitors, such as Iressa and Erbitux, is dramatically potentiated by long-term Herceptin treatment of ovarian cancer cells.

There are a lot of possibilities, but so far, I have only seen functional profiling conducted on human tumor samples, utilizing native microspheroids replete with vascular, stromal and inflammatory cells, that can analyze cellular responses in the context of the tumor microenvironment. This snapshot of cellular response recapitulates patient response to cytotoxic compounds, signal transduction inhibitors and growth factor antagonists in real time.

But you don't want me to get into that. It's as thick as pea soup!