UCSF Advocacy and Scientific Retreat

[bejuce]

As part of my recent involvement as a breast cancer advocate at UCSF's Breast Cancer SPORE ("Specialized Program of Research Excellence", sponsored by the National Cancer Institute), I had the privilege of attending their annual Advocacy Retreat and their Scientific Retreat a couple of weeks ago. I say privilege because I got to hear about the latest and greatest of breast cancer research being conducted at UCSF as well as at other centers, with a couple of presentations given by researchers at Berkeley and MD Anderson Cancer Center.

I learned many new things about the disease, and was overwhelmed in the end with the amount of new information I (hopefully) absorbed. I posted a highlight of some of the topics I heard about at my blog at bejuce.blogspot.com, and I'm posting it here too in case anyone is interested.

• I-SPY 2 Adaptive Neo-Adjuvant Trial: UCSF is spearheading a novel clinical trial design for breast cancer with the goal of determining the best possible agents for any given subset of the disease, with the ultimate goal of reducing the time for a drug in development to be approved and used by patients. During the trial, patients will be put into different regimens according to their diseases - it is clear that breast cancer is a heterogeneous disease and as such, requires heterogeneous treatment. For example, HER-2+ patients may get Taxol + Herceptin and maybe a new targeted agent (such as a Tyrosine Kinase Inhibitor like Tykerb or other agent in development), followed by AC, Triple Negative patients may get a PARP inhibitor from the start, and so on. It seems that the neo-adjuvant approach that I followed during my treatment (that is, chemo before surgery) has become more and more popular - especially for locally-advanced (like mine) and inflammatory breast cancers. The trial is adaptive because it will adapt the agents given to their patients during chemo - if a given agent is not working, another one will take its place, and so on. Seems to be a very good idea, one that I hope will attract lots of patients to make the trial successful. The trial will be run in quite a few places across the country, and has just started enrolling its first patients.

• Pharmacogenetic Studies in Breast Cancer - Tailoring Drugs to Fit Your Genes: I thought this to be a very interesting area of research, one that also makes total sense to me. This area basically tries to answer the question of why some drugs are effective in some patients, but not in others. Why is that? Because of how each individual's genetic make-up tailors the response to a given drug. The researcher presenting her work told us that the human genome has about 3 billion base pairs of DNA but just one base pair out of 1000 will be different between any two individuals (see, we are pretty much the same after all). The most common variations are what's called "single base pair differences" or "single nucleotide polymorphisms" (SNPs). She gave the example of the drug Tamoxifen that I take (and will take for 5 years) as one whose response varies depending on the presence and type of copy of a gene called "CYP2D6". It turns out that Tamoxifen is a drug that gets metabolized into endoxifen in the body by a process that depends on the CYP2D6 enzyme - it is the endoxifen that is effective in blocking the estrogen that fuels the growth of the tumor cells. Levels of a patient’s endoxifen in the blood are related to the CYP2D6 gene and variants thereof. One study she mentioned showed a 40 % survival advantage in patients having normal copies of the CYP2D6 gene. This gene is not present in about 7-8 % of the Caucasian population - for example, the first mapping of the human genome by Craig Venter did not show this gene because he did not have a copy of it. It was only later that researchers discovered its importance in the metabolism of Tamoxifen. Why is that so important? Because if a patient doesn't have this gene, it means that taking Tamoxifen will be of almost no benefit - another drug may be used in its place. I already did a blood test a month and a half ago and I'm now waiting for the results to find out if I have the gene or not.

• PARP Inhibitors: another talk that we heard focused on this new line of drugs that is showing great promise for those patients who are triple-negative (that is, those whose tumor cells do not have receptors for estrogen, progesterone, or HER-2). One very interesting finding is that some triple-negative cancers have a "basal-like" behavior (very aggressive), while others are apparently curable. So hearing that you have a triple-negative tumor is no longer as bad as it used to be because of all the research that is being put into those tumors and the new drugs and treatments that are emerging every year.

• Central Nervous Systems Metastases (aka brain mets): this to me was the most depressing part of the whole retreat. Depressing because while great strides have been made in the area, the numbers are still somewhat dismal. The researcher presenting her work - Dr. Michelle Melisko - told us that brain mets occur in about 44 % of lung cancer patients, 12 % of breast cancer patients, and 11 % of melanoma patients. The median survival time is only about 30 months from time of initial diagnosis for HER-2+ brain mets patients, but she did say that there are patients at UCSF being treated for brain mets who have been alive for 5-6 years. The distribution and presentation of brain mets include headaches (50%), focal weakness (50%), seizures (10%), and lesion site-specific (aphasia – unable to express, ataxia – inbalance, visual field defect – focal vision defect, encephalopathy – confusion, sleepiness, coma – unusual unless extensive, leptomeningeal disease – lining of brain/spinal cord). Unfortunately it appears that there is no statistically significant difference in survival for those patients that are screened and for those that are not. The treatment includes a combination of radiation therapy and surgery/radiosurgery (like Gamma Knife or Cyber Knife surgery), with systemic therapy (chemo) being explored. Longer survival is associated with age, primary tumor control, ER+, and HER-2+.

• The Bay Area Physical Sciences Oncology Center: this was by far my favorite presentation. We learned about this very innovative and novel area of research that looks into the interactions of Physics, Chemistry, Biology, and Engineering and how those interactions shape and fuel tumors in any particular tissue. The National Cancer Institute has a new Physical Sciences in Oncology initiative that is currently allocating about $200 million a year to 12 centers across the country. The goal is to foster a new field of research combining physical sciences with cancer biology and clinical oncology to establish the physical principles that shape cancer. It's all very new (the initiative started in August '09) and exciting. The presenters - Prof. Liphart from Physics at UC Berkeley and Prof. Weaver from UCSF - clearly explained how cancer needs to be understood not only from a biological perspective of single proteins, genes, genomes, or cells, but also from a mechanical/physical/systems perspective of the surrounding tissue (think lego pieces versus a functioning engine made of lego blocks). Made total sense to me. For example, the idea that breast density contributes to cancer risk is intrinsically related to the mechanical/physical forces in the tissue. In fact, as they explained, cancer has always been understood from very early on to be "stiff" tissue with a diagnosis based on shape and hardness (cancer cells tend to go where it's stiffer). Even the Egyptians in 1550 BCE knew about cancer in those terms. So far their research has showed that breast cancer cells migrate faster in a stiffer environment, different types of breast cancers have different structural organizations, and that breast cancers are often enriched for collagen which is highly cross linked and alters the material properties or stiffness of tissue. In their words, cancer is a combination of oncogenic transformation and a stiff microenvironment. I hope that funding in this area will continue to increase because it seems to be taking the right approach to dealing with the complex, system-like cancer problem from a physical perspective that is also rooted in biology.

• HER-2+ Breast Cancers: now this was very exciting to hear. Dr. Moasser, an expert in cell signaling at UCSF, is doing groundbreaking research on the Human Epidermal Growth Factor Receptor (HER) family of receptors including EGFR, HER-2, HER-3, and HER-4. His research has showed that this family of cell receptors function and signal as a unit, with its members working closely in pairs. HER-2, for example, is closely tied with HER-3. Drugs that have been successful in treating HER-2+ breast cancers (like Herceptin and Tykerb) target HER-2 by itself without much blocking of the HER-3 activity - with Herceptin being a large molecule (monoclonal antibody) that blocks the signals outside the cell and Tykerb targeting the downstream signaling inside the cell. Dr. Moasser went so far as saying that HER-2+ breast cancers will be eradicated and will be the first type of breast cancer that we will be able to cure. And why does he say that? Because HER-2+ breast cancers have a distinct driver - the overexpression of HER-2 - and as such, those cancers are simpler (of course if it were that simple it would be cured by now) and can be cured by blocking the effects of the driver. He gave the example of CML (a type of leukemia) that is driven by a BCR/abl protein. Gleevec, a drug that was developed specifically to target the effects of this protein, has completely changed the picture of this disease. Before Gleevec, patients had a dismal chance of being alive after 5 years. Now the rate at 5 years is at 95-98 % survival - as close to a cure as you can get. That is, if you can develop a drug against the cancer driver, you can cure it!!! According to his research, HER-2+ breast cancers have not yet been cured because the current drugs are not effective as blocking the HER-2/HER-3 signaling completely. For example, he showed that Tykerb, while theoretically supposed to shut off the whole cell signaling across the HER family, still leaves out some HER-3 signaling behind. His theory is then to develop drugs that more effectively target the HER-2/HER-3 signaling or that affect HER-3 by itself, combined with downstream drugs (like Tykerb), more potent drugs, or higher dose of drugs that completely block off HER-2. He talked about the fact that the dose of Tykerb given today is not effective at destroying the tumor completely in mouse models. He ran a study giving Tykerb intermittently one week on and one week off at 800 mg/kg/day instead of the currently prescribed 100 mg/kg/day and showed that at 8 times the dose, there was a much better chance of completely destroying the tumor. Of course, 8 times the dose of Tykerb would probably kill us of a heart attack or something else, so more research is still needed to find the optimal drug/dose combination to interrupt the HER signaling. He also talked about the potential for siRNA as a potent delivery system. One thing was clear from his talk - his belief (and mine too) in basic scientific research at the lab to come up with the cure.

• Circulating Tumor Cells: a couple of presentations focused on the significance of circulating tumor cells (CTCs). CTCs, as explained nicely here, "are cells that escape from the primary tumor and settle down at a secondary site to cause metastasis". Dr. Park gave a presentation in which he said that the presence of CTCs in a patient's blood is correlated with an increased risk of distant recurrence and death from cancer. Papers (such as this) have concluded that the number of CTCs is an independent predictor of progression-free survival and overall survival in patients with metastatic breast cancer. Apparently about 60% of metastatic breast cancer patients have CTCs; the number is about 30% for non-metastatic patients. A study that was presented showed that Zometa, a drug that is used to treat bone mets and is on trials to evaluate whether it can be used to also prevent bone mets from occurring, when given to patients with CTCs, was able to reduce their number. It remains to be seen whether CTCs are indeed a valuable predictor of mets and disease progression/survival, and whether targeted therapies can be developed to obliterate them before they form a colony somewhere else in the body.

• Keynote talk by UCSF Chancellor: Dr. Susan Desmond-Hellman, one of my new heroes, gave an inspiring and motivational keynote talk in which she highlighted the importance of accelerating the cancer drug development process and the potential for the next decade to have an explosion of new drugs. The link above does a pretty good job describing her talk, so I won't go into too many details here. Suffice it to say that she mentioned that there are almost 900 cancer drugs in development, with about a fraction of those being approved each year at an average time of 15 years to market. Only 2 new compounds were approved by the FDA last year. The costs are still huge - $2B per approved drug, which includes the cost of all the failed drugs. Clearly this process needs to be made faster and better. But how? That's the million - er, billion - dollar question.

• Other highlights included a presentation on cancer stem cells, a discussion during the I-SPY2 and Athena talks about a measure called the Residual Cancer Burden ("RCB") and how well it predicts survival (RCB is measured after a neo-adjuvant chemo regimen by evaluating what's left at surgery), a presentation that clearly showed that functional limitations in a patient (e.g., smoking, obesity, hypertension) are independent predictors of survival and in part explain the survival disparity between African-American and Caucasian patients, the fact that 75% of the cancers found in young women (under 40) in the first I-SPY trial were aggressive cancers with a poor prognosis, and a discussion on Physics and cancer focusing on how environmental stresses work with evolutionary forces to shape cancer dynamics.

As you can see, it was packet full of interesting and hopeful information. I hope that I'll be able to take advantage of some of these new approaches if, God forbid, I ever need them.

[chrisy]

wow. exciting stuff!!!!!

[Chelee]

Marcia, Thanks so much sharing all this. You did a great job putting it all together for us. Very interesting and exciting! Thanks again.

Chelee

[Jean]

Marcia,
Thank you - you did an outstanding job outlining the retreat information. So exciting to read.


Jean

[michka]

Thank you for sharing Marcia! Michka

[schoolteacher]

Marcia,

Thanks for letting us know what is happening.

Amelia

[Lori R]

Marcia,
Thank you so much for taking an extensive amount of time to document and pass along to us the news/updates from this leading edge forum.

You should be a medical writer for the layperson. Although I need to head out to work, I found myself glued to your write up. It was so informative!!

Very encouraging to hear about all of the possible approaches to managing this disease. Of course, I really focused on the HER2/HER3 paragraph.

Thanks again and seriously...you should consider a profession as a technical writer.

Well...finally must put down the coffee mug and get dressed for work.

Have a great day....Lori

[Hopeful]

Marcia,

Thanks first of all for attending the retreat, then sharing what you learned with us in a way that is easy to understand and makes interesting reading. Lots of encouraging information here!

Hopeful

[Jean]

Just moving this thread up....

Just lurked around and have found this:
"Dr. Moasser went so far as saying that HER-2+ breast cancers will be eradicated and will be the first type of breast cancer that we will be able to cure".

[Ellie F]

For some reason must have missed this first time round. Thanks Marcia for posting. Let's hope the cure is this year!!

ellie

"Dr. Moasser, an expert in cell signaling at UCSF, is doing groundbreaking research on the Human Epidermal Growth Factor Receptor (HER) family of receptors including EGFR, HER-2, HER-3, and HER-4".
Maybe http://www.clinicaltrials.gov/ct2/sh...m=her3&rank=6?

[Joan M]

Thanks for this post.

Joan