Possible New Drug Combo for Triple Negative - Via Harvard Gazette

From The Harvard Gazette/Harvard University:

New Hope for the Cure
Drug combination targets aggressive triple-negative breast cancer

With currently available early-detection methods for breast cancer, many people can be treated successfully. But for the 20 percent of patients with so-called triple-negative breast cancer, the outcome is bleak. Now, however, researchers from Harvard Medical School (HMS) and Baylor College of Medicine have identified a critical molecular component to the disease, one that suggests potential therapies involving combinations of FDA-approved, readily available drugs.

“Whereas many basic discoveries have the potential to impact patients’ lives within 10, 20 or 30 years, this has the potential to impact patients’ lives within one year,” says Thomas Westbrook, formerly a postdoctoral fellow at Harvard Medical School and an assistant professor of biochemistry and molecular biology at Baylor College of Medicine since 2007.

The research was published on March 4 in the journal Cell.

Triple-negative breast cancer is an aggressive disease with few therapeutic options. Patients with such tumors can be treated only with chemotherapy. If the cancer spreads, the median survival rate is one year.

The complexity of triple-negative breast cancer renders it so difficult to treat. The disease is extremely heterogeneous, characterized by hundreds of genetic mutations. Without knowing the critical molecular switches that power this type of breast cancer, researchers have no way to develop targeted therapies.

The HMS-Baylor College of Medicine team reports that an enzyme called tyrosine phosphatase PTPN12 is knocked out in 60 percent of nearly 200 triple-negative breast cancers tested. This phosphatase belongs to a class of enzymes that keeps cell-growth pathways in check and cancer at bay.

The team identified the critical enzyme by looking in petri dishes for proteins whose absence caused normal breast cells to become cancerous.

“We were looking for genes that pushed the cells over the edge,” explains Steve Elledge, the Gregor Mendel Professor of Genetics and a professor of medicine at HMS.

One of tyrosine phosphatases’ primary jobs is to turn off another group of enzymes critical for growth called receptor tyrosine kinases. The researchers reasoned that, if they could identify the enzymes that were switched on in the absence of PTPN12, they could pinpoint critical drug targets that might be used to develop therapies for patients with triple-negative breast cancer.

To identify these proteins, the team turned to HMS Associate Professor of Cell Biology Steve Gygi. By taking a look at all proteins activated in cells lacking PTPN12, the researchers found two enzymes crucial for breast cancer’s progression, or metastasis, EGFR and HER2.

In addition, the team used biochemical methods to identify a third receptor enzyme, called PDGFR-b , that was also regulated by PTPN12.

These results collectively suggest that the improper activation of these three tyrosine kinases could be the major cause of triple-negative breast cancer.

“We’ve grabbed a molecular foothold in triple-negative breast cancer,” says Westbrook, who discovered PTPN12 as a postdoctoral fellow in Elledge’s laboratory. “We are now starting to understand the disease better. Even more important, we have a rationale for a combined drug therapy for the disease.”

Their idea: to treat the disease, turn off the trio of enzymes with drugs.

To test their strategy, the team took advantage of two drugs already being used to battle other types of cancer: laptanib (Tykerb), which turns off EGFR and HER2, and sunitinib (Sutent), which turns off PDGFR-b.

The team treated mice with triple-negative breast cancers with either sunitinib or laptanib, or both. In mice treated with sunitinib alone, tumors shrank by nearly 80 percent. But in mice treated with both drugs, tumors shrank by more than 90 percent — and life expectancy more than doubled.

These results suggest that sunitinib and laptanib (or similar drugs) together may be a promising therapy for people with triple-negative breast cancer. And because both drugs are already FDA-approved and sitting on pharmacy shelves, they can be tested immediately in these patients.

“This research underscores the relation of basic bench science to human health,” says Elledge. “If you know what’s driving the cancer, you can think about targeting that for therapy.”

The team hopes to launch a phase II trial for triple-negative breast cancer by the beginning of 2012.


http://news.harvard.edu/gazette/story/2011/03/new-hope-for-the-cure/?utm_source=alumniaffairs&utm_medium=harvardmonthlyemail&utm_campaign=april11&sms_ss=email&at_xt=4daf0fdaa1c99c77%2C0

Maybe I Need a Little Cheese With This Whine

I should be celebrating today, but I just don’t have it in me. This has been one long nightmare of a week, but I think I am beginning to emerge…very slowly. After the last blog post, it seems, I just went straight downhill…and stayed there. Too long for this impatient patient.

I have been a shadow of myself this past week. And I don’t mean like Peter Pan’s crazy mischievous shadow, I mean like the gloomy, wet, dark shadows we’ve been seeing around Northwest Arkansas these past few days. The kind everyone and their dog wants gone. The weather and my health have been a perfect pairing. And, believe me, I’ve been just about as pleasant to be around…just ask David.

Truly, I don’t think my body could endure another big chemo infusion. My final infusion of Gemzar is this afternoon, but the Cis/Gem combo is history. THANK GOD!! I think it just about did me in, and this past week was proof of that.

I have spent more hours in bed than I ever imagined possible. More hours sleeping, whining, and crying, too. My poor family. When my sweet mom-in-law called to check on me, I think she was pretty sure I was near death…and I might have agreed with her. Bless them all for witnessing my complete and total loss of dignity and not running for the hills. Families are good like that, though, aren’t they? I can’t imagine going through this without them, both near and far.

So, as I gradually emerge and begin to remember what being upright is like, I return to the infusion room this afternoon and get plugged in for the last time. I will not be celebrating, but I will be praying (hard) to never darken their door again (other than the random port flush). I will remember those who have been in that room before me and who will not be returning, through no choice of their own. I won’t be kicking up my heels as I leave that place, but I will be ever so thankful for living.

Now let’s just keep it that way.

And I promise…
…more cheese next time, and much less whine.

Cisplatin, Gemzar and Me

There is a slight possibility that you landed at this blog, not because you know me and are being a faithful friend or family member, but because you googled something cancer related…like maybe Cisplatin and/or Gemcitabine (Gemzar). Before I first began this regimen of chemo, I did the exact same thing...and a few times afterward.

So, I thought it would be appropriate to give a rundown of how the Cis/Gem combo has affected me, now that I am seeing the light at the end of this long, difficult tunnel.

As of today I've undergone 11 infusions since January. I've received these in 2 infusions every three weeks. Week 1 was the wicked infusion of Cisplatin and Gemzar (a full day), week 2 was the much easier Gemzar alone (about 3-4 hours), week 3 was recovery week...multiply that by 6. I have one final infusion of Gemzar, which will occur next week.

This chemo regimen is not typically given to fight breast cancer, but there is good reason for mine. Perhaps that will be a future blog post.

My first infusion and its aftermath has already been documented, so I’ll not go into that, other than to reiterate what I’ve said before…Cisplatin is sometimes jokingly called Sickplatin (if it's possible to joke about such a thing). There is a very good reason for this. I had one chemo nurse tell me she thought it was one of the top 2 or 3 drugs that was known for bad side effects. 

Right now I am feeling those side effects, both the residual and ongoing effects that come from months of treatment, and the short term nausea and fatigue that will go away in a few days (although I have read that fatique can sometimes take months to overcome). Since my final (God willing) Cisplatin infusion was the day before yesterday, I am chipping away at this post, one paragraph at a time. Hopefully I won’t say anything too confusing, but if I do I blame it on the Zophran and Compazine, my anti-nausea meds. Not only do they dissipate the nausea, but they also tend to dissipate the thinking. And then there's chemo brain...

As far as long term side effects, I’ve had a few...

Fatigue and Red Cells –
This, I expected. Doesn’t all chemo have fatique as a side effect? When I underwent my three (unsuccessful) treatments of TAC last fall, fatique was a biggie. So I expected the same for this regimen. In my case, this fatigue thing has gotten worse each time as my red blood count has gradually dropped. This has nothing to do with my changed diet and the fact that I am no longer eating red meat. I could be eating a side of beef a week and the red blood cells would still be killed off. Thank you Cisplatin and Gemzar.

This lower RBC count led to my first injection of Aranesp several weeks ago. After going home and googling this drug, I was shocked at its possible side effects and immediately put a nix on any further injections. To put it lightly, I was unhappy and frankly, shocked. (Look for a future blog/rant on Aranesp.) My boycott of Aranesp is what led to my first blood transfusion following my last Cis/Gem infusion. Blood transfusion I can do, Aranesp no.

The fatigue, however, was unbelievable. I learn best from actually experiencing something and my lesson from this experience is that our red blood cells are REALLY, really, reeeaaly important. Diminished RBCs leads to extreme weakness, dizziness, and shortness of breath, among other things. Standing in one place for more than 2 minutes (like brushing teeth or washing face) was extraordinarily exhausting. At my lowest point I remember asking David to check on me during the night and make sure I was still breathing. I just wasn’t sure.

White Cells -
On the other hand, my white blood cells (those important little things that battle bacteria and other invading nastys in our bodies) were kept up through a shot of a drug that I do approve of, Neulasta. I called this my golden shot after I got a look at the first bill. One little injection cost $3900! Thank goodness for decent medical insurance. I guess this crazy expensive shot is still cheaper than an infection leading to a hospital stay.

Swollen Ankles -
This has progressively gotten more pronounced throughout treatment. It typically appears toward the end of a cycle and stays for about a week. Watching salt intake, drinking plenty of water, and keeping feet elevated seems to help. Since Cisplatin could possibly cause kidney damage, they watch for swelling. Mine has not been terribly severe and they have done blood work regularly to check kidney function and everything seems okay, so I’m not worried. Also, Dr. Beck said that Cis/Gem (particularly Cisplatin) has a very high salt content (it is a platinum salt) so that doesn’t help.

Appetite –
Oddly, for about 10 days following the infusion, this teeters between nausea and the need to eat every two hours (even throughout the night). If I don’t get food in my stomach regularly, the nausea and overall bad feeling increases. I think a lot of this ravenousness is related to the steroid that I get during my chemo infusion (which has also been responsible for my flushed and rosy complexion for a couple of days following the infusion). Favorite foods during my worst days have been oatmeal and Ezekiel toast, vegetable soup, beans and cornbread, organic granola, omega 3 eggs (any form), sautéed spinach, sautéed broccoli, pad thai, tacos de pollo, and watermelon.

Bad Taste –
Something that almost all chemo brings is a bad taste in the mouth. I have always read that it is a metallic taste, but I have never experienced that. Instead, I get one horrible sourish, yuck taste in my mouth for a good 10 days following the Gem/Cis infusion. It’s sour, but not like I just ate a lemon pie sour. Not a good sour. More like I’ve been licking the floor of some hoarders kitchen. Really nasty.

Eating helps (until I stop), brushing teeth helps (for about 5 minutes), peppermint gum helps (until it starts tasting sour).

Way back when, I remember thinking…"A bad taste in the mouth? How bad can that be?” Well, it can be bad. I get tired of the just plain grossness of it. Gets old in a big fat hurry.

Ototoxicity –
Somewhere between the second and third round of chemo I noticed a nonstop ringing in my ears. You know, like when there’s a tea kettle going off somewhere way back in your head. For most people this usually lasts only a few seconds, only mine suddenly wasn’t. Then I started noticing certain noises irritating and almost hurting my ears...paper crumpling, pots and pans banging in the kitchen, dogs barking. When I was listening to NPR in the car one day I thought something was wrong with their signal, or maybe my speakers, and then realized it was my hearing! That’s when it hit me that the somewhat rare Cisplatin side effect of ototoxicity was not just knocking on my door, but had let itself in!

From what I’ve read, there is a good chance that this is irreversible, but not always, so I am praying that my hearing will improve over time. Or at the very least not get any worse.

Bruising –
Less than a week ago I noticed some serious looking bruising on the back of my right leg. Really serious…black and blue and about the size of my hand. Within that bruise were several lumps. Yikes! I am not comfortable with lumps. Then I noticed other bruises on my legs, almost all with a small lump involved. The blood vessels in my leg were leaking! What the heck? I’ve had this same thing on my fingers at times over the past few years and have been told by my family doc that it’s not uncommon and nothing to worry about. Lately, I’ve had a couple of ruptures on my thumbs. The legs, however, are something entirely new and unexpected…no where have I read of such a side effect.

Of course I asked Dr. Beck about this when I saw him this week. He checked these bruises and now diminishing lumps, then shrugged, said everyone was different and chemo affected each person in its own way. Apparently small outer blood vessels that happen to be leaking are okay, the opposite of blood clots…which would be much more concerning. My platelet level has been down, which does lead to bruising, so maybe that’s the reason.

Slow Motion Hair Growth –
One of the last side effects listed for my chemo regimen is hair loss, but I was told I would not lose hair. Been there, done that…don’t want to do it again.

I was happy to know my hair would return during this treatment. However, I know the growth has still been affected. How can I tell? I only need to shave my legs every other week, as opposed to my norm of once a day. So my hair is growing, but very slowly (and very curly…future blog post coming). This is a minor side effect, but still a side effect. I’m certainly not complaining about the minimal leg shaving, that’s for sure.

Chemo Brain –
This is one side effect that has been receiving a lot of discussion and study lately. I have become a firm believer in its existence. Now, whether it is a physical or more of a psychological problem, your guess is as good as mine. I can’t help but think that it is a combination of both. Being washed throughout with toxic chemicals multiple times cannot be good for brain cells. Also, the constant stress of medical appointments, missed work, financial issues, loss of control, fear of recurrence, chemo side effects, surgery side effects, and more can really do a number on one's thought processes.

I misplace things (sometimes very important things) much more frequently than I ever have, I find myself unable to think of specific (simple) words at the oddest times, I forget the names of people I’ve known for years, and I’ve found myself placing items in the fridge that belonged in a cabinet and vice versa. Oh, and if I tell you I'm going to do something, be ready to remind me a couple of times...don't believe anything I promise.

I pray this leaves as soon as all of this poison makes its way out of my body. I want my brain back!

So, that’s a rundown of the side effects I’ve experienced over the past 4 months. I'm sure I've left out something big, thanks to chemo brain. I know these side effects are different for each person, and I know there are people who will undergo treatment with Cisplatin and Gemzar who have almost no side effects. If you are one of the lucky ones, that’s great, congratulations, and praise God! If not, just know it’s temporary and take one day and one week at a time. Allow others to help you and if they don’t volunteer, then speak up and ask!

And above all else, may God bless you and be with you through it all.

Spring Fever Infected...or Affected?

Blogging is not for the easily distracted. Shame on me for being absent for so long! Spring and sunshine and warm weather have caught my attention and my head has been turned from this computer and regular updates. For that, I apologize. I didn’t really think it was a big deal until I started getting emails from blog readers and total strangers who were concerned about me! I guess disappearing from a cancer blog can look pretty bad.

So, to these lovely readers, I apologize. I am fine and chugging along with treatments. No surprises (unless you count that one blood transfusion), no bad news (really), just a very irresponsible and spring fever infected writer.

At this very moment I am sitting in a vinyl recliner upstairs at Highland's Oncology and receiving my final round of Cisplatin and Gemcitabine (Gemzar). Hallelujah! If I’m lucky I can at least get one blog post written before the pre-meds knock me loopy.

I will have my last official treatment of Gemzar next Tuesday, then see Dr. Beck two weeks after that and be set free! As he said, he’ll “sign me off”…whatever that means. I guess they won’t be renewing my contract. (and I am praying to God that they never do!)

But then I get to learn a whole new game called radiation. I’ll be changing coaches and teams and playing a whole new sport. This sport will have a much shorter season, but I’ll get to play it daily. Good thing is, the injury list is much shorter. Other than some possible serious sunburn, peeling, and itching, I’m thinking it’ll be a breeze. Plus, the fact that I have virtually no feeling in the area that will be irradiated will make any possible tenderness irrelevant. I consider that a mastectomy perk…the first one I’ve been able to think of. When life gives you lemons...

If all stays on schedule, I should be finishing up treatment by the end of June. Sometime after that I will be scheduled for removal of the other breast and reconstruction. I look forward to reconstruction, because to me, that means hope for the future and for a mostly normal existence.

Removal of my port will be a huge milestone, too. As thin as I am, it really shows up and changes scoop necked shirts from cute to just plain creepy, so the sooner this thing is gone the better! The nurses have loved it, though. (I really should post a pic.) Sadly, the port will probably stay until my next round of scans in about three months…just in case.

Thanks for the queries and concern at my blogging absence. I will try and stay focused and keep up a bit better. I do have a lot to say…all in my head. In fact, it's been piling up in there and I'm running out of storage space! If I could just dictate a blog, that might work.