bye xeloda! - hello my old friend herceptin! and tykerb stay right where you are...

[hutchibk]

My PET showed that the bone spot on my rt iliac wing (a pelvic bone) has grown a little bit, too. (and again, my CA 15.3 was right in line with the tiny progression/ activity in my brain spots and this existing spot, yeah! CA15.3)

The plan is to drop Xeloda and add Herceptin every 3 weeks. So as of next week, I will be on my beloved Tykerb with Herceptin. Bye bye cracked heel! Hello drippy nose, welcome back!

So, anything I should know side effect wise about the Tykerb/Herceptin combo?

[Joan M]

Brenda,

I think I'll be saying "hello" to Xeloda as my onc wants me to do six cycles to back up the lung RFA I had.

I'm due for my first follow-up PET/CT next week, and I'm hoping that the lung is clear from the procedure and that there are no other spots. If this is the case, I can stick with just the the six cycles.

You did really well with the side effects of Xeloda for the 18 mos. And I'm sure you'll handle the Herceptin, too.

I hope I do just as well as you on Xeloda since I need to work to keep my medical insurance ... in fact I'm at work now (even though tecnically I work 9 to 5), due to the craziness in the markets this week.

Joan

[SoCalGal]

Hi Brenda-
Always following your path and sending good thoughts. (Have/had a puking thing last night out of the blue- don't think it's chemo/cancer related - think it's something I ate so I am still queasy and foggy but just wanted to quickly post). Herceptin-tykerb is unremarkable except that it seems to work. I have moderate sinus things - sometimes very very dry or sometimes drippy. I use a lot of tissues and a lot of AYR saline spray to keep moist. Dryness is bothersome. But I am still able to wear my contacts. I think fatigue has some play but again - nothing too severe - resting helps and exercise helps. My voice sounds raspy the days following treatment. I also get avastin ev 3 wks and zometa ev 6 weeks so some of my side effects are prob from the combo. Today was the first time I skipped Tykerb since I began. Weird. Will resume (hopefully) tomorrow.
Hope this helps. xo Flori

[hutchibk]

We truly are twinkies, Flori! Same birthday, same treatment (except for avastin), and I am sure there are other things we haven't had a chance to talk about yet... - sorry you aren't feeling well. I hate the ever-dreaded food poisoning. Please take care of yourself! I worry about ya!

I will also continue my once a month zometa... so there you go.

[Lani]

Abstract
Background. Lapatinib is a HER2 tyrosine kinase inhibitor that has clinical activity in HER2
overexpressing (HER2+) breast cancer. In vitro and clinical studies have shown that lapatinib
enhances the effects of the monoclonal antibody trastuzumab suggesting partially non‐
overlapping mechanisms of action. In order to dissect the differential mechanisms of these
agents, we have studied the effects of lapatinib and trastuzumab on receptor expression
and signaling and have explored a new potential mechanism underlying the profound
antitumor activity of the combination.
Methods. HER2+ breast cancer cells SKBR3 and MCF‐7HER2 were treated with lapatinib,
trastuzumab or both. Assays of receptor expression, phosphorylation, signalling and tumor
growth were performed. Trastuzumab‐dependent cellular cytotoxicity was measured with
different levels of HER2 expression and doses of lapatinib.
Results Lapatinib treatment of HER2+ breast cancer cells inhibited HER2 phosphorylation,
prevented ubiquitination and resulted in a marked accumulation of inactive receptors at the
cell surface. By contrast, trastuzumab caused enhanced HER2 phosphorylation,
ubiquitination and degradation of the receptor. By immunoprecipitation and computational
protein modelling techniques we further demonstrated that the lapatinib‐induced
accumulation of HER2 lead to stabilization of inactive HER2 homo‐ and hetero‐dimers.
Accumulation of HER2 induced by lapatinib and downregulation of HER2 mediated by
trastuzumab were also observed in vivo, where the combination of the two agents triggered
complete tumor regression in all cases after 10 days of treatment. Lapatinib‐induced
accumulation of HER2 at the cell surface markedly enhanced trastuzumab‐mediated ADCC.
Conclusions. Lapatinib results in a marked accumulation of inactive HER2 receptors at the
cell surface both in vitro and in vivo. This increase in receptor numbers at the cell surface
enhances ADCC by trastuzumab. We propose that this is a novel mechanism that may be
clinically relevant and exploitable in the therapy of patients with HER2+ tumors.
Lapatinib induces*accumulation*of*inactive*HER2*at*the*cell* membrane*and*enhances*
antibody‐dependent*cellular*cytotoxicity (ADCC)*mediated*by*trastuzumab:*a*novel*
mechanism*for*the*enhanced*effects*of*combined*ant i‐HER2*therapy******************************#3 594
Lapatinib induces accumulation of HER2 receptors at the cell surface
Lapatinib treatment of the HER2 overexpressing breast cancer cells SKBR‐3 and
MCF‐7HER2 resulted in accumulation of HER2 at the cell surface. Trastuzumab alone
resulted in downregulation of the receptor from the cell membrane. As for the
combined treatment with lapatinib and trastuzumab, the net result was an
accumulation of the receptor at the cell surface of a similar magnitude when
compared to lapatinib alone.
Effects of lapatinib on HER2 ubiquitination, stabilization and dimerization
We transiently expressed HA‐tagged ubiquitin in MCF‐7HER2 cells and analyzed
HER2 ubiquitination in the presence of lapatinib, trastuzumab or the combination of
both. Trastuzumab increased HER2 ubiquitination and degradation whereas, in the
presence of lapatinib, the levels of ubiquitinated receptor were barely detectable.
This was translated to increased stability of the receptor and enhanced formation of
inactive HER2‐containing dimers.
Effects of lapatinib and trastuzumab on BT474 xenografts
Both lapatinib and trastuzumab induced tumor regression of BT474 cell‐derived
xenografts. All the mice receiving the combination of lapatinib and trastuzumab
showed complete tumor regression after 10 days (day 23) of treatment. HER2
staining decreased in tumors treated with trastuzumab but increased in tumors
treated with lapatinib or the combination.
Lapatinib‐induced accumulation of inactive HER2 leads to increased ADCC in vitro
We wanted to test whether the accumulation of HER2 induced by lapatinib could increase
ADCC mediated by trastuzumab. Trastuzumab‐dependent cytotoxicity was significantly
higher in MCF‐7HER2 cells treated with lapatinib compared to untreated cells.
Proposed alternative mechanism of action of lapatinib based on HER2 accumulation
Upon ligand binding or trastuzumab treatment, the HER receptors form dimers and are
phosphorylated (P) in their kinase domains (K). Once phosphorylated, HER2 dimers initiate
signaling and undergo ubiquitination (Ub) and lysosomal degradation. Lapatinib counteracts
receptor phosphorylation, ubiquitination and degradation resulting in HER2 dimer
accumulation at the plasma membrane and rendering the cells more susceptible to the
immune‐mediated action of the anti‐HER antibodies (mAbs).
Conclusions
In conclusion, our results provide a new explanation for the enhanced effects of
the combination of lapatinib and trastuzumab. Lapatinib reduces HER2
ubiquination, prevents HER2 degradation, and induces the formation of inactive
HER2 dimers at the cell surface, which in turn provides an increase in
trastuzumab binding and a greater trastuzumab‐mediated immune response.
This is a therapeutically exploitable mechanism of action that deserves further
study in patients.
Maurizio Scaltriti1,*Chandra Verma2,*Marta*Guzman1,*José*Jimenez1,*Josep*Lluis Parra1,*Kim*Pedersen1,*Stefania Landolfi1,*
Santiago*Ramon y*Cajal1,*Joaquin Arribas1,*José*Baselga1.
1Laboratory*of*Oncology* Research,*Medical*Oncology* Service,*Vall d'Hebron University* Hospital,*Barcelona,*Spain
2Biomolecular*Modeling* &*Design*Group,*Bioinformatics*Institute,*Singapor e.*

[hutchibk]

I think in this case I might like being theraputically exploited... LOL. Thanks Lani! I truly appreciate the reassurance!!

[doh2pa]

Hi Brenda,

Sounds like a good plan. I'm very interested in this combo and how you do on it (let's face it WARRIOR WOMAN the cancer is now shaking in it's cowboy boots!). Go forth and kick ass!

[grandma2]

i was on herceptin for 15 months and it was a breeze for me. i did need steroids each time because i have severe asthma and it can cause some sob. infusion day i felt washed out and then of course couldn't sleep that night because of the steroid. i was very disappointed that i couldn't stay on it. tomorrow i start xeloda again but at 2000mg daily instead of 4000. i'm nervous about that but gotta do it. if i can tolerate it then we'll go to 2500mg. the tykerb se's vary from day to day. fatigue being the most constant. i personally think if you tolerated xeloda so well herceptin will be a walk in the park. good luck.

[Laura]

I am in somewhat of a similar situation. Bone and brain mets (brain was diagnosed January of 08- had innumerable tiny lesions – now down to one) bones are riddled with small mets. I added Herceptin back in to my treatment 9 weeks ago. I am currently on Xeloda, Tykerb, Herceptin and Zometa. I have noticed the dry/runny nose, diarrhea and Xeloda hand/foot problems. I continue to be very active. I am 40 years old with 4 children (ages 6-15). I went back on Herceptin because there was slight progression in my bones. My next brain mri is in December. Why are you pulling Xeloda?

We can continue to compare notes!

Warmly,
Laura

[grandma2]

laura, forgive me if i've asked before. chemo brain. why are you on tykerb and herceptin. i thought that was only being done in trials. yet i see many of you are on both. my onc said if we do something off protocol, then ins. wouldn't pay for it. again i apoligize for repeating myself as i'm sure i've done. thanks, gm

[Laura]

I don't post often. You are not repeating yourself. I was able to get Tykerb, Xeloda and Herceptin approved by my insurance company off label. I was on Herceptin after diagnosis, taken off when my brain mets were discovered. Then went to Tykerb/Xeloda. When small progression in my bones (which had been clear for 1 1/2 years), was noted in a PET scan in June, I added Herceptin back into my treatment. My brain has not shown any progression since I started on Tykerb - I also had WBR at brain mets diagnosis. I needed to switch oncologists to find one that would approve this combination. I will know more if this Herceptin is doing the trick for my bones in December when I have a repeat PET/CT and another brain MRI.

Warmly,
Laura

[hutchibk]

Hey Laura - you are on quite the combo... I will be on exactly the same thing (Zometa, Tykerb, Herceptin) except without Xeloda. I had a pretty complete response on Tykerb/Xeloda for my brain mets for 18 months, without any radiation... but, as we always know with mets, we eventually have to deal with something again, and as the saying goes "we can't direct the winds, but we can adjust our sails" - I am grateful for those amazing 18 months, though! Wouldn't change it for the world! Tykerb/Xeloda, I loved ya! Now I will add the Herceptin in, which I have previously been on for the 20 months before Tykerb/Xeloda, and it held me very very well. I have luckily had very little side effect from Xeloda, Tykerb or Herceptin that I am not worried. But I have never had Tykerb/Herceptin together and thought it would be worth asking those who have for any heads up of what to expect....

The thought is that hitting the HER2 from the two different targets, from the out side and the inside, we will again throw a brick wall in it's way for a (hopefully lenthy) period of time, but if that doesn't seem to do the trick, we will add in another chemo (basically throw grenades over the brick wall) and knock it back that way...

[Ceesun]

BK, You are one of the best!! And I wish you continued good luck and good health. Ceesun

[Esther]

I have been on Tykerb/Herceptin/Zometa pretty much since tykerb was approved in early 2007.

It has been a tolerable and easy treatment for me. And I'm usually the side effects queen!