towards a rational tailored approach to who should receive herceptin/lapatinib/both

[Lani]

perhaps PTEN level could serve as one biomarker:

ABSTRACT: Loss of Phosphatase and Tensin Homolog or Phosphoinositol-3 Kinase Activation and Response to Trastuzumab or Lapatinib in Human Epidermal Growth Factor Receptor 2-Overexpressing Locally Advanced Breast Cancers
[Journal of Clinical Oncology]
Purpose: Phosphatase and tensin homolog (PTEN) loss or activating mutations of phosphoinositol-3 (PI3) kinase (PIK3CA) may be associated with trastuzumab resistance. Trastuzumab, the humanized human epidermal growth factor receptor 2 (HER2) monoclonal antibody, and lapatinib, an epidermal growth factor receptor/HER2 tyrosine kinase inhibitor, are both established treatments for HER2-overexpressing breast cancers. Understanding of the cellular response to HER2-targeted therapies is needed to tailor treatments and to identify patients less likely to benefit.

Methods: We evaluated the effect of trastuzumab or lapatinib in three HER2-overexpressing cell lines. We confirmed the in vitro observations in two neoadjuvant clinical trials in patients with HER2 overexpression; 35 patients received trastuzumab as a single agent for the first 3 weeks, then docetaxel every 3 weeks for 12 weeks (trastuzumab regimen), whereas 49 patients received lapatinib as a single agent for 6 weeks, followed by trastuzumab/docetaxel for 12 weeks before primary surgery (lapatinib regimen). Apoptosis, Ki67, p-MAPK, p-AKT, and PTEN were assessed by immunohistochemistry. Genomic DNA was sequenced for PIK3CA mutations.

Results: Under low PTEN conditions, in vitro data indicate that lapatinib alone and in combination with trastuzumab was effective in decreasing p-MAPK and p-AKT levels, whereas trastuzumab was ineffective. In the clinical trials, we confirmed that low PTEN or activating mutation in PIK3CA conferred resistance to the trastuzumab regimen (P = .015), whereas low PTEN tumors were associated with a high pathologic complete response rate (P = .007).

Conclusion: Activation of PI3 kinase pathway is associated with trastuzumab resistance, whereas low PTEN predicted for response to lapatinib. These observations support clinical trials with the combination of both agents.

[Ellie F]

Hope this encourages the bean counters in England to consider lapatinib as an option for us gals here!!
Thanks Lani, another encouraging step hopefully in the right direction.

Ellie

[Julie2]

I am just wondering why for some people the comibination of Herceptin and Lapatinib is not that effective.

-Julie

[Trish]

Thanks Lani. I'm receiving Herceptin and lapatanib with Abraxane and it is working well so far (CA 153 marker dropped from 1104 to 660 in 10 weeks.) Unfortunately it is not a funded option so have relied on "generosity" of GSK to date. Hope to be able to drop the Abraxane soon and commence an anti hormonal for "maintenance" phase. Ellie, I hope lapatanib becomes easily available to you soon but if not ask your onc to approach the GlaxoSmithKline rep with a proposition.
Trish

[chrisy]

Thanks Lani,
I agree, finding how to tailor the targeted therapy to the patient is critical - both to finding and approving treatments and making the cost effectiveness work. I would have preferred the wording to be "identify patients LIKELY to benefit"rather than the negative; nevertheless the point is correct.

[Lani]

Julie it may be in those people that her3 is driving the tumor or IGFR1 has substituted or many other pathways downstream of herceptin can be "revved" up in the face of her2 blockade. The tumor can also regain/increase ER and escape via the ER pathway. Have any biopsies been done on the metastasis/metastases for ER testing?

Pertumab blocks a different area of her2 and blocks her3 as well. Any chance of getting on a trial using pertuzumab? Similarly, there are TKIs under development which work against other her family members and work on the inside of the receptor (like lapatinib, but lapatinib misses her3) rather than the outside (like herceptin, erbitux, and pertuzumab)

Lani,
You are so incredibly informative and knowlegeble. I hope that you might be able to give me some help on the following:
I am breast cancer stage IV, and have been Her2+++ positive since the beginning [10 years]. About three months ago I developed cancer on my lymphedema arm, I had three biopsys of the arm and it showed me not longer Her2 positive [fully cancerous], my oncologist failed to inform me of the new finding until last week when I asked him if the Her2 results were back. He has kept me on Herceptin nevertheless and wants me to continue with it, and when I asked him why, he stated that there is no way to know if the rest of the body is still Her 2 positive or not. I am virulently progressing under my current medications. In your research do you happen to have come across some information my doctor doesnt have. You are truly a gift to this Her2 Site. I hope I am not asking too much from you. Thank You, Patricia

[Lani]

Patricia--where are you located? I just posted on this forum that a kit has been approved in Canada (don't know who is using it yet, if anyone) which allows injection of a radionucleide --similar to the radioactive glucose used for the PET scans--which pairs radioactive Indium with hercept(fused together). This shoud allow detection of minimal residual disease which is her2+ as well as allowing better margins to be obtained with surgery of her2+ tumors)

I copy it again here--it is hot off the press in Jan 2011 journal although epublished Sept 1 2010!!

: Nucl Med Biol. 2011 Jan;38(1):129-36. Epub 2010 Sep 1.
A kit to prepare (111)In-DTPA-trastuzumab (Herceptin) Fab fragments injection under GMP conditions for imaging or radioimmunoguided surgery of HER2-positive breast cancer.
Scollard DA, Chan C, Holloway CM, Reilly RM.

Department of Pharmaceutical Sciences, University of Toronto, Toronto, ON, Canada M5S 3M2.
Abstract
INTRODUCTION: The human epidermal growth factor receptor-2 (HER2) gene is amplified in 25% of invasive breast cancers, and receptor overexpression has been noted in up to 60% of early stages of the disease [ductal carcinoma in situ (DCIS)]. Preclinical studies have revealed high tumor/blood ratios (>27:1) for (111)In-labeled Fab fragments of the HER2 monoclonal antibody, trastuzumab (Herceptin) ((111)In-DTPA-trastuzumab Fab) at 72 h pi in athymic mice bearing subcutaneous human breast cancer xenografts. Our aim in this study was to formulate a kit for preparation of (111)In-DTPA-trastuzumab Fab injection under good manufacturing practice (GMP) conditions suitable for human administration in a Phase I clinical trial of imaging and radioimmunoguided surgery (RIGS) of HER2-positive breast cancer.

METHODS: Fab fragments were produced by digestion of trastuzumab IgG (Herceptin) with immobilized papain for 20 h at 37°C. Fab fragments were purified by ultrafiltration, then reacted with a 10-fold molar excess of diethylenetriaminepentaacetic acid (DTPA) dianhydride. DTPA-Fab fragments were purified, then sterilized by filtration into unit dose glass vials (kits). Kits were tested against specifications for volume (0.9-1.1 ml), protein concentration (0.45-0.55 mg/ml), pH (5.5-6.5), DTPA substitution (0.5-4.0 mol DTPA/mol Fab), appearance (clear, colorless and particle free), labeling efficiency (≥85%), and sterility and apyrogenicity (USP XXXII). Immunoreactivity of (111)In-DTPA-trastuzumab Fab towards HER2 was measured by saturation radioligand binding assays using SKBR-3 human breast cancer cells (specifications: K(a)=0.6-9.6×10(7) L/mol; B(max)=0.6-10.4×10(6) sites/cell). (111)In-DTPA-trastuzumab Fab injection was prepared by adding 80-100 MBq of (111)InCl(3) to a single kit vial and incubating for 30 min at room temperature. (111)In-DTPA-trastuzumab Fab was assayed for the amount of radioactivity and tested for pH, radiochemical purity (RCP), appearance and sterility.

RESULTS: Pure and homogeneous Fab fragments were produced. Eleven lots of kits met established quality specifications. The labeling efficiency with (111)In was 90.6±2.2%. (111)In-DTPA-trastuzumab Fab bound specifically to HER2 on SKBR-3 cells (K(a)=4.8±2.5×10(7) L/mol and B(max)=1.6±0.8×10(6) sites/cell). Thirteen lots of (111)In-DTPA-trastuzumab injection met all established specifications. Kits were stable for 90 days and (111)In-DTPA-trastuzumab Fab injection was stable for 24 h stored at 4°C.

CONCLUSIONS: A kit was formulated under GMP conditions for the preparation of (111)In-DTPA-trastuzumab Fab injection suitable for human administration. The kits were approved by Health Canada.

Copyright © 2011 Elsevier Inc. All rights reserved.
PMID: 21220136 [

You might consider sending your most recent slides to another institution for her2 testing--MDA Anderson and Stanford, among others offer this service.

Some test + by CISH but not by FISH . It sounds like your testing was by IHC (where results are +,++ or+++. FISH results come in numbers. You can google Entrez PUBMED and put her2 testing into the subject line and look at the abstracts (and open articles) on her2 testing.

Perhaps a serum her2 test might help clear things up (available from Quest and other major labs) and/or testing for CTCs(which can be tested to see if they are her2+--at least by some labs at Dana Farber and by the lab of Stephanie Jeffries at Stanford but not available from normal clinical labs) would help tell whether there still are her2+ tumor cells in your body that need herceptin to which something else can be added.

The true and accurate makeup of your new tumor is most important and from what I have learned at conferences would warrants a second opinion. Her2 testing is notoriously difficult.

Where on your arm was the lesion? Was it in the skin vs bone vs between the two?

When you say it was not her2+ (fully cancerous) what do you mean?

Can you get/post the pathology report? Could the lesion on your arm have been something other than breast cancer?

I would be happy to post any research results, but need to know more about what this new lesion was and why they think it was related to your breast cancer but not her2 +.

They have found that those Stage IVs who are on herceptin can have all sorts of different kinds of ctcs(circulating tumor cells) floating around in their circulation--including triple negative. But we don't know enough yet to treat based on CTCs. Bone marrows seem to be better at looking for residual disease and its makeup, but are yet standard of care (and unlikely to be as most oncologists I ask reluctantly admit that they do not like doing them--it is not the patients who complain!)

If your arm lesion was in the bone and the got bone biopsies--those could be used to guide what to add to your treatment as I understand it--if all other indications showed your breast cancer remained her2+.

Please try to get additional information as you would have a totally different problem if you had a superficial melanoma of the skin of the arm than if you had a bone metastasis from a breast cancer which was no longer her2+

I am in no way qualified to give any advice, but will try to research to get you the information to enable you ask the best questions.

Hope some of this helps!Good luck

Lani:
I was in bed very ill for a couple of days, today when I returned to this Site, I found your so very kind reply to my questions to you. Thank you for your caring enough, to answer [so thoroughly and at so much lenght] even though I not a registered member of this site.
You are truly very special.
My right arm cancer is and has been for about three months, pervasive throughout my lymphedema arm flesh from my shoulder to almost my pulse. The arm's outer skin is highly inflamed with skin mets, my cancer is not in the bone, my lymph flow is almost nill, unless I massage it over the cancer [it hurts tremendously]. I was first diagnosed by my oncologist with infection to the arm and submitted to one month of antibiotics, which did not work at all. At my insistent requests my onc refered me to a dermatologist [I felt that it was cancer not infection]. The dermatologist did three punch biopsys in different places of my arm, all turned out breast cancer no longer Her2neu positive. My oncologist gave me no other information regarding it, other as I informed you, "that she wanted me to continue with Herceptin because there is no way to find out if I am still Her2 positive in other part of my body" he said....The skin metastases have since spread, invaded my Transflap right breast, and all of my right back and front toraxic regions skin.
I have read your reply to me intensily even though I am quite ignorant of medical terminologies and I plan to get very proactive regarding the matter immediately with the information you have given me. I also have one brain tumor which will be Cyberknifed soon, and spine tumors resurfacing. I am scheduled for a Pet Scan this coming week so we will see what alse...I am in severe pain. My oncologist also has said to me a couple of weeks ago, that I have at maximum three months to live if we dont change medication, but he does not know what else medication to give me. I have corresponded with Sheila on this Site, and because she appears to be doing very well with Halaven I have suggested it for me to him. He has been receptive to start me on it subject to me pre-signing that I will pay directly for the Halaven, as my insurance refuses to pay for it. I have signed for it at the cost to me of $28,600 per month he informed me. He will add Herceptin to it. Mybe next week I will start the new medication.
I am a very strong person in spite of all odds against me with my cancer, and I plan to fight against it with all my strenght. In the meantime it is informative and kind people like you to which we can turn to when our doctors let us down; For that, I thank you with all my heart. Patricia

[Lani]

At San Antonio several papers were given on how the newly approved Denosumab is more effective in dealing with painful bone mets (eg your spine) than Zoledronic acid.

Were you taking Herceptin around the time you had your arm mets biopsied?

Were they only teted by IHC rather than FISH?

THeoretically, if you get your herceptin near the time you have the biopsy and only have it tested by IHC, the herceptin can sit on the her2 receptor blocking the monoclonal antibody they use for IHC testing from getting to it and giving you a false negative result. If you only had IHC testing and not that long after you had herceptin, perhaps it would be reasonable to seek out whether the pathologists agree with the above reasoning and whether it seems reasonable to them to retest it using FISH testing. FISH testing is usually not done unless the her2 IHC testing comes back as ++ or +++

Food for thought!