Hi Gajendra,

I believe the question you are asking is whether certain mutations within the anti-HER2 Ab binding site of HER2 can confer non-responsiveness to molecularly-targeted, antibody-based therapeutic agents such as trastuzumab . The answer, theoretically, is yes i.e. if key residues are mutated that alter the herceptin-HER2 interaction to a significantly lower affinity, this would likely translate to a significant reduction in efficacy, which could be equally interpreted as non-responsiveness. However, I suspect that multiple key mutations in the ECD of HER2 would need to occur, which isn't very prevalent as far as I can tell. There are other mechanisms that result in trastuzumab non-responsiveness, including HER2 ECD cleavage and MUC4-associated HER2 binding, and I in this regard I think the following article might be of use to you;

http://www.hindawi.com/journals/ijbc/2012/761917/

Kind regards,

Jonathan

Dear Jonathan, you are right my intention was to know impact of mutation in HER2 on responsiveness of herceptin. Can we use HER2 sequence as biomarker to check whether it will response or not, like we check HER2 over expression before advising herceptin.

Good question, an opportunity to learn about it. It is not my area but I'll read, there is always something to learn. Especially when it comes to a possible cancer cure, we all care.

Respected Sir, According to me it may possible...

d1n8zc1 Protooncoprotein Her2 extracellular domain: 156 residues

d1n8zc2 Protooncoprotein Her2 extracellular domain: 162 residues

d1n8zc3 Protooncoprotein Her2 extracellular domain: 154 residues

d1n8zc4 Protooncoprotein Her2 extracellular domain: 109 residues

These all are active domains and protoooncoproteins, by Docking Process, we could find out the impact of mutation in HER2 on responsiveness of herceptin.

A bit out of context but you must be the right people here to ask.

Why is “Herceptin” so expensive? Therefore, we can say that Life has a price. Can, in this case, anybody quantify the Life's price? Or, in other words, should the society do something as to "sponsor" the research, especially when in comes to health protection? I see is rather as some industry can have monopoly for Life, license for Life.

Why I raise the issue? It appears to me, now and many other occasions that the pharmaceutical industry is resistant to Life. Do we call this economy? Is this part of the anthropogenic economy? What about the Human Rights issue? Or we, the humanity, are resistant to Human Rights. I am sorry if it is out of context, I thought that you'll not mind if I bring it up... as ... a weekend thought.

Regards,

Adrian TW

some monoclonal antibodies such as herceptin, and kinase inhibitors prevent ErbB signaling, and breast cancer promotion, but only in some patients. Considering that cancer has different causes, and more than one mutation, sometimes blocking a receptor is not sufficient. Thus, in some cases, blocking the receptor does not silence the related cell signals. These mutations can be in different proteins which are involved in the cell signaling pathway or uncommonly can be related to the HER2 receptor.

To the question if sequencing Her2 as an indicator if the cancer will respond to Herceptin: it might be a good start, as you can have truncated forms of the receptor that lack the extra cellular domain at all, which consequently would abolish any binding possibility (or one of the oncogenic forms listed above). Cells can readily circumvent downregulation of Her2 by upregulation of receptors signaling alternative pathways as mentioned above (i.e. EGFR, IGF-1R). Therefore, just because the sequence predicts perfect Herceptin binding, the cancer will not necessary respond well to treatment. Another thing to keep in mind though is that , as far as I know, Herceptin does also function through an immune-system mediated mechanism and not solely through receptor downregulation. Meaning, that there might be some benefits of the therapy even if the binding is not 100% perfect and the overall question of responsiveness is rather a complex one.

This is response to Adrian query regarding high price. If I am correct, this antibody can be made at low cost as making any antibody is not difficult. Cost is due to patent regime where one can not produce patented items except owner. For general person health is major concern but for business person health is a good business. This is the reason now number of scientists are supporting open science and open drug discovery in order to bring down cost medicines see http://crdd.osdd.net/

If one can better understand herceptin resistance to cancer by HER2 downstream signalling mechanism then herceptin selectivity/specificity towards HER2 enzyme and also its mutants need also to be carefully addressed to get the holisitic view.

Making a monoclonal antibody is relatively low-cost, but making one that is suitable for use in humans is not. The QC issues are staggeringly huge and expensive. Clinical trials are likewise very expensive to conduct - especially phase III trails, and this is done at the pharmaceutical company's cost. For each product brought to market, a dozen or more will have gone through development to the point of clinical trials, only to be found either ineffective, less effective than standard therapy or to have unwanted and dangerous side effects. The pharmaceutical company can only recoup the costs and make whatever profit they can during the patent period - some of which are relatively short. So yes, pharmaceutical companies charge a lot for therapeutic antibodies, but that underwrites a lot of research that doesn't end up yielding a product.

We have a monoclonal antibody that may be of therapeutic value, but the cost of converting it into a form suitable for clinical testing was prohibitively high, and we have had no luck getting a pharmaceutical company interested in developing it. So it sits in a freezer. That's the way it goes these days. If we had the preclinical data a decade or 2 earlier, we might have had a shot.

Back to the origianl question, I had thought that herceptin resistance was simple due to loss of the ER/PR target antigen on the breast cancer cells.

Resistance to Herceptin= Trastuzumab= Immunoglobulin G 1 (human-mouse monoclonal rhuMab HER2gamma1-chain antihuman p185(sup c-erbB2) receptor), disulfide with human-mouse monoclonal rhuMab HER2 light chain, dimer seems to be a complex process that involves differential gene expression and kinase signaling.

If you are interested in the receiving updates on herceptin, here is a pubmed rss feed that I have created: http://eutils.ncbi.nlm.nih.gov/entrez/eutils/erss.cgi?rss_guid=18_r98JPP6yWzovzV2nJpyiYS4v_XcWCE5dqkylnwtKWHPiIZ8

Here are some recent examples Good luck!:

Skp2 overexpression correlates with Akt activation and breast cancer metastasis and serves as a marker for poor prognosis in Her2-positive patients. Finally, Skp2 silencing sensitizes Her2-overexpressing tumors to Herceptin treatment Cell. 2012 May 25;149(5):1098-111.

Our results support that trastuzumab resistance mechanisms are related with deregulation of PTEN/PI3K/Akt/mTOR pathway, and/or EGFR and IGF1R overexpression in a subset of HER2-positive breast carcinomas. Br J Cancer. 2012 Apr 10;106(8):1367-73. doi: 10.1038/bjc.2012.85. Epub 2012 Mar 27.

beyond HER2 gene amplification, we might need to redefine the threshold values for HER2 positivity to improve the accuracy of the selection of cetuximab-refractory patients with wild-type KRAS that may benefit from receiving a cetuximab/trastuzumab combination Oncol Rep. 2012 Jun;27(6):1887-92. doi: 10.3892/or.2012.1732. Epub 2012 Mar 15.

The simultaneous blockade of both PI3K/Akt/mTOR and ERK pathways obtained by combining lapatinib with INK-128 acts synergistically in inducing cell death and tumor regression in breast cancer models refractory to anti-HER2 therapy. Clin Cancer Res. 2012 May 1;18(9):2603-12. Epub 2012 Mar 8.

Circulating miR-210 levels were associated with trastuzumab sensitivity, tumor presence, and lymph node metastases. These results suggest that plasma miR-210 may be used to predict and perhaps monitor response to therapies that contain trastuzumab. Cancer. 2012 May 15;118(10):2603-14. doi: 10.1002/cncr.26565. Epub 2011 Oct 5.

The major downstream signaling pathway activated by HER2 cross-talk is PI3K/mTOR, and a potential integrator of receptor cross-talk is Src-focal adhesion kinase (FAK) signaling. PI3K, Src, and FAK have independently been implicated in trastuzumab resistance. In this review, we will discuss pharmacological inhibition of HER2 cross-talk as a strategy to treat trastuzumab-refractory HER2-overexpresssing breast cancer. Curr Med Chem. 2012;19(7):1065-75

Trastuzumab resistance in breast cancer may be dependent on multifactorial reasons. The lack of EC domain of the HER-2 receptor may be the most common one ( p95 protein). And , in addition to these. cancer cells might get rid of HER-2 signaling through the activation of different gorwth pathways like IGFR...Thus, this may also result in HER-2 down-regulation and trastuzumab resistance. There is also another hypothesis about the MUC-4 protein covering the ECD domain of HER-2 and by thsi way the drug can not bind the receptor...Among all these mechanisms, p95 is the most popular one and theroreticall, yes, it is generally the result of gained mutations in the receptor.

Kind regards,

B.

1-P95 (loss of ECD)

2-Attenuation of the ADCC system.

3-Overexpression of IGF1R.

4-Active Prog./Oestrog. receptors.

5- Autophosphorylation of intracellular cascade proteins, independent of HER2 TK.

for primary resistace we can add "Unkown reasons" also.

From practical standpoint, the host Fc receptor profile may affect responses to antibodies, including Herceptin and Rituxan. Antibody biodistribution and PK profile may differ from patient to patient. Therefore, if a patient does not respond to every3-4 week infusions of Taxol, it is worthwhile to try weekly Herceptin infusions. jco.ascopubs.org/content/19/10/2587.full.pdf

Sometimes, the diagnostic tests performed to determine HER2 expression may give false positive results and this in turn may lead to a false diagnosis of Herceptin resistnce in a patient with HER2 negative cancer who should have been treated with herceptin.

Just because a patient does not respond to Herceptin alone, one should not forget that Herceptin may still be very helpful in that pateint when combined with other agents such as taxol, vinorelbine, Xeloda, or Carboplatin/Taxol doublet.

Over the years of dealing with the most advanced and challenging of cancers, especially triple negative breast Cancer (TNBC), inflammatory breast cancer, HER2-positive metastatic breast cancer (mHER2+), and secondary brain and leptomenigeal metastases, I have develop a HER2 resistance framework within which I identify seven macro-level mechanisms for trastuzumab resistance, from which others "fall out" as upstream or downstream nodes and pathways, as indicated below. These are:

(1) Binding mechanisms that include domain alterations and binding site hindrance, and ECD domain mutation.

(2) Upregulation of Alternative ErbB Ligands and Heterodimer Formation, collectively the process of dimerization of HER2 receptors

(3) Dimerization/interaction with Non-HER2 Receptors

(4) Loss of downstream controllers (PTEN/p27(kip1)

(5) Activation of downstream signaling pathways

(6) Dysregulated cancer metabolism

(7) Endocrine Pathway Escape

and each of these is discussed below. However, my aim is less to detail the low-level preclinical data and the niceties of molecular pathways, but rather more critically to relate these phenomenon to the live clinical domain, and everywhere suggest workable and evidenced (by at least Phase II+ human clinical data) solutions that demonstrably can overcome trastuzumab (TZMB) / Herceptin resistance in HER2-positive breast cancer, thus providing an integrative translational perspective on the problem.

I offer this framework and the associated clinical translations in order to extend, and integrate, the many excellent observations and insights already offered above. A somewhat fuller and illustrated PDF version of this posting is available among my ResearchGate publications for anyone interested.

(1) Binding Mechanisms

These include (1) domain alterations and binding site hindrance, and (2) TKR (tyrosine kinase receptor) domain mutation, the later as extracellular domain (ECD) mutations in the tyrosine kinase domain being associated with anti-HER2 agent resistance, but note that these affect lapatinib resistance more than strictly TZMB resistance. As to binding, overexpression of the MUC4 glycoprotein or of CD44 which each hinder HER2 from binding to TZMB; this mechanism of TZMB resistance is called steric hindrance.

We note however that this remains demonstrated only in preclinical models, and as yet we lack confirmation in the clinical setting.

A major TZMB-resistance mechanism here is generation of truncated form p95HER2 protein (truncated p95HER2 fragments), associated with clinical de novo - not acquired - resistance to TZMB and compromised HER2-positive patient outcomes, by virtue of the fact that TZMB is unable to bind to truncated receptors despite the fact that the truncated receptor remains a constitutively active receptor exhibiting kinase activity but without an extracellular domain (ECD) require to bind TZMB. We note that p95HER2 protein expression is observed in ~21% of node-negative primary tumors, ~29% in patients with 1 - 3 metastatic nodes, and ~37% in patients with >= 4 metastatic nodes [1].

In this connection, the reversible small-molecule TKI of EGFR and HER2 lapatinib (Tykerb) has shown promising activity in the subset of p95KER2-overexpressing TZMB-resistant breast tumors, as well as full-length HER2 - indeed, it is because of the binding of lapatinib to the intracellular domain of HER2 that allows it to inhibit both full-length HER2 and truncated p95HER2, as demonstrated by José Baselga's team in Spain [2]. In addition, the Blackwell Phase III randomized trial [3] found that lapatinib added to trastuzumab in TZMB-refractory patients significantly improved and more than doubled clinical benefit rates (CBR) (24.7% versus 12.4%, ) as well as significantly improving median PFS by ~4 weeks (12 weeks versus 8.1 weeks) compared to lapatinib monotherapy.

But another novel approach to overcoming TZMB resistance induced via steric hindrance of truncated p95HER2 is through deployment of heat shock proteins (HSPs), especially HSP90 inhibitors which are molecular chaperones (binding and stabilizing proteins at various intermediate stages including self-assembly called folding) required for the stability and function of several signaling proteins including ones which promote cancer cell growth and/or survival (the name derives from the fact that all cells produce them in response to many environmental insults or "stresses" - including heat, oxidation and hypoxia, acidosis, and toxic agent exposure, so they are in effect necessary for cell survival during stress). HSP90 inhibitors are unique in that, although they are directed toward a specific molecular target, HSP90 inhibitors uniquely and simultaneously inhibit multiple signaling pathways that interact to promote cancer cell survival (including all of the six hallmarks of a cancer cell: self-sufficiency in growth signals, insensitivity to antigrowth signals, evasion of apoptosis, limitless replicative potential, sustained angiogenesis, and tissue invasion and metastasis).

Preclinical data shows that administration of HSP90 inhibitors results in down-regulation of truncated p95HER2 and inhibition of cell proliferation in p95HER2-overexpressing trastuzumab-resistant breast tumor models, thus overcoming TMZB resistance. A Phase II trial of one HSP90 inhibitor tanespimycin (17-AAG) plus trastuzumab in patients with HER2-positive TZMB-refractory MBC found significant activity on PFS and OS endpoints [4]. My research has unfortunately confirmed that clinical development of tanespimycin has been abandoned, but this is being taken up in explorations of second-generation HSP90 inhibitors like ganetespib and others.

Further effective strategies for overcoming TZMB resistance have developed more recently: T-DM1 is a HER2-directed antibody-drug conjugate (ADC) combining intracellular delivery of the potent microtubule assembly inhibitor known as DM1 (a derivation of the anti-mitotic antibiotic agent maytansine), with the antitumor activity of trastuzumab. An open-label, single-arm, phase II study [5] reported very impressive response rates of 40% to T-DM1, in a population of in HER2 MBC patients all of whom had progressed on trastuzumab-based therapy, with 40% also having received prior lapatinib therapy.

T-DM1 positive results received early confirmation in the EMILIA multicenter open-label randomized Phase III trial [6] which tested T-DM1 in the second-line setting after progression on TZMB, comparing it to lapatinib plus capecitabine; not only has it shown a significant improvement in progression-free survival (PFS) ) but at ASCO 2012 and ESMO 2012 T-DM1 provided an increased median survival to 30.9 months compared to 25.1 months for lapatinib and capecitabine, along with superior objective response rates for T-DM1. T-DM1 has also been successfully combined with another anti-HER2 biological, pertuzumab (see below), with positive results in the earlier phase Ib/II trial (ASCO 2010) [7] in women with HER2-positive, locally advanced or metastatic breast cancer previously treated with trastuzumab, awaiting further robust confirmation in the three-arm randomized Phase III MARIANNE trial.

And as to pertuzumab, the recent BO17929 trial [8] found that trastuzumab plus pertuzumab combination therapy provided the clinically significant benefit to patients who progressed after sequential trastuzumab and pertuzumab monotherapy.

Collectively, these data strongly support the contention that anti-HER2 antibody therapy retains clinically meaningful activity even after the development of anti-HER2 treatment resistance, allowing a conjugated agent like T-DM1, or the new HER dimerization inhibitor (HDI) pertuzumab, to serve as an effective treatment alternative for HER2-positive previously progressed on TZMB.

We also have some promising results for neratinib, a powerful irreversible pan-HER receptor TKI operating on HER1, HER2 and HER4 and hence providing more complete HER receptor blockade than lapatinib which inhibits only HER1 and HER2, activity confirmed as monotherapy in a phase II, open-label trial [9] of both TZMB-pretreated and non-pretreated cohorts, as well as in a phase I/II trial [10] of the neratinib added to TZMB in HER2-positive metastatic breast cancer patients with prior trastuzumab exposure. Both these trials suggest an activity and benefit apparently higher than lapatinib. NEFERTT and other ongoing trial will further clarify the role of neratinib.

(2) Upregulation of Alternative ErbB Ligands and Heterodimer Formation

(Dimerization of Receptors)

Overexpression of EGFR or HER3 ligands, especially TGF-a, EGF, and heregulin may confer resistance to trastuzumab - but again, remarkably and unfortunately, not to lapatinib - noting that EGFR overexpression occurs in 30% of HER2+ patients, and heterodimer formation increases MAPK, PI3K and Src pathway activation (we return to the centrality of the Src pathway below).

Clinical Relevance: the just FDA-approved HER dimerization inhibitor (HDI) pertuzumab (commercially, Perjeta) prevents HER2-HER3 heterodimerization produces a clinical benefit rate of 50% in patients progressing on TZMB, and with exceptional patient outcomes in combination with TZMB (as shown in the Phase III CLEOPATRA trial [11] and the MGHC (Massachusetts General Hospital Cancer Center) trial [12], among others). Activity of pertuzumab + TZMB has also been confirmed in the neoadjuvant setting in the randomized Phase II NeoSphere trial [13].

(3) Dimerization/interaction with Non-HER2 Receptors

It been extensively confirmed that genetic aberrations in the PI3K/Akt pathway, which include loss-of-function PTEN deletions and activating mutations of PI3KCA, mediate trastuzumab resistance, indeed that activated PI3K/Akt/mTOR signaling alone plays a role in both acquired and de novo HER2 resistance. And in confirmation, clinical retrospective review data from Evangelia Razis and colleagues in Greece [14] has shown that PIK3CA mutations were associated with inferior time-to-progression (TTP) while associated PTEN loss was associated with decreased survival, also confirmed by Leiping Wang and colleagues in Shanghai [15], although the Shanghai study confirmed only PTEN loss as a negative prognostic, but no significant correlations were seen between PI3K pathway status and clinicopathological parameters. However I must point out here that the investigators themselves acknowledge that this "Due to a relatively smaller sample size of our study".

However, this association of PTEN loss and PIK3CA mutations with trastuzumab resistance has been recently challenged by Mattia Barbaresch and colleagues in their own retrospective review [16] of 129 HER2+ breast cancer patients, with PTEN loss being observed in 24 out of 86 informative cases, 3 of which were also PI3KCA mutated. They found that PI3K pathway activation (defined as PI3KCA mutation and/or PTEN loss) was not associated with treatment response or clinical outcome in MBC. It is clear that despite considerable data on PI3KCA mutations, negative prognosis is not conclusively established and there may have been the cofounder that since PTEN loss and PI3KCA mutation generally - but not always - co-occur, the studies finding for the influence of PI3K pathway activation as a negative prognosticator may have been driven primarily by PTEN loss, not PI3KCA mutation. I note in passing we may be able to increase PTEN levels by certain natural interventions, such as the omega-3 fish oil DHA, as there is some provisional data that microRNA-21 (miR-21) regulates the PTEN tumor suppressor gene and that upregulation of miR-21 mediates resistance to trastuzumab [17,18].

Although TZMB, lapatinib and several other biological agents induced inhibition of the HER2 oncogenic pathway, such inhibition can cause compensatory crosstalk over and activation of alternative "escape" signalling pathways. IGF1R and HER3 are two such escape signalling pathways, with aberrant activation of IGF1R, and upregulation of HER3 and consequent PI3K/Akt pathway activation, both being time-honored mechanisms of TZMB resistance, the later especially being subject to reversal by the deployment of the HER2/HER3 dimerization inhibitor, pertuzumab.

Increased signaling from the insulin pathway via IGF1-activated IGF1R that triggers the PI3K cell survival pathway, fostering TZMB resistance, and so it now appears that not only are trastuzumab resistance mechanisms triggered by deregulation of PTEN/PI3K/Akt/mTOR pathway, and/or EGFR overexpression, but also by IGF1R overexpression in a subset of HER2-positive breast carcinomas, as Gallardo and colleagues in Barcelona have recently shown [19].

Clinical Relevance: it appears the lapatinib can overcome IGF1R even when its activator, IGF1, is present, and the preclinical work of Wen Wu's team at the FDA has shown that IGFBP-2 and IGFBP-3 may serve as predictive biomarkers for trastuzumab resistance. In addition, the an IGF-1R monoclonal antibody cixutumumab (IMC-A12) being evaluated in a randomized phase II study (NCT0068493) combined with the FDA approved doublet lapatinib and capecitabine in patients with prior trastuzumab, anthracycline, and/or taxane exposure.

Src Activation and the Src-Oz Hypothesis

And more importantly, given that Src activation is common in both EGFR/IGF-1R-overexpressing and PTEN-deficient cells, it is increasing apparent to this researcher that trastuzumab resistance driven by (1) PTEN/PI3K/Akt/mTOR pathway deregulation, and/or (2) EGFR overexpression, and/or (3) IGF1R overexpression, are all mediated by the Src function which may thus serve as a common node in the promotion of TZMB resistance, especially when it is recognized that SRC kinases include EGFR, HER2, FGFR, PDGFR, and VEGFR which all activate Src the protein by phosphorylating it, also then influencing tumor necrosis factor α (TNFα) as well as the erythropoietin receptor (EpoR) which induces both the MAPK/Erk and PI3K/Akt pathways.

This has received preclinical confirmation in the research findings of Siyuan Zhang and colleagues at MD Anderson [20] which argues for combating trastuzumab resistance by targeting SRC as common node downstream of multiple resistance pathways, including IGF1R, EGFR, ERBB2, HER3, Met, and PTEN/PI3K/Akt/mTOR, as I have indicated above. This suggest that the already established Src inhibitor dasatinib (Sprycel) and the experimental Src inhibitor saracatinib may be optimal candidates for the effective reversal of TZMB resistance via modulation of all Src's multiple upstream resistance pathways.

(4) Loss of downstream controllers

Here, loss of PTEN - and the cyclin-dependent kinase inhibitor p27(kip1) which facilitates escape from cell--cycle arrest - which occurs in 25% of breast cancers, fosters TZMB resistance with activation of PI3K and with heregulin secretion.

Clinical Relevance: the HER dimerization inhibitor pertuzumab antagonizes herugulin-induced PI3K activation, and PI3K inhibitors would also clearly be relevant here.

(5) Activation of downstream signaling pathways

The downstream signaling pathways whose activation fosters TZMB resistance are (1) PI3K/Akt, (2) MEK, (3) MAPK, and, critically, (4) mTOR.

Clinical Relevance: Increased activation of the PI3K/AKT pathway correlates with resistance to trastuzumab, which can be overcome by lapatinib, in part because lapatinib not only has activity on HER2-EGFR signaling but also on HER2-HER3–activated signaling. [Some are sensitive to both trastuzumab and lapatinib as individual agents. Some are sensitive to one agent but resistant the other, and some are resistant to both HER2-targeting agents. The molecular data indicate that overlapping as well as nonoverlapping mechanisms of resistance to these agents are likely to occur in HER2-positive breast cancers.

As to the HER2-positive disease domain, inhibition of mTOR (downstream target of Akt) using everolimus (formerly RAD001, commercially Afinitor) improves response to TZMB in breast cancer models of PTEN-loss, and appears to provide some clinical benefit in a small phase I/II study [25] as well as in a multicenter Phase II trial reported at ASCO 2010 in metastatic HER2-positive patients with prior resistance to trastuzumab and taxanes [26], confirming the efficacy everolimus in combination with paclitaxel and trastuzumab for patients with trastuzumab-resistant, HER2-positive, metastatic breast cancer; based on these promising findings, the phase III BOLERO 1 trial is assessing everolimus in this same combination regimen (with trastuzumab and paclitaxel) as a first-line treatment of HER2-positive metastatic breast cancer.

Furthermore, given that activation of the mTOR pathway represents a critical escape mechanism from HER2 blockade, this suggests that the antidiabetic agent metformin, which operates as an mTOR inhibitor, and it's been shown preclinically that metformin suppresses self-renewal and proliferation of TZMB-resistant/CD44-overexpressing tumor-initiating breast cancer stem cells [21].

Trastuzumab Beyond Progression (TBP)

Preclinical data has supported the strategy of continuation of trastuzumab beyond (disease) progression, aka TBP but only recently have we received decisive support from prospective Phase III clinical data [22] besides retrospective data: the GBG 26/BIG 03-05 trial demonstrated that continuing TZMB in combination with capecitabine in HER2-positive MBC patients who had progressed on trastuzumab was superior to treating with capecitabine alone by dropping the TZMB, with improved ORR almost double the objective response rate (48.1% versus 27%, ) and median time-to-progression/TTP (8.2 months versus 5.6 months), also being further tested in the ongoing Pandora trial.

(6) Cancer Metabolism

The preclinical work of Ming Tan's team at the Mitchell Cancer Institute (University of South Alabama) [23] has shown that increased glycolysis (via HSF1 and LDH-A) contributes to TZMB resistance, so that combining TZMB with glycolysis inhibition synergistically inhibited, via more efficient inhibition of glycolysis, both trastuzumab-sensitive and -resistant breast cancers in vitro and in vivo. Shrewdly, the authors noted that since the inhibition of glycolysis by trastuzumab precedes cell growth inhibition, glycolysis inhibition is not simply a consequence of cell growth inhibition by trastuzumab.

(7) Endocrine Pathway Escape

Combined L + T treatment provides a more complete and stable inhibition of the HER network. With sustained HER2 inhibition, ER functions as a key escape/survival pathway in ER-positive/HER2-positive cells. Complete blockade of the HER network, together with ER inhibition, may provide optimal therapy in selected patients. In this connection, Dieter Koeberle and colleagues in St Gallen [24] have shown in the SAKK 23/03 proof-of-concept trial that complete resistance to both AI and trastuzumab can be overcome in a proportion of patients by combined treatment of AI and trastuzumab.

Clinical Lessons

The above demonstrates that we now have a broad spectrum of viable clinically relevant strategies to overcome trastuzumab resistance:

1. Anti-HER2 biologics:

a. lapatinib,

b. pertuzumab, and

c. T-DM1;

2. HSP90 inhibitors;

3. Irreversible pan-HER receptor TKI neratinib;

4. Src inhibitors (dasatinib, saracatinib);

5. IGF1R inhibitors (cixutumumab);

6. Trastuzumab beyond progression (TBP);

7. mTOR inhibitors (everolimus (Afinitor), metformin);

8. Dual HER2/endocrine blockade

among others at a more and various experimental levels, with some (lapatinib, pertuzumab) commercially available and FDA approved. Yet despite these strategies, we are still awaiting data and research that will help clinicians choose among these approaches in either clinical practice or the clinical trial setting, possibly with the help of response and resistance markers once these are fully articulated, to finally usher in a new generation in HER2 therapeutics where problems of anti-HER2 resistance are manageable and minimizable to the benefit of our HER2-positive breast cancer patients.

References

1. Molina MA, Sáez R, Ramsey EE, et al. NH2-terminal truncated HER-2 protein but not full-length receptor is associated with nodal metastasis in human breast cancer. Clin Cancer Res 2002;8:347–53.

2. Scaltriti M, Chandarlapaty S, Prudkin L, et al. Clinical benefit of lapatinib-based therapy in patients with human epidermal growth factor receptor 2-positive breast tumors coexpressing the truncated p95HER2 receptor. Clin Cancer Res 2010;16:2688-2695.

3. K. L. Blackwell, H. J. Burstein, A. M. Storniolo et al., “Randomized study of Lapatinib alone or in combination with trastuzumab in women with ErbB2-positive, trastuzumab-refractory metastatic breast cancer,” Journal of Clinical Oncology, vol. 28, no. 7, pp. 1124–1130, 2010.

4. S. Modi, A. Stopeck, H. Linden, et al., “HSP90 inhibition is effective in breast cancer: a phase II trial of tanespimycin (17-AAG) plus trastuzumab in patients with HER2-positive metastatic breast cancer progressing on trastuzumab,” Clinical Cancer Research, vol. 17, no. 15, pp. 5132–5139, 2011.

5. S. Vukelja, H. Rugo, C. Vogel, R. Borson, E. Tan-Chiu, and M. Birkner, “A phase II study of trastuzumab-DM1, a first-in-class HER2 antibody-drug conjugate, in patients with HER2+ metastatic breast cancer,” Cancer Research, vol. 69, supplement 2, 2009, Abstract 33.

6. Verma S, Miles D, Gianni L, et al. EMILIA Study Group. Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med 2012 Nov 8; 367(19):1783-91.

7. Miller K, Gianni L, Andre F, et al. A phase Ib/II trial of trastuzumab-DM1 (T-DM1) with pertuzumab (P) for women with HER2-positive, locally advanced or metastatic breast cancer (BC) who were previously treated with trastuzumab (T). J Clin Oncol 28:15s, 2010 (suppl; abstr 1012).

8. Cortes J, Fumoleau P, Bianchi GV, et al. Pertuzumab monotherapy after trastuzumab-based treatment and subsequent reintroduction of trastuzumab: activity and tolerability in patients with advanced human epidermal growth factor receptor 2-positive breast cancer. J Clin Oncol 2012;30:1594-1600.

9. H. J. Burstein, Y. Sun, L. Y. Dirix et al., “Neratinib, an irreversible ErbB receptor tyrosine kinase inhibitor, in patients with advanced ErbB2-positive breast cancer,” Journal of Clinical Oncology, vol. 28, no. 8, pp. 1301–1307, 2010.

10. R. Swaby, K. Blackwell, Z. Jiang, and Y. Sun, “Neratinib in combination with trastuzumab for the treatment of advanced breast cancer: A phase I/II study,” Journal of Clinical Oncology, vol. 27, supplement 15s, 2009, Abstract1004.

11. Baselga J, Cortes J, Kim SB, et al. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med 2012;366:109-119.

12. Cortés J, Fumoleau P, Bianchi GV, et al. Pertuzumab monotherapy after trastuzumab-based treatment and subsequent reintroduction of trastuzumab: activity and tolerability in patients with advanced human epidermal growth factor receptor 2-positive breast cancer. J Clin Oncol 2012 May 10; 30(14):1594-600.

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Herceptin (trastuzumab) is a humanized monoclonal antibody targeted to the Her2 receptor tyrosine kinase. Despite a robust response rate to Herceptin-based therapies in Her2-positive patients, resistance frequently arises within one year of the initial response. To address the mechanism of Herceptin resistance, we selected clonal variants of Her2-positive BT474 human breast cancer cells (BT/HerR) that are highly resistant to the anti-proliferative effects of Herceptin in the presence of 0.2 uM or 1.0 uM Herceptin. Our original report on these cell lines demonstrated sustained PI3K/Akt signaling and sensitivity to PI3K inhibitors in BT/HerR cells in the presence of Herceptin, suggesting dysregulation of that pathway as an essential component of Herceptin-resistant proliferation.

The new database on herceptin resistance in breast cancer patients

http://www.nature.com/srep/2014/140327/srep04483/full/srep04483.html

http://crdd.osdd.net/raghava/herceptinr/

Just a thought. Why not do the check for Her-2 expression with the Herceptin antibody itself in parallel? Most diagnosis of Her-2 +/- is done by pathological IHC. This way one could determine a priori if the tumor has a "non-recognizable" Her-2 protein from a therapeutic standpoint. Comparison with the standard antibody can then be very enlightening on the occurrence of Herceptin-non-binding Her-2 variants....

Also, keep in mind that there can be anti-herceptin antibodys (anti drug antibodies) lowering the halflife of the herceptin itself. This may be triggered by multiple doses of the drug, or some unlucky people just have high levels of anti-antibodies floating around.

Contact me if you want to discuss more.

Jon