brain mets triple neg current issue
compiled by   
constantine kaniklidis
  
  : : : :   Breast Cancer Watch Digest  
issue 4   |   October 18, 2008  
Postcards from the  Edge - ASCO 2008: HER2+ Disease 

There were over a hundred studies reported at ASCO 2008 on HER2-positive breast cancer, reflecting the importance of continued and aggressive research into HER2 disease.  Various themes can be discerned:

1.  cardiotoxicity of anti-HER2 therapies;
2.  rising importance of the lapatinib (Tykerb);
3.  issue of TBP - trastuzumab beyond progression; 
4.  issue of the brain as sanctuary for HER2 CNS metastasis;
5.  role of new biological therapies in HER2 disease

among several others.  In this issue, I take up what I interpret as the most critical ASCO 2008 HER2 studies. I have striven throughout to go beyond the narrow abstracts and to put the findings into the broadest context of our latest understanding of the best evidence to date about HER2-positive breast cancer.


Anti-HER2 Therapy Toxicities: Trastuzumab + Lapatinib
Chau Dang and colleagues at  Memorial Sloan Kettering Cancer Center (MSKCC)1  presented preliminary feasibility and cardiac safety findings from their pilot study of adjuvant DD-AC (4 cycles of dose-dense AC) followed by 12 weekly cycles of PTL (paclitaxel (Taxol) with trastuzumab (Herceptin) and lapatinib (Tykerb), administered for one year, in HER2+ BC.  Trastuzumab and lapatinib (PTL) were initiated in combination with paclitaxel and administered for a total duration of 1 year (dosing: Trastuzumab (Herceptin) as a loading dose of 4 mg/kg IV, then 2 mg/kg each week during paclitaxel (Taxol) administration, and then 6 mg/kg every 3 weeks thereafter, with lapatinib (Tykerb) orally administered at 1000 mg daily).  No cardiac safety issues have been identified to date, however diarrhea was the major toxicity observed with concurrent PTL paclitaxel/trastuzumab/lapatinib administration), and after a median 6-month follow-up period it was found impossible to administer of all 3 agents at the recommended doses (paclitaxel 80 mg/m2, trastuzumab 2 mg/kg, lapatinib 1000 mg daily) because of associated GI toxicity making the regimen infeasible, the study was closed early. In response to this toxicity data, the dosing schema of the comparable regimens in the ongoing international ALTTO trial (evaluating adjuvant chemotherapy with lapatinib alone vs trastuzumab alone vs the combination) is being modified in design appropriately.


HERTAX: Concurrent v Sequential Trastuzumab/Chemotherapy
The HERTAX trial2 compared the initial use of chemotherapy (docetaxel (Taxotere) plus trastuzumab (Herceptin) to sequential trastuzumab followed by chemotherapy treatment  at time of progression in patients with HER2+ MBC (metastatic breast cancer) receiving first-line chemotherapy. The power of the trial was limited by its small size (99 patients) and results were mixed: concurrent therapy yielded a higher response rate (73%) and longer (9.4 months) initial time to progression (TTP)than sequential therapy (50% RR and 3.9 months TTP), but ultimately TTP with sequential monotherapy or combination therapy was equivalent. A strong trend toward a survival advantage was suggested with the initial concurrent regimen, but none of these findings achieved statistical significance owing to the small study size.  Nonetheless, my interpretation is that the HERTAX trial suggests that the strategy of initial concurrent chemotherapy plus trastuzumab may be associated with better long-term tumor control, as compared to sequential trastuzumab followed by chemotherapy, in patients with HER2+ advanced BC.


TBP (Trastuzumab Beyond Progression):
Lapatinib + Trastuzumab

Lapatinib (Tykerb) is small molecule dual-kinase inhibitor of HER2 and EGFR (epidermal growth factor receptor), approved for use in trastuzumab (Herceptin)-treated, advanced HER2+ BC for those HER2-positive patients progressing after trastuzumab, based on the findings of RCTs which found that in combination with capecitabine (Xeloda) it improved response rate and TTP (time to progression) compared with capecitabine (Xeloda) alone.  But it should be noted that In the lapatinib (Tykerb) registration study, patients were required to discontinue trastuzumab treatment before starting on lapatinib, yet preclinical models have suggested that combined  trastuzumab + lapatinib treatment might be superior to single agent therapy, and it was precisely this hypothesis that was tested in the open-label randomized phase III trial presented by Dr. Joyce O'Shaugnessy  with US Oncology3 in heavily pretreated HER2+ patients (previously treated with anthracyclines and taxanes, averaging 5 or 6 prior chemotherapy regimens and 3 prior trastuzumab-based regimens) who had experienced overt tumor progression while on trastuzumab. The study found that despite the extensive prior therapy, the trastuzumab (intravenous at  4 mg/kg as the loading dose followed by 2 mg/kg weekly) + lapatinib (1000 mg) combination appeared to be superior to lapatinib (1500 mg) monotherapy; indeed, despite using the lower dose of lapatinib, the combination treatment  yielded both improved TTP and modest advances in response rate and clinical benefit rate, with no excess toxicity findings on the combination regimen. 

Breast Cancer Watch Commentary: Clinical Lessons
I interpret the clinical lessons from this as that:

1.       trastuzumab (Herceptin) can potentiate lapatinib activity (where otherwise lapatinib antitumor activity was low as monotherapy, although not zero somewhat surprisingly),

2.       ongoing trastuzumab therapy beyond overt progression can deliver clinically important benefits

   improved (27%) median PFS  and increased percentage (28%) of patients progression-free at six months,

   with a doubling (24/7%) of the clinical benefit rate, and

   and with a trend toward superior median OS (45%) for the combination, which showed enhanced activity beyond what might otherwise be achieved with salvage anti-HER2 therapy)

even after progression on previous taxane, anthracycline, and trastuzumab therapy, and

3.       with the only significant increase in toxicity to be expected being diarrhea;

4.       we have proof of principle that simultaneous dual signal targeting of the HER2 receptor at the extracullar and the intracellular level is of clinical benefit, what I have called elsewhere dual-HER2 blockade, and that this dual-HER2 blockade establishes clinical synergy between these two anti-HER2 agents (lapatinib and trastuzumab);

5.        it would appear that continuing trastuzumab and adding lapatinib to it in the resistance setting is a more optimal strategy than discontinuing trastuzumab and substituting lapatinib for it;

6.       I should note that many oncologists like Charles Vogel at Aptium Oncology and Dennis Slamon at UCLA, among others, use a time-based heuristic of when to follow trastuzumab with lapatinib, namely that if a relapse occurs within one year of trastuzumab initialization, then they would use lapatinib;

7.       these results are quite impressive for such a heavily pretreated, highly refractory, cohort - 28% of the lapatinib arm and 34% of the lapatinib + trastuzumab arm had 6 or more previous chemotherapy regimens at baseline - and it may in turn suggest that relativity rather than the absoluteness of trastuzumab resistance.


Breast Cancer Watch Commentary: Open Questions
It strikes me  that regardless of these impressive results, three open questions remain.  The first is selectivity:  as I noted above, this cohort had, and survived, a median of 5  to 6 prior oncotherapies coming into the study, and without the development of progressive brain metastases, and this suggests that  these patients therefore were likely significantly trastuzumab-sensitive or had relatively indolent HER2 disease, so that selection bias cannot be wholly excluded.

The second open question is far more significant still, that of dueling regimens for trastuzamab progression: this trial suggests the efficacy and viability of the  combination of lapatinib + trastuzumab, but an alternative is lapatinib + capecitabine as per the trial of Geyer et al.4 which found that lapatinib +  capecitabine was superior to capecitabine alone in women with HER2+ advanced breast cancer that has progressed after anthracycline, taxane, and trastuzumab therapy.  Granting that the Geyer and the O'Shaugnessy ASCO 2008 studies involve different patient populations, nonetheless the Geyer data find for an overall response rate (ORR) of 22% and a clinical response rate of 27%, from   lapatinib + capecitabine, which are appreciably higher than the ORR = 10% and clinical response rare = 24% found in the O'Shaugnessy ASCO 2008 trial of lapatinib + trastuzumab.  Therefore this would suggest that for progressive HER2+ disease on trastuzumab, the lapatinib + capecitabine regimen would be relatively more favorable than lapatinib + trastuzumab. 

The third and final open question is that of optimal regimen for progression to brain metastasis: as we have documented5, both lapatinib and capecitabine appear capable of crossing the blood-brain barrier (BBB) and the cerebrospinal fluid (CSF) barrier and hence may exhibit appreciable activity in breast cancer brain metastasis, although it should be noted that we currently have no direct comparative data of their relative benefits. However, that said, in the case of trastuzumab which is a large MoAb (monoclonal antibody) that theoretically should not traverse the BBB, it may nonetheless be that the development of a large metastatic tumor may disrupt the BBB, suggesting anecdotally that CNS tumor shrinkage with trastuzamab may still be viable. In addition, Charles Geyer has recently commented on and clarified the findings of his own study4: although 13 patients on capecitabine-alone developed CNS disease, only 4 on the  capecitabine + lapatinib combination did so.  Furthermore, I add here my own observation that on a trastuzumab + lapatinib combination as deployed in the O'Shaugnessy ASCO 2008, lapatinib dosing is required to be reduced for tolerability with trastuzumab to 1000 mg, raising the question of whether anti-CNS tumor efficacy is still maintained, a question that does not apply to the capecitabine + lapatinib regimen from the Geyer trial. 

Finally, I join a small but growing chorus of researchers and clinicians in advising the utmost close surveillance and radiological monitoring, possibly including serial brain MRI, of  HER2-positive patients; see for example, the conclusions of the Cross Cancer Institute team6 (" … these findings could prompt the consideration of brain prophylaxis strategies and/or serial radiologic screening to detect asymptomatic BM") and  those of the Danish team of Charlotte Kristiansen and colleagues7 ("Since half of HER2 over-expressing patients developed brain-metastases close surveillance for brain metastases (clinical and/or imaging) is necessary even during effective systemic treatment. Future investigation into prophylactic cranial irradiation strategies in high-risk patients is warranted").   


TBP (Trastuzumab Beyond Progression): 
Trastuzumab + Capecitabine

A key clinical question is whether there is a benefit to continuing trastuzumab past first-line progression - called TBP, that is, trastuzumab beyond progression - and the Breast International Group/German Breast Group (BIG/GBG) TBP study8 reported at ASCO 2008 by Gunter von Minckwitz, addresses this directly by  comparing capecitabine (Xeloda) alone with capecitabine plus trastuzumab in HER+  patients  in patients with metastatic or locally advanced breast cancer progressing on (during or after) trastuzumab (2500 mg/m2 on Days 1-14 of a 21-day cycle with or without trastuzumab 6 mg/kg every 3 weeks).  Although the trial closed early because of  poor accrual was underpowered, the TGP trial investigators were still able to compare the two alternative regimens for 156 patients.

The TBP trial found  that on the capecitabine + trastuzumab combination, the overall response rate (ORR) was 48% compared to 23% for capecitabine monotherapy,  with 75.3% clinical benefit compared to 54% for capecitabine alone, with the median time to progression (TTP)(the primary endpoint) hazard ration being .69, increased to 8.2 months compared to 5.6 months for capecitabine monotherapy, and with a trend toward an increase in overall survival (OS) extending to 25.5 months compared with 20.4 months on monotherapy. Capecitabine plus trastuzumab was well tolerated, with mild to moderate (grade 1/2) anemia and hand/foot syndrome (HFS) more common on the combination, otherwise the toxicity profiles were comparable in both the continued trastuzumab and capecitabine arm and the capecitabine-alone arm. 


Breast Cancer Watch Commentary: Clinical Lessons

1.       This provides a robust warrant for clinicians to continue anti-HER2 past first-line therapy as it indicates that continued trastuzumab beyond  progression (TBP) improves efficacy of second-line capecitabine in patients with metastatic or locally advanced BC compared with capecitabine alone, and indeed several studies suggest confirm the benefit of continued HER2-inhibition (with trastuzumab or other drugs anti-HER2 agents) is a better approach, making discontinuation of anti-HER2 therapy increasingly problematic.

2.       Still unanswered is (1) whether it would be more beneficial to add a third drug such as capecitabine, to trastuzumab and lapatinib, or (2) whether capecitabine + trastuzumab may have been just or at least as effective as capecitabine plus lapatinib, although as Kathy Miller has suggested recently in interview, a reasonable strategy in practice is that patients who progress on capecitabine plus lapatinib will commonly be switched back to another trastuzumab-containing regimen.


New Biological Therapies: Trastuzumab + Pertuzumab

In their phase II trial, Karen Gelmon with the British Columbia Cancer Agency and colleagues9 studied pertuzumab plus trastuzumab in HER2-positive metastatic  breast cancer patients whose tumors had progressed on prior trastuzumab therapy, obtaining 24% objective response to treatment, with 24% of the patients progression-free through 6 months of therapy, including a partial response rate of 16% and a complete response rate of 8%, with half of the participants experiencing a clinical benefit; most adverse events were grade 2 or less in severity, the most common side effects being diarrhea (64%), fatigue (33%), nausea/vomiting (27%), rash (26%), and headache (20%), and some mucositis.  Only 3 of 66 patients (less than 5%) experienced falling LVEF. 

Breast Cancer Watch Commentary:
Understanding Pertuzumab
:
Pertuzumab is a humanized monoclonal antibody (MoAb), targeting part of the ECD or extracellular domain (subdomain-2 , the extracellular dimerization domain (EDD)) of HER2 different than that targeted by trastuzumab (subdomain-4 of HER2), allowing it to block certain interactions between HER2 and EGFR (HER1), or HER2/3/4, and hence with potential of activity even in non-HER2-overexpressing tumor. Pertuzumab inhibits ligand-dependent growth of breast cancer cell lines apparently independently of the level of immunohistochemical expression of HER2.   Because of this, pertuzumab is now considered the first in a new class of what's called HDIs or HER2 dimerization inhibitors which inhibit the 'pairing' (dimerization) of the HER2 protein with other members of the HER family of receptors, as we know that in many cases HER1 and HER3 form heterodimers with HER2 in response to mitogenic signals, the formed heterodimers then  acting as themselves strong oncogenic signals.  What is exceptional is that pertuzumab only requires HER2 expression but is not dependent on HER2 amplification or overexpression, making it deployable in a wide range of tumor types, given that most human epithelial cells express HER2, and there is some speculation that pertuzumab may be able to overcome trastuzumab resistance.

There are several points to note in connection with the Gelmon study. Although only less than 5% of the patients experienced falling LVEF, this may underestimate the nature of cardiotoxicity that may be involved:  the recent NCI cardiotoxicity study of Chia Portera and colleagues10 found that out of 11 HER2+ MBC patients, six (54%) experienced a LVEF reduction, three with grade 1, two with grade 2, and one with grade 3 left ventricular systolic dysfunction (LVSD), and of these six, two patients had a LVEF reduction of >= 15%.  This suggests continued caution in dealing with potentially cardiotoxic agents and regimens.

In addition, I observe that preliminary data suggests HER3 inhibition may be more clinically relevant than inhibition of EGFR in HER2-amplified breast cancer, as per the recent findings of the Genetech team of Howard Stern and Si Tuen Lee-Hoeflich and colleagues11 whose findings suggest that EGFR is dispensable in HER2-amplified breast cancers and may have no clinically important role in HER2 signaling, and who therefore used in this connection pertuzumab to directly block the HER2/HER3 interaction by binding to the domain II dimerization arm of HER2. 


New Biological Therapies:  Lapatinib Plus Pazopanib

Dennis Slamon and colleagues12 conducted a short (12-week) preliminary randomized open-label phase II study of non-chemotherapy dual  all-oral multikinase inhibitor (MKI) therapy using lapatinib (Tykerb, 1500mg/d) and the anti-VEGF agent pazopanib (400mg/d) compared with lapatinib alone in 141 HER2-positive advanced and metastatic BC (metastatic breast cancer); after 12 weeks, any patients with aggressive or stable disease were taken off dual MKI therapy  and placed on trastuzumab (Herceptin). With a primary endpoint was 12-week progression, it was clear that pazopanib enhanced the antitumor efficacy of lapatinib: the dual MKI arm was associated with a a significant increase in target lesion response, and with 84% PFS (progression-free survival) compared to 63% PFS in the lapatinib monotherapy arm (hazard ratio of 0.41), although data for all patients was not available at the time of the ASCO 2008 presentation - efficacy data was missing on 20% or more of the studied patients. As to cardiotoxicity, of concern was the fact that four patients suffered a > 20% decrease in LVEF, all in the dual MKI combination arm, three of whom had previous anthracyclines treatment; all cases resolved upon discontinuation. 

In addition, estimated week 12 disease progression rate was 15.9% for the dual MKI arm vs 36.8% for lapatinib monotherapy, with responses of 36.2% and 22.2%, respectively, as well as a significantly greater week 12 decrease in maximum target lesion diameter on dual MKI therapy compared with lapatinib monotherapy (almost all patients in the dual MKI arm experienced a lesion diameter decrease)).   The dual MKI therapy was associated with an acceptable safety profile.

Breast Cancer Watch Commentary

This study provides proof of concept on the potential efficacy of dual MKI (multikinase inhibitor) therapy for HER2+ MBC using both HER2 + angiogenesis blockade, motivated in that  HER2 tumors have increased levels of VEGF, so that the investigational agent pazopanib and lapatinib affect different crosstalking pathways, and previous phase I and II trials have independently established the activity of trastuzumab plus the anti-VEGF agent bevacizumab (Avastin),  also being evaluated in the in-progress ECOG 1105 clinical trial.  In addition it should be noted that pazopanib is more than just a VEGF inhibitor:  it is a small-molecule multiple protein tyrosine kinase inhibitor of the c-kit and PDGF (platelet-derived growth factor) receptor. 

In addition, Pegram and colleagues13 tested a parallel concept of dual HER2/VEGF pathway inhibition using two intravenously administered monoclonal antibodies, trastuzumab (Herceptin) and bevacizumab (Avastin) as first-line therapy in 30 of 50 patients with HER2-amplified metastatic or locally-relapsed disease, finding objective clinical responses (all partial responses) in 46% (13 of 28) evaluable patients, with an additional 9 of 28 patients with stable disease at week 8 (11 patients remain on active treatment).  And the BETH trial14  will test the same dual strategy, trastuzumab (Herceptin) and bevacizumab (Avastin) in combination with chemotherapy , in the adjuvant setting. 

And I conclude by noting that pazopanib has also shown considerable promise in STS (soft tissue sarcoma), epithelial ovarian cancer, NSCLC (non small cell lung cancer), and RCC (renal cell carcinoma), and is in a phase III clinical trial for IBC - inflammatory breast cancer15.


New Biological Therapies: HSP90 Tanespimycin

The heat shock protein (HSP90) inhibitors are a novel class of drugs that appear capable of lowering HER2 cell surface expression, and thus might potentiate the effects of anti-HER2 treatment.   To study that possibility in patients, Shanu Modi at Memorial Sloan-Kettering Cancer Center (MSKCC) and colleagues16 conducted a phase 2 trial of the HSP90 inhibitor, tanespimycin, in combination with trastuzumab in patients with tumor progression despite prior trastuzumab therapy, finding that the overall response rate (ORR) was 26% in the 27 evaluable patients, with fatigue, nausea, and diarrhea as the most common treatment-related side effects although grade 3 toxicity was uncommon except grade 3 elevations in transaminases (alanine transaminase (ALT) and  aspartate transaminase (AST)) were noted in several patients.

Breast Cancer Watch Commentary

Heat shock protein 90 (HSP90) is a molecular chaperone (one which binds and stabilize 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, they simultaneously inhibit multiple signaling pathways that frequently interact to promote cancer cell survival.  Indeed, HSP90 inhibitors may be able to concurrently target 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 metastasis17.

The stability of the ErbB2 protein is inherently and uniquely dependent on HSP90, and inhibition of HSP90 causes a dramatic decrease in ErbB2 protein level, both in cultured cells and in animal tumor models, as suggested early by Wanping Xu at the NCI and colleagues18.  In addition, HSP90 inhibitors have potential to circumvent the genetic plasticity allowing tumor cells to evade the cytotoxicity of many oncotherapeutic agents19.

The HSP90 inhibitor tanespimycin (formerly, 17-AAG) used in the MSKCC trial is a new non-Cremophor suspension formulation of a former more toxic  Cremophor-based product.  Since HER2 and related proteins require HSP90 for proper self-assembly ("folding"), these are degraded by HSP90 inhibitors like tanespimycin, and it may be as suggested by Katerina Sidera at the Hellenic Pasteur Institute (Athens) and  colleagues20 that  there is a novel interaction between surface HSP90 and the extracellular domain (ECD) of HER-2, and as we have observed above, Modi and colleagues found a response rate of about 26%, and an impressive 57 to 63% overall benefit rate, and an encouraging potential to still provide significant benefit to tumors that are wholly trastuzumab-resistance.  These are important developments, since HSPs are critical in malignant progression of breast carcinoma and high HSP90 expression in primary breast cancer defines a population of patients with decreased survival21.  It is also highly encouraging that myelosuppression was not a dose-limiting toxicity in HSP trials to date, facilitating coadministration with chemotherapy, and I note finally that there may be a role for HSP90 inhibition in BRCA1-deficient breast cancer22.


New Biological Therapies: Trastuzumab-DM1

At ASCO 2008, Howard Burris with the Sarah Cannon Cancer Center in Nashville and coresearchers23 presented Phase I findings with the investigational agent T-DM1 (trastuzumab-DM1), a conjugate of trastuzumab (Herceptin) and the antimicrotubule DM1, with T-DM1 administered in 24 metastatic BC HER2-positive patients (once per 21-day cycle for a median of 91.6 weeks), with rather dramatic results: six objective responses, including one partial remission with a 36% shrinkage in the mediastinal area after just two cycles, and responses were exceptional: the response rate for patients who had measurable disease was 44%, and additional patients had stable disease. A companion Phase I T-DM1 study24 was also presented on the safety and pharmacokinetics of T-DM1 given IV once weekly to  advanced HER2+breast cancer patients who have progressed on a trastuzumab- containing regimen.  For those who received the weekly schedule, the response rate was 53%, an exceptionally high rate in a population with a median of 5 prior therapies, and almost two years of prior trastuzumab before reintroduction of trastuzumab in the T-DM1 conjugate.  The MTD for T-DM1 was established at 3.6 mg/kg, with objective tumor responses observed at doses at or below the MTD, and with adverse events of grade 2 or higher being infrequent and manageable. T-DM1 PK is compatible with q3-week dosing.


Breast Cancer watch Commentary

T-DM1 (trastuzumab-DM1)  is an investigational ADC, or antibody-drug conjugate, meaning a  monoclonal antibody linked with a cytotoxic agent for the selective kill,  intracellularly, of tumor cells, minimizing the impact on normal tissue.  This ADC has a proposed dual mechanism of action: anti-HER2 activity and targeted intracellular delivery of DM1, derivative of maytansine (derived naturally from a fungus), a potent antimicrotubule agent. The DM1 component is attached to trastuzumab by what's called the MCC linker molecule, with the  goal of target intracellular delivery of both drugs with high specificity to tumor-only tissue.   

ADCs (antibody-drug conjugates) are a novel cytotoxic immunotherapy approach to treating trastuzumab-resistant disease.   Ian Krop at Dana-Farber and colleagues25 had previously conducted a phase 1 dose-escalation study T-DM1 in 24 patients with trastuzumab-refractory breast cancer which found T-DM1 relatively well tolerated, associated with transient transaminitis and transient thrombocytopenia which both however resolved over time;  12 of 15 patients treated at MTD had stable disease or a partial response, and 5 with sustained stable diseases lasting from 130 to 250 days, exceptional with single-agent therapy (similar findings were presented at ASCO 200726).  Given these positive findings, the future looks quite promising for ADCs (antibody-drug conjugates) as novel cytotoxic immunotherapy, both for overcoming trastuzumab resistance and for active anti-HER2 therapy.


References

  1. Dang CT, Lin NU, Lake D, et al. Preliminary safety results of dose-dense (dd) doxorubicin and cyclophosphamide (AC) followed by weekly paclitaxel (P) with trastuzumab (T) and lapatinib (L) in HER2 overexpressed/amplified breast cancer (BCA). Proc Am Soc Clin Oncol. 2008;26:11s. Abstract 518.
  2. Bontenbal M, Seynaeve C, Stouthard J, et al. Randomized study comparing efficacy / toxicity of monotherapy trastuzumab followed by monotherapy docetaxel at progression, and combination trastuzumab/docetaxel as first line chemotherapy in HER2-neu positive metastatic breast cancer (HERTAX study). Proc Am Soc Clin Oncol. 2008;26:44s. Abstract 1014.
  3. O'Shaugnessy J, Blackwell K, Burstein HJ, et al. A randomized study of lapatinib alone or in combination with trastuzumab in heavily pretreated HER2+ metastatic breast cancer progressing on trastuzumab therapy. Proc Am Soc Clin Oncol. 2008;26:44s. Abstract 1015.
  4. Geyer CE, Forster J, Lindquist D, et al. Lapatinib plus capecitabine for HER2-positive advanced breast cancer.  N Engl J Med 2006 Dec 28; 355(26):2733-43.
  5. Kaniklidis, C.  Brain metastasis from breast cancer - a review.  Available at: http://bcwatchdigest-brain.evidencewatch.com.  Accessed Septemeber 22, 2008.
  6. Abdulkarim BS, Gabos Z, Sinha R, et al. Prognostic significance of HER-2/neu over-expression on the incidence of brain metastasis in newly diagnosed breast cancer.  Proc Am Soc Clin Oncol. 2006;24:185s. Abstract 649.
  7. Kristiansen C, Enevoldsen K, Langkjer ST. Cerebral metastasis in advanced breast cancer and the significance of HER2 status. 29th Annual San Antonio Breast Cancer Symposium, San Antonio, Texas, USA, 14–17 December 2006.
  8. Von Minckwitz G, Zielinski C, Maarteense E, et al. Capecitabine vs. capecitabine + trastuzumab in patients with HER2-positive metastatic breast cancer progressing during trastuzumab treatment: the TBP phase III study (GBG 26/BIG 3-05).  Proc Am Soc Clin Oncol.  2008;26:44s. Abstract 1025.
  9. Gelmon KA, Fumleau P, Verma S, et al. Results of a phase II trial of trastuzumab and pertuzumab in patients with HER2-positive metastatic breast cancer who had progressed during trastuzumab therapy. Proc Am Soc Clin Oncol. 2008;26:47s. Abstract 1026.
  10. Portera CC, Walshe JM, Rosing DR, et al.  Cardiac toxicity and efficacy of trastuzumab combined with pertuzumab in patients with trastuzumab-insensitive human epidermal growth factor receptor 2-positive metastatic breast cancer.  Clin Cancer Res 2008 May 1; 14(9):2710-6.
  11. Lee-Hoeflich ST, Crocker L, Yao E, et al.  A central role for HER3 in HER2-amplified breast cancer: implications for targeted therapy.  Cancer Res 2008 Jul 15; 68(14):5878-87.
  12. Slamon D, Gomez HL, Kabbinavar FF, et al. Randomized study of pazopanib + lapatinib vs lapatinib alone in patients with HER2-positive advanced or metastatic breast cancer. Proc Am Soc Clin Oncol. Abstract 1016.
  13. Pegram M, Chan D, Dichmann RA, et al. Phase II combined biological therapy targeting the HER2 proto-oncogene and the vascular endothelial growth factor using trastuzumab (T) and bevacizumab (B) as first line treatment of HER2-amplified breast cancer. Program and abstracts of the 29th Annual San Antonio Breast Cancer Symposium; December 14-17, 2006; San Antonio, Texas.  Abstract 301.
  14. ClinicalTrials.gov. A multicenter phase III randomized trial of adjuvant therapy for patients with HER2-positive node-positive or high risk node-negative breast cancer comparing chemotherapy plus trastuzumab with chemotherapy plus trastuzumab plus bevacizumab. Available at: http://clinicaltrials.gov/ct2/show/NCT00625898. Accessed October 7, 2008.
  15. ClinicalTrials.gov. A Randomized, Multicenter, Phase III Study Comparing the Combination of Pazopanib and Lapatinib Versus Lapatinib Monotherapy in Patients With ErbB2 Over-Expressing Inflammatory Breast Cancer.  Available at: http://clinicaltrials.gov/ct2/show/NCT00558103?cntry1=EU%3AIT&rank=34.  Accessed October 7, 2008.
  16. Modi S, Sugarman S, Stopeck A, et al.  Phase II trial of the Hsp90 inhibitor tanespimycin + trastuzumab in patients with HER2-positive metastatic breast cancer.  Proc Am Soc Clin Oncol. 2008;26:47s. Abstract 1027.
  17. Hanahan D, Weinberg RA.  The hallmarks of cancer. Cell 2000 Jan 7; 100(1):57-70.
  18. Xu W, Mimnaugh E, Rosser MF, et al. Sensitivity of mature Erbb2 to geldanamycin is conferred by its kinase domain and is mediated by the chaperone protein Hsp90. J Biol Chem 2001 Feb 2; 276(5):3702-8.
  19. Xu W, Neckers L.  Targeting the molecular chaperone heat shock protein 90 provides a multifaceted effect on diverse cell signaling pathways of cancer cells.  Clin Cancer Res 2007 Mar 15; 13(6):1625-9.
  20. Sidera K, Gaitanou M, Stellas D, et al. A critical role for HSP90 in cancer cell invasion involves interaction with the extracellular domain of HER-2.  J Biol Chem 2007 Dec 5.
  21. Pick E, Kluger Y, Giltnane JM, et al. High HSP90 expression is associated with decreased survival in breast cancer.  Cancer Res 2007 Apr 1; 67(7):2932-7. 
  22. Zajac M, Moneo MV, Carnero A, et al. Mitotic catastrophe cell death induced by heat shock protein 90 inhibitor in BRCA1-deficient breast cancer cell lines.  Mol Cancer Ther 2008 Aug; 7(8):2358-66.
  23. Beeram M, Burris III HA, Modi S, et al. A phase I study of trastuzumab-DM1 (T-DM1), a first-in-class HER2 antibody-drug conjugate (ADC), in patients (pts) with advanced HER2+ breast cancer (BC). Program and abstracts of the 44th American Society of Clinical Oncology Annual Meeting; May 30 - June 3, 2008; Chicago, Illinois. Abstract 1028.
  24. Holden SN, Beeram M, Krop IE, et al. A phase I study of weekly dosing of trastuzumab-DM1 (T-DM1) in patients (pts) with advanced HER2+ breast cancer (BC). Program and abstracts of the 44th American Society of Clinical Oncology Annual Meeting; May 30 - June 3, 2008; Chicago, Illinois. Abstract 1029.
  25. Krop IE, Beeram M, Modi S, et al. A phase I study of trastuzumab-DM1, a first-in-class HER2 antibody-drug conjugate, in patients with advanced HER2+ breast cancer. Breast Cancer Res Treat. 2007;106:S33. [Abstract 310].
  26. Beeram M, Krop I, Modi S, et al. A phase I study of trastuzumab-MCC-DM1 (T-DM1), a first-in-class HER2 antibody-drug conjugate (ADC), in patients (pts) with HER2+ metastatic breast cancer. Proc Am Soc Clin Oncol. 2007;25:42s. [Abstract 1042].

HER2 Receptor

Summary for Patients
The HERTAX trial2 found that for patients with HER2+ advanced BC, concurrent chemotherapy plus trastuzumab may be associated with better long-term tumor control compared to sequential trastuzumab followed by chemotherapy..

The open-label randomized phase III trial presented by Dr. Joyce O'Shaugnessy with US Oncology3 explored combined trastuzumab + lapatinib treatment in heavily pretreated HER2+ patients who had experienced overt tumor progression while on trastuzumab, demonstrating that ongoing trastuzumab therapy beyond overt progression can deliver clinically important benefits: improved PFS and doubling of the clinical benefit rate, with a trend toward superior median OS for the combination.   This provides proof of principle that simultaneous dual signal targeting of the HER2 receptor, that is, dual-HER2 blockade via trastuzumab + lapatinib is of clinical benefit with clinical synergy activity. 

Several practical lessons can be derived from this study: (1) Continuing trastuzumab and adding lapatinib to it in the resistance setting is a more optimal strategy than discontinuing trastuzumab and substituting lapatinib for it. (2) The Geyer outcomes4 of overall response rate (ORR) and clinical response rate from lapatinib + capecitabine are appreciably higher than those found in the O'Shaugnessy ASCO 2008 trial of lapatinib + trastuzumab, suggesting that for progressive HER2+ disease on trastuzumab, the lapatinib + capecitabine regimen would be relatively more favorable than lapatinib + trastuzumab.  (3) Lapatinib appears capable of crossing the blood-brain barrier (BBB) and the cerebrospinal fluid (CSF) barrier and hence may exhibit appreciable activity in breast cancer brain metastasis.  (4) Finally, I advocate from the cumulative evidence to date for brain prophylaxis strategies, possibly via lapatinib and/or capecitabine,  and/or serial radiologic screening (brain MRI) in order to detect asymptomatic brain metastases.

The Breast International Group/German Breast Group (BIG/GBG) TBP (trastuzumab beyond progression) study8 found that continued trastuzumab beyond progression improves efficacy of second-line capecitabine in patients with metastatic or locally advanced BC compared with capecitabine alone, hence the discontinuation of anti-HER2 therapy is becoming increasingly problematic.

Karen Gelmon with the British Columbia Cancer Agency and colleagues9 have shown the efficacy of pertuzumab plus trastuzumab in HER2-positive metastatic breast cancer patients whose tumors had progressed on prior trastuzumab therapy, with pertuzumab being the first of a new class of HDIs or HER2 dimerization inhibitors.

Dennis Slamon and colleagues12 provided proof of concept on the potential efficacy of dual MKI (multikinase inhibitor) therapy for HER2+ MBC using both HER2 + angiogenesis blockade, motivated in that HER2 tumors have increased levels of VEGF, so that the investigational agent pazopanib and lapatinib affect different crosstalking pathways, parallel to the previous Pegram and colleagues13 study that tested a parallel concept of dual HER2/VEGF pathway inhibition using trastuzumab (Herceptin) and bevacizumab (Avastin) as first-line therapy for HER2-amplified metastatic or locally-relapsed disease.  The success of pazopanib and lapatinib (Tykerb), as well as  trastuzumab (Herceptin) and bevacizumab (Avastin) suggests the strong molecular motivation and clinical benefit of a dual anti-HER2 and anti-angiogenic blockade.

Given that other research has established that the HER2 protein is inherently and uniquely dependent on the heat shock protein HSP90, Shanu Modi at Memorial Sloan-Kettering Cancer Center (MSKCC) and colleagues16 conducted a phase II trial of the HSP90 inhibitor, tanespimycin, in combination with trastuzumab in patients with tumor progression despite prior trastuzumab therapy, with impressive clinical benefit even in wholly trastuzumab-resistant tumors.

Finally, Howard Burris with the Sarah Cannon Cancer Center in Nashville and coresearchers23 presented Phase I findings with the investigational agent T-DM1 (trastuzumab-DM1), a conjugate of trastuzumab (Herceptin) and the antimicrotubule DM1, where T-DM1 (trastuzumab-DM1) is an ADC, or antibody-drug conjugate, meaning a monoclonal antibody linked with a cytotoxic agent for the selective kill, intracellularly, of tumor cells, minimizing the impact on normal tissue, and allowing for dual action, both anti-HER2 and intracellularly cytotoxic.  T-DM1 yielded exceptionally high response rates, and given these positive findings, the future looks quite promising for ADCs (antibody-drug conjugates) as novel cytotoxic immunotherapy, both for overcoming trastuzumab resistance and for active anti-HER2 therapy.

At this juncture, therefore, in the post-trastuzumab-only era, we have an impressively broad spectrum of potential agents (in and out of clinical trial)  including, beyond trastuzumab (Herceptin) itself, lapatinib (Tykerb), the HER2 dimerization inhibitor (HDI) pertuzumab, the anti-VEGF / antiangiogenic agent pazopanib, the heat shock protein (HSP90) tanespimycin, and the  antibody-drug conjugate (ADC) Trastuzumab-DM1, for both their anti-HER2 benefit and as adjuncts for overcoming trastuzumab resistance, and our understanding of the molecular pathways underlying HER2 disease continues to grow at a rapid pace.  


Methodology for this Review
A search of the PUBMED database was conducted without language or date restrictions, and updated again current as of date of publication, with systematic reviews and meta-analyses extracted separately. Search was expanded in parallel to include clinical trials from ClinicalTrials.gov and medical feed sources as returned from FeedNavigator provided by the National Library of Health Sciences - Terkko at the University of Helsinki. Unpublished studies were located via contextual search, and scientific databases searched using COS Workbench from Community of Science. University dissertations were search via NDLDT. Sources in languages foreign to this reviewer were translated by language translation software.


Our Dedicated Topic Pages

* subscribe * | * contact us * | * unsubscribe * | * previous issue *

Copyright © 2008. Constantine Kaniklidis. All rights reserved. Reproduction in whole or in part without permission is prohibited.