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Evidence-based Breast Cancer Treatment Guidance - The State of the Art
Compiled by: Constantine Kaniklidis, medical researcher, European Association for Cancer Research (EACR)
[ Breast Cancer Watch is a member of the Evidencewatch portal of evidence-based medicine sites ]


Breast Cancer Watch is a unique service providing the latest best evidence-based guidance on state-of-the-art breast cancer therapies, annotated with critical commentaries, and clinical practice recommendations. Critical appraisal and systematic review is undertaken aggressively with major updates monthly, and at least weekly revisions for high-impact findings. The series addresses two problems: (1) the lack of any timely single-source evidence-based systematic review of breast cancer treatment research findings for both healthcare professionals and informed patients, and (2) the rapid aging of breast cancer guidelines issued on less timely schedules (e.g., NCCN, ASCO and other guidelines).      [updated: 4/04/07]



Issues in Tamoxifen Endocrine Therapy



  • Tamoxifen + Radiotherapy: Concurrent or Sequential?

    To date there is no decisive clinical evidence that concurrent administration of tamoxifen and radiotherapy (RT) could reduce the efficacy of RT alone, or in sequential schedule with TAM. Indeed, several studies have failed to show any compromise in local or systemic control nor any significant difference in the risk of ipsilateral breast tumor recurrence, disease-free survival (DFS), or overall survival in patients receiving concomitant versus sequential TAM and RT (Harris et al., J Clin Oncol (2005): Impact of Concurrent Versus Sequential Tamoxifen With Radiation Therapy in Early-Stage Breast Cancer Patients Undergoing Breast Conservation Treatment; Ahn et al., J Clin Oncol (2005): Sequence of Radiotherapy With Tamoxifen in Conservatively Managed Breast Cancer Does Not Affect Local Relapse Rates; Pierce et al., J Clin Oncol (2005): Sequencing of Tamoxifen and Radiotherapy After Breast-Conserving Surgery in Early-Stage Breast Cancer).

    However, adverse fibrotic impact remains the most important dose-limiting toxicity of radiotherapy to soft tissue, reflected functionally in loss of range of motion and muscle strength and the development of limb edema and pain, so that the lack of compromise due to concomitant administration of RT and tamoxifen leaves open the question of whether toxicities, especially fibrotic, are significantly different between concurrent versus sequential administration. On this score, Azria et al. (Br J Cancer (2004): Concomitant use of tamoxifen with radiotherapy enhances subcutaneous breast fibrosis in hypersensitive patients) found that concomitant use of tamoxifen and radiotherapy is significantly associated with an increased incidence of grade 2 or greater subcutaneous fibrosis (so-called radiation-induced fibrosis (RIF)) and therefore, caution needs be exercised with this regimen in radiosensitive patients (see also the same findings from Ozshanin et al., SASRO Clinical Abstracts M12 (2004): Concomitant use of tamoxifen increases radiation-induced subcutaneous fibrosis in adjuvant breast cancer treatment [pdf]) who conclude that adjuvant hormonal treatment with tamoxifen should be delayed until the completion of RT, or the use of aromatase inhibitors should be considered). Given this it would appear that sequential tamoxifen + radiotherapy exhibits a more favorable efficacy:toxicity ratio than concurrent administration.

    In this context, it is important to note that six months treatment with a combination of pentoxifylline (trental), a hemorheologic agent typically used to improve blood flow in intermittent claudication, and alpha-tocopherol (Vitamin E) can significantly reduce superficial RIF (Delanian et al., J Clin Oncol (2003): Randomized, Placebo-Controlled Trial of Combined Pentoxifylline and Tocopherol for Regression of Superficial Radiation-Induced Fibrosis); see also Chiao & Lee, Ann Pharmacother (2005): Role of Pentoxifylline and Vitamin E in Attenuation of Radiation-Induced Fibrosis); and Okunieff, J Clin Oncol (2004): Pentoxifylline in the Treatment of Radiation-Induced Fibrosis who found that patients receiving pentoxifylline alone demonstrated improved active and passive range of motion and muscle strength and decreased limb edema and pain), disproving the long-standing clinical dogma that established RT sequelae like RIF (radiation-induced fibrosis) are wholly irreversible Azria et al., J Clin Oncol (2005): Radiation Therapy and Tamoxifen: Concurrent or Sequential? It's No Longer the Question!), suggesting furthermore that particularly for radiosensitive patients tamoxifen should be deferred until after completion of radiotherapy, or substituted for by an aromatase inhibitor.

    Note other efforts have shown some promise in limiting the adverse effects of radiotherapy. Supplementation with high doses of alpha-tocopherol and beta-carotene during radiation therapy appears to reduce the severity of RT treatment adverse effects, but the use of high doses of antioxidants as adjuvant therapy also appears to compromise radiation treatment efficacy in that the rate of local recurrence of the head and neck tumor tended to be higher in the supplement arm of the trial (Bairati et al., J Clin Oncol (2005): Randomized Trial of Antioxidant Vitamins to Prevent Acute Adverse Effects of Radiation Therapy in Head and Neck Cancer Patients).

    The main question concerns higher lung and subcutaneous fibrosis incidence, particularly in radiosensitive patients, and not in the entire treated population.



  • Tamoxifen Failure in ER-Negative Tumors

    As pointed out by Kathy Albain in her editorial (J Natl Cancer Inst (2004): Adjuvant Chemotherapy for Lymph Node–Negative, Estrogen Receptor–Negative Breast Cancer: A Tale of Three Trials), adjuvant tamoxifen was often prescribed on an ad hoc basis for women with receptor-negative breast cancer, a practice now decisvely demonstrated to be without foundation and wholly against the evidence base.

    The EBCTCG (Early Breast Cancer Trialist' Collaborative Group) in 1998 (EBCTCG, Lancet (1998): Tamoxifen for early breast cancer: an overview of the randomised trials) failed to find any benefit from adjuvant tamoxifen endocrine therapy in ER- (negative) tumors (see also the ZEBRA (Zoladex Early Breast Cancer Research Association) trial (Jonat et al., J Clin Oncol (2002): Goserelin Versus Cyclophosphamide, Methotrexate, and Fluorouracil as Adjuvant Therapy in Premenopausal Patients With Node-Positive Breast Cancer: The Zoladex Early Breast Cancer Research Association Study) which in finding that the LHRH analaog goserelin (Zoladex), aka "Z", for ER-positive patients was equivalent to CMF in terms of DFS, noted in their discussion that in contrast, in ER-negative tumors, CMF produced a highly significant advantage over goserelin, and that "this result is consistent with the EBCTCG overview, which showed no significant effect from adjuvant hormone therapy in ER-negative tumors", and based on this concluded by recommending that "cytotoxic therapy should remain the adjuvant treatment of choice in ER-negative tumors".

    This has been further confirmed in numerous studies including NSABP (National Surgical Adjuvant Breast and Bowel Project) B-23 (Fisher et al., J Clin Oncol (2001): Tamoxifen and Chemotherapy for Axillary Node-Negative, Estrogen Receptor–Negative Breast Cancer: Findings From National Surgical Adjuvant Breast and Bowel Project B-23), a study specifically designed to provide a decisive test of the value, if any, of TAM for the treatment of women with ER-negative tumors - more precisely, the exact objective was (1) to determine whether AC was comparable or superior to CMF when used to treat node-negative patients with ER-negative tumors, (2) whether, when given with TAM, either of those chemotherapy regimens was more effective than when administered with placebo, and (3) to resolve the indeterminacy and vagueness of the earler EBCTCG observation that "for women with tumors that have been reliably shown to be ER-negative, adjuvant tamoxifen remains a matter for research"; NSABP B-23 found that "no significant difference in any outcome was observed when chemotherapy-treated patients who received placebo were compared with those given TAM[oxifen]". Again, more precisely they found that when the CMF- and AC-treated groups were combined and women who received placebo were compared with those who received TAM, no significant difference in RFS (relapse-free survival) was observed, and that there was, likewise, no difference when RFS was related to age (=<49 aqnd =>50), with the same lack of significant difference from placebo for EFS (event-free survival ) and (5 year) overall survival. Their conclusions included that "based on the information in this report of B-23, it is difficult to justify the administration of TAM to patients with ER-negative breast tumors and negative axillary nodes" given that the study " . . . failed to demonstrate any semblance of a benefit from TAM". See also the commentary of Elledge (J Clin Oncol (2006): Tales From a Targeted Therapy) who, noting the almost certain large human patient toll, calls for accurately identify targets of targeted therapy, at the very least to determine who may and may not benefit from effective endocrine therapies such as tamoxifen, commending the absolutely vital and dispositive study of Marco Colleoni (see below for full discussion of this seminal trial) reporting for the IBCSG - the International Breast Cancer Study Group - 13-93 (International Breast Cancer Study Group, J Clin Oncol (2006): Tamoxifen After Adjuvant Chemotherapy for Premenopausal Women With Lymph Node-Positive Breast Cancer: International Breast Cancer Study Group Trial 13-93) as finally driving "a stake through the heart of the idea that tamoxifen is effective in accurately measured ER-negative tumors".

    These findings on the failure of benefit of TAM in the ER- tumor context has since these studies continued to be robust and further validated in methodologically high-quality studies: thus the SWOG team of Hutchins and colleagues (Hutchins et al., J Clin Oncol (2005): Randomized, Controlled Trial of Cyclophosphamide, Methotrexate, and Fluorouracil Versus Cyclophosphamide, Doxorubicin, and Fluorouracil With and Without Tamoxifen for High-Risk, Node-Negative Breast Cancer: Treatment Results of Intergroup Protocol INT-0102) in their Intergroup Protocol INT-0102 trial sought to determine the efficacy of the CMF regimen versus CAF in node-negative breast cancer patients, with and without tamoxifen (TAM), overall and by hormone receptor (HR) status; they found that the effect of TAM was different between the receptor status groups, with TAM being beneficial for HR+ patients (note, in the protocol of this study, hormone-responsive indicated ER+), but not for HR-negative (that is, ER-) patients, and concluded that TAM is effective in HR-positive (ER+) disease, but not in HR-negative (ER-) disease.

    Similarly, Arpino et al. (J Clin Oncol (2005): Hormone Receptor Status of a Contralateral Breast Cancer Is Independent of the Receptor Status of the First Primary in Patients Not Receiving Adjuvant Tamoxifen) found that among tamoxifen-treated patients 50% of patients with a PR+ primary breast cancer versus 27% of patients with a PR- primary tumor developed a PR+ contralateral breast cancer, suggesting that other reasons need to be explored to clarify the failure of tamoxifen to reduce the incidence of contralateral breast cancer in patients with receptor-negative primary tumor. And the GABG-IV D-93 (German Adjuvant Breast cancer Group) trial (Kaufmann et al., J Clin Oncol (2005): Tamoxifen Versus Control After Adjuvant, Risk-Adapted Chemotherapy in Postmenopausal, Receptor-Negative Patients With Breast Cancer: A Randomized Trial (GABG-IV D-93)—The German Adjuvant Breast Cancer Group) added to this knowledge, concluding that "this study contributes substantially to finalization of the presently emerging evidence that tamoxifen does not benefit women with receptor-negative breast cancer after chemotherapy".

    Mamounas (Clin Med Res (2003): NSABP Breast Cancer Clinical Trials: Recent Results and Future Directions) has offered an expert summary of the findings of the many NSABP trials current to 2003, noting that "when these results are taken together with those evaluating the effect of tamoxifen in patients with invasive breast cancer and negative estrogen receptors, they are consistent with the observation that tamoxifen has no appreciable benefit in reducing rates of recurrence or rates of contralateral breast cancer in patients with ER-negative tumors", and noting that some poorly designed and insufficiently powered early studies appeared to suggest, now known counterfactually, that tamoxifen may have some benefit in the estrogen receptor-negative context, Mamounas concludes that nonetheless "since that time, an increasing body of evidence has demonstrated that tamoxifen confers no significant advantage in patients with ER-negative tumors".

    And Albain in the editorial cited above (J Natl Cancer Inst (2004): Adjuvant Chemotherapy for Lymph Node–Negative, Estrogen Receptor–Negative Breast Cancer: A Tale of Three Trials), discusses the NSABP B-23 (see Fisher, above) and SWOG Intergroup Trials (see Hutchins, above), concludes that "these results definitively disprove the hypothesis that tamoxifen might have clinically significant cytocidal activity apart from its known interaction with the estrogen receptor".

    Finally, most recently, Marco Colleoni reporting for the IBCSG - the International Breast Cancer Study Group - 13-93 (International Breast Cancer Study Group, J Clin Oncol (2006): Tamoxifen After Adjuvant Chemotherapy for Premenopausal Women With Lymph Node-Positive Breast Cancer: International Breast Cancer Study Group Trial 13-93) which sought to evaluated the value of adjuvant tamoxifen after chemotherapy for premenopausal women with breast cancer, not only concluded that the use of tamoxifen as adjuvant therapy for patients with ER-negative tumors is not recommended, but that in fact, in an unplanned exploratory analysis, "tamoxifen had a detrimental effect on patients with ER-absent tumors compared with no tamoxifen". It is clear from these findings that (1) tamoxifen interacts differently with cellular growth contingent on ER status: short-term tamoxifen treatment yields a significant decrease of the proliferation antigen Ki-67 (a nuclear antigen associated with cell proliferation) in patients with ER+ disease, whereas no effect was observed in patients with ER- breast cancer, and (2) cross talk between tamoxifen and growth factor receptor pathways might be principally responsible for tumor progression (as also suggested by Osborne & Schiff (Breast (2003): Growth factor receptor cross-talk with estrogen receptor as a mechanism for tamoxifen resistance in breast cancer); Carolina et al., J Clin Oncol (2005): Molecular Changes in Tamoxifen-Resistant Breast Cancer: Relationship Between Estrogen Receptor, HER-2, and p38 Mitogen-Activated Protein Kinase).

    Breast Cancer Watch: On the Dispositive Nature of IBCSG 13-93 Trial
    Breast Cancer Watch, on the basis of critical appraisal of the Colleoni IBCSG 13-93 trial, judges the study to be of exceptionally high methodological quality, and of sufficient statistical power to support its conclusions, using 1,246 assessable axilliary node-positive premenopausal patients, enrolled betwenn 1993 and 1999, and evaluated in a randomized 2 x 2 factorial phase III clinical trial, with a primary decision target of comparing 5 years of tamoxifen therapy with no endocrine treatment, sensitive to ER status, and using DFS (Disease Free Survival) as primary endpoint, defined as length of time from the date of random assignment to any relapse (including ipsilateral or contralateral breast recurrence), the appearance of a second primary malignancy, or death, whichever occurred first. DFS and OS percentages were obtained using the Kaplan-Meier method, while sensitivity estimates derived from the Greenwood formula, and hazard ratios from the log-rank test; control for prognostic features testing for interactions between potential prognostic factors and treatment effects used Cox proportional hazards regression models, and the prognostic significance of chemotherapy-induced amenorrhea was assessed by a landmark analysis. Due conformance is noted with Data Safety Monitoring Committee (DSMC) protocols and standards, and the Scientific Committee of IBCSG DSMC in August 2000 recommended that (1) patients with ER-positive tumors who were randomly assigned to not receive tamoxifen be offered this treatment, and (2) in Augest 2002 Investigators were asked to consider the endocrine responsiveness and to discontinue the tamoxifen in patients with endocrine-nonresponsive disease. Patient eligibility, accrual and randomization met methodological requirements, and we discerned no potential conflicts of interest by any author, and none were declared.

    Breast Cancer Watch on basis of this critical appraisal judges all findings of the IBCSG 13-93 Trial, summarized below, to be (1) to be founded on study design of sufficient statistical and methodolical power to support those conclusions, (2) to be dispositive on the issues they address, and (3) cross-confirmed by the findings of EBCTCG (1998), the ZEBRA Trial, the NSABP B-23 TRial, the SWOG (2005) RCT, the GABG-IV D-93 Trial, the Mamounas NSABP Summary (2003), and Arpino (2005) [all cited above]:

    (1) Tamoxifen benefial effects were exclusively restricted to the ER+ cohort, for those both younger, and older than or eqaul to 40 years of age
    (2) Tamoxifen did not influence DFS in patients with ER- tumors.
    (3) Tamoxifen exhibited detrimental effects in ER-absent tumors (no expression of ER).
    (4) For patients with ER-positive disease, the achievement of chemotherapy-induced amenorrhea was significantly correlated with improved DFS, with the magnitude of effect in patients receiving tamoxifen and patients not receiving tamoxifen being comparable.
    (5) Caution is required when using endocrine therapies for women with endocrine-nonresponsive tumors at high risk of relapse.



  • Critical Note: Tamoxifen in the ER-/PR+ Context

    Breast Cancer Watch notes that in our sytematic review of the research on tamoxifen and estrogen receptor-negative tumors, many studies failed to differentiate between the strongly-endocrine-positive context, that is ER+/PR+, the singlet-endocrine positive context (ER+ OR PR+, but not both), and the strongly-endocrine negative (ER- AND PR-), but we now know that the special ER-/PR+ still represents an endocrine-positive setting that may benefit from endocrine therapy, so the question that suggests itself is whether the presence of PR+ subcontext influences the negative finding that tamoxifen does not benefit ER- tumors. We have uncovered one recent breakthrough study that addresses this otherwise overlooked issue: Michael Dowsett at Royal Marsden and coworkers (Dowsett et al., Ann Oncol (2006): Benefit from adjuvant tamoxifen therapy in primary breast cancer patients according oestrogen receptor, progesterone receptor, EGF receptor and HER2 status) retrieved the histopathological blocks of primary breast cancer patients who had been randomized to receive 2-years tamoxifen or no adjuvant therapy in two mature RCTs, finding that with respect to RFS (relapse-free survival) as the primary endpoint, benefit from tamoxifen was seen in ER-positive patients, with ER-negative patients also showing a strong trend to benefit from tamoxifen, but this was largely confined to the PR-positive group. However, Breast Cancer Watch further notes that no patients positive for HER2 benefited significantly, confirming that HER2 positive tumors are strongly resistant to tamoxifen.



  • The ER+/PR- Context

    This raises the question of what is the special status of the ER+/PR- context. It nows appears that the absence of PR reflects at the very least resistance to hormonal therapy, but recent clinical and laboratory evidence suggests that ER+/PR- breast cancers are specifically resistant to SERMs like tamoxifen, yet appear to be less resistant to estrogen withdrawal therapy via aromatase inhibitors (AIs); as recently found, ER+/PR- breast tumors might best be treated optimally by completely blocking ER action via the estrogen withdrawal activity of aromatase inhibitors, by targeted ER degradation, or by combined therapy targeting both ER and growth factor signaling pathways (Cui et al., J Clin Oncol (2005): Biology of Progesterone Receptor Loss in Breast Cancer and Its Implications for Endocrine Therapy). In addition, PR-negativity may be more than a simple lack of ER activity, but rather may reflect hyperactive cross-talk between ER and growth factor signaling pathways, especially HER2, consistent with the clinical observations finding that ER+/PR– breast cancers overexpress HER2 compared with ER+/PR+ breast cancers, and that PR-negativity correlates with high HER2 levels, as observed by Kim et al. (Clin Cancer Res (2006): Progesterone Receptor Loss Correlates with Human Epidermal Growth Factor Receptor 2 Overexpression in Estrogen Receptor–Positive Breast Cancer) in commenting on the well-recognized resistance of ER+/PR– breast cancer to antiestrogens and the fact that in ER+ breast cancers, PR-negative tumors are more aggressive than PR-positive cancers.

    It has also reported that PR- in women with an ER+ breast cancer predicts lymph node invasion independent of other predictors of lymph node invasion, especially in younger women (Neven et al. J Clin Oncol (2006): Progesterone Receptor in Estrogen Receptor–Positive Breast Cancer: The Association Between HER-2 and Lymph Node Involvement Is Age Related who also suggest that the negative association between PR and HER-2 is only seen after age 45; and that furthermore, PR, tumor grade, and tumor size were all independent predictors for a positive lymph node status in women 50 or younger at diagnosis, while in women older than age 50, only tumor size and tumor grade predicted a positive lymph node status).

    In addition, Breast Cancer Watch notes that the degree of PR-positivity plays a critical role: it is primarily premenopausal patients with tumors showing >75% PR-positivity (and of course are ER+) that are tamoxifen responsive, with an improved recurrence-free as well as overall survival (Stendahl et al., Clin Cancer Res (2006): High Progesterone Receptor Expression Correlates to the Effect of Adjuvant Tamoxifen in Premenopausal Breast Cancer Patients).

    And PR status has relevance to other endocrine agents: among women with ER+ breast cancers, the level of PR expression appears to help predict the likelihood of response to letrozole (Femara), as demonstrated by Viale et al. (SABCS (2005): Central review of ER, PgR and HER-2 in BIG 1-98 evaluating letrozole vs. tamoxifen as adjuvant endocrine therapy for postmenopausal women with receptor-positive breast cancer; see also Stuart Schnitt, J Clin Oncol (2006): Estrogen Receptor Testing of Breast Cancer in Current Clinical Practice: What's the Question?).



  • The ER-/PR+/HER2+ Context

    Thus patients with ER- / PR+ / HER2+ tumors do not benefit significantly from tamoxifen endocrine therapy, and for this population it is prudent to (1) still explore the benefit of non-tamoxifen ET (endocrine therapy), via either AIs (aromatase inhibitors) or fulvestrant (Faslodex) in an ovarian ablation (oophorectomy) or ovarian suppression (LHRH or GnRH analogs) induced postmenopausal context, with consideration of (2) deployment of additional CT (chemotherapy) and/or BT (biological therapy) modalities, the later exploiting not only the standard trastuzumab (Herceptin) regimen, but possibly also the newly discovered benefits from the EGFR TKI lapatinib (Tycerb) agent which may proved of value in overcoming endocrine resistance in the HER2-overexpressing context.




  • Tamoxifen, Endocrine Resistance and HER2+

    Cumulative research has identified two forms of resistance to tamoxifen therapy: (1) intrinsic (that is, de novo) resistance, in which ER+ tumors do not respond to tamoxifen from the outset of treatment, and (2) acquired resistance, when ER+ tumors initially responsive to tamoxifen subsequently exploit the tamoxifen–ER complexes as a stimulatory growth signal. Indeed, the phenomenon of estrogen- dependent breast cancer cell lines initially growth inhibited by tamoxifen and other SERMs becoming growth dependent on these same agents after long-term exposure to low concentrations has been playfully described as an intrinsic Jekyll-and-Hyde character (see Daniel Hayes, J Natl Cancer Inst (2004): Tamoxifen: Dr. Jekyll and Mr. Hyde? who notes its dependence on HER-2, one of four transmembrane proteins within the epidermal growth factor receptor (EGFR) family and associated phosphorylation "cross-talk"; his conclusion is sobering: "Like Dr. Jekyll, tamoxifen has clearly contributed immensely to the well-being of patients. Like Mr. Hyde, cloaked in the disguise of an agonist rather than an antagonist for its receptor, it may also have harmed some"). See also Rachel Schiff's overview of this issue in Physician's Education Resource, Biological therapy of Breast Cancer (2005): Endocrine Resistance in HER2-Overexpressing Breast Cancer: The Role of Estrogen Receptor Cross-Talk With HER2 Signaling).

    Now, it has long been conjectured that there is a not fully understood cross-talk between presence of complex cross-talk and interactions between the HER-2/tyrosine kinase pathway and the estrogen receptor (ER) pathway, with a further hypothesis based on this that HER-2-positive tumors may be significantly and clinically less responsive to certain endocrine treatments, and considerable research into tumor biology and molecular signalling pathways has been harnessed to resolve the precise dynamics involved, but until recently relevant clinical data have been conflicting, requiring the power and weight of a sophisticated evidence-based meta-analysis to finally be dispositive on the matter. This comes coutesy of the international multicenter team of Michele De Laurentis (Clin Cancer Res (2005): A Meta-Analysis on the Interaction between HER-2 Expression and Response to Endocrine Treatment in Advanced Breast Cancer) who pooled and analyzed 12 studies meeting the inclusion criteria; their principal finding was that HER-2-positive metastatic breast cancer is less responsive to any type of endocrine treatment including tamoxifen. This meta-analysis suggests that the apparently conflicting findings on this issue may be largely related to the lack of a standardized methodology for HER-2 analysis, to flawed experimental designs, and to the low statistical power of the single studies.

    It would appear that HER-2-overexpressing tumor cells might not only grow in estrogen-depleted conditions but also be resistant to selective ER modulators, especially tamoxifen, when compared with HER-2-negative cells; the precise causal chain although not fully articulated, has been recently clarified to depned critically on MPK3 (mitogen-activated protein kinase (MAPK) phosphatase 3), as MPK3 overexpression rendered ER-alpha--positive breast cancer cells resistant to tamoxifen's growth-inhibitory effects as well as enhanced tamoxifen agonist activity in endometrial cells (Cui et al., Cancer Res (2006): Elevated Expression of Mitogen-Activated Protein Kinase Phosphatase 3 in Breast Tumors: A Mechanism of Tamoxifen Resistance). See also Kurokawa et al., Cancer Res (2000): Inhibition of HER2/neu (erbB-2) and Mitogen-activated Protein Kinases Enhances Tamoxifen Action against HER2-overexpressing, Tamoxifen-resistant Breast Cancer Cells) who examined the mechanisms by which overexpression of HER2 confers antiestrogen resistance to breast tumor cells; and Shou et al., J Natl Cancer Inst (2005): Mechanisms of Tamoxifen Resistance: Increased Estrogen Receptor-HER2/neu Cross-Talk in ER/HER2–Positive Breast Cancer) who found that tamoxifen behaves as an estrogen agonist in breast cancer cells expressing high levels of HER2, resulting in de novo resistance, with the possibility that pretreatment with the EGFR TKI gefitinib (Iressa) blocked or eliminated this adverse EGFR and HER2 cross-talk with ER, eliminated tamoxifen's agonist effects, and restored its antitumor activity both in vitro and in vivo in MCF-7/HER2-18 cells; they noted that monotherapy with growth factor pathway inhibitors like gefitinib may therefore on its own have little or only modest benefits on ER+ HER2-overexpressing breast cancer, yielding a strong motivation for combining tamoxifen with gefitinib or other EGFR/HER2 pathway inhibitors to overcome de novo resistance in such tumors.

    There is also an association between Pak1 (a member of the p21-activated kinase (Pak) family, known to be involved in the progression of breast cancer) expression and resistance to tamoxifen (Holm et al., J Natl cancer Inst (2006): Association between Pak1 expression and subcellular localization and tamoxifen resistance in breast cancer patients); see also the associated commentary by Jordan (J Natl Cancer Inst (2006): Pak up Your Breast Tumor--and Grow!); from these findings, it would appear that premenopausal women with breast cancer who have overexpressing Pak1 tumors most likely will not respond to tamoxifen, and so may have to be offered alternative endocrine treatment such as the AIs or fulvestrant (Fasdlodex). Indeed, the more general clinical lesson may be that low-ER expressing tumors, PR-, and high levels of Her2/neu, EGFR, and phosphoproteins such as Pak1 are simply unlikely to respond to long-term adjuvant tamoxifen, and patients who have such tumors should probably not receive tamoxifen and be assigned to other non-tamoxifen endocrine interventions, and possibly also non-endocrine therapies such as CT (chemotherapy) and/or BT (biological therapy).

    The conclusions of the seminal meta-analysis of De Laurentis et al. (Clin Cancer Res (2005): A Meta-Analysis on the Interaction between HER-2 Expression and Response to Endocrine Treatment in Advanced Breast Cancer) are instructive to note specially here:

    (1) For metastatic breast cancer, the results of all published studies are consistent with an association between HER-2 overexpression and higher rates of endocrine therapy failure.
    (2) These results may have direct clinical implications: endocrine therapy alone should not be considered a first-choice treatment for patients with ER+/HER-2+ metastatic breast tumors.
    (3) The treatment strategy for such patients should favor either CT (chemotherapy) alone or in combination with trastuzumab (Herceptin).
    (4) Alternatively, the combination of ET (endocrine therapy) + trastuzumab (Herceptin) has the potential to overcome the (partial) resistance of such tumors to hormonal manipulations.
    (5) Or the exploitation of endocrine agents, such as the pure antiestrogen fulvestrant (Faslodex), whose antiproliferative action is not affected by HER-2 status, as demonstrated by in vitro findings.

    The study of De Placido et al. (Clin Cancer Res (2003): Twenty-year Results of the Naples GUN Randomized Trial: Predictive Factors of Adjuvant Tamoxifen Efficacy in Early Breast Cancer) examined factors potentially predictive of the efficacy of tamoxifen and found that their data support the hypothesis that tumors overexpressing HER2 might not benefit from adjuvant TAM; more specifically, in this study, HER2 status showed a marked influence on the efficacy of TAM and indeed adjuvant TAM is effective in reducing the hazard of death only among HER2-negative patients. Their conclusion therefore, was that "the most impressive result of our study is the finding that TAM was not beneficial, if not detrimental, for patients whose tumors overexpressed HER2".

    This is consonant with the earlier results of Stal and the members of the South Sweden Breast Cancer Group and the Southeast Sweden Breast Cancer Group (Ann Oncol (2000): ErbB2 status and the benefit from two or five years of adjuvant tamoxifen in postmenopausal early stage breast cancer [pdf]) who examined the relative risk of recurrence (RR) for five vs. two years of tamoxifen in relation to erbB2 (HER2) status for patients still disease-free two years after surgery, finding that whereas erbB2-negative patients showed significant benefit from prolonged treatment, no benefit was evident for erbB2(HER2)-positive patients. From these finding, the researchers concluded that "for early stage breast cancer patients treated with adjuvant tamoxifen, overexpression of erbB2 (HER2) is an independent marker of poor prognosis. The results suggest that (HER2) overexpression decreases the benefit from prolonged tamoxifen treatment".

    However, another team of the South Swedish and Southeast Swedish Breast Cancer Groups (Ryden et al., J Clin Oncol (2005): Tumor-Specific Expression of Vascular Endothelial Growth Factor Receptor 2 but Not Vascular Endothelial Growth Factor or Human Epidermal Growth Factor Receptor 2 Is Associated With Impaired Response to Adjuvant Tamoxifen in Premenopausal Breast Cancer) examined the association between adjuvant tamoxifen treatment in breast cancer and expression of VEGF-A, VEGFR2, and HER2, finding that tumor-specific expression of VEGFR2, but not VEGF-A or HER2, was associated with an impaired tamoxifen effect in hormone receptor–positive premenopausal breast cancer. It is difficult to see how to reconcile this apparently contradictory finding, but Breast Cancer Watch notes that this study, failing to find an influence of HER2-positivity on tamoxifen efficacy, appears insufficiently powered to have detected a difference given that it was restricted narrowly to just a 2 year course of tamoxifen despite the fact that true and full tamoxifen benefits have been shown to require a five year term to present unambiguously, while the earlier study included patients going out to five years as well as two years. In addition, studies typically do not test for nor control CYP2D6 phenotype in tamoxifen populations (tamoxifen's principal antitumor metabolite endoxifen is metabolized by the p450 CYP2D6 enzyme), known to striate a significant number of tamoxifen patients into a PM (Poor Metabolizer) responder group, nor to in tamoxifen users control for the use of SSRI antidepressants known to be potent CYP2D6 inhibitors, and either or both of these factors may distort and confound the findings. We will need further trials that control for these factors to be fully dispositive on the issue.

    Similarly, Arpino et al.(J Natl Cancer Inst (2005): Estrogen Receptor–Positive, Progesterone Receptor–Negative Breast Cancer: Association With Growth Factor Receptor Expression and Tamoxifen Resistance) claim that among tamoxifen-treated women with ER+/PR+ tumors, HER-2 status was not associated with worse DFS. However, this isolated finding is not cross-supported and the study suffers from severe methodological compromises:
    (1) this is a retrospective, not prospective study - and the overwhelming weight of other high methodology prospective studies systematically fail to confirm the Arpino findings - without randomization, so that the determination of treatment or no treatment was not on a randomized basis;
    (2) for most patients in the tamoxifen-treated subgroups, HER-2 status was actually not known, by the authors own admission (it was known only in a small minority of patients);
    (3) the researchers analyzed HER-2 overexpression by the nonstandard western blotting technique, rather than the standard IHC and FISH methods in clinical practice for HER-2 assessment;
    (4) the study drew from a local patient database maintained at the Breast Center at Baylor College of Medicine, but for a substantial portion of the patients reported in this database, follow-up was not obtained from primary tumor registries, and like any database study (aka, non-concurrent cohort study), there may be lack of uniformity of data recorded in the database, especially over a period of years of compilation (and potentially subjective associated interpretation);
    Given these methodological limitations, Breast Cancer Watch does not appraise the findings of the Arpinoi study to be compelling, and moreover they are against the overwhelming weight of the evidence both from prospective RCTs and meta-analyses.

    Also at odds with the Ryden and Arpino studies cited above is the highly dispositive and compelling recent study of Michael Dowsett at Royal Marsden and coworkers (Dowsett et al., Ann Oncol (2006): Benefit from adjuvant tamoxifen therapy in primary breast cancer patients according oestrogen receptor, progesterone receptor, EGF receptor and HER2 status) who retrieved the histopathological blocks of primary breast cancer patients who had been randomized to receive 2-years tamoxifen or no adjuvant therapy in two mature RCTs, finding that (1) benefit from tamoxifen was seen in both ER+ and ER-, but the benefit in the ER- context was largely restricted to the ER-/PR+ context, and (2) no patients positive for HER2 benefited significantly, confirming that HER2 positive tumors are strongly resistant to tamoxifen. Similarly the IMPACT multicenter double-blind RCT of Smith et al. (J Clin Oncol (2005): Neoadjuvant Treatment of Postmenopausal Breast Cancer With Anastrozole, Tamoxifen, or Both in Combination: The Immediate Preoperative Anastrozole, Tamoxifen, or Combined With Tamoxifen (IMPACT) Multicenter Double-Blind Randomized Trial) examined whether the clinical and/or biologic effects of neoadjuvant tamoxifen as compared with anastrozole, and with the combination of tamoxifen and anastrozole before surgery in postmenopausal women with estrogen receptor (ER) –positive, invasive, nonmetastatic breast cancer might predict for outcome in the landmark ATAC adjuvant therapy trial; it was founds that although there were no significant differences in objective response in the intent-to-treat population between patients receiving tamoxifen, anastrozole, or the combination, the objective response for patients with HER2-positive cancer was 58% for anastrozole compared with 22% for tamoxifen (see also Matthew Ellis' thoughtful commentary: J Clin Oncol (2005); Neoadjuvant Endocrine Therapy for Breast Cancer: More Questions Than Answers). Indeed, it appears that HER2 (and probably HER1 and HER3 as well, but not HER4) and PR status can identify time-dependent de novo tamoxifen resistance, in which the risk declines markedly after 3 years of tamoxifen treatment, and more parfticularly where PR- cases are also significantly more likely to relapse while on tamoxifen, and the combination of HER2+ and PR- especially so. (Tovey et al., Clin Cancer Res (2005): Can Molecular Markers Predict When to Implement Treatment with Aromatase Inhibitors in Invasive Breast Cancer?).

    A similar technique was used by Linke et al. (Clin Cancer Res (2006): A Multimarker Model to Predict Outcome in Tamoxifen-Treated Breast Cancer Patients) who examined nine molecular markers (including receptors) by semiquantitative immunohistochemistry and/or fluorescence in situ hybridization in a retrospective study of 324 stage I to III female breast cancer patients treated with tamoxifen, finding that among others, ER was statistically significant as independent factors for survival, but that the benefit of ER-positive status was moderated by ERBB2 (HER2) and PR status (among others).

    These findings confirm earlier research that expression of ErbB-1 and ErbB-2 (EGFR and HER2/neu) in breast cancer not only may cause tamoxifen resistance and infrequent response, but that ER+, ErbB-1+, and/or ErbB-2+ primary breast cancer do respond well to letrozole, suggesting that ErbB-1 and ErbB-2 signaling through ER has a ligand-dependency, and that potent estrogen deprivation therapy as afforded by the aromatase inhibitors can inhibit the growth-promoting effects of these receptor tyrosine kinases on ER+ breast cancer (Ellis et al., J Clin Oncol (2001): Letrozole Is More Effective Neoadjuvant Endocrine Therapy Than Tamoxifen for ErbB-1– and/or ErbB-2–Positive, Estrogen Receptor–Positive Primary Breast Cancer: Evidence From a Phase III Randomized Trial). Nonetheless, as demonstrated by Ellis more recently (Ellis et al., J Clin Oncol (2006): Estrogen-Independent Proliferation Is Present in Estrogen-Receptor HER2-Positive Primary Breast Cancer After Neoadjuvant Letrozole), although neoadjuvant letrozole (Femara) is clinically effective in ER+ HER2+ tumors, indicating sensitivity to short-term estrogen deprivation, continued proliferation despite ongoing letrozole or tamoxifen treatment in the majority of ER+ HER2+ samples (88%) appears to imply therapeutic resistance that may manifest later in the clinical course of the disease.

    [ It is instructive to note in this connection that researchers at the Beckman Research Institute of the City of Hope have explicitly built on these findings to demonstrate in a breast cancer xenograft model that (1) GSE (grapeseed extract) is a potent inhibitors of aromatase via its intrinsically high levels of aromatase-inhibiting procyanidin dimers, and that (2) GSE is potentially valuable in the prevention/treatment of endocrine-dependent breast cancer not only through the inhibition of aromatase activity but also via inhibition of aromatase expression (Kijima et al., Cancer Res (2006): Grape Seed Extract Is an Aromatase Inhibitor and a Suppressor of Aromatase Expression).]

    Breast Cancer Watch: On the Dispositive Nature of the De Laurentis Meta-Analysis
    Breast Cancer Watch, on the basis of critical appraisal of the De Laurentis meta-analysis, judges the meta-analysis to be of exceptionally high methodological quality, and of sufficient statistical power to support its conclusions, founded on the included 12 studies: Wright et al. (Br J Cancer (1992): Relationship between c-erbB-2 protein product expression and response to endocrine therapy in advanced breast cancer), Berns et al. (Gene (1995): Oncogene amplification and prognosis in breast cancer: Relationship with systemic treatment); Yamauchi et al. (J Clin Oncol (1997): Prediction of response to antiestrogen therapy in advanced breast cancer patients by pretreatment circulating levels of extracellular domain of the HER-2/c-neu protein); Fehm et al. (Oncology (1998): The prognostic significance of c-erbB-2 serum protein in metastatic breast cancer); Houston et al. (Br J Cancer (1999): Overexpression of c-erbB2 is an independent marker of resistance to endocrine therapy in advanced breast cancer); Jukkola et al. (Eur J Cancer (2001): c-erbB-2 Positivity is a factor for poor prognosis in breast cancer and poor response to hormonal or chemotherapy treatment in advanced disease); Lipton et al. (J Clin Oncol (2002): Elevated Serum HER-2/neu Level Predicts Decreased Response to Hormone Therapy in Metastatic Breast Cancer); Lipton et al. (J Clin Oncol (2003): Serum HER-2/neu and Response to the Aromatase Inhibitor Letrozole Versus Tamoxifen); Archer et al (Br J Cancer (1995): Expression of ras p21, p53 and c-erbB-2 in advanced breast cancer and response to first line hormonal therapy); Willsher et al. (Breast cancer Res Treat (1996): Prognostic significance of serum c-erbB-2 protein in breast cancer patients); Elledge et al. (Clin Cancer Res (1998): HER-2 expression and response to tamoxifen in estrogen receptor-positive breast cancer: a Southwest Oncology Group Study [pdf]); and Hayes et al. (Clin Cancer Res (2001): Circulating HER-2/erbB-2/c-neu (HER-2) Extracellular Domain as a Prognostic Factor in Patients with Metastatic Breast Cancer). Of these, Wright, Elledge, and Houston found in the negative, but Breast Cancer Watch notes that these studies examined whether HER-2 overexpression or amplification were predictive of response to tamoxifen, and this is an independent question from whether HER-2 expressing patients treated with tamoxifen exhibit worse prognosis, which is the focus of the other studies which collectively found in the affirmative. The meta-analysis clearly upholds the prognostic conclusion that (1) HER-2-positive metastatic breast cancer is less responsive to any type of endocrine treatment, and that (2) HER-2 overexpression is associated with higher rates of endocrine therapy failure.

    Breast Cancer Watch finds that the results of the De Laurentis meta-anlysis are cross-confirmed by the recently reported findings of Michael Dowsett at Royal Marsden and coworkers (Dowsett et al., Ann Oncol (2006): Benefit from adjuvant tamoxifen therapy in primary breast cancer patients according oestrogen receptor, progesterone receptor, EGF receptor and HER2 status) who demonstrated (1) that any benefit of tamoxifen in the ER- context was largely restricted to the ER-/PR+ context, and (2) that no patients positive for HER2 benefited significantly, and by the findings of the IMPACT multicenter double-blind RCT of Smith et al. (J Clin Oncol (2005): Neoadjuvant Treatment of Postmenopausal Breast Cancer With Anastrozole, Tamoxifen, or Both in Combination: The Immediate Preoperative Anastrozole, Tamoxifen, or Combined With Tamoxifen (IMPACT) Multicenter Double-Blind Randomized Trial) which demonstrated that the objective response for patients with HER2-positive cancer was 58% for anastrozole compared with 22% for tamoxifen. In this latter connection, Dowsett et al. (Dowsett et al., Breast Cancer Res Treat (2005): Biological characteristics of the pure antiestrogen fulvestrant: overcoming endocrine resistance) note that preclinical studies indicate that combining the pure antiestrogen fulvestrant (faslodex) with growth factor targeted agents, such as the EGFR TKI gefitinib (Iressa) or the anti-human HER2 monoclonal antibody trastuzumab (Herceptin), may result in greater anti-tumor activity than either agent alone.



  • [updated] ER+ / PR- / HER-2+ Disease

    The balance of the evidence suggest that patients with estrogen receptor positive (ER+) / progesterone receptor negative (PR-), and/or HER-2 overexpressing (HER-2+) breast carcinomas appear to derive lower benefit from endocrine treatment (see the recent exploration of this by Riccardo Pozone at the Institute for Cancer Research and Treatment (IRCC) and his coresearchers: Ponzone et al., Ann Oncol (2006): Clinical outcome of adjuvant endocrine treatment according to PR and HER-2 status in early breast cancer). The IRCC team examined retrospectively data from 972 breast cancer patients who received adjuvant endocrine therapy [tamoxifen (725), tamoxifen + LHRH/GnRH analogs (127) and aromatase inhibitors (120)] finding that:
    • (1) ER+/PR– tumours were characterised by larger size, higher tumour grade, higher Ki-67 expression, and lower mean ER, and HER-2 expression compared to versus ER+/PR+ tumors.
    • in addition to nodal status and tumor diameter, both lack of PR expression (PR-), and HER-2 overexpression (HER-2+) were associated with shorter disease-free survival (DFS).
    and hence concluding from this that PR- and HER-2+ (lack of PR expression and HER-2 overexpression) are both associated with aggressive tumor features, with PR status being stronger prognostically on the risk of recurrence in endocrine-treated breast cancer patients.

    See also the comments by Karen Gelmon, Head of the British Columbia Cancer Agency (Oncology Consultations, V. 3, No. 12 (2006): Treatment of Estrogen Receptor–Positive, HER2-Overexpressing Metastatic Breast Cancer) who noted that "we know that in hormonesensitive tumors, the most effective treatment is often hormonal treatment. Estrogen receptor–positive tumors appear to respond less well to chemotherapy, and we know that ER+/PgR– tumors may respond less well to hormonal agents, and, in particular, to tamoxifen". And in the same interview, Joanne Mortimer, Deputy Director for Clinical Affairs at the Moores UCSD Cancer Center observed that "ER+/PgR– cancers are a unique population that we need to understand better. The Southwest Oncology Group reported the importance of the PgR in predicting response to tamoxifen in advanced breast cancer [as found by A Ring & M Dowsett, Clin Breast cancer (2003): Human epidermal growth factor receptor-2 and hormonal therapies: clinical implications] . Progesterone positivity is more predictive of response to tamoxifen than the ER status" and that "the ATAC data
    did suggest that AIs were superior in this patient subset    ".

    Thus increased HER2 expression appears to be causally associated with resistance to endocrine therapy, particularly tamoxifen therapy, for both patients with both EBC (early-stage breast cancer) and MBC (metastatic breast cancer) (see Michele De Laurentis (Clin Cancer Res (2005): A Meta-Analysis on the Interaction between HER-2 Expression and Response to Endocrine Treatment in Advanced Breast Cancer), A Ring & M Dowsett, Clin Breast cancer (2003): Human epidermal growth factor receptor-2 and hormonal therapies: clinical implications, and M Dowsett, Endocr Relat Cancer (2001): Overexpression of HER-2 as a resistance mechanism to hormonal therapy for breast cancer [pdf]).

    In addition, for the subset of patients with ER+ and HER2+ tumors, letrozole (Femara) is more effective than tamoxifen, and is associated with greater antiproliferative activity, as determined by Ki67 inhibition: as found by Ellis et al., Cancer Res (2003): Letrozole Inhibits Tumor Proliferation More Effectively than Tamoxifen Independent of HER1/2 Expression Status, who in addition note that from their examination of the tamoxifen-treated ER+, HER1/2+-treated cases as a group, tamoxifen can be seen not to be an efficient antiproliferative agent overall although tamoxifen was not completely inactive), with letrozole inducing profound down-regulation of the progesterone receptor (PgR) compared to the the mixed agonist/antagonist effect of tamoxifen on PgR. In this connection, note that the IMPACT trial (Dowsett et al., Clin Cancer Res (2005): Short-Term Changes in Ki-67 during Neoadjuvant Treatment of Primary Breast Cancer with Anastrozole or Tamoxifen Alone or Combined Correlate with Recurrence-Free Survival) determined that more patients are biologically responsive to hormonal agents, by virtue of confimed changes in the Ki-67 growth index, than are recorded as clinically responsive, suggesting that estrogen does not seem to be an important cell survival agent for human breast cancer cells, given the observation that in the IMPACT trial the tumors are shrinking, but without any increase in apoptosis. (See also Ellis et al., J Clin Oncol (2006): Estrogen-Independent Proliferation Is Present in Estrogen-Receptor HER2-Positive Primary Breast Cancer After Neoadjuvant Letrozole and Dowsett et al. J Clin Oncol (2005): Biomarker Changes During Neoadjuvant Anastrozole, Tamoxifen, or the Combination: Influence of Hormonal Status and HER-2 in Breast Cancer - A Study from the IMPACT Trialists which also found significantly greater suppression of Ki67 in the anastrozole-treated group than in the tamoxifen- or combination-treated groups, in keeping with comparable observations in the ATAC trial). Finally, Bottini et al. (J Clin Oncol (2006): Randomized Phase II Trial of Letrozole and Letrozole Plus Low-Dose Metronomic Oral Cyclophosphamide As Primary Systemic Treatment in Elderly Breast Cancer Patients) investigated in their open-labeled, randomized phase II trial the activity of letrozole with or without oral metronomic cyclophophamide (50 mg/daily for 6 months) as primary systemic treatment (PST) in elderly breast cancer patients, finding that there was a significantly greater suppression of Ki67 and VEGF-A expression in the chemoendocrine metronomic group (letrozole/cyclophosphamide-treated) than in the letrozole-only group, leading to lower Ki67 and VEGF expression at post-treatment residual histology.

    Just reported are the results of the TAnDEM study (reported by Bella Kaufman of the Chaim Sheba Medical Center, and international coresearchers: Kaufman et al., Ann Oncol, V. 17, Suppl 9 (2006): Trastuzumab plus anastrozole prolongs progression-free survival in postmenopausal women with her2-positive, hormone-dependent metastatic breast cancer (MBC) [late-breaking abstract, pdf]), a randomized phase III trial begun in 2001 and evaluating anastrozole (Arimidex) + trastuzumab (Herceptin) versus anastrozole alone as first-line or second-line endocrine therapy in 208 postmenopausal women with hormone-repsonsive (ER+ and/or PR+) and HER2-overexpressing MBC. TAnDEM is the first randomized study to show that the specific subset of ‘co-positive’ patients (HER-2+ and hormone receptor positive (ER+ and/or PR+) is actually a higher-risk, more aggressive disease group. With regard to this special co-positive group, the TAnDEM study determined that patients in the anastrozole + trastuzumab arm experienced both significant improvements in PFS, at a level of doubling PFS, and clinical benefit rate (CBR), compared to patients on anastrozole monotherapy, with overall tumor response rate (ORR) being significantly higher with anastrozole + trastuzumab compared to anastrozole alone; in addition, iIn patients receiving anastrozole + trastuzumab, time to disease progression (TTP) was doubled and median overall survival (OS) prolonged by 4.6 months compared to patients receiving anastrozole montherapy, and prolonged survival was achieved despite crossover of 35%) patients to anastrozole + trastuzumab. The bioendocrine therapy (anastrozole + trastuzumab) was manageable, with no new or unexpected adverse events. Thus bioendocrine therapy with anastrozole + trastuzumab as first-line treatment of women with HER-2+ hormone-responsive MBC resulted in significant improvements in PFS (progression-free survival), CBR (clinical benefit rate), ORR (overall (tumor) response rate), TTP (time-to-progression), and OS (overall survival).

    But knowing as we do now from the above studies that AIs will exhibit superior clinical efficacy over tamoxifen in HER-2+ context with ER+ tumors, more so if PR-, is not the whole story: but whether HER2-amplified cancers were treated with tamoxifen or an AI, it was nonetheless the case that detectable proliferation continued (see Ellis et al., J Clin Oncol (2006): Estrogen-Independent Proliferation Is Present in Estrogen-Receptor HER2-Positive Primary Breast Cancer After Neoadjuvant Letrozole) and as Ellis and colleagues observed, this suggests that suppression of estrogen signaling alone might be insufficient in cells, as here, with active growth factor signaling pathways, further suggesting a role for combination regimens of trastuzumab (Herceptin) + bevacizumab (Avastin) (or + lapatinib (Tykerb)) in order to block and potentially shutdown both the EGFR (HER-2) pathway and the VEGF pathway, given that typically about 75% of patients with HER-2 amplification also have VEGF upregulation (and who typically exhibit quite poor outcomes under chemotherapy alone). In this connection, the research of Jeanne du Manoir at the Sunnybrook and Women's College Health Sciences Centre and her coresearchers (du Manoir et al., Clin Cancer Res (2006): Strategies for Delaying or Treating In vivo Acquired Resistance to Trastuzumab in Human Breast Cancer Xenografts) examined solutions to acquired trastuzumab resistance (noting that elevated levels of VEGF are detectable in trastuzumab-resistant tumors), finding that to (1) delay resistance, a daily oral low-dose metronomic cyclophosphamide (Cytoxan) regimen was found to be particularly effective, while to (2) treat acquired trastuzumab resistance once it has occurred, both the anti–vascular endothelial growth factor (anti-VEGF) antibody bevacizumab (Avastin) as well as the anti–epidermal growth factor receptor antibody cetuximab (Erbitux), were effective.
 

Copyright © 2006. Constantine Kaniklidis