Correspondence *Division of Medical Oncology, Hematology, and Radiation Oncology at the Vall d'Hebron University Hospital, Passeig de la Vall d'Hebron 119–129, 08035 Barcelona, Spain

Email jbaselga@vhebron.net

Introduction

Each year more than 210,000 and 360,000 new cases of breast cancer are diagnosed in the US and Europe, respectively.^{1, 2} More than two-thirds of these patients have hormone receptor (HR)-bearing tumors³—a subgroup that benefits from endocrine therapy. Several hormonal strategies with different mechanisms of action are currently available for the treatment of HR-expressing breast tumors.⁴ Selective estrogen receptor (ER) modulators, exemplified by tamoxifen, bind to ER and partially block its function. Other strategies, such as aromatase inhibitors (AIs) luteinizing-hormone-releasing hormone agonists and ovarian ablation exert their anti-hormonal activity by decreasing ligand levels. Finally, a third class of agents, represented by fulvestrant, induce receptor degradation.

Tamoxifen has been the most widely used adjuvant hormone therapy for the past two decades, achieving a 39% reduction in disease recurrence and a 31% reduction in mortality in ER⁺ early-stage breast cancer.⁵ The recent introduction of third-generation AIs in the adjuvant setting for postmenopausal patients, either initially, or sequentially after tamoxifen, has produced better outcomes than the previous standard treatment of 5 years of tamoxifen.^{6, 8, 9} In addition, for postmenopausal patients with ER⁺ breast cancer, AIs have shown superior efficacy in the neoadjuvant setting^{10, 11, 12} and in advanced disease^{13, 14, 15, 16, 17} compared with tamoxifen. The role of fulvestrant is still being explored, however, it is currently approved for the treatment of HR⁺ metastatic breast cancer in postmenopausal women who have experienced disease progression following anti-estrogen therapy.^{18, 19, 20}

Crosstalk between er and HER2 pathways

There is important crosstalk between ER and other receptor families, including but not restricted to the HER family,⁴ which may have important implications for the biology of breast cancer and response to therapy with hormonal agents. The biological effects of estrogens on breast cancer cells are mediated through two nuclear receptors known as ER and ER. The binding of estrogen to ER induces phosphorylation of the receptor, triggering receptor dimerization and recruitment of coregulatory proteins, and facilitating the binding of the receptor to promoter regions of DNA.⁵¹ Once activated, ERs modulate the transcription of genes that contain an estrogen response element (ERE) in their promoters (referred to as the classical genomic signaling pathway).⁵² The ER complex can also regulate gene transcription by coactivating other transcription factors like c-fos/c-jun, which bind specific nonestrogen response-element promoters of AP1 responsive genes (referred to as the nonclassical genomic signaling pathway).⁵³ Estrogen genomic signaling pathways induce the expression of genes that encode proteins important for tumor growth, such as the insulin-like growth factor I receptor (IGF-IR), cyclin D1, collagenase, insulin growth factor II (IGF-II), and VEGF.^{53, 54, 55} Genes downregulated by estrogens include the EGFR⁵⁶ and HER2;⁵⁷ many of the genes downregulated by estrogen signaling are transcriptional repressors and/or members of the transforming growth factor (TGF)- superfamily.⁵⁸

The transcriptional effects of activated ER are modulated by coregulatory proteins that function as either coactivators or corepressors of the ER complex.^{59, 60, 61} These coregulatory proteins might be tissue specific, which could explain the different effects of ER in different tissues.⁶² For example, AIB1 is an ER coactivator that is overexpressed in breast cancer cells compared with normal epithelial cells and is amplified in a small proportion of breast tumors.⁶³ Patients with HR⁺ breast cancer and high levels of AIB1 expression experience a substantially greater number of recurrences following tamoxifen treatment than do those with HR⁺ tumors and lower levels of AIB1 expression.⁶⁴

ER can also regulate cellular functions through nongenomic mechanisms known as membrane nongenomic estrogen signaling.⁴ This is where part of the crosstalk between ER and growth factor receptors seems to occur. A small pool of ER is located in the cytoplasm and non-nuclear subcellular fractions, including mitochondria and plasma membrane. This pool of ER functionally resembles growth factor ligands. Plasma-membrane-associated ER increases the levels of second messengers such as cyclic AMP within minutes,⁶⁵ and activates various tyrosine kinase receptors such as IGF-IR, EGFR, and HER2.^{66, 67, 68} ER can also associate with cellular kinases and adaptor molecules such as c-Src⁶⁹, Src homology and collagen homology protein^{70, 71} and PI3K.⁶⁷ Finally, ER-induced signaling pathways might induce EGFR ligands such as TGF⁷² and cause downregulation of EGFR⁵⁶ and HER2.⁵⁷

The crosstalk between the ER and the growth factor signaling pathway is bidirectional. A variety of kinases including MAPKs and Akt phosphorylate specific sites of the ER, leading to ligand-independent ER activation.²⁴ In addition, phosphorylation of ER coregulatory proteins by growth factor kinases regulates the ER signaling pathway. For example, phosphorylation of AIB1 by MAPK increases ER-dependent transcription,⁷³ and overexpression of AIB1 converts tamoxifen-bound ER into an estrogen agonist rather than an antagonist in MCF7 breast cancer cell lines transfected with HER2 (MCF7/HER2⁺).²⁵ This finding suggests that the crosstalk between the ER and growth factor signaling pathways has an important role in tamoxifen resistance. The EGFR TKI gefitinib (Iressa^®, AstraZeneca, London, UK) and anti-HER2 antibodies eliminate this ER/HER2 crosstalk and restore the antitumor effect of tamoxifen in MCF7 cells that express HER2.^{25, 74} In addition, increased crosstalk between ER and HER2 may contribute to secondary resistance to tamoxifen in 10–15% of HR⁺/HER2^- breast tumors.⁷⁵

Estrogen-deprivation therapies such as AIs abrogate genomic and non-genomic activities of ER and, therefore, could eliminate the crosstalk generated in the presence of estrogen or tamoxifen in HER2⁺ breast cancer.^{76, 77} Data from preclinical models, however, suggest that resistance to estrogen-deprivation therapies in HER2⁺ breast tumors might occur through at least two mechanisms: adaptation to an estrogen hypersensitive phenotype and/or by ligand-independent recruitment of coactivator complexes to estrogen-responsive promoters.^{4, 78}

Thus, in HR⁺/HER2⁺ breast tumors a vicious cycle is established between ER genomic and non-genomic mechanisms of action and the growth factor receptor network leading to enhanced cell proliferation and cell survival (Figure 1). Since these two receptors systems have the capacity to activate each other, a rational treatment strategy would be the combined targeting of both receptors.

Figure 1 ER/GF signaling pathways and molecularly targeted agents for overcoming endocrine resistance.

Estrogen activates nuclear ER (genomic pathway) and ER in or near the membrane (non-genomic pathway). Membrane associated ER binds to GF signaling components such as PI3K. E2 then activates GF signaling, activating key molecules such as Akt or RAS, and downstream molecules such as mTOR, Raf, MEK and MAPK, which promote cell proliferation and survival. In addition, signal-transduction molecules can phosphorylate and activate ER and its co-regulators to enhance the nuclear genomic ER-mediated response. Abbreviations: AI, aromatase inhibitors; Akt, protein kinase B; EGF, epidermal growth factor; EGFR, epidermal growth factor receptor; ER, estrogen receptor; GF, growth factor; HER2, human epidermal growth factor receptor 2; MAPK mitogen-activated protein kinase; MEK, MAPK kinase; MoAb, monoclonal antibodies; mTOR, mammalian target of rapamycin; PI3K, phosphatidylinositol 3-kinase; TKI, tyrosine kinase inhibitors.

Full figure and legend (118K)Figures & Tables indexDownload Power Point slide (323K)

Endocrine therapy in HER2⁺ breast cancer

An initial observation in breast-cancer cell lines transfected with HER2 is that HER2 confers resistance to tamoxifen.²⁸ This observation has been subsequently confirmed by other groups,^{25, 29, 75, 79} and retrospective analysis of clinical studies have shown a poorer outcome for patients treated with tamoxifen who express high levels of HER2 than for HER2-negative patients.^{80, 81, 82, 83} In one of these studies, the primary tumors of 241 patients who were treated at first relapse with endocrine therapy were assessed by immunohistochemistry for overexpression of HER2. In patients with HR⁺ primary tumors treated with tamoxifen (n = 170), HER2 overexpression was associated with a significantly shorter time-to-tumor progression (TTP; 5.5 months versus 11.2 months; P <0.001).⁸² There was some initial enthusiasm that HER2⁺ tumors would be more sensitive to AIs than to tamoxifen.⁷⁶ Careful analysis of published data, however, suggests that even with AIs, patients with HER2⁺ disease have a poor response.^{83, 84, 85, 86, 87, 88} For example, a phase III trial of 916 patients¹⁷ with advanced breast tumors and an unknown HER2 status treated with first-line endocrine therapy showed superiority of letrozole over tamoxifen in terms of TTP (9.4 months versus 6.0 months; P <0.0001) and overall response rate (ORR; 32% versus 21%; P = 0.0002). Nevertheless, subsequent analysis of HER2 status⁸³ revealed that in HER2⁺ patients there was no significant difference between those treated with letrozole and those treated with tamoxifen in terms of ORR (17% versus 13%; P = 0.45) or clinical benefit⁸⁹ (33% versus 26%; P = 0.31), although a strong trend towards a longer duration of response with letrozole was observed (6.1 months versus 3.3 months; P = 0.0596).⁸³ These poor results in the HER2⁺ subpopulation contrast with the median TTP observed in the HER2-negative subgroup (12.2 months in letrozole-treated patients and 8.5 months in tamoxifen-treated patients). In the second-line setting, 711 women with elevated serum concentrations of the extracellular domain of HER2 who received megestrol acetate, fadrazole, or letrozole had a shorter TTP (3.0 months versus 6.0 months; P <0.0001) and lower ORR (7% versus 20%; P <0.0001) than did women who did not have elevated levels of the extracellular domain of HER2 in serum.⁸⁴ Finally, early preliminary reports from the Breast International Group 1-98 Study (BIG 1-98) and the Arimidex or Tamoxifen Alone or in Combination (ATAC) trial, which compared tamoxifen with either letrozole or anastrozole, revealed that HER2⁺ status is associated with a significantly higher relapse rate, regardless of whether an AI or tamoxifen is administered.^{86, 88}

A small retrospective neoadjuvant study suggested that AIs obtained higher response rates than tamoxifen in HR⁺/HER2⁺ postmenopausal breast cancer.⁷⁶ The results of two subsequent studies, one of them by the group of investigators who initially reported improved benefit with AIs, indicate that the clinical efficacy of AIs in this context may be short-lived.^{85, 87} In the first study, known as the IMPACT trial,¹¹ treatment-associated changes in the nuclear proliferation marker Ki-67 were measured in tumor biopsy specimens taken at baseline and after 2 weeks and 12 weeks of treatment with anastrozole and tamoxifen.⁸⁵ The mean suppression of Ki-67 by 2 weeks of hormonal treatment was greater in the anastrozole arm than in the tamoxifen arm in HR⁺/HER2⁺ tumors, but by 12 weeks the level of suppression in the two arms was similar. This increase in Ki-67 after 12 weeks of treatment with anastrozole may be indicative of an early mechanism of escape from the antiproliferative effects of the AI in the HER2⁺ subpopulation. The second study supporting this hypothesis used fluorescence in situ hybridization (FISH) to detect HER2 gene expression in tissue samples from 305 postmenopausal women with stage II/III ER⁺ breast cancer treated in two independent neoadjuvant endocrine-therapy trials.⁸⁷ Response to letrozole, as assessed by clinical measurement, was not impaired by HER2-FISH-positive status, indicating sensitivity to short-term estrogen deprivation. However, there was significantly less Ki-67 suppression in HER2⁺ tumors following letrozole administration than in HER2-negative tumors. These findings indicate that the efficacy of estrogen-deprivation therapies might be compromised in the short-term in HR⁺/HER2⁺ breast cancers, suggesting that these tumors might display early resistance to single-agent hormonal therapy.

In summary, a median TTP of 5.6– 11.2 months and an ORR of 17–32% were achieved in patients with advanced breast cancer who were not stratified according to HER2 status and were treated with first-line endocrine therapy (Table 1).^{14, 15, 16} When the HER2⁺ subgroup are retrospectively analyzed, the median TTP and ORR for this group decreased to 3.3–6.1 months and 13–17%, respectively.⁸³ In the second-line advanced-disease setting and in those with an unknown HER2-status, endocrine treatment achieved median TTP and ORR of 4.8–5.6 months and 13–15%, respectively.^{90, 91, 92} A further HER2⁺ subgroup analysis showed that median TTP and ORR decreased to 3.0 months and 7%, respectively.⁸⁴ Taken together, these studies strongly suggest that HR⁺/HER2⁺ breast cancer may be less responsive to tamoxifen and estrogen-deprivation therapies with AIs than cancer negative for HR and HER2 expression, which could be an indication than HER2 overexpression and/or amplification results in a dominant phenotype in ER+/HER2⁺ tumors.

Table 1 Relevant trials of endocrine therapy for hormone-receptor-positive advanced breast cancer.

Full tableFigures & Tables indexDownload Power Point slide (270K)

Combined anti-HER2 and hormonal therapy

HER2-targeted strategies in preclinical models have shown a therapeutic potential to subvert endocrine resistance in HR⁺/HER2⁺ breast cancer. Although trastuzumab and chemotherapy has been the standard of care for patients with advanced HER2⁺ breast cancer, an important question is whether the subgroup of patients with HER2⁺ and HR⁺ breast tumors might also benefit from a combined anti-HER2 and hormone therapy approach. If combined hormonal and anti-HER2 therapy were efficacious, this therapy could become an option for patients with HR⁺/HER2⁺ disease. Two prospective clinical trials have been completed that address this issue. In an initial single-arm phase II study,⁹³ 33 postmenopausal patients with HR⁺ and HER2⁺ advanced breast cancer were treated with trastuzumab plus letrozole until disease progression or unacceptable toxicity. Most patients (55%) had received prior adjuvant chemotherapy and tamoxifen, and 48% had developed a recurrence while taking tamoxifen. In addition, the majority of patients had both soft tissue and visceral disease. The ORR with the combination was 26%, and the median TTP was 5.8 months. The combination was well-tolerated without unexpected toxicities. As is often the case with these types of single arm studies, the results were difficult to interpret in the absence of a control arm.

The question of combined therapy has been addressed by a multicenter phase II/III study (TrAstuzumab in Dual HER2 ER-Positive Metastatic breast cancer [TAnDEM trial]).^{20, 94} In this study, the benefit of adding trastuzumab to an AI was evaluated. A total of 208 postmenopausal patients with ER⁺ and/or progesterone receptor⁺ and HER2⁺ advanced breast cancer were randomized to first-line treatment with anastrozole plus trastuzumab (n = 103) or to anastrozole monotherapy (n = 104). The primary end point was progression-free survival (PFS). Approximately, 60% of patients had received prior endocrine therapy, and 45% and 30% of patients had lung and liver metastatic disease, respectively. The median PFS was 4.8 months for the combination group versus 2.4 months for anastrozole monotherapy (P = 0.0016). In the 147 evaluable patients with measurable disease, the ORR was significantly higher in the combination group than in the anastrozole group (20.3% versus 6.8%; P = 0.018). The clinical benefit rate, defined as the rate of complete response, partial response and stable disease 6 months of duration, was also significantly higher in the combination arm than in the monotherapy arm (42.7% versus 27.9%; P = 0.026). In terms of survival, the median overall survival (OS) was prolonged by 4.6 months in patients receiving trastuzumab and anastrazole compared with patients receiving anastrozole (28.5 months versus 23.9 months; P = 0.325). This improvement in survival was observed despite crossover of 73 (70%) patients from the anastrozole arm to the combination arm at disease progression. Treatment with the combination was manageable and well-tolerated. The incidences of the most frequent adverse events were higher in the combination arm than in the monotherapy arm: fatigue was reported in 21% of the combination group compared with 10% of the monotherapy group, while vomiting and diarrhea, respectively, were noted in 21% and 20% of the combination group and 5% and 8% of the monotherapy group. Congestive heart failure was reported in 3% of the patients in the combination arm.

The efficacy results of the TAnDEM study have demonstrated a significant improvement in PFS, ORR, and a trend towards prolonged OS with the combined treatment strategy compared with hormonal treatment alone. Although the results of the study clearly favor the combination, the low median PFS and ORR obtained in both arms is worse than would have been achieved if the same population of patients had been treated with chemotherapy and trastuzumab. Nonetheless, several additional clinical trials are ongoing and will evaluate the combination of trastuzumab with fulvestrant and other AIs.

It is unclear whether the results observed with trastuzumab and anastrozole will also be observed with other anti-HER2 agents and, in particular, with TKIs. TKIs might be better blockers of HER2 signaling than monoclonal antibodies and they might also prevent signaling of HER1; it is possible TKIs could more efficiently deprive cells of HER1 and HER2 signaling.⁹⁵ This question is being partially addressed in a phase III clinical trial (EGF30008) of lapatinib and letrozole versus letrozole alone, which has recently completed accrual (n = 1,280) of patients with tamoxifen-resistant advanced breast cancer. Although tumor expression of HER1 or HER2 is not an eligibility criterion for this study, the sheer size of the study means that a considerable number of patients with HER2 tumors have been included.

New strategies in the treatment of HR⁺/HER2⁺ breast cancer

Regardless of the outcomes of these trials, there is strong preclinical evidence in support of improved anti-HER2 combinations with hormonal therapy. For example, preclinical data indicate that blocking HER2 signaling with a three-drug anti-HER2 (trastuzumab and pertuzumab) and EGFR (gefitinib) targeted therapy combination is more effective than trastuzumab and tamoxifen or two-drug combinations in MCF7/HER2⁺ breast cancer xenografts.⁹⁵ In addition, treatment with endocrine therapy plus gefitinib, trastuzumab and pertuzumab induces complete and durable tumor regressions.⁹⁵ Thus, triple-targeted therapy with ER-targeted therapy such as tamoxifen or estrogen deprivation in MCF7/HER2⁺ tumors is highly efficacious, suggesting that both ER and HER2 cooperate to drive tumor cell survival. It is also of importance to realize that even with highly optimized 'triple' anti-HER2 therapy there is a need to proceed with hormonal blockade to achieve optimum results. These findings are supported by an observation that one of the mechanisms by which tumors acquire resistance to the EGFR and HER2 inhibitor lapatinib is via increased ER signaling.⁹⁶ Consequently, ER becomes a key regulator of cell survival and antiapoptosis in codependence with HER2 in HR⁺/HER2⁺ breast cancer cells.⁹⁶ For example, upfront administration of endocrine treatment in combination with lapatinib more-effectively induces apoptosis than does inhibition of either pathway alone and also prevents the development of anti-HER2 resistance.⁹⁶ Thus, total HER2 and HR blockade by a cocktail of agents may be required to satisfactorily intervene in the HR/HER2 crosstalk, and this is an approach that deserves to be studied in the clinic.

Another potential treatment strategy by which resistance to anti-ER–HER2 treatment might be overcome is via inhibition of various downstream intracellular kinases that override control by upstream membrane receptors such as HER2.^{97, 98, 99} For example, breast-cancer cell lines with activated PI3K/Akt/mTOR signaling are resistant to tamoxifen.^{100, 101} These tumors might be especially sensitive to mTOR inhibitors such as temsirolimus (CCI-779)¹⁰² and everolimus (RAD001).¹⁰³ Following this rationale, a randomized phase II study compared oral temsirolimus and letrozole with letrozole alone in 104 patients with HER2-unknown metastatic breast cancer.¹⁰⁴ Owing to the toxicity of the high-dose schedule, which resulted in dose delays and/or reductions or discontinuations, the protocol was amended to low-dose schedules. After the amendment, early data from 92 patients suggested that PFS could be longer for the combination arms than for the letrozole-alone arm, and, therefore, a large phase III trial was initiated. This study, however, was terminated before accrual was completed because of a lack of efficacy of the combination. The unexpected result raises the issue that phase I studies evaluating the appropriate dose of signal-transduction inhibitors should aim to identify the biologically effective dose by use of pharmacodynamic end points rather than focusing on the maximum tolerated dose. Following this premise, the toxicity profile and the molecular pharmacodynamic findings from a phase I study of RAD001 at a dose of 10 mg daily was used for further phase II–III development.¹⁰³ Interestingly, a lack of efficacy of mTOR antagonists was suggested from pharmacodynamic analyses because these agents caused a negative feedback activation of upstream signaling pathways, which induced Akt phosphorylation, protein kinase activity, and downstream signaling.¹⁰⁵ Thus, upstream inhibition of mTOR with novel PI3K inhibitors in combination with or without mTOR antagonists might be a treatment strategy worth exploring in HR⁺ breast cancer. Studies investigating treatment regimens that combine signal transduction inhibitors with hormonal treatment in HR⁺/HER2⁺ tumors have recently started, and over the next few years we will learn whether such novel approaches will produce further significant gains in treatment efficacy for HR⁺ breast cancer.

Combined anti-HER2 targeted therapy and chemotherapy

A relevant question is whether the poor response to combined hormonal and anti-HER2 therapy in the HR⁺/HER2⁺ patient population is better than could be achieved by treatment with trastuzumab alone or trastuzumab combined with chemotherapy. There is no data from clinical trials comparing trastuzumab and hormonal therapy with trastuzumab alone. Trastuzumab monotherapy is active and produces durable objective responses in women with HER2⁺ breast cancer who have not previously received chemotherapy for their metastatic disease.¹⁰⁶ In a large phase II clinical study,¹⁰⁷ 114 women were randomized to receive first-line treatment with trastuzumab 4 mg/kg loading dose, followed by 2 mg/kg weekly, or a higher 8 mg/kg loading dose, followed by 4 mg/kg weekly. The ORR was 34%, and the median TTP was 4.9 months in the subgroup of tumors with HER2 gene amplification as documented by FISH analysis (Table 2). These findings are not dissimilar to the ones obtained in the TAnDEM trial.

Table 2 Relevant clinical trials of anti-HER2-targeted therapy for HER2-positive advanced breast cancer.

Full tableFigures & Tables indexDownload Power Point slide (262K)

The combination of trastuzumab and chemotherapy offered a significant survival advantage when compared with chemotherapy alone for patients with HER2⁺ breast cancer, regardless of HR status.³⁸ In a pivotal phase III trial, 469 patients with previously untreated, HER2⁺ metastatic breast cancer were randomized to receive first-line chemotherapy (doxorubicin 60 mg/m² or epirubicin 75 mg/m² and cyclophosphamide 600 mg/m² or paclitaxel 175 mg/m²) either alone or in combination with the antibody. The primary end point of this study was TTP. The addition of trastuzumab to chemotherapy was associated with a longer median TTP (7.4 months versus 4.6 months; P <0.001), a higher ORR (50% versus 32%; P <0.001), an increase in median OS (25.1 months versus 20.3 months; P = 0.046), and a 20% reduction in the risk of death. In a similar randomized trial, 186 patients received docetaxel 100 mg/m² every 3 weeks, with or without trastuzumab in the first-line advanced-disease setting.³⁹ In all subgroups analyzed, including HR status, the combined treatment was significantly superior to chemotherapy alone in terms of ORR (61% versus 34%; P = 0.0002), median OS (31.2 months versus 22.7 months; P = 0.0325), and median TTP (11.7 months versus 6.1 months; P = 0.0001). The addition of trastuzumab did not substantially increase the toxicity profile of docetaxel. Finally, other phase II trials have shown the efficacy and safety of trastuzumab in combination with other cytotoxic agents used in daily practice in the management of breast cancer.^{108, 109}

In summary, although a considerable increase in toxicity is expected, the addition of chemotherapy to anti-HER2 therapy results in ORRs in the range 38–61%, and TTP of 6.9–10.7 months.^{38, 39} These results are far better than those obtained from upfront dual targeting with concurrent endocrine therapy and anti-HER2 therapy. Thus, in daily practice, the majority of patients with HR⁺/HER2⁺ advanced breast cancer should be offered initial treatment with cytotoxic chemotherapy in combination with anti-HER2 targeted therapy. Exceptions to this rule should include those patients who decline chemotherapy, those with comorbid conditions that preclude the administration of chemotherapy and even perhaps those rare patients with slow-growing tumors. Finally, patients who have been treated in the adjuvant setting with trastuzumab and have relapsed within a relatively short period of time, should be enrolled in clinical trials evaluating new upfront anti-HER2 treatment strategies, such as lapatinib with or without trastuzumab.

Conclusions

HR-bearing breast tumors with HER2 overexpression and/or amplification represent an unresolved clinical problem and a major cause of endocrine-treatment failure and mortality. Estrogen-deprivation strategies with AIs have clearly shown superiority over tamoxifen in the adjuvant, neoadjuvant and advanced breast cancer settings in postmenopausal patients. Early resistance to hormonal therapy, especially in the HER2⁺ patient population, however, is a significant issue with these endocrine agents.

Considerable progress has been made in trying to elucidate the basis of resistance to endocrine therapy in patients with tumors coexpressing HER2 and HR. There is increasing evidence that endocrine resistance is a consequence of bidirectional crosstalk between the ER and the EGFR family signaling networks. As a result of the increased crosstalk between HER2 and ER in HER2⁺ breast tumors, both pathways become more dependent on each other.

In order to study the effects of a combined dual-targeting of HR and HER2 pathways, a prospective phase III study (the TAnDEM trial) has compared the clinical benefit of trastuzumab and letrozole with that of letrozole alone. Although the combined treatment provides significant improvement in HR⁺/HER2⁺ advanced breast cancer, the overall benefit is modest and inferior to that seen with historical controls treated with anti-HER2 therapy plus chemotherapy. Although improved strategies to achieve a better blockade of these pathways need to be tested in the clinic, it is unclear at this time whether a combination of hormonal therapy and trastuzumab is equivalent to combined trastuzumab and chemotherapy in women with HR⁺/HER2⁺ tumors. On the basis of the data available at this time, the combination of chemotherapy with anti-HER2 therapy should be the first-line treatment option considered for patients with good performance status, visceral disease or rapidly progressing HR⁺/HER2⁺ breast tumors (Figure 2). Patients with poor performance status, nonvisceral disease, or slow-progressing tumors, who have not received previous treatment with endocrine treatment, could be considered for upfront treatment with first-line hormone therapy in combination with anti-HER2 therapy. If AIs have previously been administered, anti-HER2 monotherapy could be a valid alternative.

Figure 2 Proposed therapeutic cascade in first-line HER2-positive postmenopausal advanced breast cancer.

Patients with poor performance status, nonvisceral disease, or slow-progressing tumors who have not received previous treatment with aromatase inhibitors, should be considered for upfront treatment with first-line aromatase inhibitors in combination with anti-HER2 therapy. If aromatase inhibitors have previously been administered, anti-HER2 monotherapy could be considered. Combination chemotherapy with anti-HER2 therapy should be the first-line treatment option considered in patients with a good performance status, visceral disease or rapidly progressing HR⁺/HER2⁺ breast cancer.

Full figure and legend (62K)Figures & Tables indexDownload Power Point slide (268K)

References

1. Jemal A et al. (2006) Cancer Statistics, 2006. CA Cancer J Clin 56: 106–130 | PubMed | ISI |
2. Ferlay J et al. (2007) Estimates of the cancer incidence and mortality in Europe in 2006. Ann Oncol 18: 581–592 | Article | PubMed | ISI | ChemPort |
3. Li CI et al. (2003) Incidence of invasive breast cancer by hormone receptor status from 1992 to 1998. J Clin Oncol 21: 28–34 | Article | PubMed |
4. Osborne CK et al. (2005) Estrogen-receptor biology: continuing progress and therapeutic implications. J Clin Oncol 23: 1616–1622 | Article | PubMed | ISI | ChemPort |
5. Early Breast Cancer Trialists' Collaborative Group (2005) Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet 365: 1687–1717 | ISI |
6. Coombes RC et al. (2004) A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer. N Engl J Med 350: 1081–1092 | Article | PubMed | ISI | ChemPort |
7. The Breast International Group 1-98 Collaborative Group (2005) A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer. N Engl J Med 353: 2747–2757 | Article | PubMed | ISI |
8. ATAC Trialists' Group (2005) Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years' adjuvant treatment for breast cancer. Lancet 365: 60–62 | Article | PubMed | ISI | ChemPort |
9. Jakesz R et al. (2005) Switching of postmenopausal women with endocrine-responsive early breast cancer to anastrozole after 2 years' adjuvant tamoxifen: combined results of ABCSG trial 8 and ARNO 95 trial. Lancet 366: 455–462 | Article | PubMed | ISI | ChemPort |
10. Eiermann W et al. (2001) Preoperative treatment of postmenopausal breast cancer patients with letrozole: a randomized double-blind multicenter study. Ann Oncol 12: 1527–1532 | Article | PubMed | ISI | ChemPort |
11. Smith IE et al. (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. J Clin Oncol 23: 5108–5116 | Article | PubMed | ISI | ChemPort |
12. Cataliotti L et al. (2006) Comparison of anastrozole versus tamoxifen as preoperative therapy in postmenopausal women with hormone receptor-positive breast cancer. Cancer 106: 2095–2103 | Article | PubMed | ChemPort |
13. Bonneterre J et al. (2000) Anastrozole versus tamoxifen as first-line therapy for advanced breast cancer in 668 postmenopausal women: results of the tamoxifen or arimidex randomized group efficacy and tolerability study. J Clin Oncol 18: 3748–3757 | PubMed | ISI | ChemPort |
14. Nabholtz JM et al. (2000) Anastrozole is superior to tamoxifen as first-line therapy for advanced breast cancer in postmenopausal women: results of a North American multicenter randomized trial. J Clin Oncol 18: 3758–3767 | PubMed | ISI | ChemPort |
15. Mouridsen H et al. (2001) Superior efficacy of letrozole versus tamoxifen as first-line therapy for postmenopausal women with advanced breast cancer: results of a phase III study of the International Letrozole Breast Cancer Group. J Clin Oncol 19: 2596–2606 | PubMed | ISI | ChemPort |
16. Mouridsen H et al. (2003) Phase III study of letrozole versus tamoxifen as first-line therapy of advanced breast cancer in postmenopausal women: analysis of survival and update of efficacy from the International Letrozole Breast Cancer Group. J Clin Oncol 21: 2101–2109 | Article | PubMed | ISI | ChemPort |
17. Paridaens R et al. (2003) Mature results of a randomized phase II multicenter study of exemestane versus tamoxifen as first-line hormone therapy for postmenopausal women with metastatic breast cancer. Ann Oncol 14: 1391–1398 | Article | PubMed | ISI | ChemPort |
18. Howell A et al. (2002) Fulvestrant, formerly ICI 182,780, is as effective as anastrozole in postmenopausal women with advanced breast cancer progressing after prior endocrine treatment. J Clin Oncol 20: 3396–3403 | Article | PubMed | ISI | ChemPort |
19. Osborne CK et al. (2002) Double-blind, randomized trial comparing the efficacy and tolerability of fulvestrant versus anastrozole in postmenopausal women with advanced breast cancer progressing on prior endocrine therapy: results of a North American trial. J Clin Oncol 20: 3386–3395 | Article | PubMed | ISI | ChemPort |
20. Kaufman B et al. (2006) Trastuzumab plus anastrozole prolongs progression-free survival in postmenopausal women with HER2 positive, hormone-dependent metastatic breast cancer (MBC) [abstract #LBA2]. European Society for Medical Oncology (ESMO) Congress: 2006 29 September to 3 October; Istanbul, Turkey
21. Ring A et al. (2004) Mechanisms of tamoxifen resistance. Endocr Relat Cancer 11: 643–658 | Article | PubMed | ChemPort |
22. Massarweh S et al. (2007) Unraveling the mechanisms of endocrine resistance in breast cancer: new therapeutic opportunities. Clin Cancer Res 13: 1950–1954 | Article | PubMed | ChemPort |
23. Ali S et al. (2002) Endocrine-responsive breast cancer and strategies for combating resistance. Nat Rev Cancer 2: 101–112 | Article | PubMed | ISI |
24. Ali S et al. (1993) Modulation of transcriptional activation by ligand-dependent phosphorylation of the human oestrogen receptor A/B region. EMBO J 12: 1153–1160 | PubMed | ISI | ChemPort |
25. Shou J et al. (2004) Mechanisms of tamoxifen resistance: increased estrogen receptor-HER2/neu crosstalk in ER/HER2-positive breast cancer. J Natl Cancer Inst 96: 926–935 | Article | PubMed | ChemPort |
26. Yarden Y et al. (2001) Untangling the ErbB signalling network. Nat Rev Mol Cell Biol 2: 127–137 | Article | PubMed | ISI | ChemPort |
27. Hynes NE and Lane HA (2005) ErbB receptors and cancer: the complexity of targeted inhibitors. Nat Rev Cancer 5: 341–354 | Article | PubMed | ISI | ChemPort |
28. Benz C et al. (1992) Estrogen-dependent, tamoxifen-resistant tumorigenic growth of MCF-7 cells transfected with HER2/neu. Breast Cancer Res Treat 24: 85–95 | Article | PubMed | ISI | ChemPort |
29. Pietras R et al. (1995) HER-2 tyrosine kinase pathway targets estrogen receptor and promotes hormone-independent growth in human breast cancer cells. Oncogene 10: 2435–2446 | PubMed | ISI | ChemPort |
30. Schlessinger J (2004) Common and distinct elements in cellular signaling via EGF and FGF receptors. Science 306: 1506–1507 | Article | PubMed | ISI | ChemPort |
31. Hudziak RM et al. (1987) Increased expression of the putative growth factor receptor p185HER2 causes transformation and tumorigenesis of NIH 3T3 cells. Proc Natl Acad Sci USA 84: 7159–7163 | Article | PubMed | ChemPort |
32. Slamon DJ et al. (1989) Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science 244: 707–712 | Article | PubMed | ISI | ChemPort |
33. Yu D et al. (2000) Overexpression of ErbB2 in cancer and ErbB2-targeting strategies. Oncogene 11: 6115–6121 | Article | ChemPort |
34. Carter P et al. (1992) Humanization of an anti-p185HER2 antibody for human cancer therapy. Proc Natl Acad Sci USA 89: 4285–4289 | Article | PubMed | ChemPort |
35. Tokuda Y et al. (1996) In vitro and in vivo anti-tumour effects of a humanised monoclonal antibody against c-erbB-2 product. Br J Cancer 73: 1362–1365 | PubMed | ISI | ChemPort |
36. Baselga J et al. (1998) Recombinant humanized anti-HER2 antibody (HerceptinTM) enhances the antitumor activity of paclitaxel and doxorubicin against HER2/neu overexpressing human breast cancer xenografts. Cancer Res 58: 2825–2831 | PubMed | ISI | ChemPort |
37. Baselga J et al. (2001) Mechanism of action of trastuzumab and scientific update. Semin Oncol 28: 4–11 | Article | PubMed | ISI | ChemPort |
38. Slamon DJ et al. (2001) Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 344: 783–792 | Article | PubMed | ISI | ChemPort |
39. Marty M et al. (2005) Randomized phase II trial of the efficacy and safety of trastuzumab combined with docetaxel in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer administered as first-line treatment: The M77001 Study Group. J Clin Oncol 23: 4265–4274 | Article | PubMed | ISI | ChemPort |
40. Romond EH et al. (2005) Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 353: 1673–1684 | Article | PubMed | ISI | ChemPort |
41. Piccart-Gebhart MJ et al. (2005) Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 353: 1659–1672 | Article | PubMed | ISI | ChemPort |
42. Joensuu H et al. (2006) Adjuvant docetaxel or vinorelbine with or without trastuzumab for breast cancer. N Engl J Med 354: 809–820 | Article | PubMed | ISI | ChemPort |
43. Smith I (2006) Trastuzumab for early breast cancer. Lancet 367: 107 | Article | PubMed |
44. Geyer CE et al. (2006) Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med 355: 2733–2743 | Article | PubMed | ChemPort |
45. Baselga J et al. (2007) Objective response rate in a phase II multicenter trial of pertuzumab (P), a HER2 dimerization inhibiting monoclonal antibody, in combination with trastuzumab (T) in patients (pts) with HER2-positive metastatic breast cancer (MBC) which has progressed during treatment with T [abstract #1004]. Proc Am Soc Clin Oncol: 2007 1–5 June; Chicago, IL
46. Beeram M et al. (2007) 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 (BC) [abstract #1042]. Proc Am Soc Clin Oncol: 2007 1–5 June; Chicago, IL
47. Modi S et al. (2006) Phase I trial of KOS-953, a heat shock protein 90 inhibitor, and trastuzumab (T) [abstract #501]. Proc Am Soc Clin Oncol: 2007 June 1–5; Chicago, IL
48. Franklin MC et al. (2004) Insights into ErbB signaling from the structure of the ErbB2-pertuzumab complex. Cancer Cell 5: 317–328 | Article | PubMed | ISI | ChemPort |
49. Remillard S et al. (1975) Antimitotic activity of the potent tumor inhibitor maytansine. Science 189: 1002–1005 | Article | PubMed | ChemPort |
50. Whitesell L et al. (2005) HSP90 and the chaperoning of cancer. Nat Rev Cancer 5: 761–772 | Article | PubMed | ISI | ChemPort |
51. Osborne CK et al. (2000) Selective estrogen receptor modulators: structure, function, and clinical use. J Clin Oncol 18: 3172–3186 | PubMed | ISI | ChemPort |
52. Osborne C et al. (2001) Estrogen receptor: current understanding of its activation and modulation. Clin Cancer Res 7: 4338s–4342s | PubMed | ChemPort |
53. Kushner PJ et al. (2000) Estrogen receptor pathways to AP-1. J Steroid Biochem Mol Biol 74: 311–317 | Article | PubMed | ISI | ChemPort |
54. Nicholson RI et al. (1999) Involvement of steroid hormone and growth factor crosstalk in endocrine response in breast cancer. Endocr Relat Cancer 6: 373–387 | Article | PubMed | ChemPort |
55. Lee A et al. (2001) Crosstalk among estrogen receptor, epidermal growth factor, and insulin-like growth factor signaling in breast cancer. Clin Cancer Res 7: 4429s–4435s | PubMed | ChemPort |
56. Wilson M et al. (2002) Identification and characterization of a negative regulatory element within the epidermal growth factor receptor gene first intron in hormone-dependent breast cancer cells. J Cell Biochem 85: 601–614 | Article | PubMed | ChemPort |
57. Russell K et al. (1992) Transcriptional repression of the neu protooncogene by estrogen stimulated estrogen receptor. Cancer Res 52: 6624–6629 | PubMed | ChemPort |
58. Frasor J et al. (2003) Profiling of estrogen up- and down-regulated gene expression in human breast cancer cells: insights into gene networks and pathways underlying estrogenic control of proliferation and cell phenotype. Endocrinology 144: 4562–4574 | Article | PubMed | ISI | ChemPort |
59. McKenna NJ et al. (1999) Nuclear receptor coregulators: cellular and molecular biology. Endocr Rev 20: 321–344 | Article | PubMed | ISI | ChemPort |
60. Barnes C et al. (2004) Novel estrogen receptor coregulators and signaling molecules in human diseases. Cell Mol Life Sci 61: 281–291 | Article | PubMed | ChemPort |
61. Singh R et al. (2005) Steroid hormone receptor signaling in tumorigenesis. J Cell Biochem 96: 490–505 | Article | PubMed | ChemPort |
62. Smith CL et al. (2004) Coregulator function: a key to understanding tissue specificity of selective receptor modulators. Endocr Rev 25: 45–71 | Article | PubMed | ISI | ChemPort |
63. Anzick SL et al. (1997) AIB1, a steroid receptor coactivator amplified in breast and ovarian cancer. Science 277: 965–968 | Article | PubMed | ISI | ChemPort |
64. Osborne CK et al. (2003) Role of the estrogen receptor coactivator AIB1 (SRC-3) and HER-2/neu in tamoxifen resistance in breast cancer. J Natl Cancer Inst 95: 353–361 | Article | PubMed | ChemPort |
65. Aronica S et al. (1994) Estrogen action via the cAMP signaling pathway: stimulation of adenylate cyclase and cAMP-regulated gene transcription. Proc Natl Acad Sci USA 91: 8517–8521 | Article | PubMed | ChemPort |
66. Kahlert S et al. (2000) Estrogen receptor alpha rapidly activates the IGF-1 receptor pathway. J Biol Chem 275: 18447–18453 | Article | PubMed | ISI | ChemPort |
67. Simoncini T et al. (2000) Interaction of oestrogen receptor with the regulatory subunit of phosphatidylinositol-3-OH kinase. Nature 407: 538–541 | Article | PubMed | ISI | ChemPort |
68. Morelli C et al. (2003) Estrogen receptor-alpha regulates the degradation of insulin receptor substrates 1 and 2 in breast cancer cells. Oncogene 26: 4007–4016 | Article | ChemPort |
69. Migliaccio A et al. (2002) Src is an initial target of sex steroid hormone action. Ann NY Acad Sci 963: 185–190 | PubMed | ChemPort |
70. Van Cutsem E et al. (2007) Randomized phase III study of irinotecan and 5-FU/FA with or without cetuximab in the first-line treatment of patients with metastatic colorectal cancer (mCRC): The CRYSTAL trial [abstract]. J Clin Oncol 25: A4000
71. Song RX et al. (2002) Linkage of rapid estrogen action to MAPK activation by ER-Shc association and Shc pathway activation. Mol Endocrinol 16: 116–127 | Article | PubMed | ISI | ChemPort |
72. MacGregor Schafer J et al. (2001) Estrogen receptor mediated induction of the transforming growth factor gene by estradiol and 4-hydroxytamoxifen in MDA-MB-231 breast cancer cells. J Steroid Biochem Mol Biol 78: 41–50 | Article | PubMed | ChemPort |
73. Font de Mora J et al. (2000) AIB1 is a conduit for kinase-mediated growth factor signaling to the estrogen receptor. Mol Cell Biol 20: 5041–5047 | Article | PubMed | ChemPort |
74. Witters L et al. (1997) Enhanced anti-proliferative activity of the combination of tamoxifen plus HER-2-neu antibody. Breast Cancer Res Treat 42: 1–5 | Article | PubMed | ISI | ChemPort |
75. Gutierrez MC et al. (2005) Molecular changes in tamoxifen-resistant breast cancer: relationship between estrogen receptor, HER-2, and p38 mitogen-activated protein kinase. J Clin Oncol 23: 2469–2476 | Article | PubMed | ISI | ChemPort |
76. Ellis MJ et al. (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. J Clin Oncol 19: 3808–3816 | PubMed | ISI | ChemPort |
77. Johnston S et al. (2003) Aromatase inhibitors for breast cancer: lessons from the laboratory. Nat Rev Cancer 3: 821–831 | Article | PubMed | ISI | ChemPort |
78. Massarweh S et al. (2006) Mechanisms of tumor regression and resistance to estrogen deprivation and fulvestrant in a model of estrogen receptor-positive, HER-2/neu-positive breast cancer. Cancer Res 66: 8266–8273 | Article | PubMed | ISI | ChemPort |
79. Kurokawa H et al. (2000) Inhibition of HER2/neu (erbB-2) and mitogen-activated protein kinases enhances tamoxifen action against HER2-overexpressing, tamoxifen-resistant breast cancer cells. Cancer Res 60: 5887–5894 | PubMed | ISI | ChemPort |
80. Wright C et al. (1992) Relationship between c-erbB-2 protein product expression and response to endocrine therapy in advanced breast cancer. Br J Cancer 65: 118–121 | PubMed | ISI | ChemPort |
81. Berns E et al. (1995) Oncogene amplification and prognosis in breast cancer: relationship with systemic treatment. Gene 159: 11–18 | Article | PubMed | ISI | ChemPort |
82. Houston S et al. (1999) Overexpression of c-erbB2 is an independent marker of resistance to endocrine therapy in advanced breast cancer. Br J Cancer 79: 1220–1226 | Article | PubMed | ISI | ChemPort |
83. Lipton A et al. (2003) Serum HER-2/neu and response to the aromatase inhibitor letrozole versus tamoxifen. J Clin Oncol 21: 1967–1972 | Article | PubMed | ISI | ChemPort |
84. Lipton A et al. (2002) Elevated serum HER-2/neu level predicts decreased response to hormone therapy in metastatic breast cancer. J Clin Oncol 20: 1467–1472 | Article | PubMed | ISI | ChemPort |
85. Dowsett M et al. (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. J Clin Oncol 23: 2477–2492 | Article | PubMed | ISI | ChemPort |
86. Viale G et al. (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 [abstract #44]. In Proceedings of the San Antonio Breast Cancer Symposium: 9 December 2005, San Antonio, TX
87. Ellis MJ et al. (2006) Estrogen-independent proliferation is present in estrogen-receptor HER2-positive primary breast cancer after neoadjuvant letrozole. J Clin Oncol 24: 3019–3025 | Article | PubMed | ChemPort |
88. Dowsett M et al. (2006) Relationship between quantitative ER and PgR expression and HER2 status with recurrence in the ATAC trial [abstract #48]. In Proceedings of the San Antonio Breast Cancer Symposium: 2006 December 14–17; San Antonio, TX
89. Daly J et al. (1997) Neu differentiation factor induces ErbB2 down-regulation and apoptosis of ErbB2-overexpressing breast tumor cells. Cancer Res 57: 3804–3811 | PubMed | ChemPort |
90. Buzdar A et al. (2001) Phase III, multicenter, double-blind, randomized study of letrozole, an aromatase inhibitor, for advanced breast cancer versus megestrol acetate. J Clin Oncol 19: 3357–3366 | PubMed | ISI | ChemPort |
91. Buzdar A et al. (1998) Anastrozole versus megestrol acetate in the treatment of postmenopausal women with advanced breast carcinoma: results of a survival update based on a combined analysis of data from two mature phase III trials. Arimidex Study Group. Cancer 83: 1142–1152 | Article | PubMed | ISI | ChemPort |
92. Kaufmann M et al. (2000) Exemestane is superior to megestrol acetate after tamoxifen failure in postmenopausal women with advanced breast cancer: results of a phase III randomized double-blind trial. J Clin Oncol 18: 1399–1411 | PubMed | ISI | ChemPort |
93. Marcom PK et al. (2007) The combination of letrozole and trastuzumab as first or second-line biological therapy produces durable responses in a subset of HER2 positive and ER positive advanced breast cancers. Breast Cancer Res Treat 102: 43–49 | Article | PubMed | ChemPort |
94. Kaufman B et al. (2006) Trastuzumab plus anastrozole prolongs progression-free survival in postmenopausal women with HER2-positive, hormone-dependent metastatic breast cancer [abstract #a3]. In Proceedings of the San Antonio Breast Cancer Symposium: 2006 December 14–17; San Antonio, TX
95. Arpino G et al. (2007) Treatment of human epidermal growth factor receptor 2-overexpressing breast cancer xenografts with multiagent HER-targeted therapy. J Natl Cancer Inst 99: 694–705 | Article | PubMed | ChemPort |
96. Xia W et al. (2006) A model of acquired autoresistance to a potent ErbB2 tyrosine kinase inhibitor and a therapeutic strategy to prevent its onset in breast cancer. Proc Natl Acad Sci USA 103: 7795–7800 | Article | PubMed | ChemPort |
97. Johnston SR (2005) Clinical trials of intracellular signal transductions inhibitors for breast cancer—a strategy to overcome endocrine resistance. Endocr Relat Cancer 12: S145–S157 | Article | PubMed | ChemPort |
98. Ellis M (2004) Overcoming endocrine therapy resistance by signal transduction inhibition. Oncologist 9: 20–26 | Article | PubMed | ISI | ChemPort |
99. Johnston SR et al. (2007) Clinical strategies for rationale combinations of aromatase inhibitors with novel therapies for breast cancer. J Steroid Biochem Mol Biol 106: 180–186 | Article | PubMed | ChemPort |
100. Clark AS et al. (2002) Constitutive and inducible Akt activity promotes resistance to chemotherapy, trastuzumab, or tamoxifen in breast cancer cells. Mol Cancer Ther 1: 707–717 | PubMed | ISI | ChemPort |
101. Pancholi S et al. (2004) Elevated levels of Akt and p90rsk provide tamoxifen-resistant MCF-7 cells with a survival advantage involving Bad and Bcl-2 [abstract]. Proc Am Assoc Cancer Res 45: A5168
102. Baselga J et al. (2004) Phase II, 3-arm study of CCI-779 in combination with letrozole in postmenopausal women with locally advanced or metastatic breast cancer: preliminary results [abstract #544]. Proc Am Soc Clin Oncol 23
103. Tabernero J et al. (2005) A phase I study with tumor molecular pharmacodynamic (MPD) evaluation of dose and schedule of the oral mTOR-inhibitor everolimus (RAD001) in patients (pts) with advanced solid tumors [abstract #3007]. Proc Am Soc Clin Oncol 23
104. Carpenter JT et al. (2005) Randomized 3-arm, phase 2 study of temsirolimus (CCI-779) in combination with letrozole in postmenopausal women with locally advanced or metastatic breast cancer [abstract # 564]. Proc Am Soc Clin Oncol 23
105. O'Reilly KE et al. (2006) mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Res 66: 1500–1508 | Article | PubMed | ISI | ChemPort |
106. Hudis CA (2007) Trastuzumab—mechanism of action and use in clinical practice. N Engl J Med 357: 39–51 | Article | PubMed | ChemPort |
107. Vogel CL et al. (2002) Efficacy and safety of trastuzumab as a single agent in first-line treatment of HER2-overexpressing metastatic breast cancer. J Clin Oncol 20: 719–726 | Article | PubMed | ISI | ChemPort |
108. Burstein HJ et al. (2003) Trastuzumab and vinorelbine as first-line therapy for HER2-overexpressing metastatic breast cancer: multicenter phase II trial with clinical outcomes, analysis of serum tumor markers as predictive factors, and cardiac surveillance algorithm. J Clin Oncol 21: 2889–2895 | Article | PubMed | ISI | ChemPort |
109. Robert N et al. (2006) Randomized phase III study of trastuzumab, paclitaxel, and carboplatin compared with trastuzumab and paclitaxel in women with HER-2-overexpressing metastatic breast cancer. J Clin Oncol 24: 2786–2792 | Article | PubMed | ChemPort |

Contact the journal about this article

Subject areas under which this article appears: Medical Oncology