The role of hormonal therapy in the management of hormonal-receptor-positive breast cancer with co-expression of HER2

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1 di 26 03/10/ Subscribe Register Submit manuscript My account Search go Advanced search REVIEW Nature Clinical Practice Oncology (2008) 5, doi: /ncponc1179 (/clinicalpractice/about_site/doi.html) Received 12 November 2007 Accepted 10 January 2008 Published online: 8 July 2008 The role of hormonal therapy in the management of hormonal-receptor-positive breast cancer with co-expression of HER2 Aleix Prat and José Baselga* About the authors (/ncponc/journal/v5/n9/authors /ncponc1179.html) Correspondence *Division of Medical Oncology, Hematology, and Radiation Oncology at the Vall d'hebron University Hospital, Passeig de la Vall d'hebron , Barcelona, Spain jbaselga@vhebron.net (mailto:jbaselga@vhebron.net) SUMMARY Approximately half of breast cancers that overexpress human epidermal growth factor receptor 2 (HER2) also express hormone receptors (HRs). Although HR positivity predicts efficacy of endocrine agents, preclinical and clinical data suggest that HER2 overexpression confers intrinsic resistance to hormonal treatment. In addition, HER2 overexpression is an independent adverse prognostic factor regardless of the hormonal status of the tumor, indicating that patients with HR + /HER2 + breast tumors might not derive a benefit from single-agent hormonal therapy. These data provided a strong rationale for exploring the targeting of both HR and HER2 signaling pathways in HR + /HER2 + breast tumors to optimize hormonal therapy and overcome resistance to anti-estrogen therapy. Results from a randomized clinical trial that combined hormonal treatment with targeted anti-her2 therapy in postmenopausal women with HR + /HER2 + advanced breast cancer indicate that this novel dual-targeting strategy significantly improves outcomes compared with endocrine treatment alone. Nonetheless, other data suggest that it might achieve an inferior outcome compared with anti-her2 therapy plus chemotherapy. Therefore, targeting both the HR and HER2 signaling pathways upfront might not be the most-effective therapeutic strategy in the management of HR + /HER2 + breast cancer. We discuss the clinical implication of resistance to endocrine therapy, and describe new insights into the management of HR + /HER2 + advanced breast cancer. REVIEW CRITERIA The article is based primarily on a discussion of the TAnDEM trial results reported at the 31 st European Society for Medical Oncology Congress in Other data were obtained by searching the PubMed database. The search terms used included "trastuzumab", "tamoxifen and resistance", "tamoxifen and HER2", "aromatase inhibitors", "letrozole resistance", "anastrozole resistance",

2 di 26 03/10/ "estrogen receptor" and "HER2". In addition, proceedings from conferences of the European Society of Medical Oncology, American Society of Clinical Oncology, and the San Antonio Breast Cancer Symposium were searched for relevant abstracts. Keywords: anastrozole ( /tag/anastrozole), endocrine resistance ( /user/natureclinicalpractice/tag/endocrine%20resistance), estrogen receptor ( HER2 ( trastuzumab ( /tag/trastuzumab) INTRODUCTION Each year more than 210,000 and 360,000 new cases of breast cancer are diagnosed in the US and Europe, respectively. 1, (#B1) 2 (#B2) More than two-thirds of these patients have hormone receptor (HR)-bearing tumors 3 (#B3) 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 (#B4) 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 (#B5) The recent introduction of thirdgeneration 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, (#B6) 8, (#B8) 9 (#B9) In addition, for postmenopausal patients with ER + breast cancer, AIs have shown superior efficacy in the neoadjuvant setting 10, (#B10) 11, (#B11) 12 (#B12) and in advanced disease13, (#B13) 14, (#B14) 15, (#B15) 16, (#B16) 17 (#B17) 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, (#B18) 19, (#B19) 20 (#B20) RESISTANCE TO HORMONAL TREATMENTS Despite the clinical benefit of hormonal treatment in patients with HR + breast cancer, primary and secondary resistance to endocrine therapy remains a significant clinical problem. 21 (#B21) Phase III clinical trials of patients with metastatic breast cancer show that only a third of all HR + tumors respond radiologically to AIs given as first-line treatments. Furthermore, even those tumors that initially respond to AIs eventually develop resistance, which leads to disease progression and ultimately to patient death. 13, (#B13) 14, (#B14) 15, (#B15) 16, (#B16) 17 (#B17) In the adjuvant setting, some patients also relapse during and after 5 years of hormonal treatment. 6, (#B6) 7, (#B7) 8, (#B8) 9 (#B9) There is, therefore, a strong rationale for the identification of the mechanisms underlying endocrine resistance in order to improve the outcome of patients with HR + breast tumors. 22 (#B22) Several mechanisms of resistance to hormonal-therapy have been proposed, 23 (#B23) and include the following: downregulation of ER expression, ER mutations, altered expression of ER coregulators, and ligand-independent activation of ER and

3 di 26 03/10/ coactivators by growth factor receptor kinases. 24, (#B24) 25 (#B25) The human epidermal growth factor receptor (HER) family of receptors involved in hormone resistance includes EGFR (also known as HER1 or erbb1), HER2 (erbb2), HER3 (erbb3), and HER4 (erbb4). 26, (#B26) 27 (#B27) In particular, HER2 overexpression and/or amplification (HER2 + ) confers intrinsic resistance to endocrine treatment in preclinical models. 28, (#B28) 29 (#B29) HER2 is a ligandless receptor that forms homodimers and heterodimers with other members of the HER family, resulting in receptor activation and phosphorylation of intracellular catalytic domains. This phosphorylation leads to activation of signal transduction pathways that promote proliferation and survival such as the phosphatidylinositol 3'-kinase (PI3K)/Akt /mtor, the Erk1/2 mitogen-activated protein kinase (MAPK) and the JAK/STAT pathways. 30 (#B30) In experimental systems, HER2 overexpression drives malignant transformation of mammary epithelial cells. 31 (#B31) In patients, HER2 is overexpressed and/or amplified in 25% of breast tumors and confers a more-aggressive clinical course and a worse survival. 32, (#B32) 33 (#B33) ANTI-HER2 THERAPIES The outcome of these highly aggressive tumors has markedly improved with the development of anti-her2 therapies. Trastuzumab (Herceptin, Genentech, San Francisco, CA) is a recombinant humanized monoclonal antibody that binds with high affinity to the extracellular juxtamembrane domain of HER2 and inhibits the proliferation of human tumor cells that overexpress HER2. 34, (#B34) 35, (#B35) 36 (#B36) The mechanisms underlying the antitumor activity of trastuzumab are not clear, although it has been established that trastuzumab induces downregulation of HER2 from the cell surface membrane, blockade of metalloprotease-induced proteolytic cleavage of HER2, antibody-dependent cell-mediated cytotoxicity, and a decrease in angiogenic factors. 37 (#B37) In patients with HER2 + tumors and advanced disease, trastuzumab has single-agent activity and improves survival in the first-line setting when combined with chemotherapy. 38, (#B38) 39 (#B39) In addition, a number of well-powered clinical trials have demonstrated that administration of trastuzumab in the adjuvant setting, in combination with and/or sequentially after chemotherapy, results in an improvement in recurrence-free survival as well as overall survival. 40, (#B40) 41, (#B41) 42, (#B42) 43 (#B43) Small molecule tyrosine kinase inhibitors (TKIs) of the HER2 receptor have also shown clinical activity. Lapatinib (Tykerb, SmithKline Beecham, Cork, Ireland), a dual inhibitor of EGFR and HER2, has been shown to increase survival in patients with advanced HER2 + breast cancer in comparison with capecitabine treatment alone, capecitabine treatment in combination with lapatinib improved survival in patients with disease progression following anthracycline, taxane, and trastuzumab treatment regimens. 44 (#B44) In addition, other anti-her2 agents have been shown to be clinically active in patients refractory to trastuzumab. 45, (#B45) 46, (#B46) 47 (#B47) Pertuzumab (Omnitarg, Genentech, San Francisco, CA) is a recombinant humanized antibody currently in phase II and III clinical trials that binds to the dimerization domain of HER2 and inhibits its heterodimerization with other HER family members. 48 (#B48) Another agent currently under investigation, trastuzumab-dm1, combines the antitumor activity of trastuzumab with a highly potent inhibitor of tubulin polymerization, DM1. 49 (#B49) Finally, inhibitors of heat shock protein 90, such as KOS-953 (Tanespimycin, Kosan Biosciences Inc, Hayward, CA), promote ubiquitination and degradation of HER2. 50 (#B50) CROSSTALK BETWEEN ER AND HER2 PATHWAYS

4 di 26 03/10/ There is important crosstalk between ER and other receptor families, including but not restricted to the HER family, 4 (#B4) 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 (#B51) 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 (#B52) 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 (#B53) 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, (#B53) 54, (#B54) 55 (#B55) Genes downregulated by estrogens include the EGFR 56 (#B56) and HER2; 57 (#B57) many of the genes downregulated by estrogen signaling are transcriptional repressors and/or members of the transforming growth factor (TGF)- superfamily. 58 (#B58) The transcriptional effects of activated ER are modulated by coregulatory proteins that function as either coactivators or corepressors of the ER complex. 59, (#B59) 60, (#B60) 61 (#B61) These coregulatory proteins might be tissue specific, which could explain the different effects of ER in different tissues. 62 (#B62) 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 (#B63) 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 (#B64) ER can also regulate cellular functions through nongenomic mechanisms known as membrane nongenomic estrogen signaling. 4 (#B4) 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 (#B65) and activates various tyrosine kinase receptors such as IGF-IR, EGFR, and HER2. 66, (#B66) 67, (#B67) 68 (#B68) ER can also associate with cellular kinases and adaptor molecules such as c-src 69 (#B69), Src homology and collagen homology protein 70, (#B70) 71 (#B71) and PI3K. 67 (#B67) Finally, ER-induced signaling pathways might induce EGFR ligands such as TGF 72 (#B72) and cause downregulation of EGFR 56 (#B56) and HER2. 57 (#B57) 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 (#B24) 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 (#B73) 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 (#B25) 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, (#B25) 74 (#B74) In addition, increased crosstalk between ER and HER2 may

5 di 26 03/10/ contribute to secondary resistance to tamoxifen in 10 15% of HR + /HER2 - breast tumors. 75 (#B75) 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, (#B76) 77 (#B77) 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, (#B4) 78 (#B78) 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 (#f1) ). 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 (/ncponc/journal/v5/n9/fig_tab/ncponc1179_f1.html) ER/GF signaling pathways and molecularly targeted agents for overcoming endocrine resistance. (/ncponc/journal/v5/n9/fig_tab /ncponc1179_f1.html) 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 mitogenactivated 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) (/ncponc/journal/v5/n9/fig_tab /ncponc1179_f1.html) Figures & Tables index (/ncponc/journal/v5/n9/fig_tab /ncponc1179_ft.html) Download PowerPoint slide (323K) (/ncponc/journal/v5/n9 /slides/ncponc1179-pf1.ppt) 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 (#B28) This observation has been subsequently confirmed by other groups, 25, (#B25) 29, (#B29) 75, (#B75) 79 (#B79) 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, (#B80) 81, (#B81) 82, (#B82) 83 (#B83) 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 (#B82) There was some initial enthusiasm that HER2 + tumors would be more sensitive to AIs than to tamoxifen. 76 (#B76) Careful analysis of published data,

6 di 26 03/10/ however, suggests that even with AIs, patients with HER2 + disease have a poor response. 83, (#B83) 84, (#B84) 85, (#B85) 86, (#B86) 87, (#B87) 88 (#B88) For example, a phase III trial of 916 patients 17 (#B17) 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 = ). Nevertheless, subsequent analysis of HER2 status 83 (#B83) 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 benefit 89 (#B89) (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 = ). 83 (#B83) 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 (#B84) 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, (#B86) 88 (#B88) A small retrospective neoadjuvant study suggested that AIs obtained higher response rates than tamoxifen in HR + /HER2 + postmenopausal breast cancer. 76 (#B76) 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, (#B85) 87 (#B87) In the first study, known as the IMPACT trial, 11 (#B11) 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 (#B85) 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 (#B87) 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 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 (#t1) ). 14, (#B14) 15, (#B15) 16 (#B16) When the HER2 + subgroup are retrospectively analyzed, the median TTP and ORR for this group decreased to months and 13 17%, respectively. 83 (#B83) In the second-line advanced-disease setting and in those with an unknown HER2-status, endocrine treatment achieved median TTP and ORR of months and 13 15%, respectively. 90, (#B90) 91, (#B91) 92 (#B92) A further HER2 + subgroup

7 di 26 03/10/ analysis showed that median TTP and ORR decreased to 3.0 months and 7%, respectively. 84 (#B84) 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 (/ncponc/journal/v5/n9/fig_tab/ncponc1179_t1.html) Relevant trials of endocrine therapy for hormone-receptor-positive advanced breast cancer. (/ncponc/journal/v5/n9/fig_tab /ncponc1179_t1.html) Full table (/ncponc/journal/v5/n9/fig_tab/ncponc1179_t1.html) Figures & Tables index (/ncponc/journal/v5/n9/fig_tab /ncponc1179_ft.html) Download PowerPoint slide (270K) (/ncponc/journal/v5/n9 /slides/ncponc1179-pt1.ppt) 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 (#B93) 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, (#B20) 94 (#B94) 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 = ). 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

8 di 26 03/10/ 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 (#B95) 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 (#B95) In addition, treatment with endocrine therapy plus gefitinib, trastuzumab and pertuzumab induces complete and durable tumor regressions. 95 (#B95) 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 (#B96) Consequently, ER becomes a key regulator of cell survival and antiapoptosis in codependence with HER2 in HR + /HER2 + breast cancer cells. 96 (#B96) 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 (#B96) 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.

9 di 26 03/10/ 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, (#B97) 98, (#B98) 99 (#B99) For example, breast-cancer cell lines with activated PI3K/Akt/mTOR signaling are resistant to tamoxifen. 100, (#B100) 101 (#B101) These tumors might be especially sensitive to mtor inhibitors such as temsirolimus (CCI-779) 102 (#B102) and everolimus (RAD001). 103 (#B103) 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 (#B104) 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 signaltransduction 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 (#B103) 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 (#B105) 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 (#B106) In a large phase II clinical study, 107 (#B107) 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 (#t2) ). These findings are not dissimilar to the ones obtained in the TAnDEM trial. Table 2 (/ncponc/journal/v5/n9/fig_tab/ncponc1179_t2.html) Relevant clinical trials of anti-her2-targeted therapy for HER2-positive advanced breast cancer. (/ncponc/journal/v5/n9/fig_tab /ncponc1179_t2.html) Full table (/ncponc/journal/v5/n9/fig_tab/ncponc1179_t2.html) Figures & Tables index (/ncponc/journal/v5/n9/fig_tab /ncponc1179_ft.html)

10 0 di 26 03/10/ Download PowerPoint slide (262K) (/ncponc/journal/v5/n9 /slides/ncponc1179-pt2.ppt) 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 (#B38) 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/m 2 or epirubicin 75 mg/m 2 and cyclophosphamide 600 mg/m 2 or paclitaxel 175 mg/m 2 ) 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/m 2 every 3 weeks, with or without trastuzumab in the first-line advanced-disease setting. 39 (#B39) In all subgroups analyzed, including HR status, the combined treatment was significantly superior to chemotherapy alone in terms of ORR (61% versus 34%; P = ), median OS (31.2 months versus 22.7 months; P = ), and median TTP (11.7 months versus 6.1 months; P = ). 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, (#B108) 109 (#B109) 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 months. 38, (#B38) 39 (#B39) 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.

11 1 di 26 03/10/ 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 (#f2) ). 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 (/ncponc/journal/v5/n9/fig_tab/ncponc1179_f2.html) Proposed therapeutic cascade in first-line HER2-positive postmenopausal advanced breast cancer. (/ncponc/journal/v5/n9/fig_tab /ncponc1179_f2.html) 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) (/ncponc/journal/v5/n9/fig_tab /ncponc1179_f2.html) Figures & Tables index (/ncponc/journal/v5/n9/fig_tab /ncponc1179_ft.html) Download PowerPoint slide (268K) (/ncponc/journal/v5/n9 /slides/ncponc1179-pf2.ppt) KEY POINTS Aromatase inhibitors are the most effective endocrine agents for the treatment of postmenopausal patients with breast tumors expressing hormonal receptors (HR+); however, not all HR-expressing tumors respond to endocrine therapies and those who respond eventually become resistant Several mechanisms for resistance to hormonal therapy have been proposed, including downregulation of HR expression, HR mutations, altered expression of coregulators, and ligand-independent activation of estrogen receptor and coactivators by overexpression and/or amplification of HER2 HR+/HER2+ breast tumors are too aggressive to benefit from single-agent hormonal therapy; however, preclinical and recent clinical data indicate that such resistance might be overcome by inhibiting the HER2 pathway

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