The Breast 23 (2014) 128e136
Contents lists available at ScienceDirect
The Breast journal homepage: www.elsevier.com/brst
Review
Treatment of HER2-positive breast cancer Maria Cristina Figueroa-Magalhães 1, Danijela Jelovac 1, Roisin M. Connolly, Antonio C. Wolff* Breast Cancer Program, The Johns Hopkins Kimmel Comprehensive Cancer Center, 1650 Orleans Street, CRB1-189, Baltimore, MD 21287, USA
a r t i c l e i n f o
a b s t r a c t
Article history: Received 24 January 2013 Received in revised form 23 September 2013 Accepted 24 November 2013
The human epidermal growth factor receptor 2 gene (HER2) is overexpressed and/or amplified in w15% of breast cancer patients and was identified a quarter century ago as a marker of poor prognosis. By 1998, antibody therapy targeting the HER2 pathway was shown to demonstrably improve progression-free and overall survival in metastatic disease, and in 2005 evidence of improvement in disease-free and overall survival from the first generation of trastuzumab adjuvant trials became available. However, not all patients with HER2 overexpression benefit from trastuzumab. Second-generation studies in metastatic disease led to the approval of several new HER2-targeted therapies using small molecule tyrosine kinase inhibitors such as lapatinib, new HER2/HER3 antibodies such as pertuzumab, and the new antibody chemotherapy conjugate ado-trastuzumab emtansine. These successes supported the launch of secondgeneration adjuvant trials testing single and dual HER2-targeted agents, administered concomitantly or sequentially with chemotherapy that will soon complete accrual. HER2-positive breast cancer in the setting of HER2-targeted therapy is no longer associated with poor prognosis, and recent guidance by the US Food and Drug Administration suggests that pathologic response to HER2-targeted therapy given preoperatively may allow an earlier assessment of their clinical benefit in the adjuvant setting. An adjuvant trial of trastuzumab in patient whose tumors express normal levels of HER2 and trials of single/ dual HER2-targeting without chemotherapy are also ongoing. In this article, we review the current data on the therapeutic management of HER2-positive breast cancer. Ó 2013 Elsevier Ltd. All rights reserved.
Keywords: HER2-positive breast cancer Trastuzumab Pertuzumab Lapatinib
Introduction Breast cancer is now recognized as a heterogeneous disease characterized by various biologic drivers and related clinical outcomes. The use of systemic therapy including chemotherapy for higher proliferation tumors, endocrine therapy for patients with estrogen receptor (ER)-positive disease, and HER2-targeted therapy for all patients whose tumors overexpress HER2 likely accounts for over half of the observed reduction in breast cancer mortality in recent history [1]. The HER2-positive phenotype observed in about 15% of patients is of great scientific interest as HER2 overexpression is associated with worse clinical outcome (worse prognosis) in the absence of therapy [2]. HER2 gene amplification was first associated with worse clinical outcomes in the late 1980s by Slamon and colleagues, who went on to describe HER2 protein overexpression as a potential predictive tool for clinical use [2,3]. Fast forward a decade, and in 1998 the clinical course of HER2-positive disease was fundamentally altered upon the release of the first-generation trial * Corresponding author. E-mail address: [email protected] (A.C. Wolff). 1 Both authors equally contributed to this manuscript. 0960-9776/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.breast.2013.11.011
of trastuzumab added to chemotherapy in metastatic breast cancer (MBC) [4]. By 2005, the natural history of this breast cancer subtype in the adjuvant setting was forever changed with the release of the findings from the first generation adjuvant trials combining trastuzumab with chemotherapy, concomitantly or sequentially [5e8]. Historically, new treatments are tested first in the metastatic disease and then evaluated in the preoperative (or neoadjuvant) setting. In this context, lapatinib in 2007, then pertuzumab in 2012 and ado-trastuzumab emtansine in 2013 were approved in the US and elsewhere based on evidence showing an improvement in survival outcomes in patients with mostly trastuzumab-naïve (pertuzumab) or trastuzumab-exposed (lapatinib and adotrastuzumab emtansine) metastatic disease [9,10]. The clinical benefit demonstrated by those drugs in advanced disease has now triggered several adjuvant trials testing them in combination with chemotherapy, but also without conventional chemotherapy, using single or dual HER2-targeting drugs. A key first step in appropriately deciding on the use of HER2targeted therapy is the accurate determination of HER2 overexpression [11]. A few studies have observed as much as 25% discordance between test results from the primary and metastatic sites [12e14]. The reasons for this might include a change in biology
M.C. Figueroa-Magalhães et al. / The Breast 23 (2014) 128e136
[15e17], tumor heterogeneity [18], and analytical variability [19]. Available evidence suggests no benefit from HER2-targeted therapy in patients with HER2-negative metastatic disease [20]. However, unplanned retrospective assessment from two of the adjuvant trastuzumab trials suggest a possible benefit from trastuzumab in patients with HER2-negative disease [21,22], and this is now being prospectively tested in trial NSABP B47 for patients with normal levels of HER2 expression (NCT01275677). This review article discusses current treatment options for breast cancer patients with HER2-positive disease in the adjuvant, neoadjuvant, and metastatic setting, along with the fast moving landscape of HER2-targeted agents in clinical development. Metastatic setting Thus far, four separate HER2-targeted agents (trastuzumab, lapatinib, pertuzumab and ado-trastuzumab emtansine) have been approved for treatment of HER2-positive MBC patients. Much of their current use is driven by the design of the studies that led to their regulatory approval, but much remains unknown about their optimal use, alone or in combination. First-line therapy The approval of trastuzumab in the first-line combined with chemotherapy was based on a single phase 3 study that randomized patients with HER2-positive breast cancer and metastatic disease to an anthracycline regimen (or paclitaxel if prior anthracycline) with or without concomitant trastuzumab [4]. There was a significant improvement in median time to progression (TTP, 7.4 vs 4.6 months, p < 0.001), overall response rate (ORR, 50% vs 32%, p < 0.001), and median overall survival (OS, 25.1 vs 20.3 months; p ¼ 0.046), along with an unacceptably high risk of cardiotoxicity with the concomitant administration of trastuzumab and an anthracycline. Much has been discussed about a potential clinical synergism between platinum drugs and trastuzumab. In vitro data suggests that trastuzumab modulates platinum resistance [23] but the clinical experience has been mixed. Adding carboplatin to trastuzumab plus paclitaxel led to a greater ORR (52% vs 36%, p ¼ 0.04) and progression-free survival (PFS 10.7 vs 7.1 months, p ¼ 0.03), but not OS (35.7 vs 32.2 months, p ¼ 0.76) [24]. In contrast, no TTP, response rate (RR), or OS benefit was observed in trial BCIRG 007 with the addition of carboplatin to docetaxel and trastuzumab [25]. Trastuzumab can be safely combined with drugs like vinorelbine, [26] docetaxel [27], and capecitabine, [28,29] with observed toxicities driven primarily by the chemotherapy drug. Pertuzumab targets the dimerization of HER2 and HER3 and has clinical activity beyond the first line setting. A small multicenter single-arm trial showed that pertuzumab plus trastuzumab is an active and safe combination in patients with HER2-positive MBC whose disease progressed after prior trastuzumab [30], while a separate trial showed no benefit from pertuzumab in patients with HER2-negative disease [31]. Recently, the CLEOPATRA trial tested the concept of dual versus single HER2-targeting with the addition of pertuzumab to trastuzumab and docetaxel chemotherapy as first-line therapy in over 800 patients with HER2-positive MBC patients, where less than half of the patients had prior adjuvant chemotherapy and only w10% had prior adjuvant trastuzumab [32]. There was a significant improvement in PFS (18.5 vs 12.4 months, HR ¼ 0.62, p < 0.001) and OS (HR ¼ 0.66, p ¼ 0.008) without an apparent increase in cardiac toxicity, though with a greater risk of febrile neutropenia and diarrhea. Of interest when examining future trials that lacked a cross over design (including the recent CLEOPATRA trial of first-line pertuzumab), the clinical benefit from trastuzumab in the first pivotal
129
MBC trial was observed despite a planned cross-over from the control arm to trastuzumab upon progression. Later on, a diseasefree survival (DFS) benefit was also observed in the adjuvant HERA adjuvant trial [8] following late cross-over to the trastuzumab arm upon release of the primary efficacy data from this trial. These findings serve to highlight the impact of trastuzumab on the natural history of HER2-positive breast cancer. In total, these findings led to the recommendation by some that for patients with disease progression after trastuzumab-based therapy without pertuzumab, a line of therapy with trastuzumab plus pertuzumab (with or without a cytotoxic agent like vinorelbine or taxane) should be considered, though further research is needed regarding the optimal sequencing of anti-HER2 therapy [33]. Futhermore, biomarker analyses from the CLEOPATRA trial suggest mutations in PI3K were associated with a poor prognosis in both arms, while an abstract presentation suggest that the clinical benefit from pertuzumab was more substantial in patients with tumors showing wild-type PI3K [34]. These data have been presented in abstract form and require further confirmation. Subsequent lines of therapy Several recent randomized trials have demonstrated benefit with continuing trastuzumab therapy following disease progression on a trastuzumab-containing regimen [35,36]. One such study (GBG-26) tested capecitabine with or without trastuzumab after prior progression on trastuzumab. While it closed due to poor accrual after 156 patients and reported no significant difference in OS [37], a post-hoc analysis showed a better post-progression survival favoring continuation of trastuzumab without added toxicity. Another trial evaluated lapatinib plus capecitabine after prior anthracycline/taxane and progression on trastuzumab-based therapy [38,39], and reported a significant improvement in TTP (6.2 vs 4.3 months, p < 0.001), ORR (24% vs 14%, p ¼ 0.017), and possibly less central nervous system (CNS) events (6% vs 2%, p ¼ 0.045), favoring the addition of lapatinib to capecitabine. Preliminary results of BOLERO-3 trial have been presented thus far in abstract form. It evaluated the role of everolimus combined with vinorelbine plus trastuzumab in reversing trastuzumabresistance in heavily pretreated HER2-positive MBC patients [40]. Initial findings suggest an improvement in survival, but longer follow-up and formal peer-review of these data are needed. Ado-trastuzumab emtansine (T-DM1) combines an antibody targeting HER2 with an anti-microtubule drug [41]. A phase 1 study in 24 heavily pretreated patients with HER2-positive MBC that had progression on trastuzumab showed a clinical benefit rate (CBR) from ado-trastuzumab emtansine of 73% [42]. Observed side effects included mild, reversible thrombocytopenia, elevation of transaminases, and fatigue, but not cardiac toxicity. Ado-trastuzumab emtansine is active after prior exposure to lapatinib [43,44] and has also been tested in the first line setting [45,46]. Finally, the EMILIA registration trial randomized 991 patients previously treated with trastuzumab and a taxane to ado-trastuzumab emtansine versus lapatinib plus capecitabine. [47] There was a significant improvement in PFS favoring the ado-trastuzumab emtansine arm (9.6 vs 6.4 months, HR ¼ 0.65, p < 0.001), OS (30.9 vs 25.1 months, HR ¼ 0.68, p < 0.001), and ORR (43.6% vs 30.8%, p < 0.001), and a favorable toxicity profile except for thrombocytopenia and elevation of transaminases. Dual HER2-targeting metastatic regimens A phase 3 study of 296 patients tested lapatinib versus lapatinib plus trastuzumab in those extensively pre-treated with regimens containing trastuzumab and chemotherapy, and observed a
130
M.C. Figueroa-Magalhães et al. / The Breast 23 (2014) 128e136
significant benefit in both PFS and OS in patients treated with the combination [48,49]. While these data support the combination of trastuzumab plus lapatinib in patients with disease progression after multiple lines of trastuzumab-based treatment, a limitation was the absence of a treatment arm that continued the use of trastuzumab plus a cytotoxic drug. The synergism of the combination of trastuzumab and pertuzumab was evaluated in a phase 2 study in patients with HER2positive metastatic breast tumors who had progression on trastuzumab therapy. This combination led to an ORR of 24.2% and a CBR of 50%, and was well tolerated [30]. Encouraging results from a phase 1b/2 evaluating dual targeting of HER2 without the use of chemotherapy with a combination of ado-trastuzumab emtansine and pertuzumab were recently presented [50], and an ongoing phase 3 study is evaluating the combination of pertuzumab and ado-trastuzumab emtansine versus trastuzumab and taxane (docetaxel or paclitaxel) versus ado-trastuzumab emtansine (MARIANNE; NCT01120184). A small study of 29 patients showed some activity of pertuzumab in HER2-positive breast cancer that progressed to trastuzumab therapy. However, combining pertuzumab and trastuzumab appears to lead to a higher RR and greater CBR compared to pertuzumab monotherapy [51]. HER2-positive and HR-positive Enrollment data from various adjuvant trials, which may be biased by clinician concern and referral selection, suggest that half of the patients with HER2-positive disease also express the ER. Several studies have shown that HER2-targeted therapy is beneficial when added to endocrine therapy like an aromatase inhibitor (AI) for this patient population. In TAnDEM, 208 postmenopausal patients with HER2- and hormone receptor-positive disease were randomized to anastrozole alone or with trastuzumab [52]. Eligible patients were those who previously received tamoxifen as adjuvant or metastatic treatment, while patients previously treated with chemotherapy in the metastatic setting were excluded. ORR and PFS were significantly improved with the combination of trastuzumab plus an AI versus AI alone (20% vs 7%, and 4.8 vs 2.4 months respectively), while the OS was similar (28.5 vs 23.9 months, p ¼ 0.325) likely due to extensive cross-over to trastuzumab. Outcomes also appeared improved when trastuzumab was added to letrozole in eLEcTRA trial (ORR 27% vs 13%) [53] or when lapatinib was added to letrozole with an improved PFS (8.2 vs 3.0 months, p ¼ 0.019) but once again a similar OS (33.3 vs 32.3 months, p ¼ 0.113) [54]. However, we must note that the optimal therapy sequence for patients with HER2-positive/ER-positive disease remains unclear. One approach might be to start with endocrine therapy and trastuzumab and delay chemotherapy until disease progression. Others may prefer an induction approach using trastuzumab plus chemotherapy until maximum response followed by maintenance endocrine therapy with trastuzumab, based on indirect data from trials like CLEOPATRA.
months, and median time to subsequent treatment with WBRT of 8 months. The results of this study suggest that lapatinib combined with capecitabine can be an alternative to WBRT at first, after appropriate evaluation by a multidisciplinary team. Therefore, improved control of CNS disease in HER2-positive breast cancer is an area of great research interest. Translational Breast Cancer Research Consortium 022 trial is evaluating the single agent activity of neratinib in patients with HER2-positive breast cancer with CNS involvement (NCT01494662). Adjuvant setting In 2013, trastuzumab remained the only HER2-targeted agent approved for use in the adjuvant setting [5e8,57]. Published results from completed adjuvant trials have described its use in concomitant and sequential combination regimens with anthracycline and non-anthracycline chemotherapy (Table 1). Concomitant chemo/trastuzumab While initially designed as separate trials, the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-31 and North Central Cancer Treatment Group (NCCTG) N9831 trials were jointly analyzed due to their similar eligibility criteria and to allow an earlier evaluation of clinical outcomes. Both studies had a similar patient population, though N9831 also included women with highrisk node-negative disease. NSABP B-31 and N9831 trials randomly assigned patients to doxorubicin plus cyclophosphamide for 4 cycles followed by paclitaxel (AC-T) for 4 cycles every 3 weeks versus the same regimen with weekly trastuzumab (H) starting with the first dose of paclitaxel and continued for a full year (AC-TH). In a joint analysis that included patients similarly treated in the control (AC-T) and concomitant (AC-TH) arms of N9831 and of the NSABP B-31 trials, a significant improvement in DFS (HR 0.52, p < 0.001) and a reduction of death by 39% (OS, HR 0.61, p < 0.001) was observed with the addition of trastuzumab starting with paclitaxel versus just chemotherapy [6]. Sequential chemo/trastuzumab A third arm of N9831 tested trastuzumab after all chemotherapy completed in a sequential fashion (AC-T-H, n ¼ 1097) similar to the
Table 1 Trastuzumab in the adjuvant treatment of HER2-positive early breast cancer. Study
Patients
Regimen
OS HR/P
DFS HR (p Value)
BCIRG006 [7]
3222
AC / D AC / D þ Tr / Tr D þ Carbo þ Tr / Tr D/V / FEC D/V þ Tr / FEC CT RT / OBS. CT RT / Tr 1y CT RT / Tr 2y AC / P AC / P þ Tr / Tr
0.63/
Contents lists available at ScienceDirect
The Breast journal homepage: www.elsevier.com/brst
Review
Treatment of HER2-positive breast cancer Maria Cristina Figueroa-Magalhães 1, Danijela Jelovac 1, Roisin M. Connolly, Antonio C. Wolff* Breast Cancer Program, The Johns Hopkins Kimmel Comprehensive Cancer Center, 1650 Orleans Street, CRB1-189, Baltimore, MD 21287, USA
a r t i c l e i n f o
a b s t r a c t
Article history: Received 24 January 2013 Received in revised form 23 September 2013 Accepted 24 November 2013
The human epidermal growth factor receptor 2 gene (HER2) is overexpressed and/or amplified in w15% of breast cancer patients and was identified a quarter century ago as a marker of poor prognosis. By 1998, antibody therapy targeting the HER2 pathway was shown to demonstrably improve progression-free and overall survival in metastatic disease, and in 2005 evidence of improvement in disease-free and overall survival from the first generation of trastuzumab adjuvant trials became available. However, not all patients with HER2 overexpression benefit from trastuzumab. Second-generation studies in metastatic disease led to the approval of several new HER2-targeted therapies using small molecule tyrosine kinase inhibitors such as lapatinib, new HER2/HER3 antibodies such as pertuzumab, and the new antibody chemotherapy conjugate ado-trastuzumab emtansine. These successes supported the launch of secondgeneration adjuvant trials testing single and dual HER2-targeted agents, administered concomitantly or sequentially with chemotherapy that will soon complete accrual. HER2-positive breast cancer in the setting of HER2-targeted therapy is no longer associated with poor prognosis, and recent guidance by the US Food and Drug Administration suggests that pathologic response to HER2-targeted therapy given preoperatively may allow an earlier assessment of their clinical benefit in the adjuvant setting. An adjuvant trial of trastuzumab in patient whose tumors express normal levels of HER2 and trials of single/ dual HER2-targeting without chemotherapy are also ongoing. In this article, we review the current data on the therapeutic management of HER2-positive breast cancer. Ó 2013 Elsevier Ltd. All rights reserved.
Keywords: HER2-positive breast cancer Trastuzumab Pertuzumab Lapatinib
Introduction Breast cancer is now recognized as a heterogeneous disease characterized by various biologic drivers and related clinical outcomes. The use of systemic therapy including chemotherapy for higher proliferation tumors, endocrine therapy for patients with estrogen receptor (ER)-positive disease, and HER2-targeted therapy for all patients whose tumors overexpress HER2 likely accounts for over half of the observed reduction in breast cancer mortality in recent history [1]. The HER2-positive phenotype observed in about 15% of patients is of great scientific interest as HER2 overexpression is associated with worse clinical outcome (worse prognosis) in the absence of therapy [2]. HER2 gene amplification was first associated with worse clinical outcomes in the late 1980s by Slamon and colleagues, who went on to describe HER2 protein overexpression as a potential predictive tool for clinical use [2,3]. Fast forward a decade, and in 1998 the clinical course of HER2-positive disease was fundamentally altered upon the release of the first-generation trial * Corresponding author. E-mail address: [email protected] (A.C. Wolff). 1 Both authors equally contributed to this manuscript. 0960-9776/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.breast.2013.11.011
of trastuzumab added to chemotherapy in metastatic breast cancer (MBC) [4]. By 2005, the natural history of this breast cancer subtype in the adjuvant setting was forever changed with the release of the findings from the first generation adjuvant trials combining trastuzumab with chemotherapy, concomitantly or sequentially [5e8]. Historically, new treatments are tested first in the metastatic disease and then evaluated in the preoperative (or neoadjuvant) setting. In this context, lapatinib in 2007, then pertuzumab in 2012 and ado-trastuzumab emtansine in 2013 were approved in the US and elsewhere based on evidence showing an improvement in survival outcomes in patients with mostly trastuzumab-naïve (pertuzumab) or trastuzumab-exposed (lapatinib and adotrastuzumab emtansine) metastatic disease [9,10]. The clinical benefit demonstrated by those drugs in advanced disease has now triggered several adjuvant trials testing them in combination with chemotherapy, but also without conventional chemotherapy, using single or dual HER2-targeting drugs. A key first step in appropriately deciding on the use of HER2targeted therapy is the accurate determination of HER2 overexpression [11]. A few studies have observed as much as 25% discordance between test results from the primary and metastatic sites [12e14]. The reasons for this might include a change in biology
M.C. Figueroa-Magalhães et al. / The Breast 23 (2014) 128e136
[15e17], tumor heterogeneity [18], and analytical variability [19]. Available evidence suggests no benefit from HER2-targeted therapy in patients with HER2-negative metastatic disease [20]. However, unplanned retrospective assessment from two of the adjuvant trastuzumab trials suggest a possible benefit from trastuzumab in patients with HER2-negative disease [21,22], and this is now being prospectively tested in trial NSABP B47 for patients with normal levels of HER2 expression (NCT01275677). This review article discusses current treatment options for breast cancer patients with HER2-positive disease in the adjuvant, neoadjuvant, and metastatic setting, along with the fast moving landscape of HER2-targeted agents in clinical development. Metastatic setting Thus far, four separate HER2-targeted agents (trastuzumab, lapatinib, pertuzumab and ado-trastuzumab emtansine) have been approved for treatment of HER2-positive MBC patients. Much of their current use is driven by the design of the studies that led to their regulatory approval, but much remains unknown about their optimal use, alone or in combination. First-line therapy The approval of trastuzumab in the first-line combined with chemotherapy was based on a single phase 3 study that randomized patients with HER2-positive breast cancer and metastatic disease to an anthracycline regimen (or paclitaxel if prior anthracycline) with or without concomitant trastuzumab [4]. There was a significant improvement in median time to progression (TTP, 7.4 vs 4.6 months, p < 0.001), overall response rate (ORR, 50% vs 32%, p < 0.001), and median overall survival (OS, 25.1 vs 20.3 months; p ¼ 0.046), along with an unacceptably high risk of cardiotoxicity with the concomitant administration of trastuzumab and an anthracycline. Much has been discussed about a potential clinical synergism between platinum drugs and trastuzumab. In vitro data suggests that trastuzumab modulates platinum resistance [23] but the clinical experience has been mixed. Adding carboplatin to trastuzumab plus paclitaxel led to a greater ORR (52% vs 36%, p ¼ 0.04) and progression-free survival (PFS 10.7 vs 7.1 months, p ¼ 0.03), but not OS (35.7 vs 32.2 months, p ¼ 0.76) [24]. In contrast, no TTP, response rate (RR), or OS benefit was observed in trial BCIRG 007 with the addition of carboplatin to docetaxel and trastuzumab [25]. Trastuzumab can be safely combined with drugs like vinorelbine, [26] docetaxel [27], and capecitabine, [28,29] with observed toxicities driven primarily by the chemotherapy drug. Pertuzumab targets the dimerization of HER2 and HER3 and has clinical activity beyond the first line setting. A small multicenter single-arm trial showed that pertuzumab plus trastuzumab is an active and safe combination in patients with HER2-positive MBC whose disease progressed after prior trastuzumab [30], while a separate trial showed no benefit from pertuzumab in patients with HER2-negative disease [31]. Recently, the CLEOPATRA trial tested the concept of dual versus single HER2-targeting with the addition of pertuzumab to trastuzumab and docetaxel chemotherapy as first-line therapy in over 800 patients with HER2-positive MBC patients, where less than half of the patients had prior adjuvant chemotherapy and only w10% had prior adjuvant trastuzumab [32]. There was a significant improvement in PFS (18.5 vs 12.4 months, HR ¼ 0.62, p < 0.001) and OS (HR ¼ 0.66, p ¼ 0.008) without an apparent increase in cardiac toxicity, though with a greater risk of febrile neutropenia and diarrhea. Of interest when examining future trials that lacked a cross over design (including the recent CLEOPATRA trial of first-line pertuzumab), the clinical benefit from trastuzumab in the first pivotal
129
MBC trial was observed despite a planned cross-over from the control arm to trastuzumab upon progression. Later on, a diseasefree survival (DFS) benefit was also observed in the adjuvant HERA adjuvant trial [8] following late cross-over to the trastuzumab arm upon release of the primary efficacy data from this trial. These findings serve to highlight the impact of trastuzumab on the natural history of HER2-positive breast cancer. In total, these findings led to the recommendation by some that for patients with disease progression after trastuzumab-based therapy without pertuzumab, a line of therapy with trastuzumab plus pertuzumab (with or without a cytotoxic agent like vinorelbine or taxane) should be considered, though further research is needed regarding the optimal sequencing of anti-HER2 therapy [33]. Futhermore, biomarker analyses from the CLEOPATRA trial suggest mutations in PI3K were associated with a poor prognosis in both arms, while an abstract presentation suggest that the clinical benefit from pertuzumab was more substantial in patients with tumors showing wild-type PI3K [34]. These data have been presented in abstract form and require further confirmation. Subsequent lines of therapy Several recent randomized trials have demonstrated benefit with continuing trastuzumab therapy following disease progression on a trastuzumab-containing regimen [35,36]. One such study (GBG-26) tested capecitabine with or without trastuzumab after prior progression on trastuzumab. While it closed due to poor accrual after 156 patients and reported no significant difference in OS [37], a post-hoc analysis showed a better post-progression survival favoring continuation of trastuzumab without added toxicity. Another trial evaluated lapatinib plus capecitabine after prior anthracycline/taxane and progression on trastuzumab-based therapy [38,39], and reported a significant improvement in TTP (6.2 vs 4.3 months, p < 0.001), ORR (24% vs 14%, p ¼ 0.017), and possibly less central nervous system (CNS) events (6% vs 2%, p ¼ 0.045), favoring the addition of lapatinib to capecitabine. Preliminary results of BOLERO-3 trial have been presented thus far in abstract form. It evaluated the role of everolimus combined with vinorelbine plus trastuzumab in reversing trastuzumabresistance in heavily pretreated HER2-positive MBC patients [40]. Initial findings suggest an improvement in survival, but longer follow-up and formal peer-review of these data are needed. Ado-trastuzumab emtansine (T-DM1) combines an antibody targeting HER2 with an anti-microtubule drug [41]. A phase 1 study in 24 heavily pretreated patients with HER2-positive MBC that had progression on trastuzumab showed a clinical benefit rate (CBR) from ado-trastuzumab emtansine of 73% [42]. Observed side effects included mild, reversible thrombocytopenia, elevation of transaminases, and fatigue, but not cardiac toxicity. Ado-trastuzumab emtansine is active after prior exposure to lapatinib [43,44] and has also been tested in the first line setting [45,46]. Finally, the EMILIA registration trial randomized 991 patients previously treated with trastuzumab and a taxane to ado-trastuzumab emtansine versus lapatinib plus capecitabine. [47] There was a significant improvement in PFS favoring the ado-trastuzumab emtansine arm (9.6 vs 6.4 months, HR ¼ 0.65, p < 0.001), OS (30.9 vs 25.1 months, HR ¼ 0.68, p < 0.001), and ORR (43.6% vs 30.8%, p < 0.001), and a favorable toxicity profile except for thrombocytopenia and elevation of transaminases. Dual HER2-targeting metastatic regimens A phase 3 study of 296 patients tested lapatinib versus lapatinib plus trastuzumab in those extensively pre-treated with regimens containing trastuzumab and chemotherapy, and observed a
130
M.C. Figueroa-Magalhães et al. / The Breast 23 (2014) 128e136
significant benefit in both PFS and OS in patients treated with the combination [48,49]. While these data support the combination of trastuzumab plus lapatinib in patients with disease progression after multiple lines of trastuzumab-based treatment, a limitation was the absence of a treatment arm that continued the use of trastuzumab plus a cytotoxic drug. The synergism of the combination of trastuzumab and pertuzumab was evaluated in a phase 2 study in patients with HER2positive metastatic breast tumors who had progression on trastuzumab therapy. This combination led to an ORR of 24.2% and a CBR of 50%, and was well tolerated [30]. Encouraging results from a phase 1b/2 evaluating dual targeting of HER2 without the use of chemotherapy with a combination of ado-trastuzumab emtansine and pertuzumab were recently presented [50], and an ongoing phase 3 study is evaluating the combination of pertuzumab and ado-trastuzumab emtansine versus trastuzumab and taxane (docetaxel or paclitaxel) versus ado-trastuzumab emtansine (MARIANNE; NCT01120184). A small study of 29 patients showed some activity of pertuzumab in HER2-positive breast cancer that progressed to trastuzumab therapy. However, combining pertuzumab and trastuzumab appears to lead to a higher RR and greater CBR compared to pertuzumab monotherapy [51]. HER2-positive and HR-positive Enrollment data from various adjuvant trials, which may be biased by clinician concern and referral selection, suggest that half of the patients with HER2-positive disease also express the ER. Several studies have shown that HER2-targeted therapy is beneficial when added to endocrine therapy like an aromatase inhibitor (AI) for this patient population. In TAnDEM, 208 postmenopausal patients with HER2- and hormone receptor-positive disease were randomized to anastrozole alone or with trastuzumab [52]. Eligible patients were those who previously received tamoxifen as adjuvant or metastatic treatment, while patients previously treated with chemotherapy in the metastatic setting were excluded. ORR and PFS were significantly improved with the combination of trastuzumab plus an AI versus AI alone (20% vs 7%, and 4.8 vs 2.4 months respectively), while the OS was similar (28.5 vs 23.9 months, p ¼ 0.325) likely due to extensive cross-over to trastuzumab. Outcomes also appeared improved when trastuzumab was added to letrozole in eLEcTRA trial (ORR 27% vs 13%) [53] or when lapatinib was added to letrozole with an improved PFS (8.2 vs 3.0 months, p ¼ 0.019) but once again a similar OS (33.3 vs 32.3 months, p ¼ 0.113) [54]. However, we must note that the optimal therapy sequence for patients with HER2-positive/ER-positive disease remains unclear. One approach might be to start with endocrine therapy and trastuzumab and delay chemotherapy until disease progression. Others may prefer an induction approach using trastuzumab plus chemotherapy until maximum response followed by maintenance endocrine therapy with trastuzumab, based on indirect data from trials like CLEOPATRA.
months, and median time to subsequent treatment with WBRT of 8 months. The results of this study suggest that lapatinib combined with capecitabine can be an alternative to WBRT at first, after appropriate evaluation by a multidisciplinary team. Therefore, improved control of CNS disease in HER2-positive breast cancer is an area of great research interest. Translational Breast Cancer Research Consortium 022 trial is evaluating the single agent activity of neratinib in patients with HER2-positive breast cancer with CNS involvement (NCT01494662). Adjuvant setting In 2013, trastuzumab remained the only HER2-targeted agent approved for use in the adjuvant setting [5e8,57]. Published results from completed adjuvant trials have described its use in concomitant and sequential combination regimens with anthracycline and non-anthracycline chemotherapy (Table 1). Concomitant chemo/trastuzumab While initially designed as separate trials, the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-31 and North Central Cancer Treatment Group (NCCTG) N9831 trials were jointly analyzed due to their similar eligibility criteria and to allow an earlier evaluation of clinical outcomes. Both studies had a similar patient population, though N9831 also included women with highrisk node-negative disease. NSABP B-31 and N9831 trials randomly assigned patients to doxorubicin plus cyclophosphamide for 4 cycles followed by paclitaxel (AC-T) for 4 cycles every 3 weeks versus the same regimen with weekly trastuzumab (H) starting with the first dose of paclitaxel and continued for a full year (AC-TH). In a joint analysis that included patients similarly treated in the control (AC-T) and concomitant (AC-TH) arms of N9831 and of the NSABP B-31 trials, a significant improvement in DFS (HR 0.52, p < 0.001) and a reduction of death by 39% (OS, HR 0.61, p < 0.001) was observed with the addition of trastuzumab starting with paclitaxel versus just chemotherapy [6]. Sequential chemo/trastuzumab A third arm of N9831 tested trastuzumab after all chemotherapy completed in a sequential fashion (AC-T-H, n ¼ 1097) similar to the
Table 1 Trastuzumab in the adjuvant treatment of HER2-positive early breast cancer. Study
Patients
Regimen
OS HR/P
DFS HR (p Value)
BCIRG006 [7]
3222
AC / D AC / D þ Tr / Tr D þ Carbo þ Tr / Tr D/V / FEC D/V þ Tr / FEC CT RT / OBS. CT RT / Tr 1y CT RT / Tr 2y AC / P AC / P þ Tr / Tr
0.63/
