Treatment of HER2-positive Breast Cancer

Abstract

The human epidermal growth factor receptor 2 gene (HER2) is overexpressed and/or amplified in ~ 15% 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 second-generation 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.

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 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. ^5,6,7,8

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 trastuzumabnaïve (pertuzumab) or trastuzumab-exposed (lapatinib and ado-trastuzumab 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 HER2-targeted 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. ^12,13,14 The reasons for this might include a change in biology, ^15,16,17 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=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=0.04) and progression-free survival (PFS 10.7 vs 7.1 months, p=0.03), but not OS (35.7 vs 32.2 months, p=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 ~ 10% had prior adjuvant trastuzumab. ³² There was a significant improvement in PFS (18.5 vs 12.4 months, HR= 0.62, p<0.001) and OS (HR=0.66, p=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 MBC trial was observed despite a planned cross-over from the control arm to trastuzumab upon progression. Later on, a disease-free 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= 0.017), and possibly less central nervous system (CNS) events (6% vs 2%, p= 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 trastuzumab-resistance 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 adotrastuzumab emtansine of 73%. ⁴² Observed side effects included mild, reversible thrombocytopenia, elevation of transaminases, and fatigue, but not cardiac toxicity. Adotrastuzumab 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 adotrastuzumab emtansine arm (9.6 vs 6.4 months, HR=0.65, p< 0.001), OS (30.9 vs 25.1 months, HR=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 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 HER2-positive 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

Enrolment 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= 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= 0.019) but once again a similar OS (33.3 vs 32.3 months, p= 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.

Brain Metastasis

With improved systemic control and prolonged survival in the MBC, brain metastases may ultimately become clinically manifested in up to a third of MBC patients treated with trastuzumab. ⁵⁵ Unlike trastuzumab, lapatinib appears to have anti-tumor activity within the central nervous system. In the single-arm phase 2 LANDSCAPE study, 45 patients with HER2-positive MBC with brain metastases not previously treated with whole brain radiation (WBRT), received lapatinib plus capecitabine as first-line treatment. ⁵⁶ After median follow-up of 21 months, 29 patients had an objective CNS partial response (66%), median TTP of 6 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. ^5,6,7,8,57 Published results from completed adjuvant trials have described its use in concomitant and sequential combination regimens with anthracycline and non-anthracycline chemotherapy (Table 1).

Table 1.

Trastuzumab in the Adjuvant Treatment of HER2-positive Early Breast Cancer

Study	Patients	Regimen	OS HR/p	DFS HR (p value)
BCIRG0067	3222	AC → D AC → D+Tr → Tr D+Carbo+Tr → Tr	0.63/ <0.001	0.64 (<0.001)
FinHER5	232**	D/V → FEC D/V+Tr → FEC	0.41/ 0.07	0.42 (0.02)
HERA8	5102	CT±RT → OBS. CT±RT → Tr 1y CT±RT → Tr 2y	0.76/ 0.0005*	0.76 (<0.0001*)
NCCTG N9831 and NSABP B316	4045	AC → P AC → P+Tr → Tr	0.61/ <0.001	0.52 (<0.001)
PACS 0457	528**	FEC/ED ± RT FEC/ED ± RT → Tr	0.86/ 0.41	1.27 (NS)

Abbreviations: AC – doxorubicin and cyclophosphamide; D – docetaxel; Tr – trastuzumab; Carbo – carboplatin; V – vinorelbine; FEC – fluorouracil, epirubicin and cyclophosphamide; CT – chemotherapy; RT – radiotherapy; P – paclitaxel; ED – epirubicin and docetaxel; OS – overall survival; DFS – disease-free survival; NS – non significant.; OBS – observation.

^*8 year of follow-up.

^**patients who presented HER2-positive tumors.

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 high-risk node-negative disease. NSABP B-31and 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=1097) similar to the Herceptin Adjuvant (HERA) trial, and consequently was not included in the joint analysis. When examined alone, data from all three arms of trial N9831 showed a clear trend toward improvement in DFS for patients receiving trastuzumab concurrently with paclitaxel versus sequential (84.4% vs 80.1%, HR=0.77, p= 0.022), while no OS benefit was observed (91.9% vs 89.7%, HR=0.78, p=0.102). ⁵⁸ These data support the widespread adoption of AC-TH as the preferred approach when employing an anthracycline-based approach, despite evidence by other groups describing the potential feasibility of concomitantly administering anthracyclines with trastuzumab.

Another pivotal adjuvant trial also first reported at the 2005 annual meeting of the American Society of Clinical Oncology was the HERA trial, that tested adding one or two years of trastuzumab after completion of various standard adjuvant chemotherapy regimens. HERA randomly assigned 5102 patients to begin adjuvant trastuzumab versus no adjuvant trastuzumab after chemotherapy (median time from diagnosis, 8 months). Patients with HER2-positive disease were eligible if node-positive or if node-negative disease and tumor >1cm (T1c). At a median follow up of 4 years, one year of adjuvant trastuzumab led to a 24% reduction in recurrence (HR=0.76, p<0.0001). However, partly due to the significant cross-over (65%) from the observation arm to trastuzumab after the first results released, the OS benefit from trastuzumab in HERA became apparent when evaluated after 4 years (HR=0.85, p=0.11).⁵⁹ A recent update after a median follow-up of 8 years confirmed the DFS (HR=0.76, p< 0.0001) and OS benefit (HR=0.76, p= 0.0005) from one year of trastuzumab. ⁸ However, there was no incremental benefit from a longer duration of trastuzumab (two years) and more cardiac events were observed.

To minimize the cardiotoxicity risk, ⁴ many investigators favor non-anthracycline trastuzumab regimens as tested in the adjuvant BCIRG 006 trial. ⁷ Patients received AC followed by docetaxel, AC followed by docetaxel with one year of trastuzumab, or docetaxel plus carboplatin and trastuzumab followed by trastuzumab to complete one year of therapy (TCH). After 65 months follow up, DFS was significantly improved with the addition of trastuzumab to chemotherapy (AC-docetaxel 75%, AC-docetaxel/H 84%, and TCH 81%; compared with the control arm, HR for AC-TH was 0.64 (p<0.001) and for TCH was 0.75 (p=0.04) with a significant improvement in OS (AC-docetaxel 87%, AC-docetaxel/H 92%; HR=0.63, p<0.001), and TCH 91% (HR=0.77, p=0.038). However, despite the apparent numerical advantage of the AC-docetaxel/H over TCH, the study was not designed to directly compare these two arms.

The only of six related trial that did not show a survival benefit from adjuvant trastuzumab was FNCLCC-PACS-04. This study randomized 528 women with HER2-positive, node-positive disease to adjuvant trastuzumab or not along with an anthracycline-based (with or without docetaxel) regimen. No significant DFS or OS benefit was observed with the addition of trastuzumab, ⁵⁷ and reasons may be partly due to the smaller sample size and to a smaller degree the choice of a sequential approach with chemotherapy. Although now considered less relevant, the findings from this trial helped cement a preferential use of trastuzumab combined with chemotherapy.

Shorter duration of trastuzumab

While one year of adjuvant trastuzumab was shown to significantly improve DFS and OS in HER2-positive breast cancer, concerns about cardiotoxicity remain. In the early 2000s, the Finland Herceptin (FinHER) trial tested a shorter course of trastuzumab that at first also indicated a survival benefit among 232 patients with HER2-positive disease. FinHER randomized patients to weekly trastuzumab or not for 9 weeks concurrent with docetaxel or vinorelbine followed by FEC regimen for 3 cycles. An exploratory analyses showed a significant improvement in distant DFS in patients treated with docetaxel and trastuzumab when compared to those who received docetaxel alone (HR=0.32, p=0.029) or vinorelbine and trastuzumab (HR= 0.31, p=0.020), each of those regimens followed by FEC. ⁵

FinHER investigators are now comparing nine weeks of trastuzumab plus docetaxel and FEC with the same regimen followed by 1 year of trastuzumab therapy in the SOLD study (NCT00593697). SHORT-HER (NCT00629278) is testing 9 weeks versus 12 months of trastuzumab. Three other studies in progress are testing 6 versus 12 months of trastuzumab: PERSEPHONE (NCT00712140), a trial by the Hellenic Oncology Research Group (NCT00615602), and PHARE (NCT00381901). A report by PHARE investigators in late 2012 after a median follow-up of 42.5 months indicated that 6 months of trastuzumab is non-inferior to 12 months (HR=1.28, p=0.29 for a non-inferiority HR of 1.15).⁶⁰ However, further analysis is still required.

Adjuvant therapy for tumors smaller than 1cm

The data on the role of trastuzumab in small node-negative tumors remain scarce. Retrospective institutional series from the MD Anderson Cancer Center (MDACC) ⁶¹ and Milan ⁶² suggest small HER2-positive tumors prognostically have a poor long term outcome when compared to their HER2-negative counterparts. Of limited guidance, subgroup analyses from several randomized trials have shown a benefit with adjuvant trastuzumab irrespective of tumor size, ⁶³ though its actual absolute benefit in small stage 1 tumors (like those with T1a up to 0.5 cm disease) remains unknown. Initial data from a single-arm multicenter single arm trial of 12 weeks of paclitaxel and one year of trastuzumab in node-negative tumors up to 3 cm in size are expected to be reported by the end of 2013 (NCT00542451). Absent randomized data, this regimen might become an option for patients with small node-negative HER2-positive disease in clinical scenarios where there is concern about the potential toxicity from established regimens.

Ongoing adjuvant trials

A new generation of randomized adjuvant HER2-targeted trials including ALTTO (NCT00490139), BETH (NCT00625898), TEACH (NCT00374322), APHINITY (NCT01358877) and KATHERINE (NCT01772472) trials aims to further improve outcomes for patients with HER2-positive breast cancer (Table 2). ALTTO is evaluating dual HER2-targeting combining trastuzumab plus lapatinib to target the intracellular kinase domain (NCT00490139). A pre-planned interim analysis in 2011 recommended closure of the lapatinib alone arm, as it was considered unlikely to meet pre-specified criteria to show non-inferiority to trastuzumab. This trial is now primarily testing whether dual anti-HER2 therapy with trastuzumab and lapatinib (in sequence or in combination) is preferable to the standard arm of single agent trastuzumab, and may expand on initial observations from the preoperative NeoALTTO ⁶⁴ and TBCRC 006 ⁶⁵ trials that are further discussed below.

Table 2.

Ongoing Adjuvant Trials

Trial Name	Sample Size	Trial Design	Primary Endpoint	Comments
ALTTO NCT00490139	8400	Trastuzumab Lapatinib Tr → Lapatinib Tr + Lapatinib	DFS	On August 18,2011, the lapatinib arm was closed to recruitment.
BETH NCT00625898	3509	DCTr → Tr DCTrB → TrB DTr → FEC → Tr DTrB → FEC → TrB	IDFS	Included patients with node-positive or high risk node-negative HER2-positive breast cancer.
TEACH NCT00374322	3166	Lapatinib Placebo	DFS
APHINITY NCT01358877	4800	Pertuzumab + Tr + CT Placebo + Tr + CT	IDFS
KATHERINE NCT01772472	1484	Ado-trastuzumab emtansine Trastuzumab	IDFS	Patients who have residual tumor in the breast or positive axilla after preoperative therapy.

Abbreviations: DFS – disease-free survival; D – docetaxel; C – carboplatin; Tr – trastuzumab; B – bevacizumab; FEC – 5-fluorouracil + epirubicin + cyclophosphamide; IDFS - invasive disease-free survival.

TEACH randomized over 3000 women to receive either placebo or lapatinib for one year after neoadjuvant or adjuvant chemotherapy (without HER2-targeted therapy). After 4 years of median follow up, there were fewer DFS events in the lapatinib arm (HR=0.83, p=0.053), but prespecified criteria for improvement in outcome were not met. ⁶⁶ These data, along with the closure of the lapatinib arm of ALTTO and the observed lower response rate in the lapatinib arm of NeoALTTO suggest that lapatinib alone is not a viable option in the adjuvant setting.

BETH is evaluating blockade of both the HER2 and vascular endothelial growth factor (VEGF) pathways by combining trastuzumab with the anti-VEGF monoclonal antibody bevacizumab, based on preclinical data showing a correlation between HER2 and VEGF expression ^67,68 and on preliminary phase 2 data. ⁶⁹ Over 3000 patients were treated with docetaxel plus carboplatin (TC) with trastuzumab versus TC with trastuzumab and bevacizumab, and targeted therapy was given for one year in both arms.

Data from metastatic trials of pertuzumab ³² and ado-trastuzumab emtansine ⁴⁷ have now led to ongoing adjuvant trials. APHINITY compares standard chemotherapy (nonanthracycline or anthracycline-based) plus trastuzumab with or without pertuzumab. KATHERINE is examining the role of ado-trastuzumab emtansine versus trastuzumab in patients with HER2-positive disease who have less than a pathologic complete response (pCR) after preoperative therapy with a trastuzumab-based regimen.

Neoadjuvant Setting

Interest in the role of trastuzumab in the preoperative setting for the treatment of HER2-positive operable disease began early on in the history of this agent. A small single institution trial which randomized patients to receive preoperative chemotherapy with or without trastuzumab showed a high pCR of 65.2% in those treated with trastuzumab. ⁷⁰ An update of efficacy from this trial suggested an improvement in DFS with the addition of trastuzumab. ⁷¹ supporting that pCR could be a powerful surrogate of long-term outcomes after preoperative chemotherapy. Since then, several larger trials have been reported (Table 3).

Table 3.

Anti-HER2 Therapy in the Neoadjuvant Setting

Trastuzumab
Study	Regimen	pCR (CT + T vs. CT)
MDACC Study70	P → FEC ± Tr	65.2% vs. 26.3%
NOAH trial72	AP → P → CMF ± Tr	43% vs. 23%
GeparQuattro Study73	EC → D ± capecitabine + Tr	31.7%
TECHNO trial74	EC → P + Tr	39%
ACOSOG Z1041 (NCT 00513292)	FEC → P + Tr P + Tr → FEC + Tr	Ongoing trial

Trastuzumab vs. Lapatinib
Study	Regimen	pCR (T vs. L)
GeparQuinto75	EC → D + Tr EC → D + L	30.3% vs. 22.7%

Dual - HER2 Inhibition
Study	Regimen	pCR
NeoSphere76	D + Tr*	29%
	D + Pt*	24%
	D + Tr + Pt*	45.8%
	T + Pt*	16.8%
TRYPHAENA92	FEC + Pt + T + – Docetaxel + Pt + T	61.6%
	FEC – Docetaxel + Pt + T	57.3%
	Carboplatin + Docetaxel + T + Pt	66.2%
Neo ALTTO64	L + P#	24.7%
	Tr + P#	29.5%
	L +Tr +P#	51.3%
CHERLOB93	P → FEC + Tr	25%
	P → FEC + L	26.3%
	P → FEC + L + Tr	46.7%
NSABP B41 (NCT00486668)	AC → P + Tr	49.4%
	AC → P + L	47.4%
	AC → P + Tr + L	60.2%
TBCRC 00665	Tr + L (+ letrozole if ER-positive tumor)	27%

Abbreviations: AP – doxorubicin and paclitaxel; CMF – cyclophosphamide, methotrexate and fluorouracil; Tr – trastuzumab; FEC – fluorouracil, epirubicin and cyclophosphamide; CT – chemotherapy; P – paclitaxel; EC – epirubicin and cyclophosphamide; D – docetaxel; L – lapatinib; Pt – pertuzumab; pCR – pathologic complete response.

^*Followed by surgery and FEC or FEC + docetaxel in the double blockage group.

^#Followed by surgery and FEC + anti-HER2 therapy

The NOAH trial testing the addition of trastuzumab to doxorubicin and paclitaxel followed by paclitaxel and cyclophosphamide/methotrexate/5-fluorouracil (CMF) in higher risk patients was associated with a doubling in the pCR (43% vs 23%, p= 0.002). ⁷² Of greater interest, there was an improvement in 3-year event-free survival (EFS) favoring trastuzumab, with hazard ratios from an unadjusted Cox model showing a greater likelihood of remaining event-free among those who received trastuzumab and had a pCR in the breast. A subset of over 400 patients in the GeparQuattro trial with HER2-positive disease received neoadjuvant epirubicin/cyclophosphamide (EC) followed by docetaxel with or without capecitabine and trastuzumab, and a doubling of the pCR rate to 32% was also observed. ⁷³ A higher pCR rate was also observed in the TECHNO trial with the addition of trastuzumab to chemotherapy, along with a suggestion of improved survival outcomes. ⁷⁴

Other trials have explored combined HER2-target strategies. In the GeparQuinto trial, 620 patients were randomly assigned to receive 4 cycles of EC followed by 4 cycles of docetaxel (D) with trastuzumab or lapatinib. A higher pCR rate was observed in the trastuzumab arm (30.3% vs 22.7%, p=0.04), which reinforced concerns about the feasibility of lapatinib alone as a HER2-targeted strategy. ⁷⁵ NeoALTTO, randomized over 400 patients to trastuzumab, lapatinib, or trastuzumab plus lapatinib for 6 weeks, followed by the addition of 12 weekly doses paclitaxel. The pCR rate was higher in the lapatinib/trastuzumab/paclitaxel arm when compared to the trastuzumab/paclitaxel arm (51.3% vs 29.5%, p=0.0001), though 30% of patients stopped therapy due to excessive diarrhea secondary to the lapatinib. ⁶⁴

NEOSPHERE was the largest of such studies with 417 patients randomized to 4 cycles of docetaxel with trastuzumab (TH), docetaxel with pertuzumab (TP), all three drugs combined (THP), or just dual HER2-targeted therapy with trastuzumab and pertuzumab (HP). A higher pCR rate was observed with THP compared to TH arm (45.9% vs 29%; p= 0.014). Of greater interest, an impressive pCR rate was observed with dual anti-HER2 therapy alone (27%) in patients with HER2-positive/ER-negative disease. ⁷⁶

_ENREF_5TBCRC 006 tested lapatinib with trastuzumab without chemotherapy for 12 weeks. Of note, patients with ER-positive disease also received letrozole (plus goserelin if premenopausal) based on preclinical data suggesting the potential crosstalk between the HER2 and ER pathways. The pCR rate among 64 evaluable patients was 27% (21% in the ER-positive group and 36% in the ER-negative) with an even larger response rate of 49% when assessing patients with ≤1 cm of invasive residual disease (54% in the ER-positive vs 40% in the ER-negative, respectively). ⁶⁵ These data in aggregate suggest the potential for the use of HER2-targeted therapy without chemotherapy, especially in patients with ER-negative disease or combined with endocrine therapy if ER-positive.

Of greater impact, the preoperative studies thus far reported heavily influenced the US FDA to release a draft guidance on the potential use of pCR as a regulatory endpoint for new drug development in specific tumor subtypes, specifically HER2-positive and triple negative breast cancer. ⁷⁷ In September 2013, the Oncology Drug Advisory Committee voted to the US FDA to support a recommendation to issue an accelerated approval for pertuzumab in combination with trastuzumab and docetaxel in the neoadjuvant setting, based in part on data from the NEOSPHERE trial. Full approval would then await survival outcome data from APHINITY. In the meantime, TBCRC 026 (NCT01937117) will evaluate the role of early predictors of pCR, including imaging (positron emission tomography) and blood-based markers (plasma tumor DNA). This will be a neoadjuvant trial of pertuzumab and trastuzumab as a dual HER2-targeted therapy without chemotherapy, in an effort to identify a group of women who may be treated with HER2-therapy alone and be spared chemotherapy.

Novel HER2-Directed Therapies

Despite significant progress in the treatment and outcome of patients with HER2-positive MBC over the last 15 years, a sizeable number of patients remain at significant risk for recurrence, which highlights the need for new targeted therapies and therapeutic strategies. Research in the area of HER2-targeted therapy is extremely active, and novel agents continue to be developed at a rapid pace.

Neratinib

Neratinib (HKI-272) is an oral, irreversible pan-HER2 receptor tyrosine kinase inhibitor with activity in preclinical breast cancer studies. ⁷⁸ A phase 2 study enrolled 136 MBC patients to single agent neratinib and showed an ORR of 24% in patients previously treated with trastuzumab, and 56% in trastuzumab-naïve patients. ⁷⁹ Diarrhea was the most frequent adverse event and no significant cardiac toxicity was documented. The combination of neratinib with capecitabine yielded an ORR of 50% in 22 patients previously treated with trastuzumab and a taxane. ⁸⁰ Neratinib was also tested in a phase 1/2 study with paclitaxel and vinorelbine with promising results. ^81,82 Ongoing studies are evaluating the activity of neratinib in combination with capecitabine (NCT00741260), trastuzumab (NCT00398567), and paclitaxel (NCT00445458). A randomized trial is testing neratinib plus paclitaxel versus trastuzumab plus paclitaxel (NCT00915018). As mentioned before, neratinib is also being tested in HER2-positive MBC patients with progressive CNS disease after standard therapy (TBCRC 022, NCT01494662).

Afatinib

Afatinib (BIBW 2992) is another oral, irreversible pan-HER tyrosine kinase inhibitor. Data from a single agent phase 2 study with 41 patients with HER2-positive MBC treated with afatinib after progression on trastuzumab showed 4 patients (11%) with partial responses and 15 patients (37%) with stable disease. ⁸³ The most common side effects were diarrhea and rash. Ongoing trials are evaluating afatinib in combination with trastuzumab (NCT00950742), letrozole (NCT00708214), and in the first-line setting with trastuzumab or lapatinib (NCT00826267).

HER2-targeted therapy and PIK3CA alterations

In addition to targeting HER2 itself, alternative therapeutic approaches targeting pathways downstream of HER2 are currently being tested to attempt to overcome resistance to anti-HER2 agents. For example, the PI3K pathway is involved with several cellular systems, regulating proliferation, growth, and survival. ^84,85 Preliminary findings suggest that normal phosphatidylinositide 3-kinase (PI3K)/protein kinase B (Akt) pathway signaling is required for the anti-tumor activity of trastuzumab and that PIK3 pathway activation resulting from PTEN loss or PIK3CA mutations leads to trastuzumab resistance. ⁸⁶ Preclinical data also supports a link between the PI3K/Akt pathway as a rationale to explain the observed benefit from adding pertuzumab to trastuzumab. ^87,88 Targeting the PI3K pathway may provide a feasible strategy to overcoming resistance and improve outcomes with use of anti-HER2 therapy, pending further clinical evaluations.

Immune checkpoints and HER2-targeted therapy

Cancer cells express tumor-specific and tumor-selective antigens, and there is growing interest in the evaluation of immune-based therapies to induce targeted anti-tumor responses. Strategies under investigation are exploring combinations of HER2-targeted therapies with immune checkpoint antibodies that block inhibitory receptors on immune effector cells or their ligands. ^89,90

Given the potential cumulative toxicity and cost implications of these various combinations, the identification of biomarkers to guide treatment decision-making is imperative. Ultimately, new agents that demonstrate significant efficacy in the metastatic setting will be moved to the (neo) adjuvant setting with the goal of improving the long term cure rate for patients with HER2-positive breast cancers.

Conclusion

Upon the 1998 approval of trastuzumab in the metastatic setting, the clinical landscape of HER2-positive breast cancer was forever altered. For many patients, HER2-positive MBC has become a chronic and manageable disease with meaningful responses and long periods of stability. Inevitably, new clinical problems and disease progression in sanctuary sites like the CNS have become more common. Less than a decade after its approval for metastatic disease, HER2-targeted therapy also became a reality in the adjuvant setting. Trastuzumab is now essentially recommended for all patients with early stage HER2-positive disease, with the exception of those with very small node-negative tumors (like T1a node-negative tumors) or those with significant comorbidities and at increased risk for cardiac complications.

At the same time, not all patients benefit from trastuzumab and some go on to have disease recurrence, progression, and ultimately die from disease progression. Despite our incomplete understanding of the various mechanisms of resistance, three new drugs have confirmed activity in trastuzumab-refractory disease and have since been approved in the US and elsewhere. Clinical trials are now testing lapatinib, pertuzumab, and ado-trastuzumab emtansine in the neoadjuvant and adjuvant settings, as single and dual HER2-targeted strategies, with or without chemotherapy.

Studies are also evaluating the role of pCR as a meaningful clinical endpoint for drug approval, which could make studies more efficient and reduce time to initial approval of new drugs. There is also great interest in early predictors of outcome. Potential markers predictive of pCR and of clinical benefit, including imaging and blood markers like plasma tumor DNA, ⁹¹ are now being evaluated to help identify early on patients most likely to benefit from these strategies. In addition to correlations with pCR in the preoperative setting, such predictive markers of clinical benefit and residual risk might also help identify patients who might avoid surgery after preoperative therapy, might avoid standard chemotherapy and continue on with HER2-targeted drugs alone, and also those with a meaningful residual risk who might be candidates for additional treatment and investigational studies.

Questions still remain regarding the most optimal sequence, duration and combinations of anti-HER2 targeted agents, with and without chemotherapy, in the advanced and in the adjuvant settings. The optimal timing of the addition of pertuzumab to trastuzumab as palliative therapy and whether pertuzumab should be continued along with trastuzumab upon disease progression remains unclear. As these new HER2-targeted drugs are now being tested in the adjuvant setting, alone or in dual antibody regimens without concomitant or sequential chemotherapy, the need for accurate HER2 testing to ensure that the right patient receives the right treatment is now more critical than ever. In this regard, the American Society of Clinical Oncology and the College of American Pathologists released in late 2013, a guideline update on HER2 testing in breast cancer (NB: PubMed reference will be available in October 2013).

Our understanding regarding mechanisms of resistance to HER2-targeted therapy is still limited. Clinical applications that exploit interactions with other critical tumor pathways are still limited in scope. ⁸⁵ Studies evaluating clinical activity of regimens combining antibodies that target the HER2 pathway and immune checkpoints are also in development, and there is a growing realization of the critical need to effectively combine anti-estrogens with HER2-targeted drugs in patients with dual expression of the ER and HER2 pathways. Much remains to be understood, though the progress thus far in the clinical management of HER2-positive breast cancer portends a bright future ahead for patients and all those who care about them.