Treatment of HER2-overexpressing Metastatic Breast Cancer

Shruti Sheth

Sumanta Kumar Pal

Mark D. Pegram

INTRODUCTION

In 2013, it is estimated that 232,340 new cases of breast cancer will be diagnosed in females, and 2,240 in males, with a combined mortality of 40,030 (1). Of the new cases, approximately 6% will have de novo metastatic disease at the time of initial presentation (2). Additionally, a substantial proportion of those patients diagnosed with early-stage disease will go on to develop metastatic breast cancer (MBC) despite advances in locoregional and systemic adjuvant and neoadjuvant therapies (3). Whereas traditional cytotoxic chemotherapy (and endocrine manipulation for ER-positive disease) has been the mainstay of treatment for these patients, targeted therapeutics directed against human epidermal growth factor receptor 2 (HER2/ERBB2) emerging over the past 15 years have significantly improved outcomes for this subset of patients with MBC (4).

The receptor tyrosine kinase HER2 is a member of the ERBB family of transmembrane receptors, including HER1 (ERBB1, or EGFR), HER3 (ERBB3), and HER4 (ERBB4) (5). The ERBB family of receptors possesses a wide range of biological activities relating to malignant phenotypes, including cell proliferation, invasion, migration, angiogenesis, and cell survival. With the exception of HER2, ERBB family receptors undergo a conformational change in the ectodomain as a consequence of binding to as many as a dozen soluble ERBB ligands. This conformational change exposes a β-hairpin loop dimerization domain that facilitates EGFR, HER3, and HER4 to undergo homo- or heterodimerization (6). Dimerization leads to structural (allosteric) activation of intracellular kinase domains, with subsequent activation of a number of signal transduction cascades, including Rasmitogen-activated protein kinase (Ras-MAPK), phosphatidyl 3′ kinase-protein kinase B (PI3K-PKB/Akt), and phospholipase C-protein kinase C (PLC-PKC) pathways (7). By contrast, HER2 does not bind to any of the soluble ERBB-family ligands, and analysis of the crystal structure of the HER2 ectodomain demonstrates that the dimerization domain is natively exposed in an open conformation, suggesting that this transmembrane receptor species remains constitutively poised for dimerization (8). This unique structural property has been offered as a rationale for enhanced mitogenesis seen with increased HER2 expression levels, such as those observed in HER2-amplified tumors and in preclinical models of enforced HER2 overexpression in breast and ovarian cell line and xenograft models (9). Indeed, clinical data defining the role of HER2 in association with an aggressive tumor phenotype has served as the impetus for the development of HER2-targeted therapies. Given that as many as 20% of breast cancer patients harbor tumors with HER2 gene amplification, the clinical impact of such therapies will remain relevant for the foreseeable future (10).

HUMANIZED ANTI-HER2 MONOCLONAL ANTIBODIES AS THERAPY FOR HER2-POSITIVE MBC

Development of Trastuzumab

Initially, several murine monoclonal antibodies with anti-proliferative activity specifically against HER2-overexpressing human cancer cell lines were identified and characterized (11, 12). The complementarity-determining regions from one
of the most potent of these murine monoclonal antibodies were subsequently fused into a human IgG₁ framework, resulting in a humanized HER2-directed monoclonal antibody, trastuzumab (13). Preclinical studies of trastuzumab demonstrated that following the humanization procedure, the activity of the antibody against HER2-overexpressing cancer cell lines and xenografts was retained, particularly when used in combination with other cytotoxic therapeutics (14). Numerous studies have been conducted that focused on the mechanisms of trastuzumab-related anti-tumor activity. Several plausible hypotheses have been suggested to account for the clinical activity of trastuzumab. Resolution of the crystal structure of trastuzumab complexed with HER2 has led to identification of a trastuzumab-binding epitope in the juxtamembrane region (subdomain IV) of the HER2 ectodomain. It is possible that this juxtamembrane binding generates steric alteration of HER2 dimers to the extent that intracellular tyrosine kinase domains cannot efficiently interact and activate (8). Moreover, modification of key cell cycle regulators (i.e., increased levels of p27, a Cdk2 inhibitor) subsequent to trastuzumab binding have been observed (15). Studies additionally suggest that inhibition of HER2 ectodomain cleavage by metalloproteinases may serve as a mechanism of trastuzumab activity, because the truncated p95 fragment generated from cleavage retains intracellular kinase activity (16, 17). Alternatively, preclinical data support stimulation of antibody-dependent cellular cytotoxicity (ADCC) as an important mediator of trastuzumab’s mechanism(s) of action (18, 19).

Single-Agent Trastuzumab for Metastatic Breast Cancer

Pilot clinical trials suggested only modest activity of single-agent trastuzumab in the setting of heavily pretreated MBC with HER2-overexpression (20). Subsequently, a much larger study in a pretreated MBC population explored a dosing regimen including a loading dose of 4 mg/kg followed by 2 mg/kg weekly maintenance therapy. In a total of 213 treated patients, 8 CRs and 22 PRs were observed (ORR 15%). The median duration of response was 9.1 months, and median overall survival (OS) was 13 months (21). Clinically significant cardiac dysfunction was noted in 4.7% of patients, comprised of congestive heart failure (CHF), cardiomyopathy, or a decrease in ejection fraction (>10%). These observed cardiac adverse events, along with events reported in a concurrent trial of trastuzumab in combination with chemotherapy, prompted further examination of potential risk factors for trastuzumab-associated cardiac toxicity (22). In a preliminary review of trastuzumab-related cardiac adverse events, 9 of 10 patients with cardiac events had prior anthracycline therapy, and additionally had at least one risk factor for anthracycline-induced cardiomyopathy (including cumulative doxorubicin dose greater than 400 mg/m², radiotherapy to the left chest, age greater than 70 years, and history of hypertension) (22). Consequently, there is a “boxed warning” concerning trastuzumab-associated cardiotoxicity in the trastuzumab prescribing information, and periodic serial assessment of left ventricular ejection fraction (LVEF) by echocardiography, or by technetium (Tc-99m) stannous pyrophosphate multi-gated acquisition (MUGA) scan, is recommended as clinically indicated.

Whereas the previous two studies assessed a heavily pretreated population of metastatic HER2-positive patients, a separate trial assessed the use of trastuzumab as first-line monotherapy for HER2-overexpressing MBC. A total of 114 women were randomized to receive one of two trastuzumab dosing regimens: (i) a loading dose of 4 mg/kg followed by 2 mg/kg weekly, or (ii) a loading dose of 8 mg/kg followed by 4 mg/kg weekly. Among 111 assessable patients, 7 CRs and 23 PRs were observed (ORR 26%). Reports of cardiac dysfunction in the previously noted trials (21, 22) led to an evaluation of cardiac events in this trial. Only two patients (2%) were noted to have clinically significant cardiac dysfunction, requiring no intervention other than discontinuation of trastuzumab. Of note, variations in trastuzumab dosing did not lead to significant differences in clinical endpoints. Median OS was 25.8 months and 22.9 in those who received 4 mg/kg and 2 mg/kg, respectively (23). In summary, although trastuzumab is most commonly integrated in combination with chemotherapeutics in the clinic, and although the above data sets were generated prior to the adjuvant trastuzumab era, it is important to remember that the antibody has significant clinical activity as a single agent and may offer an important treatment consideration for patients who may not be suitable candidates for chemotherapy-based regimens.

Preclinical Rationale for Trastuzumab in Combination with Cytotoxic Therapy

As previously noted, initial studies of trastuzumab in cell lines suggested optimum efficacy of the antibody when combined with cytotoxic therapy (11). Initially, these experiments specifically assessed the combination of trastuzumab and the DNA-damaging agent cisplatin. Further preclinical studies have assessed several distinct classes of chemotherapeutics in combination with trastuzumab against a panel of four HER2-overexpressing breast cancer cell lines (SKBR3, BT-474, MDA-MB 361, and MDA-MB 453) and confirmed in vivo in HER2 overexpressing xenograft models.

Based on work done in cell lines, the efficacy of trastuzumab-based combinations using in vivo xenograft models were explored (24). Synergy has been observed using the combinations of trastuzumab with alkylating agents, platinum analogues, topoisomerase II inhibitors, and ionizing radiation. Additive interactions were observed with the combination of trastuzumab with taxanes and anthracyclines (25). Results of these experiments helped to inform and prioritize the design and conduct of subsequent clinical trials of trastuzumab in combination with cytotoxic chemotherapy (see Table 72-1).

Pivotal Trial of Trastuzumab with Chemotherapy

A pivotal phase III registration trial of trastuzumab and cytotoxic chemotherapy randomized patients to receive either standard chemotherapy alone or standard chemotherapy plus trastuzumab as first-line therapy for HER2-positive metastatic disease. HER2-overexpressors were defined as those possessing IHC scores of 2+ or 3+, using the same murine monoclonal antibody upon which trastuzumab was based, as the primary detection antibody. In this trial, patients were stratified according to their prior adjuvant treatment. Patients who had not previously received adjuvant therapy with an anthracycline received doxorubicin or epirubicin and cyclophosphamide with or without trastuzumab, whereas in those patients who had previously received adjuvant anthracycline, a regimen of paclitaxel alone or paclitaxel in combination with trastuzumab was utilized. Trastuzumab was administered at a loading dose of 4 mg/kg, followed by a maintenance dose of 2 mg/kg weekly, until the observation of disease progression. Compared to nonrecipients of trastuzumab (n = 234), patients who received trastuzumab (n = 235) had a significantly longer time to disease progression (7.4 months vs. 4.6 months, p < .001), a higher rate of objective response (50% vs. 32%, p < .001), a longer mean duration of response (9.1 months vs. 6.1 months, p < .001) and prolonged median OS (25.1 months vs. 20.3 months, p = .046) (4). Along with the trastuzumab monotherapy noted above, these data supported regulatory approval of trastuzumab for the treatment of HER2-positive MBC by the U.S. Food and Drug Administration in 1998.

TABLE 72-1 Key Trials of Trastuzumab Therapy and Associated Response Rates

Author			Year	Study Type	N	1st Line?	Regimen	RR
*Phase II Studies*
	Single Agent Therapy
		Baselga et al.	1999	Phase II	43	No	Trastzumab 250 mg loading followed by 100 mg/wk × 10 wks	12%
		Cobleigh et al.	1999	Phase II	213	No	Trastuzumab 4 mg/kg loading followed by 2 mg/kg/wk	15%
		Vogel et al.	2002	Randomized phase II	111	Yes	Trastzumab 4 mg/kg loading followed by 2 mg/kg/wk, or Trastzumab 8 mg/kg loading followed by 4 mg/kg/wk, or	26%
	Paclitaxel and Trastuzumab
		Leyland-Jones et al.	2003	Phase II	32	No	Paclitaxel 175 mg/m² q3wks with trastzumab 8 mg/kg loading followed by 6 mg/kg q3wks	59%
		Gasparini et al.	2007	Randomized phase II	118	Yes	Paclitaxel 80 mg/m²/wk alone or with trastzumab 4 mg/kg loading followed by 2 mg/kg qwk	75%^*
		Gori et al.	2004	Phase II	25	No	Paclitaxel 60-90 mg/m²/wk with trastzumab 4 mg/kg loading followed by 2 mg/kg qwk	56%
		Seidman et al.	2001	Phase II	88	No	Paclitaxel 90 mg/m²/wk with trastzumab 4 mg/kg loading followed by 2 mg/kg qwk	61%
	Docetaxel and Trastuzumab
		Esteva et al.	2002	Phase II	30	Yes^**	Docetaxel 35 mg/m²/wk with trastzumab 2 mg/kg/wk for 3 out of 4 wks/cycle	63%
		Tedesco et al.	2004	Phase II	26	Yes^**	Docetaxel 35 mg/m²/wk for 6 wks followed by 2 wks rest with trastzumab 4 mg/kg loading followed by 2 mg/kg qwk	50%
		Raff et al.	2004	Randomized phase II	17	No	Docetaxel 35 or 40 mg/m²/wk for 3 wk, then 1 wk off, with trastzumab 4 mg/kg loading (day 1) followed by 2 mg/kg qwk (days 8 and 15) of a 28-d cycle	59%
		Montemurro et al.	2004	Phase II	42	No	Docetaxel 75 mg/m² q3wks × 6 with trastzumab 4 mg/kg loading followed by 2 mg/kg qwk	67%
		Marty et al.	2005	Randomized phase II	186	Yes	Docetaxel 75 mg/m² q3wks alone or with trastzumab 4 mg/kg loading followed by 2 mg/kg qwk	61%^*
	Vinorelbine/trastuzumab
		Burstein et al.	2001	Phase II	40	No	Vinorelbine 25 mg/m²/wk with trastzumab 4 mg/kg loading followed by 2 mg/kg qwk	75%
		Jahanzeb et al.	2002	Phase II	40	Yes	Vinorelbine 30 mg/m²/wk with trastzumab 4 mg/kg loading followed by 2 mg/kg qwk	78%
		Burstein et al.	2003	Phase II	54	Yes	Vinorelbine 25 mg/m²/wk with trastzumab 4 mg/kg loading followed by 2 mg/kg qwk	68%
		Chan et al.	2006	Phase II	62	Yes	Vinorelbine 30 mg/m²/wk with trastzumab 4 mg/kg loading followed by 2 mg/kg qwk	63%
		De Maio et al.	2007	Phase II	40	No	Vinorelbine 30 mg/m²/wk on days 1 and 8 of a 3-wk cycle with trastzumab 8 mg/kg loading followed by 6 mg/kg qwk	50%
		Papaldo et al.	2006	Phase II (two-arm)	68	Yes	Vinorelbine 25 mg/m²/wk alone or with trastzumab 4 mg/kg loading followed by 2 mg/kg qwk	51%
	Capecitabine and Trastuzumab
		Schaller et al.	2007	Phase II	27	No	Capecitabine 1,250 mg/m² bid for 14 d in a 21-d cycle given with trastzumab 4 mg/kg loading followed by 2 mg/kg qwk	45%
		Bartsch et al.	2007	Phase II	40	No	Capecitabine 1,250 mg/m² bid for 14 d in a 21-d cycle given trastzumab 8 mg/kg loading followed by 6 mg/kg q3wks	20%
		Yamamoto et al.	2008	Phase II	56	No	Capecitabine 1,657 mg/m² bid for 14 d in a 21-d cycle given with trastzumab 4 mg/kg loading followed by 2 mg/kg qwk	50%
	Cisplatin and Trastuzumab
		Pegram et al.	1998	Phase II	39	No	Cisplatin 75 mg/m² on days 1, 29, and 57 with trastuzumab 250 mg loading followed by 100 mg/wk for 9 wks	24%
	Gemcitabine and Trastuzumab
		Bartsch et al.	2008	Phase II	26	No	Gemcitabine 1250 mg/m² on days 1 and 8 of a 3-wk cycle with trastzumab 8 mg/kg loading followed by 6 mg/kg q3wks	19%
	Three Drug Regimens
		Perez et al.	2005	Phase II	43	Yes	Paclitaxel 200 mg/m² q3wks and carboplatin (AUC 6 mg/mL) q3wks with trastzumab 8 mg/kg loading followed by 6 mg/kg q3wks	65%
					48	Yes	Paclitaxel 80 mg/m²/wk given with carboplatin (AUC 2 mg/mL) every 3 out of 4 wks with trastzumab 4 mg/kg loading followed by 2 mg/kg qwk	81%
		Pegram et al.	2004	Phase II	59	Yes^**	Docetaxel 75 mg/m² q3wks with carboplatin (AUC 6 mg/mL) q3wks with trastzumab 4 mg/kg loading followed by 2 mg/kg qwk	58%
					62	Yes	Paclitaxel 75 mg/m² q3wks with carboplatin (AUC 6 mg/mL) q3wks with trastzumab 4 mg/kg loading followed by 2 mg/kg qwk	79%
		Miller et al.	2001	Phase II	42	Yes	Gemcitabine 1,250 mg/m² on days 1 and 8 and paclitaxel 175 mg/m² on day 1 of a 3-wk cycle with trastzumab 4 mg/kg loading followed by 2 mg/kg qwk	67%
		Stemmler et al.	2005	Phase II	20	No	Gemcitabine 750 mg/m² with cisplatin 30 mg/m² on days 1 and 8 of a 3-wk cycle with trastzumab 4 mg/kg loading followed by 2 mg/kg qwk	40%
*Phase III Studies*
		Slamon et al.	2001	Phase III	469	No	Trastuzumab 4 mg/kg loading followed by 2 mg/kg/wk	32%
							Taxane or anthracycline with cyclophosphamide given with trastuzumab 4 mg/kg loading followed by 2 mg/kg/wk	50%
		Robert et al.	2006	Phase III	196	Yes	Paclitaxel 200 mg/m² q3wks alone with trastzumab 4 mg/kg loading followed by 2 mg/kg qwk	36%
							Paclitaxel 200 mg/m² q3wks with carboplatin (AUC 6 mg/mL) q3wks with trastzumab 4 mg/kg loading followed by 2 mg/kg qwk	57%
		Burstein et al.	2007	Phase III	81	Yes	Vinorelbine 25 mg/m²/wk with trastzumab 4 mg/kg loading followed by 2 mg/kg qwk, or	51%
							Docetaxel/Paclitaxel, investigator preference, with trastzumab 4 mg/kg loading followed by 2 mg/kg qwk	40%
		Pegram et al.	2007	Phase III	263	Yes	Docetaxel 100 mg/m² q3wks with trastzumab 4 mg/kg loading followed by 2 mg/kg qwk	73%
							Docetaxel 75 mg/m² q3wks with carboplatin (AUC 6 mg/mL) q3wks with trastzumab 4 mg/kg loading followed by 2 mg/kg qwk	73%
^Indicates RR for trastuzumab containing arm. ^***indicates first- and second-line treatment included.

In addition to providing strong support for the combination of trastuzumab with cytotoxic chemotherapy, the study also provided important insights related to cardiac toxicity. Of 63 patients who experienced symptomatic or asymptomatic cardiac dysfunction in this study, 39 patients had received the combination of anthracycline, cyclophosphamide, and
trastuzumab. A much lower rate of cardiac dysfunction was observed in the remaining groups, with an incidence of 8%, 13%, and 1% in groups that had received anthracycline and cyclophosphamide alone, paclitaxel and trastuzumab, and paclitaxel alone, respectively. Grade III or IV New York Heart Association (NYHA) cardiac dysfunction was similarly observed at a much higher frequency in the group that received combined anthracycline and trastuzumab therapy. Increasing age was noted to be a risk factor associated with cardiac dysfunction within this subgroup. Notably, cumulative anthracycline dose did not correlate with cardiac toxicity; however, the vast majority of patients in this treatment arm received the prescribed six doses of anthracycline treatment (4). Results from this trial led to caution in formulating further trials of trastuzumab therapy with concomitant anthracycline. The optimal schedule for regular cardiac follow-up has yet to determined in the metastatic setting of the treatment of HER2-positive breast cancer. Additional methods of assessing cardiac function both in terms of modality and introduction of newer methods such as biomarkers may play a role in the future of cardiac testing.

Combinations of HER2-Targeting Agents with Endocrine Therapy

Approximately half of HER2-positive MBC is also hormone receptor positive (26). Women with disease co-expressing both HER2 and one or both of the hormone receptors (ER or PR) may have less benefit from antihormonal therapies than with HER2-negative, ER positive disease (27). Preclinical studies suggest that there is cross talk between pathways related to HER2 and ER. Overexpression of HER2 was demonstrated to cause ligand independent down regulation of estrogen receptor and further suppression of ER transcripts (28). Given this association, it was thought plausible that inhibition of HER2 activity may augment endocrine therapy by enhancing ER expression. As validation of this hypothesis, the phase III TAnDEM trial randomized HER2-overexpressing, HR-positive postmenopausal patients to anastrozole alone, or the combination of anastrozole and trastuzumab. At the time of progression, patients were given the option to begin trastuzumab therapy if they were previously randomized to the monotherapy arm. Despite the crossover allowance, a modest (statistically insignificant) trend in OS was noted from combination therapy (28.5 vs. 23.9 months; p = .325) (29). Interestingly, in a post hoc exploratory analysis assessing the effects of crossover, median OS was significantly less in the group that received no trastuzumab therapy (i.e., anastrozole alone with no crossover; median OS, 17.2 months) versus survival in groups receiving anastrozole and trastuzumab initially (median OS 28.5 months) or at the time of crossover (median OS 25.1 months).

Direct HER2-tyrosine kinase inhibition with the small molecule HER2 kinase inhibitor lapatinib in combination with endocrine therapy has also been investigated. A phase I trial using the combination of lapatinib and letrozole suggested that the combination was safe and tolerable (30). Subsequently, a phase III trial was undertaken that compared the combination of letrozole plus lapatinib with letrozole plus placebo as first-line treatment of patients with HR-positive MBC, some with HER2-positive disease. Seventeen percent of the total study population (n = 1,286) had centrally confirmed HER2-positive disease with roughly equal distribution in the lapatinib and placebo groups (n = 111 and n = 108, respectively). In a pre-planned analysis of the HER2 positive population, the median PFS increased from 3 months for letrozole-placebo to 8.2 months for letrozole-lapatinib (HR = 0.71; 95% CI, 0.53-0.96; p = .019) (31). Clinical benefit, defined as objective response or stable disease for ≥6 months, was also significantly improved (29% to 48%; OR = 0.4; 95% CI, 0.2-0.8; p = .003) for the combined receptor blockade arm. There was also a (non-significant) trend toward improvement in OS. This regimen won regulatory approval by the U.S. FDA in 2010. In summary, since ER signaling has been suggested as an escape mechanism causing resistance to HER2 targeting agents, it is important to remember that ER+ tumors in the setting of HER2+ disease should also be treated with ER-directed therapies. This paradigm is also suggested by recent results from the TBCRC 006 trial, in which letrozole was used in addition to trastuzumab and lapatinib in 64 evaluable patients with HER2+/ER+ stage II/III tumors (32). Overall, in-breast pathologic complete response (pCR; _ypT_0-is) was 27% (ER+, 21%; ER-, 36%). The rate of low-volume residual disease (_ypT_1a-b) was 22% (ER+, 33%; ER-, 4%). Thus, in these patients with locally advanced HER2-positive breast cancer, this approach resulted in a high pCR rate even in the absence of chemotherapy. These data support the hypothesis that selected patients with HER2-positive tumors may not need chemotherapy, and more-complete blockade of HER receptors and ER is an effective strategy worthy of further study (32).

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