Adjuvant and Preoperative Systemic Therapy for HER2-Positive Breast Cancer

Ian E. Krop

Eric P. Winer

INTRODUCTION

HER2/neu is a member of the ErbB family of transmembrane tyrosine kinases. The family includes the epidermal growth factor receptor (EGFR), HER2, HER3, and HER4. HER2 is activated through dimerization, either with other HER2 proteins (homodimerization) or with other HER family members (heterodimerization). Once activated, HER2 potently initiates downstream signaling, including signaling through the PI3-kinase and MAP kinase pathways. As a result, HER2 activation produces an array of cellular changes leading to increased proliferation, invasiveness, angiogenesis, and enhanced survival.

Amplification of the HER2 gene occurs in approximately 20% of breast cancers (1, 2). This amplification causes marked overexpression of HER2 protein on the cell surface— typically over a million HER2 proteins per cell (3)—and leads to constitutive activation of HER2 signaling. HER2 amplified breast cancers are typically highly proliferative and are associated with adverse clinical behavior. In the absence of systemic adjuvant therapy, HER2 amplification is independently associated with a greater risk of disease recurrence in both node negative and node positive cancers (4, 5, 6 and 7). Several studies have also demonstrated that HER2 amplification is a negative prognostic feature for cancers ≤1 cm (8, 9).

Despite its negative prognostic effects, HER2 amplification and/or overexpression predicts sensitivity to several classes of chemotherapy. In Cancer and Leukemia Group B 9344, a phase III adjuvant study in patients with node positive disease in which patients were randomized to four cycles of AC (doxorubicin/cyclophosphamide) alone or AC followed by four cycles of paclitaxel, HER2 overexpression was associated with a significant benefit from the addition of the paclitaxel (10). Similar findings were observed in a phase III metastatic trial comparing epirubicin/paclitaxel (ET) with epirubicin/cyclophosphamide (EC). In that study, patients with HER2-positive cancers who received ET had improved progression-free survival and overall survival relative to the patients with HER2-positive cancers who received EC (11).

HER2-positive cancers also demonstrate specific sensitivity to anthracyclines. In MA.5, a randomized phase III adjuvant study in patients with node positive disease in which patients received either cyclophosphamide/methotrexate/fluorouracil (CMF) or cyclophosphamide/epirubicin/fluorouracil (CEF), patients with HER2-positive cancers had improved relapse-free survival (hazard ratio [HR] = 0.52, 95% CI, 0.34-0.80; p = .003) and overall survival (HR = 0.65, 95% CI, 0.42-1.02; p = .06) with the anthracycline regimen (12). Patients with HER2 negative cancers did not have an improvement in outcome with the anthracycline (interaction p value p = .01) (12). A meta-analysis of eight randomized studies comparing anthracyclinebased regimens to non-anthracycline regimens (total n = 6564) also demonstrated that anthracyclines were superior to nonanthracycline regimens in HER2-positive cancers (HR of death from any cause = 0.73, 95% CI, 0.62-0.85; p < .001), while no benefit was observed in HER2-negative cancers (HR of death from any cause = 1.03, 95% CI, 0.92-1.16; p = .6) (13). The interaction
between HER2 status and anthracycline benefit was significant (chi-square statistic for overall survival = 12.6; p < .001) (13).

The preclinical data pointing to the importance of HER2 signaling together with the clinical data demonstrating the poor prognostic effect of HER2 amplification sparked interest in utilizing HER2 as a therapeutic target. This idea led to the development of trastuzumab, a humanized monoclonal antibody specific for the extracellular domain of HER2. In preclinical studies, trastuzumab demonstrated multiple potential mechanisms of action, including inhibition of HER2 signal transduction, induction of antibody-dependent cell-mediated cytotoxicity (ADCC), and inhibition of shedding of the HER2 extracellular domain (reviewed in [14]). The clinical effectiveness of trastuzumab was evaluated in a pivotal phase III study in patients with HER2-positive metastatic breast cancer who were randomized to chemotherapy with or without trastuzumab. The chemotherapy backbone was either paclitaxel or AC, depending on whether patients had previously been exposed to anthracycline treatment. The addition of trastuzumab to chemotherapy markedly improved outcomes, with a longer time to disease progression (median, 7.4 months vs. 4.6 months; p < .001) and overall survival (25.1 months vs. 20.3 months; p = .01) compared to chemotherapy alone. (15) The benefits of trastuzumab were associated with minimal increases in toxicity, with one notable exception—the addition of trastuzumab to the anthracycline regimen caused a high incidence of symptomatic cardiomyopathy (16% had New York Heart Association class III or IV cardiac dysfunction) (15). Patients who received trastuzumab with paclitaxel (all of whom had previously received an anthracycline) had a much lower rate of severe cardiac toxicity (2%). The unequivocal benefits of trastuzumab in combination with a taxane led to the widespread use of taxane-trastuzumab combinations for patients with HER2-positive metastatic breast cancer. The synergistic benefits of trastuzumab with chemotherapy were subsequently shown to extend across a wide range of regimens. In addition, two randomized clinical trials demonstrated that continuation of trastuzumab after disease progression on a prior trastuzumab regimen is beneficial (16, 17). These studies have far reaching clinical and biologic significance, and as a result, trastuzumab based combinations are widely used in multiple lines of therapy for HER2-positive metastatic breast cancer.

The clinical benefits of trastuzumab observed in these trials provided definitive proof that targeting HER2 was an effective approach in HER2-positive breast cancer. This demonstration led to the successful development of other HER2-targeted agents, such as the EGFR/HER2 tyrosine kinase inhibitor lapatinib, the HER2 specific monoclonal antibody pertuzumab, and the antibody drug conjugate trastuzumab emtansine. All three of these agents have significant activity in patients with HER2-positive metastatic breast cancer, either combined with chemotherapy or hormonal therapy (in the case of lapatinib), combined with trastuzumab and chemotherapy (in the case of pertuzumab), or as monotherapy with trastuzumab emtansine.

The benefits of trastuzumab seen in patients with metastatic disease also provided the rationale to evaluate this agent in the adjuvant and neoadjuvant settings. In 2005, initial results from the first three phase III adjuvant trials of trastuzumab were reported, demonstrating significant improvements in diseasefree survival, and ultimately overall survival, with the addition of trastuzumab to chemotherapy in the adjuvant setting. The improvements in outcome were so impressive that adjuvant trastuzumab became the standard of care within weeks after the trial results were presented. This chapter will review these adjuvant studies and subsequent randomized adjuvant trials of HER2 directed therapy. In addition, the chapter will discuss the results of smaller neoadjuvant trials as well as future directions in the treatment of early stage HER2-positive breast cancer.

BENEFIT OF TRASTUZUMAB IN THE ADJUVANT TREATMENT OF HER2-POSITIVE BREAST CANCER

Six randomized phase III studies have evaluated the addition of trastuzumab to chemotherapy in the adjuvant setting. The details of these studies are summarized in Tables 46-1 and 46-2. All of the studies were restricted to patients with HER2-positive cancers, although the definition of HER2 positivity and the requirement for central testing differed across the trials. All the studies focused on a relatively high-risk population (node positive or high-risk node negative) and all except FinHer included at least one year of trastuzumab.

The National Surgical Adjuvant Breast and Bowel Project (NSABP) B-31 and North Central Cancer Treatment Group (NCCTG) N9831 were both conducted in North America and shared similar designs. The chemotherapy backbone consisted of four cycles of AC followed by paclitaxel. In B-31, the paclitaxel was given as 175 mg/m² every 3 weeks × 4 cycles, and in N9831 it was administered weekly for 12 weeks. Trastuzumab was administered concurrently with paclitaxel and was continued for a total of one year. In N9831, a third arm was included in which the year of trastuzumab was delayed until the completion of all chemotherapy. Because of the similarities of the trial designs, the investigators performed a pooled analysis of the two trials, combining the two control arms and the two investigational arms that involved concurrent administration of trastuzumab and paclitaxel. Patients from N9831 who received sequential paclitaxel followed by trastuzumab were excluded from this analysis. A total of 3,351 patients (1,679 in combined control group and 1,672 in combined trastuzumab group) were included. Both studies initially excluded node negative patients, but ultimately the N9831 trial was amended to include highrisk node negative patients (defined as a tumor >2 cm for hormone receptor positive cancers and tumor >1 cm for hormone receptor negative cancers), but less than 6% of the patients in the combined analysis had node negative disease.

The results from this analysis were initially presented after 2.0 years median follow-up because the results had crossed an early-stopping boundary. At that time, there were 261 DFS events in the control group and 133 in the trastuzumab group. This difference translated to a hazard ratio of 0.48 (95% CI, 0.39 to 0.59; p < .0001) (18). The addition of trastuzumab was also associated with a 33% reduction in the risk of death (p = .015) (18). The improvement in outcome seen with the addition of trastuzumab led to the approval of trastuzumab by the United States Food and Drug Administration (FDA) in 2006.

More recently, the final results from the pooled analysis of N9831/B31 were presented with 8.4 years median follow-up. With this additional follow-up, the relative benefits of trastuzumab remain robust with a 40% reduction in DFS events (HR = 0.60, 95% CI, 0.53-0.68; p < .0001) (19). The absolute improvement in DFS is 11.5%, and the majority of the events (8.2%) were distant recurrences. Overall survival was also meaningfully improved with the addition of trastuzumab with a HR = 0.63, 95% CI, 0.54-0.73; p < .0001, corresponding to an increase from 74.2% in the control arm to 82.0% in the trastuzumab arm (19). Because of the clear benefit of trastuzumab observed in the first pooled analysis in 2005, patients on the control arm of the study were offered treatment with one year of trastuzumab. A total of 413 women (20.4%) in the combined control arm elected to receive trastuzumab. These patients are included in this final analysis according to intention to treat, and if anything, this crossover would lead to an underestimation of the true benefit of trastuzumab.

TABLE 46-1 Efficacy Results of Adjuvant Studies of Trastuzumab in HER2-Positive Early Breast Cancer

Study	Patients (N)	Patient Characteristics	Treatment Regimens	Primary End Point	Median Follow-Up (yr)	DFS HR (CI; p value)	OS HR (CI; p value)
NSABP B-31/Intergroup N9831 Joint Analysis (19)	4,046	Node-positive^a	AC × 4 →P × 4 AC × 4 →P × 4 + T^b (T started concurrently with P)	DFS	8.4	0.60 (CI, 0.53-0.68, p < .0001)	0.63 (CI, 0.54-0.73, p < .0001)
HERA (38)	5,102	All except small (<1 cm) node-negative	Chemotherapy (CT) alone T for 1 yr after completion of CT T for 2 yr after completion of CT	DFS	8	0.76 (p < .0001)	0.76 (p < .0005)
BCIRG 006 (22)	3,222	Node-positive or high risk node-negative	AC × 4 →D × 4 (I) AC × 4 →D × 4 + T (II) D + Cb × 6 + T (III)	DFS	5.4	0.64 (II vs. I) (p < .0001) 0.75 (III vs. I) (p = .04)	0.63 (II vs. I) (p < .001) 0.77 (III vs. I) (p = .04)
FinHer (37)	232	Node-positive or high risk node-negative	V or D × 3 with or without T 9 wk followed by FEC × 3	DDFS	5.2	0.65 (CI, 0.38-1.12, p = .12)	0.55 (CI, 0.27-1.11) (p = .09)
PACS-04 (24)	528	Node-positive	FEC × 6 or ED × 6 with or without T	DFS	3.9	0.86 (CI, 0.61-1.22, p = .41)	1.27 (CI, 0.68-2.38, p = NS)
AC, doxorubicin; BCIRG, Breast Cancer International Research Group; Cb, carboplatin; CI, confidence interval; D, docetaxel; DFS, diseasefree survival; ED, epirubicin, docetaxel; FEC, 5-fluorouracil, epirubicin, cyclophosphamide; HERA, HERceptin Adjuvant; HR, hazard ratio; NSABP, National Surgical Adjuvant Breast and Bowel Project; PACS, Protocole Adjuvant dans le cancer du sein; OS, overall survival; P, paclitaxel; RFS, relapse-free survival; T, trastuzumab; V, Vinorelbine. NS, not significant.
^aN9831 included a small percentage of node negative patients (5.7% overall). ^bIn B31 the paclitaxel was given every 3 weeks for four cycles. In N9831, paclitaxel was weekly × 12.
Adapted from de Azambuja E, Piccart M. Adjuvant treatment of ERBB2 positive breast cancer. In: Morrow M, Harris JR, Lippman ME, Osborne CK, eds. Diseases of the Breast. 4th ed. Philadelphia, PA: Lippincott Williams & Wilkins, 2011. (Ref. 90.)

The largest adjuvant trastuzumab trial was HERA (Herceptin Adjuvant), a global, but non-U.S. trial that included a total of 5,081 evaluable patients. Like the joint analysis of N9831/B31, initial results from HERA were also reported in 2005.The study population of HERA was more heterogeneous than N9831/B31. The eligibility criteria were relatively broad, allowing both node positive and node negative patients as long as tumor size was at least 1 cm. Overall, approximately 32% of patients on the trial had negative nodes. The chemotherapy backbone in HERA was not specified apart from requiring that patients receive at least four cycles of treatment. Ninety-four percent received an anthracycline-based regimen and 26% also received a taxane. The HERA study design differed from the pooled analysis of N9831/B31 in that trastuzumab therapy was initiated after completion of all chemotherapy. The trastuzumab, which was given every 3 weeks, was mandated to begin no more than 7 weeks from day 1 of the conclusion of chemotherapy or 6 weeks from the completion of radiation or definitive surgery, whichever was last. Unlike the North American trials, HERA asked a duration question, with participants randomized to 1 or 2 years of trastuzumab, or observation.

The initial publication of HERA in 2005 reported the results of 1 year of trastuzumab versus the observation group. This first interim analysis crossed the prespecified early stopping boundary with a median follow-up of only 1 year. In that analysis, there were 127 DFS events in the 1 year of trastuzumab arm compared to 220 events in the observation arm (20). The hazard ratio for DFS events was 0.54 (95% CI, 0.43-0.67; p < .0001) (20). There was no significant effect on survival with the short follow-up time. A subsequent analysis with 8 years median follow-up continued to demonstrate improved DFS associated with 1 year of trastuzumab therapy (HR = 0.76; p < .0001) as well as a significant survival benefit (HR = 0.76; p = .0005) (21). As was the case with the North American trials, patients on the observation group were offered 1 year of trastuzumab; fully 52% crossed over, which presumably had an effect on the observed benefit of trastuzumab.

The Breast Cancer International Research Group (BCIRG) conducted the fourth large randomized trial evaluating trastuzumab in the adjuvant setting. This global study was unique in that it included an arm with a non-anthracycline regimen. Participants were randomized to a control arm of four cycles of AC followed by four cycles of docetaxel (100 mg/m²) every 3 weeks, or the same regimen with 1 year of trastuzumab starting with the first dose of docetaxel. There was also a third arm on which patients received docetaxel (100 mg/m²) and carboplatin (area under the curve of 6 mg/mL/min) given every 3 weeks for six cycles
concurrently with trastuzumab (TCH). For both of the trastuzumab arms, the trastuzumab was given weekly during the chemotherapy and then every 3 weeks to complete 1 year. The trial had broad entry criteria and included both node positive and high-risk node negative (defined as having at least one of the following criteria: tumor size >2 cm, ER and PR negative, histologic and/or nuclear grade 2-3, or age <35 years) patients. A total of 3,222 patients were enrolled, of whom approximately 29% were node negative.

TABLE 46-2 Study Design and Demographic Characteristics of the Trastuzumab Adjuvant Trials

	HERA	NSABP B-31/N9831 Joint Analysis	BCIRG 006	FinHer	PACS-04
Trastuzumab schedule	Every 3 weeks	Weekly/weekly	Weekly with CT, then every 3 weeks	Weekly	Every 3 weeks
Sequential or concurrent T	Sequential	Concurrent^a	Concurrent	Concurrent	Sequential
HER2 testing	Centralized IHC ± FISH	Centralized IHC and FISH^f	Centralized FISH	Centralized CISH	Centralized IHC ± FISH
Age <50 years (%)	51	50	52	NR	NR
Node-negative (%)	32^b	6	29^c	16^d	0
Grade 3 tumors	60	69	NA	64	66
Taxane-based CT	26	100	100	50	50
ER + and/or PR +	47	58	54	46^e	58
Baseline LVEF assessment	At completion of CT and RT	At completion of 4 AC	After surgery	After surgery	At completion of CT and RT
Cross-over to trastuzumab after first analysis (%)	50	20.9	1.6	NA	NA
AC, doxorubicin, cyclophosphamide; CISH, chromogenic in situ hybridization; CT, chemotherapy; ER estrogen receptor; FISH, fluorescence in hybridization; IHC, immunohistochemistry; LVEF, left ventricular ejection function; NA, not applicable; NR, not reported; PACS,
Protocole Adjuvant dans le cancer du sein; PR, progesterone receptor; RT, radiotherapy.
^aN9831 had a sequential arm but this was not included in the joint analysis. ^bOnly if tumor size >1cm. ^cOnly if at least one concomitant risk factor (grade >1, hormone receptor negative, tumor >2 cm, age <35y). ^dOnly if size >20 mm and PR negative. ^eER positive only. ^fInitially local HER2 testing was permitted, but the protocols were amended to require centralized testing.
Adapted from de Azambuja E, Piccart M. Adjuvant treatment of ERBB2 positive breast cancer. In: Morrow M, Harris JR, Lippman ME, Osborne CK, eds. Diseases of the Breast. 4th ed. Philadelphia, PA: Lippincott Williams & Wilkins, 2011. (Ref. 90.)

The primary endpoint of BCIRG- 006 was disease free survival. Recently, a protocol-specified analysis of the study was reported after 656 DFS events had occurred. Both trastuzumab containing arms demonstrated significantly improved DFS and overall survival relative to the AC/docetaxel control arm of the study. The 5-year diseasefree survival rate was 75% for AC/docetaxel, 81% for TCH, and 84% for AC/docetaxel/trastuzumab (22). This corresponds to a hazard ratio for the comparison of TCH and ACTH with AC/docetaxel of 0.75; p = .04, and 0.64; p < .001 respectively. The 5-year overall survival rate was 87% for AC/docetaxel, 91% for TCH, and 92% for AC/docetaxel/trastuzumab. This corresponds to a hazard ratio for the comparison of TCH with AC/docetaxel of 0.77; p = .04, and AC/docetaxel/trastuzumab with AC/docetaxel of 0.63; p < .001 (22). Unlike the N9831/B31 and HERA studies, very few patients (1.6%) on the control arm of BCIRG 006 crossed over to receive trastuzumab, so this issue did not significantly affect the impact of trastuzumab on outcomes in this study. The differences in DFS and overall survival between TCH and AC/docetaxel/trastuzumab were not significant. The study had only limited power to detect large differences in outcome between the two trastuzumabcontaining arms. While both trastuzumab-containing arms were better than the control, the anthracycline containing arm has a numeric advantage in terms of both DFS and OS. Importantly, the results do not prove equivalence of TCH to ACTH.

Two smaller randomized trials have also evaluated the adjuvant use of trastuzumab. Both the FinHer study and FNCLCC-PACS 04 study evaluated trastuzumab in the subset of patients with HER2-positive cancers (232 patients in FinHer, 528 in PACS 04) as part of larger studies comparing different chemotherapy regimens. FinHer was noteworthy for two reasons. First, the chemotherapy backbone consisted of a randomization to either vinorelbine (25 mg/m² weekly for 9 weeks) or docetaxel (100 mg/m² every 21 days), both followed by three cycles of FEC (fluorouracil 600 mg/m², epirubicin 60 mg/m², and cyclophosphamide 600 mg/m² every 21 days). Second, patients with HER2-positive cancers randomized to trastuzumab received weekly therapy for only 9 weeks, concurrent with either the vinorelbine or docetaxel. Despite the short duration, patients who received trastuzumab had an improved recurrence-free survival (RFS) at 3 years compared to those who were randomized to chemotherapy alone (89% vs. 78%; HR = 0.42; 95% CI, 0.21-0.83; p = .01) (23).

In PACS04, patients with node positive, HER2-positive cancers received either six cycles of FEC (fluorouracil 500 mg/m², epirubicin 100 mg/m², and cyclophosphamide 500 mg/m²) or ED (epirubicin 75 mg/m² and docetaxel 75 mg/m²)
every 3 weeks. A second randomization was to either observation or a year of trastuzumab (given every 3 weeks) starting after completion of the chemotherapy. In this study, the addition of trastuzumab was associated with only a minimal improvement in DFS (HR = 0.86, 95% CI, 0.61-1.22), which was not statistically significant (p = .41) (24).

BENEFIT OF TRASTUZUMAB IN THE NEOADJUVANT TREATMENT OF HER2-POSITIVE EARLY-STAGE BREAST CANCER

The clear benefit of trastuzumab in patients with metastatic disease sparked interest in evaluating trastuzumab in the neoadjuvant setting. While several small, single-arm studies demonstrated that preoperative treatment with the combination of trastuzumab and chemotherapy was feasible and active (25, 26), the first randomized trial to show a benefit to trastuzumab was conducted by the MD Anderson Cancer Center. Buzdar and colleagues randomized patients with operable stage II-IIIA HER2-positive cancers to either four cycles of paclitaxel (225 mg/m² as a 24-hour infusion every 3 weeks) followed by four cycles of FEC (500 mg/m² fluorouracil on days 1 and 4, 500 mg/m² IV cyclophosphamide and 75 mg/m² epirubicin on day 1 only of a 3-week cycle) or the same chemotherapy regimen combined with weekly trastuzumab. The trastuzumab was started concurrent with the taxane and continued throughout the chemotherapy (24 weeks). The primary objective of the study was to compare the rate of pathological complete response (pCR, defined as no residual invasive cancer in the breast or axillary nodes) between the two arms. Although the study planned to enroll 164 patients, accrual was terminated after 42 patients were randomized because a large difference in pCR rates was observed. 26.3% of patients who received chemotherapy alone had a pCR compared to 65.2% of patients who received chemotherapy with trastuzumab (27). Despite the small sample size, this difference in pCR rates was significant (p = .016). A cohort of 22 patients was subsequently enrolled and treated in a uniform fashion with the same chemotherapy and trastuzumab regimen. The pCR of this cohort was 54.5% (28). After a median follow-up of 36 months, the 3-year disease-free survival for those patients randomized to chemotherapy alone was 85.3% while no patients randomized to the trastuzumab arm had recurred (p = .041 for the comparison between arms) (28).

The benefit of neoadjuvant trastuzumab was confirmed in the larger phase III NOAH (Neoadjuvant Herceptin) trial. In this study, 235 patients with HER2-positive locally advanced (T3N1 or T4 or N2/N3, or ipsilateral supraclavicular node involvement) breast cancer received a multiagent chemotherapy regimen consisting of doxorubicin 60 mg/m² and paclitaxel 150 mg/m² every 3 weeks for three cycles, followed by paclitaxel 175 mg/m² administered every 3 weeks for four cycles. Cyclophosphamide (600 mg/m²), methotrexate (40 mg/m²), and fluorouracil (600 mg/m²) were then given on days 1 and 8 every 4 weeks for three cycles. Those patients randomized to the trastuzumab arm received the antibody every 3 weeks concurrent with the entire chemotherapy regimen. They also received trastuzumab postoperatively to complete a total of 1 year of trastuzumab therapy.

Similar to the results from the MD Anderson study, the addition of trastuzumab in NOAH led to a marked improvement in pCR rates—19% for patients who received chemotherapy alone compared to 38% for those who received chemotherapy and trastuzumab (29). With a median follow-up of 3.2 years, long-term outcomes were also improved with trastuzumab. Three-year event-free survival (defined as disease recurrence or progression, or death from any cause) was 71% (95% CI, 61-78; n = 36 events) among patients randomized to trastuzumab, vs. 56% (46-65; n = 51 events) for the patients who received chemotherapy alone (29). This difference was statistically significant with a hazard ratio of 0.59 (95% CI, 0.38-0.90; p = .013). Because of the clear benefit of trastuzumab demonstrated in the MD Anderson and NOAH neoadjuvant studies, as well as similar benefits seen in the adjuvant trials discussed earlier, all subsequent neoadjuvant trials included HER2-directed in all arms.

CARDIAC TOXICITY OF TRASTUZUMAB

In general, trastuzumab is well tolerated. In the randomized studies, rates of adverse events were similar in patients assigned to receive trastuzumab relative to that of the control group (18, 20, 22). However, as previously discussed, the pivotal metastatic study demonstrated significant evidence of cardiac toxicity with trastuzumab, particularly when combined with an anthracycline. Because of this observation, all of the adjuvant studies and many of the early neoadjuvant studies avoided concurrent use of trastuzumab with an anthracycline and required confirmation of an adequate left ventricular ejection fraction (LVEF) prior to a patient’s initiating the trastuzumab. In addition, all of these trials included extensive cardiac monitoring. The data from these randomized studies thus provide valuable information regarding the cardiac effects of trastuzumab in patients with early-stage disease, including quantification of the absolute risk of cardiac toxicity, identification of treatment regimens that are more likely to be associated with cardiac effects, and characterization of risk factors that predict a higher likelihood of cardiac toxicity.

There is no question that trastuzumab, particularly when given in conjunction with an anthracycline-based regimen, does have the potential to cause cardiac toxicity in the adjuvant setting (summarized in Table 46-3), but the absolute incidence of significant toxicity is low and the rates vary substantially across the trials. While cross-trial comparisons are complicated by the varied definition of cardiac events used in the individual studies and possible differences in the patient populations, the highest rate of symptomatic cardiac events (NYHA class III/IV CHF) was generally seen in studies in which patients received an anthracycline within weeks of initiation of trastuzumab. In N9831, NSABP B31, and the BCIRG trial, the rates of significant cardiac toxicity when a taxane-trastuzumab regimen was administered immediately following AC were 2.9%, 4.1%, and 2.0% respectively (18, 22). Patients on the TCH arm of BCIRG 006 had the lowest rate of cardiac toxicity (0.4%) (22). Interestingly, the rate of symptomatic cardiac events in patients randomized to trastuzumab in HERA (0.5%) appeared lower than that of the other trials despite the fact that 94% of patients on HERA received an anthracycline prior to the trastuzumab (20). There are several possible explanations for this observation. Of note, HERA required a LVEF of ≥55% to begin trastuzumab whereas most of the other studies required an LVEF of >50%. This difference may be particularly relevant given that several studies suggest that a baseline LVEF <55% increases the risk of trastuzumab-induced cardiotoxicity (30, 31 and 32). Another difference is that because HERA required participants to complete chemotherapy and radiotherapy before randomization, there was a longer delay between completing chemotherapy and initiation of trastuzumab relative to the other studies. The majority of patients in HERA did not
receive a taxane, in contrast to the other large studies in which taxanes were given to all patients. There are however, no data that clearly implicate prior receipt of a taxane as a risk factor for trastuzumab induced cardiac toxicity. Lastly, it has been postulated that HERA’s purely sequential design may have contributed to its low cardiac toxicity rate by extending the time interval between the anthracycline and initiation of trastuzumab. However, given the similar rates of significant cardiac events in the sequential (2.8%) and concurrent (3.3%) arms of N9831 (30), the only randomized comparison of the two approaches, it seems unlikely that the sequential design of HERA was the primary reason for its relative lack of serious cardiac toxicity.

TABLE 46-3 Cardiac Safety Results in Adjuvant Trastuzumab Trials

	HERA (20)		NSABP B-31 (18)		NCCTG N9831 (30)			BCIRG 006 (22)			PACS-04 (24)
Treatment arms	Obs	1-yr H	AC→P	AC→PH	AC→P	AC→P→H	AC→PH	AC→D	AC→DH	DCb+H	Obs	1-yr H
Women at risk (n)	1,710	1,677	872	864	664	710	570	1,050	1,068	1,056	268	260
Follow-up (yr)	1		2.4		3			5.4			3.9
Cardiac death or CHF NYHA class 3-4 (%)	0.1	0.54	0.8	4.1	0.3	2.8	3.3	0.7	2.0	0.4	0.4	1.5
AC, doxorubicin, cyclophosphamide; BCIRG, Breast Cancer International Research Group; Cb, carboplatin; CHF, congestive heart failure; D, docetaxel; H, Herceptin (trastuzumab); HERA, HERceptin Adjuvant; NSABP, National surgical Adjuvant Breast and Bowel Project; NYHA, New York Heart Association, Obs, observation; PACS, Protocole Adjuvant dans le cancer du sein; OS, overall survival; P, paclitaxel.
Note: No CHF class 3-4 and no cardiac deaths reported in the FinHer trial.
Adapted from de Azambuja E, Piccart M. Adjuvant treatment of ERBB2 positive breast cancer. In: Morrow M, Harris JR, Lippman ME, Osborne CK, eds. Diseases of the Breast. 4th ed. Philadelphia, PA: Lippincott Williams & Wilkins, 2011. (Ref. 90.)