Biologic therapy involves the delivery of a systemic agent that can be specifically targeted toward a unique cellular feature, often a component of a cell surface receptor. Over the last decade, the approach to systemic therapy in breast cancer has been revolutionized by the development and efficacious application of biologic agents. Rapid translation of laboratory data to the clinic has resulted in meaningful differences in patient outcomes.

Three biologic therapies—trastuzumab, lapatinib, and bevacizumab—are now approved for use in patients with breast cancer. Preclinical and clinical data supporting the use of these agents are the focus of this chapter.

Biology

Human epidermal growth factor receptor 2 (ErbB2/HER-2) is a 185-kd transmembrane protein overexpressed in 20% to 25% of breast cancer patients and correlated with adverse survival outcomes.1-3 Trastuzumab, a humanized monoclonal antibody to HER-2, was developed to antagonize the role of HER-2 in the progression of breast tumors. After preclinical studies demonstrated growth inhibition in breast cancer cell lines and xenograft models,4,5 phase I data revealed a favorable safety profile.6,7 Efficacy trials were subsequently initiated.

Use in Patients with Metastatic Disease

In 1996, Baselga et al6 reported the results of a phase II study assessing the efficacy of trastuzumab as a single agent in the treatment of HER-2-overexpressing metastatic breast cancer. Forty-six patients received a loading dose of trastuzumab followed by 10 weekly doses. One complete remission and 4 partial remissions were seen (11.6%) in this heavily pretreated group.6 Pegram et al7 subsequently reported the results of a similar phase II clinical trial evaluating the combination of trastuzumab and cisplatin. Thirty-nine patients with HER-2 overexpression (2+ or 3+ by immunohistochemistry [IHC]) and progressive metastatic disease on standard therapy received a loading dose followed by 8 weekly doses of trastuzumab. Those without disease progression could continue treatment with maintenance cisplatin and trastuzumab until disease progression or unacceptable toxicity. The toxicity profile seen in this trial was comparable to historical controls treated with cisplatin alone. Almost half of the patients did not progress during the study period, and a quarter had a partial response lasting a median of 5.1 months. As in the first trial, no immunologic adverse events were noted, and pharmacokinetic analysis showed no drug interaction.7 Two hundred and twenty-two patients from multiple continents were accrued to another trial evaluating response rates to weekly trastuzumab (until disease progression) in HER-2-overexpressing metastatic breast cancer patients. The overall response rate was 22% (8 complete responses) and median time to progression was 9.1 months, despite the fact that greater than 60% of the patients had received prior chemotherapy for metastatic disease. Patients with higher levels of HER-2 overexpression (3+ vs 2+) were noted to have more favorable responses to trastuzumab. Only 14% (n = 29) of patients experienced severe adverse events thought to possibly be related to study drug, several occurring in more than 1 patient as follows: pain (9), chills (5), dyspnea (2), and abdominal pain (2).8

With encouraging preliminary results, randomized trials enrolling larger numbers of patients were designed to definitively assess the efficacy of trastuzumab. One hundred and fourteen patients with HER-2-overexpressing (2+ or 3+ by IHC) metastatic breast cancer who declined first-line cytotoxic chemotherapy were randomized to 2 mg/kg of trastuzumab versus 4 mg/kg weekly. Twenty-six percent of the patients had an objective response. No clear relationship to dose level was detected.9

In a landmark trial, Slamon et al10, randomized 469 women with progressive HER-2-overexpressing (2+ or 3+ by IHC) metastatic breast cancer to chemotherapy alone (doxorubicin or epirubicin/ cyclophosphamide or paclitaxel if they had received prior adjuvant anthracycline) or chemotherapy combined with trastuzumab. Although patients had not received prior chemotherapy for metastatic disease, many had received adjuvant chemotherapy and the study regimen was chosen accordingly. The addition of trastuzumab to chemotherapy resulted in an improved median time to disease progression (7.4 vs 4.6 months), higher rate of overall response (50% vs 32%), longer duration of response (9.1 vs 6.1 months), and a significantly longer median survival (25.1 vs 20.3 months). This improvement in survival was seen despite a trial design that allowed patients progressing on chemotherapy alone to receive open-label trastuzumab.10

Unexpectedly high cardiac dysfunction was seen in 27% of patients receiving an anthracycline in combination with trastuzumab, but only 13% of patients receiving trastuzumab combined with paclitaxel (16% vs 2% with class III/IV New York Heart Association [NYHA] dysfunction). Seventy-five percent of those requiring treatment for cardiac dysfunction improved with standard medical care.10 Subsequent elegant preclinical studies confirmed the importance of HER-2 in maintenance of cardiac myocytes.11 Current recommendations for use of trastuzumab suggest avoiding concurrent use with anthracyclines and monitoring cardiac function during use. For metastatic breast cancer patients with normal cardiac function and HER-2-overexpressing disease, combination therapy with trastuzumab and chemotherapy is now standard of care.

Use in the Adjuvant Setting

Promising data in the metastatic setting led to the evaluation of adjuvant trastuzumab. In 2005, combined results of the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-31 and North Central Cancer Treatment Group (NCCTG) N9831 were reported. After definitive resection of HER-2-positive (IHC 3+ or amplified by fluorescence in situ hybridization [FISH]), node-positive, or high-risk node-negative (5.7% of cases) breast cancer, women received adjuvant doxorubicin/cyclophosphamide (AC) followed by paclitaxel with or without weekly trastuzumab (begun during paclitaxel) and followed by trastuzumab alone for a total of 52 weeks of HER-2 targeted therapy. Data was reported on over 3000 women with a median follow-up of 2 years. Disease-free survival was significantly improved from 67.1% in the control group to 85.3% in those receiving trastuzumab (hazard ratio [HR] 0.48); overall survival at 3 years was similarly significantly improved from 91.7% in the control group to 94.3% in the trastuzumab group (HR = 0.67). Eligibility was limited to women with normal ejection fraction after AC; 4.1% of women treated with trastuzumab experienced a cardiac event compared with 0.8% with chemotherapy alone.12

At the same time, Piccart-Gebhart et al13 reported results of the 1-year randomization arm of the Herceptin Adjuvant (HERA) trial, which included women with HER-2-positive (IHC 3+ or amplified by FISH) breast cancer randomized after completion of investigators’-discretion adjuvant chemotherapy (several regimens were permitted) to 1 or 2 years of trastuzumab versus no further infusional therapy (the 2-year randomization results have not been reported). This study included node-negative women at a much higher rate (32%-33%) than in the NSABP and NCCTG trials. Women received 1 year of trastuzumab therapy, 6 mg/kg every 3 weeks. An ejection fraction of 55% or greater and no prior cardiac history was required for entry onto the trial. At a median follow-up of 1 year, the HR of relapse for the trastuzumab arm was 0.54, representing an 8.4% absolute improvement in 2-year disease-free survival.13 In a subsequent report at a median of 2 years of follow-up, improved survival was seen (HR 0.66; 95% CI 0.47-0.91).14 In spite of more rigorous cardiac eligibility criteria, decreased ejection fraction occurred in 7.1% of the trastuzumab group compared with 2.2% of the observation group, and the clinical cardiotoxicity was 1.7% versus 0.06%. Finally, Breast Cancer International Research Group (BCIRG) 006, which enrolled over 3000 women with node-positive or high-risk node-negative, HER-2-positive (by FISH) breast cancer, compared chemotherapy only (AC followed by docetaxel [AC-T]) with the same chemotherapy with 1 year of trastuzumab beginning during docetaxel (AC-TH) or a novel nonanthracycline regimen of docetaxel plus carboplatin with 1 year of trastuzumab during and after chemotherapy (TCH). This study has been reported at a median of 36 months revealing a significant improvement in disease-free survival with either trastuzumab-based regimen compared with chemotherapy alone (HR 0.61 for AC-TH; HR 0.67 for TCH), and significantly less cardiotoxicity with the nonanthracycline trastuzumab regimen (0.004% TCH vs 1.8% AC-TH), suggesting that much of the benefit may be accrued without the anthracycline and toxicity can be minimized in appropriate patients.15 A very small but intriguing study, FinHER, included patients with HER-2-positive (by FISH) tumors among a larger trial examining adjuvant vinorelbine versus docetaxel followed by fluorouracil/epirubicin/cyclophosphamide (FEC). The 232 patients with HER-2-positive tumors were randomized to receive or not receive 9 weeks of trastuzumab during the chemotherapy. Results from this subgroup revealed a significantly improved 3-year recurrence-free survival in those who received trastuzumab (HR 0.42), and no significant increase in cardiac events.16 While too small to be definitive, this study raises the question of whether far shorter durations of adjuvant trastuzumab may be possible, a concept which is being tested in the AOUMODENA trial.

Together these trials brought about the widespread use of trastuzumab in the adjuvant therapy of HER-2+, node-positive, and high-risk node-negative women with breast cancer. Outstanding questions that remain include determining the optimal duration of therapy, the necessity of concurrent chemotherapy, the optimal chemotherapy backbone, and the potential utility of adding other targeted agents such as lapatinib.

Concurrent with Radiotherapy

Preclinical studies link HER-2 overexpression in breast cancer with radioresistance.17 When HER-2 is exogenously overexpressed in normal breast cancer cell lines, the HER-2-overexpressing cells acquire radioresistance compared with their parental counterparts, a phenomenon that can be reversed with exposure to trastuzumab.17,18 These results suggest that trastuzumab may be a radiosensitizer.

The most robust clinical data combining radiotherapy and trastuzumab stems from the combined NSABP/NCCTG analysis where radiation was given concurrently with trastuzumab. Regional nodal irradiation was permitted or required with the exception of internal mammary node irradiation, which was specifically prohibited in both trials. In addition to its distant effects, trastuzumab reduced local recurrence by half in treated patients.12 Whether this is an effect of the trastuzumab alone on local control, or a sensitizing interaction between the radiation and trastuzumab is unclear. Prospective studies should help to clarify the role of HER-2 in clinical radiation response.

Ongoing Trials

Multiple ongoing phase III trials are evaluating a wide range of potential trastuzumab applications from new drug combinations in the metastatic setting to the role of trastuzumab in the neoadjuvant setting (Table 88-1).

Biology

In addition to HER-2, other members of the ErbB family are known to promote tumor growth. ErbB1 (EGFR), in particular, has been linked to the growth of several solid tumor types. EGFR family members form hetero- or homodimer pairs after ligand binding that result in activation of downstream signaling pathways. Thus, targeting of multiple receptors with 1 drug is appealing. Lapatinib, a small molecule tyrosine kinase inhibitor, is a reversible inhibitor of ErbB1 (EGFR) and ErbB2 (HER-2).

Use in the Locally Advanced/Metastatic Setting

Early phase data demonstrated that lapatinib was well tolerated19,20 with diarrhea and rash the most frequent adverse events. As a result, multiple phase II/III studies were initiated to assess the clinical efficacy of lapatinib. In the first phase II evaluation of lapatinib as monotherapy, 229 women with refractory advanced or metastatic breast cancer were given 1500 mg of lapatinib once daily until disease progression. Despite the fact that more than 3 quarters of patients had received 4 or more prior treatment regimens, a clinical benefit (progression-free for at least 6 months) was seen in approximately 6% of HER-2 + patients. No correlation was seen with the level of EGFR expression. No tumor response was seen in patients who did not overexpress HER-2. The most common adverse events were diarrhea (59%), nausea (37%), and rash (32%). Nine patients experienced a decline in left ventricular ejection fraction and one was symptomatic.21

Another randomized, multicenter study examined the feasibility of lapatinib as first-line therapy. Patients with stage IIIB, IIIC, and IV HER-2-overexpressing (by FISH; confirmed centrally) breast cancer were randomized to 500 mg or 1500 mg twice daily lapatinib prior to receiving any other chemotherapy, immunotherapy, or biologic therapy. One hundred thirty-eight patients were recruited worldwide. Twenty-four percent experienced a complete or partial response with no significant dose response noted. Median duration of response was 28.4 weeks. No unexpected toxicity was noted.22 Interestingly, a recently reported phase III trial in women with progression on trastuzumab randomized patients to lapatinib or lapatinib plus ongoing trastuzumab and found that progression-free survival was improved in those with dual biologic therapy despite progression on one.23