Annals of Oncology Advance Access originally published online on January 12, 2006
Annals of Oncology 2006 17(4):630-636; doi:10.1093/annonc/mdj110
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© 2006 European Society for Medical Oncology
A phase II study on metastatic breast cancer patients treated with weekly vinorelbine with or without trastuzumab according to HER2 expression: changing the natural history of HER2-positive disease
1 Division of Medical Oncology A, Regina Elena Cancer Institute; 2 Department of Pathology, Regina Elena Cancer Institute; 3 Department of Clinical Pathology, Cytogenetic Unit; 4 Cardiology Unit, Regina Elena Cancer Institute; 5 Biostatistics Unit, Regina Elena Cancer Institute, Rome, Italy
* Correspondence to: Dr G. Ferretti, Division of Medical Oncology "A", Regina Elena Cancer Institute, Via Elio Chianesi 53, 00144 Rome, Italy. Tel: +39 06 526 65354. E-mail: gia.fer{at}flashnet.it
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Abstract |
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Purpose: To observe whether in pretreated metastatic breast cancer patients with HER2-positive disease vinorelbine plus trastuzumab can produce different overall response rate (ORR), time to progression (TTP), and overall survival (OS) from women with HER2-negative tumors treated with vinorelbine alone.
Methods: Between June 2000 and January 2004, 68 consecutive women were enrolled: 33 patients received vinorelbine (V) alone, while 35 patients were given trastuzumab plus vinorelbine (T+V) according to HER2 expression determined by immunohistochemistry. In tumors scored +2, HER2 gene amplification was determined by fluorescence in situ hybridization.
Results: In patients treated with V (HER2-negative tumors) the ORR was 27.3%, while in those given T+V (HER2 positive tumors) the ORR was 51.4%. The median duration of response was 8 months for women treated with V and 10 months for those who received T+V. Patients given T+V had a longer TTP (9 months) and OS (27 months) than those receiving V alone (6 months and 22 months respectively). Toxicity was mild in both groups. Concerning cardiotoxicity in T+V group, 7 patients (20%) had left ventricular systolic disfunction.
Conclusion: Our data suggest that trastuzumab can change the natural history of HER2-positive metastatic breast cancer. In fact, when treated with trastuzumab, women with HER2-positive disease had better prognosis than patients with HER2-negative tumors. Conducting a formal phase III trial comparing vinorelbine alone vs vinorelbine plus trastuzumab in HER2-positive metastatic breast cancer women could be debatable.
Key words: weekly vinorelbine, trastuzumab, HER2, metastatic breast cancer
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introduction |
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TopAbstractintroductionpatients and methodsresultsdiscussionReferences |
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Overexpression of HER2, which occurs in 15–25% of human breast cancer [1
, 2], is associated with malignant transformation [3–7]. HER2-overexpressing (HER2-positive) breast cancer is known to be associated with particularly aggressive disease and poor prognosis [8–11]. Binding of trastuzumab to HER2 blocks growth-stimulating intracellular signaling, decreases the cellular repair capacity after chemo- and radiotherapy, and possibly also improves the apoptosis capacity [12, 13]. The antibody has been shown to impart therapeutic effects either alone [14, 15] or in combination with chemotherapy [16–18]. In three randomized studies it has been reported that the synergistic or additive interactions between trastuzumab and chemotherapy greatly improved the efficacy in advanced breast cancer [19–21]. However, the use in clinical practice of anthracycline-including regimens in combination with trastuzumab has been limited by drug-associated cardiac toxicity [22].
Vinorelbine used as a single agent has demonstrated a good efficacy both as first-line (41–50%) and as second-line (25–40%) chemotherapy for metastatic breast cancer [23, 24]. In vitro studies have suggested that the combination of trastuzumab and vinorelbine exerts synergistic activity [17, 25, 26]. In fact, the results of recent clinical studies of this combination in untreated or heavily pretreated patients with HER2-positive metastatic breast tumors [27–35] have shown high objective response rates (68–78%] with mild hematological and non-hematological toxicities. Vinorelbine did not increase the cardiac toxicity of trastuzumab.
Based on these evidences, we have conducted a phase II study including 68 consecutive metastatic breast cancer patients treated with weekly vinorelbine with or without trastuzumab according to HER2 overexpression in order to determine whether in patients with HER2-positive disease vinorelbine plus trastuzumab would produce different ORR, TTP and OS from patients with HER2-negative disease treated with vinorelbine alone.
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patients and methods |
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Patients were required to have cytologically or histologically diagnosis of metastatic breast carcinoma. They had received at least one prior chemotherapy regimen for metastatic breast cancer and had not received previous chemotherapy including vinorelbine. Patients were given prior adjuvant chemotherapy and hormonal therapy. A bi-dimensionally measurable disease, adequate general health status and absence of active concomitant illnesses are required. Patients had a Performance Status (ECOG)
2 and a life expectancy 
3 months. They were neither pregnant nor nursing. Patients with symptomatic central nervous system metastases were excluded. Patients were required to have a left ventricular ejection fraction (EF) of 50%. Patients pretreated with taxanes showing neuropathy exceeding grade 1 according to the World Health Organization (WHO) criteria were excluded. Patients were required to have an absolute neutrophil count more than 1500/µl, platelet count more than 100,000/µl, bilirubin less than 2 mg/dl, transaminases less than 3 x upper normal limit (UNL). Patients did not receive other concurrent antineoplastic therapy. Patients had concluded any radiotherapy or chemotherapy at least 2 weeks and/or hormonal therapy at least 1 month before treatment. Patients had recovered from all chemotherapy or radiation therapy toxicities in excess of grade 1 before initiating treatment. Patients could receive concomitant bisphosphonate treatment. HER2 overexpression was determined by immunohistochemistry (IHC). IHC was performed using the DAKO HercepTest kit. Patients with tumors scored as +3 positive for HER2 were eligible. In case of tumors scored +2, women with tumors showing HER2 gene amplification determined by fluorescence in situ hybridization (FISH) were considered eligible.
treatment plan
The treatment was given in an outpatient setting. The dose of vinorelbine was 25 mg/m2 weekly administered into a central vein over 15 min. For HER2 3+ or HER2 2+/FISH+ breast cancer patients receiving trastuzumab, vinorelbine was given on the same day and after trastuzumab administration, with the exception of the first administration in which trastuzumab was given on day 1 and vinorelbine on day 2. The initial infusion of trastuzumab was 4 mg/kg intravenous (IV) administration over the course of 90 min; subsequently, trastuzumab was given weekly at 2 mg/kg IV administered over 30 min. Chemotherapy ± trastuzumab was administered until documented disease progression, unacceptable toxicity or patient refusal.
The vinorelbine dose was adjusted each week on the day of therapy, based on hematological and/or non-hematological toxicity. Adjustments in the dose of vinorelbine (25% dose reduction) were made in patients who experienced grade 
hematological toxicity, grade 4 febrile neutropenia, grade 4 neutropenia persisting for 7 days or grade 4 thrombocytopenia. The Granulocyte-Coloning Support Factor (G-CSF) was used in case of treatment delay of more than 2 weeks because of neutropenia or for febrile neutropenia. Hematologic support with recombinant human erythropoietin was applied at the investigator's discretion. Delays in vinorelbine dosing of 1 week were applied for both grade 2 or higher neutropenia and thrombocytopenia. Vinorelbine dose was reduced of 25% in case of grade 2 neurologic toxicity until it resolved to grade 1 or less. If grade 3 non-hematologic occurred, the vinorelbine administration was delayed until the side effect resolved to grade 1 or lower. If toxicity persisted more than 3 weeks, patients were taken off the study, as were patients with grade 4 non-hematologic toxicity.
No adjustments in the dose of trastuzumab were permitted. Patients treated with trastuzumab had left ventricular ejection fraction (LVEF) measured every 12 weeks. Patients with asymptomatic decrease of LVEF more than 20% from baseline or less than the lower normal limit (as measured by echocardiography) or with symptomatic congestive heart failure were taken off the study.
study analysis
Toxicity and response to therapy were determined according to WHO criteria. Patients who received at least 8 weeks of vinorelbine and trastuzumab were evaluable for efficacy, and patients who received at least one dose were evaluable for toxicity. The antitumor activity of the combination was assessed every 12 weeks by radiological evaluation (magnetic resonance imaging, computed tomography scan, chest x-rays) or physical examination. Dose-intensity was calculated according to the method of Hryniuk and Goodyear [36].
The primary end point of this study was the overall response rate (ORR) (according to WHO criteria), while duration of overall response, time to progression (TTP) and overall survival (OS) were considered as secondary end-points.
statistical Analysis
Patients were consecutively accrued in a phase II single-center study. According to HER2 status, the accrual goal in each group called for a total of 33 patients required to have at least one prior chemotherapy regimen for metastatic breast cancer. A total of seven responders among 33 patients were considered adequate to justify further study of the regimen. This sample size was identified to exclude drug combination with an activity lower than 10% and considering interesting a 30% response rate. The power of this single stage design was 80% at a significance level of 5%. Survival curves were estimated with the Kaplan-Meier method and statistics were reported with their confidence intervals.
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results |
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Sixty-eight consecutive women were enrolled into the trial between June 2000 and January 2004: 33 patients received only vinorelbine (V) administration, while 35 patients were given trastuzumab plus vinorelbine (T+V). The characteristics of the two groups are summarized in Table 1. HER2 protein expression was determined by IHC in all women and HER2 gene amplification was evaluated by FISH in the 10 patients having tumors with HER2 2+ staining. FISH resulted positive in 8/10 patients with tumors showing HER2 2+ staining. This result was repeated and confirmed. Patients having tumors with HER2 3+ (26 patients) or HER2 2+/FISH+ (eight patients) were treated with association of T+V, while patients without HER2 overespression were treated with V alone. Regarding the two women with HER2 2+/FISH– breast cancer, one patient received T+V, while the other was given V alone.
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The clinical characteristics were well balanced between the two groups (Table 1): the main differences were the different percentage of patients with positive estrogen and/or progestinic receptors between the two groups and the higher percentage of women with soft tissue as metastatic site in in V+T group. All patients had previously received anthracycline-based regimen (adjuvant setting: 15 patients in V group and 22 in T+V group; metastatic setting: 21 and 17 patients in V group and T+V group, respectively) and prior taxane-containing regimens in 61 (96%) patients (adjuvant setting: 5 patients in both groups; metastatic setting: 24 and 25 patients in V group and T+V group, respectively). Three women of the T+V group had been previously administered trastuzumab-containing antineoplastic therapy for metastatic disease. Six and 11 women were premenopausal and 27 and 24 patients were postmenopausal in V and T+V, respectively. Median number of metastatic sites was 2 for both groups (range 1–3 for V alone and range 1–4 for association treatment). Median number of previous chemotherapy lines received for metastatic disease was 2 (range 1–4) for both groups. The progression free interval was longer for V group than for T+V group: 42 months and 35 months, respectively. Median number of chemotherapy administrations in the study were 12 (range 2–53) and 15 (range 2–32) in V group and T+V group respectively, and a median of 23 (range 1–102) weeks of trastuzumab administration was given.
The projected dose of vinorelbine was 25 mg/m2/week in both groups, and the delivered dose of vinorelbine was 70.8% (17.7 mg/m2/week) and 89.7% (22.4 mg/m2/week) in V group and T+V group, respectively. The delivered dose intensity of trastuzumab was 98%. There were no dose adjustments for trastuzumab.
efficacy
All patients in both groups were evaluable for efficacy (Table 2). The 33 patients of V group obtained one complete response and 8 partial responses (overall response rate 27.3%, CI 12.1–42.5); 12 women showed stable disease (36.4%) and 12 progressive disease (36.4%). The 35 patients of T+V group achieved one complete response and 17 partial responses (overall response rate 51.4%, CI 32.9–68); 10 patients had stable disease (28.6%) and seven progressive disease (20%).
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The median duration of response was 8.0 months (range 7–17) for those treated with V and 10.0 (range 4–31) for the group receiving T+V. The clinical benefit (ORR + SD
6 months) was 54.5% in patients receiving V and 71.4% in those who received the combination therapy, with a median duration of 8 months (range 6–17) and 10 months (range 4–31), respectively. Most patients on study had previously received either an anthracycline-based or taxane-based regimen, or both. Among the patients previously treated with anthracycline-based chemotherapy, the response rate was 25.8% and 50% for V and T+V, respectively. Considering patients previously treated with anthracyclines and taxanes the response rate was 15.3% for V group and 48% for the combination group. Response rates were also analyzed as a function of the level of HER2 overexpression in T+V group. For women with HER2 +3 overexpression the response rate was 61.5% (16/26 patients), whereas among those patients with tumors HER2 2+/FISH+ the response rate was 25% (2/8 patients). The patient with tumor HER2 2+/FISH– showed no response to T+V. Patients receiving T+V therapy tended to have longer time to progression (TTP) and overall survival (OS) than those receiving V alone: TTP 9.0 months (IC: 7–11) and 6.0 months (IC: 4–8) and OS 27 months (IC: 19–35) and 22 months (IC: 12–32) in T+V group and in V alone group, respectively (P = 0.06). The median follow up was 17 months (range 1–43).
Among patients with progressive disease, 26.3% (5 of 19 patients) were discovered to have new central nervous system (CNS) metastases as their site of progression, of whom four had been treated with combination therapy.
toxicity
All the patients were assessable for toxicity. The grades of treatment-related toxicity encountered in the study are listed in Table 3. Neutropenia G3-G4 was observed in 51% of patients treated with V alone and in 49% of patients given T+V. Neutropenia was usually brief and non-cumulative, and was manageable with dose adjustments. There were 2 cases (6%) of febrile neutropenia in the V alone group; the event resolved by V dose reduction. The G-CSF support was used in 35% of patients receiving V alone, while in only 18% of patients given the combination. Low-grade anemia was common; however, grade 3 anemia occurred in two (6%) and one (3%) of the patients in the chemotherapy only and combination group, respectively. Additionally, no severe thrombocytopenia was registered, with the exception of one case (3%) of grade 3 thrombocytopenia in the V group. Thus, neutropenia and one case of thrombocytopenia was the only grade 4 hematological toxicity observed during the study.
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The main causes for vinorelbine dose adjustment were neutropenia and hepatic toxicity. In 24% of patients the weekly dose of V alone group was reduced by 25% for persistent grade 3 neutropenia (15%), grade 4 thrombocytopenia (3%) and grade 3 hypertransaminasemia (6%); in 9% of patients the drug was omitted for grade 3–4 neutropenia. In the association therapy group there were 14.5% of patients with chemotherapy reduced by 25% for grade G3-4 neutropenia (8.5%) and liver toxicity (6%).
Peripheral neuropathy G1-G2 affected 24% and 20% patients in V and T+V group, respectively; none exceeded grade 2, and no V dose adjustment was required as a result of neuropathy. Many of the women with neuropathy had pre-existing symptoms from prior taxane-based treatments. Trastuzumab-related infusion reactions (acute arterial hypertension, tachycardia, a mild dyspnea and headache) were observed in three (8.5%) patients; none of these events required hospitalization and none precluded therapy prosecution. Asthenia was frequent in this patient population: in V alone group we observed a mild, moderate and severe asthenia in 24%, 9% and 3% of patients, respectively while in T+V in 20%, 6% and 3% of patients, respectively.
Concerning cardiotoxicity in the T+V group, 7 patients (20%) had left ventricular systolic dysfunction: four (11%) and two (6%) patients had a decline of LVEF >10% and >20% respectively; 1 patient had symptomatic congestive heart failure responsive to medical therapy. Three patients with a decline of LVEF >10% and >20% and the patient with symptomatic congestive heart failure experienced a prior doxorubicin and epirubicin exposure in excess of 240 mg/m2 and 480 mg/m2, respectively. In subsequent follow-up, off of trastuzumab treatment, five of the seven patients recovered their LVEF to baseline levels. Four patients were subsequently retreated with trastuzumab with adequate monitoring of their cardiac function (echocardiography). Declines in LVEF were observed at a median of 14 weeks of trastuzumab administrations (range 12–51). The median LVEF at baseline was 62% (50%-72%). At week 12 the median LVEF was 59%. None of the 27 patients with LVEF greater than 50% at week 12 experienced an absolute decline in LVEF of greater than 10%. In contrast, four of the eight patients noted at week 12 to have LVEF 50% developed more severe cardiotoxicity: one decline in LVEF of 10%, two declines in LVEF of 20%, and one symptomatic congestive heart failure.
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discussion |
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In an era where HER2-positive breast cancer is more and more being treated as a distinct clinical entity, the question immediately arises as to whether we can include HER2-positive breast cancer women in trials recruiting patients regardless of HER2 status. This is formally a phase II trial in which we showed that patients with HER2-negative metastatic breast cancer treated with vinorelbine alone had a worse clinical outcome than HER2-positive metastatic breast cancer patients treated with vinorelbine plus trastuzumab. It is known that HER2 overexpression is an unfavorable prognostic factor in breast cancer [8
]. It has been reported that the increased proliferation of tumor cells with HER2 overexpression compared with HER2-negative cells [18, 25] could lead to a more rapid recovery from the cytotoxic effects of chemotherapy despite the tumor's initial chemosensitivity [37, 38]. In fact, patients with HER2-positive tumors relapsed more quickly after chemotherapy than patients with HER2-negative tumors, despite the higher initial response rate [39].
In this paper, as preliminarily reported in 2003 [40], we provocatively suggest that the assumption that HER2-positive tumors have a worse prognosis [8, 9, 11] could be no longer valid when treated with trastuzumab. However, it must be highlighted that the concept of worse prognosis was based on retrospective trials in the pre-trastuzumab era. It has been reported that positivity for c-erbB-2 is significantly associated with node positivity, large tumor size, high grade of malignancy, low receptor status, postmenopausal status, and with a shorter overall survival [41]. In our series, women with HER2-overexpressing tumors tended to have a lower percentage of endocrine-responsive disease (45.7 vs 60.6%) and a shorter progression-free interval (35 vs 42 months) (Table 1). However, with the use of trastuzumab, women with HER2-positive disease appeared to do far better than did patients with HER2-negative tumors, exhibiting consistently higher rates of response, longer time to progression, and improved overall survival. These data are confirmed by a recent little study performed on 20 patients with metastatic breast cancer [42]: of the seven evaluable women with HER2+ tumors, the combination of docetaxel, carboplatin and trastuzumab yielded a 43% RR and a median TTP of 217 days compared with only an 8% RR with a median TTP of 118 days for the 13 evaluable patients with HER2-negative tumors who received docetaxel and carboplatin alone. In addition, Kirsch at al. [43] analyzed retrospectively 91 patients with brain metastases from breast cancer; 45 patients had tumors that did overexpress HER2; 35 of these women received trastuzumab. These authors found that patients with HER2-overexpressing breast cancer had a significantly longer OS (median 23 months vs 10 months, P = 0.0016) after the development of brain metastases. On the other hand, it has been demonstrated that women with HER2-negative breast tumors do not benefit from the addition of T. Seidman et al. [44] evaluated the activity of the combination of trastuzumab and paclitaxel in women with HER2-overexpressing tumors and in those with tumors showing normal HER2 expression: the difference in response rate between patients with tumors having normal HER2 expression compared with those showing HER2 overexpression was statistically significant for all assay methods used. In another phase II trial of trastuzumab plus docetaxel in 16 metastatic breast cancer patients, 6 of 7 responders had 3+ HER2 staining by IHC (HercepTest), while most of the remaining 9 patients who did not respond had 2+ staining [45]. Finally, in a recent study where HER2-negative patients treated with paclitaxel were randomized to receive associated trastuzumab, no difference in response rate, time to progression or overall survival was observed between the two groups [46]. Formally, a comparison of ORR, TTP and OS between two cohort of patients should be done within a prospective randomized trial, and the combination of trastuzumab with vinorelbine versus vinorelbine alone could be a novelty, since it was never published. However, it is unlikely that such a study could be conducted nowadays, because in HER2-positive tumors chemotherapy alone as first-line treatment has been replaced with a combination of chemotherapy and trastuzumab [19–21], and a trial without trastuzumab in HER2-positive breast cancer patients would be ethically inappropriate. Unfortunately, little clinical information is available on the association between HER2 status and response to chemotherapy with vinorelbine-based regimens.
Our data on efficacy resemble those previously reported in literature in pretreated patients for metastatic disease, either for vinorelbine alone [47–52] or for vinorelbine plus trastuzumab [27, 53]. Hematological toxicity was comparable with that previously reported as well, either for single agent [54] or for the combination [27]. Cardiac dysfunction appears to improve in most patients who receive supportive medical treatment, in some cases even when trastuzumab is continued. In a small phase II study of 40 in part pretreated breast cancer women receiving trastuzumab plus vinorelbine [27], no patients developed symptomatic CHF, but in our study 1 patient had a symptomatic congestive heart failure resolved by appropriate medical therapy. In our series, four (11%) and 2 (6%) patients had a decline of ejection ventricular fraction >10% and >20% respectively. One patient with a decline of LVEF >10%, 2 patients with a decline of LVEF >20%, and 1 patient with symptomatic congestive heart failure experienced a prior doxorubicin and epirubicin exposure in excess of 240 mg/m2 and 480 mg/m2, respectively. In our trial, in subsequent follow-up, off of trastuzumab treatment, 5 of the 7 patients recovered their LVEF to baseline levels. Four patients were subsequently retreated with trastuzumab with adequate monitoring of their cardiac function (echocardiography). Declines in LVEF were rather delayed in time (median of 14 weeks of trastuzumab administrations, range 12–51].
Decades of randomized clinical trials on the front-line treatment of metastatic breast cancer have never been able to show so remarkable differences in TTP and OS as the three randomized trials comparing chemotherapy with chemotherapy plus trastuzumab in women with HER2-overexpressing metastatic breast cancer [19–21] have been able to do. In the pre-trastuzumab era, retrospective analyses have shown that HER2 overexpression is an adverse prognostic factor associated with an increased risk of disease recurrence and death. Our study demonstrated that women with HER2-overexpressing metastatic breast cancer, when treated with trastuzumab and vinorelbine, had a better prognosis than those with HER2-negative disease treated with vinorelbine alone. In the trastuzumab era, this drug has changed the natural history of HER2-positive breast cancer, either in the metastatic [19–21] or, according to the most recent evidences, in the adjuvant setting [55, 56].
Received for publication September 13, 2005. Revision received November 11, 2005. Accepted for publication November 14, 2005.
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References |
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