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

Purpose: To observe whether in pretreated metastatic breastcancer patients with HER2-positive disease vinorelbine plustrastuzumab can produce different overall response rate (ORR),time to progression (TTP), and overall survival (OS) from womenwith HER2-negative tumors treated with vinorelbine alone. Methods: Between June 2000 and January 2004, 68 consecutivewomen 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 determinedby fluorescence in situ hybridization. Results: In patients treated with V (HER2-negative tumors) theORR was 27.3%, while in those given T+V (HER2 positive tumors)the ORR was 51.4%. The median duration of response was 8 monthsfor women treated with V and 10 months for those who receivedT+V. Patients given T+V had a longer TTP (9 months) and OS (27months) than those receiving V alone (6 months and 22 monthsrespectively). Toxicity was mild in both groups. Concerningcardiotoxicity in T+V group, 7 patients (20%) had left ventricularsystolic disfunction. Conclusion: Our data suggest that trastuzumab can change thenatural history of HER2-positive metastatic breast cancer. Infact, when treated with trastuzumab, women with HER2-positivedisease had better prognosis than patients with HER2-negativetumors. Conducting a formal phase III trial comparing vinorelbinealone vs vinorelbine plus trastuzumab in HER2-positive metastaticbreast cancer women could be debatable. Key words: weekly vinorelbine, trastuzumab, HER2, metastatic breast cancer     

EGFR,pMAPK, pAkt and PTEN status by immunohistochemistry: correlation with clinical outcome in HER2-positive metastatic breast cancer patients treated with trastuzumab

BackgroundIn an attempt to identify markers of resistance to trastuzumab, we evaluated both the profiling of human epidermal growth factor receptor 2 (HER2)-positive tumor cells measuring the relative levels of EGFR, pMAPK, pAkt and PTEN and their correlations with clinical outcome in HER2-positive metastatic breast cancer patients treated with trastuzumab.Patients and methodsTumor tissues for this retrospective analysis were available from 45 out of 76 patients with metastatic breast cancer treated from April 1999 to March 2006 with trastuzumab-based therapy at our Institution. Evaluations of EGFR, pMAPK, pAkt and PTEN status by immunohistochemistry (IHC) were carried out on all 45 tissue samples and their correlations with response to trastuzumab, incidence of central nervous system (CNS) metastases, time to progression (TTP), overall survival from diagnosis of breast cancer (OS1), from diagnosis of metastatic disease (OS2) and from the start of trastuzumab (OS3) were analyzed.ResultsWe observed that TTP (P = 0.001) and median OS2 and OS3 were significantly longer in patients responsive to trastuzumab-based regimen compared with nonresponsive patients. EGFR, pMAPK, pAkt and PTEN status by IHC were not significantly associated with response to trastuzumab, TTP, overall survival (OS1, OS2, OS3) and CNS metastases incidence. A trend for shorter OS3 was observed for pMAPK-positive patients compared with pMAPK-negative patients (22.8 versus 31.2 months; P = 0.076). Median OS1 resulted shorter in 22 pAkt-positive patients (69.8 months) compared with 23 pAkt-negative patients (108.2 months); P = 0.091. It is likely that high expression of pMAPK (pMAPK-positive status) or pAkt (pAkt-positive status) could identify a subgroup of HER2-positive tumors with high activity of proliferation and survival pathways and with resistance to trastuzumab.ConclusionsIn HER2-positive metastatic breast cancers, EGFR, pMAPK, pAkt and PTEN status evaluated by IHC was not significantly associated with response to trastuzumab, TTP, OS and CNS metastases incidence. However, HER2 status determined by IHC and/or FISH assays may not be sufficient to predict response to trastuzumab-based therapy.     

Randomized phase II trial of gemcitabine-cisplatin with or without trastuzumab in HER2-positive non-small-cell lung cancer.

BACKGROUND: Trastuzumab provides significant clinical benefits in HER2-positive metastatic breast cancer patients when administered in combination with chemotherapy. Chemotherapy has also been shown to be beneficial in some patients with advanced non-small-cell lung cancer (NSCLC). The present randomized phase II trial examined the effect of adding trastuzumab to a standard chemotherapeutic combination (gemcitabine-cisplatin) in patients with HER2-positive NSCLC. PATIENTS AND METHODS: Patients with untreated stage IIIB/IV HER2-positive NSCLC received up to six 21-day cycles of gemcitabine 1250 mg/m(2) (days 1 and 8) and cisplatin 75 mg/m(2) (day 1). Patients in the trastuzumab arm received trastuzumab 4 mg/kg intravenously (i.v.) followed by 2 mg/kg/week i.v. until progression. RESULTS: Of 619 patients screened, 103 were eligible. Fifty-one patients were treated with trastuzumab plus gemcitabine-cisplatin and 50 with gemcitabine-cisplatin alone. Efficacy was similar in the trastuzumab and control arms: response rate 36% versus 41%; median time to progression 6.3 versus 7.2 months; and median progression-free survival (PFS) 6.1 versus 7 months. Response rate (83%) and median PFS (8.5 months) appeared relatively good in the six trastuzumab-treated patients with HER2 3+ or fluorescence in situ hybridization (FISH)-positive NSCLC. Addition of trastuzumab to gemcitabine-cisplatin was well tolerated, side-effects were as expected, and trastuzumab did not exacerbate the known toxicity of gemcitabine and cisplatin. Symptomatic cardiotoxicity was observed in one trastuzumab-treated patient. Serum trastuzumab concentrations in the presence of gemcitabine-cisplatin were comparable to those of trastuzumab alone. CONCLUSIONS: Trastuzumab plus gemcitabine-cisplatin is well tolerated. Clinical benefit was not observed. Although HER2 3+/FISH-positive patients may benefit from trastuzumab, the subgroup is too small to provide definitive information. No significant effect of gemcitabine-cisplatin on trastuzumab pharmacokinetics was observed.     

曲妥珠单抗联合吉西他滨治疗ＨＥＲ２阳性的转移性乳腺癌

目的：探讨曲妥珠单抗（赫赛汀）联合吉西他滨（ＧＥＭ）治疗表皮生长因子受体２（ＨＥＲ２）阳性的转移性乳腺癌（ＭＢＣ）的疗效和不良反应。方法：ＨＥＲ２阳性的ＭＢＣ女性患者９例,给予ＧＥＭ１０００ｍｇ／ｍ^２,静脉滴注,ｄ１、ｄ８、ｄ１５,４周重复;赫赛汀静脉滴注,首次４ｍｇ／ｋｇ,其后每周１次,２ｍｇ／ｋｇ,连续使用。结果：９例患者中,ＣＲ１例（１１.１％）,ＰＲ６例（６６.７％）,ＳＤ和ＰＤ各１例（１１.１％）,有效率（ＲＲ）为７７.８％,疾病控制率（ＤＣＲ）为８８.９％;中位肿瘤进展时间（ＴＴＰ）为１８个月,中位总生存时间（ＯＳ）为２３个月。主要毒性反应是骨髓抑制和消化道反应,且均为Ⅰ ～Ⅱ度。结论：赫赛汀联合吉西他滨对于难治性转移性乳腺癌是有效且安全的治疗方案。     

A phase II study of afatinib (BIBW 2992), an irreversible ErbB family blocker, in patients with HER2-positive metastatic breast cancer progressing after trastuzumab

Afatinib is an oral, ErbB family blocker, which covalently binds and irreversibly blocks all kinase-competent ErbB family members. This phase II, open-label, single-arm study explored afatinib activity in human epidermal growth factor receptor 2 (HER2)-positive breast cancer patients progressing after trastuzumab treatment. Patients had stage IIIB/IV HER2-positive metastatic breast cancer, with progression following trastuzumab or trastuzumab intolerance and an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. Patients received 50 mg afatinib once-daily until disease progression. Primary endpoint was objective response rate (Response Evaluation Criteria in Solid Tumors 1.0), with tumor assessments every 8 weeks. Forty-one patients were treated. Patients had received a median of three prior chemotherapy lines (range, 0-15) and 68.3% had received trastuzumab for >1 year. Four patients (10% of 41 treated; 11% of evaluable patients) had partial response. Fifteen patients (37% of 41) had stable disease as best response and 19 (46% of 41) achieved clinical benefit. Median progression-free survival was 15.1 weeks (95% confidence interval [CI]: 8.1-16.7); median overall survival was 61.0 weeks (95% CI: 56.7-not evaluable). Most frequent common terminology criteria for adverse events grade 3 treatment-related adverse events were diarrhea (24.4%) and rash (9.8%). Afatinib monotherapy was associated with promising clinical activity in extensively pretreated HER2-positive breast cancer patients who had progressed following trastuzumab treatment.     

A phase II study of weekly vinorelbine and trastuzumab in patients with HER2-positive metastatic breast cancer

BACKGROUND: Trastuzumab combined with cytotoxic agents presents encouraging results in metastatic breast cancer (MBC), but cardiac toxicity limits some combinations. The synergism shown with trastuzumab and the favorable tolerability profile of vinorelbine provided the rationale for investigating this combination. PATIENTS AND METHODS: Patients with HER2-positive MBC who had received <2 lines of chemotherapy for metastatic disease were included. Vinorelbine (25 mg/m2 on day 2, then weekly on day 1) and trastuzumab (4 mg/kg on day 1, then 2 mg/kg weekly) were administered for a maximum of 6 cycles (1 cycle=3 weeks). RESULTS: A total of 52 patients were enrolled. The median age was 50 years (range, 26-79 years). Ninety percent of the patients had received adjuvant chemotherapy, 42% received a first line of chemotherapy for MBC, and 69% had disease at visceral sites. The overall response rate was 58% (95% CI, 43%-71%). The median time to progression and overall survival were 7 months (95% CI, 5-9 months) and 26 months (95% CI, 20-32 months), respectively. Grade 4 neutropenia was present in 3 courses; neutropenic fever was not reported. The main grade 3 nonhematologic toxicities were asthenia, neuropathy, diarrhea, alopecia, and nausea/vomiting. No patients experienced serious cardiac toxicity. CONCLUSION: These results confirm that weekly vinorelbine/trastuzumab is an active and safe regimen in patients with HER2-positive MBC with an unfavorable prognosis.     

Trastuzumab monotherapy versus combination therapy for treating recurrent breast cancer: time to progression and survival

Background HER2 expression is an important prognostic and predictive factor of treatment efficacy in breast cancer. Trastuzumab, in particular, is a key drug in the treatment of HER2-positive recurrent breast cancer. However, the difference in treatment efficacy between trastuzumab monotherapy and combination therapy with chemotherapy is unclear. In order to elucidate this point, both treatments were compared in terms of efficacy by metastatic site, time to progression (TTP), and survival. Patients and methods The subjects were 1,471 breast cancer patients who had been evaluated for HER2 expression between 1998 and March 2006; 74 of these had recurrent breast cancer that had been treated with trastuzumab. Of these 74 patients, 39 received trastuzumab alone and 45 trastuzumab in combination with chemotherapy. The items of investigation were clinical effect, TTP, survival, biological markers such as ER/PgR, proliferation (Ki67) or p53 overexpression, nuclear grade, performance status (PS), lymph node metastasis, and tumor size. Results The HER2-positive rate was 23.3%, and the degree of malignancy in these HER2-positive patients was high; postoperative disease-free survival (DFS) was low. However, this tendency was clear in patients with hormone-responsive breast cancer. In patients with hormone-non-responsive breast cancer, HER2 negativity had a significantly higher Ki67 value, and there was no difference in DFS between patients with HER2-positive and -negative tumors. Among the 74 patients with recurrent breast cancer, the response rate to trastuzumab was 64.9%; however, among patients who received the combination treatment, the response rate was 86%. In patients with liver metastasis, the effect of trastuzumab alone was low, but that of the combination treatment was significantly high. TTP was 5.7 months and 15.9 months with trastuzumab alone and the combination therapy, respectively. Furthermore, a significant difference was seen in post-treatment survival; however, there was no significant difference in survival after a recurrence. In the multivariate analysis on factors for TTP, PS, clinical effect, and combination treatment were significant. However, good PS and early treatment were the significant factors in post-treatment survival. Conclusions The effect of trastuzumab in patients with recurrent breast cancer who received the combination treatment was significantly high and TTP was long. However, this was not a significant factor in terms of overall survival. In particular, a good PS and early treatment were important in post-treatment survival. This article is based on a presentation delivered at Symposium 3, “Molecular target therapy: basics and clinical application,” held on 30 June 2007 at the 15th Annual Meeting of the Japanese Breast Cancer Society in Yokohama.     

Safety and efficacy of trastuzumab every 3 weeks combined with cytotoxic chemotherapy in patients with HER2-positive recurrent breast cancer: findings from a case series

BACKGROUND: Trastuzumab has been repeatedly shown to result in significant clinical benefits and was subsequently accepted as the treatment of choice for HER2-positive advanced breast cancer - particularly as first-line treatment in combination with taxanes and as monotherapy in the second-line or third-line setting. Trastuzumab is currently licensed as a weekly treatment, although a 3-weekly schedule could be used conveniently in combination with other cytotoxic agents that are administered on a 3-weekly basis in metastatic breast cancer. PATIENTS AND METHODS: We determined the safety of i.v. trastuzumab (8 mg/kg followed by 6 mg/kg) every 3 weeks in combination with chemotherapeutic agents administered in 3-weekly courses (docetaxel, vinorelbine and capecitabine) in 31 patients with HER2-positive recurrent locoregional and/or metastatic breast cancer. RESULTS: 3-weekly trastuzumab appeared to be as well tolerated as the standard once-weekly schedule. All myelosuppressive adverse events and the majority of non-hematological adverse events were typical and characteristic of the individual concomitant cytotoxic agents. Transient trastuzumab-related infusion reactions occurred in 5 patients and 1 patient developed cardiac dysfunction, which recovered after discontinuation of trastuzumab. Efficacy appeared favourable: 18 clinical responses (3 complete and 15 partial) and 8 disease stabilizations gave an overall response rate of 58% (70% in the 20 patients receiving first-line therapy). Median progression-free and overall survival times were 9.9 months (95% CI: 6.3-13.5) and 23.1 months (95% CI: 19.2-27.0), respectively. CONCLUSIONS: These findings will likely encourage further evaluation of this more convenient 3-weekly trastuzumab regimen in patients with HER2-positive metastatic breast cancer.     

Biweekly docetaxel and weekly trastuzumab treatment in HER 2-overexpressing metastatic breast cancer patients

Docetaxel and trastuzumab can be considered to be active drugs for HER 2-overexpressing metastatic breast cancer (MBC). This study was conducted to determine the activity of combination therapy with docetaxel and trastuzumab in MBC patients by assessing the response rate (RR), time to progression (TTP) and safety. We administered the combination of docetaxel 30-40 mg/m(2) biweekly and trastuzumab using a 4 mg/kg loading dose and thereafter 2 mg/kg weekly. Between October 2001 and December 2004, 14 patients with HER 2 positive (3+ by immunohistochemistry) MBC were enrolled in this study. The overall RR was 50.0% (7/14), with 1 CR, 6 PR, 3 NC and 4 PD. Median follow-up time was 15.0 months, while the median TTP was 10.8 months,and the median OS 21.8 months.     

Remarkable response with pembrolizumab plus albumin-bound paclitaxel in 2 cases of HER2-positive metastatic breast cancer who have failed to multi-anti-HER2 targeted therapy

In clinical practice, one subgroup patients of breast cancer might have developed resistance to multi-anti-HER2 targeted drugs(trastuzumab, lapatinib and/or T-DM1) and can not benefit from the anti-HER2 targeted therapy continuously. We attempt to change the next therapic way for these patients. Two patients with metastatic breast cancer who have failed to multi-anti-HER2 targeted therapy were treated with pembrolizumab (2 mg/Kg, day1) plus albumin-bound paclitaxel (125 mg/m², day1,8) every 3 weeks. CT evaluation and HER2 ECD test were performed every 2 cycles. Both of the two patients achieved remarkable response with Partial Remission (PR), meanwhile serum HER2 ECD levels (the upper normal limit is 15 ng/ml) showed a remarkable decreases(compared to the base line decreases 75% and 60% respectively). The results indicate that regimen of pembrolizumab combination with albumin-bound paclitaxel might produce response in patients with HER2-positive metastatic breast cancer who have failed to multi-anti-HER2 targeted therapy.     

Phase II study of weekly docetaxel alone or in combination with trastuzumab in patients with metastatic breast cancer

This study was designed to determine the efficacy and toxicity of weekly docetaxel in metastatic breast cancer when given alone (for HER2/neu negative disease) or with trastuzumab (for HER2/neu overexpressing disease). Patients with metastatic breast carcinoma received docetaxel given on 2 different schedules (group 1A, 33 mg/m2 weekly [n = 21]; group 1B, 40 mg/m2 weekly for 3 weeks with 1 week off [n = 14]). Patients with HER2/neu overexpressing disease also received trastuzumab 4 mg/kg on day 1, then 2 mg/kg on days 8 and 15 of each 28-day cycle (group 2). Fifty-two patients were treated with docetaxel alone (group 1A/B, n = 35) or in combination with trastuzumab (group 2, n = 17). Prior taxane therapy given every 3 weeks had been used for metastatic disease in 19 of 35 patients (54%) in group 1A/B and in 2 of 17 patients (12%) in group 2. The mean delivered dose intensity of docetaxel was 29 mg/m2 per week. Partial response occurred in 7 of 35 patients (21%; 95% exact binomial confidence interval [CI], 9%-38%) treated with docetaxel alone, including 3 of 19 taxane-pretreated patients (16%) and 4 of 16 taxane-naive patients (25%). Partial response occurred in 10 of 17 patients (59%; 95% CI, 34%-82%) treated with docetaxel/trastuzumab. The most common grade 3/4 toxicities, occurring in more than or equal to 10% of patients, included neutropenia (21%), pulmonary toxicity (12%), and hyperglycemia (10%). The median times to disease progression were 4.5 months (95% CI, 2.5-6.5 months) in the docetaxel group and 8.5 months (95% CI, 4.5-12.5 months) in the docetaxel/trastuzumab group. Weekly docetaxel/trastuzumab is an effective regimen for patients with HER2/neu overexpressing metastatic breast cancer. Weekly docetaxel may be effective in as many as 20% of patients who had progressive disease after treatment with taxanes given every 3 weeks.     

Ribociclib Plus Trastuzumab in Advanced HER2-Positive Breast Cancer: Results of a Phase 1b/2 Trial

BackgroundSignaling through the cyclin-dependent kinase 4 and 6 (CDK4/6) pathway can mediate therapeutic resistance in HER2-positive breast cancer. Preclinical studies have demonstrated that CDK4/6 inhibitors can resensitize resistant HER2-positive breast cancer to anti-HER2 therapies.Patients and MethodsWe conducted a phase 1b/2 study of ribociclib (400 mg per day on a continuous schedule) plus trastuzumab (6 mg/kg every 3 weeks) in patients with advanced HER2-positive breast cancer previously treated with trastuzumab, pertuzumab, and trastuzumab emtansine. There were no restrictions on the number of prior therapy lines. Primary objective was clinical benefit rate at 24 weeks, and secondary objectives included safety, objective response, rate and progression-free survival. The study was enrolled at ClinicalTrials.gov as NCT02657343.ResultsFrom March 2016 to March 2017, 13 patients were enrolled. One patient was found to have HER2-negative disease and did not receive treatment. Median number of prior lines in the metastatic setting was 5 (range, 0-14); 67% had hormone receptor–positive disease. No dose-limiting toxicities were observed during the safety run-in phase, and ribociclib was thus dosed at 400 mg per day continuously for the expansion cohort. Grade 3 adverse events were observed in 4 patients (33.3%) and included neutropenia (n = 2) as well as fatigue and pain in 1 patient each. No grade 4/5 adverse events or QTc prolongation were observed. One patient (8.3%) experienced stable disease > 24 weeks; no objective responses were observed, and median progression-free survival was 1.33 months (95% confidence interval, 0.92-2.57).ConclusionContinuous low-dose ribociclib (400 mg) plus trastuzumab is safe, with no new safety concerns. The limited activity observed in this study suggests that further study of CDK4/6 inhibitor/anti-HER2 combinations should focus on a less pretreated population.     

Clinical activity of trastuzumab and vinorelbine in women with HER2-overexpressing metastatic breast cancer.

PURPOSE: To determine the response rate and toxicity profile of trastuzumab administered concurrently with weekly vinorelbine in women with HER2-overexpressing advanced breast cancer. PATIENTS AND METHODS: Forty women with HER2-positive (+3 by immunohistochemistry, n = 30; +2 or positive, n = 10) breast cancer were enrolled onto a study of trastuzumab (4 mg/kg x 1, 2 mg/kg weekly thereafter) and vinorelbine (25 mg/m2 weekly, with dose adjusted each week for neutrophil count). Eighty-two percent of women had received prior chemotherapy as part of adjuvant (30%), metastatic (25%), or both (28%) treatment, including substantial portions of patients who had previously received either anthracyclines (20%), taxanes (15%), or both types (38%) of chemotherapy. RESULTS: Responses were observed in 30 of 40 patients (overall response rate, 75%, conditional corrected 95% confidence interval, 57% to 89%). The response rate was 84% in patients treated with trastuzumab and vinorelbine as first-line therapy for metastatic disease, and 80% among HER2 +3 positive patients. High response rates were also seen in women treated with second- or third-line therapy, and among patients previously treated with anthracyclines and/or taxanes. Combination therapy was feasible; patients received concurrent trastuzumab and vinorelbine in 93% of treatment weeks. Neutropenia was the only grade 4 toxicity. No patients had symptomatic heart failure. Grade 2 cardiac toxicity was observed in three patients. Prior cumulative doxorubicin dose in excess of 240 mg/m2 and borderline pre-existing cardiac function were associated with grade 2 cardiac toxicity. CONCLUSION: Trastuzumab in combination with vinorelbine is highly active in women with HER2-overexpressing advanced breast cancer and is well tolerated.     

Neoadjuvant trastuzumab and docetaxel in breast cancer: preliminary results

Trastuzumab/chemotherapy combinations have already shown superior results in metastatic breast cancer patients. The purpose of this study is to determine the clinical efficacy of neoadjuvant trastuzumab and docetaxel in women with locally advanced breast cancer, with or without metastatic disease. Treatment-naive women with HER2-overexpressing locally advanced breast cancer, with or without metastatic disease, were included. Patients received trastuzumab 4 mg/kg loading dose intravenously then 2 mg/kg weekly. On day 22, docetaxel 100 mg/m2 every 3 weeks for 4 cycles was added to weekly trastuzumab. Patients then underwent surgery and subsequent 4 cycles of AC (doxorubicin/cyclophosphamide; 60/600 mg/m2) without trastuzumab. Weekly trastuzumab was resumed 1 month after completion of AC and continued for a year. Preliminary results from the first 22 patients with median follow-up of 15.5 months (range, 2-38 months) are reported. Of these, 9 patients (40.9%) had inflammatory breast cancer, and 6 patients (27.3%) had stage IV breast cancer. Seventeen of 22 patients (77.3%) had objective clinical response, with a clinical complete response in 9 patients (40.9%). Two patients (9.1%) had decline in cardiac function and 7 patients (31.8%) experienced neutropenia, with 2 deaths (9.1%) from neutropenic sepsis. Eight patients (36.4%) have relapsed, 3 with local skin recurrence (13.6%) and 5 with distant recurrence, of whom 1 had liver metastasis (4.5%) and 4 had brain metastasis (18.2%). Combined neoadjuvant trastuzumab and docetaxel induced high clinical response rates for HER2-overexpressing breast cancer, in particular for inflammatory breast cancer. A high rate of brain metastasis was noted, particularly in patients with baseline metastatic disease.     

Pertuzumab in combination with trastuzumab and docetaxel for HER2-positive metastatic breast cancer

Overexpression of HER2 – found in approximately 15–20% of all breast cancers – is a negative prognostic factor. Although trastuzumab significantly improves the prognosis of HER2-positive breast cancer, half of the patients with metastatic breast cancer experience disease progression within 1 year. Pertuzumab is a novel HER2-targeted humanized monoclonal antibody that binds to the dimerization domain of HER2 and acts synergically with trastuzumab in inhibiting tumor progression. The CLEOPATRA trial demonstrated that adding pertuzumab to trastuzumab plus docetaxel significantly prolonged progression-free survival and overall survival without increasing severe adverse events. Conclusively, pertuzumab was approved by the US FDA in June 2012 for use in combination with trastuzumab and docetaxel for the treatment of patients with HER2-positive metastatic breast cancer. Furthermore, various clinical trials to evaluate the efficacy and safety of pertuzumab combined with other cytotoxic agents are ongoing at present. Thus, pertuzumab has been becoming important for the treatment of patients with HER2-positive metastatic breast cancer.     

曲妥珠单抗联合多西紫杉醇治疗Her-2/neu高表达转移性乳腺癌的疗效和不良反应

背景与目的:大约有20%～30%的乳腺癌患者Her-2/neu高表达,Her-2/neu高表达与患者的不良预后密切相关.化疗药物联合曲妥珠单抗可以显著提高Her-2/neu高表达乳腺癌患者的化疗有效率和生存率,多西紫杉醇是近年来治疗乳腺癌有效的化疗药物之一.本研究旨在观察曲妥珠单抗联合多西紫杉醇治疗Her-2/neu高表达转移性乳腺癌的疗效与不良反应.方法:22例Her-2/neu高表达转移性乳腺癌患者接受曲妥珠单抗联合多西紫杉醇方案治疗,曲妥珠单抗的首次剂量为8 mg/kg,以后的剂量为6 mg/kg.多西紫杉醇75mg/m2,每21 d重复一次.按WHO疗效评价标准评价疗效,按WHO化疗药物急性和亚急性不良反应评价标准评价不良反应.结果:全组22例患者共完成96个周期化疗(中位数3周期,范围2～6周期),所有患者均可评价疗效.22例患者中完全缓解2例,部分缓解12例,病情稳定4例,病情进展4例,客观有效率(CR PR)63.64%,中位疾病进展时间5.4个月,1年生存率59%.全组患者均可评价不良反应,主要不良反应为骨髓抑制,其中Ⅲ～Ⅳ度白细胞减少发生率为54.5%,部分患者有发热(第一次输注曲妥珠单抗时出现)和轻度的心肌劳损.结论:曲妥珠单抗联合多西紫杉醇方案治疗Her-2/neu高表达转移性乳腺癌近期疗效较高,不良反应轻,患者可以耐受.     

A phase II study of lapatinib monotherapy in chemotherapy-refractory HER2-positive and HER2-negative advanced or metastatic breast cancer

BackgroundThe efficacy and tolerability of the epidermal growth factor receptor/human epidermal growth factor receptor type 2 (HER2) tyrosine kinase inhibitor lapatinib in refractory metastatic breast cancer were assessed.Patients and methodsIn a phase II, open-label study, patients with previously treated HER2-positive (n = 140) or HER2-negative (n = 89) metastatic breast cancer received once-daily oral lapatinib 1500 mg/day.ResultsMost (76%) patients had received four or more lines of prior therapy. The response rate in the HER2-positive cohort was 4.3% by investigator assessment and 1.4% by independent assessment. Both assessments established that ∼6% of HER2-positive patients derived clinical benefit from lapatinib, being progression free for ≥6 months. No objective tumor responses occurred in the HER2-negative cohort. Independent review assessments of median time to progression and median progression-free survival were similar in the HER2-positive and HER2-negative cohorts (9.1 and 7.6 weeks, respectively). All responders exhibited HER2 overexpression (3+ by immunohistochemistry), and five of six responders were HER2 amplified by FISH. Lapatinib-related adverse events, including diarrhea (54%), rash (30%), and nausea (24%), were primarily mild to moderate in severity.ConclusionsLapatinib monotherapy had modest clinical activity in HER2-positive metastatic breast cancer that progressed on prior trastuzumab regimens. No apparent clinical activity was observed in chemotherapy-refractory, HER2-negative disease.     

Study of three-weekly docetaxel and weekly trastuzumab treatment in HER 2-overexpressing metastatic breast cancer patients

Docetaxel and trastuzumab can be considered to be active drugs for HER 2-overexpressing metastatic breast cancer (MBC). This study was conducted to determine the activity of combination therapy with docetaxel and trastuzumab in MBC patients (pts) by assessing the response rate (RR), time to progression (TTP) and safety. We administered the combination of docetaxel 70 mg/m2 every 3 weeks and trastuzumab using a 4 mg/kg loading dose and thereafter 2 mg/kg weekly. One cycle was three weeks. Between March 2002 and May 2003, 40 pts with HER 2-positive (3+by immunohistochemistry 39, FISH+1) MBC were enrolled in this study, and 39 pts proved eligible. The overall RR was 72% (28/39) [95%CI 55.1%-85.0%], with 6 CR, 22 PR, 7 SD, 1 PD and 3 NE. The median follow-up time was 14.3 months, while the TTP was 6.5 months (range, 0.6-19.8), median OS has not yet been reached. The number of pts assessable for safety was 40. Hematological Grade 3-4 toxicities were leukopenia 87.5% (35/40) and neutropenia 82.5% (33/40). Non-hematological Grade 3 toxicities were weight gain in 2 pts, and anorexia, neuropathy, fever and rash in one pt each. The combination of docetaxel and trastuzumab was a well-tolerated and very active regimen for the treatment of pts with HER 2-overexpressing MBC.     

Phase II study of bevacizumab in combination with trastuzumab and capecitabine as first-line treatment for HER-2-positive locally recurrent or metastatic breast cancer

We report the first results from a phase II, open-label study designed to evaluate the efficacy and safety of bevacizumab in combination with trastuzumab and capecitabine as first-line therapy for human epidermal growth factor receptor (HER)-2-positive locally recurrent (LR) or metastatic breast cancer (MBC). Patients were aged ≥18 years with confirmed breast adenocarcinoma, measurable LR/MBC and documented HER-2-positive disease. Patients received bevacizumab (15 mg/kg on day 1) plus trastuzumab (8 mg/kg on day 1 of cycle 1, 6 mg/kg on day 1 of each subsequent cycle) plus capecitabine (1,000 mg/m2 twice daily, days 1-14) every 3 weeks until disease progression, unacceptable toxicity, or consent withdrawal. Eighty-eight patients were enrolled; 40 (46%) are still on study treatment. The median follow-up was 8.8 months (range, 0.9-17.1 months). The overall response rate, the primary endpoint, was 73% (95% confidence interval [CI], 62%-82%), comprising 7% complete and 66% partial responses. The median progression-free survival interval was 14.4 months (95% CI, 10.4 months to not reached [NR]), with 35 events. The median time to progression was 14.5 months (95% CI, 10.5 months to NR), with 33 events. Treatment was well tolerated; main side effects were grade 3 hand-foot syndrome (22%), grade ≥3 diarrhea (9%), and grade ≥3 hypertension (7%). Overall, 44% of patients experienced grade ≥3 treatment-related adverse events and 13 patients discontinued capecitabine because of toxicity, but continued with bevacizumab and trastuzumab. Heart failure was seen in two patients. The combination of bevacizumab, trastuzumab, and capecitabine was clinically active as first-line therapy for patients with HER-2-positive MBC, with an acceptable safety profile and no unexpected toxicities.     

曲妥珠单抗治疗HER2+乳腺癌的临床进展

临床研究显示曲妥珠单抗与化疗联合用于人表皮生长因子受体2(HER2)+转移性乳腺癌的治疗以及早期乳腺癌的新辅助和辅助治疗,能显著延长患者的生存时间.其与内分泌治疗联合治疗HER2+且雌激素受体阳性的转移性乳腺癌,疗效优于单纯内分泌治疗.曲妥珠单抗联合其他靶向治疗药物,能够逆转肿瘤对曲妥珠单抗的耐药.疾病进展后继续应用曲妥珠单抗仍可使患者生存受益.