The success story of trastuzumab emtansine,a targeted therapy in HER2-positive breast cancer

Trastuzumab emtansine is a unique antibody–drug conjugate targeting selectively human epidermal growth factor receptor 2 (HER2)-positive breast cancer cells, thus conferring high efficacy with minimal systemic toxicities. Trastuzumab emtansine consists of a monoclonal antibody trastuzumab and potent cytotoxic agent DM1, combined together through a stable thioether bond. First-in-man phase I study set the maximum tolerated dose at 3.6 mg/kg given intravenously on a 3-weekly regimen. In phase II studies, trastuzumab emtansine at 3.6 mg/kg provided objective tumour responses and clinical benefit with an encouraging safety profile. Over these studies, trastuzumab emtansine had favourable pharmacokinetics. No accumulation of trastuzumab emtansine or catabolites was observed even after repeated dosing and free DM1 was very low in circulation. The stability of trastuzumab emtansine in circulation justifies the minimal systemic toxicity observed. Recently, a randomised international open-label phase III study confirmed the efficacy and safety of trastuzumab emtansine versus lapatinib plus capecitabine in patients with HER2-positive locally advanced or metastatic breast cancer. Overall survival was significantly improved in the trastuzumab emtansine arm. Safety outcomes were also favourable. The adverse events traditionally related to chemotherapy were markedly lower or absent with trastuzumab emtansine. Cardiotoxicity, frequently observed in HER2-directed therapy, was not reported. Although thrombocytopenia and elevations in hepatic enzymes were reported with trastuzumab emtansine, these events were reversible and manageable. Ongoing trials investigating trastuzumab emtansine as a single-agent or in combination with other agents, will determine the place of trastuzumab emtansine in the current therapeutic strategies deployed for HER2-metastatic breast cancer.     

Preoperative therapy with trastuzumab and paclitaxel in a stage IV advanced breast cancer with complete pathologic response

A 53-year-old woman had a 105x100 mm tumor on her right breast with a 55x36 mm-sized bleeding ulcer of the skin and ipsilateral axillary and cervical lymph nodes swelling (T4bN3cM1, Stage IV). Core needle biopsy and immunohistochemistry of breast tumor showed invasive ductal carcinoma with negative hormone receptor (ER-, PgR-) and overexpression of HER 2 (Hercep Test score 3+). She was treated with weekly trastuzumab (initially 4 mg/kg followed by 2 mg/kg every week), and a combination of tri-weekly paclitaxel (175 mg/m(2), 6 courses). After 3 courses of administration, the breast tumor subsided, the ulcer became flat, and axillary and cervical nodes completely disappeared. Clinical CR was obtained after 6 courses of treatment, and mastectomy with axillary clearance was then performed. Histopathology of the breast and lymph nodes showed complete disappearance of cancer cells (pCR, Grade 3+3 (d) +3 (n)). The combination of trastuzumab and paclitaxel is a promising regimen for HER 2 positive advanced breast cancer.     

A phase I-II study of combined blockade of the ErbB receptor network with trastuzumab and gefitinib in patients with HER2 (ErbB2)-overexpressing metastatic breast cancer

PURPOSE: To determine the safety, and efficacy of the epidermal growth factor receptor tyrosine kinase inhibitor gefitinib in combination with trastuzumab in patients with metastatic HER2-positive metastatic breast cancer. EXPERIMENTAL DESIGN: Patients with HER2-overexpressing breast cancer were treated with trastuzumab 2 mg/kg/week and gefitinib 250 to 500 mg/day. The primary end point of the study was to increase the proportion progression-free from 50% to 65% at 6 months in chemotherapy-naive patients and from 50% to 70% at 3 months in patients previously treated with chemotherapy in the metastatic setting. RESULTS: In the phase I study, all patients treated with gefitinib 500 mg/day developed grade 3 diarrhea. The phase II study was conducted using trastuzumab and gefitinib 250 mg/day. One patient achieved a complete response, 2 had a partial response, and 6 had stable disease for an overall response rate of 9% and a clinical benefit rate of 28% (9 of 32). Median time to progression (TTP) was 3 months (95% confidence interval, 2.3-4.1) in patients with no prior systemic therapy in the metastatic setting (n = 23). In patients treated with prior systemic therapy (n = 9), the median TTP of 5.3 months (95% confidence interval, 2.8-8.1). Overall median survival was 27 months. TTP was similar in EGFR-positive compared with EGFR-negative patients. CONCLUSIONS: Gefitinib 250 mg/day was the maximal dose that can be safely administered with weekly trastuzumab. Interim analysis of the efficacy suggested that the combination was unlikely to result in clinical benefit compared with trastuzumab alone. These results do not support the use of this combination in patients with HER2-positive breast cancer.     

A case of HER2 overexpressing advanced breast cancer with CTF therapy [cyclophosphamide, pirarubicin (THPADM), fluorouracil] showed long-term effectiveness after paclitaxel shock

A 53-year-old woman with left breast tumor was diagnosed as bilateral breast cancer(left; T3N3M0, Stage III C/right; T2N0M0, Stage II )in our hospital, both of which were revealed as invasive ductal carcinoma shown to be ER-negative, PgR negative and HER2-positive by core needle biopsy. In December 2004, paclitaxel and trastuzumab combination therapy was tried, but she went into shock just during administration of paclitaxel, and this therapy was discontinued. After that the triweekly CTF therapy was tried as an anthracycline containing regimen, and the lymph node metastases obtained a complete response after a month and a 38. 5% reduction of left primary breast tumor, which was the best response observed after three months. Time to progression was prolonged to 7 months(9 cycles). Although febrile neutropenia occurred in the first cycle, the therapy could be continued safely thereafter as an outpatient. Anthracycline-containing regimens are likely to be avoided because of the difficulty of combining with trastuzumab in the treatment of HER2 overexpressing advanced/metastatic breast cancer. But the CTF therapy of less cardiotoxicity and less alopecia, can expect longer use and better QOL as an alternative for HER2 overexpressing advanced/metastatic breast cancer patients.     

Phase II trial of preoperative paclitaxel, gemcitabine, and trastuzumab combination therapy in HER2 positive stage II/III breast cancer: The Korean Cancer Study Group BR 07-01

An addition of trastuzumab preoperatively to chemotherapy for human epidermal growth factor receptor 2 (HER2) positive breast cancer improved relapse-free survival (RFS). This study was designed to evaluate the efficacy and safety of preoperative paclitaxel, gemcitabine, and trastuzumab (PGH) combination for HER2-positive breast caner. Pathologically, proven node positive stage II/III breast cancer patients with adequate organ function and no history of anti-cancer therapy were eligible. Patients received weekly trastuzumab with paclitaxel 80 mg/m(2) and gemcitabine 1,200 mg/m(2) on days 1 and 8, every 3 weeks for 6 cycles. Postoperatively, patients completed trastuzumab for 1 year and hormone therapy for 5 years if indicated. All patients received postoperative radiation therapy. Of 53 enrolled patients with a median tumor of 5.3 (range, 2.0 to >12) cm; 43.4%, T3/T4; 75.4%, N2/N3; and 45.3%, positive hormone receptors. The pathologic complete response (pCR) rate was 58.5% in both tumor and lymph nodes. Grade 3/4 adverse events were neutropenia (32%), febrile neutropenia (0.6%), and transient elevation of AST/ALT (1.6%) during a total of 318 cycles. All patients maintained normal cardiac function. With a median follow-up of 40 months, 3-year RFS rate was 84% with 91.7% distant metastasis-free survival rates. Remarkable pCR rate was obtained with non-anthracycline-based PGH therapy for HER2-positive stage II/III breast cancer. Adverse events were mild with few incidences of febrile neutropenia.     

Preoperative therapy with trastuzumab and paclitaxel followed by sequential adjuvant doxorubicin/cyclophosphamide for HER2 overexpressing stage II or III breast cancer: a pilot study.

PURPOSE: Trastuzumab combined with chemotherapy improves outcomes for women with human epidermal growth factor receptor 2 (HER2) overexpressing advanced breast cancer. We conducted a pilot study of preoperative trastuzumab and paclitaxel, followed by surgery and adjuvant doxorubicin and cyclophosphamide chemotherapy in earlier stage breast cancer. PATIENTS AND METHODS: Patients with HER2-positive (2+ or 3+ by immunohistochemistry) stage II or III breast cancer received preoperative trastuzumab (4 mg/kg x 1, then 2 mg/kg/wk x 11) in combination with paclitaxel (175 mg/m(2) every 3 weeks x 4). Patients received adjuvant doxorubicin and cyclophosphamide chemotherapy following definitive breast surgery. Clinical and pathologic response rates were determined after preoperative therapy. Left ventricular ejection fraction and circulating levels of HER2 extracellular domain were measured serially. RESULTS: Preoperative trastuzumab and paclitaxel achieved clinical response in 75% and complete pathologic response in 18% of the 40 women on study. HER2 3+ tumors were more likely to respond than 2+ tumors (84% v 38%). No unexpected treatment-related noncardiac toxicity was encountered. Four patients developed grade 2 cardiotoxicity (asymptomatic declines in left ventricular ejection fraction). Baseline HER2 extracellular domain was elevated in 24% of patients and declined with preoperative therapy. Immunohistochemical analyses of posttherapy tumor specimens indicated varying patterns of HER2 expression following trastuzumab-based treatment. CONCLUSION: Preoperative trastuzumab and paclitaxel is active against HER2 overexpressing early-stage breast cancer and may be feasible as part of a sequential treatment program including anthracyclines. The observed changes in cardiac function merit further investigation. Correlative analyses of HER2 status may facilitate understanding of tumor response and resistance to targeted therapy.     

A case of HER2-positive metastatic breast cancer responding to trastuzumab plus gemcitabine combination therapy

A 60-year-old woman was admitted to the hospital with left thigh pain. She had undergone mastectomy and axillary lymph node dissection for right breast cancer (T3N2M0) five years and two months earlier. The pathological diagnosis then was invasive ductal carcinoma with axillaryly mph node metastases. Hormone receptors and HER2 status were negative and positive (3+), respectively. The patient received adjuvant chemotherapy and radiotherapy, but bone metastases appeared 18 months after surgery. Although trastuzumab-combination chemotherapy with taxane and/or capecitabine was given, bone metastases in thoracic vertebra resulted in incomplete paralysis in both legs. She underwent thoraco-lumbar vertebral fixation 10 months before admission. A PET/CT revealed multiple bone metastases in the left femur as well as vertebrae, and CEA rose markedly. She received radiotherapy and trastuzumab monotherapy in addition to bisphosphonate. Temporarily, CEA decreased, but because recurrence nests were recognized in the supraclavicle and mediastinum after the eight-month treatment, trastuzumab monotherapy was followed by trastuzumab plus vinorelbine combined therapy. This regimen markedly reduced CEA after three months, but it rose again over the following three months. As S-1-combined therapy was not effective, trastuzumab+gemcitabine (1 g/week and two weeks on/one week off) combined therapy was started. CEA decreased markedly after 4 cycles, and FDG accumulation in the recurrence region was markedly improved. The adverse event during this treatment was minor, and PS was sufficiently maintained. These results suggest that trastuzumab plus gemcitabine combination therapy is effective for HER2-positive metastatic breast cancer.     

Re-evaluation of HER2 status in metastatic breast cancer and tumor-marker guided therapy with vinorelbine and trastuzumab

BACKGROUND: HER2 is overexpressed in 20-30% of breast cancers. Compared to chemotherapy alone, chemotherapy with trastuzumab improves clinical outcome in patients with HER2-positive metastatic breast cancer (MBC). In general, HER2 status in a primary lesion predicts the status of metastases, so that biopsy of metastatic lesions appears unnecessary. CASE REPORT: A 39-year old woman was diagnosed with primary breast cancer in November 2000. Using the method and scoring system of the DAKO Hercep Test, the tumor has shown low HER2 expression (DAKO score 1+). After failure of several chemotherapy regimens for metastatic disease (liver, skeletal), the patient underwent CT-guided needle biopsy of the liver which showed HER2 positive adenocarcinoma (DAKO score 3+). In consequence, the patient was treated with vinorelbine (30 mg/m2 d1,8,15 q4w) and trastuzumab (4 mg/kg loading dose, 2 mg/kg weekly). During a treatment period of 4 months imaging results as well as tumor marker kinetics indicated an excellent response with sustained decrease of tumor markers. A retrospective analysis of the HER2 shed antigen in metastatic stage revealed excessively increased serum levels and supports HER2 overexpression observed in liver metastasis. The kinetics of the HER2 shed antigen during therapy for metastatic disease were found to be in phase with the kinetics of CEA and CA15-3. CONCLUSION: This case report demonstrates that re-evaluation of the HER2 status may be helpful in single patients not sufficiently responding to treatment of metastatic disease. Determination of HER2 overexpression may be facilitated by a determination of the HER2 shed antigen level in peripheral blood.     

A case of metastatic pancreatic cancer which trastuzumab+capecitabine combination therapy was effective

A 61-year-old woman presented with carcinoma of the left breast(T2N1M0, stage II B), which enforced left Bt+R1. In May 2008, the patient underwent preoperative chemotherapy consisting of 4 courses of FEC 75(fluororracil, epirubicin, and cyclophosphamide). Pathological examination revealed that the lesion was a papillotubular carcinoma,(ER-, PgR-, HER2 3+). In September, 2009, CT scans revealed metastases of the cervical lymph nodes and pancreas. Examination of biopsy specimens from the left cervical lymph nodes revealed that the metastases were from breast cancer(ER-, PgR-, HER2 3+). To treat the recurrences, combination therapy with trastuzumab+capecitabine was introduced in October, 2009. CT scans obtained in May 2010 revealed complete response of the metastases of the lymph nodes and pancreas. It is difficult to distinguish a metastases from a primary pancreatic cancer, but the present case was considered to be one of metastic pancreatic cancer because the findings were in agreement with the expression time of lymph node metastasis. Follow-up CT scans revealed that CR was maintained by the combination therapy of trastuzumab+capecitabine.     

Trastuzumab plus docetaxel in HER2/neu-positive non-small-cell lung cancer: a California Cancer Consortium screening and phase II trial

HER2 is reported to be overexpressed in 20% of cases of non-small-cell lung cancer (NSCLC), principally adenocarcinoma. Trastuzumab is a monoclonal antibody against HER2 that, when combined with a taxane, improves survival compared with chemotherapy alone in advanced breast cancer. In view of these observations, we conducted a phase II HER2 screening and efficacy trial of trastuzumab plus weekly docetaxel in cases of advanced NSCLC in which primary platinum-based therapy had failed. Patients with advanced or metastatic NSCLC were screened for HER2 overexpression by immunohistochemistry. Patients with HER2-positive tumors (2+ or 3+) were initially randomized to either single-agent trastuzumab or docetaxel. After completing 2 treatment cycles, all patients went on to receive the trastuzumab/docetaxel combination regardless of response to the single agents. Treatment consisted of docetaxel 30 mg/m2 weekly for 6 weeks followed by a 2-week break and trastuzumab 4 mg/kg intravenously on week 1 followed by 2 mg/kg per week thereafter. Cycle length was 8 weeks. Sixty-nine patients with NSCLC (33 men, 36 women) were screened between August 1999 and March 2001. Only 13 patients (19%) had HER2-positive disease; all 13 enrolled in the efficacy trial. Of 9 patients receiving docetaxel alone, 1 partial response (PR) was seen. None responded to trastuzumab alone. The overall outcomes to the sequence of single-agent therapy followed by combination therapy included a PR rate in 8% of cases, stable disease in 23%, progression in 46%, and nonassessable disease in 23%. Estimated event-free and overall survival times were 4.3 and 5.7 months, respectively. Treatment was well tolerated. The screening component of this trial demonstrated that the target population for trastuzumab therapy in NSCLC is relatively small. Because of the limited clinical activity of trastuzumab-based therapy in this cohort and the similar disappointing reports from other studies of trastuzumab in NSCLC, this trial was closed to further accrual. In view of the limited target population for HER2 inhibition, future efforts and resources should be directed toward molecular targets other than HER2 in NSCLC.     

Isolated central nervous system metastases in patients with HER2-overexpressing advanced breast cancer treated with first-line trastuzumab-based therapy.

PURPOSE: The aim of this study was to characterize the prevalence and predictors of central nervous system (CNS) metastasis among women with HER2-overexpressing metastatic breast cancer receiving trastuzumab-based therapy. METHODS: The frequency and time course of isolated CNS progression were characterized among women with HER2-positive metastatic breast cancer, receiving chemotherapy with or without trastuzumab as first-line treatment for metastatic disease in two clinical trials. The first trial was a multicenter randomized phase III study of chemotherapy (doxorubicin/cyclophosphamide or paclitaxel) +/- trastuzumab, and the second was a multicenter phase II trial of vinorelbine + trastuzumab. All patients had measurable disease and were free of symptomatic CNS disease at initiation of study treatment. RESULTS: Nearly 10% of patients receiving trastuzumab in combination with chemotherapy developed isolated CNS metastases as first site of tumor progression. Progression in the CNS tended to be a later event than progression at other sites among women receiving trastuzumab-based therapy. Trastuzumab-based treatment did not substantially delay onset of CNS metastases as initial site of progression. Following diagnosis with primary breast cancer, tumors with HER2 gene amplification tend to be associated with greater risk of isolated CNS progression compared with those lacking gene amplification. CONCLUSIONS: Patients with HER2-overexpressing metastatic breast cancer are at risk for isolated CNS progression, reflecting improved peripheral tumor control and patient survival through use of trastuzumab-based therapy, and a relative lack of CNS activity with trastuzumab. Clinicians should be aware of this association. Better treatments for CNS recurrences are needed.     

Adding hormonal therapy to chemotherapy and trastuzumab improves prognosis in patients with hormone receptor-positive and human epidermal growth factor receptor 2-positive primary breast cancer

Adjuvant hormonal therapy for hormone receptor (HR)-positive primary breast cancer patients and a human epidermal growth factor receptor 2 (HER2)-targeted agent for HER2-positive primary breast cancer patients are standard treatment. However, it is not well known whether adding hormonal therapy to the combination of preoperative or postoperative chemotherapy and HER2-targeted agent contributes any additional clinical benefit in patients with HR-positive/HER2-positive primary breast cancer regardless of cross-talk between HR and HER2. We retrospectively reviewed records from 897 patients with HR-positive/HER2-positive primary breast cancer with clinical stage I–III disease who underwent surgery between 1988 and 2009. We determined the overall survival (OS) and disease-free survival (DFS) rates according to whether they received hormonal therapy or not and according to the type of hormonal therapy, tamoxifen and aromatase inhibitor, they received. The median followup time was 52.8 months (range 1–294.6 months). Patients who received hormonal therapy with chemotherapy and trastuzumab (n = 128) had significantly higher OS and DFS rates than did those who received only chemotherapy and trastuzumab (n = 46) in log-rank analysis (OS 96.1 vs. 87.0 %, p = 0.023, DFS 86.7 vs. 78.3 %, p = 0.029). There was no statistical difference in OS or DFS between those given an aromatase inhibitor and those given tamoxifen. In multivariate analysis, receiving hormonal therapy in addition to the combination of chemotherapy and trastuzumab was the sole independent prognostic factor for DFS (hazard ratio 0.446; 95 % CI 0.200–0.992; p = 0.048), and there was a similar trend in OS. Our study supported that hormonal therapy, whether in the form of an aromatase inhibitor or tamoxifen, confers a survival benefit when added to chemotherapy and trastuzumab in patients with HR-positive/HER2-positive primary breast cancer. Adjuvant treatment without hormonal therapy is inferior for this patient population.     

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.     

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.     

Combination of trastuzumab and vinorelbine in metastatic breast cancer

BACKGROUND: Since the clinical introduction of trastuzumab (Herceptin) for metastatic breast cancers that overexpress human epidermal growth factor receptor 2 (HER2), this anticancer agent has played an important role in breast cancer treatment. We examined the effects of trastuzumab and vinorelbine (Navelbine) as a second- or third-line therapy in 24 patients whose HER2-positive tumors did not respond to or relapsed after administration of trastuzumab alone or in combination with taxane. METHODS: Trastuzumab was administered at 2 mg/kg (loading dose 4 mg/kg) once weekly and vinorelbine at 25 mg/m(2) once weekly. The median treatment duration was 118.5 days (range, 22-351 days). RESULTS: The response rate was 42% (95% confidence interval (CI): 22%-63%). The adverse events of NCI-CTC grade 3 or above consisted of neutropenia in three patients; other adverse events, including vasculitis, generalized fatigue, anemia and thrombocytopenia, were grade 1 or 2. All adverse events were reversible after treatment withdrawal and were easily manageable. CONCLUSION: A combination of trastuzumab and vinorelbine can be safely administered on an outpatient basis, and is useful in the treatment of patients with HER2-overexpressing metastatic breast cancer.     

Safety and activity of docetaxel and trastuzumab in HER2 overexpressing metastatic breast cancer: a pilot phase II study

We conducted a pilot phase II trial of trastuzumab administered concurrently with docetaxel in women with HER2-overexpressing advanced breast cancer. Twenty-five women with HER2-positive (3+ by immunohistochemistry = 16, 2+ = 9) metastatic breast cancer received docetaxel (75 mg/m every 3 weeks for 6 cycles) and trastuzumab (4 mg/kg loading dose, 2 mg/kg weekly thereafter). Twenty-three patients (92%) had visceral metastatic involvement. Twenty-three patients had received prior chemotherapy as part of adjuvant (18), metastatic (2), and both (3) treatment. The number of cycles administered was 121 (median 6, range 1-6). Symptomatic cardiotoxicity (GIII) occurred in one patient. The most common grade GIII/IV toxicity was neutropenia (80% of the cycles), although febrile neutropenia did not occur. No other GIII/IV toxicities were observed. Response rate was 70% (1 complete response and 15 partial responses) in 23 evaluable patients. The combination of docetaxel and trastuzumab is well tolerated and has clinically meaningful antitumor activity.     

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.     

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.     

18F-fluorodeoxyglucose (FDG) PET/CT after two cycles of neoadjuvant therapy may predict response in HER2-negative,but not in HER2-positive breast cancer

The aim of this prospective study was to assess the ability of 18F-fluorodeoxyglucose (¹⁸FDG) positron emission tomography/computed tomography (PET/CT) scanning to predict pathological complete response (pCR) in breast cancer, and to investigate whether timing of the scan and trastuzumab treatment influence the accuracy of pCR prediction in human epidermal growth factor receptor 2 (HER2) positive breast cancer patients. We treated 81 locally advanced breast cancer patients with four cycles of neoadjuvant chemotherapy (NAC). HER2-negative breast cancer patients received NAC alone, while HER2-positive breast cancer patients received NAC plus trastuzumab. ¹⁸FDG PET/CT scans were scheduled at baseline and after the second cycle of NAC. Axillary lymph node (ALN) dissection was performed after the last cycle of neoadjuvant therapy. Relative changes in standardized uptake values (SUV) between the two PET/CT scans (ΔSUV) in primary tumors and ALN metastases were calculated. There were 75 patients with 150 PET/CT scans in the final analysis, including 41 HER2-negative and 34 HER2-positive cases. In the HER2-negative group, the ΔSUV predicted overall and ALN pCR; the receiver operating characteristics-areas under curve (ROC-AUC) were 0.87 and 0.80 (P = 0.0014 and 0.031, respectively) and the negative predictive values were 94% and 89% respectively. However, in the HER2-positive group, ΔSUV could predict neither overall nor ALN pCR; the ROC-AUCs were only 0.56 and 0.53, with P = 0.53 and 0.84, respectively. Hence, the ΔSUV after two cycles of neoadjuvant therapy could predict pCR in HER2-negative patients treated with NAC alone, but not in HER2-positive patients treated with NAC plus trastuzumab.     

Three cases of metastatic breast cancer, resistant to pre-chemo and/or endocrine therapy, markedly improved with UFT and cyclophosphamide oral combination therapy

The cases of 3 female patients with metastatic breast cancer treated with oral UFT and cyclophosphamide (CPA) are reported. Patient 1 had lymph node and bone metastases. Patient 2 had bone metastasis. Patient 3 had skin, lymph node, and peritoneal metastases. All had a history of mastectomy and chemo- and/or endocrine therapy for metastatic lesions. Patients 2 and 3 had also undergone CAF combination chemotherapy. However, the lesions did not change. UFT 400 mg and CPA 100 mg, everyday, were administered to patient 1. UFT 400 mg and CPA 100 mg, 2 weeks, and UFT 400 mg, 2 weeks, were given every 4 weeks to patient 2. UFT 300 mg and CPA 150 mg, 6 weeks per 8 weeks were given to patient 3. Improvements in the metastatic lesions were seen 4 weeks after the beginning of UFT and CPA therapy. Therapy is now continuing, and no patients had a progression of the disease. All had leukopenia 2 or 4 weeks after the beginning of this therapy, and two temporarily stopped the therapy. No other side-effect was observed. Oral UFT and CPA combination therapy was considered useful for metastatic breast cancer. To prevent leukopenia and prolong the term of treatment efficacy, a treatment regimen will need to be established.