HER2-overexpressing Metastatic Breast Cancer Research Articles

Trastuzumab Associated with Successive Cytotoxic Therapies Beyond Disease Progression in Metastatic Breast Cancer

Purpose To determine the activity of successive trastuzumab-containing regimens in HER2-overexpressing metastatic breast cancer (MBC) as well as the response rate (RR), time to progression (TTP), and predictive factors for response. Patients and Methods We performed a descriptive retrospective study of trastuzumab activity in patients with HER2-overexpressing MBC treated at our hospital from October 1999 to October 2003. Results Fifty-eight patients were evaluated, in whom an overall RR (complete response plus partial response) of 39.7% was obtained for first-time administration of trastuzumab; stable disease (SD) was seen in 29.3%, and the clinical benefit rate was 69%. Median TTP was 6 months (range, 1 months to > 39 months). A total of 31 patients (53.4%) received a second trastuzumab-containing regimen, with an RR of 25.8%; SD was seen in 12.9%, and the clinical benefit rate was 38.7%. Median TTP was 3 months (range, 1 months to > 22 months). A total of 8 patients (14.3%) received a third trastuzumab-containing regimen. The RR for the third trastuzumab regimen was 12.5%; SD was seen in 12.5%, and the clinical benefit rate was 25%. Median TTP was 2 months (range, 1 months to > 12 months). A total of 4 patients (7.1%) received a fourth trastuzumab-containing regimen, with an RR of zero and SD in 25%. Predictive factors for response were disease in soft tissue or bone ( P = 0.03; odds ratio [OR], 3.25; 95% confidence interval [CI], 1.08–9.8) and metastases at > 2 sites ( P = 0.03; OR, 6.2; 95% CI, 1.25–30.9). We observed a better RR in the second trastuzumab-containing regimen when the patient responded to the first regimen ( P = 0.03; OR, 13.2; 95% CI, 1.36–126). Conclusion Trastuzumab-containing regimens beyond disease progression in MBC show activity even in heavily pretreated patients. The activity noted does not allow us to ascertain the independent contribution of trastuzumab in this setting. There were more responses in patients with few metastases in the soft tissues or bone. Patients who have shown a previous response to trastuzumab can show a response to a second trastuzumab-containing regimen.

412 POSTER High incidence of brain metastases in HER2-overexpressing metastatic breast cancer (MBC) patients (pts) treated with trastuzumab and chemotherapy

412 POSTER High incidence of brain metastases in HER2-overexpressing metastatic breast cancer (MBC) patients (pts) treated with trastuzumab and chemotherapy

425 POSTER Influence of trastuzumab on the incidence of brain metastasis in patients with Her2-overexpressing metastatic breast cancer

425 POSTER Influence of trastuzumab on the incidence of brain metastasis in patients with Her2-overexpressing metastatic breast cancer

EGFR activity in Her-2 over-expressing metastatic breast cancer: evidence for simultaneous phosphorylation of Her-2/neu and EGFR

EGFR activity in Her-2 over-expressing metastatic breast cancer: evidence for simultaneous phosphorylation of Her-2/neu and EGFR

High Efficacy of Gemcitabine and Cisplatin Plus Trastuzumab in Patients with HER2-overexpressing Metastatic Breast Cancer: A Phase II Study

Effective and tolerable regimens are sought specifically in women who have been pre-treated with anthracyclines and taxanes. Gemcitabine and cisplatin plus trastuzumab has shown synergistic activity in vitro, and provides a new mechanism of drug interaction. This multicentre phase II study aimed to evaluate the efficacy and tolerability of gemcitabine and cisplatin plus trastuzumab in previously treated patients with metastatic breast cancer (MBC). Previously treated patients with human epidermal growth factor receptor 2 (HER2) overexpressing MBC were enrolled in a multicentre phase II study (DAKO Hercep Test 3+). Treatment consisted of gemcitabine (750 mg/m2), cisplatin (30 mg/m2) given on days 1 and 8 every 3 weeks, and trastuzumab (4 mg/kg loading dose, 2 mg/kg weekly). Twenty patients were recruited, all of whom had previously received chemotherapy (12 pre-treated with taxanes, 18 pre-treated with anthracyclines seven pre-treated with taxanes and trastuzumab). A median of six cycles of the study treatment was delivered. There were eight partial responses, for an overall response rate of 40% (95% confidence interval 16.5-63.5%). The clinical benefit rate (complete response plus partial response plus stable disease) was 80% (95% CI 54.2-95.8%). The response rate in patients who had already received a trastuzumab-based regimen for MBC was 57.1% (95% CI 7.7-100%). Median time to progression was 10.2 months, and median overall survival was 18.8 months. Main toxicities were leukopenia (grade 3 in 55% of patients) and thrombocytopenia (grade 3 in 35% and grade 4 in 5% of patients). Non-haematological toxicity was rarely severe. Combination chemotherapy with gemcitabine and cisplatin plus trastuzumab is well tolerated and active in patients with HER2 overexpressing MBC, even after prior exposure to anthracyclines and taxanes.

EGFR activity in HER-2 over-expressing metastatic breast cancer: evidence for simultaneous phosphorylation of Her-2/neu and EGFR

Her-2/neu overexpression is an important prognostic parameter in breast cancer patients and has become a response predictor for trastuzumab treatment. Nevertheless, while trastuzumab is highly effective in many Her-2/neu overexpressing tumors, some do not respond. The reason for the differential effect is unknown, but it has been hypothesized that the complex interactions between Her-2/neu and other members of the EGFR family are involved in trastuzumab resistance. We have analyzed the protein expression of Her-2/neu, EGFR, and their activated forms, ptyr-1248 Her-2/neu, ptyr-845 EGFR and ptyr-1173 EGFR, in 57 Her-2/neu overexpressing breast tumors and investigated potential correlations between the receptors. By performing immunohistochemistry on paraffin-embedded tissue sections, we found that ptyr-845 EGFR was significantly co-expressed with Her-2/neu and ptyr-1248 Her-2/neu (p=0.043 and p=0.040, respectively), while ptyr-1173 EGFR was only correlated to Her-2/neu expression (p=0.042). Interestingly, EGFR and its activated forms were all significantly inversely correlated with PgR expression (p=0.011, p=0.033 and p=0.032, respectively), and ptyr-845 EGFR was also inversely correlated with ER expression (p=0.008). While we have previously shown that serum levels of the extracellular component of Her-2/neu are associated with tumoral ptyr-1248 Her-2/neu expression, we did not find a similar relationship between serum EGFR and intratumoral total/activated EGFR. We did, however, observe significantly higher levels of serum EGFR in women with 3+ overexpression of HER-2/neu (p=0.047). Taken together, we have demonstrated the activation pattern of EGFR and Her-2/neu in Her-2/neu overexpressing breast cancer. We suggest that EGFR inhibition might enhance the efficacy of trastuzumab by preventing cross-phosphorylation.

Characteristics of patients with brain metastases receiving trastuzumab for HER2 overexpressing metastatic breast cancer

The intention of this retrospective analysis was to describe the characteristics of patients with brain metastasis (BM) receiving trastuzumab for HER2 overexpressing metastatic breast cancer (MBC). A specific focus was the relation of BM occurrence to remission status of visceral disease during trastuzumab treatment. Patients with MBC presenting between March 2000 and May 2004 were included in this retrospective analysis. HER2 overexpression was determined by immunohistochemistry (IHC; DAKO Hercep Test). Trastuzumab was applied at a loading dose of 4 mg/kg and a maintenance dose of 2 mg/kg. Among 136 HER2 overexpressing patients (DAKO score 3+), 42 patients with BM were identified during follow-up (30.9%). Negative hormone receptor expression (estrogen receptor (ER) and progesterone receptor (PgR)) correlated with incidence of BM (42.8% vs. 23.4%; P=0.01). There was no correlation of the development of BM with regard to tumor grading and patient age. In patients who developed BM, the median interval between visceral and brain metastasis was 14 months (range 0-69 months). At the time BM was diagnosed, 14 out of 42 patients responded to trastuzumab-based treatment schedules (OR: 33.3%, 95% CI 18.5-48.2%). Median survival from diagnosis of BM was 13 months (range 0-60 months). The median overall survival calculated from first diagnosis of metastasis was not significantly shorter in patients with BM than in patients without BM (37 vs. 47 months; P=0.07 log rank). Trastuzumab is highly effective for the treatment of liver and lung metastasis in HER2 overexpressing patients, while it is apparently ineffective for treating or preventing BM. Since one third of HER2 overexpressing patients with MBC developed BM despite effective trastuzumab treatment, new treatment strategies and closer surveillance may be warranted for these patients.

The role of serum HER2 as an alternative to fluorescence in situ hybridization for HER2 in metastatic breast cancer

681 Background: Measuring HER2 is required for the selection of metastatic breast cancer (MBC) patients for trastuzumab therapy. Since the guideline was widely accepted that recommended initial testing of tissue samples by immunohistochemistry (IHC), acceptance of 0/1+ as negative, 3+ as positive and further testing by fluorescent in situ hybridization (FISH) just in 2+ IHC, FISH study is particulary important in IHC 2+ cases to predict therapeutic response of trastuzumab therapy. Recently serum HER2 has been studied to be a complement to IHC or FISH, however, the association between serum HER2 level and HER2 gene amplification was not fully known. This study aimed to evaluate the relationship between serum HER2 level and FISH for HER2 to know whether serum HER2 can be used as an alternative to FISH for HER2 in HER2 overexpressing MBC. Methods: The HER2 overexpression was determined by IHC using polyclonal rabbit anti-human c-erbB-2 oncoprotein (Code A0485; DAKO Corp, CA, USA), and FISH analysis was performed using the PathVysion HER-2 DNA Probe Kit (Vysis, Downers Grove, IL, USA) on tissue from 126 MBC patients between Feb 2002 and Nov 2004. Serum HER2 was measured by immunoassay using Bayer ADVIA Centaur. Statistical analysis was performed using Mann-Whitney test and optimal serum HER2 values for differentiation between FISH+ (amplification) and FISH- (non-amplification) determined by receiver operating characteristics curve (ROC) analysis. Results: A total of 126 patients with HER2 overexpressing MBC with median age of 51 years included. IHC was 2+ and 3+ in 65 (52%) and 61 (48%) tumors, respectively and HER2 amplification by FISH was observed in 28% of IHC 2+ (16/58) and 100% of IHC3+ tumors (2/2). Serum HER2 levels showed significant difference at 30.6 ± 76.90 and 639.6 ± 1797.5 μg/L (mean ± SD, P = 0.01) in FISH- vs. FISH+ groups, but it was not significantly different in IHC 2+ vs. IHC 3+ groups (P = 0.54). ROC analysis showed 95% specificity at 100 μg/L with 78% positive predictive value. Conclusions: Serum HER2 may be a useful marker to predict HER2 gene amplification specifically in HER2 2+ by IHC with optimal value at 100 μg/L with 95% specificity and 78% positive predictive value. No significant financial relationships to disclose.

Brain metastases (BM) in patients treated with trastuzumab for HER2 overexpressing metastatic breast cancer (MBC): Incidence and survival

1568 Objective: This retrospective analysis was performed to determine the incidence of brain metastasis (BM) in patients with HER2 overexpressing metastatic breast cancer (MBC). A specific focus was the relation of BM occurrence to remission status of visceral disease during trastuzumab treatment. Methods: Patients with MBC were included in this retrospective analyses from March 2000 to May 2004. HER2 overexpression was determined by immunohistochemistry (IHC; DAKO Hercep Test). Trastuzumab was applied at a loading dose of 4mg/kg and a weekly maintenance dose of 2 mg/kg. Results: Among 136 HER2 overexpressing patients (DAKO score 3+), fourty-two patients were identified with BM during follow-up (30.9%). A negative hormone receptor expression (ER and PgR) correlated with the incidence of BM (42.8% vs 23.4%; p=0.01). There was no correlation of the development of BM with regard to tumor grading and patient age (BM 54.5 vs without BM 50 years; p=0.27). In patients who developed BM, the median interval between visceral and brain metastasis was 14 months (range, 0–69 months). At the time BM was diagnosed, 14 out of 42 patients responded to trastuzumab based treatment schedules (OR: 33.3%, 95% CI 18.5–48.2%). Tumor growth control (OR + SD) was achieved in 47.6% of patients (95% CI 31.9–63.4%). Median survival from diagnosis of BM was 13 months (range, 0–60 months). The median overall survival calculated from first diagnosis of metastasis was shorter in patients with BM (37 months) as compared to patients without BM (47 months), but this difference did not reach the level of significance (p=0.07 log rank). Conclusion: Trastuzumab is highly effective for treatment of liver- and lung metastasis in HER2 overexpressing patients, while it is apparently ineffective to treat or prevent BM. Since one third of HER2 overexpressing patients with MBC developed BM despite effective trastuzumab treatment, new treatment strategies and closer surveillance may be warranted for these patients. No significant financial relationships to disclose.

Clinicopathological study of brain metastases in breast cancer patients treated with or without trastuzumab

693 Background: Trastuzumab plays the important role in the treatment of patients with HER2 overexpressing metastatic breast cancer. Since its introduction into the treatment strategy of metastatic breast cancer, brain metastases during trastuzumab therapy have been frequently observed. Only a few studies have compared the risk of brain metastases in patients treated with or without trastuzumab. Methods: We conducted the retrospective and clinicopathological study of the fifty-seven patients with brain metastases treated in our hospital between 1989 and 2003. Those fourteen patients with brain metastases were surgically removed to be pathologically compared with primary tumors. Results: Twenty-seven patients were positive for HER2, while the remaining thirty patients were negative. The time from the first recurrence to brain metastases and the median overall survival time were not significantly different between HER2 positive and negative patients. Nineteen patients were treated with the trastuzumab-based therapy out of twenty seven HER2 positive patients. The time from the first recurrence to brain metastases was 17.4months for those patients who received trastuzumab-based therapy, while 8.3 months for the patients who did not receive trastuzumab (p<0.01). The survival period after brain metastases was 9.8months for the patients who received trastuzumab, while 1.1 months for the patients who did not receive trastuzumab (p<0.01). The median overall survival period was 51.8 month for those patients who received trastuzumab and 34.4 months for the patients who did not received trastuzumab(p<0.01). The fourteen tumors of the brain had the same HER2 status to primary tumors, except one tumor changed negative. Conclusions: This study showed that trastuzumab patients with brain metastases have survived significantly longer interval after first recurrence and the development of brain metastases, when comparing with control group. No significant financial relationships to disclose.

Phase II trial of gemcitabine plus trastuzumab in minimally pretreated HER2 overexpressing metastatic breast cancer

704 Background: Gemcitabine is an exciting novel deoxcytidine analog demonstrating synergism, when combined with trastuzumab, in human breast cancer cell lines. Trastuzumab plus chemotherapy, has yielded superior ORR, TTP, as well as survival as compared to chemotherapy alone in HER2+ tumors. This study evaluates the clinical activity of gemcitabine administered with trastuzumab in minimally pretreated HER2 amplified MBC. Methods: Eligibility: Pts with HER2 3+ or FISH + tumors, 0–1 prior MBC regimens, bidimensional disease, doxorubicin < 360 mg/m2, and LVEF ≥ 50%. Treatment consisted of gemcitabine 1000 mg/m2 days 1, 8, 15, q28 days in conjunction with 4 mg/kg trastuzumab D1 and then 2 mg/kg for 8 consecutive weeks followed by D1, 8, 15 administration of a q28d schedule with gemcitabine, both continuing until disease progression or toxicity. Results: 40 pts were enrolled between 7–5–01 & 11–19–04 with 33 evaluable for response. Median age is 57. 28 pts were HER2 3+ and 6 FISH+. Sites of metastatic disease included 13 lung, 19 liver, 16 bone, 17 soft tissue; the majority of pts had ≥ 2 metastatic sites of disease. 21 pts had prior adjuvant therapy, 21 pts prior doxorubicin & 26 pts prior taxanes. 19 pts had no prior MBC therapy, 17 pts-1 line, 3 pts ≥ 2 lines of MBC therapy. Clinical benefit rate of 66% was noted with 3 CRs, 8 PRs and 11 with SD. 11 pts progressed and 4 are unevaluable. A median of 3.5 cycles were delivered (range 1 - 14). G 3/4 heme toxicity was notable for neutropenia in 21 pts- accompanied by fever in only 1 pt, thrombocytopenia-5, and anemia-1pt. G 3/4 non-heme toxicity consisted of fatigue-5, pulmonary-4, nausea-4, vomiting-3, and edema-2 pts. Cardiac dysfunction was noted in 1 pt. Median survival was 18.8 mo with a median PFS of 3.9 mo. Conclusion: Gemcitabine plus trastuzumab is safe and well tolerated in minimally pretreated HER2+ MBC pts, the majority of whom were anthracycline and taxane pretreated. This preliminary analysis supports the suggestion of enhanced anti-tumor activity between gemcitabine and trastuzumab, with the preliminary median survival surpassing that expected for either agent alone at this juncture of treatment. Final data to be presented. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Genentech, Lilly Oncology Genentech, Lilly Oncology Genentech, Lilly Oncology

Multicenter phase II study of trastuzumab (H) and capecitabine (X) as first- or second-line treatment in HER2 over-expressing metastatic breast cancer (Japan Breast Cancer Study Group: JBCSG-003)

802 Background: H and X are active in MBC and are synergistic in pre-clinical models. Methods: We are conducting a multi-center phase II trial to evaluate the safety and efficacy of capecitabine (1...

Trastuzumab (T) and CNS metastases in women with HER-2 positive metastatic breast cancer (MBC)

683 Background: A high rate of CNS metastases has been described in women with MBC over-expressing HER-2 who receive T-based therapy. The aim of this study was to examine the frequency of and potential risk factors for CNS metastases in these women. Our a priori hypotheses were that in MBC patients treated with T, CNS metastases occurred: 1) more frequently than historical controls, and 2) in women with controlled systemic disease. Methods: A retrospective cohort study of 28 patients with MBC cancer over-expressing HER-2 and treated with T and chemotherapy was performed. Results: 22/25 (88%) patients who initially responded to T had progressed by the time of analysis. CNS metastases occurred in 11/28 (39%) patients and the remaining 11 patients had progressed elsewhere. At diagnosis of CNS metastases, 9/11 (82%) patients had controlled systemic disease (CR=2, PR=6, SD=1, PD=2 patients). There were trends for patients with CNS metastases to have > 1 site of metastatic disease at the commencement of T therapy (P=0.06), and to be hormone receptor negative at initial diagnosis (P=0.14). The median time to diagnosis of CNS metastases after the commencement of T therapy was 30.8 months (range 16–49). The median survival after diagnosis of CNS metastases was 30.6 months (range 4–75). Conclusions: Historically, CNS metastases have been reported to occur in 10–16% of women with MBC, with a median survival of < 1 year. This study demonstrates a significantly higher rate of CNS metastases (39%) in HER-2 positive MBC patients treated with T. At CNS metastases most patients had controlled systemic disease and the median survival after CNS relapse was over 2 years. We suggest aggressive management of CNS disease in this population. Additional strategies to decrease the incidence of CNS metastases in these patients may include prophylactic whole brain irradiation and the development of novel pharmacological agents with successful CNS penetration. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Australian New Zealand Breast Cancer Trials Group, Genentech, Roche Roche

Relevance of EGFR expression in colorectal cancer

In a recent issue of Annals of Oncology, Spano and colleagues reported their study of epidermal growth factor receptor (EGFR) expression by immunohistochemistry in 148 patients with colorectal cancer [1.Spano J.P. Lagorce C. Atlan D. et al.Impact of EGFR expression on colorectal cancer patient prognosis and survival.Ann Oncol. 2005; 16: 102-108Abstract Full Text Full Text PDF PubMed Scopus (367) Google Scholar]. The aim of this study was to analyse the relationship between EGFR reactivity and various histological and clinical characteristics and survival. Multivariate analysis found significant overexpression in the T3 stage while there was no impact on overall survival. This study suggests some comments. Regarding eventual prognostic impact, the first handicap is the high frequency (80%) of overexpression, which is consistent with other studies. EGFR has been extensively studied in many tumours providing a number of data. Although the authors discuss the expression of EGFR among the different sites of the colon, the notable variation in expression between primary and secondary sites has not been discussed [2.Scartozzi M. Bearzi I. Berardi R. Mandolesi A. Fabris G. Cascinu S. Epidermal growth factor receptor (EGFR) status in primary colorectal tumors does not correlate with EGFR expression in related metastatic sites: implications for treatment with EGFR-targeted monoclonal antibodies.J Clin Oncol. 2004; 22: 4720-4726Crossref Scopus (247) Google Scholar]. As rapidly evoked in the last sentence, somatic mutations of the EGFR can play a major role, which has been clearly demonstrated in lung cancer [3.Lynch T.J. Bell D.W. Sordella R. et al.Specific activating mutations in the epidermal growth factor receptor and responsiveness of non-small-cell lung cancer to gefitinib.N Engl J Med. 2004; 350: 2129-2139Crossref PubMed Scopus (10043) Google Scholar, 4.Pao W. Miller V. Zakowski M. et al.EGF receptor gene mutations are common in lung cancer from ‘never smokers’ and are associated with sensitivity of tumors to gefitinib and erlotinib.Proc Natl Acad Sci USA. 2004; 101: 13306-13311Crossref PubMed Scopus (3891) Google Scholar]. Until now, about 30 mutations have been determined within the kinase domain of EGFR in lung cancer with a wide variation of frequency according to several baseline characteristics including gender, ethnic group or histological subtypes. Thus, there is a relatively high frequency of mutations in women, in smokers, or in Japanese patients with non-small-cell lung cancer. EGFR mutations can enhance tyrosine kinase activity in response to EGF and increase the efficacy of anti-EGFR such as gefitinib or erlotinib [3.Lynch T.J. Bell D.W. Sordella R. et al.Specific activating mutations in the epidermal growth factor receptor and responsiveness of non-small-cell lung cancer to gefitinib.N Engl J Med. 2004; 350: 2129-2139Crossref PubMed Scopus (10043) Google Scholar, 4.Pao W. Miller V. Zakowski M. et al.EGF receptor gene mutations are common in lung cancer from ‘never smokers’ and are associated with sensitivity of tumors to gefitinib and erlotinib.Proc Natl Acad Sci USA. 2004; 101: 13306-13311Crossref PubMed Scopus (3891) Google Scholar]. Increased expression of the multiple ligands, including EGF, TGF-α, epiregulin or amphiregulin, can also play a major role. To illustrate this, the prognostic value of EGFR in tumours of the head and neck, oesophagus, larynx, pancreas, lung, ovary, stomach or bladder was generally revealed when combined with increased EGF, TGF-α or both. Of note, the prognostic value of EGFR expression remains unproven in breast and lung cancers. Moreover, the multiple signalling pathways following on from the activation of EGFR have their own impact on the tumoral potential. Thus, many actors interfere with EGFR, minimising its proper impact. In line with this, there is no apparent correlation between the expression of EGFR and response to certain targeted drugs, such as cetuximab, in metastatic colorectal cancer [5.Cunningham D. Humblet Y. Siena S. et al.Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer.N Engl J Med. 2004; 351: 337-345Crossref PubMed Scopus (4585) Google Scholar]. Tyrosine kinase inhibitors might interfere with the phosphorylation of several of these pathways such as Ras/ Raf/mitogen-activated protein kinase, or phosphatidylinositol 3′-kinase-Akt. Thus, eventual prognostic impact of EGFR might be reversed by targeted drugs such as illustrated in patients with metastatic breast cancer overexpressing HER2 and treated by trastuzumab. For all these reasons, the crude expression of EGFR probably does not belong to the most crucial biomarkers such as those selecting candidates to adjuvant systemic therapy among stage II patients, or predicting response to a given drug.

Cerb-B2 ou Her-2 : marqueur d'intérêt dans la prise en charge du cancer du sein ?

Breast cancer is a public health problem due to its high frequency. The cancerisation process is characterized in part by the dysfunction of cellular communication pathway, like on one implicating Her-2. Her-2 is overexpressed by 30% in breast cancer and is associated with poor prognosis, with a decrease overall survival and a shortening time to disease progression. The Her-2/neu oncogene is involved in the development of breast cancer by amplification and/or overexpression of its product, the Her-2 protein that takes a considerable importance as a potential therapeutic target with specific antitumoral therapies. Besides, more and more studies demonstrated the relevance of Her-2 serum level as a predictive marker in the setting of metastatic breast cancer overexpressing Her-2.

Targeting c-erbB2 and Other Receptors of the C-ErbB Family: Rationale and Clinical Applications

The c-erbB family of receptors includes four distinct receptors, namely c-erb B1, 2, 3 and 4 (HER1, 2, 3 and 4, respectively). Trastuzumab (T) is a recombinant humanized anti-HER2 monoclonal antibody that binds the extracellular domain of the receptor and blocks intracellular signalling. In clinical studies of T, either alone or in combination with chemotherapy, in HER2 overexpressing metastatic breast cancer patients, a significant benefit was obtained—improved response rates and survival, when T was combined with chemotherapy. Several trials of adjuvant T, either singly or in combination with chemotherapy, are in progress in early breast cancer patients. Pertuzumab defines a new class of HER2 inhibitors, “dimerization inhibitors” that block both homo- and hetero-dimerization of HER2. In preclinical studies pertuzumab is inhibitory to breast, prostate and non small cell lung cancer cell lines, both over and non overexpressing HER2. In phase I clinical trials pertuzumab has shown activity in a number of human cancers. A phase II program is in progress.

Effect of Cardiac Dysfunction on Treatment Outcomes in Women Receiving Trastuzumab for HER2-Overexpressing Metastatic Breast Cancer

Trastuzumab improves time to disease progression (TTP) and survival when added to chemotherapy for HERpositive metastatic breast cancer (MBC), but it is associated with infrequent cardiac dysfunction (CD). We analyzed data from a previous pivotal randomized trial of 469 women with HER2-overexpressing MBC. The aim was to determine the benefit of adding trastuzumab to chemotherapy in terms of TTP that was free of CD, including all CD, moderate or severe (New York Heart Association class III/IV) CD only, or moderate or severe CD that did not improve with cardiac therapy. We also assessed moderate or severe CD-free survival. We assessed the impact of trastuzumab for these indices on the entire cohort and on specific chemotherapy subsets. Median TTP or any CD improved when trastuzumab was added to all chemotherapy (4.6 months vs. 6.6 months with trastuzumab, P = 0.0001), an anthracycline (doxorubicin or epirubicin) plus cyclophosphamide (AC; 6.0 months vs. 6.6 months, P = 0.24), and paclitaxel (2.8 months vs. 6.6 months, P = 0.0001). When defined as time to moderate or severe CD, median TTP improved when trastuzumab was added to all chemotherapy (4.6 months vs. 7.0 months, P = 0.0001), AC (6.0 months vs. 7.2 months, P = 0.02), and paclitaxel (2.8 months vs. 6.9 months, P = 0.0001). There was no statistical difference between moderate and severe CD-free survival with trastuzumab added to chemotherapy. Outcomes improved with trastuzumab despite CD. In particular, the benefit from trastuzumab/paclitaxel outweighed the potential risk of CD in patients with MBC. These types of analyses will be critical for trials assessing trastuzumab as adjuvant therapy.

Randomized phase III study of trastuzumab, paclitaxel, and carboplatin versus trastuzumab and paclitaxel in women with HER-2 overexpressing metastatic breast cancer: An update including survival

573 Purpose: This randomized multicenter phase III trial evaluated the efficacy and safety of trastuzumab with paclitaxel 175 mg/m2 and carboplatin AUC=6 (TPC) versus trastuzumab with paclitaxel 175 mg/m2 (TP) in women with HER-2 overexpressing metastatic breast cancer. Methods: Between November 1998 and May 2002, 196 patients (pts) with HER-2 overexpression of 2+ or 3+ by immunohistochemistry were randomized; 188 were eligible; 93 pts received TPC and 95 pts received TP. In both arms, chemotherapy was delivered every 3 weeks for at least 6 cycles and weekly trastuzumab until progression. Results: Overall response (OR) and time to progression (TTP) were significantly improved with TPC compared to TP; OR for TPC was 52%, compared to 36% for TP (P = .04). Median TTP was 11.9 months for TPC and 6.8 months for TP (P = .02). This improvement was greater in HER2 3+ pts, with OR of 57% versus 37% (P = .03), and median TTP of 14.6 months vs 6.9 months (P = .006), for TPC and TP, respectively. There was a trend in the overall survival in favor of TPC of 42.1 months compared to TP with 33.3 months (P= 0.27); in IHC 3+ patients median OS of 42.1 months for TPC vs 30.6 months for TP (P=0.11). Therapy was well tolerated on both arms of the study. Grade 3/4 neutropenia and thrombocytopenia were more common with TPC, as expected. There was no difference in fever/neutropenia, neuropathy, fatigue, and other toxicities between study arms. There was one case of congestive heart failure, seen in the TP arm. Conclusion: The addition of carboplatin to paclitaxel and trastuzumab significantly improved response rate and TTP in pts with a trend to improved overall survival with HER-2 overexpressing metastatic breast cancer. Treatment was well tolerated. Supported by Bristol-Myers Squibb, Plainsboro, NJ. and Genentech, South San Francisco, CA, USA Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bristol-Myers Squibb Bristol-Myers Squibb Study support with grants for clinical trials from Bristol-Myers Squibb; clinical trial support from Aventis; clinical trial support from Eli Lilly Bristol-Myers Squibb Bristol-Myers Squibb

Randomized phase III study of trastuzumab, paclitaxel, and carboplatin versus trastuzumab and paclitaxel in women with HER-2 overexpressing metastatic breast cancer: An update including survival

573 Purpose: This randomized multicenter phase III trial evaluated the efficacy and safety of trastuzumab with paclitaxel 175 mg/m2 and carboplatin AUC=6 (TPC) versus trastuzumab with paclitaxel 175 mg/m2 (TP) in women with HER-2 overexpressing metastatic breast cancer. Methods: Between November 1998 and May 2002, 196 patients (pts) with HER-2 overexpression of 2+ or 3+ by immunohistochemistry were randomized; 188 were eligible; 93 pts received TPC and 95 pts received TP. In both arms, chemotherapy was delivered every 3 weeks for at least 6 cycles and weekly trastuzumab until progression. Results: Overall response (OR) and time to progression (TTP) were significantly improved with TPC compared to TP; OR for TPC was 52%, compared to 36% for TP (P = .04). Median TTP was 11.9 months for TPC and 6.8 months for TP (P = .02). This improvement was greater in HER2 3+ pts, with OR of 57% versus 37% (P = .03), and median TTP of 14.6 months vs 6.9 months (P = .006), for TPC and TP, respectively. There was a trend in...

Gemcitabine, vinorelbine and trastuzumab combination (GemVinT) as second-third line therapy for HER-2 overexpressing metastatic breast cancer (MBC)

759 Background: The addition of Trastuzumab (T) to chemotherapy as first-line therapy is associated with significant improvement in response rate (RR), time to progression (TTP) and overall survival (OS), in HER-2 overexpressing MBC. However, the efficacy of T combined with chemotherapy is presently object of evaluation in MBC pretreated with chemotherapy ± T. We evaluated in this phase II study the safety and efficacy of GemVinT as second-third line therapy for HER-2 overexpressing MBC, pretreated with anthracyclines and/or taxanes and/or T. Methods: Eligible patients had HER-2 positive disease (ICH 2+ or 3+), PS ≤ 2, normal LVEF. Pts were treated with weekly T (4 mg/Kg on day 1 and then 2 mg/Kg), in combination with Gem (800 mg/m2) and Vin (25 mg/m2) on days 1 and 8, every 21 days. Pts were re-staged every 3 cycles. Results: 26 pts were enrolled onto the study, median age 58 years (range 41–74), median ECOG PS 0 (range 2–0), median number of metastatic sites 3 (range 1–8), prior first line chemotherapy ...