Chemotherapy In HER2 Research Articles

Kongressbericht vom 31. Annual San Antonio Breast Cancer Symposium von 10.–14.12.2008

Das 31. San Antonio Breast Cancer Symposium bestätigte den seit Jahren bestehenden Trend weg von risikoorientierter Behandlung hin zur maßgeschneiderten Diagnostik und Therapie des Mammakarzinoms. Wie auch in den vergangenen Jahren wurden zu gleichen Teilen Ergebnisse aus der Grundlagenforschung und Präklinik sowie klinische Studien vorgestellt und diskutiert. Neben den klassischen Themen wie antihormoneller, zielgerichteter Therapie und Chemotherapie standen in diesem Jahr auch disseminierte Tumorzellen im wissenschaftlichen Fadenkreuz. Immer wieder wurde auf Unterschiede in der primären Tumorentstehung im Gegensatz zur Metastasierung (Metastasensuppressorgene, Unterschiede im Ansprechen bestimmter Therapeutika in der adjuvanten oder palliativen Situation) hingewiesen. Im Bereich der antihormonellen Therapie der postmenopausalen Patientin zeigten die Aromatasehemmer erneut ihre therapeutische Überlegenheit gegenüber Tamoxifen bei zum Teil deutlich mehr Nebenwirkungen. Auch für upfront in der Adjuvanz eingesetztes Letrozol konnte in der Intention-to-treat-Analyse der BIG-1-98-Studie kein Gesamtüberlebensvorteil gezeigt werden. Nachdem in der TEAM-Studie auch für Exemestan ein Vorteil im Ansprechen gegenüber Tamoxifen demonstriert werden konnte, wird unser Upfront-Portefeuille um diese Substanz erweitert. Bei der Vorstellung der 36-Monate-Follow-up-Daten der ZOFAST-Studie konnte die signifikant geringere Knochendichteabnahme bei Zoledronsäurebehandlung bestätigt sowie ein signifikant besseres krankheitsfreies Überleben demonstriert werden. Dafür scheinen, das haben andere Studien (AZURE) bestätigt, direkte tumordestruierende Wirkungen zuständig zu sein. Im Bereich der Chemotherapie und der zielgerichteten Therapien konnte jetzt erstmalig auch in der Neoadjuvanz gezeigt werden, dass die Kombination von Chemotherapie und Trastuzumab neben einer deutlichen Ansprechverbesserung auch mit einer Prognoseverbesserung verbunden ist. Bei metastasierten Patienten erhärten sich die Fakten für einen Nutzen der Therapie mit Trastuzumab jenseits des Progresses. Wie bereits für andere Antikörper und Small Molecules konnte auch für Lapatinib die Überlegenheit in einer Kombination mit Letrozol im Gegensatz zur Monotherapie mit Letrozol bei metastasierten Her-2/neu hormonrezeptorpositiven Patienten gezeigt werden. Neue Substanzen wie Neratanib, ein Pan-ErbB-Tyrosinkinase-Hemmer und T‐DM1 (ein Konjugatwirkstoff aus Trastuzumab und Deacetylmaytansin, einem Spindelgift) wurden in ersten Studien getestet und verdienen eine weitere wissenschaftliche Beschäftigung.

Phase II trial of neoadjuvant 5-fluorouracil, epirubicin and cyclophosphamide (FEC100) followed by weekly paclitaxel and trastuzumab (PH) for HER2 positive breast cancer (Kinki Multidisciplinary Breast Oncology Group; KMBOG-0402).

Abstract Abstract #3160 Background: Achievement of pathological complete response (pCR) by primary systemic chemotherapy (PST) correlates with improved disease-free survival in operable breast cancer patients. Based on data of the higher pCR rate with concomitant chemotherapy and trastuzumab (H) presented by the randomized prospective trial (Buzdar AU, et al: JCO 23:3676-85; 2005), we performed a multi-center, prospective phase II study to assess the addition of H to primary systemic chemotherapy in HER2+ pts in Japan.
 Methods: Generally, the concomitant combination therapy with anthracycline-containing regimens and H is not recommended because of the increasing rate of cardiac toxicity. This study was designed to evaluate the efficacy and safety of PST for the operable breast cancer with HER2+ phenotype. PST is the sequential chemotherapy with 4 cycles of FEC100 followed by 12 times in combination with weekly paclitaxel (P) 80mg/m2 and H 2mg/kg (PH x 12).. The inclusion criteria is pts with histopathologically confirmed invasive breast carcinoma, T1-3N+M0/T2-3N0M0, HER2 positive by FISH or immunohistochemistry (IHC) 3+, PS=0-1, adequate hematologic, renal, hepatic and cardiac function and a written informed consent. The study was designed to detect a pCR rate of >43% in at least 42 pts. The evaluation of pathological response was carried out on all the surgical specimens sliced every 5 mm interval.
 Results: From Dec 2004 to Dec 2007, 43 pts were enrolled. Pre-reviewed data is now available for all pts: median age 56 [26-75 years]; 15 (35%) pre-menopausal; median clinical tumor size 40 mm [15-80]; 14 (33%) were ER-positive phenotype. All pts had a normal cardiac function before entry and after FEC→PH. No episodes of serious adverse events were reported. Febrile neutropenia was observed on 5 pts (12%). Grade 2 or 3 neuropathy was limited to 4 pts (9%). Other grade 3 non-hematological toxicities were not observed. Two pts requested to stop the treatment with P after 6 times of infusion because of neuropathy, edema and hyperpigmentation on the face, however, they had completed 12 times of H infusion. After PST, breast conservative surgery was done in 38 patients (88%) and mastectomy in 5 (12%). The overall pCR rate was 60% (26/43), and 6 of 26 pts had only component of DICS.
 Conclusions: In HER2+ pts, PST with FEC100x4 followed by PHx12 was active and promising, achieving high pathological complete response without significant toxicity. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3160.

Lapatinib (L) with weekly paclitaxel (P) as first-line therapy for patients (pts) with HER2+ metastatic breast cancer (MBC).

Abstract Abstract #3145 L, an oral tyrosine kinase inhibitor of EGFR/HER2, is active as monotherapy and in combination with chemotherapy for HER2+ MBC. In a planned subgroup analysis of a Ph III trial, EGF30001, L (1500mg QD) + P (175mg/m2 q3w), significantly improved overall response rate (ORR) and progression free survival (PFS) compared with P alone as initial therapy for HER2+ MBC. Here we report final results of a phase II, single-arm multicenter trial, EGF105764, assessing activity of L with weekly P in first line MBC.
 Methods: Safety and efficacy of L (1500 mg QD)+P (80 mg/m2/wk x 3q wk) was evaluated in 57 pts with newly diagnosed, HER2 FISH+, Stage IV MBC. Primary endpoint was ORR.
 Results and Discussion: All pts had ECOG PS ≤1, no pt received previous trastuzumab but 61% received prior adjuvant/neo-adjuvant chemo- or anti-hormonal therapy. Median time from prior chemotherapy was 63 weeks. No patient had suspected baseline CNS disease. At time of data cut-off, 41 (72%) pts progressed or withdrawn. The median duration of L treatment was 45 (range 2-87) wks, and 26 (range 0 to 80) wks for P. The investigator-assessed ORR was 77% (44/57), with 3 CR and 41 PR, (95% CI: 64.2, 87.3) with a median duration of response (DoR) of 42.3 wks (95% CI: 37.7, 64.1). The independently confirmed ORR was 51% (29/57), with 0 CR and 29 PR, (95% CI: 37.3, 64.4) with a median DoR of 39.7 wk (95% CI: 26.9, 50.0). CNS relapse was reported in 4/41 pts (10%). Most common AEs were diarrhoea (56%, ≥gr3: 5%), neutropenia (44%, ≥gr3: 26%), rash (40%, ≥gr3: 3%), fatigue (25%, ≥gr3: 0%), and neurological (25%, ≥gr3: 0%). Four pts had 1 dose reduction of L (2 due to diarrhoea) and 19 pts had ≥1 dose delay (6 due to diarrhoea). Dose reductions for P occurred in 7 pts; 45 pts had ≥1 dose delay (63% due to toxicity). There were no protocol defined LVEF decreases.
 In the 86pt subset with HER2+ tumors in EGF30001, the investigator reported ORR was 63% in the L+q3w P and 38% for P+placebo. The safety profile of L+P used qw or q3w is comparable: diarrhoea all grades (56% vs 58%), rash all grades (40% vs 43%), and neurological events all grades (25% vs 26%). Neutropenia (all grades) was more common in the qw schedule of P (44% vs 26%), but the incidence of ≥gr3 was comparable (26% vs 21%, for qw vs 3qw respectively).
 Conclusions: L + weekly P as first-line therapy for HER2+ MBC was well tolerated and produced a high, investigator assessed ORR of 77%. These data suggest that the combination of L and P (at any schedule) may be an option for newly diagnosed patients with HER2+ MBC. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3145.

First-Line Chemotherapy for HER-2–Negative Metastatic Breast Cancer Patients Who Received Anthracyclines as Adjuvant Treatment

The treatment decision for patients with metastatic breast cancer who have received anthracyclines within the course of adjuvant chemotherapy is troublesome, particularly if trastuzumab and hormonal treatment are not indicated. In the first part of this review we discuss the value of retreatment with anthracyclines, a topic that has been indirectly evaluated by retrospective studies with conflicting results and within a small phase III trial with a negative outcome. Evidence on liposomal anthracyclines is also reviewed. In the second part of the review, alternative options of first-line chemotherapy are discussed. These include taxanes as single agents, taxanes in combination with other cytotoxic drugs, combinations without anthracyclines and taxanes, and innovative treatments including target-based agents. Both the amount and the quality of evidence on these treatments are poor. Few phase III studies are available and most of them have been performed with registrative aims sponsored by the companies who own the winning drug. Beyond indications derived from such studies, there is a great need for more clinical research in this setting.

Assessment of pathological complete response (pCR) to neoadjuvant dose-dense chemotherapy in HER2+ patients with locally advanced breast cancer (LABC) treated with trastuzumab (T) compared with HER2+ and HER2- patients treated without T

11057 Purpose: To identify Her2+expression as predictive factor for pCR to T in pts with LABC treated with neoadjuvant chemotherapy. Methods: A total of 127 newly diagnosed stage II-III, including inflammatory tumors, breast cancer pts were reviewed. Median age was 47,7 (r 26,4 - 73,6). Median tumor size was 5 cm (1–10). 57 (44,8%) were T2, 33 (26%) T3 and 37 (29,2%) T4 (25 of them inflammatory). 59 (46,5%) pts were clinically lymph node positive before treatment. 50 pts (39,4%) were hormonal receptor negative, and 38 (30,4%) Her2+. The pts received one of the 2 chemotherapy regimens every 2 weeks with prophylactic growth factors support: A) epirubicin 90 mg/m2-cyclophophamide 600 mg/m2 d1 for 3 cycles, followed by a second sequence with paclitaxel (P) 150 mg/m2- gemcitabine (G) 2500 mg/m2 d1 ± T 2mg/kg/wk according to status Her2 (n= 73); B) adriamicin 40mg/m2 d1 plus P 150mg/m2-G 2000 mg/m2 d2 for 6 cycles (n=54). Subsequently pats underwent surgery and radiotherapy and/or adjuvant hormonal therapy according to institutional practice. Results: 43 (33,9 %) pts achieved a pCR (absence of invasive tumor in the breast). The pts were classified in two groups to analyze the influence of the treatment with T on pCR: (1) Her2+ pats treated with T (20 pts): pCR 50%; (2) The rest of the pts, treated only with chemotherapy (107 pts: 18 Her2+ and 89 Her2- ): pCR 32% (p=0.068). Breast-conserving surgery was performed in 77 pts (60,6%). Conclusions: Both dose dense chemotherapy regimens were highly effective in terms of pCR. Although there were not a significative correlation of Her2+ status and trastuzumab therapy with pCR, probably due to the small number of pts, a favorable tendency was seen in the group of Her2+ tumors treated with T. At the meeting, analysis of the correlation of pCR with progression free survival will be presented. No significant financial relationships to disclose.

Phase II trial of vinorelbine (V) days 1+8 every 3 weeks and trastuzumab (T) weekly as first-line chemotherapy for HER2+ metastatic breast cancer (MBC)

1091 Background: Weekly V and T as 1. line therapy in patients (pts) with HER2+ MBC is highly effective with reported response rates (RR) from 61–86% and median time to progression (TTP) 8.5–16 months. This study examined V given twice every 3 weeks. Methods: Eligible pts had HER2+ (IHC 3+ or FISH) MBC with measurable disease by RECIST criteria, no prior chemotherapy or T for MBC, and LVEF > 50%. They received V 35 mg/m2 i.v. days 1+8 every 3 weeks (= 1 cycle) and T weekly (4 mg/kg loading dose, 2 mg/kg thereafter i.v.) until progression or unacceptable toxicity. Planned sample size was 50, but the study was replaced by a randomised trial at 46 pts, all of them eligible. Primary endpoint was RR, secondary endpoints included TTP, overall survival (OS) and toxicity. Results: From December 2001-July 2004 46 pts were recruited at 4 centers. They received 11 (1–54) cycles (median, range). V dose was reduced due to neutropenia in 7.5% of cycles and for other reasons in 14.5%. V treatment was delayed due to neutropenia in 7.8% of cycles and for other reasons in 4.7% of cycles. Median received V dose intensity was 0,78. Cardiotoxicity: asymptomatic reduction of LVEF > 20% or >10% to below 50%: 8 pts (3 to below 50%). Toxicity grade III-IV (pts): Neutropenia: 11. Infections: 5 (one septic death). Constipation 2. 43 pts have progressed and 32 have died. RR: CR: 9 (20%) PR: 13 (28%) SD 11 (24%) (SD> 6 months 9 (20%)) PD: 10 (22%) NE: 3 (7%). Median duration of response: 18.0 months. Median TTP: 11.0 months (95% confidence interval (95%CI) 7.6–14.4). Median OS: 25.4 months (95%CI 22.7–28.0). After progression 24 received docetaxel, 14 capecitabine, 6 epirubicine, and 11 endocrine therapy. Conclusions: V given twice every 3 weeks and T weekly is a highly active and well-tolerated 1. Line treatment for HER2+MBC. Recruitment into the trial was stopped at 46 pts in favor of a phase III-trial which is ongoing in the Nordic countries comparing V (days 1+8) + T with docetaxel+T every 3 weeks. No significant financial relationships to disclose.

Trastuzumab and vinorelbine or taxane chemotherapy for HER2+ metastatic breast cancer: The TRAVIOTA study

650 Background: The optimal trastuzumab/chemotherapy regimen for advanced breast cancer is not known. We performed a multicenter, randomized clinical trial to compare TRastuzumab And VInorebline Or TAxane (TRAVIOTA) chemo- and bio-therapy combination treatment given on a weekly schedule for HER2+ metastatic breast cancer. Patients and Methods: Eligible patients had stage IV breast cancer, measurable disease (by RECIST criteria), HER2+ tumors (IHC 3+ or FISH+), no prior chemotherapy or trastuzumab for advanced breast cancer, and LVEF > 50%. Patients were randomized 1:1 to trastuzumab (4 mg/kg loading dose, 2 mg/kg weekly thereafter) with either weekly vinorelbine (25 mg/m2) or weekly taxane (paclitaxel 80 mg/m2 or docetaxel 35 mg/m2, selected by the treating investigator). The primary endpoint was response rate. The study opened in August 2001 and planned to accrue 250 patients. It was closed in December 2003 having accrued only 85 patients. Results are presented for the 81 patients who received any protocol-based therapy. Results: Patients receiving trastuzumab and vinorelbine tended to have higher response rates and TTP than those assigned trastuzumab and taxane therapy but the results were not statistically significant (see Table ). Vinorelbine therapy was associated with more frequent grade 3 or 4 hematological toxicity and dose delay because of myelosuppression. Other toxicities generally reflected the known side effects of the chemotherapy agents. Conclusions: The TRAVIOTA study suggests at least comparable clinical activity of trastuzumab with vinorelbine as with weekly taxane chemotherapy in HER2+ metastatic breast cancer, with side effect profiles consistent with previous experience with these regimens. [Table: see text] [Table: see text]

Normal cardiac biopsy results following co-administration of doxorubicin (A), Cyclophosphamide (C) and trastuzumab (H) to women with HER2 positive metastatic breast cancer

572 Background: Trastuzumab (Herceptin, H) extends overall survival when administered with chemotherapy (CT) to patients (pts) with HER2+ metastatic breast cancer (MBC). An increase in cardiac dysfunction (CD) was seen in pts who received H + CT (paclitaxel or AC) in a phase III study. The mechanism by which H contributes to CD may include a pharmacokinetic (PK) interaction or increased cardiac sensitivity to A. This phase I study evaluated the PK of A, C, and H; the utility of CD monitoring by LVEF (echocardiogram (EC)/nuclear multigated cardiac scan (NCS)), by cardiac biopsy, and cardiac serum marker surveillance. Methods: Inclusion criteria: ages 18–60, no prior internal mammary/mediastinal XRT, no prior A or prior CT for HER2+ MBC. Pts received weekly H (4mg/kg load, 2mg/kg weekly) with AC (60/600) q3w x 6. Cardiac evaluations included physical examination, LVEF, and cardiac biopsy after C4 and/or at s/sx of CD. Biopsies were graded using published methods. Plasma for cardiac markers and PK was obtain...

HER-2/neu als prädiktiver Faktor beim Mammakarzinom

Amplification of the HER-2/neu gene resulting in overexpression of the p185HER-2 growth factor receptor occurs in approximately 25-30% of early stage breast cancers and is associated with a poor prognosis. HER-2/neu has also become a marker for predicting the response to anti-HER-2/neu monoclonal antibodies, which have been shown to improve the response rate, response duration, and overall survival in combination with chemotherapy in HER-2/neu amplified metastatic breast cancers. Recent data suggest an association between the degree of HER-2/neu overexpression and the response to anti-HER-2/neu monoclonal antibodies. HER-2/neu is also a potential predictive marker for response to chemotherapy or endocrine therapy. Controversies about the detection of HER-2/neu in archival breast tumor specimens and pitfalls of retrospective subgroup analysis complicate the interpretation of studies of the predictive value of HER-2/neu. As a result there is no conclusive evidence for resistence towards cyclophosphamide, methotrexate, and fluorouracil in HER-2/neu-positive breast cancers. Retrospective studies suggest an increased response to doxorubicin-containing chemotherapeutic regimens in HER-2/neu-positive breast cancers. Data on taxanes are inconclusive. HER-2/neu overexpression is also inversely associated with estrogen receptor (ER) positivity, but in cases where ER and HER-2/neu are coexpressed tamoxifen efficacy is in question. Large cooperative trials have not confirmed a deleterious effect of tamoxifen in such cases. In conclusion, HER-2/neu may be a useful marker for predicting the response to chemotherapy agents, antiestrogens, and therapeutic anti-HER-2/neu monoclonal antibodies.