Matteo Clavarezza

Retreatment with trastuzumab-based therapy after disease progression following lapatinib in HER2-positive metastatic breast cancer.

BACKGROUND Preclinical data suggest that treatment with lapatinib reinduces sensitivity to trastuzumab in human epidermal growth factor receptor 2(HER2)-positive breast cancer cells. PATIENTS AND METHODS Between January 2007 and November 2010, 179 HER2-positive metastatic breast cancer patients were treated with lapatinib and capecitabine at nine Italian institutions. We evaluated the clinical outcome of 69 patients (38.5%) retreated with trastuzumab after lapatinib progression. RESULTS Visceral metastases were identified in 51 (74%) and brain metastases in 16 patients (23%). All patients were pretreated with both trastuzumab- and lapatinib-based therapy. We observed with retreatment with trastuzumab-based therapy: 1 complete remission (2%), 18 partial remission (29%) and 10 stable disease ≥6 months (14%) and 47% of clinical benefit (CB). Median duration of response was 8.1 months [95% confidence interval (CI) 5.5-10.7]. No unexpected toxic effects occurred. At a median follow-up of 13 months, median progression-free survival was 4.9 months (95% CI 4.2-5.6) and overall survival (OS) 19.4 months (95% CI 14.0-25.0). Median OS was longer for patients experiencing CB (not reached versus 13.4 months for patients without CB, P = 0.002). Brain involvement was associated with lower median OS (17.3 versus 23.3 months for patients without brain disease; P = 0.021). CONCLUSION Retreatment with trastuzumab-based therapy showed CB in 47% of patients progressing during lapatinib-based therapy, leading to a prolonged OS.

Adjuvant chemotherapy of pT1a and pT1b breast carcinoma: results from the NEMESI study

BackgroundThe prognosis of pT1a-pT1b breast cancer (BC) used to be considered very good, with a 10-y RFS of 90%. However, some retrospective studies reported a 10-y RFS of 81%–86% and suggested benefit from adjuvant systemic therapy.MethodsTo evaluate the variables that determined the choice of adjuvant chemotherapy and the type of chemotherapy delivered in pT1a-pT1b BC, we analysed the small tumours enrolled in the NEMESI study.ResultsOut of 1,894 patients with pathological stage I-II BC enrolled in NEMESI, 402 (21.2%) were pT1a-pT1b. Adjuvant chemotherapy was delivered in 127/402 (31.59%). Younger age, grading G3, high proliferative index, ER-negative and HER2-positive status were significantly associated with the decision to administer adjuvant chemotherapy. An anthracycline without taxane regimen was administered in 59.1% of patients, anthracycline with taxane in 24.4%, a CMF-like regimen in 14.2% and taxane in 2.4%. Adjuvant chemotherapy was administered in 88.4% triple-negative and 73.46% HER2-positive pT1a-pT1b BC. Adjuvant trastuzumab was delivered in 30/49 HER2-positive BC (61.2%).ConclusionsAdjuvant chemotherapy was delivered in 31.59% T1a-pT1b BC treated at 63 Italian oncological centres from January 2008 to June 2008. The choice to deliver chemotherapy was based on biological prognostic factors. Anthracycline-based chemotherapy was administered in 83.5% patients.

AVAREG: a phase II, randomized, noncomparative study of fotemustine or bevacizumab for patients with recurrent glioblastoma

BACKGROUND Few prospective studies have assessed the role of bevacizumab and included a control arm with standard treatments for recurrent glioblastoma. We conducted a noncomparative phase II trial (AVAREG) to examine the efficacy of bevacizumab or fotemustine in this setting. METHODS Eligible patients were randomized 2:1 to receive bevacizumab (10 mg/kg every 2 weeks) or fotemustine (75 mg/m(2) on days 1, 8, and 15, then 100 mg/m(2) every 3 weeks after a 35-day interval). The primary endpoint was 6-month overall survival (OS) rate (OS-6). No formal efficacy comparison was made between the treatment arms. RESULTS Ninety-one patients were enrolled (bevacizumab n = 59; fotemustine n = 32). Median age was 57 years (range, 28-78 y), and patients had Eastern Cooperative Oncology Group performance status of 0 (n = 42), 1 (n = 35), or 2 (n = 14). OS-6 rate was 62.1% (95% confidence interval [CI], 48.4-74.5) with bevacizumab and 73.3% (95% CI, 54.1-87.7) with fotemustine. OS-6 rates were lower in bevacizumab-treated patients with MGMT promoter methylated tumors than in those with unmethylated tumors (50% and 85%, respectively), but higher in fotemustine-treated patients (87.5% and 50%, respectively). OS rates at 9 months were 37.9% (95% CI, 25.5-51.6) and 46.7% (95% CI, 28.3-65.7) with bevacizumab and fotemustine, respectively, and median OS was 7.3 months (95% CI, 5.8-9.2) and 8.7 months (95% CI, 6.3-15.4), respectively. Toxicity was as expected with the 2 agents. CONCLUSION Single-agent bevacizumab may have a role in patients with recurrent glioblastoma.

414ORANDOMIZED PHASE II TRIAL AVAREG (ML25739) WITH BEVACIZUMAB (BEV) OR FOTEMUSTINE (FTM) IN RECURRENT GBM: FINAL RESULTS FROM THE RANDOMIZED PHASE II TRIAL

ABSTRACT Aim: The treatment of recurrent glioblastoma (GBM) remains an open issue and the role of BEV has been largely debated since only few data compared this agent with the standard agents. Methods: A multicenter, open label, randomized (2:1), non-comparative phase II study (EudraCT 2011-001363-46; AVAREG - ML25739) with BEV 10 mg/m2 iv every 2 weeks or FTM 75 mg/m2 iv day 1-8-15 followed, after a 35 days interval, by FTM 100 mg/m2 every 3 weeks was conducted. Primary endpoint was overall survival at 6 months (OS6). Stratification factors were age ( 55 yrs) and resection for recurrent disease (yes vs no). Results: 91 patients (pts) with recurrent GBM were enrolled among 10 Italian centers between 11/2011 and 9/2012. Median age was 57 yrs (range: 28-78), ECOG PS was 0/1/2 in 42/35/14 pts. All pts received RT/TMZ accordingly with EORTC 26981-22981/NCIC CE3. Time from diagnosis to 1st recurrence was 331 days in the BEV arm and 460 days in the FTM arm. At the time of recurrence, 21 pts (23.1%) underwent re-resection before the inclusion into the study (13/8 pts in BEV/FTM arms, respectively). Fifty-nine pts were enrolled in the BEV arm and 32 pts in the FTM arm. OS6 was 62.1% (95%CI: 48.4 - 74.5) and 73.3% (95%CI: 54.1 - 87.7), OS9 was 37.9% (95%CI: 25.5–51.6) and 46.7% (95%CI 28.3–65.7) in the BEV and FTM arms, respectively. Median OS was 7.3 months (95%CI: 5.8 - 9.2) in the BEV arm and 8.7 months (95%CI: 6.3-15.4) in the FTM arm. In the BEV arm, OS6 and OS9 were 77.8% (95%CI: 57.7–91.4) and 59.3% (95%CI: 38.8 - 77.6) in pts ≤55 yrs, and were 48.4% (95%CI: 30.1 - 66.9) and 19.3% (95%CI: 7.4 - 37.5) in pts >55 yrs. HR for OS in BEV group for pts >55 yrs compared with pts ≤55 yrs was 2.0 (95%CI: 1.0-4.1, p = 0.05). G 3-4- toxicity BEV FTM Neutropenia 1 (1.7%) 4 (12.5%) Thrombocytopenia 0 7 (21.9%) Intestinal perforation 2 (3.4%) 0 Cerebral ischaemia/haemorrage 2 (3.4%) 0 Pulmonary embolism 1 (1.7%) 0 Acute myocardial infarction 1 (1.7%) 0 Conclusions: BEV in recurrent GBM showed survival rates superimposable with FTM. Disclosure: V. Zagonel: Roche – Speaker; M. Reni: Genentech - Advisory board; G. Rosti: Roche - Speaker A. Galli: Roche – employee; S. Doria: Roche – employee; All other authors have declared no conflicts of interest.

Phase II open-label study of bevacizumab combined with neoadjuvant anthracycline and taxane therapy for locally advanced breast cancer

BACKGROUND Neoadjuvant anthracycline- and taxane-based chemotherapy is frequently administered in breast cancer. Pathological complete response (pCR) rates vary according to clinical disease stage and biology of breast cancer. The critical role of angiogenesis in the progression of breast cancer, together with significantly improved efficacy when bevacizumab is combined with chemotherapy in the metastatic setting, provides a strong rationale for evaluating the integration of bevacizumab into neoadjuvant chemotherapy regimens. METHODS A single-arm, multicentre, phase II, open-label study evaluated four 3-weekly cycles of FEC (5-fluorouracil 600 mg/m(2), epirubicin 90 mg/m(2) and cyclophosphamide 600 mg/m(2)) followed by 12 cycles of weekly paclitaxel (80 mg/m(2)) in combination with bevacizumab 10 mg/kg every 2 weeks as neoadjuvant therapy for HER2-negative stage III locally advanced or inflammatory breast carcinoma. The primary endpoint was pCR rate. RESULTS Planned treatment was completed in 49 of the 56 enrolled patients. In the intent-to-treat population, the pCR rate was 21% and the clinical response rate was 59%. Breast-conserving surgery was achieved in 34% of patients. In the subgroup of 15 patients with triple-negative disease, the pCR rate was 47%. Grade 3 adverse events in ≥5% of patients were neutropenia, leucopenia, asthenia, and rash. One case each of hypertensive retinopathy and post-operative wound complication, both after treatment completion, were considered probably related to bevacizumab. There were no treatment-related deaths and no cardiac function abnormalities. CONCLUSIONS This study indicates that FEC followed by weekly paclitaxel with bevacizumab is an active neoadjuvant regimen for locally advanced breast cancer, with no major safety concerns. CLINICAL TRIAL REGISTRATION NCT00559845.

Biological characterization and selection criteria of adjuvant chemotherapy for early breast cancer: experience from the Italian observational NEMESI study

BackgroundInternational treatment guidelines recommend administration of adjuvant chemotherapy in early breast cancer based on clinical, prognostic and predictive parameters.MethodsAn observational study (NEMESI) was conducted in 63 Italian oncology centres in patients with early breast cancer. Age, performance status, concomitant disease, menopausal status, histology, tumor dimension (pT), axillary lymph node status (pN), grading (G), estrogen and progesterone receptor (ER and PgR), proliferative index (ki67 or MIB-1), human epidermal growth factor receptor 2 (HER2) and type of adjuvant treatment were recorded. The primary objective of the study was to define parameters influencing the decision to prescribe adjuvant chemotherapy and the type of chemotherapy.ResultsData for 1894 patients were available. 69.0% postmenopausal, 67.0% pT1, 22.3% pTmic/pT1a/pT1b, 61.0% pN0, 48.7% luminal A, 18.1% luminal B, 16.1% HER2 positive, 8.7% triple negative, 8.4% unknown. 57.8% received adjuvant chemotherapy: 38.1% of luminal A, 67.3% luminal B, 88.2% HER2-positive, 97.6% triple negative. Regimens administered: 9.1% CMF-like, 48.8% anthracyclines, 38.4% anthracyclines plus taxanes, 3.7% taxanes alone. Increasing pT/pN and, marginally, HER2-positive were associated with the prescription of anthracyclines plus taxanes. Suboptimal schedules (CMF-like or AC/EC or FEC-75) were prescribed in 37.3% receiving chemotherapy, even in HER2-positive and triple negative disease (36.5% and 34.0%, respectively).ConclusionsThis study showed an overprescription of adjuvant chemotherapy for early breast cancer, particularly referred to luminal A. pT, pN and, marginally, HER2 were the principal determinants for the choice of chemotherapy type. Suboptimal chemotherapy regimens were adopted in at least one third of HER2-positve and triple negative.

Abstract P1-11-20: Open-Label Phase II Study of Neoadjuvant Bevacizumab Combined with FEC→Paclitaxel in Patients with Inflammatory or Locally Advanced Breast Cancer

Background: There is strong evidence that VEGF plays an important role in the pathogenesis and progression of human breast cancer. Bevacizumab, a monoclonal antibody, specifically inhibits VEGF. The combination of first-line bevacizumab with chemotherapy significantly improved the activity in comparison to chemotherapy alone in three randomized phase III trials in metastatic breast cancer patients (pts). In early breast cancer, the FEC→Paclitaxel regimen is a highly active standard therapy. Therefore we initiated a trial to evaluate the combination of bevacizumab with this efficacious chemotherapy regimen for the treatment of stage III or inflammatory early breast cancer (LABC). Patients and Methods: The study is designed to evaluate a sequential regimen of FEC90 followed by the combination of paclitaxel and bevacizumab as neoadjuvant therapy in patients with HER2-negative locally advanced (stage III or inflammatory) breast cancer. Patients are treated with neoadjuvant FEC 600/90/600 mg/m2 q21d x 4, followed by paclitaxel 80 mg/m2 weekly x 12 combined with bevacizumab 10 mg/kg q2w x 6. Patients undergo surgery 4 weeks after completing chemotherapy. Pathologic complete response (pCR), the primary endpoint, is defined as no evidence of invasive tumor in the final surgical sample both in the breast and axilla. Secondary endpoints include objective clinical response rate (RR), disease-free interval, overall survival, rate of breast-conserving surgery, and the safety of the regimen. Results: Between Feb 2008 and Dec 2009, 54 pts (mean age of 51±7.5 years) were enrolled into the study. To date, 32 pts have completed neoadjuvant treatment and surgery and are evaluable for response. Baseline characteristics in these 32 patients were as follows: cT3/cT4b: 20 (63%) and/or cN2/cN3: 14 (43%); estrogen receptor (ER) positive: 24 (75%) and 8 (25%) triple-negative (TN), defined as ER negative, progesterone receptor-(PgR-) negative, and HER2 negative. Histological type was ductal carcinoma in 24 patients (75%), lobular carcinoma in 4 (13%), inflammatory breast cancer in 1 (3%), and other in 3 (9%). Mastectomy was performed in 22 patients (69%) and breast-conserving surgery in 10 patients (31%). After neoadjuvant treatment, 8/32 patients (25%) achieved a pCR. Conclusions: This open-label, multicenter, phase II study demonstrated that the FEC→Paclitaxel plus bevacizumab combination is a highly active neoadjuvant treatment for HER2-negative locally advanced breast cancer. A 25% of pCR in this group of pts with high tumor burden, i.e. the LABC, is oneof the most promising chemotherapeutic regimen if confirmed in the final analyis. Results for all 54 pts enrolled will be presented at the meeting. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P1-11-20.

Adjuvant Chemotherapy for the Treatment of HER2-Positive Early Breast Cancer

HER2-positive breast cancer is characterized by high chemosensitivity. Anthracycline-based chemotherapy is recognized as a very effective adjuvant treatment in HER2-positive disease. One of the possible explanations is the co-amplification of TOPO II-alpha and HER2. However, recent data seem to demonstrate that HER2 and TOPO II-alpha seem to be less predictive of anthracycline-based chemotherapy efficacy than chromosome 17 polysomy. Chromosome 17 polysomy is present in 21–40% of breast cancer and for this reason benefit of anthracycline-based chemotherapy seems to be not restricted only to HER2-positive disease. Trastuzumab added to chemotherapy administered for one year is associated with improvement in disease-free survival and sometimes in overall survival compared to chemotherapy alone. Efficacy of trastuzumab in the adjuvant setting seems to be increased if administered concomitantly with chemotherapy instead of sequentially. However, the interpretation of longer follow-up results is difficult because of a large crossover from the control arm to trastuzumab.