Continuing trastuzumab beyond disease progression: outcomes analysis in patients with metastatic breast cancer

INTRODUCTION: We performed a retrospective analysis of HER2-overexpressing metastatic breast cancer patients to describe clinical outcomes of those who, despite progression of the disease (PD), maintained trastuzumab for multiple chemotherapy lines. We also compared survival of these patients with that of those who halted trastuzumab at first PD. METHODS: We identified 101 patients treated between July 2000 and January 2007. Nineteen were still receiving the first-line trastuzumab-based treatment without evidence of PD and were not included in this analysis. Of the remaining 82 patients, 59 retained trastuzumab for one or more additional lines of chemotherapy after PD, according to our institution policy. Twenty-three patients who changed treating institution and stopped trastuzumab at first progression were used as a control group. RESULTS: For patients retaining trastuzumab, the median follow-up was 39.6 months. Clinical outcomes showed the typical degradation between first and second lines of therapy which we would expect by halting trastuzumab at first progression. Response rates were 35\% and 16\% and median times to progression were 7.25 and 5.25 months for the first and second lines of trastuzumab therapy, respectively. The median overall survival (OS) rates were 70 months for patients who retained trastuzumab and 56 months for patients who halted the drug (hazard ratio [HR] 0.87, 95\% confidence interval [CI] 0.51 to 1.18; P = 0.52). If we consider OS from the start of trastuzumab therapy, the figures are 53.9 and 34.8 months, respectively (HR 0.78, 95\% CI 0.58 to 1.32; P = 0.2). CONCLUSION: A nonstatistically significant trend of improved survival for patients retaining trastuzumab is observed. This is in line with most retrospective analyses and recent randomized data. Retaining trastuzumab after progression is a reasonable option, but further randomized data are warranted to better define its role in comparison with other available options.

Extended Adjuvant Endocrine Treatment in Luminal Breast Cancers in the Era of Genomic Tests

In patients with early-stage endocrine receptor-positive (ER+) breast cancer (BC), adjuvant endocrine therapy (ET) for 5 years is the standard of care. However, for some patients, the risk of recurrence remain high for up to 15 years after diagnosis and extended ET beyond 5 years may be a reasonable option. Nevertheless, this strategy significantly increases the occurrence of side effects. Here we summarize the available evidence from randomized clinical trials on the efficacy and safety profile of extended ET and discuss available clinical and genomic tools helpful to select eligible patients in daily clinical practice

Randomised phase 3 open-label trial of first-line treatment with gemcitabine in association with docetaxel or paclitaxel in women with metastatic breast cancer: a comparison of different schedules and treatments

BACKGROUND: This open-label study compared docetaxel/gemcitabine vs. paclitaxel/gemcitabine and a weekly (W) vs. 3-weekly (3 W) schedule in metastatic breast cancer (MBC). METHODS: Patients relapsed after adjuvant/neoadjuvant anthracycline-containing chemotherapy were randomized to: A) gemcitabine 1000 mg/m(2) Day 1,8 + docetaxel 75 mg/m(2) Day 1 q3W; B) gemcitabine 1250 mg/m(2) Day 1,8 + paclitaxel 175 mg/m(2) Day 1 q3W; C) gemcitabine 800 mg/m(2) Day 1,8,15 + docetaxel 30 mg/m(2) Day 1,8,15 q4W; D) gemcitabine 800 mg/m(2) Day 1,15 + paclitaxel 80 mg/m(2) Day 1,8,15 q4W. Primary endpoint was time-to-progression (TTP). Secondary endpoints were overall survival (OS) and overall response rate (ORR). RESULTS: Interim analysis led to accrual interruption (241 patients enrolled of 360 planned). Median TTP (months) was 8.33 (95% CI: 6.19-10.16) with W and 7.51 (95% CI: 5.93-8.33) with 3 W (p=0.319). No differences were observed in median TTP between docetaxel and paclitaxel, with 85.6% and 87.0% of patients progressing, respectively. OS did not differ between regimens/schedules. ORR was comparable between regimens (HR: 0.882; 95% CI: 0.523-1.488; p=0.639), while it was significantly higher in W than in the 3 W (HR: 0.504; 95% CI: 0.299-0.850; p=0.010) schedule. Grade 3/4 toxicities occurred in 69.2% and 71.9% of patients on docetaxel and paclitaxel, and in 65.8% and 75.2% in W and 3 W. CONCLUSIONS: Both treatment regimens showed similar TTP. W might be associated with a better tumour response compared with 3 W. TRIAL REGISTRATION: Clinicaltrial.gov ID NCT0023689

Fluorouracil and dose-dense chemotherapy in adjuvant treatment of patients with early-stage breast cancer: An open-label, 2 × 2 factorial, randomised phase 3 trial

Background: Whether addition of fluorouracil to epirubicin, cyclophosphamide, and paclitaxel (EC-P) is favourable in adjuvant treatment of patients with node-positive breast cancer is controversial, as is the benefit of increased density of dosing. We aimed to address these questions in terms of improvements in disease-free survival. METHODS: In this 2 × 2 factorial, open-label, phase 3 trial, we enrolled patients aged 18-70 years with operable, node positive, early-stage breast cancer from 81 Italian centres. Eligible patients were randomly allocated in a 1:1:1:1 ratio with a centralised, interactive online system to receive either dose-dense chemotherapy (administered intravenously every 2 weeks with pegfilgrastim support) with fluorouracil plus EC-P (FEC-P) or EC-P or to receive standard-interval chemotherapy (administered intravenously every 3 weeks) with FEC-P or EC-P. The primary study endpoint was disease-free survival, assessed with the Kaplan-Meier method in the intention-to-treat population. Our primary comparisons were between dose schedule (every 2 weeks vs every 3 weeks) and dose type (FEC-P vs EC-P). This study is registered with ClinicalTrials.gov, number NCT00433420. FINDINGS: Between April 24, 2003, and July 3, 2006, we recruited 2091 patients. 88 patients were enrolled in centres that only provided standard-intensity dosing. After a median follow-up of 7·0 years (interquartile range [IQR] 4·5-6·3), 140 (26%) of 545 patients given EC-P every 3 weeks, 157 (29%) of 544 patients given FEC-P every 3 weeks, 111 (22%) of 502 patients given EC-P every 2 weeks, and 113 (23%) of 500 patients given FEC-P every 2 weeks had a disease-free survival event. For the dose-density comparison, disease-free survival at 5 years was 81% (95% CI 79-84) in patients treated every 2 weeks and 76% (74-79) in patients treated every 3 weeks (HR 0·77, 95% CI 0·65-0·92; p=0·004); overall survival rates at 5 years were 94% (93-96) and 89% (87-91; HR 0·65, 0·51-0·84; p=0·001) and for the chemotherapy-type comparison, disease-free survival at 5 years was 78% (75-81) in the FEC-P groups and 79% (76-82) in the EC-P groups (HR 1·06, 0·89-1·25; p=0·561); overall survival rates at 5 years were 91% (89-93) and 92% (90-94; 1·16, 0·91-1·46; p=0·234). Compared with 3 week dosing, chemotherapy every 2 weeks was associated with increased rate of grade 3-4 of anaemia (14 [1·4%] of 988 patients vs two [0·2%] of 984 patients; p=0·002); transaminitis (19 [1·9%] vs four [0·4%]; p=0·001), and myalgias (31 [3·1%] vs 16 [1·6%]; p=0·019), and decreased rates of grade 3-4 neutropenia (147 [14·9%] vs 433 [44·0%]; p<0·0001). Addition of fluorouracil led to increased rates of grade 3-4 neutropenia (354 [34·5%] of 1025 patients on FEC-P vs 250 [24·2%] of 1032 patients on EC-P; p<0·0001), fever (nine [0·9%] vs two [0·2%]), nausea (47 [4·6%] vs 28 [2·7%]), and vomiting (32 [3·1%] vs 15 [1·4%]). INTERPRETATION: In patients with node-positive early breast cancer, dose-dense adjuvant chemotherapy improved disease-free survival compared with standard interval chemotherapy. Addition of fluorouracil to a sequential EC-P regimen was not associated with an improved disease-free survival outcome

Efficacy and safety of T-DM1 in the 'common-practice' of HER2+ advanced breast cancer setting: a multicenter study

Ado-trastuzumab emtansine (T-DM1) is an antibody-drug conjugate approved for the treatment of patients with human epidermal growth factor receptor 2 (HER2)-positive, metastatic breast cancer (mBC). The aim of this 'field-practice' study was to investigate the efficacy and safety of T-DM1, focusing on treatment line, previous lapatinib treatment and patterns of metastasis. Three hundred and three patients with HER2-positive mBC who received T-DM1 were identified by reviewing the medical records of 24 Italian Institutions. One hundred fourty-nine (49%) and 264 (87%) had received prior hormonal treatment and/or anti-HER2 targeted therapy, respectively. Particularly, 149 patients had been previously treated with lapatinib. The objective response rate (ORR) was 36.2%, and 44.5% when T-DM1 was administrated as second-line therapy. Considering only patients with liver metastases, the ORR was 44.4%. The median progression-free survival (PFS) was 7.0 months in the overall population, but it reached 9.0 and 12.0 months when TDM-1 was administered as second- and third-line treatment, respectively.In conclusion, in this 'real-word' study evaluating the effects of T-DM1 in patients with HER2-positive mBC who progressed on prior anti-HER2 therapies, we observed a clinically-relevant benefit in those who had received T-DM1 in early metastatic treatment-line and in subjects previously treated with lapatini

Biopsy confirmation of metastatic sites in breast cancer patients:clinical impact and future perspectives

Determination of hormone receptor (estrogen receptor and progesterone receptor) and human epidermal growth factor receptor 2 status in the primary tumor is clinically relevant to define breast cancer subtypes, clinical outcome,and the choice of therapy. Retrospective and prospective studies suggest that there is substantial discordance in receptor status between primary and recurrent breast cancer. Despite this evidence and current recommendations,the acquisition of tissue from metastatic deposits is not routine practice. As a consequence, therapeutic decisions for treatment in the metastatic setting are based on the features of the primary tumor. Reasons for this attitude include the invasiveness of the procedure and the unreliable outcome of biopsy, in particular for biopsies of lesions at complex visceral sites. Improvements in interventional radiology techniques mean that most metastatic sites are now accessible by minimally invasive methods, including surgery. In our opinion, since biopsies are diagnostic and changes in biological features between the primary and secondary tumors can occur, the routine biopsy of metastatic disease needs to be performed. In this review, we discuss the rationale for biopsy of suspected breast cancer metastases, review issues and caveats surrounding discordance of biomarker status between primary and metastatic tumors, and provide insights for deciding when to perform biopsy of suspected metastases and which one (s) to biopsy. We also speculate on the future translational implications for biopsy of suspected metastatic lesions in the context of clinical trials and the establishment of bio-banks of biopsy material taken from metastatic sites. We believe that such bio-banks will be important for exploring mechanisms of metastasis. In the future,advances in targeted therapy will depend on the availability of metastatic tissue

Endocrine therapy in premenopausal women with breast cancer: a critical appraisal of current evidence

Nearly 60% of all breast cancer premenopausal women are diagnosed with a hormone receptor positive tumor and, therefore, are candidates for adjuvant hormonal therapy. Treatment with tamoxifen for at least 5\ua0years has been for a long time the standard of care, as it is associated with overall positive clinical outcomes. However, in the last decade, a number of studies on adjuvant endocrine therapy in premenopausal women with hormone receptor positive breast cancer have been published, adding a bulk of evidence to existing knowledge in this field. A critical appraisal of their results appears necessary in order to put the recently collected data into the current framework of treatment, and to discuss the several issues that remain open. Here, we review the most recent evidence on the following: the optimal duration of tamoxifen treatment, results of the studies comparing tamoxifen alone to tamoxifen plus ovarian function suppression (OFS), results of the studies comparing tamoxifen plus OFS to aromatase inhibitors plus OFS

L'exemestane nel trattamento del carcinoma mammario: recenti acquisizioni.

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