Ursula Pluschnig

Capecitabine and Trastuzumab in Heavily Pretreated Metastatic Breast Cancer

PURPOSE In human epidermal growth factor 2 (HER-2)-positive advanced breast cancer, taxanes or vinorelbine plus trastuzumab are among the most widely applied options in the first-line setting. We evaluated the efficacy and tolerability of capecitabine plus trastuzumab after anthracycline and docetaxel or vinorelbine failure and prior trastuzumab exposure. PATIENTS AND METHODS Forty consecutive patients were included. Capecitabine was administered at a dose of 1,250 mg/m(2) bid for 14 consecutive days in 3-week cycles, with dose modifications if necessary. Trastuzumab was administered every 3 weeks. Time to progression (TTP) was defined as primary end point. Response was evaluated every 3 months using International Union Against Cancer criteria. RESULTS TTP was a median of 8 months, and overall survival was 24 months. No significant difference was found for second-line and beyond second-line treatment. A complete response (CR) was observed in 2.5%, partial response (PR) in 17.5%, stable disease lasting at least 6 months (SD) in 50%, resulting in a clinical benefit rate (CR + PR + SD > or = 6 months) of 70%. Diarrhea (5%) and hand-foot syndrome (15%) were the only treatment-related adverse events that occurred with grade 3 or 4 intensity. Three patients (7.5%) developed brain metastases while receiving therapy. CONCLUSION Capecitabine plus trastuzumab appears to be an effective and safe option in a heavily pretreated population. Therefore, a direct comparison of this regimen with capecitabine monotherapy in this setting is warranted.

A combined high temporal and high spatial resolution 3 Tesla MR imaging protocol for the assessment of breast lesions: initial results.

Purpose:To develop a 3.0 Tesla breast imaging protocol that combines high temporal and spatial resolution three-dimensional MR sequences for quantitative time course and morphologic analysis of breast lesions. Materials and Methods:Thirty-four patients were included in the study (age range, 31–82; mean age, 54.3). The study protocol was approved by the Institutional Review Board and written informed consent was obtained from all patients. The magnetic resonance imaging protocol included: a coronal T1-weighted volume-interpolated-breathhold-examination sequence, focused on high temporal resolution for optimal assessment of the contrast-enhancement behavior of lesions (SI 1.7 mm isotropic; TA 3.45 minutes for 17 measurements); a coronal T1-weighted turbo fast-low-angle-shot-three-dimensional sequence, with water-excitation and fat suppression, focused on high spatial resolution for morphologic analysis (SI 1 mm isotropic; TA 2 minutes); and a repeated coronal volume-interpolated-breathhold-examination sequence for detection of washout. Lesion size and morphology were assessed. Region-of-interests for suspicious areas were manually drawn and evaluated for contrast-enhancement behavior by plotting intensity courses against time. Sensitivity and specificity with a 95% confidence interval and the negative predictive value and positive predictive value were calculated. Diagnostic accuracy was assessed. The histopathological diagnoses were used as a standard of reference. Results:Fifty-five lesions were detected in 34 patients. All malignant breast lesions were identified correctly. There were 5 false-positive lesions. The sensitivity of contrast-enhanced magnetic resonance imaging of the breast at 3 T was 100%, with a 95% confidence interval (CI) of 90.6% to 100%. The specificity was 72.2%, with a 95% CI of 49.1% to 87.5%. The positive predictive value was 0.88 and the negative predictive value was 1. Diagnostic accuracy was 91% with a 95% CI of 80.4% to 96.1%. Conclusion:Our prospective study demonstrates that the presented 3 Tesla MR imaging protocol, comprising both high temporal and high spatial resolution, enables accurate detection and assessment of breast lesions.

Analysis of trastuzumab and chemotherapy in advanced breast cancer after the failure of at least one earlier combination: An observational study

BackgroundCombining trastuzumab and chemotherapy is standard in her2/neu overexpressing advanced breast cancer. It is not established however, whether trastuzumab treatment should continue after the failure of one earlier combination. In this trial, we report our experience with continued treatment beyond disease progression.MethodsFifty-four patients, median age 46 years, range 25–73 years, were included. We analysed for time to tumour progression (TTP) for first, second and beyond second line treatment, response rates and overall survival.ResultsMedian time of observation was 24 months, range 7–51. Response rates for first line treatment were 7.4% complete remission (CR), 35.2% partial remissions (PR), 42.6% stable disease > 6 months (SD) and 14.8% of patients experienced disease progression despite treatment (PD). Corresponding numbers for second line were 3.7% CR, 22.2% PR, 42.6% SD and 31.5% PD; numbers for treatment beyond second line (60 therapies, 33 pts 3rd line, 18 pts 4th line, 6 pts 5th line, 2 pts 6th line and 1 patient 7th line) were 1.7% CR, 28.3% PR, 28.3% SD and 41.6% PD respectively. Median TTP was 6 months (m) in the first line setting, and also 6 m for second line and beyond second line. An asymptomatic drop of left ventricular ejection fraction below 50% was observed in one patient. No case of symptomatic congestive heart failure was observed.ConclusionThe data presented clearly strengthen evidence that patients do profit from continued trastuzumab treatment. The fact that TTP did not decrease significantly from first line to beyond second line treatment is especially noteworthy. Still, randomized trials are warranted.

Impact of anti-HER2 therapy on overall survival in HER2-overexpressing breast cancer patients with brain metastases

Background:Trastuzumab-based therapy after diagnosis of brain metastases (BM) may improve survival due to prolonged systemic disease control. We investigated whether lapatinib may yield additional survival benefit.Methods:Eighty patients with BM from HER2-positive breast cancer were identified. Karnofsky Performance Score (KPS) of at least 70 was required. We included a control group of 37 patients treated before 2003, when continuation of trastuzumab after diagnosis of BM was not yet recommended. Remainders received either trastuzumab or lapatinib and trastuzumab (either concomitantly or sequentially) with or without chemotherapy.Results:Median overall survival (OS) in patients receiving trastuzumab after diagnosis of BM was 13 months; corresponding numbers were 9 months in patients treated with chemotherapy, and 3 months with radiotherapy alone. Median OS was not reached in the lapatinib group. Addition of lapatinib prolonged OS over trastuzumab alone (P=0.002). After correction for potential confounders, lapatinib therapy remained an independent positive predictor for survival (HR 0.279; P=0.012).Interpretation:This retrospective single-centre study suggests that the introduction of lapatinib improved survival in patients with BM from HER2-positive breast cancer. Patients with KPS ⩾70 may benefit when treated with lapatinib in addition to trastuzumab after completion of local therapy.

Brain metastases free survival differs between breast cancer subtypes

Background:Brain metastases (BM) are frequently diagnosed in patients with HER-2-positive metastatic breast cancer; in addition, an increasing incidence was reported for triple-negative tumours. We aimed to compare brain metastases free survival (BMFS) of breast cancer subtypes in patients treated between 1996 until 2010.Methods:Brain metastases free survival was measured as the interval from diagnosis of extracranial breast cancer metastases until diagnosis of BM. HER-2 status was analysed by immunohistochemistry and reanalysed by fluorescent in situ hybridisation if a score of 2+ was gained. Oestrogen-receptor (ER) and progesterone-receptor (PgR) status was analysed by immunohistochemistry. Brain metastases free survival curves were estimated with the Kaplan–Meier method and compared with the log-rank test.Results:Data of 213 patients (46 luminal/124 HER-2/43 triple-negative subtype) with BM from breast cancer were available for the analysis. Brain metastases free survival differed significantly between breast cancer subtypes. Median BMFS in triple-negative tumours was 14 months (95% CI: 11.34–16.66) compared with 18 months (95% CI: 14.46–21.54) in HER-2-positive tumours (P=0.001) and 34 months (95% CI: 23.71–44.29) in luminal tumours (P=0.001), respectively. In HER-2-positive patients, co-positivity for ER and HER-2 prolonged BMFS (26 vs 15 m; P=0.033); in luminal tumours, co-expression of ER and PgR was not significantly associated with BMFS. Brain metastases free survival in patients with lung metastases was significantly shorter (17 vs 21 months; P=0.014).Conclusion:Brain metastases free survival in triple-negative breast cancer, as well as in HER-2-positive/ER-negative, is significantly shorter compared with HER-2/ER co-positive or luminal tumours, mirroring the aggressiveness of these breast cancer subtypes.

Ovarian function suppression and fulvestrant as endocrine therapy in premenopausal women with metastatic breast cancer

BACKGROUND Endocrine therapy is the preferred treatment for hormone-receptor (HR) positive metastatic breast cancer. In premenopausal patients, ovarian function suppression with goserelin in combination with anastrozole yielded promising results in phase II studies. Fulvestrant, a pure antioestrogen, yields high rates of disease stabilisation in postmenopausal women. Therefore, we investigated the feasibility and safety of fulvestrant plus goserelin in premenopausal women with HR-positive metastatic breast cancer. METHODS Premenopausal patients with metastatic breast cancer eligible for endocrine treatment received fulvestrant 250 mg and goserelin 3.6 mg every four weeks as first- to fourth-line therapy. Clinical benefit rate (CBR; response rate plus disease stabilisation ≥ 6 months) was defined as the primary study end-point. Time to progression (TTP) and overall survival (OS) were estimated using the Kaplan-Meier product limit method. FINDINGS Twenty-six patients received treatment as scheduled. 81% were pre-treated with tamoxifen and 69% had received prior aromatase inhibitors in combination with goserelin. The majority of patients (69%) presented with visceral metastases. Complete response was observed in a single patient, partial response in three and disease stabilisation ≥ 6 months in eleven patients, resulting in a CBR of 58%. Median TTP was 6 months (95%confidence interval (CI), 2.4-9.6) and OS 32 months (95%CI, 14.28-49.72), respectively. INTERPRETATION Results suggest that the combination of fulvestrant and goserelin offers promising activity in premenopausal patients and further investigation is warranted.

The biomarker TP53 divides patients with neoadjuvantly treated esophageal cancer into 2 subgroups with markedly different outcomes. A p53 Research Group study

BACKGROUND Fluorouracil and cisplatin have been used most frequently as neoadjuvant therapy for esophageal cancer. Both drugs are believed to act via a p53-dependent apoptosis pathway. The TP53 gene is frequently mutated in esophageal cancer. OBJECTIVE To test the value of TP53 as a biomarker prognosing outcome in patients with neoadjuvantly treated esophageal cancer. PATIENTS AND METHODS The investigation included 36 patients with primary operable esophageal cancer who were treated neoadjuvantly with cisplatin and fluorouracil. The TP53 genotype was assessed from paraffin-embedded diagnostic tumor biopsies using a standardized gene-specific TP53 sequencing protocol (mark53 kit; mark53 Ltd, Vienna, Austria). RESULTS Mutations in the TP53 gene were present in 50% of tumors. Two-year overall survival rates were 55.6% in patients with a normal TP53 marker status, compared with 16.7% in those with a mutant TP53 gene. In patients with normal TP53, neoadjuvant treatment resulted in significant advantages in terms of tumor-associated survival (P=.0049) and overall survival (P=.0304) compared with those with mutant TP53. The median tumor-associated survival was 34.2 months for patients with normal TP53, compared with 8.9 months for those with mutant TP53. The latter had a 3-fold higher risk of dying (hazard ratio, 3.01; 95% confidence interval, 1.359-6.86). CONCLUSIONS The biomarker TP53 divides esophageal cancer patients into 2 categories with markedly different outcomes: patients with a normal TP53 marker status may experience notable benefits from neoadjuvant chemotherapy with cisplatin/fluorouracil, whereas those with a mutant TP53 marker status appear to be at risk for lack of response.

Breast-conserving surgery for T3/T4 breast cancer: an analysis of 196 patients

IntroductionBreast conservation therapy (BCT) increases quality of life and self-esteem of breast cancer patients. In special cancer centers up to 90% of patients are treated with BCT. T3/T4 breast cancer is one of the few contraindications for BCT. However, retrospective data suggest that BCT may be eligible in selected cases of T3/T4 breast cancer.MethodWe analyzed retrospectively 196 breast cancer patients (operated between 1995 and 2004) suffering from T3/T4 tumors and compared BCT and radiotherapy with mastectomy in these patients in terms of overall survival (OS), local recurrence free-survival (LRFS) and breast cancer-related death (BCRD).ResultDemographic data showed no significant differences in prognostic factors between patients treated with mastectomy compared with BCT. Kaplan-Meier curves demonstrated no significant difference for OS, LRFS and BCRD between the two groups.DiscussionOur data strongly suggest that BCT with R0 resection followed by radiotherapy is feasible in patients with T3/T4 breast cancer. Prospective studies have to be performed to further investigate this issue.

Her2 and Progesterone Receptor Status Are Not Predictive of Response to Fulvestrant Treatment

Purpose: It has been hypothesized that response to endocrine therapy for breast cancer depends on Her2 and progesterone receptor status, grading, and tumor proliferation rate. In this study, we evaluated factors that are potentially predictive of response and time to progression in patients treated with fulvestrant. Experimental Design: One hundred fifty-five patients were included and followed prospectively. Patients received fulvestrant at standard dose by i.m. injection. Response was evaluated every 3 months using International Union Against Cancer criteria. Time to progression and overall survival were estimated with the Kaplan-Meier product limit method. A multivariate analysis was done to evaluate factors potentially influencing response and time to progression. Results: We observed a partial response in 19 patients (12.3%), stable disease ≥6 months in 56 patients (36.1%), stable disease >3 months but <6 months in 7 patients (4.5%), and progressive disease in 73 patients (47.1%). Median time to progression was 5 months, and median overall survival was 27 months. Probability of achieving clinical benefit was significantly associated with a low proliferation rate (P = 0.015), nonvisceral metastatic sites (P = 0.023), and first-line therapy (P = 0.023). First-line therapy was also associated with prolonged time to progression (P = 0.003). Conclusions: Response rate and time to progression are shown to be independent of Her2 status, grading, and progesterone receptor status. This is probably caused by the unique mechanism of action associated with fulvestrant: Due to receptor down-regulation, it blocks nuclear, cytoplasmatic, and membrane-bound estrogen receptor. Therefore, it seems to inhibit the cross-talk between growth factor receptor signaling and estrogen receptor in a more effective manner.

Plasma HMGB‐1 after the initial dose of epirubicin/docetaxel in cancer

The response of breast cancer patients to neoadjuvant chemotherapy (NCT) is highly heterogeneous, and reliable predictive instruments remain to be defined. High‐mobility group box‐1 (HMGB‐1) protein is a cell death marker, which is easily detectable in plasma. We hypothesized that the initial dose of NCT with epirubicin/docetaxel induces changes in plasma HMGB‐1 which could allow for an early prediction of response to therapy.