Robert M. Mader

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.

Do we need HER-2/neu testing for all patients with primary breast carcinoma?

HER‐2/neu is a valuable prognostic marker in primary breast carcinoma. Controversy surrounds the correlation between HER‐2/neu expression and other prognostic markers, as has been discussed in preclinical and clinical studies. The objective of the current study was to investigate the probability, calculated using parameters that are assessed routinely in clinical practice, that patients with breast carcinoma had positive HER‐2/neu status.

Resistance to 5-Fluorouracil

1. Primary and secondary resistance to the widely used antimetabolite 5-fluorouracil (5-FU) are common phenomena in cancer chemotherapy. Because 5-FU still remains the agent of choice in the treatment of, for example, colorectal cancer, circumvention of resistance is of vital importance. 2. Resistance to fluoropyrimidines is a multifactorial event, which includes transport mechanisms, metabolism, molecular mechanisms, protection from apoptosis, and resistance via cell cycle kinetics. To date, the prediction of primary resistance to 5-FU in the clinic is limited to few studies focusing mainly on the key enzyme thymidylate synthase. To gain a deeper insight into the key events responsible for 5-FU resistance in vivo, the evaluation of additional parameters such as other (fluoro)pyrimidine converting enzymes, the mutational status of regulators of apoptosis, and tumour angiogenesis is currently under investigation. 3. Most studies on the circumvention of fluoropyrimidine resistance refer to preclinical investigations and were rarely confirmed in clinical trials. Although our understanding of resistance to 5-FU leaves many open questions, the fundamental insights accomplished during the last years provide a rational understanding to exceed the bounds of the actual therapeutic schedules.

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.

Application of HPLC-ICP-MS to speciation of cisplatin and its degradation products in water containing different chloride concentrations and in human urine

Cisplatin, mono- and diaquacisplatin were measured in aquatic samples and in diluted urine of a cancer patient by HPLC-ICP-MS. On-line IDMS was applied for accurate, species unspecific quantification. Limits of detection of 0.74, 0.69 and 0.65 µg L−1 (3 s criterion) were calculated for cisplatin, monoaqua- and diaquacisplatin, respectively. Degradation kinetics of 6 × 10−6 M cisplatin were determined over a period of 48 h in solutions containing 100, 50 and 0 mg L−1 chloride, showing the suitability of the HPLC-ICP-MS method for kinetic model studies. The first order rate constants k1 of cisplatin aquation for the three chloride concentrations were 1.79 × 10−5, 1.68 × 10−5 and 2.06 × 10−5 s−1. For cisplatin anatation (second order reverse reaction), rate constants of k−1 = 6.5 × 10−3, 5.8 × 10−3 and 4.1 × 10−3 M−1 s−1 could be assessed. At low chloride levels, no equilibrium was established between cisplatin and its degradation products. It was found that the intermediately formed mono- and diaquacisplatin-products started to decay after several hours. Diluted urine of a cancer patient contained the parent drug cisplatin and a considerable fraction of highly active monoaquacisplatin, as well as several unknown platinum species.

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.

Prognostic markers in breast cancer: the reliability of HER2/neu status in core needle biopsy of 325 patients with primary breast cancer

ZusammenfassungHintergrundDie Bestimmung einer HER2/neu-Überexpression im Gewebe eines Mammakarzinoms gibt Aufschluss über einen wichtigen prognostischen und prädiktiven Marker. Eine Überexpression von HER2/neu ist beim Mammakarzinom mit einer schlechten Prognose assoziiert. Da die Nadelbiopsie zunehmend in der Diagnostik des Mammakarzinoms angewandt wird, war es unser Ziel die Zuverlässigkeit der HER2/neu-Bestimmung in der Nadelbiopsie bei Patientinnen mit primärem Mammakarzinom zu evaluieren.Patienten und MethodenWir untersuchten an 325 Patientinnen mit primärem Mammakarzinom die Genauigkeit der immunhistochemischen HER2/neu-Bestimmung in der Nadelbiopsie verglichen mit dem Operationspräparat. Bei Patientinnen mit stark positivem HER2/neu Status wurde zusätzlich eine Fluoreszenz in situ Hybridisierung (FISH) der Nadelbiopsie durchgeführt.ErgebnisseDie Genauigkeit der HER2/neu-Bestimmung in der Nadelbiopsie verglichen mit dem Operationspräparat durch Immunhistochemie alleine war 92% und konnte durch zusätzliche FISH Analyse auf 96% und werden (gewichteter Kappa Koeffizient: 0,86).DiskussionWir konnten an diesem großen Patientenkollektiv zeigen, dass die Bestimmung von HER2/neu in der Nadelbiopsie beim Mammakarzinom verlässlich ist. Bei immunhistochemisch stark positivem HER2/neu Status in der Nadelbiopsie sollte dies durch FISH überprüft werden, um die Zahl der falsch positiven Ergebnisse zu minimieren.SummaryIntroductionThe assessment of HER2/neu overexpression in tissue provides information about one of the most relevant prognostic and predictive markers in breast cancer: overexpression of HER2/neu is associated with worse prognosis in primary breast cancer. Since core needle biopsy is increasingly used for the diagnosis of breast cancer, the purpose of this study was to assess the reliability of HER2/neu evaluation using this technique in patients with primary breast cancer.Patients and methodsWe investigated the accuracy of immunohistochemical assessment of HER2/neu in core needle biopsies compared with surgically obtained specimens in 325 patients with primary breast cancer. In patients strongly positive for HER2/neu, additional fluorescence in situ hybridization (FISH) analysis of needle biopsies was performed.ResultsUsing immunohistochemistry alone, accuracy of HER2/neu assessment in core biopsies in relation to surgically removed specimens was 92% and increased to 96% with additional FISH analysis (weighted Kappa coefficient: 0.86).DiscussionAs proven with this large series of patients, the assessment of HER2/neu status by core needle biopsy in breast cancer is accurate. Notwithstanding, in order to minimize the number of false-positive results, strongly positive core needle biopsies identified using immunohistochemistry should be confirmed by FISH analysis.

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.

Influence of neoadjuvant therapy with epirubicin and docetaxel on the expression of HER2/neu in patients with breast cancer.

AbstractBackground. In primary breast cancer, the expression levels of biological markers relevant to the progression of the disease may be altered by administration of anticancer drugs. Since neoadjuvant chemotherapy with epirubicin and docetaxel is increasingly used in advanced breast cancer, our purpose was to assess the influence of this neoadjuvant chemotherapy on the expression of the growth factor receptor HER2/neu. Patients and methods. We investigated changes of HER2/neu status by immunohistochemistry (IHC) and applied additional fluorescence in situ hybridization (FISH) in patients with potential modulation of HER2/neu status after administration of neoadjuvant chemotherapy with docetaxel and epirubicin in 97 breast cancer patients. The influence of neoadjuvant chemotherapy on HER2/neu expression was calculated by correlation of HER2/neu status before and after chemotherapy. Results. The accuracy of HER2/neu assessment before and after neoadjuvant chemotherapy by IHC combined with FISH analysis in selected cases was 100%. The evaluation of HER2/neu status in these patients by IHC alone yielded accuracy of 93%. Neoadjuvant chemotherapy with epirubicin and docetaxel caused no significant modulation of HER2/neu status (p = 0.66). Discussion. The administration of epirubicin and docetaxel in the neoadjuvant setting is not associated with significant changes of HER2/neu status in primary breast cancer. As a consequence, drug resistance or sensitivity is not induced by modulation of HER2/neu expression. Moreover, the time of assessment of the HER2/neu status is not a critical factor under neoadjuvant therapy with epirubicin and docetaxel.

Quantification of cisplatin, carboplatin and oxaliplatin in spiked human plasma samples by ICP-SFMS and hydrophilic interaction liquid chromatography (HILIC) combined with ICP-MS detection

Therapeutic drug monitoring addresses the determination of the free and intact drug in patient blood. The free fraction of cancerostatic platinum compounds (CPC) is determined by measurement of total platinum levels in plasma ultrafiltrate. In this work, as a starting point, the distribution of cisplatin, carboplatin and oxaliplatin among different blood compartments, i.e. whole blood, plasma, residue (pellet fraction), plasma-ultrafiltrate and protein-residue fraction, was assessed in an ex vivo experiment via ICP-SFMS measurement of total platinum after microwave digestion. The results clearly showed that the distribution is independent of the initial concentration but dependent on the used drug. The platinum in the plasma-ultrafiltrate amounted to 16.8 ± 1.3%, 56.8 ± 0.1% and 10.4 ± 1.0% for cisplatin, carboplatin and oxaliplatin, respectively. Acetonitrile precipitation of plasma samples delivered corresponding results simplifying and accelerating (5 min vs. 150 min for plasma ultrafiltration and total digestion) sample preparation. This method could be ideally combined with a novel speciation analytical approach using hydrophilic interaction liquid chromatography (HILIC) with ICP-QMS detection. A comparison of the total platinum levels to species selective results revealed that 88.0 ± 12.0% of cisplatin and 106.4 ± 7.7% of carboplatin were present as parent drug, whereas only 34.3 ± 0.4% of oxaliplatin were present in the intact state.