Alois Lang

2-18fluoro-deoxy-D-glucose Positron Emission Tomography Is a Reliable Predictor for Viable Tumor in Postchemotherapy Seminoma: An Update of the Prospective Multicentric SEMPET Trial

PURPOSEnTo define the clinical value of 2-18fluoro-deoxy-D-glucose positron emission tomography (FDG PET) as a predictor for viable residual tumor in postchemotherapy seminoma residuals in a prospective multicentric trial.nnnPATIENTS AND METHODSnFDG PET studies in patients with metastatic pure seminoma who had radiographically defined postchemotherapy residual masses were correlated with either the histology of the resected lesion or the clinical outcome documented by computer tomography (CT), tumor markers, and/or physical examination during follow-up. The size of the residual lesions on CT, either >3 cm or < or =3 cm, was correlated with the presence or absence of viable residual tumor.nnnRESULTSnFifty-six FDG PET scans of 51 patients were assessable. All 19 cases with residual lesions >3 cm and 35 (95%) of 37 with residual lesions < or =3 cm were correctly predicted by FDG PET. The specificity, sensitivity, positive predictive value, and negative predictive value of FDG PET were 100% (95% CI, 92% to 100%), 80% (95% CI, 44% to 95%), 100%, and 96%, respectively, versus 74% (95% CI, 58% to 85%), 70% (95% CI, 34% to 90%), 37%, and 92%, respectively, for CT discrimination of the residual tumor by size (>3 cm/< or =3 cm).nnnCONCLUSIONnThis investigation confirms that FDG PET is the best predictor of viable residual tumor in postchemotherapy seminoma residuals and should be used as a standard tool for clinical decision making in this patient group.

BRCA1‐related breast cancer in Austrian breast and ovarian cancer families: Specific BRCA1 mutations and pathological characteristics

We identified 17 BRCA1mutations in 86 Austrian breast and ovarian cancer families (20%) that were screened for mutations by denaturing high‐performance liquid chromatography (DHPLC) and the protein<0B> <0R>truncation test (PTT). Eleven distinct mutations were detected, 4 of them (962del4, 2795del4, 3135del4 and L3376stop) not previously reported in families of non‐Austrian origin. In addition, 6 rare missense mutations (allele frequency < 1%) with unknown biological effects were identified. Four mutations occurred more than once in the Austrian population: 2795del4 (3 times), Cys61Gly (3 times) 5382insC (2 times) and Q1806stop (2 times). Haplotype analysis of the 4 recurrent mutations suggested a common ancestor for each of these. Thirty‐four breast cancer cases from 17 families with BRCA1 mutations were further analyzed. We observed a low median age of onset (39.5 years). Sixty‐eight percent of all BRCA1 breast cancer cases had negative axillary lymph nodes. This group showed a significant prevalence of a negative estrogen and progesterone receptor status and stage I tumors compared with an age‐related, node‐negative control group. The prevalence of grade III tumors was marginally significant . Survival analysis either with a control group matched for age (within 5 years), grade, histologic subtype and estrogen receptor status, or with an age‐related, node‐negative comparison group, showed no statistical difference. Int. J. Cancer 77:354–360, 1998.

Pathologic Complete Response With Six Compared With Three Cycles of Neoadjuvant Epirubicin Plus Docetaxel and Granulocyte Colony-Stimulating Factor in Operable Breast Cancer: Results of ABCSG-14

PURPOSEnPreoperative (neoadjuvant) chemotherapy for operable breast cancer downstages tumors initially not suitable for breast-conserving surgery. A pathologic complete response (pCR) to neoadjuvant chemotherapy may be a surrogate for longer overall survival, but this beneficial effect remains to be established. This phase III trial evaluated whether doubling the number of cycles of neoadjuvant treatment increased the pCR rate.nnnPATIENTS AND METHODSnPatients with biopsy-proven breast cancer (T1-4a-c, N+/-, M0; stage I to III) were eligible and randomly assigned to either three or six cycles of epirubicin 75 mg/m2 and docetaxel 75 mg/m2 on day 1 and granulocyte colony-stimulating factor on days 3 through 10 (ED+G), every 21 days. The primary end point was the pCR rate of the breast tumor. Secondary end points were pathologic nodal status after surgery and the rate of breast-conserving surgery.nnnRESULTSnA total of 292 patients were accrued, and 288 patients were assessable for efficacy and safety. Groups were well balanced for known prognostic factors. Six cycles of ED+G, compared with three cycles, resulted in a significantly higher pCR rate (18.6% v 7.7%, respectively; P = .0045), a higher percentage of patients with negative axillary status (56.6% v 42.8%, respectively; P = .02), and a trend towards more breast-conserving surgery (75.9% v 66.9%, respectively; P = .10). Rates of adverse events were similar, and no patients died on treatment.nnnCONCLUSIONnDoubling the number of neoadjuvant ED+G cycles from three to six results in higher rates of pCR and negative axillary nodal status with no excess of adverse effects. Thus, six cycles of ED+G should be the standard neoadjuvant treatment for operable breast cancer if this combination is chosen.

CYP2D6 Metabolism and Patient Outcome in the Austrian Breast and Colorectal Cancer Study Group Trial (ABCSG) 8

Purpose: Controversy exists about CYP2D6 genotype and tamoxifen efficacy. Experimental Design: A matched case–control study was conducted using the Austrian Breast and Colorectal Cancer Study Group Trial 8 (ABCSG8) that randomized postmenopausal women with estrogen receptor (ER)-positive breast cancer to tamoxifen for 5 years (arm A) or tamoxifen for 2 years followed by anastrozole for 3 years (arm B). Cases had disease recurrence, contralateral breast cancer, second non–breast cancer, or died. For each case, controls were identified from the same treatment arm of similar age, surgery/radiation, and tumor–node—metastasis (TNM) stage. Genotyping was conducted for alleles associated with no (PM; *3, *4, *6), reduced (IM; *10, and *41), and extensive (EM: absence of these alleles) CYP2D6 metabolism. Results: The common CYP2D6*4 allele was in Hardy–Weinberg equilibrium. In arm A during the first 5 years of therapy, women with two poor alleles [PM/PM: OR, 2.45; 95% confidence interval (CI), 1.05–5.73, P = 0.04] and women with one poor allele (PM/IM or PM/EM: OR, 1.67; 95% CI, 0.95–2.93; P = 0.07) had a higher likelihood of an event than women with two extensive alleles (EM/EM). In years 3 to 5 when patients remained on tamoxifen (arm A) or switched to anastrozole (arm B), PM/PM tended toward a higher likelihood of a disease event relative to EM/EM (OR, 2.40; 95% CI, 0.86–6.66; P = 0.09) among women on arm A but not among women on arm B (OR, 0.28; 95% CI, 0.03–2.30). Conclusion: In ABCSG8, the negative effects of reduced CYP2D6 metabolism were observed only during the period of tamoxifen administration and not after switching to anastrozole. Clin Cancer Res; 19(2); 500–7. ©2012 AACR.

Azacitidine in 302 patients with WHO-defined acute myeloid leukemia: results from the Austrian Azacitidine Registry of the AGMT-Study Group

Data on efficacy and safety of azacitidine in acute myeloid leukemia (AML) with >30xa0% bone marrow (BM) blasts are limited, and the drug can only be used off-label in these patients. We previously reported on the efficacy and safety of azacitidine in 155 AML patients treated within the Austrian Azacitidine Registry (clinicaltrials.gov identifier NCT01595295). We herein update this report with a population almost twice as large (nu2009=u2009302). This cohort included 172 patients with >30xa0% BM blasts; 93xa0% would have been excluded from the pivotal AZA-001 trial (which led to European Medicines Agency (EMA) approval of azacitidine for high-risk myelodysplastic syndromes (MDS) and AML with 20–30xa0% BM blasts). Despite this much more unfavorable profile, results are encouraging: overall response rate was 48xa0% in the total cohort and 72xa0% in patients evaluable according to MDS-IWG-2006 response criteria, respectively. Median OS was 9.6 (95xa0% CI 8.53–10.7)u2009months. A clinically relevant OS benefit was observed with any form of disease stabilization (marrow stable disease (8.1xa0months), hematologic improvement (HI) (9.7xa0months), or the combination thereof (18.9xa0months)), as compared to patients without response and/or without disease stabilization (3.2xa0months). Age, white blood cell count, and BM blast count at start of therapy did not influence OS. The baseline factors LDH >225xa0U/l, ECOG ≥2, comorbidities ≥3, monosomal karyotype, and prior disease-modifying drugs, as well as the response-related factors hematologic improvement and further deepening of response after first response, were significant independent predictors of OS in multivariate analysis. Azacitidine seems effective in WHO-AML, including patients with >30xa0% BM blasts (currently off-label use). Although currently not regarded as standard form of response assessment in AML, disease stabilization and/or HI should be considered sufficient response to continue treatment with azacitidine.

Epirubicin and docetaxel with or without capecitabine as neoadjuvant treatment for early breast cancer: final results of a randomized phase III study (ABCSG-24)

BACKGROUNDnThis randomized phase III trial compared pathologic complete response (pCR) rates of early breast cancer (EBC) following neoadjuvant epirubicin-docetaxel (ED)±capecitabine (C), and evaluated the addition of trastuzumab in HER2-positive tumors.nnnPATIENTS AND METHODSnPatients with invasive breast cancer (except T4d) were randomly assigned to receive six 3-weekly cycles of ED (both 75 mg/m2)±C (1000 mg/m2, twice daily, days 1-14). Patients with HER2-positive disease were further randomized to receive trastuzumab (8 mg/kg, then 6 mg/kg every 3 weeks) or not. Primary end point: pCR rate at the time of surgery.nnnRESULTSnFive hundred thirty-six patients were randomized to ED (n=266) or EDC (n=270); 93 patients were further randomized to trastuzumab (n=44) or not (n=49). pCR rate was significantly increased with EDC (23.0% versus 15.4% ED, P=0.027), and nonsignificantly further increased with trastuzumab (38.6% EDC versus 26.5% ED, P=0.212). Rates of axillary node involvement at surgery and breast conservation were improved with EDC versus ED, but not significantly; the addition of trastuzumab had no further impact. Hormone receptor status, tumor size, grade, and C (all P≤0.035) were independent prognostic factors for pCR. Trastuzumab added to ED±C significantly increased the number of serious adverse events (35 versus 18; P=0.020), mainly due to infusion-related reactions.nnnCONCLUSIONnThese findings show that the integration of C into a neoadjuvant taxane-/anthracycline-based regimen is a feasible, safe, and effective treatment option, with incorporation of trastuzumab in HER2-positive disease.nnnCLINICAL TRIAL NUMBERnNCT00309556, www.clinicaltrials.gov.

Phenotypic and functional deficiencies of leukaemic dendritic cells from patients with chronic myeloid leukaemia.

Summary. Chronic myeloid leukaemia (CML) dendritic cells (DC) are possible candidates for inducing antileukaemic immunity. This study aimed to investigate the frequency, phenotype and function of blood‐derived leukaemic DC in comparison with DC from healthy donors using flow cytometric assays and mixed leucocyte reaction (MLR). Immature leukaemic DC displayed a reduced endocytotic capacity as compared with healthy controls. Moreover, in vitro maturation of leukaemic DC was found to be deficient. Expression of CD80, CD83, CD86, and major histocompatibility complex class I and class II antigens were reduced on lipopolysaccharide (LPS)‐matured leukaemic DC but were enhanced by a mixture of interleukin 1β (IL‐1β), IL‐6, tumour necrosis factor‐α (TNF‐α) and prostaglandin E2 (PGE2). Upon stimulation with bacterial LPS, intracellular TNF‐α and IL‐8 production was diminished in maturing DC from CML patients. This distinct cytokine deficiency was overcome when leukaemic DC were stimulated with cytokines/PGE2. MLR showed fully functional leukaemic DC after TNF‐α‐induced maturation, but a reduced proliferative alloresponse of leukaemic peripheral blood mononuclear cells. Further, intracellular production of cytokines in CML‐derived T cells was markedly reduced. These data indicated that, in CML, the maturation response of leukaemic monocyte‐derived DC to a natural stimulus like LPS is abnormal and may be caused by an aberrant TNF‐α response in these cells. Thus, TNF‐α alone or in combination with pro‐inflammatory and T‐cell stimulatory cytokines should be considered as an adjuvant for DC‐based immunotherapy in CML.

Invasive ductal carcinoma and invasive lobular carcinoma of breast differ in response following neoadjuvant therapy with epidoxorubicin and docetaxel + G-CSF

PurposePreoperative chemotherapy in patients with primary breast cancer treated with anthracyclines and taxanes results in high response rates, allowing breast conserving surgery (BCS) in patients primarily not suitable for this procedure. Pathological responses are important prognostic parameters for progression free and overall survival. We questioned the impact of histologic type invasive ductal carcinoma (IDC) versus invasive lobular carcinoma (ILC) on response to primary chemotherapy.Patients and Methods161 patients with breast cancer received preoperative chemotherapy consisted of epidoxorubicin 75xa0mg/m2 and docetaxel 75xa0mg/m2 administered in combination with granulocyte-colony stimulating factor (G-CSF) on days 3–10 (EDxa0+xa0G). Pathological complete response (pCR), biological markers and type of surgery as well as progression free and overall survival were compared between IDC and ILC.ResultsOut of 161 patients, 124 patients presented with IDC and 37 with ILC. Patients with ILC were less likely to have a pCR (3% vs. 20%, Pxa0<xa00.009) and breast conserving surgeries (51% vs. 79%, Pxa0<xa00.001). Patients with ILC tended to have oestrogen receptor positive tumors (86% vs. 52%, Pxa0<xa00.0001), HER 2 negative tumors (69% vs. 84%), and lower nuclear grade (nuclear grade 3, 16% vs. 46%, Pxa0<xa00.001). Patients with ILC tended to have longer time to progression (TTP) (42xa0months vs. 26xa0months) and overall survival (69xa0months vs. 65xa0months).ConclusionsOur results indicate that patients with ILC achieved a lower pCR rate and ineligibility for BCS to preoperative chemotherapy, but this did not result in a survival disadvantage. Because of these results new strategies to achieve a pCR are warranted.

Long‐term follow‐up of patients with hairy cell leukaemia treated with pentostatin: lymphocyte subpopulations and residual bone marrow infiltration

Summary. Peripheral blood lymphocyte (PBL) subsets and bone marrow biopsies were analysed in six patients with hairy cell leukaemia (HCL) treated with 2′‐deoxycoformycin (pentostatin, DCF) according to a phase II trial of the EORTC Leukemia Cooperative Group. All patients responded to DCF with four complete and two partial remissions according to conventional criteria.

Azacitidine in CMML: Matched-pair analyses of daily-life patients reveal modest effects on clinical course and survival

Recent data suggest that azacitidine may be beneficial in CMML. We report on 48 CMML-patients treated with azacitidine. Overall response rates were high (70% according to IWG-criteria, including 22% complete responses). Monocyte count and cytogenetics adversely affected survival, whereas age, WHO-type, FAB-type, and spleen size did not. Matched-pair analyses revealed a trend for higher two-year-survival for azacitidine as compared to best supportive care (62% vs. 41%, p=0.067) and longer OS for azacitidine first-line vs. hydroxyurea first-line (p=0.072, median OS 27.7 vs. 6.2 months). This report reinforces existing evidence that azacitidine is safe and efficacious in both myelodysplastic and myeloproliferative CMML.