A. De Matteis

The relevance of the CD4+ CD26- subset in the identification of circulating Sézary cells.

Background  The lack of specific markers for the phenotyping of circulating neoplastic T cells in Sézary syndrome (SS) patients makes it difficult both to ascertain the presence of clonal cells and to quantify the tumour burden in the peripheral blood. In previous reports we showed that the lack of CD26 (dipeptidyl‐aminopeptidase IV) is a characteristic feature of circulating Sézary cells (SC).

Prognostic factors in Sézary syndrome: A multivariate analysis of clinical, haematological and immunological features

BACKGROUND Sézary syndrome (SS) prognostic factors are not well defined because of the rarity of this disease. The specific goal of this prospective study was to assess by multivariate analysis the predictive value with respect to survival of a series of clinical, haematological and immunological parameters taken at SS diagnosis. PATIENTS AND METHODS A cohort of 62 SS patients diagnosed and followed since 1975 was examined, and 51 were included in the multivariate analysis model. RESULTS The median survival time was 31 months (range: 1 month-15.7+ years), and the five-year survival rate 33.5%. The following variables were found by univariate analysis to be associated with a poor prognosis at the time of SS diagnosis: previous history of mycosis fungoides (P = 0.013), high number of circulating leukocytes (P = 0.001), Sézary cells (SC) (P < 0.001) and CD4+ cells (P < 0.001), presence of large circulating SC (P < 0.001), above normal range LDH serum levels (P = 0.015), presence of PAS-positive inclusions in the cytoplasm of circulating SC (P < 0.001), high CD4/CD8 ratio (P = 0.004) and a CD7 negative circulating SC phenotype (P < 0.001). Among them, the stepwise multivariate analysis selected as adverse independent prognostic factors: PAS-positive cytoplasmic inclusions (P = 0.001), CD7 negative phenotype (P = 0.018) and presence of large circulating SC (P = 0.045). CONCLUSIONS Two low-/high-risk groups have been singled out on the basis of the risk index. Patients with no or one adverse prognostic feature(s) (risk index < or = 1; n = 31) share a slow disease course and a relatively favorable prognosis (five-year survival: 58%); on the other hand, patients with 2 or 3 adverse prognostic feature (risk index > 1; n = 20) are characterized by an aggressive disease course not modifiable by traditional therapies (five-year survival: 5%).

Biology, prognosis and response to therapy of breast carcinomas according to HER2 score

BACKGROUND The standardization of the HER2 score and recent changes in therapeutic modalities points to the need for a reevaluation of the role of HER2 in recently diagnosed breast carcinoma. PATIENTS AND METHODS A multicenter, retrospective study of 1794 primary breast carcinomas diagnosed in Italy in 2000/2001 and scored in HER2 four categories according to immunohistochemistry was conducted. RESULTS Ductal histotype, vascular invasion, grade, MIB1 positivity, estrogen and progesterone receptor expression differed significantly in HER2 3+ tumors compared with the other categories. HER2 2+ tumors almost showed values intermediate between those of the negative and the 3+ subgroups. The characteristics of HER2 1+ tumors were found to be in between those of HER2 0 and 2+ tumors. With a median follow-up of 54 months, HER2 3+ status was associated with higher relapse rates in node-positive and node-negative subgroups, while HER2 2+ only in node positive. Analysis of relapses according to type of therapy provided evidence of responsiveness of HER2-positive tumors to chemotherapy, especially taxanes. CONCLUSIONS The present prognostic significance of HER2 is correlated to receptor expression level and points to the need to consider HER2 2+ and HER2 3+ tumors as distinct diseases with different outcomes and specific features.

Is epirubicin effective in first-line chemotherapy of metastatic breast cancer (MBC) after an epirubicin-containing adjuvant treatment? A single centre phase III trial.

The aim of the study was to demonstrate the superiority of docetaxel and epirubicin vs docetaxel alone as first-line therapy in metastatic breast cancer patients pretreated with adjuvant or neoadjuvant epirubicin. We compared single agent docetaxel 100 mg m−2 (D) with the combination of docetaxel 80 mg m−2 and epirubicin 75 mg m−2 (ED). The response rate (72 vs 79%), the progression-free survival (median 9 vs 11 months) and the overall survival (median 18 vs 21 months) were not significantly different between the ED (n=26) and D arms (n=25), respectively. Leucopaenia, nausea and stomatitis were significantly worse with ED. In conclusion, epirubicin should not be administered in combination with taxanes in metastatic breast cancer patients relapsed after an anthracycline-based adjuvant or neoadjuvant therapy.

Biological Characteristics and Medical Treatment of Breast Cancer in Young Women—A Featured Population: Results from the NORA Study

Background. The present paper described the biological characteristics and clinical behavior of young women in the cohort NORA study Patients and Methods. From 2000–2002, patients (N > 3500) were enrolled at 77 Italian hospitals. Women aged ≤50 years (N = 1013) were stratified into age groups (≤35, 36–40, 41–45, and 46–50 years). The relationship between age and patient characteristics, cancer presentation, and treatment was analyzed. Results. Younger women more frequently had tumors with ER/PgR-negative(χ 2 = 7.07; P = .008), HER2 amplification (χ 2 = 5.76; P = .01), and high (≥10%) Ki67 labelling index (χ 2 = 9.53; P = .002). Positive nodal status, large tumors, and elevated Ki67 all associated with the choice for chemotherapy followed by endocrine therapy in hormone receptor-positive patients (P < .0001). At univariate analysis, ER-ve status, chemotherapy and age resulted as the only statistically significant variables (HR = 2.02, P = .004, and >40 versus ≤40, P < .0001, resp.). At multivariate analysis, after adjustment for significant clinical and pathological factors, age remains a significant prognostic variable (HR = 0.93, P = .0021). Conclusion. This cohort study suggests that age per sè is an important prognostic factor. The restricted role of early diagnosis and the aggressive behavior of cancer in this population make necessary the application of targeted medical strategies crucial.

Bone effect of adjuvant tamoxifen, letrozole or letrozole plus zoledronic acid in early-stage breast cancer: the randomized phase 3 HOBOE study

BACKGROUND To measure bone mineral density (BMD) reduction produced by letrozole as compared with tamoxifen and the benefit of the addition of zoledronic acid. PATIENTS AND METHODS A phase 3 trial comparing tamoxifen, letrozole or letrozole+zoledronic acid in patients with hormone receptor-positive early breast cancer was conducted; triptorelin was given to premenopausal patients. Two comparisons were planned: letrozole versus tamoxifen and letrozole+zoledronic acid versus letrozole. Primary end point was the difference in 1-year change of T-score at lumbar spine (LTS) measured by dual energy X-ray absorptiometry scan. RESULTS Out of 483 patients enrolled, 459 were available for primary analyses. Median age was 50 (range 28-80). The estimated mean difference (95% confidence interval [CI]) in 1-year change of LTS was equal to -0.30 (95% CI -0.44 to -0.17) in the letrozole versus tamoxifen comparison (P<0.0001) and to +0.60 (95% CI +0.46 to +0.77) in the letrozole+zoledronic acid versus letrozole comparison (P<0.0001). Bone damage by letrozole decreased with increasing baseline body mass index in premenopausal, but not postmenopausal, patients (interaction test P=0.004 and 0.47, respectively). CONCLUSIONS In the HOBOE (HOrmonal BOne Effects) trial, the positive effect of zoledronic acid on BMD largely counteracts damage produced by letrozole as compared with tamoxifen. Letrozole effect is lower among overweight/obese premenopausal patients.

256OWEEKLY DOCETAXEL (WD) VS CMF AS ADJUVANT CHEMOTHERAPY FOR ELDERLY EARLY BREAST CANCER (EBC) PATIENTS (PTS): FINAL RESULTS FROM THE RANDOMISED PHASE 3 ELDA TRIAL

ABSTRACT Aim: Evidence on adjuvant chemotherapy in elderly EBC pts is poor. The ELDA trial tested whether wD is more effective than CMF (NCT00331097). Methods: EBC pts, 65 to 79 years old, were eligible if they had metastatic nodes or average to high risk of recurrence according to 2001 St.Gallen criteria. Pts were randomly assigned to wD (35 mg/m2 dd 1, 8, 15) or CMF (cyclophosphamide 600 mg/m2, methotrexate 40 mg/m2, fluorouracil 600 mg/m2, dd 1, 8), both every 4 wks and given for 4 cycles in ER+ pts and 6 cycles in ER- ones. With 178 events, the study would have 80% power to detect a 0.65 hazard ratio (HR) of disease-free survival (DFS) with bilateral alpha = 0.05. Quality of life (QoL) was assessed with EORTC C30 and BR23 tools; activity of daily living (ADL), instrumental ADL (IADL) and Charlson score for comorbidities were assessed. ER+ and HER2+ pts received endocrine treatment and trastuzumab after chemotherapy, respectively. Results: From July 2003 to April 2011, 302 pts were randomized and 299 (152 CMF, 147 wD) were evaluable. Median age was 71. Hypertension (62%), arthropathy (34%) osteoporosis (17%) and controlled diabetes (16%) were the most frequent comorbidities. At baseline: pT1 44%, pN0 37%, G3 64%, ER+ 75%, HER2+ 19%. After 5.5 years median follow-up, with a plateau of DFS after 108 events (50 with CMF and 58 with wD), the Independent Data Monitoring Committee recommended to anticipate final analysis. HR of DFS for wD vs CMF was 1.20 (95% CI: 0.82-1.75, p = 0.35); HR of death was 1.23 (95% CI: 0.73-2.07, p = 0.42); outcome is similar at multivariable analysis, also including ADL, IADL and Charlson scores. QoL was significantly worse with wD for emesis, appetite loss, diarrhoea, body image, future perspective, side effects and hair loss items. Hematologic toxicity, mucositis and nausea were significantly worse with CMF, while allergy, fatigue, hair loss, onicopathy, dysgeusia, diarrhoea, abdominal pain, neuropathy, cardiac and skin toxicity were significantly worse with wD. There were 1 toxic death with CMF and 2 with wD. Conclusions: The ELDA trial shows that wD is not more effective than CMF, and produces worse QoL and toxicity. CMF remains a standard for elderly EBC pts. (Partially supported by Sanofi-Aventis). Disclosure: All authors have declared no conflicts of interest.

1480OSYMPTOMATIC TOXICITIES EXPERIENCED DURING ANTI-CANCER TREATMENT: COMPARISON OF PATIENTS' AND PHYSICIANS' REPORTING IN THREE RANDOMIZED CONTROLLED TRIALS (RCTS)

ABSTRACT Aim: Information available about symptomatic toxicities of anti-cancer treatments is based on reports made by clinicians in clinical trials, not on direct reporting by patients (pts). Therefore, some side effects could be under-reported. This analysis aims to compare reporting by pts and physicians of six key toxicities. Methods: Pts enrolled in 3 RCTs (NCT00331097, NCT00349219, NCT00385606) were included. In one RCT, elderly pts with breast cancer received adjuvant chemotherapy, in the other two RCTs pts with advanced non-small cell lung cancer received first-line treatment. Toxicity was prospectively collected by investigators. At the end of each treatment cycle, pts filled in EORTC quality of life (QoL) questionnaires. Cycles were evaluable if both toxicity evaluation and QoL were available. Analysis was limited to the first three cycles. Rates of anorexia, nausea, vomiting, constipation, diarrhea and hair loss reported by pts and physicians are described. For each, relative under-reporting is calculated (cycles with toxicity reported by pts but not physicians). Results: Overall, 1090 pts and 2482 cycles were included. Toxicity rates reported by physicians were always lower than reported by pts (Table). For cycles when pts reported toxicity (any severity), the proportion of relative under-reporting by physicians ranged from 54.2% to 80.2%. Examining only cycles when patients reported “very much” toxicity, the proportion of relative under-reporting by physicians ranged from 22.2% to 62.1%. Toxicity Toxicity reported by pts (% cycles) Toxicity reported by pts and by physicians (% cycles) % under-reporting Anorexia 46.2 9.2 80.2 Nausea 45.3 20.8 54.2 Vomiting 16.8 7.2 57.4 Constipation 37.5 7.8 79.2 Diarrhea 22.7 8.9 61.0 Hair loss 42.7 13.9 67.4 Conclusions: Subjective toxicities are at high risk of under-reporting by physicians, even when prospectively collected within RCTs. Our findings strongly support the incorporation of patient-reported information into toxicity reporting in clinical trials. Disclosure: All authors have declared no conflicts of interest.

Abstract P2-17-01: Phase II Study of Bevacizumab in Combination with Docetaxel and Capecitabine for the First-Line Treatment of Patients with Locally Recurrent or Metastatic Breast Cancer

Background: Docetaxel (T; Taxotere) with capecitabine (X) is active against metastatic breast cancer (MBC); bevacizumab (B) has demonstrated efficacy with taxanes in the first-line setting. This study was conducted to assess the efficacy and safety of TX-B in patients (pts) with MBC. Patients and methods: In this single-arm, multicenter phase II study, pts received first-line bevacizumab 15 mg/kg and docetaxel 60 mg/m 2 on day 1, plus capecitabine 900 mg/m 2 twice per day on days 1-14 every 21 days. The treatment was administrated for 3 cycles and in case of objective response or stable disease at that time, pts were treated with 3 additional cycles. More courses of chemotherapy were administered at Investigator9s discretion. Bevacizumab was continued until progressive disease, patient refusal, or unacceptable toxicity. Primary end point was progression-free survival (PFS) and secondary end points were tumor response rate (RR), overall survival (OS), and toxicity. Results: We report data from the first 30 pts enrolled. Median age was 54 (37-72). Eight (27%) pts had triple-negative disease, while 18 (60%) were hormone-receptor positive. HER2 status was recognized as negative in 25 (84%) pts. TX-B was administered for a median of seven cycles. Five complete and 13 partial responses were observed (overall RR 60%). Median response duration was 12 months. Median OS and PFS were 26 and 11 months, respectively. Grade 3/4 adverse events included tromboembolism (10%), neutropenia (23%), hand-foot syndrome (13%), stomatitis (10%). The median TX doses administered per cycle were 60 mg/m2 and 660 mg/m2, respectively. Ten (33%) pts required dose reductions of docetaxel, while capecitabine dose was reduced in 15 (50%) pts. Results of all the 80 assessable pts entered in the study will be presented at the meeting. Conclusion: TX-B demonstrated significant activity with an acceptable toxicity profile. Maintenance therapy with B is possible for a long period of stable tumor disease. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P2-17-01.

Endocrine effects of adjuvant letrozole versus tamoxifen in hormone responsive postmenopausal early breast cancer patients: results from the HOBOE randomized trial.

CTRC-AACR San Antonio Breast Cancer Symposium: 2008 Abstracts Abstract #1150 Purpose. We compared the endocrine effects of 6 and 12 months of adjuvant letrozole versus tamoxifen in postmenopausal patients with hormone responsive early breast cancer, within an ongoing phase 3 trial (HOrmonal adjuvant treatment BOne Effects – HOBOE, ClinicalTrial.gov id: [NCT00412022][1]). Patients and M ethods . Patients were randomised to receive tamoxifen or letrozole ± zoledronate. Serum values of 17-b-estradiol, FSH, LH, testosterone, dehydroepiandrosterone-solphate, progesterone, and cortisol were measured at baseline, after 6 and 12 months of treatment. For each hormone, baseline, 6 and 12-month values were compared between treatment groups, by the exact Wilcoxon-Mann-Whitney test. Results. At December 31, 2006, 157 postmenopausal patients had been enrolled into the study; baseline data were available for 139 patients (88.5%), 43 assigned to tamoxifen and 96 assigned to letrozole. Median age was 61 and 62 years in the two groups, respectively. Baseline values were similar between the two groups for all hormones. At 6 and 12 months, levels of 17-b-estradiol were significantly lower with letrozole as compared with tamoxifen (p=0.0003 and p<0.0001, respectively). Patients treated with letrozole also showed higher levels of progesterone and testosterone at 6 (p=0.001 and p=0.01, respectively) and 12 months (p=0.004 and p=0.02, respectively) than those treated with tamoxifen. FSH and LH were lower (all p<0.0001 for both hormones), while cortisol was higher (p=0.003 at 6 and 0.001 at 12 months) with tamoxifen than with letrozole. Conclusion . To our knowledge, this is the first study reporting on endocrine effects of letrozole as adjuvant treatment of postmenopausal early breast cancer and allowing a prospective comparison with tamoxifen. Adjuvant letrozole and tamoxifen result in significantly distinct endocrine effects. Such differences can explain the higher efficacy of letrozole as compared to tamoxifen. Long-term impact needs to be studied. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1150. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00412022&atom=%2Fcanres%2F69%2F2_Supplement%2F1150.atom