Valeria Forestieri

Taxane-Based Combinations As Adjuvant Chemotherapy of Early Breast Cancer: A Meta-Analysis of Randomized Trials

PURPOSE We conducted a meta-analysis of randomized trials that evaluated the efficacy of incorporating taxanes into anthracycline-based regimens for early breast cancer (EBC). We aimed to determine whether this approach improves disease-free survival (DFS) and overall survival (OS) and whether benefits are maintained across relevant patient subgroups. METHODS Studies were retrieved by searching the PubMed database and the proceedings of major conferences. We extracted hazard ratios (HR) and 95% CIs for DFS and OS from each trial and obtained pooled estimates using an inverse-variance model. RESULTS Thirteen studies were included in the meta-analysis (N = 22,903 patients). The pooled HR estimate was 0.83 (95% CI, 0.79 to 0.87; P < .00001) for DFS and 0.85 (95% CI, 0.79 to 0.91; P < .00001) for OS. Risk reduction was not influenced by the type of taxane, by estrogen receptor (ER) expression, by the number of axillary metastases (N1 to 3 v N4+), or by the patients age/menopausal status. Sensitivity analysis showed that taxanes given in combination with anthracyclines, unlike sequential administration, did not significantly improve OS. However, the test for interaction showed that HR did not differ between the two schedules (P = .54). Taxane administration resulted in an absolute 5-year risk reduction of 5% for DFS and 3% for OS. CONCLUSION The addition of a taxane to an anthracycline-based regimen improves the DFS and OS of high-risk EBC patients. The DFS benefit was independent of ER expression, degree of nodal involvement, type of taxane, age/menopausal status of patient, and administration schedule.

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. FUNDING Bristol-Myers Squibb, Pharmacia, and Dompè Biotec.

Thalidomide in combination with oral daily cyclophosphamide in patients with pretreated hormone refractory prostate cancer: a phase I clinical trial.

Aim. This is a phase I study investigating the toxicity and the potential efficacy of thalidomide and oral cyclophosphamide in patients with hormone refractory prostate cancer (HRPC), previously treated with docetaxel-based regimens. Methods. Two dose levels of thalidomide (100 and 200 mg every day) were studied. Patients were accrued to each dose level in cohorts of 3 starting from dose 1 level (100 mg). Thalidomide was started on day 1 at the assigned dose and continued for 4 consecutive weeks; oral cyclophosphamide (50 mg for day) was given for 4 consecutive weeks (1 cycle) starting on the same day initiating thalidomide. Toxicity was evaluated every 2 weeks; changes in prostate-specific antigen (PSA) levels were evaluated every cycle. Treatment was planned for 4 cycles. Results. 16 men were treated. 10 patients in cohort 1 and 6 in cohort 2 were enrolled respectively. Grade 1-2 constipation, peripheral neuropathy and fatigue were the most common side effects, noted in 7 (44%), 6 (37.5%) and 3 (19%) patients, respectively. 3 patients stopped the treatment at level 2, during the first cycle, for toxicity. Those 3 patients were evaluable only for toxicity. The MTD was 100 mg thalidomide. 13 patients completed 2 cycles. 2 patients (15%) had a > 50% decrease in PSA, while in 1 patient (8%) the PSA decrease was less of 50%. Overall PSA decrease was of 23%. Conclusions. The oral combination of thalidomide and cyclophosphamide is well tolerated and appears to be associated with biochemical response in this population. Future phase II trials, in pre-treated and untreated patients, are needed to evaluate clinical efficacy of this regimen in HRPC.

Combined effect of obesity and diabetes on early breast cancer outcome: a prospective observational study

Background Previous studies suggested that obesity and diabetes were correlated with breast cancer outcome. The aim of the present study was to investigate the prognostic effect of obesity and diabetes on the outcome of early breast cancer patients. Materials and Methods Overall, 841 early breast cancer patients were prospectively enrolled between January 2009 and December 2013. Study population was divided into four groups: (1) patients without obesity or diabetes; (2) patients with only diabetes; (3) patients with only obesity; and (4) patients with both diabetes and obesity. Categorical variables were analyzed by the chi-square test and survival data by the log-rank test. Results At diagnosis, obese and diabetic patients were more likely to be older (p < 0.0001) and post-menopausal (p < 0.0001) and to have a tumor larger than 2 cm (p < 0.0001) than patients in groups 1–3. At univariate analyses, obese and diabetic patients had a worse disease-free survival (p = 0.01) and overall survival (p = 0.001) than did patients without obesity and diabetes. At multivariate analyses, the co-presence of obesity and diabetes was an independent prognostic factor for disease-free survival (hazard ratio=2.62, 95% CI 1.23–5.60) but not for overall survival. Conclusions At diagnosis, patients with obesity and diabetes were older, had larger tumors and a worse outcome compared to patients without obesity or diabetes. These data suggest that metabolic health influences the prognosis of patients affected by early breast cancer.

Body weight and risk of molecular breast cancer subtypes among postmenopausal Mediterranean women

Breast cancer (BC) is the most common malignant tumor in women, obesity is associated with increased BC incidence and mortality and high levels of circulating insulin may negatively impact on cancer incidence. In the present study, we investigated whether the strength of several anthropometric and metabolic parameters varies between BC molecular subtypes. Eligible cases were 991 non-metastatic BC patients recruited between January 2009 and December 2013. Anthropometric, clinical and immunohistochemical features were measured. Multivariate logistic regression models were built to assess HER2 positive BC risk, comparing (a) triple positive (TP) with luminal A, luminal B and triple negative (TN) and (b) HER2-enriched group with luminal A, luminal B and TN. We stratified patients in pre- and post-menopause: significant differences emerged for luminal A in relation to age: they were more likely to be older compared to other groups. Among postmenopausal patients, the adjusted multivariate analysis showed that high BMI and high waist circumference were inversely correlated to TP subtype when compared to luminal B (OR=0.48 and OR=0.49, respectively). Conversely, HOMA-IR was a risk factor for TP when compared to luminal A and TN (OR=2.47 and OR=3.15, respectively). Our findings suggest a potential role of higher abdominal fat in the development of specific BC molecular subtypes in postmenopausal women. Moreover, they support a potential role of insulin resistance in the development of HER2 positive BC, although this role appears to be stronger when hormone receptors are co-expressed, suggesting a difference in the etiology of these two BC subtypes.

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.

HER2 status and efficay of taxane-based adjuvant therapy of early breast cancer (EBC): a metanalysis of randomized trials involving 7,831 patients.

CTRC-AACR San Antonio Breast Cancer Symposium: 2008 Abstracts Abstract #707 Background . Taxanes have recently been introduced in the adjuvant treatment of EBC yielding on average an improvement of disease-free-survival (DFS) and overall survival (OS) as compared to anthracycline-based regimens (De Laurentiis et al., JCO 2008). It has been questioned, however, that this average benefit may be driven largely by improved outcome in a restricted subset of patients. Particularly, it has been suggested that only patients with HER2+ tumors may derive benefits from taxane administration (Pritchard et al. JCO 2008). We performed a meta-analysis on the interaction between HER2 status and the efficacy of adjuvant taxane-based therapy by pooling subsets data of the available randomized trials. Methods. We searched the Pubmed database to identify randomized trials that compared taxane-based with non-taxane-based adjuvant chemotherapy regimens for EBC and reported efficacy data according to HER2 status. We also searched the proceedings of major international conferences to identify relevant trials with subset analyses. Hazard Hatios (HRs) for DFS were pooled across the studies according to HER2 status by inverse variance weighting. A pooled test for treatment by HER2 status interaction was performed by weighted linear meta-regression. All statistical tests were two-sided. Results. Six studies were eligible for this analysis, accounting for 11,631 patients, of whom 7,831 had HER2 status information available. Overall, taxanes were superior to non-taxane-based regimens in terms of DFS with a pooled HR = 0.85 (95%CI: 0.77-0.93). At pooled subgroup analysis taxanes yielded a statistically significant DFS improvement both in HER2+ disease (n = 1,730), with a pooled HR = 0.78 (95% CI: 0.67 to 0.92; p = 0.004), and in HER2 - disease (n = 6,101), with a pooled HR = 0.88 (95% CI = 0.79 to 0.98; p = 0.02). A test for interaction showed that there is no statistically-significant difference in the efficacy of taxane-based chemotherapy according to HER2 status (p=0.27). ![][1] Discussion. There is no evidence of interaction between HER2 status and taxane efficacy in EBC. HER2 status should not be used to decide which patients are candidate to adjuvant taxane-based therapy. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 707. [1]: /embed/graphic-1.gif

It is no longer the time to disregard thyroid metastases from breast cancer: a case report and review of the literature

BackgroundMetastases to the thyroid gland are more frequent than previously thought, although most of them are occult or not clinically relevant. Overall, only 42 cases of metastases to thyroid from breast cancer have been reported thus far. Here we report the case of a patient with breast cancer metastatic to the thyroid. We also review the 42 previously reported cases (published between 1962 and 2012). This is the first review about metastases to thyroid gland from breast cancer.Case presentationA 64-year-old woman of Caucasian origin was diagnosed with a lobular invasive carcinoma of the breast (luminal A, stage II). She received adjuvant chemotherapy, followed by endocrine therapy. During follow-up, fine-needle cytology of a thyroid nodule revealed malignant cells that were estrogen-positive, which suggested a diagnosis of metastases to the thyroid. Imaging did not reveal any other metastatic site and showed only enlargement of the left thyroid lobe and an inhomogeneous pattern of colloid and cystic degeneration and calcifications. The patient underwent left hemithyroidectomy. Histology of thyroid tissue showed a colloid goitre containing dispersed small atypical neoplastic cells with eccentric nuclei. Immunohistochemistry showed cytokeratin-19 and oestrogen receptor, but not tireoglobulin, e-cadherin or cytokeratin-7, thereby confirming metastases from a lobular breast carcinoma. Hormonal treatment is ongoing.ConclusionThis case report and first review of the literature on metastases to thyroid from breast cancer highlight the importance of a correct early diagnostic work-up in such cases. Indeed, a primary lesion should be distinguished from metastases given the different treatment protocol related to primary cancer and the clinical impact on prognosis.

Abstract P3-06-15: Breast cancer molecular profile according to BMI and menopausal status

Introduction: High body mass index (BMI) is considered a risk factor for breast cancer onset and is correlated with bad prognosis in breast cancer patients. However, very few studies have associated clinical and molecular tumor characteristics with the patients’ BMI at the time of breast cancer diagnosis. The present study analyses how BMI influences tumor biology and correlates with different molecular subtypes according to menopausal status in a large cohort of patients with new diagnoses of early breast cancer (EBC). Methods: Overall 967 patients with a new diagnosis of EBC from 2007 till 2012 were recruited for this study. Clinical and tumor characteristics such as age, menopausal status, weight, height, tumor size (T), grading, estrogen receptor (ER), progesterone receptor (PgR), human epidermal growth factor receptor 2 (HER2) status, were prospectively collected. BMI was categorized into two groups (low: ≤25; high: >25). Associations between BMI and clinicopathological variables were performed by χ2 test. Results: A total of 594 (61%) post-menopause and 373 (39%) pre-menopause women were enrolled. Regardless of menopausal status, patients with high BMI were older (p<0.0001) and had larger tumors (p<0.0001). However, among postmenopausal patients, high BMI correlates with increased ER expression (p = 0.015), lower HER2 expression (p = 0.05) and less aggressive tumor subtypes as luminal A (p = 0.043). In the same patient subset, women with low BMI were more likely to develop a Luminal B, HER2 like or TN breast cancer. No correlation was observed between tumor molecular phenotypes and BMI among premenopausal women. Conclusion: Among postmenopausal patient, high BMI is associated with less aggressive and more endocrine sensitive EBC. This is consistent with the hypotheses that higher estrogen exposure of breast tissue in women with higher BMI may drive growth of these cancers. If further confirmed, our data suggests that weight control in this subset of women may help to prevent cancer development. View this table: Table 1 Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P3-06-15.