Search

Deregulation of cell cycle, via cyclin D/CDK/pRb pathway, is frequently observed in breast cancer lending support to the development of drugs targeting the cell cycle control machinery, like the inhibitors of the cycline-dependent kinases (CDK) 4 and 6. Up to now, three CDK4/6 inhibitors have been approved by FDA for the treatment of hormone receptor-positive (HR+), HER2-negative metastatic breast cancer. These agents have been effective in improving the clinical outcomes, but the development of intrinsic or acquired resistance can limit the efficacy of these treatments. Clinical and translational research is now focused on investigation of the mechanism of sensitivity/resistance to CDK4/6 inhibition and novel therapeutic strategies aimed to improve clinical outcomes. This review summarizes the available knowledge regarding CDK4/6 inhibitor, the discovery of new biomarkers of response, and the biological rationale for new combination strategies of treatment.

Replication

Aim The aim of the study is to analyse whether letrozole (L) and zoledronic acid plus L (ZL) are more effective than tamoxifen (T) as adjuvant endocrine treatment of premenopausal patients with breast cancer with hormone receptor–positive (HR+) tumours. Patients and methods In a phase 3 trial, 1065 premenopausal patients with HR + early breast cancer received triptorelin to suppress ovarian function and were randomly assigned (1:1:1) to adjuvant T, L or ZL for 5 years. Cancer recurrence, second breast or non-breast cancer and death were considered events for the intention-to-treat disease-free survival (DFS) analysis. Results With a 64-month median follow-up and 134 reported events, the disease-free rate at 5 years was 85.4%, 93.2% and 93.3% with T, L and ZL, respectively (overall P = 0.008). The hazard ratio for a DFS event was 0.52 (95% confidence interval [CI], 0.34 to 0.80; P = 0.003) with ZL vs T, 0.72 (95% CI, 0.48 to 1.07; P = 0.06) with L vs T and 0.70 (95% CI, 0.44 to 1.12; P = 0.22) with ZL vs L. With 36 deaths, there was no significant difference in overall survival (P = 0.14). Treatment was stopped for toxicity or refusal in 7.3%, 7.3% and 16.6% patients, and in the safety population, grade 3–4 side-effects were reported in 4.2%, 6.9% and 9.1% patients treated with T, L or ZL, respectively. Conclusion HOBOE study shows that in premenopausal patients with early breast cancer undergoing ovarian function suppression with triptorelin, ZL significantly improves DFS, while worsening compliance and toxicity, as compared with T. ( NCT00412022 )

The introduction of CDK4/6 inhibitors in combination with endocrine therapy (ET) represents the most relevant advance in the management of hormone receptor (HR) positive, HER2-negative metastatic breast cancer over the last few years. This meta-analysis of randomized controlled trials (RCTs) is aimed to better characterize the efficacy of CDK4/6 inhibitors in some relevant subgroups and to test heterogeneity between different compounds with a particular focus on their ability to improve overall survival (OS). Pooled estimates of hazard ratios (HRs) were computed for progression-free survival (PFS), OS, and objective response rate (ORR) analysis in predefined subgroups to better understand treatment effect concerning specific patients’ characteristics. To estimate the absolute benefit in terms of PFS, pooled survival curves were generated by pooling the data of all trials. A total of eight RCTs were included. Adding a CDK4/6 inhibitor to ET is beneficial in terms of PFS, irrespective of the presence or not of visceral metastases, the number of metastatic sites, and the length of the treatment-free interval (TFI). The addition of CDK4/6 inhibitors produces a significant OS improvement, both in aromatase inhibitor (AI)-sensitive (HR 0.75, 95% CI) and AI-resistant patients (HR 0.77, 95% CI [0.67–0.89]). Pooled data from each single drug show that palbociclib remains the only class member not showing a statistically significant HR for OS (HR 0.83, 95% CI [0.68–1.02]).

Background: Uncertainty exists about the optimal schedule of adjuvant treatment of breast cancer with aromatase inhibitors and, to our knowledge, no trial has directly compared the three aromatase inhibitors anastrozole, exemestane, and letrozole. We investigated the schedule and type of aromatase inhibitors to be used as adjuvant treatment for hormone receptor-positive early breast cancer. Methods: FATA-GIM3 is a multicentre, open-label, randomised, phase 3 trial of six different treatments in postmenopausal women with hormone receptor-positive early breast cancer. Eligible patients had histologically confirmed invasive hormone receptor-positive breast cancer that had been completely removed by surgery, any pathological tumour size, and axillary nodal status. Key exclusion criteria were hormone replacement therapy, recurrent or metastatic disease, previous treatment with tamoxifen, and another malignancy in the previous 10 years. Patients were randomly assigned in an equal ratio to one of six treatment groups: oral anastrozole (1 mg per day), exemestane (25 mg per day), or letrozole (2·5 mg per day) tablets upfront for 5 years (upfront strategy) or oral tamoxifen (20 mg per day) for 2 years followed by oral administration of one of the three aromatase inhibitors for 3 years (switch strategy). Randomisation was done by a computerised minimisation procedure stratified for oestrogen receptor, progesterone receptor, and HER2 status; previous chemotherapy; and pathological nodal status. Neither the patients nor the physicians were masked to treatment allocation. The primary endpoint was disease-free survival. The minimum cutoff to declare superiority of the upfront strategy over the switch strategy was assumed to be a 2% difference in disease-free survival at 5 years. Primary efficacy analyses were done by intention to treat; safety analyses included all patients for whom at least one safety case report form had been completed. Follow-up is ongoing. This trial is registered with the European Clinical Trials Database, number 2006-004018-42, and ClinicalTrials.gov, number NCT00541086. Findings: Between March 9, 2007, and July 31, 2012, 3697 patients were enrolled into the study. After a median follow-up of 60 months (IQR 46–72), 401 disease-free survival events were reported, including 211 (11%) of 1850 patients allocated to the switch strategy and 190 (10%) of 1847 patients allocated to upfront treatment. 5-year disease-free survival was 88·5% (95% CI 86·7–90·0) with the switch strategy and 89·8% (88·2–91·2) with upfront treatment (hazard ratio 0·89, 95% CI 0·73–1·08; p=0·23). 5-year disease-free survival was 90·0% (95% CI 87·9–91·7) with anastrozole (124 events), 88·0% (85·8–89·9) with exemestane (148 events), and 89·4% (87·3 to 91·1) with letrozole (129 events; p=0·24). No unexpected serious adverse reactions or treatment-related deaths occurred. Musculoskeletal side-effects were the most frequent grade 3–4 events, reported in 130 (7%) of 1761 patients who received the switch strategy and 128 (7%) of 1766 patients who received upfront treatment. Grade 1 musculoskeletal events were more frequent with the upfront schedule than with the switch schedule (924 [52%] of 1766 patients vs 745 [42%] of 1761 patients). All other grade 3–4 adverse events occurred in less than 2% of patients in either group. Interpretation: 5 years of treatment with aromatase inhibitors was not superior to 2 years of tamoxifen followed by 3 years of aromatase inhibitors. None of the three aromatase inhibitors was superior to the others in terms of efficacy. Therefore, patient preference, tolerability, and financial constraints should be considered when deciding the optimal treatment approach in this setting. Funding: Italian Drug Agency.

Exemestane (Exe) in combination with Everolimus (Eve) represents an important treatment option for patients diagnosed with hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2‑) metastatic breast cancer (MBC), which was previously treated with non‑steroidal aromatase inhibitors (NSAI). Data from unselected populations may be useful for defining the optimal therapeutic algorithm within a clinical setting. Data from 264 HR+, HER2‑ MBC patients who received Exe‑Eve treatment in combination, following the failure of NSAIs was retrospectively analyzed. Different lines of endocrine treatment (ET) were investigated to evaluate the efficacy and toxicity of the treatment within the ‘everyday clinical practice’ population. The disease control rate (DCR) was 73.1%, with no statistically significant difference among the different settings. At a median follow‑up of 42 months, the median progression free survival (PFS) was 11.6, 9.7 and 7.5 months for patients treated with Exe‑Eve as first, second or third line therapy, respectively. There was a statistically significant correlation with younger age, no previous adjuvant chemotherapy (CT), no previous adjuvant endocrine therapy (ET), HT duration ≥36 months, involvement of liver and/or lung, no prior CT for metastatic disease and PS=0 at the start of treatment. The median overall survival (OS) was 33.0 months; at a median follow‑up of 67 months, the median OS was 43.1, 31.7 and 27.9 months in patients treated with Exe‑Eve in first, second or third line therapy, respectively. On multivariate analysis, diabetes and previous CT for metastatic disease were revealed to correlate with a worse outcome. Conversely, the presence of mucositis was significantly associated with long‑term survival. Overall, Exe‑Eve was typically well tolerated and the majority toxicities were G1 or 2, while treatment discontinuation due to unacceptable toxicity was only required in 5.7% of patients. Despite the limitations due to the observational nature of this study, the findings suggest that treatment with Exe‑Eve is an active and safe therapeutic option for endocrine‑sensitive MBC patients in a real‑world clinical setting, regardless of treatment lines.

BACKGROUND: ExteNET showed that 1 year of neratinib, an irreversible pan-HER tyrosine kinase inhibitor, significantly improves 2-year invasive disease-free survival after trastuzumab-based adjuvant therapy in women with HER2-positive breast cancer. We report updated efficacy outcomes from a protocol-defined 5-year follow-up sensitivity analysis and long-term toxicity findings. METHODS: In this ongoing randomised, double-blind, placebo-controlled, phase 3 trial, eligible women aged 18 years or older (≥20 years in Japan) with stage 1-3c (modified to stage 2-3c in February, 2010) operable breast cancer, who had completed neoadjuvant and adjuvant chemotherapy plus trastuzumab with no evidence of disease recurrence or metastatic disease at study entry. Patients who were eligible patients were randomly assigned (1:1) via permuted blocks stratified according to hormone receptor status (hormone receptor-positive vs hormone receptor-negative), nodal status (0 vs 1-3 vs or ≥4 positive nodes), and trastuzumab adjuvant regimen (given sequentially vs concurrently with chemotherapy), then implemented centrally via an interactive voice and web-response system, to receive 1 year of oral neratinib 240 mg/day or matching placebo. Treatment was given continuously for 1 year, unless disease recurrence or new breast cancer, intolerable adverse events, or consent withdrawal occurred. Patients, investigators, and trial funder were masked to treatment allocation. The predefined endpoint of the 5-year analysis was invasive disease-free survival, analysed by intention to treat. ExteNET is registered with ClinicalTrials.gov, number NCT00878709, and is closed to new participants. FINDINGS: Between July 9, 2009, and Oct 24, 2011, 2840 eligible women with early HER2-positive breast cancer were recruited from community-based and academic institutions in 40 countries and randomly assigned to receive neratinib (n=1420) or placebo (n=1420). After a median follow-up of 5·2 years (IQR 2·1-5·3), patients in the neratinib group had significantly fewer invasive disease-free survival events than those in the placebo group (116 vs 163 events; stratified hazard ratio 0·73, 95% CI 0·57-0·92, p=0·0083). The 5-year invasive disease-free survival was 90·2% (95% CI 88·3-91·8) in the neratinib group and 87·7% (85·7-89·4) in the placebo group. Without diarrhoea prophylaxis, the most common grade 3-4 adverse events in the neratinib group, compared with the placebo group, were diarrhoea (561 [40%] grade 3 and one [BACKGROUND: ExteNET showed that 1 year of neratinib, an irreversible pan-HER tyrosine kinase inhibitor, significantly improves 2-year invasive disease-free survival after trastuzumab-based adjuvant therapy in women with HER2-positive breast cancer. We report updated efficacy outcomes from a protocol-defined 5-year follow-up sensitivity analysis and long-term toxicity findings.METHODS: In this ongoing randomised, double-blind, placebo-controlled, phase 3 trial, eligible women aged 18 years or older (≥20 years in Japan) with stage 1-3c (modified to stage 2-3c in February, 2010) operable breast cancer, who had completed neoadjuvant and adjuvant chemotherapy plus trastuzumab with no evidence of disease recurrence or metastatic disease at study entry. Patients who were eligible patients were randomly assigned (1:1) via permuted blocks stratified according to hormone receptor status (hormone receptor-positive vs hormone receptor-negative), nodal status (0 vs 1-3 vs or ≥4 positive nodes), and trastuzumab adjuvant regimen (given sequentially vs concurrently with chemotherapy), then implemented centrally via an interactive voice and web-response system, to receive 1 year of oral neratinib 240 mg/day or matching placebo. Treatment was given continuously for 1 year, unless disease recurrence or new breast cancer, intolerable adverse events, or consent withdrawal occurred. Patients, investigators, and trial funder were masked to treatment allocation. The predefined endpoint of the 5-year analysis was invasive disease-free survival, analysed by intention to treat. ExteNET is registered with ClinicalTrials.gov, number NCT00878709, and is closed to new participants.FINDINGS: Between July 9, 2009, and Oct 24, 2011, 2840 eligible women with early HER2-positive breast cancer were recruited from community-based and academic institutions in 40 countries and randomly assigned to receive neratinib (n=1420) or placebo (n=1420). After a median follow-up of 5·2 years (IQR 2·1-5·3), patients in the neratinib group had significantly fewer invasive disease-free survival events than those in the placebo group (116 vs 163 events; stratified hazard ratio 0·73, 95% CI 0·57-0·92, p=0·0083). The 5-year invasive disease-free survival was 90·2% (95% CI 88·3-91·8) in the neratinib group and 87·7% (85·7-89·4) in the placebo group. Without diarrhoea prophylaxis, the most common grade 3-4 adverse events in the neratinib group, compared with the placebo group, were diarrhoea (561 [40%] grade 3 and one [INTERPRETATION: At the 5-year follow-up, 1 year of extended adjuvant therapy with neratinib, administered after chemotherapy and trastuzumab, significantly reduced the proportion of clinically relevant breast cancer relapses-ie, those that might lead to death, such as distant and locoregional relapses outside the preserved breast-without increasing the risk of long-term toxicity. An analysis of overall survival is planned after 248 events.FUNDING: Wyeth, Pfizer, and Puma Biotechnology.

Financial difficulties, measured by the EORTC C30 questionnaire, were associated with worse quality of life and shorter overall survival of cancer patients enrolled in 16 academic clinical trials performed within the Italian public health system. The pooled database included 3670 patients with lung, breast or ovarian cancer. This finding support further studies on financial toxicity in Europe. Background Cancer may cause financial difficulties, but its impact in countries with public health systems is unknown. We evaluated the association of financial difficulties with clinical outcomes of cancer patients enrolled in academic clinical trials performed within the Italian public health system. Patients and methods Data were pooled from 16 prospective multicentre trials in lung, breast or ovarian cancer, using the EORTC quality of life (QOL) C30 questionnaire. Question 28 scores financial difficulties related to disease or treatment in four categories from ‘not at all’ to ‘very much’. We defined financial burden (FB) as any financial difficulty reported at baseline questionnaire, and financial toxicity (FT) as score worsening in a subsequent questionnaire. We investigated (i) the association of FB with clinical outcomes (survival, global QOL response [questions 29/30] and severe toxicity), and (ii) the association of FT with survival. Multivariable analyses were performed using logistic regression models or the Cox model adjusting for trial, gender, age, region and period of enrolment, baseline global QOL and, where appropriate, FB and global QOL response. Results are reported as odds ratio (OR) or hazard ratio (HR) with 95% confidence intervals (CI). Results At baseline 26% of the 3670 study patients reported FB, significantly correlated with worse baseline global QOL. FB was not associated with risks of death (HR 0.94, 95% CI 0.85–1.04, P = 0.23) and severe toxicity (OR 0.90, 95% CI 0.76–1.06, P = 0.19) but was predictive of a higher chance of worse global QOL response (OR 1.35, 95% CI 1.08–1.70, P = 0.009). During treatment, 2735 (74.5%) patients filled in subsequent questionnaires and 616 (22.5%) developed FT that was significantly associated with an increased risk of death (HR 1.20, 95% CI 1.05–1.37, P = 0.007). Several sensitivity analyses confirmed these findings. Conclusion Even in a public health system, financial difficulties are associated with relevant cancer patients outcomes like QOL and survival. Clinical Trials number Any registered clinical trial number should be indicated after the abstract.

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/m2 on day 1, plus capecitabine 900 mg/m2 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 Investigator's 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.

Purpose To compare the endocrine effects of 6 months of adjuvant treatment with letrozole + triptorelin or tamoxifen + triptorelin in premenopausal patients with early breast cancer within an ongoing phase 3 trial (Hormonal Adjuvant Treatment Bone Effects study). Patients and Methods Prospectively collected hormonal data were available for 81 premenopausal women, of whom 30 were assigned to receive tamoxifen + triptorelin and 51 were assigned letrozole + triptorelin ± zoledronate. Serum 17-β-estradiol (E2), follicle-stimulating hormone (FSH), luteinizing hormone (LH), Δ4-androstenedione, testosterone, dehydroepiandrosterone-sulfate, progesterone, adrenocorticotropic hormone (ACTH), and cortisol were measured at baseline and after 6 months of treatment. For each hormone, 6-month values were compared between treatment groups by the Wilcoxon-Mann-Whitney exact test. Results Median age was 44 years for both groups of patients. Letrozole + triptorelin (± zoledronate) induced a stronger suppression of median E2 serum levels (P = .0008), LH levels (P = .0005), and cortisol serum levels (P < .0001) compared with tamoxifen + triptorelin. Median FSH serum levels were suppressed in both groups, but such suppression was lower among patients receiving letrozole, who showed significantly higher median FSH serum levels (P < .0001). No significant differences were observed for testosterone, progesterone, ACTH, androstenedione, and dehydroepiandrosterone between the two groups of patients. Conclusion Letrozole in combination with triptorelin induces a more intense estrogen suppression than tamoxifen + triptorelin in premenopausal patients with early breast cancer.

Purpose Information about symptomatic toxicities of anticancer treatments is not based on direct report by patients, but rather on reports by clinicians in trials. Given the potential for under-reporting, our aim was to compare reporting by patients and physicians of six toxicities (anorexia, nausea, vomiting, constipation, diarrhea, and hair loss) within three randomized trials. Patients and Methods In one trial, elderly patients with breast cancer received adjuvant chemotherapy; in two trials, patients with advanced non–small-cell lung cancer received first-line treatment. Toxicity was prospectively collected by investigators (graded by National Cancer Institute Common Toxicity Criteria [version 2.0] or Common Terminology Criteria for Adverse Events [version 3]). At the end of each cycle, patients completed the European Organisation for Research and Treatment of Cancer quality-of-life questionnaires, including toxicity-related symptom items. Possible answers were “not at all,” “a little,” “quite a bit,” and “very much.” Analysis was limited to the first three cycles. For each toxicity, agreement between patients and physicians and under-reporting by physicians (ie, toxicity reported by patients but not reported by physicians) were calculated. Results Overall, 1,090 patients (2,482 cycles) were included. Agreement between patients and physicians was low for all toxicities. Toxicity rates reported by physicians were always lower than those reported by patients. For patients who reported toxicity (any severity), under-reporting by physicians ranged from 40.7% to 74.4%. Examining only patients who reported “very much” toxicity, under-reporting by physicians ranged from 13.0% to 50.0%. Conclusion Subjective toxicities are at high risk of under-reporting by physicians, even when prospectively collected within randomized trials. This strongly supports the incorporation of patient-reported outcomes into toxicity reporting in clinical trials.

Triple-negative breast cancer (TNBC) has a significant clinical relevance of being associated with a shorter median time to relapse and death and does not respond to endocrine therapy or other available targeted agents. Increased aggressiveness of this tumor, as well as resistance to standard drug therapies, may be associated with the presence of stem cell populations within the tumor. Several stemness markers have been described for the various histological subtypes of breast cancer, such as CD44, CD24, CD133, ALDH1, and ABCG2. The role of these markers in breast cancer is not clear yet and above all there are conflicting opinions about their real prognostic value. To investigate the role of CSCs markers in TNBC cancerogenesis and tumor progression, we selected 160 TNBCs samples on which we detected protein expression of CD44, CD24, CD133, ALDH1, and ABCG2 by immunohistochemistry. Our results highlighted a real prognostic role only for CD44 in TNBCs. All other CSCs markers do not appear to be related to the survival of TNBC patients. In conclusion, despite the fact that the presence of the cancer stem cells in the tumor provides important information on its potential aggressiveness, today their detection by immunohistochemistry is not sufficient to confirm their role in carcinogenesis, because specific markers probably are not yet identified.

Evidence on adjuvant chemotherapy for elderly early breast cancer patients is poor, due to the low number of phase 3 trials. ELDA shows that weekly docetaxel does not prolong DFS compared with standard CMF and worsens quality of life. Non-hematological toxicity is worse with weekly docetaxel. Age, comorbidities and functioning geriatric scales may be predictive of non-hematological side effects. Background Evidence on adjuvant chemotherapy in older women with breast cancer is poor. We tested whether weekly docetaxel is more effective than standard chemotherapy. Patients and methods We carried out a multicenter, randomized phase III study. Women aged 65–79, operated for breast cancer, with average to high risk of recurrence, were allocated 1 : 1 to CMF (cyclophosphamide 600 mg/m², methotrexate 40 mg/m², fluorouracil 600 mg/m², days 1, 8) or docetaxel (35 mg/m2 days 1, 8, 15) every 4 weeks, for four or six cycles according to hormone receptor status. Primary end point was disease-free survival (DFS). A geriatric assessment was carried out. Quality of life (QoL) was assessed with EORTC C-30 and BR-23 questionnaires. Results From July 2003 to April 2011, 302 patients were randomized and 299 (152 allocated CMF and 147 docetaxel) were eligible. After 70-month median follow-up, 109 DFS events were observed. Unadjusted hazard ratio (HR) of DFS for docetaxel versus CMF was 1.21 [95% confidence interval (CI) 0.83–1.76,P = 0.32]; DFS estimate at 5 years was 0.69 with CMF and 0.65 with docetaxel. HR of death was 1.34 (95% CI 0.80–2.22,P = 0.26). There was no interaction between treatment arms and geriatric scales measuring patients' ability or comorbidities. Hematological toxicity, mucositis and nausea were worse with CMF; allergy, fatigue, hair loss, onychopathy, dysgeusia, diarrhea, abdominal pain, neuropathy, cardiac and skin toxicity were worse with docetaxel. One death was attributed to CMF and two to docetaxel. Increasing age, impairment in instrumental daily living activities, number of comorbidities and docetaxel treatment were independently associated with severe nonhematological toxicity. QoL was worse with docetaxel for nausea-vomiting, appetite loss, diarrhea, body image, future perspective, treatment side-effects and hair loss items. Conclusions Weekly docetaxel is not more effective than standard CMF as adjuvant treatment of older women with breast cancer and worsens QoL and toxicity. ClinicalTrials.gov NCT00331097.

PURPOSE: To investigate the value of the addition of either cisplatin (CDDP) or lonidamine (LND) to epirubicin (EPI) in the first-line treatment of advanced breast cancer. PATIENTS AND METHODS: Three hundred seventy-one metastatic breast cancer patients with no prior systemic chemotherapy for advanced disease were randomized to receive either EPI alone (60 mg/m2 on days 1 and 2 every 21 days), EPI and CDDP (30 mg/m2 on days 1 and 2 every 21 days), EPI and LND (450 mg orally daily, given continuously), or EPI, CDDP, and LND. Time to progression, response rates, side effects, and survival were compared according to the 2 × 2 factorial design of this study. RESULTS: The groups were well balanced with respect to prognostic factors. Time to progression did not differ in the comparison between CDDP arms and non-CDDP arms (median, 10.9 months v 9.4 months, respectively; P = .10) or between that of LND arms and non-LND arms (median, 10.8 months v 9.9 months, respectively; P = .47), nor did overall survival. The response rate did not significantly differ in the comparison between LND arms and non-LND arms (62.9% v 54.0%, P = .08). No difference in treatment activity was observed between CDDP arms and non-CDDP arms. Toxicity was significantly higher in the CDDP arms, leading to CDDP dose adjustment in 40% of cases. The most frequent side effects were of a hematologic and gastrointestinal nature. The addition of LND produced more myalgias and fatigue. CONCLUSION: Neither CDDP nor LND was able to significantly improve the time to progression obtained by EPI. CDDP, however, significantly worsened the drug’s tolerability.

BACKGROUND The objective of this study was to test the activity and toxicity of epirubicin plus docetaxel as primary chemotherapy for women with large, operable (T2; > 3 cm) or locally advanced (Stage III) breast carcinoma, including patients with inflammatory breast carcinoma. METHODS In this single-center, open-label, single-stage, Phase II trial, epirubicin (75 mg/m2; intravenous bolus) followed by docetaxel (80 mg/m2; 1-hour intravenous infusion) was administered on Day 1 of each cycle for four cycles. RESULTS Nine of 30 patients (30%) had inflammatory breast carcinoma. Twenty-three patients (76.7%; 95% confidence interval, 57.7–90.1) had a clinical objective response that was complete in 6 patients (20%). Twenty-seven patients (90%) underwent surgery that was conservative in 5 patients (16.7%). Pathologic response evaluation revealed four complete responses (13.3%; 95% confidence interval, 3.8–30.7). Grade 4 neutropenia was recorded in 80.0% of patients, and febrile neutropenia was recorded in one-third of patients. Anemia and thrombocytopenia were never severe. Other side effects were diarrhea (26.6%), oral mucositis (43.3%), and emesis (26.6%). CONCLUSIONS Neoadjuvant chemotherapy with epirubicin plus docetaxel was a feasible treatment and was active in an unfavorable series of patients with locally advanced breast carcinoma, including patients with inflammatory breast carcinoma. Cancer 2002;94:895–901. © 2002 American Cancer Society. DOI 10.1002/cncr.20335

515 Background: Uncertainty still exists regarding the optimal schedule of adjuvant treatment of breast cancer with aromatase inhibitors (AI) and no trial has ever compared all the three AI. Methods: FATA-GIM3 is a multicenter, open label, 2x3 factorial phase 3 randomized study of adjuvant A, E and L upfront (UP - for 5 years) or sequentially (SEQ - for 3 years after 2 years of T) in postmenopausal HR breast cancer pts. Two comparisons were planned: UP vs SEQ and A vs E vs L. DFS (including local or distant relapse, second breast or non-breast cancer, DCIS and death, whichever came first) was the primary end-point; 2% at 5 yrs (corresponding to a HR of 0.79) was defined as the minimum difference required to declare superiority of UP vs SEQ. With two-tailed alfa 0.05, power 80%, 669 events and the enrolment of 3600 patients were planned. Following Data Monitoring Committee advice, final analysis was performed after 5yrs median follow-up. For each comparison a Cox regression model was applied adjusted by stratification factors and stratified by the other treatment factor. Analyses were based on intention-to-treat. Results: from 3/2007 to 7/2012, 3697 patients were enrolled at 76 centres. Median age 64, pT1 69.7% , pN0 64.3%, ER and PgR positive 88.9%, HER2 positive 8.9%, previous chemotherapy 38.3%. At 60 months median follow-up, 401 events were reported. 5yrs DFS was 89.8 with UP and 88.5 with SEQ (delta 1.32%, 95% CI -0.90-3.54; HR 0.89, 95% CI 0.73-1.08; P=0.23). 5yrs DFS was 90.0 with A, 88.0 with E and 89.4 with L (P=0.19). Conclusions: in the FATA-GIM3 trial there is a small non statistically significant DFS advantage for UP vs SEQ. No significant difference is evident among the three AI. Supported by the FARM5K3MEE AIFA grant from the Italian Drug Agency. Clinical trial information: NCT00541086.

Data currently available are insufficient to demonstrate a real utility for CA 15-3 in the diagnosis, staging or surveillance of breast cancer patients following primary treatment. The aim of this study was to determine if there was a correlation between supranormal CA 15-3 serum levels and clinical and biological variables in breast cancer patients at first disease relapse. From October 1988 to March 1998, 430 consecutive patients entered the study. Overall CA 15-3 sensitivity was 60.7%. Elevated CA 15-3 levels were found more frequently in patients with liver metastases (74.6%) and in those with pleural effusion (75.7%). CA 15-3 sensitivity was 70.4% in patients with estrogen-receptor-positive (ER+) primary tumors and 45.9% in those with estrogen-receptor-negative (ER-) tumors (p0.0001). In patients with a limited extent of disease, marker sensitivity was 57.7% in ER+ tumors and 25.7% in ER- tumors (p0.0001). Logistic regression analysis showed ER status, disease extent and pleural effusion as independent variables associated with CA 15-3 positivity. The multivariate Cox analysis showed ER and disease extent as independent variables predicting overall survival, whereas CA 15-3 failed to be statistically significant. CA 15-3 was an independent variable only when the disease extent variable was removed. This study suggests that CA 15-3 in advanced breast cancer patients is a marker of both disease extent and ER status. The direct relationship with ER status indicates that CA 15-3 diagnostic sensitivity in the early detection of disease recurrence could be greater in ER+ patients than in ER- ones. Furthermore, this suggests that patients with elevated CA 15-3 levels could have disease that is more sensitive to hormone manipulation than those with normal CA 15-3 values.

Background: Therapeutic approach for patients with metastatic breast cancer (MBC) is still controversial. This study was conducted to assess the efficacy and safety of bevacizumab in combination with docetaxel plus capecitabine as first-line treatment for MBC. The feasibility of bevacizumab maintenance therapy in this setting was also evaluated. Patients and methods: In this single-arm, multicenter phase II study, patients received bevacizumab 15 mg/kg and docetaxel 60 mg/m2 on day 1, plus capecitabine 900 mg/m2 twice daily on days 1-14 every 21 days. Treatment was administered for up to 6 cycles, then bevacizumab continued until progressive disease. The primary end point was progression-free survival (PFS); secondary end points were tumor response rate, overall survival, and toxicity. Results: Seventy-nine eligible patients were treated with bevacizumab in combination with docetaxel plus capecitabine. The overall response rate was 61 %, with a complete response rate of 8 % and a median duration of response of 10 months. At a median follow-up of 28 months, the median PFS was 11 months. Fifty-two (65 %) patients received bevacizumab maintenance therapy for a median duration of 7 months (range 1 to 33+). Neutropenia was the most common grade 3-4 toxicity (28.1 % of patients), and two fatal adverse events occurred (septic shock and gastrointestinal perforation). Conclusions: Bevacizumab in combination with docetaxel and capecitabine demonstrates significant activity and quite acceptable toxicity profile as first-line treatment of MBC. Subsequent maintenance therapy with bevacizumab is feasible for a long period of stable disease. Results deserve confirmation. © 2013 Springer-Verlag Berlin Heidelberg.

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

Background To evaluate whether weekly schedules of docetaxel-based chemotherapy were superior to 3-weekly ones in terms of quality of life in locally advanced or metastatic breast cancer. Methods Patients with locally advanced or metastatic breast cancer, aged ≤ 70 years, performance status 0-2, chemotherapy-naive for metastatic disease, were eligible. They were randomized to weekly or 3-weekly combination of docetaxel and epirubicin, if they were not treated with adjuvant anthracyclines, or docetaxel and capecitabine, if treated with adjuvant anthracyclines. Primary end-point was global quality of life change at 6-weeks, measured by EORTC QLQ-C30. With two-sided alpha 0.05 and 80% power for 35% effect size, 130 patients per arm were needed. Results From February 2004 to March 2008, 139 patients were randomized, 70 to weekly and 69 to 3-weekly arm; 129 and 89 patients filled baseline and 6-week questionnaires, respectively. Global quality of life was better in the 3-weekly arm (p = 0.03); patients treated with weekly schedules presented a significantly worsening in role functioning and financial scores (p = 0.02 and p < 0.001). Neutropenia and stomatitis were worse in the 3-weekly arm, where two toxic deaths were observed. Overall response rate was 39.1% and 33.3% in 3-weekly and weekly arms; hazard ratio of progression was 1.29 (95% CI: 0.84-1.97) and hazard ratio of death was 1.38 (95% CI: 0.82-2.30) in the weekly arm. Conclusions In this trial, the weekly schedules of docetaxel-based chemotherapy appear to be inferior to the 3-weekly one in terms of quality of life in patients with locally advanced or metastatic breast cancer. Trial registration ClinicalTrials.gov NCT00540800.

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 III trial. Patients and Methods Patients were randomly assigned to receive tamoxifen, letrozole, or letrozole plus zoledronic acid. Serum values of estradiol, follicle-stimulating hormone (FSH), luteinizing hormone (LH), testosterone, dehydroepiandrosterone-sulphate (DHEA-S), progesterone, and cortisol were measured at baseline and after 6 and 12 months of treatment. For each hormone, changes from baseline at 6 and 12 months were compared between treatment groups, and differences over time for each group were analyzed. Results Hormonal data were available for 139 postmenopausal patients with a median age of 62 years, with 43 patients assigned to tamoxifen and 96 patients assigned to letrozole alone or combined with zoledronic acid. Baseline values were similar between the two groups for all hormones. Many significant changes were observed between drugs and for each drug over time. Namely, three hormones seemed significantly affected by one drug only: estradiol that decreased and progesterone that increased with letrozole and cortisol that increased with tamoxifen. Both drugs affected FSH (decreasing with tamoxifen and slightly increasing with letrozole), LH (decreasing more with tamoxifen than with letrozole), testosterone (slightly increasing with letrozole but not enough to differ from tamoxifen), and DHEA-S (increasing with both drugs but not differently between them). Zoledronic acid did not have significant impact on hormonal levels. Conclusion Adjuvant letrozole and tamoxifen result in significantly distinct endocrine effects. Such differences can explain the higher efficacy of letrozole as compared with tamoxifen.

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.

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.

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

578 Background: Few data have been reported on endocrine effects of combining LHRH-analogues with aromatase inhibitors (AI) in premenopausal patients. However, promising data in postmenopausal patients make this information interesting in view of extending adjuvant AI to premenopausal patients. We are conducting a phase 3 trial (Hormonal adjuvant treatment bone effects (HOBOE)) comparing tamoxifen (Tam), letrozole (L) and L + zoledronate (Z) for the effect on bone mineral density at 1 year. Postmenopausal and premenopausal patients are eligible, the latter also receiving monthly triptorelin (Tr). Methods: This analysis is limited to 76 premenopausal patients with early endocrine-responsive breast cancer, 28 treated with Tam+Tr and 48 with L+Tr±Z, assuming that Z has no endocrine effects. Serum 17-β-estradiol, FSH, LH, Δ4-androstenedione, testosterone, dehydroepiandrosterone-solphate, progesterone, ACTH and cortisol are measured at baseline and after 6 months of treatment. We compared, for each hormone, 6-month values between treatment groups by applying Exact Wilcoxon-Mann-Whitney test. Results: Baseline values for all the hormones were comparable between treatment groups. At 6 months, statistically significant differences were found for estradiol, FSH, LH and cortisol (see table , with median and range values by treatment group). No differences were found in plasma levels of testosterone, progesterone, ACTH, androstenedione, and dehydroepiandrosterone between the two groups. Conclusions: These data support that letrozole compared to tamoxifen, in combination with triptorelin, induces a more intense estrogen suppression also in premenopausal patients. Such evidence makes reasonable the hypothesis that the higher efficacy of letrozole versus tamoxifen shown in postmenopausal patients could be confirmed also in premenopausal patients. [Table: see text] No significant financial relationships to disclose.

Background Few data are available on compliance and safety of adjuvant chemotherapy when indicated in elderly breast cancer patients; CMF (cyclophosphamide, methotrexate, fluorouracil) can be reasonably considered the most widely accepted standard of treatment. Methods We retrospectively reviewed compliance and safety of adjuvant CMF in patients older than 60. The treatment was indicated if patients had no severe comorbidity, a high-risk of recurrence, and were younger than 75. Toxicity was coded by NCI-CTC. Toxicity and compliance were compared between two age subgroups ( Results From March 1991 to March 2002, 180 patients were identified, 100 older than 60 and younger than 65, and 80 aged 65 or older. Febrile neutropenia was more frequent among older patients (p = 0.05). Leukopenia, neutropenia, nausea, cardiac toxicity and thrombophlebitis tended to be more frequent or severe among elderlies, while mucositis tended to be more evident among younger patients, all not significantly. Almost one half (47%) of the older patients receiving concomitant radiotherapy experienced grade 3–4 haematological toxicity. Compliance was similar in the two groups, with 6 cycles administered in 86% and 79%, day-8 chemotherapy omitted at least once in 36% and 39%, dose reduction in 27% and 38%, prolonged treatment duration (≥ 29 weeks) in 10% and 11% and need of G-CSF in 9% and 18%, among younger and older patients, respectively. Conclusion Our data show that, in a highly selected population of patients 65 or more years old, CMF is as feasible as in patients older than 60 and younger than 65, but with a relevant burden of toxicity. We suggest that prospective trials in elderly patients testing less toxic treatment schemes are mandatory before indicating adjuvant chemotherapy to all elderly patients with significant risk of breast cancer recurrence.

Aims and Background It has been demonstrated that breast cancer screening induces a 30% reduction of specific mortality. In May 1990, we started a pilot screening program to assess the feasibility of carrying out such a program in Campania (southern Italy). Herein we report the results of the first round of the program from three municipalities (Giugliano, Mugnano and Qualiano) that lie within the local health district no. 23, close to the city of Naples. Methods Women between the ages of 50 and 69 years were sent a personalized letter inviting them to attend the screening test; those not responding were sent a second invitation. The screening test consisted of clinical examination followed by two-view mammography. Second–level diagnostic tools were sonography, fine needle aspiration (manual, echo-guided and stereotaxic) and surgical biopsy. Results Out of 5,732 women invited for the first round, 1,813 (31.6%) attended the screening. Attendance rate was higher among younger women. Ninety-one women were positive at the screening test and underwent further examination (recall rate, 5.0%). Among them, 19 had surgical biopsy (biopsy rate, 1.0%) that led to breast cancer diagnosis in 11 cases. The benign/malignant biopsy rate was 0.73. Detection rate was 6.07 × 1,000 screened women and varied among age categories, increasing within the 60–69 subgroup; detection rate/expected incidence ratio in the overall group was 4.5 and also increased within the older age category. Seven out of 11 cancers were at UICC stage 0-I. Among 327 self-referring women, 38 were positive (recall rate, 11.6%), and 14 underwent biopsy (biopsy rate, 4.3%), which showed cancer in 7 cases (benign/malignant biopsy rate, 1.0). In addition, 2 inflammatory cancers were diagnosed without surgical biopsy. Thus 9 cancer cases were detected in this group. Self-referring women differed from responding women in that they had a higher frequency of symptoms or familiar history of cancer, and a higher educational level and awareness of preventive medicine. Clinical examination added no diagnostic advantage in the responding group but did not significantly worsen the recall rate. In the self-referring group, one case of inflammatory cancer was missed by mammography and diagnosed by clinical examination. Conclusion The early results (recall rate = 5%, detection rate/expected incidence ratio = 4.5, benign/malignant biopsy rate = 0.73, advanced cancers = 36.4%) are encouraging and indicate the validity of the program. Strategies to improve attendance rate are planned.