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Background We reported the results of an Italian large retrospective analysis that evaluated the effectiveness and safety of T-DM1 in ‘field-practice’ breast cancer patients. We performed a sub-analysis to investigate the clinical activity of T-DM1 in patients with brain metastases (BMs). Methods The records of 87 adult women with HER2-positive breast cancer and BMs treated with T-DM1 were reviewed. Their clinical outcomes were compared with those of 216 patients without central nervous system (CNS) involvement. Results Response to T-DM1 treatment in BMs was available for 53 patients in the BM group (60.9%): two patients reported a complete response (3.8%), 11 patients obtained partial response (20.7%; overall response rate: 24.5%), 16 patients had a stable disease (30.1%). Regarding extracranial disease, a total of 77 and 191 patients were evaluable for response in BM group and non-BM group, respectively. The overall response rate was 35.1% in the BM group and 38.3% in the non-BM group; disease control rate was 53.3% and 66.6%, respectively. At a median follow-up of 16 months (range: 1–55), median cumulative progression-free survival (PFS) was 7 months (95% CI: 5.4–8.6) in the BM group and 8 months (95% CI: 5.7–10.3) in the non-BM group. In the second-line setting, PFS was 5 (95% CI: 3.1–6.9) versus 11 (95% CI: 7.1–14.9) months (p = 0.01). Overall survival was 14 months (95% CI: 12.2–15.8) in the BM group and 32 months (95% CI: 24.4–39.6) in the non-BM group (p Conclusions T-DM1 is active in breast cancer patients with BMs.

Ado-trastuzumab emtansine (T-DM1) is an antibody-drug conjugate approved for the treatment of patients with human epidermal growth factor receptor 2 (HER2)-positive, metastatic breast cancer (mBC). The aim of this ‘field-practice’ study was to investigate the efficacy and safety of T-DM1, focusing on treatment line, previous lapatinib treatment and patterns of metastasis. Three hundred and three patients with HER2-positive mBC who received T-DM1 were identified by reviewing the medical records of 24 Italian Institutions. One hundred fourty-nine (49%) and 264 (87%) had received prior hormonal treatment and/or anti-HER2 targeted therapy, respectively. Particularly, 149 patients had been previously treated with lapatinib. The objective response rate (ORR) was 36.2%, and 44.5% when T-DM1 was administrated as second-line therapy. Considering only patients with liver metastases, the ORR was 44.4%. The median progression-free survival (PFS) was 7.0 months in the overall population, but it reached 9.0 and 12.0 months when TDM-1 was administered as second- and third-line treatment, respectively. In conclusion, in this ‘real-word’ study evaluating the effects of T-DM1 in patients with HER2-positive mBC who progressed on prior anti-HER2 therapies, we observed a clinically-relevant benefit in those who had received T-DM1 in early metastatic treatment-line and in subjects previously treated with lapatinib.

Background: T-DM1 showed remarkable activity in metastatic HER-2 positive breast cancer (mBC) and it was recently approved for clinical use in patients (pts) who previously failed Trastuzumab- and Taxanes-based therapies. Currently, little is known on the performance of T-DM1 in a “real life” scenario. Therefore, we investigated effectiveness and safety of T-DM1 in Italian daily practice. Methods: Pts baseline characteristics and clinical outcome of pts with HER-2 positive mBC treated with T-DM1 between 2013 and 2015 at 20 Italian Institutions were retrospectively collected and analyzed. Results: 300 pts were included in our analysis. Median age was 51 years (27-78); visceral metastases were present in 204 (68%) pts and brain metastases in 86 (29%). It is noteworthy that 111 (37%) pts received T-DM1 as pure second line, 83 (28%) as third line and 96 (32%) as further lines. Moreover 10 (3%) pts had T-DM1 as first line because disease recurrence occurred during or adjuvant trastuzumab of within 6 months of its completion. The overall response rate (ORR) was 40%, global disease control rate (gDCR) 64%, median progression-free survival (PFS) 7.0 months (C.I.95%: 5.6-8.4) and overall survival (OS) at 2 years 63%. Pts with 1, 2 and 3 or more metastatic site had OS at 2 years of 87%, 67% and 46%, respectively (p Conclusions: To our knowledge, this is the first real life, multicenter retrospective analysis evaluating efficacy and safety of T-DM1 in pretreated HER-2 positive mBC pts. We observed remarkable results in terms of PFS and OS, especially when T-DM1 was given early in the course of metastatic disease. Shortened PFS in patients progressing after pertuzumab suggest further analyses to better define possible molecular mechanisms of cross-resistences between two molecules. As a whole there was no evidence of significant or unexpected toxicities. Although these findings should be taken with caution due to the retrospective analysis and the different lines of previous treatment considered, we confirmed the potential therapeutic role of T-DM1 across a heterogeneous population of HER-2 positive mBC patients. The final analysis will be presented to the meeting. Citation Format: Fabi A, De Laurentiis M, Caruso M, Valle E, Moscetti L, Santini D, Cannita K, Carbognin L, Ciccarese M, Rossello R, Arpino G, Leonardi V, Montemurro F, La Verde N, Generali DG, Zambelli A, Scandurra G, Russillo M, Paris I, D'Ottavio AM, Filippelli G, Giampaglia M, Stani S, Fabbri A, Alesini D, Giannarelli D, Cognetti F. T-DM1 in HER2 positive advanced breast cancer patients: Real world practice from a multicenter observational study [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-21-11.

2Debioclinic, Charenton-Le-Pont. France Summary Purpose: Oxaliplatin (L-OHP), a new platinum analogue, is an active drug in colorectal and ovarian cancer. In this phase II study we explored tolerability and activity of oxaliplatin as a single agent in metastatic breast carcinoma patients. Patients and methods: Fourteen anthracycline pretreated advanced breast cancer patients were enrolled. Oxaliplatin was given at 130 mg/m2 on day 1 and repeated every three weeks. Analysis of toxicity, response rate and survival was performed. Results: The median number of courses per patient was four (range 2-6). The median administered dose-intensity was 43.3 mg/m2/week (range 32.5-43.3) which represents 100% of projected dose-intensity. No severe toxicity was encountered. Three patients developed acute transient laryngeal symptoms. Three patients displayed a partial response (21%), (95% confidence interval (CI): 0%-43%), two stable disease (14%) and nine progressed (64%). Response lasted five, four and five months respectively. Median survival was 12 months. Conclusions: In this limited experience, oxaliplatin appeared to be well tolerated and moderately active in advanced anthracycline-pretreated breast cancer patients. Combination chemotherapy with other active drugs such as 5-fluorouraci l (5-FU), anthracyclines and taxanes should represent the next step of development of this new drug.

In this phase II study, we explored tolerability and activity of vinorelbine administered according to a dose-dense weekly schedule with hematopoietic growth factor support in pretreated, advanced breast cancer patients.From January 1994 to March 1996, 40 patients with metastatic breast cancer, pretreated with at least one prior anthracycline-containing regimen, were entered into the study.median age 53 years (range 32-70); ECOG performance status 0-1: 34 patients, 2: 6 patients; dominant visceral metastatic disease: 15 patients, dominant non-visceral: 25; anthracycline-refractory/resistant: 2 patients, sensitive: 38 patients. Six patients were treated as first-line therapy for metastatic disease and 34 in second- or subsequent lines. All patients received vinorelbine at the dose of 25 mg/m2/week as a short intravenous infusion, together with routine antiemetic medication. Granulocyte-colony stimulating factor (Lenograstim) at the dose of 150 microg/m2 subcutaneously on day 3 was included in the treatment schedule.The median number of treatment weeks was 23 (range: 4-24), with a delivered dose-intensity (DDI) of 23.8 mg/m2/week (range: 18.7-25, 95.2% of projected dose-intensity). Toxicity was mild, with non-complicated neutropenia being the main toxicity observed (grade 3-4 in 25% of the patients but only 2% of treatment weeks). Overall response rate was 52.5%, with complete responses in 12.5% of patients. Median duration of the response and median time to progression were 10 and 9 months, respectively. Median overall survival was 19 months.Dose-dense weekly vinorelbine is safe and effective with minimal toxicity in pretreated advanced breast cancer patients.

Summary Background This study was designed to explore the effectiveness and tolerability of a weekly regimen of epirubicin and vinorelbine plus granulocyte colony-stimulating factor (G-CSF). Patients and methods Fifty-two patients with previously untreated advanced breast cancer were treated with epirubicin (25 mg/m2/week) and vinorelbine (25 mg/m2/week) with G-CSF support, for 24 consecutive weeks. Results The median number of courses per patient was 22 (range 10–24). The administered dose intensity was 23 mg/m2for both epirubicin and vinorelbine. Ten complete responses (19%) and 30 partial responses (58%) were obtained, for an overall response rate of 77%. None of the patients progressed during treatment. The median response duration and time to progression were both 10 months. A total of 1065 courses were assessed for toxicity. Grade 3 neutropenia was the most common toxic manifestation, (39% of patients), without febrile neutropenia or neutropenic sepsis. Two patients had grade 3 cardiac toxicity, which regressed without sequelae. Median survival was 31 months, with a median follow-up of 24 months (range 9–40). Conclusions Owing to its effectiveness and tolerability, the weekly regimen of epirubicin and vinorelbine plus G-CSF may represent an acceptable alternative for patients with untreated metastatic breast cancer. It could be tested in the adjuvant and neoadjuvant setting.

This study was designed to evaluate the efficacy and tolerability of a weekly schedule of epirubicin in combination with docetaxel in the first-line treatment of patients with metastatic breast cancer (MBC). A total of 43 women with MBC not previously treated with chemotherapy for metastatic disease received weekly epirubicin 25 mg m(-2) and docetaxel 25 mg m(-2) for a maximum of five cycles (total cumulative epirubicin dose ofor =900 mg m(-2)). Dose reduction was not permitted. Objective response and evaluation of toxicity profile were the primary study end points; time to progression and overall survival were secondary end points. Patients were followed for a median of 21 (4-38) months. Analysis was by intent to treat; 33 patients completed five cycles of therapy, and the median dose of epirubicin administered to the 43 patients was 23 mg m(-2). Twenty-five patients (58%) achieved a partial response and one (2%) achieved a complete response. An additional 12 patients (28%) had stable disease. The median time to progression was 11 months (95% confidence intervals (CI) 7-14) overall, and 13 months (95% CI 12-14) in the 26 patients who responded to treatment. Median overall survival was 25 months for responders and 14 months for nonresponders. Grade 3/4 neutropenia occurred in 16% of patients and in 6% of cycles. One patient developed cardiac toxicity (20% reduction in left ventricular ejection fraction). The combination of epirubicin plus docetaxel is highly active in MBC, with a manageable toxicity profile. Such a weekly schedule might provide a valuable treatment option for MBC.

We conducted a phase II study to determine the activity and tolerability of weekly paclitaxel, 5-fluorouracil (5-FU) and folinic acid plus granulocyte colony-stimulating factor (G-CSF) support in anthracycline-pre-treated or -resistant metastatic breast cancer patients. The phase II study was designed following the Simon optimal-two stage method. Patients received paclitaxel 80 mg/m 2 , folinic acid 10 mg/m 2 and bolus infusion of 5-FU 300 mg/m 2 every week plus G-CSF on day 3 for 24 consecutive weeks in the absence of disease progression. From May 1998 to May 2000, 51 patients entered the study. Patients received a median relative dose intensity of 97.5% (range 81-100%). No severe toxicities were observed. Seven patients (14%) experienced neutropenia grade 2. Seven patients (14%) experienced grade 2 anemia. Two patients (4%) experienced severe asthenia. Three out of 50 evaluable patients [6%, 95% confidence interval (CI) 2-12.6%] showed a complete response, whereas 23 (46%, 95% Cl 32.2-59.8%) had a partial response, with an overall response rate of 52% (95% Cl 38.2-65.8%). In addition, eight patients (15.7%) had stable disease. In the 13 patients untreated for metastatic disease, the overall response rate was 92.3% (Cl 77.8-100), with one complete response and 11 partial responses (84.6% Cl 65-100%). In the whole group, the median time to progression and overall survival were 8 (range 1-18) and 14 months (95% Cl 11-17), respectively. Thus, in metastatic breast cancer patients pre-treated with anthracyclines, the weekly administration of paclitaxel, 5-FU and folinic acid with G-CSF support seems to be extremely tolerable and active.

Docetaxel has proven effective in advanced breast cancer. Myelosuppression and cumulative fluid retention syndrome are troublesome, potentially avoidable toxicities. In this consecutive cohort study, docetaxel (100 mg/m2 by 1 hour i.v. infusion, q3 weeks) activity and toxicity was explored in 56 anthracycline-pretreated patients (eligible: 55: median age: 51 years [range: 28-68 years]; median performance status: 0 [range: 0-3]) with metastatic breast cancer, using two different granulocyte colony-stimulating factor and steroid pre- and postmedication schedules. Twenty-nine patients (group A) received a 5-day oral prednisone premedication, and 26 (group B) received 4-day low-dose i.m. dexamethasone; group B patients also received prophylactic granulocyte colony-stimulating factor. All patients were evaluable for toxicity and 53 for response. Prophylactic granulocyte colony-stimulating factor significantly lowered the incidence of grade III-IV neutropenia and neutropenic fever (p = 0.0001 and 0.01, respectively). The incidence of moderate-severe fluid retention syndrome was lower in patients receiving i.m. dexamethasone (p = 0.08). Overall response rate was 53% (4 complete responses/24 partial responses, 95% confidence interval 39.4-66.2%); 32% have stable disease and 15% progressive disease. In 21 anthracycline-refractory/resistant patients, as well as in 10 paclitaxel-pretreated patients, the overall response rate was 50%. Docetaxel is highly active in anthracycline- and paclitaxel-pretreated metastatic breast cancer, with manageable toxicity. Optimal use of both granulocyte colony-stimulating factor support and steroid premedication deserves further investigation.

Lonidamine has been demonstrated to potentiate the cytotoxic activity of several antineoplastic drugs, for example anthracyclines. Moreover, epirubicin is considered one of the most active drugs in advanced breast cancer, although optimal dose and schedule remains to be defined. In the present study we have treated 51 patients with advanced breast cancer with a combination of lonidamine (450 mg/day orally from day 1 throughout treatment) and epirubicin (25 mg/m2 i.v.) administered according to a weekly schedule for 24 weeks. Objective responses were observed in 29 out of 51 patients (57%; CR 16%, PR 41%). Liver metastases responded in eight out of 12 evaluable patients (67%). Average response duration was 12.4 months and median overall survival was 23 months (range 1-90+). Toxicity was negligible. The combination of weekly epirubicin and lonidamine is feasible and active in advanced breast cancer patients.

In the present report, we retrospectively analyzed the impact of the timing of surgery during menstrual cycle on disease‐free and overall survival of 248 premenopausal patients with stage I/Il breast cancer who underwent surgery followed by anthracycline‐containing adjuvant chemotherapy. With a median follow‐up of 5 years, no statistically significant differences were observed in disease‐free or overall survival between women operated upon during the follicular (days 0–14) and the luteal (days 15–32) phase of the menstrual cycle. The impact on disease‐free and overall survival of lymph‐node status, tumor size and hormone receptor expression, but not of the phase of the menstrual cycle at the time of surgery, was confirmed by univariate and multivariate analysis. However, when combined with hormone receptor status, the phase of the menstrual cycle at the time of surgery proved useful to better define the prognosis of primary breast cancer patients, with significantly longer disease‐free and overall survival for patients operated upon during the follicular phase and with positive hormone receptors.