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HER2 +- amplified breast cancer patients derive benefit from treatment with anti-HER2-targeted therapy. Though adjuvant treatment is based on final pathology, decisions regarding neoadjuvant chemotherapy are made in the preoperative setting with imaging playing a key role in staging. We examined the accuracy of pre-operative imaging in determining pathological tumor size (pT) in patients undergoing upfront surgery. Early (cT1–T2N0) HER2 + breast cancer patients who underwent upfront surgery between 2015 and 2016 were identified from a prospective institutional database. We compared data for both clinical and final pathologic stage. Only those who underwent magnetic resonance imaging (MRI), mammography, and ultrasound in the preoperative setting were included in the analysis. Adjuvant treatment regimens were reviewed. We identified 87 cT1–2N0 patients with invasive HER2 + breast cancer who underwent upfront surgery. Median age was 52 years (IQR 43, 58) and median tumor size was 1.1 cm (IQR 0.5, 1.6). Fifteen patients (17%) were upstaged to stage II/III based on final pathology. Thirty-seven patients were T1cN0 on final pathology; 8 were cT1a–bN0 preop and 12 had pT overestimated by MRI by an average of 1.5 cm (> 0.5–1.5 cm). Compared to both mammography and MRI, the imaging modality most predictive of pT was ultrasound (p = 0.000072 ultrasound vs mammography and 0.000042 ultrasound vs MRI). For small HER2 + cN0 tumors undergoing upfront surgery, ultrasound was the imaging modality most predictive of pT. MRI overestimated tumor size in approximately 40% of patients. MRI may not accurately discriminate low-volume tumor burden in the breast and carries the potential of overtreatment in the upfront setting.

Purpose: Activating mutations in PIK3CA promote resistance to HER2-targeted therapy in breast cancer; however, inhibition of PI3K alone leads to escape via feedback upregulation of HER3. Combined inhibition of HER2, HER3, and PI3K overcomes this mechanism preclinically. Patients and Methods: This phase I study investigated the MTD of alpelisib given in combination with trastuzumab and LJM716 (a HER3-targeted antibody) in patients with PIK3CA-mutant HER2-positive (HER2+) metastatic breast cancer (MBC) using the continual reassessment method. Secondary analyses included efficacy and exploratory correlative studies. Results: Ten patients were treated initially with daily alpelisib (arm A). Grade ≥3 adverse events seen in ≥2 patients included diarrhea (n = 6), hypokalemia (n = 3), abnormal liver enzymes (n = 3), hyperglycemia (n = 2), mucositis (n = 2), and elevated lipase (n = 2). The MTD of alpelisib in arm A was 250 mg daily. This prompted the opening of arm B in which 11 patients received intermittently dosed alpelisib. Grade ≥3 adverse events seen in ≥2 patients included diarrhea (n = 5), hypokalemia (n = 3), and hypomagnesemia (n = 2). The MTD of alpelisib in arm B was 350 mg given 4 days on, 3 days off. Among 17 patients assessed, 1 had a partial response, 14 had stable disease, and 2 had disease progression at best response. Five patients had stable disease for >30 weeks. mRNA profiling of pre- and on-treatment tissue demonstrated PIK3CA target engagement by alpelisib via induction of downstream signaling and feedback pathways. Conclusions: Combination treatment with alpelisib, trastuzumab, and LJM716 was limited by gastrointestinal toxicity. Further efforts are warranted to target the PI3K pathway in HER2+ MBC.

Background: Denosumab is approved to prevent fragility fractures in patients with osteoporosis at high risk for fracture and to prevent bone loss in patients with breast and prostate cancer who receive endocrine therapy. The antiresorptive effect of denosumab rapidly dissipates when it is delayed or discontinued, but the risk for, and incidence of, multiple clinical vertebral fractures in patients with breast cancer after stopping denosumab is currently unclear. Question/Purposes: We sought to identify the incidence of clinical vertebral fractures in patients with breast cancer who received at least 2 doses of denosumab (60 mg) and then discontinued the medication. Methods: We conducted a retrospective chart review to identify patients with a history of breast cancer who were treated with denosumab between June 1, 2010, and July 18, 2018, at Memorial Sloan Kettering Cancer Center. We identified 335 postmenopausal women and 1 man with nonmetastatic breast cancer who received their final denosumab injection at least 6.5 months earlier. Data recorded included baseline bone density and the incidence of vertebral fractures after denosumab discontinuation. Results: The median age of patients was 62 years. Patients received between 2 and 13 denosumab doses before drug discontinuation. Most of the patients (310; 92.3%) were also treated with aromatase inhibitors. Of the 194 patients with baseline bone density data, 50 (25.8%) had normal bone density, 97 (50.0%) had osteopenia, and 47 (24.2%) had osteoporosis. The median follow-up duration from the last denosumab dose was 18.5 months. We identified 1 case of spontaneous vertebral fractures after denosumab stoppage. We found no cases of osteonecrosis of the jaw or atypical femur fracture. Most of the patients (88%) had a gap in denosumab dosing. Conclusions: Clinicians treating patients with breast cancer—especially those continuing to take aromatase inhibitors—should be aware of the possible risks of delaying doses of or discontinuing denosumab and should educate their patients accordingly. Prospective studies are needed to fully evaluate the risks of stopping or delaying denosumab.

Despite recent refinements to the 21-gene g score, allowing a better identification of patients who may derive no benefit from the addition of adjuvant chemotherapy to that of endocrine therapy, patients with early breast cancer still stand to be over-treated in the setting of clinical and/or genomic uncertainty or discordance. Here we describe and demonstrate a potential approach of further refining the OncotypeDX risk score by metabolomic analysis of serum. In a clinical dataset (N = 87), the risk of recurrence was further sub-stratified by metabolomic signature, with an effective splitting of each Oncotype risk classification. A total of seven recurrences were recorded, with metabolomic analysis accurately predicting six of these. Contrastingly, the genomic risk score of the seven recurrences ranged across all three Oncotype classifications (one recurrence occurred in the “low”-risk group, three in the “intermediate” group and three in the “high”-risk group).

Neoadjuvant endocrine therapy (NET) is effective in downstaging large hormone receptor-positive (HR+) breast cancers and increasing rates of breast-conserving surgery (BCS), but data regarding nodal pathologic complete response (pCR) are sparse. We reported nodal and breast downstaging rates with NET, and compared axillary response rates following NET and neoadjuvant chemotherapy (NAC). Consecutive stage I–III breast cancer patients treated with NET and surgery from January 2009 to December 2019 were identified from a prospectively maintained database. Nodal pCR rates were compared between biopsy-proven node-positive patients treated with NET, and HR+/HER2- patients treated with NAC from November 2013 to July 2019. 127 cancers treated with NET and 338 with NAC were included. NET recipients were older, more likely to have lobular and lower-grade tumors, and higher HR expression. With NET, the nodal pCR rate was 11% (4/38) of biopsy-proven cases, and the breast pCR rate was 1.6% (2/126). Nodal-dowstaging rates with NET and NAC were not significantly different (11% vs 18%; P = 0.37). Patients achieving nodal pCR with NET versus NAC were older (median age 70 vs 50, P = 0.004) and had greater progesterone receptor (PR) expression (85% vs 13%, P = 0.031), respectively. Of patients not candidates for BCS due to a large tumor relative to breast size, 36/47 (77%) became BCS-eligible with NET (median PR expression 55% vs 5% in those remaining ineligible, P

Aim: To evaluate clinical vertebral fractures after denosumab discontinuation in patients with breast cancer. Methods: To evaluate the occurrence of clinical vertebral fractures after denosumab discontinuation, we conducted a retrospective chart review to identify patients with a history of breast cancer who were treated with denosumab between June 1, 2010 and July 18, 2018 at Memorial Sloan Kettering Cancer Center. We identified 335 postmenopausal female patients and one male patient with nonmetastatic breast cancer who received at least two doses of denosumab (60 mg) and had received their final denosumab injection at least 6.5 months earlier. Results: The median age of patients was 62 years (54–69). Patients received between two and 13 denosumab doses before drug discontinuation. The majority of patients (310; 92.3%) were also treated with aromatase inhibitors. Of the 194 patients with baseline bone-density data, 50 (25.8%) had normal bone density, 97 (50.0%) had osteopenia, and 47 (24.2%) had osteoporosis. The median follow-up duration from the last denosumab dose was 18.5 months (12.5–23.5). We identified one case of spontaneous vertebral fractures after denosumab stoppage. We found no cases of osteonecrosis of the jaw or atypical femur fracture. A majority of patients (88%) had a gap in denosumab dosing. Conclusions: Patients with breast cancer—especially those taking aromatase inhibitors—taking denosumab should be warned of the risks of delaying denosumab. Larger prospective studies are needed to fully evaluate the risks of stopping or delaying denosumab

Background: The epichaperome is a new cancer target required for tumor survival (Joshi et al. Nature Reviews Cancer 2018). PU-H71 is a synthetic, purine scaffold epichaperome inhibitor that binds to the ATP-binding site of HSP90 specifically when HSP90 is integrated into the epichaperome (Rodina et al. Nature 2016). It has demonstrated antitumor activity in multiple xenograft models. Furthermore, sequential administration of nab-paclitaxel and PU-H71 in TNBC xenograft models augmented epichaperome levels, and in turn resulted in super-synergistic drug action with ablation of xenografted tumors and cures in mice. Methods: This is an open label phase1b study of PU-H71 + nab-paclitaxel in pts with HER2- MBC. Pts received nab-paclitaxel at a standard dose of 260mg/m2 IV Q 3weeks. PU-H71 was administered IV 6 hrs (+/-1 hr) post nab-paclitaxel Q3weeks in 2 escalating dose levels (225mg/m2 and 300 mg/m2). All pts underwent FDG PET/CT every 6 weeks. Additionally, patients had the option to enroll on a separate diagnostic PU-PET protocol to measure epichaperome expression prior to initiating treatment on the phase 1b study, wherein they received a single dose of up to 11mci of 124I-PU-H71 IV and underwent imaging at 3-4hrs and 20-24 hrs. Primary objective was to establish the MTD/RP2D of this regimen. Secondary objectives were to assess PK of PU-H71 + nab-paclitaxel and clinical efficacy. Exploratory analysis included correlation of epichaperome expression at baseline using PU-PET with tumor response. Results: 12 patients (5 ER+/HER2- ; 7 TNBC) were enrolled (6 at 225mg/m2 of PU-H71 and 6 at 300mg/m2). Median Age: 54 yrs (range: 37-71). Median ECOG: 0. Median lines of therapy in the metastatic setting: 6 (range 1-11) including prior taxanes in 75% of pts. Most common toxicities included diarrhea G1 58%; G2 7%, G3 7%) that was easily managed with anti-diarrheal agents, G1 fatigue (25%), G1/2 peripheral neuropathy (17%), G1 hyperglycemia (67%), G1 increases in alk phos (58%), AST (50%) and ALT (42%). Hematological toxicities included G3 leukopenia (42%), G3/4 neutropenia (67%), G3 anemia (50%) and G2 thrombocytopenia (17%). There were no DLTs. 33% (4/12) had PR, 58% (7/12) achieved SD with only 1 PD at the time of first scan; 5 pts are currently ongoing including 2 TNBC pts with PR who have been on therapy > 7 months. PK data will be presented. 8/12 patients also underwent PU-PET at baseline. A higher tumor to muscle SUV ratio at 24 hrs on PU-PET predicted response and increased PU-H71 retention on PU-PET at 24 hrs correlated with a longer duration of response. Conclusion: The RP2D of PU-H71 was 300mg/m2 with 260mg/m2 of nab-paclitaxel administered IV every 3 weeks. The regimen is well tolerated with promising clinical activity in this heavily pre-treated cohort. Tumor epichaperome expression at baseline using PU-PET has the potential to serve as a predictive biomarker of response. A Phase 2 trial of this combination along with baseline PU-PET is currently planned. Citation Format: Jhaveri K, Dunphy M, Wang R, Comen E, Fornier M, Moynahan ME, Bromberg J, Ma W, Patil S, Taldone T, Rodina A, Sterlin V, Khoshi S, Lewis J, Norton L, Chiosis G, Modi S. Tumor epichaperome expression using 124I PU-H71 PET (PU-PET) as a biomarker of response for PU-H71 plus nab-paclitaxel in HER2 negative (HER2-) metastatic breast cancer (MBC) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-20-03.

Background Overexpression and activation of tyrosine kinase Src has been linked to breast carcinogenesis and bone metastases. We showed the feasibility of combining the SRC inhibitor dasatinib with weekly paclitaxel in patients with metastatic breast cancer (MBC) and herein report the subsequent phase II trial. Patients and Methods Patients had received ≤ 2 chemotherapy regimens for measurable, HER2-negative MBC. Patients received paclitaxel and dasatinib (120 mg daily) and were assessed according to Response Evaluation Criteria in Solid Tumors for overall response rate (ORR), the primary end point. Secondary end points included progression-free survival (PFS) and overall survival (OS). A 30% ORR (n = 55) was deemed worthy of further investigation. Exploratory biomarkers included N-telopeptide (NTX) and plasma vascular epidermal growth factor (VEGF) receptor 2 as predictors of clinical benefit. Results From March 2010 to March 2014, 40 patients, including 2 men enrolled. The study was stopped early because of slow accrual. Overall, 32 patients (80%) had estrogen receptor-positive tumors and 23 (58%) had previously received taxanes. Of the 35 assessable patients, 1 (3%) had complete response and 7 (20%) partial response, resulting in an ORR of 23%. The median PFS and OS was 5.2 (95% confidence interval [CI], 2.9-9.9) and 20.6 (95% CI, 12.9-25.2) months, respectively. As expected, fatigue (75%), neuropathy (65%), and diarrhea (50%) were common side effects, but were generally low-grade. Median baseline NTX was similar in patients who had clinical benefit (8.2 nmol BCE) and no clinical benefit (10.9 nmol BCE). Similarly, median baseline VEGF levels were similar between the 2 groups; 93.0 pg/mL versus 83.0 pg/mL. Conclusion This phase II study of dasatinib and paclitaxel was stopped early because of slow accrual but showed some clinical activity. Further study is not planned.

1062 Background: We assessed the antitumor activity of cabozantinib, a potent multi-receptor oral tyrosine kinase inhibitor with activity against MET, RET, VEGFR2, and AXL, in patients with hormone-receptor positive (HR+) breast cancer with bone metastases. Methods: In this single-arm multicenter phase II study, patients with HR+, HER2- metastatic breast cancer and ≥ 1 prior line of therapy received an initial starting dose of 100 mg cabozantinib, later reduced to 60 mg per day. The primary endpoint was bone scan response rate determined by independent central review and defined as percent change of bone scan area from baseline. The target bone scan response rate was 30% compared to a null response rate of 10%. Secondary endpoints included objective response rate (ORR) by RECIST v1.1, progression free (PFS) and overall survival (OS). Bone scan and CT were obtained every 12 weeks. Results: Among 52 enrolled patients, median age was 55, and 54% and 42% had > 2 lines prior endocrine and chemotherapy, respectively and 18 (35%) had bone-only disease. 20 (38%) experienced a partial bone scan response and 6 (12%) had stable disease (SD). 16 (31%) patients discontinued study prior to week 12 assessment for early clinical progression or toxicity, and three (6%) had missing follow-up scans. Best extra-osseous overall response revealed SD in 26 (50%), but no objective responses. In 25 patients with bone scan disease control at 12 weeks, only 3 (12%) developed extra-osseous progression. Median PFS was 4.3 months (90% CI 2.8 - 5.5) and OS was 19.6 months (90% CI 18.0 – 26.8). In a landmark analysis, patients with bone scan disease control at 12 weeks had longer OS (median 24.2 months, 90% CI 16.4 – 31.7) than those without (median OS 13.3 months, 90% CI 9.5 – 18.2), with a hazard ratio of 0.37 (90% CI 0.21 – 0.65). Most common grade 3 or 4 toxicities were hypertension (10%), anorexia (6%), diarrhea (6%), fatigue (4%) and hypophosphatemia (4%). Dose reduction or delay occurred in 42 (81%) patients. Conclusions: This study met its primary endpoint with bone scans improved in 38% of patients with metastatic HR+ breast cancer and remained stable in an additional 12% with cabozantinib treatment. Bone scan response correlated with improved OS. This is the first reported study in breast cancer to use bone scan response as a primary endpoint. Further studies with cabozantinib in HR+ breast cancer and additional validation of bone scan response as a surrogate for clinical benefit in breast cancer are warranted. Clinical trial information: NCT01441947 .

Summary Background Endocrine therapy-based neoadjuvant treatment for luminal breast cancer allows efficient testing of new combinations before surgery. The activation of the phosphatidylinositol-3-kinase (PI3K) pathway is a known mechanism of resistance to endocrine therapy. Taselisib is an oral, selective PI3K inhibitor with enhanced activity against PIK3CA-mutant cancer cells. The LORELEI trial tested whether taselisib in combination with letrozole would result in an increased proportion of objective responses and pathological complete responses. Methods In this multicentre, randomised, double-blind, parallel-cohort, placebo-controlled phase 2, study, we enrolled postmenopausal women (aged ≥18 years) with histologically confirmed, oestrogen receptor (ER)-positive, HER2-negative, stage I–III, operable breast cancer, from 85 hospitals in 22 countries worldwide. To be eligible, patients had have an Eastern Cooperative Oncology Group (ECOG) performance status 0–1, adequate organ function, and had to have evaluable tumour tissue for PIK3CA genotyping. Patients were randomly assigned (1:1) by means of a permuted block algorithm (block size of four) via an interactive voice or web-based response system, to receive letrozole (2·5 mg/day orally, continuously) with either 4 mg of oral taselisib or placebo (on a 5 days-on, 2 days-off schedule) for 16 weeks, followed by surgery. Randomisation was stratified by tumour size and nodal status. Site staff, patients, and the sponsor were masked to treatment assignment. Coprimary endpoints were the proportion of patients who achieved an objective response by centrally assessed breast MRI and a locally assessed pathological complete response in the breast and axilla (ypT0/Tis, ypN0) at surgery in all randomly assigned patients and in patients with PIK3CA-mutant tumours. Analyses were done in the intention-to-treat population. This trial is registered with ClinicalTrials.gov , number NCT02273973 , and is closed to accrual. Findings Between Nov 12, 2014, and Aug 12, 2016, 334 participants were enrolled and randomly assigned to receive letrozole and placebo (n=168) or letrozole and taselisib (n=166). Median follow-up was 4·9 months (IQR 4·7–5·1). The study met one of its primary endpoints: the addition of taselisib to letrozole was associated with a higher proportion of patients achieving an objective response in all randomly assigned patients (66 [39%] of 168 patients in the placebo group vs 83 [50%] of 166 in the taselisib group; odds ratio [OR] 1·55, 95% CI 1·00–2·38; p=0·049) and in the PIK3CA-mutant subset (30 [38%] of 79 vs 41 [56%] of 73; OR 2·03, 95% CI 1·06–3·88; p=0·033). No significant differences were observed in pathological complete response between the two groups, either in the overall population (three [2%] of 166 in the taselisib group vs one [1%] of 168 in the placebo group; OR 3·07 [95% CI 0·32–29·85], p=0·37) or in the PIK3CA-mutant cohort (one patient [1%) vs none [0%]; OR not estimable, p=0·48). The most common grade 3–4 adverse events in the taselisib group were gastrointestinal (13 [8%] of 167 patients), infections (eight [5%]), and skin–subcutaneous tissue disorders (eight [5%]). In the placebo group, four (2%) of 167 patients had grade 3 or worse vascular disorders, two (1%) had gastrointestinal disorders, and two (1%) patients had grade 3 or worse infections and infestations. There was no grade 4 hyperglycaemia and grade 3 cases were asymptomatic. Serious adverse events were more common in the taselisib group (eight [5%] patients with infections and seven [4%] with gastrointestinal effects) than in the placebo group (one [1%] patient each with grade 3 postoperative wound and haematoma infection, grade 4 hypertensive encephalopathy, grade 3 acute cardiac failure, and grade 3 breast pain). One death occurred in the taselisib group, which was not considered to be treatment-related. Interpretation The increase in the proportion of patients who achieved an objective response from the addition of taselisib to endocrine therapy in a neoadjuvant setting is consistent with the clinical benefit observed in hormone receptor-positive, HER2-negative, metastatic breast cancer. Funding Genentech and F Hoffmann-La Roche.

SUMMARY Eribulin mesylate is a novel nontaxane microtubule inhibitor, approved by the US FDA and EMA for the treatment of patients with metastatic breast cancer (MBC). This approval was based upon a pivotal Phase III trial where eribulin demonstrated a survival benefit compared with treatment of physician's choice in MBC patients who received at least two regimens in the metastatic setting. However, a subsequent Phase III study failed to demonstrate superiority of eribulin over capecitabine, in MBC patients who had received two or less regimens in the advanced setting. A pooled analysis of these two studies confirmed the survival benefit of eribulin compared with control. We will review the pivotal early-phase data and Phase III trials of eribulin, describe the role of eribulin for MBC, and summarize future directions in the development of this agent for both metastatic and early-stage breast cancer.

Purpose The CLEOPATRA (Clinical Evaluation of Trastuzumab and Pertuzumab) study demonstrated superior progression-free survival (PFS) and overall survival when pertuzumab was added to trastuzumab and docetaxel. Paclitaxel given once per week is effective and less toxic than docetaxel. We performed a phase II study to evaluate the efficacy and safety of pertuzumab and trastuzumab with paclitaxel given once per week. Patients and Methods Patients with metastatic human epidermal growth factor receptor 2–positive breast cancer with zero to one prior therapy were enrolled. Treatment consisted of paclitaxel 80 mg/m2 once per week plus trastuzumab (8 mg/kg loading dose → 6 mg/kg) once every 3 weeks plus pertuzumab (840 mg loading dose → 420 mg) once every 3 weeks, all given intravenously. The primary end point was 6-month PFS assessed by Kaplan-Meier methods. Results From January 2011 to December 2013, we enrolled 69 patients: 51 (74%) and 18 (26%) treated in first- and second-line metastatic settings, respectively. At a median follow-up of 21 months (range, 3 to 38 months), 6-month PFS was 86% (95% CI, 75% to 92%). The median PFS was 19.5 months (95% CI, 14 to 26 months) overall. PFS was 24.2 months (95% CI, 14 months to not reached [NR]) and 16.4 months (95% CI, 8.5 months to NR) for those without and with prior treatment, respectively. At 1 year, Kaplan-Meier PFS was 70% (95% CI, 56% to 79%) overall, 71% (95% CI, 55% to 82%) for those without prior therapy, and 66% (95% CI, 40% to 83%) for those with prior therapy. Treatment was well-tolerated; there was no febrile neutropenia or symptomatic left ventricular systolic dysfunction. Conclusion Paclitaxel given once per week with trastuzumab and pertuzumab is highly active and well tolerated and seems to be an effective alternative to docetaxel-based combination therapy.

Introduction Aromatase-inhibitors (AIs) are commonly used for treatment of patients with hormone-receptor positive breast carcinoma, and are known to induce bone density loss and increase the risk of fractures. The current standard-of-care screening tool for fracture risk is bone mineral density (BMD) by dual-energy X-ray absorptiometry (DXA). The fracture risk assessment tool (FRAX®) may be used in conjunction with BMD to identify additional osteopenic patients at risk of fracture who may benefit from a bone-modifying agent (BMA). The trabecular bone score (TBS), a novel method of measuring bone microarchitecture by DXA, has been shown to be an independent indicator of increased fracture risk. We report how the addition of TBS and FRAX®, respectively, to BMD contribute to identification of elevated fracture risk (EFR) in postmenopausal breast cancer patients treated with AIs. Methods 100 patients with early stage hormone-positive breast cancer treated with AIs, no prior BMAs, and with serial DXAs were identified. BMD and TBS were measured from DXA images before and following initiation of AIs, and FRAX® scores were calculated from review of clinical records. EFR was defined as either: BMD ≤−2.5 or BMD between −2.5 and −1 plus either increased risk by FRAX® or degraded microstructure by TBS. Results At baseline, BMD alone identified 4% of patients with EFR. The addition of FRAX® increased detection to 13%, whereas the combination of BMD, FRAX® and TBS identified 20% of patients with EFR. Following AIs, changes in TBS were independent of changes in BMD. On follow-up DXA, BMD alone detected an additional 1 patient at EFR (1%), whereas BMD+ FRAX® identified 3 additional patients (3%), and BMD+FRAX®+TBS identified 7 additional patients (7%). Conclusions The combination of FRAX®, TBS, and BMD maximized the identification of patients with EFR. TBS is a novel assessment that enhances the detection of patients who may benefit from BMAs.

Background: Src kinase plays an important role in proliferation, survival, angiogenesis and metastasis in several malignancies including breast cancer. Therefore, inhibition of Src and other tyrosine kinases (TKs) represents a novel therapeutic approach. Dasatinib is a potent inhibitor of 5 oncogenic TKs, inhibits VEGF-stimulated proliferation, has potent bone anti-resorptive activity and selectively inhibits basal-type breast cancer growth. Preclinically, the combination of dasatinib and paclitaxel had superior antitumor activity to either agent alone. In a previous phase I study, we determined that, in combination with weekly paclitaxel, the optimum dose of dasatinib was 120mg. Of note, 4/9 (44%) patients treated at or above this dasatinib dose level had objective tumor response. We now present results from the phase II trial of this combination. Methods: Patients with MBC, ECOG PS 0–1, normal hepatic, renal, marrow function were eligible. Patients had measurable, HER2-negative metastatic breast cancer (MBC), ≤2 prior therapies for MBC. Treatment consisted of weekly paclitaxel 80 mg/m2 IV 3/4 weeks + Dasatinib 120mg orally daily. Response was assessed by RECIST after every 8 weeks of therapy. Simon's two-stage optimal design was used to test the null hypothesis of a 15% response rate (RR) against the alternative of a 30% RR. In stage I, planned enrollment was 23 patients based on Type I and Type II errors of 10%. If 4 or more responses are observed, enrollment will be extended to 55 patients. Exploratory correlative biomarkers of clinical benefit include Src phosphorylation (p-Src) in peripheral blood mononuclear cells, plasma levels of VEGFR2 and collagen Type IV, circulating tumor cells (CTCs) and tumor gene expression profiling. Results: 21 patients (19 females, 2 male) have enrolled; median age 48 (range 30–79). Patients received a median of 1 prior therapy for MBC (range 0–2). 6 patients are not assessable for response: 1 has received Conclusion: Data from this phase II has demonstrated preliminary evidence of activity for weekly paclitaxel and dasatinib 120mg in patients with MBC. These findings are consistent with data from this dose level in the earlier phase I study. Predictive biomarkers of clinical benefit are under investigation. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P5-20-07.

Background: Despite recent improvements in breast cancer outcomes, patients (pts) with high-risk, early-stage breast cancer continue to experience recurrences and death due to disease. Chemotherapy regimens with the ability to extend survival remain an important drug development goal. Eribulin mesylate has demonstrated antitumor activity and improved overall survival (OS) in pts with heavily pretreated, locally recurrent or metastatic breast cancer when compared to treatment of physician's choice. This study examines the feasibility of eribulin as adjuvant therapy following dose-dense (dd) doxorubicin (A) and cyclophosphamide (C) in patients with early-stage breast cancer. Methods: Eligible pts have histologically confirmed, HER2-normal, stage I-III invasive breast cancer and adequate bone marrow, liver, and renal function. Treatment consists of dd AC (A 60mg/m2 IV; C 600mg/m2 IV) on Day 1 of each 14-day cycle x4 cycles, followed by eribulin mesylate 1.4mg/m2 IV over 2–5min on Days 1 and 8 every 21 days x4 cycles. Radiation/hormonal therapy were allowed per standard of care. The primary objective of feasibility is defined as the ability to complete 4 cycles of eribulin without a treatment-related dose delay (defined as >2 days) or reduction. Feasibility rates will be reported for pts with and without growth factor use. Secondary/exploratory endpoints include evaluation of the safety via NCI-CTCAEv4 of 4 cycles of AC followed by 4 cycles of eribulin, and 3-year disease-free survival and OS. Results: As of 5/22/12, 46 of 80 planned pts have been treated; 38 pts have had ≥1 dose of eribulin and are evaluable for eribulin-related toxicity. Pt characteristics are as follows: median age 50 yrs (27–65 yrs); 100% female; ECOG of 0=81.6%; breast cancer stage at study entry: stg 1: 7.5%; stg 2: 72.5%, stg 3: 20%. Select treatment-related AEs are reported as total (all cycles) and eribulin-related events; many AEs overlapped during treatment (Table). Serious treatment-related AEs were reported in 2 pts, the most common (5.3%) being febrile neutropenia attributed to AC. Currently, 13 pts have had eribulin dose modification or delays; 10 of the events were related to eribulin (7 reductions, 5 delays, 1 withdraw). Eribulin-related AEs associated with dose delay or reduction are: 6 gr-3 neutropenia, 1 gr-3 febrile neutropenia, 1 gr-3 peripheral neuropathy, 1 gr-3 respiratory infection, 1 gr-3 fatigue. Six pts have discontinued (DC) treatment (2 AEs, 1 disease recurrence, 3 withdrew consent). Five of the 6 pts requiring eribulin delay/modification due to neutropenia were able to complete therapy with growth factor support. One pt DC eribulin therapy due to neuropathy. Conclusions: Preliminary results from this study suggest that adjuvant treatment with eribulin following dose-dense AC therapy has an acceptable safety profile. Accrual is ongoing and study completion is anticipated prior to SABCS 2012. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-13-11.

Patients with breast cancer, which lacks ER, PR, and HER2; “triple negative” (TNBC), are at increased risk of brain metastases (BMs). However, the impact of modern therapy on the risk of BMs and outcomes remains largely unknown. In this retrospective, single-institution study we assessed the incidence of BMs, the therapeutic options, and overall survival, in a recent cohort of patients with TNBC. Women diagnosed with early stage TNBC from January 1, 1998 to December 31, 2007 were identified through institutional databases. Electronic medical records were reviewed to assess patterns of recurrence, treatment, and survival. In total, 1,323 patients, median age 53 years (range 20–91), were identified. There were 298 patients (23%) who developed metastatic disease, of whom, 99 (33%) developed BMs, representing 7.5% of the entire cohort. Following BM diagnosis, treatment consisted of: radiotherapy 87 (88%) patients, resection 26 (26%) patients, and systemic chemotherapy 70 (71%) patients, with a median of 1.0 (range 0–8) chemotherapy regimens. The actuarial median survival from diagnosis of BMs is 5 months (95% CI 4–7 months). This single-institution, retrospective study confirms that the prognosis for patients with BMs from TNBC remains poor. This group of patients urgently needs improved therapies.

Purpose Dose-limiting neuropathy is a major adverse event associated with most of the microtubule-stabilizing agent-based chemotherapy regimens. Ixabepilone, a semisynthetic analogue of the natural epothilone B, has activity against a wide range of tumor types. Peripheral neuropathy (PN), associated with ixabepilone treatment, is usually mild to moderate, predominantly sensory and cumulative. Preclinical studies demonstrate that ixabepilone and taxanes produce a similar neurotoxicity profile. Methods We searched databases of phase II/III clinical trials involving patients receiving ixabepilone as a monotherapy or in combination with capecitabine for incidences of neuropathy. Potential risk factors for grade 3/4 PN were identified by a Cox regression analysis on a dataset of 1,540 patients with different tumor types across multiple studies. Results Rates for incidence of ixabepilone-induced severe PN (Common Terminology Criteria for Adverse Events grade 3/4) ranged from 1% in early untreated breast cancer up to 24% in heavily pretreated metastatic breast cancer; grade 4 PN was rare (≤1%). Common symptoms included numbness, paresthesias, and sometimes dysesthesias. Cox regression analysis identified only preexisting neuropathy as a risk factor for increased ixabepilone-associated PN. The management of PN has been primarily through dose adjustments (dose delays and/or dose reduction). Patients had resolution of their neuropathy within a median time of 5 to 6 weeks. Conclusions PN is a dose-limiting toxicity associated with ixabepilone treatment, is reversible in most patients, and can be managed with dose reduction and delays. Electronic supplementary material The online version of this article (doi:10.1007/s00520-012-1384-0) contains supplementary material, which is available to authorized users.

Breast cancer that lacks expression of estrogen/progesterone receptors and overexpression of the human epidermal growth factor receptor2 (HER2), i.e. triple-negative breast cancer (TNBC), is not amenable to current targeted therapies and carries a poor prognosis. This review discusses the natural history of TNBC and published literature in the relevant treatment landscape, with a focus on newer therapies. Compared with other subtypes of breast cancer, TN tumors have higher response rates to neoadjuvant chemotherapy; however, this advantage is not clearly translated into the metastatic setting and has not improved these patients' overall survival. Numerous cytotoxic and targeted strategies have demonstrated efficacy or are under investigation. Strategies showing promise in this difficult-to-treat group of patients include cytotoxic therapy with platinum-containing agents, ixabepilone, and novel targeted approaches such as poly(ADP-ribose) polymerase inhibitors.

Anthracycline-based regimens form a cornerstone of the adjuvant and neoadjuvant treatment of breast cancer. Extensive data from clinical trials with long-term follow-up have shown that such regimens significantly prolong overall and disease-free survival, compared with non-anthracycline-based regimens. In recent years, however, the proven benefits of anthracyclines have been challenged because of concerns over toxicity, and evidence that the benefits may be confined to certain patient subgroups, such as those with over-expression of the HER2 or TOP2A genes. Nevertheless, the available evidence suggests that it is premature to consider discarding anthracycline therapy. Although cardiotoxicity is a recognised limitation of long-term anthracycline treatment, clinically overt heart failure is uncommon and associated mortality is low. Similarly, the risk of acute myeloid leukaemia or myelodysplastic syndrome is low during anthracycline treatment. Although there are some data to suggest that the efficacy of anthracyclines may vary between patient subgroups, reliable prospective data to support this are sparse. Future prospective studies, and advances in the identification and validation of potential tumour biomarkers, can be expected to facilitate the targeting of anthracycline therapy to patients who are most likely to benefit.

Background Prognostic tools in early breast cancer are inadequate. The evolving field of metabolomics may allow more accurate identification of patients with residual micrometastases. Patients and methods Forty-four early breast cancer patients with pre- and postoperative serum samples had metabolomic assessment by nuclear magnetic resonance. Fifty-one metastatic patients served as control. Differential clustering was identified and used to calculate individual early patient ‘metabolomic risk’, calculated as inverse distance of each early patient from the metastatic cluster barycenter. Metabolomic risk was compared with Adjuvantionline 10-year mortality assessment. Results Innate serum metabolomic differences exist between early and metastatic patients. Preoperative patients were identified with 75% sensitivity, 69% specificity and 72% predictive accuracy. Comparison with Adjuvantionline revealed discordance. Of 21 patients assessed as high risk by Adjuvantionline, 10 (48%) and 6 (29%) were at high risk by metabolomics in pre- and postoperative settings, respectively. Of 23 low-risk patients by Adjuvantionline, 11 (48%) preoperative and 20 (87%) postoperative patients were at low risk by metabolomics. Conclusions This study identifies metabolomic discrimination between early and metastatic breast cancer. Micrometastatic disease may account for metabolomic misclassification of some early patients as metastatic. Metabolomics identifies more patients as low relapse risk compared with Adjuvantionline. Further exploration of this metabolomic fingerprint is warranted.

Boney involvement develops in approximately 73% of patients with metastatic breast carcinoma, 68% of patients with prostate can- cer, and in nearly all patients with multiple myeloma. 1 Before the introduction of bisphosphonates, patients with carcinoma that had metastasized to bones were often hospitalized for skeletal-related events (SREs) such as pain, hypercalcemia, spinal cord compromise, andpathologicfractures,whichledtosignificantmorbidityandmor- tality, reduced quality of life, and high cost of care. Randomized trials show that bisphosphonates, including pamidronate and zoledronic acid,significantlydecreasetheincidenceofSREsinpatientswithbone metastases. 2-4 TheUSFoodandDrugAdministrationapprovedthese compoundsforthetreatmentofmetastaticbonediseaseintheUnited States, and both agents were quickly adopted in clinical practice. Two other bisphosphonates, clodronate and ibandronate, have been ap- provedoutsideoftheUnitedStatesfortreatmentofpatientswithbone metastases (Table 1). Metastatic bone lesions can be osteolytic (bone destruction that results from increased bone resorption), osteoblastic (increased bone formation), or both. Metastatic bone disease associated with breast cancer is often predominantly osteolytic, whereas lesions from pros- tatecancerarepredominantlyosteoblastic.However,bonemetastases

IMPORTANCE: Endocrine therapy-induced alopecia (EIA) has been anecdotally reported but not systematically described. OBJECTIVE: To characterize EIA in patients with breast cancer. DESIGN, SETTING, AND PARTICIPANTS: Retrospective cohort study of 112 patients with breast cancer, diagnosed with EIA from January 1, 2009, to December 31, 2016, the patients were examined at the dermatology service in a large tertiary care hospital and comprehensive cancer center. MAIN OUTCOMES AND MEASURES: The clinical features, alopecia-related quality of life (QoL), and response to minoxidil of EIA in patients with breast cancer were assessed. Data from the Hairdex Questionnaire was used to assess the impact of the alopecia on patients QoL. Higher score indicates lower QoL (0-100 score). Efficacy of minoxidil was measured at 3 or 6 months by a single-blinded investigator through standardized clinical photographs of the scalp. RESULTS: A total of 112 female patients with breast cancer were included (median [range] age, 60 [34-90] years). A total of 104 patients (93%) had standardized clinical photographs; of these, 59 patients (53%) had trichoscopy images available at baseline, and 46 patients (41%) were assessed for response to minoxidil. Alopecia was attributed to aromatase inhibitors in 75 patients (67%) and tamoxifen in 37 (33%). Severity was grade 1 in 96 of 104 patients (92%), and the pattern was similar to androgenetic alopecia. The predominant trichoscopic feature at baseline was the presence of vellus hairs and intermediate- and thick-diameter terminal hair shafts. A negative impact on QoL was reported, with a higher effect in the emotion domain according to the Hairdex score (mean [SD], 41.8 [21.3]; P

Cancer patients commonly use dietary supplements to "boost immune function". A polysaccharide extract from Grifola frondosa (Maitake extract) showed immunomodulatory effects in preclinical studies and therefore the potential for clinical use. Whether oral administration in human produces measurable immunologic effects, however, is unknown.In a phase I/II dose escalation trial, 34 postmenopausal breast cancer patients, free of disease after initial treatment, were enrolled sequentially in five cohorts. Maitake liquid extract was taken orally at 0.1, 0.5, 1.5, 3, or 5 mg/kg twice daily for 3 weeks. Peripheral blood was collected at days -7, 0 (prior to the first dosing), 7, 14, and 21 for ex vivo analyses. The primary endpoints were safety and tolerability.No dose-limiting toxicity was encountered. Two patients withdrew prior to completion of the study due to grade I possibly related side effects: nausea and joint swelling in one patient; rash and pruritus in the second. There was a statistically significant association between Maitake and immunologic function (p0.0005). Increasing doses of Maitake increased some immunologic parameters and depressed others; the dose-response curves for many endpoints were non-monotonic with intermediate doses having either immune enhancing or immune suppressant effects compared with both high and low doses.Oral administration of a polysaccharide extract from Maitake mushroom is associated with both immunologically stimulatory and inhibitory measurable effects in peripheral blood. Cancer patients should be made aware of the fact that botanical agents produce more complex effects than assumed, and may depress as well as enhance immune function.

A feasibility-phase II study was conducted to assess the cardiotoxicity of weekly trastuzumab, epirubicin, and paclitaxel in patients with human epidermal growth factor receptor-2-positive metastatic breast cancer. Untreated patients with human epidermal growth factor receptor-2-positive advanced breast cancer received trastuzumab (day 1), and epirubicin (25 mg/m2) and paclitaxel (80 mg/m2) (day 2) on a weekly basis. The rate of patients with left-ventricular ejection fraction (L-VEF) reduction greater than 10% after 12 weeks was the primary end point. According to a two-stage model, an initial step with 15 patients was required; after 11 patients without toxicity, a second step with 21 patients was planned. After 255 courses in 15 patients (median treatment weeks: 18), the relative dose intensity was 94.7%. At 12 weeks, three patients (20%) displayed a L-VEF reduction greater than 10%, six and six (40%) patients showed a L-VEF reduction < or =10% or no change, respectively. Baseline, -12 weeks, and -24 weeks median L-VEF was 69% (range 61-77), 65% (range 60-76), and 65% (range 55-73), respectively. No EKG/cardiac signs were present. Thirteen patients had grade 3 alopecia and two patients had grade 3 asthenia, in the absence of severe hematological toxicity. Objective responses were observed in 11 patients (73.3%, 95% confidence interval 51.0-95.7), with 10 partial. The weekly administration of trastuzumab-epirubicin-paclitaxel is extremely tolerable, also with regard to L-VEF reduction. These results allowed entrance to the second step of the study.

Purpose Granulocyte-colony stimulating factor (G-CSF) was used in CALGB 9741 to support dose-dense sequential chemotherapy with doxorubicin and cyclophosphamide (AC) followed by paclitaxel (P) (Citron et al. J Clin Oncol 21:1431–1439, 2003). However, myelosuppression is not known to be dose or schedule limiting for paclitaxel. We therefore conducted this trial to determine the need for routine G-CSF, using the pegylated product (pG-CSF), support during the paclitaxel component of dose-dense sequential chemotherapy in women with early stage breast carcinoma (BC). Patients and methods Eligible patients received dose-dense chemotherapy consisting of four cycles of AC followed by four cycles of P at two week intervals. pG-CSF (NeulastaTM) was administered after each of four cycles of AC but was held after P. Planned enrollment was 59 pts. Results Of the first 15 patients, nine completed therapy without delays due to neutropenia but 6 (40%) did not, leading to implementation of the pre-specified early termination rule. Overall, 85% of P doses were successfully delivered on time. The mean treatment delay for the entire group due to neutropenia was 0.75 days. There was no significant correlation between neutropenia and prior WBC, ANC, or concurrent treatment with trastuzumab. Pts with neutropenia tended to be younger (Mean age 43.5) and have a lower BSA (1.65 m2). There were no febrile episodes due to omission of pG-CSF. Conclusion When paclitaxel is administered in a dose-dense fashion without growth factor support brief treatment delays are common. Further study is needed to identify the minimal pG-CSF administration that will avoid treatment delays.

Taxanes have become fundamental in the treatment of early and advanced breast cancer. However, tumors vary in their sensitivity to these agents; resistance can be acquired or de novo resistance can occur. Epothilones and associated analogs are novel microtubule-stabilizing agents that induce apoptosis and promote cell death. There is now a growing body of clinical data describing the efficacy of epothilones in breast cancer patients who have progressed on taxanes and anthracyclines. This culminated with US FDA approval in October 2007 of ixabepilone (Ixempra, Brystol Myers Squibb, NJ, USA) either as single agent or in combination with capecitabine for the treatment of breast cancer, which has progressed after prior therapies. The results of ongoing and future randomized clinical trials will further define how epothilones, in particular ixabepilone, will be integrated into the management of early and metastatic breast cancer. In parallel, the search for biomarkers predictive of sensitivity to epothilones continues in an attempt to tailor these therapies to patients with greater accuracy.

Purpose Dose-dense (dd) doxorubicin and cyclophosphamide (AC) followed by paclitaxel (P) is superior to every 3-weekly AC followed by P. Given the demonstrated cardiac safety for trastuzuamb (T) with conventionally scheduled AC followed by P, we tested the safety of dd AC followed by P with T. The primary end point was cardiac safety, and the secondary end points were time to recurrence and overall survival. Methods Patients with HER-2/neu immunohistochemistry (IHC) 3+ or fluorescent in situ hybridization (FISH)-amplified breast cancer and baseline left ventricular ejection fraction (LVEF) of ≥ 55% were enrolled, regardless of tumor size or nodal status. Treatment consisted of AC (60/600 mg/m2) × 4 followed by P (175 mg/m2) × 4 every 2-weekly with pegfilgrastim (6 mg on day 2) + T ×1 year. LVEF by radionuclide scan was obtained at baseline, at months 2, 6, 9, and 18. Results From January 2005 to November 2005, 70 patients were enrolled. The median age was 49 years (range, 27 to 72 years); median LVEF at baseline was 68% (range, 55% to 81%). At month 2 in 70 of 70 patients, the median LVEF was 67% (range, 58% to 79%); at month 6 in 67 of 70 patients, it was 66% (range, 52% to 75%); at month 9 in 68 of 70 patients, it was 65% (range, 50% to 75%); and at month 18 in 48 of 70 patients, it was 66% (range, 57% to 75%). As of December 1, 2007, the median follow-up was 28 months (range, 25 to 35 months). One patient (1%) experienced conestive heart failure (CHF). There were no cardiac deaths. Conclusion Dose-dense AC followed by P/T followed by T is feasible and is not likely to increase the incidence of cardiac events compared to established regimens.

Purpose Ixabepilone (BMS-247550) is an epothilone analog that optimizes the properties of naturally occurring epothilone B. Natural epothilones and their analogs promote tumor cell death by binding to tubulin and stabilizing microtubules, causing apoptosis. This international phase II trial assessed the activity of ixabepilone in patients with metastatic breast cancer (MBC) that was resistant to taxane therapy. Patients and Methods MBC patients, who had experienced disease progression while receiving or within 4 months of taxane therapy (6 months if adjuvant taxane only), and who had a taxane as their last regimen, received ixabepilone (1- or 3-hour infusion of 50 mg/m2 or 3-hour infusion of 40 mg/m2 every 3 weeks). Results Of 49 patients treated with 40 mg/m2 ixabepilone during 3 hours, 35 (73%) had experienced disease progression within 1 month of their last taxane dose. The response rate was 12% (95% CI, 4.7% to 26.5%). All responses (n = 6) were partial; five of six patients had not responded to prior taxane therapy. In responders, the median response duration was 10.4 months. In 20 patients (41%), stable disease was the best outcome. Median time to progression was 2.2 months (95% CI, 1.4 to 3.2 months); median survival was 7.9 months. For treated patients across all cohorts (intent-to-treat population), the response rate was also 12% (eight of 66). Treatment-related adverse events in the study were manageable and primarily grade 1/2. Treatment-related neuropathy was mostly sensory and mild to moderate. Conclusion Ixabepilone (40 mg/m2 as a 3-hour infusion every 3 weeks) demonstrates promising antitumor activity and an acceptable safety profile in patients with taxane-resistant MBC.

Purpose: Because Cancer and Leukemia Group B 9741 trial showed a benefit for every 14-day administration of chemotherapy compared with every 21-day treatment, we hypothesized that even greater dose density would be more effective. We conducted a pilot trial to assess the feasibility of dose-dense chemotherapy consisting of a standard regime at 10- to 11-day intervals in the adjuvant/neoadjuvant setting. A 2-day window was allowed for scheduling logistics. Experimental Design: Thirty-nine women with early-stage breast carcinoma were accrued from April 2004 to October 2004. Median age was 47 years (range, 26-67 years). Patients received therapy with 100 mg/m2 epirubicin and 600 mg/m2 cyclophosphamide (EC) q 10 to 11 days for four cycles followed by 175 mg/m2 paclitaxel q 10 to 11 days for four cycles, all with filgrastim support (300 μg s.c. daily) from day 2 to 24 h before the next treatment. Results: Thirty-five (90%) patients completed all planned therapy. The median intertreatment interval was 10 days (range, 8-28 days). Cycles (80.7%) were delivered at no more than 10- to 11-day intervals. There were five dose reductions of 25% for grade 3 nonhematologic toxicity in five patients. Six (16%) patients developed febrile neutropenia defined as temperature >38°C with absolute neutrophil count Conclusions: Therapy with EC for four cycles followed by paclitaxel for four cycles at 10- to 11-day intervals is feasible. The ∼30% reduction in intertreatment interval compared with every 14-day treatment could increase the efficacy of adjuvant chemotherapy.

Background Dual anti-HER2 therapy is effective for HER2-amplified breast cancer. Weekly paclitaxel, trastuzumab, and full-dose lapatinib (PTL) is not feasible because of grade 3 diarrhea. We conducted a phase II feasibility study of dose-dense (DD; every other week) PTL ( ClinicalTrials.gov identifier, NCT01827163 ). Patients and Methods Eligible patients had HER2-positive breast cancer, tumor size ≤ 3 cm, and negative nodes. Treatment included paclitaxel (175 mg/m2 × 4, every 2 weeks with pegfilgrastim), trastuzumab (4 mg/kg load and then 2 mg/kg weekly), and lapatinib (1000 mg daily). After paclitaxel × 4, trastuzumab (6 mg/kg every 3 weeks) plus lapatinib were continued for 1 year. The primary endpoint was feasibility, defined as (1) > 80% of patients completing PTL without a dose delay or reduction, (2) grade 3 diarrhea rate Results From May 2013 to November 2013, we enrolled 20 of 55 planned patients. The median age was 49 years (range, 34-74 years). One patient had immediate paclitaxel hypersensitivity and was deemed inevaluable. Only 13 of 19 evaluable patients (68%) completed PTL without a dose delay or reduction or unacceptable toxicities. Only 3 of 19 (16%) had grade 3 diarrhea. Rash was frequent, with all grades in 18 of 19 (95%) and grade 3 in 2 of 19 (11%). The study was stopped early because of excess toxicity. Conclusion The discontinuation rate during DD PTL was high, owing, in part, to an unexpectedly high incidence of rash. The trial was halted, because the initial discontinuation rate from overall toxicity made it unlikely that full accrual would demonstrate feasibility.

OBJECTIVES: To examine the toxicity experienced by a cohort of older women receiving adjuvant chemotherapy for breast cancer and the longitudinal effect on their functional status and quality of life (QOL). DESIGN: A geriatric assessment measuring functional status, comorbidity, mood, nutritional status, and QOL was performed before chemotherapy, at the end of chemotherapy, and 6 months later. SETTING: This prospective longitudinal study was conducted at Memorial Sloan-Kettering Cancer Center, New York, New York. PARTICIPANTS: Fifty patients aged 65 and older with Stage I to III breast cancer receiving any adjuvant chemotherapy; 49 were evaluable. MEASUREMENTS: The chemotherapy regimen and the toxicity to chemotherapy were recorded. A geriatric assessment was performed before the start of chemotherapy, on completion of chemotherapy, and 6 months after completion of chemotherapy. QOL testing was performed at the same times. RESULTS: Patients (mean age 68, range 65–84) received an anthracycline-based chemotherapy regimen (n=15) or cyclophosphamide 600 mg/m2 intravenously (IV), methotrexate 40 mg/m2 IV, 5-fluorouracil 600 mg/m2 IV every 3 weeks for eight cycles (n=34). Grade 3 or 4 toxicity occurred in 53% (n=26), hematological toxicity in 27% (n=13), and nonhematological toxicity in 31% (n=15). Despite toxicity, there was no significant longitudinal change in functional status or QOL. CONCLUSION: Despite toxicity from adjuvant chemotherapy, this cohort of relatively young older patients maintained their functional status and QOL from before chemotherapy to 6 months postchemotherapy. Subtle changes in higher-order functioning would require assessment using different geriatric assessment tools.

OBJECTIVES: To report on the longitudinal cognitive functioning of older women receiving adjuvant chemotherapy for breast cancer. DESIGN: Neuropsychological and functional status testing were performed before chemotherapy and 6 months after chemotherapy. SETTING: Cancer center. PARTICIPANTS: Thirty-one patients aged 65 and older with Stage I to III breast cancer. Of the 31 patients enrolled, three refused posttesting, and 28 were evaluable. MEASUREMENTS: The following domains of cognitive function were examined: attention; verbal memory; visual memory; and verbal, spatial, psychomotor, and executive functions. RESULTS: Participants had a mean age of 71 (range 65–84): 39% Stage I, 50% Stage II, and 11% Stage III. The number of scores 2 standard deviations (SDs) below the norm were calculated for each patient before and 6 months after chemotherapy; 14 (50%) had no change, 11 (39%) worsened, and three (11%) improved (P=.05). Seven patients (25%) experienced a decline in cognitive function, defined as a 1-SD decline from pre- to posttesting in two or more neuropsychological domains. Exploratory analyses revealed no significant difference between functional status, comorbidity, and depression scale scores and change in overall quality-of-life scores before and after chemotherapy. CONCLUSION: In this cohort of older women receiving adjuvant chemotherapy, a subset experienced a decline in cognitive function from before chemotherapy to 6 months after chemotherapy. Further prospective study is needed to confirm these observations and to identify the subgroup at special risk.

Introduction The purpose of this retrospective study was to determine the clinical utility of serum HER2/neu in monitoring metastatic breast cancer patients undergoing trastuzumab-based therapy and to compare these results with those obtained using cancer antigen (CA) 15-3. We also sought to determine whether early changes in serum HER2/neu concentrations could be a predictor of progression-free survival. Methods Sera were obtained retrospectively from 103 women at four medical institutions. Patients eligible for participation were women with metastatic breast cancer who had HER2/neu tissue overexpression and were scheduled to be treated with trastuzumab with or without additional therapies as per the established practices of the treating physicians. A baseline serum sample for each patient was taken before trastuzumab-based therapy was started. Patients were subsequently monitored over 12 to 20 months and serum samples were taken at the time of clinical assessment and tested with Bayer's HER2/neu and CA15-3 assays. Results Concordance between clinical status in patients undergoing trastuzumab-based treatment and HER2/neu and CA15-3 used as single tests was 0.793 and 0.627, respectively, and increased to 0.829 when the tests were used in combination. Progression-free survival times did not differ significantly in patients with elevated baseline HER2/neu concentrations (≥ 15 ng/mL) and those with normal concentrations (77% or ≤ 77% of her baseline concentration. The median progression-free survival times for these two groups were 217 and 587 days, respectively. A similar trend was observed for a subcohort of patients treated specifically with a combination of trastuzumab and taxane. Conclusion These findings indicate that serum HER2/neu testing is clinically valuable in monitoring metastatic breast cancer patients undergoing trastuzumab-based treatment and provides additional value over the commonly used CA15-3 test. The percentage of baseline HER2/neu concentrations in the early weeks after the start of therapy may be an early predictor of progression-free-survival.

Background: Taselisib is an oral, potent, selective inhibitor of Class I PI3-kinase (PI3K) alpha, gamma, and delta isoforms with enhanced activity against PIK3CA mutant cancer cells. LORELEI trial demonstrated a significant improvement in ORR (objective response rate) centrally assessed by MRI with neoadjuvant taselisib plus letrozole compared to letrozole plus placebo in all randomized patients as well as in the PIK3CA mutant cohort (Saura et al, ESMO 2017). Methods: 334 postmenopausal women with newly diagnosed ER+/HER2-, untreated, Stage I-III operable breast cancer and evaluable tumor tissue for PIK3CA genotyping were randomized (1:1) to receive daily letrozole (2.5 mg) with either taselisib (4 mg on a 5 days on/ 2 days off schedule) or placebo for 16 weeks, followed by surgery. Tumor tissue collection was performed at baseline, week 3 (W3) and at surgery. Secondary objectives included, but were not restricted to, ORR assessed by MRI in patients with PIK3CA wild type (WT) tumors, ORR using alternative methods of tumor assessment (ultrasound, mammogram and clinical breast exam) in all patients and patients with PIK3CA mutant and WT tumors, central assessment of Ki67 at different timepoints (baseline, W3 and surgery), and the centrally derived PEPI score. Central Ki67 was assessed by two independent readers blinded to treatment arms and PIK3CA status (Vall D'Hebron Institute of Oncology, Barcelona). Results: ORR by centrally assessed MRI was similar in the two treatment arms in patients with PIK3CA WT tumors (45.7 vs 40.4% for taselisib and placebo, respectively). ORR assessed by breast US was also significantly higher with taselisib compared to placebo in all randomized patients and in the PIK3CA mutant cohort. The highest concordance rate between MRI and other imaging modalities was found with breast ultrasound (53.7%). Centrally assessed Ki67 changes are reported in Table 1. Ki67 values decreased from baseline to W3 and from baseline to surgery in both treatment arms. No significant differences in the decrease of Ki67 values between treatment arms were detected. Unplanned analysis of Complete Cell Cycle Arrest (CCCA) at W3 was numerically higher with taselisib than with placebo in all randomized patients (49.6% vs 38.5%) and in the PIK3CA mutant cohort (60.9% vs 47.5%). Due to the variability in timing between the last dose of taselisib (median time 11 days; interquartile range 6-16 days) and tissue collection at surgery, considering the half-life of taselisib of approximately 40 hours, centrally derived PEPI score is not interpretable. Ki67 proportional changes, %Taselisib + letrozolePlacebo + letrozoleBaseline to W3All patients-83.8-80.4PIK3CA mutant-84.5-79.1PIK3CA WT-82.8-81.1Baseline to surgeryAll patients-75.6-80.5PIK3CA mutant-71.9-79.9PIK3CA WT-78.2-81.2 Conclusion: Among the investigated alternative methods for assessing ORR, breast ultrasound performed similar to MRI. Decrease in the Ki67 values from baseline to W3 and to surgery were observed in both treatment arms. The time interval between taselisib cessation and tissue collection at surgery are being further investigated. Clinical trial information: NCT02273973 Citation Format: de Azambuja E, Saura C, Nuciforo P, Frantal S, Oliveira M, Zardavas D, Jallitsch-Halper A, de la Pena L, Dubsky P, Lombard JM, Vuylsteke P, Castaneda Altamirano C, Sanchez C, Ballestrero A, Colleoni M, Santos Borges G, Ciruelos E, Bardia A, Fornier M, Boer K, Wilson TR, Stout TJ, Hsu JY, Shi Y, Piccart M, Baselga J, Gnant M. Ki67 changes and PEPI score in the LORELEI trial: A phase II randomized, double-blind study of neoadjuvant letrozole plus taselisib versus letrozole plus placebo in postmenopausal women with ER-positive/HER2-negative early-stage breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr PD5-04.

Purpose : Metabolomics is a global study of metabolites in biological samples. In this study we explored whether serum metabolomic spectra could distinguish between early and metastatic breast cancer patients and predict disease relapse. Methods : Serum samples were analysed from women with metastatic ( n = 95) and predominantly oestrogen receptor (ER) negative early stage ( n = 80) breast cancer using high resolution nuclear magnetic resonance spectroscopy. Multivariate statistics and a Random Forest classifier were used to create a prognostic model for disease relapse in early patients. Results : In the early breast cancer training set ( n = 40), metabolomics correctly distinguished between early and metastatic disease in 83.7% of cases. A prognostic risk model predicted relapse with 90% sensitivity (95% CI 74.9–94.8%), 67% specificity (95% CI 63.0–73.4%) and 73% predictive accuracy (95% CI 70.6–74.8%). These results were reproduced in an independent early breast cancer set ( n = 40), with 82% sensitivity, 72% specificity and 75% predictive accuracy. Disease relapse was associated with significantly lower levels of histidine ( p = 0.0003) and higher levels of glucose ( p = 0.01), and lipids ( p = 0.0003), compared with patients with no relapse. Conclusions : The performance of a serum metabolomic prognostic model for disease relapse in individuals with ER-negative early stage breast cancer is promising. A confirmation study is ongoing to better define the potential of metabolomics as a host and tumour-derived prognostic tool.

A multicenter NCI-sponsored phase II study was conducted to analyze the safety and efficacy of the combination of ixabepilone with trastuzumab in patients with metastatic HER2-positive breast cancer.Two cohorts were enrolled: cohort 1 had received no prior chemotherapy or trastuzumab for metastatic disease and cohort 2 had received 1-2 prior trastuzumab-containing regimens for metastatic disease. Patients in both cohorts received ixabepilone 40 mg/m(2) as a 3-h infusion and trastuzumab on day 1 of a 21-day cycle. Tumor biomarkers that may predict response to trastuzumab were explored.Thirty-nine women entered the study with 15 patients in cohort 1 and 24 patients in cohort 2. Across both cohorts, the overall RR was 44%, with a clinical benefit rate (CR + PR + SD for at least 24 weeks) of 56%. Treatment-related toxic effects included neuropathy (grade ≥2, 56%), leukopenia (grade ≥2, 26%), myalgias (grade ≥2, 21%), neutropenia (grade ≥2, 23%), and anemia (grade ≥2, 18%).This represents the first study of the combination of ixabepilone with trastuzumab for the treatment of metastatic HER2-positive breast cancer. These results suggest that the combination has encouraging activity as first and subsequent line therapy for metastatic breast cancer.

Elevated levels of COX-derived prostaglandin E2 (PGE2) occur in inflamed tissues. To evaluate the potential links between inflammation and breast cancer, levels of urinary prostaglandin E metabolite (PGE-M), a stable end metabolite of PGE2, were quantified. We enrolled 400 patients with breast cancer: controls with early breast cancer (n = 200), lung metastases (n = 100), and metastases to other sites (n = 100). Patients completed a questionnaire, provided urine, and had measurements of height and weight. Urinary PGE-M was quantified by mass spectrometry. Ever smokers with lung metastasis who had not been exposed to nonsteroidal anti-inflammatory drugs (NSAIDs) had the highest PGE-M levels. PGE-M levels were increased in association with elevated body mass index (BMI; P < 0.001), aging (P < 0.001), pack-year smoking history (P = 0.02), lung metastases (P = 0.02), and recent cytotoxic chemotherapy (P = 0.03). Conversely, use of NSAIDs, prototypic inhibitors of COX activity, was associated with reduced PGE-M levels (P < 0.001). On the basis of the current findings, PGE-M is likely to be a useful biomarker for the selection of high-risk subgroups to determine the use of interventions that aim to reduce inflammation and possibly the development and progression of breast cancer, especially in overweight and obese women. Cancer Prev Res; 6(5); 428–36. ©2013 AACR.

Purpose: Bevacizumab confers benefits in metastatic breast cancer but may be more effective as adjuvant therapy. We evaluated the cardiac safety of bevacizumab plus dose-dense doxorubicin–cyclophosphamide (ddAC) → nanoparticle albumin–bound (nab)-paclitaxel in human epidermal growth factor receptor 2 normal early-stage breast cancer. Experimental Design: Eighty patients with normal left ventricular ejection fraction (LVEF) were enrolled. Bevacizumab was administered for 1 year, concurrently with ddAC → nab-paclitaxel then as a single agent. LVEF was evaluated at months 0, 2, 6, 9, and 18. This regimen was considered safe if fewer than three cardiac events or fewer than two deaths from left ventricular dysfunction occurred. Correlative studies of cardiac troponin (cTn) and plasma renin activity (PRA) were conducted. Results: The median age was 48 years (range, 27–75 years), and baseline LVEF was 68% (53%–82%). After 39 months' median follow-up (5–45 months): median LVEF was 68% (53%–80%) at 2 months (n = 78), 64% (51%–77%) at 6 months (n = 66), 63% (48%–77%) at 9 months (n = 61), and 66% (42%–76%) at 18 months (n = 54). One patient developed symptomatic LV dysfunction at month 15. Common toxicities necessitating treatment discontinuation were hypertension (HTN, 4%), wound-healing complications (4%), and asymptomatic LVEF declines (4%). Neither cTn nor PRA predicted congestive heart failure (CHF) or HTN, respectively. Conclusions: Bevacizumab with ddAC → nab-paclitaxel had a low rate of cardiac events; cTn and PRA levels are not predictive of CHF or HTN, respectively. The efficacy of bevacizumab as adjuvant treatment will be established in several ongoing phase III trials. Clin Cancer Res; 17(10); 3398–407. ©2011 AACR.

Cyclophosphamide/methotrexate/fluorouracil (CMF) is a proven adjuvant option for patients with early-stage breast cancer. Randomized trials with other regimens demonstrate that dose-dense (DD) scheduling can offer greater efficacy. We investigated the feasibility of administering CMF using a DD schedule.Thirty-eight patients with early-stage breast cancer were accrued from March 2008 through June 2008. They were treated every 14 days with C 600, M 40, F 600 (all mg/m2) with PEG-filgrastim (Neulasta®) support on day 2 of each cycle. The primary endpoint was tolerability using a Simon's 2-stage optimal design. The design would effectively discriminate between true tolerability (as protocol-defined) rates of ≤ 60% and ≥ 80%.The median age was 52-years-old (range, 38-78 years of age). Twenty-nine of the 38 patients completed 8 cycles of CMF at 14-day intervals.Dose-dense adjuvant CMF is tolerable and feasible at 14-day intervals with PEG-filgrastim support.

Background Despite recent advances in treating patients with metastatic breast cancer (MBC), outcomes remain poor. Ixabepilone is a semisynthetic analogue of epothilone B with low susceptibility to multiple mechanisms of tumor-cell resistance. This review examined the results of 2 phase III clinical trials of ixabepilone in patients with drug-resistant or heavily pretreated, locally advanced breast cancer or MBC. Patients and Methods In both studies, women with locally advanced breast cancer or MBC pretreated with, or resistant to, taxanes or anthracyclines were randomly assigned to ixabepilone plus capecitabine, or capecitabine alone, until disease progression or unacceptable toxicity occurred. Results Ixabepilone plus capecitabine significantly prolonged progression-free survival (PFS) compared with capecitabine alone. The median PFS was prolonged by 1.5 months and 1.8 months in the 2 studies (hazard ratio, P ≥ .001). These observations remained valid within several patient subsets: those receiving ixabepilone as first-line therapy, those with taxane-resistant disease, and those with particularly poor prognostic features. Ixabepilone plus capecitabine significantly improved overall survival (OS) compared with capecitabine in patients with symptomatic disease (12.3 vs. 9.5 months, respectively; P = .015). Peripheral neuropathy with ixabepilone was generally reversible and was effectively managed by dosage reduction in most patients. Ixabepilone did not exacerbate capecitabine-induced hand-foot syndrome or diarrhea. Conclusion The results of these 2 large phase III trials suggest that ixabepilone plus capecitabine may improve treatment outcomes for patients with locally advanced breast cancer or MBC resistant to, or heavily pretreated with, taxanes or anthracyclines, even in those with poor prognostic features.

At present, metastatic breast cancer (MBC) remains an incurable disease, with the goals of care aimed at maximizing the patient's duration and quality of life. Treatment options for a patient with MBC have become more efficacious and numerous. In addition to endocrine and chemotherapy agents, a number of targeted agents, including trastuzumab and bevacizumab, are available. The option to use novel agents combined with a multitude of standard chemotherapies has further enhanced the landscape of therapeutic options. As such, specific regimens must be evaluated within the framework of the individual patient, answering such questions as whether to treat with sequential single agents or combination regimens as well as which agents to use and in what sequence. The concept of personalized care is even more apparent in the setting of MBC, where the goal of palliation is intrinsically more nuanced than that of curative intent. This review will broadly assess the evidence for current treatment options with attention to varying clinical scenarios. Ultimately, delivering quality of care necessitates balancing an understanding of evidence-based data with sensitive attention to quality-of-life goals.

PurposePreclinical models suggest that the use of anti–vascular endothelial growth factor (anti-VEGF) therapy with antiestrogens may prevent or delay the development of endocrine therapy resistance. We therefore performed a feasibility study to evaluate the safety of letrozole plus bevacizumab in patients with hormone receptor–positive metastatic breast cancer (MBC).MethodsPatients with locally advanced breast cancer or MBC were treated with the aromatase inhibitor (AI) letrozole (2.5 mg orally daily) and the anti-VEGF antibody bevacizumab (15 mg/kg intravenously every 3 weeks). The primary end point was safety, defined by grade 4 toxicity using the National Cancer Institute Common Toxicity Criteria, version 3.0. Secondary end points included response rate, clinical benefit rate, and progression-free survival (PFS). Prior nonsteroidal AIs (NSAIs) were permitted in the absence of progressive disease.ResultsForty-three patients were treated. After a median of 13 cycles (range, 1 to 71 cycles), select treatment-related toxicities included hypertension (58%; grades 2 and 3 in 19% and 26%), proteinuria (67%; grades 2 and 3 in 14% and 19%), headache (51%; grades 2 and 3 in 16% and 7%), fatigue (74%; grades 2 and 3 in 19% and 2%), and joint pain (63%; grades 2 and 3 in 19% and 0%). Eighty-four percent of patients had at least stable disease on an NSAI, confounding efficacy results. Partial responses were seen in 9% of patients and stable disease ≥ 24 weeks was noted in 67%. Median PFS was 17.1 months.ConclusionCombination letrozole and bevacizumab was feasible with expected bevacizumab-related events of hypertension, headache, and proteinuria. Phase III proof-of-efficacy trials of endocrine therapy plus bevacizumab are in progress (Cancer and Leukemia Group B 40503).

Recently, a greater understanding of tumor biology, including the use of genetic signatures, has led to a more precise classification of breast cancer. This has translated into a more granular assessment of risk-benefit calculations for the selection of patients for adjuvant therapies. For unselected patients, anthracyclines offer a survival benefit over non-anthracycline-based regimens, but are associated with long-term risks including congestive heart failure. Until recently, the benefit of anthracyclines in older patients with early breast cancer was largely extrapolated from studies involving younger cohorts. Emerging data now suggest that for appropriately selected older patients anthracyclines offer distinct benefits and are associated with a manageable toxicity profile. This review will focus on the benefits and risks of anthracyclines in older patients with various subtypes of breast cancer.

Bone health and maintenance of bone integrity are important components of comprehensive cancer care. Many patients with cancer are at risk for therapy-induced bone loss, with resultant osteoporotic fractures, or skeletal metastases, which may result in pathologic fractures, hypercalcemia, bone pain, and decline in motility and performance status. Effective screening and timely interventions are essential for reducing bone-related morbidity. Management of long-term bone health requires a broad knowledge base. A multidisciplinary health care team may be needed for optimal assessment and treatment of bone-related issues in patients with cancer. Since publication of the previous NCCN Task Force Report: Bone Health in Cancer Care in 2009, new data have emerged on bone health and treatment, prompting NCCN to convene this multidisciplinary task force to discuss the progress made in optimizing bone health in patients with cancer. In December 2012, the panel members provided didactic presentations on various topics, integrating expert judgment with a review of the key literature. This report summarizes issues surrounding bone health in cancer care presented and discussed during this NCCN Bone Health in Cancer Care Task Force meeting.

Purpose To assess locoregional outcomes of inflammatory breast cancer (IBC) patients who received standard fractionation radiation with daily skin bolus and taxanes as part of combined-modality therapy (CMT). Methods and materials We retrospectively reviewed the charts of 107 patients diagnosed with IBC between January 1995 and March 2006 who presented to our department for adjuvant radiation therapy (RT). Results All patients received chemotherapy (95% anthracycline and 95% taxane), modified radical mastectomy, and RT to the chest wall and regional lymphatics using standard fractionation to 50 Gy and daily skin bolus. The RT to the chest wall was delivered via electrons (55%) or photons (45%) in daily fractions of 180 cGy (73%) or 200 cGy (27%). Scar boost was performed in 11%. A majority (84%) of patients completed the prescribed treatment. Median follow-up was 47 months (range, 10-134 months). Locoregional control (LRC) at 3 years and 5 years was 90% and 87%, respectively. Distant metastases-free survival (DMFS) at 3 years and 5 years was 61% and 47%, respectively. Conclusions Excellent locoregional control was observed in this population of IBC patients who received standard fractionation radiation with daily skin bolus and taxanes as part of combined-modality therapy. Distant metastases-free survival remains a significant therapeutic challenge.

BACKGROUND. Previous reports based on small patient numbers suggested that changes in serum HER-2/neu levels may predict response or lack of response to trastuzumab-based therapies in metastatic breast cancer (MBC). The objectives of this study were to pool data from 307 patients with MBC from 7 medical institutions to validate that the serum HER-2/neu profile predicts patient resistance to trastuzumab and to establish a clinically relevant cutoff. METHODS. This was an international, multicenter, retrospective analysis of individual pooled data from 307 patients with MBC who were treated with first-line trastuzumab-based therapy. Serum was collected at baseline and 30 to 120 days after the initiation of trastuzumab therapy. A serum HER-2/neu decrease ≥20% (receiver operating curve analysis) was defined as a significant HER-2/neu change. RESULTS. Of the 307 patients with MBC, 191 patients (62%) had a significant decline (>20%) in serum HER-2/neu and 116 patients (38%) did not. The objective response rate was 57% for patients who achieved this decline in serum HER-2/neu (>20%) compared with 28% for patients who did not. Patients who achieved this decline in serum HER-2/neu also had a significantly longer time to disease progression (320 days vs 180 days; P < .0001), longer duration of response (369 days vs 230 days; P = .008), and longer overall survival (898 days vs 593 days; P < .018). CONCLUSIONS. In this pooled analysis of 307 patients with MBC, individuals who did not achieve a significant decline (≥20%) in serum HER-2/neu levels had decreased benefit from trastuzumab-based therapy, and these patients should be considered for clinical trials evaluating additional HER-2/neu-targeted interventions. Cancer 2008. © 2008 American Cancer Society.

Background Drugs that target microtubules, including paclitaxel (Taxol) and docetaxel (Taxotere), are among the most commonly prescribed anticancer therapies. However, the utility of taxane-based therapies is limited by difficulties with formulation, administration, and resistance induced by P-glycoprotein. The epothilones are a novel class of antimicrotubule agents that have demonstrated antitumor activity in the setting of resistance. Design This review summarizes clinical studies of epothilones in patients with metastatic breast cancer. Data were identified by searches of PubMed and the Proceedings of the American Society of Clinical Oncology annual meetings from 2000 to 2006. Results The epothilones have demonstrated promising antitumor activity and manageable toxicity in phase II studies of heavily pretreated patients with metastatic breast cancer, including patients with resistance to taxanes and other cytotoxic agents. Neuropathy associated with ixabepilone appears to be schedule dependent and comparable to that observed with paclitaxel. Ixabepilone appears to be active in combination with capecitabine. Conclusions Ongoing and planned trials promise to elucidate the benefits of ixabepilone in combination with other agents including capecitabine, bevacizumab, and trastuzumab in patients with metastatic breast cancer as well as those receiving neo-adjuvant therapy.

Background In five randomized clinical trials (RCTs), adjuvant trastuzumab (T) for early stage breast cancer with human epidermal growth-factor receptor-2 over-expression/gene-amplification has shown to decrease the risk of both recurrence and death. The issue regarding the long-term safety profile of such drug is still open; in particular, questions remain about long-term cardiotoxicity, and specific patterns of relapse such as brain metastases (BM). In order to quantify the magnitude of these two risks, and then balance those with the survival outcome, a literature-based meta-analysis was performed. Methods All phase III trials were considered eligible. A literature-based meta-analysis was accomplished, and event-based relative risk ratios with 95% confidence interval were derived. A fixed- and a random-effect model according to the inverse variance and the Mantel–Haenzel method were applied. Heterogeneity test was applied as well. Absolute differences (AD) and the Number of patients Needed to Treat or to Harm (NNT/NNH) were calculated. Safety end-points were: (1) Chronic Heart Failure (CHF) grade III-IV rate, (2) Significant reduction of left-ventricular-ejection-fraction (L-FEV) rate and (3) BM rate. In order to quantify the magnitude of the significant benefit already found in the original RCTs, Efficacy end-points were: (1) disease-free survival (DFS) and (2) overall survival (OS). Results Five RCTs were gathered (11,187 patients); at an average 2-years follow-up, all data was available for the safety and efficacy end-points, while three RCTs reported results for BM analysis (6,738 patients). When considering RCTs with trastuzumab administered for 1 year, a significant increased risk of grade III–IV Congestive Heart Failure (CHF) was found in the T-arm, with an AD of 1.61% (p