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To evaluate health related quality of life (HRQOL) in TEACH, a phase III randomized placebo controlled trial of 12 months of adjuvant lapatinib in HER2 positive (HER2+) early breast cancer which demonstrated marginal benefit in disease-free survival.Women on TEACH completed the Short Form 36-item health survey (version2; SF-36v2) at the baseline, six and 12 months after therapy initiation and six monthly thereafter. Mean changes were compared between treatment groups for two summary measures (Physical and Mental Component Summary scores; PCS and MCS) and eight domain measures (physical functioning, role physical, bodily pain, general health, vitality, social functioning, role emotional and mental health), and in patients discontinuing therapy. A five-point change was deemed a Minimally Clinically Important Difference (MCID). Response analysis compared the proportion of patients demonstrating a MCID in HRQOL, and a regression analysis identified predictors of worsening HRQOL.3074 (97%) subjects completed baseline SF-36v2. During the initial 12 months, summary SF-36v2 scores decreased in both arms but did not reach Minimally Clinically Important Difference (MCID) despite significant incidences of diarrhoea and rash in lapatinib treated patients. At six months, women receiving lapatinib had more significant reductions (p0.01 versus placebo) in social functioning. Early treatment discontinuations were more frequent on lapatinib (32% versus 18%), and were associated with more substantial decrements of HRQOL in both arms. For those discontinuing primarily due to adverse events, decrements in HRQOL reached MCID in Mental Summary scores (MCS) only. Lower baseline HRQOL was a significant predictor of worsening HRQOL (p0.05).Despite frequent but usually mild toxicities, adjuvant lapatinib is not associated with clinically significant decreases in overall HRQOL. These placebo-controlled results may also help to inform physicians and patients using lapatinib in metastatic HER2 positive breast cancer.GlaxoSmithKline. The AVON Foundation NY supported PEG, DF and BM and The Friends of the Mater Foundation supported FB.

Worldwide, many patients with HER2-positive early stage breast cancer do not receive trastuzumab-the standard adjuvant treatment. We investigated the efficacy and safety of adjuvant lapatinib for patients with trastuzumab-naive HER2-positive early-stage breast cancer, started at any time after diagnosis.This study was a placebo-controlled, multicentre, randomised phase 3 trial. Women outpatients from 405 [corrected] centres in 33 countries [corrected] with HER2-positive early-breast cancer who had previously received adjuvant chemotherapy but not trastuzumab were randomly assigned (1:1) to receive daily lapatinib (1500 mg) or daily placebo for 12 months. Randomisation was done with a computer-generated sequence, stratified by time since diagnosis, lymph node involvement at diagnosis, and tumour hormone-receptor status. Investigators, site staff, and patients were masked to treatment assignment. The primary endpoint was disease-free survival in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT00374322.Between August, 2006, and May, 2008, 3161 women were enrolled and 3147 were assigned to lapatinib (n=1571) or placebo (n=1576). After a median follow-up of 47·4 months (range 0·4-60·0) in the lapatinib group and 48·3 (0·7-61·3) in the placebo group, 210 (13%) disease-free survival events had occurred in the lapatinib group versus 264 (17%) in the placebo group (hazard ratio [HR] 0·83, 95% CI 0·70-1·00; p=0·053). Central review of HER2 status showed that only 2490 (79%) of the randomised women were HER2-positive. 157 (13%) of 1230 confirmed HER2-positive patients in the lapatinib group and in 208 (17%) of 1260 in the placebo group had a disease-free survival event (HR 0·82, 95% 0·67-1·00; p=0·04). Serious adverse events occurred in 99 (6%) of 1573 patients taking lapatinib and 77 (5%) of 1574 patients taking placebo, with higher incidences of grade 3-4 diarrhoea (97 [6%] vs nine [1%]), rash (72 [5%] vs three [1%]), and hepatobiliary disorders (36 [2%] vs one [1%]).Our data show that there was no significant difference in disease-free survival between groups when analysed in the intention-to-treat population. However, exploratory analyses restricted to patients who had HER2-positive disease confirmed by central fluorescence in-situ hybridisation review suggested marginal benefit with lapatinib in terms of disease-free survival. Thus lapatinib might be an option for women with HER2-positive breast cancer who do not or cannot receive adjuvant trastuzumab.GlaxoSmithKline.

Introduction: CTCs play a critical role in BCa metastases. Molecular and genomic characterization of CTCs may help to predict BCa prognosis and identify which patients may derive treatment benefit, especially for those with metastatic or recurrent disease. However, CTCs are present at very low concentrations in the peripheral blood and their enrichment and expansion is technically challenging. Here we describe an ex vivo CTC culture workflow to expand CTCs for patients with Stage III/IV BCa. Methods: Duplicate whole blood samples (7.5ml/each) were collected in EDTA tubes from 16 patients with stage III/IV BCa patients before or after systemic therapy and stored at 15-30 °C until processing. CTC enumeration was performed on one of the samples from each patient using the CELLSEARCH® System to confirm the presence of >=5 CTCs per 7.5mL of blood. CTCs enrichment was performed on the second sample from each patient using the ParsortixTM System (ANGLE PLC), a microfluidic based technology that captures rare cells based on size and deformability. Using a proprietary Cell Separation Cassette with a critical gap size of 6.5μm, the Parsortix System captured viable CTCs from the blood inside the cassette. The CTCs were then harvested by inverting the flow direction and flushing the CTCs from the cassette into 210μL of PBS. The harvested CTCs were transferred and grown in ultralow attachment plates containing RPMI-1640 medium supplemented with EGF (20ng/ml), basic FGF (20ng/ml), B27 (10ml), and 1×Antibiotic-antimycotic. CTCs were cultured in a humid 37oC incubator with 5% CO2 and 4% O2. CTC counting was performed every week using a hemocytometer. DNA isolation of the CTC culture was performed on Day 21 using DNAzol. Results: All 16 patients had >=5 CTCs as defined by the CELLSEARCH System (based on cellular morphology and the correct phenotype of CK+, EpCAM+, DAPI+ and CD45-) at the time of the blood collection. Using the Parsortix System, highly purified CTCs (ranging in number from 300 to 17,250 cells) were isolated from the blood samples for each of the 16 patients and placed into culture (day 0). During the first week, the CTCs could be expanded to 3.5 - 5.5 fold, and then to 9.5 - 22.5 fold during the second week, to maximum amount of 112,500 within 14 days. The isolated CTCs were maintained without altered morphology at the same concentrations until Day 21. An average of 186ng and 1200ng of DNA could be isolated and purified from ~10,000 and ~110,000 cultured CTCs, respectively. Conclusions: We identified and optimized a workflow for the recovery and culturing of CTCs from Stage III/IV BCa patients, demonstrating that cell-size dependent isolation using the Parsortix System allows for effective ex vivo culture. With further optimization, this strategy may be utilized for organoids development for drug testing and molecular analysis, representing an important tool for personalized precision therapy. Citation Format: Qiang Zhang, Youbin Zhang, Lisa Ellen Flaum, Brian Helfand, Lorenzo Gerratana, William Gradishar, Leonidas Platanias, Massimo Cristofanilli, Massimo Cristofanilli. A novel ex vivo culture workflow to enrich and expand circulating tumor cells (CTCs) from patients with stage III/IV breast cancer (BCa) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-370.

The review summarizes the outcomes of several landmark trials involving aromatase inhibitors that helped formulate current therapeutic approaches recommended by the American Society of Clinical Oncology for breast carcinoma treatment.