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Background: A significant amount of DCIS is ER negative and/or overexpresses HER2. This provides an opportunity to test molecular therapy in DCIS. In xenograft models and cell lines, T boosts RT effectiveness. In T-treated HER2+ patients, apoptosis occurs within 1 wk of single agent T use, with T found in ductal aspirates. Ample safety evidence for T exists. T given during whole breast irradiation (WBI) may improve results for lumpectomy (Lx) resected HER2+ DCIS. A trial to examine this question will enhance the understanding of breast tumor biology and the prevention of such tumors and could possibly extend breast-conserving surgery benefits for women with DCIS. Method: After Lx for pure DCIS, each patient's DCIS lesion is centrally tested for HER2 by IHC analysis. HER2 2+ tumors undergo FISH analysis. HER2 3+ or FISH+ patients can be randomly assigned to 2 doses of T, 3 weeks apart during WBI or to WBI alone. Women ≥18 yrs. with a margin-clear Lx for pure DCIS, with ECOG status 0/1 who are clinically or pathologically node negative are eligible. Centrally tested DCIS must be HER2 +. ER and/or PR status must be known before randomization. Primary aims are to determine if T decreases ipsilateral breast cancer recurrence, ipsilateral skin cancer recurrence, or ipsilateral DCIS. Secondary aims are to determine the benefit of T in preventing regional or distant recurrence and contralateral invasive breast cancer or DCIS. B-43 will determine if DFS, recurrence-free interval, and OS can be improved with the use of T. 2000 patients will be accrued over 7.9 yrs, with a definitive analysis of primary endpoints performed at163 ipsilateral breast cancer events (7.5-8 yrs. after protocol initiation) with an 80% power to detect a hazard reduction of 36%, from 1.73 ipsilateral breast cancer events per 100 pt-yrs to 1.11 events per 100 pt-yrs. The 36% observed reduction in the hazard of IIBCR- SCR-DCIS on the T arm is based on a projection of 40% hazard reduction if the compliance were perfect, with a 10% noncompliance rate. As of 5-31-12, 939 patients have been randomized. NCT00769379Grant support: PHS NCI-U10-CA-69651, -12027, and NCI P30-CA-14599 from the US NCI and Genentech, Inc. [ABSTRACT FROM AUTHOR]

The role of MRI in the management of breast carcinoma is rapidly evolving from its initial use for specific indications only to a more widespread use on all women with newly diagnosed early stage breast cancer. However, there are many concerns that such widespread use is premature since detailed correlation of MRI findings with the underlying histopathology of the breast lesions is still evolving and clear evidence for improvements in management and overall prognosis of breast cancer patients evaluated by breast MRI after their initial cancer diagnosis is lacking. In this paper, we would like to bring attention to a benign lesion that is frequently present on MRI-guided breast biopsies performed on suspicious MRI findings in the affected breast of patients with a new diagnosis of breast carcinoma. [ABSTRACT FROM AUTHOR]

Background: The gold standard end point in randomized clinical trials in metastatic breast cancer (MBC) is overall survival (OS). Although therapeutics have been approved based on progression-free survival (PFS), its use as a primary end point is controversial. We aimed to assess to what extent PFS may be used as a surrogate for OS in randomized trials of anti-HER2 agents in HER2+ MBC. Methods: Eligible trials accrued HER2+ MBC patients in 1992-2008. A correlation approach was used: at the individual level, to estimate the association between investigator-assessed PFS and OS using a bivariate model and at the trial level, to estimate the association between treatment effects on PFS and OS. Correlation values close to 1.0 would indicate strong surrogacy. Results: We identified 2545 eligible patients in 13 randomized trials testing trastuzumab or lapatinib. We collected individual patient data from 1963 patients and retained 1839 patients from 9 trials for analysis (7 first-line trials). During follow-up, 1072 deaths and 1462 progression or deaths occurred. The median survival time was 22 months [95% confidence interval (CI) 21-23 months] and the median PFS was 5.7 months (95% CI 5.5-6.1 months). At the individual level, the Spearman correlation was equal to = 0.67 (95% CI 0.66-0.67) corresponding to a squared correlation value of 0.45. At the trial level, the squared correlation between treatment effects (log hazard ratios) on PFS and OS was provided by R² = 0.51 (95% CI 0.22-0.81). Conclusions: In trials of HER2-targeted agents in HER2+ MBC, PFS moderately correlates with OS at the individual level and treatment effects on PFS correlate moderately with those on overall mortality, providing only modest support for considering PFS as a surrogate. PFS does not completely substitute for OS in this setting. [ABSTRACT FROM AUTHOR]

Background:Bevacizumab has broad anti-tumour activity, but substantial risk of hypertension. No reliable markers are available for predicting bevacizumab-induced hypertension.Methods:A genome-wide association study (GWAS) was performed in the phase III bevacizumab-based adjuvant breast cancer trial, ECOG-5103, to evaluate for an association between genotypes and hypertension. GWAS was conducted in those who had experienced systolic blood pressure (SBP) >160 mm Hg during therapy using binary analysis and a cumulative dose model for the total exposure of bevacizumab. Common toxicity criteria (CTC) grade 3-5 hypertension was also assessed. Candidate SNP validation was performed in the randomised phase III trial, ECOG-2100.Results:When using the phenotype of SBP>160 mm Hg, the most significant association in SV2C (rs6453204) approached and met genome-wide significance in the binary model (P=6.0 × 10−8; OR=3.3) and in the cumulative dose model (P=4.7 × 10−8; HR=2.2), respectively. Similar associations with rs6453204 were seen for CTC grade 3-5 hypertension but did not meet genome-wide significance. Validation study from ECOG-2100 demonstrated a statistically significant association between this SNP and grade 3/4 hypertension using the binary model (P-value=0.037; OR=2.4).Conclusions:A genetic variant in SV2C predicted clinically relevant bevacizumab-induced hypertension in two independent, randomised phase III trials. [ABSTRACT FROM AUTHOR]

Background: In an open-label, randomized, phase 3 trial, we compared the efficacy and safety of paclitaxel with that of paclitaxel plus bevacizumab, a monoclonal antibody against vascular endothelial growth factor, as initial treatment for metastatic breast cancer.Methods: We randomly assigned patients to receive 90 mg of paclitaxel per square meter of body-surface area on days 1, 8, and 15 every 4 weeks, either alone or with 10 mg of bevacizumab per kilogram of body weight on days 1 and 15. The primary end point was progression-free survival; overall survival was a secondary end point.Results: From December 2001 through May 2004, a total of 722 patients were enrolled. Paclitaxel plus bevacizumab significantly prolonged progression-free survival as compared with paclitaxel alone (median, 11.8 vs. 5.9 months; hazard ratio for progression, 0.60; P<0.001) and increased the objective response rate (36.9% vs. 21.2%, P<0.001). The overall survival rate, however, was similar in the two groups (median, 26.7 vs. 25.2 months; hazard ratio, 0.88; P=0.16). Grade 3 or 4 hypertension (14.8% vs. 0.0%, P<0.001), proteinuria (3.6% vs. 0.0%, P<0.001), headache (2.2% vs. 0.0%, P=0.008), and cerebrovascular ischemia (1.9% vs. 0.0%, P=0.02) were more frequent in patients receiving paclitaxel plus bevacizumab. Infection was more common in patients receiving paclitaxel plus bevacizumab (9.3% vs. 2.9%, P<0.001), but febrile neutropenia was uncommon (<1% overall).Conclusions: Initial therapy of metastatic breast cancer with paclitaxel plus bevacizumab prolongs progression-free survival, but not overall survival, as compared with paclitaxel alone. (ClinicalTrials.gov number, NCT00028990 [ClinicalTrials.gov].). [ABSTRACT FROM AUTHOR]

Background ZW25, a novel IgG1 bispecific antibody, targets HER2 domains ECD2 and ECD4, resulting in multiple differentiated and unique mechanisms of action, including improved receptor internalization and downregulation relative to trastuzumab. Safety, anti-tumor activity, and biomarker data from an ongoing phase 1 trial of ZW25 monotherapy in solid tumors other than breast cancer, are presented here. Methods Eligible patients with HER2 IHC 3+, IHC 2+/FISH+, or IHC 2+/FISH- tumors confirmed by central review of fresh or archival biopsies, who had progressed on all standard therapies, were enrolled. Patients were treated with single agent ZW25 at 10 mg/kg QW or 20 mg/kg Q2W Assessments included tumor evaluations (RECIST 1.1 Q8W), circulating tumor DNA (ctDNA), and standard safety evaluations. Results A total of 43 patients were treated, including 17 patients with gastroesophageal adenocarcinoma (GEA), 6 with biliary cancers, 10 with colorectal cancer, and 10 other cancers. The median number of prior therapies was 3 (range 1-6) for all patients. For GEA and non-GEA patients, 88% and 35% respectively received at least one prior HER2 therapy. The most common treatment-related adverse events (all Grade 1 or 2) were diarrhea (49%) and infusion related reaction (34%). The objective response rate (all partial response (PR)) for response evaluable patients was 41% (14/34), stable disease (SD) in 38% (13/34), and progressive disease in 21% (7/34). The majority of patients (74%; 25/34) experienced a decrease in the sum of diameters for their target lesions. Compared to FISH, the positive predictive value of HER2 amplification in pre-dose C1D1 ctDNA was 90% (95% CI 79-96%), negative predictive value 45% (25-67%), and diagnostic accuracy 79% (63-90%). Disease control (PR or SD) > 5 months was associated with lower level of copy number adjusted mutational variant allele frequency in pre-treatment ctDNA (Mann Whitney p = 0.0085). Conclusions ZW25 has been well tolerated with promising single agent activity in heavily pre-treated patients. These data support further clinical development of this bispecific antibody in HER2-expressing solid tumors. Clinical trial identification Identifier: NCT02892123. Legal entity responsible for the study Zymeworks Inc. Funding Zymeworks Inc. Disclosure D-Y. Oh: Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Novartis; Advisory / Consultancy: Genentech/Roche; Advisory / Consultancy: Merck Serono; Advisory / Consultancy: Bayer; Advisory / Consultancy: Taiho; Advisory / Consultancy: ASLAN; Advisory / Consultancy: Halozyme; Advisory / Consultancy: Zymeworks; Research grant / Funding (self): AstraZeneca; Research grant / Funding (self): Novartis; Research grant / Funding (self): Array; Research grant / Funding (self): Eli Lilly; Research grant / Funding (self): Green Cross. E. Hamilton: Speaker Bureau / Expert testimony: Genentech/Roche; Advisory / Consultancy: Flatiron Health; Advisory / Consultancy: Pfizer; Advisory / Consultancy: Casadian Therapeutics; Research grant / Funding (self): Zymewors; Research grant / Funding (self): Pfizer; Research grant / Funding (self): Casadian Therapeutics; Research grant / Funding (self): Hutchinson. M. Beeram: Speaker Bureau / Expert testimony: Genentech. K-W. Lee: Honoraria (self): BMS; Honoraria (self): Eli Lilly; Research grant / Funding (self): ALX Oncology; Research grant / Funding (self): Array BioPharma; Research grant / Funding (self): ASLAN Pharma; Research grant / Funding (self): AstraZeneca/MedImmune; Research grant / Funding (self): Five Prime; Research grant / Funding (self): Green Cross Corp; Research grant / Funding (self): LSK BioPharma; Research grant / Funding (institution): Macrogenics; Research grant / Funding (self): Merck MGaA; Research grant / Funding (self): MSD; Research grant / Funding (self): Ono Pharma; Research grant / Funding (self): Pfizer; Research grant / Funding (self): Pharmacyclics; Travel / Accommodation / Expenses: BMS. Y-K. Kang: Advisory / Consultancy: ONO; Advisory / Consultancy: BMS; Advisory / Consultancy: Daehwa; Advisory / Consultancy: LSK BioPharma; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Macrogenics; Advisory / Consultancy: Zymeworks; Advisory / Consultancy: Blue print; Advisory / Consultancy: Merck Serono; Advisory / Consultancy: Novartis; Advisory / Consultancy: Astellas; Research grant / Funding (self): Roche; Research grant / Funding (self): Novartis. J. Chaves: Honoraria (self): PLLC. C. Vaklavas: Advisory / Consultancy: Genentech; Advisory / Consultancy: Daiichi-Sankyo; Research grant / Funding (self): Genentech; Research grant / Funding (self): Roche; Research grant / Funding (self): Pfizer; Research grant / Funding (self): Incyte; Research grant / Funding (self): Novartis; Research grant / Funding (self): Pharmacyclics; Research grant / Funding (self): Tracon; Research grant / Funding (self): Innocrin; Research grant / Funding (self): Zymeworks; Research grant / Funding (self): H3 Biomedicine. E. Elimova: Advisory / Consultancy: BMS; Honoraria (self): Zymeworks; Spouse / Financial dependant, Spouse: Merck employee in vaccine global division: Merck. C. Ferrario: Honoraria (self): Pfizer; Honoraria (self): Bayer; Honoraria (self): Novartis; Honoraria (self): AstraZeneca; Honoraria (self): Merck; Honoraria (self): Astellas; Advisory / Consultancy: Genomic health; Advisory / Consultancy: Merck; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Bayer; Speaker Bureau / Expert testimony: Novartis; Research grant / Funding (self): Amgen; Research grant / Funding (self): Astellas; Research grant / Funding (self): AstraZeneca; Research grant / Funding (self): Bayer; Research grant / Funding (self): Casadian Therapeutics; Research grant / Funding (self): Celldex; Research grant / Funding (self): Lilly; Research grant / Funding (self): Merck; Research grant / Funding (self): Novartis. A. Fortenberry: Shareholder / Stockholder / Stock options, Full / Part-time employment: Zymeworks. G. Rowse: Shareholder / Stockholder / Stock options, Full / Part-time employment: Zymeworks. T. Gray: Shareholder / Stockholder / Stock options, Full / Part-time employment: Zymeworks. R. Lai: Shareholder / Stockholder / Stock options, Full / Part-time employment: Zymeworks. F. Meric Bernstam: Research grant / Funding (self): Novartis; Research grant / Funding (self): AstraZeneca; Research grant / Funding (self): Calithera; Research grant / Funding (self): Aileron; Research grant / Funding (self): Bayer; Research grant / Funding (self): Jounce; Research grant / Funding (self): CytoMx; Research grant / Funding (self): eFFECTOR; Research grant / Funding (self): Zymeworks; Research grant / Funding (self): PUMA Biotech; Research grant / Funding (self): Curis; Research grant / Funding (self): Millennium; Research grant / Funding (self): Daiichi Sankyo; Research grant / Funding (self): AbbVie; Research grant / Funding (self): Guardant Health; Research grant / Funding (self): Takeda, Seattle Genetics, GlaxoSmithKline; Research grant / Funding (self), Travel / Accommodation / Expenses: Taiho, Genentech, Debiopharm Group, Pfizer; Consulting: Pieris, Dialectica, Sumitomo Dainippon, Samsung Bioepis, Aduro, OrigiMed, Xencor, Jackson Laboratory, Zymeworks, Kolon Life Science, Parexel Internationa; Advisory / Consultancy: Inflection Biosciences, GRAIL, Darwin Health, Spectrum, Mersana, and Seattle Genetics. All other authors have declared no conflicts of interest. [ABSTRACT FROM AUTHOR]

Background: Trastuzumab emtansine (T-DM1) is a HER2-targeted antibody-drug conjugate composed of the humanized monoclonal antibody trastuzumab, the potent cytotoxic agent DM1 (a microtubule inhibitor), and a stable thioether linker. To estimate typical pharmacokinetic (PK) parameter values and interpatient variability, a population PK model for T-DM1 was previously developed from 1 phase 1 (0.3 to 4.8 mg/kg in qw or q3w regimens) and 2 phase 2 (3.6 mg/kg q3w) trials (Gupta, J Clin Pharmacol2012). The model reported here has been updated with additional data from 2 randomized trials (phase 2 TDM4450g and phase 3 EMILIA, 3.6 mg/kg q3w). Another phase 2 trial (TDM4688g) was used for external validation of the model. The effect of demographic and pathophysiological covariates on the PK of T-DM1 was explored to better understand the clinical factors that might affect exposure and clinical outcome for individual patients. Methods: For the current analysis, 9934 T-DM1 serum concentration-time data points from 671 patients were simultaneously fitted using NONMEM® software. T-DM1 concentration-time data to date are best described using a 2-compartment linear model. All relevant and plausible covariates likely to have an effect on T-DM1 systemic exposure, or likely to have clinical relevance, were explored for possible correlation with the key T-DM1 PK parameters of clearance (CL) and central volume of distribution (Vc). These covariates include those related to demographics, renal and hepatic function, disease status, and treatment history. Results: The estimated CL for T-DM1 is 0.68 L/day, Vc is 3.13 L, and the terminal half-life is 3.94 days. Interindividual variability (IIV) of the base model is 25.6% and 17.5% for CL and Vc, respectively. Patients with greater body weight, sum of longest dimension of target lesions, serum concentration of shed HER2 extracellular domain, and aspartate aminotransferase concentrations, as well as patients with lower serum albumin and baseline trastuzumab concentrations, have statistically faster CL. Patients with greater body weight also have statistically larger Vc. Incorporation of these covariates (P<0.001 by likelihood ratio test) decreased IIV of CL and Vc to 19.1 % and 11.7%, respectively. All covariates together explain 44.4% and 55.8% of IIV in CL and Vc, respectively. The model sensitivity analysis suggests that a patient with a statistically significant PK covariate value at the 5th or 95th percentile of the population will have a <20% difference in cumulative exposure (as represented by area under the T-DM1 concentration-time curve) compared with a typical patient with a median covariate value. Conclusions: A relatively small IIV for the estimated T-DM1 PK parameters of CL and Vc was observed. None of the evaluated covariates had a clinically meaningful magnitude of effect on T-DM1 exposure (<20% difference for patients with 5th and 95th percentiles vs patients with median value of covariates) that would justify a further dose adjustment. The body weight-based dose of 3.6 mg/kg q3w without further correction for other factors is considered appropriate in ongoing clinical trials. [ABSTRACT FROM AUTHOR]