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Background: In the KATHERINE study (NCT01772472), patients with residual invasive early breast cancer (EBC) after neoadjuvant chemotherapy (NACT) plus human epidermal growth factor receptor 2 (HER2)-targeted therapy had a 50% reduction in risk of recurrence or death with adjuvant trastuzumab emtansine (T-DM1) versus trastuzumab. Here, we present additional exploratory safety and efficacy analyses. Patients and methods: KATHERINE enrolled HER2-positive EBC patients with residual invasive disease in the breast/ axilla at surgery after NACT containing a taxane (AE anthracycline, AE platinum) and trastuzumab (AE pertuzumab). Patients were randomized to adjuvant T-DM1 (n ¼ 743) or trastuzumab (n ¼ 743) for 14 cycles. The primary endpoint was invasive disease-free survival (IDFS). Results: The incidence of peripheral neuropathy (PN) was similar regardless of neoadjuvant taxane type. Irrespective of treatment arm, baseline PN was associated with longer PN duration (median, 105-109 days longer) and lower resolution rate (w65% versus w82%). Prior platinum therapy was associated with more grade 3-4 thrombocytopenia in the T-DM1 arm (13.5% versus 3.8%), but there was no grade !3 hemorrhage in these patients. Risk of recurrence or death was decreased with T-DM1 versus trastuzumab in patients who received anthracycline-based NACT [hazard ratio (HR) ¼ 0.51; 95% confidence interval (CI): 0.38-0.67], non-anthracycline-based NACT (HR ¼ 0.43; 95% CI: 0.22-0.82), presented with cT1, cN0 tumors (0 versus 6 IDFS events), or had particularly high-risk tumors (HRs ranged from 0.43 to 0.72). The central nervous system (CNS) was more often the site of first recurrence in the T-DM1 arm (5.9% versus 4.3%), but T-DM1 was not associated with a difference in overall risk of CNS recurrence. Conclusions: T-DM1 provides clinical benefit across patient subgroups, including small tumors and particularly high-risk tumors and does not increase the overall risk of CNS recurrence. NACT type had a minimal impact on safety.

Respiratory mechanics were compared using conventional and forced oscillation techniques in six conscious horses and a mechanical model of the equine respiratory system. The parameters calculated from conventional airflow and esophageal pressure measurements were pulmonary resistance and dynamic compliance. The impedance of the respiratory system was measured at 1, 2, and 3 Hz with the forced oscillation technique, and respiratory system resistance, compliance, inertance, and resonant frequency were calculated. Pulmonary resistance was 1.0 +/- 0.3 cmH2O.l-1.s, and pulmonary dynamic compliance was 2.4 +/- 0.6 l/cmH2O. With the use of the forced oscillation system, respiratory resistance was 1.61 +/- 0.50 cmH2O.l-1.s at 1 Hz, compliance was 0.195 +/- 0.075 l/cmH2O, inertance was 0.026 +/- 0.0095 cmH2O.l-1.s2, and resonant frequency was 2.40 +/- 0.25 Hz. Data collected from a model of the respiratory system showed a close correlation between resistance and compliance measured with the two systems. This study demonstrates that the forced oscillation technique is a useful method for noninvasive measurement of respiratory mechanics in horses.

Young, S. S., D. Tesarowski, and L. Viel. Frequency dependence of forced oscillatory respiratory mechanics in horses with heaves. J. Appl. Physiol. 82(3): 983-987, 1997.-The effect of measurement frequency on respiratory mechanics was investigated in six horses with reversible allergic airway disease. Total respiratory impedance was measured at 1.5, 2.0, 3.0, and 5.0 Hz by using the forced oscillation technique with the horses in remission, after acute antigenic challenge producing clinical heaves, and with heaves but after the administration of 2 mg fenoterol by inhalation. The slopes of the magnitude (0Zrs0) and real part (R) of total respiratory impedance over the frequency range 1.5-3 Hz changed significantly after antigenic challenge and fenoterol. The ratio of R at 2 Hz to R at 3 Hz, however, discriminated better among the three conditions. Compliance and resonant frequency (calculated by using a three-element model) changed significantly after antigenic challenge and fenoterol, but inertance did not. We concluded that horses with heaves showed frequency dependence of R and 0Zrs0 at frequencies up to 3 Hz and that parameters derived from a three-element model were useful indicators of small airway obstruction in the horse. resistance; compliance; inertance; resonant frequency; airway obstruction THE MECHANICAL PROPERTIES of the respiratory system have been known for many years (15) to change with measurement frequency, an effect called frequency dependence. This phenomenon is much more marked in respiratory disease, particularly obstructive respiratory disease, and the subject was extensively reviewed by Cutillo and Renzetti (4). Frequency dependence of resistance has also been used to measure the response to bronchial challenge with histamine (19).The forced oscillation technique is particularly suitable for measuring changes in respiratory mechanics with frequency because it measures total respiratory impedance over a range of frequencies in a rapid, noninvasive manner. The technique is well tolerated by conscious, unsedated animals including larger species, such as cattle (5, 6) and ponies (22). We have previously shown how the forced oscillation technique can be used to measure total respiratory impedance in normal Standardbred horses (23). The purpose of this study was to investigate the effect of measurement frequency on total respiratory impedance in horses with naturally occurring reversible allergic airway disease. MATERIALS AND METHODSSix adult horses (three Standardbred, one Thoroughbred, one Arabian cross, and one Quarterhorse) affected by naturally occurring reversible allergic airway obstruction (heaves) and accustomed to being handled were used in the experiment. Their mean weight was 512 6 28 (SD) kg, and their mean age was 12.7 6 2.3 yr. The horses were housed and cared for in accordance with the recommendations of the Canadian Council on Animal Care, and the experimental protocol was approved by the Animal Care Committee of the University of Guelph. The horses were kept at pasture for sev...

Following chemotherapy and human epidermal growth factor 2 (HER2)-targeted neoadjuvant therapy for HER2-positive early breast cancer, residual invasive breast cancer at surgery may be HER2-negative on retesting in some patients. We evaluated outcomes with T-DM1 and trastuzumab in patients randomized in the phase III KATHERINE trial based on HER2-positive central testing of the pre-treatment core biopsy with HER2-negative central testing on their corresponding surgical specimen after neoadjuvant treatment. In the 70/845 (8.3%) patients with HER2-negative residual disease on retesting at surgery, there were 11 IDFS events in the 42 trastuzumab-treated patients (26.2%) and none in the 28 T-DM1-treated patients, suggesting that T-DM1 should not be withheld in this patient population.