Citations

Abstract Background: Based on recent breast cancer literature, we hypothesized that there could be substantive differences in apparent efficacy estimates using a log-normal (LN) survival model rather than with standard Kaplan-Meier (K-M) or Cox model methods. While both Cox and LN survival analyses offer greater specification by individual patient characteristics, the LN model may more robustly estimate survival under model misspecification. Methods: We recently pooled data for 5 NCIC CTG primary breast cancer trials: MA.5, MA.12, MA.14, MA.21, and MA.27. The total patient count for patients who received at least 1 dose of trial therapy is 11,253. Compilation included definition of STEEP endpoints (C Hudis, JCO, 2008) and standardized factor categorizations. The primary endpoint is Breast Cancer Free Interval (BCFI) defined as the time from randomization until recurrence: first local invasive or DCIS; regional, or distant; contralateral invasive or DCIS; or death from breast cancer. We found substantive evidence of non-proportionality for 7 factors compiled for the meta-analyses. In this work, we fit multivariate Cox and LN models with these 7 factors, lymph node status and pathologic T status. We then compare BCFI efficacy estimates for patient and tumour characteristics at 1-, 3-, and 5-years obtained with K-M, Cox, and LN models. Results: There was evidence that the Cox assumption of proportional hazards was violated for 7 factors: age, menopausal status, hormone receptor status, anthracycline use, chemotherapy use, race, and ECOG performance status. Differences between models were intrinsically affected by timing and extent of non-proportionality; there was no consistent pattern. In particular, investigations to date indicate efficacy estimates with absolute differences between K-M, Cox and LN estimates which varied by time of assessment: at 1-year 0.0 to 6.7%, at 3-years 0.4 to 18.6%, and at 5-years 0.2 to 17.0%. BCFI estimates with the K-M were inconsistently closer to those with the LN or Cox model: for K-M to Cox at 1-year 0.4 to 5.2%, at 3-years 0.4 to 15%, at 5-years 0.4 to 14.3%; for K-M to LN at 1-year 0.0 to 6.7%, at 3-years 0.5 to 18.6%, at 5-years 0.2 to 17.0%; for Cox to LN at 1-year 0.8 to 1.8%, at 3-years 1.9 to 6.0%, at 5-years 0.6 to 5.7%. K-M and Cox models have step-wise adjustments at events for K-M and Cox, rather than smooth modeling with the LN. Discussion: Even with reasonably large population subgroups, there were substantive differences in apparent survival (0.0 to 18.6%) between K-M, Cox and LN model types. The magnitude of differences in survival estimates was large enough to be clinically relevant and warrant further consideration as we evaluate new therapies and prognostic/predictive factors. We will be statistically investigating framework robustness under differing levels of model misspecification. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-14-01.

Abstract BACKGROUND: Mammographic percent dense area, the percent ratio of dense to total breast area in a mammogram, is one of the strongest measures of a woman's risk of breast cancer. However, systematic differences have been observed between readers and mammography technologies (film and digital) that could cause clinically inconsistent associations with risk. The purpose of this study was to evaluate inter- and intra-reproducibility of percent dense area between readers and between film and digital technologies. METHODS: One hundred digitized film mammograms were randomly selected with 25 films in each of quartile of percent density and read by two readers at two different sites (Mayo Clinic and UCSF). The readers had extensive experience and were also jointly trained at university of Toronto using Cumulus software. After training, all films were read twice with at least one year between duplicate readings. The Mayo clinic reading used Cumulus while UCSF used custom semiautomatic software to estimate total and dense tissue area. In addition, digitized films and unprocessed full field digital mammograms of the same women were assessed by one reader. The time between the film and digital acquisitions ranged from nine to twenty-four months. Interclass correlation coefficient (ICC) was calculated for each comparison. RESULTS: The intra- and inter-observer ICCs, consistency for film images, were 0.96 (UCSF) and 0.97 (Mayo), and 0.96 (UCSF vs. Mayo). We found ICC between film and digital mammograms for percent dense area was 0.88. The digital mammogram had 9% significantly higher total breast area and 5% significantly lower percent density area compared to film. CONCLUSIONS: Similarly trained readers had a high reproducibility regardless of the software used. Our results suggest centralized reader training should enable pooling of film breast density results from different clinics. However, pooling film and digital results would need careful calibration due to lower measured percent dense areas than on film. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-08-03.

Abstract Background Aromatase inhibitors (AIs) are standard adjuvant therapy for postmenopausal women with hormone receptor-positive breast cancer. We previously reported that racial/ethnic minority women receiving an AI in NCIC CTG MA.17 experienced fewer hot flashes, fatigue, and arthralgias than Caucasians (Moy B et al. Ann Oncol 2006;17:1637). Here we examined whether race affected clinical outcomes in the MA.27 AI trial comparing exemestane (E) with anastrozole (A). Methods: Fisher's exact test was used to compare observed side effects (0 vs grades 1–5) between minority and Caucasian women. Adverse events (AE), including menopausal symptoms, were assessed according to the Common Terminology Criteria of the National Cancer Institute (version 3.0). ITT univariate test of race effects on overall survival (OS) was determined with a stratified log-rank test, while multivariate testing was with stratified Cox regression. Results: Among 7312 for whom race was known, distribution was: Caucasian (n=6939; 95%); black (n=235; 3%); Asian/Native Hawaiian/Pacific Islander (n=93); 1%; American Indian (n=39; 1%); and mixed race (n=6). Among women treated with E, minorities reported a significantly lower incidence of hot flashes (45% vs. 56%; p=0.003) and fatigue (34% vs. 46%; p=0.001) compared to Caucasians. Similarly with A, minority women reported significantly fewer hot flashes (47% vs. 58%; p=0.002) and lower cholesterol (12% vs. 18%; p=0.01); however, they reported more headaches than Caucasians (16% vs. 10%; p=0.01). Caucasian women were more likely to discontinue therapy due to AE or side effects (32% vs. 24%). There was a significant OS interaction (p=0.02) between race and treatment with minority women on E having fewer deaths than those on A. Caucasian women had HR of E to A of 0.98 (95% CI 0.81−1.20), p=0.85, while minorities had HR of E to A of 0.72 (95% CI 0.33−1.58), p=0.41. Conclusions: Minority women tolerated AIs better and were also more compliant than Caucasians, supporting our previous findings. A significant interaction between race and type of AI therapy for OS was seen, favoring exemestane in minority women. Replication of these findings in larger cohorts is necessary. Since race/ethnicity may serve as a surrogate for genetic differences, our findings suggest pharmacogenomic differences which require further research. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-14-02.

The manner in which the administration of epinephrine, norepinephrine, isoproterenol, and atrophic modifies the cardiovascular response to exercise has been studied in 12 dogs. In control observations, exercise increased the cardiac output by 116 per cent, the heart rate by 102 per cent, and the stroke volume by 8 per cent. When epinephrine was infused during identical exercise, the cardiac output was similar; however, the stroke volume was increased by 50 per cent. During infusion of norepinephrine, the cardiac output was reduced by 11 per cent compared with that during control exercise, and the stroke volume was increased by 25 per cent. With isoproterenol, the cardiac output exceeded that during control exercise, but the stroke volume was unchanged. Prior to administration of atropine, the cardiac output at rest averaged 4.2 L. per minute. After injection of atropine, the cardiac output averaged 3.7 L. per minute, the heart rate increased from 121 to 249 beats per minute, and the stroke volume decreased from 35 to 15 ml. Before atropinization, the cardiac output, heart rate, and stroke volume during exercise were increased by 95, .90, and 2 per cent over the resting values; after atropinization, the corresponding increases were 110, 7, and 100 per cent. Thus, while cardiac output during exercise normally is regulated mainly by changes in the heart rate, the stroke volume may make a major contribution under other circumstances.

The effect of exercise on the pulmonary circulation was studied in a group of 6 intact dogs and in a second group of 4 subjected to ligation and division of the left pulmonary artery. Observations were made with the dogs standing and running on a horizontal treadmill up to the maximal speed they could maintain for periods of at least 2 minutes, usually 12 or 14 km./hr. Continuous records were made of the difference in pressure between the main pulmonary artery (PA) and a pulmonary-artery wedge (PAW) position. Cardiac output was determined by the indicator-dilution method, with injection of indocyanine (cardiogreen) dye into the main pulmonary artery and continuous sampling from the root of the aorta. The mean transit time of indicator betweell the pulmonary and aortic valves was obtained from the dilution curves, a correction being made for the transit time through the sampling apparatus. From these measurements the blood volume of the lungs and left heart chambers was derived. In the intact dogs, cardiac output increased approximately threefold from rest to severe exercise. There was an increase of only 12 per cent to 50 per cent in PA minus PAW pressure. Thus a continued fall occurred in pulmonary vascular resistance. The blood volume of the lungs and left heart of 3 intact dogs was measured. In 2 it did not change through the range of activity, and in the third the increase with maximal exercise was 18 per cent. The dogs with ligated left pulmonary artery also showed a threefold increase in output with severe exercise. Since the entire output passed through a single lung, the effect on the pulmonary vessels was comparable to that of a sixfold increase in output in a normal dog. Despite such large flows, in 3 of 4 dogs the difference between PA and PAW pressure rose only 37 per cent to 50 per cent. The volume of blood in the lungs and left heart was unchanged between rest and 8 km./hr., and at higher speeds showed a 0 per cent to about 20 per cent increase.

Measurements of stroke volume were made in dogs during graded exercise on a horizontal treadmill up to the maximal exercise which they could maintain for 2 to 3 minutes. Eleven series of experiments were performed on 7 dogs. The cardiac output was measured by the indicator-dilution technic and the heart rate was measured from the aortic pressure tracing. At all grades of exercise, there was little or no change in stroke volume. Even with severe exercise, when the cardiac output had increased from 1.5 to 3.5 (average, 2.4) times the values obtained with the dog standing at rest, the stroke volume showed less than 5 per cent change over resting values in 5 experiments on 4 dogs, while in the remainder the increases were 8, 11, 11, 14, 15, and 19 per cent. Thus, the increase in cardiac output in the untrained exercising dog is almost directly proportional to the increase in heart rate. This is in contrast to other situations, such as the combination of exercise with infusion of catecholamines, where an increase in stroke volume may make an important contribution to the increase in cardiac output.

The indicator-dilution method was used in the dog in an attempt to define the proportion of the "central" blood volume contained in the lung vessels. When injections were made into the pulmonary artery with sampling from the femoral artery only half or even less of the calculated blood volume could be accounted for by the lungs. When a venous injection site was used, the proportion in the lungs was reduced to a third or less. Thus when peripheral sites are used for the inscription of indicator-dilution curves few deductions can be made about either the actual volume or even relative changes in the volume of blood in the lungs.

The lateral saphenous vein of the dog was perfused with homologous blood at constant flow. Changes in driving pressure were used to measure active changes in venous tone. Administration of tranylcypromine greatly reduced the activity of monoamine oxidase in the vein and increased its response to electric stimulation of the lumbar sympathetic chain and to norepinephrine infusions. Administration of pyrogallol (a catechol-O-methyl transferase inhibitor) also increased the response of the vein to adrenergic stimulation. These chemicals did not alter the increase in the sensitivity of the venous smooth muscle to sympathetic nerve impulses and infused norepinephrine produced by cooling the perfusate. Thus, the potentiating effect of local cooling on the response of the cutaneous veins to adrenergic stimulation cannot be explained by interference with the local enzymatic inactivation of catecholamines.

Acetylstrophanthidin, 0.3 to 10 µg/ml, caused contraction of helical strips of the dog cutaneous vein in an organ bath at 37°C. A latent period of 12 to 60 minutes preceded the contraction. During this time, the vein exhibited a progressive increase in response to transmural electric stimulation and added norepinephrine. As the dose of acetylstrophanthidin was increased, the latent period shortened and the increased response during the latent period was potentiated. When the contraction caused by 10 µg/ml was maximal, no additional contraction occurred with electric stimulation; the response to electric stimulation was only partially restored by the repeated washing out of the drug, despite relaxation of the strip to almost base-line tension. Since transmural electric stimulation causes contraction by release of tissue catecholamines, these experiments demonstrate that digitalis glycosides sensitize the cutaneous veins of the dog to adrenergic stimulation. This was confirmed in dogs anesthetized with pentobarbital. Intravenous injections of acetylstrophanthidin and digoxin, in doses too small (12.5 to 15.5 µ/kg) to cause direct constriction of the lateral saphenous vein, potentiated the constriction of this vein caused by electric stimulation of the lumbar sympathetic chain.

The cutaneous veins of the dog constrict and dilate with local cooling and warming, respectively. This response, which is dependent on the integrity of the adrenergic nerves, might be explained by an altered response of the smooth muscle to a given frequency of sympathetic nerve impulses or by local temperature receptors that initiate alterations in sympathetic nerve activity. In the lateral saphenous vein perfused at 42°, 27°, and 17°C, the constriction caused by stimulation of lumbar sympathetic nerves was 40%, 160%, and 200%, respectively, of that at 37°C; the constriction caused by norepinephrine at the same temperatures was 70%, 187%, and 318% of that at 37°C. Division of the dorsal spinal roots from L-1 to S-1 made no difference to the veno-constrictor response to local cooling. It is concluded that an alteration in the sensitivity of the smooth muscle to arriving sympathetic nerve impulses accounts for the venous responses to local temperature changes seen in the intact dog.