Differences in sensitivity to new therapies between primary and metastatic breast cancer: A need to stratify the tumor response?

OBJECTIVE: We compared therapeutic response of Varlitinib + Capecitabine (VC) versus Lapatinib + Capecitabine (LC) in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer after trastuzumab therapy by assessing changes in target lesion (TL) diameter and volume per location. METHODS: We retrospectively analyzed the CT data of the ASLAN001-003 study (NCT02338245). We analyzed TL size and number at each location focusing on therapeutic response from baseline to Week 12. We used TL diameter and volume to conduct an inter-arm comparison of the response according to: RECIST 1.1; stratified per TL location and considering TLs independently. Multiple pairwise intra-arm comparisons of therapeutic responses were performed. Considering TL independently, weighted models were designed by adding weighted mean TL responses grouped by location. RESULTS: We evaluated 42 patients (88 TL) and 35 patients (74 TL), respectively, at baseline and Week 12. We found reductions in breast TL burden in the VC arm compared to the LC arm (p = 0.002 (diameter), p < 0.001 (volume)). Responses and TL sizes at baseline were not correlated. Explained variabilities of volume change per TL location, patient and patient:TL interaction were 36%, 10% and 4% (VC), and 13%, 1% and 23%, (LC). A test of inter-arm difference of responses yielded p = 0.07 (diameter), and p < 0.001 (volume). CONCLUSIONS: The therapeutic responses differed across tumors' locations; the magnitude of the differences of responses across the tumors' locations were drug-dependent. Stratified analysis of the response by tumor location improved drug comparisons and is a powerful tool to understand TL heterogeneity.

Enhanced vertebra to disk ratio as a new semi-quantitative imaging biomarker for Gaucher disease patients.

PURPOSE: Gaucher disease (GD) is an inherited lysosomal storage disorder. The Vertebral Disk Ratio (VDR) is a semi-quantitative imaging biomarker designed to diagnose and monitor GD. Computed from standard T1 MRI images, the VDR is derived from 2D segmentations. This study aimed to evaluate the 3D version of VDR, namely eVDR, and analyze the performances of two eVDR-derived response criteria for GD patients. METHODS: Three datasets were used: 8 longitudinal GD patients, 13 non-GD patients, and 2 longitudinal GD patients with known Bone Marrow Burden (BMB) scores. Two eVDR-derived response criteria were tested: 1) a parametric version (PeVDR) averaging all eVDR measures recorded for the 5 lumbar vertebrae; and 2) a non-parametric version (NPeVDR), considering all eVDR measures as independent and evaluating therapeutic response in a paired fashion. Analyses included assessment of reader variability in eVDR (3D) versus VDR (2D) and comparison with BMB response criteria. RESULTS: The repeatability of eVDR (3D) versus VDR (2D) demonstrated no difference in mean values but a lower variance (p < 0.004). The PeVDR intra-reader variability had a standard deviation < 0.1 with a coefficient of variation < 5%; the inter-reader variability featured a Limit of Agreement < 5% and a Bias < 3%. Observational comparison of eVDR and BMB scoring and sensitivity indicated a correlation between PeVDR and BMB, with an improved sensitivity with the NPeVDR version. CONCLUSIONS: Based on a standard MRI sequence, the eVDR imaging biomarker and its derived response criteria improved GD assessments and could help assessing other bone marrow diseases.

Pubertal timing and breast density in young women: a prospective cohort study.

BACKGROUND: Earlier age at onset of pubertal events and longer intervals between them (tempo) have been associated with increased breast cancer risk. It is unknown whether the timing and tempo of puberty are associated with adult breast density, which could mediate the increased risk. METHODS: From 1988 to 1997, girls participating in the Dietary Intervention Study in Children (DISC) were clinically assessed annually between ages 8 and 17 years for Tanner stages of breast development (thelarche) and pubic hair (pubarche), and onset of menses (menarche) was self-reported. In 2006-2008, 182 participants then aged 25-29 years had their percent dense breast volume (%DBV) measured by magnetic resonance imaging. Multivariable, linear mixed-effects regression models adjusted for reproductive factors, demographics, and body size were used to evaluate associations of age and tempo of puberty events with %DBV. RESULTS: The mean (standard deviation) and range of %DBV were 27.6 (20.5) and 0.2-86.1. Age at thelarche was negatively associated with %DBV (p trend = 0.04), while pubertal tempo between thelarche and menarche was positively associated with %DBV (p trend = 0.007). %DBV was 40% higher in women whose thelarche-to-menarche tempo was 2.9 years or longer (geometric mean (95%CI) = 21.8% (18.2-26.2%)) compared to women whose thelarche-to-menarche tempo was less than 1.6 years (geometric mean (95%CI) = 15.6% (13.9-17.5%)). CONCLUSIONS: Our results suggest that a slower pubertal tempo, i.e., greater number of months between thelarche and menarche, is associated with higher percent breast density in young women. Future research should examine whether breast density mediates the association between slower tempo and increased breast cancer risk.

Radiology workflow for RECIST assessment in clinical trials: Can we reconcile time-efficiency and quality?

PURPOSE: In oncology clinical trials, nonconformity issues are frequently reported. Radiological workload is increasing, thus reducing radiologists' availability and affecting diagnostic quality. We compared performances of a standard radiological workflow (SW) and a novel "hybrid workflow" (HW). METHOD: We prospectively studied imaging data of 40 patients included in RECIST 1.1 clinical trials. Ninety-six time-points were reviewed by 7 radiologists and one trained technologist. Nonconformities using the SW were retrieved from hospital archives. For the HW, radiologists performed all baseline evaluations; the technologist made subsequent measurements. Finally, the radiologists checked the technologist's findings before confirming the evaluations. The HW enabled implementation of an electronic reporting system. An independent body compared SW and HW reading times and nonconformity occurrences. RESULTS: Using SW, 19 types of nonconformity were found: blank report (13%); unsigned report (11%); undocumented change of tumor burden (10%); undocumented new lesions (9%); missing/wrong patients' appointment dates (7%); undocumented tumor location (5%); error in tumor burden change (5%). SW and HW nonconformities affected 55% (179/323) and 5% (2/40) of reports, respectively (p < 0.001). HW nonconformities were: one inaccurate login name was used on the platform, and one erroneous time-point number. On average, SW required 11'30″ [10'06″; 13'20″] per time-point. HW required 1'35″ [40″; 5'08″] for radiologists, and 12'18″ [11'12″; 14'18″] for the technologist. CONCLUSIONS: HW significantly reduced the number of trial nonconformities and saved 87% of radiologists' time while enabling them to apply their expertise to final decisions. HW could offer an effective opportunity for cost reduction associated with improved imaging trial quality.

Discrepancies of assessments in a RECIST 1.1 phase II clinical trial - association between adjudication rate and variability in images and tumors selection.

BACKGROUND: In imaging-based clinical trials, it is common practice to perform double reads for each image, discrepant interpretations can result from these two different evaluations. In this study we analyzed discrepancies that occurred between local investigators (LI) and blinded independent central review (BICR) by comparing reader-selected imaging scans and lesions. Our goal was to identify the causes of discrepant declarations of progressive disease (PD) between LI and BICR in a clinical trial. METHODS: We retrospectively analyzed imaging data from a RECIST 1.1-based, multi-sites, phase II clinical trial of 179 patients with adult small cell lung cancer, treated with Cabazitaxel compared to Topotecan. Any discrepancies in the determination of PD between LI and BICR readers were reviewed by a third-party adjudicator. For each imaging time point and reader, we recorded the selected target lesions, non-target lesions, and new lesions. Odds ratios were calculated to measure the association between discrepant declarations of PD and the differences in reviewed imaging scans (e.g. same imaging modality but with different reconstruction parameters) and selected lesions. Reasons for discrepancies were analyzed. RESULTS: The average number of target lesions found by LI and BICR was respectively 2.9 and 3.4 per patient (p < 0.05), 18.4% of these target lesions were actually non-measurable. LI and BICR performed their evaluations based on different baseline imaging scans for 59% of the patients, they selected at least one different target lesion in 85% of patients. A total of 36.7% of patients required adjudication. Reasons of adjudication included differences in 1) reporting new lesions (53.7%), 2) the measured change of the tumor burden (18.5%), and 3) the progression of non-target lesions (11.2%). The rate of discrepancy was not associated with the selection of non-measurable target lesions or with the readers' assessment of different images. Paradoxically, more discrepancies occurred when LI and BICR selected exactly the same target lesions at baseline compared to when readers selected not exactly the same lesions. CONCLUSIONS: For a large proportion of evaluations, LI and BICR did not select the same imaging scans and target lesions but with a limited impact on the rate of discrepancy. The majority of discrepancies were explained by the difference in detecting new lesions. TRIAL REGISTRATION: ARD12166 ( https://clinicaltrials.gov/ct2/show/NCT01500720 ).

Intake of dietary carbohydrates in early adulthood and adolescence and breast density among young women.

PURPOSE: Carbohydrate intake increases postprandial insulin secretion and may affect breast density, a strong risk factor for breast cancer, early in life. We examined associations of adolescent and early adulthood intakes of total carbohydrates, glycemic index/load, fiber, and simple sugars with breast density among 182 young women. METHODS: Diet was assessed using three 24-h recalls at each of five Dietary Intervention Study in Children (DISC) clinic visits when participants were age 10-19 years and at the DISC06 Follow-Up Study clinic visit when participants were age 25-29 years. Associations between energy-adjusted carbohydrates and MRI-measured percent dense breast volume (%DBV) and absolute dense breast volume (ADBV) at 25-29 years were quantified using multivariable-adjusted mixed-effects linear models. RESULTS: Adolescent sucrose intakes and premenarcheal total carbohydrates intakes were modestly associated with higher %DBV (mean %DBVQ1 vs Q4, 16.6 vs 23.5% for sucrose; and 17.2 vs 22.3% for premenarcheal total carbohydrates, all Ptrend ≤ 0.02), but not with ADBV. However, adolescent intakes of fiber and fructose were not associated with %DBV and ADBV. Early adulthood intakes of total carbohydrates, glycemic index/load, fiber, and simple sugars were not associated with %DBV and ADBV. CONCLUSIONS: Insulinemic carbohydrate diet during puberty may be associated with adulthood breast density, but our findings need replication in larger studies. Clinical Trials Registration ClinicalTrials.gov Identifier, NCT00458588 April 9, 2007; NCT00000459 October 27, 1999.

Dietary Fat Intake During Adolescence and Breast Density Among Young Women.

BACKGROUND: Lack of association between fat intake and breast cancer risk in cohort studies might be attributed to the disregard of temporal effects during adolescence when breasts develop and are particularly sensitive to stimuli. We prospectively examined associations between adolescent fat intakes and breast density. METHOD: Among 177 women who participated in the Dietary Intervention Study in Children, dietary intakes at ages 10-18 years were assessed on five occasions by 24-hour recalls and averaged. We calculated geometric mean and 95% confidence intervals for MRI-measured breast density at ages 25-29 years across quartiles of fat intake using linear mixed-effect regression. RESULTS: Comparing women in the extreme quartiles of adolescent fat intakes, percent dense breast volume (%DBV) was positively associated with saturated fat (mean = 16.4% vs. 21.5%; Ptrend < 0.001). Conversely, %DBV was inversely associated with monounsaturated fat (25.0% vs. 15.8%; Ptrend < 0.001) and the ratio of polyunsaturated fat to saturated fat (P/S ratio; 19.1% vs. 14.3%; Ptrend < 0.001). When examining intake by pubertal stages, %DBV was inversely associated with intake of polyunsaturated fat (20.8% vs. 16.4%; Ptrend = 0.04), long-chain omega-3 fat (17.8% vs. 15.8%; Ptrend < 0.001), and P/S ratio (22.5% vs. 16.1%; Ptrend < 0.001) before menarche, but not after. These associations observed with %DBV were consistently observed with absolute dense breast volume but not with absolute nondense breast volume. CONCLUSIONS: In our study, adolescent intakes of higher saturated fat and lower mono- and polyunsaturated fat are associated with higher breast density measured approximately 15 years later. IMPACT: The fat subtype composition in adolescent diet may be important in early breast cancer prevention. Cancer Epidemiol Biomarkers Prev; 25(6); 918-26. ©2016 AACR.

Early Life Body Fatness, Serum Anti-Müllerian Hormone, and Breast Density in Young Adult Women.

BACKGROUND: Emerging evidence suggests positive associations between serum anti-Müllerian hormone (AMH), a marker of ovarian function, and breast cancer risk. Body size at young ages may influence AMH levels, but few studies have examined this. Also, no studies have examined the relation of AMH levels with breast density, a strong predictor of breast cancer risk. METHODS: We examined associations of early life body fatness, AMH concentrations, and breast density among 172 women in the Dietary Intervention Study in Children (DISC). Height and weight were measured at baseline (ages 8-10) and throughout adolescence. Serum AMH concentrations and breast density were assessed at ages 25-29 at the DISC 2006 Follow-up visit. We used linear mixed effects models to quantify associations of AMH (dependent variable) with quartiles of age-specific youth body mass index (BMI) Z-scores (independent variable). We assessed cross-sectional associations of breast density (dependent variable) with AMH concentration (independent variable). RESULTS: Neither early life BMI nor current adult BMI was associated with AMH concentrations. There were no associations between AMH and percent or absolute dense breast volume. In contrast, women with higher AMH concentrations had significantly lower absolute nondense breast volume (Ptrend < 0.01). CONCLUSIONS: We found no evidence that current or early life BMI influences AMH concentrations in later life. Women with higher concentrations of AMH had similar percent and absolute dense breast volume, but lower nondense volume. IMPACT: These results suggest that AMH may be associated with lower absolute nondense breast volume; however, future prospective studies are needed to establish temporality. Cancer Epidemiol Biomarkers Prev; 25(7); 1151-7. ©2016 AACR.

Body fatness during childhood and adolescence and breast density in young women: a prospective analysis.

INTRODUCTION: Overweight and obesity in childhood and adolescence are associated with reduced breast cancer risk, independent of adult body mass index (BMI). These associations may be mediated through breast density. METHODS: We prospectively examined associations of early life body fatness with adult breast density measured by MRI in 182 women in the Dietary Intervention Study in Children (DISC) who were ages 25-29 at follow-up. Height, weight, and other factors were measured at baseline (ages 8-10) and annual clinic visits through adolescence. We used linear mixed-effects models to quantify associations of percent breast density and dense and non-dense breast volume at ages 25-29 with quartiles of age-specific youth body mass index (BMI) Z-scores, adjusting for clinic, treatment group, current adult BMI, and other well-established risk factors for breast cancer and predictors of breast density. RESULTS: We observed inverse associations between age-specific BMI Z-scores at all youth clinic visits and percent breast density, adjusting for current adult BMI and other covariates (all p values <0.01). Women whose baseline BMI Z-scores (at ages 8-10 years) were in the top quartile had significantly lower adult breast density, after adjusting for current adult BMI and other covariates [least squares mean (LSM): 23.4 %; 95 % confidence interval (CI): 18.0 %, 28.8 %] compared to those in the bottom quartile (LSM: 31.8 %; 95 % CI: 25.2 %, 38.4 %) (p trend <0.01). Significant inverse associations were also observed for absolute dense breast volume (all p values <0.01), whereas there were no clear associations with non-dense breast volume. CONCLUSIONS: These results support the hypothesis that body fatness during childhood and adolescence may play an important role in premenopausal breast density, independent of current BMI, and further suggest direct or indirect influences on absolute dense breast volume. CLINICAL TRIALS REGISTRATION NUMBER: NCT00458588 ; April 9, 2007.

Adolescent endogenous sex hormones and breast density in early adulthood.

INTRODUCTION: During adolescence the breasts undergo rapid growth and development under the influence of sex hormones. Although the hormonal etiology of breast cancer is hypothesized, it remains unknown whether adolescent sex hormones are associated with adult breast density, which is a strong risk factor for breast cancer. METHODS: Percentage of dense breast volume (%DBV) was measured in 2006 by magnetic resonance imaging in 177 women aged 25-29 years who had participated in the Dietary Intervention Study in Children from 1988 to 1997. They had sex hormones and sex hormone-binding globulin (SHBG) measured in serum collected on one to five occasions between 8 and 17 years of age. Multivariable linear mixed-effect regression models were used to evaluate the associations of adolescent sex hormones and SHBG with %DBV. RESULTS: Dehydroepiandrosterone sulfate (DHEAS) and SHBG measured in premenarche serum samples were significantly positively associated with %DBV (all P trend ≤0.03) but not when measured in postmenarche samples (all P trend ≥0.42). The multivariable geometric mean of %DBV across quartiles of premenarcheal DHEAS and SHBG increased from 16.7 to 22.1 % and from 14.1 to 24.3 %, respectively. Estrogens, progesterone, androstenedione, and testosterone in pre- or postmenarche serum samples were not associated with %DBV (all P trend ≥0.16). CONCLUSIONS: Our results suggest that higher premenarcheal DHEAS and SHBG levels are associated with higher %DBV in young women. Whether this association translates into an increased risk of breast cancer later in life is currently unknown. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov Identifier, NCT00458588 April 9, 2007; NCT00000459 October 27, 1999.

Dietary energy density is positively associated with breast density among young women.

BACKGROUND: Breast density is an established predictor of breast cancer risk, and there is considerable interest in associations of modifiable lifestyle factors, such as diet, with breast density. OBJECTIVE: To determine whether dietary energy density (ED) is associated with percent dense breast volume (%DBV) and absolute dense breast volume (ADBV) in young women. DESIGN: A cross-sectional analysis was conducted with women who participated in the Dietary Intervention Study in Children Follow-Up Study. %DBV and ADBV were measured by magnetic resonance imaging. Diet was assessed by three 24-hour recalls. Dietary ED (kilocalories/gram) was calculated using three methods: food only, food and caloric beverages, and food and all beverages. PARTICIPANTS/SETTING: One hundred seventy-two women (aged 25 to 29 years) who were enrolled in the Dietary Intervention Study in Children Follow-Up Study. Participants who reported breast augmentation or reduction surgery or were pregnant or lactating within 3 months before breast density assessment were excluded. MAIN OUTCOME MEASURES: ADBV and %DBV. STATISTICAL ANALYSES PERFORMED: Multivariable linear mixed effects models were used. Final models were adjusted for race, smoking status, education, parity, duration of sex hormone use, whole body percent fat, childhood body mass index z score, and energy from beverages. RESULTS: After adjustment, each 1 kcal/g unit increase in food-only ED was associated with a 25.9% (95% CI 6.2% to 56.8%) increase in %DBV (P=0.01). Childhood body mass index z score modified the association between food-only ED and %DBV such that a significant positive association was observed only in women who were heavier as children. Food-only ED was not associated with ADBV in all women, but a borderline significant positive association was observed in women who had higher childhood body mass index z scores. CONCLUSIONS: This is the first report to suggest a potential role for dietary ED in breast density; the effects of long-term exposure to high-ED diets on breast cancer risk remain unknown.

Endogenous sex hormones and breast density in young women.

BACKGROUND: Breast density is a strong risk factor for breast cancer and reflects epithelial and stromal content. Breast tissue is particularly sensitive to hormonal stimuli before it fully differentiates following the first full-term pregnancy. Few studies have examined associations between sex hormones and breast density among young women. METHODS: We conducted a cross-sectional study among 180 women ages 25 to 29 years old who participated in the Dietary Intervention Study in Children 2006 Follow-up Study. Eighty-five percent of participants attended a clinic visit during their luteal phase of menstrual cycle. Magnetic resonance imaging measured the percentage of dense breast volume (%DBV), absolute dense breast volume (ADBV), and absolute nondense breast volume (ANDBV). Multiple-linear mixed-effect regression models were used to evaluate the association of sex hormones and sex hormone-binding globulin (SHBG) with %DBV, ADBV, and ANDBV. RESULTS: Testosterone was significantly positively associated with %DBV and ADBV. The multivariable geometric mean of %DBV and ADBV across testosterone quartiles increased from 16.5% to 20.3% and from 68.6 to 82.3 cm(3), respectively (Ptrend ≤ 0.03). There was no association of %DBV or ADBV with estrogens, progesterone, non-SHBG-bound testosterone, or SHBG (Ptrend ≥ 0.27). Neither sex hormones nor SHBG was associated with ANDBV except progesterone; however, the progesterone result was nonsignificant in analysis restricted to women in the luteal phase. CONCLUSIONS: These findings suggest a modest positive association between testosterone and breast density in young women. IMPACT: Hormonal influences at critical periods may contribute to morphologic differences in the breast associated with breast cancer risk later in life.

Repeatability of quantitative MRI measurements in normal breast tissue.

PURPOSE: To evaluate the variability and repeatability of repeated magnetic resonance imaging (MRI) measurements in normal breast tissues between and within subjects. METHODS: Eighteen normal premenopausal subjects underwent two contrast-enhanced MRI scans within 72 hours or during the same menstrual phase in two consecutive months. A subset of nine women also completed diffusion-weighted imaging (DWI). Fibroglandular tissue (FGT) density and FGT enhancement were measured on the contrast-enhanced MRI. Apparent diffusion coefficient (ADC) values were computed from DWI. Between- and within-subject coefficients of variation (bCV and wCV, respectively) were assessed. Repeatability of all measurements was assessed by the coefficient of repeatability (CR) and Bland-Altman plots. RESULTS: The bCV of FGT density and FGT enhancement at visit 1 and visit 2 ranged from 47% to 63%. The wCV was 13% for FGT density, 22% for FGT enhancement, and 11% for ADC. The CRs of FGT density and FGT enhancement were 0.15 and 0.19, respectively, and for ADC, it was 6.1 x 10(-4) mm(2)/s. CONCLUSIONS: We present an estimate of the variability and repeatability of MR measurements in normal breasts. These estimates provide the basis for understanding the normal variation of healthy breast tissue in MRI and establishing thresholds for agreement between measurements.

Agreement of mammographic measures of volumetric breast density to MRI.

BACKGROUND: Clinical scores of mammographic breast density are highly subjective. Automated technologies for mammography exist to quantify breast density objectively, but the technique that most accurately measures the quantity of breast fibroglandular tissue is not known. PURPOSE: To compare the agreement of three automated mammographic techniques for measuring volumetric breast density with a quantitative volumetric MRI-based technique in a screening population. MATERIALS AND METHODS: Women were selected from the UCSF Medical Center screening population that had received both a screening MRI and digital mammogram within one year of each other, had Breast Imaging Reporting and Data System (BI-RADS) assessments of normal or benign finding, and no history of breast cancer or surgery. Agreement was assessed of three mammographic techniques (Single-energy X-ray Absorptiometry [SXA], Quantra, and Volpara) with MRI for percent fibroglandular tissue volume, absolute fibroglandular tissue volume, and total breast volume. RESULTS: Among 99 women, the automated mammographic density techniques were correlated with MRI measures with R(2) values ranging from 0.40 (log fibroglandular volume) to 0.91 (total breast volume). Substantial agreement measured by kappa statistic was found between all percent fibroglandular tissue measures (0.72 to 0.63), but only moderate agreement for log fibroglandular volumes. The kappa statistics for all percent density measures were highest in the comparisons of the SXA and MRI results. The largest error source between MRI and the mammography techniques was found to be differences in measures of total breast volume. CONCLUSION: Automated volumetric fibroglandular tissue measures from screening digital mammograms were in substantial agreement with MRI and if associated with breast cancer could be used in clinical practice to enhance risk assessment and prevention.

Menstrual and reproductive characteristics and breast density in young women.

PURPOSE: Breast density is strongly related to breast cancer risk, but determinants of breast density in young women remain largely unknown. METHODS: Associations of reproductive and menstrual characteristics with breast density measured by magnetic resonance imaging were evaluated in a cross-sectional study of 176 healthy women, 25-29 years old, using linear mixed effects models. RESULTS: Parity was significantly inversely associated with breast density. In multivariable adjusted models that included non-reproductive variables, mean percent dense breast volume (%DBV) decreased from 20.5 % in nulliparous women to 16.0 % in parous women, while mean absolute dense breast volume (ADBV) decreased from 85.3 to 62.5 cm(3). Breast density also was significantly inversely associated with the age women started using hormonal contraceptives, whereas it was significantly positively associated with duration of hormonal contraceptive use. In adjusted models, mean %DBV decreased from 21.7 % in women who started using hormones at 12-17 years of age to 14.7 % in those who started using hormones at 22-28 years of age, while mean ADBV decreased from 86.2 to 53.7 cm(3). The age at which women started using hormonal contraceptives and duration of hormone use were inversely correlated, and mean %DBV increased from 15.8 % in women who used hormones for not more than 2.0 years to 22.0 % in women who used hormones for more than 8 years, while mean ADBV increased from 61.9 to 90.4 cm(3) over this interval. CONCLUSIONS: Breast density in young women is inversely associated with parity and the age women started using hormonal contraceptives but positively associated with duration of hormone use.

MRI enhancement in stromal tissue surrounding breast tumors: association with recurrence free survival following neoadjuvant chemotherapy.

RATIONALE AND OBJECTIVES: Normal-appearing stromal tissues surrounding breast tumors can harbor abnormalities that lead to increased risk of local recurrence. The objective of this study was to develop a new imaging methodology to characterize the signal patterns of stromal tissue and to investigate their association with recurrence-free survival following neoadjuvant chemotherapy. MATERIALS AND METHODS: Fifty patients with locally-advanced breast cancer were imaged with dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) before (V1) and after one cycle (V2) of adriamycin-cytoxan therapy. Contrast enhancement in normal-appearing stroma around the tumor was characterized by the mean percent enhancement (PE) and mean signal enhancement ratio (SER) in distance bands of 5 mm from the tumor edge. Global PE and SER were calculated by averaging all stromal bands 5 to 40 mm from tumor. Proximity-dependent PE and SER were analyzed using a linear mixed effects model and Cox proportional hazards model for recurrence-free survival. RESULTS: The mixed effects model displayed a decreasing radial trend in PE at both V1 and V2. An increasing trend was less pronounced in SER. Survival analysis showed that the hazard ratio estimates for each unit decrease in global SER was statistically significant at V1 [estimated hazard ratio = 0.058, 95% Wald CI (0.003, 1.01), likelihood ratio p = 0.03]; but was not so for V2. CONCLUSIONS: These findings show that stromal tissue outside the tumor can be quantitatively characterized by DCE-MRI, and suggest that stromal enhancement measurements may be further developed for use as a potential predictor of recurrence/disease-free survival following therapy.

Adolescent and young adult exposure to physical activity and breast density.

PURPOSE: The objective of this study is to examine the role of early lifetime exposure to physical activity on magnetic resonance imaging-determined breast density measures. METHODS: Associations of adolescent (high school (ages 14-17 yr) and early adulthood, post-high school (ages 18-21 yr) and past year) leisure-time physical activity, as well as a principal component score including all three estimates, were examined with percent dense breast volume (%DBV) and absolute dense breast volume (ADBV) in a cross-sectional analysis of 182 healthy women, ages 25-29 yr, enrolled in the Dietary Intervention Study in Children Follow-up Study (DISC06). Generalized linear mixed models were used to examine associations after adjustment for relevant covariates for the entire analytic sample. Analyses were repeated in nulliparous women and hormonal contraceptive nonusers. RESULTS: Physical activity during high school and post-high school were not statistically significantly related to %DBV or ADBV in multivariable models. Past year physical activity was positively related to %DBV in the unadjusted and partially adjusted models (P < 0.001 and P = 0.01, respectively), which did not adjust for body mass index (BMI). After additional adjustment for childhood and early adulthood BMI, this association became nonstatistically significant. The relation between past year physical activity and ADBV was not statistically significant. These findings were similar in nonusers of hormonal contraceptives. No statistically significant relations were found in nulliparous women or between the principal component score and %DBV or ADBV. CONCLUSION: Results from this study are consistent with previous research suggesting that physical activity during adolescence and early adulthood is unrelated to breast density.

Height, adiposity and body fat distribution and breast density in young women.

INTRODUCTION: Breast density is one of the strongest risk factors for breast cancer, but determinants of breast density in young women remain largely unknown. METHODS: Associations of height, adiposity and body fat distribution with percentage dense breast volume (%DBV) and absolute dense breast volume (ADBV) were evaluated in a cross-sectional study of 174 healthy women, 25 to 29 years old. Adiposity and body fat distribution were measured by anthropometry and dual-energy X-ray absorptiometry (DXA), while %DBV and ADBV were measured by magnetic resonance imaging. Associations were evaluated using linear mixed-effects models. All tests of statistical significance are two-sided. RESULTS: Height was significantly positively associated with %DBV but not ADBV; for each standard deviation (SD) increase in height, %DBV increased by 18.7% in adjusted models. In contrast, all measures of adiposity and body fat distribution were significantly inversely associated with %DBV; a SD increase in body mass index (BMI), percentage fat mass, waist circumference and the android:gynoid fat mass ratio (A:G ratio) was each associated significantly with a 44.4 to 47.0% decrease in %DBV after adjustment for childhood BMI and other covariates. Although associations were weaker than for %DBV, all measures of adiposity and body fat distribution also were significantly inversely associated with ADBV before adjustment for childhood BMI. After adjustment for childhood BMI, however, only the DXA measures of percentage fat mass and A:G ratio remained significant; a SD increase in each was associated with a 13.8 to 19.6% decrease in ADBV. In mutually adjusted analysis, the percentage fat mass and the A:G ratio remained significantly inversely associated with %DBV, but only the A:G ratio was significantly associated with ADBV; a SD increase in the A:G ratio was associated with an 18.5% decrease in ADBV. CONCLUSION: Total adiposity and body fat distribution are independently inversely associated with %DBV, whereas in mutually adjusted analysis only body fat distribution (A:G ratio) remained significantly inversely associated with ADBV in young women. Research is needed to identify biological mechanisms underlying these associations.

Diffusion-weighted MRI: influence of intravoxel fat signal and breast density on breast tumor conspicuity and apparent diffusion coefficient measurements.

Promising recent investigations have shown that breast malignancies exhibit restricted diffusion on diffusion-weighted imaging (DWI) and may be distinguished from normal tissue and benign lesions in the breast based on differences in apparent diffusion coefficient (ADC) values. In this study, we assessed the influence of intravoxel fat signal on breast diffusion measures by comparing ADC values obtained using a diffusion-weighted single shot fast spin-echo sequence with and without fat suppression. The influence of breast density on ADC measures was also evaluated. ADC values were calculated for both tumor and normal fibroglandular tissue in a group of 21 women with diagnosed breast cancer. There were systematic underestimations of ADC for both tumor and normal breast tissue due to intravoxel contribution from fat signal on non-fat-suppressed DWI. This ADC underestimation was more pronounced for normal tissue values (mean difference=40%) than for tumors (mean difference=27%, P<.001) and was worse in women with low breast tissue density vs. those with extremely dense breasts (P<.05 for both tumor and normal tissue). Tumor conspicuity measured by contrast-to-noise ratio was significantly higher on ADC maps created with fat suppression and was not significantly associated with breast density. In summary, robust fat suppression is important for accurate breast ADC measures and optimal lesion conspicuity on DWI.

Topographic enhancement mapping of the cancer-associated breast stroma using breast MRI.

In animal and laboratory models, cancer-associated stroma, or elements of the supporting tissue surrounding a primary tumor, has been shown to be necessary for tumor evolution and progression. However, little is understood or studied regarding the properties of intact stroma in human cancer in vivo. In addition, for breast cancer patients, the optimal volume of local tissue to treat surrounding a primary tumor is not clear. Here, we performed an interdisciplinary study of normal-appearing breast tissue using breast magnetic resonance imaging (MRI), correlative histology and array comparative genomic hybridization to identify a cancer-associated stroma in humans. Using a novel technique for segmenting breast fibroglandular tissue, quantifiable topographic percent enhancement mapping of the stroma surrounding invasive breast cancer was found to be significantly elevated within 2 cm of the tumor edge. This region was also found to harbor increased microvessel density, and genomic changes that were closely associated with host normal breast tissue. These findings indicate that a cancer-associated stroma may be identified and characterized in human breast cancer using non-invasive imaging techniques. Identification of a cancer-associated stroma may be further developed to help guide local therapy to reduce recurrence and morbidity in breast cancer patients.