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Purpose: The role of zoledronic acid (ZOL), a bone-targeted bisphosphonate, in the treatment of patients with breast cancer remains an active area of study. Here, we report the long-term outcomes of a randomized placebo-controlled phase II clinical trial in which ZOL treatment was added to neoadjuvant chemotherapy in women with locally advanced breast cancer., Methods: 120 women with clinical stage II-III (≥ T2 and/or ≥ N1) newly diagnosed breast cancer were randomized to receive either 4 mg intravenous ZOL every 3 weeks for 1 year (17 total doses) beginning with the first dose of neoadjuvant chemotherapy, or chemotherapy alone. Clinical endpoints included time to recurrence (TTR), time to bone recurrence (TTBR), time to non-bone recurrence (TTNBR), breast cancer survival (BCS) and overall survival (OS)., Results: With a median follow-up interval of 14.4 years, there were no significant differences in any of the clinical endpoints studied between the control and ZOL groups in the overall study population. However, ER+/HER2- patients younger than age 45 who were treated with ZOL had significantly worse TTR and TTNBR with a trend towards worse TTBR, BCS and OS (TTR: P = 0.024, HR 6.05 [1.26-29.1]; TTNBR: P = 0.026, HR 6.94 [1.26-38.1]; TTBR: P = 0.054, HR 6.01 [0.97-37.1]; BCS: P = 0.138, HR 4.43 [0.62-31.7]; OS: P = 0.138, HR 4.43 [0.62-31.7]). These differences were not seen in older ER+/HER2- patients or triple-negative patients of any age., Conclusion: Addition of ZOL to neoadjuvant therapy did not significantly affect clinical outcomes in the overall study population but was associated with increased extra-skeletal recurrence and a trend towards worse survival in ER+/HER2- patients younger than age 45. These findings suggest caution when using zoledronic acid in young, premenopausal women with locally advanced breast cancer and warrant further investigation. Clinical Trial Registration Number NCT00242203, Date of Registration: 10/17/2005.

Little is known about quality-of-life (QOL) differences over time between incident ductal carcinoma in situ (DCIS) and early-stage invasive breast cancer (EIBC) cases as compared with same-aged women without breast cancer (controls). We prospectively recruited and interviewed 1,096 women [16.8% DCIS, 33.3% EIBC (25.7% Stage I; and 7.6% Stage IIA), 49.9% controls; mean age 58; 23.7% non-white] at mean 6.7 weeks (T1), and 6.2 (T2), 12.3 (T3), and 24.4 months (T4) after surgery (patients) or screening mammogram (controls). We tested two hypotheses: (1) DCIS patients would report lower levels of QOL compared with controls but would report similar QOL compared with EIBC patients at baseline; and (2) DCIS patients' QOL would improve during 2-year follow-up and approach levels similar to that of controls faster than EIBC patients. We tested hypothesis 1 using separate general linear regression models for each of the eight subscales on the RAND 36-item Health Survey, controlling for variables associated with at least one subscale at T1. Both DCIS and EIBC patients reported lower QOL at T1 than controls on all subscales (each P<0.05). We tested hypothesis 2 using generalized estimating equations to examine change in each QOL subscale over time across the three diagnostic groups adjusting for covariates. By T3, physical functioning, role limitations due to physical problems, energy/fatigue, and general health each differed significantly by diagnostic group at P<0.05, because of larger differences between EIBC patients and controls; but DCIS patients no longer differed significantly from controls on any of the QOL subscales. At T4, EIBC patients still reported worse physical functioning (P=0.0001) and general health (P=0.0017) than controls, possibly because of lingering treatment effects. DCIS patients' QOL was similar to that of controls two years after diagnosis, but some aspects of EIBC patients' QOL remained lower.

Fear of cancer recurrence (FCR) is a common and persistent concern among breast cancer survivors. Little is known about factors associated with FCR in women with ductal carcinoma in situ (DCIS) or early invasive breast cancer (EIBC). Women with first primary DCIS, or stages I-IIA breast cancer were prospectively enrolled in a quality-of-life study and completed interviews at 4-6 weeks, 6 months, and 2 years after definitive surgical treatment. In three stepwise multivariable linear regression models, including both time-independent and time-varying variables measured at each respective interview, we identified independent correlates of mean FCR scores (range 1-6) using four items from the Concern About Recurrence Scale (CARS) at 2-year follow-up. Of 506 disease-free patients at 2-year follow-up (mean [SD] age, 58 [10] years; 81% White; 34% DCIS), the average FCR score of 2.0 was low. However, 145 (29%) reported moderate-to-high levels of FCR (scores 3.0-6.0). All three models showed that younger age, stage IIA breast cancer (vs. DCIS), lower social support, and elevated anxiety were consistently associated with higher FCR at 2-year follow-up (each P < 0.05; final models R (2) = 0.25-0.32). DCIS patients reported lower FCR than stage IIA patients (each P ≤ 0.01) but had similar FCR as stage I patients. Although mean FCR was low, 29% of DCIS and EIBC survivors reported moderate-to-high levels of FCR at 2-year follow-up. Management of anxiety, provision of social support, and patient education may help reduce FCR among DCIS and EIBC survivors, especially among younger survivors.

Breast cancer patients' perceived risk of recurrence has been associated with psychological distress. Little is known about the change of patients' perceived risk of recurrence over time and factors associated with their recurrence-risk perceptions. We prospectively recruited 549 newly diagnosed early-stage breast cancer patients; patients completed interviews at 6 weeks, 6 months, 1 year, and 2 years after definitive surgical treatment. A random-effects regression model with repeated ordinal measurements was used to estimate the relationship between perceived risk of recurrence and demographic, medical, and psychosocial factors. We analyzed data from 535 patients [34% ductal carcinoma in situ (DCIS); 20% non-white] who reported their perceived risk at one or more interviews. At the first interview, 16% reported having no lifetime risk of recurrence, and another 16% reported ≥ 50% risk of recurrence, including 15% of DCIS patients. Patients who were white (OR = 5.88, 95% CI 3.39-10.19) and had greater state anxiety (OR = 1.04, 95% CI 1.02-1.07) were more likely, while patients who received radiotherapy (OR = 0.72, 95% CI 0.54-0.96) and had more social support (OR = 0.59, 95% CI 0.46-0.75) were less likely to report higher risk of recurrence. Cancer stage was not significantly associated with perceived risk of recurrence. Perceived risk of recurrence did not change significantly over time. Educating early-stage breast cancer patients about their actual risk could result in more realistic recurrence-risk perceptions, and increasing social support could help alleviate anxiety associated with exaggerated risk perceptions.

Several gene expression profiles have been reported to predict breast cancer response to neoadjuvant chemotherapy. These studies often consider breast cancer as a homogeneous entity, although higher rates of pathologic complete response (pCR) are known to occur within the basal-like subclass. We postulated that profiles with higher predictive accuracy could be derived from a subset analysis of basal-like tumors in isolation. Using a previously described "intrinsic" signature to differentiate breast tumor subclasses, we identified 50 basal-like tumors from two independent clinical trials associated with gene expression profile data. 24 tumor data sets were derived from a 119-patient neoadjuvant trial at our institution and an additional 26 tumor data sets were identified from a published data set (Hess et al. J Clin Oncol 24:4236-4244, 2006). The combined 50 basal-like tumors were partitioned to form a 37 sample training set with 13 sequestered for validation. Clinical surveillance occurred for a mean of 26 months. We identified a 23-gene profile which predicted pCR in basal-like breast cancers with 92% predictive accuracy in the sequestered validation data set. Furthermore, distinct cluster of patients with high rates of cancer recurrence was observed based on cluster analysis with the 23-gene signature. Disease-free survival analysis of these three clusters revealed significantly reduced survival in the patients of this high recurrence cluster. We identified a 23-gene signature which predicts response of basal-like breast cancer to neoadjuvant chemotherapy as well as disease-free survival. This signature is independent of tissue collection method and chemotherapeutic regimen.

The effect of caregiving roles on risk of elevated depressed mood over 12 months was examined in early-stage (0-IIA) breast cancer patients and same-aged women without breast cancer. Women were interviewed 4-6 weeks, 6 months, and 12 months following definitive surgical treatment (patients) or routine screening mammogram (controls). The Center for Epidemiologic Studies-Depression Scale was administered at each interview and dichotomized for analysis (<16 [little/no depressed mood] vs. >or=16 [elevated depressed mood]). Participants were categorized as having no caregiving responsibilities, caregiving for children or other persons, or caregiving for both children and others (multiple caregiving roles). Two multivariable marginal logistic regression models with repeated measures were fit (one each for patients and controls) to examine the effect of caregiving roles on elevated depressed mood, using generalized estimating equations to account for intra-individual correlations. Of 1096 participants (mean age 58; 76% white), 1019 with caregiving data were included in the analysis. Compared with baseline, patients with multiple caregiving roles (23/521 patients) were at increased risk of elevated depressed mood at 6 months (adjusted odds ratio [aOR], 7.20; 95% confidence interval [CI], 1.17-44.46; P = 0.034), and controls with multiple caregiving roles (15/498 controls) were at decreased risk of elevated depressed mood at 12-month follow-up (aOR, 0.12; 95% CI, 0.02-0.97; P = 0.047). Patients with multiple caregiving roles were more likely while controls were less likely to report elevated depressed mood over time, suggesting a need to identify patients with multiple caregiving roles early during their treatment.