Danielle Awad

Randomized, Blinded, Sham-Controlled Trial of Acupuncture for the Management of Aromatase Inhibitor–Associated Joint Symptoms in Women With Early-Stage Breast Cancer

PURPOSE Women with breast cancer (BC) treated with aromatase inhibitors (AIs) may experience joint symptoms that can lead to discontinuation of effective therapy. We examined whether acupuncture improves AI-induced arthralgias in women with early-stage BC. METHODS We conducted a randomized, controlled, blinded study comparing true acupuncture (TA) versus sham acupuncture (SA) twice weekly for 6 weeks in postmenopuasal women with BC who had self-reported musculoskeletal pain related to AIs. TA included full body/auricular acupuncture and joint-specific point prescriptions, whereas SA involved superficial needle insertion at nonacupoint locations. Outcome measures included the Brief Pain Inventory-Short Form (BPI-SF), Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and Modified Score for the Assessment of Chronic Rheumatoid Affections of the Hands (M-SACRAH) obtained at baseline and at 3 and 6 weeks. Results Of 51 women enrolled, 43 women were randomly assigned and 38 were evaluable. Baseline characteristics were comparable between the two groups. Our primary end point was the difference in mean BPI-SF worst pain scores at 6 weeks, which was lower for TA compared with SA (3.0 v 5.5; P < .001). We also found differences between TA and SA in pain severity (2.6 v 4.5; P = .003) and pain-related interference (2.5 v 4.5; P = .002) at 6 weeks. Similar findings were seen for the WOMAC and M-SACRAH scores. The acupuncture intervention was well-tolerated. CONCLUSION Women with AI-induced arthralgias treated with TA had significant improvement of joint pain and stiffness, which was not seen with SA. Acupuncture is an effective and well-tolerated strategy for managing this common treatment-related side effect.

Randomized Double-Blind Placebo-Controlled Trial of Acetyl-L-Carnitine for the Prevention of Taxane-Induced Neuropathy in Women Undergoing Adjuvant Breast Cancer Therapy

PURPOSE Chemotherapy-induced peripheral neuropathy (CIPN) is common and leads to suboptimal treatment. Acetyl-L-carnitine (ALC) is a natural compound involved in neuronal protection. Studies have suggested ALC may be effective for the prevention and treatment of CIPN. PATIENTS AND METHODS A 24-week randomized double-blind trial comparing ALC (3,000 mg per day) with placebo in women undergoing adjuvant taxane-based chemotherapy was conducted. The primary objective was to determine if ALC prevents CIPN as measured by the 11-item neurotoxicity (NTX) component of the Functional Assessment of Cancer Therapy (FACT) -Taxane scale at 12 weeks. Secondary objectives included changes in 24-week end points, functional status (FACT-Trial Outcome Index [TOI]), fatigue (Functional Assessment of Chronic Illness Therapy [FACIT] -Fatigue), and NTX grade. RESULTS A total of 409 patients were evaluable (208 received ALC; 201, placebo). In a multivariate linear regression, week-12 scores were 0.9 points lower (more CIPN) with ALC than placebo (95% CI, -2.2 to 0.4; P = .17), whereas week-24 scores were 1.8 points lower with ALC (95% CI, -3.2 to -0.4; P = .01). Patients receiving ALC were more likely to have a > 5-point decrease in FACT-NTX scores (38% v 28%; P = .05), and FACT-TOI scores were 3.5 points lower with ALC (P = .03). Grade 3 to 4 neurotoxicity was more frequent in the ALC arm (eight v one). No differences between arms were observed for FACIT-Fatigue or other toxicities. Serum carnitine level increased with ALC but remained stable with placebo. CONCLUSION There was no evidence that ALC affected CIPN at 12 weeks; however, ALC significantly increased CIPN by 24 weeks. This is the first study to our knowledge showing that a nutritional supplement increased CIPN. Patients should be discouraged from using supplements without proven efficacy.

The Congenital Heart Disease Genetic Network Study Rationale, Design, and Early Results

Congenital heart defects (CHD) are the leading cause of infant mortality among birth defects, and later morbidities and premature mortality remain problematic. Although genetic factors contribute significantly to cause CHD, specific genetic lesions are unknown for most patients. The National Heart, Lung, and Blood Institute-funded Pediatric Cardiac Genomics Consortium established the Congenital Heart Disease Genetic Network Study to investigate relationships between genetic factors, clinical features, and outcomes in CHD. The Pediatric Cardiac Genomics Consortium comprises 6 main and 4 satellite sites at which subjects are recruited, and medical data and biospecimens (blood, saliva, cardiovascular tissue) are collected. Core infrastructure includes an administrative/data-coordinating center, biorepository, data hub, and core laboratories (genotyping, whole-exome sequencing, candidate gene evaluation, and variant confirmation). Eligibility includes all forms of CHD. Annual follow-up is obtained for probands <1-year-old. Parents are enrolled whenever available. Enrollment from December 2010 to June 2012 comprised 3772 probands. One or both parents were enrolled for 72% of probands. Proband median age is 5.5 years. The one third enrolled at age <1 year are contacted annually for follow-up information. The distribution of CHD favors more complex lesions. Approximately, 11% of probands have a genetic diagnosis. Adequate DNA is available from 97% and 91% of blood and saliva samples, respectively. Genomic analyses of probands with heterotaxy, atrial septal defects, conotruncal, and left ventricular outflow tract obstructive lesions are underway. The scientific community’s use of Pediatric Cardiac Genomics Consortium resources is welcome.

Prevention of Bone Loss by Zoledronic Acid in Premenopausal Women Undergoing Adjuvant Chemotherapy Persist up to One Year following Discontinuing Treatment

CONTEXT Adjuvant chemotherapy is associated with significant reductions in bone mineral density (BMD) in premenopausal women with breast cancer (BC) that is prevented with zoledronic acid (ZA) every 3 months for 1 yr. OBJECTIVE The aim of the study was to examine the effect on BMD of discontinuing ZA during the subsequent year. DESIGN We conducted a randomized, double-blind trial. PATIENTS Premenopausal women (mean age, 42 yr) undergoing adjuvant chemotherapy for BC participated in the study. INTERVENTION ZA (4 mg iv every 3 months) vs. placebo was administered for 12 months. OUTCOME MEASURES We measured percentage change in BMD and bone turnover markers at 12 and 24 months (1 yr after last infusion). RESULTS Of 101 women randomized, 85 completed 12-month and 62 completed 24-month evaluations. In the placebo group, serum C-telopeptide (CTX) increased progressively over the first 12 months, returned toward baseline but remained significantly above baseline by 24 months. Lumbar spine BMD decreased from baseline by 5.5% at 12 and 6.3% at 24 months. Similarly, by 24 months, total hip and femoral neck BMD declined by 2.6 and 2.4%, respectively. In ZA patients, BMD remained stable (P < 0.0001 compared to placebo). Serum CTX declined significantly by 6 months, but returned to baseline by 12 months, remaining there at 24 months. CONCLUSIONS Premenopausal women receiving chemotherapy for BC sustained significant bone loss during the first year, without recovery during the second year. ZA effectively prevented bone loss during the first year of chemotherapy. BMD remained stable 1 yr after completion of ZA. Serum CTX increased significantly by 12 and 24 months. More frequent administration may be required to suppress bone resorption in this patient population.

Comorbidities and Risk of Chemotherapy-Induced Peripheral Neuropathy Among Participants 65 Years or Older in Southwest Oncology Group Clinical Trials

BACKGROUND Neuropathy is a debilitating toxicity associated with various chemotherapy agents. We evaluated the association between common comorbid conditions and the development of peripheral neuropathy in patients treated with taxane-based chemotherapy. METHODS We examined the Southwest Oncology Group database to identify phase II and III trials that included taxane therapy from 1999 to 2011. We linked the Southwest Oncology Group clinical records to Medicare claims data according to Social Security number, sex, and date of birth. The following disease conditions potentially associated with peripheral neuropathy were evaluated: diabetes, hypothyroidism, hypercholesterolemia, hypertension, varicella zoster, peripheral vascular disease, and autoimmune diseases. Multivariate logistic regression was used to model the odds of experiencing grade 2 to 4 neuropathy. RESULTS A total of 1,401 patients from 23 studies were included in the analysis. Patients receiving paclitaxel were more likely to experience grade 2 to 4 neuropathy compared with docetaxel (25% v 12%, respectively; OR, 2.20; 95% CI, 1.52 to 3.18; P < .001). The inclusion of a platinum agent was also associated with greater neuropathy (OR, 1.68; 95% CI, 1.18 to 2.40; P = .004). For each increase in age of 1 year, the odds of neuropathy increased 4% (P = .006). Patients with complications from diabetes had more than twice the odds of having neuropathy (OR, 2.13; 95% CI, 1.31 to 3.46; P = .002) compared with patients with no diabetes. In contrast, patients with autoimmune disease were half as likely to experience neuropathy (OR, 0.49; 95% CI, 0.24 to 1.02; P = .06). The other conditions were not associated with neuropathy. CONCLUSION We found that in addition to drug-related factors, age and history of diabetes were independent predictors of the development of chemotherapy-induced peripheral neuropathy. Interestingly, we also observed that a history of autoimmune disease was associated with reduced odds of neuropathy. Patients with diabetic complications may choose to avoid paclitaxel or taxane plus platinum combination therapies if other efficacious options exist.

Randomized Multicenter Placebo-Controlled Trial of Omega-3 Fatty Acids for the Control of Aromatase Inhibitor–Induced Musculoskeletal Pain: SWOG S0927

PURPOSE Musculoskeletal symptoms are the most common adverse effects of aromatase inhibitors (AIs) and can result in decreased quality of life and discontinuation of therapy. Omega-3 fatty acids (O3-FAs) can be effective in decreasing arthralgia resulting from rheumatologic conditions and reducing serum triglycerides. PATIENTS AND METHODS Women with early-stage breast cancer receiving an AI who had a worst joint pain/stiffness score ≥ 5 of 10 using the Brief Pain Inventory-Short Form (BPI-SF) were randomly assigned to receive either O3-FAs 3.3 g or placebo (soybean/corn oil) daily for 24 weeks. Clinically significant change was defined as ≥ 2-point drop from baseline. Patients also completed quality-of-life (Functional Assessment of Cancer Therapy-Endocrine Symptoms) and additional pain/stiffness assessments at baseline and weeks 6, 12, and 24. Serial fasting blood was collected for lipid analysis. RESULTS Among 262 patients registered, 249 were evaluable, with 122 women in the O3-FA arm and 127 in the placebo arm. Compared with baseline, the mean observed BPI-SF score decreased by 1.74 points at 12 weeks and 2.22 points at 24 weeks with O3-FAs and by 1.49 and 1.81 points, respectively, with placebo. In a linear regression adjusting for the baseline score, osteoarthritis, and taxane use, adjusted 12-week BPI-SF scores did not differ by arm (P = .58). Triglyceride levels decreased in patients receiving O3-FA treatment and remained the same for those receiving placebo (P = .01). No between-group differences were seen for HDL, LDL, or C-reactive protein. CONCLUSION We found a substantial (> 50%) and sustained improvement in AI arthralgia for both O3-FAs and placebo but found no meaningful difference between the groups.

Identifying Predictors of Taxane-Induced Peripheral Neuropathy Using Mass Spectrometry-Based Proteomics Technology

Major advances in early detection and therapy have significantly increased the survival of breast cancer patients. Unfortunately, most cancer therapies are known to carry a substantial risk of adverse long-term treatment-related effects. Little is known about patient susceptibility to severe side effects after chemotherapy. Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect of taxanes. Recent advances in genome-wide genotyping and sequencing technologies have supported the discoveries of a number of pharmacogenetic markers that predict response to chemotherapy. However, effectively implementing these pharmacogenetic markers in the clinic remains a major challenge. On the other hand, recent advances in proteomic technologies incorporating mass spectrometry (MS) for biomarker discovery show great promise to provide clinically relevant protein biomarkers. In this study, we evaluated the association between protein content in serum exosomes and severity of CIPN. Women with early stage breast cancer receiving adjuvant taxane chemotherapy were assessed with the FACT-Ntx score and serum was collected before and after the taxane treatment. Based on the change in FACT-Ntx score from baseline to 12 month follow-up, we separated patients into two groups: those who had no change (Group 1, N = 9) and those who had a ≥20% worsening (Group 1, N = 8). MS-based proteomics technology was used to identify proteins present in serum exosomes to determine potential biomarkers. Mann–Whitney–Wilcoxon analysis was applied and maximum FDR was controlled at 20%. From the serum exosomes derived from this cohort, we identified over 700 proteins known to be in different subcellular locations and have different functions. Statistical analysis revealed a 12-protein signature that resulted in a distinct separation between baseline serum samples of both groups (q<0.2) suggesting that the baseline samples can predict subsequent neurotoxicity. These toxicity-associated biomarkers can be further validated in larger retrospective cohorts for their utility in identifying patients at high risk for CIPN.

Prospective Evaluation of Joint Symptoms in Postmenopausal Women Initiating Aromatase Inhibitors for Early Stage Breast Cancer.

Background: Aromatase inhibitors (AIs) are widely prescribed to postmenopausal women for the adjuvant treatment of hormone-sensitive breast cancer. However, musculoskeletal complaints, including joint pain and stiffness, are common, and can lead to nonadherence and treatment discontinuation. The aim of this study was to characterize the natural history of the AI-induced arthralgia syndrome. Methods: Postmenopausal women with stage I-III breast cancer initiating adjuvant AI therapy were enrolled. All patients completed the following questionnaires at baseline and every 3 months for a year: Modified Brief Pain Inventory-Short Form (BPI-SF), Western Ontario and McMaster Universities Osteoarthritis (WOMAC) index and the Modified Assessment of Chronic Rheumatoid Affections of the Hands (M-SACRAH). Higher scores reflect worsening joint symptoms. Quality of life was assessed using the Functional Assessment of Cancer Therapy-Endocrine Subscale (FACT-ES), where higher scores signify improved well-being. Hand grip strength was measured at each visit with a Martin dynamometer. Paired t-tests were performed to compare follow-up evaluations to baseline. Results: A total of 34 patients have been enrolled to date. Three-month data is available on 22; six-month data on 12. Median age: 60 (42-81); White/Black/Hispanic/Asian: 13/6/2/1; median BMI (kg/m 2 ): 28 (20-43). Compared to baseline, there was a statistically significant increase in BPI pain severity and pain-related interference at 3 and 6 months. Significant changes in the M-SACRAH were seen as early as 3 months, but no difference in grip strength was detected. Participants reported significantly more endocrine-related symptoms on the FACT-ES at 3 and 6 months after initiating AI therapy. Conclusions: Treatment with adjuvant AI therapy is associated with significant worsening of joint pain and stiffness which was seen as early as 3 months and persisted at the 6 month evaluation. Understanding the natural history of this toxicity and validating appropriate measures to be used in interventions to prevent and treat AI-induced arthralgias are critical. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5044.

Abstract P3-08-12: Influence of a clinic-based survivorship intervention on dietary change and lifestyle recommendations among Hispanic and non-Hispanic women following adjuvant therapy for breast cancer

BACKGROUND: In 2006, the IOM released a report citing the importance of “survivorship plans” to improve quality-of-life. Little has been done to evaluate their efficacy with regard to uptake of dietary and lifestyle recommendations. METHODS: Women with early-stage breast cancer were randomized within 6 weeks of completing adjuvant therapy to a survivorship intervention or a control group. Randomization was stratified by ethnicity and subjects were not aware that they were randomized. All subjects were provided the NCI publication, “Facing Forward: Life after Cancer Treatment.” The survivorship intervention group also met with a nurse (1 hour) and nutritionist (1 hour) to receive a treatment summary, surveillance and personalized lifestyle recommendations, based on guidelines from the American Cancer Society and American Institute for Cancer Research. At baseline, 3 and 6 months, both groups completed questionnaires on diet, lifestyle, and perceived health. Linear regression analyses adjusted for ethnicity evaluated the effects of the intervention on comprehension and uptake of lifestyle recommendations. Additional models were run to evaluate the interaction between intervention and ethnicity. RESULTS: Among 126 women (60 control group, 66 survivorship intervention) mean age was 54 yrs, 48% were Hispanic, and randomized groups were well-balanced by baseline characteristics. Of note, at baseline, compared to non-Hispanics, Hispanics reported lower SES, poorer knowledge of healthy lifestyle behaviors (e.g., diet, physical activity, weight, dietary supplements), lower intake of fruits and vegetables, less recreational physical activity, lower consumption of alcohol, and a lower overall health rating (all P<0.05). After adjusting for ethnicity, at month 3 the intervention group compared to the control group reported greater knowledge of how to eat a healthy diet (P = 0.047), greater knowledge of appropriate use of dietary supplements (P = 0.006), higher levels of physical activity (P = 0.03), and higher intake of fish (P = 0.005). At month 6, the only difference that persisted was greater knowledge of a healthy diet (P = 0.01). In models assessing an interaction between intervention condition and ethnicity, compared to Hispanics, the intervention had a stronger effect on increasing non-Hispanics’ belief that a healthy diet was important to prevent breast cancer recurrence (P = 0.02). CONCLUSIONS: Compared to only receiving written survivorship materials, a survivorship intervention that included written materials plus a 1 hour personalized lifestyle counseling session was associated with short-term increased knowledge of lifestyle recommendations, change in physical activity and change in dietary behaviors among a multi-ethnic group of breast cancer survivors. Behavioral effects were not observed beyond 3 months. A single 1 hour lifestyle consultation is likely not enough to achieve and maintain lifestyle recommendations. To facilitate long-term behavioral change among breast cancer survivors in the adjuvant setting, culturally competent behavioral interventions should be developed to increase knowledge of and the capabilities needed to meet lifestyle recommendations. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P3-08-12.

Abstract P5-15-03: Baseline joint pain predicts severity of subsequent joint symptoms in women initiating aromatase inhibitors for early stage breast cancer

Background: Aromatase inhibitors (AIs) are the standard adjuvant treatment of hormone-sensitive breast cancer (BC) in postmenopausal women. However, these therapies are associated with musculoskeletal complaints which may lead to non-adherence and early discontinuation. The aim of this study was to characterize the natural history of the AI-induced arthralgia. Methods: Postmenopausal women with stage I-III BC were prospectively enrolled at the onset of adjuvant AI therapy. Subjects completed the Brief Pain Inventory (BPI) questionnaire at baseline, 3, 6, 9, and 12 months. BPI worst pain scores were categorized as 0-3, 4-6 and 7-8. Multiple logistic regression analysis was used to evaluate the association between baseline factors and having a 2-point worsening in BPI worst pain score. A Cox-proportional hazards model was used to evaluate factors that influenced the time to first 2-point worsening in pain score. Clinically significant change was defined as ≥2-point increase from baseline. Those with a baseline BPI worst pain score of ≥9 were removed from analysis. Results: Among 180 consented subjects, 1 was found to be ineligible due to being perimenopausal, 42 subjects were lost to follow up, 17 subjects came off their AI and 8 subjects dropped out. Mean age was 61; 60% were white, 32% Black, 10%, Asian and 31% were Hispanic; 86% started on anastrazole; 24% had a change in AI. At baseline, 76 women had a BPI worst pain score between 0-3; 28 between 4-6; and 18 had 7+. Seventy subjects (64%) experienced at least a 2-point worsening of BPI from baseline and women who developed a 2-point worsening had a lower mean baseline BPI (2.57 vs. 3.75) compared to those who did not. Those experiencing an initial worsening in the first 6 months of therapy improved over time; while the patients experiencing BPI worsening at 9 months, continued to have progressive increase in BPI. In a multiple logistic regression model adjusting for AI switching, BMI, age, baseline score, prior chemotherapy, osteoarthritis, and prior hormone replacement therapy, those who had a baseline worst pain score between 4-6 (p=0.04) or 7+ (p=0.005) were less likely to develop a 2-point worsening in BPI at 12 months from baseline. Similarly, those with a baseline worst pain categorization of 7+ had a hazard ratio of 0.34 for time to 2-point worsening. Conclusions: Women with low baseline BPI score are more likely to develop worsening BPI score over time. Women who develop symptoms later in the course of their therapy are at greatest risk for persistent symptoms. This has implications for studies evaluating interventions for prevention of AI arthralgias. Citation Format: Lea Baer, Katherine D Crew, Danielle Awad, Kevin Kalinsky, Matt Maurer, Dawn L Hershman. Baseline joint pain predicts severity of subsequent joint symptoms in women initiating aromatase inhibitors for early stage breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-15-03.