Katherine D. Crew

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.

Zoledronic Acid Prevents Bone Loss in Premenopausal Women Undergoing Adjuvant Chemotherapy for Early-Stage Breast Cancer

PURPOSE Adjuvant chemotherapy for breast cancer (BC) may be associated with increased rates of bone loss and decreased bone mineral density (BMD) and may lead to premature osteoporosis and increased fracture risk. We examined whether zoledronic acid (ZA) prevents bone loss in premenopausal women receiving chemotherapy for early-stage BC. PATIENTS AND METHODS This study is a randomized, double-blind, multicenter, phase III trial comparing ZA (4 mg intravenously every 3 months) versus placebo for 1 year. Premenopausal women underwent serial BMD measurements before initiating chemotherapy and at 6 and 12 months. The primary outcome was percent change in lumbar spine (LS) BMD at 6 months. Secondary outcomes were percent change at any BMD site and markers of bone turnover at 12 months. Linear mixed model analysis for repeated measures was performed. RESULTS Of 101 women who were randomly assigned and completed baseline evaluation, 96 completed the 6-month evaluation, and 85 completed the 12-month evaluation. Baseline characteristics were comparable between the groups. Mean age was 42 years. Placebo was associated with significant decline in LS BMD at both 6 (2.4%) and 12 (4.1%) months. Similarly, total hip BMD declined by 0.8% at 6 months and 2.6% at 12 months. In contrast, BMD remained stable in ZA patients (P < .0001 compared with placebo). CONCLUSION Premenopausal women receiving chemotherapy for BC sustained significant bone loss at the LS and hip, whereas BMD remained stable in women who received ZA. Administration of ZA during the first year of chemotherapy is an effective and well-tolerated strategy for preventing bone loss.

High Prevalence of Vitamin D Deficiency Despite Supplementation in Premenopausal Women With Breast Cancer Undergoing Adjuvant Chemotherapy

PURPOSE Vitamin D deficiency is associated with increased breast cancer risk and decreased breast cancer survival. The purpose of this study was to determine the prevalence of vitamin D deficiency, as measured by serum 25-hydroxyvitamin D (25-OHD), in premenopausal women at initiation of adjuvant chemotherapy for breast cancer and after 1 year of vitamin D supplementation. PATIENTS AND METHODS The study included 103 premenopausal women from the northeastern United States with stages I to III breast cancer who received adjuvant chemotherapy and participated in a 1-year zoledronate intervention trial. All patients were prescribed vitamin D(3) (cholecalciferol) 400 IU and calcium carbonate 1,000 mg daily. At baseline and at 6 and 12 months, bone mineral density (BMD) measurements were obtained and blood was collected and analyzed in batches for serum 25-OHD. Vitamin D deficiency was defined as serum 25-OHD less than 20 ng/mL, insufficiency as 20 to 29 ng/mL, and sufficiency as 30 ng/mL or greater. RESULTS At baseline, 74% of women were vitamin D deficient (median, 17 ng/mL). Vitamin D deficiency was slightly less common in white women (66%) compared with black (80%) and Hispanic (84%) women. After vitamin D supplementation for 1 year, less than 15% of white and Hispanic women, and no black women, achieved sufficient 25-OHD levels. Vitamin D levels did not correlate with baseline BMD and were not altered by chemotherapy or bisphosphonate use. CONCLUSION Vitamin D deficiency is highly prevalent in women with breast cancer. The current recommended dietary allowance of vitamin D is too low to increase serum 25-OHD greater than 30 ng/mL. Optimal dosing for bone health and, possibly, improved survival has yet to be determined.

Association between Plasma 25-Hydroxyvitamin D and Breast Cancer Risk

Vitamin D has been associated with decreased risk of several cancers. In experimental studies, vitamin D has been shown to inhibit cell proliferation and induce differentiation and apoptosis in normal and malignant breast cells. Using a population-based case-control study on Long Island, New York, we examined the association of breast cancer with plasma 25-hydroxyvitamin D (25-OHD) levels, a measure of vitamin D body stores. In-person interviews and blood specimens were obtained from 1,026 incident breast cancer cases diagnosed in 1996 to 1997 and 1,075 population-based controls. Plasma 25-OHD was measured in batched, archived specimens by Diasorin RIA. The mean (SD) plasma 25-OHD concentration was 27.1 (13.0) and 29.7 (15.1) ng/mL in the cases and controls, respectively (P < 0.0001). Plasma 25-OHD was inversely associated with breast cancer risk in a concentration-dependent fashion (Ptrend = 0.002). Compared with women with vitamin D deficiency (25-OHD, <20 ng/mL), levels above 40 ng/mL were associated with decreased breast cancer risk (odds ratio, 0.56; 95% confidence interval, 0.41-0.78). The reduction in risk was greater among postmenopausal women (odds ratio, 0.46; 95% confidence interval, 0.09-0.83), and the effect did not vary according to tumor hormone receptor status. In summary, these results add to a growing body of evidence that adequate vitamin D stores may prevent breast cancer development. Whereas circulating 25-OHD levels of >32 ng/mL are associated with normal bone mineral metabolism, our data suggest that the optimal level for breast cancer prevention is ≥40 ng/mL. Well-designed clinical trials are urgently needed to determine whether vitamin D supplementation is effective for breast cancer chemoprevention.

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.

Changes in markers of ovarian reserve and endocrine function in young women with breast cancer undergoing adjuvant chemotherapy

Premenopausal women undergoing chemotherapy are at risk for amenorrhea and impaired fertility. The objective of the current study was to assess levels of mullerian inhibitory substance (MIS), estradiol (E2), follicle‐stimulating hormone (FSH), and menstrual status, in women undergoing chemotherapy.

Polymorphisms in Nucleotide Excision Repair Genes, Polycyclic Aromatic Hydrocarbon-DNA Adducts, and Breast Cancer Risk

Genes involved in the nucleotide excision repair (NER) pathway, which removes bulky DNA adducts, are potential low-penetrance cancer susceptibility genes. We recently reported an association between detectable polycyclic aromatic hydrocarbon (PAH)-DNA adducts and breast cancer risk. Using a population-based breast cancer case-control study on Long Island, New York, we examined whether polymorphisms in NER genes modified the association between PAH-DNA adducts and breast cancer risk. We examined polymorphisms in ERCC1 (3′-untranslated region 8092C/A), XPA (5′-untranslated region −4G/A), XPD (Asp312Asn in exon 10), XPF (Arg415Gln in exon 8), and XPG (Asp1104His in exon 15) in 1,053 breast cancer cases and 1,102 population-based controls. The presence of at least one variant allele in XPD was associated with a 25% increase in the odds ratio [OR, 1.25; 95% confidence interval (95% CI), 1.04-1.50] for breast cancer. The increase associated with homozygosity of the variant alleles for XPD and ERCC1 was stronger among those with detectable PAH-DNA adduct levels (OR, 1.83; 95% CI, 1.22-2.76 and OR, 1.92; 95% CI, 1.14-3.25 for detectable versus nondetectable adducts and homozygous wild-type genotype for XPD and ERCC1, respectively). We found no association between XPA, XPF, and XPG genotypes, PAH-DNA adducts, and breast cancer risk. When we combined genotypes for these NER pathway genes, there was a significant trend for increasing breast cancer risk with increasing number of putative high-risk alleles. Overall, this study suggests that the risk of breast cancer may be elevated among women with polymorphisms in NER pathway genes and detectable PAH-DNA adducts. (Cancer Epidemiol Biomarkers Prev 2007;16(10):2033–41)

A Pilot Randomized Controlled Trial of a Commercial Diet and Exercise Weight Loss Program in Minority Breast Cancer Survivors

Obesity is associated with poorer breast cancer outcomes and losing weight postdiagnosis may improve survival. As Hispanic and black women have poorer breast cancer prognosis than non‐Hispanic whites diagnosed at similar age and stage, and have higher rates of obesity, effective weight loss strategies are needed. We piloted a randomized, waitlist‐controlled, crossover study to examine the effects and feasibility of the commercial Curves weight loss program among Hispanic, African American and Afro‐Caribbean breast cancer survivors.

Phase IB Randomized, Double-Blinded, Placebo-Controlled, Dose Escalation Study of Polyphenon E in Women with Hormone Receptor–Negative Breast Cancer

Epidemiologic data support an inverse association between green tea intake and breast cancer risk, and numerous experimental studies have shown the antitumor effects of its main component, epigallocatechin gallate (EGCG). We conducted a phase IB dose escalation trial in women with a history of stage I to III hormone receptor–negative breast cancer of an oral green tea extract, polyphenon E (Poly E) 400, 600, 800 twice daily or matching placebo for 6 months. The primary endpoint was to determine the maximum tolerated dose (MTD), defined as the dose that causes 25% dose-limiting toxicity (DLT, grade ≥II). Assignment to dose level was based upon an adaptive design, the continual reassessment method. A mammogram and random core biopsy of the contralateral breast were obtained at baseline and 6 months and serial blood/urine collections every 2 months for biomarker analyses. Forty women were randomized: 10 to placebo, 30 to Poly E (16 at 400 mg, 11 at 600 mg, 3 at 800 mg). There was one DLT at 400 mg (grade III rectal bleeding), three DLTs at 600 mg (grade II weight gain, grade III indigestion and insomnia), and one DLT at 800 mg (grade III liver function abnormality). The DLT rate at 600 mg was 27% (3 of 11). Pharmacologic levels of total urinary tea polyphenols were achieved with all three dose levels of Poly E. Using a novel phase I trial design, we determined the MTD for Poly E to be 600 mg twice daily. This study highlights the importance of assessing toxicity for any chemopreventive agent being developed for chronic use in healthy individuals. Cancer Prev Res; 5(9); 1144–54. ©2012 AACR.

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.