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Genetic testing for hereditary breast and ovarian cancer (HBOC) is recommended for breast cancer patients diagnosed at age ≤ 50 years. Our objective was to examine racial/ethnic differences in genetic testing frequency and results among diverse breast cancer patients. A retrospective cohort study among women diagnosed with breast cancer at age ≤ 50 years from January 2007 to December 2017 at Columbia University in New York, NY. Among 1503 diverse young breast cancer patients, nearly half (46.2%) completed HBOC genetic testing. Genetic testing completion was associated with younger age, family history of breast cancer, and earlier stage, but not race/ethnicity or health insurance status. Blacks had the highest frequency of pathogenic/likely pathogenic (P/LP) variants (18.6%), and Hispanics and Asians had the most variants of uncertain significance (VUS), 19.0% and 21.9%, respectively. The percentage of women undergoing genetic testing increased over time from 15.3% in 2007 to a peak of 72.8% in 2015. Over the same time period, there was a significant increase in P/LP and VUS results. Due to uncertainty about the clinical implications of P/LP variants in moderate penetrance genes and VUSs, our findings underscore the need for targeted genetic counseling education, particularly among young minority breast cancer patients. [ABSTRACT FROM AUTHOR]

Background: Overweight or obese women with breast cancer (BC) have a higher risk of distant recurrence and death compared to normal weight women. There is increasing evidence that insulin significantly mediates these adverse clinical outcomes. Laboratory and population studies demonstrate that metformin offers a protective BC effect through reduction of serum insulin levels and direct modulation of cellular protein synthesis and growth through AMPK pathway signaling. Our aim is to assess the biologic impact of metformin on blood- and tumor- based markers on insulin, IGF and AMPK/mTOR pathway signaling, and/or proliferation in operable BC patients with a body mass index (BMI) ≥ 25 kg/m². Methods: The study was an open-label pre-surgical trial with metformin 1500 mg PO per day (500 mg am/1000 mg pm) for 2-4 weeks prior to surgical resection in 35 overweight or obese patients with invasive BC (n = 25) or ductal carcinoma in situ (n = 10) and no history of diabetes. The primary endpoint was to assess a reduction in tumor proliferation. We have 80% power to detect a 30% decrease in Ki-67 in invasive BCs from baseline to post-metformin values (two-sample t-test, 0.05). Secondary endpoints include changes in BMI and insulin resistance markers, such as fasting serum insulin, lipid panel, glucose, leptin, and adiponectin. Tumor markers will be compared to untreated historical controls matched by age, BMI, and tumor characteristics. Results: Between Oct 2009 to Aug 2011, we screened 116 patients, enrolling 35 with newly diagnosed BC: 18/34 overweight (27.6: 25.1-29.7) and 16/34 obese (35.9: 30.5-46.4). Hispanic women made up 80% of the population (28/35). The median metformin duration was 22 days (1-64). All took metformin until the evening prior to surgery, except 2 (1 withdrew and 1 stopped early after surgery delay). More than half had a prior diagnosis of hypertension and a third had hypercholesterolemia. In the invasive BC cohort (n = 25), 19/25 (76%) were HR+/HER2-. The most common grade I-II included self-limiting diarrhea, flatulence, abdominal pain, fatigue, and anorexia. Grade III events included abdominal pain (n = 1) and diarrhea (n = 3). The change in blood markers are described in the table. Tumor Ki-67 (immunohistochemistry) and pathway signaling analyses (reverse protein microarray) are ongoing. Conclusions: Our study is unique to other pre-surgical metformin trials due to the enrichment of overweight/obese BC patients and the ethnically diverse population. We observed a significant decrease in serum cholesterol and leptin with metformin, and a trend toward lower insulin, HOMA, and adiponectin. No significant changes in glucose or IGFP-3 levels are noted. We are awaiting tumor-based biomarker evaluation. Pre-surgical trials can assess an agent's biological effect prior to long-term intervention trials. [ABSTRACT FROM AUTHOR]

Background: Aromatase inhibitors (AIs) are widely prescribed to postmenopausal women for the adjuvant treatment of hormone-sensitive breast cancer (BC). However, musculoskeletal complaints can lead to nonadherence and early discontinuation. The aim of this study was to characterize the natural history of the AI-induced arthralgia syndrome and determine predictors of worsening symptoms. Methods: Postmenopausal women with stage I-III BC 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 worse symptoms. Quality of life was assessed using the Functional Assessment of Cancer Therapy-Endocrine Subscale (FACT-ES). Hand grip strength was measured at each visit with a Martin dynamometer. Paired t-tests were performed to compare follow-up evaluations to baseline. Linear Regression was performed to evaluate the association between baseline symptoms and change in symptoms. Results: A total of 169 patients have been consented, 3-month data is available on 102; 6-month data on 85. Median age: 63 (42-89); White/Black/Asian/Hispanic: 61.48/30.33/3.28/25.6; median BMI (kg/m2): 28 (12-50). Compared to baseline, there was a statistically significant increase in BPI pain severity and endocrine related symptoms on the FACT-ES at 3 and 6 months. Significant changes in the BPI pain interference, M-SACRAH pain and stiffness, WOMAC function, physical well-being on the FACT-ES, trial outcome index and pinch grip strength were seen at 3 months; however these changes did not remain significant at 6 months. Logistic regression models evaluating predictors of patient reported outcome measures and grip strength were performed. Baseline score was the strongest predictor of worsening symptoms (p < 0.01) after correcting for age, prior chemotherapy and baseline joint conditions. Conclusions: Treatment with adjuvant AI therapy is associated with significant worsening of joint pain and stiffness which is most prominent at the 3 months evaluation. Patients with baseline joint symptoms are at greatest risk for worsening symptoms on AIs. [ABSTRACT FROM AUTHOR]

Background: Randomized studies investigating adjuvant bisphosphonates in women with breast cancer are ongoing. While bisphosphonates would be expected to prevent the deterioration of bone microarchitecture that accompanies hormone or chemotherapy, complete suppression of osteoclast activity for prolonged periods of time can decrease repair of micro-cracks, and possibly lead to decreased bone strength. While bone strength is governed by the amount of bone present, trabecular and cortical components of bone microarchitecture also contribute independently to bone strength. We aimed to characterize the effects of long-term bisphosphonates on bone microarchitecture in women with breast cancer using high-resolution peripheral quantitative computed tomography (HR-pQCT) of the distal radius and tibia. Methods: We conducted a cross-sectional study involving early stage breast cancer patients treated with bisphosphonates on the S0307 clinical trial. Women were randomized to receive zoledronic acid, oral clodronate or oral ibandronate in doses far higher than those used in osteoporosis treatment as per protocol. After 18-36 months of bisphosphonate therapy, participates underwent a one-time evaluation of areal bone mineral density (aBMD) of the 1/3 radius, lumbar spine, and hip by dual energy x-ray absorptiometry (DXA), and cortical and trabecular volumetric BMD (vBMD) and trabecular microarchitecture of the radius and tibia by HR-pQCT. HR-pQCT measurements were compared to healthy young premenopausal women and age-matched Caucasian women. Results: Baseline characteristics of the 12 enrolled patients: median age of 53 (range 40- 67); white/Hispanics 7/5; pre/postmenopausal 4/8; mean body mass index 28.7 kg/m2 (20.9-34.8); average time on bisphosphonates 20 months (18-30); zoledronic acid/clodronate/ibandronate 5/6/1. The median aBMD DXA T-score of the 1/3 radius, lumbar spine and total hip were normal at +0.3, +0.1, and +0.2, respectively. Mean total, cortical, and trabecular vBMD of the radius as measured by HR-pQCT were 330±71, 905±55, and 146±35 mg hydroxyapatite/cm3, respectively. Mean cortical thickness was 0.803±0.170 mm, and mean trabecular number was 1.9±0.2. Mean total, cortical, and trabecular vBMD of the tibia were 285±54, 880±54, and 150±38 mg hydroxyapatite/cm3, respectively. Mean cortical thickness was 1.135±0.264 mm, and mean trabecular number was 1.7±0.3. There were no statistically significant differences between study group and each control. However, results were more similar to healthy young premenopausal control than the age-matched control. Conclusion: Women on long-term bisphosphonate therapy for breast cancer had normal aBMD by DXA and normal cortical and trabecular vBMD, cortical thickness and trabecular number at the peripheral skeleton compared to healthy young women and age-matched women. This preliminary data is reassuring for cancer survivors if benefits from this therapy are established in the adjuvant setting. [ABSTRACT FROM AUTHOR]

Background: In 2005, the Institute of Medicine released a report citing the importance of comprehensive treatment summaries or "survivorship plans" for cancer patients completing adjuvant therapy. However, little is known about the best approach or the impact of these interventions on patient well-being. We compared quality of life, treatment satisfaction and cancer impact measures between a minimal or more intensive intervention. Methods: The study was conducted at a single-institution academic breast cancer practice. Women with non-metastatic breast cancer were randomized within six weeks of completing adjuvant therapy (chemotherapy/radiation therapy) to a minimal intervention group (MG) or intensive intervention group (IG). The MG group was given the NCI publication, "Facing Forward: Life after Cancer Treatment" by lay research staff. The intensive group received the same NCI publication; met in person for 1 hour with a nurse practitioner who provided a treatment summary, surveillance and screening recommendations, and information on risk for late effects; and met in person for 1 hour with a nutritionist to review lifestyle recommendations. Subjects were informed that they were in a study of cancer survivors but unaware they were being randomized. The randomization was stratified by ethnicity (Hispanic/non-Hispanic). Both groups completed the 81 -item impact of cancer instrument (IOC), functional assessment of chronic illness therapy-treatment satisfaction-patient satisfaction questionnaire (FACIT-TS-PS) and assessment of survivor concerns (AOC) at baseline, 3 and 6 months. Group t-tests and between group linear regression analyses were performed controlling for ethnicity. Results: Of 140 patients who signed consent, 126 women (66 non-Hispanic, 60 Hispanic) completed baseline questionnaires, 109 completed 3 month, and 109 completed 6 month assessments. The groups were well balanced with regard to age (mean = 54), race, marital status, income and employment status. There were no statistically significant differences between the MG and IG on the 8 domains that comprise the FACIT-TS-PS at 3 and 6 months. The health worry scale of the AOC was lower in the IG (p = 0.006) compared to MG, indicating less health worry and the negative outlook score of the IOC was higher in the MG (p = 0.043) compared to IG at 3 months. At baseline, 3 and 6 months, Hispanic women compared to non-Hispanic women had significantly higher (worse) ACS and IOC health worry (p < 0.001), social life interference (p = 0.01) and meaning of cancer scales (p = 0.0004), but also had greater trust in medical professionals (p = 0.029). Conclusions: We did not observe a difference in most of the IOC or treatment satisfaction scores between the MG and IG interventions at 3 or 6 months, nor did we find any significant change from baseline in either group. However, less health worry and less negative outlook were seen in the IG compared to the MG. At baseline and follow-up, Hispanic women in both interventions compared to non-Hispanic women had more extreme scores on most measures. Despite minimal difference between the interventions, the intensive intervention was more time-consuming and used more health care resources. [ABSTRACT FROM AUTHOR]

Background: Selective estrogen receptor modulators (SERMs) have been shown to decrease breast cancer incidence among high-risk women, but uptake for prevention has been poor. Observational studies have demonstrated that serum 25-hydroxyvitamin D (25-OHD) is inversely related to breast cancer risk, such that levels >40 ng/ml are associated with about a 40% reduction in breast cancer risk compared to women who are vitamin D deficient (25-OHD <20 ng/ml). Uncertainty remains about whether vitamin D supplementation will reduce breast cancer risk, the optimal dose of vitamin D, and the target level of serum 25-OHD. We examined the safety of high dose vitamin D and the effects on serum 25-OHD in women at high risk for breast cancer. Methods: Forty high-risk women (defined as a 5-year Gail risk ³1.67%, lobular or ductal carcinoma in situ [LCIS/DCIS], BRCA1/BRCA2 mutation carrier, or stage I/II invasive breast cancer in remission for >5 years) were assigned to a 1-year intervention of vitamin D3 20,000 or 30,000 IU weekly. Other eligibility criteria included baseline mammographic density (MD) ≥25%, serum 25-OHD ≤ 32 ng/ml, no current SERM use and no history of kidney stones. Women underwent a digital mammogram at baseline and 12 months, and serial blood draws every 3 months. In addition, random core breast biopsies were conducted in premenopausal women, whereas postmenopausal women underwent a breast MRI at baseline and 12 months. Participants were monitored for toxicity, particularly hypercalcemia and hypercalciuria, every 3 months. The primary objective is to determine the safety and feasibility of high-dose vitamin D in this study population. Secondary objectives are to determine changes in breast density and blood-based biomarkers (25-OHD, 1,25(OH)D, PTH, IGF-I, IGFBP-3). Serum 25-OHD was measured by Diasorin radioimmunoassay. Results: From November 2007 to January 2011, 292 women were screened and 142 were ineligible. Main reasons for ineligibility (%) included 25-OHD >32 ng/ml (27), opted for SERM (23), prior kidney stones (11), and MD <25% (9). Of the 40 enrolled participants: median age 50 years (range, 37-73); pre/postmenopausal: 20/20; white/hispanic/black/asian: 19/14/6/1; median body mass index 26.6 kg/m² (20-39.6); elevated Gail risk/LCIS/DCIS/stage I or II breast cancer: 20/10/8/2; mean baseline serum 25-OHD 20.2 ng/ml (9-31). Currently, 1 participant is on-study, 31 completed the intervention, 6 were lost to follow-up, 1 withdrew due to hypercalciuria (spot urine Ca/Cr >0.37) and 1 withdrew due to dyspepsia. Mean serum 25- OHD rose to 47 ng/ml at 3 months, 49.1 ng/ml at 6 months, and 53.7 ng/ml (range, 26-77) at 12 months. No significant hypercalcemia (serum Ca >10.5 mg/dl) occurred at either dose level. Imaging and biomarker analyses are ongoing. Discussion: We have demonstrated that a 1-year intervention of high-dose vitamin D3 is well tolerated and can increase serum 25-OHD above a target level of 40 ng/ml. This preliminary data has informed an ongoing phase IIb randomized placebo-controlled trial (SWOG 0812) of high-dose vitamin D in 200 high-risk premenopausal women and highlights the importance of early phase breast cancer chemoprevention trials with intermediate biomarker endpoints to test novel agents. [ABSTRACT FROM AUTHOR]

Introduction: Women with atypical hyperplasia (AH) or lobular carcinoma in situ (LCIS) have a significantly increased risk of breast cancer, which can be substantially reduced with antiestrogen therapy for chemoprevention. However, antiestrogen therapy for breast cancer risk reduction remains underutilized. Improving knowledge about breast cancer risk and chemoprevention among high-risk patients and their healthcare providers may enhance informed decision-making about this critical breast cancer risk reduction strategy., Methods/design: We are conducting a cluster randomized controlled trial to evaluate the effectiveness and implementation of patient and provider decision support tools to improve informed choice about chemoprevention among women with AH or LCIS. We have cluster randomized 26 sites across the U.S. through the SWOG Cancer Research Network. A total of 415 patients and 200 healthcare providers are being recruited. They are assigned to standard educational materials alone or combined with the web-based decision support tools. Patient-reported and clinical outcomes are assessed at baseline, after a follow-up visit at 6 months, and yearly for 5 years. The primary outcome is chemoprevention informed choice after the follow-up visit. Secondary endpoints include other patient-reported outcomes, such as chemoprevention knowledge, decision conflict and regret, and self-reported chemoprevention usage. Barriers and facilitators to implementing decision support into clinic workflow are assessed through patient and provider interviews at baseline and mid-implementation., Results/discussion: With this hybrid effectiveness/implementation study, we seek to evaluate if a multi-level intervention effectively promotes informed decision-making about chemoprevention and provide valuable insights on how the intervention is implemented in U.S., Trial Registration: NCT04496739., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Vitamin D deficiency is a potentially modifiable risk factor that may be targeted for breast cancer prevention. We examined the safety, feasibility, and biomarker effects of high-dose vitamin D among women at high risk for breast cancer. Forty high-risk women, defined as a 5-year breast cancer risk ≥1.67% per the Gail model, lobular or ductal carcinoma in situ , were assigned to a 1-year intervention of vitamin D3 20,000 IU or 30,000 IU weekly. Participants were monitored for toxicity every 3 months, underwent serial blood draws at baseline, 6 and 12 months, and a digital mammogram at baseline and 12 months. Biomarker endpoints included serum 25-hydroxyvitamin D [25(OH)D], 1,25-dihydroxyvitamin D [1,25(OH) 2 D], parathyroid hormone (PTH), insulin-like growth factor (IGF-1), IGF binding protein (IGFBP-3), and mammographic density (MD) using Cumulus software. From November 2007 to January 2011, we enrolled 40 women; 37 were evaluable at 6 months and 30 at 12 months. One patient was taken off study for hypercalciuria; otherwise, the intervention was well tolerated. From baseline to 12 months, mean serum 25(OH)D and 1,25(OH) 2 D rose from 20.0 to 46.9 ng/ml and 69.7 to 98.1 pg/ml, respectively (p<0.01). Serum PTH decreased by 12% at 6 months and IGF-1/IGFBP-3 ratio decreased by 4.3% at 12 months (p<0.05). There was no significant change in MD regardless of menopausal status or dose level. We demonstrated that 1 year of high-dose vitamin D3 was associated with a significant increase in circulating vitamin D levels and favorable effects on IGF signaling, but no significant change in MD., Competing Interests: Declarations The authors have no potential conflicts of interest to disclose.