Dl Hershman

Abstract PD03-03: Pre-surgical Trial of Metformin in Overweight and Obese, Multi-ethnic Patients with Newly Diagnosed Breast Cancer

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/m 2 . 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 agent9s biological effect prior to long-term intervention trials. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr PD03-03.

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.

P4-11-06: Uptake of Selective Estrogen Receptor Modulators and Other Breast Cancer Prevention Strategies among High-Risk Women Seen in a Breast Center.

Background: Selective estrogen receptor modulators (SERMs), tamoxifen and raloxifene, are FDA-approved for breast cancer (BC) risk reduction. However, uptake has been poor in the prevention setting, partly due to a lack of knowledge in the medical community about BC prevention and public misconceptions about the risks of SERMs. We assessed demographic and clinical factors that influence SERM uptake among high-risk women seen in an academic breast center, where specialized risk counseling is provided by a breast surgeon or medical oncologist. Methods: Potential subjects included high-risk women seen for an initial consultation by Breast Surgery or Medical Oncology. Eligibility for SERM use included a 5-year Gail risk ≥1.67%, lobular carcinoma in situ (LCIS), BRCA mutation carrier, or estrogen receptor (ER)-positive and/or progesterone receptor (PR)-positive ductal carcinoma in situ (DCIS). Demographic and BC risk factor data was collected from self-administered questionnaires. Clinical data, including prior/current SERM use, was abstracted from medical chart review. Differences in distribution of risk factors, between women who ever took a SERM and those who did not, were examined using chi-square statistics or Fisher9s exact test. Multivariable logistic regression models were used to calculate odds ratios (OR) and 95% confidence intervals using SERM use as the dependent variable. Results: Among 247 high-risk women enrolled between March 2007 and January 2011, median age 51 (17-82); White/Hispanic/Black/Asian (%): 55/32/7/6. 85% of women were undergoing annual mammography, 94% had a breast biopsy, 19% genetic testing, and 71% Medical Oncology referral. Among 181 (73%) women eligible for a SERM, Gail risk ≥1.67%/LCIS/DCIS/BRCA mutation (%): 35/22/39/3; 83 (46%) ever took a SERM, including 62 on tamoxifen and 21 on raloxifene. Early SERM discontinuation was only 7%. In multivariable analysis, significant predictors of SERM uptake included risk category (DCIS vs. Gail risk ≥1.67%/LCIS/BRCA mutation), higher income, higher body mass index (BMI), and referral to Medical Oncology. In terms of this high-risk population meeting American Cancer Society (ACS) behavioral guidelines for cancer prevention, 53% had a BMI Conclusions: Among high-risk women seen at a specialized breast center, application of clinical recommendations such as screening mammography, genetic testing, and SERM uptake were relatively high, suggesting that a comprehensive approach to the management of high-risk women is feasible. However, meeting ACS nutrition and physical activity guidelines for cancer prevention was limited, perhaps due to a lack of reimbursable staff to implement these guidelines. Breast cancer risk assessment and available interventions for prevention among high-risk women are underutilized in the U.S. Future studies should focus on the development and delivery of breast cancer prevention strategies. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-11-06.

Abstract PD7-03: Cost-effectiveness analysis of intraoperative radiotherapy for ductal carcinoma in situ

Background Whole breast radiation therapy (WBRT) following lumpectomy for ductal carcinoma in situ (DCIS) is standard of care, however, the risk of local recurrence with and without radiation ranges as low as 0.9% vs. 6.7% over 7 years. Intraoperative radiotherapy (IORT) is a potential alternative with advantages of decreased toxicity to adjacent organs, convenience, and improved quality of life. While prospective trials of IORT for DCIS are ongoing, the objective of this study was to estimate the cost-effectiveness of IORT vs. WBRT vs. no radiation for DCIS. Methods We developed a Markov model using TreeAge Pro 2016 to evaluate the cost-effectiveness of WBRT, IORT, and no radiation in patients with DCIS following lumpectomy. Health states included disease free, local recurrence (ipsilateral DCIS or invasive cancer), distant recurrence or death due to breast cancer, and death due to non-breast cancer causes. A 10-year time horizon and societal perspective were used. Model input parameters were derived from the literature. Costs reflected 2016 Medicare rates. The primary endpoint was incremental cost-effectiveness ratio (ICER), defined as the difference in cost, divided by the difference in quality-adjusted life years (QALYs) of two interventions. We performed analyses of subgroups defined according to DCIS risk (histologic grade, Oncotype Dx® DCIS recurrence score, low risk per RTOG 9804 criteria) and endocrine therapy use (none, tamoxifen, aromatase inhibitor). Sensitivity analyses explored uncertainty in the model. Results IORT was the most cost-effective strategy, with an increase of 0.18 QALYs at an incremental cost of

Abstract P5-13-14: Factors associated with multidisciplinary care in the management of early stage breast cancer

4,728, corresponding to an ICER of

Abstract P4-01-06: Diffuse optical tomography can predict pathologic complete response in patients with HER2+ or triple negative breast cancer undergoing neoadjuvant chemotherapy

26,943/QALY when compared with no radiation therapy. WBRT resulted in an increase in 0.18 QALYs at an incremental cost of

Abstract PD4-05: Complementary and alternative medicine use and breast cancer chemotherapy initiation: The BQUAL study

6859, corresponding to an ICER of

Abstract P3-07-52: Identification of serum biomarkers associated with Akt inhibitor MK-2206-induced toxicity in a pre-surgical breast cancer (BC) trial

39,085/QALY. For both strategies, the ICERs did not exceed the willingness to pay (WTP) threshold of

Abstract P1-07-21: Use of serum tumor markers and high cost imaging in women with metastatic breast cancer

100,000. IORT remained the most cost-effective strategy across DCIS risk groups, but was more cost-effective in higher risk patients, as demonstrated by lower ICERs. In low risk DCIS defined by RTOG 9804 criteria, no radiation was most cost-effective. The ICERs for IORT and WBRT,

Abstract PD4-04: Psychosocial factors related to interruptions in adjuvant hormonal therapy among women with breast cancer: The breast cancer quality of care study (BQUAL)

152,753 and