Improve Breast Cancer Outcomes Research Articles

Abstract P1-13-11: Adjuvant treatment of early-stage breast cancer with eribulin mesylate following dose-dense doxorubicin and cyclophosphamide: preliminary results from a phase 2, single-arm feasibility study

Abstract Background: Despite recent improvements in breast cancer outcomes, patients (pts) with high-risk, early-stage breast cancer continue to experience recurrences and death due to disease. Chemotherapy regimens with the ability to extend survival remain an important drug development goal. Eribulin mesylate has demonstrated antitumor activity and improved overall survival (OS) in pts with heavily pretreated, locally recurrent or metastatic breast cancer when compared to treatment of physician's choice. This study examines the feasibility of eribulin as adjuvant therapy following dose-dense (dd) doxorubicin (A) and cyclophosphamide (C) in patients with early-stage breast cancer. Methods: Eligible pts have histologically confirmed, HER2-normal, stage I-III invasive breast cancer and adequate bone marrow, liver, and renal function. Treatment consists of dd AC (A 60mg/m2 IV; C 600mg/m2 IV) on Day 1 of each 14-day cycle x4 cycles, followed by eribulin mesylate 1.4mg/m2 IV over 2–5min on Days 1 and 8 every 21 days x4 cycles. Radiation/hormonal therapy were allowed per standard of care. The primary objective of feasibility is defined as the ability to complete 4 cycles of eribulin without a treatment-related dose delay (defined as >2 days) or reduction. Feasibility rates will be reported for pts with and without growth factor use. Secondary/exploratory endpoints include evaluation of the safety via NCI-CTCAEv4 of 4 cycles of AC followed by 4 cycles of eribulin, and 3-year disease-free survival and OS. Results: As of 5/22/12, 46 of 80 planned pts have been treated; 38 pts have had ≥1 dose of eribulin and are evaluable for eribulin-related toxicity. Pt characteristics are as follows: median age 50 yrs (27–65 yrs); 100% female; ECOG of 0=81.6%; breast cancer stage at study entry: stg 1: 7.5%; stg 2: 72.5%, stg 3: 20%. Select treatment-related AEs are reported as total (all cycles) and eribulin-related events; many AEs overlapped during treatment (Table). Serious treatment-related AEs were reported in 2 pts, the most common (5.3%) being febrile neutropenia attributed to AC. Currently, 13 pts have had eribulin dose modification or delays; 10 of the events were related to eribulin (7 reductions, 5 delays, 1 withdraw). Eribulin-related AEs associated with dose delay or reduction are: 6 gr-3 neutropenia, 1 gr-3 febrile neutropenia, 1 gr-3 peripheral neuropathy, 1 gr-3 respiratory infection, 1 gr-3 fatigue. Six pts have discontinued (DC) treatment (2 AEs, 1 disease recurrence, 3 withdrew consent). Five of the 6 pts requiring eribulin delay/modification due to neutropenia were able to complete therapy with growth factor support. One pt DC eribulin therapy due to neuropathy. Conclusions: Preliminary results from this study suggest that adjuvant treatment with eribulin following dose-dense AC therapy has an acceptable safety profile. Accrual is ongoing and study completion is anticipated prior to SABCS 2012. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-13-11.

Influence of Primary Care on Breast Cancer Outcomes Among Medicare Beneficiaries

We used the Surveillance Epidemiology and End Results (SEER)-Medicare database to explore the association between primary care and breast cancer outcomes. Using a retrospective cohort study of 105,105 female Medicare beneficiaries with a diagnosis of breast cancer in SEER registries during the years 1994-2005, we examined the total number of office visits to primary care physicians and non-primary care physicians in a 24-month period before cancer diagnosis. For women with invasive cancers, we examined the odds of diagnosis of late-stage disease, according to the American Joint Commission on Cancer (AJCC) (stages III and IV vs stages I and II), and survival (breast cancer specific and all cause) using logistic regression and proportional hazards models, respectively. We also explored whether including noninvasive cancers, such as ductal carcinoma in situ (DCIS), would alter results and whether prior mammography was a potential mediator of associations. Primary care physician visits were associated with improved breast cancer outcomes, including greater use of mammography, reduced odds of late-stage diagnosis, and lower breast cancer and overall mortality. Prior mammography (and resultant earlier stage diagnosis) mediated these associations in part, but not completely. Similar results were seen for non-primary care physician visits. Results were similar when women with DCIS were included in the analysis. Medicare beneficiaries with breast cancer had better outcomes if they made greater use of a primary care physician's ambulatory services. These findings suggest adequate primary medical care may be an important factor in achieving optimal breast cancer outcomes.

Older patients with breast cancer: is there bias in the treatment they receive?

Breast cancer is the most frequent malignant tumor in women worldwide and as breast cancer incidence increases with increasing age, over 40% of new cases are diagnosed in women older than 65 years of age. However, older patients are not treated to the same extent as younger patients and increasing age at diagnosis predicts deviation from guidelines for all treatment modalities. Evidence-based medicine in older patients is lacking as they are usually excluded from clinical trials often because of existing comorbidities and limited life expectancy. Accordingly, there is a higher competing risk of death from other causes than breast cancer compared with younger patients and this may have led to the false interpretation that prognosis of breast cancer in older patients is relatively good. However, every treatment modality should be evaluated during treatment decision making. Multimodal therapy should not be routinely withheld as data show that disease-specific mortality increases with age, probably due to undertreatment. Prognostic markers, fitness and comorbidities rather than chronological age should determine optimal, individualized therapy. It is recommended that treatment decisions should be discussed in a multidisciplinary setting, ideally in combination with any form of geriatric assessment, to improve breast cancer outcome in the older population.

Clinical Perspective: Influence of Modifiable Lifestyle Factors, Body Weight, Physical Activity, and Alcohol on Breast Cancer Outcome

Observational studies associate obesity and physical inactivity with adverse breast cancer outcome. Whether weight loss/maintenance or increase in physical activity after diagnosis can improve breast cancer outcome is not established. While alcohol use increases breast cancer risk, the role of alcohol in altering breast cancer outcome is not established. Only two full-scale randomized clinical trials have evaluated lifestyle change in early-stage, resected breast cancer and they provide mixed results. Despite strong preclinical evidence and identified potential mediating factors, only one full-scale lifestyle intervention trial is currently ongoing, SUCCESS-C, which will evaluate a program of weight reduction and increased physical activity in an adjuvant setting. On the basisi of current evidence, weight loss/maintenance and physical activity increase/maintenance can reasonably be recommended for breast cancer patients with early-stage disease. However, the strength of the recommendation awaits definitive randomized clinical trial evidence.

Arthralgia, AI induced side events: incidence, feature and consequences

After a decade of endocrine adjuvant treatment with AI (Aromatase inhibitors), it is documented that they are somewhat superior to tamoxifen, in postmenopausal women with hormone receptor-positive breast cancer. However, compared with tamoxifen, an elevated incidence of arthralgia (pain in one or more joints), has been observed during AI treatment, symptoms more important and problematic than anticipated. The potential mechanisms behind AI-induced arthralgia are not well understood, even if estrogen withdrawal may probably play a role. The frequency is not well-established within the population and clinical predictors of these related arthralgia remain unclear, but this adverse event may result in poor adherence to treatment; interventions to ameliorate are often not efficient and at least, patients and physicians can be dissuading from completing the full AI treatment. Patient educations about some management of arthralgia symptoms can helping patients adhere to AI treatment and improve breast cancer outcomes. For some authors, the occurrence of joint or vasomotor symptoms might be a predictor of treatment effectiveness and might be useful when reassuring patients who present with them, but nevertheless in reality, this opinion is insufficient to avoid adherence. The association between emergent musculoskeletal symptoms and improved outcomes have not been described as consistent in most of experiences.

Abstract LB-329: Use of insulin sensitizers is associated with better hormone-receptor pattern and improved breast cancer outcomes

Abstract Hormone-receptor negative, HR(-), phenotype occurs frequently in diabetic women and is one of the worst prognostics in breast cancer (BC). We hypothesized that, by reducing insulin resistance in diabetics with BC, we could modify the HR status to improve BC outcomes. Our study explored for the first time whether specific diabetes mellitus (DM) therapy may be associated with more favorable HR status and improved BC prognosis as well as with lower insulin resistance and inflammation in this population. Diabetics newly diagnosed with BC between 2003 and 2010 (Roswell Park Cancer Institute) were retrospectively reviewed (n 225). HR status, outcomes, comorbidities and drug therapy were abstracted from medical records, the Institute's Breast Surgery Database and Tumor Registry. Follow up began at BC diagnosis and ended with first recurrence and/or death, or last follow-up. Plasma levels of inflammatory cytokines, adipokines, CRP and C-peptide were determined by Luminex in specimens donated at the time of BC diagnosis prior to chemotherapy or surgery. A total of 98 cases, DM+BC, and their matched controls, BC only (n 196) were analyzed. Fully adjusted hazard/odds ratios (HR/OR) and 95% confidence intervals (CI)s representing the association between DM drugs intake, HR status, specific biomarker levels and a defined BC event were computed with Cox proportional hazards model. Kaplan-Meyer analysis with log-rank statistics was also performed. After a median follow up of 30 months, patients receiving insulin sensitizers (IS) were found to have better disease-free survival (log rank X2 16.63, p 0.002), and overall survival (log rank X2 15.11, p 0.004) compared to those receiving exogenous insulin (Ins) or secretagogues (S), drugs stimulating insulin secretion. Intake of S was associated with elevated C-reactive protein, CRP (OR 1.98, CI 0.52-7.55, p 0.03) and C-peptide (OR 4.98, CI 1.03-24.03, p 0.01). As compared to BC only, the use of Ins in diabetics with BC was associated with higher levels (ng/ml) of CRP (3.62 vs 2.71, F 2.00, p 0.1), TNFa (6.98 vs 5.46, F 1.11, p 0.35), IL-8 (6.27 vs 4.74, F 1.36, p 0.25) and respectively lower leptin (1403.32 vs 1701.91, F 1.96, p 0.1) and C-peptide (322.97 vs 547.83, F 6.83, p 0.0001); adiponectin levels did not change. As compared to IS, S intake was suggestively associated with HR(-) status, although this not significant given the low sample size; OR 6.79, CI 0.65-70.97, p 0.28 for the estrogen receptor (ER) and OR 6.45, CI 1-41.58, p 0.15 for the progesterone receptor (ER). ER negative phenotype occurred more frequently in Ins receivers (OR 3.27) and S (OR 1.73) than IS (OR 0.24), when compared to BC with no DM, p 0.16. Addition of IS to the S regimen lowered this risk (OR 1.53 vs 1.73). Our data suggests that better outcomes may be achieved if IS are used for DM management in BC patients. We further speculate that our findings may also have an impact on prevention of anti-estrogen resistance. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-329. doi:1538-7445.AM2012-LB-329

Abstract SY26-01: Screening and cancer prevention in underdeveloped environments: A global view

Abstract SY26-01: Screening and cancer prevention in underdeveloped environments: A global view

High prevalence of BRCA1 and BRCA2 mutations in unselected Nigerian breast cancer patients

Inherited mutations in the BRCA1 and BRCA2 genes are the strongest genetic predictors of breast cancer and are the primary causes of familial breast/ovarian cancer syndrome. The frequency, spectrum and penetrance of mutant BRCA1/BRCA2 alleles have been determined for several populations, but little information is available for populations of African ancestry, who suffer a disproportionate burden of early onset breast cancer. We have performed complete sequence analysis of all BRCA1 and BRCA2 exons and intron-exon boundaries for 434 Nigerian breast cancer patients from the University College Hospital in Ibadan, Nigeria. In contrast to previous suggestions that BRCA1/BRCA2 mutation frequencies are low or undetectable in African American populations, we find that Nigerian breast cancer patients have an exceptionally high frequency of BRCA1 and BRCA2 mutations (7.1 and 3.9%, respectively). Sixteen different BRCA1 mutations were detected, seven of which have never been reported previously, while thirteen different BRCA2 mutations were seen, six of which were previously unreported. Thus, our data support enrichment for genetic risk factors in this relatively young cohort. To improve breast cancer outcomes, we suggest that family-based models of risk assessment and genetic counseling coupled with interventions to reduce breast cancer risk should be broadly disseminated in Nigeria and other underserved and understudied populations.

Improving Breast Cancer Outcomes among Women in China: Practices, Knowledge, and Attitudes Related to Breast Cancer Screening

Background. Breast cancer is a major public health issue and the most commonly diagnosed cancer for women worldwide. Despite lower incidence rates than those living in Western countries, breast cancer incidence among Chinese women has increased dramatically in the past 20 years. Nevertheless, there is a paucity of studies reporting the attitudes toward and practices of breast cancer screening among Chinese women. Methods. This cross-sectional study examined the practices, knowledge, and attitudes toward breast cancer screening (BCS) on a convenience sample of 400 Chinese women. Results. Among study participants, 75% of the women never had a mammogram and the top three barriers reported were low priority, feeling OK, and lack of awareness/knowledge toward breast cancer screening. The results from the logistic regression model showed increased self-efficacy; having performed monthly self-exams, and having had clinical breast exams in the past two years were significant correlates while demographic variables were not correlated with screening behaviors. Conclusion. The findings provide a foundation to better understand beliefs and practices of Chinese women toward BCS and highlight the critical need for general public, health professionals, and the health care system to work collaboratively toward improving the quality of breast cancer care in this population.

P4-12-05: Impact of the Lifestyle Intervention Study in Adjuvant Treatment of Early Breast Cancer (LISA) Weight Loss Intervention upon Physical Activity.

Abstract Observational evidence shows a relationship between obesity and poor prognosis in breast cancer (BC). Physical activity (PA) is an important component of weight loss and maintenance, but most large-scale interventions in BC patients have produced only modest improvements in activity. We sought to evaluate changes in PA in women participating in LISA, a randomized trial coordinated by the Ontario Clinical Oncology Group which was designed to examine the impact of a telephone-based weight loss intervention (WLI) upon disease free survival in BC patients. Methods: Participants were randomized 1:1 to the WLI or educational control (EC) group. Eligibility included diagnosis of Stage I-III BC, BMI ≥24 kg/m2, and treatment with letrozole. The WLI, based on the Diabetes Prevention Program, focused on weight reduction through calorie restriction and increased physical activity. Delivery involved 19 calls, mailings and a participant manual. The PA goal was 150 minutes/week. PA was measured using the International Physical Activity Questionnaire (Short Form) at baseline, 6, 12, and 18 months. Changes in time (minutes/week) spent sitting and engaging in moderate, vigorous, and walking activities were compared between groups. Results 338 women were randomized to WLI (n=171) or EC (n=167) from 20 centers in Canada and the USA. The study was discontinued due to loss of funding. The WLI arm lost significantly more weight than EC arm, with mean weight loss of 6.1% of body weight vs. 0.6% at 12 months (p<0.001). Activity data are presented in Table 1. At baseline, participants were inactive; median vigorous activity was zero minutes/week and median time spent sitting was more than 35 hours/week. WLI participants reported significantly higher participation in vigorous, moderate and walking activities, and lower levels of sedentary behavior, compared to controls at 6 and 12 months. Higher levels of PA were significantly associated with increased weight loss at all time periods. Factors associated with increases in activity included higher baseline BMI (p=0.014), lower baseline activity (p<0.001) and assignment to the WLI arm (p=0.02). Women assigned to WLI increased their PA during the intervention period (p=0.017) even after adjusting for other significant baseline factors. Conclusion Participants in the LISA WLI reported significantly higher levels of PA compared with controls. Activity increased most in women who were heavier and less active at baseline. Further study of this WLI as a potential means to improve BC outcomes is warranted. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-12-05.

The cost-utility of adjuvant chemotherapy using docetaxel and cyclophosphamide compared with doxorubicin and cyclophosphamide in breast cancer.

The adoption of a chemotherapeutic regimen in oncologic practice is a function of both its clinical and its economic impacts on cancer management. For breast cancer, U.S. Oncology trial 9735 reported significant improvements in disease-free and overall survival favoring adjuvant tc (docetaxel 75 mg/m(2) and cyclophosphamide 600 mg/m(2) every 3 weeks for 4 cycles) compared with ac (doxorubicin 60 mg/ m(2) and cyclophosphamide 600 mg/m(2) every 3 weeks for 4 cycles). We carried out an economic evaluation to examine the cost-utility of adjuvant tc relative to ac, in terms of cost per quality-adjusted life year (qaly) gained, given the improved breast cancer outcomes and higher costs associated with the tc regimen. A Markov model was developed to calculate the cumulative costs and qalys gained over a 10-year horizon for hypothetical cohorts of women with breast cancer treated with ac or with tc. Event rates, costs, and utilities were derived from the literature and local resources. Efficacy and adverse events were based on results reported from U.S. Oncology trial 9735. The model takes a third-party direct payer perspective and reports its results in 2008 Canadian dollars. Costs and benefits were both discounted at 3%. At a 10-year horizon, tc was associated with $3,960 incremental costs and a 0.24 qaly gain compared with ac, for a favorable cost-utility of $16,753 per qaly gained. Results were robust to model assumptions and input parameters. Relative to ac, tc is a cost-effective adjuvant chemotherapy regimen, with a cost-effectiveness ratio well below commonly applied thresholds.

Improvement in Breast Cancer Outcomes Over Time: Are Older Women Missing Out?

Women aged ≥ 75 years account for 40,000 breast cancers/yr and are the most rapidly growing demographic. Recent data demonstrated that breast cancer death rates in the US population are declining, but it is not known whether death rates have declined similarly for older and younger women. We examined the following two outcomes: the rate of breast cancer death in the general population and the risk of breast cancer death in newly diagnosed patients, and we compared change over time in these outcomes for older versus younger women. By using data from National Vital Statistics Reports that spanned from 1990 to 2007, the yearly change in the age-specific rate of breast cancer death was characterized with linear regression. With the use of the Surveillance, Epidemiology, and End Results nine-registry cohort that spanned from 1980 to 1997, the yearly change in age-specific risk of breast cancer death was characterized by using competing-risks regression adjusted for race and stage. Relative to 1990, the rate of breast cancer death in the general population decreased by 2.5%/yr for women age 20 to 49 years, 2.1%/yr for women age 50 to 64 years, 2.0%/yr for women age 65 to 74 years, and 1.1%/yr for women age ≥ 75 years. From 1980 to 1997, the adjusted risk of breast cancer death in newly diagnosed patients decreased by 3.6%/yr for women age less than 75 years versus 1.3%/yr for women age ≥ 75 years (P < .001). Over this time interval, the 10-year absolute risk of breast cancer death decreased by 15.3% for women age 50 to 64 years (from 31.9% to 16.6%) but by only 7.5% (from 24.8% to 17.4%) for women age ≥ 75 years. Breast cancer outcomes have preferentially improved in women age less than 75 years. Focused research is needed to improve outcomes in older women.

Statin treatment use in diabetic patients with breast cancer: A potential C-reactive protein mediated benefit.

173 Background: Statin treatment has not yet been evaluated in relation to breast cancer (BC) prognosis in diabetes mellitus (DM) patients. Reported decreased survival following BC in women with metabolic syndrome, led us to investigate whether specific statin therapy may lead to improved BC survival. Reported associations between elevated C-reactive protein (CRP) levels at the time of diagnosis with worse cancer prognosis, and CRP-lowering properties of statin treatment in non-cancer patients, led us to investigate whether statin use is associated with lower CRP levels at the time of BC diagnosis and with improved BC outcomes. Methods: All DM patients newly diagnosed with BC between 2003 and 2007 (Roswell Park Cancer Institute) were retrospectively reviewed (n = 225). BC pathology, outcomes, existing comorbidities and drug therapy were documented. Follow up began at BC diagnosis and ended with first confirmed recurrence and/or death, or last date of follow-up. Hazard ratios (HR) and 95% confidence intervals (CI)s representing the association between statins, BC and a defined event were computed with Cox proportional hazards model. CRP plasma levels were determined by enzyme-linked immunosorbent assay in specimens donated at the time of BC diagnosis. A total of 98 study patients, DM+BC, and their matched controls, BC only (n = 196) were analyzed. Results: After a median follow up of 30 months, patients receiving statins for cholesterol management were found to have better disease-free survival (HR 0.27, 95% CI: 0.10, 0.71, X2 = 7.31, p = 0.06), and lower overall mortality (HR 0.23, 95% CI: 0.08, 0.66, X2 = 7.80, p = 0.05) compared to patients not receiving any cholesterol management medication. CRP levels have ranged between 0.2 and 21 mg/L and clinically relevant levels ( &gt; 3mg/L) were noted in the study group. Conclusions: This study explored for the first time the association between statin therapy and BC prognosis in DM. We observed improved outcomes in statin-treated patients. While we currently analyze statin therapy in relationship with baseline CRP levels and BC prognosis, our existing findings suggest that statins have the potential to improve BC outcomes potentially through lowering overall inflammation.

Flaxseed and Breast Cancer: What Should We Tell Our Patients?

In the United States alone, there are approximately 2.6 million survivors of breast cancer. This population is highly motivated to initiate lifestyle changes in diet and exercise to improve their prognosis. Dietary lignans have been identified as potentially protective against breast cancer via estrogen-dependent and independent anticarcinogenic activity. Lignans are bioactive, non-nutrient, noncaloric phenolic plant compounds that are found in large amounts in flaxseeds and sesame seeds and in small amounts in whole grains, legumes, and certain fruits and vegetables (Table 1). For example, one half cup of whole wheat meal is estimated to provide approximately 325 g lignans, whereas one half cup of flaxseed provides approximately 275,000 g lignans. In humans, lignans are metabolized by the gut microflora into enterolignans; enterolactone is the main metabolite. Therefore, enterolactone concentrations in serum, plasma, and urine have been used as biomarkers of dietary lignans. The article by Buck et al that accompanies this editorial investigates the association of enterolactone with breast cancer outcomes. Specifically, the authors found that among 1,140 patients with breast cancer who were postmenopausal, serum enterolactone concentrations in the highest quartile were associated with an approximate 40% reduced risk of overall mortality (hazard ratio, 0.58; 95% CI, 0.34 to 0.99) and distant disease (hazard ratio, 0.62; 95% CI, 0.35 to 1.09). Although this is the first such study in survivors of breast cancer, these findings are supported by a recent meta-analysis that indicates that enterolactone biomarkers are associated with a statistically significant 28% reduced risk of incident breast cancer. The use of serum enterolactone as an exposure measure offers many advantages in comparison with assessment of dietary intake. Use of a biomarker eliminates the considerable error and bias in dietary self-reporting. In addition, this biomarker bypasses numerous problems that are associated with establishing the lignan content of foods, which can vary substantially within a food according to variety, crop season, location, and processing methods. Finally, the reliability coefficient for serum enterolactone is 0.55, which suggests that this measure provides a reasonably robust estimate of usual exposure. Given this objective evidence that a biomarker of lignan intake improves breast cancer outcomes, should we declare success and recommend that our patients with breast cancer supplement their diet with flaxseed? When considering the study by Buck et al, it is instructive (and sobering) to recall the demise of the carotenoid hypothesis regarding -carotene and chemoprevention of lung cancers. In the 1980s, there was considerable epidemiologic evidence that higher dietary intake of fruits and vegetables and blood levels of -carotene (a marker of fruit and vegetable intake) were associated with a lower risk of epithelial cancers. These epidemiologic studies were bolstered by laboratory research that identified several plausible biologic mechanisms by which -carotene could act to reduce tumor incidence. In response, two large trials were launched to test the effect of -carotene supplements on lung cancer incidence in high-risk populations (eg, smokers). Unexpectedly, both trials found that -carotene supplementation increased the incidence of lung cancers as well as cardiovascular and all-cause mortality. A subsequent review of randomized trials of antioxidant supplements, including 25 trials of -carotene, concluded that use of this supplement increased overall mortality by 7% (relative risk, 1.07; 95% CI, 1.02 to 1.11). These findings reversed the trend toward widespread use of -carotene supplements and fortification of common foods with this compound and likely resulted in many lives saved. A striking observation in both of these trials was that higher baseline serum -carotene concentrations were strongly associated with a reduced risk of lung cancer, although supplementation with -carotene in this same population increased the risk of lung cancer. A number of interpretations of these apparently paradoxical findings have been put forward. For example, it is possible that the physiological effects of relatively low blood concentrations of compounds (such as -carotene or enterolactone) obtained from a mixed diet do not predict the effect of high-dose supplementation, particularly in an Table 1. Major Food Sources of Lignans

Abstract B68: The influence of primary care on breast cancer outcomes among Medicare beneficiaries

Abstract Introduction: Primary care physicians (PCP) are integral in the early detection of cancer. Patients who are referred to a PCP, or who are assigned a PCP, are more likely to undergo most forms of cancer screening including mammograms and clinical breast examinations. PCPs may also ensure more timely diagnosis after screening abnormalities and prevent diagnostic delay. The Medicare-SEER database was used to explore the possibility of an association between primary care visits and breast cancer outcomes. With the usage of Medicare-SEER data, age, gender, and racial disparities exist. Methods: A retrospective cohort study design was used to evaluate 109,188 women that were Medicare beneficiaries and diagnosed with breast cancer in SEER registries during the years of 1994–2005. This data was used to analyze the association between primary care encounters and breast cancer outcomes. Health services related to cancer prevention and screening have been shown to occur in the ambulatory setting. The total number of ambulatory physician encounters and the percentage of such encounters with a primary care physician (PCP) were examined over a 24 month period before cancer diagnosis. Women with invasive cancers odds of late American Joint Commission on Cancer (AJCC) stage at diagnosis (stages III and IV vs. stages I and II) and survival (breast cancer specific and all cause) were examined using logistic regression and proportional hazards models respectively. Whether including non-invasive cancers (such as ductal carcinoma in situ, DCIS) would alter results and whether prior mammography was a potential mediator of associations was also explored. Results: Increasing numbers of ambulatory physician encounters were associated with improved breast cancer outcomes. In addition, subjects having between 40 and 60 percent of all encounters with PCPs were most likely to have had prior mammograms, least likely diagnosed at late stage, and to have lower breast cancer and all-cause mortality. Prior mammography mediated these associations in part but not completely. Results were unchanged when women with DCIS were included in the analysis. The average age of women involved in this study was 77 years old and 86 percent of the sample were non-minority. Conclusions: Although there is the existence of age, racial, and gender disparities because of the use of the Medicare-SEER data, using this information helps to identify better care tactics for aging women. Medicare beneficiaries with breast cancer had better outcomes if they had greater use of ambulatory care and care that was balanced between primary and specialty providers. These findings suggest adequate primary medical care may be an important factor in achieving optimal breast cancer outcomes. Citation Information: Cancer Epidemiol Biomarkers Prev 2011;20(10 Suppl):B68.

Vitamin D and breast cancer: interpreting current evidence.

Preclinical investigations and selected clinical observational studies support an association between higher vitamin D intake and 25-hydroxyvitamin D levels with lower breast cancer risk. However, the recently updated report from the Institute of Medicine concluded that, for cancer and vitamin D, the evidence was 'inconsistent and insufficient to inform nutritional requirements'. Against this background, reports examining vitamin D intake, 25-hydroxyvitamin D levels and breast cancer incidence and outcome were reviewed. Current evidence supports the pursuit of several research questions but not routine 25-hydroxyvitamin D monitoring and vitamin D supplementation to reduce breast cancer incidence or improve breast cancer outcome.

A phase III randomized trial of metformin versus placebo on recurrence and survival in early-stage breast cancer (BC) (NCIC Clinical Trials Group MA.32).

TPS103 Background: There has been a recent convergence of epidemiologic, clinical and preclinical evidence suggesting metformin (a biguanide used to treat type 2 diabetes) may lower BC risk and improve BC outcomes. This evidence raises the intriguing possibility that metformin may act (i) indirectly by lowering circulating insulin levels (secondary to reduced hepatic gluconeogenesis) leading to reduced insulin/IGF-I receptor mediated PI3K signaling in BC cells or (ii) directly on tumor cells, largely via an AMPK mediated mechanism, leading to mTOR inhibition. Methods: NCIC CTG led, CTEP sponsored, randomized, phase III trial of metformin 850 mg po bid vs placebo bid for 5 years. Eligibility criteria: pTIcNO (and > one: grade 3, ER/PR-, HER2Neu+, lymphovascular invasion, Oncotype DX recurrence score>25, Ki67>14%) or pT2/T3 N0 or pT1-3 N1-3. Standard adjuvant therapy (chemotherapy, hormone, biologics) Adequate organ function and PS Age 18-75 Endpoints: Primary: invasive disease free survival (IDFS). Secondary: overall survival, distant disease free survival, BC free survival, adverse events, new diabetes, cardiovascular hospitalizations, BMI, insulin resistance syndrome attributes (ATP III criteria), Quality of Life, diet and physical activity. Correlative studies: Embedded correlative research examines prognostic factors and targets and predictors of metformin benefit.Variables include: Fasting Insulin, glucose, Homeostasis Model Assessment (HOMA) (baseline, 6 months, end of treatment): genomic/gene expression analysis of blood and tumour, tumor insulin receptor (IR), IGF-IR, tumor molecular markers of target pathways (LKBI, PI3K (STMN1), PKB/Akt (P-PKB/Akt,) mTOR (P-4E-BP1) and IRS-1 (P-IRS-1); Fatigue sub-study with biological correlates (NSABP led). Statistical design: Planned accrual is 3,582 subjects over 3 years with 3 more years follow-up. Target hazard ratio is 0.76 (5 year IDFS of 88.4% vs 85%, power 0.80, 2-tail type 1 error of 0.05). Two interim analyses are planned. Conduct to Date: Study activation: June 2010. Enrollment: 145 subjects. In Nov 2010 a DSMC review supported trial continuation.

Multivitamin use and breast cancer outcomes in women with early-stage breast cancer: the Life After Cancer Epidemiology study

Little is known about the relation of multivitamin use to breast cancer outcomes. 2,236 women diagnosed from 1997 to 2000 with early-stage breast cancer (Stage I ≥ 1 cm, II, or IIIA) were enrolled about 2 years post-diagnosis, primarily from the Kaiser Permanente Northern California Cancer Registry (83%). Multivitamin use pre-diagnosis and post-diagnosis was assessed via mailed questionnaire. Outcomes were ascertained yearly by self-report and verified by medical record review. Delayed-entry Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI), adjusting for sociodemographic, tumor, and lifestyle factors. Overall, 54 and 72% of the cohort reported using multivitamins pre- and post-diagnosis, respectively. A total of 380 recurrences, 212 breast cancer deaths, and 396 total deaths were confirmed. Compared to never use, multivitamin use after diagnosis was not associated with any outcome (recurrence HR = 0.92; 95% CI: 0.71, 1.20; total mortality HR = 0.92; 95% CI: 0.71, 1.19). Compared to never use, persistent use of multivitamins from pre- to post-diagnosis was associated with a non-significant decreased risk of recurrence (HR = 0.76; 95% CI: 0.54, 1.06) and total mortality (HR = 0.79; 95% CI: 0.56, 1.12). The protective associations were limited to women who had been treated by radiation only (P for trend = 0.048 and 0.083 for recurrence and total mortality, respectively) and both radiation and chemotherapy (P for trend = 0.015 and 0.095 for recurrence and total mortality, respectively). In stratified analyses, women who consistently used multivitamins before and after diagnosis and ate more fruits/vegetables (P for trend = 0.008) and were more physically active (P for trend = 0.034) had better overall survival. Multivitamin use along with practice of other health-promoting behaviors may be beneficial in improving breast cancer outcomes in select groups of survivors.

Abstract 3339: A role for CXCR4 signalling in the regulation of normal and malignant breast stem cell activity

Abstract CXCR4 is a chemokine receptor specific for stromal derived factor-1 (SDF-1) and is highly expressed in breast cancer cell lines and primary breast cancer samples. Elevated expression of CXCR4 in breast cancer is linked to poor prognosis. CXCR4 signalling has been reported to be important in breast cancer migration and metastasis formation but its role is yet to be fully elucidated. Our previously published data have shown that a stem cell-enriched population of cells can be obtained by harvesting anoikis resistant cells which survive in early mammosphere culture (Harrison et al., Cancer Res; 2010, 70 (2), 709-18). We collected anoikis resistant cells 12 hours after plating out into the mammosphere culture to obtain stem cell-enriched populations from 2 immortalised (MCF10A, 226L) and 3 malignant breast cell lines (MCF7, T47D, SKBR3). Anoikis resistant cells harvested at 12 hours had a significantly higher mammosphere colony-forming efficiency than their unsorted monolayer cells (2-4 fold increase, p &amp;lt; 0.05) suggesting stem cell enrichment. In limiting dilution transplantation assays into athymic Nude mice, MCF7 and T47D anoikis resistant cells had a 12 and 16-fold enrichment for tumor formation respectively, compared to the unsorted monolayer cells. Using an Agilent custom microarray, we found that CXCR4 expression was consistently upregulated in these stem cell-enriched populations compared with monolayer cells (2.0 and 6.8 fold; normal and malignant cell line averages respectively). We further investigated the function of CXCR4 in vitro using the mammosphere assay to assess stem cell activity. AMD3100 (Sigma), a CXCR4 antagonist and lentiviral CXCR4 shRNA were used to inhibit and recombinant soluble SDF-1 to stimulate the pathway. In the normal breast cell line MCF10a, SDF-1 addition significantly reduced mammosphere formation in a dose dependent manner (200ng/ml; 25% decrease, t = 4.320, p &amp;lt; 0.001) and this could be rescued by the addition of AMD3100. Inhibiting the CXCR4 pathway stimulated primary mammosphere formation in the breast cancer cell lines T47D and MCF7 using either 20uM AMD3100 (T47D; 34% increase, t = 3.017, p &amp;lt; 0.01) or lentiviral CXCR4 shRNA (T47D; 97% increase, t = 6.288 p &amp;lt; 0.005, MCF7; 48% increase, t = 3.026, p &amp;lt; 0.05). In vivo data has already shown the importance of the CXCR4/SDF-1 pathway in metastasis formation in breast cancer. Our data takes suggests that CXCR4 signalling, as well as its role in migration and homing, is important in maintaining stem cell activity. Thus CXCR4 targeted therapy, alongside current standards of care, may improve breast cancer outcomes. Funding: Biotechnology and Biological Sciences Research Council (BBSRC), Vertex Pharmaceuticals (Europe) Limited, Breast Cancer Campaign and Cancer Research UK (CRUK). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3339. doi:10.1158/1538-7445.AM2011-3339

Abstract P5-11-15: Modeling for Response Predictive Factors in Adjuvant Endocrine Therapy: Impact on Preferential Benefits of Tamoxifen and Aromatase Inhibitors

Abstract Background: The Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) observed significant improvements in breast cancer (BC) outcomes following adjuvant tamoxifen (TAM) and/or aromatase inhibitor (AI) therapy relative to natural history (NH) without endocrine therapy. In unselected populations, upfront AI for 5-years appears to be associated with improved disease-free survival (DFS) relative to 5-years of TAM alone. BC outcomes for TAM and AI in the EBCTCG meta-analyses, however, may reflect composite outcomes for heterogeneous sub populations of patients with varying responsiveness to TAM and AI's. A number of studies suggest that response to endocrine therapy (excellent vs poor) with TAM (TAM-excellent vs TAM-poor responders) and AI (AI-excellent vs AI-poor responders) may be related to TAM metabolizer status (non impaired vs impaired) and body mass index (normal vs high), respectively. This study examines the potential impact of these predictive factors on BC outcomes following TAM or AI therapy to determine the adjuvant endocrine monotherapy associated with improved BC outcomes for postmenopausal women with breast cancer. Methods: A generic state-transition model was developed to compute BC outcomes over a 10-year horizon in hypothetical cohorts of postmenopausal women receiving 5-years of adjuvant TAM (TAM cohort) or AI (AI cohort) or no endocrine therapy (NH cohort). We estimated DFS rates and cumulative life-years associated with NH, TAM and AI in unselected cohorts as well as sub-cohorts with varying responsiveness to TAM or AI. BC outcomes in the unselected cohorts were derived from the EBCTCG meta-analyses. BC outcomes in the sub-cohorts of TAM-excellent vs TAM-poor responders and AI-excellentvs AI-poor responders were based on varying combinations of responder proportions (excellent vs poor) and odd ratios (ORs) of BC outcomes in excellent vs poor responders that are plausible within the composite BC outcomes observed in the unselected TAM and AI cohorts. The model assumes that BC outcomes in poor responders could not be worse than BC outcomes for NH. Sensitivity analyses were conducted, and the impact of varying 10-year baseline recurrence risk without endocrine therapy was examined to reflect the natural spectrum of breast cancer disease encountered. Results: Two-way sensitivity analyses are provided for TAM and AI predictive factors to determine which adjuvant endocrine therapy (TAM vs AI) may be associated with improved BC outcomes based on the prevalence of the response predictive factors and their relative impact on BC outcomes. The plausible combinations of prevalence and OR for TAM excellent responders in the TAM cohort as well as AI poor responders in the AI cohort that predict improved BC outcomes with TAM relative to AI monotherapy are provided. Sensitivity analyses will be presented. Conclusions: Adjuvant endocrine monotherapy with TAM may be associated with improved BC outcomes in TAM-excellent responders compared to an unselected AI cohort or in an unselected TAM cohort compared to AI-poor responders. The choice of optimal adjuvant endocrine therapy may depend upon the prevalence of treatment predictive factors and their relative impact on BC outcomes. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P5-11-15.