Improve Breast Cancer Outcomes Research Articles

Evaluation of Cytotoxicity Effects of Combination Nano-Curcumin and Berberine in Breast Cancer Cell Line

Background: Berberine and Nano-curcumin are two herbal medicines with strong anti-cancer effects on tumor cells, but low toxicity on normal cells, when used alone. Breast cancer is known as the most common cancer in women and second deadly one. In this study, we evaluated the cytotoxicity effects of combination Berberine and Nano-curcumin in breast cancer cell line to see whether they have further synergism cytotoxicity on MCF-7 breast cancer cell line. Methods: The cytotoxicity effects of Berberine and Nano-curcumin alone and in combination, were evaluated in MCF-7 cell lines using MTT cytotoxicity test. Statistical analysis is done through one-way ANOVA and Tukey multiple range tests. Results: Analyzing results of this study showed that cytotoxicity of Nano-curcumin was higher than Berberine in a dose-dependent manner. The IC50 of combination Berberine and Nano-curcumin was lower and showed higher cytotoxicity in MCF-7 cells compared with the time we use each of these drugs alone. Conclusion: In this study co-treatment of Berberine and Nano-curcumin significantly inhibited the growth of MCF-7 breast cancer cell line and resulted in synergism cytotoxicity effects. These results indicated on their potency to further combination of these two drugs with other agents and common chemotherapies to improve breast cancer outcomes.

CA15-3/MUC1 in CCTG MA-32 (NCT01101438): A phase III RCT of the effect of metformin vs. placebo on invasive disease free and overall survival in early stage breast cancer (BC).

557Background: The diabetes drug metformin may improve BC outcomes through enhanced obesity-related physiology or direct anti-tumor effects. We studied the effect of metformin on CA15-3 (the solubl...

Vav1 downmodulates Akt in different breast cancer subtypes: a new promising chance to improve breast cancer outcome.

Targeting different members of the Akt pathways is a promising therapeutic chance in solid tumors including breast cancer. The variable expression levels of Akt isoforms with opposite effects on tumor growth and metastasis, however, make it difficult to select the inhibitors to be used for specific breast tumor subtypes. Using in vitro and in vivo models, we demonstrated here that Vav1, ectopically expressed in invasive breast tumors derived cells, downmodulates Akt acting at expression and/or activation levels depending on tumor subtype. The decreased p‐Akt1 (Ser473) levels are a common effect of Vav1 upmodulation, suggesting that, in breast tumor‐derived cells and independently of their phenotype, Vav1 interferes with signaling pathways ended to specifically recruit Akt1. Only in ER‐negative cell lines, the silencing of Vav1 induced the expression but not the activation of Akt2. A retrospective analysis of early invasive breast tumors allowed to establish the prognostic significance of the p‐Akt/Vav1 relationship. In particular, low Vav1 levels negatively influence the follow‐up of patients with low p‐Akt in their primary tumors and subjected to adjuvant chemotherapy. As the use of specific or pan Akt inhibitors may not be sufficient or may even be detrimental, increasing the levels of Vav1 could be a new approach to improve breast cancer outcomes. This might be particularly relevant for tumors with a triple‐negative phenotype, for which target‐based therapies are not currently available.

Association between lifestyle factors and completion of neoadjuvant chemotherapy for breast cancer.

91 Background: Completion of chemotherapy has been associated with improved breast cancer outcomes. We evaluated whether lifestyle factors, such as physical activity and diet, may contribute to neoadjuvant chemotherapy completion in breast cancer. Methods: We conducted a retrospective study of women treated with neoadjuvant chemotherapy for early stage (I-III) breast cancer. A medical record review recorded BMI, blood pressure, diabetes and hypertension medication, and chemotherapy completion. Completers received full doses of all prescribed chemotherapy, with or without cycle delays. We conducted a telephone survey about exercise and fruit/vegetable intake (>5 servings/day) during the year prior to cancer diagnosis. Exercisers completed at least 7.5 MET-hours/week (i.e., 150 minutes of moderate-intensity exercise). Multi-variable adjusted analyses were conducted to identify factors associated with chemotherapy completion. Results: Sixty-seven patients (45%) answered the survey. Chemotherapy completers were on average 11 years younger than non-completers (p<0.001), more likely premenopausal (p=0.02), and less likely on diabetes medication (p=0.05). Exercisers were more likely to complete chemotherapy than non-exercisers (p=0.002). After controlling for age, diastolic blood pressure, menopausal status, and diabetes medication, the adjusted odds ratio for exercise on chemotherapy completion was 4.1 (95% CI 1.1 – 15.3) (p=0.04). Conclusions: Women who reported exercising at recommended levels in the year prior to breast cancer diagnosis were more likely to complete neoadjuvant chemotherapy regimens, suggesting a potentially important role for lifestyle factors in chemotherapy completion. Factors associated with chemotherapy completion [Table: see text]

Abstract P3-12-04: Efficacy of extended adjuvant aromatase inhibitors in subgroups of women with early breast cancer

Abstract Background: Randomized trials (RCTs) have reported improvements in breast cancer outcomes from extending treatment with aromatase inhibitors (AIs) beyond the initial 5 years after diagnosis. It is uncertain whether this effect is consistent in different subgroups. Methods: We identified RCTs that compared extended AIs to placebo or no treatment using a systematic search of MEDLINE. The search was supplemented by a review of abstracts from the American Society of Clinical Oncology and San Antonio Breast Cancer Symposium meetings between 2013 and 2016. Hazard ratios (HRs) and 95% confidence intervals (CI) for disease-free survival (DFS) were extracted or estimated from forest plots and included in a meta-analysis using generic inverse variance and random effects modelling. Pre-specified subgroups included age (<60 ± 5 years vs. ≥60 ± 5 years), tumor size (≤2 cm vs. >2 cm), nodal status (positive vs. negative), hormone receptor status (estrogen [ER] and progesterone receptor [PR] positive vs. ER or PR positive) and administration of adjuvant chemotherapy (yes vs. no). Results: Seven trials comprising 16,349 patients were analyzed. Studies designs and prior endocrine therapy are shown in Table 1 Table 1: Characteristics of included studies.TrialTreatment ArmsSample sizePrior endocrine treatmentABCSG 6aAnastrozole 3 years vs. none387/ 469Tamoxifen± aminoglutethimide: 100%, 5 yearsMA 17Letrozole 5 years vs. placebo2572/ 2577Tamoxifen: 100%, ∼5 yearsNSABP B-33Exemestane 5 years vs. placebo783/ 779Tamoxifen: 100%, ∼5 yearsDutch DATAAnastrozole 6 years vs,. anastrozole 3 years827/ 833Tamoxifen: 100%, 2-3 yearsIDEALLetrozole 5 years vs. letrozole 2.5 years903/ 898Any endocrine treatment (tamoxifen/AIs/sequence of tamoxifen+ AIs): 100%, 5 yearsMA.17RLetrozole 5 years vs. placebo959/ 959AIs: 100%, ∼5 years Prior tamoxifen: 79.3%NSABP B-42Letrozole 5 years vs. placebo1959/ 1964Any endocrine treatment (AIs/sequence of tamoxifen+ AIs): 100%, 5 years . The pooled effect of prolonged treatment with AIs in different subgroups is shown in the Table 2. Table 2: Intra-subgroup comparison of longer AIs treatment effect by subgroupsSubgroup ASubgroup BHR (95% CI) Subgroup AHR (95% CI) Subgroup BP for differenceAge <60 ± 5Age ≥60 ± 50.83 (0.70-0.99)0.85 (0.74-0.97)0.64T >2 cmT ≤2 cm0.77 (0.55-1.06)0.88 (0.68-1.13)0.44N positiveN negative0.72 (0.63-0.83)0.83 (0.64-1.08)0.22ER and PR positiveER or PR positive0.68 (0.44-1.04)1.03 (0.53-2.02)0.27Adjuvant chemotherapyNone0.71 (0.59-0.86)0.80 (0.65-0.98)0.51 Overall, the effect of prolonged AIs was similar in all subgroups. However, non-significantly greater effect sizes were seen in patient with larger tumors, nodal involvement, presence of both ER and PR expression and those treated with adjuvant chemotherapy. Conclusions: Extended treatment with adjuvant AIs is associated with similar relative improvements in DFS in all subgroups analyzed. The greater effect size seen in node positive and large tumor subgroups and the higher baseline risk of recurrence will likely translate to a higher absolute benefit from extended AIs in these groups. Citation Format: Goldvaser H, Algorashi I, Ribnikar D, Majeed H, Ocana A, Seruga B, Templeton AJ, Amir E. Efficacy of extended adjuvant aromatase inhibitors in subgroups of women with early breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-12-04.

Abstract P6-12-03: Utilization of bioimpedance spectroscopy in the prevention of chronic breast cancer related lymphedema

Abstract Background: With improved breast cancer outcomes, an increasing focus on sequelae of treatment as part of survivorship has emerged. Breast cancer related lymphedema (BCRL) represents one such sequelae. Increasing data and recent NCCN guidelines support the use of prospective BCRL surveillance to allow for early detection and intervention as a method to reduce chronic, irreversible BCRL. Therefore, this study was performed to evaluate the impact early detection and treatment of BCRL in breast cancer patients undergoing prospective surveillance with bioimpedance spectroscopy (BIS). Methods: From 8/2010 through 12/2016, 206 patients were evaluated with BIS as part of a prospective surveillance program.The protocol included pre-operative assessment with BIS as well as post-operative assessments with BIS at regular intervals. Patients with L-Dex readings increasing by more than 10 from baseline were considered to have subclinical BCRL and treated with a compression sleeve for 4 weeks. For the purpose of this analysis, high-risk was defined as receipt of ALND, regional nodal irradiation, or taxane chemotherapy. Chronic BCRL was defined as the need for complex decongestive physiotherapy. Results: A total of 206 patients were analyzed, with a mean age of 61 years old and a median follow up of 25.9 months. Overall, 17% of patients had least one high-risk feature, 8% had two factors, and 7% had all three factors. A total of 21 patients (9.8%) were diagnosed with subclinical BCRL. Increased rates of subclinical BCRL were seen in patients undergoing ALND (23% vs. 7%, p=0.01) with ALND and receipt of RNI associated with development of subclinical BCRL. At last follow-up, no patients had persistent, chronic BCRL following early, conservative intervention measures. Conclusions: The results of this study support prospective surveillance and early treatment utilizing BIS. Intervention triggered by subclinical BCRL detection with an elevated L-Dex score was associated with a very low rate of chronic BCRL. Citation Format: Kaufman D, Shah C, Vicini F. Utilization of bioimpedance spectroscopy in the prevention of chronic breast cancer related lymphedema [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P6-12-03.

Abstract P2-10-09: Clinical correlations of serum vitamin D in patients undergoing neoadjuvant systemic therapy and survival outcomes for operable breast cancer

Abstract Introduction: There has been increasing interest in the potential benefit of vitamin D to improve breast cancer outcomes. Pre-clinical studies suggest vitamin D enhances chemotherapy-induced cell death. We previously reported (Thomas A SABCS 2016) that low serum vitamin D levels were associated with not attaining a pathologic complete response (pCR) following breast cancer neoadjuvant chemotherapy (NAC). We report here the impact of vitamin D on survival parameters in an expanded cohort of patients. Methods: Patients from two Iowa registries who had serum vitamin D level measured before or during NAC were included. French patients enrolled in a previous study of the impact of NAC on vitamin D and bone metabolism were also eligible for this study. Vitamin D deficiency was defined as < 20 ng/mL. pCR was defined as no residual invasive disease in breast and lymph nodes. Survival was defined from the date of diagnosis to the date of relapse (PFS) or date of death (OS). Results: The study included 327 women. Median age was 51 years. Patients presented with HER2+, HR+/HER2- and triple negative (TN) tumors in 28.5%, 43.9% and 27.6% of the cases respectively. In this expanded cohort, vitamin D deficiency remained associated with the odds of not attaining pCR (OR 1.64; 95%CI: 1.02-2.66, p=0.04). Median follow-up was 5.33 years (range 0.5 to 9.8 years). Of these patients, there were 54 relapse and 52 deaths. In multivariate analysis, stage III disease, TN phenotype and the inability to achieve pCR were independently associated with a worse survival (Table 1). Table 1 PFS (Hazard Ratio, 95%CI)pOS (Hazard Ratio, 95%CI)pStage I - II1 1 III2.78 (1.56 – 4.95)0.0012.82 (1.57 - 5.05)0.001Tumor phenotype HR+/HER2-1 1 HER2+3.00 (1.28 – 7.06)0.0121.78 (0.76 – 4.08)0.174TN7.37 (3.26 – 16.69)< 0.0016.50 (3.07 – 13.76)< 0.001NAC response Non-pCR1 1 pCR0.19 (0.08 – 0.45)< 0.0010.22 (0.09 – 0.55)< 0.001Vitamin D < 20 ng/mL1 1 ≥ 20 ng/mL1.01 (0.57 – 1.78)0.971.03 (0.58 – 1.84)0.92 Vitamin D deficiency was not significantly associated with survival parameters in the general population; however a trend was seen in the TN population regarding the correlation with PFS (90 patients, 5-year PFS 60.4% vs. 72.3%, p=0.18). Conclusion: Vitamin D deficiency is associated with the inability to reach pCR in breast cancer undergoing NAC. A trend for worse survival was seen in the TN subgroup. The strong association between vitamin D deficiency and the inability to reach pCR warrant further evaluation in the TN subgroup. Prospective interventional studies are needed to elucidate if maintaining vitamin D levels during NAC, a highly modifiable variable, may be utilized to improve cancer outcomes, particularly in TN breast cancers. Citation Format: Viala M, Chiba A, Thezenas S, Delmond L, Lamy P-J, Mott SL, Schroeder MC, Thomas A, Jacot W. Clinical correlations of serum vitamin D in patients undergoing neoadjuvant systemic therapy and survival outcomes for operable breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P2-10-09.

Abstract P3-05-10: Impact of neoadjuvant systemic therapy on sTIL in breast cancer

Abstract Background Multiple studies have shown a correlation between the presence of stromal tumor infiltrating lymphocytes (sTIL) and breast cancer outcomes. Higher sTIL are associated with higher rates of pCR, DFS, and OS. These findings have been primarily observed in TNBC and in HER2+ rather than in HR+, which overall has lower sTIL. Despite this growing body of prognostic evidence, there is little data comparing sTIL at diagnosis to sTIL after neoadjuvant systemic treatment. Understanding the impact of treatment on sTIL may lead to novel techniques to increase host immune response in the tumor microenvironment. The objective of this study was to correlate sTIL in paired samples before and after standard neoadjuvant systemic therapy, and then to identify the direction and magnitude of change in sTIL along with any associated features. Methods Institutional pathology database was queried for invasive breast carcinoma with “yp” in staging designation. From July 2013 to September 2016, there were 122 cases identified. When cases were excluded due to unavailable biopsy slides, there were 61 cases remaining. Needle biopsy and finalsurgical specimens were evaluated using International TIL Working Group 2014 guidelines and reported as a whole number percentage. In specimens with pCR, where there are no applicable guidelines, sTIL were determined by estimating the lymphoplasmacytic infiltrate in the tumor bed. Additional information gathered from the electronic medical record included patient age, clinical TNM stage, breast cancer subtype (HR+, HER2+, TNBC), neoadjuvant systemic therapy regimen (anthracycline, nonanthracycline, Trastuzumab-containing, endocrine), and response to treatment (pCR, residual invasive disease). A negative binomial generalized linear mixed model was used for analysis. Results Overall the sTIL declined from biopsy to surgery by about 36% (β = -0.448, S.E. = 0.223, pvalue = 0.045). However, there were 19/61 patients who had an increase in sTIL with neoadjuvant systemic therapy. For this group, the mean biopsy sTIL was 9.7% while the mean surgery sTIL was 28.7%, significantly higher than the mean biopsy (p-value < 0.001). This group was not associated with age, stage, breast cancer subtype, or regimen. We examined our results in the 37/61 patients who did not achieve pCR. In all breast cancer subtypes, this group had an increase from biopsy to surgery in sTIL, with no significant difference between treatment regimens. Increasing age was significantly associated with lower sTIL in both biopsy and surgery specimens (p-value = 0.033). For every decade increase in age, sTIL decreased by about 37%. Discussion Overall the sTIL declined from biopsy to surgery. In the group of patients with an increase in sTIL, there was no significant correlation with systemic treatment regimen. There was a nonsignificant trend towards increasing sTIL and residual disease at surgery. We hypothesize that the host immune response declined after tumor eradication in pCR and remained active when residual disease was present. Increasing age was significantly associated with lower sTIL. Further work to identify additional factors associated with sTIL is needed to guide efforts to alter the immune response for improved breast cancer outcomes. Citation Format: Armaghani A, Asirvatham R, Mramba L, Daily K. Impact of neoadjuvant systemic therapy on sTIL in breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-05-10.

Influence of control group therapy on the benefit from dose-dense chemotherapy in early breast cancer: a systemic review and meta-analysis.

Results from clinical trials of adjuvant dose-dense chemotherapy in patients with breast cancer are inconsistent. A systematic search of MEDLINE identified studies comparing the efficacy of dose-dense adjuvant chemotherapy to a standard treatment. The primary analysis included studies that used identical regimens in the experimental and control groups, but varied only dose density. A secondary analysis included studies that used either different drugs or doses in the experimental and the control groups. Hazard ratios (HRs) and 95% confidence intervals were computed for disease-free survival (DFS) and overall survival (OS) and pooled in a meta-analysis. Subgroup analyses and meta-regression explored drug schedules utilized in control groups and the influence of clinicopathologic variables on benefit from dose-dense therapy. The primary analysis included 5 studies comprising 9819 patients while the secondary analysis included 6 studies comprising 9679 patients. Dose-dense treatment significantly improved DFS (HR 0.85, p<0.001) and OS (HR 0.86, p=0.008) in the primary analysis. Similar results were observed in the secondary analysis. Dose-dense schedule was important primarily in studies utilizing paclitaxel every 3weeks as the control group (interaction p=0.04 for DFS interaction p=0.001 for OS). A significantly greater relative magnitude of benefit was observed in pre-menopausal women and those with nodal involvement, but there was no influence of hormone receptor status on results. Adjuvant dose-dense regimens improve breast cancer outcomes. It remains uncertain whether the observed benefit reflects the impact of dose density or the inferiority of paclitaxel every 3weeksas a control group.

Efficacy of buparlisib in treating breast cancer

ABSTRACTIntroduction: Breast cancer is the most frequent cancer in women. Despite a decline in breast cancer mortality, prognosis of advanced breast cancer remains poor. In a desperate need to improve breast cancer outcomes, newer agents that target molecular pathways are being tested. Deregulation of the phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) is frequently found in breast cancer. This can lead to resistance of endocrine therapy and anti-HER2 therapies. Targeting this pathway may restore sensitivity to these compounds. Buparlisib (BKM-120) is an orally active pan-PI3K inhibitor evaluated in different tumor types.Areas covered: Buparlisib is one of the most investigated PI3K inhibitors. Preclinical and clinical studies of buparlisib in breast cancer are analyzed and discussed. This article reviews the status of buparlisib, completed and ongoing trials, and its safety.Expert opinion: PI3K inhibitors show promising results in breast cancer. However, we raise a number of issues including the identification of biomarkers to predict treatment response and strategies to counteract resistance. Moreover, its toxicity profile could limit its extensive use.

Influence of socioeconomic factors and distance to radiotherapy on breast-conserving surgery rates for early breast cancer in regional Australia; implications of change.

Breast conserving surgery rates are affected by many factors including distance to radiotherapy and tumor-related features. Numerous studies have found women who must travel further for radiotherapy are more likely to choose mastectomy and avoid radiotherapy. We examined relationships between socioeconomic group, distance to radiotherapy services and mastectomy rates across a range of rural and metropolitan settings. We used a dataset extracted from the Evaluation of Cancer Outcomes Barwon South Western Registry, which captured data on new breast cancer diagnoses in the southwest region of Victoria, Australia. Using logistic regression, we modeled treatment choice of women with early breast cancer (mastectomy vs breast conserving surgery) using explanatory variables that included distance to radiotherapy, and area-level socioeconomic data from the Australian Bureau of Statistics, while controlling for clinical factors. Mastectomy was associated with tumor size, nodal burden and younger age at surgery. Distance to a radiotherapy center was also strongly associated with increased rates of mastectomy for women who traveled 100-200km for radiotherapy (odds ratio=1.663; P=0.03) compared to the reference group who were within 100km of radiotherapy. No socioeconomic differences were seen between the two groups. A strong association between distance to radiotherapy and the type of surgery for early breast cancer was found. Improving access to radiotherapy therefore has the potential to improve breast cancer outcomes for women in regional Australia.

Extended adjuvant intermittent letrozole versus continuous letrozole in postmenopausal women with breast cancer (SOLE): a multicentre, open-label, randomised, phase 3 trial

In animal models of breast cancer, resistance to continuous use of letrozole can be reversed by withdrawal and reintroduction of letrozole. We therefore hypothesised that extended intermittent use of adjuvant letrozole would improve breast cancer outcome compared with continuous use of letrozole in postmenopausal women. We did the multicentre, open-label, randomised, parallel, phase 3 SOLE trial in 240 centres (academic, primary, secondary, and tertiary care centres) in 22 countries. We enrolled postmenopausal women of any age with hormone receptor-positive, lymph node-positive, and operable breast cancer for which they had undergone local treatment (surgery with or without radiotherapy) and had completed 4-6 years of adjuvant endocrine therapy. They had to be clinically free of breast cancer at enrolment and without evidence of recurrent disease at any time before randomisation. We randomly assigned women (1:1) to treatment groups of either continuous use of letrozole (2·5 mg/day orally for 5 years) or intermittent use of letrozole (2·5 mg/day orally for 9 months followed by a 3-month break in years 1-4 and then 2·5 mg/day during all 12 months of year 5). Randomisation was done by principal investigators or designee at respective centres through the internet-based system of the International Breast Cancer Study Group, was stratified by type of previous endocrine therapy (aromatase inhibitors only vs selective oestrogen receptor modulators only vs both therapies), and used permuted block sizes of four and institutional balancing. No one was masked to treatment assignment. The primary endpoint was disease-free survival, analysed by the intention-to-treat principle using a stratified log-rank test. All patients in the intention-to-treat population who initiated protocol treatment during their period of trial participation were included in the safety analyses. This study is registered with ClinicalTrials.gov, number NCT00553410, and EudraCT, number 2007-001370-88; and long-term follow-up of patients is ongoing. Between Dec 5, 2007, and Oct 8, 2012, 4884 women were enrolled and randomised after exclusion of patients at a non-adherent centre, found to have inadequate documentation of informed consent, immediately withdrew consent, or randomly assigned to intervention groups in error. 4851 women comprised the intention-to-treat population that compared extended intermittent letrozole use (n=2425) with continuous letrozole use (n=2426). After a median follow-up of 60 months (IQR 53-72), disease-free survival was 85·8% (95% CI 84·2-87·2) in the intermittent letrozole group compared with 87·5% (86·0-88·8) in the continuous letrozole group (hazard ratio 1·08, 95% CI 0·93-1·26; p=0·31). Adverse events were reported as expected and were similar between the two groups. The most common grade 3-5 adverse events were hypertension (584 [24%] of 2417 in the intermittent letrozole group vs 517 [21%] of 2411 in the continuous letrozole group) and arthralgia (136 [6%] vs 151 [6%]). 54 patients (24 [1%] in the intermittent letrozole group and 30 [1%] in the continuous letrozole group) had grade 3-5 CNS cerebrovascular ischaemia, 16 (nine [<1%] vs seven [<1%]) had grade 3-5 CNS haemorrhage, and 40 (19 [1%] vs 21 [1%]) had grade 3-5 cardiac ischaemia. In total, 23 (<1%) of 4851 patients died while on trial treatment (13 [<1%] of 2417 patients in the intermittent letrozole group vs ten [<1%] of 2411 in the continuous letrozole group). In postmenopausal women with hormone receptor-positive breast cancer, extended use of intermittent letrozole did not improve disease-free survival compared with continuous use of letrozole. An alternative schedule of extended adjuvant endocrine therapy with letrozole, including intermittent administration, might be feasible and the results of the SOLE trial support the safety of temporary treatment breaks in selected patients who might require them. Novartis and the International Breast Cancer Study Group.

Toxicity of Extended Adjuvant Therapy With Aromatase Inhibitors in Early Breast Cancer: A Systematic Review and Meta-analysis.

A number of randomized controlled trials (RCTs) have reported improvement in breast cancer outcomes from extending treatment with aromatase inhibitors (AIs) beyond the initial five years after diagnosis. However, the toxicity profile of extended AIs is uncertain. We identified RCTs that compared extended AIs to placebo or no treatment using MEDLINE and a review of abstracts from key conferences between 2013 and 2016. Odds ratios (ORs), 95% confidence intervals (CIs), absolute risks, and the number needed to harm (NNH) were computed for prespecified safety and tolerability outcomes including cardiovascular events, bone fractures, second cancers (excluding new breast cancer), treatment discontinuation for adverse events, and death without recurrence. All statistical tests were two-sided. Seven trials comprising 16 349 patients met the inclusion criteria. Longer treatment with AIs was associated with increased odds of cardiovascular events (OR = 1.18, 95% CI = 1.00 to 1.40, P = .05, NNH = 122), bone fractures (OR = 1.34, 95% CI = 1.16 to 1.55, P < .001, NNH = 72), and treatment discontinuation for adverse events (OR = 1.45, 95% CI = 1.25 to 1.68, P < .001, NNH = 21). Longer treatment with AIs did not influence the odds of either second malignancy (OR = 0.93, 95% CI = 0.73 to 1.18, P = .56) or deaths without breast cancer recurrence (OR = 1.11, 95% CI = 0.90 to 1.36, P = .34). Extended treatment with AIs is associated with an increased risk of cardiovascular events and bone fractures. There is no statistically significant increase in deaths without breast cancer recurrence among patients receiving longer treatment with AIs. These data should be taken into account when considering extended adjuvant AIs.

The Breast and Cervical Cancer Early Detection Program, Medicaid, and breast cancer outcomes among Ohio's underserved women.

As an organized screening program, the national Breast and Cervical Cancer Early Detection Program (BCCEDP) was launched in the early 1990s to improve breast cancer outcomes among underserved women. To analyze the impact of the BCCEDP on breast cancer outcomes in Ohio, this study compared cancer stages and mortality across BCCEDP participants, Medicaid beneficiaries, and "all others." This study linked data across the Ohio Cancer Incidence Surveillance System, Medicaid, the BCCEDP database, death certificates, and the US Census and identified 26,426 women aged 40 to 64 years who had been diagnosed with incident invasive breast cancer during the years 2002-2008 (deaths through 2010). The study groups were as follows: BCCEDP participants (1-time or repeat users), Medicaid beneficiaries (women enrolled in Medicaid before their cancer diagnosis [Medicaid/prediagnosis] or around the time of their cancer diagnosis [Medicaid/peridiagnosis]), and all others (women identified as neither BCCEDP participants nor Medicaid beneficiaries). The outcomes included advanced-stage cancer at diagnosis and mortality. A multivariable logistic and survival analysis was conducted to examine the independent association between the BCCEDP and Medicaid status and the outcomes. The percentage of women presenting with advanced-stage disease was highest among women in the Medicaid/peridiagnosis group (63.4%) and lowest among BCCEDP repeat users (38.6%). With adjustments for potential confounders and even in comparison with Medicaid/prediagnosis beneficiaries, those in the Medicaid/peridiagnosis group were twice as likely to be diagnosed with advanced-stage disease (adjusted odds ratio, 2.20; 95% confidence interval, 1.83-2.66). Medicaid/peridiagnosis women are at particularly high risk to be diagnosed with advanced-stage disease. Efforts to reduce breast cancer disparities must target this group of women before they present to Medicaid. Cancer 2017;123:3097-106. © 2017 American Cancer Society.

Toxicity of extended adjuvant aromatase inhibitors therapy in postmenopausal breast cancer patients: A systematic review and meta-analysis.

549 Background: Aromatase inhibitors (AI) are a gold standard adjuvant endocrine therapy for postmenopausal women with breast cancer. A number of randomized trials (RCTs) have reported modest improvements in breast cancer outcomes from extending treatment with AI beyond the initial 5 years after diagnosis. However, less in known about the toxicity of extended AI compared with no therapy. Methods: We conducted a systematic review of MEDLINE to identify RCTs that compared extended AI to placebo or no treatment. The search was supplemented by a review of abstracts from the American Society of Clinical Oncology and San Antonio Breast Cancer Symposium meetings between 2013 and 2016. Odds ratios (ORs), 95% confidence intervals (CI), absolute risks, and the number needed to harm (NNH) associated with one adverse event were computed for prespecified safety and tolerability outcomes including cardiovascular disease, bone fractures, second cancers (excluding new breast cancer), treatment discontinuation due to adverse events and death without recurrence. Results: Seven trials comprising 16349 patients met the inclusion criteria. Longer treatment with AI was associated with increased odds of cardiovascular disease (OR = 1.18, 95% CI 1.00-1.40, P=0.05; NNH = 122) and bone fractures (OR = 1.34, 95% CI 1.16 - 1.55, P &lt; 0.001; NNH = 72). Compared to control, longer AI therapy was associated with a higher odds of treatment discontinuation due to adverse events (OR = 1.45, 95% CI 1.25 - 1.68, P &lt; 0.001; NNH = 20). Longer AI therapy did not influence the odds of second cancers (OR = 0.93, 95% CI 0.73-1.18, P = 0.56). There was a numerical excess of death without recurrence with longer AI therapy, but this was not statistically significant (OR = 1.11, 95% CI 0.9 - 1.36, P = 0.34). Conclusions: Longer durations of AI use are associated with increased cardiovascular events and bone fracture. There is a numerical, but non-statistically significant excess of deaths without breast cancer recurrence among patients receiving longer AI therapy. These data should be taken into account when considering extended adjuvant AI therapy for breast cancer patients.

Long term cardiac outcomes and anthracycline exposure in breast cancer survivors: A retrospective cohort data linkage and competing risks analysis.

553 Background: Anthracycline chemotherapy is used frequently in adjuvant breast cancer treatment but there is clinical trial evidence of cardiac toxicity. Attempts to quantify this risk in routine care have been limited by follow up time &amp; confounding factors. The aim of this project was to exploit rich Scottish NHS datasets for this purpose. Methods: Patients treated surgically for stage I-III invasive breast cancer between 2000 &amp; 2010 were identified from a local cancer database (Edinburgh Cancer Centre). Outcomes were captured by linkage to the Scottish Morbidity &amp; death Records. Follow-up was until March 2016. The primary outcome was a cardiac event or cardiac death, identified from coding. Analysis used the Latouche approach (estimating cause-specific hazards &amp; sub-distribution hazards) for the primary outcome &amp; the competing risks of death from breast cancer &amp; death from other causes. Results were adjusted for age, deprivation (SIMD), co-morbidity (Charlson), year of diagnosis, side of radiotherapy, cancer stage, grade, ER &amp; HER 2 status. Results: 4080 patients were identified, 1658 received an anthracycline containing regime, 297 received non-anthracycline chemotherapy &amp; 2125 received no chemotherapy. A total of 33946 women years were analysed. During median follow up of 8.2 years there were 448 cardiac events &amp; 559 breast cancer deaths. After adjustments there was no association between anthracycline use &amp; cardiac outcomes (HR 0.9, 95% CI 0.67-1.21). There was an increased risk of breast cancer death (HR 1.66, 95% CI 1.28-2.16).Age &amp; Charlson score were associated with an increased cardiac risk. Stage &amp; grade were statistically associated with breast cancer death. Conclusions: No increased risk of cardiac events was seen in women treated with anthracyclines, they can be safely used in carefully selected patients. This data suggests selection may be over-cautious, a lower threshold for treatment may lead to improved breast cancer outcomes. Rich routine health datasets &amp; appropriate analysis methods make outcomes monitoring feasible in Scotland. Oncologists are skilled at assessing both cardiac risk factors &amp; breast cancer risk.

Novel Targeted Agents and Immunotherapy in Breast Cancer.

The treatment of breast cancer is generally determined according to breast cancer subtype: hormone receptor-positive (luminal), triple-negative (basal-like), and HER2-overexpressing breast cancer. Recent years have seen the development of exciting novel and potent therapeutics based on molecular pathways, immune modulation, and antibody conjugates. In this article, we cover new and emerging therapeutic areas and ongoing clinical trials that may result in further improvements in breast cancer outcomes.

Therapeutic Bone-Modifying Agents in the Nonmetastatic Breast Cancer Setting: The Controversy and a Value Assessment.

Clinical trials and meta-analyses investigating bisphosphonates as an adjuvant breast cancer therapy have shown a consistent trend, with postmenopausal women and women receiving ovarian suppression with gonadotropin-releasing hormone therapy gaining improved breast cancer outcomes with the use of adjuvant bisphosphonate therapy. The interpretation of these data is controversial, because the primary endpoints of the majority of adjuvant bisphosphonate studies have been negative. Pros and cons as well as the value of adjuvant bisphosphonate therapy are discussed here.

Abstract IS-1: IS-1 Breast cancer initiative 2.5 (BCI2.5): A framework for systematic improvement in global breast cancer outcomes

Abstract Globally, breast cancer is the most common cancer among women, and the most likely cause of female cancer deaths. High-income countries (HICs) have made the most progress in improving breast cancer outcomes. Between 1990 and 2014, breast cancer death rates dropped by 34% in the US attributable to the combination of improved earlier detection and effective adjuvant therapies. By contrast, breast cancer is an increasingly urgent problem in low- and middle-income countries (LMICs), where historically low incidence rates have been rising by up to 5% per year. The strides seen in HICs have not been mirrored in LMICs where optimal management strategies from wealthy countries cannot be fully implemented due to significant resource constraints related to limited personal resources, underdeveloped health care infrastructure, lack of pharmaceuticals and cultural barriers. The Breast Health Global Initiative (BHGI) created and validated resource-stratified guidelines (RSGs) as a comprehensive tool set whereby health care systems can be evaluated for their capacity to deliver breast cancer care with existing resources. These RSGs define a prioritization scheme for resource allocation that illustrates a framework for gap analysis to identify when critical resources are missing in a given system. RSGs can provide a platform for policy makers to prepare for breast cancer's rising tide. Paired with assessments to identify key barriers that prevent patients from receiving necessary services, resource-stratified guidelines provide a framework for analyzing healthcare delivery systems as a basis for improving patient outcomes. Once a comprehensive plan is devised, phased implementation is needed to build systems that are functional and sustainable. BHGI is now collaborating with other organizations to support the global campaign Breast Cancer Initiative 2.5 (BCI2.5), a collaborative framework to engage policy makers, governments, non-governmental organizations, clinicians and patient advocates to build breast healthcare capacity in LMICs. In Peru from 2011 to 2016, the Community-based Program for Breast Health (CPBH) was conducted as a collaboration between PATH, the Ministry of Health of Peru, the National Cancer Institute of Peru, and the Regional Cancer Institute to successfully increase awareness of breast cancer among women, improve capacity for early detection among health workers, and create stronger linkages to higher level care. CPBH provides an example of how BCI2.5 strategies can promote resource-appropriate interventions in breast healthcare in LMICs. In alignment with this successful model, BCI2.5 presents a 4-phase resource-stratified implementation approach to improving breast healthcare: (Phase I) systematic triage and diagnosis of palpable breast disease; (Phase II) resource-adapted stage-appropriate treatment planning; (Phase III) systematic interventions to downstage clinically detectable disease; and (Phase IV) upgrade diagnostic systems for management of non-palpable disease as a prerequisite to image-based (mammographic) screening. This BCI2.5 model of resource-stratified phased implementation can be extended to develop functional sustainable programs in cancer diagnosis, treatment and palliation for breast cancer. Citation Format: Anderson BO. IS-1 Breast cancer initiative 2.5 (BCI2.5): A framework for systematic improvement in global breast cancer outcomes [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr IS-1.

Abstract B52: Describing Adherence to Dietary Guidelines in Overweight African American Breast Cancer Survivors

Abstract Background African American women have the greatest breast cancer mortality and shortest survival rates of any racial or ethnic group. Increased adherence to general population dietary guidelines has been linked to improved breast cancer outcomes. Limited information exists on the dietary habits and level of adherence to general population dietary recommendations in African American breast cancer survivors (AABCS). Objective We explored differences in diet quality assessed via HEI and AHEI by demographic and anthropometric characteristics. Design A cross-sectional analysis of the baseline interview including a food frequency questionnaire. Participants/setting Study participants were recruited and enrolled in the Moving Forward intervention study. Moving Forward was a randomized, community-based, 6-month weight management intervention for AABCS. Main outcome measures Adherence to population-based dietary recommendations was assessed by the Healthy Eating Index-2010 (HEI) and the Alternate Healthy Eating Index-2010 (AHEI). Statistical analyses performed We calculated standard descriptive statistics for nutrient intakes, including total and components scores from HEI and AHEI. Linear regression analysis was conducted to determine the relationship between socio-demographic factors and dietary adherence. Results Participants had a mean age of 57 and were approximately seven years post-initial breast cancer diagnosis. The mean HEI total score was 65.1 (range: 38.9-93.9; max score 100) and mean AHEI total score was 56.8 (range: 25.00 - 85.8; max score 110) indicating sub-optimal diet quality. In the adjusted analysis, HEI and AHEI total scores were positively associated with education, income, moderate physical activity (HEI only) and negatively associated with waist-hip ratio, and smoking status. Conclusion Generally, non-smokers, who reported more moderate physical activity, more years of education, and smaller waist circumferences had better quality diets compared to other participants. Understanding deficiencies in the diet of AABCS will help to inform the development of effective lifestyle interventions for this at-risk group. Citation Format: Sparkle Springfield, Angela Odoms-Young, Lisa Tussing-Humphreys, Sally Freels, Giamila Fantuzzi, Melinda Stolley. Describing Adherence to Dietary Guidelines in Overweight African American Breast Cancer Survivors. [abstract]. In: Proceedings of the Ninth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2016 Sep 25-28; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2017;26(2 Suppl):Abstract nr B52.