Breast Cancer Treatment Outcome Research Articles

Prospective Observational Study of Breast Cancer Treatment Outcomes for UK Women Aged 18–40 Years at Diagnosis: The POSH Study

Breast cancer at a young age is associated with poor prognosis. The Prospective Study of Outcomes in Sporadic and Hereditary Breast Cancer (POSH) was designed to investigate factors affecting prognosis in this patient group. Between 2000 and 2008, 2956 patients aged 40 years or younger were recruited to a UK multicenter prospective observational cohort study (POSH). Details of tumor pathology, disease stage, treatment received, and outcome were recorded. Overall survival (OS) and distant disease-free interval (DDFI) were assessed using Kaplan-Meier curves. All statistical tests were two-sided. Median age of patients was 36 years. Median tumor diameter was 22 mm, and 50% of patients had positive lymph nodes; 59% of tumors were grade 3, 33.7% were estrogen receptor (ER) negative, and 24% were human epidermal growth factor receptor 2 (HER2) positive. Five-year OS was higher for patients with ER-positive than ER-negative tumors (85.0%, 95% confidence interval [CI] = 83.2% to 86.7% vs 75.7%, 95% CI = 72.8% to 78.4%; P < .001), but by eight years, survival was almost equal. The eight-year OS of patients with ER-positive tumors was similar to that of patients with ER-negative tumors in both HER2-positive and HER2-negative subgroups. The flexible parametric survival model for OS shows that the risk of death increases steadily over time for patients with ER-positive tumors in contrast to patients with ER-negative tumors, where risk of death peaked at two years. These results confirm the increased frequency of ER-negative tumors and early relapse in young patients and also demonstrate the equally poor longer-term outlook of young patients who have ER-positive tumors with HER2-negative or -positive disease.

Profile and Predictors of Long-term Morbidity in Breast Cancer Survivors

A sound understanding of the benefits of different treatment options and their health-related quality of life (HRQoL) impacts is required for optimal breast cancer care. A cross-sectional cohort study was conducted to determine the prevalence and severity of persistent functional decrements and symptoms and identify demographic, clinical and treatment variables associated with poorer outcomes. Four hundred English-speaking women treated for ductal carcinoma-in-situ or stage I to III breast cancer between 1999 and 2009, at least 12months after surgery and currently disease free, were randomly selected and invited to complete (1) the Breast Cancer Treatment Outcome Scale and (2) the EORTC core Quality of Life Questionnaire, version 3. The response rate was 85.60%. Many participants reported moderate to severe decrements in a number of HRQoL domains, including functional well-being (15%), cosmetic status (32%) and overall quality of life (21%). There were significant associations (p<.05) between younger age and poorer HRQoL but none between time since surgery and morbidity (p>.05). Different treatments were associated with different HRQoL impacts. Poorer functional status was predicted by axillary dissection (p=.011), and adjuvant radiotherapy was a significant predictor of breast-specific pain (p<.05). Many breast cancer survivors report long-term morbidity that is unaffected by time since surgery. The significant associations between the extent of locoregional therapies and poorer HRQoL outcomes emphasize the importance of the safe tailoring of these treatments.

Influence of ABCB1 genetic variants in breast cancer treatment outcomes

BackgroundTransportation of anticancer drugs such as anthracyclines across the membrane is regulated by P-glycoprotein encoded by the human multidrug resistance gene 1 (ABCB1). Polymorphisms in the ABCB1 gene (1236C>T, 2677G>T/A, 3435C>T) have been found to be associated with intrinsic and acquired cross resistance to these anticancer drugs. Therefore, the aim of this study is to evaluate the influence of ABCB1 gene polymorphisms in breast cancer treatment outcomes in terms of response and toxicity. MethodResponse to neo-adjuvant chemotherapy was evaluated in 100 patients while grade 2–4 toxicity was followed in 207 patients, who had undergone FEC/FAC chemotherapy. Genotyping for ABCB1 polymorphisms was done by PCR-RFLP. Chi square and logistic regression analyses were used to calculate Odd's ratio using SPSS ver 17.0. A meta analysis was also performed using Comprehensive Meta Analysis Ver 2. ResultsIn response evaluation, 1236C>T polymorphism was significantly associated with treatment response for CT genotype [OR=5.17(1.3–20.2), P=0.018] and in dominant model (CC vs CT+TT) [OR=4.63(1.25–17.0), P=0.021]. In the toxicity group, the T allele of 1236C>T was associated with grade 2–4 tocxicity [OR 1.48(1.00–2.20), P=0.049] and the association was also significant in the recessive model [OR 1.88(1.05–3.39), P=0.033]. For other two SNPs 2677G>T/A and 3435C>T no association was seen with either treatment response or grade 2–4 toxicity. In meta analysis, no overall association was found. ConclusionIn our study, significant association was seen for ABCB1 1236C>T polymorphism with treatment response. The meta analysis did not show overall association with treatment outcomes.

The impact of estrogen receptor (ER), progesterone receptor (PR), and HER-2 receptor status on treatment of patients with advanced breast cancer.

e11580 Background: There are many variables that affect treatment options and outcomes in advanced breast cancer. The expression of ER, PR and HER2 are key in determining prognosis and management. The traditional management of breast cancer did not involve biopsy of metastatic sites. Recent studies indicate that, in a significant number of patients, there is a change in receptor status in the metastasis, and this may alter treatment. There have been many retrospective studies looking at the change in the ER/PR status of the metastatic site. Change in treatment as a result has been less of a focus. Our objective is to document the likelihood of a change in receptor status and the impact of this on treatment. Methods: This is a single center retrospective chart review. Ethics approval has been obtained through Memorial Univeristy of Newfoundland. The Dr. H. Bliss Murphy Cancer Centre database was used to identify 250 patients in Newfoundland who were diagnosed with metastatic breast cancer between January 2006 and November 2011. The review includes patients diagnosed with de novo metastases and those who developed metastases following adjuvant treatment. The information we are collecting includes ER, PR, and HER2 status of original tumour, whether metastases were biopsied and the results of the biopsy. We are also documenting all treatments administered. Results: The percentage of patients who underwent biopsy of metastases, the likelihood of change in receptor status and the likelihood of change in treatment will be calculated. Approximately half of the charts that met our criteria have been reviewed. Of those 125 patients, 35 had a biopsy specimen analyzed for ER/PR and HER2 status. 6 of these 35 patients had a change in their hormone receptor status, and 3 had a change in their HER2 status. The likelihood of change in treatment recommendations will be determined once all the data have been reviewed. These results will be available for the 2013 ASCO meeting. Conclusions: ER, PR and HER2 status may change from initial diagnosis of breast cancer to metastatic disease. This has important implications for treatment and prognosis, suggesting that biopsy of metastatic sites should be routine.

Abstract 1396: Response of primary culture of breast cancer to hypoxia and drug treatment.

Abstract Breast cancer is a heterogeneous disease. Several subtypes of breast cancer have been characterized and corresponding treatment strategies have been devised. However, outcomes are not always satisfactory for a variety of reasons including individual variation in age, race, disease stages, and genetic variations. In order to improve the outcomes of breast cancer treatment, personalized treatment has been developed based on molecular profiling and genetic testing of each individual patient. To compliment the development of personalized treatment based on molecular data from genetic profiling, we hypothesized that culture of primary breast cancer tissue could provide a cell-based model that could be utilized in the evaluation of the response of individual breast cancer to therapeutic agents. In this model, breast cancer samples were cultured in matrigel. To identify the cell types that grew in the matrigel, the cells were subjected to the staining with antibodies against cytokeratin5, cytokeratin14, cytokeratin18, ER, vimentin, E-cadherin, N-cadherin, α-SMA, and β-catenin. The results demonstrated that the cells which grew from breast cancer tissue were heterogeneous, including epithelial and stromal cells. Further analysis of the effect of oxygen indicated that the growth of breast cancer cells increased by 1.4-1.5 fold with 5% O2 compared to growth with 21% O2. Interestingly, hypoxia did not stimulate growth of normal breast tissue. Very intriguingly, growth under hypoxic conditions demonstrated differential responses to several chemotherapeutic agents. In these studies cell proliferation was assayed at 5% and 21% O2 of primary cultures of normal and cancerous breast cells treated with doxorubicin, LY294002, and PHA665752 (c-Met inhibitor). With doxorubicin treatment normal breast cells under hypoxia showed significant drug resistance at 0.1 μM and 1 μM compared to normoxia (P&amp;lt;0.05) while breast cancer cells were similarly responsive to doxorubicin under normoxic and hypoxic conditions. With LY294002 treatment hypoxic breast cancer cells showed an increased drug resistance at 10 and 40μM (P&amp;lt;0.05) while hypoxic normal breast cells showed a significant increase in drug resistance at only 40 μM compared to normoxic cells. The effects of PHA665752 on cell proliferation were not affected by hypoxia for either normal or breast cancer cells. In conclusion, cells grown from breast cancer tissue are heterogeneous in cell type. These primary cells show some differential responses to hypoxia condition and drug treatment. An advantage of this primary cell culture model is that it contains cancer cells in the context of their respective native supportive stromal cells, thus creating a microenvironment that is similar to what obtains in vivo. Therefore, this in vitro primary culture model may have potential applications for the testing of drugs predicted to be effective for personalized treatment of breast cancer. Citation Format: Hong Yin, Patrick Adegboyega, Mylinh Smith Smith, Jonathan Glass. Response of primary culture of breast cancer to hypoxia and drug treatment. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1396. doi:10.1158/1538-7445.AM2013-1396

Abstract 1314: HDAC inhibitor entinostat reverses letrozole resistance in MCF-7Ca xenografts through modulation of Her-2.

Abstract Development of aromatase inhibitors (AIs) has significantly improved the treatment outcome of hormone responsive post-menopausal breast cancer. However, not all tumors respond initially and others eventually acquire resistance. Using our hormone sensitive human aromatase expressing MCF-7Ca xenograft model, we also saw that although AI letrozole provides a longer control over tumor growth, tumors eventually began to grow. Furthermore, we observed that Her-2 protein levels within the tumors were upregulated as early as 4 weeks (as tumors were responding). Her-2 levels increased further as the tumors became resistant. A cell line was isolated from these Long-Term Letrozole Treated tumors (LTLT-Ca), which showed increased Her-2 and reduction in ERα and aromatase. The increase in Her-2 protein levels was not accompanied by gene amplification but we observed that Her-2 protein in LTLT-Ca cells was more stable and had a longer half-life than that in MCF-7Ca cells. In addition, when MCF-7Ca cells were deprived of estrogen (E2W) or treated with letrozole, stability of Her-2 protein was immediately increased, suggesting that lower estrogen levels stabilize Her-2. In order to identify novel approaches to restoring sensitivity to AIs, we treated letrozole resistant MCF-7Ca tumors with histone deacetylase (HDAC) inhibitor entinostat (ENT). Addition of ENT to either letrozole or exemestane in letrozole resistant MCF-7Ca tumors led to increased ERα expression, aromatase activity and significantly inhibited further tumor growth, along with downregulation of Her-2, p-Her-2, p-MAPK and p-Akt. Based on the observations made in letrozole resistant tumors treated with entinostat (with or without letrozole), we hypothesized that entinostat reverses letrozole resistance due to modulation of Her-2. Entinostat reduced interaction between HSP-90 and Her-2 in entinostat treated tumors, resulting in degradation of Her-2. Based on the findings that Her-2 is upregulated even when the tumors are responding, we evaluated the effect of adding entinostat to letrozole from the start of treatment in the MCF-7Ca xenografts. Tumors of MCF-7Ca cells were allowed to form in the presence of androstenedione (Δ4A), aromatizable substrate for estrogen. When the tumors reached ∼300mm3, the mice were grouped to receive Δ4A 100μg/day (control), letrozole (1μg/day), entinostat (50μg/day) or combination of entinostat plus letrozole. Mice receiving letrozole treatment had significantly lower tumor growth rate than control (p=0.0001), so did mice treated with the combination of entinostat plus letrozole (p&amp;lt;0.0001). The growth rate of tumors treated with entinostat + letrozole was similar to the growth rate of letrozole alone suggesting that in the absence of acquired or de novo resistance pathways the addition of entinostat did not provide benefit beyond the aromatase inhibitor alone. Citation Format: Gauri J. Sabnis, Armina Kazi, Olga Goloubeva, Saranya Chumsri, Angela Brodie. HDAC inhibitor entinostat reverses letrozole resistance in MCF-7Ca xenografts through modulation of Her-2. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1314. doi:10.1158/1538-7445.AM2013-1314

Effect of selumetinib on the growth of anastrozole-resistant tumors

Despite significant improvement in the treatment outcome of hormone responsive postmenopausal breast cancer, some patients eventually acquire resistance to aromatase inhibitors (AIs). Using our MCF-7Ca xenograft model, we observed that although AIs such as anastrozole initially inhibit tumor growth effectively, tumors eventually began to grow. Our previous data show that anastrozole-resistant tumors upregulate growth factor receptor pathways as they adapt to grow in the low estrogen environment. Therefore, in the current study, we investigated the effect of inhibiting the growth factor receptor pathways with a MEK-1/2 inhibitor selumetinib (AZD6244, ARRY-142866). We treated the mice with anastrozole-resistant tumors with selumetinib alone or in combination with anastrozole. MCF-7Ca cells were inoculated sc into ovariectomized athymic nude mice supplemented throughout the experiment with androstenedione (100 μg/day), the substrate for aromatase conversion to estrogen. Once the tumors reached a measurable size (~300 mm(3)), the mice were treated with anastrozole (200 μg/day), supplemented with androstenedione (Δ(4)A). The tumors in the anastrozole group doubled in volume after 6 weeks, at which time the animals were regrouped to receive the following treatments: (i) anastrozole, (ii) anastrozole withdrawal (Δ(4)A alone), (iii) selumetinib (25 mg/kg/d, bid, po), and (iv) selumetinib + anastrozole, (n = 10 mice/group). The treatments were given for 6 weeks (till week 12) and then the mice were euthanized, the tumors were collected and analyzed. The tumors of mice treated with selumetinib + anastrozole had significantly lower growth rates than those treated with single agents (p = 0.008). Western blot analysis of the tumors showed that treatment with anastrozole resulted in upregulation of proteins in the growth factor receptor cascade such as p-mTOR, pAkt, pMEK, and pMAPK. This was accompanied by downregulation of ERα protein, consistent with previous findings. The treatment of mice with selumetinib resulted in downregulation of activated MAPK, along with p-mTOR, which likely resulted in upregulation of ERα. Our results suggest that inhibition of the growth factor receptor pathway with selumetinib can reverse anastrozole resistance.

Abstract P3-11-03: Treatment outcomes for early stage male breast cancer: a single centre retrospective case-control study

Abstract Background: Male breast cancer (BC) is a rare disease with a reported incidence of 1%, and treatment strategies are therefore driven by studies conducted in the female BC population. There is also limited information with regards to treatment outcomes for men with early stage BC, particularly when compared with their female counterparts. The objective of this study is to compare the disease free survival (DFS) and overall survival (OS) of males with early stage BC compared to age and stage matched females in a single institution. Methods: A retrospective matched case-control study was conducted to compare male and female pts treated for stage 0 to IIIB BC, at the Ottawa Hospital Cancer Centre, between 1981 and 2009. Matching of male and female pts was done based on age at diagnosis (+/− 2 years), year of diagnosis (+/− 1 year), and disease stage. Data regarding surgery, adjuvant radiation, chemotherapy, and endocrine therapy was collected. Overall survival and disease-free survival were calculated using Kaplan-Meir analysis. Results: A total of 144 pts (72 female; 72 male) were eligible for this study; median age at diagnosis for both groups was 74 years (r: 30–85). Median follow-up was 54 months (r: 2–204) for males and 54 months (r: 4–241) for females. All 72 men underwent mastectomy compared to 38 females (53%). Forty-four (61%) females received adjuvant radiation therapy compared to 29 (40%) males. Twenty (28%) females received adjuvant chemotherapy, compared to 23 (31%) males. All female pts had estrogen receptor positive (ER+) disease, while 59 males (13 unknown) had ER+ disease. An equal number of males and females (79%) received endocrine treatment. The mean DFS for females was 127 months (25th percentile 33 months; median 104 months; 75th percentile 174 months), compared to 93 months (25th percentile 46 months; median 88 months; 75th percentile 112 months) for males (p = 0.62). Mean OS for females was 117 months (25th percentile 40 months; median 107 months; 75th percentile 136 months), and 124 months (25th percentile 48 months; median 90 months; 75th percentile 128 months) for males (p = 0.35). In multivariate analysis, the only parameter that affected both DFS and OS was stage at diagnosis (hazard ratio 0.42, 95% CI 0.18–1.00; hazard ratio 0.25, 96% CI 0.09–0.68). Conclusions: This is one of the largest case-cohort studies to report on treatment outcomes of early stage male BC pts treated in a non-trial setting. Male pts received comparable systemic therapy (chemotherapy/endocrine) as their female counterparts and DFS and OS were similar. These results add to current evidence from population studies that male sex is not a poor prognostic factor for treatment outcomes in early stage BC. The development of a national male breast cancer registry would facilitate the evaluation of modern treatment strategies and patient outcomes in this population. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-11-03.

Abstract P4-16-01: Accelerated hypofractionated whole breast radiotherapy for localized breast cancer: the effect of a boost on patient reported long-term cosmetic outcome

Abstract PURPOSE: Equivalent long-term local control and cosmetic outcomes between conventional and accelerated, hypofractionated whole breast radiotherapy (AWBRT) for early-stage breast cancer have been demonstrated. However, there is uncertainty about the long-term cosmetic outcome of a boost to the tumor bed following AWBRT (AWBRT+B). The primary outcome of this study was to evaluate the cosmetic effect of a boost using a patient reported questionnaire. The cosmetic subscale in the questionnaire was used to compare the appearance of the treated versus non treated breast between the boost and non-boost groups. MATERIALS AND METHODS: Between 2000 and 2005, 4392 women 75 years and under with unilateral early-stage breast cancer received AWBRT alone or AWBRT+B. Random samples of 800 women treated with AWBRT alone and 800 women treated with AWBRT+B were identified from the 3960 women still alive at least 5 years after treatment without contralateral disease. The women were contacted by mail to complete a questionnaire based on the Breast Cancer Treatment Outcomes Scale (22 questions regarding cosmetic, pain and functional outcomes). Cochrane-Armitage (CA) trend test and Wilcoxon Rank-sum (WR) were used to compare baseline patient and treatment variables to long-term cosmetic outcomes between the two treatment groups. RESULTS: 312 women (154 received AWBRT alone and 158 received AWBRT+B) completed the questionnaire. The median (range) age of respondents was 57 (40–75) years in the AWBRT alone group and 52 (32–75) years in the AWBRT+B group (p &amp;lt; 0.001). The median (range) follow-up time after radiotherapy treatment was 8.7 (5.5–11.5) years in the AWBRT alone group and 7.8 (5.5–11.5) years in the AWBRT+B group (p &amp;lt; 0.001). Boost doses ranged between 7.5 Gy in 3 fractions to 16 Gy in 8 fractions. The most commonly used boost regimen was 10 Gy in 4 fractions (70% of respondents). Women treated with AWBRT+B also had higher T stage, higher grade, were more likely to have had chemotherapy and trended towards having an increased number of positive nodes compared to the AWBRT alone group. Current weight, ER status, and use of hormonal therapy were similar between both groups. When comparing the overall appearance of the treated to untreated breast, there was no significant difference between the women who received AWBRT alone and those who received AWBRT+B (42% stating no or slight difference vs. 41%) (p = 0.87 CA). Focusing on the cosmetic subscale in the questionnaire, the average summed score for the AWBRT alone group was slightly worse to the score for the AWBRT+B group (2.3 vs. 2.1, p = 0.02 WR). On the functional subscale, the average summed score for the AWBRT alone group was worse than the AWBRT+B group (1.8 versus 1.5, p &amp;lt; 0.001 WR). On the pain subscale, the average summed score for the AWBRT alone group was better than the AWBRT+B group (1.6 versus 2.0, p &amp;lt; 0.0001 WR). However, when the pain subscale was only applied to the area around the scar, the two groups were similar (2.0 for AWBRT alone and 2.0 for AWBRT+B, p = 0.71). CONCLUSION: Similar to conventionally fractionated WBRT, patients who receive a boost after AWBRT self-report long-term slightly worse cosmetic and pain outcomes compared AWBRT alone. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P4-16-01.

Improved Local Control Rate in 3-dimensional Radiation Therapy Era in Early Breast Cancer After Breast-conserving Surgery

From 1980s several randomized trials have shown that breast-conserving surgery followed by radiotherapy (breast-conserving therapy [BCT]), is as effective as mastectomy for the treatment of breast cancer in the aspect of survival. However, higher local recurrence rate in BCT group was consistently reported in long-term results. This study comprehensively reviewed the clinical data and treatment outcomes of early breast cancer of one institution. We focused on the local recurrence rate and survival according to treatment regimens. Background

Germline variation in TP53 regulatory network genes associates with breast cancer survival and treatment outcome.

Germline variation in the TP53 network genes PRKAG2, PPP2R2B, CCNG1, PIAS1 and YWHAQ was previously suggested to have an impact on drug response in vitro. Here, we investigated the effect on breast cancer survival of germline variation in these genes in 925 Finnish breast cancer patients and further analyzed five single nucleotide polymorphisms (SNPs) in PRKAG2 (rs1029946, rs4726050, rs6464153, rs7789699) and PPP2R2B (rs10477313) for 10-year survival in breast cancer patients, interaction with TP53 R72P and MDM2-SNP309, outcome after specific adjuvant therapy and correlation to tumor characteristics in 4,701 invasive cases from four data sets. We found evidence for carriers of PRKAG2-rs1029946 and PRKAG2-rs4726050 having improved survival in the pooled data (HR 0.53, 95% CI 0.3-0.9; p = 0.023 for homozygous carriers of the rare G-allele and HR 0.85, 95% CI 0.7-0.9; p = 0.049 for carriers of the rare G allele, respectively). PRKAG2-rs4726050 showed a significant interaction with MDM2-SNP309, with PRKAG2-rs4726050 rare G-allele having a dose-dependent effect for better breast cancer survival confined only to MDM2 SNP309 rare G-allele carriers (HR 0.45, 95% CI 0.2-0.7; p = 0.001). This interaction also emerged as an independent predictor of better survival (p = 0.047). PPP2R2B-rs10477313 rare A-allele was found to predict better survival (HR 0.82, 95% CI 0.6-0.9; p = 0.018), especially after hormonal therapy (HR 0.66, 95% CI 0.5-0.9; p = 0.048). These findings warrant further studies and suggest that genetic markers in TP53 network genes such as PRKAG2 and PPP2R2B might affect prognosis and treatment outcome in breast cancer patients.

Patient-related factors influencing time between first signs of breast cancer (BC) and appointment for medical visit (AMV): An international survey.

9046 Background: Reducing diagnostic delays may improve treatment outcomes in BC. We investigated in various countries patient-related factors influencing time to seeking medical advice for signs of BC. Methods: A total of 4,816 female BC patients from 10 countries were surveyed using a uniform questionnaire translated into local languages. Time between first patient-detected signs of BC and AMV was measured using categorized time scales. Out of 14 original items on a multiple scale measuring BC-related attitudes and behaviors, 5 factors were extracted and used for further analysis: distrust in medical system and success of therapy, disregard of signs, fear of BC, practicing regular breast self-examination and support from friends and family. Results: In the subset of 2,870 patients with self-detected BC who provided complete answers to relevant variables, the mean time to AMV varied in particular countries from 3.4 to 6.2 weeks (grand mean of 4.7 weeks), with 39% of cases with a delay of &gt;4 weeks. Overall, patient attributes that significantly influenced time to AMV were: distrust (p&lt;1E-36), disregard (p=1.26E-30), fear (p=2.65E-16), self-examination (p=1.31E-21), place of living (p=3.5E-3) and education (p=2.73E-3). Multilevel analysis indicated that significant differences among particular countries were only due to slopes of distrust and disregard included in general regression model. The model enhanced with the two abovementioned random effects provided significant improvement in predicting time to AMV. Re-estimation of the model based solely on data from individual countries produced 10 significant equations with varied coefficients for distrust and disregard (see table). Conclusions: Patient-related factors contribute considerably to delay in the diagnosis of BC. Differences between particular countries call for country-specific approaches. [Table: see text]

Comparison of treatment patterns and outcomes in metastatic breast cancer (MBC) patients initiated on trastuzumab versus lapatinib: A retrospective analysis.

e11076 Background: The National Comprehensive Cancer Network (NCCN) guidelines recommend trastuzumab- or lapatinib-based therapies as the preferred agents for metastatic HER2-positive breast cancer. Few studies have compared treatment patterns and outcomes in MBC patients (pts) treated with trastuzumab vs. lapatinib. The objective of this study is to compare rates of new metastatic sites, discontinuation, healthcare resource utilization, and costs in MBC pts initiated on lapatinib vs trastuzumab. Methods: Adult women with MBC initiated on trastuzumab or lapatinib on or after 03/13/2007 (lapatinib FDA-approval date) were selected in the PharMetrics® Integrated Database (2000-2011). Pts were followed from trastuzumab or lapatinib initiation date up to the end of continuous healthcare plan enrollment/data availability, whichever occurred first. New metastatic sites and discontinuation rates (gap ≥45 consecutive days) were compared among trastuzumab and lapatinib pts using multivariate Cox proportional-hazards models. Incremental healthcare resource utilization and monthly costs (2010 USD; measured from a payer perspective) were estimated using multivariate generalized linear models. Results: Among the643 pts selected, 381 and 262 pts were initiated on trastuzumab and lapatinib, respectively. After multivariate adjustment, compared to trastuzumab pts, lapatinib pts had a higher rate of new metastases (hazard ratio [HR]=1.65; p&lt;.001) and treatment discontinuation (HR=1.57; p&lt;.001). There was no statistically significant difference in total healthcare cost between lapatinib and trastuzumab pts (p=.397). The incidence of medical visits associated with treatment administration was lower in lapatinib pts (Incidence rate ratio [IRR]=0.34; p&lt;.001), however, the incidence of other outpatient visits was significantly higher in lapatinib pts (IRR=1.19; p&lt;.001). Conclusions: Whileboth cohorts presented similar healthcare costs, pts initiated on lapatinib showed higher rates of new metastatic sites, discontinuation, more outpatient visits (non treatment-related), but fewer medical visits associated with treatment administration.

Abstract 2919: Effect of selumetinib and AZD8055 on the growth of anastrozole resistant tumors

Abstract Despite significant improvement in the treatment outcome of hormone responsive post-menopausal breast cancer, some eventually acquire resistance to AIs. Using our MCF-7Ca xenograft model, we observed that although, AI anastrozole inhibited tumor growth, tumors eventually began to grow. Our previous data shows that anastrozole resistant tumors upregulate growth factor receptor pathways as they adapt to grow in the low estrogen environment. In the current study, we investigated the effect of inhibiting the growth factor receptor pathways with two signal transduction inhibitors. We treated the mice with anastrozole resistant tumors with selumetinib (AZD6244, ARRY-142866); an MEK 1/2 inhibitor and AZD8055; a dual mTORC1 and mTORC2 inhibitor, alone or in combination with anastrozole. MCF-7Ca cells were inoculated sc into ovariectomized athymic nude mice supplemented with androstenedione (100 μg/d), the substrate for aromatase conversion to estrogen. Once the tumors reached a size of ∼300mm3, the mice were assigned to one of two treatment groups so that mean tumor volumes were not significantly different (p=0.98) at the start of treatment: control, anastrozole (200μg/d). All animals continued to be supplemented with androstenedione (≥4A). The tumors in the anastrozole group doubled after 6 weeks. At week 6, the animals were regrouped into six groups such that the mean tumor volumes were not significantly different (p=0.18). The mice received the following treatments (i) anastrozole, (ii) anastrozole withdrawal (≥4A alone), (iii) selumetinib (25mg/kg/d, bid, po), (iv) selumetinib + anastrozole, (v) AZD8055 (20mg/kg/d, po), (vi) AZD8055 + anastrozole (n=10 mice/group). The treatments were given for 6 weeks (till week 12) and then the mice were euthanized, tumors were collected and analyzed. Using mixed effects model, the growth rates of tumors (≥i) between different groups of treatments were compared. The tumors of mice treated with selumetinib + anastrozole had significantly lower growth rate than both single agents (p=0.008). The growth rate of tumors of mice treated with AZD8055 + anastrozole was marginally lower than the single agents (p=0.058). Western blotting analysis of the tumors showed that treatment with anastrozole resulted in upregulation of proteins in the growth factor receptor cascade such as p-mTOR, pAkt, pMEK and pMAPK. This was accompanied by downregulation of ERα protein, consistent with previous findings. This suggests that anastrozole resistance results in adaptation of the tumors to growth factor receptor pathway. When the tumors were treated with signal transduction inhibitors such as selumetinib or AZD8055, the respective pathways were effectively inhibited, which resulted in upregulation of ERα. Our results suggest that inhibition of growth factor receptor pathway with selumetinib or AZD8055 can reverse anastrozole 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 2919. doi:1538-7445.AM2012-2919

Abstract 4297: Racial/ethnic disparities in breast cancer radiosensitivity

Abstract Purpose: To evaluate radiotherapy (RT)-related skin toxicity and its relationship to quality of life (QOL) outcomes in a tri-racial/ethnic cohort. Methods: We evaluated the first 172 patients in an ongoing prospective study of conservatively managed breast cancer patients using the validated Breast Cancer Treatment Outcome Scale (BCTOS) questionnaire to assess RT-related QOL, and NCI CTCAE v3.0 criteria to assess skin toxicity (ST). BCTOS was completed prior to and at RT completion, and skin toxicity was assessed at week 3 and RT completion. We recorded patient demographics, body mass index (BMI), disease and treatment characteristics and used Student's t-test and regression for statistical analysis. We divided BCTOS parameters into 3 domains: physical appearance/function, personal reaction to RT, and worst pain in the last 4 weeks. Results: Completed BCTOS questionnaires were available for 145 patients (84%) included in this analysis. Patients were 17.2% non-Hispanic white (NHW), 60.7% Hispanic white (HW), 19.3% black (B), and 2.8% other. 18.6% had DCIS, 52.4% stage I, and 29% stage II-III invasive breast cancer. 30.3% had BMI &amp;lt;25, 28.3% 25-29.99, and 41.4% γ30. All patients had BCS followed by RT +/− systemic therapy; median breast dose 50 Gy + 10 Gy boost. At RT completion, all patients had ST: 46.2% Grade (Gr) 1, 50.3% Gr 2, and 3.4% Gr 3. In the entire cohort, there was a significant increase from baseline to RT completion in all QOL domains: Post minus baseline mean difference in physical appearance/function was 7.7 points (p&amp;lt;0.001), personal reaction to RT 8.1 points (p&amp;lt;0.0001), and pain 3.9 points (p&amp;lt;0.001). For physical appearance/function, greater differences were found with higher ST grade (10.4 for Gr 2/3 vs. 4.5 for Gr 1, p=0.01), by race (15.6 points for B vs. 5.9 points for HW and 5.3 points for NHW/other, p=0.003), and increasing BMI (3.6 for &amp;lt;25, 6.8 for 25-29.99, and 11.2 for α30, p=0.019). For worst pain in last 4 weeks, greater differences were found with increasing BMI (1.8 for &amp;lt;25, 2.8 for 25-29.99, and 6.1 for α30, p=0.037) and borderline significant increase with ST grade (2.3 for Gr 1 vs. 5.2 for Gr 2/3, p=0.057). There were no significant differences in personal reaction to RT. With respect to physical appearance/function, there was significant interaction between race/ethnicity and BMI (p=0.015). Among women with BMI α30, there were significant effect of B race (p=0.010) and worst toxicity grade (p=0.02). Conclusion: In a diverse cohort of breast cancer patients, RT affected all QOL domains of the BCTOS. RT-induced ST was more common among B patients and those with higher BMI and correlated with physical appearance/function and pain. Underlying etiology for variation in RT-related breast symptoms is unknown and may relate to genetic, biologic, and/or environmental factors. Our ongoing study with a targeted sample size of 1,000 may shed light on the mechanisms of racial/ethnic disparities in RT outcomes of breast cancer patients. 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 4297. doi:1538-7445.AM2012-4297

Demography and Treatment Outcomes of Triple Negative Breast Cancer in the Eastern North Carolina Population: A Single Institution Study

Triple negative breast cancer (TNBC) constitutes about 11-20% of all cases of breast cancer. TNBC has a particularly aggressive clinical course and worse prognosis, especially in African American (AA) women compared to white women. This retrospective study aims to investigate TNBC in the eastern North Carolina population, report treatment outcomes, and determine the rate of local recurrence.

The effects of clinical trials on improving breast cancer care at a single institution.

198 Background: We reported in 2011 at the Society of Surgical Oncology a 19 year retrospective at a single academic institution which identified practice differences between surgical oncologists and general surgeons which were associated with a significant survival advantage. Clinical trial participation was much higher amongst patients treated by a surgical oncologist. Methods: This is an IRB approved, retrospective review of all breast cancer patients receiving primary treatment at a single institution from 1/1/2001 to 12/31/2008. Details of pathology, surgical therapy, chemotherapy, hormonal therapy and radiation therapy were compared between patients participating in clinical trials and those not participating. The specific trials were segregated as to type (tissue banking, therapeutic, prevention, etc.) to understand differential effects if any between type of trial participation. Results: During the time period, there were 1220 patients who received primary breast cancer treatment at this institution. The mean age was 55.6 and mean follow-up &gt;40 months. Stage distribution was stage 0 - 16.8%, Stage 1 - 26.6%, Stage 2 - 33.1%, Stage 3 - 15.9%, and Stage 4 - 6.1%. Patients participating in any clinical trial numbered 468 and 752 participated in no clinical trials. Overall survival (clinical trial 98.8% vs. not in clinical trial 75.7%; p&lt;0.0001). Overall the use of breast conservation was more likely in clinical trial participants (54.3% vs. 44.4%; p&lt;0.0001). The completion of chemotherapy was more likely in clinical trial participants (52.4% vs. 49.5%; p=0.02).The successful completion of systemic therapies (chemo and hormonal) was more likely also (71.4% vs. 64.0%; p=0.009). The type of trial (tissue banking vs. therapeutic) had no effect on improved outcomes. Overall the best predictor of better outcomes was to be treated by a high volume clinical trial enrolling physician. Conclusions: High volume clinical trial enrollment is associated with the best overall treatment outcomes in breast cancer whether trials are directly related to therapeutic changes or not. Each individual in the breast center treating team can have dramatic effect on outcomes by improving their clinical trial enrollment and participation.

Demography and treatment outcomes of triple-negative breast cancer: A single institution study.

179 Background: Triple negative breast cancer (TNBC) constitutes about 11-20% of all cases of breast cancer. TNBC has particularly aggressive clinical course and worse prognosis especially in African American (AA) women compared to white women. This retrospective study aims to investigate TNBC in the eastern North Carolina (NC) population, report treatment outcomes and determine the rate of recurrence. Methods: 202 TNBC patients treated at our institution between 1/01 and 11/09 were included in this analysis. Eastern NC has an AA population higher than the national average (30.2% vs. 12.4%) which is reflected in our patient demographics with 111 (55%) AA, 84 (41.6%) White, 5 (2.5%) Hispanic and 2 (1%) Chinese patients. Stage distribution was 41 (20%) stage I, 97 (48%) stage II, 37 (18%) stage III, 16 (8%) stage IV disease. Six patients (3%) had a diagnosis of DCIS and 5 (3%) were unknown. Majority was (79%) poorly differentiated carcinoma followed by moderately differentiated (13%) carcinoma. Variables were compared between groups using two-sample t-tests. Kaplan Meier curves were generated for overall survival (OS). Group was compared by log rank test. Results: The median FU time was 4.73 years (1.2–10.2). Median age at diagnosis was 53 (22-88) years overall, 51 years for AA and 57 years for White (p=0.01) patients. The overall median survival was 32.18 months with no difference between AA (32.39 months) and white (29.7 months) patients (p=0.785). 160 patients with stage I-III disease received chemotherapy with 96 patients (60%) receiving adjuvant and 64 (40%) receiving neoadjuvant therapy. The median survival for adjuvant patients was 37.08 months (6.87–113) vs 26.48 months (1.51–87.49) for neoadjuvant patients (p=0.001). 27 (14%) patients with stage I-III diseases experienced a local recurrence, 31 patients (15%) experienced distal recurrence with a median time to failure of 25.6 months. Conclusions: This study demonstrated no significant difference in median survival between AA and white patients; however, AA women were diagnosed at a younger age compared to white women. Patients treated with adjuvant chemotherapy had a significantly greater median survival when compared to patients receiving neoadjuvant treatment.

Do Reexcisions Impair Aesthetic Outcome in Breast Conservation Surgery? Exploratory Analysis of a Prospective Cohort Study

Reexcision is a clinically relevant aspect of oncological breast conservation surgery. The influence of reexcision on aesthetic outcome is described differently in the literature. Our aim was to analyze this question in a well-defined cohort with standardized study instruments. A total of 439 patients from a prospectively followed cohort were included in this analysis. Aesthetic results were assessed by the Breast Cancer Treatment Outcome Scale (BCTOS) aesthetic status. Dates of assessments were shortly after surgical interventions and before surgery. Group comparison was performed between patients with reexcisions (80 cases; 18%) and patients without reexcision (359 cases; 82%). We considered variables of differing distribution between the two groups that could hypothetically influence BCTOS aesthetic status in a nonparametric analysis of covariance (ANCOVA). The aesthetic status of patients with reexcisions was found to be significantly worse than for patients with a single breast conservation surgery (P < 0.0001) when tested by a nonparametric ANCOVA model. Because patients with reexcisions had more noninvasive tumors (25% vs. 8%, P = 0.0001) and tumors were larger in patients with reexcision (P = 0.01), we included these variables as possible covariates in the multivariate model. The model was adjusted for the BCTOS aesthetic status before and shortly after the first surgery. Our findings suggest that reexcision in breast conservation surgery impairs aesthetic outcome, at least when assessed shortly after surgery.

Re: Measuring Surgery-Specific Aspects of Quality of Life in Oncologic Breast Surgery-Measuring Aesthetic and Functional Outcome Using the BCTOS (Breast Cancer Treatment Outcome Scale)

Re: Measuring Surgery-Specific Aspects of Quality of Life in Oncologic Breast Surgery-Measuring Aesthetic and Functional Outcome Using the BCTOS (Breast Cancer Treatment Outcome Scale)