Stage Breast Research Articles

Taxpas: Epidemiological and Survival Data in Breast Cancer Patients Treated with a Docetaxel-Based Chemotherapy Regimen in South Africa

Breast cancer is the leading cancer among South African women. There is limited South African epidemiological data on triple-negative breast cancer (TNBC). Taxpas was a nonrandomized observational survey conducted in multiple centres in South Africa from April 2004 to December 2010. 1632 female patients diagnosed with breast cancer, with a median age of 51 years, were enrolled in the survey. Patients were treated on a docetaxel-based chemotherapy regimen. The objective of the study was to assess epidemiological data and survival data. The incidence of TNBC was 14%. The one-year survival rate for the total cohort was 84%. The one-year survival rate for patients with early stage and metastatic breast cancer was recorded as 94% and 65%, respectively. Patients with TNBC stage III (all ages) and stage IV (≤50 years) had statistically significant worse 1-year survival rate compared to N-TNBC patients of the same age and stages. Conclusion. The incidence of TNBC in South Africa which is 14% is comparable to global incidence. The 1-year survival data for certain subgroups supports the literature saying that TNBC carries a worse prognosis compared to N-TNBC. Women ≤50 years diagnosed with late stage TNBC carried the worst prognosis in this survey.

A mixed effects model to estimate timing and intensity of pubertal growth from height and secondary sexual characteristics

Aim: To estimate and compare pubertal growth timing and intensity in height, Tanner stage markers and testis volume.Subjects and methods: Data on height, genital stage, breast stage and pubic hair stage, testis volume and menarche in 103 boys and 74 girls from the Edinburgh Longitudinal Growth Study were analysed. The SITAR model for height and a novel mixed effects logistic model for Tanner stage and testis volume provided estimates of peak velocity (PV, intensity) and age at peak velocity (APV, timing), both overall (from fixed effects) and for individuals (random effects).Results: Based on the six markers, mean APV was 13.0–14.0 years in boys and 12.0–13.1 years in girls, with between-subject standard deviations of ∼1 year. PV for height was 8–9 cm/year by sex and for testis volume 6 ml/year, while Tanner stage increased by 1.2–1.8 stages per year at its peak. The correlations across markers for APV were 0.6–0.8 for boys and 0.8–0.92 for girls, very significantly higher for girls (p = 0.005). Correlations for PV were lower, −0.2–0.6.Conclusions: The mixed effects models perform well in estimating timing and intensity in individuals across several puberty markers. Age at peak velocity correlates highly across markers, but peak velocity less so.

Onset of Breast Development in a Longitudinal Cohort

There is growing evidence of pubertal maturation occurring at earlier ages, with many studies based on cross-sectional observations. This study examined age at onset of breast development (thelarche), and the impact of BMI and race/ethnicity, in the 3 puberty study sites of the Breast Cancer and the Environment Research Program, a prospective cohort of >1200 girls. Girls, 6 to 8 years at enrollment, were followed longitudinally at regular intervals from 2004 to 2011 in 3 geographic areas: the San Francisco Bay Area, Greater Cincinnati, and New York City. Sexual maturity assessment using Tanner staging was conducted by using standardized observation and palpation methods by trained and certified staff. Kaplan-Meier analyses were used to describe age at onset of breast maturation by covariates. The age at onset of breast stage 2 varied by race/ethnicity, BMI at baseline, and site. Median age at onset of breast stage 2 was 8.8, 9.3, 9.7, and 9.7 years for African American, Hispanic, white non-Hispanic, and Asian participants, respectively. Girls with greater BMI reached breast stage 2 at younger ages. Age-specific and standardized prevalence of breast maturation was contrasted to observations in 2 large cross-sectional studies conducted 10 to 20 years earlier (Pediatric Research in Office Settings and National Health and Nutrition Examination Survey III) and found to have occurred earlier among white, non-Hispanic, but not African American girls. We observed the onset of thelarche at younger ages than previously documented, with important differences associated with race/ethnicity and BMI, confirming and extending patterns seen previously. These findings are consistent with temporal changes in BMI.

Comparison of Sonography With Sonographically Guided Fine‐Needle Aspiration Biopsy and Core‐Needle Biopsy for Initial Axillary Staging of Breast Cancer

The purpose of this study was to determine the roles of sonography and sonographically guided fine-needle aspiration biopsy and core-needle biopsy for initial axillary staging of breast cancer. Of 220 patients with breast cancer who underwent preoperative or prechemotherapy sonography for axillary staging, 52 patients who underwent sonographically guided fine-needle aspiration biopsy and core-needle biopsy for cortical thickening or a compressed hilum of lymph nodes on sonography were prospectively enrolled. Sonography and fine-needle aspiration biopsy/core-needle biopsy findings were compared with final pathologic results from sentinel lymph node biopsy or axillary lymph node dissection. Forty-eight patients met the final study criteria; we excluded 4 who had received primary systemic chemotherapy and showed negative fine-needle aspiration biopsy/core-needle biopsy results and negative final postoperative pathologic results. The positive predictive value of axillary sonography was 54%. The sensitivity and specificity of fine-needle aspiration biopsy were 73% and 100%, respectively, and those of core-needle biopsy were 77% and 100%. Results did not differ significantly between sonographically guided core-needle biopsy and fine-needle aspiration biopsy. The complication rates of fine-needle aspiration biopsy and core-needle biopsy were both 4%, and fine-needle aspiration biopsy and core-needle biopsy cost $180 and $350, respectively. Both sonographically guided fine-needle aspiration biopsy and core-needle biopsy were useful for axillary staging of breast cancer with high sensitivity. However, fine-needle aspiration biopsy is recommended based on the advantages of low cost and minimal invasiveness.

Disease Free Survival among Molecular Subtypes of Early Stage Breast Cancer between 2001 and 2010 in Iran

Breast cancer is the most common cancer among women. Molecular subtypes are important in determining prognosis. This study evaluated five-year disease-free survival among four molecular subtypes in patients with early stages of breast cancer. In this retrospective descriptive-analytical study, information on patients with breast cancer between 2001-2010 was evaluated. Five hundred ninety two patients in the early stages of breast cancer (stages 1 and 2) were selected to undergo anthracycline-based chemotherapy. Relapse, death or absence (censor) were considered as the end of the study. Patients based on ER, PR and HER-2 expression were divided into four subtypes (luminal A, luminal B, HER-2 enriched and triple negative). Information based upon questionnaire was analysed. To show the patients survival rate, life table and Kaplan-Meyer methods were used, and for comparing mean survival among different groups, the Log-Rank test was utilized. Mean age at diagnosis was 47.9±9.6. Out of the 592 patients, 586 were female (99%) and 6 were male (1%). Considering breast cancer molecular subtypes, 361 patients were in the luminal A group (61%), 49 patients in the luminal B group (8.3%), 48 patients in the HER-2 enriched group (8.1%) and 134 in the triple negative group (22.6%). Mean disease-free survival was 53.7 months overall, 55.4 months for the luminal A group, 48.3 months for the luminal B group, 43 months for the HER-2enriched group and 54.6 months for the triple negatives. Disease free survival differed significantly among the molecular subtypes (p value=0.0001). The best disease-free survival rate was among the luminal A subgroup and the worst disease-free survival rate was among the HER-2 enriched subgroup. Disease free survival rate in the HER-2 positive groups (luminal B and HER-2 enriched) was worse than the HER-2 negative groups (luminal A and triple negative).

PC-FACS

PC-FACS

Effects of gonadotropin-releasing hormone analog treatment on glucose and lipid metabolism in girls with idiopathic central precocious puberty

Objective To assess the effects of gonadotropin-releasing hormone analog on glucose and lipid metabolism in girls with idiopathic central precocious puberty(ICPP). Methods A total of 26 girls(aged 6-8 years, breast stage B2) with ICPP were followed up in Department of Endocrinology, Shenzhen Children's Hospital from Jan. 2008 to Jun. 2011. Those girls received triptorelin therapy for 12 months. Before and the end of the 6th month, the 12th month of the treatment, body mass index(BMI) was calculated, fasting plasma glucose(FPG), fasting plasma insulin(FPI), total cholesterol, triacylglycerols, high density lipoprotein cholesterol, low density lipoprotein cholesterol, apolipoprotein A, apolipoprotein B and estradiol(E2) were measured. Insulin sensitivity was estimated by homeostasis model assessment of insulin resistance(HOMA-IR). Twenty age-matched prepuberty girls were set as controls. Results 1. Before treatment, BMI, FPG, FPI and HOMA-IR in ICPP girls had no significant difference compared with the controls.2. After 6 months treatment of triptrolin, serum E2 concentration in ICPP girls declined from(30.5±9.8) ng/L at the beginning of treatment to(11.2±4.6) ng/L at the end of 6th month(P<0.01); The end of 12th month of the treatment, FPG and FPI had no significant difference compared with that before of the treatment, but BMI increased from(16.46±1.10) kg/m2 to(18.35±1.30) kg/m2, the difference was significant(P<0.05), HOMA-IR increased from 1.24±0.30 to 2.08±0.40, the difference was significant(P<0.05).3. Lipid metabolism parameters remained unchangeable after 12 months of triptrolin treatment. Conclusion Triptorelin may lead to raise of BMI and HOMA-IR in girls with ICPP at 12 months after treatment. Key words: Idiopathic central precocious puberty; Gonadotropin-releasing hormone analog; Body mass index; Insulin resistance

The age of onset of pubertal development in healthy Thai girls in Khon Kaen, Thailand

Background: Onset of puberty has shifted toward a younger age in the 21 st century. The useful pubertal assessment in the individual child must be based on recent and reliable reference data from the same population. However, currently representative pubertal data for Thai girls are lacking. Objective: We determined the current prevalence and mean ages at onset of pubertal characteristics in healthy urban Thai girls in Khon Kaen Province, northeast Thailand. Methods: A cross-sectional study was carried out between January and July 2011. Five hundred and three schoolgirls aged 7 to 16 years were enrolled. All were in good physical health. Stages of breast and pubic hair development were rated on girls by Tanner’s criteria. Assessment was performed by a trained pediatrician. Data on menstruation were collected by the status quo method. Results: Median (range) ages of the onset of thelarche and pubarche were 9.3 (7.8 to 13.4) and 10.8 (8.9 to 14.5) years, with the mean±SD of 10.1±1.2 and 11.6±1.2 years, respectively. One hundred and eighteen girls had experienced menstruation. The median (range) age of menarche was 11.2 (10.0 to 14.0) years. Mean age was 11.6±0.8 years. The mean ages of pubarche and menarche decreased from the previous study significantly (p <0.001). Conclusions: The secular trend in decline of the ages of pubarche and menarche were observed in urban Khon Kaen Thai girls. These data can be used as the reference of normal pubertal development in Thai girls in Khon Kaen to determine precocious or delayed puberty.

Use of aromatase inhibitor in a girl with peripheral precocious puberty

This girl presented with problem of vaginal bleeding at 6 year 2 month old. There was no medication history. Physical examination showed that she was tall with height 122.7 cm (97th percentile) and weight was 23.1 Kg (75-90th percentile). Early pubertal sign was present with Breast stage 2 and pubic hair stage 1. She did not have skin pigmentation and has no bone deformity or fracture. Investigations suggested peripheral precocious puberty with grossly elevated serum estradiol 2293 pmol/L with suppressed LH < 0.2 IU/L and FSH < 0.2 IU/L, which also failed to rise in the Gonadotrophin stimulation test. Bone age was advanced to 7 to 8 year old. Pelvic ultrasound showed a 3.6 cm cystic lesion in left ovary and the uterus size was prominent with endometrial echoes. Skeletal survey did not show bony lesion. The clinical diagnosis was peripheral precocious puberty from autonomous functioning ovary cyst. The girl showed progression with recurrent vaginal bleeding and further breast development. To stop further vaginal bleeding and prevent later compromised height, Letrozole, an aromatase inhibitor, was commenced at dose of 1.25 mg daily. Breast size regressed and serum estradiol dropped to nadir of <73 pmol/L. The ovary cyst resolved 2 months after starting Letrozole but was again detected after stopped treatment at 7 years old. The girl went into true puberty around when she approached 9 year old with progression of breast development and growth spurt. The height at last follow up at 10- year 10 month old was 154 cm (97th percentile) and has not yet started menarche. Repeated ultrasound at 8 year 9 month old showed that the ovary cyst again resolved. The case demonstrated that the potent, long-acting aromatase inhibitor Letrozole is effective in arresting sexual precocious puberty resulting from autonomous functioning ovary cyst. The girl goes into normal puberty and attains growth spurt. Further follow up is required to monitor normal menstruation pattern.

Urinary cadmium and the timing of pubertal development in girls

BACKGROUND Cadmium is a reproductive toxin and carcinogen that exhibits estrogen-like activity. In addition to smoking, exposure to cadmium occurs from inhalation of polluted air and diet. Little is known about whether exposure to cadmium affects pubertal development in girls. AIMS Our aim was to determine whether urinary cadmium concentration was associated with the attainment of menarche and Tanner's stages of estrogenic (breast) and androgenic (pubic hair) development. METHODS A total of 211 girls between the ages of 10 and 13 years and primarily non-Hispanic white or Chinese provided an overnight urine specimen and completed an interview and self-assessment of Tanner's stage of breast and pubic hair development at baseline and annually for up to two years. Attainment of menarche was assessed monthly. Urinary cadmium and creatinine concentrations were measured using inductively coupled plasma mass spectrometry and a modified-rate Jaffe method, respectively. Cox proportional hazards regression was used to evaluate whether cadmium was associated with age at menarche and cumulative logit regression to evaluate whether cadmium was associated with stage of breast and pubic hair development. RESULTS The mean creatinine-adjusted cadmium concentration was 0.24 µg/g (SD=0.12 µg/g); it was highest among 10-year olds (0.29 µg/g creatinine) and decreased with age (mean among 13-year olds=0.23 µg/g; Kruskal-Wallis p=0.05). Chinese girls had higher cadmium levels than non-Hispanic white girls (0.30 vs. 0.23 µg/g; p=0.006). Girls with the highest unadjusted cadmium concentrations (? 0.4 vs. &lt;0.2 µg/L) were less likely to have attained menarche (hazard ratio=0.42; 95% confidence interval=0.23-0.78; p-trend=0.007). They also had a lower Tanner stage of pubic hair growth (odds ratio=0.24; 95% confidence interval=0.07-0.81). Breast development stage was not associated with cadmium concentration. CONCLUSIONS These findings suggest that cadmium exposure may delay pubertal development in girls.

Age of thelarche and menarche in contemporary US females: a cross-sectional analysis.

A recent secular trend towards earlier thelarche has been suggested. The aim of this study is to examine normative ages of thelarche and menarche in contemporary US females. Trained physicians documented Tanner breast stage by observation in a cross-sectional cohort. Age of menarche was self-reported. The subjects were healthy female children and adolescents. The mean age of thelarche was determined by probit analysis and the mean age of menarche was determined by using a normal time-to-event model. Mean age of thelarche was 9.7 years among 610 females aged 3.0-17.9 years (70% non-Hispanic Caucasian (NHC), 14% African-Americans, 7% Hispanic, 9% "other"). The mean age of menarche was 12.8 years for NHC, with African-Americans having menarche 0.6 years earlier. Thelarche occurred earlier than recently reported, while age of menarche remained unchanged, this supported a persistent secular trend towards earlier thelarche but stable age of menarche. This suggests that the observed thelarche is gonadotropin-independent or the tempo of pubertal advancement has slowed.

Obstructive sleep apnea (OSA) in preadolescent girls is associated with delayed breast development compared to girls without OSA.

Adults with obstructive sleep apnea (OSA) have lower sex steroid levels than controls. We sought to determine whether OSA also interferes with reproductive hormones in adolescence by tracking the pace of pubertal development. One hundred seventy-two children in the Tucson Children's Assessment of Sleep Apnea study (TuCASA) underwent two home polysomnographic studies, spaced 4-5 years apart. Height and weight were measured at both visits, and Tanner staging of breasts/genitals and pubic hair were self-assessed by a pictorial questionnaire at follow-up. Eighty-seven girls and 85 boys, age 8.9 ± 1.6 years (mean ± SD) at baseline and 13.4 ± 1.6 years at follow-up, participated. Twenty-seven percent of participants were over-weight or obese at baseline, and the majority remained so at follow-up. Twenty-six percent of girls and 28% of boys met criteria for OSA, defined as a respiratory disturbance index (RDI) ≥ 1/h associated with a 3% desaturation (RDI 3%), at baseline. There was an inverse relationship between baseline log RDI 3% and Tanner breast stage at follow-up (coefficient -1.3, p = 0.02) in girls after adjusting for age (p < 0.001), body mass index (p < 0.005), and ethnicity. Girls with OSA at baseline were more than 1 Tanner breast stage behind girls without OSA at follow-up. OSA did not affect genital development in boys or pubic hair development in either sex. OSA in preadolescent girls predicts delayed breast development relative to girls without OSA. Sleep fragmentation and/or hypoxia seen in OSA may interfere with reproductive development in girls.

Young breast cancer patients' involvement in treatment decisions: the major role played by decision‐making about surgery

The objective of this study is to investigate young breast cancer patients' preferred and actual involvement in decision-making about surgery, chemotherapy, and adjuvant endocrine therapy (AET). A total of 442 women aged 18-40 years at the time of the diagnosis participated in the region-wide ELIPPSE40 cohort study (southeastern France). Logistic regression analyses were performed on various factors possibly affecting patients' preferred and perceived involvement in the decisions about their cancer treatment. The women's mean age was 36.8 years at enrollment. Preference for a fully passive role in decision-making was stated by 20.7% of them. It was favored by regular breast surveillance (p = 0.04) and positive experience of being informed about cancer diagnosis (p = 0.02). Patients' preferences were independently associated with their reported involvement in decision-making about surgery (p = 0.01). A fully passive role in decision-making about chemotherapy and AET was more likely to be reported by patients who perceived their involvement in decision-making about surgery as having been fully passive (adjusted odds ratio = 4.8, CI95% [2.7-8.7], and adjusted odds ratio = 9.8, CI95% [3.3-29.2], respectively). This study shows a significant relationship between the use of antidepressants and involvement in decision-making about surgery, and confirms the relationship between impaired quality of life (in the psychological domain) and a fully passive role in decisions about cancer treatment. Patients' involvement in decision-making about chemotherapy and AET was strongly influenced by their experience of decision-making about surgery, regardless of their tumor stage and history of breast or ovarian cancer. When decisions are being made about surgery, special attention should be paid to facilitating breast cancer patients' involvement in the decision-making.

SU-E-T-566: Optimization of Permanent Seed Implant Dosimetry Incorporating Tissue Heterogeneity

Purpose: Seed brachytherapy is currently used for adjuvant radiotherapy of early stage prostate and breast cancer patients. In this technique low dose rate (LDR) radioactive seeds are permanently implanted across the treatment volume to deliver a prescribed amount of dose. The current standard for calculation of dose surrounding the brachytherapy seeds is based on American Association of Physicist in Medicine Task Group No. 43 (TG43 formalism) which generates the dose in homogeneous water medium. For low energy sources and especially in breast, the absorbed dose is highly influenced by heterogeneities. Our work focuses on the development of a dose calculation algorithm similar to TG43 applicable in heterogeneous media. Methods: An Inhomogeneity Correction Factor (ICF) is introduced as the ratio of absorbed dose in tissue to that in water medium. ICF is a function of tissue properties and independent of source structure. The absorbed dose in tissue can then be calculated by multiplying the dose as calculated by the TG43 formalism times ICF. We used Monte Carlo simulations in a heterogeneous model of breast to benchmark the improvements achieved in the calculation of dose using the ICF methodology. Results: The dose distributions obtained through applying ICF to TG43 protocol agreed very well with those of Monte Carlo simulations. Over all and across the whole calculation domain, the mean relative error was reduced from 40.8% to 12.7% when ICF correction factor is applied to the TG43 protocol. Conclusion: We have developed a new analytical dose calculation method which enables personalized dose calculations in heterogeneous media. The methodology offers several advantages including the use of standard TG43 formalism, fast calculation time and extraction of the ICF parameters directly from Hounsfield Units. Funding: NSERC

MDS/AML risk post-breast cancer and association with age: SEER data 2001-2009.

554 Background: Increased acute myeloid leukemia (AML) incidence has been identified post chemotherapy and radiation treatment for primary breast cancer (BC). Risk has not been evaluated in large populations or included myelodysplastic syndrome (MDS). Methods: We used 2001-2009 Surveillance, Epidemiology and End Results (SEER) database records to identify a cohort of first primary stage I-III BC patients. We identified subsequent MDS/AML diagnoses in the BC cohort, using SEER to query appropriate ICD-O-3 codes. We compared observed MDS/AML rates in the BC cohort to expected rates, estimated for first primary MDS/AML in the entire population, and calculated observed/expected rate ratios with 95% confidence intervals (CI) with age adjustment. Due to SEER data limitations, disease stage was used as a proxy for likelihood of radiation and chemotherapy treatment. Results: BC case distribution by stage was 51% stage I, 39% stage II and 11% stage III. Age distribution was 26% 20-49, 38% 50-64 and 36% 65+ years. Out of 306,691 BC cases, 470 had a subsequent diagnosis of MDS or AML (.15%) with 19% among women age 20-49 years, 36% women age 50-64 and 45% among women age 65+ years. Age adjusted number of expected myeloid leukemia cases is 171. Follow up time to myeloid leukemia diagnosis was on average 2.92 years post BC diagnosis (range .25-8.75 years). Myeloid leukemia cases were 56% AML and 44% MDS. We found an overall increased risk of MDS/AML among all age (20-65+)/all stage (I-III) breast cancer cases compared to the general population (RR=2.75, 95% CI 2.51, 3.00). Risk increased with increasing BC stage: stage I (RR=1.87, 95% CI 1.61, 2.16), stage II (RR=3.57, 95% CI 3.12, 4.06), and stage III (RR=5.66, 95% CI 4.45, 7.07) and decreased with increasing age with the highest risk among women age 20-49 (RR=10.60, 95% CI 8.57, 12.92) (age 50-64 (RR=5.60, 95% CI 4.79, 6.49), age 65+ (RR=1.81, 95% CI 1.57, 2.06)). Conclusions: Patients with stage I-III breast cancer have a significant high risk of MDS/AML post BC diagnosis increasing with higher stage cancer, most likely the result of radiation and/or chemotherapy treatment. Younger age women, 20-49 years, appear to be the most susceptible to this outcome.

Tubular carcinomas of the breast: A comparison of features and survival outcomes versus low grade ductal and lobular carcinomas in the SEER database.

e11596 Background: Tubular carcinoma of the breast (TC) is a rare histologic subtype of breast cancer considered to have a favorable prognosis relative to other histologies. TC is by definition low grade. TC is described to have clinical behavior similar to low grade ductal and lobular breast cancers, but due to its infrequent presentation, long-term follow-up studies of TC are lacking. Methods: The Surveillance, Epidemiology and End Results database was queried to include the years 1988-2009, selecting for patients with either grade 1 TC or grade 1 ductal and lobular breast cancer (G1BC). Data collected included age at diagnosis, race, stage, receptor status, overall survival, and surgery type. Two Cox proportional hazard models were assessed for differences between TC and G1BC, adjusting for age at diagnosis. Results: In SEER 18, 115,945 cases of TC+G1BC breast cancer are found, with 6.1% classified as TC. Of TC cases, 91% are stage 1, while 71% of GIBC are stage 1. Presenting stage 3 or 4 disease occurred in only 4.7% of G1BC versus 0.68% of TC cases. Due to the rarity of advanced disease, we analyzed early stage disease. For early Stage (1-2) breast cancer, mean age was 61.5 years for TC and 63.5 years for G1BC. The TC cases were 92% white, 4% black, 97% Estrogen Receptor (ER) positive, 82% Progesterone Receptor (PR) positive. Of G1BC cases, 88% were white, 5% black, 96% ER positive, 84% PR positive. Treatment differed with 76% of TC patients receiving lumpectomy versus G1BC where 65% received lumpectomy (p&lt;0.001). There was no significant difference in overall survival between Stage I TC and G1BC (p=0.98), or between Stage II TC and G1BC (p=0.075), with the survival estimate higher for TC. Conclusions: In this large-scale analysis, TC was limited to early stage disease and there was no difference in overall survival between patients with early stage TC and early stage GIBC. There were similar receptor statuses and baseline characteristics, but more conservative surgical treatment in TC. Because no survival difference exists for early stage disease, the finding of tubular histology to guide treatment decisions may not be warranted.

Pubertal characteristics among schoolgirls in Riyadh, Saudi Arabia

Puberty is the gradual transition period between childhood and adulthood. Many factors may contribute to the onset of puberty. The objective of the study was to determine the age of onset of secondary pubertal characteristics among Saudi Arabian girls. A cross-sectional study was conducted using a cluster sample design. Seven hundred and twenty-five schoolgirls between the ages of 6 and 16 years from diverse socioeconomic levels were included. During physical examinations, the height and weight of the girls were recorded, and the stages of breast and pubic hair development were determined according to Tanner stages; axillary hair development was determined according to modified stages. The median age at Tanner stage 2 for breast and pubic hair development was 10 years. The median age at stage 2 in modified scales for axillary hair development was 12 years. In conclusion, the median age of the onset of breast development at Tanner stage 2 for Saudi girls in Riyadh is lower than what has been reported in some countries in Europe, South Africa, Turkey and India but similar to girls in Hong Kong, China and white girls in the USA, which may support secular trends of an earlier onset of puberty.

Admission to the Intensive Care Unit and Well-being in Patients With Advanced Chronic Illness

To describe the association of intensive care with trajectories of functional, emotional, social, and physical well-being in patients with 3 common advanced illnesses. Cross-sectional cohort study of 42 patients admitted to the intensive care unit selected from 210 patients with stage IV breast, prostate, or colon cancer or stage IIIb or IV lung cancer; New York Heart Association class III or IV congestive heart failure; and chronic obstructive pulmonary disease with hypercapnea (Pco2 > 46 mm Hg). Scores on subscales of the Functional Assessment of Chronic Illness Therapy-General survey were measured monthly for 6 months before and after admission to the intensive care unit and were analyzed by using the unit admission date as a point of discontinuous change to illustrate trajectories before and after the admission. Overall, trajectories of well-being declined sharply after admission to the intensive care unit. Declines in physical, functional, and emotional well-being were statistically significant. During the 6 months after admission, physical, functional, and emotional well-being scores trended back up to baseline while social well-being scores continued to decline. Well-being trajectories declined sharply after admission to the intensive care unit, with recovery in the subsequent 6 months, and may be characterized by common patterns. These results help to better describe intensive care as a marker for advancing illness in patients with advanced chronic illness.

Abstract 2143: Anti-TGFβ antibody treatment rescues doxorubicin- mediated bone loss in preclinical osteolytic breast cancer metastasis models.

Abstract Anthracyclines (doxorubicin) are one of the most effective and widely used chemotherapeutic agent for the treatment of several cancer types, including early stage and metastatic breast cancer. However, doxorubicin has been known to cause long-term bone damage and growth defects in patients with childhood cancers, which was also confirmed by several preclinical studies. This raises concern regarding the usage of doxorubicin for the treatment of patients with metastatic breast cancer who are already at increased risk of osteolytic bone damage leading to severe bone loss due to. A number of clinical and preclinical studies have indicated that doxorubicin causes both long term and short term bone damages by lowering bone mineral density, increasing bone loss and may disrupt bone homeostasis by directly affecting bone marrow stem cells, however, the underlying mechanism is poorly understood. We have previously reported that treatment with doxorubicin increases circulating levels of TGFβ, a cytokine which has been implicated in the increase in osteoclast differentiation and survival, suppression of osteoblast differentiation and has been associated with advancement of breast cancer to bone metastasis. We hypothesize, breast cancer patients undergoing doxorubicin treatment will experience accelerated bone loss due to an increase in serum TGFβ levels and blocking TGFβ will rescue this bone loss, at least partially. We have tested the efficacy of anti-TGFβ antibody 1D11, in blocking doxorubicin-mediated bone damage in cardiac injection and orthotopic models of breast cancer to bone metastasis. X-ray image analysis revealed that doxorubicin treatment resulted in an eightfold increase in osteolytic lesion areas (P=0.002) and microCT analysis has shown almost 50% decrease in BV/TV (P=0.0005), in a preclinical murine model metastatic breast cancer. Doxorubicin treatment has also decreased BV/TV in non-tumor bearing animals, suggesting a direct damaging effect of this agent to bone at the sites which are not affected by cancer infestation. As anticipated, treatment with anti-TGFβ antibody 1D11 was able to rescue doxorubicin-mediated bone loss in all three preclinical models tested. At the cellular level, direct effect of doxorubicin treatment on the bone marrow microenvironment included decreased osteoblast survival and reduced mineralized matrix formation and increased osteoclast formation, thereby affecting both bone formation and bone resorption. Taken together, we conclude that, doxorubicin therapy decreases bone formation and increases bone resorption causing additional bone loss in patients with osteolytic bone disease and an anti-TGFβ therapy may be affective in controlling that bone loss. Citation Format: Tapasi Rana, Anwesa Chakrabarti, Michael Freeman, Swati Biswas. Anti-TGFβ antibody treatment rescues doxorubicin- mediated bone loss in preclinical osteolytic breast cancer metastasis models. [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 2143. doi:10.1158/1538-7445.AM2013-2143

Abstract 5327: Upregulation of miR-10b associated with breast cancer metastasis to brain .

Abstract Background: Breast cancer is the most common non-skin cancer amongst women in the US. Breast cancer-related mortality is primarily due to metastatic disease, especially brain metastasis which also impacts patient's quality of life. The molecular mechanism of brain metastasis of breast cancer is largely unknown; however, finding molecular signatures of the primary breast cancer that have the propensity for brain metastasis would be very important for designing optimal primary treatment of breast cancer to prevent and eliminate brain metastasis. To that end targeting MicroRNAs (miRNAs) could become a novel prognostic and therapeutic strategy to prevent the future development of brain metastasis. Design: Breast cancer cases with brain metastasis diagnosed from 1994-2011 were retrieved from the computerized hospital database. The study cohort comprised of breast cancer cases with brain metastasis (n=18) and age, stage and follow-up matched breast cancer cases without brain metastasis (n= 10). All cases were microscopically reviewed to select tumor blocks with &amp;gt;50% tumor cells. RNA was extracted from formalin fixed paraffin embedded tumor tissue blocks. The miRNA expression analysis was done using RT-PCR. Data was statistically analyzed to determine the clinical significance using the Wilcoxon signed rank test. Results: Among several miRNAs that were analyzed in this study, we found that miR-10b was highly expressed in the primary breast cancer specimens of patients who subsequently developed brain metastasis compared to those who did not develop brain metastasis. Interestingly, the expression of miR-10b was reduced in brain metastatic specimens compared to primary breast cancer specimens. Using Wilcoxon signed rank test, there was statistically significant difference between the paired tumors from breast cancers and brain metastasis (p value &amp;lt;0.001). Conclusions: Increased expression of miR-10b appears to be associated with metastatic potential of the primary breast cancer; however, once the cancer metastasized to the brain (homing), its level was reduced. This interesting finding requires further mechanistic studies. Clinical relevance: Our findings are clinically very relevant since miR-10b could serve as a potential target for anti-metastatic therapy. The expression of miR-10b could be silenced using miR-10b antagomirs (chemically modified anti-miRNA oligonucleotides) for the prevention of brain metastasis, whereas once brain metastasis develops then it could be treated with miR-10b mimics for inducing its expression for the treatment. Therefore, development of miRNA-based prophylactic therapies could serve as personalized medicine against future brain metastasis of breast cancer which will improve patients’ quality of life and improve overall survival. Citation Format: Seema Sethi, Aamir Ahmad, Sandeep Mittal, Rouba Ali, Wei Chen, Fazlul H. Sarkar. Upregulation of miR-10b associated with breast cancer metastasis to brain . [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 5327. doi:10.1158/1538-7445.AM2013-5327