Thyroid Papillary Microtumor: Validation of the (Updated) Porto Proposal Assessing Sex Hormone Receptor Expression and Mutational BRAF Gene Status.

Given the high incidence and excellent prognosis of many papillary thyroid microcarcinomas, the Porto proposal uses the designation papillary microtumor (PMT) for papillary microcarcinomas (PMCs) without risk factors to minimize overtreatment and patients' stress. To validate Porto proposal criteria, we examined a series of 190 PMC series, also studying sex hormone receptors and BRAF mutation. Our updated Porto proposal (uPp) reclassifies as PMT incidental PMCs found at thyroidectomy lacking the following criteria: (a) detected under the age of 19 years; (b) with multiple tumors measuring >1 cm adding up all diameters; and (c) with aggressive morphologic features (extrathyroidal extension, angioinvasion, tall, and/or hobnail cells). PMCs not fulfilling uPp criteria were considered "true" PMCs. A total of 102 PMCs were subclassified as PMT, 88 as PMC, with no age or sex differences between subgroups. Total thyroidectomy and iodine-131 therapy were significantly more common in PMC. After a median follow-up of 9.6 years, lymph node metastases, distant metastases, and mortality were only found in the PMC subgroup. No subgroup differences were found in calcifications or desmoplasia. Expression of estrogen receptor-α and estrogen receptor-ß, progesterone receptor, and androgen receptor was higher in PMC than in nontumorous thyroid tissue. BRAF mutations were detected in 44.7% of PMC, with no differences between subgroups. In surgical specimens, the uPp is a safe pathology tool to identify those PMC with extremely low malignant potential. This terminology could reduce psychological stress associated with cancer diagnosis, avoid overtreatment, and be incorporated into daily pathologic practice.

Association between selenium intake and breast cancer risk: results from the Women's Health Initiative.

PURPOSE: It has been hypothesized that selenium (Se) can prevent cancer, and that Se deficiency may be associated with an increased risk of breast cancer. However, findings from epidemiological studies have been inconsistent. The objective of this study was to assess the association between Se intake and risk of breast cancer in the Women's Health Initiative (WHI). METHODS: This study included 145,033 postmenopausal women 50-79 years who completed baseline questionnaires between October 1993 and December 1998, which addressed dietary and supplemental Se intake and breast cancer risk factors. The association between baseline Se intake and incident breast cancer was examined in Cox proportional hazards analysis. RESULTS: During a mean follow-up of 15.5 years, 9487 cases of invasive breast cancer were identified. Total Se (highest versus lowest quartile: HR 1.00, 95% CI 0.92-1.09, Ptrend = 0.66), dietary Se (highest versus lowest quartile: HR 0.99, 95% CI 0.89-1.08, Ptrend = 0.61), and supplemental Se (yes versus no: HR 0.99, 95% CI 0.95-1.03) were not associated with breast cancer incidence. CONCLUSIONS: This study indicates that Se intake is not associated with incident breast cancer among postmenopausal women in the United States. Further studies are needed to confirm our findings by using biomarkers such as toenail Se to reduce the potential for misclassification of Se status.

Contemporary outcomes of metastatic breast cancer among 22,000 women from the multicentre ESME cohort 2008-2016.

AIM: Real-world data inform the outcome comparisons and help the development of new therapeutic strategies. To this end, we aimed to describe the full characteristics and outcomes in the Epidemiological Strategy and Medical Economics (ESME) cohort, a large national contemporary observational database of patients with metastatic breast cancer (MBC). METHODS: Women aged ≥18 years with newly diagnosed MBC and who initiated MBC treatment between January 2008 and December 2016 in one of the 18 French Comprehensive Cancer Centers (N = 22,109) were included. We assessed the full patients' characteristics, first-line treatments, overall survival (OS) and first-line progression-free survival, as well as updated prognostic factors in the whole cohort and among the 3 major subtypes: hormone receptor positive and HER2-negative (HR+/HER2-, n = 13,656), HER2-positive (HER2+, n = 4017) and triple-negative (n = 2963) tumours. RESULTS: The median OS of the whole cohort was 39.5 months (95% confidence interval [CI], 38.7-40.3). Five-year OS was 33.8%. OS differed significantly between the 3 subtypes (p < 0.0001) with a median OS of 43.3 (95% CI, 42.5-44.5) in HR+/HER2-; 50.1 (95% CI, 47.6-53.1) in HER2+; and 14.8 months (95% CI, 14.1-15.5) in triple-negative subgroups, respectively. Beyond performance status, the following variables had a constant significant negative prognostic impact on OS in the whole cohort and among subtypes: older age at diagnosis of metastases (except for the triple-negative subtype), metastasis-free interval between 6 and 24 months, presence of visceral metastases and number of metastatic sites ≥ 3. CONCLUSIONS: The ESME program represents a unique large-scale real-life cohort on MBC. This study highlights important situations of high medical need within MBC patients. DATABASE REGISTRATION: clinicaltrials.gov Identifier NCT032753.

Assessment of the efficacy of successive endocrine therapies in hormone receptor-positive and HER2-negative metastatic breast cancer: a real-life multicentre national study.

BACKGROUND: For luminal metastatic breast cancer (MBC), endocrine therapy (ET) is the recommended initial treatment before chemotherapy. Our objective was to evaluate the efficacy of multiple ET lines in a real-life study. METHODS: The Breast Cancer Epidemiological Strategy and Medical Economics (ESME) project analysed data from all patients with systemic treatment for MBC initiated between 2008 and 2014 in one of the 18 French Comprehensive Cancer Centres. The primary end-point was the successive progression-free survival (PFS) evaluation. RESULTS: The ESME research programme included 9921 patients with hormone receptor-positive (HR+)/human epidermal growth factor receptor 2 (HER2) negative (HER2-) MBC. Before any chemotherapy, 4195 (43.4%), 1252 (29.8%) and 279 (6.6%) patients received one, two or three ET ± targeted therapy, respectively. The median PFS for first-, second- and third-line ET ± targeted therapy was 11.5 (95% confidence interval [CI], 10.8-12.1), 5.8 (95% CI, 5.3-6.1) and 5.5 (95% CI, 4.6-6.3) months, respectively. In a multivariate analysis, time from diagnosis to metastatic recurrence (P < 0.0001), presence of symptoms at metastatic relapse (P = 0.01), number of metastatic sites (P = 0.0003) and their localisation (P < 0.0001) were prognostic factors for PFS1. Duration of previous PFS was the only prognostic factor for subsequent PFS (10% threshold). Ten percent of the patients showed long-term response to ET, with a total treatment duration before chemotherapy ≥43.6 months. CONCLUSIONS: Median PFS in our HR+/HER2- real-life cohort is similar to median first-line PFS reported in clinical trials, regardless of ET used as second- and third-line treatment. Despite the international consensus on early initiation of ET, the latter is not prescribed in most of the cases. Patients with a low tumour burden may achieve prolonged response on ET.

Use of letrozole after aromatase inhibitor-based therapy in postmenopausal breast cancer (NRG Oncology/NSABP B-42): a randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: The optimal duration of extended therapy with aromatase inhibitors in patients with postmenopausal breast cancer is unknown. In the NSABP B-42 study, we aimed to determine whether extended letrozole treatment improves disease-free survival after 5 years of aromatase inhibitor-based therapy in women with postmenopausal breast cancer. METHODS: This randomised, double-blind, placebo-controlled, phase 3 trial was done in 158 centres in the USA, Canada, and Ireland. Postmenopausal women with stage I-IIIA hormone receptor-positive breast cancer, who were disease-free after about 5 years of treatment with an aromatase inhibitor or tamoxifen followed by an aromatase inhibitor, were randomly assigned (1:1) to receive 5 years of letrozole (2·5 mg orally per day) or placebo. Randomisation was stratified by pathological node status, previous tamoxifen use, and lowest bone mineral density T score in the lumbosacral spine, total hip, or femoral neck. The primary endpoint was disease-free survival, defined as time from randomisation to breast cancer recurrence, second primary malignancy, or death, and was analysed by intention to treat. To adjust for previous interim analyses, the two-sided statistical significance level for disease-free survival was set at 0·0418. This study is registered with ClinicalTrials.gov, number NCT00382070, is active, and is no longer enrolling patients. FINDINGS: Between Sept 28, 2006, and Jan 6, 2010, 3966 patients were randomly assigned to receive letrozole (n=1983) or placebo (n=1983). Follow-up information was available for 3903 patients for the analyses of disease-free survival. Median follow-up was 6·9 years (IQR 6·1-7·5). Letrozole treatment did not significantly improve disease-free survival (339 disease-free survival events were reported in the placebo group and 292 disease-free survival events were reported in the letrozole group; hazard ratio 0·85, 95% CI 0·73-0·999; p=0·048). 7-year disease-free survival estimate was 81·3% (95% CI 79·3-83·1) in the placebo group and 84·7% (82·9-86·4) in the letrozole group. The most common grade 3 adverse events were arthralgia (47 [2%] of 1933 patients in the placebo group vs 50 [3%] of 1941 patients in the letrozole group) and back pain (44 [2%] vs 38 [2%]). The most common grade 4 adverse event in the placebo group was thromboembolic event (eight [<1%]) and the most common grade 4 adverse events in the letrozole group were urinary tract infection, hypokalaemia, and left ventricular systolic dysfunction (four [<1%] each). INTERPRETATION: After 5 years of aromatase inhibitor-based therapy, 5 years of letrozole therapy did not significantly prolong disease-free survival compared with placebo. Careful assessment of potential risks and benefits is required before recommending extended letrozole therapy to patients with early-stage breast cancer. FUNDING: National Cancer Institute, Korea Health Technology R&D Project, Novartis.

Long-Term Prognostic Risk After Neoadjuvant Chemotherapy Associated With Residual Cancer Burden and Breast Cancer Subtype.

Purpose To determine the long-term prognosis in each phenotypic subset of breast cancer related to residual cancer burden (RCB) after neoadjuvant chemotherapy alone, or with concurrent human epidermal growth factor receptor 2 (HER2)-targeted treatment. Methods We conducted a pathologic review to measure the continuous RCB index (wherein pathologic complete response has RCB = 0; residual disease is categorized into three predefined classes of RCB index [RCB-I, RCB-II, and RCB-III]), and yp-stage of residual disease. Patients were prospectively observed for survival. Three patient cohorts received paclitaxel (T) followed by fluorouracil, doxorubicin, and cyclophosphamide (T/FAC): original development cohort (T/FAC-1), validation cohort (T/FAC-2), and independent validation cohort (T/FAC-3). Another validation cohort received FAC chemotherapy only, and a fifth cohort received concurrent trastuzumab (H) with sequential paclitaxel and fluorouracil, epirubicin, and cyclophosphamide (FEC; H+T/FEC). Phenotypic subsets were defined by hormone receptor (HR) and HER2 status at diagnosis, classified as HR-positive/HER2-negative, HER2-positive (HR-negative/HER2-positive or HR-positive/HER2-positive), or triple receptor-negative. Relapse-free survival estimates were determined from Kaplan-Meier analysis and compared using the log-rank test. Results Five cohorts (T/FAC-1 [n = 219], T/FAC-2 [n = 262], T/FAC-3 [n = 342], FAC [n = 132], and H+T/FEC [n = 203]) had median event-free follow-up of 13.5, 9.1, 6.8, 16.4, and 7.1 years, respectively. Continuous RCB index was prognostic within each phenotypic subset, independent of other clinical-pathologic variables. RCB classes stratified prognostic risk overall, within each phenotypic subset, and within yp-stage categories. Estimates of 10-year relapse-free survival rates in the four RCB classes (pathologic complete response, RCB-I, RCB-II, and RCB-III) were 86%, 81%, 55%, and 23% for triple receptor-negative; 83%, 97%, 74%, and 52% for HR-positive/HER2-negative in the combined T/FAC cohorts; and 95%, 77%, 47%, and 21% in the H+T/FEC cohort. Conclusion RCB was prognostic for long-term survival after neoadjuvant chemotherapy in all three phenotypic subsets of breast cancer. Our institutional findings should be externally validated.

[Study on effect of total matrines and extracts from Periplaneta americana on negative endometrial cancer cell JEC of progesterone receptors].

To study the effect of total matrines and extracts from Periplaneta americana on negative endometrial cancer cell JEC of progesterone receptors. After detecting the effect of total matrine, extracts from P. americana and their combination on JEC cells' growth inhibition, cell cycle, P53 and c-erbB-2 gene protein expressions through MTT, flow cytometry instrument and Western blot method, the author found that, (1) MTT: total matrines and extracts from P. americana could inhibit the growth of JEC cell, with significant increase in the inhibitory effect in the combination group. (2) Flow cytometry instrument: the cell cycle at G0/G1 increased after the treatment with total matrines, the cell cycle at G2/M increased after the treatment with extracts from periplaneta americana, and the ratio of G0/G1 cell cycle in the combination group was significantly higher than the other groups, with inhibition in cell growth and statistical difference in inter-group comparison (P < 0.05). (3) Western blot: the expression level of P53 increased and c-erbB-2 decreased after the treatment with total matrines, extracts from P. americana and their combination on JEC cell, with statistical difference in inter-group comparison (P < 0.05). The above results suggested that total matrines, extracts from P. americana and their combination could induce cell cycle arrest and inhibit the growth of JEC cell by up-regulating P53 and down-regulating the c-erbB-2 level.

The Actual Role of Receptors as Cancer Markers, Biochemical and Clinical Aspects: Receptors in Breast Cancer.

A biomarker is a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention. The discovery and development of proper biomarkers is a critical part of modern oncology. Among the many different types of biomarkers, cell receptors have demonstrated important roles as diagnostic, prognostic, and predictive biomarkers in cancer research and therapy, leading to their integration into drug development trials. In breast cancer, Estrogen/Progesterone receptors and HER2/neu receptors are two good examples of biomarkers that are prognostic of outcomes, as well as predictive of response to certain therapies. Limitations exist, however, such as the invasive procedures required obtaining tissue, and the difficulty measuring the actual distribution of the receptors. Thus, continued efforts to develop receptors as comprehensive cancer biomarkers with novel approaches is mandated to further advance the modern oncology.

Clinical utility of genetic signatures in selecting adjuvant treatment: Risk stratification for early vs. late recurrences.

Adjuvant endocrine therapy (ET) reduces the odds of distant recurrence and mortality by nearly one-half in women with hormone receptor (HR) positive early stage breast cancer. While the risk of recurrence is lower for HR positive than negative patients during the first 5-7 years, HR positive patients suffer ongoing recurrences between 0.5 and 2% year over subsequent years. Extended adjuvant ET further reduces recurrence during this late phase of follow-up. ET is associated with post-menopausal side effects (hot flashes, sexual dysfunction, mood changes, and weight gain), and occasional major toxicities (thrombosis and endometrial cancer with tamoxifen; bone mineral loss and possibly heart disease with AIs) persist throughout therapy. Accurate and reliable estimates of the risk of recurrence after five years of ET for women with prior HR positive breast cancer would permit appropriate extended ET decisions. The risk of long-term relapse is related to lymph node status and size of tumor, but these are relatively crude. Several groups have investigated whether multi-parameter tumor biomarker tests might identify those patients whose risk of recurrence is so low that extended ET is not justified. These assays include IHC4, the 21-gene "OncotypeDX", the 12-gene "Endopredict," the PAM50, and the 2-gene "Breast Cancer Index (BCI)" assays. The clinical validity of all these tests for this use context have been established, with at least one paper for each that shows a statistically significant difference in risk of distant recurrence during the 5-10 years after the initial five years of adjuvant endocrine therapy. However, the stakes are high, and although each of these represents a "prospective retrospective" study, they require further validation in subsequent datasets before they should be considered to have "clinical utility" and are used to withhold potentially life-saving treatment. Perhaps more importantly, the clinical breast cancer community, and especially the patient, need to determine how low the risk of late recurrence needs to be to forego the toxicities and side effects of extended adjuvant ET.

Mammographic breast density: Predictive value for pathological response to neoadjuvant chemotherapy in breast cancer patients.

BACKGROUND: This study aims to evaluate the relation between mammographic breast density (BD) and pathological response to neoadjuvant chemotherapy. METHODS: In this retrospective study, 241 breast cancer patients who received neoadjuvant chemotherapy were included. BD was assessed in mammograms already performed at diagnosis. Pathological complete response (pCR) and pathological stage were correlated with BD, tumour phenotype and other clinico-pathological factors. RESULTS: Patients with low BD had better pCR compared to those with high density (30.5% vs 19.5% respectively, OR = 1.8, 95% CI = 0.98-3.3, p = 0.056) which was more pronounced after adjustment with body mass index (BMI) (OR = 2.4, 95% CI = 1.2-4.8, p = 0.011). HER2-positive disease (32.5% vs. 18.4%, OR = 2.2, 95% = 1.2-4.0, p = 0.01), lower BMI (OR = 1.1, 95% CI = 1.03-1.15, p = 0.004) and lower clinical stage (p = 0.002) were significant predictors of pCR in univariate analysis. In multivariate analysis, low BD (OR = 2.7, 95% CI = 1.3-5.5, p = 0.006) and lower BMI (OR = 1.1, 95% CI = 1.03-1.17, p = 0.003) were independent predictors of better pCR, while early clinical stage (I, II) was of borderline significance (OR = 2.6, 95% CI = 0.99-6.7, p = 0.052). High BD (OR = 1.8, 95% CI = 1.1-3.2, p = 0.03), advanced clinical stage (III) (OR = 1.5, 95% CI = 1.03-2.1, p = 0.03) and higher BMI (OR = 1.06, 95% CI = 1.02-1.11, p = 0.006) were significant predictors of advanced pathological stage. CONCLUSION: Low mammographic BD, low BMI and early clinical stage were associated with improved pCR rate and lower pathological stage after neoadjuvant chemotherapy. BD had more pronounced association with response to chemotherapy after adjustment with BMI.

The actual scenario of neoadjuvant chemotherapy of breast cancer in developing country: a report of 80 cases of breast cancer from a tertiary cancer center in India.

BACKGROUND: Preoperative or neoadjuvant chemotherapy is an option in patients with large operable breast cancer to facilitate the breast conservation and to downstage the disease to make inoperable breast cancer to operable one. It is also called the window of opportunity; it provides a unique opportunity to derive biological information related to tumor response. Neoadjuvant chemotherapy has been compared with standard, postoperative adjuvant chemotherapy with goals of improving survival and facilitating local therapies. Unfortunately, neoadjuvant chemotherapy does not seem to improve overall survival. There is a lack of data from India regarding the neoadjuvant chemotherapy. The present study was carried out to assess the response to neoadjuvant chemotherapy in breast cancer. MATERIALS AND METHODS: We retrospectively analyzed the records of patients who were started on neoadjuvant chemotherapy (NACT) at our center for 1 year (August 2012 to July 2013). Case files were thoroughly reviewed, and patient's characteristics (age, pre-/postmenopausal status, family history of breast/ovarian/other cancer), mode of detection, treatment, and histological features were analyzed. RESULTS: Out of 322 patients with breast cancer registered in our institute, 80 patients received neoadjuvant chemotherapy. Median age was 45 years. The most common presentation was left-sided breast lump (Lt > Rt) with a median duration of symptoms was 4 months. Postmenopausal patients (53.75 %) were more than premenopausal (46.25 %). Seventy-two patients were stage III and 8 were stage II disease. Bilateral breast cancer was seen in 8 patients. Most common histological type was invasive ductal carcinoma (95 %). Estrogen receptor (ER) and/or progesterone (PR) positive were seen in 47 (58.75 %) patients. Ten patients were HER2 positive and ER/PR negative, and 5 patients were triple positive. Triple-negative patients were 22 (27.5 %). The most common neoadjuvant chemotherapy protocol used was FEC. Clinical response before surgery was CR 13 %, PR 68.68 %, stable disease 11.62 %, and progressive disease 4.65 %. Pathological CR was seen in 6.9 % of tumors. Nodal status at surgery was ypN0-40 %, ypN1-28. 5 %. ypN2-27 %, and ypN3-4.28 %. CONCLUSION: In a population of predominantly locally advanced patients, NACT with anthracyclines yielded pCR rates comparable to published studies. There were a high proportion of HER2-positive patients, most of whom could not receive anti-HER2 therapy due to financial reasons.

Distant invasive breast cancer recurrence risk in human epidermal growth factor receptor 2-positive T1a and T1b node-negative localized breast cancer diagnosed from 2000 to 2006: a cohort from an integrated health care delivery system.

PURPOSE: To determine the invasive recurrence (IR) risk among patients with small, node-negative human epidermal growth factor receptor 2 (HER2) -positive breast cancer. PATIENTS AND METHODS: Among 16,975 consecutive patients with invasive breast cancer diagnosed from January 1, 2000, to December 31, 2006, in a large, integrated health care system, we identified a cohort of 234 patients with HER2-positive T1aN0M0 or T1bN0M0 (T1abN0M0) disease with a median follow-up of 5.8 years. Kaplan-Meier methods were used to estimate the percentage of patients who were free of invasive recurrence (recurrence-free interval [RFI]) at 5 years for both distant (DRFI) and local (LRFI) recurrences. RESULTS: Of 15 IRs, 47% were locoregional only. Among T1ab patients not treated with adjuvant trastuzumab or chemotherapy (n = 171), the 5-year invasive DRFI was 98.2% (95% CI, 94.5% to 99.4%); it was 99.0% (95% CI, 93.0% to 99.9%) for T1a patients, and 97.0% (95% CI, 88.6% to 99.2%) for T1b patients. Locoregional plus distant 5-year invasive RFI was 97.0% (95% CI, 90.9% to 99.0%) for T1a and 91.9% (95% CI, 81.5% to 96.6%) for T1b patients; it was 89.4% (95% CI, 70.6% to 96.5%) for T1b tumors reported at 1.0 cm. T1b tumors reported at 1.0 cm accounted for 24% of the T1ab cohort, 61% of the cohort total tumor volume, and 75% of distant recurrences. Invasive RFI for T1b 1.0 cm tumors was lower than that for T1a tumors: 84.5% versus 97.4% (P = .009). CONCLUSION: The distant IR risk of T1a HER2-positive breast cancer appears quite low. The distant IR risk in T1b patients, particularly those with 1.0-cm tumors, is higher. Potential risk differences for T1a and T1b, including the 1.0-cm tumors, should be considered when making treatment decisions.

Outcomes by tumor subtype and treatment pattern in women with small, node-negative breast cancer: a multi-institutional study.

PURPOSE: Treatment decisions for patients with T1a,bN0M0 breast cancer are challenging. We studied the time trends in use of adjuvant chemotherapy and survival outcomes among these patients. PATIENTS AND METHODS: This was a prospective cohort study within the National Comprehensive Cancer Network Database that included 4,113 women with T1a,bN0M0 breast cancer treated between 2000 and 2009. Tumors were grouped by size (T1a, T1b), biologic subtype defined by hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) status, and receipt of chemotherapy with or without trastuzumab. RESULTS: Median follow-up time was 5.5 years. Eight percent of patients with HR-positive/HER2-negative tumors were treated with chemotherapy. Fifty-two percent of those with HER2-positive or HR-negative/HER2-negative breast cancers received chemotherapy, with an increase over the last decade. Survival outcomes diverged by subtype and size, but the 5-year distant relapse-free survival (DRFS) did not exceed 10% in any subgroup. The 5-year DRFS for patients with T1a tumors untreated with chemotherapy ranged from 93% to 98% (n = 49 to 972), and for patients with T1b tumors, it ranged from 90% to 96% (n = 17 to 2,005). Patients with HR-positive/HER2-negative disease had the best DRFS estimates, and patients with HR-negative/HER2-negative tumors had the lowest. In this observational, nonrandomized cohort study, the 5-year DRFS for treated patients with T1a tumors was 100% for all subgroups (n = 12 to 33), and for patients with T1b tumors, it ranged from 94% to 96% (n = 88 to 241). CONCLUSION: Women with T1a,b tumors have an excellent prognosis without chemotherapy. Size and tumor subtype may identify patients in whom the rate of recurrence justifies consideration of chemotherapy. These patients represent an optimal group for evaluating less toxic adjuvant regimens to maintain efficacy while minimizing short- and long-term risks.

HAGE (DDX43) is a biomarker for poor prognosis and a predictor of chemotherapy response in breast cancer.

BACKGROUND: HAGE protein is a known immunogenic cancer-specific antigen. METHODS: The biological, prognostic and predictive values of HAGE expression was studied using immunohistochemistry in three cohorts of patients with BC (n=2147): early primary (EP-BC; n=1676); primary oestrogen receptor-negative (PER-BC; n=275) treated with adjuvant anthracycline-combination therapies (Adjuvant-ACT); and primary locally advanced disease (PLA-BC) who received neo-adjuvant anthracycline-combination therapies (Neo-adjuvant-ACT; n=196). The relationship between HAGE expression and the tumour-infiltrating lymphocytes (TILs) in matched prechemotherapy and postchemotherapy samples were investigated. RESULTS: Eight percent of patients with EP-BC exhibited high HAGE expression (HAGE+) and was associated with aggressive clinico-pathological features (Ps<0.01). Furthermore, HAGE+expression was associated with poor prognosis in both univariate and multivariate analysis (Ps<0.001). Patients with HAGE+did not benefit from hormonal therapy in high-risk ER-positive disease. HAGE+and TILs were found to be independent predictors for pathological complete response to neoadjuvant-ACT; P<0.001. A statistically significant loss of HAGE expression following neoadjuvant-ACT was found (P=0.000001), and progression-free survival was worse in those patients who had HAGE+residual disease (P=0.0003). CONCLUSIONS: This is the first report to show HAGE to be a potential prognostic marker and a predictor of response to ACT in patients with BC.

Effects of zoledronic acid on bone mineral density in premenopausal women receiving neoadjuvant or adjuvant therapies for HR+ breast cancer: the ProBONE II study.

UNLABELLED: The effects of bisphosphonates on altered bone turnover marker (BTM) levels associated with adjuvant endocrine or chemotherapy in early breast cancer have not been systematically investigated. In ProBONE II, zoledronic acid decreased these elevated BTM levels and increased bone mineral density (BMD) during adjuvant therapy, consistent with its antiresorptive effects. INTRODUCTION: Adjuvant chemotherapy or endocrine therapy for early hormone receptor-positive breast cancer (HR(+) BC) is associated with rapid BMD loss and altered BTM levels. Adjuvant bisphosphonate studies demonstrated BMD increases, but did not investigate BTM effects. The randomized, double-blind, ProBONE II study investigated the effect of adjuvant zoledronic acid (ZOL) on BMD and BTM in premenopausal women with early HR(+) BC. METHODS: Seventy premenopausal women with early HR(+) BC received adjuvant chemotherapy and/or endocrine therapy plus ZOL (4 mg IV every 3 months) or placebo for 24 months. Primary endpoint was change in lumbar spine BMD at 24 months versus baseline. Secondary endpoints included femoral neck and total femoral BMD changes, changes in BTM, and safety. RESULTS: Lumbar spine BMD increased 3.14% from baseline to 24 months in ZOL-treated participants versus a 6.43% decrease in placebo-treated participants (P < 0.0001). Mean changes in T- and Z-scores, and femoral neck and total femoral BMD, showed similar results. Bone resorption marker levels decreased ∼ 55% in ZOL-treated participants versus increases up to 65% in placebo-treated participants (P < 0.0001 for between-group differences). Bone formation marker (procollagen I N-terminal propeptide) levels decreased ∼ 57% in ZOL-treated participants versus increases up to 45% in placebo-treated participants (P < 0.0001 for between-group differences). Adverse events were consistent with the established ZOL safety profile and included one case of osteonecrosis of the jaw after a tooth extraction. CONCLUSIONS: Adding ZOL to adjuvant therapy improved BMD, reduced BTM levels, and was well tolerated in premenopausal women with early HR(+) BC receiving adjuvant chemotherapy and/or endocrine therapy.

Clinicopathological profile of female Sudanese patients with locally advanced breast cancer.

BACKGROUND: In Sudan, breast cancer is one of the most common malignancy affecting women and the incidence rates appear to be rising. Unfortunately, most of the patients presented in advanced stage. OBJECTIVE: To obtain information on demographic characteristics, clinicopathological profile and factors related to late presentation. MATERIALS AND METHODS: Descriptive study. 144 patients who presented from April 2009 through May 2011 with locally advanced breast cancer were included in this study. RESULTS: 144 patients ranging in age from 25-71 years (mean 47 years) were included in the study. Of these 62.5% were premenopausal women. More than 60% of the patients presented after > 1 year following onset of symptoms. 68% of patients attributed their late presentation for lack of education and financial aspects. CONCLUSION: Our study shows that locally advanced breast cancer patients presented at a younger age. Lack of education, financial issues and dependency on traditional medicine are encountered for this late presentation. We suggest that the attitude of Sudanese females towards breast cancer has to change through continuous but targeted public education.

Differential sensitivity of Pak5, Pak6, and Pak5/Pak6 double-knockout mice to the stimulant effects of amphetamine and exercise-induced alterations in body weight.

OBJECTIVES: PAK5 and PAK6 are protein kinases highly expressed in the brain. Previously, we observed that Pak6 knockout mice gained significantly more weight during development than Pak5 knockout mice as well as wild-type controls and double-knockout mice lacking both Pak5 and Pak6. In this study, we assessed the effects of exercise on food intake and weight gain of these mice as well as their sensitivity to the stimulant effects of amphetamine. METHODS: Mice of each genotype were placed in cages with free access to run wheel exercise or in cages without run wheels for a total of 74 days. Food and fluid intake as well as body weight of each mouse were measured on a weekly basis. Finally, mice were given a high dose of amphetamine and activity levels were observed immediately thereafter for 90 minutes. Brains and testes of mice were assayed for protein levels of the estrogen alpha and progesterone receptors. RESULTS: While run wheel mice consumed significantly more food, they weighed less than non-run wheel mice. In addition, although Pak6 knockout mice consumed the same amount of food as wild-type mice, they were significantly heavier regardless of run wheel condition. Pak5 knockout mice were found to be more active than other genotypes after amphetamine treatment. Finally, protein levels of the progesterone and estrogen alpha receptors were altered in brain and testes of the Pak6 knockout mice. DISCUSSION: Collectively, these data suggest that PAK6 play a role in weight gain unrelated to exercise and caloric intake and that Pak5 knockout mice are more sensitive to the stimulant effects of amphetamine.

Young breast cancer: A single center experience.

BACKGROUND: Breast cancer in women aged less than 35 years is uncommon and accounts for 1-2% of all breast cancer in the West. There is a paucity of data on young breast cancer from India. The aim of this study was to analyze the clinical, pathological, prognostic factors and outcome in young breast cancer patients. MATERIALS AND METHODS: This analysis was performed in 251 patients aged <35 years or less (defined as breast cancer in the young), who were registered at our institute over an 11 year period between 2001 and 2011. RESULTS: The median age was 31 years (range 18-35). Positive family history (siblings and parents) was elicited in only 10 patients. The TNM stage distribution was: Stage I was 2.5%, stage II - 20.5%, stage III - 55% and stage IV - 22%. The median clinical tumor size was 5.1 cm. Modified radical mastectomy was the most common surgical procedure and this was done in 79% of cases. 40% of tumors were high grade and 60% had pathological node positive disease. Estrogen and Progesterone and human epidermal growth factor receptor 2/neu positivity were 33% and 29% respectively. Triple negative breast cancer constituted 31% of patients. With a median follow-up of 30 months, 3 years relapse free survival and overall survival was 51% and 66%. CONCLUSION: Young women constituted 8% of breast cancer cases. Advanced disease at presentation and triple negativity (nearly one third of patients) results poor outcome.

The effect of estradiol, progesterone, and melatonin on estrous cycling and ovarian aromatase expression in intact female mice.

OBJECTIVE: Melatonin and progesterone levels decline during the perimenopause. Both hormones inhibit estrogen action and endometrial cancer, but little is known about how they act in combination. Therefore, the interplay of progesterone (P4) and melatonin was investigated in intact female mice. STUDY DESIGN: Three P4 doses, low (25mg), mid (50mg), and high (100mg), combined with 0.5mg 17ß-estradiol (E), were administered in the diet (per 1800kcal) for 30 days. Hormone therapy (HT) with the low P4 dose (estradiol/low progesterone replacement therapy (EPLRT)) was used to create an excess estrogen environment to mimic perimenopause. Half the mice were treated with melatonin (M) 15mg/L in the drinking water at night. RESULTS: The unbalanced EPLRT treatment increased estrogen-regulated responses. Specifically, mice treated with EPLRT had significantly higher levels of ovarian aromatase mRNA versus control, which was prevented in the presence of higher doses of P4 and/or the addition of melatonin. The number of days in estrus also increased in EPLRT-treated versus control mice with no change in the length or number of complete estrous cycles. Melatonin, combined with all doses of P4, increased the number of days spent in estrus, but not the length or number of estrous cycles compared to melatonin alone; however, two-way ANOVA revealed a significant interaction between melatonin and P4 dose for days in estrus and for number of cycles. Although none of the E2 and P4 combinations significantly affected uterine weight compared to control, melatonin addition to the low or mid P4 HT resulted in slightly higher uterine weights compared to melatonin-treated mice. Melatonin significantly increased uterine estrogen receptor alpha (ERα) and progesterone receptor A levels compared to control animals. HT, added in combination with melatonin, reduced ERα levels back to control levels, but PR levels remained elevated albeit intermediary to those achieved with melatonin alone. CONCLUSION: The findings that melatonin supplementation inhibits ovarian aromatase expression and increases uterine receptors in mice given an HT that mimics perimenopause may have important clinical applications for the improvement of menopause-related conditions, like menorrhagia, associated with high levels of E2 and low levels of P4.