Androgen receptor status predicts response to chemotherapy, not risk of breast cancer in Indian women

<p>Abstract</p> <p>Background</p> <p>Considerably little is known about the biological role and clinical significance of androgen receptor expression in breast cancer. The objectives of this study were to characterize <it>AR</it>-CAG repeat genotypes in a cohort of women with breast cancer and to determine the influence of AR on response to neoadjuvant chemotherapy and clinical outcome.</p> <p>Materials and methods</p> <p>Genotyping of the <it>AR </it>CAG repeat region was done on 70 patients and 80 healthy aged- matched female controls. To assess response to NACT, tissue samples from 30 LABC cases were evaluated quantitatively by real time for AR mRNA expression. The clinical response was correlated with both the pre and post chemotherapy AR expression. The CAG alleles did not show differences between cases and controls when the mean of short, long and average length of both CAG alleles was considered. However, analysis when done defining short allele as CAGn < 20 (AR1) and the long as CAGn ≥ 20 (AR2), risk was found associated with AR2 allele with marginal significance (P = 0.09). Stratification by age of onset, FH, stage, grade ER and AR status failed to reveal any association with breast cancer risk. Genotype carriers with ≥20 CAGn showed decrease of AR mRNA expression although significance could not be established (P = 0.47). Tumours in responders had the higher AR mRNA expression levels in pre neo-adjuvant chemotherapy condition (p < 0.02) which got reduced after neoadjuvant chemotherapy and the difference was found to be significant (P = 0.014).</p> <p>Conclusions</p> <p>Although, expansion of the CAGn in the <it>AR </it>gene doesn't show any major effect on breast cancer risk, patients with positive AR expression, pre neoadjuvant chemotherapy, were found to be good responders and a decrease in mRNA level of <it>AR </it>gene related to the chemotherapy-induced apoptosis could serve as an important independent predictor of response to NACT.</p

Role of p-glycoprotein expression in predicting response to neoadjuvant chemotherapy in breast cancer-a prospective clinical study

BACKGROUND: Neoadjuvant chemotherapy (NACT) is an integral part of multi-modality approach in the management of locally advanced breast cancer. It is vital to predict response to chemotherapy in order to tailor the regime for a particular patient. The prediction would help in avoiding the toxicity induced by an ineffective chemotherapeutic regime in a non-responder and would also help in the planning of an alternate regime. Development of resistance to chemotherapeutic agents is a major problem and one of the mechanisms considered responsible is the expression of 170-k Da membrane glycoprotein (usually referred to as p-170 or p-glycoprotein), which is encoded by multidrug resistance (MDR1) gene. This glycoprotein acts as an energy dependent pump, which actively extrudes certain families of chemotherapeutic agents from the cells. The expression of p-glycoprotein at initial presentation has been found to be associated with refractoriness to chemotherapy and a poor outcome. Against this background a prospective study was conducted using C219 mouse monoclonal antibody specific for p-glycoprotein to ascertain whether pretreatment detection of p-glycoprotein expression could be utilized as a reliable predictor of response to neoadjuvant chemotherapy in patients with breast cancer. PATIENTS AND METHODS: Fifty cases of locally advanced breast cancer were subjected to trucut(® )biopsy and the tissue samples were evaluated immunohistochemically for p-glycoprotein expression and ER, PR status. The response to neoadjuvant chemotherapy was assessed clinically and by using ultrasound after three cycles of FAC regime (cyclophosphamide 600 mg/m(2), Adriamycin 50 mg/m(2), 5-fluorourail 600 mg/m(2 )at an interval of three weeks). The clinical response was correlated with both the pre and post chemotherapy p-glycoprotein expression. Descriptive studies were performed with SPSS version 10. The significance of correlation between tumor response and p-glycoprotein expression was determined with chi square test. RESULTS: A significant relationship was found between the pretreatment p-glycoprotein expression and clinical response. The positive p-glycoprotein expression was associated with poor clinical response rates. When the clinical response was correlated with p-glycoprotein expression, a statistically significant negative correlation was observed between the clinical response and p- glycoprotein expression (p < 0.05). There was another significant observation in terms of development of post NACT p-glycoprotein positivity. Before initiation of NACT, 26 patients (52%) were p-glycoprotein positive and after three cycles of NACT, the positivity increased to 73.5% patients. CONCLUSION: The study concluded that pretreatment p-glycoprotein expression predicts and indicates a poor clinical response to NACT. Patients with positive p-glycoprotein expression before initiation of NACT were found to be poor responders. Thus pretreatment detection of p-glycoprotein expression may be utilized, as a reliable predictor of response to NACT in patients with breast cancer The chemotherapy induced p-glycoprotein positivity observed in the study could possibly explain the phenomenon of acquired chemoresistance and may also serve as an intermediate end point in evaluating drug response particularly if the adjuvant therapy is planned with the same regime

Early tracheostomy in closed head injuries: experience at a tertiary center in a developing country – a prospective study

Abstract Background An important factor contributing to the high mortality in patients with severe head trauma is cerebral hypoxia. The mechanical ventilation helps both by reduction in the intracranial pressure and hypoxia. Ventilatory support is also required in these patients because of patient's inability to protect the airway, persistence of excessive secretions, and inadequacy of spontaneous ventilation. Prolonged endotracheal intubation is however associated with trauma to the larynx, trachea, and patient discomfort in addition to requirement of sedatives. Tracheostomy has been found to play an integral role in the airway management of such patients, but its timing remains subject to considerable practice variation. In a developing country like India where the intensive care facilities are scarce and rarely available, these critical patients have to be managed in high dependency cubicles in the ward, often with inadequately trained nursing staff and equipment to monitor them. An early tracheostomy in the selected group of patients based on Glasgow Coma Score(GCS) may prove to be life saving.Against this background a prospective study was contemplated to assess the role of early tracheostomy in patients with isolated closed head injury. Methods The series consisted of a cohort of 50 patients admitted to the surgical emergency with isolated closed head injury, that were not considered for surgery by the neuro-surgeon or shifted to ICU, but had GCS score of less than 8 and SAPS II score of more than 50. First 50 case records from January 2001 that fulfilled the criteria constituted the control group. The patients were managed as per ATLS protocol and intubated if required at any time before decision to perform tracheostomy was taken. These patients were serially assessed for GCS (worst score of the day as calculated by senior surgical resident) and SAPS scores till day 15 to chart any changes in their status of head injuries and predictive mortality. Those patients who continued to have a GCS score of 50 for more than 24 hours (to rule out concussion or recovery) underwent tracheostomy. All these patients were finally assessed for mortality rate and hospital stay, the statistical analysis was carried out using SPSS10 version. The final outcome (in terms of mortality) was analyzed utilizing chi-square test and p value Results At admission both tracheostomy and non-tracheostomy groups were matched with respect to GCS score and SAPS score. The average day of tracheostomy was 2.18 ± 1.0038 days. The GCS scores on days 1, 2, 3, 4, 5, 10 between tracheostomy and non-tracheostomized group were comparable. However the difference in the GCS scores was statistically significant on day 15 being higher in the tracheostomy group.Thus early tracheostomy was observed to improve the mortality rate significantly in patients with isolated closed head injury Conclusion It may be concluded that early tracheostomy is beneficial in patients with isolated closed head injury which is severe enough to affect systemic physiological parameters, in terms of decreased mortality and intubation associated complications in centers where ICU care is not readily available. Also, in a selected group of patients, early tracheostomy may do away with the need for prolonged mechanical ventilation.</p