Predictors of Toxicity in a Randomized Study of Consolidation Chemoradiation Versus Observation After First Line Chemotherapy in Advanced Gall Bladder Cancers.

Purpose: Gall bladder cancers (GBC) usually presents in advanced stage. First-line chemotherapy (CT) is the standard of care, and there is no other option for responders than to wait for disease progression. We conducted a randomized study of consolidation chemoradiation (CTRT) versus observation in responders to first line CT (NCT05493956), which showed an improvement in overall survival by 6 months and therefore is practice changing. We are reporting the toxicity and factors predicting toxicity due to CTRT so that it informs appropriate patient selection. Methods and Materials: Responders to first line CT (partial response, stable disease) were randomized to CTRT versus observation after 4 cycles. CTRT was delivered by 3D conformal radiotherapy (along-with concurrent capecitabine at 1250 mg/m2) to a dose of 45 Gy in 25 fractions to GBC and lymphatics followed by a boost of 9 Gy in 5 fractions to the GBC. Toxicities documented during CTRT were recorded using the Radiation Therapy Oncology Group criteria. Dose volume data were correlated with the radiation induced side effects. Results: Among 135 patients enrolled both arms are well balanced demographically, and 58% patients had T4 tumors, 42% had N2 and 15% had paraaortic lymph node, and 27% underwent upfront stenting. Grade 3 adverse events, such as anemia, dyspepsia, hepatotoxicity (Child Pugh B), and gastrointestinal bleed due to CTRT was observed in 9%, 1.5%, 13%, and 5.8%, respectively. Age >58 years (P = .02), planning target volume (PTV) 1 volume (>919 cc, P = .02), PTV2 volume (>380 cc, P = .01), mean liver dose (>28 Gy, P = .07), and liver V40 (>50%, P = .02) predicted radiation-induced liver disease. A receiver operating curve analysis revealed a cut-off value of PTV1 volume of 800 cc (sensitivity and specificity of 75% and 54%) and PTV2 volume of 300 cc (sensitivity and specificity of 81% and 65%) for prediction of hepatotoxicity. Duodenum V45 >45% (P = .02) predicted grade 3 anemia. Numerically high V15 duodenum (98%, P = .11), large PTV2 volume >484 cc (P = .06) and prior stenting had predilection for gastrointestinal bleed. Conclusions: Consolidation CTRT is tolerable in those with PTV1 volume less than 800 cc.

Raised carbohydrate antigen 19-9 levels detect recurrences and impacts overall and disease-free survival in radically resected gallbladder cancer: A simple surveillance marker?

Background: There are no established markers which can be used for surveillance after curative resection in gallbladder carcinoma (GBC). Though carbohydrate antigen 19-9 (CA 19-9) has low specificity as a diagnostic marker, its role as a surveillance marker has not been explored. The aim of this study is to evaluate the predictive ability of CA 19-9 as a surveillance marker to detect recurrences on follow-up. Methods: A retrospective analysis of a prospectively maintained database of radically resected GBC who were either on observation or completed adjuvant therapy (chemotherapy or chemoradiation) were followed up 3 monthly with CA 19-9 and ultrasound (US) abdomen for the first 2 years and 6 monthly CA 19-9 and US for further 3 years. Patients with raised CA 19-9 and a recurrent lesion on US abdomen were confirmed with contrast-enhanced computed tomography (CECT) abdomen and fine-needle aspiration cytology (FNAC) of recurrent lesion to establish the diagnosis of recurrence. The performance of CA 19-9 levels (20 and more units/mL) for prediction of recurrence and its impact on survival was estimated. Results: Out of sixty patients on follow-up, 40% recurred: loco-regional (16.7%) and distant metastases (23.4%). The sensitivity, specificity, positive predictive value, and negative predictive value of CA 19-9 in detecting recurrence were 79.1%, 97.2%, 95%, and 87.5%, respectively. The median disease-free survival was 56 months versus 15 months (P = 0.008, hazard ratio [HR]: 7.4 [1.3-40]) and the median overall survival was not reached versus 20 months (P = 0.000, HR: 10.7 [confidence interval 4.2-27.3]) for CA 19-9 levels less than and more than 20 ng/mL. Conclusions: Based on the high positive and negative predictive value in our dataset, CA 19-9 can be used as a surveillance biomarker for follow-up of radically resected GBC. Raised levels of >20 ng/mL should be correlated with imaging findings and any suspicious lesion should be confirmed for recurrence by FNAC and CECT abdomen. Levels >20 ng/mL should be taken as a threshold for suspecting recurrence.

Consolidative radiation in partial responders/unresectable/recurrent disease after first-line/salvage chemotherapy in poor-risk nonseminomatous germ cell tumor prolongs survival: A new paradigm?

The role of radiotherapy (RT) in partial radiographic response (PR)/unresectable has not been evaluated earlier in nonseminomatous germ cell tumor (NSGCT). Can the PR/unresectable be treated with consolidation RT instead of surgery? This approach will allow avoidance of surgical morbidity and be an additional tool for treatment. We report a series of five cases with poor prognosis NSGCT, who were treated with consolidation RT after PR/un-resectable disease and complete serum marker decline. The median survival of these patients was 52 months (range 21-112 months).

Consolidation chemoradiation (cCTRT) improves survival in responders to first-line chemotherapy (CT) in locally advanced gallbladder cancer (LA-GBC): A new standard of care?

Introduction: Chemotherapy (CT) is the standard of care in advanced gallbladder cancer (GBC). Should locally advanced GBC (LA-GBC) with response to CT and good performance status (PS) be offered as consolidation chemoradiation (cCTRT) to delay progression and improve survival? There is a scarcity of literature on this approach in the English literature. We present our experience with this approach in LA-GBC. Materials and Methods: After obtaining ethics approval, we reviewed the records of consecutive GBC patients from 2014 to 2016. Out of 550 patients, 145 were LA-GBC who were initiated on chemotherapy. A contrast-enhanced computed tomography (CECT) abdomen was done to evaluate the response to treatment, according to the RECIST (Response Evaluation Criteria in Solid Tumors) criteria. All responders to CT (PR and SD) with good PS but unresectable were treated with cCTRT. Radiotherapy was given to GB bed, periportal, common hepatic, coeliac, superior mesenteric, and para-aortic lymph nodes up to a dose of 45 to 54 Gy in 25 to 28 fractions along with concurrent capecitabine at the rate of 1,250 mg/m2. Treatment toxicity, overall survival (OS), and factors affecting OS were computed based on Kaplan-Meier and Cox regression analysis. Results: ">The median age of patients was 50 years (interquartile range [IQR] = 43-56 years), and men to women ratio was 1:3. A total of 65% and 35% patients received CT and CT followed by cCTRT, respectively. The incidence of Grade 3 gastritis and diarrhea was 10% and 5%, respectively. Responses were partial response (PR; 65%), stable disease (SD; 12%), progressive disease (PD; 10%), and nonevaluable (NE; 13%) because they did not complete six cycles of CT or were lost to follow-up. Among PR, 10 patients underwent radical surgery (six after CT and four after cCTRT). At a median follow-up of 8 months, the median OS was 7 months with CT and 14 months with cCTRT (P = 0.04). The median OS was 57 months, 12 months, 7 months, and 5 months for complete response (CR) (resected), PR/SD, PD, and NE (P = 0.008), respectively. OS was 10 months and 5 months for Karnofsky performance status (KPS) >80 and <80 (P = 0.008), respectively. PS (hazard ratio [HR] = 0.5), stage (HR = 0.41), and response to treatment (HR = 0.05) were retained as independent prognostic factors. Conclusions: CT followed by cCTRT appears to improve survival in responders with good PS.

Post-chemotherapy target volumes are safe as boost volume for intact breast radiotherapy in locally advanced breast cancer.

PURPOSE: The purpose of our study is to evaluate the challenges in identification of postoperative complexes (POC), the utility of clips in delineation of clinical target volume for boost in LABC downstaged with neoadjuvant chemotherapy (NACT) and to correlate this with patterns of recurrence. METHODS AND MATERIALS: LABC patients who underwent NACT followed by BCS and radiotherapy (2007-2014) were the subject of our analysis. The data on visibility and characteristics of postoperative cavity (POC), concordance of its volume with clip volume on radiation planning scan were retrieved. A 1 cm margin beyond POC was delineated as a clinical target volume (CTV). Postoperative whole breast and supraclavicular radiotherapy (50 Gy/25fractions/5wk or 42.4 Gy/16#/3 wk) followed by boost (10-16 Gy/5-8#/1-1.5wk) were delivered. Patterns of recurrence were evaluated. RESULTS: Out of 60 patients, 28.3% patients had stage II disease and 71.7% had stage III disease. 25% patients achieved pathological CR (complete response). The median POC volume was 30 cc and the median clip volume was 40 cc. The concordance of POC volume with clip volume was seen in 80%. Clips served as a good surrogate for POC in 80% of patients. At a median follow-up of 65 months (IQ range 32-84 months), and a lost to follow-up rate of 11.6 %, 3.3% (n = 2) patients had local recurrence (LR) and 8.3% (n = 5) had regional recurrence (LRR) in the supraclavicular region. CONCLUSIONS: Delineation of post NACT excision cavity as POC for boost radiotherapy is safe. Clips serve as a good surrogate for CTV delineation in 75% patients.

Does CA 19-9 Have Prognostic Relevance in Gallbladder Carcinoma (GBC)?

BACKGROUND: There is a scarce data on prognostic relevance of carbohydrate antigen (CA 19-9). This retrospective study was undertaken to evaluate its prognostic relevance in different prognostic subsets of gallbladder carcinoma (GBC). MATERIALS AND METHODS: One hundred forty-one patients of GBC treated between January 2012 and December 2014 were the subjects of this retrospective analysis. Baseline CA 19-9 levels of four cohorts of patients: extended cholecystectomy (EC), simple cholecystectomy (SC) with residual or recurrent disease, locally advanced disease (LAGBC) and metastatic disease were ascertained. The difference in its median baseline values among above groups was ascertained. The effect of clinicopathological variables, treatment-related variables and CA 19-9 on overall survival (OS) was also evaluated. AUC curve was computed to evaluate its performance. RESULTS: The median baseline levels of CA 19-9 were significantly different [10 units/ml, 24 units/ml, 48 units/ml and 75 units/ml in EC (n = 33), SC (n = 21), LAGBC (n = 38) and metastatic disease (n = 49), respectively, (p value 0.001)]. The median OS was also significantly different [24, 15, 7 and 6 months in EC, SC, LAGBC and metastatic disease, respectively, (p value 0.001)]. Univariate analysis revealed a significant influence of log transformed value of CA 19-9, CA 19-9 levels < or >20 units or 35 units, surgery vs. none and chemoradiation vs. chemotherapy on OS. On multivariate analysis, only treatment-related variables were significant (HR 1.1, 95% CI 1.026-1.19, p = 0.009). AUC curve was 0.63 for all patients and 0.72 for EC group. CONCLUSIONS: The median values of baseline CA 19-9 predict the burden of disease. Raised levels of serum CA 19-9 beyond 20 units/ml should be used for prognostication purposes after EC. A level beyond 35 units has a trend towards prognostication in other prognostic groups and needs to be evaluated in large subset of patients.

Potential for adaptive dose escalation in radiotherapy for patients with locally advanced non-small-cell lung cancer in a low mid income setting.

OBJECTIVE: To evaluate the effect of tumour volume regression on adaptive treatment planning, reduction in doses to organs at risk (OARs) and dose escalation. METHODS: 20 patients undergoing radical chemoradiotherapy were imaged in the fifth week of radiotherapy (CT_45) to evaluate differences in tumour volume regression between concurrent and sequential chemoradiotherapy. Replanning was carried out in the CT_45 in those with >20% regression (n = 10) and evaluated for change in target coverage indices (the coverage index and external volume index) and doses to the OAR [mean lung dose, V20 and V5 of whole and ipsilateral lung (MLDWL, V20WL, V5WL, MLDIL, V20IL, V5IL); mean oesophagus dose, V50oesophagus; and maximum spinal cord doses]. The feasibility of maximum dose escalation was explored keeping the limit of the OAR below their tolerance limits. RESULTS: Tumour regression was higher with concurrent chemoradiotherapy as compared with sequential chemoradiotherapy (p = 0.02). With the adaptive plan, the mean coverage index improved from 0.96 (±0.14) to 1.29 (±0.36), the mean external volume index changed from 1.39(±0.60) to 1.41(±0.56) and the reduction in doses to the OARs were MLDWL 10.6%, V20WL 1.3%, V5WL 1.2%, MLDIL 6.6%, V20IL 1.5%, V5IL 2.3%, mean oesophagus dose 7%, V50oesophagus 31% and maximum cord dose 0.35%. Dose escalation was possible in four patients in CT_45. CONCLUSION: There is 35% reduction in tumour volume with chemoradiotherapy at 45 Gy which allows improvement in conformality, reduction in doses to the OARs and dose escalation in 40% of patients. Advances in knowledge: This article emphasizes that adaptive planning with a single diagnostic scan at 45 Gy has the potential for improvement of radiotherapy planning indices, dose escalation while respecting the dose to the OAR. This simple strategy can be helpful in radiotherapy planning upto 60 Gy in 40% of the patients of locally advanced non-small-cell lung cancer in countries with limited resources.

Radiological Downstaging with Neoadjuvant Therapy in Unresectable Gall Bladder Cancer Cases.

BACKGROUND: Gall bladder cancer (GBC) usually presents as unresectable or metastatic disease. We conducted a feasibility study to evaluate the effect of neoadjuvant therapy (NAT) on radiologic downstaging and resectability in unresectable GBC cases. MATERIALS AND METHODS: Patients with locally advanced disease were treated with chemoradiotherapy [CTRT] ( external radiotherapy (45Gy) along with weekly concurrent cisplatin 35mg/ m2 and 5-FU 500 mg) and those with positive paraaortic nodes were treated with neoadjuvant chemotherapy [NACT (cisplatin 25mg/m2 and gemcitabine 1gm/m2 day 1 and 8, 3 weekly for 3 cycles). Radiological assessment was according to RECIST criteria by evaluating downstaging of liver involvement and lymphadenopathy into complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD). RESULTS: A total of 40 patients were evaluated from January 2012 to December 2014 (CTRT=25, NACT=15). Pretreatment CT scans revealed involvement of hilum (19), liver infiltration (38), duodenum involvement (n=22), colon involvement (n=11), N1 involvement (n=11), N2 disease (n=8), paraaortic LN (n=15), and no lymphadenopathy (n=6). After neoadjuvant therapy, liver involvement showed CR in 11(30%), PR in 4 (10.5%), SD in 15 (39.4%) and lymph node involvement showed CR in 17 (50%), PR in 6 (17.6%), SD in 4 (11.7 %). Six patients (CTRT=2, NACT=4) with 66.6 % and 83% downstaging of liver and lymphnodes respectively underwent extended cholecystectomy. There was 16.6 % and 83.3% rates of histopathological CR of liver and lymph nodes. All resections were R0. CONCLUSIONS: Neoadjuvant therapy in unresectable gall bladder cancer results in a 15% resectability rate. This approach has a strong potential in achieving R0 and node negative disease. Radiologic downstaging (CR+PR) of liver involvement is 40.5% and lymphadenopathy is 67.5%. Nodal regression could serve as a predictor of response to neoadjuvant therapy.

Association of Wnt signaling pathway genetic variants in gallbladder cancer susceptibility and survival.

Gallbladder cancer (GBC) is the most common malignancy of the biliary tract with adverse prognosis and poor survival. Wnt signaling plays an important role in embryonic development and regeneration of tissues in all the species. Deregulation of expression and mutations in this pathway may lead to disease state such as cancer. In this study, we assessed the association of common germline variants of Wnt pathway genes (SFRP2, SFRP4, DKK2, DKK3, WISP3, APC, ß-catenin, AXIN-2, GLI-1) to evaluate their contribution in predisposition to GBC and treatment outcomes. The study included 564 GBC patients and 250 controls. Out of 564, 200 patients were followed up for treatment response and survival. Tumor response (RECIST 1.1) was recorded in 116 patients undergoing non-adjuvant chemotherapy (NACT). Survival was assessed by Kaplan-Meier curve and Cox-proportional hazard regression. Single locus analysis showed significant association of SFRP4 rs1802073G > T [p value = 0.0001], DKK2 rs17037102C > T [p value = 0.0001], DKK3 rs3206824C > T [p value = 0.012], APC rs4595552 A/T [p value = 0.021], APC rs11954856G > T [p value = 0.047], AXIN-2 rs4791171C > T [p value = 0.001], ß-catenin rs4135385A > G [p value = 0.031], and GLI-1 rs222826C > G [p value = 0.001] with increased risk of GBC. Gene-gene interaction using GMDR analysis predicted APC rs11954856 and AXIN2 rs4791171 as significant in conferring GBC susceptibility. Cox-proportional hazard model showed GLI-1 rs2228226 CG/GG and AXIN-2 rs4791171 TT genotype higher hazard ratio. In recursive partitioning, AXIN-2 rs4791171 TT genotype showed higher mortality and hazard. Most of studied genetic variants influence GBC susceptibility. APC rs11954856, GLI-1 rs2228226, and AXIN-2 rs4791171 were found to be associated with poor survival in advanced GBC patients.

Association of cancer stem cell markers genetic variants with gallbladder cancer susceptibility, prognosis, and survival.

Genes important to stem cell progression have been involved in the genetics and clinical outcome of cancers. We investigated germ line variants in cancer stem cell (CSC) genes to predict susceptibility and efficacy of chemoradiotherapy treatment in gallbladder cancer (GBC) patients. In this study, we assessed the effect of SNPs in CSC genes (surface markers CD44, ALCAM, EpCAM, CD133) and (molecular markers NANOG, SOX-2, LIN-28A, ALDH1A1, OCT-4) with GBC susceptibility and prognosis. Total 610 GBC patients and 250 controls were genotyped by using PCR-RFLP, ARMS-PCR, and TaqMan allelic discrimination assays. Chemotoxicity graded 2-4 in 200 patients and tumor response was recorded in 140 patients undergoing neoadjuvant chemotherapy (NACT). Differences in genotype and haplotype frequency distributions were calculated by binary logistic regression. Gene-gene interaction model was analyzed by generalized multifactor dimensionality reduction (GMDR). Overall survival was assessed by Kaplan-Meier survival curve and multivariate Cox-proportional methods. ALCAM Ars1157Crs10511244 (P = 0.0035) haplotype was significantly associated with GBC susceptibility. In GMDR analysis, ALCAM rs1157G>A, EpCAM rs1126497T>C emerged as best significant interaction model with GBC susceptibility and ALDH1A1 rs13959T>G with increased risk of grade 3-4 hematological toxicity. SOX-2 rs11915160A>C, OCT-4 rs3130932T>G, and NANOG rs11055786T>C were found best gene-gene interaction model for predicting response to NACT. In both Cox-proportional and recursive partitioning ALCAM rs1157GA+AA genotype showed higher mortality and hazard ratio. ALCAM gene polymorphisms associated with GBC susceptibility and survival while OCT-4, SOX-2, and NANOG variants showed an interactive role with treatment response.

Evaluation of miR-27a, miR-181a, and miR-570 genetic variants with gallbladder cancer susceptibility and treatment outcome in a North Indian population.

INTRODUCTION: miR-27a, miR-181a, and miR-570 genetic variants have been found to play an important role in many cancers, but their contribution in gallbladder carcinoma (GBC) has not been explored. Therefore, we investigated the role of these micro RNA (miRNA) genetic variants in terms of GBC susceptibility, therapeutic response, toxicities associated with chemo-radiotherapy and survival outcome. METHODS: This study included 606 GBC patients and 200 healthy controls. From among the larger study cohort, 219 patients receiving adjuvant or palliative chemo-radiotherapy as per disease status were followed up for toxicity profile. Treatment response was recorded in 159 patients who received palliative chemo-radiotherapy. Genotypes were determined using allelic discrimination assay. Statistical analysis was carried out with SPSS version 16. Generalized multifactor dimensionality reduction (GMDR) analysis was performed for gene-gene interactions. Survival analysis was performed using Kaplan-Meier and Cox regression tests. RESULTS: In univariate logistic regression analysis, no association with any of the studied polymorphisms was found in overall GBC susceptibility. Furthermore, univariate and multivariate analyses revealed no significant association with response to chemo-radiotherapy. In GMDR analysis, miR-27ars895819, miR-570rs4143815, and miR-181ars12537 combination was found as the best gene-gene interaction model for susceptibility and treatment response. Furthermore, miR-27ars895819miR-181ars12537 was associated with neutropenia toxicity in patients undergoing chemo-radiotherapy. However, miRNA variants had no influence over the survival outcomes of GBC patients (locally advanced, metastatic). CONCLUSION: In conclusion, the miRNA variants cumulatively influence GBC susceptibility and treatment outcomes.

Relationship of MTHFR and NQO1 Pharmacogenetics and Chemotherapy Clinical Outcomes in Breast Cancer Patients.

The study aimed at evaluating the influence of MTHFR 677C>T and NQO1 609C>T polymorphisms in toxicity and response to chemotherapy in breast cancer patients. These two genes are involved in the folate homeostasis and bioactivation of chemotherapeutic drugs, respectively. In this study, 243 patients treated with FEC/FAC/methotrexate chemotherapy regimen were recruited and followed up for toxicity (NCI-CTCAE ver. 3). While out of 243 patients, 115 patients who received neo-adjuvant chemotherapy (NACT) were followed for treatment response. Genetic analysis of MTHFR 677C>T and NQO1 609C>T was done by PCR-restriction fragment length polymorphism. We found significant association of variant genotype (TT) of NQO1 609C>T with grade 2-4 toxicity [OR 0.33 (0.13-0.88), P = 0.027] and with grade 2-4 anemia [OR 0.34 (0.12-0.95), P = 0.041]. However, no association of MTHFR 677C>T was seen with either response to NACT or drug-induced toxicity. The study provides useful information for prediction of clinical outcomes in breast cancer patients in terms of NQO1 609C>T by evaluating its association with chemotherapy-induced toxicity.

Human resources for cancer control in uttar pradesh, India: a case study for low and middle income countries.

For addressing the growing burden of cancer in low and middle income countries, an important first step is to estimate the human resources required for cancer control in a country, province, or city. However, few guidelines are available to decision makers in that regard. Here, we propose a methodology for estimating the human and other resources needed in the state of Uttar Pradesh (UP), India as a case study. Information about the population of UP and its cities was obtained from http://citypopulation.de/. The number of new cancer cases annually for the commonest cancers was estimated from GLOBOCAN 2008. For estimating the human resources needed, the following assumptions were made: newly diagnosed cancer patients need pathology for diagnosis and for treatment surgery, chemotherapy, and/or radiotherapy. The percentage of patients requiring each of those modalities, their average lengths of stay as in-patients, and number of in-patient oncology beds were estimated. The resources already available in UP were determined by a telephone survey and by searching the websites of radiation therapy centers and medical colleges. Twenty-four radiation oncologists at 24 cancer centers in 10 cities responded to the survey. As detailed in this manuscript, an enormous shortage of human resources for cancer control exists in UP. Human resources are the key to diagnosing cancers early and treating them appropriately. Addressing the shortage will not be easy but we hope that the methodology described here can guide decision makers and form a framework for discussion among the various stakeholders. This methodology is readily adaptable to local practices and data.

Late effects of cancer treatment in breast cancer survivors.

Postoperative radiation therapy (RT) and chemotherapy,both reduces the risk of local recurrence and extends overall survival in patients with breast cancer (BC). Concerns have, however, been raised about the risk of acute and chronic side effects in breast cancer survivors as the number of treated individuals is large and their expected survival is long compared to most patients with other malignant diseases. Cardiac toxicity, reproductive dysfunction, pneumonitis (RP),arm lymph edema, neuropathy, skin changes are examples of the wide range of complications that has been associated with adjuvant treatment.

Assessment of clinical outcomes in breast cancer patients treated with taxanes: multi-analytical approach.

Polymorphisms in genes encoding CYPs (Phase I) and ABCB1 (Phase III) enzymes may attribute to variability of efficacy of taxanes. The present study aims to find the influence of CYP and ABCB1 gene polymorphisms on taxanes based clinical outcomes. 132 breast cancer patients treated with taxanes based chemotherapy were genotyped for CYP3A4*1B, CYP3A5*3, CYP1B1*3, CYP2C8*3, ABCB1 1236C>T, 2677G>T/A and 3435C>T polymorphisms using PCR-RFLP. Associations of genetic variants with clinical outcomes in terms of response in 58 patients receiving neo-adjuvant chemotherapy (NACT), and chemo-toxicity in 132 patients were studied. Multifactor dimensionality reduction (MDR) analysis was performed to evaluate higher order gene-gene interactions with clinical outcomes. Pathological response to taxane based NACT was associated with GA genotype as well as A allele of CYP3A5*3 polymorphism (Pcorr=0.0465, Pcorr=0.0465). Similarly, association was found in dominant model of CYP3A5*3 polymorphism with responders (Pcorr=0.0465). Haplotype analysis further revealed ACYP3A4-ACYP3A5 haplotype to be significantly associated with responders (Pcorr=0.048). In assessing toxicity, significant association of variant (TT) genotype and T allele of ABCB1 2677G>T/A polymorphism, was found with 'grade 1 or no leucopenia' (Pcorr=0.0465, Pcorr=0.048). On evaluating higher order gene-gene interaction models by MDR analysis, CYP3A5*3; ABCB11236C>T and ABCB1 2677G>T/A; ABCB1 3435C>T and CYP1B1*3 showed significant association with treatment response, grade 2-4 anemia and dose delay/reduction due to neutropenia (P=0.024, P=0.004, P=0.026), respectively. Multi-analytical approaches may provide a better assessment of pharmacogenetic based treatment outcomes in breast cancer patients treated with taxanes.

Ipsilateral lung dose volume parameters predict radiation pneumonitis in addition to classical dose volume parameters in locally advanced NSCLC treated with combined modality therapy.

PURPOSE: The purpose was to determine the correlation of clinical factors and lung dose volume parameters with significant radiation pneumonitis (RP) in non-small cell lung cancer patients treated with combined modality therapy. MATERIALS AND METHODS: Between January 2008 and December 2010, 52 patients of non-small cell lung cancer were treated with combined modality therapy with radical intent. Radiation pneumonitis was correlated with ipsilateral (V20 ipsi, V5 ipsi and MLD ipsi) and whole lung (V20, V5, and MLD) dose volume parameters. Clinical factors like pulmonary function tests (PFT), site of tumor, planning target volume, and type of treatment were also correlated with incidence of significant pneumonitis. RESULTS: Out of 52 patients, 35.3% developed grade 2 or more pneumonitis. On univariate analysis, factors significantly correlating with radiation pneumonitis were V5 (P = 0.002), V5 ipsi (P = 0.000), V20 (P = 0.019), V20 ipsi (P = 0.004), MLD (P = 0.008) and MLD ipsi (P = 0.008). On multivariate analysis, V5 ipsi was retained as the most significant factor. Concurrent chemoradiation caused significantly more RP than neoadjuvant chemoradiation (P = 0.004). A cutoff of 65% for V5 ipsi had a sensitivity of 65% and a specificity of 91%. CONCLUSION: The correlation between pneumonitis and dosimetric constraints has been validated. Adding ipsilateral V20, V5, and MLD to the classical total lung constraints identifies patients likely to develop pulmonary toxicity in patients undergoing chemoradiation.

CD44 gene polymorphisms in breast cancer risk and prognosis: a study in North Indian population.

BACKGROUND: Cell surface biomarker CD44 plays an important role in breast cancer cell growth, differentiation, invasion, angiogenesis and tumour metastasis. Therefore, we aimed to investigate the role of CD44 gene polymorphisms in breast cancer risk and prognosis in North Indian population. MATERIALS & METHODS: A total of 258 breast cancer patients and 241 healthy controls were included in the case-control study for risk prediction. According to RECIST, 114 patients who received neo-adjuvant chemotherapy were recruited for the evaluation of breast cancer prognosis. We examined the association of tagging SNP (rs353639) of Hapmap Gujrati Indians in Houston (GIH population) in CD44 gene along with a significant reported SNP (rs13347) in Chinese population by genotyping using Taqman allelic discrimination assays. Statistical analysis was done using SPSS software, version 17. In-silico analysis for prediction of functional effects was done using F-SNP and FAST-SNP. RESULTS: No significant association of both the genetic variants of the CD44 gene polymorphisms was found with breast cancer risk. On performing univariate analysis with clinicopathological characteristics and treatment response, we found significant association of genotype (CT+TT) of rs13347 polymorphism with earlier age of onset (P = 0.029, OR = 0.037). However, significance was lost in multivariate analysis. For rs353639 polymorphism, significant association was seen with clinical tumour size, both at the genotypic (AC+CC) (P = 0.039, OR = 3.02) as well as the allelic (C) (P = 0.042, OR = 2.87) levels. On performing multivariate analysis, increased significance of variant genotype (P = 0.017, OR = 4.29) and allele (P = 0.025, OR = 3.34) of rs353639 was found with clinical tumour size. In-silico analysis using F-SNP, showed altered transcriptional regulation for rs353639 polymorphism. CONCLUSIONS: These findings suggest that CD44 rs353639 genetic variants may have significant effect in breast cancer prognosis. However, both the polymorphisms- rs13347 and rs353639 had no effect on breast cancer susceptibility.

Pharmacogenetic influence of GST polymorphisms on anthracycline-based chemotherapy responses and toxicity in breast cancer patients: a multi-analytical approach.

BACKGROUND AND OBJECTIVE: Chemotherapeutic drug treatment outcomes are genetically determined. Polymorphisms in genes encoding phase II drug metabolizing enzyme glutathione-S-transferase (GST) can possibly predict treatment outcomes, and can be of prognostic significance in breast cancer patients. The aim of this study was to determine the role of genetic variations in GST in predicting response to, and toxicity of, anthracycline-based chemotherapy in breast cancer patients. METHOD: Two hundred and seven patients treated with anthracycline-based chemotherapy were genotyped for GSTM1 and GSTT1 deletion polymorphisms, and GSTP1 Ile105Val (rs1695), by polymerase chain reaction (PCR)/ PCR-restriction fragment length polymorphism (RFLP). Genetic variations were correlated with tumor response to neo-adjuvant chemotherapy (NACT) in 100 patients, and with chemo-toxicity in 207 who received adjuvant chemotherapy or NACT, using Chi-square and logistic regression. Higher order gene-gene interactions with treatment outcomes were characterized by multifactor dimensionality reduction (MDR) analysis. RESULTS: In single-locus analysis, Ile/Val and Ile/Val+Val/Val genotypes of the GSTP1 Ile105Val (rs1695) polymorphism reached statistical significance with grade 2-4 anemia (P=0.019, P=0.027). On performing gene-gene interaction analysis, GSTM1 null-GSTP1 Ile/Val was significantly associated with response to NACT (P=0.032). On evaluating higher order gene-gene interaction models by MDR analysis, GSTM1 and GSTP1 Ile105Val; GSTM1 and GSTT1; and GSTT1 and GSTP1 Ile105Val showed significant association with treatment response, grade 2-4 anemia, and dose delay/reduction due to neutropenia (P=0.046, P=0.027, P=0.026), respectively. CONCLUSION: Multi-analytical strategies may serve as a better tool for characterization of pharmacogenetic-based breast cancer treatment outcomes.