Shona Nag

A Randomized, Double-Blind, Placebo-Controlled, Phase II Study of Oral Talactoferrin in Combination with Carboplatin and Paclitaxel in Previously Untreated Locally Advanced or Metastatic Non-small Cell Lung Cancer

Introduction: The aim of the study is to investigate the activity and safety of oral talactoferrin (TLF) plus carboplatin and paclitaxel (C/P) in patients with previously untreated stage IIIB/IV non-small cell lung cancer. Methods: Patients (n = 110) were randomly assigned to receive C/P plus either TLF (C/P/T) or placebo (C/P/P). The primary objective of this exploratory study was assessment of confirmed response rate (RR) in the prospectively defined evaluable population with a one-tailed p = 0.05. Secondary objectives included assessment of progression-free survival (PFS), duration of response, overall survival (OS), and safety. Results: The trial met the primary end point of improvement in confirmed RR in the prospectively defined evaluable population. Compared with the C/P/P group, RR increased in the C/P/T group by 18% (29–47%; p = 0.05) and 15% (27–42%; p = 0.08) in the evaluable and intent-to-treat populations, respectively. Compared with the C/P/P group, the C/P/T group had a longer median PFS (4.2 versus 7.0 months), OS (8.5 versus 10.4 months), and duration of response (5.5 versus 7.6 months), although the differences were not statistically significant. Adverse events (AEs) were consistent with C/P therapy. There were fewer total AEs (472 versus 569; two-tailed p = 0.003) and grade 3/4 AEs (78 versus 105; p = 0.05) in the C/P/T group compared with the C/P/P group. Conclusion: TLF, in combination with C/P, demonstrated an apparent improvement in RR, PFS, and OS in patients with previously untreated stage IIIB/IV non-small cell lung cancer and appears to enhance activity without significant additional toxicity. These results need to be confirmed in a phase III trial.

Neoadjuvant Doxorubicin/Cyclophosphamide Followed by Ixabepilone or Paclitaxel in Early Stage Breast Cancer and Evaluation of βIII-Tubulin Expression as a Predictive Marker

BACKGROUND This randomized phase II trial was designed to compare the rate of pathologic complete response (pCR) induced by neoadjuvant cyclophosphamide plus doxorubicin (AC) followed by ixabepilone or paclitaxel in women with early stage breast cancer (BC). Expression of βIII-tubulin as a predictive marker was also evaluated. PATIENTS AND METHODS Women with untreated, histologically confirmed primary invasive breast adenocarcinoma received four cycles of AC followed by 1:1 randomization to either ixabepilone 40 mg/m2 (3-hour infusion) every 3 weeks for four cycles (n = 148) or weekly paclitaxel 80 mg/m2 (1-hour infusion) for 12 weeks (n = 147). All patients underwent a core needle biopsy of the primary cancer for molecular marker analysis prior to chemotherapy. βIII-Tubulin expression was assessed using immunohistochemistry. RESULTS There was no significant difference in the rate of pCR in the ixabepilone treatment arm (24.3%; 90% confidence interval [CI], 18.6-30.8) and the paclitaxel treatment arm (25.2%; 90% CI, 19.4-31.7). βIII-Tubulin-positive patients obtained higher pCR rates compared with βIII-tubulin-negative patients in both treatment arms; however, βIII-tubulin expression was not significantly associated with a differential response to ixabepilone or paclitaxel. The safety profiles of both regimens were generally similar, although neutropenia occurred more frequently in the ixabepilone arm (grade 3/4: 41.3% vs. 8.4%). The most common nonhematologic toxicity was peripheral neuropathy. CONCLUSIONS Neoadjuvant treatment of early stage BC with AC followed by ixabepilone every 3 weeks or weekly paclitaxel was well tolerated with no significant difference in efficacy. Higher response rates were observed among βIII-tubulin-positive patients.

Clinical Experience with Gefitinib in Indian Patients

Introduction: Treatment options are limited in patients with advanced or refractory non-small cell lung cancer and lead to suboptimal outcome and/or benefit. The epidermal growth factor tyrosine kinase inhibitor gefitinib (IRESSA) has been approved in many countries. Increased responsiveness to gefitinib has been demonstrated in particular subsets of patients, for example never smokers and patients of Asian origin. However, to date, little is known of its use specifically in patients from India. Methods: Retrospective ad hoc analysis of clinical data from experience with gefitinib in patients with advanced NSCLC from India enrolled in the IRESSA Survival Evaluation in Lung (ISEL) study (n = 77) or included in the gefitinib expanded-access program in India (n = 133). Results: Among Indian patients enrolled in the ISEL study, median survival was 6.4 months with gefitinib and 5.1 month with placebo. The objective response rate in Indian patients was 14% with gefitinib versus 0% with placebo. In ISEL, tolerability data from Indian patients were consistent with the overall study population. In the Indian gefitinib expanded-access program, median survival was 6 months and gefitinib was well tolerated. Conclusions: Gefitinib seems well tolerated in Indian patients with advanced NSCLC, with some clinical benefit observed.

Evidence for the association of Epstein‐Barr Virus in breast cancer in Indian patients using in‐situ hybridization technique

Epstein‐Barr Virus (EBV) is etiologically linked to Burkitt lymphoma (BL), nasopharyngeal carcinoma, post‐transplant lymphomas, Hodgkin disease, and possibly other tumors. However, the association of oncogenic EBV with breast carcinoma (BC) is still controversial and a matter of debate. We aimed to study the presence of EBV genome in BC cases in Indian patients and its association with the clinicopathological features. The formalin fixed paraffin embedded tissues from 83 women with primary invasive BC were studied for the presence of EBV by in‐situ hybridization (ISH) technique for Epstein‐Barr Virus Encoded RNA (EBER) with appropriate controls. Correlation of EBER‐ISH positivity with clinicopathological features was performed using Fisher exact test and P<.05 was considered as significant. Eighty‐three BC cases were comprised of 47 (56.5%) triple negative breast cancers (TNBC), 17 (20.5%) hormone positive and 19 (22.9%) HER2 positive cases. Of 83 cases, 25 cases (30.1%) were positive for EBER‐ISH test. The positivity was restricted to the tumor cells and not seen in the surrounding breast lobules. EBER‐ISH positivity was statistically associated with larger tumor size (52.6% in >5 cm tumors vs 19.3% in ≤5 cm; P=.014) and with TNBCs (21/47 [44.7%] in TNBCs vs 4/36 [11.1%] in non‐TNBCs; P=.001). A possible causal association of EBV in BC cases in Indian patients is suggested by high frequency of EBER‐ISH positivity noted in our study. This might have therapeutic significance because of the possible role of EBV specific cytotoxic T cells in targeting EBV associated tumor cells and can be considered as a potential targeted therapy. To the best of our knowledge, this is the first study from India to address this issue using EBER‐ISH technique.

Emerging Prognostic and Predictive Biomarkers for Triple Negative Breast Cancer

Triple negative breast cancer (TNBC) is associated with a poor prognosis especially in the advanced setting and continues to pose a challenge for oncologists worldwide. Several biomarkers for this disease have been described. Recently the heterogeneity of TNBC has changed our perspective toward this disease. Differential response of TNBC to chemotherapy, poor prognosis of patients with residual disease following neoadjuvant chemotherapy, and the immunogenicity underlying TNBC make the management of this disease even more complex. Multiple signaling pathways and dynamic pathway programming are the hallmarks of TNBC. Newer trials for this disease therefore, need to be innovative and include biomarker enrichment and adaptive designs. This article highlights the emerging prognostic and predictive biomarkers for TNBC and discusses possible targets for future therapeutic strategies.

Germline Testing for Predisposition to Breast/Ovarian Cancer Should Only be Offered to Selected Patients with Epithelial Ovarian Cancer

BackgroundGermline mutations involving the BRCA1 or BRCA2 gene are seen in 8–15% of ovarian cancer. The recent years have witnessed a growing interest among clinicians and patients alike for ‘genetic testing’ for identification of deleterious mutations which are implicated in the cancer-forming process. Most studies in the literature have employed age of onset, a positive family history and serous histology as important criteria to recommend genetic counselling and testing as these are associated with the highest probability of detecting germline mutations.Perspective The probability of mutation detection in newly diagnosed patients of ovarian cancer is 8–22%. Not every mutation detected is of clinical significance. Moreover, the considerable costs and technical limitations of BRCA1/2 mutation analysis, and the potential risk of fostering additional psychological burden on all newly diagnosed cancer patients, make a strong case to subject only a select high-risk group of ovarian cancer patients to genetic counselling and further testing. BRCA1/2 is emerging as an important predictive biomarker for ovarian cancer.Conclusion As opportunities to detect genetic mutations expand, we must alert ourselves to the risks and potential benefits of exploring such opportunities. While PARP inhibitors are an exciting new treatment for ovarian cancers, the efficacy is not restricted only to germline BRCA-mutated patients. The scientific evidence available today, for germline testing in all ovarian cancer patients at best, can be considered speculative.

mTOR inhibition in management of advanced breast cancer

The mTOR pathway is becoming increasingly important in several cancers including breast cancer. This review will focus on the role of its inhibition in the management of advanced breast cancer.