A randomized phase II evaluation of weekly gemcitabine plus pazopanib versus weekly gemcitabine alone in the treatment of persistent or recurrent epithelial ovarian, fallopian tube or primary peritoneal carcinoma.

OBJECTIVE: Angiogenesis inhibition is a valuable strategy for ovarian cancer (EOC). Pazopanib (paz) is a potent small molecular inhibitor of VEGF-1, -2, -3, PDGFR, c-kit, and has activity as a single agent in ovarian cancer. We designed a trial to assess the benefit of adding paz to gemcitabine (gem) in patients with recurrent EOC. METHODS: An open-label, randomized, multi-site, phase 2 trial was conducted (NCT01610206) including patients with platinum resistant or sensitive disease, ≤ 3 prior lines of chemotherapy, and measurable/evaluable disease. Patients were randomly assigned to weekly gem 1000 mg/m2 on days 1 and 8 of a 21 day cycle, with or without paz 800 mg QD, stratified by platinum sensitivity and number of prior lines (1 vs 2 or 3). The primary endpoint was PFS. RESULTS: 148 patients were enrolled 2012-2017. Median age was 63 years (30-82); 60% were platinum resistant; median surveillance was 13 months (0.4-54 months). Median PFS was 5.3 (95% CI, 4.2-5.8) vs 2.9 months (95% CI, 2.1-4.1) in the gem arm. The PFS effect was most pronounced in the platinum resistant group (5.32 vs 2.33 months Tarone-Ware p < 0.001). There was no difference in OS. Overall RR (PR 20% vs 11%, Chi-squre p = 0.02) and DCR (80% vs 60%, Chi-square p < 0.001) were higher in the combination. High grade AEs in the combination arm included ≥ Grade 3: hypertension (15%), neutropenia (35%), and thrombocytopenia (12%). CONCLUSIONS: The addition of paz to gem enhanced anti-tumor activity; those with platinum-resistant disease derived the most benefit from combination therapy, even in the setting of receiving prior bevacizumab.

Genetic and epigenetic alterations in the tumour, tumour margins, and normal buccal mucosa of patients with oral cancer.

Despite adequate surgical resection, oral squamous cell carcinoma (OSCC) shows a high rate of recurrence and metastasis, which could be explained by the presence of molecular alterations in seemingly normal tumour margins and the entire oral mucosa. The aims of this study were (1) to assess the presence of gene amplification (c-Myc and HER2) and promoter methylation (p14 and p16) in the tumours, tumour margins, and unaffected oral mucosa of 40 OSCC patients, and (2) to evaluate the possibility of using these alterations as prognostic markers. c-Myc and HER2 genes were quantified by means of real-time PCR (qPCR), and p14 and p16 methylation status was determined by methylation-specific PCR (MSP PCR). All tissues examined exhibited molecular alterations in various proportions. Tumour tissues, as expected, showed the highest prevalence of alterations, while oral mucosa showed the lowest. Multiple alterations (co-alterations) in tumours and tumour margins were significantly more frequent than in unaffected oral mucosa (P<0.001 and P=0.027, respectively). HER2 amplification in margin tissue (P<0.001) and swabs (P=0.013), as well as the existence of three co-alterations in margins (P=0.001) and macroscopically unaffected oral mucosa (P<0.001) were correlated with shorter disease-specific survival.

A phase I trial of paclitaxel, cisplatin, and veliparib in the treatment of persistent or recurrent carcinoma of the cervix: an NRG Oncology Study (NCT#01281852).

Background: Preclinical studies demonstrate poly(ADP-ribose) polymerase (PARP) inhibition augments apoptotic response and sensitizes cervical cancer cells to the effects of cisplatin. Given the use of cisplatin and paclitaxel as first-line treatment for persistent or recurrent cervical cancer, we aimed to estimate the maximum tolerated dose (MTD) of the PARP inhibitor veliparib when added to chemotherapy. Patients and methods: Women with persistent or recurrent cervical carcinoma not amenable to curative therapy were enrolled. Patients had to have received concurrent chemotherapy and radiation as well as possible consolidation chemotherapy; have adequate organ function. The trial utilized a standard 3 + 3 phase I dose escalation with patients receiving paclitaxel 175 mg/m2 on day 1, cisplatin 50 mg/m2 on day 2, and escalating doses of veliparib ranging from 50 to 400 mg orally two times daily on days 1-7. Cycles occurred every 21 days until progression. Dose-limiting toxicities (DLTs) were assessed at first cycle. Fanconi anemia complementation group D2 (FANCD2) foci was evaluated in tissue specimens as a biomarker of response. Results: Thirty-four patients received treatment. DLTs (n = 1) were a grade 4 dyspnea, a grade 3 neutropenia lasting ≥3 weeks, and febrile neutropenia. At 400 mg dose level (DL), one of the six patients had a DLT, so the MTD was not reached. Across DLs, the objective response rate (RR) for 29 patients with measurable disease was 34% [95% confidence interval (CI), 20%-53%]; at 400 mg DL, the RR was 60% (n = 3/5; 95% CI, 23%-88%). Median progression-free survival was 6.2 months (95% CI, 2.9-10.1), and overall survival was 14.5 months (95% CI, 8.2-19.4). FANCD2 foci was negative or heterogeneous in 31% of patients and present in 69%. Objective RR were not associated with FANCD2 foci (P = 0.53). Conclusions: Combining veliparib with paclitaxel and cisplatin as first-line treatment for persistent or recurrent cervical cancer patients is safe and feasible. Clinical trial information: NCT01281852.

The amplification of c-erb-B2 in cancer-free surgical margins is a predictor of poor outcome in oral squamous cell carcinoma.

The tumour subtype, TNM classification, and histopathological data are sometimes not sufficient for understanding and assessing the behaviour of oral cancers. In an attempt to find additional markers of tumour biology and behaviour, this study sought to determine the incidence and consequently the relevance of c-erb-B2, c-Myc, and H-ras gene alterations in tumour-free margins of oral squamous cell carcinoma (OSCC). Fifty samples of OSCC were analyzed for c-erb-B2 and c-Myc amplification by real-time polymerase chain reaction and for H-ras point mutations by sequencing. A relatively high incidence of genetic lesions was detected: 22% of cases had c-erb-B2 and 30% had c-Myc amplification, whilst only 12% harboured H-ras mutations. Kaplan-Meier analysis and the log-rank test showed statistically significant differences in 5-year survival rates and relapse between patients with tumour margins positive for c-erb-B2 amplification and those with margins that were negative (P=0.002). H-ras and c-Myc alterations could not be associated with tumour behaviour. Molecular analysis of margins, targeting cancer genes, could identify additional, independent predictors of risk and outcome in OSCC.

Aromatase and breast cancer.

Several aromatase inhibitors and also new antiestrogens are now available for treating breast cancer. We have developed a model to compare the antitumor efficacy of these agents and to explore strategies for their optimal use. Results from the model have been predictive of clinical outcome. In this model, tumors are grown in ovariectomized, immunodeficient mice from MCF-7 human breast cancer cells transfected with the aromatase gene (MCF-7Ca). The possibility that blockade of estrogen action and estrogen synthesis may be synergistic was explored by treating mice with the aromatase inhibitor letrozole and the antiestrogen tamoxifen alone and in combination. The results indicated that letrozole alone was better than all other treatments. In addition, when tamoxifen treatment was no longer effective, tumor growth was significantly reduced in mice switched to letrozole treatment. However, tumors ultimately began to grow during continued treatment. To investigate the mechanisms by which tumors eventually adapt and grow during letrozole treatment, we determined the expression of signaling proteins in tumors during the course of letrozole treatment compared to the tumors of control mice. Tumors initially up-regulated the ER while responding to treatment, but subsequently receptor levels decreased in tumors unresponsive to letrozole. Also, Her-2 and adapter proteins (p-Shc and Grb-2) as well as all of the signaling proteins in the MAPK cascade (p-Raf, p-Mekl/2, and p-MAPK), but not in the Pl3/Akt pathway, were increased in tumors no longer responsive to letrozole. To investigate whether sensitivity to letrozole could be regained, cells were isolated from the letrozole resistant tumors (LTLT) and treated with inhibitors of the MAPKinase pathway (PD98059 and UO126). These compounds reduced MAPK activity and increased ER expression. EGFR/Her-2 inhibitors, gefitinib and AEE78S although not effective in the parental MCF-70a cells, restored the sensitivity of LTLT cells to letrozole. In xenografts, beginning treatment with letrozole and faslodex to down regulate the ER prevented increases in Her-2 and activation of MAPK and was highly effective in inhibiting tumor growth throughout 29 weeks of treatment. These results suggest that blocking both ER- and growth factor-mediated transcription may delay development of resistance and maintain growth inhibition of ER+ breast cancer.