Experimental evidence from several sources has identi®ed a link between mismatch repair de®ciency and cytotoxic drug resistance. Selection for cisplatin resistance in the human ovarian cancer cell line A2780, results in loss of expression of the mismatch repair protein hMLH1 in most (90%) of the resultant cisplatin-resistant cell lines. Here we demonstrate that the cisplatin sensitive parental cell line displays methylation of the promoter of only one hMLH1 allele, but that the resistant cell lines all exhibit hyper-methylation of the promoters of both hMLH1 alleles. Full methylation of all sites tested was found to be invariably associated with loss of hMLH1 expression, whereas a partial increase in methylation appears compatible with either loss or maintenance of expression. In addition treatment of two of the resistant cell lines with 5-azacytidine, a known inhibitor of methylation, results in re-expression of hMLH1. Clonogenic assays demonstrate that the 5-azacytidine treated cells show increased sensitivity to cisplatin. Furthermore, 12.5% (3/ 24) of ovarian tumours show hypermethylation of the hMLH1 promoter. Expression of hMLH1 is absent in the tumours that are hypermethylated, while all the unmethylated tumours still express the protein. This analysis suggests that methylation of the hMLH1 promoter may be a common mechanism for loss of hMLH1 expression, and possibly for cisplatin-resistance, in ovarian cancer.

The value of combination chemotherapy in advanced oesophagogastric cancer has been clarified. Three randomized clinical trials have demonstrated the superiority of chemotherapy over best supportive care alone (Murad et al, 1993;Pyrhonen et al, 1995;Glimelius et al, 1997). However, the optimal regimen has not yet been established. The combination of 5-fluorouracil (5-FU), adriamycin and methotrexate (FAMTX) has been considered standard therapy, with superior response and survival rates compared with previous regimens (Wils et al, 1991;Kelsen et al, 1992). A combination of cisplatin, epirubicin, leucovorin and 5-FU (PELF) has also demonstrated impressive response rates in a randomized study (Cocconi et al, 1994). The regimen of epirubicin, cisplatin and 5-FU (ECF) was developed at the Royal Marsden Hospital (RMH) and first reported in 1991 (Cunningham et al, 1991). The three drugs in this regimen were selected on the basis of their single agent activity in upper gastrointestinal tract tumours (Beer et al, 1983;Cersosimo and Hong, 1986;Machover et al, 1986), and on the synergy demonstrated between 5-FU and cisplatin in preclinical models (Etienne et al, 1991). The 5-FU is delivered as a protracted infusion as this schedule has produced higher response rates with less myelotoxicity compared with bolus administration in patients with colorectal cancer (Lokich et al, 1989). Following the demonstration of response rates of 71% with moderate toxicity in a phase II study (Findlay et al, 1994), we undertook a multicentre randomized study comparing ECF with FAMTX in advanced oesophagogastric cancer. The initial results of this trial were reported in 1996 when recruitment was completed (Webb et al, 1997). At that stage, an advantage for ECF in response rate and survival was evident. However, median follow-up was only 6.1 months and only 75% of patients had died. We now present a final survival analysis with all patients followed up for 26.9 months or more (median 44 months), and 95% of patients having died. METHODSOur methods have been described previously (Webb et al, 1997). Briefly, patients with inoperable adenocarcinoma or undifferentiated carcinoma of the oesophagus, oesophagogastric junction, or stomach were randomized to receive ECF or FAMTX chemotherapy. ECF chemotherapy was administered through a central venous catheter placed in the subclavian vein. 5-FU was given as a continuous intravenous infusion at a dose of 200 mg m -2 day -1 for up to 6 months. Epirubicin (50 mg m -2 ) and cisplatin (60 mg m -2 ) were given every 3 weeks to a maximum of 8 cycles. FAMTX chemotherapy comprised methotrexate 1500 mg m -2 and 5-FU 1500 mg m -2 on day 1, and doxorubicin 30 mg m -2 on day 15. Cycles were repeated every 28 days to a maximum of 24 weeks. Patients were followed up with clinical and symptomatic SummaryWe report the final results of a prospectively randomized study that compared the combination of epirubicin, cisplatin and protracted venous infusion fluorouracil (5-FU) (ECF regimen) with the standard combination of 5-...

Purpose: To evaluate the efficacy of the aromatase inhibitor letrozole in preselected estrogen receptor (ER)^positive relapsed epithelial ovarian cancer patients and to identify markers that predict endocrine-sensitive disease. Experimental Design: This was a phase II study of letrozole 2.5 mg daily until clinical or marker evidence of disease progression in previously treated ER-positive ovarian cancer patients with a rising CA125 that had progressed according to Rustin's criteria. The primary end point was response according to CA125 and response evaluation criteria in solid tumors (RECIST) criteria. Marker expression was measured by semiquantitative immunohistochemistry in sections from the primary tumor. Results: Of 42 patients evaluable for CA125 response, 7 (17%) had a response (decrease of >50%), and 11 (26%) patients had not progressed (doubling of CA125) following 6 months on treatment. The median time taken to achieve the CA125 nadir was 13 weeks (range 10-36). Of 33 patients evaluable for radiological response, 3 (9%) had a partial remission, and 14 (42%) had stable disease at 12 weeks. Eleven patients (26%) had a PFS of >6 months. Subgroup analysis according to ER revealed CA125 response rates of 0% (immunoscore, 150-199), 12% (200-249), and 33% (250-300); P = 0.028, m 2 for trend. Expression levels of HER2, insulin-like growth factor binding protein 5, trefoil factor 1, and vimentin were associated with CA125 changes on treatment. Conclusions: This is the first study of a hormonal agent in a preselected group of ER-positive ovarian cancer patients. A signature of predictive markers, including low HER2 expression, predicts response.

Capecitabine is a tolerable oral outpatient therapy that shows promising clinical activity in a variety of cancers. The recommended phase II dose is 2,510 mg/m2 daily administered by this intermittent schedule.

Endometrioid ovarian carcinoma (EnOC) demonstrates substantial clinical and molecular heterogeneity. Here, we report whole exome sequencing of 112 EnOC cases following rigorous pathological assessment. We detect a high frequency of mutation in CTNNB1 (43%), PIK3CA (43%), ARID1A (36%), PTEN (29%), KRAS (26%), TP53 (26%) and SOX8 (19%), a recurrently-mutated gene previously unreported in EnOC. POLE and mismatch repair protein-encoding genes were mutated at lower frequency (6%, 18%) with significant co-occurrence. A molecular taxonomy is constructed, identifying clinically distinct EnOC subtypes: cases with TP53 mutation demonstrate greater genomic complexity, are commonly FIGO stage III/IV at diagnosis (48%), are frequently incompletely debulked (44%) and demonstrate inferior survival; conversely, cases with CTNNB1 mutation, which is mutually exclusive with TP53 mutation, demonstrate low genomic complexity and excellent clinical outcome, and are predominantly stage I/II at diagnosis (89%) and completely resected (87%). Moreover, we identify the WNT, MAPK/RAS and PI3K pathways as good candidate targets for molecular therapeutics in EnOC.