Genomic profiling of pelvic genital type leiomyosarcoma in a woman with a germline CHEK2:c.1100delC mutation and a concomitant diagnosis of metastatic invasive ductal breast carcinoma.

We describe a woman with the known pathogenic germline variant CHEK2:c.1100delC and synchronous diagnoses of both pelvic genital type leiomyosarcoma (LMS) and metastatic invasive ductal breast carcinoma. CHEK2 (checkpoint kinase 2) is a tumor-suppressor gene encoding a serine/threonine-protein kinase (CHEK2) involved in double-strand DNA break repair and cell cycle arrest. The CHEK2:c.1100delC variant is a moderate penetrance allele resulting in an approximately twofold increase in breast cancer risk. Whole-genome and whole-transcriptome sequencing were performed on the leiomyosarcoma and matched blood-derived DNA. Despite the presence of several genomic hits within the double-strand DNA damage pathway (CHEK2 germline variant and multiple RAD51B somatic structural variants), tumor profiling did not show an obvious DNA repair deficiency signature. However, even though the LMS displayed clear malignant features, its genomic profiling revealed several characteristics classically associated with leiomyomas including a translocation, t(12;14), with one breakpoint disrupting RAD51B and the other breakpoint upstream of HMGA2 with very high expression of HMGA2 and PLAG1 This is the first report of LMS genomic profiling in a patient with the germline CHEK2:c.1100delC variant and an additional diagnosis of metastatic invasive ductal breast carcinoma. We also describe a possible mechanistic relationship between leiomyoma and LMS based on genomic and transcriptome data. Our findings suggest that RAD51B translocation and HMGA2 overexpression may play an important role in LMS oncogenesis.

Phase II study of oral ridaforolimus in women with recurrent or metastatic endometrial cancer.

OBJECTIVE: The phosphatidylinositol-3 kinase/serine-threonine kinase PI3K/AKT pathway is postulated to be central to cancer cell development. Activation of this pathway is believed to promote angiogenesis, protein translation and cell cycle progression. A large percentage of endometrial carcinomas have demonstrated mutations within this regulation pathway which result in constitutional activation. The downstream effector protein mammalian target of rapamycin (mTOR) acts as a critical checkpoint in cancer cell cycling and is a logical target for drug development. The efficacy and tolerability of the oral mTOR inhibitor ridaforolimus were evaluated in this study. METHODS: This phase II study evaluated the single agent tolerability and activity of oral ridaforolimus administered at a dose of 40mg for 5 consecutive days followed by a 2day break, in women with recurrent or metastatic endometrial carcinoma who had received no chemotherapy in the metastatic setting. RESULTS: 31 of 34 patients were evaluable. Three partial responses (8.8%) were observed with response duration ranging between 7.9 and 26.5months. An additional 18 patients showed disease stabilization (52.9%) for a median duration of 6.6months. Response rates were not affected by previous chemotherapy exposure. No correlation was found between response and mutation status. CONCLUSION: Oral ridaforolimus was reasonably tolerated and demonstrated modest activity in women with recurrent or metastatic endometrial cancers. Potential synergy between mTOR inhibition, angiogenesis and hormonal pathways warrants ongoing evaluation.

Ongoing evaluation of ease-of-use and usefulness of wireless tablet computers within an ambulatory care unit.

This ongoing research is to assess user acceptance of wireless convertible tablet portable computers in their support of patient care within the clinic environment and to determine their impact on workload reduction for the information staff. A previous publication described our initial experience with a limited wireless environment. There, we tested the premise that wireless convertible tablet computers were equivalent to desktop computers in their support of user tasks. Feedback from users demonstrated that convertible tablet computers were not able to replace desktop computers. Poor network access was a weakness as well as the "cognitive overhead" encountered due to technical problems. This paper describes our further experience with a centre-wide wireless implementation while using a new wireless device. The new tablets, which have some unique functions that existing desktop computers do not provide, have been well received by the clinicians.

Carboplatin plus paclitaxel for advanced or recurrent uterine malignant mixed mullerian tumors. The British Columbia Cancer Agency experience.

OBJECTIVES: Uterine MMMTs are aggressive malignancies that are rarely cured by purely local therapies. Effective chemotherapy is needed. The phase III proven, ifosfamide-based combinations are inconvenient and costly. Carboplatin and paclitaxel (CT) are easy to deliver and is effective against endometrial carcinoma and should be against MMMT (as they are now regarded as epithelial in nature). METHODS: A review of all women with uterine MMMT treated with CT. Paclitaxel 175 mg/m2 over 3 h preceded carboplatin (AUC 5-6) every 4 weeks for 3-6 cycles+/-subsequent pelvic irradiation. RESULTS: Twenty-eight newly diagnosed women (20 evaluable) and 12 recurrent (11 evaluable) were treated. Response rates were 60% (12 of 20, CR 5, PR 7) and 55% (6 of 11, CR 2, PR 4) with median PFS of 16 and 12 months. Dose reduction occurred in 5%, treatment delay in 10%. CONCLUSIONS: Carboplatin-paclitaxel is effective against uterine MMMT, with similar efficacy to ifosfamide combinations. It is more convenient, less costly and easy to deliver.

Pegylated liposomal doxorubicin and trastuzumab in HER-2 overexpressing metastatic breast cancer: a multicenter phase II trial.

PURPOSE: Cardiotoxicity precludes the concurrent use of doxorubicin and trastuzumab. Because pegylated liposomal doxorubicin (PLD) has equal efficacy but significantly less cardiotoxicity than conventional doxorubicin, this phase II study assessed the rate of cardiotoxicity and efficacy of first-line PLD plus trastuzumab in HER-2-positive metastatic breast cancer (MBC). PATIENTS AND METHODS: Women with HER-2-positive, measurable MBC, and a baseline left ventricular ejection fraction (LVEF) > or = 55% were treated with PLD 50 mg/m2 every 4 weeks for six cycles and weekly trastuzumab (4 mg/kg loading dose then 2 mg/kg thereafter). Cardiotoxicity was defined as symptomatic congestive heart failure (CHF) with > or = 10% decline in LVEF to below lower limits of normal, > or = 15% decline in LVEF without symptomatic CHF, or less than 10% LVEF decline to less than 45%. RESULTS: Thirty women were enrolled, 13 had received prior adjuvant anthracyclines. A median 5.5 cycles of PLD were administered. Mean baseline LVEF was 62.8%, 59.5% after cycle four, and 58.3% after cycle six. Three patients (10%) developed protocol-defined cardiotoxicity. No patients developed symptomatic CHF. Response rate was 52%, with an additional 38% stable disease rate. At a median follow-up of 13.9 months, the median progression-free survival was 12.0 months; median overall survival has not yet been reached. The most common adverse events were grade 3 hand-foot syndrome (30%) and grade 3/4 neutropenia (27%). CONCLUSION: The combination of PLD and trastuzumab is a well tolerated and active regimen in HER-2-positive MBC. Cardiotoxicity was observed, but limited to asymptomatic declines in LVEF. Further evaluation of this combination is warranted.