Post-surgical ctDNA-based molecular residual disease detection in patients with stage I uterine malignancies.

INTRODUCTION: Among uterine malignancies, endometrial cancer (EC) is the most common cancer of the female reproductive tract. Traditionally, risk stratification in EC is determined by standard clinicopathological risk factors. Although circulating tumor DNA (ctDNA) has emerged as a prognostic biomarker in various malignancies, its clinical validity in EC remains to be established. METHODS: In this analysis of real-world data, 267 plasma samples from 101 patients with stage I EC were analyzed using a tumor-informed ctDNA assay (Signatera™ bespoke mPCR-NGS). Patients were followed post-surgically and monitored with ctDNA testing for a median of 6.8 months (range: 0.37-19.1). RESULTS: Patients who tested ctDNA-positive at both their first time point and longitudinally experienced inferior recurrence-free survival (RFS) (HR = 6.2; p = 0.0006 and HR = 15.5; p < 0.0001, respectively), and showed a recurrence rate of 58% and 52%, vs. 6% and 0%, respectively for the ctDNA-negative patients. Most ctDNA-positive patients had high-risk histologies or sarcoma, versus low-risk and high-intermediate risk (H-IR) EC. Furthermore, patients with high-risk histologies who were ctDNA-positive showed shorter RFS compared to those who tested negative (HR = 9.5; p = 0.007), and those who tested positive in the low/H-IR cohort (HR = 0.25; p = 0.04). Post-surgically, detectable ctDNA was highly prognostic of clinical outcome and remained the only significant risk factor for recurrence when adjusted for clinicopathological risk factors, such as histologic risk group, mismatch repair (MMR), and p53 status. CONCLUSION: Incorporating ctDNA monitoring along with traditional known risk factors may aid in identifying patients with stage I EC who are at highest risk of recurrence, and possibly aid in treatment stratification.

Diffuse intra-abdominal splenosis presenting as carcinomatosis exhibiting positron emitted tomography hypermetabolic activity.

•Splenosis can mimic carcinomatosis upon many imaging modalities.•History of splenectomy must be considered when evaluating carcinomatosis.•Scintigraphy is the preferred for confirming the presence of splenosis.

Phase III trial of induction gemcitabine or paclitaxel plus carboplatin followed by paclitaxel consolidation in ovarian cancer.

OBJECTIVE: The safety and efficacy of gemcitabine plus carboplatin (GC) or paclitaxel plus carboplatin (TC) induction regimens with or without paclitaxel consolidation therapy were assessed in ovarian cancer (OC). METHODS: Patients with stage IC-IV OC were randomized to either GC (gemcitabine 1,000 mg/m(2), days 1 and 8, plus carboplatin area under the curve [AUC] 5, day 1) or TC (paclitaxel 175 mg/m(2) plus carboplatin AUC 6, day 1) every 21 days for up to six cycles. Patients with complete response (CR) were allowed optional consolidation with paclitaxel 135 mg/m(2) every 28 days for ≤ 12 months. Patients without CR received single-agent crossover therapy at induction doses/schedules until CR, disease progression (PD), or unacceptable toxicity. PD or death in 636 patients was required to compare induction arms with 80% statistical power for progression-free survival (PFS), the primary endpoint. RESULTS: Randomized induction therapy was received by 820 of 919 patients enrolled; 352 patients with CR received paclitaxel consolidation whereas 155 patients without CR received single-agent crossover therapy. PFS was similar for GC and TC (median, 20.0 and 22.2 months, respectively; P=.199). Despite high censoring rates (>52%), overall survival was longer for TC (median, 57.3 versus 43.8 months for GC; P=.013). Controlling for patient characteristics including performance status, residual tumor size, and tumor stage, there was no statistical difference in a multivariate analysis (HR=1.22; 95% CI=0.99-1.52; P=.067). CONCLUSIONS: GC does not improve PFS over TC as first-line induction chemotherapy in OC. Although favoring TC, overall survival analyses were limited by the study design and high censoring rates.

Are prediction models for Lynch syndrome valid for probands with endometrial cancer?

Currently, three prediction models are used to predict a patient's risk of having Lynch syndrome (LS). These models have been validated in probands with colorectal cancer (CRC), but not in probands presenting with endometrial cancer (EMC). Thus, the aim was to determine the performance of these prediction models in women with LS presenting with EMC. Probands with EMC and LS were identified. Personal and family history was entered into three prediction models, PREMM(1,2), MMRpro, and MMRpredict. Probabilities of mutations in the mismatch repair genes were recorded. Accurate prediction was defined as a model predicting at least a 5% chance of a proband carrying a mutation. From 562 patients prospectively enrolled in a clinical trial of patients with EMC, 13 (2.2%) were shown to have LS. Nine patients had a mutation in MSH6, three in MSH2, and one in MLH1. MMRpro predicted that 3 of 9 patients with an MSH6, 3 of 3 with an MSH2, and 1 of 1 patient with an MLH1 mutation could have LS. For MMRpredict, EMC coded as "proximal CRC" predicted 5 of 5, and as "distal CRC" three of five. PREMM(1,2) predicted that 4 of 4 with an MLH1 or MSH2 could have LS. Prediction of LS in probands presenting with EMC using current models for probands with CRC works reasonably well. Further studies are needed to develop models that include questions specific to patients with EMC with a greater age range, as well as placing increased emphasis on prediction of LS in probands with MSH6 mutations.

A phase II trial of weekly 1-hour paclitaxel as second-line therapy for endometrial and cervical cancer.

BACKGROUND: The efficacy of weekly paclitaxel has not been well characterized in either cervical or endometrial cancer. METHODS: Eligible women had disseminated endometrial or squamous cell cancer of the cervix, one prior chemotherapy regimen, measurable disease, and a Gynecologic Oncology Group (GOG) performance status of 0-2. At entry, all laboratory results were within normal limits. Paclitaxel 80 mg/m(2) was administered by intravenous infusion over 1 h every 7 days. Response served as the endpoint of the trial. RESULTS: Forty-four patients were registered, and 15 of 16 patients with endometrial cancer and 20 of 28 patients with cervical cancer were evaluable for response. Four of the 15 (26.7%) endometrial cancer patients responded to treatment, with one complete response of 22 weeks and three partial responses. Stable disease was present in 26.7%. Two of the 20 (10%) cervical cancer patients responded to treatment, with one complete response of 25 weeks and one partial response of 14 weeks. Stable disease was present in 35%. Adverse effects were minimal and easily managed with dose adjustments as needed. CONCLUSION: Although confirmatory larger trials are needed, weekly paclitaxel appears promising for advanced endometrial carcinoma, and possibly for squamous cell carcinoma of the cervix.

Phase III randomized trial of intravenous cisplatin plus a 24- or 96-hour infusion of paclitaxel in epithelial ovarian cancer: a Gynecologic Oncology Group Study.

PURPOSE: This study was undertaken to assess if prolonged paclitaxel administration in combination with cisplatin improves overall survival (OS) in epithelial ovarian cancer (EOC). PATIENTS AND METHODS: Eligible patients with suboptimal stage III or IV EOC, fallopian tube, or primary peritoneal cancer were randomly allocated to receive six cycles of cisplatin 75 mg/m2 and either paclitaxel 135 mg/m2 during 24 hours (arm 1) or paclitaxel 120 mg/m2 during 96 hours (arm 2). RESULTS: Planned accrual was 324 patients; 293 were enrolled before the study was closed as a result of a scheduled interim futility analysis. There were 13 ineligible patients; thus, 140 patients in each arm were assessable. In arm 1, 80% of patients completed all six cycles compared with 83% of patients in arm 2. Grade 4 granulocytopenia was more common in arm 1 (79% v 54%; P < .001) whereas grade 3 or worse anemia was more severe in arm 2 (6% v 18%; P < .003). The median progression-free survival was 1.03 years for arm 1 versus 1.05 years for arm 2. The median OS was 2.49 and 2.54 years for arms 1 and 2, respectively. There have been 237 reported deaths. The relative death rate was approximately 12% greater in arm 2 (hazard ratio, 1.12; 95% CI, 0.860 to 1.45). CONCLUSION: Patients with advanced EOC have a relatively poor prognosis. The results of treatment with cisplatin and paclitaxel are not significantly improved by prolonging the paclitaxel infusion from 24 to 96 hours.

Phase II clinical trial of docetaxel in refractory squamous cell carcinoma of the cervix: a Gynecologic Oncology Group Study.

OBJECTIVE: A phase II study was conducted to evaluate the antitumor activity and adverse effects of docetaxel in patients with previously treated squamous cell carcinoma of the cervix. METHODS: Eligible patients were to have measurable disease and not more than one prior chemotherapy regimen. Docetaxel 100 mg/m was administered intravenously over 1 hour. This treatment was repeated every 21 days until progression of disease or adverse effects prohibited further therapy. RESULTS: Twenty-seven patients were entered onto this study, of whom 23 were eligible and evaluable. There were 2 (8.7%) partial responses. Eight patients (34.8%) had stable disease and 9 patients (39.1%) had increasing disease. The median time to progression was 3.8 months (range, 1.2-11.7 months), while median survival time was 7.0 months (range, 1.8-23.0 months). The most frequently reported adverse events were neutropenia, infection, gastrointestinal, and constitutional. CONCLUSIONS: Docetaxel has minimal activity in refractory squamous cell carcinoma of the cervix at the dose and schedule tested.

Screening for Lynch syndrome (hereditary nonpolyposis colorectal cancer) among endometrial cancer patients.

Endometrial cancer is the most common cancer in women with Lynch syndrome. The identification of individuals with Lynch syndrome is desirable because they can benefit from increased cancer surveillance. The purpose of this study was to determine the feasibility and desirability of molecular screening for Lynch syndrome in all endometrial cancer patients. Unselected endometrial cancer patients (N = 543) were studied. All tumors underwent microsatellite instability (MSI) testing. Patients with MSI-positive tumors underwent testing for germ line mutations in MLH1, MSH2, MSH6, and PMS2. Of 543 tumors studied, 118 (21.7%) were MSI positive (98 of 118 MSI high and 20 of 118 MSI low). All 118 patients with MSI-positive tumors had mutation testing, and nine of them had deleterious germ line mutations (one MLH1, three MSH2, and five MSH6). In addition, one case with an MSI-negative tumor had abnormal MSH6 immunohistochemical staining and was subsequently found to have a mutation in MSH6. Immunohistochemical staining was consistent with the mutation result in all seven truncating mutation-positive cases but was not consistent in two of the three missense mutation cases. We conclude that in central Ohio, at least 1.8% (95% confidence interval, 0.9-3.5%) of newly diagnosed endometrial cancer patients had Lynch syndrome. Seven of the 10 Lynch syndrome patients did not meet any published criteria for hereditary nonpolyposis colorectal cancer, and six of them were diagnosed at age >50. Studying all endometrial cancer patients for Lynch syndrome using a combination of MSI and immunohistochemistry for molecular prescreening followed by gene sequencing and deletion analysis is feasible and may be desirable.

Adenocarcinoma of the uterine cervix with choriocarcinomatous metastasis.

BACKGROUND: Nongestational choriocarcinoma, in very rare instances, has been described as a component of other malignancies with a tendency for a very poor prognosis. CASE: A 55 year old woman was diagnosed with adenocarcinoma of the cervix, and incompletely treated with only external beam radiation. Adjuvant radical hysterectomy demonstrated no residual tumor, but the patient developed a tumor metastasis mimicking a pulmonary artery thrombus which by histology and immunohistochemistry was pure choriocarcinoma. While chemotherapy was successful in achieving a complete remission, the patient succumbed to complications of her pulmonary metastasis. CONCLUSION: Choriocarcinomatous dedifferentiation of cervical adenocarcinoma is extremely rare, with only one other case reported in the literature. While the prognosis for patients with such a tumor is generally poor, aggressive combination chemotherapy may be of benefit in some.

Trimetrexate in the treatment of recurrent or advanced leiomyosarcoma of the uterus: a phase II study of the Gynecologic Oncology Group.

OBJECTIVE: This study was conducted to determine the objective response of trimetrexate in patients with advanced or recurrent leiomyosarcoma of the uterus. METHODS: Eligibility was restricted to patients with measurable disease who had received no more than one prior chemotherapy regimen, who had adequate bone marrow, renal, and hepatic function, and who had recovered from previous therapy. Trimetrexate was begun at 5 mg/m2/day orally for 5 days every other week, with dose modifications specified by study design. RESULTS: Of 28 patients entered into the study, 27 were evaluable for toxicity and 23 for response. Prior therapy included radiation (7 patients) and/or chemotherapy (10 patients). Measurable disease was extrapelvic in 20 cases and confined to the pelvis in 3. The overall response rate was 4.3%; there were no complete responses and 1 partial response. Toxicities were mild to moderate with no treatment-related deaths. Hematological toxicity was most common, consisting of leukopenia (grade 1 to 2, 8 patients; grade 3 or 4, 2 patients), thrombocytopenia (grade 1 to 2, 10 patients; grade 3 or 4, 1 patient), and anemia (grade 1 to 2, 6 patients; grade 3 or 4, 4 patients. Severe (grade 3 or 4) nonhematologic toxicity was uncommon: nausea/vomiting/gastrointestinal (3 patients) and neurological (1 patient). Progression-free and overall survival, in months, was 2.2 (range: 0.9-13.4) and 7.2+ (range: 1.0-13.4+), respectively. CONCLUSION: Although toxicity is acceptable, trimetrexate at this dose and schedule is ineffective therapy for patients with recurrent leiomyosarcoma. Further development of this specific regimen for this indication is unwarranted.