Complete sequencing of TP53 predicts poor response to systemic therapy of advanced breast cancer

TP53 has been implicated in regulation of the cell cycle, DNA repair, and apoptosis. We studied, in primary breast tumors through direct cDNA sequencing of exons 2-11, whether TP53 gene mutations can predict response in patients with advanced disease to either first-line tamoxifen therapy (202 patients, of whom 55% responded) or up-front (poly)chemotherapy (41 patients, of whom 46% responded). TP53 mutations were detected in 90 of 243 (37%) tumors, and one-fourth of these mutations resulted in a premature termination of the protein. The mutations were observed in 32% (65 of 202) of the primary tumors of tamoxifen-treated patients and in 61% (25 of 41) of the primary tumors of the chemotherapy patients. TP53 mutation was significantly associated with a poor response to tamoxifen [31% versus 66%; odds ratio (OR), 0.22; 95% confidence interval (CI), 0.12-0.42; P < 0.0001]. Patients with TP53 gene mutations in codons that directly contact DNA or with mutations in the zinc-binding domain loop L3 showed the lowest response to tamoxifen (18% and 15% response rates, respectively). TP53 mutations were related, although not significantly, to a poor response to up-front chemotherapy (36% versus 63%; OR, 0.34; 95% CI, 0.09-1.24). In multivariate analysis for response including the classical parameters age and menopausal status, disease-free interval, dominant site of relapse, and levels of estrogen receptor and progesterone receptor, TP53 mutation was a significant predictor of poor response in the tamoxifen-treated group (OR, 0.29; 95% CI, 0.13-0.63; P = 0.0014). TP53-mutated and estrogen receptor-negative (<10 fmol/mg protein) tumors appeared to be the most resistant phenotype. Interestingly, the response of patients with TP53 mutations to chemotherapy after tamoxifen was not worse than that of patients without these mutations (50% versus 42%; OR, 1.35, nonsignificant). The median progression-free survival after systemic treatment was shorter for patients with a TP53 mutation than for patients with wild-type TP53 (6.6 and 0.6 months less for tamoxifen and up-front chemotherapy, respectively). In conclusion, TP53 gene mutation of the primary tumor is helpful in predicting the response of patients with metastatic breast disease to tamoxifen therapy. The type of mutation and its biological function should be considered in the analyses of the predictive value of TP53.     

The urokinase system of plasminogen activation and prognosis in 2780 breast cancer patients

The antigen levels of components of the urokinase-type plasminogen activator (uPA) system of plasminogen activation are correlated with prognosis in several types of cancers, including breast cancer. In the present study involving 2780 patients with primary invasive breast cancer, we have evaluated the prognostic importance of the four major components of the uPA system [uPA, the receptor uPAR (CD87), and the inhibitors PAI-1 and PAI-2]. The antigen levels were determined by ELISA in cytosols prepared from primary breast tumors. The levels of the four factors significantly correlated with each other; the Spearman rank correlation coefficients (r(s)) ranged from 0.32 (between PAI-2 and PAI-1 or uPAR) to 0.59 (between uPA and PAI-1). The median duration of follow-up of patients still alive was 88 months. In the multivariate analyses for relapse-free survival (RFS) and overall survival (OS), we defined a basic model including age, menopausal status, tumor size and grade, lymph node status, adjuvant therapy, and steroid hormone receptor status. uPA, uPAR, PAI-1, and PAI-2 were considered as categorical variables, each with two cut points that were established by isotonic regression analysis. Compared with tumors with low levels, those with intermediate and high levels showed a relative hazard rate (RHR) and 95% confidence interval (95% CI) of 1.22 (1.02-1.45) and 1.69 (1.39-2.05) for uPA, and 1.32 (1.14-1.54) and 2.17 (1.74-2.70) for PAI-1, respectively, in multivariate analysis for RFS in all patients. Compared with tumors with high PAI-2 levels, those with intermediate and low levels showed a poor RFS with a RHR (95% CI) of 1.30 (1.14-1.48) and 1.76 (1.38-2.24), respectively. Similar results were obtained in the multivariate analysis for OS in all patients. Furthermore, uPA and PAI-1 were independent predictive factors of a poor RFS and OS in node-negative and node-positive patients. PAI-2 also added to the multivariate models for RFS in node-negative and node-positive patients, and in the analysis for OS in node-negative patients. uPAR did not further contribute to any of the multivariate models. A prognostic score was calculated based on the estimates from the final multivariate model for RFS. Using this score, the difference between the highest and lowest 10% risk groups was 66% in the analysis for RFS at 10 years and 61% in the analysis for OS. Moreover, separate prognostic scores were calculated for node-negative and node-positive patients. In the 10% highest risk groups, the proportion of disease-free patients was only 27 +/- 6% and 9 +/- 3% at 10 years for node-negative and node-positive patients, respectively. These proportions were 86 +/- 4% and 61 +/- 6% for the corresponding 10% lowest risk groups of relapse. We conclude that several components of the uPA system are potential predictors of RFS and OS in patients with primary invasive breast cancer. Knowledge of these factors could be helpful to assess the individual risk of patients, to select various types of adjuvant treatment and to identify patients who may benefit from targeted therapies that are currently being developed.     

Detection of endometrial adenocarcinoma in two asymptomatic postmenopausal women receiving tamoxifen. A report of two cases

BACKGROUND: Tamoxifen has been linked to an increased risk for the development of endometrial adenocarcinoma. The majority of these carcinomas present with postmenopausal bleeding. The current standard is to undertake sampling only after the onset of bleeding. CASES: Two cases illustrate the utility of transvaginal saline infusion sonohysterography (TVS/SIS) in the detection of endometrial carcinoma prior to the onset of bleeding. CONCLUSION: Annual TVS/SIS may be useful for screening asymptomatic, tamoxifen-exposed patients with a uterus in situ and is likely to be more acceptable to such patients than annual biopsies.     

The effect of natural and surgically constructed aortopulmonary shunts on hemodynamic function in tetralogy of Fallot.

A hemodynamic model has been developed for the patient with tetralogy of Fallot. Equations representing the circulatory flow pattern and oxygen balance in this disease were incorporated into a computer program. With the computer model it is possible to simulate the effect of natural and surgically constructed aortopulmonary shunt flow on hemodynamic function in tetralogy of Fallot. Graphic representations of the computer output are presented which show how aortopulmonary shunt flow influences the physiology of exercise and hypoxic episodes. An explanation is advanced for the lack of correlation between resting arterial oxygen saturation and the incidence of hypoxic episodes. The model demonstrates the effect of surgical aortopulmonary shunts in eliminating hypoxic spells.     

Outcome of pregnancy in homozygous sickle cell disease

OBJECTIVE: Previous reports on pregnancy in homozygous sickle cell (SS) disease are biased by hospital-based, more severely affected subjects and may have underestimated recurrent early pregnancy losses. We report pregnancy outcome in a representative sample of SS subjects subsequently referred to as "subjects" or "sickle cell subjects," and matched normal controls followed from birth. METHODS: The outcomes of 94 pregnancies in 52 subjects and 157 pregnancies in 68 controls followed in a cohort study from birth are presented. Outcome measures included the age at menarche, interval to first pregnancy, outcome of pregnancy, and maternal complications. Possible predictors of low birth weight are assessed. Outcomes were compared by the Kaplan-Meier analysis for interval to first pregnancy and by Student t test, chi(2) test, or Fisher exact test, as appropriate. Correction was made for multiple testing, and multiple linear regression was used for analysis of birth weight. RESULTS: Compared with controls, SS subjects had later menarche (median age 15.4 versus 13.0 years) and first pregnancy (median age 23.7 versus 20.1 years), and more spontaneous abortions (36% versus 10%). Babies of SS subjects had a lower gestational age (P <.001) and lower birth weight (P <.001), the latter being significantly affected by sickle-related events in pregnancy. There was no difference in pregnancy-induced hypertension, preeclampsia, or antepartum or postpartum hemorrhage, but a retained placenta was marginally more common in SS subjects (Fisher exact test, P =.007 after adjustment for multiple testing). Two SS subjects died, a mortality rate of 2.1%. CONCLUSION: The increased fetal loss and maternal morbidity in mothers with homozygous sickle cell disease is confirmed. LEVEL OF EVIDENCE: II-2     

Phase II trial of gemcitabine as second-line chemotherapy of uterine leiomyosarcoma: a Gynecologic Oncology Group (GOG) Study

OBJECTIVE: To determine the antitumor activity and toxicity profile of gemcitabine as second-line chemotherapy in patients with recurrent or persistent uterine leiomyosarcoma (LMS). METHODS: Intravenous gemcitabine was administered over 30 min at a dose of 1000 mg/m(2) on days 1, 8, 15, with cycles repeated every 28 days. Eligibility criteria included measurable disease, performance status 0-2, adequate bone marrow function, creatinine <1.5 mg%, bilirubin <1.5x institutional normal, SGOT/alkaline phosphatase <3x institutional normal, and signed informed consent. Standard Gynecologic Oncology Group (GOG) toxicity and response criteria were utilized. RESULTS: Forty-eight patients were enrolled on the study. Three were deemed ineligible upon central pathology review, another received an inadequate course of protocol treatment, and two others were not reassessed for response; thus 44 patients were evaluable for toxicity and 42 for toxicity and response. The median age was 52.5 (range: 31-82) years. Thirty-five patients had received prior chemotherapy and 11 had undergone prior radiotherapy. Sites of measurable disease were pelvic (n = 9) and extrapelvic (n = 35). A median of two (range: 1-13) cycles was received. The schedule was well tolerated; there were no treatment-related deaths. The only grade 4 toxicities included neutropenia (n = 7), nausea and vomiting (n = 2), and dermatologic (n = 1). One (2.3%) patient achieved a complete response and eight (18.2%) experienced a partial response, for an overall response rate of 20.5%. CONCLUSION: Gemcitabine demonstrates activity in patients with persistent or recurrent uterine LMS and should be considered in multiagent regimens treating this patient population.     

Cisplatin as initial chemotherapy in ovarian carcinosarcomas: a Gynecologic Oncology Group study

OBJECTIVES: Carcinosarcomas of the ovary are rare; hence, although most patients recur after surgical resection or have metastatic disease at the time of diagnosis, only anecdotal information is available concerning the activity of cytotoxic drugs against these lesions. The Gynecologic Oncology Group (GOG) initiated a concerted effort to study cytotoxic therapy for these cancers in 1976. This report presents data on cisplatin, the first of the agents to be studied in this disease. METHODS: One hundred thirty-six eligible patients with ovarian carcinosarcoma received cisplatin (50 mg/m(2)) every 3 weeks until disease progression or unacceptable toxicity. RESULTS: Among 44 patients evaluable for response, one complete (2%) and eight partial (18%) responses resulted. An additional 10 (23%) patients exhibited stable disease, while 25 (57%) had increasing disease. Median progression-free survival in 130 patients evaluable for this endpoint was 5.2 months. Median survival in the same 130 patients was 11.7 months. Adverse effects >/=grade 2 among the 132 patients evaluable for toxicity included leukopenia (14%), neutropenia (17%), thrombocytopenia (2%), anemia (10%), nausea and vomiting (40%), azotemia (3%), neurotoxicity (4%), fever (2%), and tinnitus (1%). CONCLUSIONS: These data provide the first objective evidence that cisplatin is active as an initial therapy for patients who have carcinosarcoma of the ovary. The overall response rate (20%) is similar to that seen in carcinosarcomas of the uterus.