Comparison of the Ability of Different Clinical Treatment Scores to Estimate Prognosis in High-Risk Early Breast Cancer Patients: A Hellenic Cooperative Oncology Group Study.

BACKGROUND-AIM: Early breast cancer is a heterogeneous disease, and, therefore, prognostic tools have been developed to evaluate the risk for distant recurrence. In the present study, we sought to develop a risk for recurrence score (RRS) based on mRNA expression of three proliferation markers in high-risk early breast cancer patients and evaluate its ability to predict risk for relapse and death. In addition the Adjuvant! Online score (AOS) was also determined for each patient, providing a 10-year estimate of relapse and mortality risk. We then evaluated whether RRS or AOS might possibly improve the prognostic information of the clinical treatment score (CTS), a model derived from clinicopathological variables. METHODS: A total of 1,681 patients, enrolled in two prospective phase III trials, were treated with anthracycline-based adjuvant chemotherapy. Sufficient RNA was extracted from 875 samples followed by multiplex quantitative reverse transcription-polymerase chain reaction for assessing RACGAP1, TOP2A and Ki67 mRNA expression. The CTS, slightly modified to fit our cohort, integrated the prognostic information from age, nodal status, tumor size, histological grade and treatment. Patients were also classified to breast cancer subtypes defined by immunohistochemistry. Likelihood ratio (LR) tests and concordance indices were used to estimate the relative increase in the amount of information provided when either RRS or AOS is added to CTS. RESULTS: The optimal RRS, in terms of disease-free survival (DFS) and overall survival (OS), was based on the co-expression of two of the three evaluated genes (RACGAP1 and TOP2A). CTS was prognostic for DFS (p<0.001), while CTS, AOS and RRS were all prognostic for OS (p<0.001, p<0.001 and p = 0.036, respectively). The use of AOS in addition to CTS added prognostic information regarding DFS (LR-Δχ2 8.7, p = 0.003), however the use of RRS in addition to CTS did not. For estimating OS, the use of either AOS or RRS in addition to CTS added significant prognostic information. Specifically, the use of both CTS and AOS had significantly better prognostic value vs. CTS alone (LR-Δχ2 20.8, p<0.001), as well as the use of CTS and RRS vs. CTS alone (LR-Δχ2 4.8, p = 0.028). Additionally, more patients were scored as high-risk by AOS than CTS. According to immunohistochemical subtypes, prognosis was improved in the Luminal A (LR-Δχ2 7.2, p = 0.007) and Luminal B (LR-Δχ2 8.3, p = 0.004) subtypes, in HER2-negative patients (LR-Δχ2 23.4, p<0.001) and in patients with >3 positive nodes (LR-Δχ2 23.9, p<0.001) when AOS was added to CTS. CONCLUSIONS: The current study has shown a clear benefit in predicting overall survival of high-risk early breast cancer patients when combining CTS with either AOS or RRS. The combination of CTS and AOS adds significant prognostic information compared to CTS alone for DFS, while the combination of CTS with either AOS or RRS has better prognostic value than CTS alone for OS. These findings could possibly add on the information needed for the best risk prediction strategy in high-risk early breast cancer patients in a rather simple and inexpensive way, especially in Luminal A and B subtypes, HER2-negative patients and those with >3 positive nodes.

Current chemotherapeutic options for the treatment of advanced bladder cancer: a review.

Advanced bladder cancer is a disease with a high recurrence rate and metastatic capacity exhibiting a poor outcome. The pathologic stage and nodal involvement are independent prognostic factors for survival after cystectomy, and in locally advanced or metastatic disease, the performance status and the presence of visceral metastases have been correlated with treatment outcome. The regimen methotrexate-vinblastine-adriamycin-cisplatin (MVAC) has been the treatment of choice for decades and later the combination of cisplatin with gemcitabine became also the new standard of care, by demonstrating a more favorable toxicity profile. Also, carboplatin-gemcitabine and taxanes have been useful alternatives for patients unfit for cisplatin-based treatment. Additionally, the evaluation of certain chemotherapeutic agents has produced promising results in the second-line setting. Lastly, the past decade has provided information on the molecular mechanism of bladder cancer offering a personalized approach and optimizing the management of the disease.

Correlation of CYP1A1, GSTP1 and GSTM1 gene polymorphisms and lung cancer risk among smokers.

Lung cancer is the leading cause of cancer mortality worldwide and tobacco smoking has been established as its biggest risk factor. Cigarette smoke contains several carcinogens. Most of them need to be activated by phase I enzymes, such as cytochrome P450 (CYP), while phase II enzymes, such as glutathione S-transferases are responsible for the detoxification of activated forms. The present study aimed to determine the role of CYP1A1, GSTP1 and GSTM1 gene polymorphisms in smoking-related lung cancer risk. It also aimed to investigate the association of the above polymorphisms with clinicopathological parameters, as well as their effect on survival. One hundred newly diagnosed lung cancer patients with advanced disease and 125 healthy controls with a smoking history participated in the study. The participants were screened for the presence of the following polymorphisms: MspI (CYP1A1), Ile105Val (GSTP1) and GSTM1 deletion. The above polymorphisms were also examined with regards to gender, age, histological type and survival. GSTP1 Ile/Val and GSTM1-null genotypes were associated with increased lung cancer risk and the presence of the combination of the three non-wild-type genotypes increases susceptibility to lung cancer (OR 3.328, 95% CI=1.681-6.587, p=0.001). In the non-small cell lung cancer group, the GSTP1 homozygous variant was significantly associated with increased lung cancer risk (p=0.008) and shorter survival. The results of this study suggest that the GSTP1 Ile/Val genotype and GSTM1 deletion contribute to increased lung cancer susceptibility. Moreover, GSTP1 Val/Val genotype is associated with increased lung cancer risk and shorter survival in non-small cell lung cancer patients.

Epithelial ovarian cancer: focus on targeted therapy.

Ovarian cancer remains the leading cause of gynecological cancer-related mortality in the Western World despite the advances in surgical techniques and chemotherapy regimens over the past three decades. Although response rates and complete responses in advanced disease are >80% and 40-60%, respectively, after first-line treatment with carboplatin and paclitaxel, most of the patients will eventually relapse with a median progression-free survival of 18 months. Currently, research efforts have improved our understanding on the molecular biology of ovarian cancer and novel targeted treatment strategies are likely to contribute to the management of the disease and give the chance to an individualized therapeutic approach.

Late complications of chemotherapy in testicular cancer.

Cisplatin-based treatment has significantly increased survival in testicular cancer patients. Therefore, there has been enough interest for the late toxic effects of chemotherapy which affect the quality of life of the cancer survivors. These toxic effects may either persist or present long after the end of chemotherapy and involve the impairment of renal function, neurotoxicity, pulmonary toxicity and vascular disease. Also, a major issue experienced by a large number of patients is infertility, which has been improved due to modified surgical techniques, reduced treatment intensity, the use of sperm cryopreservation and methods of assisted reproduction. Physicians should also be aware of the risk of secondary malignancy development. Therefore, close follow-up of the testicular cancer survivors as well as, focus on minimizing treatment complications through improvement of treatment strategies are warranted.

Parallel morning and evening surge in stroke onset, blood pressure, and physical activity.

BACKGROUND AND PURPOSE: A circadian variation with a morning peak on waking and arising is known to occur in both blood pressure (BP) and cardiovascular event onset. A second peak in BP has been described to occur after an afternoon sleep (siesta). This study was designed to investigate the hypothesis that the 2-peak diurnal variation of BP is dependent on physical activity and occurs in parallel with the diurnal variation of stroke onset. METHODS: The diurnal variation of stroke onset was compared with the diurnal variation of BP, pulse rate (PR), and physical activity in 3 independent groups of Greek hypertensives 51 to 80 years of age (633 stroke patients, 379 subjects with 24-hour ambulatory BP monitoring, and 50 subjects with 24-hour physical activity monitoring through wrist devices). RESULTS: The diurnal variation of stroke onset, BP, and PR all showed 1 morning and 1 evening peak with a decline in the afternoon and at night that occurred in parallel with the diurnal variation in physical activity (P<0.001 for differences among morning, afternoon, evening, and nighttime intervals in BP, PR, activity, and stroke). The afternoon decline in BP, PR, and activity was significant only in subjects with a siesta. CONCLUSIONS: The 2-peak diurnal variation in stroke onset occurred in parallel with the variation in BP, PR, and physical activity. These data support the hypothesis that an abrupt change in physical activity is not only a major determinant of the 2-peak diurnal variation of BP but also an important triggering factor for a cerebrovascular event.