Gwo-Fuang Ho

Adjuvant! Online is overoptimistic in predicting survival of Asian breast cancer patients.

BACKGROUND Adjuvant! Online is a free web-based tool which predicts 10-year breast cancer outcomes and the efficacy of adjuvant therapy in patients with breast cancer. As its prognostic performance has only been validated in high income Caucasian populations, we validated the model in a middle income Asian setting. METHODS Within the University Malaya Hospital-Based Breast Cancer Registry, all 631 women who were surgically treated for invasive non-metastatic breast cancer between 1993 and 2000 were identified. The discriminative performance of Adjuvant! Online was tested using receiver operating characteristic (ROC) analysis. Calibration of the model was evaluated by comparing predicted 10-year overall survival with observed 10-year survival. FINDINGS Adjuvant! Online was fairly capable in discriminating between good and poor survivors, as attested by the area under ROC curve of 0.73 (95% Confidence Interval: 0.69-0.77). Overall, Adjuvant! Online predicted 10 year survival (70.3%) was significantly higher than the observed 10 year survival (63.6%, difference of 6.7%; 95% CI: 3.0-10.4%). The model was especially overoptimistic in women under 40 years and in women of Malay ethnicity, where survival was overestimated by approximately 20% (95% CI: 9.8-29.8%) and 15% (95% CI: 5.3-24.5%) respectively. INTERPRETATION Even though Adjuvant! Online is capable of discriminating between good and poor survivors, it systematically overestimates survival. These findings suggest that the model requires adaptation prior to use in Asian settings.

Metformin synergizes 5-fluorouracil, epirubicin, and cyclophosphamide (FEC) combination therapy through impairing intracellular ATP production and DNA repair in breast cancer stem cells

Metformin, an AMPK activator, has been reported to improve pathological response to chemotherapy in diabetic breast cancer patients. To date, its mechanism of action in cancer, especially in cancer stem cells (CSCs) have not been fully elucidated. In this study, we demonstrated that metformin, but not other AMPK activators (e.g. AICAR and A-769662), synergizes 5-fluouracil, epirubicin, and cyclophosphamide (FEC) combination chemotherapy in non-stem breast cancer cells and breast cancer stem cells. We show that this occurs through an AMPK-dependent mechanism in parental breast cancer cell lines. In contrast, the synergistic effects of metformin and FEC occurred in an AMPK-independent mechanism in breast CSCs. Further analyses revealed that metformin accelerated glucose consumption and lactate production more severely in the breast CSCs but the production of intracellular ATP was severely hampered, leading to a severe energy crisis and impairs the ability of CSCs to repair FEC-induced DNA damage. Indeed, addition of extracellular ATP completely abrogated the synergistic effects of metformin on FEC sensitivity in breast CSCs. In conclusion, our results suggest that metformin synergizes FEC sensitivity through distinct mechanism in parental breast cancer cell lines and CSCs, thus providing further evidence for the clinical relevance of metformin for the treatment of cancers.

The predictive accuracy of PREDICT: a personalized decision-making tool for Southeast Asian women with breast cancer.

Abstract Web-based prognostication tools may provide a simple and economically feasible option to aid prognostication and selection of chemotherapy in early breast cancers. We validated PREDICT, a free online breast cancer prognostication and treatment benefit tool, in a resource-limited setting. All 1480 patients who underwent complete surgical treatment for stages I to III breast cancer from 1998 to 2006 were identified from the prospective breast cancer registry of University Malaya Medical Centre, Kuala Lumpur, Malaysia. Calibration was evaluated by comparing the model-predicted overall survival (OS) with patients’ actual OS. Model discrimination was tested using receiver-operating characteristic (ROC) analysis. Median age at diagnosis was 50 years. The median tumor size at presentation was 3 cm and 54% of patients had lymph node-negative disease. About 55% of women had estrogen receptor-positive breast cancer. Overall, the model-predicted 5 and 10-year OS was 86.3% and 77.5%, respectively, whereas the observed 5 and 10-year OS was 87.6% (difference: −1.3%) and 74.2% (difference: 3.3%), respectively; P values for goodness-of-fit test were 0.18 and 0.12, respectively. The program was accurate in most subgroups of patients, but significantly overestimated survival in patients aged <40 years, and in those receiving neoadjuvant chemotherapy. PREDICT performed well in terms of discrimination; areas under ROC curve were 0.78 (95% confidence interval [CI]: 0.74–0.81) and 0.73 (95% CI: 0.68–0.78) for 5 and 10-year OS, respectively. Based on its accurate performance in this study, PREDICT may be clinically useful in prognosticating women with breast cancer and personalizing breast cancer treatment in resource-limited settings.

Prognostic role of adjuvant radiotherapy in triple-negative breast cancer: A historical cohort study

The value of adjuvant radiotherapy in triple‐negative breast cancer (TNBC) is currently debated. We assessed the association between adjuvant radiotherapy and survival in a large cohort of Asian women with TNBC. Women diagnosed with TNBC from 2006 to 2011 in five Asian centers (N = 1,138) were included. Survival between patients receiving mastectomy only, breast‐conserving therapy (BCT, lumpectomy and adjuvant radiotherapy) and mastectomy with radiotherapy were compared, and adjusted for demography, tumor characteristics and chemotherapy types. Median age at diagnosis was 53 years (range: 23–96 years). Median tumor size at diagnosis was 2.5 cm and most patients had lymph node‐negative disease. The majority of patients received adjuvant chemotherapy (n = 861, 76%) comprising predominantly anthracycline‐based regimes. In 775 women with T1‐2, N0‐1, M0 TNBCs, 5‐year relative survival ratio (RSR) was highest in patients undergoing mastectomy only (94.7%, 95% CI: 88.8–98.8%), followed by BCT (90.8%, 95% CI: 85.0–94.7%), and mastectomy with radiotherapy (82.3%, 95% CI: 73.4–88.1%). The adjusted risks of mortality between the three groups were not significantly different. In 363 patients with T3‐4, N2‐3, M0 TNBCs, BCT was associated with highest 5‐year RSR (94.1%, 95% CI: 81.3–99.4%), followed by mastectomy with radiotherapy (62.7%, 95% CI: 54.3–70.1%), and mastectomy only (58.6%, 95% CI: 43.5–71.6%). Following multivariable adjustment, BCT and mastectomy with radiotherapy remained significantly associated with lower mortality risk compared to mastectomy only. Overall, adjuvant radiotherapy was associated with higher survival in women aged <40 years, but not in older women. Adjuvant radiotherapy appears to be independently associated with a survival gain in locally advanced as well as in very young TNBC.

Do Clinical Features and Survival of Single Hormone Receptor Positive Breast Cancers Differ from Double Hormone Receptor Positive Breast Cancers

The significance of the single hormone receptor positive phenotype of breast cancer is still poorly understood. The use of hormone therapy has been found to be less effective for this type, which has a survival outcome midway between double positive and double negative phenotypes. The aim of this study was to investigate differences in patient and tumor characteristics and survival between double-receptor positive (ER+PR+), double receptor negative (ER-PR-) and single receptor positive (ER+PR- and ER-PR+) breast cancer in an Asian setting. A total of 1,992 patients with newly diagnosed stage I to IV breast cancer between 2003 and 2008, and where information on ER and PR were available, were included in this study. The majority of patients had ER+PR+ tumors (n=903: 45.3%), followed by 741 (37.2%) ER-PR-, 247 (12.4%) ER+PR-, and 101 (5.1%) ER-PR+ tumors. Using multivariate analysis, ER+PR- tumors were 2.4 times more likely to be grade 3 compared to ER+PR+ tumors. ER+PR- and ER-PR+ tumors were 82% and 86% respectively less likely to be grade 3 compared with ER-PR- tumors. ER-PR+ tumours were associated with younger age. There were no survival differences between patients with ER+PR+ and ER-PR+ tumors. However, ER+PR- tumors have poorer survival compared with ER+PR+ tumours. ER-PR- tumours had the worst survival. Adjuvant hormonal therapy with tamoxifen was found to have identical survival advantage in patients with ER+PR+ and ER-PR+ tumors whereas impact was slightly lower in patients with ER+PR- tumors. In conclusion, we found ER+PR- tumors to be more aggressive and have poorer survival when compared to ER+PR+ tumors, while patients with ER-PR+ tumours were younger, but had a similar survival to their counterparts with ER+PR+ tumours.

Advanced Stage at Presentation Remains a Major Factor Contributing to Breast Cancer Survival Disparity between Public and Private Hospitals in a Middle-Income Country

Background: Survival disparities in cancer are known to occur between public and private hospitals. We compared breast cancer presentation, treatment and survival between a public academic hospital and a private hospital in a middle-income country. Methods: The demographics, clinical characteristics, treatment and overall survival (OS) of 2767 patients with invasive breast carcinoma diagnosed between 2001 and 2011 in the public hospital were compared with 1199 patients from the private hospital. Results: Compared to patients in the private hospital, patients from the public hospital were older at presentation, and had more advanced cancer stages. They were also more likely to receive mastectomy and chemotherapy but less radiotherapy. The five-year OS in public patients was significantly lower than in private patients (71.6% vs. 86.8%). This difference was largely attributed to discrepancies in stage at diagnosis and, although to a much smaller extent, to demographic differences and treatment disparities. Even following adjustment for these factors, patients in the public hospital remained at increased risk of mortality compared to their counterparts in the private hospital (Hazard Ratio: 1.59; 95% Confidence Interval: 1.36–1.85). Conclusion: Late stage at diagnosis appears to be a major contributing factor explaining the breast cancer survival disparity between public and private patients in this middle-income setting.