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.

Opportunistic mammography screening provides effective detection rates in a limited resource healthcare system.

BACKGROUND: Breast cancer is the leading cause of cancer deaths in women world-wide. In low and middle income countries, where there are no population-based mammographic screening programmes, late presentation is common, and because of inadequate access to optimal treatment, survival rates are poor. Mammographic screening is well-studied in high-income countries in western populations, and because it has been shown to reduce breast cancer mortality, it has become part of the healthcare systems in such countries. However the performance of mammographic screening in a developing country is largely unknown. This study aims to evaluate the performance of mammographic screening in Malaysia, a middle income country, and to compare the stage and surgical treatment of screen-detected and symptomatic breast cancer. METHODS: A retrospective review of 2510 mammograms performed from Jan to Dec 2010 in a tertiary medical centre is carried out. The three groups identified are the routine (opportunistic) screening group, the targeted (high risk) screening group and the diagnostic group. The performance indicators of each group is calculated, and stage at presentation and treatment between the screening and diagnostic group is analyzed. RESULTS: The cancer detection rate in the opportunistic screening group, targeted screening group, and the symptomatic group is 0.5 %, 1.25 % and 26 % respectively. The proportion of ductal carcinoma in situ is 23.1 % in the two screening groups compared to only 2.5 % in the diagnostic group. Among the opportunistic screening group, the cancer detection rate was 0.2 % in women below 50 years old compared to 0.65 % in women 50 years and above. The performance indicators are within international standards. Early-staged breast cancer (Stage 0-2) were 84.6 % in the screening groups compared to 61.1 % in the diagnostic group. CONCLUSION: From the results, in a setting with resource constraints, targeted screening of high risk individuals will give a higher yield, and if more resources are available, population-based screening of women 50 and above is effective. Opportunistic mammographic screening is feasible and effective in a middle income country with performance indicators within international standards. Waiting until women are symptomatic will lead to more advanced cancers.

Determinants of choice of surgery in Asian patients with early breast cancer in a middle income country.

BACKGROUND: Breast-conserving surgery (BCS) plus radiotherapy is equivalent to modified radical mastectomy (MRM) in terms of outcome. However there is wide variation in mastectomy rates dependent both on tumour and patient characteristics. OBJECTIVE: This study aimed to assess the determinants of surgery choice in Asian patients with early breast cancer in a middle-income country. MATERIALS AND METHODS: 184 patients with early breast cancer treated between Jan 2008 and Dec 2010 were recruited to complete a questionnaire. Chi-square test was used to analyze the association between surgery choice and demographic and tumour factors, surgeon recommendation, family member and partner opinions, fear of recurrence, avoidance of second surgery, fear of disfigurement, interference with sex life, fear of radiation and loss of femininity. RESULTS: 85 (46%) had BCS while 99 (54%) had mastectomy. Age >60, Chinese ethnicity, lower education level, and larger tumour size were significantly associated with mastectomy. Surgeon recommendation was important in surgery choice. Although both groups did not place much importance on interference with sex life, 14.1% of the BCS group felt it was very important compared to 5.1% in the mastectomy group and this was statistically significant. There was no statistical difference between the two groups in terms of the other factors. When analyzed by ethnicity, significantly more Malay and Indian women considered partner and family member opinions very important and were more concerned about loss of femininity compared to Chinese women. There were no statistical differences between the three ethnic groups in terms of the other factors. CONCLUSIONS: When counseling on surgical options, the surgeon has to take into account the ethnicity, social background and education level, age and reliance on partner and family members. Decision-making is usually a collective effort rather than just between the patient and surgeon, and involving the whole family into the process early is important.

Rationale of excisional biopsy after the diagnosis of benign radial scar on core biopsy: a single institutional outcome analysis.

BACKGROUND: Radial scar (RS) is characterized by a fibroelastic core with entrapped ducts and lobules. Association with carcinoma is not uncommon. There is some dilemma as to the need for excisional biopsy or follow-up after RS diagnosis on core biopsy. AIM: To determine the necessity of excisional biopsy after the diagnosis of benign RS by core biopsy. STUDY DESIGN: A total of 67 RS specimens associated with benign findings on core biopsy obtained between 2003 and 2008 were reviewed. They were grouped by their accompanying histopathologic features found upon subsequent surgical excision: benign, high-risk lesion (HRL), or carcinoma. Demographic features, radiologic findings, and needle gauge were compared within subgroups. RESULTS: After surgical excision, 15 (22.4%) patients in the benign group were upgraded to a HRL, 4 (5.9%) patients were upgraded to carcinoma, and 48 (71.6%) remained benign. We found that malignancy is associated with RS more frequently if the patient is older and postmenopausal. Other variables such as symptoms at presentation, presence and type of abnormality on mammography (Breast Imaging Reporting and Data System score), breast density, size of biopsy needle used, and number of core samples retrieved did not help to predict the presence of carcinoma. CONCLUSIONS: The HRL and cancer upgrade rate of RS, requiring further intervention such as surgery or chemoprevention, is 28% in this study. However, we found that age and menopausal status may be taken into consideration when making the decision to follow up or excise the RS diagnosed on core biopsy. There is insufficient data to support the predictive value of any variables. Therefore, RS associated with benign findings on core biopsy should be excised.

Risk of treatment related death and febrile neutropaenia with taxane-based adjuvant chemotherapy for breast cancer in a middle income country outside a clinical trial setting.

BACKGROUND: The risk of treatment-related death (TRD) and febrile neutropaenia (FN) with adjuvant taxane- based chemotherapy for early breast cancer is unknown in Malaysia despite its widespread usage in recent years. This study aims to determine these rates in patients treated in University Malaya Medical Centre (UMMC). PATIENTS AND METHODS: Patients who were treated with adjuvant taxane-based chemotherapy for early breast cancer stages I, II or III from 2007-2011 in UMMC were identified from our UMMC Breast Cancer Registry. The TRD and FN rates were then determined retrospectively from medical records. TRD was defined as death occurring during or within 30 days of completing chemotherapy as a consequence of the chemotherapy treatment. FN was defined as an oral temperature >38.5°C or two consecutive readings of >38.0°C for 2 hours and an absolute neutrophil count <0.5x109/L, or expected to fall below 0.5x109/L. RESULTS: A total of 622 patients received adjuvant chemotherapy during this period. Of these patients 209 (33.6%) received taxane-based chemotherapy. 4 taxane-based regimens were used namely the FEC-D, TC, TAC and AC-PCX regimens. The commonest regimen employed was the FEC-D regimen accounting for 79.9% of the patients. The FN rate was 10% and there was no TRD. CONCLUSION: Adjuvant taxane-based chemotherapy in UMMC for early breast cancer has a FN rate of 10%. Primary prophylactic G-CSF should be considered for patients with any additional risk factor for FN.