C.H. Yip

Catastrophic health expenditure and 12-month mortality associated with cancer in Southeast Asia: results from a longitudinal study in eight countries

One of the biggest obstacles to developing policies in cancer care in Southeast Asia is lack of reliable data on disease burden and economic consequences. In 2012, we instigated a study of new cancer patients in the Association of Southeast Asian Nations (ASEAN) region – the Asean CosTs In ONcology (ACTION) study – to assess the economic impact of cancer. The ACTION study is a prospective longitudinal study of 9,513 consecutively recruited adult patients with an initial diagnosis of cancer. Twelve months after diagnosis, we recorded death and household financial catastrophe (out-of-pocket medical costs exceeding 30 % of annual household income). We assessed the effect on these two outcomes of a range of socio-demographic, clinical, and economic predictors using a multinomial regression model. The mean age of participants was 52 years; 64 % were women. A year after diagnosis, 29 % had died, 48 % experienced financial catastrophe, and just 23 % were alive with no financial catastrophe. The risk of dying from cancer and facing catastrophic payments was associated with clinical variables, such as a more advanced disease stage at diagnosis, and socioeconomic status pre-diagnosis. Participants in the low income category within each country had significantly higher odds of financial catastrophe (odds ratio, 5.86; 95 % confidence interval, 4.76–7.23) and death (5.52; 4.34–7.02) than participants with high income. Those without insurance were also more likely to experience financial catastrophe (1.27; 1.05–1.52) and die (1.51; 1.21–1.88) than participants with insurance. A cancer diagnosis in Southeast Asia is potentially disastrous, with over 75 % of patients experiencing death or financial catastrophe within one year. This study adds compelling evidence to the argument for policies that improve access to care and provide adequate financial protection from the costs of illness.

Factors affecting estrogen receptor status in a multiracial Asian country: An analysis of 3557 cases

Estrogen receptor (ER) positive rates in breast cancer may be influenced by grade, stage, age and race. This study reviews the ER positive rates over a 15-year period at the University Malaya Medical Centre, Kuala Lumpur, Malaysia. Data on ER status of 3557 patients from 1994 to 2008 was analyzed. ER status was determined by immunohistochemistry with a cut-off point of 10%. ER positivity increased by about 2% for every 5-year cohort, from 54.5% in 1994-1998 to 58.4% in 2004-2008. Ethnicity and grade were significantly associated with ER positivity rates: Malay women were found to have a higher risk of ER negative tumors compared with Chinese women. Grade 1 cancers were nine times more likely to be ER positive compared with grade 3 cancers. In summary, the proportion of ER positive cancers increased with each time period, and ethnicity and grade were independent factors that influenced ER positive rates.

Improving outcomes in breast cancer for low and middle income countries.

Abstract Breast cancer is the most common cancer in women world-wide. Incidence rates in low- and middle-income countries (LMICs) are lower than in high income countries; however, the rates are increasing very rapidly in LMICs due to social changes that increase the risk of breast cancer. Breast cancer mortality rates in LMICs remain high due to late presentation and inadequate access to optimal care. Breast Surgery International brought together a group of breast surgeons from different parts of the world to address strategies for improving outcomes in breast cancer for LMICs at a symposium during International Surgical Week in Helsinki, Finland in August 2013. A key strategy for early detection is public health education and breast awareness. Sociocultural barriers to early detection and treatment need to be addressed. Optimal management of breast cancer requires a multidisciplinary team. Surgical treatment is often the only modality of treatment available in low-resource settings where modified radical mastectomy is the most common operation performed. Chemotherapy and radiotherapy require more resources. Endocrine therapy is available but requires accurate assessment of estrogen receptors status. Targeted therapy with trastuzumab is generally unavailable due to cost. The Breast Health Global Initiative guidelines for the early detection and appropriate treatment of breast cancer in LMICs have been specifically designed to improve breast cancer outcomes in these regions. Closing the cancer divide between rich and poor countries is a moral imperative and there is an urgent need to prevent breast cancer deaths with early detection and optimal access to treatment.

Breast health in developing countries

Abstract Breast cancer is one of the leading cancers world-wide. While the incidence in developing countries is lower than in developed countries, the mortality is much higher. Of the estimated 1 600 000 new cases of breast cancer globally in 2012, 794 000 were in the more developed world compared to 883 000 in the less developed world; however, there were 198 000 deaths in the more developed world compared to 324 000 in the less developed world (data from Globocan 2012, IARC). Survival from breast cancer depends on two main factors – early detection and optimal treatment. In developing countries, women present with late stages of disease. The barriers to early detection are physical, such as geographical isolation, financial as well as psychosocial, including lack of education, belief in traditional medicine and lack of autonomous decision-making in the male-dominated societies that prevail in the developing world. There are virtually no population-based breast cancer screening programs in developing countries. However, before any screening program can be implemented, there must be facilities to treat the cancers that are detected. Inadequate access to optimal treatment of breast cancer remains a problem. Lack of specialist manpower, facilities and anticancer drugs contribute to the suboptimal care that a woman with breast cancer in a low-income country receives. International groups such as the Breast Health Global Initiative were set up to develop economically feasible, clinical practice guidelines for breast cancer management to improve breast health outcomes in countries with limited resources.

Health-related quality of life and psychological distress among cancer survivors in Southeast Asia: results from a longitudinal study in eight low- and middle-income countries

BackgroundA better understanding of health-related quality of life (HRQoL) and psychological distress in cancer survivors can raise awareness, promote the development of policies in cancer survivorship care, and facilitate better targeted use of limited resources in low- and middle-income countries (LMICs). The main objectives of this paper were therefore to assess HRQoL and the prevalence of psychological distress amongst cancer survivors in Southeast Asia and identify risk factors of these outcomes.MethodsThe ACTION study was a longitudinal study in eight LMICs in Southeast Asia with 5249 first time cancer survivors followed up at 1 year after diagnosis. HRQoL was assessed using the EORTC QLQ-C30 and EQ-5D. Psychological distress (anxiety and depression) was assessed using the Hospital Anxiety and Depression Scale. General linear models and multiple logistic regression were used to identify independent predictors of HRQoL and psychological distress.ResultsOne year after diagnosis, the mean EORTC QLQ-C30 global health score for survivors was 66.2 out of 100 (SD 22.0), the mean index score on the EQ-5D was 0.74 (SD 0.23), 37% of survivors had at least mild levels of anxiety, and 46% showed at least mild levels of depression. Poorest HRQoL and highest prevalence of anxiety and depression were seen in patients with lung cancer and lymphomas, while highest scores and least psychological distress were seen in female patients with breast and cervical cancer. The most significant predictor of poor HRQoL and psychological distress outcomes was cancer stage at diagnosis. Age, co-morbidities, treatment, and several socioeconomic factors were associated with HRQoL and psychological distress.ConclusionsCancer survivors in LMICs in Southeast Asia have impaired HRQoL and substantial proportions have psychological distress. Patients with advanced cancer stages at diagnosis and those in a poor socioeconomic position were most at risk of such poor outcomes. Supportive interventions for cancer patients that address wider aspects of patient wellbeing are needed, as well as policies that address financial and other barriers to timely treatment.A better understanding of health-related quality of life (HRQoL) and psychological distress in cancer survivors can raise awareness, promote the development of policies in cancer survivorship care, and facilitate better targeted use of limited resources in low- and middle-income countries (LMICs). The main objectives of this paper were therefore to assess HRQoL and the prevalence of psychological distress amongst cancer survivors in Southeast Asia and identify risk factors of these outcomes. The ACTION study was a longitudinal study in eight LMICs in Southeast Asia with 5249 first time cancer survivors followed up at 1 year after diagnosis. HRQoL was assessed using the EORTC QLQ-C30 and EQ-5D. Psychological distress (anxiety and depression) was assessed using the Hospital Anxiety and Depression Scale. General linear models and multiple logistic regression were used to identify independent predictors of HRQoL and psychological distress. One year after diagnosis, the mean EORTC QLQ-C30 global health score for survivors was 66.2 out of 100 (SD 22.0), the mean index score on the EQ-5D was 0.74 (SD 0.23), 37% of survivors had at least mild levels of anxiety, and 46% showed at least mild levels of depression. Poorest HRQoL and highest prevalence of anxiety and depression were seen in patients with lung cancer and lymphomas, while highest scores and least psychological distress were seen in female patients with breast and cervical cancer. The most significant predictor of poor HRQoL and psychological distress outcomes was cancer stage at diagnosis. Age, co-morbidities, treatment, and several socioeconomic factors were associated with HRQoL and psychological distress. Cancer survivors in LMICs in Southeast Asia have impaired HRQoL and substantial proportions have psychological distress. Patients with advanced cancer stages at diagnosis and those in a poor socioeconomic position were most at risk of such poor outcomes. Supportive interventions for cancer patients that address wider aspects of patient wellbeing are needed, as well as policies that address financial and other barriers to timely treatment.

The Will Rogers phenomenon in the staging of breast cancer – Does it matter?

INTRODUCTION Changes in the American Joint Commission on Cancer staging for breast cancer occurred when the 5th Edition was updated to the 6th Edition. OBJECTIVE To investigate how these changes affected stage and survival. METHODS 3127 cases of breast cancer were restaged. RESULTS Late stages increased from 27.7% to 38.1%. The five-year survival improved in Stage 2 (82.9-86.1%) and Stage 3 (50.6-59%). DISCUSSION Stage shift leads to an erroneous impression that women are presenting with later stages and stage-specific survival is improving. CONCLUSION Standardizing cancer staging is important when reporting stage and survival in different time periods.

Roles of Ki67 in Breast Cancer - Important for Management?

BACKGROUND The three standard biomarkers used in breast cancer are the estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2). The Ki-67 index, a proliferative marker, has been shown to be associated with a poorer outcome, and despite absence of standardization of pathological assessment, is widely used for therapy decision making. We aim to study the role of the Ki-67 index in a group of Asian women with breast cancer. MATERIALS AND METHODS A total of 450 women newly diagnosed with Stage 1 to 3 invasive breast cancer in a single centre from July 2013 to Dec 2014 were included in this study. Univariable and multivariable logistic regression was used to determine the association between Ki-67 (positive defined as 14% and above) and age, ethnicity, grade, mitotic index, ER, PR, HER2, lymph node status and size. All analyses were performed using SPSS Version 22. RESULTS In univariable analysis, Ki -67 index was associated with younger age, higher grade, ER and PR negativity, HER2 positivity, high mitotic index and positive lymph nodes. However on multivariable analysis only tumour size, grade, PR and HER2 remained significant. Out of 102 stage 1 patients who had ER positive/PR positive/HER2 negative tumours and non-grade 3, only 5 (4.9%) had a positive Ki-67 index and may have been offered chemotherapy. However, it is interesting to note that none of these patients received chemotherapy. CONCLUSIONS Information on Ki67 would have potentially changed management in an insignificant proportion of patients with stage 1 breast cancer.

Abstract P3-13-03: Association between Ethnicity and Survival after Breast Cancer in a Multi-Ethnic Asian Setting: Results from the Singapore-Malaysia Hospital-Based Breast Cancer Registry

Background: Little is known on the impact of ethnicity on survival after breast cancer in the multi-ethnic Asian setting. Material and Methods: Using the multi-institutional Singapore-Malaysia hospital-based breast cancer registry, we investigated the association between ethnicity and risk of mortality after breast cancer in 3,366 patients diagnosed between 1990 and 2007 (Chinese: 77%, Malay: 15%, Indian: 8%). Kaplan-Meier analysis was used to estimate overall cumulative survival (OS). Multivariable hazard ratios (HR) adjusted for tumor and treatment characteristics were computed using Cox regression analysis after splitting follow-up time along the age-axis and calendar-time axis. Results: Malay patients presented at younger age compared to Chinese and Indians (47years vs 52years vs 53years, respectively, P After adjustment for tumor and treatment characteristics, Malay patients had approximately 60% higher risk of death than the Chinese (HR:1.57; 95%CI:1.40-1.77). Indian ethnicity was not significantly associated with risk of mortality after breast cancer compared to Chinese (HR:1.12; 95%CI: 0.98-1.30). Conclusion: In the Asian setting, Malay ethnicity seems to be associated with significantly poorer survival after breast cancer, independent of tumor and treatment profile. The underlying reasons for this association are unclear but may be explained by variations in susceptibility to treatment, co-morbidity and lifestyle after diagnosis of breast cancer. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-13-03.

Identification of a recurrent BRCA1 exon 21-22 genomic rearrangement in Malay breast cancer patients.

To the Editor: Germline mutations in BRCA1 and BRCA2 are associated with increased risk to breast and ovarian cancer and their discovery has led to the accurate identification of high-risk individuals. The majority of mutations identified in BRCA1 and BRCA2 are point mutations, small deletions and insertions but large genomic rearrangements (LGRs), though rare, also contribute to the spectrum of disease-causing mutations in BRCA1 and BRCA2 (1–3). The frequency of LGRs varies across different populations, from none in French–Canadians, to 1.3% in Asians and 6.7% in Latin American/Caribbean high-risk patients (1–6). To date, recurrent LGRs have been identified particularly in Dutch and Hispanic populations and one recurrent BRCA2 LGR has been reported in two unrelated Southern Chinese families (5, 7, 8). In this study, we have analysed the overall prevalence of BRCA1 and BRCA2 genomic rearrangements in a multiethnic cohort of Malaysian breast cancer patients, characterized the breakpoints of the rearrangements and report a recurrent LGR found in three unrelated Malay families. A total of 524 breast cancer patients were selected for germline analysis on the basis of age of onset and family history of breast and/or ovarian cancer (4). Germline analysis was conducted using direct DNA sequencing and multiplex ligation-dependent probe amplification (MLPA) using MLPA BRCA1-P002C-1 and BRCA2-P045-B2 kits (MRC-Holland, Amsterdam, Netherlands). The characterization of genomic rearrangement breakpoints was performed by long-range polymerase chain reaction (PCR) using a series of primers (Table S1, Supporting Information) flanking the putative rearrangement regions. Amplified products of abnormal size were subjected to DNA sequencing and sequence alignment to the human genome (GRCh37/hg19) on the UCSC Genome Browser (http://genome.ucsc.edu) (4). All genomic rearrangements were annotated using HGVS nomenclature (www.hgvs.org) with the GenBank reference sequence L78833 and AY436640 for BRCA1 and BRCA2, respectively. LGRs account for 7 of the 42 BRCA1 mutation carriers and 2 of the 38 BRCA2 mutation carriers identified among the 524 breast cancer patients tested (Table S3). We mapped the breakpoints of the rearrangements and characterized the mutational mechanisms by analysing the breakpoints at nucleotide sequence level (Fig. 1). Two genomic rearrangements in BRCA1 were identified in more than one family (Table 1). First, deletion of exon 3 was identified in a Punjabi and an Indian family and long-range PCR analysis showed distinct rearrangement breakpoints between these two families. Second, deletion of exon 21-22, which removes 43 amino acids from the C-terminal BRCT domain and is predicted to lead to BRCT folding defects, was found in three unrelated Malay women. All three women shared the same Alu-mediated deletion of 3,430 base pairs and a common haplotype (Table S2). All three women were diagnosed with early-onset breast cancer (mean age 34.6 years), of which two were of the triple-negative subtype, but none reported family history of breast or ovarian cancer (Fig. S1). This recurrent rearrangement accounts for 7.1% (3/42) of the BRCA1 mutations in our study, and 20% (2/10) of the BRCA1 mutations among the Malays. Our study shows that LGRs in BRCA1 and BRCA2 constitute 17% of BRCA1 carriers and 5% of BRCA2 carriers, and 1.3% and 0.4% respectively of the highand moderate-risk breast cancer patients analysed. In particular, we report a novel recurrent deletion of exon 21-22 in BRCA1 in Malay families. Unlike previous studies in Asians, we report that LGRs are significant and recommend that screening of LGRs should be conducted together with whole gene sequencing in BRCA1 and BRCA2 for high-risk patients to ensure comprehensive detection of mutations.

Early Diagnosis of Breast Cancer in the Absence of Population-Based Mammographic Screening in Asia

Purpose of ReviewAsia is made up of mainly low- and middle-income countries, where the majority of breast cancer presents as late-stage disease where survival is poor even with treatment. We review methods of early diagnosis of breast cancer in countries where population-based mammographic screening is not feasible.Recent findingsWhile there is insufficient evidence that breast self-examination and clinical breast examination (CBE) lead to a reduction in breast cancer mortality, recent trials have shown that screening with CBE successfully reduces stage at diagnosis, which may translate to improved breast cancer survival with longer follow-up. CBE may have an educational component whereby women with new breast lumps may seek care earlier.SummaryOvercoming sociocultural barriers to early detection in Asia is important before any early detection programme can be implemented. Public education, together with strengthening existing public health services, is key to earlier diagnosis of breast cancer.