Breast cancer is a significant global health issue: An updated analysis by the International Agency for Research on Cancer estimated that there were 1.38 million new breast cancer cases diagnosed in 2008 and confirmed that it remains the most frequent cause of cancer death in women worldwide. Despite significant improvements in cancer incidence rates and outcomes in recent decades in high-income countries, breast cancer case-fatality rates are unacceptably high in low- and middle-income countries [LMCs]. With an ever-ageing and increasing population worldwide, the number of new cancer cases will continue to grow in decades to come.
As well described by Dr. Anderson in this issue of ONCOLOGY, the Breast Health Global Initiative [BHGI] developed a number of evidence-based breast cancer guidelines aimed at resource-limited regions in an effort to improve breast cancer outcomes in LMCs. These guidelines include strategies believed to be acceptable and feasible to implement in LMCs, and relate to breast cancer early detection, diagnosis, and treatment. The BHGI gives specific recommendations reflective of the varying levels of resources available in each country.
The estimated global cost of treating breast cancer in 2009 was 24 billion US dollars. However, the costs of many of the interventions for breast cancer early detection and treatment are unaffordable for many. The BHGI guideline, which outlines treatment resource allocation, acknowledges this potential barrier. For instance, it recommends tamoxifen as a low-cost drug that should be considered the most basic level of adjuvant hormonal therapy for women with hormone receptor [HR]-positive disease, based on a clear survival advantage over mere observation. The lack of an overall survival advantage from the upfront use of aromatase inhibitors over tamoxifen in large randomized trials of postmenopausal women is noted, and it states that this class of agents should be considered only if resources allow. Oophorectomy is cited as a reasonable adjuvant endocrine strategy alone or in combination with tamoxifen in premenopausal women. In fact, the feasibility of this strategy was reported in Vietnamese patients with early breast cancer who were randomized to oophorectomy plus tamoxifen versus observation, and Love et al reported a significant five-year overall survival benefit favoring the intervention [78% vs 70%, respectively, P = .041]. Equally important, a cost-effectiveness analysis of this intervention showed a cost of $350 per year of life saved.
HR-positive is the most common breast cancer phenotype in LMC, and assertions to the contrary likely reflect false-negative results and the poor quality of predictive biomarker testing often observed even in high-income countries. Immunohistochemistry [IHC] is the best-established method to assess estrogen [ER] and progesterone [PgR] status, and the multidisciplinary effort required to perform accurate and high quality performance is not trivial. As an example, Uy et al in the Philippines noted a significant discordance in rates of ER-positive disease in breast cancer specimens obtained by core biopsy and mastectomy [68% and 53% respectively, P =.0002]. Upon auditing internal procedures, they noted a difference in how surgical specimens were handled; delays in initiation of fixation procedures and frequent use of old formalin meant that fresh tissues could be exposed to cold ischemia times of an hour or longer before being brought to the pathologist. Subsequent standardization of tissue collection and transfer procedures eliminated these preanalytical variables and the rates of ER-positive disease in surgical specimens corrected upwards [from 53% to 65%, P =.02]. This and other reports indicate that the rates of ER-positive breast cancer are similar between LMCs and higher-income countries,[9,10] suggesting that prior reports showing a preponderance of ER-negative phenotypes in LMC likely reflected inadequate testing and high rates of false-negative results. Perhaps surprising to many, low-quality predictive biomarker testing can also be observed even in high-income countries; up to 20% of specimens determined to be locally ER-negative have been found to have some ER expression upon central retesting, as part of an ongoing multinational randomized adjuvant trial.
In 2010, the American Society of Clinical Oncology and the College of American Pathologists developed and jointly released evidence-based guidelines limited to IHC and with the aim of improving the quality of ER and progesterone-receptor (PgR) testing. These guidelines ensure that other platforms like gene expression profiling will be examined when correlation data linked to clinical outcome become available. Aside from the factors discussed above relating to specimen handling (preanalytical) and assay performance (analytical), another important variable arises from different interpretations of the definition of hormone-responsive status (postanalytical). ER and PgR should be deemed positive if ≥ 1% tumor nuclei stain positive in the presence of adequate internal/external controls, as high-level evidence suggests that levels as low as 1% positive staining are associated with significant benefit from adjuvant endocrine therapy.
The provision of resource-directed guidelines by the BHGI to LMCs is commendable; however, many barriers still remain relating to their implementation. A Global Task Force on Expanded Access to Cancer Care and Control in Developing Countries (GTF.CCC) was established in 2009 in order to promote awareness about observed disparities in cancer care across countries and to implement steps to close this gap. Only about 5% of global resources for cancer are spent in developing countries, and international initiatives that were successfully implemented to address the Human Immunodeficiency Virus [HIV]  and multi-drug resistant tuberculosis epidemics  could also significantly impact the cancer burden in LMCs. GTF.CCC aims to collaborate with existing initiatives to educate the public regarding misconceptions and stigma relating to a diagnosis of cancer; produce and maximize cancer prevention strategies (including vaccination programs); procure and finance delivery of cost-effective drugs for cancer treatment and palliation; and expand health systems and delivery of care. Financial support for these efforts can feasibly be obtained from both public and private sources, as has been done in the case of HIV, and would result in a significant improvement in survival and quality of life for millions.
In conclusion, international efforts are required to facilitate cancer control and care in LMCs. Inequalities in diagnostic and treatment interventions exist and dramatically affect breast cancer mortality in LMCs. We can no longer afford to ignore this and the time for action is now. Cancer is the second most-common cause of death in LMCs and breast cancer the most common cause of female death in LMCs. Resource-sensitive management guidelines presented in this issue of ONCOLOGY, and strategies outlined by the GTF.CCC require immediate implementation to tackle this significant global health issue.
Financial Disclosure: The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
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