Essential medicines for breast cancer in low and middle income countries

Despite substantial progress made in its treatment possibilities, breast cancer survival is still poor in LMICs. This might be due to lack of access to different components of care including systemic therapy. Selection of essential medicines was explored in this study as a prerequisite of access to medicines. First generation chemotherapies were frequently found in the NEMLs of the studied countries (>70 %). Endocrine therapy was also well represented with tamoxifen being included in 75 % of the NEMLs, whereas treatment of HER2 overexpressed tumors (in both early and advanced stages) was hardly possible with the selected essential medicines. Except for luminal A breast cancer, selection of essential medicines did not allow treatment of early breast cancer subtypes in many LMICs. Guideline- recommended treatments were less frequently included in the NEMLs of low income countries than in middle income countries. In advanced breast cancer, all components of therapy (except for HER2-targeted therapies) were included in over half of the NEMLs with no significant differences across income levels. Compared to the other regions, the Eastern Mediterranean and African regions less frequently incorporated full breast cancer treatment components for both early and advanced breast cancer. Across all different breast cancer types, newer NEMLs were more frequently aligned with clinical guidelines.

Considering the fact that breast cancer is the most burdensome type of cancer among women, the selection of therapies for different disease stages is suboptimal. Treatments for late stages were more frequently selected as essential medicines compared to (several) early stages. In early breast cancer, treatment was mainly absent for luminal B (HER2-) in low income countries and for triple negative and special histological types in low and lower middle income countries. This finding can be interpreted as a rational response to health care priorities of resource-constrained countries. Due to lack of screening programs, diagnostic facilities, routine checkups and cultural barriers for educating women for self-examinations, breast cancer is usually diagnosed at late stages in low income countries [5, 12, 24, 25]. In addition, low income countries have to prioritize their decisions, owing to their very limited health care budgets which hardly exceeded an average of US$30 per capita in 2011 [26].

The choice of chemotherapeutic regimens - which were included to a relatively high extent in the NEMLs - might have been heavily influenced by the WHO model list of essential medicines. This can explain the absence of epirubicine based regimens in the majority of the NEMLs studied, since epirubicine is absent in the WHO model list [27, 28]. The only major deviation from the WHO model list are taxanes which have a low rate of inclusion in the NEMLs despite being listed by the WHO. This might be attributable to their late inclusion in the WHO model list in 2011; it needs additional time before medicines appear on the majority of NEMLs. Besides, in the years prior to 2011, affordability of taxanes was of concern for healthcare systems in LMICs [29‐31].

Inclusion of aromatase inhibitors’ (AIs) was low compared to tamoxifen. The cost of AIs might have hampered their selection despite their therapeutic benefits [4]. In recent years patent protection of some AIs expired and a price decline was already observed [32]. Subsequently LMICs may consider AIs for inclusion on their NEML as the affordability concern is fading away. In addition, a careful trade off may need to be made by policymakers in view of the limited resources, whether priority should be given to additional hormonal therapies. HR+ breast cancer corresponds to the majority of breast cancer cases and thus has a crucial role in treatment. However the magnitude of benefit gained by substitution of AIs with Tamoxifen in post-menopausal patients may need to be compared with that of adding a HER-2 targeted therapy to the current practice in a smaller group of patients.

A very low rate of inclusion of “all components” of treatment for HER2 overexpressed types of breast cancer (which constitute nearly one fourth of all cases [33]) in the NEMLs in both stages was evident. This was mainly due to the absence of HER2-targeted therapies while patients may still benefit from favorable effects of chemotherapy regimens. For inclusion of HER2-targeted therapies a great deal of controversy should always be addressed, even in developed countries. The percentage of patients with HER2 overexpression may vary across LMICs and the information is lacking in many of these jurisdictions. The massive economic burden incurred to health care systems, cost effectiveness concerns and recent reports of resistance against therapy are examples of these controversies [34‐37]. Besides, molecular diagnostic tests for appropriate patient selection are often not integrated in routine daily practice in LMICs due to the lack of resources and equipment [38]. Trastuzumab was first approved over 1.5 decade ago, and its patent will expire soon which will provide an opportunity for better access to the medicine for patients in LMICs [39]. Due attention to the rational use of trastuzumab will remain a concern even when inclusion in the NEMLs will become feasible.

Rank of breast cancer (in terms of incidence and mortality among all cancer types in women) in eastern Mediterranean and African regions is comparable with the global pattern [1]. Other priorities in those health care systems might have hindered inclusion of breast cancer medicines in the NEMLs in those regions. The main common diseases to tackle in those regions are lower respiratory infections, diarrheal disease, preterm birth complications and tuberculosis as well as malaria and HIV/AIDS for the African and cardiovascular disease for the Eastern Mediterranean regions [40, 41].

This study has some limitations. While the most recent breast cancer guidelines -at the time of survey -were studied, the majority of the NEMLs investigated were dated prior to these guidelines. However, the latest available update of a NEML should be considered valid until revision. Our analysis was based on international consensus guidelines while clinical practice might vary across and within the studied countries. Treatment of secondary metastasis (e.g., treatment of bone and brain metastasis), palliative care and medicines for management of adverse events and side effects were not included in our study, despite their essential role in the course of treatment. In addition, as previously mentioned, pharmacotherapy is only one component of breast cancer care. In the entire procedure of treatment of breast cancer a substantial degree of disparity in access and quality of care might be observed [42]. For example in some countries in Africa estrogen receptor identification is not yet routinely accessible [43]. A systemic approach to explore availability of all contributing elements of care for breast cancer, would be a next step for further study.

Although guidelines for management of breast cancer in LMICs have been published in literature, to our knowledge this study is the first global study attempting to explore decisions made for selection of systemic therapy of breast cancer in LMICs, which in turn may have direct implications for the availability of medicines for treatment of breast cancer. Previous research showed that in general essential medicines selected on NEMLs were more available than those not selected as essential medicines, highlighting the importance of adequate selection to ensure optimal access [44]. It is of prime priority to conduct direct availability studies on oncology medicines in LMICs to confirm these findings.