Introduction

Dr. Julie Gralow, the Chief Medical Officer and Executive Vice President of the American Society of Clinical Oncology (ASCO), delivered the plenary talk during session 7 of the 2023 Summit on Cancer Health Disparities. She gave a captivating talk on a topic that deserves special attention, “Precision Medicine in Low- and Middle-Income Countries.” She began by describing the history of precision medicine in oncology. Until the late 1990s, systemic anti-cancer therapy could not utilize the principles of precision oncology. Trastuzumab was the first drug approved using a drug-diagnostic co-development model in HER2-positive metastatic breast cancer. In the early 2000s, the introduction of imatinib as targeted therapy for chronic myeloid leukemia (CML) transformed its care. Precision oncology has come a long way, using genomic and whole exome sequencing to develop anti-cancer treatments.

Barriers to Precision Oncology in Low and Middle-income Countries (LMICs)

There are several barriers to delivering precision oncology in LMICs, including limited access to diagnostic tools and technology, limited accessibility and affordability of targeted drugs, limited infrastructure and resources to support precision oncology, and limited availability of trained healthcare providers and specialists. These barriers that lead to an inequality in access to precision oncology have several downstream effects, including leading to adverse patient outcomes, placing clinicians in difficult ethical positions, putting a strain on societal resources, and causing severe financial distress for patients and their families. Dr. Gralow then discussed the issues with the availability, accessibility, and affordability of cancer medicines in LMICs. While oncology drug prices tend to be lower in LMICs, this does not necessarily mean they are more affordable. A study by Goldstein and colleagues compared the prices of eight anti-cancer drugs (bevacizumab, bortezomib, dasatinib, erlotinib, imatinib, pemetrexed, rituximab, and trastuzumab) between high-income countries (HICs) (Australia, Israel, the United Kingdom, and the United States) upper-middle-income countries (UMICs) (China and South Africa) and LMICs (India).¹ The median drug price was highest in the US when drug prices based on local currencies were converted to US dollars. However, when accounting for the purchasing power parity index to convert from local currency to US dollars, drug prices in the UMICs and LMICs were higher than in the US. For example, the cost for four weeks of trastuzumab, based on the purchasing power parity index conversion, would be $6,849 in the US, $8,068 in South Africa, $12,228 in India, and $14,261 in China.¹

Some models to improve drug access and procurement are donation programs or patient access programs, differential pricing based on gross domestic product, payer agreements, regional/pooled procurement, and innovative global financing initiatives.

Availability, Accessibility, and Affordability of Cancer Medicines

The World Health Organization (WHO) created the Model List of Essential Medicines (EML) to aid countries in selecting effective, safe, and affordable medicines. The EML provides evidence-based recommendations to policymakers, helping prioritize valuable drugs.² To be listed on the WHO EML for cancer, the EML Cancer Medicines Working Group suggests using the European Society of Medical Oncology Magnitude of Clinical Benefit Scale and requires a minimum of 4-6 months of overall survival gain without compromising the quality of life.² The 2015 EML included targeted therapies like trastuzumab, rituximab, and imatinib. The current 2021 version added bortezomib, dasatinib, nilotinib, erlotinib, everolimus, ibrutinib, nivolumab, and pembrolizumab for various cancer types.

A global cross-sectional study was conducted to determine the medications oncologists consider crucial in treating cancer and whether these priority medicines are reflected in the WHO EML. The study also assessed the availability of these essential cancer medicines for patients receiving regular clinical care.³ Based on 948 respondents, of the 20 most commonly chosen crucial cancer medications, 19 (95%) are presently included in the WHO EML. Six of the top 20 essential drugs in HICs were targeted/immunotherapy agents. On the other hand, of the top 20 drugs in LMICs, 70% were cytotoxic or hormonal agents, and 65% were older agents approved by the FDA pre-2000. The proportion of respondents indicating universal availability of each top 20 medication was 9-54% in low-lower-middle-income countries (LLMICs), 13–90% in UMICs, and 68–94% in HICs. The risk of catastrophic expenditure for each top 20 medication was 13–68% in LLMICs, 2–41% in UMICs, and 0-9% in HICs. These data show significant barriers to access to core cancer medicines exist worldwide. Access to these medications seemed limited by household affordability rather than availability.³

The top three responses from a 2021 ASCO international members survey that asked, “How can ASCO add value to you, your patients, and cancer care in your country?” were access to essential drugs, pathological diagnosis, and the development of cancer registries. The Access to Essential Cancer Medicines Stakeholder Summit Meeting was convened during the ASCO annual meeting in June 2022 to address several topics, including access to oncology medications. One such initiative is the Max Foundation, a non-profit global health organization that partners with pharma, biotech, academia, physicians, and patients to increase access to cancer medications, including targeted therapies. The Max Foundation promotes local health system strengthening in LMICs by developing a global network of physicians and cancer centers who can interpret labs, diagnose patients, and prescribe medications. The first program centered on providing targeted cancer therapies for CML, beginning with imatinib in 2001.⁴ CML patients who received treatment through The Max Foundation have comparable survival rates to those treated in high-resource settings.^5,6 Additional medications have been added to The Max Foundation drug access program over time, with ribociclib, letrozole, and asciminib added in 2023. Another initiative to increase access to essential oncology medicines in LLMICs is the Union for International Cancer Control (UICC) Access to Oncology Medicines (ATOM) Coalition.⁷ ATOM aims to improve the capacity of LLMICs to receive and use cancer medications by coordinating its efforts and sharing best practices. ATOM partners with those with experience and expertise in production, manufacturing, registration, logistics, oncology, delivery, utilization, monitoring, and evaluation. ATOM prioritizes medicines that are included in the WHO EML, which includes generic, biosimilar, and patented medications. ATOM’s strategies to obtain medications are donation, tiered pricing, at-cost pricing, or voluntary licensing agreements. To achieve ATOM’s objectives, it supports registration and capacity building within the country to provide the necessary drugs and diagnostics, treatment plans, and monitoring/evaluation of their effectiveness.⁷ ASCO contributes to the ATOM coalition through capacity building, leadership development and education, quality improvement, and monitoring and evaluation, which in turn, ensures the appropriate use of the medication with the patients.

Availability, Accessibility, and Affordability of Diagnostics

Extreme inequities exist in access to high-quality pathology caused by a lack of physical infrastructure, access to reagents/supplies, and the lack of pathology-specific personnel. The American Society of Clinical Pathology (ASCP) Partners for Cancer Diagnosis and Treatment in Africa Initiative aims to reduce these disparities through personnel training, procurement of equipment, textbooks, conference support, and networking opportunities for African pathologists. In addition, the use of telepathology is now a vital part of the effort to bring knowledge and skills from other nations to various locations. Similarly, the Max Foundation has improved its ability to diagnose and monitor CML cases by developing a quantitative RT-PCR assay for BCR-ABL that can be used on the GeneXpert machine. The “Spot on CML” Project, a collaboration between the Radich Lab (Fred Hutchinson Cancer Center), the Max Foundation, and the International CML Foundation, is an innovative method of sample collection to diagnose CML.⁸ Dried blood spots are used for the detection of BCR-ABL. Patients can provide samples that can be batched and sent by mail, resulting in significant cost savings compared to shipping fresh blood.⁸

Growing Capacity and Infrastructure for Precision Medicine

Next-generation sequencing (NGS) has progressed from analyzing a few genes to analyzing panels of hundreds of genes. However, oncology providers around the world may find it challenging to understand genomics data, interpret results, and recommend therapies for their patients due to several factors - including the complexity of panels, a limited understanding of the genomic data, and a high number of uncertain significance variants or equivocal copy number alterations.

Molecular tumor boards (MTBs) consist of a team of specialists, including medical oncologists, surgical oncologists, radiation oncologists, pathologists, molecular pathologists, and geneticists, among others. They come together to review and discuss genomic results and suggest treatment options based on either standard-of-care or clinical trial-based approaches. The availability of this multidisciplinary team is usually limited to academic cancer centers and integrated health systems. For example, genetic and genomic testing is unavailable in Romania and accessible only through a single center for patients with metastatic breast cancer. From December 2019-March 2023, approximately 40 cases from Romania have been presented at an MTB accessed through the international “Our Cancer Genomes” MTB (Vanderbilt-Ingram Cancer Center), which is open and accessible to all oncology providers.⁹

Another example of an initiative to increase the capacity of precision oncology is the National Cancer Grid of India (NCG)- a network of 300 cancer centers, research institutions, patient groups, and professional societies across India. The NCG aims to improve access to cancer treatment and reduce costs. It does so through initiatives such as pooled drug procurement and a “traveling school” of pathology where experts in cancer pathology and surgery conduct workshops in remote locations to educate physicians in those locations.

Precision Medicine in Low- and Middle-Income Countries: The Path Forward

Dr. Gralow ended her talk with an urgent plea to push for affordable, equitable access to precision cancer diagnostics and therapies through novel partnerships, creative solutions, and international cooperation.

Panel Discussion

After Dr. Gralow’s presentation, a panel discussion was conducted by Dr. Hannah Linden (Clinical Director of the Breast Cancer Program, Fred Hutchinson Cancer Center) and Dr. Ana Maria Lopez (Vice Chair of Medical Oncology and Chief of Cancer Services, Sidney Kimmel Cancer Center), with a panel consisting of Dr. Julie Gralow, Dr. Marianne Dubard-Gault (Medical Director of the Cancer Genetics Program,

Fred Hutchinson Cancer Center), Ms. LaToya Williams (Strategic Director, Health Equity Ambassador - Community Initiatives, American Cancer Society), and Dr. Katherine Van Loon (Director of the Global Cancer Program, UCSF Helen Diller Family Comprehensive Cancer Center). Ms. Latoya opened with an account of her battle with breast cancer and how stigma and unawareness led to a delay in her diagnosis. Dr. Dubard-Gault then expanded on the conversation on how genetic testing is beneficial not only to cancer patients but also to their families. However, significant barriers exist to testing in family members, including fear and social stigma. Dr. Van Loon drew from her experience as a gastrointestinal medical oncologist on the stigma associated with a cancer diagnosis, especially in areas like Sub-Saharan Africa, and how it is essential to work together to change that narrative.

Question and Answer (Q&A) Session

Dr. Sid Yadav opened the Q&A session with a question about what initiatives ASCO was a part of to ensure high-quality data were available from LMICs, since data from studies from the US may not apply to other countries. Dr. Gralow explained how ASCO is helping with funding for clinical trials from pharmaceutical companies to conduct clinical trials in areas like Latin America and Sub-Saharan Africa. Dr. Van Loon also acknowledged that data is lacking from LMICs to draft guidelines that can be universally applied. Dr. Matthew Meranda asked Dr. Gralow whether quality and disability-adjusted life years are considered when choosing medications on the WHO EML. Dr. Gralow answered how the WHO EML is a list of the medicines that need to be available at the bare minimum and how adding these indices to determine the need could complicate matters. Dr. Erika Ruiz made a point for education in cancers other than breast since awareness about these cancers in the public is lacking. Dr. Gralow said she agreed with Dr. Ruiz’s statement and that pilot programs must be successfully conducted before adding additional endeavors. Following that, Dr. Lopez thanked the panelists and the audience for participating in the Q&A session, signaling an end to the discussion.

Conflict of Interest

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Ethical statements

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Acknowledgement

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Author contributions

i. All authors: conception and design

ii. All authors: data collection and assembly

iii. ML: data analysis, manuscript writing

All authors have approved the manuscript