New Type of Medicine Tackles Undruggable Molecular Targets
Although targeted therapies have had a profound effect on cancer medicine, only approximately 20% of proteins in cancer cells can be targeted by currently available medicines. Many of the undruggable targets include important molecules in pathways that suppress (eg, TP53 and APC) or promote (eg, RAS and MYC) tumor growth. One of the reasons these targets are undruggable is that, historically, it has been difficult to block these pathways with small molecules, and protein drugs do not easily penetrate the cell.
A new class of drugs, known as stapled peptides, has emerged as a promising way to target protein-protein interactions. These small proteins have an artificial chemical bridge, or staple, that holds them in a specific shape that allows them to penetrate the cell.
In an early clinical trial, researchers demonstrated for the first time that a stapled peptide is effective in patients.100 The peptide targeted the interaction between MDM2 and MDMX-TP53 in patients with solid tumors and lymphoma without p53 mutations. The treatment, ALRN-6924, stalled cancer growth in 45% of 55 patients. A larger clinical trial is underway (ClinicalTrials.gov identifier: NCT02264613).
Emerging Role for Precision Medicine in Cancer Prevention
The concept of precision medicine as applied to cancer prevention is in its nascent stages. In this first phase, scientists are focusing on inherited cancer syndromes, such as BRCA-related breast and ovarian cancers and Lynch syndrome.
For patients with inherited genetic susceptibility to cancer, the hope is to one day replace crude, one-size-fits-all cancer risk reduction approaches, such as preventive surgery, with personalized approaches that take into account not only a person's genetic make-up and family history, but also the composition of microbes in their body, their diet, lifestyle, and environmental factors.101
Scientists are only beginning to understand how the complex interplay of all these factors raises or lowers the chance of developing cancer in an individual with an inherited cancer gene mutation. It is also not clear why changes in genes with broad functions, such as the DNA repair and MMR genes, predispose people for certain, but not all cancers.
Large-scale genomics studies are providing insights by which to fine-tune cancer risk assessment for each person. For example, it seems that certain changes in mitochondrial DNA lower the risk of breast cancer in patients with BRCA mutations. Genomic information, along with reproductive and family history, lifestyle, and other factors, may help patients decide whether and when to have preventive surgery.
Scientists are also exploring the possibility of using immune-based approaches, such as vaccines for cancer prevention in healthy people with cancer predisposition syndromes.102 The idea is to harness the immune system to recognize and eliminate premalignant cells on the basis of their molecular characteristics. With the new national investment in cancer prevention through the Cancer Moonshot initiative and cutting-edge technologies, such as sequencing the genomes of individual cells, the opportunity to advance this field is closer than ever.
Understanding Health Disparities: Path to Better Care For All
Cancer is becoming one of the most pressing health care challenges worldwide. Between 2005 and 2015, the number of patients with cancer increased worldwide by 33%.103 According to the Global Burden of Disease study, issued in late 2017, cancer is the second leading cause of death from non-communicable diseases, which cause 72% of deaths worldwide.25
Whereas many countries have experienced decreases in cancer mortality over the last decade, cancer deaths increased in Sub-Saharan Africa and certain other regions lacking in health care infrastructure (this study was funded in part by a grant from the NIH).103 Seven of 10 cancer deaths occur in regions of Africa, Asia, and Central and South America, where access to cancer screening and treatment is limited.104
Even within high-resource countries, such as the United States, certain communities experience greater cancer incidence, shorter survival, and more deaths from cancer. During the last 60 years, socioeconomic, education, and racial/ethnic inequities in cancer mortality have persisted and even widened in some cases.105
Recently published studies reveal that the root causes of cancer disparities in the United States are complex. Researchers found that black patients across all socioeconomic groups have higher cancer mortality than white patients. Another study found that people from the poorest communities were more likely to be diagnosed with advanced cancer, regardless of whether they had health insurance.
ASCO Issues Recommendations for Reducing Cancer Disparities Among Sexual and Gender Minority Populations
Sexual and gender minority (SGM) populations, including individuals who are lesbian, gay, bisexual, transgender, and intersex, bear a disproportionate cancer burden that stems from several factors, such as lower rates of cancer screening and a hesitancy on the part of SGM patients to disclose their sexual orientation to providers because of a fear of stigmatization.
On April 3, 2017, ASCO issued recommendations to address the needs of SGM populations as they relate to cancer. The recommendations, published in a policy statement in the Journal of Clinical Oncology, are designed to focus attention on the challenges that face the SGM community, including discrimination and greater risk of anxiety and depression, resulting in disparate care. The statement also provides concrete steps that can help minimize health disparities among SGM individuals.
In addition, patterns of disparity have been changing. For example, during the 1950s, black people had lower all-cancer mortality than did white people, but since the 1960s, all-cancer mortality rates have been significantly higher for black people than for white people across all socioeconomic groups. Differences are particularly pronounced for some cancers. Within each socioeconomic group, black women have two times higher cervical cancer mortality, and 50% higher breast cancer mortality rates than white women and black men have two times higher prostate cancer mortality rate than white men.105
Socioeconomic disparities have also reversed over time. In 1950, people in the most-deprived socioeconomic group had a 27% lower cancer mortality rate than those in the most affluent group, but by 2010 to 2014, the most deprived group had a 22% higher cancer mortality than their most affluent counterparts.105
Although patients from disadvantaged communities benefit most from health insurance coverage, insurance alone does not overcome the mortality gap. In one study, patients in the poorest communities were more likely to have advanced cancer at diagnosis and less likely to receive cancer-directed surgery than those from the least disadvantaged communities, regardless of health insurance status (this study was funded, in part, by a grant from the NIH/NCI).106 Another analysis demonstrated that among people with no health insurance, black patients had rates of cancer mortality that were similar to those of white patients, but had higher mortality rates among either Medicaid or private insurance groups.107
Even with access to health care, patients may not seek care for many reasons that include having insurance but no health care available nearby, not knowing how to access the health care system, or lack of trust in the health care system.
Other research suggests that socioeconomic disparities in cancer death rates may in part be a result of modifiable behaviors that increase the risk of cancer. The 2015 National Health Index Survey showed that prevalence of smoking, obesity, physical inactivity, and inadequate intake of fruit and vegetables was higher among people with lower education and income levels, and rates of cancer screening were lower.
Taken together, this body of research suggests that addressing cancer disparities and achieving equity calls for multifaceted approaches that are focused on efforts to improve prevention, screening, and access to high-quality cancer care.
A Policy Focus: Giving Medicaid Patients Equal Access to Clinical Trials
Most private insurance plans and Medicare are required to cover the routine costs of care for patients who participate in clinical trials. Routine care includes items and services that a payer would cover for a patient who is not enrolled in a clinical trial, such as office visits, radiology exams, and laboratory tests; however, Medicaid is not required to cover these routine costs for patients.
For researchers to understand how different populations respond to cancer treatment and address disparities in cancer outcomes, all types of patients should have the opportunity to participate in cancer trials. Unfortunately, patients from racial and ethnic minority groups that are over-represented in the Medicaid program make up just a small subset of clinical trial participants.
ASCO strongly encourages policymakers to guarantee that Medicaid covers routine care costs for patients in clinical trials so that more patients with Medicaid can participate in cancer research.
A Policy Focus: Addressing Health Disparities in Cancer Care
Significant cancer health disparities continue to exist in certain populations. Race, ethnicity, socioeconomic status, and geography all affect patient health outcomes, and racial and ethnic minorities and individuals of lower socioeconomic status experience worse cancer outcomes.
To address this issue, ASCO, with the American Association for Cancer Research, the American Cancer Society, and the NCI, released a joint statement to foster cooperation across the cancer research community to ensure that all patients, regardless of demographics, socioeconomic status, or the communities in which they live, benefit from cancer research (the statement was published in Journal of Clinical Oncology108).
The statement called for defining and improving data measures and tools for cancer disparities research, addressing disparities in cancer incidence, addressing cancer survival disparities, improving community engagement in cancer research, and redesigning clinical trials to acknowledge and address cancer disparities.