Improving Women's Health: Advances,Failures and Cancer Genome Prospects

“…genomic revolution provides rational promises for a better understanding of the genetic and epigenetic coding.”

Cancer is a major health problem. Each year over 1,150,000 women are diagnosed with breast cancer and 500,000 women are diagnosed worldwide with cervix uteri cancer followed by cancer sites in the colorectum, lung, ovary and corpus uteri [1]. A further increase in incidence and mortality rates is estimated for the next decade [2]. Global cancer rates could further increase by 50% to 15 million new cases in the year 2020 and, according to the World Cancer Report, cancer is predicted to overtake heart disease as the world's leading cause of mortality [101].

“…the NIH and the NCI in the USA strongly support the development of new molecular diagnostics and novel therapeutics…”

Currently, despite advances in the prevention, early detection and treatment in the USA, millions of women are newly diagnosed with cancer and the cancer kills most of these women, particularly when the diagnosis is delayed [3]. The American Cancer Society reports that women have a one in three risk of developing cancer lifetime [4,102]. The need for a change in the design of anticancer strategy is obvious. Currently, the NIH and the NCI in the USA strongly support the development of new molecular diagnostics and novel therapeutics in recognition of the limitations of modern biomarkers, and cytotoxic and biologic agents [4].

Various research strategies by the private and public sector are now being evaluated. They include single gene-based medical tests, vaccines for the prevention and treatment of gynecologic cancers, multigene assays known also as gene expression signatures, cancer stem cells, nanotechnology for more active drug delivery and other innovative developments, which are currently tested in preclinical and clinical studies to assess their clinical validity and clinical utility. Nonetheless, with a few exceptions, in the absence of evidence from Phase III, large-scale randomized controlled trials, the clinical application of new biomarkers and novel drugs is moderate. This article is focused on the standard of care and its limitations in the management of female cancer, as well as the expectations and challenges in oncological outcome improvements faced with the new era of human and cancer genomes sequencing. Although the advent of high-throughput sequencing technology has revolutionized biomedical research, its clinical application is limited [5,6]. At the beginning of the second postgenomic decade, we are now facing an explosion in genomic technology. This revolution is derived from the unpreceded ability of the latest DNA sequencing technology to identify causal (also called ‘driver’) mutations driving cancer initiation and metastasis. The ability of the latest DNA sequencing technology to provide in-depth understanding of the nature of cancer provides significant expectations for dramatic improvements in the management of female cancer. But what are these challenges?

Current molecular research advances & limitations

Over the last 2 decades, important advances have been occurring in both the prevention and treatment setting.

Early detection of cancer is crucial for achieving long-term survival. Screening programs for the general population, including mammography, colonoscopy and colposcopy have been standardized and have increased the rates of early detection of the most common breast cancer, colorectal cancer and cervix uteri cancer, respectively. However, many low-risk women undergo an unnecessary screening and, often, false-positive results leads to further nonuseful diagnostic imaging examinations and biopsies with adverse effects on quality of life. Efforts are underway for individualized risk prediction and prevention. However, achieving personalized screening and prevention is still a major challenge and an elusive goal.

The first steps towards personalized risk prediction-based prevention have been achieved with the identification of women at high risk for developing hereditary cancer. Primary prevention of hereditary breast–ovarian cancer syndrome and colorectal–endometrial cancer (Lynch syndrome) for individual women with a family history of a positive genetic testing for heritable mutations in BRCA1/BRCA2 and mismatched-repair genes, respectively, is now feasible [7–9]. However, approximately 25% of mutation carriers never develop cancer in their life and, thus, despite its efficacy, prophylactic surgery for these women is not only unnecessary but it also has adverse effects. Moreover, these hereditary cancer syndromes are rare, whereas for the vast majority of women who will develop cancer no accurate robust predictor exists [9,10].

“This revolution is derived from the unprecedented ability of the latest DNA sequencing technology to identify causal … mutations driving cancer initiation and metastasis.”

In the standardized multimodal treatment of women with established cancer diagnosis, the addition of systemic targeted therapy can improve outcomes. Over the last decade, the advent of these biologic agents has provided widespread excitement. The list of these drugs approved by the US FDA has grown rapidly and many others are undergoing preclinical and clinical testing. However, clinical success measured by overall survival benefit is limited. With an isolated clinical success of trastuzumab – an anti-HER2 signaling pathway inhibitor – added to chemotherapy in the adjuvant treatment of breast cancer [11–14], no other targeted agent has been translated into clinical use in the adjuvant setting for any other major cancer type. Indeed, several of these biologic agents including monoclonal antibodies and small molecule tyrosine kinase inhibitors have been approved by the FDA only for the treatment of patients with metastatic disease.

Even in an advanced, metastatic or recurrence setting, substantial limitations have merged by Phase-III, randomized controlled trials. First, the anti-EGF receptor monoclonal antibody cetuximab and the tyrosine kinase inhibitors erlotinib or gefitinib are active only in genotyping selected patients with metastatic colorectal cancer or metastatic non-small-cell lung cancer, respectively [15–18].

These limitations in the prevention and treatment of cancer urgently suggest the need for new research strategies. Current efforts by biotechnology, the pharmaceutical industry and academia are driven by the recognition and understanding of the molecular mechanisms, explaining the failures of the present generation of biomarkers and targeted drugs. Such an in-depth understanding can lead to innovative approaches in how to overcome current challenges and achieve the development of robust biomarkers and active drugs

Personal genomics

The advent of next-generation sequencing (NGS) technology [19] now provides rational promise for discovering the genetic variants and molecular mechanisms underlying cancer [20]. Despite this genomic revolution, we are still some distance away from genomic medicine [21]. The ability of massively parallel genome sequencing technology for the simultaneous analysis of millions of variants across the genome permits the identification of causal, mutations underlying cancer. This NGS-based assessment in both protein-coding DNA and noncoding DNA can lead to the completion of mutations catalog for major cancer types including breast cancer [22].

“Another big challenge, is how to understand the complex interactions between genes, molecules and signaling pathways.”

Several international consortiums have been launched, including the ‘1000 Genome Project’. The recently launched International Cancer Genome Consortium (ICGC) will reveal the repertoire of driver mutations for many cancer types [23]. The ICGC will coordinate systematic large-scale cancer genome studies in more than 25,000 cancer genomes at the genomic, epigenomic and transcriptomic levels. Genome sequencing will be performed in tumors from 50 different cancer types and/or subtypes that are of clinical and societal importance across the globe. More recent complete genome sequencing in cancer along with other recent systematic studies of cancer genomes, reveal that cancer is much more heterogeneous and complicated than we have previously thought [22,24–26].

Genetic regulation

Although NGS can identify most of the causal genome variants involved in cancer, the complexity of genetic regulation is one of the great wonders of nature, and it presents a daunting challenge to unravel [27]. The latest exciting research to explore the functional role of genes and life biodiversity include sequencing of noncoding DNA [28], identification of defects in epigenome [27,29,30], and prediction of complex gene–gene and gene–environment interactions [31–34].

Complex biological systems

Beyond genome and epigenome exploration, an understanding of genetic regulation in complex species, such as humans, still remains a great challenge. Another big challenge, is how to understand the complex interactions between genes, molecules and signaling pathways [31–34]. However, no standard statistical or computational method has been developed to predict such complex networks. Exciting research is underway to predict the inference of biological systems that are considered essential for the development of novel biomarkers and highly effective drugs in cancer [35]. Such a new and promising method is now proposed by Wood [36]. This new statistical approach requires only the ability to simulate the observed data on a system from the dynamic model about which inferences are required [36]. The complexity of the genotype–phenotype map and the challenges in how to predict phenotypic heterogeneity among patients with the same cancer type, tumor stage and clinicopathologic features, requires innovative developments in biomedical, bioinformatics and mathematical sciences.

Conclusion

Advances in standard, translational and single-gene-based molecular research have standardized the approaches in the primary prevention, early detection and treatment of cancer in women. This evidence-based standardization has saved the lives of million of women worldwide.

Nonetheless, global prevalence and mortality rates still remain alarmingly high and a further increase of these rates is expected for the year 2020.

At the beginning of the second postgenomic decade, genomic revolution provides rational promises for a better understanding of the genetic and epigenetic coding. The latest human genome sequencing technology now permits international consortiums to perform systematic, large-scale cancer genome studies. Results of these genomic studies may highlight molecular mechanisms underlying cancer origin and metastasis and are fundamental steps towards dramatic improvements in women's cancer healthcare.