Next Generation Sequencing – The future of Treatment

“I am a big believer of what is called as Cure me, Don’t just try to experiment for my survival. Medicine, especially in Cancer cure is a must according to your own body genome alterations, physiology, value system and unique conditions.” – Dr. Pramod Kumar Julka (Former Dean & Head of Dept Of Oncology, All India Institute of Medical Sciences).

Many biological discoveries about cancer have been the product of a reductionist approach, which focuses on modeling phenomena with as few major actors and interactions as possible. This reductionist thinking led the initial theories on carcinogenesis to be centered on how many “hits” or genetic mutations were necessary for a tumor to develop. It was assumed that each type of cancer would progress through a similar, if not identical, process of genetic hits. Indeed, there are a handful of cancer types, such as chronic myelogenous leukemia, that feature a single and pathognomonic DNA mutation. Working on this assumption, early methods to explore the genomic foundations of different cancers involved targeted exploration of specific variants and genes in a low-throughput fashion . However, most cancers are genetically complex, and are better defined by the activation of signaling pathways rather than a defined set of mutations.

The increased affordability and reliability of sequencing, has led to the integration of genome science into clinical practice. The use of these data to assist in diagnosis is generally referred to as precision medicine.The concept of precision medicine goes hand in hand with an understanding of the cancer genome as determined by NGS. In this review, we will explore the expanding NGS methodologies, analytical methods, and clinical applications that are driving precision cancer medicine.

India unlike most of the western countries is hence in an alarming need of such precision medication cancer care to treat specific form of genetic mutation diversity in Breast Cancer. Our country is facing a peculiar issue with younger population getting hit by the Molecular type of Triple Negative Breast Cancer which is even more deadly than other common forms of the disease.Thereby, calling for precision medication based on individual patient’s genetic make-up and molecular profiling of their own body, to identify the point mutations specifically and then apply the appropriate medication.

Triple-negative breast cancer (TNBC) is a molecularly diverse disease. Triple-negative disease encompasses more than one molecular subtype.The major components of triple-negative tumors in molecular assays are the basal-like and, more recently, the uncommon but intriguing claudin-low molecular subtypes.Basal-like breast cancers have several molecular characteristics. These include low signals for the ER-related gene cluster and the HER-2–related gene clusters.For this reason, these tumors generally (although not always) are negative for ER, PR, and HER-2 on clinical assays.Specific inherited mutations in BRCA1 andBRCA2 increase the risk of female breast and ovarian cancers. According to the most recent estimates, 55 to 65 % ofwomen who inherit a BRCA1 mutation and around 45%who inherit a BRCA2 mutation will develop breast cancer

The shared characteristics between tumors arising in BRCA1 mutation carriers and sporadic tumors include a variety of pathologic features, as well as a high p53 mutation rate, the basal phenotype, EGFR expression, and an X-chromosome inactivation pattern. Researchers are interested in the similarities between BRCA1 and sporadic basal-like breast cancers because BRCA1 plays an important role in mediating the DNA damage response. This has implications for targeted agents, including poly(ADP-ribose) polymerase (PARP) inhibitors, and also for certain chemotherapeutic agents.PARP inhibition may be another therapeutically valuable mechanism in patients with triple-negative disease.We are currently on the threshold of a revolution in breast cancer research thanks to the emergence of novel technologies based on next generation sequencing (NGS).The NGS or second-generation sequencing technologies have the advantage that enormous numbers of sequencing reactions can be performed in parallel in a time- and cost-effective manner.Breast tumors have at least one DNA rearrangement that can be detected by low coverage DNA-sequencing and that is not present in normal DNA. This approach could be used as an accurate non-invasive indicator of the tumor burden and provide an early indication of treatment efficacy or disease recurrence.

NGS is inextricably intertwined with the realization of precision medicine in oncology. While it is unlikely to obviate traditional pathologic diagnosis in its current state, it allows a more complete picture of cancer etiology than can be seen with any other modality. However, precision cancer medicine and large-scale NGS testing will require novel approaches towards ensuring evidence-based medicine. Treating each genetic abnormality as an independent variable when hundreds or thousands are queried in every patient will require new trial designs and statistical methods to ensure the utility of these approaches. Broadly, clinicians and translational researchers will need to continue to engage in direct dialog, both within and across institutions, to advance the integration of genomic information and clinical phenotypes, and enable precision cancer medicine through NGS approaches.

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