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Next-generation sequencing at the forefront of precision medicine

Next-generation sequencing at the forefront of precision medicine


World Cancer Day provides a platform to raise awareness of the latest advances in oncology that are transforming both patient care and clinician practice around the world. In this regard, next-generation sequencing (NGS) continues to be at the forefront of precision medicine in oncology.

The overall goal of NGS in clinical oncology is to identify genetic alterations unique to each patient, thereby creating a uniquely personalized therapeutic approach. As the list of viable gene targets in cancer grows, NGS uses comprehensive profiles to detect oncogenic mutations and identify potential FDA-approved therapeutics, immunotherapies, and personalized therapies. We recommend clinical trial options.

Comprehensive genomic profiling, such as an NGS panel conducted at the Florida Cancer Specialists & Research Institute (FCS), identifies actionable mutations in most patients. NGS technology rapidly sequences multiple targets simultaneously.

Patient tumor samples are first submitted to the laboratory, evaluated by pathologists, and then passed through a molecular pipeline that includes DNA/RNA extraction, library preparation, sequencing, bioinformatics, analysis, and reporting. increase. We rely on a professional team of experts to carry out these tasks with the common mindset that helping our patients achieve the best possible outcomes is our top priority. .

cancer prevalence

The National Comprehensive Cancer Network (NCCN) recommends NGS for multiple tumor types including non-small cell lung, breast, colon, ovarian and pancreatic cancer. As both environmental and genetic factors are involved in the pathogenesis of these diseases, it is imperative to understand the molecular profile of each tumor through molecular diagnostics.

Currently, the prevalence of these diseases is:

  • Lung cancer is the leading cause of cancer-related deaths in the United States. Survival rates are low and the prognosis for terminal cancer remains poor.1
  • Breast cancer remains the most common cancer worldwide, and the detection of promising molecular biomarkers is helping advance diagnosis, treatment, and other treatments.2
  • Colorectal cancer, the third most commonly diagnosed cancer in the United States, is experiencing a year-on-year decline in mortality due to effective cancer screening. However, early-onset colon cancer is on the rise, the cause of which remains unknown.3
  • Ovarian cancer is the fifth leading cause of cancer-related mortality in women in the United States. The main therapeutic approach is immunotherapy. As some patients do not respond to immunotherapy, NGS plays a role in identifying other biomarkers such as homologous repair defects and proficiency phenotypes and factors that control the tumor microenvironment.Four
  • Although relatively rare, pancreatic cancer is projected to become the second leading cause of cancer-related deaths by 2030 due to its rapidly increasing annual incidence. Most patients are diagnosed at an advanced stage because pancreatic cancer screening is not available. or metastatic disease.Five

Given these statistics and trends, the importance of technological advances becomes clear for a more individualized precision medicine approach based on an individual’s molecular profile. NGS uses precious and limited tissue samples to identify novel biomarker candidates for early diagnosis and to powerful results with shorter turnaround times than previous sequential testing strategies to guide treatment decisions. can provide

The Solid Tumor Profile used in FCS analyzes over 500 genes, including Tumor Mutation Burden (TMB), an FDA-approved companion diagnostic (CDx) biomarker relevant to FDA-approved pembrolizumab (Keytruda) indications allows us to detect key biomarkers of Solid tumors not possible with small panels.6

In addition to identifying relevant genetic variants and TMBs, our Solid Tumor Profile includes microsatellite instability (MSI). NTRK and other fusions in conjunction with concurrent analysis of NCCN-recommended driver mutations. BRAF, ERBB2 (HER2), MET, RET, NTRK, ROS1, EGFRand ALK.

Role of NGS in cancer therapy

Analysis of somatic mutations in solid tumors using targeted NGS-based assays has become a standard of care in precision medicine, and it is important that physicians and patients recognize the efficacy of this method.

By testing TMB using a large multigene panel, clinicians can learn about anti-programmed cell death 1 (anti-PD1) antibodies and/or a patient’s eligibility for clinical trials, which can be useful in drug development. It also helps in accelerating the7

Clinicians should be familiar with the types of genomic variants reported by laboratories, the techniques used to determine results, and understand the limitations of current testing methods and reporting. As technology evolves and becomes more cost-effective, the use of molecular tests may prove more specific and improve outcomes for more patients.

Knowing a patient’s genomic profile allows physicians to make the best decisions regarding treatment for their current state of disease. Treatment includes FDA-approved drugs and contraindicated drugs if specific variants are present.

For example, the recently approved sotorasib (Lumakras) for adult patients with advanced or metastatic non-small cell carcinoma with the KRAS G12C mutation,8 not only advanced an improved and more individualized approach to precision medicine, but also opened new avenues for exploring this drug in other tumor types harboring the same variant mutations.

A complete molecular profile using NGS can also identify drugs that should not treat a patient under the NCCN Clinical Practice Guidelines for Non-Small Lung Cancer.9 Using the example of sotrasib, the NCCN guidelines caution that KRAS mutations are predictive of lack of therapeutic benefit from EGFR TKIs.

NGS technology detects these single-nucleotide mutations, copy-number mutations, fusions, splice variants, and many other biomarkers to complement therapeutic decisions with the goal of reaching patients in remission and progression-free survival. helps.

Physicians are strongly encouraged to reach out and consult with molecular experts to further understand evolving techniques, interpretations, and new treatments available to patients. If a patient’s profile is unique and there are no treatments available, there are often clinical trials available for them.

Many are provided by FCS physicians or by one of the three FCS drug development units. Our in-house precision oncology team helps match patients to clinical trials and molecular counselors. Additionally, you can work with your doctor to answer questions and provide guidance.

germ cell test

NGS has not only taken a step forward in precision medicine in terms of detecting somatic mutations, resistance mechanisms, and quantifying mutational burden, but has also established a platform that enables the detection of germline mutations.

Detection of germline mutations is of critical importance in the treatment of breast, ovarian, prostate, pancreatic and colon cancers. This is because FDA-approved treatments, such as his PARP inhibitor for advanced prostate cancer patients, are in certain mutations. They also help inform families who should be encouraged to begin genetic counseling early in life.

According to current guidelines, all ovarian cancer patients should undergo genetic testing. but also BRCA1 and BRCA2 Genes Genes, mutations that predispose to ovarian cancer RAD51C and RAD51D Increased risk of ovarian cancer.10 RAD51C/D It is important for preventive care and may make a difference in prognosis.

Several other hereditary cancers are associated with various genes that play critical roles in DNA damage response pathways, such as the mismatch repair genes in Lynch syndrome. TP53 In Li-Fraumeni syndrome, STK11 In Peutz-Jeghers syndrome, Check 2, WORK51, BRIP1, PALB2 and MUTYH-associated polyposis.11,12

The growing demand for germline testing in cancer and the shortage of genetic counselors have created a need for alternative medical models, with oncologists taking a more active role in the implementation of germline testing. The NCCN Guidelines provide extensive resources for germline evaluation, as well as other considerations for NGS testing.

Looking to the future possibilities of NGS

NGS has evolved significantly over the years, moving from research to clinical use due to the amount of genomics data collected during sequencing. NGS continues to move into more areas of cancer care to better support clinical practice.

In addition, NGS can bring many discoveries to clinical practice not only for the treatment of patients with somatically-mutated solid and heme tumors, but also for germline testing. In addition, NGS opens up other testing possibilities, such as whole-genome sequencing for homologous recombination defect testing. And the many other targetable biomarkers that have been discovered and recommended for action will continue to reshape oncology care for many more World Cancer Days to come. .


1. Kruglyak KM, Lin E, Ong FS. Next-generation sequencing and its application to diagnosis and treatment of lung cancer. Adv Exp Med Biol. 2016;890:123-36. Doi: 10.1007/978-3-319-24932-2_7

2. Loibl S, Poortmans P, Morrow M, et al. breast cancer. lancet. May 8, 2021;397(10286):1750-1769. Doi: 10.1016/S0140-6736(20)32381-3

3. Thanikachalam K, Khan G. Colorectal cancer and nutrition. nutrients. 2019-01-14;11(1):164. Doi: 10.3390/nu11010164

4. FDA has approved pembrolizumab for adults and children with TMB-H solid tumors. news release. June 17, 2020. Date accessed: December 13, 2022.

5. Morand S, Devanaboyina M, Staats H, et al. Ovarian cancer immunotherapy and personalized medicine. Int J Mol Sci. 2021 Jun 18;22(12):6532. Doi: 10.3390/ijms22126532

6. Rahib L, Smith BD, Aizenberg R, et al. Cancer Incidence and Mortality Projections to 2030: The Unexpected Burden of Thyroid, Liver, and Pancreatic Cancers in the United States. cancer research. 2014 Jun 1;74(11):2913-21. Doi: 10.1158/0008-5472.CAN-14-0155

7. Mosele F, Remon J, Mateo J, et al. Recommendations for the use of next-generation sequencing (NGS) for patients with metastatic cancer: A report from the ESMO Precision Medicine Working Group. Yearbook of Onkor. 2020 Nov;31(11):1491-1505.

8. FDA grants accelerated approval of sotorasib for KRAS G12C-mutant NSCLC. news release. May 28, 2021. Date accessed: December 13, 2022.

9. Ettinger DS, Wood DE, Eisner DL, et al. Non-Small Cell Lung Cancer, Version 3.2022, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2022 May;20(5):497-530. Doi: 10.6004/jnccn.2022.0025

10. Soukupova J, Lhotová K, Janatová M, et al. Germline mutations in RAD51C and RAD51D and genetic predisposition to ovarian cancer. Clin on call. Winter 2021;34(1):26-32. English. Doi: 10.48095/ccko202126

11. Pietragara A, Arcieri M, Marchetti C et al. Ovarian cancer predisposition beyond the BRCA1 and BRCA2 genes. Int J Gynecologic cancer. 2020 Nov;30(11):1803-1810. Doi: 10.1136/ijgc-2020-001556

12. Ma H, Brosens LAA, Offerhaus GJA, Pathology and genetics of other hereditary colorectal cancer. Pathology. 2018 Jan;50(1):49-59. Doi: 10.1016/j.pathol.2017.09.004




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