Update on Genetic Testing in Cancer and Targeted Therapy

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Cancer, a leading cause of mortality, is associated with aberrant genes. Many of the most recent advances in oncology have been related to the field of precision medicine.

Clinical molecular testing of solid tumours is most frequently performed for those biomarkers with strong evidence supporting clinical usefulness as a diagnostic, prognostic, or therapeutic biomarker. These biomarkers typically have extensive literature supporting their clinical use and are recommended by professional guidelines.

The variety of technologies emerging enables more precise and robust analysis of circulating tumour-derived DNA (ctDNA) extracted from blood with sufficient sensitivity and specificity to accurately detect cancer biomarkers. The currently validated ctDNA assays have been compared against tissue genotyping.

The biomarker information is based mainly on the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology (NCCN Guidelines), NCCN Biomarkers Compendium (NCCN.org, Accessed February 6, 2019), Cancer Council and FDA recommendations and approvals (for the full definitions of all genes).

Tumour Molecular Profiling

The presence or absence of activated therapeutic driver mutations or gene targets (e.g., B-RAF Oncogene [BRAF] in melanoma, Kirsten RAS Oncogene [KRAS] in colorectal cancer and epidermal growth factor receptor [EGFR] mutation or anaplastic lymphoma kinase (ALK) rearrangements in non-small cell lung cancers [NSCLC]) is currently employed to guide treatment decisions.

Driver Mutations Guide Treatment Decisions

The introduction of targeted therapies in lung, colon, melanoma and breast cancer have contributed to a significant increase in overall survival (OS) related to these diseases.

Genetic variants identified in cancer are known to be associated with increased or decreased sensitivity to targeted therapy such as tyrosine kinase inhibitors (TKIs). For example, while PIK3CA and EGFR mutations are sensitive to TKIs, RAS and BRAF are known to be resistant(1-2). Crizotinib is an ALK/ROS1/MET inhibitor that is already FDA approved in ALK-positive or ROS1-positive NSCLC but also has proven clinical activity in cases of MET exon 14 alterations and MET amplification(3). PD-L1 expression in metastatic NSCLC can benefit from FDA approved pembrolizumab monotherapy under specific criteria(4).

Recently, a third-generation EGFR TKI, which is effective in tumours harbouring the p.T790M EGFR mutation was approved in Australia for patients with NSCLC following progression on an EGFR TKI(5-8). In breast cancer, mutated PIK3CA has become an attractive therapeutic target in breast cancer therapy and a number of agents targeting the PIK pathway are currently in clinical development(9-10).

Targeted therapy with anti-BRAF inhibitors (BRAFi) remains the first-line treatment for melanoma tumours that harbour a BRAF mutation, particularly in Australia(11-12). Other oncogenic driver mutations have been identified in melanomas for which targeted therapies have demonstrated clinical activity. Detection of cKIT mutations may guide the selection of KIT TKIs (imatinib and sunitinib) for the melanoma treatment(13).

New Guidelines: Broadening Molecular Profiling Boundaries

Recent NCCN guidelines recommended additional genetic biomarkers for different types of cancer tissues.

Lung cancer therapy continues to follow the genomic testing paradigm. The new NCCN guidelines recommend testing for EGFR, ALK, ROS1, BRAF, and PD-L1 for all patients with NSCLC at baseline before treatment(14-19).

Universal Microsatellite instability (MSI) testing at the time of initial diagnosis for all stages of colorectal tumours is now recommended to determine whether patients have a germline mutation indicative of Lynch syndrome(20-21). Those with neurotrophic receptor tyrosine kinase fusion oncogene family (NTRK) are candidates for treatment with larotrectinib(22).

In addition to breast and ovarian cancers, germline mutations, mainly BRCA1/2, along with somatic mutation testing are recently recommended by NCCN guidelines for both pancreatic and prostate cancers(23-24). In prostate cancer, BRCA1/BRCA2 can occur in 20-25% of all advanced prostate cancer(24). Although ATM testing is not yet recommended by the NCCN as a predictive measure, Na et al., showed that germline BRCA2 and ATM mutations distinguish lethal from indolent prostate cancers and are associated with shorter survival times and earlier age at death(25).

Tumour Biomarkers Have a Prognostic Role

Molecular oncology biomarkers may play a prognostic role. In thyroid cancer, BRAF p.V600E mutation occurs in ~40% of patients with papillary thyroid carcinoma (PTC) and is associated with a more aggressive disease. In pancreatic cancer, mutation in codon 12 of KRAS is a very common event, occurring in up to 90% of pancreatic cancers, which can predict a poorer prognosis(26-27).

Liquid Biopsy: Circulating Tumour DNA (ctDNA) Testing

The advent of molecular profiling overcame the limitations of traditional solid tumour classification methods, which relied on the morphology of tumour cells and the surrounding tissue.

Tissue biopsy is considered to be the gold standard. However, tissue biopsy-based tumour diagnosis has many limitations. For instance, tumour heterogeneity, the detection of early-stage tumour or residual lesions is unsatisfactory, and its application in the evaluation of treatment efficacy, resistance, relapse and prognosis is also limited.

The use of liquid biopsy profiling has proven useful in selected clinical scenarios. The first ctDNA liquid biopsy approved for use in clinical settings was in lung cancer patients for the identification of EGFR mutations for first line therapy or identifying resistance mutations that will allow for treatment with third generation EGFR inhibitors(28-31).

In colorectal cancer, ctDNA could also be used to track clonal evolution and targeted drug responses. In patients with metastatic colorectal cancer who developed resistance to EGFR antibodies, analysis of ctDNA identified the emergence of polyclonal and heterogeneous patterns of mutation in KRAS, NRAS, BRAF, or EGFR with mutations found in 96% of panitumumab- or cetuximab refractory patients. Subsequently, Misale et al., were able to illustrate a way to use this information to overcome treatment resistance(32-33).

Furthermore, studies demonstrate better outcomes when no tumour-derived DNA is found in patients following surgery or chemotherapy in colorectal cancer patients, whereas those with whom tumour DNA is still present do better with the addition of more aggressive targeted treatment or chemotherapy(32, 34).

In melanoma there is no liquid biopsy test approved in the clinical settings at present. Nevertheless several studies showed the utility of ctDNA as a diagnostic, predictive and prognostic biomarker for patients on anti-BRAF treatment(32, 35-36).

Moreover, ctDNA can also ease the decision in the daily clinical practice when radiological evaluation is problematic especially for patients receiving PD-1 inhibitor immunotherapy. In this context, an important advantage of ctDNA is the possibility of non-invasive serial testing for monitoring treatment response and resistance to therapy(37).

Finally, precision medicine in cancer is moving that quickly especially in the malignant heme space and is now a part of our standard practice. While with new challenges, it will continue to move forward with more discoveries to come.


References

1- Yang CH et al., (2008) J Clin Oncol 26(16):2745–2753

2- Sequist LV et al., (2008) J Clin Oncol 26(15):2442–2449

3- Kawakami H et al., (2014) Cancers (Basel) 6:1540-1552.

4- Reck M et al., (2016) N Engl J Med. 375:1823-1833.

5- Thress K et al., (2015) Lung Cancer 90:509-515.

6- Wu Y et al., (2017) Br J cancer 116:175-185.

7- Yu H et al., (2013) Clin Cancer Res 19:2240–2247.

8- AstraZeneca. (2016) TAGRISSO (osimertinib mesilate) product information

9- Lee JW, et al., (2005) Oncogene 24(8):1477–1480

10- Levine DA, (2005) Clin Cancer Res 11(8):2875–2878

11- Spagnolo F et al., (2015) Onco Targets Ther 8:157-168.

12- Brose MS et al., (2002) Cancer Res 62(23):6997–7000

13- Minor DR et al., (2012) Clin Cancer Res 18:1457-63.

14- Pai-Scherf L et al., (2017) Oncologist 22:1392-1399.

15- Li BT et al., (2018) J Clin Oncol 36:2532-2537.

16- Paik PK et al., (2015) Cancer Discov 5:842-849. doi:10.1158/2159-8290.CD-14-1467

17- Lee SH et al., (2017) Ann Oncol 28:292-297.

18- Drilon A et al., (2016) Lancet Oncol 17:1653-1660.

19- Lindeman NI, et al., (2018) J Mol Diagn 20:129-159.

20- Sinicrope FA, Sargent DJ. (2009) Curr Opin Oncol 21:369-373.

21- Ribic CM et al., (2003) N Engl J Med 349:247-257.

22- US Food and Drug Administration. FDA approves larotrectinib for solid tumors with NTRK gene fusions. Silver Spring, MD: US Food and Drug Administration; 2018. fda.gov/Drugs/ Infor matio nOnDr ugs/Appro vedDr ugs/ucm62 6720.htm. Accessed February 6, 2019.

23- Waddell N et al., (2015) Nature 518:495-501.

24- Carroll PR et al., (2016). J Natl Compr Canc Netw 14:509-519.

25- Na R et al., (2017) Eur Urol 71:740-747.

26- Cohen Y et al., (2004) Clin Cancer Res 10(8):2761–2765

27- Xing M et al., (2005) J Clin Endocrinol Metab 90(12):6373–6379

28- John T et al., (2017) Asia-Pacific J of Clin Oncol 13:296-303.

29- Daniels M et al., (2011) Cancer Lett 312:43-54.

30- Premarket approval P150044 d Cobas EGFR MUTATION TEST V2. Cited 2016; Available from: https://www.accessdata.fda.gov/ scripts/cdrh/cfdocs/cfpma/ pma.cfm?id¼P150044

31- Calapre L et al., (2017) Cancer Letters 404:62-69.

32- Bettegowda C et al., (2014) Sci Transl Med 6:224ra24.

33- Misale S et al., (2014) Sci Transl Med 6:224ra26.

34- Tie J et al., (2016) Sci Transl Med 8:346ra92

35- Spagnolo F et al., (2015) Onco Targets Ther 8:157–168.

36- Garcia-Murillas I et al., (2015) Sci Transl Med 7 (302):302ra133–302ra133.

37- Gray E et al., (2015) Oncotarget 6(39):42008–42018.

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About Author

Mirette Saad

Associate Professor Mirette Saad is a Consultant Chemical Pathologist and the National Clinical Director of Molecular Genetic Pathology at Australian Clinical Labs. At Clinical Labs, A/Prof Mirette Saad leads the Molecular Genetic testing for Non-Invasive Prenatal Testing (NIPT), carrier screening, personalised drug therapy and cancer. She is a member of the RCPA Chemical Pathology Advisory Committee and a Chair of precision medicine services at Australian Clinical Labs.

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