Early Detection and Molecular Testing Evolving for NSCLC

Hongbin Chen, MD, PhD

As with many cancers, early detection (before the onset of symptoms) offers the possibility for less expensive treatment and better outcomes in patients with non-small cell lung cancer (NSCLC).^1,2To this end, screening for patients at high risk (particularly heavy smokers) can lead to earlier diagnosis and better survival.²

Results from the National Lung Screening Trial (NLST) showed that, compared with chest x-ray, death from lung cancer could be reduced by 20% among current and former heavy smokers through a screening process using spiral computed tomography (CT), and this led to the ACS issuance of screening guidance in 2013.^1,3

Abraham Chachoua, MD, on the Challenges of Treating Lung Cancer

Chachoua is the director of the Thoracic Oncology Research Program at the Laura and Isaac Perlmutter Cancer Center, NYU Langone Medical Center.

Low-dose helical CT (LDCT) scanning has been recommended by the ACS for patients considered high risk for NSCLC, namely, current or former smokers (who quit within past 15 years) who are aged 55 to 74 years, in otherwise good health, and who have a minimum 30 pack-year history.^1,3The ACS emphasizes, however, that because screening also entails risks, it should be a shared decision-making process between the clinician and the patient, including discussion of the benefits and uncertainties associated with screening.^1,3

Hongbin Chen, MD, PhD, assistant professor of oncology in the department of medicine at Roswell Park Cancer Institute in Buffalo, New York, noted that results from the NLST established LDCT as the most updated screening method, and that, while there remain issues of regulatory approval and insurance coverage, his institution has a screening program in place for high-risk patients as outlined by the ACS.

“Heavy smokers, defined as 30 pack-years or above, or former smokers who quit 15 years ago… this is the studied population in the NLST trial, and that is [the population of patients] applicable to the recommendation for screening,” Chen said.

For screening to be most effective, however, it is important that benefits outweigh the potential risks.²Principle risks associated with screening include radiation exposure, adverse events, costs associated with unnecessary diagnostic interventions, and overdiagnosis (ie, the diagnosis and subsequent treatment of an indolent cancer that would not result in death).^2,4,5There is also the potential impact of incidental or inconsequential findings (eg, cardiovascular issues, other unrelated lesions/abnormalities, benign or otherwise) that may require additional clinical and/or radiologic follow-up; this must also be considered with any widely implemented screening program.^4,5

Regarding assessment of the screening findings, Chen said, “You really need to have an experienced, multidisciplinary team who can manage those cases, in an established center, with a lung cancer screening program.”

Chen explained that such a team would generally include a radiologist, an interventional pulmonologist, thoracic surgeons, and medical oncologists.

Moving Forward

Commenting on the potential for false-positive results, Chen emphasized that “You need to have someone with experience to identify these abnormalities, or suspected abnormalities, then from there you can move forward with what to do, such as a biopsy. There will still be false-positives, but the point is, if we do [screening] as prescribed, then the outcomes should be better in terms of reducing the lung cancer mortality.”Lingering, unresolved issues for lung cancer screening include the optimal frequency and duration of screening, how to best manage nodules that are deemed indeterminate, and the overall cost efficacy of screening.^2,4In the future, relevant biomarkers can be expected to more accurately identify at-risk populations for screening; this, combined with continued developments of more sensitive imaging procedures, may enhance acceptance and use of screening programs.^2,6

The findings of NLST have nonetheless shown that screening for NSCLC is feasible and beneficial, and as it gains greater acceptance across more centers nationwide, researchers hope that early diagnosis of NSCLC will become a reality for more patients, because only 25% to 30% of patients now present with disease that is localized and potentially curable.⁵

Clinical Pearls

• Screening for patients at high risk can lead to earlier diagnosis and better survival in patients with NSCLC.
• Results from the NLST showed that, compared with chest x-ray, death from lung cancer could be reduced by 20% among current and former heavy smokers through a screening process using spiral CT.
• This finding led to the ACS issuance of screening guidance in 2013.
• Once detected and diagnosed through biopsy, molecular testing may provide rapid assessment of mutations that, if detected, could influence treatment decisions.
• This year (2014), the ASCO CPG committee announced its endorsement of the College of American Pathologists/International Society for the Study of Lung Cancer/Association of Molecular Pathologists (CAP/IASLC/AMP) guidelines for molecular testing.

“Approximately 75% of patients present with advanced disease,” said Grace K. Dy, MD, associate professor of oncology in the department of medicine at Roswell Park Cancer Institute. Her institution uses low-dose CT scanning with fluorescent bronchoscopy to evaluate central airways as a screening method for high-risk patients, according to Dy. She acknowledged both benefit and risk in screening high-risk patients.

Grace K. Dy, MD

After Diagnosis: Molecular Testing

“Low-dose CT chest as screening in the high-risk population can decrease deaths due to lung cancer. The caveat is that many positive findings maybe false-positive, [and] thus there is ongoing research on the clinical utility and validity of ancillary diagnostics (eg, blood-based biomarkers such as circulating tumor cells; measurement of volatile gases in exhaled breath, etc) that can improve sensitivity/specificity of nodules detected with imaging scans,” Dy stated.Once NSCLC has been detected and appropriately diagnosed through biopsy, molecular testing is paving the way for rapid assessment of mutations that, if detected, could influence early treatment decisions. This year (2014), the American Society for Clinical Oncology (ASCO) Clinical Practice Guidelines Committee (CPGC) announced its endorsement of the College of American Pathologists/International Society for the Study of Lung Cancer/Association of Molecular Pathologists (CAP/IASLC/AMP) guidelines for molecular testing.^7,8

These guidelines consist of 37 recommendations about when and how to perform molecular testing for epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), and other gene mutations, and how to best implement such testing in patients with advanced-stage lung adenocarcinoma, or those with an adenocarcinoma component, regardless of clinical characteristics.⁸

The findings of this testing could identify patients for whom treatment with targeted therapies, most notably the tyrosine kinase inhibitors (TKIs), could be of benefit, and the ASCO CPGC endorsement is an important step in standardizing molecular testing practices.⁸Dy emphasized that the ASCO group endorsement is only pertinent for patients with advanced disease, does not really apply to early detection per se, and that molecular testing is meant to identify patients who will be suitable candidates for targeted therapy. Chen added that molecular testing is the first thing to do after a definitive diagnosis has been made, using tissue from the biopsy, if available.

“If [the biopsy] tissue is not sufficient, we recommend, in those patients who have nonsquamous lung cancer, to maybe undergo another biopsy, so we don’t miss those mutations if they are positive. The reason is that studies have shown that those patients who have those mutations, and who receive targeted therapies, benefit from the treatment, rather than standard chemotherapy,” Chen explained.

References

1. American Cancer Society. Cancer Facts and Figures 2014. Available at: http://www.cancer.org/acs/groups/content/@research/documents/webcontent/acspc-042151.pdf. Accessed November 4, 2014.
2. Gutierrez A, Suh R, Abtin F, Genshaft S, Brown K. Lung cancer screening.Semin Intervent Radiol. 2013;30(2):114-120.
3. Wender R, Fontham ET, Barrera E Jr, et al. American Cancer Society lung cancer screening guidelines.CA Cancer J Clin. 2013;63(2):107-117.
4. Finigan JH, Kern JA. Lung cancer screening: past, present and future.Clin Chest Med. 2013;34(3):365-371.
5. Marshall HM, Bowman RV, Yang IA, Fong KM, Berg CD. Screening for lung cancer with low-dose computed tomography: a review of current status.J Thorac Dis. 2013;5(suppl 5):S524-S539. doi:10.3978/j.issn.2072-1439.2013.09.06.
6. Park YS. Lung cancer screening: subsequent evidences of national lung screening trial.Tuberc Respir Dis (Seoul). 2014;77(2):55-59.
7. ASCO Endorses Molecular Testing Guideline for Lung Cancer. Available at: http://www.onclive.com/web-exclusives/ASCO-Endorses-Molecular-Testing-Guideline-for-Lung-Cancer. Accessed November 6, 2014.
8. Leighl NB, Rekhtman N, Biermann WA, et al. Molecular Testing for Selection of Patients With Lung Cancer for Epidermal Growth Factor Receptor and Anaplastic Lymphoma Kinase Tyrosine Kinase Inhibitors: American Society of Clinical Oncology Endorsement of the College of American Pathologists/International Association for the Study of Lung Cancer/Association for Molecular Pathology Guideline [published online ahead of print October 13, 2014.J Clin Oncol. pii: JCO.2014.57.3055.