Molecular Diagnostics in NSCLC with David Berz, MD, PhD, and Philip Bonomi, MD - Episode 3

David Berz, MD, PhD, and Philip Bonomi, MD Discuss Use of Liquid Biopsies Over Surgical Biopsies

What are the benefits of using a liquid biopsy over surgical biopsy for patients with recurrent NSCLC and metastatic disease?

BERZ:Although the somatic mutations leading to secondary resistance to first and second generation tyrosine kinase inhibitors within the EGFR space are understood to happen on the tissue base, tissue diagnostics can be complicated in certain settings. These complications can arise from the tissue acquisition itself, due to patients progressing in difficult to access areas like the bone. The processing can be rather challenging in the pre and post fixation settings as well. Artifacts can occur by virtue of the tissue preparation and conservation of the specimen, and these procedures could be quite uncomfortable at times to the patient.

BONOMI:Some patients are not eager to do another biopsy, as these procedures are associated with some discomfort and risk, though usually not severe. Even though some patients will opt for a biopsy, you will not always get an adequate specimen, meaning a mutational analyses cannot be performed.

The advantage of a liquid biopsy is that you can obtain blood and do genomic analyses on the circulating DNA. The only concern is if a patient has a relatively small tumor burden, there may not be enough circulating DNA to identify it. In patients who have a significant amount of tumor bulk, you can usually find enough DNA to analyze it.

BERZ:Although historically medical professionals feel as though the glomerular filter cannot negotiate molecular sizes beyond 50 kilodalton, we have recently identified sizable DNA fragments between 180 and 360 base pairs that allow us to pursue those molecular diagnostics, not only in the serum but also in the urine.

BONOMI:I think that information will be useful in patients that have a low tumor burden due to those fragments being more concentrated in the urine. The other advantage of liquid biopsies is that you would be able to more easily find a mutation. The circulating DNA in the serum is more likely to give you a more global picture of what is going on in a tumor and it might detect T790M mutations in the serum where you might not detect it with a biopsy of a mass.

BERZ:That is a very important aspect of this type of diagnostic. As we know fora prioriprimary driver mutations, there are subsets detected within primary tumors where a certain molecular heterogeneity is identified.

Naoko T. is a 74-year-old retired high school teacher originally from Nagoya, Japan. She currently lives in San Diego, California and enjoys tennis and traveling with her husband.

  • In July of 2013, the patient was diagnosed with NSCLC after presenting to her PCP with dyspnea and intermittent back and chest pain; cardiac workup was negative, and the patient has no history of smoking
  • Initial CT scan showed a large mass in the right lower lobe and 2 small lesions in the T9 and T10 vertebra, suspicious for metastatic disease
  • Biopsy and histology of the primary mass and metastatic lesion showed TTF-1+, p40 -, p60 - consistent with bronchogenic adenocarcinoma NSCLC
  • Mutational analysis on the primary mass showed EGFR exon 19 deletion and no other actionable mutations
  • Biopsy and histology of the primary mass and metastatic lesion showed TTF-1+, p40 -, p60 - consistent with bronchogenic adenocarcinoma NSCLC
  • She is initiated on systemic therapy with erlotinib for metastatic disease
  • After 5 cycles, the patient displays good response, with clinical improvement and radiologic improvement in primary and metastatic lesions

In November 2014, after several months of stable disease, the patient returns for follow-up visit with worsening back pain, and her CT scan is consistent with progression of metastatic lesions.

  • Biopsy and mutational analysis of the thoracic lesion is unsuccessful due to limited DNA content, and the patient is initiated on a second-generation EGFR TKI, with presumed resistance to erlotinib
  • After 2 cycles, the patient developed severe diarrhea and fatigue requiring hospitalization and was not reinitiated on therapy
  • A brief trial of systemic chemotherapy was also unsuccessful due to febrile neutropenia requiring hospitalization

At this point, the patient declined further treatment, and by March 2015, she returned with worsening dyspnea and declining performance status

  • A second biopsy of the thoracic lesion is attempted, and allelotyping shows no actionable mutation; sample is T790M negative
  • Patient is also screened for circulating tumor DNA in urine, which shows T790M-positive disease
  • She is initiated on a third-line TKI and shows clinical and radiologic improvement following 3 cycles