A New Finding Offers an Explanation and Hope After Failure of Targeted Therapy

Many patients, like "David," respond well to targeted therapeutic options but eventually develop resistance. David responded well to erlotinib for over a year until his disease began to progress. Identification of a PI3KCA mutation helped to explain, at least in part, the development of resistance and identify a clinical trial for which he was eligible, giving David and his family additional hope.

About "David"

In this molecular profile, our fictional patient, David, is a 68 year-old man who never smoked, and visited his doctor because of a cough and shortness of breath.

Imaging studies identified a mass in his lower right lung, enlarged lymph nodes, and metastases to his bone and left adrenal gland. Fine needle aspirate (FNA) of his lung tumor revealed adenocarcinoma, consistent with a lung primary tumor.

David’s physician initially sent his tissue for testing using a lung cancer mutation panel from a commercial reference lab. An EGFR L858 mutation was revealed, and David’s physician prescribed erlotinib. His tumor shrunk dramatically and his symptoms resolved.

However, after 14 months, a new CT scan showed progression of disease. David’s physician spoke to him about changing his treatment to chemotherapy, but David was reluctant to do so after tolerating erlotinib so well. David asked if there was a possibility that other mutations present in tumor could lead to additional treatment options. His doctor recommended re-biopsy and broader genomic testing. David agreed, and further testing revealed his tumor harbored a PI3KCA mutation in addition to the EGFR mutation that had been discovered through hotspot analysis.

Actionable Information

• Further genomic testing led to detection of a mutation that led to an understanding of why EGFR therapy may have failed. New presence of PI3KCA mutation has been described as one potential mechanism of acquired resistance to EGFR tyrosine kinase inhibitors.
• David was presented several ongoing clinical trial options, and he opted for evaluation for the clinical trial with an AKT inhibitor for which he proved eligible.

References

1. Maemondo M, Inoue A, Kobayashi K, et al. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med. 2010;362:2380-8.
2. Mitsudomi T, Morita S, Yatabe Y, et al. Gefitinib versus cisplatin plus docetaxel in patients with non-small-cell lung cancer harbouring mutations of the epidermal growth factor receptor (WJTOG3405): an open label, randomised phase 3 trial. Lancet Oncol. 2010;11:121-8.
3. Mok TS, Wu YL, Thongprasert S, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009;361:947-57.
4. Sequist, L, et al. Genotypic and Histological Evolution of Lung Cancers Acquiring Resistance to EGFR Inhibitors. Sci Transl Med. 2011. Vol. 3, Issue 75, p. 75ra26.

Note: This fictional, composite story, which includes data from actual representative patient cases, conveys how information from comprehensive genomic testing may impact treatment for management and care of people suffering from cancer.