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Case history

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Image not available. A 59-year-old woman presented with painful lumps on her scalp that had developed over several months. A core biopsy identified adenocarcinoma consistent with a lung primary. Staging CT scans revealed a 5 cm left upper lobe lung primary, local adenopathy, and liver and bone metastases. Her tumour was negative for an ALK fusion and EGFR activating mutations. Her medical history was significant for a 30 pack-year smoking history. Her functional status was excellent (Eastern Cooperative Oncology Group 0) and her weight was stable.

She consented to participate in a cancer genomics study. Her scalp tumour was re-biopsied for comprehensive genomic analysis in the Personalized Oncogenomics (POG) project*.1 A sample of her blood was taken for 'normal' DNA. This and the tumour sample had in-depth DNA sequencing (40× normal DNA and 80× tumour DNA) and the tumour sample underwent RNA sequencing. As the genomic sequencing and bioinformatic analysis of this amount of data take 10 weeks, the patient started on standard first line chemotherapy with cisplatin and gemcitabine. She completed four cycles, and CT imaging demonstrated a partial response. Six weeks after completion, however, she noticed increasing pain and growth of her scalp lesions; a repeat CT identified tumour growth in all sites of her disease.

By this time her POG results were complete and they identified a rare but previously described activating mutation in the tyrosine-binding domain of ERBB2 (also known as HER2) (in-frame insertion in exon 20: pTyr772_Ala775dup).2 This mutation was found by comprehensive sequencing because of POG, but it is one that is commonly included on hospital-based or commercially available sequencing panels. There were no somatic KRAS mutations and there was a six copy gain in the thymidylate synthase gene (DNA) and a correspondingly high RNA expression, which may correlate with resistance to pemetrexed. Her CD274 (the gene encoding programmed death-ligand 1 [PD-L1]) had a four copy gain and the RNA was very highly expressed (in the 97th percentile compared with The Cancer Genome Atlas dataset for lung cancers).

An integral part of the POG study is a discussion of each case at a multidisciplinary cancer genomics tumour board. It was the consensus of the group that the ERBB2 mutation was a good target. Off-label access to afatinib was obtained, and after 1 week on this treatment the patient experienced significant pain relief and regression of her scalp lesions. CT imaging after 2 months demonstrated a partial response that was maintained for 5 months until, unfortunately, the patient developed progressive disease in the leptomeninges and had to stop afatinib to receive radiation.

This patient was treated based on research results with an off-label therapy. Is this justifiable? Should this only be done in the context of a clinical trial?

If this patient had breast or colon cancer, would that change the decision to try afatinib?

Would immunotherapy have been a 'better' treatment option?

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This patient was treated based on research results ...

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