A women who had never smoked tobacco and was well until the age of 30 years presented with a bloody discharge from the nipple of the right breast. This discharge proved to be the result of extensive ductal carcinoma in situ, comedo type, which was accompanied by a 2 mm focus of stromal invasion and metastases in eight of 17 axillary lymph nodes. The tumour was strongly positive for ERBB2 by immunohistochemistry (IHC; fi gure 1A), but negative for epidermal growth factor receptor (EGFR). ERBB2 was amplifi ed (>35 copies per cell; fi gure 2A) by fl uorescence in-situ hybridisation (FISH) analysis, and balanced trisomy of chromosome 7 with equivalent copies of EGFR and chromosome enumeration probe (CEP) 7 was noted. The patient was treated with adjuvant doxorubicin and low-dose cyclophosphamide followed by high-dose cyclophosphamide, carboplatin, and thiotepa (STAMP V protocol) and autologous stem-cell transplantation. Radiation treatment to the right (ipsilateral) chest-wall was also started. During her clinical assessment, the patient reported that her mother had been diagnosed with bilateral breast cancer at age 35 years and died at the age of 46 years. The patient has four siblings (three sisters and one brother). One sister had been diagnosed with liposarcoma of the breast at the age of 26 years and was alive and under observation. The maternal grandmother had developed breast cancer at the beginning of her fi fth decade of life and died of the disease at the age of 48 years. Because of this history, the family was referred to the Hereditary Cancer Clinic at the University of Colorado, USA, for counselling and genetic testing. Initial testing for BRCA1 and BRCA2 was negative. However, the sister with liposarcoma tested positive for a missense point mutation in TP53 exon 8, at base 14487 (CGT→CAT) resulting in an amino-acid substitution (R273H). This mutation is currently reported in 4% of families with Li-Fraumeni syndrome. Our patient also tested positive for this mutation (fi gure 3A). Radiation was discontinued after discovery of the mutation because of concern that it would contribute to the formation of new primary tumours. Chemotherapy had already been completed. Of the remainder of the immediate family, the brother and another sister tested positive for the mutation. While the patient was being treated, the second sister, who was positive for the TP53 mutation, developed breast cancer at age 33 years and remains under observation. Up to now the brother is without evidence of malignancy as is the third sister who is the only immediate family member without the mutation. 4 years after our patient was diagnosed with breast cancer, a slowly growing 2·7 cm mass was removed from the lower lobe of the left lung (contralateral to the breast lesion) by wedge resection. This tumour was an adenocarcinoma, but was histologically dissimilar to the breast carcinoma, having bronchioloalveolar histological features. ICH showed this tumour to be strongly positive for both thyroid transcription factor 1 (TTF-1) and EGFR (fi gure 1B) and negative for ERBB2. FISH analysis documented high polysomy for the EGFR locus (8 copies per cell; fi gure 2B) and amplifi cation of ERBB2, but at a lower level (10 copies per cell) than seen in the breast tumour. Finally, the previously identifi ed TP53 mutation was confi rmed by mutational analysis of lung-tumour DNA extracted from formalin-fi xed wet tissue. EGFR exons 18, 19, and 21, were also sequenced. A 15-base inframe deletion in exon 19 of EGFR (fi gure 3B) encompassed bases 2413 to 2428 (codon 746 to 750) of the coding sequence and corresponded to a region previously reported as deleted in lung adenocarcinoma. A completion lobectomy with lymph-node sampling was then undertaken with the fi nding of a residual microscopic focus of tumour at the biopsy site and a solitary level V lymph-node metastasis (American Joint Committee on Cancer pathology stage IIIA [T1N2MX]). After surgery, the patient was treated with four cycles of gemcitabine and carboplatin and was then given the small-molecule EGFR blocker, erlotinib. However, she developed a severe skin rash and was unable to tolerate the recommended dose of erlotinib (100 mg). Despite her therapeutic regimen, the lung tumour recurred as a cytology-positive pleural eff usion 1 year after initial lung resection. Li-Fraumeni syndrome is a hereditary cancer predisposition syndrome that is transmitted as an autosomal dominant trait and is most commonly associated Lancet Oncol 2007; 8: 559–60