Melphalan as a treatment for BRCA-related ovarian carcinoma: can you teach an old drug new tricks?

Late-stage ovarian carcinoma is almost universally fatal. BRCA mutations are associated with an improved outcome and enhanced sensitivity to platinum chemotherapy, yet recurrence and platinum resistance remain a major problem and highly effective regimens following platinum failure do not yet exist. Here we report a remarkable case of cure following platinum-resistant stage III ovarian carcinoma in a woman with a BRCA2 mutation. The patient was subsequently treated with oral melphalan therapy and has not recurred in over 25 years. Melphalan is a bifunctional alkylator that creates inter- and intra-strand DNA cross-links. In a pharmaceutical screen, melphalan was shown to be selectively toxic to BRCA2-deficient breast cancer cell lines and produced a longer relapse-free survival in mice than did cisplatin or olaparib. There is increasing evidence to consider BRCA mutation status when selecting chemotherapy regimens, and melphalan treatment for BRCA-related ovarian cancer merits further investigation. Focusing attention on long-term survivors may provide new mechanistic insights into the biology of chemo-responsiveness.

Homozygous BUB1B mutation and susceptibility to gastrointestinal neoplasia.

A patient received a diagnosis of adenocarcinoma of the ampulla of Vater at 34 years of age. Two decades later, adenomatous polyps were found, followed by multiple primary invasive adenocarcinomas of both the colon and the stomach. Premature chromatid separation and mosaic variegated aneuploidy, combined with structural chromosomal abnormalities, were detected in his cells. We identified a germline homozygous intronic mutation, c.2386-11A→G, in the spindle-assembly checkpoint gene BUB1B, which creates a de novo splice site that is favored over the authentic (i.e., preferentially used) site. Our findings expand the phenotype associated with BUB1B mutations and the mosaic variegated aneuploidy syndrome to include common adult-onset cancers and provide evidence for the interdependency of the APC protein (encoded by the adenomatous polyposis coli gene) and the BUBR1 protein (encoded by BUB1B) in humans. (Funded by the Turner Family Cancer Research Fund and others.).

A rare case of pulmonary cryptococcal inflammatory myofibroblastic tumor diagnosed by fine needle aspiration cytology.

In a recent outbreak in British Columbia (BC), Canada, Cryptococcus gattii, a rare species of Cryptococcus, was noted to affect primarily immunocompetent hosts and cause limited pulmonary or CNS disease. We herein report a rare case of a pulmonary inflammatory myofibroblastic tumor caused by a Cryptococcus infection, presumed to be of the gattii species, in a 20-year-old immunocompetent college student from Vancouver, BC who presented with a large lung mass. The diagnosis was first made on the fine needle aspirate (FNA) material and was confirmed on the concurrent histologic core biopsy. Cryptococcal inflammatory myofibroblastic tumors have been reported, but neither in the lung nor in the setting of an immunocompetent host. Pulmonary cryptococcosis should therefore be considered in the differential diagnosis of a lung mass, even in an immunocompetent host, especially if the clinical history reveals recent travel to British Columbia where Cryptococcus gattii is endemic.

Microglandular adenosis or microglandular adenoma? A molecular genetic analysis of a case associated with atypia and invasive carcinoma.

AIMS: Microglandular adenosis (MGA) is a rare breast lesion, which has long been considered to be hyperplastic. However, atypical forms of MGA (AMGA) and invasive carcinomas arising in the background of MGA are recorded. Recent studies have suggested that MGA may be a non-obligate precursor of invasive carcinomas that are negative for hormone receptors and lack HER-2 overexpression (triple-negative phenotype). The aim of this study was to determine whether MGA is clonal and whether it harbours chromosomal aberrations similar to those found in matched invasive ductal carcinoma of no special type (IDC-NST). METHODS AND RESULTS: We report on a case comprising MGA, AMGA and a high-grade IDC-NST. The three components were separately microdissected and subjected to genetic analysis with high-resolution microarray comparative genomic hybridisation. Identical genetic changes were detected in all components with subsequent acquisition of additional genetic aberrations in the invasive component, suggesting that MGA was the substrate for the development of the invasive carcinoma. Immunohistochemistry revealed concordant profiles across all components, characterized by triple-negative phenotype and variable positivity for basal markers. CONCLUSIONS: Similar to adenomas, MGA is, at least in some cases, a clonal lesion and may be a non-obligate precursor of a subgroup of high-grade triple-negative and basal-like breast carcinomas.

Eleven years disease-free: role of chemotherapy in metastatic BRCA2-related breast cancer.

BACKGROUND: Infiltrating ductal carcinoma of the breast, staged as pT1N3, was diagnosed in a 41-year-old premenopausal French-Canadian woman. Rapid nodal recurrence progressed to diffuse bone metastases, despite tamoxifen and megestrol. Following enrollment in an in-house study protocol, she received high-dose anthracycline-based induction chemotherapy followed by tandem autologous bone marrow transplantation with high-dose alkylator and platinum-based conditioning regimens. Upon full remission, protocol-mandated locoregional breast and prophylactic cranial radiation was delivered. Complete clinical and radiologic remission has been maintained in the 11 years since study enrolment, which prompted further investigation. INVESTIGATIONS: Pedigree construction and BRCA1/2 mutation analysis. DIAGNOSIS: A BRCA2 8765delAG mutation was identified, in the context of unusual and sustained complete remission from widely metastatic breast cancer. MANAGEMENT: The patient is now followed at a multidisciplinary high-risk prevention clinic because BRCA2 mutations are associated with increased risk of ovarian and breast cancers. This case supports the possibility of differential treatment response in BRCA2-positive breast cancer, although this remains to be conclusively demonstrated.

A case of Cowden's syndrome presenting with gastric carcinomas and gastrointestinal polyposis.

BACKGROUND: A 73-year-old white man was referred to a cancer genetics clinic for evaluation of a approximately 20-year history of mixed upper and lower gastrointestinal polyposis, including hyperplastic, inflammatory and adenomatous polyps, colonic ganglioneuromas, and associated diffuse, esophageal glycogenic acanthosis. Two synchronous gastric carcinomas had been identified before referral and the patient had undergone a total gastrectomy, omentectomy and cholecystectomy. Multiple hyperplastic polyps and small, sessile polyps were also observed in the gastrectomy specimen. INVESTIGATIONS: History and physical examination, upper and lower gastrointestinal endoscopy and biopsy, genetic testing, molecular pathology investigations (immunohistochemistry), thyroid ultrasonography, fine-needle aspiration of a thyroid nodule. DIAGNOSIS: Cowden's syndrome. MANAGEMENT: Genetic counseling, thyroidectomy, vitamin B(12) supplementation, continued endoscopic surveillance and genetic testing of at-risk family members.