Rapid disease progression in a patient with mismatch repair-deficient and cortisol secreting adrenocortical carcinoma treated with pembrolizumab

Context: Metastatic adrenocortical carcinoma (ACC) is an aggressive malignancy with a poor prognosis and limited therapeutic options. A subset of ACC is due to Lynch syndrome, an inherited tumour syndrome resulting from germline mutations in mismatch repair (MMR) genes. It has been demonstrated that several cancers characterised by MMR-deficiency are sensitive to immune checkpoint inhibitors that target PD-1. Here, we provide the first report of PD-1 blockade by pembrolizumab in a patient with Lynch syndrome and progressive cortisol-secreting metastatic ACC. Case report: A 58-year old female with known Lynch syndrome who presented with severe Cushing’s syndrome was diagnosed with a cortisol-secreting ACC. Three months following surgical resection and adjuvant mitotane therapy the patient developed metastatic disease and persistent hypercortisolaemia. She commenced pembrolizumab, but her second cycle was delayed due to a transient transaminitis. Computed tomography performed after twelve weeks and 2 cycles of pembrolizumab administration revealed significant disease progression and treatment was discontinued. Seven weeks later, the patient became jaundiced and died rapidly with fulminant liver failure. Conclusion: Treatment of MMR-deficient cortisol-secreting ACC with pembrolizumab may be ineffective due to supra-physiological levels of circulating corticosteroids, which may in turn mask severe drug-induced organ damage

Epidemiology of basal-like breast cancer

Risk factors for the newly identified “intrinsic” breast cancer subtypes (luminal A, luminal B, basal-like and human epidermal growth factor receptor 2-positive/estrogen receptor-negative) were determined in the Carolina Breast Cancer Study, a population-based, case–control study of African-American and white women. Immunohistochemical markers were used to subtype 1,424 cases of invasive and in situ breast cancer, and case subtypes were compared to 2,022 controls. Luminal A, the most common subtype, exhibited risk factors typically reported for breast cancer in previous studies, including inverse associations for increased parity and younger age at first full-term pregnancy. Basal-like cases exhibited several associations that were opposite to those observed for luminal A, including increased risk for parity and younger age at first term full-term pregnancy. Longer duration breastfeeding, increasing number of children breastfed, and increasing number of months breastfeeding per child were each associated with reduced risk of basal-like breast cancer, but not luminal A. Women with multiple live births who did not breastfeed and women who used medications to suppress lactation were at increased risk of basal-like, but not luminal A, breast cancer. Elevated waist-hip ratio was associated with increased risk of luminal A in postmenopausal women, and increased risk of basal-like breast cancer in pre- and postmenopausal women. The prevalence of basal-like breast cancer was highest among premenopausal African-American women, who also showed the highest prevalence of basal-like risk factors. Among younger African-American women, we estimate that up to 68% of basal-like breast cancer could be prevented by promoting breastfeeding and reducing abdominal adiposity

Development of cancer risk prediction models into tools for use in clinical settings

Meeting abstract P19.07C from 50th European-Society-of-Human-Genetics (ESHG) Conferenc

Rapid disease progression in a patient with mismatch repair-deficient and cortisol secreting adrenocortical carcinoma treated with pembrolizumab

Context: Metastatic adrenocortical carcinoma (ACC) is an aggressive malignancy with a poor prognosis and limited therapeutic options. A subset of ACC is due to Lynch syndrome, an inherited tumour syndrome resulting from germline mutations in mismatch repair (MMR) genes. It has been demonstrated that several cancers characterised by MMR-deficiency are sensitive to immune checkpoint inhibitors that target PD-1. Here, we provide the first report of PD-1 blockade by pembrolizumab in a patient with Lynch syndrome and progressive cortisol-secreting metastatic ACC. Case report: A 58-year old female with known Lynch syndrome who presented with severe Cushing’s syndrome was diagnosed with a cortisol-secreting ACC. Three months following surgical resection and adjuvant mitotane therapy the patient developed metastatic disease and persistent hypercortisolaemia. She commenced pembrolizumab, but her second cycle was delayed due to a transient transaminitis. Computed tomography performed after twelve weeks and 2 cycles of pembrolizumab administration revealed significant disease progression and treatment was discontinued. Seven weeks later, the patient became jaundiced and died rapidly with fulminant liver failure. Conclusion: Treatment of MMR-deficient cortisol-secreting ACC with pembrolizumab may be ineffective due to supra-physiological levels of circulating corticosteroids, which may in turn mask severe drug-induced organ damage