Saturday, 17 March 2018

Initial Response to Therapy with Fulvestrant and Cyclin-Dependent Kinase 4/6 Inhibitor in a Male with Stage IV Breast Cancer


Male breast cancer (MaBC) accounts for less than 1% of breast cancers (BC). Based on the low incidence of MaBC, information from randomized clinical trials is not available. Therefore, the same guidelines for palliative endocrine therapy in women with advanced BC are generally followed for men. Endocrine therapy (ET) represents the first line of treatment for male patients with stage IV disease in the absence of a visceral crisis. However, resistance to ET in hormone receptor positive advanced breast cancer is common, and given sufficient time, most patients are faced with disease progression. In this report we describe the case of a male that experienced systemic recurrence of BC following adjuvant therapy for locally advanced disease. First line endocrine treatment was combined with a cyclin-dependent kinase 4/6 inhibitor, leading to a dramatic radiographic and clinical response.

Male breast cancer (MaBC) accounts for less than 1% of breast cancers (BC). In the United States, males were expected to account for only 2600 of the estimated 249,260 cases of breast cancer during 2016 projections. The worldwide variation of MaBC resembles that of BC in women, with higher rates in North America and Europe and lower rates in Asia. Although the epidemiologic literature on female breast cancer (FBC) is extensive, little is known about the etiology of MaBC; it appears to be associated with marital status, previous breast and testicular pathology, gynecomastia and liver diseases. Due to its rarity, information from randomized clinical trials is not available. Men tend to be diagnosed with locally advanced or metastatic disease more frequently than women; more than 40% of patients have stage III or IV disease at diagnosis.They also have a proportionately higher mortality, although outcomes for male and female patients with breast cancer are similar when survival is adjusted for age at diagnosis and stage of disease. The association between estrogen levels and breast cancer in men is of interest because estrogen-related risk factors have been strongly implicated in the etiology of FBC. Obesity has been implicated in the etiology of MaBC due to higher circulating estrogen levels and has consistently been associated with an increased risk of MaBC. Men with a mutation in the BRCA2 gene have an increased risk of breast cancer with a lifetime risk of about 6 in 100. BRCA1 mutations can also cause breast cancer in men, but the risk is lower - about 1 in 100. Histologically, the majority of breast cancers in men are infiltrating ductal carcinomas, but the entire spectrum of histological variants of breast cancer has been seen. Papillary and lobular carcinoma are seen in less than 2% of the cases. About 80% of MaBC are hormone receptor positive (HR+), 15% overexpress human epidermal growth factor receptor 2 (HER2), and 4% are triple negative (estrogen receptor (ER), progesterone receptor (PR), and HER2/neu negative). 

In terms of gene expression profile, recent studies by Johansson and colleagues have revealed two subgroups: luminal M1 and luminal M2. These subgroups demonstrated differences in tumor biological features and outcome, and differed from the intrinsic subgroups described in FBC. Luminal M2 tumors were characterized by high expression of immune response genes and genes associated with ER signaling. On the other hand, luminal M1 tumors, despite being ER positive (ER+) by immunohistochemistry, showed a lower correlation to genes associated with ER signaling and displayed a more aggressive phenotype and worse prognosis. Since gene expression is typically related to protein expression, examination of the differences between MaBC and FBC were studied at the hormone receptor (HR) immunohistochemical level in a large series of 514 matched cases. Strikingly, hierarchical clustering in FBC revealed ERα clustered together with PR, while in MBC, ERα clustered with the androgen receptor (AR) suggesting a clinically actionable difference between genders in HR biology. Although MaBC is typically considered ERα driven, there are distinct molecular features found in MaBC, which could be used as targets for currently available or yet undeveloped therapies. 

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